HK1230199B - Indolin-2-one or pyrrolo-pyridin-2-one derivatives - Google Patents

Description

Indolin-2-one or pyrrolo-pyridin-2-one derivatives

The present invention relates to indolin-2-one or pyrrolo-pyridin-2-one derivatives of the following general formula

in

Ar ¹ is phenyl or a five- or six-membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O, wherein the N-heteroatom in the heteroaryl group can be oxidized to N ⁺ -(O ⁻ );

^R1 is lower alkyl, halogen, cyano or cycloalkyl;

Ar ² is a five- or six-membered heteroaryl group containing one, two, three or four heteroatoms selected from N, S or O, wherein the N-heteroatom in the heteroaryl group can be oxidized to N ⁺ -(O ^- ), or is a benzo[b]thienyl group;

^R2 is hydrogen, lower alkyl, halogen, cyano, hydroxy-substituted lower alkyl, halogen-substituted lower alkyl, amino-substituted lower alkyl, alkoxy-substituted lower alkyl, amide-substituted lower alkyl, or cycloalkyl;

X is CH or N;

n is 1 or 2;

m is 1 or 2;

The invention also relates to pharmaceutically acceptable salts, racemic mixtures, or corresponding enantiomers and/or optical isomers and/or stereoisomers thereof.

WO9106545 describes a close structure for preventing the aggregation of both red blood cells and platelets, which contains a phenyl-substituted imidazole moiety for Ar ¹ and no heteroaryl group at position Ar ^2. EP2108641 and WO2008046083 disclose a very broad range of similar compounds that are inhibitors of p38 N-activated protein kinase for the treatment of inflammatory diseases and benign prostatic hyperplasia, respectively.

It has now been discovered that compounds of formula I can be used to treat CNS diseases. The compounds described have been shown to reverse hyperlocomotion induced by L-687,414 ((3R,4R)-3-amino-1-hydroxy-4-methyl-pyrrolidin-2-one, an NMDA glycine site antagonist), a behavioral pharmacokinetic mouse model for schizophrenia described by D. Alberati et al. in Pharmacology, Biochemistry and Behavior, 97 (2010), 185-191. The authors describe that hyperlocomotion induced by L-687,414 is inhibited by a range of known antipsychotic drugs. Compounds of formula I exhibit significant activity in this model. These findings suggest antipsychotic activity for the compounds of the invention, making them useful in treating positive (psychosis) and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, resistant depression, anxiety disorders, Alzheimer's disease, autism, Parkinson's disease, chronic pain, borderline personality disorder, sleep disturbances, chronic fatigue syndrome, stiffness, anti-inflammatory effects in arthritis, and balance problems.

In addition to the above-mentioned reversal of the L-687,414-induced hypermobility experiment, some compounds of the present invention have been tested in an automated system in which the behavior of compound-treated mice in response to a variety of challenges is captured by digital video and analyzed with a computer algorithm (Roberds et al., Frontiers in Neuroscience, 2011, Vol. 5, Art. 103 , 1-4; Vadim Alexandrov, Dani Brunner, Taleen Hanania, Emer Leahy Eur. J. Pharmacol. 2015, 750, 82-99). In this way, the neuropharmacological effects of the test compounds can be predicted by similarity to large classes of compounds such as antipsychotics, anxiolytics, and antidepressants. Examples 9, 25, 48, and 53 show similarity to atypical antipsychotics. The results are shown in Table 2.

In addition to the above-mentioned experiments, it has been demonstrated that certain compounds of the formula I are also ENT1 inhibitors (equilibrative nucleoside transporter 1). The therapeutic potential of ENT1 inhibitors is described in the literature for the treatment of the following diseases, either directly or indirectly (via adenosine and/or adenosine receptor regulated effects): autoimmune diseases (US 2006/253263), cancer (WO9857643), viral and fungal infections (WO2004060902), neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, psychiatric disorders, psychotropic substance abuse, ADHD, depression, epilepsy, anxiety, schizophrenia (WO0168105, EP 1252910, EP1612210, WO2009018275), autism spectrum disorders (Susan A. Masinoa, Masahito Kawamura Jr., Jessica L. Cotea, Rebecca B. Williams, David N. Ruskina, Neuropharmacology, 2013, 68, 116-121, pain (WO2009062990, WO2009064497), inflammation, asthma (US 2007213296, Inflammationresearch, 2011, 60, 75-76), cardiovascular disease (Trends in Pharmacological science, 2006, 27, 416-425), sleep disorders (Psychopharmacology, 1987, 91, 434-439) and ophthalmology and inflammatory retinal diseases (World Journal of Diabetes, vol. 1, 12-18).

Schizophrenia is a complex mental illness that typically presents in late adolescence or early adulthood, with a worldwide prevalence of approximately 1% of the adult population, and has a significant social and economic impact. The diagnostic criteria for schizophrenia by the Association of European Psychiatrists (ICD) and the American Psychiatric Association (DSM) require the presence of two or more characteristic symptoms: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior (positive symptoms), or negative symptoms (alogia, affective flattening, lack of motivation, anhedonia). In general, people with schizophrenia have functional impairments that may begin in childhood, persist throughout adult life, and prevent most patients from maintaining normal work or otherwise functioning in society. Compared to the general population, they also have a shortened lifespan and suffer from a wide range of rising morbidity of various other neuropsychiatric syndromes, including psychotropic drug abuse, obsessive-compulsive syndrome and abnormal involuntary movements. Schizophrenia is also associated with a wide range of following diseases: cognitive impairment, bipolar disorder, major depression and anxiety, and its severity limits the functioning of the patient, even when psychotic symptoms are well controlled. The main treatment for schizophrenia is the administration of antipsychotics. However, antipsychotics, such as risperidone (risperidone), olanzapine (olanzapine) can not significantly alleviate the negative symptoms and cognitive dysfunction.

Antipsychotic drugs have shown clinical efficacy in the treatment of the following disorders:

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

Schizoaffective disorders : These disorders include both psychotic and affective symptoms, falling between bipolar disorder (with depressive and manic episodes, alcohol and drug addiction, and psychotropic substance abuse) and schizophrenia. J. Clin. Psychiatry, 2010, 71, S2, 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, 1029-104, International J. of Neuropsychopharmacology, 2012, 1-12; J. of Neuropsychopharmacology, 2011, 0, 0 , 1-15

Mood disorders : J. Psychopharmacol. 2012, Jan 11, CNS Drugs, 2010, 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, 2011, 26, 6

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, 2012, 678, 55-60

The present invention relates to novel compounds of the formula I and to the use of compounds of the formula I and pharmaceutically acceptable salts thereof for the treatment of CNS diseases associated with positive symptoms (psychosis) and negative symptoms of schizophrenia, psychotropic substance abuse, alcohol and drug addiction, obsessive-compulsive disorder, cognitive impairment, bipolar disorder, mood disorders, major depression, refractory depression, anxiety disorders, Alzheimer's disease, autism, Parkinson's disease, chronic pain, borderline personality disorder, neurodegenerative diseases, sleep disorders, chronic fatigue syndrome, stiffness, inflammatory diseases, asthma, Huntington's disease, ADHD, amyotrophic lateral sclerosis, epilepsy, effects in arthritis, autoimmune diseases, viral and fungal infections, cardiovascular diseases, ophthalmic and inflammatory retinal diseases and balance problems.

Further objects of the present invention are medicaments containing the novel compounds and processes for the preparation of compounds of formula I, combinations of compounds of formula I with commercially available antipsychotics, antidepressants, anxiolytics or mood stabilizers, and methods for the treatment of CNS disorders as described above.

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

A common antipsychotic used to treat schizophrenia is olanzapine. Olanzapine (Zyprexa) belongs to a class of drugs called 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 psychotic disorders, long-term treatment of bipolar disorder and in combination with fluoxetine for the treatment of depressive episodes associated with bipolar disorder and for the treatment of treatment-resistant depression.

The compounds of the present invention can be combined with antipsychotic drugs such as olanzapine (Zyprexa), clozapine (Clozaril), risperidone (Risperdal), aripiprazole (Abilify), amisulpride (Solian), asenapine (Saphris), blonanserin (Lonasen), clotipine (Entumine), iloperone (Fanapt), lurasidone (Latuda), mosapramine (Cremin), paliperidone (Inyega), perospirone (Lullan), quetiapine (Seroquel), remopride (Roxiam), sertindole (Serdolect), sulpiride (sulpiride), (Sulpirid, Eglonyl), ziprasidone (Geodon, Zeldox), zotepine (Nipolept), haloperidol (Haldol, Serenace), droperidol (Droleptan), chlorpromazine (Thorazine, Largactil), fluphenazine (Prolixin), perphenazine (Trilafon), prochlorperazine (Compazine), thioridazine (Mellaril, Melleril), trifluoperazine (Stelazine), triflupromazine (Vesprin), levomepromazine (Nozinan), promethazine (Phenergan), pimozide (Orap), and cyanomemazine (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 present invention can be combined with antidepressants such as selective serotonin reuptake inhibitors [citalopram (Celexa), escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), fluvoxamine (Luvox), sertraline (Zoloft, Lustral)], serotonin norepinephrine reuptake inhibitors [duloxetine (Cymbalta), milnacipran (Ixel, Savella), venlafaxine (Effexor), desvenlafaxine (Pristiq), tramadol (Tramal, Ultram), sibutramine (Meridia, Reductil)], serotonin antagonists and reuptake inhibitors [etoperidone (Axiomin, Eton in), lubazodone (YM-992, YM-35, 995), nefazodone (Serzone, Nefadar), trazodone (Desyrel)], norepinephrine reuptake inhibitors [reboxetine (Edronax), viloxazine (Vivalan), atomoxetine (Strattera)], norepinephrine-dopamine reuptake inhibitors [bupropion (Wellbutrin, Zyban), dexmethylphenidate (Focalin), methylphenidate (Ritalin, Concerta)], norepinephrine-dopamine releasers [amphetamine (Adderall), dextroamphetamine (Dexedrine), dextromethamphetamine (Dextromethamphetamine)] tamine) (Desoxyn), lisdexamfetamine (Vyvanse)], tricyclic antidepressants [amitriptyline (Elavil, Endep), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), dothiepin (Prothiaden), doxepin (Adapin, Sinequan), imipramine (Tofranil), lofepramine (Feprapax, Gamanil, Lomont), nortriptyline (Pamelor), protriptyline (Vivactil), trimipramine (Surmontil)], tetracyclic antidepressants [amoxapine (Asendin), maprotiline (Ludiomil), mianserin (Bolvidon, Norval, Tolvon), mirtazapine (Remeron)], monoamine oxidase inhibitors [isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), selegiline [L-deprenil] (Eldepryl, Zelapar, Emsam), tranylcypromine (Parnate), pyrindole (Pirazidol)], 5-HT1A receptor agonists [buspirone (Buspar), tandospirone (Sediel), vilazodone (Viibryd)], 5-HT2 receptor antagonists [agomelatine (Valdoxan), nefazodone (Nefadar, Serzone), selective serotonin reuptake enhancers [tianeptine (Tianeptine)].

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 mirtazapine (Remeron).

The compounds can also be combined with anxiolytics such as alprazolam (Helex, Xanax, Xanor, Onax, Alprox, Restyl, Tafil, Paxal), brometazapine, bromazepam (Lectopam, Lexotanil, Lexotan, Bromam), brotizolam (Lendormin, Dormex, Sintonal, Noctilan), chlordiazepoxide (Librium, Risolid, Elenium), cinazepam (Gerodorm), clonazepam (Rivotril, Klonopin, Iktorivil, Paxam), clorazepate (Tranxene, Tranxilium), clotiazepam (Veratran, Clozan, Rize), clorazepam (Sepazon, O lcadil), dilozepam (Dadumir), diazepam (Antenex, Apaurin, Apzepam, Apozepam, Hexalid, Pax, Stesolid, Stedon, Valium, Vival, Valaxona), estazolam (ProSom), etizolam (Etilaam, Pasaden, Depas), flunitrazepam (Rohypnol, Fluscand, Flunipam, Ronal, Rohydorm), flurazepam (Dalmadorm, Dalmane), flutorazepam (Restas), halazepam (Paxipam), ketazola (Anxon), loprazolam (Dormonoct), lorazepam (Ativan, Temesta, Tavor, Lorabenz ), lormetazepam (Loramet, Noctamid, Pronoctan), medazepam (Nobrium), midazolam (Dormicum, Versed, Hypnovel, Dormonid), nimetazepam (Erimin), nitrazepam (Mogadon, Alodorm, Pacisyn, Dumolid, Nitrazadon), nordiazepam (Madar, Stilny), oxazepam (Seresta, Serax, Serenid, Serepax, Sobril, Oxabenz, Oxapax), phenazepam (Phenazepam), pineazepam (Domar), prazepam (Lysanxia, Centrax), prizepam, quazepam (Doral), temazepam (Restoril, Noxazepam), dapoxetine (Dapoxetine ... rmison, Euhypnos, Temaze, Tenox), tetrahydrozepam (Mylostan), triazolam (Halcion, Rilamir), clobazam (Frisium, Urbanol), eszopiclone (Lunesta), zaleplon (Sonata, Starnoc), zolpidem (Ambien, Nytamel, Stilnoct, Stilnox, Zoldem, Zolnod), zopiclone (Imovane, Rhovane, Ximovan; Zileze; Zimocloone; Zimovane; Zopitan; Zorclone), pregabalin (Lyrica), and gabapentin (Fanatrex, Gabarone, Gralise, Neurontin, Nupentin).

A preferred embodiment of the present invention is a combination wherein the marketed antianxiety drug is alprazolam (Helex, Xanax, Xanor, Onax, Alprox, Restyl, Tafil, Paxal), chlordiazepoxide (Librium, Risolid, Elenium), clonazepam (Rivotril, Klonopin, Iktorivil, Paxam), diazepam (Antenex, Apaurin, Apzepam, Apozepam, Hexalid, Pax, Stesolid, Stedon, Valium, Vival, Valaxona), estazolam (ProSom), eszopiclone (Lunesta), zaleplon (Sonata, Starnoc), zolpidem (Ambien, Nytamel, Stilnoct, Stilnox, Zoldem, Zolnod), pregabalin (Lyrica), or gabapentin (Fanatrex, Gabarone, Gralise, Neurontin, Nupentin).

Another object of the invention is a 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 procognitive compounds such as donepezil (Aricept), galantamine (Razadyne), rivastigmine (Exelon), and memantine (Namenda).

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

As used herein, the term "lower alkyl" refers to a saturated straight or branched chain group containing 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, etc. Preferred alkyl groups are groups having 1 to 4 carbon atoms.

As used herein, the term "lower alkoxy" refers to an alkyl group as defined above, wherein the alkyl residue is attached via an oxygen atom.

As used herein, the term "hydroxy-substituted lower alkyl" refers to a group wherein the alkyl residue is as defined above wherein at least one hydrogen atom is replaced by a hydroxy group.

As used herein, the term "halogen-substituted lower alkyl" refers to a group wherein the alkyl residue is as defined above wherein at least one hydrogen atom is replaced by a halogen atom.

As used herein, the term "amino-substituted lower alkyl" refers to a group wherein the alkyl residue is as defined above wherein at least one hydrogen atom is replaced by _NH2 .

As used herein, the term "amide-substituted lower alkyl" refers to a group wherein the alkyl residue is as defined above wherein at least one hydrogen atom is replaced by C(O)N(CH ₃ ) ₂ or C(O)NH ₂ .

As used herein, the term "alkoxy-substituted lower alkyl" refers to a group wherein the alkyl residue is as defined above wherein at least one hydrogen atom is replaced by an alkoxy group.

The term "cycloalkyl" refers to an alkyl ring having 3 to 6 carbon ring atoms.

The term "halogen" refers to chlorine, iodine, fluorine and bromine.

The term "five- or six-membered heteroaryl containing one, two, three or four heteroatoms selected from N, S or O" refers to an aromatic ring selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, isoxazolyl, tetrazolyl, 1,2,4-thiadiazolyl, isothiazolyl or oxazolyl.

The term "wherein the N-heteroatom in the heteroaryl group can be oxidized to N ⁺ -(O ^- )" refers to, for example, the following groups

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.

One embodiment of the invention is a compound wherein X is CH. Another embodiment of the invention is a compound from this group wherein Ar ¹ and Ar ² are both six-membered heteroaryl groups containing one, two or three heteroatoms selected from N, S or O, such as the following compounds

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridin-4-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridin-3-yl)indolin-2-one

3,3-Dimethyl-1-(2-methylpyridin-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(6-methylpyrimidin-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1,6-bis(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(6-methylpyridin-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(6-methylpyridin-3-yl)-1-(2-methylpyridin-4-yl)indolin-2-one

3,3-Dimethyl-1,6-bis(2-methylpyridin-4-yl)indolin-2-one

6-(4-fluoropyridin-3-yl)-3,3-dimethyl-1-(2-methylpyridin-4-yl)indolin-2-one

1-(5-Fluoro-2-methylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

5-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinonitrile

1-(6-(Hydroxymethyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(6-cyclopropylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridin-2-yl)indolin-2-one

1-(2-fluoropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(3-fluoropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(2-Fluoro-5-methylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(6-methylpyridazin-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(3-chloropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(5-methylpyrimidin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(5-methylpyridin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(5-methylpyridin-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(4-methylpyridin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(6-methylpyridin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(2-methylpyrimidin-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(4-methylpyrimidin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(2,6-dimethylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(4,6-dimethylpyrimidin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(2,6-dimethylpyrimidin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(4,5-dimethylpyridin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(5,6-dimethylpyridin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(5,6-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridazin-3-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrazin-2-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrimidin-2-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(4-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1,6-bis(5-methylpyrimidin-2-yl)indolin-2-one

3,3-Dimethyl-1,6-bis(5-methylpyrazin-2-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrimidin-4-yl)indolin-2-one

1-(5-cyclopropylpyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

5-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carbonitrile

1-(6-cyclopropylpyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(4,5-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(4,5-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(4,6-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

5-(3,3-Dimethyl-1-(5-methylpyrimidin-2-yl)-2-oxoindolin-6-yl)-2-methylpyrimidine 1-oxide

1-(2-(Hydroxymethyl)pyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-[2-(Aminomethyl)pyrimidin-5-yl]-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indol-2-one

3-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-6-methylpyridazine 1-oxide

3-(3,3-dimethyl-6-(2-methyl-1-oxidopyrimidin-5-yl)-2-oxoindolin-1-yl)-6-methylpyridazine 1-oxide

1-(2-(Fluoromethyl)pyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(6-methylpyridazin-3-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

6-(4-Fluorophenyl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

1-(5-chloropyrimidin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(2-chloropyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(2,6-dichloropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(2-cyclopropylpyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(5-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indol-2-one

1-(6-chloropyridazin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(2-chloro-6-methylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridazin-4-yl)indolin-2-one

1-(6-chloro-2-methylpyrimidin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(5-methylpyridazin-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(6-chloropyridazin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(3-methylpyrazin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(4-chloropyrimidin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(6-(Methoxymethyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(5-cyclopropylpyridazin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(5-methylpyrazin-2-yl)-1-(6-methylpyrazin-2-yl)indolin-2-one

3,3-Dimethyl-6-(5-methylpyrazin-2-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

1-(6-cyclopropylpyridazin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(6-methyl-2-pyridyl)indolin-2-one

3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(2-methylpyrimidin-4-yl)indolin-2-one

3,3-Dimethyl-6-(5-methylpyrazin-2-yl)-1-(6-methylpyridazin-3-yl)indolin-2-one

1-(5-fluoropyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)nicotinoylnitrile

3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(2-methyl-4-pyridyl)indolin-2-one

3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(5-methyl-3-pyridyl)indolin-2-one

6-(5-fluoro-3-pyridyl)-3,3-dimethyl-1-(6-methylpyrazin-2-yl)indolin-2-one

3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(2-methyl-4-pyridyl)indolin-2-one

3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(6-methyl-3-pyridyl)indolin-2-one

3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(5-methyl-3-pyridyl)indolin-2-one

6-(5-fluoro-3-pyridyl)-3,3-dimethyl-1-(5-methylpyrazin-2-yl)indolin-2-one

6-(5-Fluoro-6-methyl-3-pyridyl)-3,3-dimethyl-1-(5-methylpyrazin-2-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(5-(trifluoromethyl)pyridin-3-yl)indolin-2-one

1-(5-(Hydroxymethyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(2-methylpyrimidin-4-yl)indolin-2-one

5-[3,3-dimethyl-1-(6-methylpyrazin-2-yl)-2-oxo-dihydroindolin-6-yl]pyrimidine-2-carbonitrile, or

1-(5-ethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one.

Another embodiment of the present invention is a compound from the group (X=CH) wherein Ar ¹ is a six-membered heteroaryl containing one, two or three heteroatoms selected from N, S or O, and Ar ² is a five-membered heteroaryl containing one, two or three heteroatoms selected from N, S or O, for example the following compounds

3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(1,5-dimethyl-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(6-methylpyridin-3-yl)indolin-2-one

3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyridin-4-yl)indolin-2-one

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(6-methylpyridin-3-yl)indolin-2-one

6-(4-fluoropyridin-3-yl)-3,3-dimethyl-1-(1-methyl-1H-imidazol-4-yl)indolin-2-one

6-(4-fluoropyridin-3-yl)-3,3-dimethyl-1-(1-methyl-1H-pyrazol-3-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(5-methylthiophen-2-yl)indolin-2-one

3,3-Dimethyl-1-(1-methyl-1H-imidazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-3-yl)indolin-2-one

1-(1,2-dimethyl-1H-imidazol-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(5-ethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(2-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(1-methyl-1H-1,2,4-triazol-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-4-yl)indolin-2-one

1-(1H-imidazol-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(3-methyl-1H-pyrazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(4-methyl-1H-imidazol-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(3-methylisoxazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(1H-imidazol-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

1-(1-ethyl-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(2H-tetrazol-5-yl)indolin-2-one

3,3-Dimethyl-1-(2-methyl-2H-tetrazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

3,3-Dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(3-methylisothiazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(5-methylthiazol-2-yl)indolin-2-one

1-(1-Isopropyl-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(5-methylpyrazin-2-yl)indolin-2-one

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)indolin-2-one

1-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one, or

2-(3-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide.

Another embodiment of the present invention is a compound from the group (X=CH) wherein Ar ¹ is a five-membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O, and Ar ² is a six-membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O, for example the following compounds

3,3-Dimethyl-6-(4-methylimidazol-1-yl)-1-(6-methyl-3-pyridyl)indolin-2-one

6-(4-cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methyl-4-pyridyl)indolin-2-one

3,3-Dimethyl-6-(4-methylimidazol-1-yl)-1-(2-methyl-4-pyridyl)indolin-2-one

3,3-Dimethyl-6-(1-methyl-1H-pyrazol-3-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(1-methyl-1H-imidazol-4-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

6-(4-Isopropylimidazol-1-yl)-3,3-dimethyl-1-(6-methyl-3-pyridyl)indolin-2-one

3,3-Dimethyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(6-methyl-3-pyridyl)indolin-2-one

3,3-Dimethyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(2-methyl-4-pyridyl)indolin-2-one

6-(4-Isopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methyl-4-pyridyl)indolin-2-one

6-(4-Isopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)indolin-2-one

6-(4-cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-Dimethyl-6-(4-methylimidazol-1-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

3,3-dimethyl-6-(2-methyloxazol-5-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one, or

3,3-Dimethyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one.

Another embodiment of the present invention is a compound from the group (X=CH) wherein Ar ¹ and Ar ² are both five-membered heteroaryl groups containing one, two or three heteroatoms selected from N, S or O, for example the following compounds

6-(4-Isopropylimidazol-1-yl)-3,3-dimethyl-1-(1-methylpyrazol-3-yl)indolin-2-one

6-(4-cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(1-methylimidazol-4-yl)indolin-2-one

6-(4-cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(1-methylpyrazol-3-yl)indolin-2-one

3,3-Dimethyl-1-(1-methylimidazol-4-yl)-6-(2-methyloxazol-5-yl)indolin-2-one

3,3-Dimethyl-6-(2-methyloxazol-5-yl)-1-(1-methylpyrazol-3-yl)indolin-2-one

3,3-dimethyl-1-(1-methylimidazol-4-yl)-6-(5-methyl-1,3,4-oxadiazol-2-yl)indolin-2-one, or

3,3-Dimethyl-6-(4-methyl-1H-imidazol-1-yl)-1-(1-methyl-1H-imidazol-4-yl)indolin-2-one.

Another embodiment of the present invention is a compound from the group (X=CH) wherein Ar ² is benzo[b]thienyl and the other substituents are as described above, for example the following compound

1-(Benzo[b]thiophen-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one.

One embodiment of the present invention is a compound wherein X is N and the other substituents are as described above, for example the following compound

3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

3,3-Dimethyl-1-(2-methylpyridin-4-yl)-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

3,3-Dimethyl-1-(6-methylpyridazin-3-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

3,3-dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one, or

6-(4-Fluorophenyl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one.

The compound of formula I and its pharmaceutically acceptable salts of the present invention can be prepared by methods known in the art, for example, by the following method, which comprises:

a) the compound of the following formula

React with the following compound

(R ² ) _n -Ar ² -Y 8

Producing compound of formula I

wherein Y is Cl, Br or I and the other groups have the meanings described above, and,

If necessary, the obtained compound is converted into a pharmaceutically acceptable acid addition salt.

The preparation of the compounds of formula I of the present invention can be carried out in a sequential or convergent synthetic route. The synthesis of the compounds of the present invention is shown in the following scheme. The techniques required for implementing the reaction and purification of the resulting products are known to those skilled in the art. Unless otherwise indicated, the substituents and symbols used in the following method descriptions have the meanings given herein before.

In more detail, the compound of formula I can be prepared by the method given below, by the method given in the examples or by similar methods. The appropriate reaction conditions for the single reaction step are known to those skilled in the art. The reaction sequence is not limited to the order shown in the scheme, but depends on the starting material and its respective reactivity, the order of reactions steps can be freely changed. The starting material is commercially available or can be prepared by a method similar to the method given below, by the method described in the examples or by methods known in the art.

Solution 1

Compounds of formula I (Scheme 1) wherein ^Ar1 = unsubstituted and substituted pyrimidine, pyridine, pyrazole, and imidazole and X = CH or N can be prepared by dimethylation of 6-halo-oxindole 1 (Y = Cl, Br, I) with Me-LG (LG is a leaving group such as iodide, bromide, chloride, tosylate) in the presence of a base such as potassium tert-butoxide and copper(I) bromide-dimethylsulfide complex to provide compound 2. Compounds of general formula 2 can be coupled with boronic acid 4 or boronic ester 5 in the presence of a palladium catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base such as potassium acetate or sodium carbonate to provide arylated compound 7. Alternatively, compound 7 can be prepared via boronic ester 3 and then coupled with aryl-halide 6 (Y = Cl, Br, I). Introduction of the second aryl residue ( ^Ar2- ( ^R2 ) _n ) can be achieved by coupling compound 7 with an aryl-halide 8 in the presence of copper(I) iodide, a ligand such as N,N'-dimethylethylenediamine and a base such as potassium carbonate to provide compounds of formula I.

Option 2

Imidazoles of formula Ia (Scheme 2) can be prepared from halogen-hydroxyindole 2 (Y = Cl, Br, I) by protecting the amine group using a p-methoxybenzyl protecting group (PMB), followed by coupling the protected product 9 with a substituted imidazole 10 ( ^R1 = alkyl or cycloalkyl) in the presence of copper bromide, a ketone such as 2-acetyl-cyclohexanone, and a base such as potassium carbonate to provide the PMB-protected imidazole 11. Deprotection of the PMB group can be achieved using a strong acid such as TFA to provide the indolinone 12. Coupling of 12 with a substituted aryl halide 8 (Y = Cl, Br, I) can be achieved in the presence of copper iodide, a ligand such as N,N'-dimethylethylenediamine, and a base such as potassium carbonate, or using boronic acid 14, copper acetate, and a base such as sodium bis(trimethylsilyl)amide to provide the target imidazole Ia.

Option 3

Diazoles of formula Ib (Scheme 3) can be prepared from halogen-hydroxyindole 2 (Y = Cl, Br, I) by carbonylation with carbon monoxide in methanol in the presence of a ferrocene-palladium catalyst. Hydrolysis of the methyl ester 15 using, for example, sodium hydroxide produces the acid 16, which is reacted with acetohydrazide in the presence of EDCI and 1H-benzo[d][1,2,3]triazol-1-ol to provide acetohydrazide 17. Cyclization of 17 using p-toluenesulfonyl chloride provides diazole 18, which is reacted with a substituted aryl halide (Y = Cl, Br, I) to provide compounds of formula Ib.

Option 4

Azoles of formula Ic (Scheme 4) can be prepared from protected halo-oxindole 9 (Y = Cl, Br, I) and azole 19 in the presence of palladium diacetate and 2-dicyclohexylphosphino)biphenyl and a base such as potassium carbonate to provide protected azole 20. Deprotection of the PMB group can be achieved using a strong acid such as TFA to provide indolinone 21. Coupling of 21 with substituted aryl halides 8 (Y = Cl, Br, I) can be achieved in the presence of copper iodide, a ligand such as N,N′-dimethylethylenediamine and a base such as potassium carbonate to provide the target azole Ic.

Option 5

The carboxylic acid 16 described above in Scheme 3 can be converted to the N-hydroxy-C-methyl-carbonimino derivative 22, for example, by addition of N-hydroxy-acetamidine, and subsequently converted to the corresponding -[1,2,4]oxadiazole 23, for example, by thermal dehydration. Coupling of 23 with substituted aryl halide 8 (Y═Cl, Br, I) can be achieved in the presence of copper iodide, a ligand such as N,N′-dimethylethylenediamine, and a base such as potassium carbonate to provide the target oxadiazole Id.

Option 6

The presence of exchangeable/acidic protons on certain heteroaromatic rings (e.g., 5-membered rings) may hinder the coupling reaction to 7. In such cases, protecting groups (PP, such as tetrahydropyranyl, tert-butylcarbamate, trimethylsilylethoxymethyl, etc.) can be used, which facilitates the generation of compound 24.

The introduction and removal of these protecting groups follow methods known to those skilled in the art (see Protective groups in organic synthesis, 3rd edition, Wiley interscience, T.H. Greene and P.G.M. Wuts).

Subsequent removal of the protecting group provides compounds Ie, which can optionally be further substituted by alkylation with alkyl halides (X = Cl, Br, I) to provide compounds of general formula If.

Option 7

The use of an oxidizing agent (e.g., m-chloroperbenzoic acid) for 26 can provide N-oxide derivatives of formula Ig, Ih, and/or Ii. The regioselectivity and number of such N-oxidations depend on the relative electron density of the heteroaromatic groups and the stoichiometry of the reaction conditions. Separation of the different products may require the use of HPLC.

Option 8

The addition of cyanogen bromide to compounds of formula 7 can be achieved using a strong base such as sodium hydride. Sodium azide can be reacted with 26 in the presence of a copper or zinc catalyst to provide tetrazoles of formula Ik. This process is known as "click-chemistry." Tetrazoles can be alkylated with alkyl halides 25 (X = C, Br, I) and a base such as potassium carbonate to provide compounds of formula Il.

Experimental part

The following examples are provided to illustrate the present invention. They should not be construed as limiting the scope of the invention, but merely as representative thereof.

abbreviation :

Boc, tert-butoxycarbonyl;

DIPEA, diisopropylethylamine;

DMAP, dimethylaminopyridine;

DMF, dimethylformamide;

DMSO, dimethyl sulfoxide;

EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

EtOAc, ethyl acetate;

HOBt, 1-hydroxybenzotriazole;

MeOH, methanol;

NMP, N-methyl-2-pyrrolidone;

PMB, p-methoxybenzyl;

TFA, trifluoroacetic acid;

THF, tetrahydrofuran.

General : Silica gel chromatography was performed on an ISCO Combi Flash Companion using cartridges filled with silica gel (Columns, TELOS™ Flash Columns) or silica-NH 2 gel (TELOS™ Flash NH 2 Columns) or on glass columns on silica gel 60 (32-60 mesh). MS: Mass spectrometry (MS) was measured on a Perkin-Elmer SCIEX API 300 using ion spray positive or negative methods.

Example 1

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridin-4-yl)indolin-2-one

a) 6-Bromo-3,3-dimethyl-indolin-2-one

To a suspension of potassium tert-butyrate (12.8 g) in anhydrous THF (80 ml) at 0° C. was added portionwise 6-bromoindolin-2-one (5.0 g) followed by copper (I) bromide-dimethylsulfide complex (470 mg). MeI (6.82 g) was added dropwise over 45 min, maintaining the internal temperature below 8° C. The mixture was warmed to 22° C. and stirred for 16 hours. The mixture was quenched with saturated aqueous ammonium chloride at 0° C. and diluted with TBME and water. The organic layer was dried, evaporated, and the residue was purified by flash chromatography (silica gel, EtOAc/n-heptane, 1:1) to provide the title compound (5.17 g) as a brown solid (5.17 g, 91%). MS (m/z): 240.4/242.4 [(M+H) ⁺ ].

b) 3,3-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin- 2-one

A suspension of 6-bromo-3,3-dimethyl-indolin-2-one (1.00 g), bis(pinacolato)diboron (1.60 g), and potassium acetate (0.83 g) in DMSO (14 ml) was flushed with argon, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (152 mg) and stirred at 110° C. for 16 h. The mixture was partitioned between aqueous hydrochloric acid (0.1 M) and EtOAc, the organic layer was dried, evaporated, and the residue was purified by flash chromatography (silica gel, gradient, 0% to 80% EtOAc in n-heptane) to provide the title compound (0.92 g, 77%) as a light yellow solid. MS (m/z): 288.2 [(M+H) ⁺ ].

c) 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

A suspension of 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (200 mg) and 5-bromo-2-methylpyrimidine (181 mg) in 1,4-dioxane (2 ml) and aqueous sodium carbonate (2 M) was flushed with argon, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg) and stirring at 115° C. for 3 h. The mixture was evaporated and the residue was purified by flash chromatography (silica gel, gradient, 0% to 10% MeOH in dichloromethane) to provide the title compound (148 mg, 84%) as a brown solid. MS (m/z): 254.2 [(M+H) ⁺ ].

d) 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridin-4-yl)indolin-2-one (Example 1)

A suspension of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg) and 4-iodopyridine (97 mg) in acetonitrile (1.5 ml) was flushed with argon, followed by the addition of potassium carbonate (120 mg), copper (I) iodide (8 mg), and N,N'-dimethylethylenediamine (7 mg) and continued stirring at 120° C. in a microwave oven for 1.5 h. The mixture was partitioned between water and EtOAc, the organic layer was dried, evaporated, and the residue was purified by flash chromatography (silica gel, 30% to 100% EtOAc in n-heptane). Fractions containing the compound were evaporated and the residue was crystallized from n-heptane/EtOAc to provide the title compound (64 mg, 49%) as a light brown solid. MS (m/z): 331.2 [(M+H) ⁺ ].

Example 2

3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 2 was prepared in analogy to Example 1d using 4-bromo-1-methyl-1H-imidazole to provide the title compound (59%) as an off-white solid. MS (m/z): 334.3 [(M+H) ⁺ ].

Example 3

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridin-3-yl)indolin-2-one

Example 3 was prepared analogously to Example 1d using 3-iodopyridine to provide the title compound (50%) as white needles. MS (m/z): 331.3 [(M+H) ⁺ ].

Example 4

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 4 was prepared in analogy to Example 1d using 3-iodo-1-methyl-1H-pyrazole to provide the title compound (75%) as an off-white solid. MS (m/z): 334.2 [(M+H) ⁺ ].

Example 5

1-(1,5-dimethyl-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 5 was prepared in analogy to Example 1d using 3-bromo-1,5-dimethyl-1H-pyrazole to provide the title compound (67%) as an off-white solid. MS (m/z): 348.3 [(M+H) ⁺ ].

Example 6

3,3-Dimethyl-1-(2-methylpyridin-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 6 was prepared analogously to Example 1d using 4-bromo-2-methylpyridine to provide the title compound (79%) as a white foam. MS (m/z): 345.3 [(M+H) ⁺ ].

Example 7

3,3-Dimethyl-1-(6-methylpyrimidin-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 7 was prepared in analogy to Example 1d using 4-bromo-6-methylpyrimidine to provide the title compound (27%) as a yellow solid. MS (m/z): 346.2 [(M+H) ⁺ ].

Example 8

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrimidin-5-yl)indolin-2-one

Example 8 was prepared in analogy to Example 1d using 5-bromopyrimidine to provide the title compound (55%) as a light yellow solid. MS (m/z): 332.2 [(M+H) ⁺ ].

Example 9

3,3-Dimethyl-1,6-bis(2-methylpyrimidin-5-yl)indolin-2-one

Example 9 was prepared in analogy to Example 1d using 5-bromo-2-methylpyrimidine to provide the title compound (28%) as a white solid. MS (m/z): 346.2 [(M+H) ⁺ ].

Example 10

3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(6-methylpyridin-3-yl)indolin-2-one

a) 3,3-Dimethyl-6-(6-methylpyridin-3-yl)indolin-2-one

A mixture of 6-bromo-3,3-dimethylindolin-2-one (250 mg) from Example 1a and 6-methylpyridine-3-boronic acid (214 mg) in 1,4-dioxane (4 ml) and aqueous sodium carbonate (1.3 ml) was flushed with argon, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (38 mg) was added and stirring was continued at 115° C. for 6 h. The mixture was evaporated and the residue was purified by flash chromatography (silica gel, gradient, 10% to 100% EtOAc in n-heptane) to provide the title compound (205 mg, 78%) as an off-white solid. MS (m/z): 253.3 [(M+H) ⁺ ].

b) 3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(6-methylpyridin-3-yl)indolin-2-one (Example 10)

The title compound was prepared and obtained (55%) as a light yellow solid from 3,3-dimethyl-6-(6-methylpyridin-3-yl)indolin-2-one and 4-bromo-1-methyl-1H-imidazole in analogy to Example 1d. MS (m/z): 333.3 [(M+H) ⁺ ].

Example 11

3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyridin-4-yl)indolin-2-one

a) 3,3-Dimethyl-6-(2-methylpyridin-4-yl)indolin-2-one

The title compound was prepared and obtained (49%) as a light brown solid in analogy to Example 10a using 2-methylpyrimidine-5-boronic acid. MS (m/z): 253.3 [(M+H) ⁺ ].

b) 3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyridin-4-yl)indolin-2-one (Example 11)

The title compound was prepared and obtained (43%) as a brown oil from 3,3-dimethyl-6-(2-methylpyridin-4-yl)indolin-2-one and 4-bromo-1-methyl-1H-imidazole in analogy to Example 1d. MS (m/z): 333.2 [(M+H) ⁺ ].

Example 12

3,3-Dimethyl-1-(6-methylpyridin-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 12 was prepared in analogy to Example 1d using 5-bromo-2-methylpyridine to provide the title compound (65%) as a white solid. MS (m/z): 345.2 [(M+H) ⁺ ].

Example 13

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(6-methylpyridin-3-yl)indolin-2-one

Example 13 was prepared in analogy to Example 10b using 3-iodo-1-methyl-1H-pyrazole to provide the title compound (76%) as a light yellow oil.MS (m/z): 333.2 [(M+H) ⁺ ].

Example 14

6-(4-fluoropyridin-3-yl)-3,3-dimethyl-1-(1-methyl-1H-imidazol-4-yl)indolin-2-one

a) 6-(4-fluoropyridin-3-yl)-3,3-dimethylindolin-2-one

The title compound was prepared and obtained (19%) as a light brown solid in analogy to Example 10a using 4-fluoropyridine-3-boronic acid pinacol ester. MS (m/z): 257.3 [(M+H) ⁺ ].

b) 6-(4-fluoropyridin-3-yl)-3,3-dimethyl-1-(1-methyl-1H-imidazol-4-yl)indolin-2-one (Example 14)

The title compound was prepared and obtained (39%) as a brown solid from 6-(4-fluoropyridin-3-yl)-3,3-dimethylindolin-2-one and 4-bromo-1-methyl-1H-imidazole in analogy to Example 1d. MS (m/z): 337.2 [(M+H) ⁺ ].

Example 15

3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

a) 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

A suspension of 6-chloro-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (200 mg, prepared according to Woolford et al., WO 2012143726) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (336 mg) in 1,4-dioxane (4 ml) and aqueous sodium carbonate (2M, 1 ml) was flushed with argon, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg) and stirring was continued at 110° C. for 5 h. The mixture was evaporated and the residue was purified by flash chromatography (silica gel, gradient, 0% to 10% MeOH in dichloromethane) to provide the title compound (221 mg, 85%) as a brown solid. MS (m/z): 255.1 [(M+H) ⁺ ].

b) 3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2 -c]pyridin-2(3H)-one (Example 15)

The title compound was prepared and obtained (29%) as a white solid from 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one and 4-bromo-1-methyl-1H-imidazole in analogy to Example 1d. MS (m/z): 335.2 [(M+H) ⁺ ].

Example 16

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

Example 16 was prepared in analogy to Example 1d from 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one from Example 15a and 3-iodo-1-methyl-1H-pyrazole to provide the title compound (91%) as a light brown solid. MS (m/z): 335.2 [(M+H) ⁺ ].

Example 17

3,3-Dimethyl-1-(2-methylpyridin-4-yl)-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

Example 17 was prepared in analogy to Example 1d from 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one from Example 15a and 4-bromo-2-methylpyridine to provide the title compound (74%) as a brown solid. MS (m/z): 346.2 [(M+H) ⁺ ].

Example 18

3,3-Dimethyl-6-(4-methylimidazol-1-yl)-1-(6-methyl-3-pyridyl)indolin-2-one

a) 6-Bromo-1-(4-methoxybenzyl)-3,3-dimethyl-1,3-dihydroindolin-2-one

To a solution of 6-bromo-3,3-dimethyl-1,3-dihydroindolin-2-one (4.00 g) from Example 1a in DMF (40 ml) was added cesium carbonate (3.50 g) and 4-methoxybenzyl chloride (5.00 g) and stirring was continued at 80° C. for 16 h. The mixture was partitioned between water and EtOAc, the organic layer was dried, evaporated and the residue was purified by flash chromatography (silica gel, EtOAc/n-heptane, 1:4) to provide the title compound (3.50 g, 58%) as an off-white solid. MS (m/z): 362.0 [(M+H) ⁺ ].

b) 1-(4-methoxybenzyl)-3,3-dimethyl-6-(4-methyl-imidazol-1-yl)-1,3-dihydroindolin-2-one

A mixture of 6-bromo-1-(4-methoxybenzyl)-3,3-dimethyl-1,3-dihydroindolin-2-one (0.50 g), potassium carbonate (0.21 g), and 4-methylimidazole (0.57 g) in NMP (2.5 ml) was flushed with argon, followed by the addition of CuBr (20 mg) and 2-acetyl-cyclohexanone (39 mg) and continued stirring at 135° C. for 16 h. The mixture was partitioned between water and EtOAc, the organic layer was dried, evaporated, and the residue was purified by flash chromatography (silica gel, EtOAc/n-heptane, 3:2) to provide the title compound (0.17 g, 35%) as a light yellow solid. MS (m/z): 361.8 [(M+H) ⁺ ].

c) 3,3-Dimethyl-6-(4-methyl-imidazol-1-yl)-1,3-dihydroindolin-2-one

A solution of 1-(4-methoxybenzyl)-3,3-dimethyl-6-(4-methyl-imidazol-1-yl)-1,3-dihydroindolin-2-one (170 mg) in TFA (10 ml) was heated at 110° C. for 72 h. The mixture was evaporated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution and EtOAc. The organic layer was dried, evaporated, and the residue was purified by flash chromatography (silica gel, EtOAc) to provide the title compound (70 mg, 61%) as a light yellow solid. MS (m/z): 241.8 [(M+H) ⁺ ].

d) 3,3-Dimethyl-6-(4-methylimidazol-1-yl)-1-(6-methyl-3-pyridyl)indolin-2-one ( Example 18)

To a suspension of 3,3-dimethyl-6-(4-methyl-imidazol-1-yl)-1,3-dihydroindolin-2-one (70 mg), 2-methylpyridine-5-boronic acid (80 mg), DMAP (106 mg), and copper acetate (56 mg) in anhydrous toluene (2 ml) was added sodium bis(trimethylsilyl)amide (1 M in THF, 0.06 ml) at 25° C. while bubbling dry air through the mixture and stirring was continued at 95° C. for 16 h. The mixture was partitioned between aqueous hydrochloric acid (2 M) and EtOAc, the organic layer was dried, evaporated, and the residue was purified by flash chromatography (silica gel, EtOAc/MeOH, 95:5) to provide the title compound (36 mg, 37%) as a brown solid. MS (m/z): 333.1 [(M+H) ⁺ ].

Example 19

3,3-Dimethyl-6-(6-methylpyridin-3-yl)-1-(2-methylpyridin-4-yl)indolin-2-one

Example 19 was prepared in analogy to Example 10b using 4-bromo-2-methylpyridine to provide the title compound (51%) as a light yellow oil.MS (m/z): 344.2 [(M+H) ⁺ ].

Example 20

3,3-Dimethyl-1,6-bis(2-methylpyridin-4-yl)indolin-2-one

Example 20 was prepared in analogy to Example 11b using 4-bromo-2-methylpyridine to provide the title compound (65%) as a white foam. MS (m/z): 344.3 [(M+H) ⁺ ].

Example 21

6-(4-cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methyl-4-pyridyl)indolin-2-one

a) 6-(4-Cyclopropyl-imidazol-1-yl)-3,3-dimethyl-1,3-dihydro-indol-2-one

Analogously to Examples 18a-c, using 4-cyclopropylimidazole (prepared according to Chen, Y., WO2010096395) in step 18b, the title compound was prepared and obtained (58%) as a yellow solid. MS (m/z): 267.9 [(M+H) ⁺ ].

b) 6-(4-cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methyl-4-pyridyl)indolin-2-one (Example 21)

The title compound was prepared in analogy to Example 18d from 6-(4-cyclopropyl-imidazol-1-yl)-3,3-dimethyl-1,3-dihydro-indol-2-one and 2-methyl-pyridine-4-boronic acid (boronic acid) to provide the title compound (9%) as a yellow solid. MS (m/z): 358.9 [(M+H) ⁺ ].

Example 22

3,3-Dimethyl-6-(4-methylimidazol-1-yl)-1-(2-methyl-4-pyridyl)indolin-2-one

Example 22 was prepared in analogy to Example 18d using 2-methylpyridine-4-boronic acid to provide the title compound (22%) as an off-white solid. MS (m/z): 332.9 [(M+H) ⁺ ].

Example 23

6-(4-fluoropyridin-3-yl)-3,3-dimethyl-1-(1-methyl-1H-pyrazol-3-yl)indolin-2-one

Example 23 was prepared in analogy to Example 14b using 3-iodo-1-methyl-1H-pyrazole to provide the title compound (74%) as a light yellow oil. MS (m/z): 337.2 [(M+H) ⁺ ].

Example 24

6-(4-fluoropyridin-3-yl)-3,3-dimethyl-1-(2-methylpyridin-4-yl)indolin-2-one

Example 24 was prepared analogously to Example 14b using 4-bromo-2-methylpyridine to provide the title compound (37%) as a light yellow foam. MS (m/z): 348.1 [(M+H) ⁺ ].

Example 25

1-(5-Fluoro-2-methylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 25 was prepared in analogy to Example 1d using 4-bromo-5-fluoro-2-methylpyridine to provide the title compound (21%) as a colorless oil.MS (m/z): 363.2 [(M+H) ⁺ ].

Example 26

3,3-Dimethyl-6-(1-methyl-1H-pyrazol-3-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

a) 3,3-Dimethyl-6-(1-methyl-1H-pyrazol-3-yl)indolin-2-one

The title compound was prepared in analogy to Example 1c using 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one from Example 1b and 3-iodo-1-methyl-1H-pyrazole to provide the title compound (26%) as an off-white solid. MS (m/z): 242.1 [(M+H) ⁺ ].

b) 3,3-Dimethyl-6-(1-methyl-1H-pyrazol-3-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one (Example 26)

The title compound was prepared from 3,3-dimethyl-6-(1-methyl-1H-pyrazol-3-yl)indolin-2-one in analogy to Example 1d using 5-bromo-2-methylpyrimidine to provide the title compound (59%) as a colorless oil. MS (m/z): 334.2 [(M+H) ⁺ ].

Example 27

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(5-methylthiophen-2-yl)indolin-2-one

Example 27 was prepared in analogy to Example 1d using 2-iodo-5-methylthiophene to provide the title compound (38%) as a white solid. MS (m/z): 350.2 [(M+H) ⁺ ].

Example 28

3,3-Dimethyl-1-(1-methyl-1H-imidazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 28 was prepared in analogy to Example 1d using 5-bromo-1-methyl-1H-imidazole to provide the title compound (18%) as a yellow solid. MS (m/z): 334.2 [(M+H) ⁺ ].

Example 29

3,3-Dimethyl-6-(1-methyl-1H-imidazol-4-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

a) 3,3-Dimethyl-6-(1-methyl-1H-pyrazol-3-yl)indolin-2-one

The title compound was prepared in analogy to Example 1c using 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one from Example 1b and 4-iodo-1-methyl-1H-imidazole to provide the title compound (16%) as a brown solid. MS (m/z): 242.2 [(M+H) ⁺ ].

b) 3,3-Dimethyl-6-(1-methyl-1H-imidazol-4-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one (Example 29)

The title compound was prepared in analogy to Example 1d from 3,3-dimethyl-6-(1-methyl-1H-pyrazol-3-yl)indolin-2-one and 5-bromo-2-methylpyrimidine to provide the title compound (34%) as an off-white solid. MS (m/z): 334.2 [(M+H) ⁺ ].

Example 30

5-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)picolinonitrile

Example 30 was prepared in analogy to Example 1d using 5-bromopicolinonitrile to provide the title compound (66%) as a white foam. MS (m/z): 356.2 [(M+H) ⁺ ].

Example 31

1-(6-(Hydroxymethyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 31 was prepared in analogy to Example 1d using (5-bromopyridin-2-yl)methanol to provide the title compound (55%) as a white solid. MS (m/z): 361.2 [(M+H) ⁺ ].

Example 32

1-(6-cyclopropylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 32 was prepared in analogy to Example 1d using 5-bromo-2-cyclopropylpyridine to provide the title compound (26%) as a white solid. MS (m/z): 371.2 [(M+H) ⁺ ].

Example 33

6-(4-Isopropylimidazol-1-yl)-3,3-dimethyl-1-(6-methyl-3-pyridyl)indolin-2-one

a) 6-(4-Isopropyl-imidazol-1-yl)-3,3-dimethyl-1,3-dihydro-indol-2-one

Analogously to Examples 18a-c, in step 18b, 4-isopropylimidazole (prepared according to Dolby et al., US20050101785) was used to prepare and obtain (67%) the title compound as an off-white solid. MS (m/z): 269.9 [(M+H) ⁺ ].

b) 6-(4-Isopropylimidazol-1-yl)-3,3-dimethyl-1-(6-methyl-3-pyridyl)indolin-2-one (Example 33)

Example 33 was prepared in analogy to Example 18d from 6-(4-isopropyl-imidazol-1-yl)-3,3-dimethyl-1,3-dihydro-indol-2-one and 2-methyl-pyridine-4-boronic acid to provide the title compound (25%) as a yellow solid. MS (m/z): 360.8 [(M+H) ⁺ ].

Example 34

3,3-Dimethyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(6-methyl-3-pyridyl)indolin-2-one

a) 3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester

A solution of 6-bromo-3,3-dimethyl-1,3-dihydroindolin-2-one (5.00 g), DIPEA (26.9 g) and DMF (5 ml) in methanol (40 ml) was flushed with argon, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.20 g) was added and stirring was continued at 100° C. under 150 psi CO pressure in an autoclave for 18 h. The mixture was evaporated and the residue was partitioned between water and EtOAc, the organic layer was dried, evaporated and the residue was purified by flash chromatography (silica gel, gradient, 30% EtOAc in n-heptane) to provide the title compound (3.0 g, 66%) as a brown solid. MS (m/z): 220.0 [(M+H) ⁺ ].

b) 3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid

To a solution of methyl 3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylate (6.00 g) in THF (60 ml) was added LiOH (11.5 g) and water (10 ml) and stirring was continued at 25° C. for 18 h. The mixture was evaporated, the residue was dissolved in ice-cold water, the pH was adjusted to 5-6 using aqueous hydrochloric acid (6N, 40 ml), the suspension was filtered, and the residue was dried to provide the title compound (3.50 g, 62%) as a light yellow solid. MS (m/z): 204.1 [(MH) ⁻ ].

c) 3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid N′-acetyl-hydrazide

To a solution of 3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (2.00 g) and acetic hydrazide (0.81 g) in anhydrous DMF (5 ml) was added HOBt (1.58 g), EDCI (2.20 g) and DIPEA (4.3 ml) and stirring was continued at 25° C. for 18 h. The mixture was evaporated to provide the crude title compound (2.20 g, 82%), which was used in the next step without further purification. MS (m/z): 262.1 [(M+H) ⁺ ].

d) 3,3-Dimethyl-6-(5-methyl-[1,3,4] oxadiazol-2-yl)-1,3-dihydroindolin-2-one

To a solution of crude 3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid N'-acetyl-hydrazide (43) (1.40 g) in DMF (5 ml) and acetonitrile (10 ml) was added tosyl chloride (1.50 g) and triethylamine (2.2 ml) and stirring was continued at 25°C for 18 h. The mixture was evaporated and the residue was partitioned between water and EtOAc, the organic layer was dried, evaporated and the residue was purified by flash chromatography (silica gel, gradient, 30% EtOAc in n-heptane) to provide the title compound (0.50 g, 38%). MS (m/z): 244.2 [(M+H) ⁺ ].

e) 3,3-Dimethyl-6-(5-methyl-1,3,4 -oxadiazol-2-yl)-1-(6-methyl-3-pyridyl)indolin -2-one (Example 34)

The title compound was prepared and obtained as an off-white solid (29%) from 3,3-dimethyl-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-1,3-dihydroindolin-2-one and 5-bromo-2-methyl-pyridine in analogy to Example 1d. MS (m/z): 335.1 [(M+H) ⁺ ].

Example 35

3,3-Dimethyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(2-methyl-4-pyridyl)indolin-2-one

Example 35 was prepared in analogy to Example 1d from 3,3-dimethyl-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-1,3-dihydroindolin-2-one from Example 34d and 4-bromo-2-methyl-pyridine to provide the title compound (27%) as an off-white solid. MS (m/z): 335.2 [(M+H) ⁺ ].

Example 36

6-(4-Isopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methyl-4-pyridyl)indolin-2-one

A mixture of 6-(4-isopropyl-imidazol-1-yl)-3,3-dimethyl-1,3-dihydro-indol-2-one (150 mg) from Example 33a, 4-bromo-2-methyl-pyridine (116 mg) and potassium carbonate (169 mg) in acetonitrile (10 ml) was flushed with argon, then CuI (10 mg) and N,N′-dimethylethylenediamine (16 mg) were added and stirring was continued at 110° C. for 5 h. The mixture was partitioned between water and EtOAc, the organic layer was dried, evaporated and the residue was purified by flash chromatography (silica gel, EtOAc) to provide the title compound (24%) as a yellow solid. MS (m/z): 361.0 [(M+H) ⁺ ].

Example 37

6-(4-Isopropylimidazol-1-yl)-3,3-dimethyl-1-(1-methylpyrazol-3-yl)indolin-2-one

Example 37 was prepared analogously to Example 36 from 6-(4-isopropyl-imidazol-1-yl)-3,3-dimethyl-1,3-dihydro-indol-2-one from Example 33a and 3-bromo-1-methyl-1H-pyrazole to provide the title compound (31%) as an off-white solid. MS (m/z): 349.8 [(M+H) ⁺ ].

Example 38

6-(4-Isopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)indolin-2-one

Example 38 was prepared analogously to Example 36 from 6-(4-isopropyl-imidazol-1-yl)-3,3-dimethyl-1,3-dihydro-indol-2-one from Example 33a and 5-bromo-2-methyl-pyrimidine to provide the title compound (31%) (29%) as a light yellow solid. MS (m/z): 361.9 [(M+H) ⁺ ].

Example 39

6-(4-cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(1-methylimidazol-4-yl)indolin-2-one

Example 39 was prepared analogously to Example 36 from 6-(4-cyclopropyl-imidazol-1-yl)-3,3-dimethyl-1,3-dihydro-indol-2-one from Example 21a and 4-bromo-1-methyl-1H-imidazole to provide the title compound (31%) as a light yellow solid. MS (m/z): 347.9 [(M+H) ⁺ ].

Example 40

6-(4-cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(1-methylpyrazol-3-yl)indolin-2-one

Example 40 was prepared analogously to Example 36 from 6-(4-cyclopropyl-imidazol-1-yl)-3,3-dimethyl-1,3-dihydro-indol-2-one from Example 21a and 3-bromo-1-methyl-pyrazole to provide the title compound (33%) as a gray solid. MS (m/z): 347.8 [(M+H) ⁺ ].

Example 41

6-(4-cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)indolin-2-one

Example 41 was prepared analogously to Example 36 from 6-(4-cyclopropyl-imidazol-1-yl)-3,3-dimethyl-1,3-dihydro-indol-2-one from Example 21a and 5-bromo-2-methyl-pyrimidine to provide the title compound (28%) as a light yellow semisolid. MS (m/z): 359.9 [(M+H) ⁺ ].

Example 42

3,3-Dimethyl-1-(1-methylimidazol-4-yl)-6-(2-methyloxazol-5-yl)indolin-2-one

a) 1-(4-Methoxy-benzyl)-3,3-dimethyl-6-(2-methyl- oxazol-5-yl)-1,3-dihydro-indol-2- one

A suspension of 6-bromo-1-(4-methoxybenzyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (1.00 g), 2-methyloxazole (0.50 g), and potassium carbonate (1.15 g) in 1,4-dioxane (10 ml) was flushed with argon, followed by the addition of palladium diacetate (31 mg) and 2-(dicyclohexylphosphino)biphenyl (10 mg) and stirring at 110° C. for 16 h. The mixture was partitioned between water and EtOAc, the organic layer was dried, evaporated, and the residue was purified by flash chromatography (silica gel, gradient, 0-50% EtOAc in n-heptane) to provide the title compound (0.45 g, 45%) as a yellow liquid. MS (m/z): 363.0 [(M+H) ⁺ ].

b) 3,3-Dimethyl-6-(2-methyl- oxazol-5-yl)-1,3-dihydro-indol-2-one

A solution of 1-(4-methoxy-benzyl)-3,3-dimethyl-6-(2-methyl-oxazol-5-yl)-1,3-dihydro-indol-2-one (450 mg) in TFA (20 ml) was heated at 110° C. for 72 h. The mixture was partitioned between saturated aqueous sodium bicarbonate solution and EtOAc, the organic layer was dried, evaporated, and the residue was purified by flash chromatography (silica gel, EtOAc/n-heptane, 4:1) to provide the title compound (200 mg, 66%) as an off-white solid. MS (m/z): 243.3 [(M+H) ⁺ ].

c) 3,3-Dimethyl-1-(1-methylimidazol-4-yl)-6-(2-methyloxazol -5-yl)indolin-2-one ( Example 42)

Example 42 was prepared in analogy to Example 1d from 3,3-dimethyl-6-(2-methyl-oxazol-5-yl)-1,3-dihydro-indol-2-one and 4-bromo-1-methyl-1H-imidazole to provide the title compound (30%) as a yellow solid. MS (m/z): 323.0 [(M+H) ⁺ ].

Example 43

3,3-Dimethyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

Example 43 was prepared in analogy to Example 1d from 3,3-dimethyl-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-1,3-dihydroindolin-2-one from Example 34d and 5-bromo-2-methyl-pyrimidine to provide the title compound (40%) as an off-white solid. MS (m/z): 336.6 [(M+H) ⁺ ].

Example 44

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridin-2-yl)indolin-2-one

Example 44 was prepared in analogy to Example 1d using 2-iodopyridine to provide the title compound (53%) as a white solid. MS (m/z): 331.2 [(M+H) ⁺ ].

Example 45

1-(2-fluoropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 45 was prepared in analogy to Example 1d using 2-fluoro-4-iodopyridine to provide the title compound (70%) as a white foam. MS (m/z): 349.1 [(M+H) ⁺ ].

Example 46

1-(3-fluoropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 46 was prepared in analogy to Example 1d using 3-fluoro-4-iodopyridine to provide the title compound (23%) as a white foam. MS (m/z): 349.2 [(M+H) ⁺ ].

Example 47

1-(2-Fluoro-5-methylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 47 was prepared in analogy to Example 1d using 2-fluoro-4-iodo-5-methylpyridine to provide the title compound (6%) as a white foam. MS (m/z): 363.2 [(M+H) ⁺ ].

Example 48

3,3-Dimethyl-1-(6-methylpyridazin-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 48 was prepared in analogy to Example 1d using 3-iodo-6-methylpyridazine to provide the title compound (67%) as a light yellow solid. MS (m/z): 346.2 [(M+H) ⁺ ].

Example 49

3,3-Dimethyl-6-(2-methyloxazol-5-yl)-1-(1-methylpyrazol-3-yl)indolin-2-one

Example 49 was prepared in analogy to Example 1d from 3,3-dimethyl-6-(2-methyl-oxazol-5-yl)-1,3-dihydro-indol-2-one and 3-bromo-1-methyl-1H-pyrazole to provide the title compound (22%) as an off-white solid. MS (m/z): 323.1 [(M+H) ⁺ ].

Example 50

1-(Benzo[b]thiophen-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 50 was prepared in analogy to Example 1d using 4-bromobenzo[b]thiophene to provide the title compound (5%) as a white solid. MS (m/z): 386.2 [(M+H) ⁺ ].

Example 51

3,3-Dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 51 was prepared in analogy to Example 1d using 2-bromo-5-methyl-1,3,4-oxadiazole to provide the title compound (31%) as a white solid. MS (m/z): 336.2 [(M+H) ⁺ ].

Example 52

1-(3-chloropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 52 was prepared in analogy to Example 1d using 4-bromo-3-chloropyridine to provide the title compound (21%) as a light yellow solid. MS (m/z): 365.1/367.1 [(M+H) ⁺ ].

Example 53

3,3-Dimethyl-1-(5-methylpyrimidin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 53 was prepared in analogy to Example 1d using 2-bromo-5-methylpyrimidine to provide the title compound (60%) as an off-white solid. MS (m/z): 346.2 [(M+H) ⁺ ].

Example 54

3,3-Dimethyl-1-(1-methylimidazol-4-yl)-6-(5-methyl-1,3,4-oxadiazol-2-yl)indolin-2-one

Example 54 was prepared in analogy to Example 1d from 3,3-dimethyl-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-1,3-dihydroindolin-2-one from Example 34d and 4-bromo-1-methyl-1H-imidazole to provide the title compound (25%) as an off-white solid. MS (m/z): 324.0 [(M+H) ⁺ ].

Example 55

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-3-yl)indolin-2-one

Example 55 was prepared analogously to Example 1d using tert-butyl 3-iodo-1H-pyrazole-1-carboxylate to provide the title compound (41%) as a white solid. The Boc-group was cleaved under the reaction conditions. MS (m/z): 320.1 [(M+H) ⁺ ].

Example 56

3,3-Dimethyl-1-(5-methylpyridin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 56 was prepared in analogy to Example 1d using 2-bromo-5-methylpyridine to provide the title compound (74%) as a white solid. MS (m/z): 345.2 [(M+H) ⁺ ].

Example 57

3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 57 was prepared in analogy to Example 1d using 2-bromo-5-methylpyrazine to provide the title compound (35%) as an off-white solid. MS (m/z): 346.2 [(M+H) ⁺ ].

Example 58

3,3-Dimethyl-6-(4-methylimidazol-1-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

Example 58 was prepared analogously to Example 36 from 3,3-dimethyl-6-(4-methyl-imidazol-1-yl)-1,3-dihydroindolin-2-one from Example 18c and 5-bromo-2-methyl-pyrimidine to provide the title compound (31%) as an off-white solid. MS (m/z): 333.8 [(M+H) ⁺ ].

Example 59

3,3-Dimethyl-1-(5-methylpyridin-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 59 was prepared in analogy to Example 1d using 3-bromo-5-methyl-pyridine to provide the title compound (49%) as a white solid. MS (m/z): 345.2 [(M+H) ⁺ ].

Example 60

3,3-Dimethyl-1-(4-methylpyridin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 60 was prepared in analogy to Example 1d using 2-bromo-4-methyl-pyridine to provide the title compound (72%) as a white solid. MS (m/z): 345.2 [(M+H) ⁺ ].

Example 61

3,3-Dimethyl-1-(6-methylpyridin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 61 was prepared in analogy to Example 1d using 2-bromo-6-methyl-pyridine to provide the title compound (67%) as a white solid. MS (m/z): 345.2 [(M+H) ⁺ ].

Example 62

3,3-Dimethyl-1-(2-methylpyrimidin-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 62 was prepared in analogy to Example 1d using 4-chloro-2-methyl-pyrimidine to provide the title compound (6%) as a white solid. MS (m/z): 346.2 [(M+H) ⁺ ].

Example 63

3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 63 was prepared in analogy to Example 1d using 2-bromo-6-methylpyrazine to provide the title compound (60%) as an off-white solid. MS (m/z): 346.2 [(M+H) ⁺ ].

Example 64

3,3-Dimethyl-1-(4-methylpyrimidin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 64 was prepared in analogy to Example 1d using 2-bromo-4-methylpyrimidine to provide the title compound (50%) as a white solid. MS (m/z): 346.2 [(M+H) ⁺ ].

Example 65

1-(1,2-dimethyl-1H-imidazol-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 65 was prepared in analogy to Example 1d using 4-bromo-1,2-dimethyl-1H-imidazole to provide the title compound (8%) as a white solid. MS (m/z): 348.2 [(M+H) ⁺ ].

Example 66

1-(2,6-dimethylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 66 was prepared in analogy to Example 1d using 4-bromo-2,6-dimethylpyridine to provide the title compound (52%) as an off-white solid. MS (m/z): 359.2 [(M+H) ⁺ ].

Example 67

1-(4,6-dimethylpyrimidin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 67 was prepared in analogy to Example 1d using 2-bromo-4,6-dimethylpyrimidine to provide the title compound (50%) as a white solid. MS (m/z): 360.2 [(M+H) ⁺ ].

Example 68

1-(2,6-dimethylpyrimidin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 68 was prepared in analogy to Example 1d using 4-bromo-2,6-dimethylpyrimidine to provide the title compound (46%) as a white solid. MS (m/z): 360.2 [(M+H) ⁺ ].

Example 69

1-(4,5-dimethylpyridin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

Example 69 was prepared in analogy to Example 1d using 2-bromo-4,5-dimethylpyridine to provide the title compound (50%) as a white solid. MS (m/z): 359.2 [(M+H) ⁺ ].

Example 70

1-(5,6-dimethylpyridin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

a) 6-Bromo-3,3-dimethyl-indolin-2-one (CAS[158326-84-2])

To a suspension of potassium tert-butyrate (12.8 g) in anhydrous tetrahydrofuran (80 ml) at 0° C. was added portionwise 6-bromoindolin-2-one (5.0 g, CAS [99365-40-9]) followed by copper(I) bromide-dimethylsulfide complex (470 mg). Methyl iodide (6.82 g) was added dropwise over 45 min, maintaining the internal temperature below 8° C. The mixture was warmed to 22° C. and stirring continued for 16 hours. The mixture was quenched with saturated aqueous ammonium chloride at 0° C. and diluted with tert-butyl methyl ether and water. The organic layer was dried, evaporated, and the residue was purified by flash chromatography (silica gel, ethyl acetate/n-heptane, 1:1) to provide the title compound (5.17 g) as a brown solid (5.17 g, 91%). MS (m/z): 240.4/242.4 [(M+H) ⁺ ].

b) 3,3-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin- 2-one

A suspension of 6-bromo-3,3-dimethyl-indolin-2-one (1.00 g), bis(pinacolato)diboron (1.60 g), and potassium acetate (0.83 g) in dimethyl sulfoxide (14 ml) was flushed with argon, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (152 mg) and stirred at 110° C. for 16 h. The mixture was partitioned between aqueous hydrochloric acid (0.1 M) and EtOAc, the organic layer was dried, evaporated, and the residue was purified by flash chromatography (silica gel, gradient, 0% to 80% ethyl acetate in n-heptane) to provide the title compound (0.92 g, 77%) as a light yellow solid. MS (m/z): 288.2 [(M+H) ⁺ ].

c) 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

A suspension of 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (200 mg) and 5-bromo-2-methylpyrimidine (181 mg) in 1,4-dioxane (2 ml) and aqueous sodium carbonate (2 M) was flushed with argon, followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg) and stirring at 115° C. for 3 h. The mixture was evaporated and the residue was purified by flash chromatography (silica gel, gradient, 0% to 10% methanol in dichloromethane) to provide the title compound (148 mg, 84%) as a brown solid. MS (m/z): 254.2 [(M+H) ⁺ ].

d) 1-(5,6-dimethylpyridin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

A degassed suspension of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 395 μmol, eq: 1.00) and 6-bromo-2,3-dimethylpyridine (88.1 mg, 474 μmol, eq: 1.20), potassium carbonate (120 mg, 869 μmol, eq: 2.20), copper (I) iodide (7.52 mg, 39.5 μmol, eq: 0.10), N,N′-dimethylethylenediamine (6.96 mg, 8.5 μl, 79.0 μmol, eq: 0.20) and acetonitrile (2 ml) was heated to 120° C. for 18 h.

The mixture was partitioned between water (10 mL) and dichloromethane (10 mL), then the aqueous layer was extracted with dichloromethane, the combined organic layers were dried, evaporated and the residue was purified by chromatography on silica gel to provide the desired compound as a white solid (73 mg, 52%). MS (m/z) = 359.2 [M+H] +.

Example 71

3,3-Dimethyl-6-(2-methyloxazol-5-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

a) 6-Bromo-1-(4-methoxybenzyl)-3,3-dimethylindolin-2-one

To a solution of 6-bromo-3,3-dimethylindolin-2-one (3 g, 12.5 mmol, eq: 1.00, CAS [158326-84-2], Example 70 step a) and 1-(chloromethyl)-4-methoxybenzene (1.96 g, 1.69 ml, 12.5 mmol, eq: 1.00) in dimethylformamide (90 ml) was added cesium carbonate (4.07 g, 12.5 mmol, eq: 1.00) at 22°C. The reaction mixture was heated at 80°C and stirred for 6 h. The volatiles were removed in vacuo and the residue was partitioned between water and ethyl acetate, then extracted with ethyl acetate (2 x 150 ml). The combined organic layers were washed with water, dried, evaporated and the residue was purified by chromatography on silica gel to provide the desired compound as a light red oil (3.98 g, 88%). MS(m/z)=360.1/362.1[M+H]+.

b) 1-(4-methoxybenzyl)-3,3-dimethyl-6-( oxazol-5-yl)indolin-2-one

A degassed mixture of 6-bromo-1-(4-methoxybenzyl)-3,3-dimethylindolin-2-one (720 mg, 2 mmol, eq: 1.00, step a of Example 71), palladium(II) acetate (22.5 mg, 100 μmol, eq: 0.05), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-iso-propylbiphenyl (96.1 mg, 200 μmol, eq: 0.1), pivalic acid (81.7 mg, 92.8 μl, 800 μmol, eq: 0.4), potassium carbonate (829 mg, 6.00 mmol, eq: 3), dimethylacetamide (7.5 ml) and oxazole (276 mg, 4.00 mmol, eq: 2) was heated to 115° C. in an oil bath for 15 h. After cooling to 22°C, the reaction mixture was directly purified by chromatography on silica gel to provide the desired compound as a light yellow oily solid (500 mg, 72%).MS (m/z) = 349.2 [M+H] +.

c) 1-(4-methoxybenzyl)-3,3-dimethyl-6-(2-methyl oxazol-5-yl)indolin-2-one

To a solution of 1-(4-methoxybenzyl)-3,3-dimethyl-6-(oxazol-5-yl)indolin-2-one (200 mg, 574 μmol, eq. 1.00, Example 71, step b) in tetrahydrofuran (4 ml) was added a solution of borane tetrahydrofuran complex in tetrahydrofuran (1 M, 689 μl, 689 μmol, eq. 1.2) at room temperature. After 30 minutes, the solution was cooled to -78°C and a solution of n-butyllithium in hexane (1.6 M, 431 μl, 689 μmol, eq. 1.2) was added. After 15 minutes at -78°C, iodomethane (97.8 mg, 43.0 μl, 689 μmol, eq. 1.2) was added and the mixture was allowed to warm to -20°C and stirred at that temperature for 4 hours. Then, a solution of acetic acid in ethanol (5% v/v, 10.3 g, 9.86 ml, 8.61 mmol, eq.: 15) was added and the reaction mixture was stirred at room temperature overnight. The mixture was partitioned between saturated aqueous sodium bicarbonate solution and diethyl ether and then extracted with ether. The combined organic layers were washed with brine, dried, evaporated and the residue was purified by chromatography on silica gel to provide the desired compound as a light yellow solid (36 mg, 17%). MS (m/z) = 363.2 [M+H] +.

d) 3,3-dimethyl-6-(2-methyl oxazol-5-yl)indolin-2-one

A solution of 1-(4-methoxybenzyl)-3,3-dimethyl-6-(2-methyloxazol-5-yl)indolin-2-one (35 mg, 96.6 μmol, eq. 1.00, Example 71, step c) was dissolved in trifluoroacetic acid (661 mg, 446 μl, 5.79 mmol, eq. 60) and the reaction mixture was reacted in a microwave at 140° C. for 1 h. The volatiles were removed in vacuo and the green residue was purified by chromatography on silica gel to provide the desired compound as a light brown solid (15.9 mg, 68%). MS (m/z) = 243.1 [M+H]+.

e) 3,3-dimethyl-6-(2-methyl oxazol-5-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, Step d, using 3,3-dimethyl-6-(2-methyloxazol-5-yl)indolin-2-one (Example 71, Step d) and 5-bromo-2-methyl-pyrimidine as starting materials. Off-white solid. Yield: 29%. MS (m/z) = 335.4 (M+H) ⁺

Example 72

3,3-Dimethyl-6-(4-methyl-1H-imidazol-1-yl)-1-(1-methyl-1H-imidazol-4-yl)indolin-2-one

a) 3,3-Dimethyl-6-(4-methylimidazol-1-yl)indolin-2-one

In a sealed tube, a degassed mixture of 6-bromo-3,3-dimethylindolin-2-one (150 mg, 625 μmol, Eq: 1.00, CAS [158326-84-2], Example 70, step a), 4-methyl-1H-imidazole (256 mg, 3.12 mmol, Eq: 5.0), potassium carbonate (90.7 mg, 656 μmol, Eq: 1.05) and 2-acetylcyclohexanone (21.9 mg, 20.3 μl, 156 μmol, Eq: 0.25) in N-methylpyrrolidone (1.2 ml) and copper (I) chloride (6.18 mg, 62.5 μmol, Eq: 0.1) was stirred at 130° C. for 24 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate, then extracted with ethyl acetate. The combined organic layers were dried, evaporated and the residue was purified by chromatography on silica gel followed by reverse phase HPLC to provide the desired compound as a white solid (39 mg, 26%).

MS (m/z) = 242.2 [M+H] +.

b) 3,3-dimethyl-6-(4-methyl-1H-imidazol-1-yl)-1-(1-methyl-1H-imidazol-4-yl)indoline- 2-Keto

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(4-methylimidazol-1-yl)indolin-2-one (Example 72, step a) and 4-bromo-1-methyl-1H-imidazole as starting materials. Yellow solid. Yield: 33%.

MS (m/z) = 322.2 [M+H] +.

Example 73

3,3-Dimethyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

a) 3,3-Dimethyl-2-oxo-indoline-6-carboxylic acid methyl ester

To a yellow solution of methyl 2-oxoindoline-6-formate (6.24 g, 31.7 mmol, eq.: 1) and methyl iodide (9.08 g, 4 ml, 64 mmol, eq.: 2.02) in anhydrous dimethylformamide (90.5 ml) was added a suspension of NaH in mineral oil (60% w/w, 2.54 g, 63.4 mmol, eq.: 2) portionwise over 1.5 h while controlling the exotherm with a water bath. The reaction mixture was carefully poured onto an ice-cold mixture of 11 g sodium bicarbonate, water (150 mL) and ethyl acetate (150 mL). The resulting mixture was extracted with ethyl acetate and the organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.

The residue was triturated with heptane/ethyl acetate 1 : 1 and the precipitate was filtered and washed with heptane/ethyl acetate 1 : 1. The solid was dried in vacuo to afford the desired product as a light brown solid (5.026 g, 72%).

MS (m/z) = 218.1 [M+H] +.

b) 3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid

To 3,3-dimethyl-2-oxo-dihydroindole-6-methyl-formiate (6.0g, 27.4mmol, embodiment 73 step a) solution in tetrahydrofuran (60ml) add lithium hydroxide (11.5g, 273.9mmol) and water (10ml).Mixture is stirred 12h at 25 ℃.After reaction is complete, solvent is removed in vacuo.Ice-water (100ml) is added in reaction mixture and by adding hydrochloric acid (6N, 40ml) the pH value of reaction mixture is adjusted to 5-6.Form white precipitate, filter and wash with water (2x25ml), then dry under vacuum, thereby provide required product (3.5g, 62%), be dark brown solid.

MS (m/z): 204.1 (M-H)-.

c) N-[(E)-N-Hydroxy-C-methyl-carbonimino]-3,3-dimethyl-2-oxo-dihydroindole-6-carboxamide

To a solution of 3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (1.5 g, 7.317 mmol, Example 73 step b) and N-hydroxy-acetamidine (0.54 g, 7.317 mmol) in anhydrous THF (10 ml) and dimethylformamide (1 ml) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphaninane-2,4,6-trioxide (3.45 g, 10.976 mmol) and triethylamine (3.0 ml, 21.9 mmol). The resulting mixture was stirred at 25° C. for 18 h. The solvent was removed under vacuum to provide the desired product (1.5 g, 78%). The product was used in the next step without further purification.

MS (m/z) = 262.2 [M+H] ⁺ .

d) 3,3-dimethyl-6-(3-methyl-[1,2,4] oxadiazole-5-yl)-1,3-dihydro-indol-2-one

A solution of N-[(E)-N-hydroxy-C-methyl-carbonimino]-3,3-dimethyl-2-oxo-dihydroindole-6-carboxamide (1.5 g, 5.74 mmol, Example 73, step c) in dioxane (25 ml) was heated at 100° C. for 16 h. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel to provide the desired compound as an off-white solid (300 mg, 21%).

MS (m/z) = 242.2 [M-H]-.

e) 3,3-dimethyl-6-(3-methyl-1,2,4- oxadiazol-5-yl)-1-(2-methylpyrimidin-5-yl)indole Indole-2-one

The title compound was prepared by analogy with Example 70, Step d, using 3,3,3-dimethyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-1,3-dihydro-indol-2-one (Example 73, Step d) and 5-bromo-2-methyl-pyrimidine as starting materials. Pale yellow solid. Yield: 24%.

MS (m/z) = 336.0 [M+H] ⁺ .

Example 74

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-iodo-1-methyl-1H-pyrazole as starting materials. A light brown solid. Yield: 9%. MS (m/z) = 334.2 (M+H) ⁺

Example 75

1-(5,6-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-bromo-2,3-dimethylpyridine as starting materials. White solid. Yield: 52%. MS (m/z) = 359.2 (M+H) ⁺

Example 76

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridazin-3-yl)indolin-2-one

The title compound was prepared in analogy to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 3-bromopyridazine (CAS [88491-61-6]) as starting materials. White solid. Yield: 71%.

MS (m/z) = 332.2 (M+H ⁾

Example 77

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrazin-2-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2-iodopyrazine as starting materials. White solid. Yield: 55%. MS (m/z) = 332.3 (M+H) ⁺

Example 78

1-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 3-bromo-1,5-dimethyl-1H-1,2,4-triazole (CAS [56616-93-4]) as starting materials. An off-white solid was obtained. Yield: 65%.

MS (m/z) = 349.2 (M+H ⁾

Example 79

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrimidin-2-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2-bromopyrimidine (CAS [4595-60-2]) as starting materials. White solid. Yield: 32%. MS (m/z) = 332.1 (M+H) ⁺

Example 80

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 4-bromo-1-methyl-1H-pyrazole (CAS [15803-02-8]) as starting materials. White solid. Yield: 30%. MS (m/z) = 334.2 (M+H) ⁺

Example 81

3,3-Dimethyl-1-(2-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

a) 2-[(4-iodo-2-methyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane

In a 50ml three-necked flask equipped with a magnetic stirrer, diaphragm, thermometer and argon balloon, 3.34g of 4,5-diiodo-2-methylimidazole ([73746-44-8]) was dissolved in 30ml of anhydrous tetrahydrofuran. To this solution was added dropwise 6.9ml (1.10 equivalents) of butyl lithium 1.6M/hexane at -75°C to -65°C. After the initial addition of butyl lithium, the solution became a milky white suspension, which became a yellow solution after further addition of butyl lithium. The reactants were stirred at -75°C for 10min, and then 1.85ml (1.75g, 11.0mmol, 1.05 equivalents) of 2-(trimethylsilyl)-ethoxymethyl chloride was added dropwise at -75°C. The reactants were allowed to warm to room temperature. The solution is cooled to -75 ℃ and 6.2ml (1.00 equivalents) of butyl lithium 1.6M/ hexane are added dropwise, keeping the temperature below -65 ℃.After 30min at -75 ℃, 2ml (5.0 equivalents) of methanol are added dropwise at -75 ℃. The mixture is stirred for 10min at -75 ℃. Saturated aqueous ammonium chloride solution (3mL) is added and the mixture is warmed to room temperature, then distributed between water and ethyl acetate, and the water layer is extracted with ethyl acetate, then dried in vacuo. The residue is passed through the chromatographic purification on silica gel, thereby providing the required compound (1.27g, 37%).

b) 3,3-dimethyl-1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4- 1-Methyl-2-pyrimidin-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one:

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 4-iodo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (Example 81, step a) as starting materials ^. Yellow solid. Yield: 91%. MS (m/z) = 464.3 (M+H)

c) 3,3-Dimethyl-1-(2-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)indoline-2-yl ketone

To a solution of 3,3-dimethyl-1-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one (164 mg, 354 μmol, eq: 1.00) in dichloromethane (3 mL) and ethanol (244 mg, 310 μl, 5.31 mmol, eq: 15) was added trifluoroacetic acid (1.61 g, 1.09 ml, 14.1 mmol, eq: 40). The reaction mixture was stirred at 22° C. for 20 h. Ethanol (3 ml) was added and the reaction mixture was stirred at 70° C. for 20 h, resulting in evaporation of dichloromethane. The volatiles were removed in vacuo. The residue was partitioned between saturated aqueous sodium carbonate solution and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried and evaporated.

The residue was purified by chromatography on silica gel to provide the desired compound as a white solid (53 mg, 45%).MS (m/z) = 334.2 [M+H] + .

Example 82

3,3-Dimethyl-1-(1-methyl-1H-1,2,4-triazol-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, Step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, Step c) and 3-bromo-1-methyl-1H-1,2,4-triazole as starting materials. Off-white solid. Yield: 80%. MS (m/z) = 335.2 [M+H]+.

Example 83

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-4-yl)indolin-2-one

A suspension of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 395 μmol, eq. 1.00, see Example 70, step c) and tert-butyl 4-iodo-1H-pyrazole-1-carboxylate (139 mg, 474 μmol, eq. 1.20) was mixed in acetonitrile (2 ml). Potassium carbonate (120 mg, 869 μmol, eq. 2.20) was added, followed by copper (I) iodide (7.52 mg, 39.5 μmol, eq. 0.10) and N,N′-dimethylethylenediamine (6.96 mg, 8.5 μl, 79.0 μmol, eq. 0.20), and the mixture was heated to 120° C. in an oil bath for 20 h and then to 160° C. in a microwave for 2 h.

The mixture was partitioned between water and dichloromethane, the aqueous layer was extracted three times with dichloromethane and the combined organic layers were dried and evaporated.

The residue was purified by chromatography on silica gel to provide the desired compound as a colorless foam (16 mg, 13%). MS (m/z) = 320.2 [M+H] + .

Example 84

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(4-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-iodo-4-methylpyrimidine (CAS [91749-26-7]) as starting materials. Off-white solid. Yield: 11%. MS (m/z) = 346.2 [M+H]+.

Example 85

1-(1H-imidazol-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

a) tert-Butyl 4-bromo-1H-imidazole-1-carboxylate

4-bromo-1H-imidazole (2.59g, 17.6mmol, equivalent: 1.00) and di-tert-butyl dicarbonate (4.04g, 4.3ml, 18.5mmol, equivalent: 1.05) are merged with tetrahydrofuran (19ml).Dimethylaminopyridine (43.1mg, 352μmol, equivalent: 0.02) is added and the reaction is stirred at 25 ℃ for 1.5h.The thick reaction mixture is concentrated in a vacuum.Residue is placed in ethyl acetate and washed with 1M hydrochloric acid solution, water, saturated sodium bicarbonate and salt water.The organic layer is dried and concentrated in a vacuum to provide the required compound, which is a pale solid (4.2g, 95%).

b) 1-(1H-imidazol-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and tert-butyl 4-bromo-1H-imidazole-1-carboxylate (Example 85, step a) as starting materials. A pale yellow solid was obtained. Yield: 12%.

MS (m/z) = 320.2 [M+H] ⁺ .

Example 86

3,3-Dimethyl-1-(3-methyl-1H-pyrazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one hydrochloride

a) 3,3-dimethyl-1-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-6-(2-methyl Pyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, Step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, Step c) and 5-iodo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as starting materials. A pale yellow oil was obtained. Yield: 33%.

MS (m/z) = 418.3 [M+H] ⁺ .

b) 3,3-Dimethyl-1-(3-methyl-1H-pyrazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one hydrochloride

To a pale yellow solution of 3,3-dimethyl-1-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one (55 mg, 132 μmol, eq: 1.00) in dichloromethane (1 ml) was added hydrochloric acid (4 M) in dioxane (329 μl, 1.32 mmol, eq: 10) and the mixture was stirred at 22° C. for 4 h. The solvent was concentrated in vacuo and the residue was crystallized from ethyl acetate (5 ml) to provide the desired compound as an off-white solid (18 mg, 35%). MS (m/z) = 334.2 [M+H] ⁺ .

Example 87

3,3-Dimethyl-1-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

In a microwave tube, acetonitrile (3 ml) was added to a mixture of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 395 μmol, eq. 1.00, see Example 70, step c) and 4-bromo-1-methyl-1H-1,2,3-triazole (76.7 mg, 474 μmol, eq. 1.2). The solvent was degassed by bubbling nitrogen through the suspension for 10 minutes. N,N′-dimethylethylenediamine (6.96 mg, 8.5 μl, 79.0 μmol, eq. 0.2) was then added at 22° C., followed by potassium carbonate (136 mg, 987 μmol, eq. 2.5) and copper (I) iodide (7.52 mg, 39.5 μmol, eq. 0.1). The tube was inerted, sealed and the mixture was heated in a microwave at 170°C for 30 minutes.

The mixture was treated with 2 ml of water and extracted with ethyl acetate (2 x 2 ml).The organic layer was dried, filtered and concentrated in vacuo.

The residue was purified by chromatography on silica gel to provide the desired compound as a white solid (8 mg, 6%).MS (m/z) = 335.2 [M+H] ⁺ .

Example 88

3,3-Dimethyl-1-(4-methyl-1H-imidazol-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared in a manner analogous to Example 87 using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, Step c) and tert-butyl 2-bromo-4-methyl-1H-imidazole-1-carboxylate as starting materials. White solid. Yield: 6%. MS (m/z) = 334.2 [M+H] ⁺ .

Example 89

3,3-Dimethyl-1-(3-methylisoxazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

To a mixture of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 395 μmol, eq. 1.00, see Example 70, step c), 5-iodo-3-methylisoxazole (99.0 mg, 474 μmol, eq. 1.2) and cesium carbonate (322 mg, 987 μmol, eq. 2.5) was added dioxane (1 ml). The solvent was degassed by bubbling nitrogen through the suspension for 10 minutes. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (9.41 mg, 19.7 μmol, eq. 0.05) was then added at 22° C., followed by tris(dibenzylideneacetone)dipalladium(0) (3.62 mg, 3.95 μmol, eq. 0.01). The tube was filled with inert gas, sealed and the mixture was heated to 120°C for 2 h. The mixture was treated with 2 ml of water and extracted with ethyl acetate (3 x 2 ml). The organic layer was dried, filtered and concentrated in vacuo.

The residue was purified by chromatography on silica gel to provide the desired compound as a light yellow solid (5 mg, 3%).MS (m/z) = 335.2 [M+H] ⁺ .

Example 90

3,3-Dimethyl-1,6-bis(5-methylpyrimidin-2-yl)indolin-2-one

a) 3,3-Dimethyl-6-(5-methylpyrimidin-2-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step c, using 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (Example 70, step b) and 2-bromo-5-methylpyrimidine as starting materials. Off-white solid. Yield: 43%. MS (m/z) = 254.2 [M+H] ⁺

b) 3,3-Dimethyl-1,6-bis(5-methylpyrimidin-2-yl)indolin-2-one

In a sealed tube, argon was bubbled through a suspension of 3,3-dimethyl-6-(5-methylpyrimidin-2-yl)indolin-2-one (80 mg, 316 μmol, eq. 1.00) and 2-bromo-5-methylpyrimidine (65.6 mg, 379 μmol, eq. 1.20) in acetonitrile (2.5 ml) for 5 min. Potassium carbonate (96.0 mg, 695 μmol, eq. 2.20) was added, followed by copper (I) iodide (6.02 mg, 31.6 μmol, eq. 0.10) and N,N′-dimethylethylenediamine (5.57 mg, 6.8 μl, 63.2 μmol, eq. 0.20), and the mixture was heated to 130° C. in a microwave for 1 h. The mixture was partitioned between water (10 ml) and dichloromethane (10 ml). The aqueous layer was extracted three times with dichloromethane (3 x 10 ml) and the combined organic layers were dried and evaporated.

The residue was purified by chromatography on silica gel to provide the title compound as an off-white solid (83 mg, 76%).MS (m/z) = 346.2 [M+H] ⁺ .

Example 91

3,3-Dimethyl-1,6-bis(5-methylpyrazin-2-yl)indolin-2-one

a) 3,3-Dimethyl-6-(5-methylpyrazin-2-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (Example 70, step b) and 2-bromo-5-methylpyrazine as starting materials. White solid. Yield: 63%. MS (m/z) = 254.2 [M+H] ⁺

b) 3,3-Dimethyl-1,6-bis(5-methylpyrazin-2-yl)indolin-2-one

The title compound was prepared by analogy with Example 90, step b, using 3,3-dimethyl-6-(5-methylpyrazin-2-yl)indolin-2-one (Example 91, step a) and 2-bromo-5-methylpyrazine as starting materials. Off-white solid. Yield: 68%. MS (m/z) = 346.2 [M+H] ⁺ .

Example 92

1-(1H-imidazol-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

a) 2-(Imidazol-1-ylmethoxy)ethyl-trimethyl-silane

Sodium hydride (60% w/w, 5.2g, 130mmol, equivalent: 1.30) in mineral oil is suspended in 240ml tetrahydrofuran and cooled to 0 ℃. A solution of imidazole (6.8g, 100mmol, equivalent: 1.00) dissolved in 100ml tetrahydrofuran is slowly dropped to the reaction mixture and continued to stir at room temperature for 45min. The reaction mixture is then cooled with an ice bath and 2-(trimethylsilyl)ethoxymethyl chloride (16.67g, 17.64ml, 100mmol, equivalent: 1.00) is added, and the suspension is stirred at room temperature overnight. The reaction is quenched by adding saturated sodium bicarbonate. The solvent is evaporated and the residue is extracted twice with ethyl acetate. The combined organic layer is washed with water, dried and concentrated in a vacuum.

The residue was purified by Kugelrohr distillation to provide the title compound as a colorless liquid (18.6 g, 93%).

b) 2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

2-(Imidazol-1-ylmethoxy)ethyl-trimethyl-silane (2 g, 10 mmol, eq: 1.00, Example 92 step a) was dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to -78°C. n-Butyllithium (1.6 M in hexane, 6.93 ml, 11 mmol, eq: 1.10) was added dropwise for 20 min. The reaction solution was warmed to 0°C and stirred at 0°C for 5 min. It was then cooled to -60°C and a solution of iodine (2.81 g, 11 mmol, eq: 1.10) in 10 ml of anhydrous tetrahydrofuran was added for 10 min. The cooling bath was removed and the solution was allowed to warm to room temperature. The reaction was quenched with water and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with sodium carbonate and brine, dried and concentrated in vacuo.

The residue was purified by chromatography on silica gel to provide the title compound as a light yellow oil (2.34 g, 71%).

c) 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl 1H-imidazol-2-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (Example 92, step b) as starting materials. Yellow oil. Yield: 15%. MS (m/z) = 450.3 (M+H) ⁺

d) 1-(1H-imidazol-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

To a solution of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)indolin-2-one (35 mg, 77.8 μmol, Eq: 1.00, Example 92, Step c) in tetrahydrofuran (1 ml) was added tetrabutylammonium fluoride (1 M in THF) (311 μl, 311 μmol, Eq: 4.00) and the mixture was stirred at room temperature for 20 h. The mixture was partitioned between water (10 ml) and dichloromethane (10 ml), the aqueous layer was extracted twice with dichloromethane (2 x 10 ml), and the combined organic layers were dried and concentrated in vacuo.

The residue was purified by preparative HPLC to provide the desired compound as a white solid (3 mg, 14%).MS (m/z) = 320.2 [M+H] ⁺ .

Example 93

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrimidin-4-yl)indolin-2-one

To a mixture of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 395 μmol, eq. 1.00, Example 70, Step c), 4-bromopyrimidine hydrochloride (154 mg, 790 μmol, eq. 2), and cesium carbonate (450 mg, 1.38 mmol, eq. 3.5) was added degassed dioxane (3 ml). Palladium(II) acetate (17.7 mg, 79.0 μmol, eq. 0.2) was then added at room temperature, followed by 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (Xantphos) (68.5 mg, 118 μmol, eq. 0.3). The tube was filled with inert gas, sealed, and the mixture heated to 115° C. for 2 h. The reaction was concentrated in vacuo.

The residue was purified by chromatography on silica gel followed by precipitation in pentane to provide the title compound as a light brown solid (60 mg, 47%).MS (m/z) = 332.2 [M+H] ⁺ .

Example 94

1-(1-ethyl-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, Step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, Step c) and 1-ethyl-3-iodo-1H-pyrazole as starting materials. White solid. Yield: 8%. MS (m/z) = 348.2 [M+H] ⁺ .

Example 95

1-(5-cyclopropylpyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2-bromo-5-cyclopropylpyrazine as starting materials. Pale brown solid. Yield: 85%. MS (m/z) = 372.2 [M+H] ⁺ .

Example 96

5-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrazine-2-carbonitrile

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-bromopyrazine-2-carbonitrile as starting materials. White solid. Yield: 33%. MS (m/z) = 357.1 [M+H] ⁺ .

Example 97

1-(6-cyclopropylpyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2-bromo-6-cyclopropylpyrazine as starting materials. Pale brown solid. Yield: 89%. MS (m/z) = 372.2 [M+H] ⁺ .

Example 98

1-(4,5-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, Step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, Step c) and 3-bromo-4,5-dimethylpyridine as starting materials. White solid. Yield: 2%. MS (m/z) = 359.2 [M+H] ⁺ .

Example 99

3,3-Dimethyl-1-(4-methylpyridin-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 3-bromo-4-methylpyridine as starting materials. White solid. Yield: 4%. MS (m/z) = 345.2 [M+H] ⁺ .

Example 100

1-(4,6-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, Step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, Step c) and 5-bromo-2,4-dimethylpyridine as starting materials. White solid. Yield: 3%. MS (m/z) = 359.2 [M+H] ⁺ .

Example 101

5-(3,3-Dimethyl-1-(5-methylpyrimidin-2-yl)-2-oxoindolin-6-yl)-2-methylpyrimidine 1-oxide

To a solution of 3,3-dimethyl-1-(5-methylpyrimidin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one (20 mg, 57.9 μmol, eq.: 1.00, Example 53) in dichloromethane (0.6 ml) was added meta-chloroperbenzoic acid (19 mg, eq.: 1.3) at 22°C and the mixture was stirred at 22°C for 2 days. The mixture was partitioned between saturated aqueous sodium carbonate solution (5 ml, 2N) and dichloromethane (5 ml). The aqueous layer was extracted with dichloromethane (3 x 5 ml) and the combined organic layers were dried, concentrated in vacuo, and the residue was purified by chromatography on silica gel to provide the desired compound as an off-white solid (8 mg, 38%). MS (m/z) = 362.1 [M+H] ⁺ .

Example 102

1-(2-(Hydroxymethyl)pyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared analogously to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 116, step a) and (5-bromopyrimidin-2-yl)methanol (prepared as previously described, for example, by Hasnik, Zbynek et al., Synlett, (4), 543-546; 2008) as starting materials. Pale brown solid. Yield: 31%. MS (m/z) = 362.2 (M+H) ⁺

Example 103

1-[2-(Aminomethyl)pyrimidin-5-yl]-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indol-2-one

a) N-[[5-[3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxo-dihydroindolin-1-yl]pyrimidin-2-yl] tert-Butyl]methyl]carbamate

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 116, step a) and tert-butyl (5-bromopyrimidin-2-yl)methylcarbamate as starting materials. Off-white solid. Yield: 74%. MS (m/z) = 464.4.3 (M+H) ⁺

b) 1-[2-(Aminomethyl)pyrimidin-5-yl]-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indol-2-one

To a solution of tert-butyl (5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)pyrimidin-2-yl)methylcarbamate (100 mg, 217 μmol, Eq: 1.00, Example 103, step a) in dichloromethane (1 ml) was added trifluoroacetic acid (248 mg, 167 μl, 2.17 mmol, Eq: 10) at 0°C, and the mixture was stirred at 0°C for 15 min and at 22°C for 16 h.

The reaction mixture was basified by dropwise addition of aqueous sodium hydroxide solution (2N, pH about 14), then extracted with dichloromethane, dried and evaporated.

The combined organic layers were dried, concentrated in vacuo and the residue was purified by chromatography on silica gel to provide the desired compound as an off-white solid (36 mg, 46%).

MS (m/z) = 361.2 [M+H] +

Example 104

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(2H-tetrazol-5-yl)indolin-2-one

a) 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxo-indoline-1-carbonitrile

To a solution of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (300 mg, 1.18 mmol, eq. 1.00, Example 70, step c) in dimethylformamide (4.5 ml) was added a suspension of sodium hydride in oil (60%, 62.0 mg, 1.42 mmol, eq. 1.2) at 0°C. The mixture was warmed to 22°C and stirred for 30 min. Cyanogen bromide (163 mg, 1.54 mmol, eq. 1.3) was added to the pale yellow solution at 0°C and stirred at 22°C for 1.5 h.

The reaction mixture was concentrated in vacuo and the residue was partitioned between water (10 ml) and ethyl acetate (10 ml).The aqueous layer was extracted three times with ethyl acetate (3 x 10 ml).

The combined organic layers were dried, concentrated in vacuo and the residue was purified by chromatography on silica gel to provide the desired compound as a white solid (230 mg, 70%).

MS (m/z) = 279.2 [M+H] ⁺

b) 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(2H-tetrazol-5-yl)indolin-2-one

To a solution of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindoline-1-carbonitrile (100 mg, 359 μmol, Eq: 1.00, Example 104, step a) in a mixture of dimethylformamide (3 ml), water (2 ml) and isopropanol (1 ml) were added sodium azide (70.1 mg, 1.08 mmol, Eq: 3.00) and zinc bromide (68.8 mg, 305 μmol, Eq: 0.85) at 0° C. The reaction mixture was stirred at 0° C. for 16 h.

The volatiles were removed in vacuo and the residue was stirred in dichloromethane (15 ml).The suspension was filtered and the filtrate was concentrated in vacuo to afford a colorless oil.

The oil was crystallized from boiling EtOH (5 ml) to provide the title compound (61 mg, 53%) as a white solid.MS (m/z) = 322.1 [M+H] ⁺ .

Example 105

3,3-Dimethyl-1-(2-methyl-2H-tetrazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

To a suspension of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1-(2H-tetrazol-5-yl)indolin-2-one (60 mg, 187 μmol, eq.: 1, Example 110) in acetone (2.5 ml) was added potassium carbonate (51.6 mg, 373 μmol, eq.: 2.00) and methyl iodide (53 mg, 23.4 μl, 373 μmol, eq.: 2.00) at 0°C. The reaction mixture was stirred at 22°C for 20 h. Methyl iodide (26.5 mg, 11.7 μl, 187 μmol, eq.: 1) was further added and the mixture was stirred at 50°C for 16 h. The mixture was partitioned between water (10 ml) and dichloromethane (10 ml), and the aqueous layer was extracted three times with dichloromethane (3 x 10 ml).

The combined organic layers were dried, concentrated in vacuo and the residue was purified by chromatography on silica gel to provide the desired compound as an off-white solid (10 mg, 16%).

MS (m/z) = 336.2 [M+H] +

Example 106 and Example 107

3-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-6-methylpyridazine 1-oxide

and 3-(3,3-dimethyl-6-(2-methyl-1-oxidopyrimidin-5-yl)-2-oxoindolin-1-yl)-6-methylpyridazine 1-oxide

To a solution of 3,3-dimethyl-1-(6-methylpyridazin-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one (100 mg, 290 μmol, Eq: 1, Example 48) in dichloromethane (3 ml) was added m-CPBA (100 mg, Eq: 1.25) at 22° C. The reaction mixture was stirred at 22° C. for 20 h.

The reaction was partitioned between aqueous sodium carbonate solution (10% m/m, 10 ml) and dichloromethane (10 ml) and the aqueous layer was extracted with dichloromethane (3 x 10 ml).

The combined organic layers were dried, concentrated in vacuo and the residue was purified by chromatography on silica gel to provide 2 fractions:

Fraction 1: 3-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-6-methylpyridazine 1-oxide (44 mg, 42%) as a light yellow solid

Rf (dichloromethane/methanol 15:1) = 0.25 (UV) LC-MS: m/z = 362.3 [M+H] +

Fraction 2: 3-(3,3-dimethyl-6-(2-methyl-1-oxidopyrimidin-5-yl)-2-oxoindolin-1-yl)-6-methylpyridazine 1-oxide (15 mg, 14%) as a white solid, Rf (dichloromethane/methanol 15:1) = 0.20 (UV), MS (m/z) = 378.3 [M+H]+

Example 108

1-(2-(Fluoromethyl)pyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

a) 5-Bromo-2-(fluoromethyl)pyrimidine

To a solution of (5-bromopyrimidin-2-yl)methanol (400 mg, 2.12 mmol, eq.: 1) in dichloromethane (11 ml) was added diethylaminosulfur trifluoride (409 mg, 336 μl, 2.54 mmol, eq.: 1.20). The reaction mixture was stirred at room temperature for 4 h and then partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane.

The combined organic layers were dried, concentrated in vacuo and the residue was purified by chromatography on silica gel to provide the desired compound as an off-white solid (110 mg, 27%).

MS (m/z) = 191.0/193.0 [M+H] +

b) 1-(2-(Fluoromethyl)pyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared analogously to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-bromo-2-(fluoromethyl)pyrimidine (Example 108, step a) as starting materials. White solid. Yield: 90%.

MS (m/z) = 364.2 (M+H ⁾

Example 109

3,3-Dimethyl-1-(6-methylpyridazin-3-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

a) 3,3-Dimethyl-6-(2-methyl-4-pyridyl)-1H-pyrrolo[3,2-c]pyridin-2-one

A degassed suspension of 6-chloro-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (400 mg, 2.03 mmol, eq: 1, prepared according to Woolford et al., WO 2012143726), (2-methylpyridin-4-yl)boronic acid (418 mg, 3.05 mmol, eq: 1.5) in dioxane (8.14 ml), aqueous sodium carbonate solution (2M, 2.03 ml) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (74.4 mg, 102 μmol, eq: 0.05) was heated at 110° C. in a sealed vial for 6 h. The volatiles were removed in vacuo and the residue was purified by chromatography on silica gel to provide the desired compound as a light brown solid (415 mg, 77%). MS (m/z) = 254.2 (M+H) ⁺

b) 3,3-dimethyl-1-(6-methylpyridazin-3-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c] Pyridin-2(3H)-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 109, step a) and 3-iodo-6-methylpyridazine (CAS [1618-47-9]) as starting materials. White solid. Yield: 80%. MS (m/z) = 346.2 (M+H) ⁺

Example 110

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 116, step a) and 4-iodo-1-methyl-1H-pyrazole as starting materials. White foam. Yield: 97%. MS (m/z) = 334.2 (M+H) ⁺

Example 111

3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 116, step a) and 4-iodo-1-methyl-1H-imidazole as starting materials. White solid. Yield: 81%.

MS (m/z) = 334.2 (M+H ⁾

Example 112

6-(4-Fluorophenyl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one

a) 6-(4-Fluorophenyl)-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2-one

The title compound was prepared analogously to Example 109, step a, using 6-chloro-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (prepared according to Woolford et al., WO 2012143726) and (4-fluorophenyl)boronic acid as starting materials. White solid. Yield: 47%.

MS (m/z) = 257.2 (M+H ⁾

b) 6-(4-fluorophenyl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine-2 (3H)-Ketone

The title compound was prepared by analogy with Example 70, step d, using 6-(4-fluorophenyl)-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2-one (Example 112, step a) and 5-bromo-2-methylpyrimidine hydrochloride as starting materials. White solid. Yield: 88%. MS (m/z) = 349.3 (M+H) ⁺

Example 113

1-(5-chloropyrimidin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-chloro-2-iodopyrimidine as starting materials. White solid. Yield: 84%. MS (m/z) = 366.2 (M+H) ⁺

Example 114

1-(2-chloropyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2-chloro-5-iodopyrimidine as starting materials. White solid. Yield: 20%. MS (m/z) = 366.2 (M+H) ⁺

Example 115

1-(2,6-chloropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2,6-dichloro-4-iodopyridine as starting materials. White solid. Yield: 63%. MS (m/z) = 399.2 (M+H) ⁺

Example 116

1-(2-cyclopropylpyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-bromo-2-cyclopropylpyrimidine as starting materials. Off-white solid. Yield: 70%. MS (m/z) = 372.3 (M+H) ⁺

Example 117

1-(5-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indol-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2,5-dichloropyrazine as starting materials. White solid. Yield: 6%. MS (m/z) = 366.2 (M+H) ⁺

Example 118

1-(6-chloropyridazin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 3,6-dichloropyridazine as starting materials. White solid. Yield: 2%. MS (m/z) = 366.2 (M+H) ⁺

Example 119

1-(2-chloro-6-methylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 4-bromo-2-chloro-6-methylpyridine as starting materials. Pale yellow solid. Yield: 42%. MS (m/z) = 379.2 (M+H) ⁺

Example 120

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridazin-4-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 4-bromopyridazine as starting materials. Off-white solid. Yield: 42%. MS (m/z) = 332.2 (M+H) ⁺

Example 121

1-(6-chloro-2-methylpyrimidin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 4,6-dichloro-2-methylpyrimidine as starting materials. Off-white solid. Yield: 10%. MS (m/z) = 380.2 (M+H) ⁺

Example 122

3,3-Dimethyl-1-(5-methylpyridazin-3-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 3-bromo-5-methylpyridazine as starting materials. White solid. Yield: 7%. MS (m/z) = 346.2 (M+H) ⁺

Example 123

3,3-Dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-bromo-3-methyl-1,2,4-thiadiazole as starting materials. Off-white solid. Yield: 21%. MS (m/z) = 352.2 (M+H) ⁺

Example 124

3,3-Dimethyl-1-(3-methylisothiazol-5-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-bromo-3-methylisothiazole as starting materials. Off-white solid. Yield: 94%. MS (m/z) = 351.2 (M+H) ⁺

Example 125

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(5-methylthiazol-2-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2-bromo-5-methylthiazole as starting materials. A light brown solid. Yield: 74%. MS (m/z) = 351.2 (M+H) ⁺

Example 126

1-(6-chloropyridazin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-bromo-3-chloropyridazine as starting materials. Off-white solid. Yield: 66%. MS (m/z) = 366.1 (M+H) ⁺

Example 127

3,3-Dimethyl-1-(3-methylpyrazin-2-yl)-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2-bromo-3-methylpyrazine as starting materials. Off-white solid. Yield: 88%. MS (m/z) = 346.1 (M+H) ⁺

Example 128

1-(4-chloropyrimidin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 2-bromo-4-chloropyrimidine as starting materials. White solid. Yield: 7%. MS (m/z) = 366.2 (M+H) ⁺

Example 129

1-(6-(Methoxymethyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared analogously to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-bromo-2-(methoxymethyl)pyridine as starting materials. A white foam was obtained. Yield: quantitative

MS (m/z) = 375.2 (M+H ⁾

Example 130

1-(5-cyclopropylpyridazin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

a) 3-Chloro-5-cyclopropylpyridazine

A degassed mixture of 5-bromo-3-chloropyridazine (50 mg, 258 μmol, eq.: 1) and cyclopropylboronic acid (33.3 mg, 388 μmol, eq.: 1.5) in dioxane (923 μl) and aqueous sodium carbonate solution (2 M, 369 μl) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (18.9 mg, 25.8 μmol, eq.: 0.1) was heated to 100° C. overnight. The mixture was diluted with dichloromethane, adsorbed onto silica gel, dried in vacuo, and the residue was purified by flash chromatography on silica gel to provide the title compound (27 mg, 68%) as a yellow, viscous oil. MS (m/z): 155.0 [(M+H) ⁺ ].

b) 1-(5-cyclopropylpyridazin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 3-chloro-5-cyclopropylpyridazine (Example 130, step a) as starting materials. White solid. Yield: 43%. MS (m/z) = 372.2 (M+H ⁾

Example 131

1-(1-Isopropyl-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

a) 3-(3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-1H-pyrazole-1-carboxylate Tert-butyl ester

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and tert-butyl 3-iodo-1H-pyrazole-1-carboxylate as starting materials. Pale yellow solid. Yield: 40%. MS (m/z) = 420.2 (M+H) ⁺

b) 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-3-yl)indolin-2-one

A mixture of tert-butyl 3-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-1H-pyrazole-1-carboxylate (80 mg, 191 μmol, eq: 1, Example 131, step a) dissolved in dioxane (3 ml) and a solution of hydrochloric acid in dioxane (95.4 μl, 381 μmol, eq: 2) was stirred at room temperature for 16 h. Additional solution of hydrochloric acid in dioxane (95.4 μl, 381 μmol, eq: 2) was added and the reaction mixture was heated to 50° C. for another 6 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography followed by HPLC to provide 22 mg (36%) of the desired product as a white solid. MS (m/z) = 320.1 (M+H) ⁺

c) 1-(1-Isopropyl-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indoline-2-yl ketone

A mixture of 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-3-yl)indolin-2-one (25 mg, 78.3 μmol, eq. 1, Example 131, step b), cesium carbonate (51 mg, 157 μmol, eq. 2.00), and 2-iodopropane (20.4 mg, 12 μl, 117 μmol, eq. 1.5) dissolved in dimethylformamide (833 μl) was stirred at room temperature for 20 h. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography followed by HPLC to provide 12 mg (42%) of the desired product as a white solid. MS (m/z) = 362.2 (M+H) ⁺

Example 132

3,3-Dimethyl-6-(5-methylpyrazin-2-yl)-1-(6-methylpyrazin-2-yl)indolin-2-one

a) 3,3-Dimethyl-6-(5-methylpyrazin-2-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step c, using 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (Example 70, step b) and 2-bromo-5-methylpyrazine as starting materials. White solid. Yield: 63%. MS (m/z) = 254.2 (M+H) ⁺

b) 3,3-Dimethyl-6-(5-methylpyrazin-2-yl)-1-(6-methylpyrazin-2-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(5-methylpyrazin-2-yl)indolin-2-one (Example 132, step a) and 2-bromo-6-methylpyrazine as starting materials. White solid. Yield: 93%. MS (m/z) = 346.2 (M+H) ⁺

Example 133

3,3-Dimethyl-6-(5-methylpyrazin-2-yl)-1-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(5-methylpyrazin-2-yl)indolin-2-one (Example 132, step a) and 5-bromo-2-methylpyrimidine hydrochloride as starting materials. White solid. Yield: 86%. MS (m/z) = 346.2 (M+H) ⁺

Example 134

1-(6-cyclopropylpyridazin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 3-bromo-6-cyclopropylpyridazine as starting materials. White solid. Yield: 87%. MS (m/z) = 372.1 (M+H) ⁺

Example 135

3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(6-methyl-2-pyridyl)indolin-2-one

a) 6-Bromo-3,3-dimethyl-1-(6-methylpyrazin-2-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (Example 70, step a) and 2-bromo-6-methyl-pyrazine as starting materials. Off-white solid. Yield: 84%. MS (m/z) = 331.8 (M+H) ⁺

b) 3,3-dimethyl-1-(6-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolane-2-yl) 2,3-dihydro-1H-indol-2-one

The title compound was prepared by analogy with Example 136, step b, using 6-bromo-3,3-dimethyl-1-(6-methylpyrazin-2-yl)indolin-2-one (Example 135, step a) as the starting material. Off-white solid. Yield: 96%. MS (m/z) = 379.8 (M+H) ⁺

c) 3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(6-methyl-2-pyridyl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-1-(6-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 135, step b) and 2-bromo-6-methyl-pyridine as starting materials. Off-white solid. Yield: 33%. MS (m/z) = 344.8 (M+H) ⁺

Example 136

3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(2-methylpyrimidin-4-yl)indolin-2-one

a) 6-Bromo-3,3-dimethyl-1-(5-methylpyrazin-2-yl)-2,3-dihydro-1H-indol-2-one

The title compound was prepared similarly to Example 70, step d, using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (Example 70, step a) and 2-bromo-5-methyl-pyrazine as starting materials. Off-white solid. Yield: 62%. MS (m/z) = 333.8 (M+H) ⁺

b) 3,3-dimethyl-1-(5-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolane-2-yl) 2,3-dihydro-1H-indol-2-one

A degassed suspension of 6-bromo-3,3-dimethyl-1-(5-methylpyrazin-2-yl)-2,3-dihydro-1H-indol-2-one (1.7 g, 5.12 mmol, Example 136, step a), potassium acetate (1.004 g, 10.24 mmol), bis(pinacolato)diboron (1.559 g, 6.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.418 g, 0.51 mmol) in dioxane (20 mL) was stirred at 110° C. for 6 h. The reaction mixture was filtered and concentrated under vacuum and purified by chromatography on silica gel to provide the desired product as a white solid (33%).

MS (m/) z = 379.9 (M+H) ⁺

c) 3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(2-methylpyrimidin-4-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-1-(5-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 136, step b) and 4-bromo-2-methyl-pyrimidine as starting materials. White solid. Yield: 33%. MS (m/z) = 346.0 (M+H) ⁺

Example 137

3,3-Dimethyl-6-(5-methylpyrazin-2-yl)-1-(6-methylpyridazin-3-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(5-methylpyrazin-2-yl)indolin-2-one (Example 132, step a) and 3-iodo-6-methyl-pyridazine as starting materials. Off-white solid. Yield: 73%. MS (m/z) = 346.1 (M+H) ⁺

Example 138

3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(5-methylpyrazin-2-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(5-methylpyrazin-2-yl)indolin-2-one (Example 132, step a) and 3-iodo-1-methyl-1H-pyrazole as starting materials. Pale yellow solid. Yield: 65%. MS (m/z) = 334.2 (M+H) ⁺

Example 139

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)indolin-2-one

The title compound was prepared by analogy with Example 131, step c, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-3-yl)indolin-2-one (Example 131, step b) and 2,2,2-trifluoroethyl iodide as starting materials. White solid. Yield: 15%. MS (m/z) = 402.2 (M+H) ⁺

Example 140

1-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 131, step c, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-3-yl)indolin-2-one (Example 131, step b) and 2-bromoethyl methyl ether as starting materials. White solid. Yield: 27%.

MS (m/z) = 378.2 (M+H ⁾

Example 141

2-(3-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide

The title compound was prepared by analogy with Example 131, step c, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-3-yl)indolin-2-one (Example 131, step b) and 2-chloro-N,N-dimethylacetamide as starting materials. White solid. Yield: 40%. MS (m/z) = 405.2 (M+H) ⁺

Example 142

1-(5-fluoropyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 3-bromo-5-fluoropyridine as starting materials. White solid. Yield: quantitative. MS (m/z) = 349.1 (M+H) ⁺

Example 143

5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxoindolin-1-yl)nicotinoylnitrile

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 5-bromonicotinonitrile as starting materials. Off-white solid. Yield: 98%. MS (m/z) = 356.1 (M+H) ⁺

Example 144

3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(2-methyl-4-pyridyl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-1-(6-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 135, step b) and 4-bromo-2-methyl-pyridine as starting materials. White solid. Yield: 38%. MS (m/z) = 344.9 (M+H) ⁺

Example 145

3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(5-methyl-3-pyridyl)indolin-2-one

The title compound was prepared similarly to Example 70, step c, using 3,3-dimethyl-1-(6-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 135, step b) and 3-bromo-5-methyl-pyridine as starting materials. Off-white solid. Yield: 34%. MS (m/z) = 344.9 (M+H) ⁺

Example 146

6-(5-fluoro-3-pyridyl)-3,3-dimethyl-1-(6-methylpyrazin-2-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-1-(6-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 135, step b) and 3-bromo-5-fluoro-pyridine as starting materials. Off-white solid. Yield: 37%. MS (m/z) = 348.8 (M+H ⁾

Example 147

3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(2-methyl-4-pyridyl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-1-(5-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 136, step b) and 4-bromo-2-methyl-pyridine as starting materials. White solid. Yield: 46%. MS (m/z) = 344.9 (M+H) ⁺

Example 148

3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(6-methyl-3-pyridyl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-1-(5-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 136, step b) and 5-bromo-2-methyl-pyridine as starting materials. White solid. Yield: 23%. MS (m/z) = 344.8 (M+H) ⁺

Example 149

3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(5-methyl-3-pyridyl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-1-(5-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 136, step b) and 3-bromo-5-methyl-pyridine as starting materials. White solid. Yield: 25%. MS (m/z) = 344.9 (M+H) ⁺

Example 150

6-(5-fluoro-3-pyridyl)-3,3-dimethyl-1-(5-methylpyrazin-2-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-1-(5-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 136, step b) and 3-bromo-5-fluoro-pyridine as starting materials. White solid. Yield: 37%. MS (m/z) = 349.2 (M+H ⁾

Example 151

6-(5-Fluoro-6-methyl-3-pyridyl)-3,3-dimethyl-1-(5-methylpyrazin-2-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-1-(5-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 136, step b) and 5-bromo-3-fluoro-2-methyl-pyridine as starting materials. White solid. Yield: 53%. MS (m/z) = 363.0 (M+H) ⁺

Example 152

3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(5-(trifluoromethyl)pyridin-3-yl)indolin-2-one

The title compound was prepared analogously to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 3-bromo-5-(trifluoromethyl)pyridine as starting materials. White solid. Yield: quantitative.

MS (m/z) = 399.1 (M+H ⁾

Example 153

1-(5-(Hydroxymethyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and (5-bromopyridin-3-yl)methanol as starting materials. White solid. Yield: 75%. MS (m/z) = 361.2 (M+H) ⁺

Example 154

3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(2-methylpyrimidin-4-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step c, using 3,3-dimethyl-1-(6-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 135, step b) and 4-bromo-2-methyl-pyrimidine as starting materials. Off-white solid. Yield: 46%. MS (m/z) = 346.1 (M+H) ⁺

Example 155

5-[3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-2-oxo-dihydroindolin-6-yl]pyrimidine-2-carbonitrile

The title compound was prepared similarly to Example 70, step c, using 3,3-dimethyl-1-(6-methylpyrazin-2-yl)-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-2-one (Example 135, step b) and 5-bromopyrimidine-2-carbonitrile as starting materials. Off-white solid. Yield: 16%. MS (m/z) = 357.3 (M+H) ⁺

Example 156

1-(5-ethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared similarly to Example 70, step d, using 3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indolin-2-one (Example 70, step c) and 3-bromo-5-ethylpyridine as starting materials. White solid. Yield: 96%. MS (m/z) = 359.2 (M+H) ⁺

Example 157

6-(2-cyclopropylpyrimidin-5-yl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)indolin-2-one

a) 6-Bromo-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared analogously to Example 70, step d, using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-indol-2-one (Example 70, step a) and 5-bromo-2-methyl-pyrimidine as starting materials. Off-white solid. Yield: 39%.

MS m/z＝334.2(M+H ⁾

b) 3,3-dimethyl-1-(2-methylpyrimidin-5-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan Pentan-2-yl)indolin-2-one

The title compound was prepared in analogy to Example 136, step b, using 3-bromo-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)indolin-2-one (Example 157, step a) as the starting material. It was an off-white solid and was used in the next step without further purification.

MS m/z＝380.0(M+H ⁾

c) 6-(2-cyclopropylpyrimidin-5-yl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)indolin-2-one

The title compound was prepared by analogy with Example 70, step c, using 3,3-dimethyl-1-(2-methylpyrimidin-5-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (Example 157, step b) and 5-bromo-2-cyclopropyl-pyrimidine as starting materials. An off-white solid. Yield over two steps: 14%.

MS m/z＝372.1(M+H ⁾

Biological assays and data

It has now been found that compounds of formula I can be used in the treatment of CNS diseases.

The described formula I compound reduces the excessive movement induced by L-687,414-. This is assessed in the following manner: using a computerized Digiscan 16 animal activity monitoring system (Digiscan 16 Animal Activity Monitoring System) (Omnitech Electronics, Columbus, Ohio) to quantify motor activity. Animals are maintained on a 12h light/dark cycle and experiments are performed during the light phase. Each activity monitoring chamber consists of a Plexiglas box (41×41×28cm; W×L×H) with sawdust embedded in the floor, which is surrounded by invisible horizontal and vertical infrared sensor beams. The test box is separated by a Plexiglas cross, thereby providing a 20×20cm activity space for each mouse. The cage is connected to a Digiscan analyzer, which is connected to a computer that constantly collects beam status information. The recording of the photoelectric beam interruption for a single animal is performed every 5 minutes during the experimental period and the sum of the first 6 periods is used as the final parameter. At least 8 mice are used in each treatment group. Compounds were administered orally (p.o.) 15 minutes prior to a subcutaneous (s.c.) injection of 50 mg/kg L-687,414, or intraperitoneally (i.p.) simultaneously with a 50 mg/kg subcutaneous injection of L-687,414. Mice were then transferred from their home cages to the recording chamber for a 15-min acclimation period and allowed to freely explore the new environment. Horizontal activity was then recorded for a 30-min period. The % inhibition of L-687,414-induced hyperlocomotion was calculated according to the following formula:

((Veh) + L-687, 414 level activity - drug + L-687, 414 level activity) / vehicle + L-687, 414 level activity) x 100

_ID50 values, defined as the dose of each compound that produces 50% inhibition of L-687,414-induced hyperlocomotion, were calculated by linear regression analysis of the dose-response data using an Excel-based computer fitting program.

Since the data are not assumed to be normally distributed, the group treated with the test compound is statistically compared with the control (vehicle treated) group using a one-tailed Mann-Whitney U test. Statistically, the Mann-Whitney U test (also referred to as the Mann-Whitney-Wilcoxon (MWW) or Wilcoxon rank sum test) is a nonparametric statistical hypothesis test for evaluating whether one of the two samples of independent observations tends to have a larger value than the other. It is one of the most well-known nonparametric significance tests. The p value gives the probability that the two groups are significantly different from each other and the value of <0.05 is generally recognized as a standard, which means that the two groups are actually different from each other and have >95% chance. The p value given in Table 1 is a one-tailed one because only the expected and test motor power decreases (Mann, H.B., Whitney, D.R. (1947), " On a Test of Whether one of Two Random Variables is Stochastically Larger than the Other ", Annals of Mathematical Statistics, 18 (1), 50-60).

Measuring adenosine transport activity

To measure adenosine transport activity in ENT-1 mammalian cells, stable cells expressing the mouse ENT-1 transporter were plated at a density of 60,000 cells/well in 96-well culture plates on day 1 in complete DMEM/F12 medium supplemented with glutamax, 10% FBS, and 10 μg/ml puromycin. On day 2, the medium was aspirated and the cells were washed twice with uptake buffer (10 mM Hepes-Tris, pH 7.4, containing 150 mM NaCl, 1 mM CaCl ₂ , 2.5 mM KCl, 2.5 mM MgSO ₄ , 10 mM D-glucose) (UB). For inhibition experiments, cells were then incubated with various concentrations of compound and 1% final DMSO at room temperature. Nonspecific uptake was defined in the presence of 10 μM S-(4-nitrobenzyl)-6-thioinosine (NBTI, Sigma Cat# N2255).

A solution containing 6 nM [2,8- ³ H]-adenosine (40 Ci/mmol, American Radiolabeled Chemicals Inc, Cat# ART 0287A) was then immediately added to the wells. The plates were then incubated for 20 minutes with gentle shaking, and the reaction was terminated by aspirating the mixture and washing with ice-cold UB (three times). The cells were lysed by adding scintillation fluid, shaken for 3 hours, and radioactivity in the cells was assessed using a microplate scintillation counter (TopCount NXT, Packard).

Table 1

Effects of the compounds of formula I on ENT1 inhibition and L-687,414-induced hypermobility

As mentioned above, some compounds have been tested in PsychoGenics(R), an assay system developed by PsychoGenics Inc.

Used to compare the behavioral characteristics of the test compound with the behavioral characteristics database of reference compounds obtained from a large group of clinically approved compounds (grouped according to indications). In this way, the neuropharmacological effects of the test compound can be predicted by similarity to large classes of compounds such as antipsychotics, anxiolytics and antidepressants. This method is ideally suited for screening a collection of existing drugs or drug candidates with previously unknown neuropharmacology, which can accelerate the development of new and unexpected treatments for mental illness.

Some compounds of the present invention were injected intraperitoneally at different doses 15 minutes before the test. Each treatment group used at least 8 mice. The digital video of the subjects was processed with a computer version algorithm to extract more than 2000 relevant measurements, including the frequency and duration of many different behavioral states. The results of the classification were presented as a bar graph for each compound and dose (mg/kg), with the Y-axis representing the relative probability that the test compound will show efficacy in a specific CNS indication.

The bar graphs of Example compounds 9, 25, 48, and 53 at a dose of 5 mg/kg are shown in Figure 1. For comparison, the behavioral profiles of the atypical antipsychotics clozapine, olanzapine, and risperidone are shown in Figure 2. The compounds of the present invention exhibit similar characteristics to those of the atypical antipsychotics. An independent analysis was performed on the unclassified data to determine the similarity of the Example compounds to the active doses of known atypical antipsychotics. For this analysis, we used the discrimination ratio as a measure of the separability between the two drugs, that is, how "distinguishable" one drug is from the other. A ratio of 50% (or 0.5) corresponds to zero distinguishability. Empirical data have shown that the threshold ratio for reliable separation is above 70%, that is, two drugs showing a discrimination ratio of less than 70% are considered similar, while a discrimination ratio of more than 70% indicates that the two drugs are not similar. The following table shows the similarity analysis of selected compounds of the present invention and several atypical antipsychotics. In most cases, the Example compounds showed similarity to risperidone, clozapine, and olanzapine, with a discrimination ratio of ≤0.70.

Table 2: Similarity analysis of compounds of formula I (5 mg/kg) showing effects

Clozapine Olanzapine Risperidone Example 9 0.65 0.66 0.69 Example 25 0.61 0.62 0.74 Example 48 0.58 0.61 0.67 Example 53 0.59 0.61 0.62

Therefore, it is believed that the compounds of the present invention have similar efficacy to known atypical antipsychotics.

Figure 1: Profiles of compounds 9, 25, 49 and 53 (5 mg/kg) - similar to the profiles of atypical antipsychotics.

Figure 2: Characteristics of the atypical antipsychotics clozapine, olanzapine, and risperidone at different doses.

The compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicines, for example in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, the administration can also be achieved rectally, for example in the form of suppositories, or parenterally, for example in the form of injections.

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed together with pharmaceutically inert inorganic or organic carriers for the production of pharmaceutical preparations. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.; however, depending on the properties of the active substance, a carrier is generally not 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, etc. Adjuvants such as alcohols, polyols, glycerol, vegetable oils, etc. can be used for injection of water-soluble salts of the compounds of formula (I), but are generally not required. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

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

As mentioned above, a medicament containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient is also an object of the present invention, as is a process for producing such a medicament, which comprises bringing one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof and, if desired, one or more other therapeutically valuable substances, together with one or more therapeutically inert carriers, into a galenical dosage form. The active compounds can also be used in the form of their prodrugs.

As also mentioned before, the use of the compounds of formula (I) 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.

Dosage can vary over a wide range and will certainly be adapted to individual needs in each particular case. In general, the effective dose for oral or parenteral administration is 0.01-20 mg/kg/day, with 0.1-10 mg/kg/day being preferred for all such indications. The daily dose for an adult weighing 70 kg is correspondingly between 0.7-1400 mg/day, preferably 7 to 700 mg/day.

Preparation of pharmaceutical compositions containing the compounds of the present invention:

Tablets of the following composition are manufactured in the usual manner:

Manufacturing steps

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

2. Dry the granules at 50°C.

3. Pass the granules through a suitable grinding device.

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

Prepare capsules of the following composition:

Manufacturing steps

1. Mix ingredients 1, 2 and 3 in a suitable blender for 30 minutes.

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

3.Put into suitable capsules.

The compound of formula I, lactose, and corn starch are first mixed in a blender and then in a mill. The mixture is returned to the blender; talc is added and mixed thoroughly. The mixture is then machine-filled into suitable capsules, such as hard gelatin capsules.

Prepare an injection of the following composition:

Element mg/injection. Compounds of formula I 3 polyethylene glycol 400 150 Acetic acid Adjust to pH 5.0 Water for injection Adjust to 1.0ml

Manufacturing steps

The compound of formula I is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 with acetic acid. The volume is adjusted to 1.0 ml by adding the remainder of water. The solution is filtered, filled into bottles using an appropriate excess, and sterilized.

Claims (25)

1. A compound of the following formula in Ar ¹ is a phenyl group or a five- or six-membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O, wherein the N-heteroatom in the heteroaryl group can be oxidized to N ⁺ -( ^O- ); ^R1 is a _C1-7 alkyl, halogen, cyano, or _C3-6 cycloalkyl; Ar ² is a five- or six-membered heteroaryl group containing one, two, three or four heteroatoms selected from N, S or O, wherein the N-heteroatom in the heteroaryl group can be oxidized to N ⁺ -( ^O- ) or benzo[b]thiophene group; ^R2 is hydrogen, _C1.7 alkyl, halogen, cyano, hydroxy-substituted _C1-7 alkyl, halogen-substituted _C1-7 alkyl, amino-substituted _C1-7 alkyl, alkoxy-substituted _C1-7 alkyl, amide-substituted _C1-7 alkyl, or _C3-6 cycloalkyl. X is CH or N; n is 1 or 2; m is 1 or 2; Its medicinal salts, racemic mixtures, or their corresponding enantiomers and/or their optical isomers and/or stereoisomers. 2. The compound of formula I according to claim 1, wherein X is CH. 3. The compound of formula I according to claim 2, wherein ^Ar1 and ^Ar2 are both six-membered heteroaryl groups containing one, two or three heteroatoms selected from N, S or O. 4. A compound, wherein the compound is: 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridin-4-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridin-3-yl)dihydroindole-2-one 3,3-Dimethyl-1-(2-methylpyridin-4-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(6-methylpyrimidin-4-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1,6-bis(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(6-methylpyridin-3-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(6-methylpyridin-3-yl)-1-(2-methylpyridin-4-yl)dihydroindole-2-one 3,3-Dimethyl-1,6-bis(2-methylpyridin-4-yl)dihydroindole-2-one 6-(4-Fluoropyridin-3-yl)-3,3-dimethyl-1-(2-methylpyridin-4-yl)dihydroindole-2-one 1-(5-fluoro-2-methylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxodihydroindol-1-yl)pyridinecarboxynitrile 1-(6-(hydroxymethyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(6-Cyclopropylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridin-2-yl)dihydroindole-2-one 1-(2-Fluoropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(3-Fluoropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(2-fluoro-5-methylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(6-methylpyridazin-3-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(3-chloropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(5-methylpyrimidin-2-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(5-methylpyridin-2-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(5-methylpyridin-3-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(4-methylpyridin-2-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(6-methylpyridin-2-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(2-methylpyrimidin-4-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(4-methylpyrimidin-2-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(2,6-dimethylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(4,6-dimethylpyrimidin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(2,6-dimethylpyrimidin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(4,5-dimethylpyridin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(5,6-dimethylpyridin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(5,6-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridazin-3-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrazin-2-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrimidin-2-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(4-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1,6-bis(5-methylpyrimidin-2-yl)dihydroindole-2-one 3,3-Dimethyl-1,6-bis(5-methylpyrazin-2-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyrimidin-4-yl)dihydroindole-2-one 1-(5-Cyclopropylpyrazin-2-yl)-3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxodihydroindol-1-yl)pyrazin-2-carboxynitrile 1-(6-Cyclopropylpyrazin-2-yl)-3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(4,5-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(4,5-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(4,6-dimethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 5-(3,3-dimethyl-1-(5-methylpyrimidin-2-yl)-2-oxodihydroindole-6-yl)-2-methylpyrimidin 1-oxide 1-(2-(hydroxymethyl)pyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-[2-(aminomethyl)pyrimidin-5-yl]-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indol-2-one 3-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxodihydroindole-1-yl)-6-methylpyridazine 1-oxide 3-(3,3-dimethyl-6-(2-methyl-1-oxypyrimidin-5-yl)-2-oxodihydroindol-1-yl)-6-methylpyridazine 1-oxide 1-(2-(fluoromethyl)pyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(6-methylpyridazin-3-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one 6-(4-Fluorophenyl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one 1-(5-chloropyrimidin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(2-chloropyrimidin-5-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(2,6-Dichloropyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(2-Cyclopropylpyrimidin-5-yl)-3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(5-chloropyrazin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)indol-2-one 1-(6-Chlorpyridazin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(2-chloro-6-methylpyridin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(pyridazin-4-yl)dihydroindole-2-one 1-(6-chloro-2-methylpyrimidin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindol-2-one 3,3-Dimethyl-1-(5-methylpyridazin-3-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(6-Chlorpyridazin-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(3-methylpyrazin-2-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(4-chloropyrimidin-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(6-(methoxymethyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(5-Cyclopropylpyridazin-3-yl)-3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindol-2-one 3,3-Dimethyl-6-(5-methylpyrazin-2-yl)-1-(6-methylpyrazin-2-yl)dihydroindole-2-one 3,3-Dimethyl-6-(5-methylpyrazin-2-yl)-1-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(6-Cyclopropylpyridazin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(6-methyl-2-pyridyl)dihydroindole-2-one 3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(2-methylpyrimidin-4-yl)dihydroindole-2-one 3,3-Dimethyl-6-(5-methylpyrazin-2-yl)-1-(6-methylpyridazin-3-yl)dihydroindole-2-one 1-(5-Fluoropyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 5-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxodihydroindol-1-yl)nicotinamide 3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(2-methyl-4-pyridyl)dihydroindole-2-one 3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(5-methyl-3-pyridyl)dihydroindole-2-one 6-(5-fluoro-3-pyridyl)-3,3-dimethyl-1-(6-methylpyrazin-2-yl)dihydroindole-2-one 3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(2-methyl-4-pyridyl)dihydroindole-2-one 3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(6-methyl-3-pyridyl)dihydroindole-2-one 3,3-Dimethyl-1-(5-methylpyrazin-2-yl)-6-(5-methyl-3-pyridyl)dihydroindole-2-one 6-(5-fluoro-3-pyridyl)-3,3-dimethyl-1-(5-methylpyrazin-2-yl)dihydroindole-2-one 6-(5-fluoro-6-methyl-3-pyridyl)-3,3-dimethyl-1-(5-methylpyrazin-2-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(5-(trifluoromethyl)pyridin-3-yl)dihydroindole-2-one 1-(5-(hydroxymethyl)pyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(6-methylpyrazin-2-yl)-6-(2-methylpyrimidin-4-yl)dihydroindole-2-one 5-[3,3-dimethyl-1-(6-methylpyrazin-2-yl)-2-oxo-dihydroindol-6-yl]pyrimidin-2-carboxynitrile, or 1-(5-ethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one. 5. The compound of formula I according to claim 2, wherein Ar ¹ is a six-membered heteroaryl containing one, two or three heteroatoms selected from N, S or O, and Ar ² is a five-membered heteroaryl containing one, two or three heteroatoms selected from N, S or O. 6. A compound, wherein the compound is: 3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)dihydroindol-2-one 3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(6-methylpyridin-3-yl)dihydroindol-2-one 3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyridin-4-yl)dihydroindol-2-one 3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(6-methylpyridin-3-yl)dihydroindole-2-one 6-(4-Fluoropyridin-3-yl)-3,3-dimethyl-1-(1-methyl-1H-imidazol-4-yl)dihydroindol-2-one 6-(4-Fluoropyridin-3-yl)-3,3-dimethyl-1-(1-methyl-1H-pyrazol-3-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(5-methylthiophen-2-yl)dihydroindole-2-one 3,3-Dimethyl-1-(1-methyl-1H-imidazol-5-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(5-methyl-1,3,4-diazol-2-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-3-yl)dihydroindole-2-one 1-(1,2-Dimethyl-1H-imidazol-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(5-ethylpyridin-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(2-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)dihydroindol-2-one 3,3-Dimethyl-1-(1-methyl-1H-1,2,4-triazol-3-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1H-pyrazol-4-yl)dihydroindole-2-one 1-(1H-imidazol-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindol-2-one 3,3-Dimethyl-1-(3-methyl-1H-pyrazol-5-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(4-methyl-1H-imidazol-2-yl)-6-(2-methylpyrimidin-5-yl)dihydroindol-2-one 3,3-Dimethyl-1-(3-methylisoazol-5-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 1-(1H-imidazol-2-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindol-2-one 1-(1-Ethyl-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(2H-tetrazol-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(2-methyl-2H-tetrazol-5-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one 3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one 3,3-Dimethyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(3-methylisothiazo-5-yl)-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(5-methylthiazolyl-2-yl)dihydroindol-2-one 1-(1-Isopropyl-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(5-methylpyrazin-2-yl)dihydroindole-2-one 3,3-Dimethyl-6-(2-methylpyrimidin-5-yl)-1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)dihydroindole-2-one 1-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one, or 2-(3-(3,3-dimethyl-6-(2-methylpyrimidin-5-yl)-2-oxodihydroindol-1-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide. 7. The compound of formula I according to claim 2, wherein Ar ¹ is a five-membered heteroaryl containing one, two or three heteroatoms selected from N, S or O, and Ar ² is a six-membered heteroaryl containing one, two or three heteroatoms selected from N, S or O. 8. The compound of formula I according to claim 7, wherein the compound is: 3,3-Dimethyl-6-(4-methylimidazol-1-yl)-1-(6-methyl-3-pyridyl)dihydroindole-2-one 6-(4-Cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methyl-4-pyridyl)dihydroindole-2-one 3,3-Dimethyl-6-(4-methylimidazol-1-yl)-1-(2-methyl-4-pyridyl)dihydroindol-2-one 3,3-Dimethyl-6-(1-methyl-1H-pyrazol-3-yl)-1-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(1-methyl-1H-imidazol-4-yl)-1-(2-methylpyrimidin-5-yl)dihydroindole-2-one 6-(4-isopropylimidazol-1-yl)-3,3-dimethyl-1-(6-methyl-3-pyridyl)dihydroindole-2-one 3,3-Dimethyl-6-(5-methyl-1,3,4-diazol-2-yl)-1-(6-methyl-3-pyridyl)dihydroindole-2-one 3,3-Dimethyl-6-(5-methyl-1,3,4-diazol-2-yl)-1-(2-methyl-4-pyridyl)dihydroindole-2-one 6-(4-isopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methyl-4-pyridyl)dihydroindole-2-one 6-(4-Isopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)dihydroindol-2-one 6-(4-Cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(5-methyl-1,3,4-diazol-2-yl)-1-(2-methylpyrimidin-5-yl)dihydroindole-2-one 3,3-Dimethyl-6-(4-methylimidazol-1-yl)-1-(2-methylpyrimidin-5-yl)dihydroindol-2-one 3,3-Dimethyl-6-(2-methylazol-5-yl)-1-(2-methylpyrimidin-5-yl)dihydroindole-2-one, or 3,3-Dimethyl-6-(3-methyl-1,2,4-diazol-5-yl)-1-(2-methylpyrimidin-5-yl)dihydroindole-2-one. 9. The compound of formula I according to claim 2, wherein ^Ar1 and ^Ar2 are both five-membered heteroaryl groups containing one, two or three heteroatoms selected from N, S or O. 10. The compound of formula I according to claim 9, wherein the compound is: 6-(4-isopropylimidazol-1-yl)-3,3-dimethyl-1-(1-methylpyrazol-3-yl)dihydroindole-2-one 6-(4-Cyclopropylimidazol-1-yl)-3,3-Dimethyl-1-(1-methylimidazol-4-yl)dihydroindol-2-one 6-(4-Cyclopropylimidazol-1-yl)-3,3-dimethyl-1-(1-methylpyrazol-3-yl)dihydroindol-2-one 3,3-Dimethyl-1-(1-methylimidazol-4-yl)-6-(2-methylazol-5-yl)dihydroindol-2-one 3,3-Dimethyl-6-(2-methylazol-5-yl)-1-(1-methylpyrazol-3-yl)dihydroindole-2-one 3,3-Dimethyl-1-(1-methylimidazol-4-yl)-6-(5-methyl-1,3,4-diazol-2-yl)dihydroindol-2-one, or 3,3-Dimethyl-6-(4-methyl-1H-imidazol-1-yl)-1-(1-methyl-1H-imidazol-4-yl)dihydroindol-2-one. 11. The compound of formula I according to claim 2, wherein Ar ² is benzo[b]thiophene, and the other substituents are as described in claim 1. 12. The compound of formula I according to claim 11, wherein the compound is: 1-(benzo[b]thiophen-4-yl)-3,3-dimethyl-6-(2-methylpyrimidin-5-yl)dihydroindole-2-one. 13. The compound of formula I according to claim 1, wherein X is N and the other substituents are as described in claim 1. 14. The compound of formula I according to claim 13, wherein the compound is: 3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one 3,3-Dimethyl-1-(1-methyl-1H-pyrazol-3-yl)-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one 3,3-Dimethyl-1-(2-methylpyridin-4-yl)-6-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one 3,3-Dimethyl-1-(6-methylpyridazin-3-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one 3,3-Dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one 3,3-Dimethyl-1-(1-methyl-1H-imidazol-4-yl)-6-(2-methylpyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one, or 6-(4-fluorophenyl)-3,3-dimethyl-1-(2-methylpyrimidin-5-yl)-1H-pyrrolo[3,2-c]pyridine-2(3H)-one. 15. A composition of a compound according to any one of claims 1-14 with a known commercially available antipsychotic, antidepressant, anxiolytic, or mood stabilizer. 16. The composition of claim 15, wherein the commercially available antipsychotic is olanzapine, clozapine, risperidone, aripiprazole, or ziprasidone. 17. The composition of claim 15, wherein the commercially available antidepressant is citalopram, etanercept, paroxetine, fluoxetine, sertraline, duloxetine, mirtazapine, venlafaxine, or miltazapine. 18. The composition of claim 15, wherein the commercially available anxiolytic is alprazolam, nitrazepam, clonazepam, diazepam, estazolam, eszopiclone, zaleplon, zolpidem, pregabalin, or gabapentin. 19. The composition of claim 15, wherein the commercially available mood stabilizer is carbamazepine, lamotrigine, lithium, and valproic acid. 20. A method for preparing a compound according to any one of claims 1-14, the method comprising: The following compounds Reaction with compounds of the following formula (R ² ) _n -Ar ² -Y 8 Compound I Wherein Y is Cl, Br, or I, and the other groups are as defined in any one of claims 1-14, and, If necessary, the obtained compound can be converted into a pharmaceutical acid addition salt. 21. The compound according to any one of claims 1-14 prepared by the method according to claim 20. 22. The compound according to any one of claims 1-14, which is used as a therapeutically active substance. 23. A pharmaceutical composition comprising a compound according to any one of claims 1-14 and a therapeutically active carrier, the pharmaceutical composition being used to treat CNS disorders associated with: positive and negative symptoms of schizophrenia, psychotropic substance abuse, alcohol and drug addiction, obsessive-compulsive disorder, cognitive impairment, bipolar disorder, mood disorders, major depressive disorder, treatment-resistant depression, anxiety disorders, Alzheimer's disease, autism, Parkinson's disease, chronic pain, borderline personality disorder, neurodegenerative diseases, sleep disorders, chronic fatigue syndrome, rigidity, inflammatory diseases, asthma, Huntington's disease, ADHD, amyotrophic lateral sclerosis, epilepsy, role in arthritis, autoimmune diseases, viral and fungal infections, cardiovascular diseases, ophthalmological and inflammatory retinal diseases, and balance problems. 24. Use of the compound according to any one of claims 1-14 in the preparation of a medicament for the treatment of CNS disorders associated with: positive and negative symptoms of schizophrenia, psychotropic substance abuse, alcohol and drug addiction, obsessive-compulsive disorder, cognitive impairment, bipolar disorder, mood disorders, major depressive disorder, treatment-resistant depression, anxiety disorders, Alzheimer's disease, autism, Parkinson's disease, chronic pain, borderline personality disorder, neurodegenerative diseases, sleep disorders, chronic fatigue syndrome, rigidity, inflammatory diseases, asthma, Huntington's disease, ADHD, amyotrophic lateral sclerosis, epilepsy, role in arthritis, autoimmune diseases, viral and fungal infections, cardiovascular diseases, ophthalmic and inflammatory retinal diseases, and balance problems. 25. The compound according to any one of claims 1-14, for the treatment of CNS disorders associated with: positive and negative symptoms of schizophrenia, psychotropic substance abuse, alcohol and drug addiction, obsessive-compulsive disorder, cognitive impairment, bipolar disorder, mood disorders, major depressive disorder, treatment-resistant depression, anxiety disorders, Alzheimer's disease, autism, Parkinson's disease, chronic pain, borderline personality disorder, neurodegenerative diseases, sleep disorders, chronic fatigue syndrome, rigidity, inflammatory diseases, asthma, Huntington's disease, ADHD, amyotrophic lateral sclerosis, epilepsy, arthritis, autoimmune diseases, viral and fungal infections, cardiovascular diseases, ophthalmic and inflammatory retinal diseases, and balance problems.