HK1230199A1

HK1230199A1 - Indolin-2-one or pyrrolo-pyridin-2-one derivatives

Info

Publication number: HK1230199A1
Application number: HK17104010.9A
Authority: HK
Inventors: 汉斯．希尔珀特; 萨宾．克尔茨维斯基; 罗兰德．胡姆; 西奥多．施托尔; 托尔斯滕．穆泽; 让-马克．普朗谢; 德尔菲娜．高福赫托
Original assignee: 豪夫迈·罗氏有限公司
Priority date: 2014-06-26
Filing date: 2015-06-23
Publication date: 2017-12-01

Description

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

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

Wherein

Ar¹Is 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^-)；

R¹Is lower alkyl, halogen, cyano or cycloalkyl;

Ar²is 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 ]]A thienyl group;

R²is hydrogen, lower alkyl, halogen, cyano, lower alkyl substituted by hydroxy, lower alkyl substituted by halogen, lower alkyl substituted by amino, lower alkyl substituted by alkoxy, lower alkyl substituted by amide, or is cycloalkyl;

x is CH or N;

n is 1 or 2;

m is 1 or 2;

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

WO9106545 describes a structure for preventing the approach of clumps of both red blood cells and platelets, for Ar¹Containing phenyl-substituted imidazole moiety in Ar²The position(s) is free of heteroaryl. EP2108641 and WO2008046083 disclose a very broad range of similar compounds which are inhibitors of p38 nitrogen-activated protein kinase for the treatment of inflammatory diseases and benign prostatic hyperplasia, respectively.

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

In addition to the reverse L-687, 414-induced hypermobility assay described above, some compounds of the present invention have been shownIn a medium test ofIs an automated system in which compound-treated mice's behavior in response to a variety of challenges is captured by digital video and analyzed using computer algorithms (robeds et al, Frontiers in neuroscience, 2011, vol.5,Art.1031-4; vadim Alexandrov, Dani Brunner, talenenhanania, Emer Leahy eur.j. pharmacol.2015, 750, 82-99). In this way, the neuro-pharmacological effects of the test compounds can be predicted by their similarity to a broad class of compounds such as antipsychotics, anxiolytics and antidepressants. Examples 9, 25, 48 and 53 show similarities 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 formula I are also ENT1 inhibitors (equilibrium nucleoside transporter 1). The therapeutic potential of ENT1 inhibitors is described in the literature, directly or indirectly (via the effects of adenosine and/or adenosine receptor modulation), as being useful for the treatment of the following diseases: 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 (amyotrophic comparative systemic sclerosis), psychiatric diseases, substance abuse, ADHD, depression, epilepsy, anxiety, schizophrenia (WO0168105, EP 1252910, EP1612210, WO2009018275), autism spectrum disorders (Susan A. Masinoa, Masahiton Kawamura J., Jessica L. Cotea, Recoccua B. Williams, David N. skin, Neuromycology, 2013, 68, 116-eye disease 121, pain (WO 2002006490497), inflammation, asthma (US 20090 2007213296, respiratory disease, 2011-2011, ophthalmic diseases (WO 2004060434, J. ophthalmological disease, WO2009064497), ophthalmic diseases (Psychia, WO 2009090 2007213296, sleep eye disease, 2011-eye disease, ophthalmological disease, ophthalmologic, vol.1, 12-18).

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

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

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

schizoaffective disorder (Schizoafffective disorders): including psychosis and affective symptoms, which fall into the range between bipolar disorder (with depressive and manic episodes, alcohol and drug addiction, substance abuse) and schizophrenia. 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.ofNeuropsychopharmacology，2011，0，0，1-15

mood disorder：J.Psychopharmacol.2012，Jan 11，CNS Drugs，2010，2，131-61

Autism:Current opinion inpediatrics，2011，23，621-627；J.Clin.Psychiatry，2011，72，9，1270-1276

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

Parkinson 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

Objects of the present invention are novel compounds of formula I and the use of compounds of formula I and their pharmaceutically acceptable salts for the treatment of CNS disorders associated with: positive (psychosis) and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment resistant depression, anxiety disorders, alzheimer's disease, autism, parkinson's disease, chronic pain, borderline personality disorder, neurodegenerative disease, sleep disorders, chronic fatigue syndrome, stiffness, inflammatory disease, asthma, huntington's disease, ADHD, amyotrophic lateral sclerosis, epilepsy, effects in arthritis (effects in arthritis), autoimmune disease, viral and fungal infections, cardiovascular disease, ophthalmological and inflammatory retinal disease and balance problems.

Further objects of the invention are medicaments containing such novel compounds as well as processes for the preparation of compounds of formula I, the combination of a compound of formula I with a commercially available antipsychotic, antidepressant, anxiolytic or mood stabilizer and methods for the treatment of CNS disorders as described above.

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

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

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

The compounds of the invention may be combined with antipsychotics such as olanzapine (Zyprexa), clozapine (Clozaril), risperidone (Risperdal), aripiprazole (Abilify), amisulpride (Solian), asenapine (asenapine) (Saphris), blonanserin (Lonasen), chlorothiapine (Entumine), iloperidone (Fanapt), lurasidone (lurasidone) (lada), mosapamide (Cremin), paliperidone (Inyega), peropiropiroctone (lulan), quetiapine (Seroquel), remoxiam (roxam), schritdolle (serdolle) (serdolite), sulpiride (sulpiride) (sulpiride, egonyl), ziprasidone (geodone, zeoxx), tezophil (pololazine), haloperidol (sedafluorine), ziprasidone (chlorphenirazine), chlorphenirazine (s (chlorphenirazine), chlorphenirazine (trozine), chlorphenirazine (chlorphenirazine), chlorphenirazine (s (chlorphenirazine), chlorphenirazine (s, chlorpheniramine (chlorphen, Trifluoropropylamine (Vesprin), levomepromazine (Nozinan), promethazine (Phenergan), pimozide (Orap) and cyanomesalamine (Tercian).

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

In addition, the compounds of the invention may be combined with antidepressants such as selective 5-hydroxytryptamine reuptake inhibitors [ citalopram (Celexa), escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), fluvoxamine (Luvox), sertraline (Zoloft, Lustral) ], 5-hydroxytryptamine norepinephrine reuptake inhibitors [ duloxetine (Cymbalta), milnacipran (Ixel, Savella), venlafaxine (Effexor), desvenlafaxine (Pristq), tramadol (Tramal, Ultram), sibutramine (Meridia, Reducil) ], 5-hydroxytryptamine antagonists and reuptake inhibitors [ Axiopiperazone (Iomin, Etonin), lubazolidone (Lubadone) (YM-992, YM-35, nevirazone (Redox), nevirazone (Rezax), nevirazone (Revax) inhibitors (Rexpyrax), nevirazone (Redox) (Dexprox) (Reynax), norfloxacin (Rexprox), norfloxacin (Reynax) inhibitors [ Evone (Rexprox (Rexperzine), Reynax, Viloxazine (Vivalan), tomoxetine (strttera) ], norepinephrine-dopamine reuptake inhibitors [ bupropion (Wellbutrin, Zyban), Dexmethylphenidate (Dexmethylphenidate) (Focalin), methylphenidate (Ritalin, certa) ], norepinephrine-dopamine-releasing agents [ amphetamine (Adderall), dexamphetamine (dexaine), dexmethamphetamine (dexmethamphetamine) (Desoxyn), lisdexamphetamine (Lisdexamfetamine) (Vyvanse) ], tricyclic antidepressants [ amitriptyline (Elavil, Endep), clomipramine (Anafranil), desipramine (norpramine, perfrnane), polysuflipine [ Dothiepin (prothia), doxepin (adopterine), doxepin (lutemeprobamate), lutemeprobrazine (luteolin), lutemeprobine (luteolin), lutemeprobine (lutetium), lutepinine (lutepinine), lutepinine (e), lutepinine (lutepinine), lutepinine (e), lutepinine (lutepinine), lutepinine (loxapine), lutepinine (lox, Norval, Tolvon), mirtazapine (Remeron) ], monoamine oxidase inhibitors [ isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), selegiline [ L-diprenil ] (Eldepryl, Zelapar, Emsam), tranylcypropylammonium (Parnate), pirlindole (Pirazidol) ], 5-HT1A receptor agonists [ buspirone (Buspar), tandospirone (Sediel), vilazodone (Viibryd) ], 5-HT2 receptor antagonists [ agomelatine (Valdoxan), nefazodone (Nefadar, Serzone ], selective 5-hydroxytryptamine reuptake promoters [ Tianeptine (Tieepepine) ].

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

The compounds may also be combined with anxiolytics such as alprazolam (Helex, Xanax, Xanor, Onax, Alprox, Restyl, Tafil, Paxal), bromotacrine, bromoazepam (Lectopam, Lexotanil, Lexotan, Bromam), bromozolam (Lendormin, Dormex, Sinonal, Noctilan), chlordiazepoxide (Librium, Risolid, Elenium), Sinopram (Gerodorn), clonazepam (Rivotril, Klonopin, Iktorivi, Paxam), loratadine (Tranxene, nxilium), chlorothiazepam (Veratran, Clozan, Rize), chlorambu (Veratrix, Rize), chlorambu (Levotrex, Xan, Ox), chlorambum (Lectopamin, Levoxam, Oxun), bromhexedron (Levoxam, Oxun), brom (Levoxam), Levoxam (Levoxam, OxunAzolazone (Sepazon, Olcadil), diazepam (Dadumir), diazepam (Antenex, Apaurin, Apzepam, Apozepam, Hexalid, Pax, Stesolid, Stedon, Valium, Vival, Valaxona), estazolam (ProSom), etizolam (Etilaam, Pasaden, Depas), flunitrazepam (Rohypnol, Fluscan, fluunipam, Ronal, Rohydydorm), fluzepam (Dalma, Dalman), Fluocipam (Restas), Halirapam (Paxipam), Katazolam (Anxon), Loprazolam (Doxon), Loxoclononant (Loratam), Loctraxane (S), Oxiram (Oxiram), Oxiram, Nozamide (Oxiram), Oxiram, and N, Oxiram, and other, Temazepam (Restoril, Normison, Euhypnos, Temaze, Tenox), tetrahydrozepam (Mylostan), triazolam (Halcion, Rilamir), clobazam (Frisium, Urbanol), eszopiclone (Lunesta), zaleplon (Sonata, St)arnoc), zolpidem (Ambien, Nytamel, Stilnoct, Stilnox, Zoldem, Zolnod), zopiclone (imoven, Rhovane, Ximovan; zileze; zimoclone; zimovane; zopitan; zorclone), pregabalin (Lyrica) and gabapentin (Fanatrex, Gabarone, Gralise, Neurontin, Nupentin).

A preferred embodiment of the invention is a combination wherein the commercially available anxiolytic is alprazolam (Helex, Xanax, Xanor, Omax, Alprox, Restyl, Tafil, Paxal), chlordiazepoxide (Librium, Risolid, Elenium), clonazepam (Rivotril, Klonopin, Iktorivil, Paxam), diazepam (anteex, Apaurin, Apzepam, Apozepam, Hexalid, Pax, Stesolid, Stedon, Valium, Vival, Valaxona), estazolam (Protinan Som), eszopiclone (Lunestab), zaleplon (Sonata, Starnoc), zolpidem (Ambien, Nytame, Stilnoct, Stilnox, Zollinem), Zollin (Zollin), Pentapron (Necalin, or Facaritin).

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

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

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

As used herein, the term "lower alkyl" 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, and the like. Preferred alkyl groups are those 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 NH₂And (4) replacing.

As used herein, the term "amide-substituted lower alkyl" refers to a group wherein the alkyl residue is defined above, wherein at least one hydrogen atom is replaced by C (O) N (CH)₃)₂Or C (O) NH₂And (4) replacing.

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 group 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, isotriazolylOxazolyl, tetrazolyl, 1, 2, 4-thiadiazolyl, isothiazolyl orAn azole group.

The term "wherein the N-heteroatom in the heteroaryl group may be oxidized to N⁺-(O^-) "means, 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.

An embodiment of the invention is a compound, wherein X is CH. Another embodiment of the invention are the compounds from this group, wherein Ar¹And Ar²Are all six-membered heteroaryl groups containing one, two or three heteroatoms selected from N, S or O, e.g. 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) pyridinecarbonitrile

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, 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-methylpyrimidin-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-pyridinyl) 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) nicotinonitrile

3, 3-dimethyl-1- (6-methylpyrazin-2-yl) -6- (2-methyl-4-pyridinyl) indolin-2-one

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

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

3, 3-dimethyl-1- (5-methylpyrazin-2-yl) -6- (2-methyl-4-pyridinyl) indolin-2-one

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

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

6- (5-fluoro-3-pyridinyl) -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-indolin-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) where Ar is¹Is a six membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O, and Ar²Is a five-membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O, for example

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-methyliso-isoi)Azol-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) where Ar is¹Is a five membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O, and Ar²Is a six membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O, e.g. the following compounds

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

6- (4-Cyclopropylimidazol-1-yl) -3, 3-dimethyl-1- (2-methyl-4-pyridinyl) indolin-2-one

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

3, 3-dimethyl-6- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) -1- (6-methyl-3-pyridinyl) indolin-2-one

3, 3-dimethyl-6- (5-methyl-1, 3, 4-)Oxadiazol-2-yl) -1- (2-methyl-4-pyridinyl) indolin-2-one

6- (4-isopropylimidazol-1-yl) -3, 3-dimethyl-1- (2-methyl-4-pyridinyl) 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-methyl) methyl esterOxazol-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) where Ar is¹And Ar²Are all five-membered heteroaryl groups containing one, two or three heteroatoms selected from N, S or O, e.g. 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-methyl)Azol-5-yl) indolin-2-ones

3, 3-dimethyl-6- (2-methyl) methyl esterOxazol-5-yl) -1- (1-methylpyrazole-3-yl) indolin-2-ones

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) where Ar is²Is benzo [ b]Thienyl, and other substituents are as described above, for example the following compounds

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

An embodiment of the invention are compounds wherein X is N and the other substituents are as described above, for example the following compounds

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

a) reacting a compound of the formula

With a compound of the formula

(R²)_n-Ar²-Y 8

To produce the compound of formula I

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

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

The preparation of the compounds of formula I according to the invention can be carried out in a sequential or convergent synthetic route. The synthesis of the compounds of the invention is shown in the following scheme. The skill required to carry out the reaction and the purification of the resulting product is known to those skilled in the art. Unless indicated to the contrary, the substituents and indices used in the following description of the methods have the meanings given herein before.

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

Scheme 1

Ar¹Compounds of formula I (scheme 1) which are unsubstituted and substituted pyrimidines, pyridines, pyrazoles and imidazoles 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) -dimethylsulfide complex to afford compound 2. Can be carried out on a palladium catalyst such as [1, 1' -bis (diphenylphosphino) ferrocene]Coupling of the compound of formula 2 with boronic acid 4 or boron ester 5 in the presence of palladium (II) dichloride and a base such as potassium acetate or sodium carbonate provides arylated compound 7. Alternatively, compound 7 can be prepared via boronic ester 3 and subsequent coupling with aryl-halide 6(Y ═ Cl, Br, I). A second aryl radical (Ar)²-(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 the compound of formula I.

Scheme 2

Imidazoles of formula Ia (scheme 2) may be prepared from halo-hydroxyindole 2(Y ═ Cl, Br, I) in the following manner: protection of the amine group using a p-methoxybenzyl protecting group (PMB), after which the protected product 9 is reacted with a substituted imidazole 10 (R) in the presence of copper bromide, a ketone such as 2-acetyl-cyclohexanone and a base such as potassium carbonate¹Alkyl or cycloalkyl) to provide PMB-protected imidazole 11. Deprotection of the PMB group can be achieved using a strong acid such as TFA to provide 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 with boronic acid 14, copper acetate, and a base such as sodium bis (trimethylsilyl) amide, to provide the target imidazole Ia.

Scheme 3

Of the formula IbOxadiazoles (scheme 3) can be prepared from halogen-oxindole 2(Y ═ Cl, Br, I) by: carbonylation with carbon monoxide in methanol and in the presence of a ferrocene-palladium catalyst. Hydrolysis of methyl ester 15 using, for example, sodium hydroxide, produces acid 16, which is reacted in EDCI and 1H-benzo [ d ]][1，2，3]Reacting with acethydrazide in the presence of triazole-1-ol to provide acethydrazide 17. Cyclization of 17 using p-toluenesulfonyl chloride providesOxadiazole 18 which is reacted with a substituted aryl halide (Y ═ Cl, Br, I) to provide a compound of formula Ib.

Scheme 4

Of formula IcAzole (scheme 4) can be prepared from protected halogen-hydroxyanilines in the presence of palladium diacetate and 2-dicyclohexylphosphino) biphenyl and a base such as potassium carbonateIndole 9(Y ═ Cl, Br, I) andpreparation of oxazole 19 to provide protectedAn 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 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 targetAnd (3) oxazole Ic.

Scheme 5

The carboxylic acids 16 described above in scheme 3 may be converted to the N-hydroxy-C-methyl-carboimino derivatives 22, e.g. by addition of N-hydroxy-acetamidine, and subsequently converted to the corresponding- [1, 2, 4] derivatives, e.g. by dehydration under heat]Oxadiazole 23. 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 targetOxadiazole Id.

Scheme 6

Exchangeable/acidic protons present on certain heteroaromatic rings (e.g. 5-membered rings) may be detrimental to the coupling reaction to 7. In this case, a protecting group (PP, e.g., tetrahydropyranyl, t-butylcarbamate, trimethylsilylethoxymethyl, etc.) may be used, which facilitates production of compound 24.

The introduction and removal of these protecting groups follows methods known to those skilled in the art (see protective groups in organic synthesis, third edition, Wiley inteerscience, t.h.greene and p.g.m.wuts).

Subsequent removal of the protecting group affords compound Ie, which may optionally be further substituted by alkylation with alkyl halides (X ═ Cl, Br, I), to afford compounds of general formula If.

Scheme 7

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

Scheme 8

Addition of cyanogen bromide to the compound 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 the tetrazole of formula Ik. This process is called "click-chemistry". Tetrazoles may be alkylated by 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 invention. They should not be construed as limiting the scope of the invention but merely as being representative thereof.

Abbreviations：

Boc, tert-butoxycarbonyl;

DIPEA, diisopropylethylamine;

DMAP, dimethylaminopyridine;

DMF, dimethylformamide;

DMSO, dimethylsulfoxide;

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 purpose: silica gel chromatography using packing with silica gel (Cartridges of Columns, TELOSTM Flash Columns) or silica-NH 2 gel (TELOSTM Flash NH2 Columns) were loaded onto the ISCO Combi Flash company or onto silica gel 60(32-60 mesh,) On a glass column. MS: mass Spectra (MS) were 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 (12.8g) in anhydrous THF (80ml) was added 6-bromoindolin-2-one (5.0g) in portions at 0 deg.C, followed by copper (I) bromide-dimethylsulfide complex (470 mg). MeI (6.82g) was added dropwise over 45min, maintaining the internal temperature below 8 ℃, the mixture was warmed to 22 ℃ and stirring was continued for 16 hours. The mixture was quenched with saturated aqueous ammonium chloride at 0 ℃ and diluted with TBME and water. The organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, EtOAc/n-heptane, 1: 1) to provide the title compound (5.17g) as a brown solid (5.17g, 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) indoline- 2-ketones

A suspension of 6-bromo-3, 3-dimethyl-indolin-2-one (1.00g), bis (pinacolato) diboron (1.60g), potassium acetate (0.83g) in DMSO (14ml) was rinsed with argon and then with [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (152mg) was treated and stirring was continued at 110 ℃ for 16 h. The mixture was partitioned between aqueous hydrochloric acid (0.1M) 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 afford the title compound (0.92g, 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

3, 3-dimethyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indolin-2-one (200mg) and 5-bromo-2-methylpyrimidine (181mg) were added to 1, 4-bisThe suspension in an alkane (2ml) and aqueous sodium carbonate (2M) was flushed with argon and then [1, 1' -bis (diphenylphosphino) ferrocene was added]Palladium (II) dichloride (26mg) and stirring at 115 ℃ was continued 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 afford the title compound (148mg, 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 (100mg) and 4-iodopyridine (97mg) in acetonitrile (1.5ml) was washed with argon, followed by addition of potassium carbonate (120mg), copper (I) iodide (8mg) and N, N' -dimethylethylenediamine (7mg) and stirring continued in a microwave oven at 120 ℃ 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 crystallized from n-heptane/EtOAc to afford the title compound (64mg, 49%) as a pale brown solid. MS (m/z): 331.2[ (M + H)⁺]。

Example 2

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 in analogy to example 1d, using 3-iodopyridine to provide the title compound (50%) as white needles. MS (m/z): 331.3[ (M + H)⁺]。

Example 4

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

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

Example 6 was prepared in analogy 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

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

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

6-bromo-3, 3-dimethylindolin-2-one from example 1a (250mg) and 6-methylpyridine-3-boronic acid (214mg) were added to 1, 4-bisA mixture of an alkane (4ml) and aqueous sodium carbonate (1.3ml) was flushed with argon, followed by addition of [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (38mg) and stirring at 115 ℃ was continued 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 (205mg, 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)

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

Example 11

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

Prepared in analogy to example 10a using 2-methylpyrimidine-5-boronic acid and to obtain (49%) the title compound as light brown solid. 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)

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

Example 12

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

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

a)6- (4-Fluoropyridin-3-yl) -3, 3-Dimethylindoline-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)

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

Example 15

a)3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) -1H-pyrrolo [3, 2-c]Pyridin-2 (3H) -ones

Reacting 6-chloro-3, 3-dimethyl-1H-pyrrolo [3, 2-c ]]Pyridin-2 (3H) -one (200mg, prepared according to Woolford et al, WO 2012143726) and 2-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (336mg) in 1, 4-bisA suspension in an alkane (4ml) and aqueous sodium carbonate (2M, 1ml) was flushed with argon, followed by addition of [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (37mg) and stirring at 110 ℃ was continued 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 afford the title compound (221mg, 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)

In analogy to example 1d, 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 were prepared and the title compound was obtained (29%) as a white solid. MS (m/z): 335.2[ (M + H)⁺]。

Example 16

Analogously to example 1d, starting from 3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) -1H-pyrrolo [3, 2-c ] from example 15a]Pyridin-2 (3H) -one and 3-iodo-1-methyl-1H-pyrazole preparation example 16 provided the title compound (91%) as a pale brown solid. MS (m/z): 335.2[ (M + H)⁺]。

Example 17

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

Example 18

a)6-bromo-1- (4-methoxybenzyl) -3, 3-dimethyl-1, 3-indolin-2-one

To a solution of 6-bromo-3, 3-dimethyl-1, 3-indolin-2-one from example 1a (4.00g) in DMF (40ml) was added cesium carbonate (3.50g) and 4-methoxybenzyl chloride (5.00g) and stirring was continued at 80 ℃ 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 afford the title compound (3.50g, 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-indolin-2-one

A mixture of 6-bromo-1- (4-methoxybenzyl) -3, 3-dimethyl-1, 3-indolin-2-one (0.50g), potassium carbonate (0.21g) and 4-methylimidazole (0.57g) in NMP (2.5ml) was washed with argon, then CuBr (20mg) and 2-acetyl-cyclohexanone (39mg) were added and stirring continued at 135 ℃ 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 (0.17g, 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-indolin-2-one

A solution of 1- (4-methoxybenzyl) -3, 3-dimethyl-6- (4-methyl-imidazol-1-yl) -1, 3-indolin-2-one (170mg) in TFA (10ml) was heated at 110 ℃ for 72 h. The mixture was evaporated and the residue was taken up in saturated carbonic acidThe organic layer was dried, evaporated and the residue purified by flash chromatography (silica gel, EtOAc) to afford the title compound (70mg, 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-pyridinyl) indolin-2-one (exce EXAMPLE 18)

To a suspension of 3, 3-dimethyl-6- (4-methyl-imidazol-1-yl) -1, 3-indolin-2-one (70mg), 2-methylpyridine-5-boronic acid (80mg), DMAP (106mg) and copper acetate (56mg) in anhydrous toluene (2ml) was added sodium bis (trimethylsilyl) amide (1M in THF, 0.06ml) while dry air was bubbled through the mixture and stirring was continued at 95 ℃ for 16h at 25 ℃. The mixture was partitioned between aqueous hydrochloric acid (2M) 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 (36mg, 37%) as a brown solid. MS (m/z): 333.1[ (M + H)⁺]。

Example 19

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

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

In analogy to examples 18a-c, the title compound was prepared and obtained (58%) as a yellow solid in step 18b using 4-cyclopropylimidazole (prepared according to Chen, y., WO 2010096395). MS (m/z): 267.9[ (M + H)⁺]。

b)6- (4-Cyclopropylimidazol-1-yl) -3, 3-dimethyl-1- (2-methyl-4-pyridinyl) 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) to provide the title compound (9%) as a yellow solid. MS (m/z): 358.9[ (M + H)⁺]。

Example 22

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

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

Example 24 was prepared in analogy 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

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

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

Example 27

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

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

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

In analogy to example 1c, 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-1-ol were usedH-imidazole the title compound was prepared 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

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

Example 31

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

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

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

The title compound was prepared and obtained (67%) as an off-white solid in analogy to examples 18a-c using 4-isopropylimidazole (prepared according to Dolby et al, US 20050101785) in step 18 b. MS (m/z): 269.9[ (M + H)⁺]。

b)6- (4-isopropylimidazol-1-yl) -3, 3-dimethyl-1- (6-methyl-3-pyridinyl) 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

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-indolin-2-one (5.00g), DIPEA (26.9) and DMF (5ml) in methanol (40ml) was washed with argon and then [1, 1' -bis (diphenylphosphino) ferrocene was added]Palladium (II) dichloride (1.20g) and stirring at 100 ℃ in an autoclave at 150psi CO pressure was continued for 18 h. The mixture was evaporated and the residue 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 afford the title compound (3.0g, 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 (6.00g) in THF (60ml) were added LiOH (11.5g) and water (10ml) and stirring was continued at 25 ℃ for 18H. The mixture was evaporated, the residue was dissolved in ice-cold water, the pH was adjusted to 5-6 using aqueous hydrochloric acid (6N, 40ml), the suspension was filtered and the residue was dried to give the title compound (3.50g, 62%) as a pale yellow solid. MS (m/z): 204.1[ (M-H)^-]。

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 (2.00g) and acetic acid hydrazide (0.81g) in anhydrous DMF (5ml) were added HOBt (1.58g), EDCI (2.20g) and DIPEA (4.3ml) and stirring was continued at 25 ℃ for 18H. The mixture was evaporated to afford the crude title compound (2.20g, 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-indolin-2-ones

To a solution of crude 3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indole-6-carboxylic acid N' -acetyl-hydrazide (43) (1.40g) in DMF (5ml) and acetonitrile (10ml) were added tosyl chloride (1.50g) and triethylamine (2.2ml) and stirring was continued at 25 ℃ for 18H. The mixture was evaporated and the residue 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 afford the title compound (0.50g, 38%). MS (m/z): 244.2[ (M + H)⁺]。

e)3, 3-dimethyl-6- (5-methyl-1, 3, 4-) Diazol-2-yl) -1- (6-methyl-3-pyridyl) indoline Do-2-one (example 34)

Analogously to example 1d, starting from 3, 3-dimethyl-6- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -1, 3-indolin-2-one and 5-bromo-2-methyl-pyridine were prepared and the title compound was obtained as an off-white solid (29%). MS (m/z): 335.1[ (M + H)⁺]。

Example 35

Analogously to example 1d, starting from 3, 3-dimethyl-6- (5-methyl- [1, 3, 4] from example 34d]Oxadiazol-2-yl) -1, 3-indolin-2-one and 4-bromo-2-methyl-pyridine preparation example 35 was prepared to provide the title compound (27%) as an off-white solid. MS (m/z): 335.2[ (M + H)⁺]。

Example 36

A mixture of 6- (4-isopropyl-imidazol-1-yl) -3, 3-dimethyl-1, 3-dihydro-indol-2-one from example 33a (150mg), 4-bromo-2-methyl-pyridine (116mg) and potassium carbonate (169mg) in acetonitrile (10ml) was washed with argon, then CuI (10mg) and N, N' -dimethylethylenediamine (16mg) were added and stirring continued at 110 ℃ 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 afford the title compound (24%) as a yellow solid. MS (m/z): 361.0[ (M + H)⁺]。

Example 37

Example 37 was prepared in analogy 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

In analogy to example 36, example 38 was prepared 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

Example 39 was prepared in analogy 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

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

EXAMPLE 41

In analogy to example 36, example 41 was prepared 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 semi-solid. MS (m/z): 359.9[ (M + H)⁺]。

Example 42

3, 3-dimethyl1- (1-methylimidazol-4-yl) -6- (2-methyl) phenylAzol-5-yl) indolin-2-ones

a)1- (4-methoxy-benzyl) -3, 3-dimethyl-6- (2-methyl- Oxazol-5-yl) -1, 3-dihydro-indole-2- Ketones

Mixing 6-bromo-1- (4-methoxybenzyl) -3, 3-dimethyl-1, 3-dihydro-indol-2-one (1.00g) and 2-methylOxazole (0.50g) and potassium carbonate (1.15g) in 1, 4-bisThe suspension in alkane (10ml) was flushed with argon, then palladium diacetate (31mg) and 2- (dicyclohexylphosphino) biphenyl (10mg) were added and stirring was continued at 110 ℃ 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 afford the title compound (0.45g, 45%) as a yellow liquid. MS (m/z): 363.0[ (M + H)⁺]。

b)3, 3-dimethyl-6- (2-methyl- Azol-5-yl) -1, 3-dihydro-indol-2-ones

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

c)3, 3-dimethyl-1- (1-methylimidazol-4-yl) -6- (2-methyl) Azol-5-yl) indolin-2-one (shimeji) EXAMPLE 42)

Analogously to example 1d, starting from 3, 3-dimethyl-6- (2-methyl-)Oxazol-5-yl) -1, 3-dihydro-indol-2-one and 4-bromo-1-methyl-1H-imidazole preparation example 42 provided the title compound (30%) as a yellow solid. MS (m/z): 323.0[ (M + H)⁺]。

Example 43

Analogously to example 1d, starting from 3, 3-dimethyl-6- (5-methyl- [1, 3, 4] from example 34d]Oxadiazol-2-yl) -1, 3-indolin-2-one and 5-bromo-2-methyl-pyrimidine preparation example 43 fromTo 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

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

Preparation of the compound using 3-fluoro-4-iodopyridine in analogy to example 1dExample 46 to provide the title compound (23%) as a white foam. MS (m/z): 349.2[ (M + H)⁺]。

Example 47

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

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-methyl) methyl esterAzol-5-yl) -1- (1-methylpyrazol-3-yl) indolin-2-one

Analogously to example 1d, starting from 3, 3-dimethyl-6- (2-methyl-)Oxazol-5-yl) -1, 3-dihydro-indol-2-one and 3-bromo-1-methyl-1H-pyrazole preparation example 49 provided 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

In analogy to example 1d, use was made of 4-bromobenzo [ b ]]Thiophene example 50 was prepared to provide the title compound (5%) as a white solid. MS (m/z): 386.2[ (M + H)⁺]。

Example 51

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

Example 52

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

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-ones

Analogously to example 1d, starting from 3, 3-dimethyl-6- (5-methyl- [1, 3, 4] from example 34d]Oxadiazol-2-yl) -1, 3-indolin-2-one and 4-bromo-1-methyl-1H-imidazole preparation example 54 provides 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 in analogy to example 1d, using 3-iodo-1H-pyrazole-1-carboxylic acid tert-butyl ester to provide the title compound (41%) as a white solid. The Boc-group is cleaved off under the reaction conditions. MS (m/z): 320.1[ (M + H)⁺]。

Example 56

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

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

Example 58 was prepared in analogy to example 36 from 3, 3-dimethyl-6- (4-methyl-imidazol-1-yl) -1, 3-indolin-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

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

Example 60

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

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

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

Example 63

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

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

Analogously to example 1d, use is made4-bromo-1, 2-dimethyl-1H-imidazole example 65 was prepared to provide the title compound (8%) as a white solid. MS (m/z): 348.2[ (M + H)⁺]。

Example 66

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

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

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

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

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

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

A suspension of 6-bromo-3, 3-dimethyl-indolin-2-one (1.00g), bis (pinacolato) diboron (1.60g), potassium acetate (0.83g) in dimethyl sulfoxide (14ml) was washed with argon and then with [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (152mg) was treated and stirring was continued at 110 ℃ for 16 h. The mixture was partitioned between aqueous hydrochloric acid (0.1M) 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 afford the title compound (0.92g, 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

3, 3-dimethyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indolin-2-one (200mg) and 5-bromo-2-methylpyrimidine (181mg) were added to 1, 4-bisThe suspension in an alkane (2ml) and aqueous sodium carbonate (2M) was flushed with argon and then [1, 1' -bis (diphenylphosphino) ferrocene was added]Palladium (II) dichloride (26mg) and stirring at 115 ℃ was continued 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 afford the title compound (148mg, 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 (100mg, 395. mu. mol, eq: 1.00) and 6-bromo-2, 3-lutidine (88.1mg, 474. mu. mol, eq: 1.20), potassium carbonate (120mg, 869. mu. mol, eq: 2.20), copper (I) iodide (7.52mg, 39.5. mu. mol, eq: 0.10), N' -dimethylethylenediamine (6.96mg, 8.5. mu.l, 79.0. mu. mol, eq: 0.20) and acetonitrile (2ml) was heated to 120 ℃ for 18 h.

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

Example 71

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

b)1- (4-methoxybenzyl) -3, 3-dimethyl-6- (4-methoxy-benzyl) -methyl ester Azol-5-yl) indolin-2-ones

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

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

To 1- (4-methoxybenzyl) -3, 3-dimethyl-6- (at room temperatureOxazol-5-yl) indolin-2-one (200mg, 574 μmol, equivalents: 1.00, example 71 step b) solution in tetrahydrofuran (4ml) a solution of borane tetrahydrofuran complex in tetrahydrofuran (1M, 689 μ l, 689 μmol, eq: 1.2). After 30 minutes, the solution was cooled to-78 ℃ and n-butyl addedA solution of lithium in hexane (1.6M, 431. mu.l, 689. mu. mol, eq: 1.2). After 15 minutes at-78 deg.C, iodomethane (97.8mg, 43.0. mu.l, 689. mu. mol, eq: 1.2) was added and the mixture was warmed to-20 deg.C and stirred at this temperature for 4 h. A solution of acetic acid in ethanol (5% v/v, 10.3g, 9.86ml, 8.61mmol, eq: 15) was then added and the reaction mixture was stirred at room temperature overnight. The mixture was partitioned between saturated aqueous sodium bicarbonate and diethyl ether, then extracted with diethyl ether. The combined organic layers were washed with brine, dried, evaporated and the residue purified by chromatography on silica gel to afford the desired compound as a pale yellow solid (36mg, 17%). MS (M/z) ═ 363.2[ M + H]+。

d)3, 3-dimethyl-6- (2-methyl) methyl ester Azol-5-yl) indolin-2-ones

1- (4-methoxybenzyl) -3, 3-dimethyl-6- (2-methyl)Solution of oxazol-5-yl) indolin-2-one (35mg, 96.6 μmol, equivalents: 1.00, example 71 step c) was dissolved in trifluoroacetic acid (661mg, 446 μ l, 5.79mmol, eq: 60) and the reaction mixture was reacted in a microwave at 140 ℃ for 1 h. The volatiles were removed in vacuo and the green residue was purified by chromatography on silica gel to afford the desired compound as a pale brown solid (15.9mg, 68%). MS (M/z) ═ 243.1[ M + H]+。

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

In analogy to example 70 step d, using 3, 3-dimethyl-6- (2-methyl)The title compound was prepared from oxazol-5-yl) indolin-2-one (example 71 step d) and 5-bromo-2-methyl-pyrimidine as starting materials. Off-white solid. Yield: 29 percent. 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 (150mg, 625. mu. mol, eq: 1.00, CAS [158326-84-2], example 70 step a), 4-methyl-1H-imidazole (256mg, 3.12mmol, eq: 5.0), potassium carbonate (90.7mg, 656. mu. mol, eq: 1.05) and 2-acetylcyclohexanone (21.9mg, 20.3. mu.l, 156. mu. mol, eq: 0.25) in N-methylpyrrolidone (1.2ml) and copper (I) chloride (6.18mg, 62.5. mu. mol, eq: 0.1) was stirred at 130 ℃ for 24H. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, then extracted with ethyl acetate. The combined organic layers were dried, evaporated and the residue purified by chromatography on silica gel followed by reverse phase HPLC to afford the desired compound as a white solid (39mg, 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-ketones

The title compound was prepared in analogy to 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 percent.

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-carboxylate (6.24g, 31.7mmol, eq: 1) and methyl iodide (9.08g, 4ml, 64mmol, eq: 2.02) in anhydrous dimethylformamide (90.5ml) was added a suspension of NaH in mineral oil (60% w/w, 2.54g, 63.4mmol, eq: 2) in portions over 1.5h while controlling the exotherm using a water bath. The reaction mixture was carefully poured onto an ice-cold mixture of-11 g sodium bicarbonate, water (150mL) 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 pale brown solid (5.026g, 72%).

MS(m/z)＝218.1[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-indoline-6-carboxylate (6.0g, 27.4mmol, example 73 step a) in tetrahydrofuran (60ml) were added lithium hydroxide (11.5g, 273.9mmol) and water (10 ml). The mixture was stirred at 25 ℃ for 12 h. After completion of the reaction, the solvent was removed in vacuo. Ice-water (100ml) was added to the reaction mixture and the pH of the reaction mixture was adjusted to 5-6 by the addition of hydrochloric acid (6N, 40 ml). A white precipitate formed which was filtered and washed with water (2 × 25ml) and then dried under vacuum to afford the desired product (3.5g, 62%) as a dark brown solid.

MS(m/z)：204.1(M-H)-.

c) N- [ (E) -N-hydroxy-C-methyl-carboimino group]-3, 3-dimethyl-2-oxo-indoline-6-carboxamide

To a solution of 3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indole-6-carboxylic acid (1.5g, 7.317mmol, example 73, step b) and N-hydroxy-acetamidine (0.54g, 7.317mmol) in anhydrous THF (10ml) and dimethylformamide (1ml) were added 2, 4, 6-tripropyl-1, 3, 5, 2, 4, 6-trioxatriphospha-cyclohexane-2, 4, 6-trioxide (3.45g, 10.976mmol) and triethylamine (3.0ml, 21.9 mmol). The resulting mixture was stirred at 25 ℃ for 18 h. The solvent was removed under vacuum to afford the desired product (1.5g, 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)] Oxadiazol-5-yl) -1, 3-dihydro-indol-2-ones

Reacting N- [ (E) -N-hydroxy-C-methyl-carboimino group]-3, 3-dimethyl-2-oxo-indoline-6-carboxamide (1.5g, 5.74mmol, example 73 step c) in bisA solution in an alkane (25ml) was heated at 100 ℃ for 16 h. Will be reversedThe mixture was concentrated in vacuo and purified by chromatography on silica gel to afford the desired compound as an off-white solid (300mg, 21%).

MS(m/z)＝242.2[M-H]-。

e)3, 3-dimethyl-6- (3-methyl-1, 2, 4-) Diazol-5-yl) -1- (2-methylpyrimidin-5-yl) dihydroindoline Indole-2-ones

In analogy to example 70 step d, using 33, 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 were used as starting materials to prepare the title compound. A pale yellow solid. Yield: 24 percent.

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 in analogy 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. Light brown solid. Yield: 9 percent. MS (M/z) ═ 334.2(M + H)⁺

Example 75

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 5-bromo-2, 3-dimethylpyridine as starting materials. A white solid. Yield: 52 percent. 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 the title compound was prepared in 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

In analogy to example 70 step d, using 3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) indolin-2-one (example 70 step c) and 2-The title compound was prepared using iodopyrazine as the starting material. A white solid. Yield: and 55 percent. MS (M/z) ═ 332.3(M + H)⁺

Example 78

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-bromo-1, 5-dimethyl-1H-1, 2, 4-triazole (CAS [56616-93-4]) as starting materials. Off-white solid. Yield: 65 percent.

MS(m/z)＝349.2(M+H)⁺

Example 79

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

In analogy 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 ]]) The title compound was prepared as the starting material. A white solid. Yield: 32 percent. MS (M/z) ═ 332.1(M + H)⁺

Example 80

In analogy 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)]) The title compound was prepared as the starting material. A white solid. Yield: 30 percent. MS (M/z) ═ 334.2(M + H)⁺

Example 81

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

In a 50ml three-necked flask equipped with a magnetic stirrer, septum, 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 6.9ml (1.10 equivalents) of butyllithium 1.6M/hexane were added dropwise at-75 ℃ to-65 ℃. After the initial addition of butyl lithium, the solution became a milky white suspension, which became a yellow solution upon further addition of butyl lithium. The reaction was stirred at-75 ℃ for 10min, then 1.85ml (1.75g, 11.0mmol, 1.05 eq.) of 2- (trimethylsilyl) -ethoxymethyl chloride was added dropwise at-75 ℃. The reaction was allowed to warm to room temperature. The solution was cooled to-75 ℃ and 6.2ml (1.00 eq) of butyllithium 1.6M/hexane was added dropwise, keeping the temperature below-65 ℃. After 30min at-75 ℃, 2ml (5.0 equiv.) of methanol was added dropwise at-75 ℃. The mixture was stirred at-75 ℃ for 10 min. Saturated aqueous ammonium chloride (3mL) was added and the mixture was allowed to warm to room temperature, then partitioned between water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate and then dried in vacuo. The residue was purified by chromatography on silica gel to give the desired compound (1.27g, 37%).

b)3, 3-dimethyl-1- (2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole-4- Yl) -6- (2-methylpyrimidin-5-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 4-iodo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (example 81 step a) as starting materials. Yellow solid. Yield: 91 percent. MS (M/z) ═ 464.3(M + H)⁺

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

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 (164mg, 354. mu. mol, eq: 1.00) in dichloromethane (3mL) and ethanol (244mg, 310. mu.L, 5.31mmol, eq: 15) was added trifluoroacetic acid (1.61g, 1.09mL, 14.1mmol, eq: 40). The reaction mixture was stirred at 22 ℃ for 20 h. Ethanol (3ml) was added and the reaction mixture was stirred at 70 ℃ for 20h, 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 afford the desired compound as a white solid (53mg, 45%). MS (M/z) ═ 334.2[ M + H ] +.

Example 82

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-bromo-1-methyl-1H-1, 2, 4-triazole as starting materials. Off-white solid. Yield: 80 percent. 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 (100mg, 395. mu. mol, eq: 1.00, see example 70, step c) and tert-butyl 4-iodo-1H-pyrazole-1-carboxylate (139mg, 474. mu. mol, eq: 1.20) was combined in acetonitrile (2 ml). Potassium carbonate (120mg, 869. mu. mol, eq: 2.20) and then copper (I) iodide (7.52mg, 39.5. mu. mol, eq: 0.10) and N, N' -dimethylethylenediamine (6.96mg, 8.5. mu.l, 79.0. mu. mol, eq: 0.20) were added and the mixture was heated to 120 ℃ in an oil bath for 20h and then to 160 ℃ 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 afford the desired compound as a colorless foam (16mg, 13%). MS (M/z) ═ 320.2[ M + H ] +.

Example 84

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 5-iodo-4-methylpyrimidine (CAS [91749-26-7]) as starting materials. Off-white solid. Yield: 11 percent. 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) 4-bromo-1H-imidazole-1-carboxylic acid tert-butyl ester

4-bromo-1H-imidazole (2.59g, 17.6mmol, eq: 1.00) and di-tert-butyl dicarbonate (4.04g, 4.3ml, 18.5mmol, eq: 1.05) were combined with tetrahydrofuran (19 ml). Dimethylaminopyridine (43.1mg, 352. mu. mol, eq: 0.02) was added and the reaction stirred at 25 ℃ for 1.5 h. The crude reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 1M hydrochloric acid solution, water, saturated sodium bicarbonate and brine. The organic layer was dried and concentrated in vacuo to afford the desired compound as an off-white 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 in analogy to example 70 step d, using 3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) indolin-2-one (example 70 step c) and 4-bromo-1H-imidazole-1-carboxylic acid tert-butyl ester (example 85 step a) as starting materials. A pale yellow solid. Yield: 12 percent.

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-ones

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 5-iodo-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole as starting materials. A light yellow oil. Yield: 33 percent.

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 salt

To a light 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 (55mg, 132. mu. mol, equivalent: 1.00) in dichloromethane (1ml) was addedHydrochloric acid (4M) in an alkane (329. mu.l, 1.32mmol, eq: 10) and the mixture was stirred at 22 ℃ for 4 h. Will be provided withThe solvent was concentrated in vacuo and the residue was crystallized from ethyl acetate (5ml) to give the desired compound as an off-white solid (18mg, 35%). MS (M/z) ═ 334.2[ M + H]⁺。

Example 87

Acetonitrile (3ml) was added to a mixture of 3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) indolin-2-one (100mg, 395. mu. mol, eq: 1.00, see example 70 step c) and 4-bromo-1-methyl-1H-1, 2, 3-triazole (76.7mg, 474. mu. mol, eq: 1.2) in a microwave tube. The solvent was degassed by bubbling nitrogen through the suspension for 10 minutes. N, N' -dimethylethylenediamine (6.96mg, 8.5. mu.l, 79.0. mu. mol, eq: 0.2) was then added at 22 ℃ followed by potassium carbonate (136mg, 987. mu. mol, eq: 2.5) and copper (I) iodide (7.52mg, 39.5. mu. mol, eq: 0.1). The tube was filled with an inert gas (inert), sealed and the mixture was heated in a microwave at 170 ℃ for 30 minutes.

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

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

Example 88

The title compound was prepared in analogy to example 87, using 3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) indolin-2-one (example 70 step c) and 2-bromo-4-methyl-1H-imidazole-1-carboxylic acid tert-butyl ester as starting materials. A white solid. Yield: 6 percent. MS (M/z) ═ 334.2[ M + H]⁺。

Example 89

To 3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) indolin-2-one (100mg, 395. mu. mol, equivalent: 1.00, see example 70 step c), 5-iodo-3-methyliso-soindolA mixture of oxazole (99.0mg, 474. mu. mol, eq: 1.2) and cesium carbonate (322mg, 987. mu. mol, eq: 2.5) was added to the reaction mixtureAlkane (1 ml). The solvent was degassed by bubbling nitrogen through the suspension for 10 minutes. 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (9.41mg, 19.7. mu. mol, eq: 0.05) was then added at 22 ℃ and then tris (dibenzylideneacetone) dipalladium (0) (3.62mg, 3.95. mu. mol, eq: 0.01) was added. The tube was filled with inert gas, sealed and the mixture was heated to 120 ℃ for 2 h. The mixture was treated with 2ml water and extracted with ethyl acetate (3X 2ml)And (6) taking. The organic layer was dried, filtered and concentrated in vacuo.

The residue was purified by chromatography on silica gel to afford the desired compound as a light yellow solid (5mg, 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 in analogy 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: and 43 percent. 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 (80mg, 316. mu. mol, eq: 1.00) and 2-bromo-5-methylpyrimidin (65.6mg, 379. mu. mol, eq: 1.20) in acetonitrile (2.5ml) for 5 min. Potassium carbonate (96.0mg, 695. mu. mol, eq: 2.20) was added, and then copper (I) iodide (6.02mg, 31.6. mu. mol, eq: 0.10) and N, N' -dimethylethylenediamine (5.57mg, 6.8. mu.l, 63.2. mu. mol, eq: 0.20) were added, and the mixture was heated to 130 ℃ in a microwave for 1 h. The mixture was partitioned between water (10ml) and dichloromethane (10 ml). The aqueous layer was extracted three times with dichloromethane (3 × 10ml) 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 (83mg, 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 in analogy 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. A white solid. Yield: and 63 percent. 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 in analogy to 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 percent. 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 in mineral oil (60% w/w, 5.2g, 130mmol, eq: 1.30) was suspended in 240ml tetrahydrofuran and cooled to 0 ℃. A solution of imidazole (6.8g, 100mmol, eq: 1.00) dissolved in 100ml of tetrahydrofuran was slowly dropped to the reaction mixture and stirring was continued at room temperature for 45 min. The reaction mixture was then cooled with an ice bath and 2- (trimethylsilyl) ethoxymethyl chloride (16.67g, 17.64ml, 100mmol, eq: 1.00) was added and the suspension was stirred at room temperature overnight. The reaction was quenched by the addition of saturated sodium bicarbonate. The solvent was evaporated and the residue was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried and concentrated in vacuo.

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

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

2- (imidazol-1-ylmethoxy) ethyl-trimethyl-silane (2g, 10mmol, eq: 1.00, example 92 step a) was dissolved in anhydrous tetrahydrofuran (20ml) and cooled to-78 ℃. N-butyllithium (1.6M in hexane, 6.93ml, 11mmol, eq: 1.10) was added dropwise for 20 min. The reaction solution was warmed to 0 ℃ and stirred at 0 ℃ for 5 min. It was then cooled to-60 ℃ and added to a solution of iodine (2.81g, 11mmol, eq: 1.10) in 10ml of anhydrous tetrahydrofuran 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 afford the title compound as a light yellow oil (2.34g, 71%).

c)3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) -1- (1- ((2- (trimethylsilyl) ethoxy) methyl Radical) -1H-imidazol-2-yl) dihydroindoleIndole-2-ones

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 2-iodo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazole (example 92 step b) as starting materials. A yellow oil. Yield: 15 percent. 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 (35mg, 77.8 μmol, eq: 1.00, example 92 step c) in tetrahydrofuran (1ml) was added tetrabutylammonium fluoride (1M in THF) (311 μ l, 311 μmol, eq: 4.00) and the mixture was stirred at room temperature for 20H. The mixture was partitioned between water (10ml) and dichloromethane (10ml), the aqueous layer was extracted twice with dichloromethane (2 × 10ml), and the combined organic layers were dried and concentrated in vacuo.

The residue was purified by preparative HPLC to afford the desired compound as a white solid (3mg, 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 (100mg, 395. mu. mol, eq: 1.00, example 70 step c), 4-bromopyrimidine hydrochloride (154mg, 790. mu. mol, eq: 2) and cesium carbonate (450mg, 1.38mmol, eq: 3.5) was added degassed di-bromopyrimidine hydrochlorideAlkane (3 ml). Palladium (II) acetate (17.7mg, 79.0. mu. mol, eq: 0.2) was then added at room temperature, followed by 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos) (68.5mg, 118. mu. mol, eq: 0.3). The tube was filled with inert gas, sealed and the mixture was heated to 115 ℃ for 2 h. The reaction was concentrated in vacuo.

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

Example 94

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 1-ethyl-3-iodo-1H-pyrazole as starting materials. A white solid. Yield: 8 percent. MS (M/z) ═ 348.2[ M + H]⁺。

Example 95

In analogy to example 70 step d, using 3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) dihydroIndol-2-one (example 70 step c) and 2-bromo-5-cyclopropylpyrazine as starting materials. Light brown solid. Yield: 85 percent. MS (M/z) ═ 372.2[ M + H]⁺。

Example 96

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 5-bromopyrazine-2-carbonitrile as starting materials. A white solid. Yield: 33 percent. MS (M/z) ═ 357.1[ M + H]⁺。

Example 97

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 2-bromo-6-cyclopropylpyrazine as starting materials. Light brown solid. Yield: 89 percent. MS (M/z) ═ 372.2[ M + H]⁺。

Example 98

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-bromo-4, 5-dimethylpyridine as starting materials. A white solid. Yield: 2 percent. 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 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-bromo-4-methylpyridine as starting materials. A white solid. Yield: 4 percent. MS (M/z) ═ 345.2[ M + H]⁺。

Example 100

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 5-bromo-2, 4-dimethylpyridine as starting materials. A white solid. Yield: 3 percent. MS (M/z) ═ 359.2[ M + H]⁺。

Example 101

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

Example 102

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 116 step a) and (5-bromopyrimidin-2-yl) methanol (prepared as described previously, for example, by Hasnik, Zbynek et al, Synlett, (4), 543-546; 2008) as starting materials. Light brown solid. Yield: 31 percent. MS (M/z) ═ 362.2(M + H)⁺

Example 103

a) N- [ [5- [3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) -2-oxo-indolin-1-yl group]Pyrimidine-2- Base of]Methyl radical]Carbamic acid tert-butyl ester

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 116 step a) and tert-butyl (5-bromopyrimidin-2-yl) methylcarbamate as starting materials. Off-white solid. Yield: 74 percent. 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 (100mg, 217. mu. mol, eq: 1.00, example 103 step a) in dichloromethane (1ml) was added trifluoroacetic acid (248mg, 167. mu.l, 2.17mmol, eq: 10) at 0 ℃ and the mixture was stirred at 0 ℃ for 15min and at 22 ℃ 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 afford the desired compound as an off-white solid (36mg, 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 (300mg, 1.18mmol, eq: 1.00, example 70 step c) in dimethylformamide (4.5ml) was added a suspension of sodium hydride in oil (60%, 62.0mg, 1.42mmol, eq: 1.2) at 0 ℃. The mixture was warmed to 22 ℃ and stirring was continued for 30 min. Cyanogen bromide (163mg, 1.54mmol, eq: 1.3) was added to the pale yellow solution at 0 ℃ and stirring was continued for 1.5h at 22 ℃.

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

The combined organic layers were dried, concentrated in vacuo and the residue was purified by chromatography on silica gel to afford the desired compound as a white solid (230mg, 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 (100mg, 359. mu. mol, eq: 1.00, example 104 step a) in a mixture of dimethylformamide (3ml), water (2ml) and isopropanol (1ml) was added sodium azide (70.1mg, 1.08mmol, eq: 3.00) and zinc bromide (68.8mg, 305. mu. mol, eq: 0.85) at 0 ℃. The reaction mixture was stirred at 0 ℃ 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 (5ml) to provide the title compound (61mg, 53%) as a white solid. MS (M/z) ═ 322.1[ M + H]⁺。

Example 105

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

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

MS(m/z)＝336.2[M+H]+

Example 106 and example 107

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 (100mg, 290. mu. mol, eq.: 1, example 48) in dichloromethane (3ml) was added m-CPBA (100mg, eq.: 1.25) at 22 ℃. The reaction mixture was stirred at 22 ℃ for 20 h.

The reaction was partitioned between aqueous sodium carbonate (10% m/m, 10ml) and dichloromethane (10ml) and the aqueous layer was extracted with dichloromethane (3 × 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 (44mg, 42%) as a pale yellow solid

Rf (dichloromethane/methanol 15: 1) ═ 0.25(UV) LC-MS: m/z is 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 (15mg, 14%) as a white solid, Rf (dichloromethane/methanol 15: 1) ═ 0.20(UV), MS (M/z) ═ 378.3[ M + H ] +

Example 108

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

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

The combined organic layers were dried, concentrated in vacuo and the residue was purified by chromatography on silica gel to afford the desired compound as an off-white solid (110mg, 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 in analogy 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. A white solid. Yield: 90 percent.

MS(m/z)＝364.2(M+H)⁺

Example 109

a)3, 3-dimethyl-6- (2-methyl-4-pyridyl) -1H-pyrroleAnd [3, 2-c ]]Pyridin-2-ones

Reacting 6-chloro-3, 3-dimethyl-1H-pyrrolo [3, 2-c ]]Pyridin-2 (3H) -one (400mg, 2.03mmol, eq: 1, prepared according to Woolford et al, WO 2012143726), (2-methylpyridin-4-yl) boronic acid (418mg, 3.05mmol, eq: 1.5) in dioxaneAlkane (8.14ml), aqueous sodium carbonate (2M, 2.03ml) and [1, 1' -bis (diphenylphosphino) ferrocene]A degassed suspension of palladium (II) dichloride (74.4mg, 102. mu. mol, eq: 0.05) was heated in a sealed vial at 110 ℃ for 6 h. The volatiles were removed in vacuo and the residue was purified by chromatography on silica gel to afford the desired compound as a light brown solid (415mg, 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) -ones

In analogy to 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 ]]) The title compound was prepared as the starting material. A white solid. Yield: 80 percent. MS (M/z) ═ 346.2(M + H)⁺

Example 110

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 116 step a) and 4-iodo-1-methyl-1H-pyrazole as starting materials. White foam-likeA compound (I) is provided. Yield: 97 percent. MS (M/z) ═ 334.2(M + H)⁺

Example 111

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 116 step a) and 4-iodo-1-methyl-1H-imidazole as starting materials. A white solid. Yield: 81 percent.

MS(m/z)＝334.2(M+H)⁺

Example 112

a)6- (4-fluorophenyl) -3, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridin-2-ones

The title compound was prepared in analogy 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. A white solid. Yield: and 47 percent.

MS(m/z)＝257.2(M+H)⁺

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

In analogy to example 70 step d, using 6- (4-fluorophenyl) -3, 3-dimethyl-1H-pyrrolo [3, 2-c)]The title compound was prepared from pyridin-2-one (example 112 step a) and 5-bromo-2-methylpyrimidine hydrochloride as starting materials. A white solid. Yield: 88 percent. MS (M/z) ═ 349.3(M + H)⁺

Example 113

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 5-chloro-2-iodopyrimidine as starting materials. A white solid. Yield: 84 percent. MS (M/z) ═ 366.2(M + H)⁺

Example 114

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 2-chloro-5-iodopyrimidine as starting materials. A white solid. Yield: 20 percent. 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 in analogy 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. A white solid. Yield: and 63 percent. MS (M/z) ═ 399.2(M + H)⁺

Example 116

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 5-bromo-2-cyclopropylpyrimidine as starting materials. Off-white solid. Yield: 70 percent. MS (M/z) ═ 372.3(M + H)⁺

Example 117

In analogy to example 70 step d, using 3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) indolin-2-one (example 70 stepStep c) and 2, 5-dichloropyrazine as starting materials. A white solid. Yield: 6 percent. MS (M/z) ═ 366.2(M + H)⁺

Example 118

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, 6-dichloropyridazine as starting materials. A white solid. Yield: 2 percent. MS (M/z) ═ 366.2(M + H)⁺

Example 119

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 4-bromo-2-chloro-6-methylpyridine as starting materials. A pale yellow solid. Yield: 42 percent. 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 in analogy 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 percent. MS (M/z) ═ 332.2(M + H)⁺

Example 121

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 4, 6-dichloro-2-methylpyrimidine as starting materials. Off-white solid. Yield: 10 percent. MS (M/z) ═ 380.2(M + H)⁺

Example 122

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-bromo-5-methylpyridazine as starting materials. A white solid. Yield: 7 percent. MS (M/z) ═ 346.2(M + H)⁺

Example 123

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 5-bromo-3-methyl-1, 2, 4-thiadiazole as starting materials. Off-white solid. Yield: 21 percent. MS (M/z) ═ 352.2(M + H)⁺

Example 124

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 5-bromo-3-methylisothiazole as starting materials. Off-white solid. Yield: 94 percent. MS (M/z) ═ 351.2(M + H)⁺

Example 125

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 2-bromo-5-methylthiazole as starting materials. Light brown solid. Yield: 74 percent. MS (M/z) ═ 351.2(M + H)⁺

Example 126

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 5-bromo-3-chloropyridazine as starting materials. Off-white solid. Yield: 66 percent. MS (M/z) ═ 366.1(M + H)⁺

Example 127

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 2-bromo-3-methylpyrazine as starting materials. Off-white solid. Yield: 88 percent. MS (M/z) ═ 346.1(M + H)⁺

Example 128

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 2-bromo-4-chloropyrimidine as starting materials. A white solid. Yield: 7 percent. MS (M/z) ═ 366.2(M + H)⁺

Example 129

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 5-bromo-2- (methoxymethyl) pyridine as starting materials. White foam. Yield: quantification of

MS(m/z)＝375.2(M+H)⁺

Example 130

a) 3-chloro-5-cyclopropylpyridazine

5-bromo-3-chloropyridazine (50mg,258 μmol, equivalent weight: 1) and cyclopropylboronic acid (33.3mg, 388 μmol, equivalent: 1.5) in twoAlkane (923. mu.l) and aqueous sodium carbonate solution (2M, 369. mu.l), [1, 1' -bis (diphenylphosphino) ferrocene]The degassed mixture in palladium (II) dichloride (18.9mg, 25.8. mu. mol, eq: 0.1) was heated to 100 ℃ 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 (27mg, 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 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-chloro-5-cyclopropylpyridazine (example 130 step a) as starting materials. A white solid. Yield: 43% MS (M/z) ═ 372.2(M + H)⁺

Example 131

a)3- (3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) -2-oxoindolin-1-yl) -1H-pyrazole-1-carboxylic acid methyl ester Tert-butyl ester

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-iodo-1H-pyrazole-1-carboxylic acid tert-butyl ester as starting materials. A pale yellow solid. Yield: 40 percent. MS(m/z)＝420.2(M+H)⁺

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

Will dissolve in3- (3, 3-dimethyl-6- (2-methylpyrimidin-5-yl) -2-oxoindolin-1-yl) -1H-pyrazole-1-carboxylic acid tert-butyl ester in an alkane (3ml) (80mg, 191. mu. mol, eq: 1, example 131 step a) and in bisA mixture of hydrochloric acid solution in an alkane (95.4. mu.l, 381. mu. mol, eq: 2) was stirred at room temperature for 16 h. Adding an additional in twoHydrochloric acid solution in alkane (95.4. mu.l, 381. mu. mol, eq: 2) and the reaction mixture was heated to 50 ℃ for an additional 6 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography, then HPLC to afford 22mg (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) indolin-2- Ketones

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

Example 132

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

The title compound was prepared in analogy 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. A white solid. Yield: and 63 percent. 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 in analogy to 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. A white solid. Yield: 93 percent. MS (M/z) ═ 346.2(M + H)⁺

Example 133

The title compound was prepared in analogy 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. A white solid. Yield: 86 percent. MS (M/z) ═ 346.2(M + H)⁺

Example 134

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-bromo-6-cyclopropylpyridazine as starting materials. A white solid. Yield: 87 percent. MS (M/z) ═ 372.1(M + H)⁺

Example 135

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

The title compound was prepared in analogy 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 percent. MS (M/z) ═ 331.8(M + H)⁺

b)3, 3-dimethyl-1- (6-methylpyrazin-2-yl) -6- (tetramethyl-1, 3, 2-dioxaborolan-2-) Radical) -23-dihydro-1H-indol-2-ones

In analogy to example 136 step b, using 6-bromo-3, 3-dimethyl-1- (6-methylpyrazin-2-yl) indolin-2-oneExample 135 step a) the title compound was prepared as the starting material. Off-white solid. Yield: 96 percent. MS (M/z) ═ 379.8(M + H)⁺

c)3, 3-dimethyl-1- (6-methylpyrazin-2-yl) -6- (6-methyl-2-pyridinyl) indolin-2-one

The title compound was prepared in analogy 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 2-bromo-6-methyl-pyridine as starting materials. Off-white solid. Yield: 33 percent. MS (M/z) ═ 344.8(M + H)⁺

Example 136

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

The title compound was prepared in analogy 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 percent. MS (M/z) ═ 333.8(M + H)⁺

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

6-bromo-3, 3-dimethyl-1- (5-methylpyrazin-2-yl) -2, 3-dihydro-1H-indol-2-one (1.7g, 5.12mmol, example 136 step a), potassium acetate (1.004g, 10.24mmol), bis (pinacolato) diboron (1.559g, 6.14mmol), [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride dichloromethane complex (0.418g, 0.51mmol) in bisThe degassed suspension in alkane (20mL) was stirred at 110 ℃ for 6 h. The reaction mixture was filtered and concentrated in vacuo and purified by chromatography on silica gel to afford 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 in analogy to 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. A white solid. Yield: 33 percent. MS (M/z) ═ 346.0(M + H)⁺

Example 137

The title compound was prepared in analogy 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 percent. MS (M/z) ═ 346.1(M + H)⁺

Example 138

The title compound was prepared in analogy 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. A pale yellow solid. Yield: 65 percent. MS (M/z) ═ 334.2(M + H)⁺

Example 139

The title compound was prepared in analogy to 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. A white solid. Yield: 15 percent. 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 in analogy to 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. A white solid. Yield: 27 percent.

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 in analogy to 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. A white solid. Yield: 40 percent. MS (M/z) ═ 405.2(M + H)⁺

Example 142

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-bromo-5-fluoropyridine as starting materials. A white solid. Yield: and (4) quantifying. MS (M/z) ═ 349.1(M + H)⁺

Example 143

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 5-bromonicotinonitrile as starting materials. Off-white solid. Yield: 98 percent. MS (M/z) ═ 356.1(M + H)⁺

Example 144

The title compound was prepared in analogy 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-pyridine as starting materials. A white solid. Yield: 38 percent. MS (M/z) ═ 344.9(M + H)⁺

Example 145

In analogy 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 stepStep b) and 3-bromo-5-methyl-pyridine as starting materials the title compound was prepared. Off-white solid. Yield: 34 percent. MS (M/z) ═ 344.9(M + H)⁺

Example 146

The title compound was prepared in analogy 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-fluoro-pyridine as starting materials. Off-white solid. Yield: 37 percent. MS (M/z) ═ 348.8(M + H)⁺

Example 147

The title compound was prepared in analogy to 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. A white solid. Yield: 46 percent. MS (M/z) ═ 344.9(M + H)⁺

Example 148

The title compound was prepared in analogy to 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. A white solid. Yield: 23 percent. MS (M/z) ═ 344.8(M + H)⁺

Example 149

The title compound was prepared in analogy to 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. A white solid. Yield: 25 percent. MS (M/z) ═ 344.9(M + H)⁺

Example 150

Analogously to example 70, step c, 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 the title compound was prepared. A white solid. Yield: 37 percent. MS (M/z) ═ 349.2(M + H)⁺

Example 151

The title compound was prepared in analogy to 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. A white solid. Yield: 53 percent. MS (M/z) ═ 363.0(M + H)⁺

Example 152

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-bromo-5- (trifluoromethyl) pyridine as starting materials. A white solid. Yield: and (4) quantifying.

MS(m/z)＝399.1(M+H)⁺

Example 153

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 (5-bromopyridin-3-yl) methanol as starting materials. A white solid. Yield: 75 percent. MS (M/z) ═ 361.2(M + H)⁺

Example 154

The title compound was prepared in analogy 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 percent. MS (M/z) ═ 346.1(M + H)⁺

Example 155

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

The title compound was prepared in analogy 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 percent. MS (M/z) ═ 357.3(M + H)⁺

Example 156

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-bromo-5-ethylpyridine as starting materials. A white solid. Yield: 96 percent. 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 in analogy 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 percent.

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 Pentane-2-yl) indolin-2-ones

The title compound was prepared in analogy to example 136 step b, using-bromo-3, 3-dimethyl-1- (2-methylpyrimidin-5-yl) indolin-2-one (example 157 step a) as starting material. Off-white solid. 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 in analogy to 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. Off-white solid. Yield in step 2: 14 percent.

MS m/z＝372.1(M+H)⁺

Biological assays and data

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

The compounds of formula I described reduce L-687, 414-induced hyperlocomotion. This is evaluated by: a computerized Digiscan 16 Animal Activity monitoring system (Digiscan 16 Animal Activity monitoring system) (Omnitech Electronics, Columbus, Ohio) was used to quantify locomotor Activity. Animals were kept in a 12h light/black cycle and the experiment was performed during the light phase. Each activity monitoring room consists of a Plexiglas box (41X 28 cm; W X L X H) with sawdust embedded in the floor, surrounded by invisible horizontal and vertical infrared sensor beams. The test chambers were separated by Plexiglas crosses, providing 20X 20cm of activity space for each mouse. The cage was connected to a Digiscan analyzer, which was connected to a computer that constantly collected the beam status information. The recording of the photo-beam interruption for individual animals was performed every 5 minutes for the duration of the experimental period and the sum of the first 6 periods was used as final parameter. At least 8 mice were used in each treatment group. The compounds were administered orally (p.o.) 15 minutes prior to subcutaneous injection (s.c. injection) of 50mg/kg of L-687, 414, or by intraperitoneal injection (i.p.) simultaneously with subcutaneous injection of 50mg/kg of L-687, 414. The mice were then transferred from their home cages to the recording room for a 15-min acclimation period, allowing free exploration of the new environment. Horizontal activity was then recorded for a period of 30-min. The% inhibition of L-687, 414-induced hyperlocomotion was calculated according to the following formula:

((vehicle (Veh) + L-687, 414 horizontal Activity-drug + L-687, 414 horizontal Activity)/vehicle + L-687, 414 horizontal Activity) x100

ID₅₀Values, defined as the dose of each compound that produced 50% inhibition of L-687, 414-induced hyperlocomotion, were calculated by linear regression analysis of dose-response data using an Excel-based computer fitting program.

Since the data do not assume a normal distribution, the group treated with the test compound was statistically compared with the control (vehicle-treated) group using the one-tailed Mann-Whitney U test. Statistically, the Mann-Whitney U test (also known as the Mann-Whitney-Wilcoxon (mww) or Wilcoxon rank-sum test) is a non-parametric statistical hypothesis test used to assess whether one of two samples of independent observations tends to have a greater value than the other. It is one of the best known non-parametric significance tests. The p-value gives the probability that the two groups differ significantly from each other and a value of < 0.05 is generally accepted as a criterion, which means that there is a > 95% chance that the two groups actually differ from each other. The p-values given in Table 1 are one-tailed, as only a decrease in motility is expected and tested (Mann, H.B., Whitney, D.R. (1947), "On a Test of leather one of Two Random variations is Stochastically Large the Other", Annals of chemical statics, 18(1), 50-60).

Measurement of adenosine transport Activity

To measure adenosine transport activity of 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 in complete DMEM/F12 medium supplemented with glutamax, 10% FBS and 10 μ g/ml puromycin on day 1. On day 2, the medium was aspirated and the cells were plated with uptake buffer (10mM Hepes-Tris, pH 7.4, containing 150mM NaCl, 1mM CaCl₂，2.5mM KCl，2.5mM MgSO₄10 mMD-glucose) (UB) was washed twice. For inhibition experiments, cells were then incubated with different concentrations of compound and 1% final concentration of DMSO at room temperature. Nonspecific uptake was defined in the presence of 10. mu. M S- (4-nitrobenzyl) -6-thioinosine (NBTI, Sigma Cat # N2255).

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

TABLE 1

Effect of Compounds of formula I on the inhibition of ENT1 and on L-687, 414-induced fast locomotion

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

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

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

The bar graphs of example compounds 9, 25, 48 and 53 at a dose of 5mg/kg are shown in figure 1. For comparison, the behavioral profile of the atypical antipsychotics clozapine, olanzapine and risperidone are shown in figure 2. The compounds of the present invention exhibit characteristics similar to those of atypical antipsychotics. The unclassified data were analyzed independently to determine the similarity of the example compounds to the active dose of known atypical antipsychotics. For this analysis, we used the recognition rate as a measure of the separability between two drugs, i.e., "distinguishability" of one drug from the other. A ratio equal to 50% (or 0.5) corresponds to zero distinguishability. Empirical data has shown that two drugs with threshold ratios above 70% for reliable separation, i.e. showing discrimination ratios below 70%, are considered similar, whereas discrimination ratios above 70% indicate that the two drugs are not similar. The following table shows the similarity analysis of selected compounds of the present invention to several atypical antipsychotics. In most cases, the example compounds show similarities to risperidone, clozapine, and olanzapine with a discrimination ratio ≦ 0.70.

Table 2:in thatSimilarity analysis of Compounds of formula I showing Effect (5mg/kg)

	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

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

FIG. 1: of compounds 9, 25, 49 and 53(5mg/kg)Characteristics-similar to those of atypical antipsychotics.

FIG. 2: method for treating various doses of the atypical antipsychotics clozapine, olanzapine and risperidoneAnd (5) characterizing.

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

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the manufacture of pharmaceutical preparations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance, however, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like may be used in the aqueous injection solutions of the water-soluble salts of the compounds of formula (I), but are generally not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

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

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

As also mentioned before, the use of a compound of formula (I) for the preparation of a medicament useful for the prevention and/or treatment of the above mentioned diseases is also an object of the present invention.

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

Preparation of pharmaceutical compositions comprising the compounds of the invention:

tablets of the following composition were manufactured in the usual manner:

manufacturing steps

1. Ingredients 1, 2, 3 and 4 were mixed and granulated with purified water.

2. The granules were dried at 50 ℃.

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

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

Capsules of the following composition were made:

manufacturing steps

1. Ingredients 1, 2 and 3 were mixed in a suitable mixer for 30 minutes.

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

3. Packaging into suitable capsule.

The compound of formula I, lactose and corn starch are first mixed in a stirrer and then in a mill. Returning the mixture to the mixer; talc was added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, for example hard gelatin capsules.

An injection of the following composition was made:

composition (I)	mg/injection.
		A compound of formula I	3
Polyethylene glycol 400	150
		Acetic acid	Adjusting the pH value to 5.0
Water for injection	Adjusted to 1.0ml

Manufacturing steps

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

Claims

1. A compound of the formula

Wherein

R¹Is lowLower alkyl, halogen, cyano or cycloalkyl;

Ar²is 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 benzo [ b ]]A thienyl group;

x is CH or N;

n is 1 or 2;

m is 1 or 2;

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

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

3. A compound of formula I according to claim 2, wherein Ar¹And Ar²Are all six membered heteroaryl groups containing one, two or three heteroatoms selected from N, S or O.

4. A compound of formula I according to claim 3, wherein the compound is:

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-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-bis (2-methylpyridin-4-yl) indolin-2-one

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

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

5. A compound of formula I according to claim 2, wherein Ar¹Is composed of one, two or threeA six membered heteroaryl group with a heteroatom selected from N, S or O, and Ar²Is a five membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O.

6. A compound of formula I according to claim 5, wherein the compound is:

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

1- (1H-imidazol-2-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

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

7. A compound of formula I according to claim 2, wherein Ar¹Is a five membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O, and Ar²Is a six membered heteroaryl group containing one, two or three heteroatoms selected from N, S or O.

8. A compound of formula I according to claim 7, wherein the compound is:

9. A compound of formula I according to claim 2, wherein Ar¹And Ar²Are all five membered heteroaryl groups containing one, two or three heteroatoms selected from N, S or O.

10. A compound of formula I according to claim 9, wherein the compound is:

11. A compound of formula I according to claim 2, wherein Ar²Is benzo [ b]Thienyl, and other substituents as defined inThe method as described in claim 1.

12. A compound of formula I according to claim 11, wherein the compound is:

13. A compound of formula I according to claim 1, wherein X is N and the other substituents are as described in claim 1.

14. A compound of formula I according to claim 13, wherein the compound is:

15. A combination of a compound of formula I according to any one of claims 1-14 with a known marketed antipsychotic, antidepressant, anxiolytic or mood stabilizer.

16. The combination according to claim 15, wherein the marketed antipsychotic drug is olanzapine (Zyprexa), clozapine (Clozaril), risperidone (Risperdal), aripiprazole (Abilify) or ziprasidone.

17. The combination according to claim 15, wherein the marketed antidepressant is citalopram (Celexa), escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), sertraline (Zoloft, Lustral), duloxetine (Cymbalta), milnacipran (Ixel, Savella), venlafaxine (Effexor) or Miltazapine (Remeron).

18. The combination according to claim 15, wherein the commercially available anxiolytic is alprazolam (Helex, Xanax, Xanor, Onax, Alprox, Restyl, Tafil, Paxal), chlordiazepoxide (Librium, Risolid, Elenium), clonazepam (Rivotril, Klonopin, iktorivi, Paxam), diazepam (antex, Apaurin, Apzepam, Apozepam, Hexalid, Pax, Stesolid, Stedon, Valium, Vival, valxona), estazolam (prom), izozopiclone (Lunesta), zaleplon (Sonata, Starnoc), zolpidem (Ambien, nyame, stilinnoct, galinolx, Zoldem, zolpidem), zolpidem (zanolitan), juvenin (r), or gabapentin (gabapentin ).

19. The combination according to claim 15, wherein the commercially available mood stabilizer is carbamazepine (Tegretol), lamotrigine (Lamictal), lithium (Eskalith, Lithane, Lithobid) and valproic acid (Depakote).

20. A process for the preparation of a compound of formula I according to any one of claims 1-14, which process comprises:

reacting a compound of the formula

With a compound of the formula

(R²)_n-Ar²-Y 8

To produce the compound of formula I

21. A compound according to any one of claims 1-14, when manufactured by a process according to claim 20.

22. A compound according to any one of claims 1-14 for use as therapeutically active substance.

23. A pharmaceutical composition comprising a compound according to any one of claims 1-14 and a therapeutically active carrier for use in the treatment of a CNS disease associated with: positive (psychosis) and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment resistant depression, anxiety disorders, alzheimer's disease, autism, parkinson's disease, chronic pain, borderline personality disorder, neurodegenerative disease, sleep disorders, chronic fatigue syndrome, stiffness, inflammatory disease, asthma, huntington's disease, ADHD, amyotrophic lateral sclerosis, epilepsy, effects in arthritis, autoimmune diseases, viral and fungal infections, cardiovascular disease, ophthalmological and inflammatory retinal disease and balance problems.

24. Compounds of formula I according to any one of claims 1-14

Wherein

R¹Is lower alkyl, halogen, cyano or cycloalkyl;

Ar²is 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^-) Or is benzo [ b ]]A thienyl group;

R²is hydrogen, lower alkyl, halogen, cyano, hydroxy-substituted lower alkyl, halogen-substituted lower alkyl, amino-substituted lower alkyl, alkoxy-substituted lower alkyl, lower alkyl-C (O) N (CH)₃)₂Or is cycloalkyl;

x is CH or N;

n is 1 or 2;

m is 1 or 2;

and pharmaceutically acceptable salts, racemic mixtures, or the corresponding enantiomers and/or optical isomers and/or stereoisomers thereof, for use in the treatment of CNS disorders associated with: positive (psychosis) and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment resistant depression, anxiety disorders, alzheimer's disease, autism, parkinson's disease, chronic pain, borderline personality disorder, neurodegenerative disease, sleep disorders, chronic fatigue syndrome, stiffness, inflammatory disease, asthma, huntington's disease, ADHD, amyotrophic lateral sclerosis, epilepsy, effects in arthritis, autoimmune diseases, viral and fungal infections, cardiovascular disease, ophthalmological and inflammatory retinal disease and balance problems.

25. Use of a compound of formula I according to any one of claims 1-14 for the preparation of a medicament for the treatment of CNS diseases associated with: positive (psychosis) and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment resistant depression, anxiety disorders, alzheimer's disease, autism, parkinson's disease, chronic pain, borderline personality disorder, neurodegenerative disease, sleep disorders, chronic fatigue syndrome, stiffness, inflammatory disease, asthma, huntington's disease, ADHD, amyotrophic lateral sclerosis, epilepsy, effects in arthritis, autoimmune diseases, viral and fungal infections, cardiovascular disease, ophthalmological and inflammatory retinal disease and balance problems.

26. A compound according to any one of claims 1-14 for use in the treatment of a CNS disease associated with: positive (psychosis) and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment resistant depression, anxiety disorders, alzheimer's disease, autism, parkinson's disease, chronic pain, borderline personality disorder, neurodegenerative disease, sleep disorders, chronic fatigue syndrome, stiffness, inflammatory disease, asthma, huntington's disease, ADHD, amyotrophic lateral sclerosis, epilepsy, effects in arthritis, autoimmune diseases, viral and fungal infections, cardiovascular disease, ophthalmological and inflammatory retinal disease and balance problems.

27. A method for the treatment of CNS diseases related to positive (psychosis) and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment resistant depression, anxiety disorders, alzheimer's disease, autism, parkinson's disease, chronic pain, borderline personality disorder, neurodegenerative disease, sleep disorders, chronic fatigue syndrome, stiffness, inflammatory disease, asthma, huntington's disease, ADHD, amyotrophic lateral sclerosis, epilepsy, effects in arthritis, autoimmune disease, viral and fungal infections, cardiovascular diseases, ophthalmic and inflammatory retinal diseases and balance problems, which method comprises administering an effective amount of a compound according to any one of claims 1-14.

28. The invention as described above.