HK1181651A - Combinations comprising atypical antipsychotics and taar1 agonists - Google Patents

Abstract

The present invention relates to a pharmaceutical combination for the treatment of schizophrenia and acute manic episodes associated with bipolar disorders, comprising a compound which is active on a trace amine-associated receptor 1 (TAAR1 agonist) and an antipsychotic drug. It has surprisingly been found that such a combination can reduce metabolic side effects which appear if using an antipsychotic drug alone.

Description

Combinations comprising an atypical antipsychotic and a TAAR1 agonist

The present invention relates to a pharmaceutical combination for the treatment of schizophrenia and acute manic episodes associated with bipolar disorder comprising a compound active on trace amine associated receptor1 (TAAR1 agonist) and an antipsychotic drug. It has surprisingly been found that such a combination is capable of reducing the metabolic side effects which occur when antipsychotic drugs are used alone.

Schizophrenia is a serious chronic psychotic disorder, with an estimated prevalence in the range of 1.4 to 4.6/1000 population.

Schizophrenic disorders and depression are caused by genetic and environmental factors, which for schizophrenia include possible neurodevelopmental abnormalities in grey and white matter structures. On the basis of the symptomatic phenomenon of both diseases, disturbances in monoaminergic neurotransmission (e.g. 5-hydroxytryptamine, epinephrine and norepinephrine) have been proposed.

These pathways are widely present in the CNS and thus potentially can affect multiple areas involved in emotional processing, cognition and behavior. Until recently, the excess dopamine hypothesis was the main pathophysiological theory of schizophrenia, largely based on the efficacy of D2 antagonists in controlling the acute exacerbations of this disease.

Symptoms of schizophrenia, typically occurring during adolescence or early adulthood, are often classified as positive, negative or cognitive. Positive symptoms include hallucinations, delusions, and severe confusion. Negative symptoms are a group of deficits that include poverty of emotion, apathy, poverty of speech, loss of interest, and social withdrawal. Cognitive symptoms, such as deficits in attention and working memory, are prominent features of the disease and have been identified as effective predictors of social outcome.

Current atypical antipsychotics, in addition to being associated with significant side effects, are primarily effective in managing positive symptoms with minimal effect on negative symptoms and cognitive function. The efficacy of cognitive symptoms and improvement of negative symptoms are the most unmet needs in schizophrenia.

The first generation of drugs were effective but associated with significant extrapyramidal symptom incidence, while the second generation (atypical) antipsychotics appear to have lower extrapyramidal side effect incidence and may be more effective in treating cognition, but increase the incidence and severity of metabolic syndrome.

A 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 clozapine (clozapine tablet (Clozaril)), risperidone (Risperdal)), aripiprazole (Abilify), and ziprasidone (Geodon). Olanzapine binds to alpha-1, dopamine, histamine, muscarinic and 5-hydroxytryptamine type 2 (5-HT2) receptors.

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

Treatment with antipsychotics, such as olanzapine, can result in serious side effects. The food and drug administration requires that all atypical antipsychotics include warnings as to the risk of developing hyperglycemia and diabetes, both of which are factors in the metabolic syndrome. These effects may be associated with the ability of the drug to induce weight gain. Adverse effects of myocardial metabolism, such as weight gain, obesity, hypertension, and lipid and carbohydrate abnormalities, are particularly problematic in the developmental process, as they predict adult obesity, metabolic syndrome, cardiovascular morbidity, and malignancy, especially if used in children and adolescents.

With olanzapine, and other antipsychotics of its class, there may be an increased risk of elevated blood glucose levels and diabetes.

According to studies in JAMA during the period of 10 months 28 days (JAMA, 2009, day 10 months 28, 302(16), 1765-73), many pediatric and adolescent patients receiving second generation antipsychotic drugs experience significant weight gain, along with different adverse effects on cholesterol and triglyceride levels and other metabolic measurements.

The authors state that "increasingly, the myocardial metabolism of second generation antipsychotic drugs has attracted attention. Adverse effects of myocardial metabolism, such as age-inappropriate weight gain, obesity, hypertension, and lipid and carbohydrate abnormalities, are particularly problematic in the developmental process, as they predict adult obesity, metabolic syndrome, cardiovascular morbidity, and malignancy ". Based on the background information in this paper, the myocardial metabolism of these drugs has not been fully studied in children and adolescents who have not previously received them.

Christoph u. correll, MD, Zucker Hillside Hospital (hilsen Hospital), North Shore-Long Island Jewish health system (North Shore-Long Island jew healthcare system), Glen Oaks, and The Feinstein Institute for medical Research, new york manhattan, and The same have conducted studies of weight and metabolic changes in a group of 272 pediatric patients (aged 4-19 years) who had not previously received an antipsychotic. Patients had a spectrum of emotions (47.8%), a spectrum of schizophrenia (30.1%) and a spectrum of disruptive or aggressive behavior (22.1%) disorders. 15 patients who were excluded from participation or not supporting drug treatment were used as a comparison group. The patient was treated with the antipsychotic drug aripiprazole, olanzapine, quetiapine, or risperidone for 12 weeks.

After the mid-10.8 weeks of treatment, there was an average increase of 8.5kg (18.7lbs) using olanzapine (n ═ 45), 6.1kg (13.4lbs) using quetiapine (n ═ 36), 5.3kg (11.7lbs) using risperidone (n ═ 135), and 4.4kg (9.7lbs) using aripiprazole (n ═ 41), compared to the minimum weight change of 0.2kg (0.4lbs) in the untreated control group (n ═ 15). The authors write that each antipsychotic drug is associated with a significant increase in fat mass and waist circumference. "in general, 10% to 36% of patients transition to an overweight or obese state within 11 weeks. "

Researchers have also found that during the study, with olanzapine and quetiapine, statistical significance was achieved for adverse changes in total cholesterol, triglycerides, non-High Density Lipoprotein (HDL) cholesterol, and the ratio of triglycerides to HDL cholesterol. "with risperidone, triglyceride levels were significantly increased. The change from baseline to endpoint of metabolism was not significant with aripiprazole or in the untreated control group. Patients receiving quetiapine have a moderately high incidence of hyperglycemia and metabolic syndrome, while patients receiving olanzapine experience the highest incidence. "

The authors noted these results as being noteworthy in that they included fat mass and waist circumference, which were associated with metabolic syndrome in adults treated with antipsychotic drugs and heart disease in the general population. "furthermore, abnormal child body weight and metabolic state adversely affect adult cardiovascular outcomes via these risk factors or the persistence of independent or accelerated mechanisms. "

"our results, along with data from the first episode study, suggest that guidelines for antipsychotic exposure in susceptible pediatric and adolescent patients who first received an antipsychotic should consider more frequent (e.g., twice a year) monitoring of myocardial metabolism after the first 3 months of treatment. Finally, in view of poor physical health outcomes and poor metabolic monitoring in severe psychiatric disorders, the benefits of second generation antipsychotics must be balanced against their myocardial metabolic risk by careful assessment of their applicable indications, consideration of low risk alternatives and proactive adverse monitoring and management, the authors speculate as such.

In the collaborative review, Christopher k. varley, MD and jonmtcclelan, MD writing, of Seattle Children hospital in Seattle, Washington (Seattle Children's hospital, Seattle, Washington): these findings suggest that there are other factors to consider regarding the use of atypical antipsychotics in children and adolescents.

These drugs may be life-saving for young adults with severe psychosis (schizophrenia, as typically defined for bipolar disorder, or the severe attacks associated with autism). However, given the risk of weight gain and the long-term risk of cardiovascular and metabolic problems, the widespread and increasing use of atypical antipsychotics in children and adolescents should be reconsidered. "

There is a need for new therapies with improved safety and tolerability profiles relative to current atypical antipsychotics. For example, new treatments should not be associated with those side effects or adverse reactions described above.

It has now surprisingly been found that the combination of an antipsychotic drug with trace amounts of an amine-associated receptor1 agonist has the potential to reduce the incidence of metabolic syndrome and positive symptoms in schizophrenia as well as acute manic episodes associated with bipolar disorder.

Metabolic syndrome is a combination of medical disorders that increase the risk of developing diabetes and cardiovascular disease. Risk factors include, for example, abdominal obesity (excess adipose tissue in and near the abdomen), dyslipidemia, elevated blood pressure, insulin resistance, or glucose intolerance.

Trace amines (p-tyramine, β -Phenylethylamine (PEA), octopamine, and tryptamine) are present throughout the CNS, are closely juxtaposed to the monoaminergic pathway, and are much lower at endogenous levels than these neurotransmitters. Their rarity is due in part to their high turnover rate as a good substrate for MAO A/B. Trace amines are structurally related, co-localized and released with typical biogenic amine neurotransmitters. Indicating that they are neuromodulators of typical neurotransmitters, such as dopamine, 5-hydroxytryptamine and norepinephrine, the levels of which are targets of all known antidepressants and most antipsychotics currently on the market or in the clinic. Abnormalities in trace amine physiology have long been associated with schizophrenia and mood disorders. In schizophrenia, increased urinary PEA (so-called endogenous amphetamine) levels have been proposed, as well as alterations in tryptamine and para-tyramine metabolism, including enzymes involved in the synthetic and catabolic pathways of these molecules.

Thus, the identification of specific receptors for trace amines may lead to the development of specific drugs targeting this novel neuromodulator system, which have clinical applications in conditions such as schizophrenia, bipolar disorder and depression.

Recently, a family of G-protein coupled receptors has been identified and named as Trace Amine Associated Receptors (TAARs), of which TAAR1 is the best characterized and primary target of endogenous trace amines. TAAR1 is expressed in brain structures associated with psychiatric disorders, particularly in critical areas where modulation of dopamine (ventral tegmental area) and 5-hydroxytryptamine (nucleus ventriculi) occurs, but also in the amygdala, hypothalamus, nucleus accumbens, olfactory cortex and hypothalamus. TAAR1 may be a novel target for antipsychotics with high differentiation potential, exploring a fundamental novel mechanism of action based on the effects of modulation of dopaminergic and glutamatergic neurotransmission. Thus, even in the absence of trace amine deficiency, it can be predicted that neuromodulatory effects on monoaminergic pathways lead to an improvement in schizophrenia. Furthermore, the TAAR gene closely corresponds to one of the major genetic susceptibility loci of schizophrenia, SCZD 5.

Based on the above, TAAR1 agonists should be effective agents for the treatment of psychiatric disorders, both directly and indirectly by affecting the monoaminergic pathway. TAAR1 agonists that have been extensively studied in non-clinical trials are indicative of antipsychotic, pre-cognitive, antidepressant and anti-addictive activity, leading to the belief that: it may constitute a novel class of drugs for the treatment of schizophrenia and mood disorders. Based on this study, TAAR1 agonists may have the potential to treat schizophrenic patients with better efficacy, including alleviation of negative and cognitive symptoms currently untreatable with existing therapies, and possibly reduction of substance abuse in these patients. Finally, these drugs may provide significant benefits to schizophrenic patients, allowing control of positive symptoms without increasing metabolic syndrome, considering their beneficial metabolic, anti-diabetic effects.

Compounds have been selected from a group of TAAR1 agonists, which are described in WO08/092785, WO08/098857, WO2010/010014 and PCT/EP2010/070045 and have the following structures:

wherein the content of the first and second substances,

R¹is hydrogen, deuterium, tritium, C_1-7Alkyl, hydroxy, C_1-7Alkoxy, C substituted by halogen_1-7Alkyl, C substituted by halogen_1-7-alkoxy, halogen, phenyl optionally substituted by halogen, or is phenoxy, benzyl, benzyloxy, -COO-C_1-7-alkyl, -O- (CH)₂)_o-O-C_1-7-alkyl, NH-cycloalkyl, cycloalkyl or tetrahydropyran-4-yloxy, wherein the substituents may be the same or different for n > 1;

x is a bond, -CHR-, -CHRCHR' -, -OCH₂-，-NRCHR’，-OCHRCHR’，-CH₂OCHR-，-CH₂CH₂CH₂-，-SCH₂-，-S(O)₂CH₂-，-CH₂SCH₂-，-CH₂N(R)CH₂-, -cycloalkyl-CH₂-or SiRR' -CH₂-；

R/R' may be independently of one another hydrogen, C_1-7Alkyl or C substituted by halogen_1-7-an alkyl group;

R²is hydrogen, phenyl or C_1-7-an alkyl group;

y is phenyl, naphthyl, thienyl, pyridyl, cycloalkyl, 1, 2, 3, 4-tetrahydro-naphthalen-2-yl, 2, 3-dihydrobenzo [1, 4] dioxin-6-yl or benzo [1, 3] dioxol-5-yl;

n is 0, 1, 2 or 3;

o is 2 or 3;

or a pharmaceutically suitable acid addition salt thereof,

more specifically, the TAAR 1receptor agonist is of the structure:

wherein the content of the first and second substances,

R¹is hydrogen, C_1-7Alkyl, hydroxy, C_1-7Alkoxy, C substituted by halogen_1-7Alkyl, C substituted by halogen_1-7-alkoxy or halogen, wherein for n ═ 2 the substituents may be the same or different;

x is a bond, -NRCHR ', -CHRCHR ' or-OCHRCHR ';

R/R' may be independently of one another hydrogen, C_1-7-an alkyl group;

n is 1 or 2;

or is a compound of formula II

Wherein the content of the first and second substances,

r is hydrogen or C_1-7-an alkyl group;

R¹is- (CH)₂)_n-(O)_o-heterocycloalkyl, optionally substituted by C_1-7-alkyl, hydroxy, halogen or by- (CH)₂)_p-aryl substitution;

n is 0, 1 or 2;

o is 0 or 1;

p is 0, 1 or 2;

R²is cycloalkyl, heterocycloalkyl, or is aryl or heteroaryl, wherein the aromatic ring is optionally substituted with one or two substituents selected from: c_1-7Alkyl, halogen, heteroaryl, CF₃，OCF₃，OCH₂CF₃，C_1-7-alkoxy, CH₂-C_1-7-alkoxy radical, C_2-7-alkynyl or cyano;

x is a bond, -NR' -, -CH₂NH-，-CHR”-，-(CH₂)_q-O-or- (CH)₂)₂-；

R' is hydrogen or C_1-7-an alkyl group,

r' is hydrogen, C_1-7-alkyl radical, C_1-7-an alkoxy group,

q is 0, 1 or 2;

or a pharmaceutically suitable acid addition salt thereof,

or more specifically a compound of formula II-1:

wherein the content of the first and second substances,

r is hydrogen;

R¹is pyrrolidinyl;

R²is aryl or heteroaryl, wherein the aromatic ring is optionally substituted with halogen;

x is a bond or-NR' -;

r' is hydrogen or C_1-7-an alkyl group,

or a pharmaceutically suitable acid addition salt thereof.

As used herein, the term "C_1-7-alkoxy "denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom.

As used herein, the term "C substituted with halogen_1-7-alkyl "denotes an alkyl group as defined above in which at least one hydrogen atom is replaced by halogen, e.g. CF₃，CHF₂，CH₂F，CH₂CF₃，CH₂CH₂CF₃，CH₂CF₂CF₃And the like.

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

The term "cycloalkyl" is an alkylene ring containing from 3 to 6 carbon ring atoms.

The term "alkynyl" represents a straight-chain or branched hydrocarbon residue containing a triple bond and up to 7, preferably up to 4, carbon atoms, such as, for example, ethynyl or 2-propynyl.

The term "aryl" relates to an aromatic carbocyclic ring, such as a benzene ring or a naphthalene ring, preferably a benzene ring.

The term "heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 9-to 10-membered bicyclic ring which may contain 1, 2 or 3 heteroatoms selected from nitrogen, 20 oxygen and/or sulfur, such as pyridyl, pyrazolyl, pyrimidinyl, benzimidazolyl, quinolinyl and isoquinolinyl.

The term "heterocycloalkyl" refers to a non-aromatic 5 to 6 membered monocyclic ring, which may contain 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and/or sulfur, such as piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl or thiomorpholinyl.

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.

Specific compounds which have been used in the following examples are as follows:

s1 ═ 4- ((S) -2-phenyl-butyl) -4, 5-dihydro-Azol-2-ylamines

S2 ═ 4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro-Azol-2-ylamines

S3 ═ 4- (4-chloro-2-trifluoromethyl-phenyl) -4, 5-dihydro-Azol-2-ylamines

S4 ═ 4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Azol-2-ylamines

S5 ═ 3- [ (S) -1- ((S) -2-amino-4, 5-dihydro-Azol-4-ylmethyl) -propoxy]-phenol

S6 ═ 5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

S7 ═ 4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

S8 ═ 1- (5-chloro-pyridin-2-yl) -3- (4-pyrrolidin-3-yl-phenyl) urea

S9 ═ S) -4- [ (S) -1- (4-fluoro-phenyl) -ethoxymethyl]-4, 5-dihydro-Azol-2-ylamines

S10 ═ 5-chloro-pyrimidine-2-carboxylic acid {4- [2- ((S) -2-amino-4, 5-dihydro-Oxazol-4-yl) -ethyl]-phenyl } -amides

S11 ═ N- {4- [2- ((S) -2-amino-4, 5-dihydro-Oxazol-4-yl) -ethyl]-phenyl } -4-chloro-benzamide

S12 ═ 2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

S13 ═ S-N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

S14 ═ S-N- (4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide

S15 ═ S) -1- (4-fluorobenzyl) -3- (4- (morpholin-2-yl) phenyl) urea

S16 ═ S) -1- (3-cyanophenyl) -3- (4- (morpholin-2-yl) phenyl) urea and

s17 ═ S) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide.

It has surprisingly been shown that the combination of an antipsychotic drug, in particular olanzapine, with the above mentioned TAAR1 agonist can reduce some undesired metabolic side effects.

The purpose of the invention is:

-a combination of an atypical antipsychotic and a TAAR1 agonist, wherein the preferred atypical antipsychotic is olanzapine and the preferred TAAR1 agonist is a compound of formula I, I-1, II or II-1. More specifically, the TAAR1 agonist is a compound selected from S1 to S17.

Novel compounds S2 encompassed by formula I or I-1 which are (S) -4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro-Oxazol-2-ylamine.

-a combination comprising olanzapine and a TAAR1 agonist for use in the treatment of schizophrenia and manic episodes associated with bipolar disorder at a reduced incidence of metabolic syndrome, wherein said reduced incidence of metabolic syndrome results from having an anti-diabetic efficacy in reducing blood glucose excursions, fat mass and body weight.

-use of a combination comprising olanzapine and a TAAR1 agonist for the treatment of schizophrenia and manic episodes associated with bipolar disorder at a reduced incidence of metabolic syndrome, wherein said reduced incidence of metabolic syndrome results from having an anti-diabetic efficacy of reducing blood glucose excursions, fat mass and body weight.

-use of a combination comprising olanzapine and a TAAR1 agonist for the manufacture of a medicament for the treatment of schizophrenia and manic episodes associated with bipolar disorder at a reduced incidence of metabolic syndrome, wherein said reduced incidence of metabolic syndrome results from having an anti-diabetic efficacy of reducing blood glucose excursion, fat mass and body weight.

-a method for the treatment of schizophrenia and manic episodes associated with bipolar disorder at a reduced incidence of metabolic syndrome resulting from an anti-diabetic efficacy with reduced glycemic volatility, fat mass and waist (girth), comprising administering to a person in need of such treatment an effective amount of a combination comprising an atypical antipsychotic and a TAAR1 agonist.

-a method for the treatment of schizophrenia and manic episodes associated with bipolar disorder at a reduced incidence of metabolic syndrome, wherein said reduced incidence of metabolic syndrome results from having an anti-diabetic efficacy of reducing glycemic volatility, fat mass and waist, wherein the atypical antipsychotic is olanzapine and the TAAR1 agonist is as described in formula I, I-1, II and II-1.

-a pharmaceutical composition comprising an atypical antipsychotic in combination with a TAAR1 agonist as described in formula I, I-1, II and II-1, together with pharmaceutically acceptable excipients for the treatment of schizophrenia and manic episodes associated with bipolar disorder at a reduced incidence of metabolic syndrome, wherein said reduced incidence of metabolic syndrome is caused by an anti-diabetic efficacy with reduced glycemic volatility, fat mass and body weight.

The TAAR1 agonist may be prepared as follows:

example S1

(S) -4- ((S) -2-phenyl-butyl) -4, 5-dihydro-Azol-2-ylamines

a) (R) -1-iodomethyl-propyl) -benzene

To a solution of triphenylphosphine (15.4g, 59mmol) and imidazole (3.99g, 59mmol) in dichloromethane (150ml) was added iodine (14.9g, 50mmol) portionwise at room temperature at a rate that did not raise the temperature of the reaction mixture above 30 ℃. To the mixture was then added a solution of (R) -2-phenyl-butan-1-ol (7.34g, 41mmol, CAS16460-75-6) in dichloromethane (50ml) and the mixture was then stirred at room temperature overnight. Then, the user can use the device to perform the operation,the mixture was concentrated in vacuo and the residue was resuspended in ether, and the resulting crystals were collected by filtration. The filtrate was concentrated in vacuo and the residue triturated in heptane. The resulting crystals were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO)₂heptane/EtOAc) to give a colorless oil, (6.38g, 60%).

b) (2R, 5S) -2-isopropyl-3, 6-dimethoxy-5- ((S) -2-phenyl-butyl) -2, 5-dihydro-pyrazine

A solution of (2R) - (-) -2, 5-dihydro-3, 6-dimethoxy-2-isopropylpyrazine (4.25g, 23.1mmol) in tetrahydrofuran (30ml) was cooled to-78 deg.C, then n-butyllithium (1.6M in hexane, 15.1ml, 24.2mmol) was added and the mixture was stirred for 1 hour. A solution of ((R) -1-iodomethyl-propyl) -benzene (6.30g, 24.2mmol) in tetrahydrofuran (30ml) was added dropwise over 30 minutes and the mixture was stirred overnight while allowing to slowly warm from-70 ℃ to room temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the mixture was extracted with ether. The organic layer was separated, washed with saturated brine, and then with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂heptane/EtOAc) to give a light yellow oil (4.69g, 64%); ms (isp): 317.0([ M + H)]⁺)。

c) (2S, 4S) -2-amino-4-phenyl-hexanoic acid methyl ester

To a solution of trifluoroacetic acid (3.4ml) in water (440ml) was added dropwise over 15 minutes a solution of (2R, 5S) -2-isopropyl-3, 6-dimethoxy-5- ((S) -2-phenyl-butyl) -2, 5-dihydro-pyrazine (4.69g, 14.8mmol) in acetonitrile (75 ml). The mixture was stirred at room temperature overnight, then made basic by adding saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate. The phases were separated and the organic phase was washed successively with water and with saturated brine, then with Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂EtOAc/heptane) to give a yellow oil (2.78g, 85%); ms (isp): 222.1([ M + H)]⁺)。

d) (2S, 4S) -2-amino-4-phenyl-hex-1-ol

To a suspension of lithium aluminium hydride (121mg, 3.18mmol) in tetrahydrofuran (8ml) was added a solution of methyl (2S, 4S) -2-amino-4-phenyl-hexanoate (320mg, 1.45mmol) in tetrahydrofuran (10ml) and the mixture was stirred for 16 h. The reaction was quenched by dropwise addition of ethyl acetate, then acidified to pH5 by addition of hydrochloric acid, and then made basic by addition of saturated aqueous sodium bicarbonate. The mixture was taken up in ethyl acetate/tetrahydrofuran (1: 1), the phases were separated and the organic phase was washed successively with water and with saturated brine. Then the organic phase is treated with Na₂SO₄Dried and concentrated in vacuo. The residue was chromatographed (column: from Separtis)Flash-NH₂(ii) a Eluent: dichloromethane/MeOH) gave a yellow oil, (116mg, 42%); ms (isp): 194.4([ M + H)]⁺)。

e) (S) -4- ((S) -2-phenyl-butyl) -4, 5-dihydro- Azol-2-ylamines

To a stirred, cooled (0 ℃) solution of (2S, 4S) -2-amino-4-phenyl-hex-1-ol (270mg, 1.40mmol) and sodium acetate (229mg, 2.70mmol) in methanol (20ml) was added dropwise a solution of cyanogen bromide (180mg, 1.68mmol) in methanol (2ml) over 10 minutes. The mixture was then allowed to warm to room temperature and stirring was continued for 16 hours. The mixture was concentrated in vacuo, and the residue was taken up in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate and with saturated brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed (column: from Se)Of partisFlash-NH₂(ii) a Eluent: heptane/EtOAc/MeOH) to afford a light yellow solid. Ms (isp): 219.3([ M + H)]⁺)。

S2

(S) -4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro-Azol-2-ylamines

a) (RS) -amino- (3-fluoro-2-methyl-phenyl) -acetonitrile

To a stirred solution of 3-fluoro-2-methyl-benzaldehyde (5.0g) in methanol (20ml) were added successively an ammonia solution (40.5ml, 7M solution in methanol) and tetraisopropyl orthotitanate (12.6ml), and the resulting mixture was stirred at room temperature for 1 hour. Trimethylsilyl cyanide (4.69ml) was then added dropwise and stirring was continued overnight at room temperature. The reaction mixture was poured onto ice water (400ml), and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with brine, then dried over sodium sulfate and concentrated in vacuo to give (RS) -amino- (3-fluoro-2-methyl-phenyl) -acetonitrile (5.90g, quant.)) as an orange solid.¹H NMRδ(CDCl₃，300MHz)：7.39(1H，d，J＝7.3Hz)，7.31(1H，m)，7.17(1H，dd，J＝9.6&9.6Hz)，5.16(1H，t，J＝7.8Hz)，5.16(1H，d，J＝7.8Hz)，2.26(1H，d，J＝2.1Hz)。

b) (RS) -amino- (3-fluoro-2-methyl-phenyl) -acetic acid

(RS) -amino- (3-fluoro-2-methyl-phenyl) -acetonitrile (5.89g) was suspended in 5N aqueous hydrochloric acid (40ml) and the mixture was added under refluxThe heat was applied for 18 hours. The mixture was then extracted with ethyl acetate and the aqueous phase was concentrated in vacuo. The residue was resuspended in isopropanol and again concentrated in vacuo. The residue was put into water and neutralized by dropwise addition of a 1N NaOH aqueous solution, whereby white crystals were slowly formed. The crystals were collected by filtration and dried in vacuo at 50 ℃ to give (RS) -amino- (3-fluoro-2-methyl-phenyl) -acetic acid (7.1g, quantitative) as an off-white solid. Ms (isp): 184.1([ M + H)]⁺)。

c) (RS) -2-amino-2- (3-fluoro-2-methyl-phenyl) -ethanol

To a stirred solution of lithium borohydride in THF (48.9ml, 2M solution) under an argon atmosphere was added dropwise chlorotrimethylsilane (25.0 ml). The resulting suspension was cooled to 0 ℃ and (RS) -amino- (3-fluoro-2-methyl-phenyl) -acetic acid (7.1g) was added in portions, whereby the temperature of the reaction mixture briefly rose to 45 ℃. The ice bath was removed and stirring was then continued at room temperature for 90 minutes. The mixture was quenched by dropwise addition of methanol (20ml) and then concentrated in vacuo. The residue was suspended in ethyl acetate and washed with 2N aqueous NaOH. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give (RS) -2-amino-2- (3-fluoro-2-methyl-phenyl) -ethanol (1.83g, 28%) as a pale yellow solid. Ms (isp): 170.3([ M + H)]⁺)。

d) (RS) -4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro- Azol-2-ylamines

To a stirred, cooled (0 ℃) solution of (RS) -2-amino-2- (3-fluoro-2-methyl-phenyl) -ethanol (1.82g) and sodium acetate (1.72g) in methanol (17ml) was added dropwise a solution of cyanogen bromide (1.18g) in methanol (8ml) over 10 minutes. The mixture was then stirred at 0 ℃ for 1 hour, then allowed to warm to room temperature and continued stirring for 2 hoursThen (c) is performed. The mixture was concentrated in vacuo and the residue was resuspended in water and made basic by the addition of 1M aqueous sodium hydroxide. The mixture was then extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: dichloromethane/methanol) to give (RS) -4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro-one as a pale yellow solidOxazol-2-ylamine (0.85g, 41%). Ms (isp): 195.3([ M + H)]⁺)。

e) (+) - (S) -4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro- Oxazol-2-ylamine and (-) - (R) -4- (3-fluoro-2- Methyl-phenyl) -4, 5-dihydro- Azol-2-ylamines

Separation of (RS) -4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro-Oxazol-2-ylamine to give (-) - (R) -4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro-Azol-2-ylamine (white solid; MS (ISP) 195.3([ M + H))]⁺) And (+) - (S) -4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro-Azol-2-ylamine (white solid; MS (ISP) 195.3([ M + H))]⁺))。

S3

(+) - (S) -4- (4-chloro-2-trifluoromethyl-phenyl) -4, 5-dihydro-Azol-2-ylamines

a) (RS) -4- (4-chloro-2-trifluoromethyl-phenyl) -4, 5-dihydro- Azol-2-ylamines

This is prepared analogously to example S2 (steps a-d) starting from 4-chloro-2-trifluoromethyl-benzaldehyde instead of 3-fluoro-2-methyl-benzaldehyde. A white solid. Ms (isp): 267.1([{³⁷Cl}M+H]⁺)，265.0([{³⁵Cl}M+H]⁺)。

b) (+) - (S) -4- (4-chloro-2-trifluoromethyl-phenyl) -4, 5-dihydro- Azol-2-ylamine and (-) - (R) -4- (4-chloro) -2-trifluoromethyl-phenyl) -4, 5-dihydro- Azol-2-ylamines

Separation of (RS) -4- (4-chloro-2-trifluoromethyl-phenyl) -4, 5-dihydro-Oxazol-2-ylamine to give (+) - (S) -4- (4-chloro-2-trifluoromethyl-phenyl) as a first fraction) -4, 5-dihydro-Azol-2-ylamine (white solid; MS (ISP) 267.1 ([. fwdarw.) ]³⁷Cl}M+H]⁺)，265.0([{³⁵Cl}M+H]⁺) And (-) - (R) -4- (4-chloro-2-trifluoromethyl-phenyl) -4, 5-dihydro-Azol-2-ylamine (white solid; MS (ISP) 267.1 ([. fwdarw.) ]³⁷Cl}M+H]⁺)，265.0([{³⁵Cl}M+H]⁺))。

S4

(S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Azol-2-ylamines

a) (S) -4- [ (ethyl-phenyl-amino) -methyl]-2, 2-dimethyl- Oxazolidine-3-carboxylic acid tert-butyl ester

Under argon atmosphere at room temperature to (R) - (+) -4-formyl-2, 2-dimethyl-3-Adding molecular sieve into solution of oxazolidinecarboxylic acid tert-butyl ester (681mg, CAS95715-87-0) in 1, 2-dichloroethane (10ml)(1.5g) and N-ethylaniline (0.25 ml). After stirring at room temperature for 15 minutes, a portion of triacetoxy was addedSodium borohydride (1.68g), followed by addition of acetic acid (5 drops) and stirring continued at room temperature overnight. The mixture was carefully added with 10% KHCO₃(15ml) quench. The two-phase mixture was stirred at room temperature for 20 minutes and filtered. Aqueous phase of filtrate with CH₂Cl₂And (4) back extraction. The combined organic matter is treated with H₂O and brine, MgSO₄Dried, filtered and concentrated in vacuo. The crude product is purified by column chromatography (SiO)₂(ii) a Gradient: cyclohexane- > cyclohexane/EtOAc 4: 1) to give (S) -4- [ (ethyl-phenyl-amino) -methyl-l as an orange viscous oil]-2, 2-dimethyl-Oxazolidine-3-carboxylic acid tert-butyl ester (469mg, 57%). Ms (isp): 335.5([ M + H)]⁺)

b) (S) -2-amino-3- (ethyl-phenyl-amino) -propan-1-ol

Under argon atmosphere at room temperature to (S) -4- [ (ethyl-phenyl-amino) -methyl]-2, 2-dimethyl-Oxazolidine-3-carboxylic acid tert-butyl ester (462mg) in diTo a stirred solution in an alkane (5.85ml) was added HCl solution (4M in bis)In an alkane; 4.14 ml). The mixture was stirred at room temperature overnight and concentrated. The residue was taken up in EtOAc and washed with 10% aqueous potassium bicarbonate. The aqueous layer was back extracted with EtOAc. The combined organics were washed with water, then brine, and MgSO₄Dried and concentrated in vacuo. The crude product is purified by column chromatography (SPE flash NH2 column, aminopropyl-functionalized silica; CH (CH)₂Cl₂MeOH 9: 1) to give (S) -2-amino-3- (ethyl-phenyl-amino) -propan-1-ol as a light brown viscous oil (133mg, 62%). Ms (isp): 195.1([ M + H)]⁺)

c) (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro- Azol-2-ylamines

To a solution of (S) -2-amino-3- (ethyl-phenyl-amino) -propan-1-ol (128mg) in THF (5ml) under an argon atmosphere at room temperature were added potassium carbonate (182mg) and a solution of cyanogen bromide (140mg) in THF (5 ml). Stirring was continued at room temperature for 21 hours. The mixture (off-white suspension) was diluted with EtOAc and washed with H₂And O washing. The aqueous phase was back-extracted with EtOAc. The combined organics were washed with brine, over MgSO₄Dried, filtered and concentrated in vacuo. The crude product is purified by column chromatography (SPE flash NH2 column, aminopropyl-functionalized silica; gradient: CH (CH)₂Cl₂-＞CH₂Cl₂MeOH 9: 1) to give (S) -4- [ (ethyl-phenyl-amino) -methyl) as an off-white solid]-1, 5-dihydro-Oxazol-2-ylamine (108mg, 75%). Ms (isp): 220.4([ M + H)]⁺)

S5

3- [ (S) -1- ((S) -2-amino-4, 5-dihydro-Azol-4-ylmethyl) -propoxy]-phenol

a) (S) -4- ((R) -2-hydroxy-butyl) -2, 2-dimethyl- Oxazolidine-3-carboxylic acid tert-butyl ester and (S) -4- ((S) -2- Hydroxy-butyl) -2, 2-dimethyl- Oxazolidine-3-carboxylic acid tert-butyl ester

Under argon atmosphere at room temperature to (S) -2, 2-dimethyl-4- (2-oxo-ethyl) -A solution of ethyl magnesium bromide in diethyl ether (42.6ml of a 3M solution) was added dropwise to a stirred solution of tert-butyl oxazolidine-3-carboxylate (15.5g of CAS147959-19-1) in anhydrous diethyl ether (100ml) and stirring was continued for 1 hour. The reaction mixture was then quenched by careful addition of water (10ml) and the mixture was filtered through decalite. The filtrate was washed successively with water and with saturated brine, then the organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc 100: 0 → 50: 50) to obtain (S) -4- ((R) -2-hydroxy-butyl) -2, 2-dimethyl-Tert-butyl oxazolidine-3-carboxylate (7.30g) and (S) -4- ((S) -2-hydroxy-butyl) -2, 2-dimethyl-T-butyl oxazolidine-3-carboxylate (6.44g), a colorless oil for both compounds. (S) -4- ((R) -2-hydroxy-butyl) -2, 2-dimethyl-Oxazolidine-3-carboxylic acid tert-butyl ester:¹H NMRδ(CDCl₃300 MHz): 4.52(1H, br.d, J ═ 3.3Hz), 4.23(1H, m), 4.00(1H, dd, J ═ 8.7 and 5.4Hz), 3.66(1H, d, J ═ 8.7Hz), 3.40(1H, m), 1.79(1H, td, J ═ 11.4 and 2.1Hz), 1.60-1.44(16H, m), 0.95(3H, t, J ═ 7.5 Hz). (S) -4- ((S) -2-hydroxy-butyl) -2, 2-dimethyl-Oxazolidine-3-carboxylic acid tert-butyl ester:¹H NMRδ(CDCl₃，300MHz)：4.12(1H，m)，3.98(1H，dd，J＝9.0&5.7Hz)，3.82(1H，m)，3.55(1H，m)，2.88(1H，br.s)，1.79(1H，m)，1.70-1.40(16H，m)，0.95(3H，t，J＝7.5Hz)。

b) (S) -4- [ (S) -2- (3-benzyloxy-phenoxy) -butyl]-2, 2-dimethyl- Oxazolidine-3-carboxylic acid tert-butyl ester

To a stirred solution of 3-benzyloxy-phenol (264mg) in THF (5ml) were added sequentially triphenylphosphine (364mg) and di-tert-butyl azodicarboxylate (309mg), and the resulting yellow solution was stirred at room temperature for 15 minutes. Then (S) -4- ((R) -2-hydroxy-butyl) -2, 2-dimethyl-A solution of tert-butyl oxazolidine-3-carboxylate (300mg) in THF (5ml) and the resulting mixture was stirred at 70 ℃ for 90 minutes. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product is purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc 100: 0 → 70: 30) to give (S) -4- [ (S) -2- (3-benzyloxy-phenoxy) -butyl as a colorless viscous oil]-2, 2-dimethyl-Oxazolidine-3-carboxylic acid tert-butyl ester (1.35g, 34%). Ms (isp): 456.4([ M + H)]⁺)。

c) (2S, 4S) -2-amino-4- (3-benzyloxy-phenoxy) -hex-1-ol

To a solution of trifluoroacetic acid (0.07ml) in water (6ml) was added dropwise (S) -4- [ (S) -2- (3-benzyloxy-phenoxy) -butyl]-2, 2-dimethyl-A solution of tert-butyl oxazolidine-3-carboxylate (135mg) in acetonitrile (1 ml). The mixture was heated at 80 ℃ for 4 hours with mechanical shaking. The mixture was then cooled to room temperature and diluted with 1N aqueous sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulfate and concentrated in vacuo to give (2S, 4S) -2-amino-4- (3-benzyloxy-phenoxy) -hex-1-ol (94mg, quant.) as a pale yellow viscous oil. Ms (isp): 316.1([ M + H)]⁺)。

d) (S) -4- [ (S) -2- (3-benzyloxy-phenoxy) -butyl]-4, 5-dihydro- Azol-2-ylamines

To a stirred mixture of (2S, 4S) -2-amino-4- (3-benzyloxy-phenoxy) -hex-1-ol (90mg) and sodium acetate (46mg) in methanol (2ml) under an argon atmosphere was added a solution of cyanogen bromide (37mg) in methanol (1 ml). The mixture was stirred for 18 hours and then diluted with 1N aqueous sodium hydroxide solution. The mixture was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product is passed through column chromatography (column: from Separtis)Flash-NH₂(ii) a Gradient: dichloromethane/MeOH 100: 0 → 95: 5) to give (S) -4- [ (S) -2- (3-benzyloxy-phenoxy) -butyl) as a pale yellow gum]-4, 5-dihydro-Oxazol-2-ylamine (69mg, 71%). Ms (isp): 341.1([ M + H)]⁺)。

e)3- [ (S) -1- ((S) -2-amino-4, 5-dihydro- Azol-4-ylmethyl) -propoxy]-phenol

To (S) -4- [ (S) -2- (3-benzyloxy-phenoxy) -butyl at room temperature]-4, 5-dihydro-To a solution of oxazol-2-ylamine (60mg) in methanol (3ml) was added 10% palladium on charcoal (19 mg). The mixture was stirred at room temperature under a hydrogen atmosphere (1atm) for 1 hour. The catalyst was removed by filtration through decalite, washed with methanol and with dichloromethane, and the filtrate was concentrated in vacuo to give 3- [ (S) -1- ((S) -2-amino-4, 5-dihydro-Azol-4-ylmethyl) -propoxy]-phenol (44mg, quantitative); ms (isp): 251.2([ M + H)]⁺)。

S6

(RS) -4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

a) (RS) -3- [4- (4-chloro-benzoylamino) -phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred suspension of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.9g, CAS908334-28-1) in THF (50ml) were added triethylamine (2.0ml) and 4-chloro-benzoyl chloride (0.93ml) in that order, and stirring was continued at room temperature for 3 hours. Then, the mixture was diluted with ethyl acetate. Water was added and acidified to pH1 by addition of 1M aqueous hydrochloric acid. The organic phase was separated and washed successively with aqueous sodium hydroxide solution and with saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo to give (RS) -3- [4- (4-chloro-benzoylamino) -phenyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (2.42g, 83%) which was used in the next step without further purification.

b) (RS) -4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride

To (RS) -3- [4- (4-chloro-benzoylamino) -phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.36g) in THF (30ml) was added dropwise hydrogen chloride in diA solution in alkane (22ml, 4M solution), and the mixture was heated at 60 ℃ overnight. Then, the mixture was cooled to 0 ℃, and the resulting crystals were collected by filtration, washed with diethyl ether, and then dried in vacuo at 60 ℃ to give (RS) -4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide hydrochloride (1.65g, 83%) as a white crystalline solid. Ms (isp): 303.2([{³⁷Cl}M+H]⁺)，301.3([{³⁵Cl}M+H]⁺)。

S7

(RS) -1- (5-chloro-pyridin-2-yl) -3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

a) (RS) -3- {4- [3- (5-chloro-pyridin-2-yl) -ureido]-phenyl } -pyrrolidine-1-carboxylic acid tert-butyl ester

Method for preparing 2-amino-5-chloro-pyridine (1.01g) in dichloroethane (20ml)To the stirred suspension was added triphosgene (831mg) in portions. Triethylamine (2.22ml) was then added dropwise and the mixture was stirred at 50 ℃ for 1 hour. The mixture was then concentrated in vacuo to give a beige solid containing a mixture of triethylammonium chloride and 5-chloro-2-isocyano-pyridine. This solid was then added to a stirred solution of tert-butyl (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylate (350mg, CAS908334-28-1) and N, N-diisopropylethylamine (0.68ml) in dichloroethane (6ml) and the resulting mixture was stirred at 60 ℃ overnight. Then, the mixture was diluted with dichloromethane and washed with water. The phases were separated and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- {4- [3- (5-chloro-pyridin-2-yl) -ureido as an off-white solid]-phenyl } -pyrrolidine-1-carboxylic acid tert-butyl ester (212mg, 38%). Ms (isp): 419.2([{³⁷Cl}M+H]⁺)，417.2([{³⁵Cl}M+H]⁺)。

b) (RS) -1- (5-chloro-pyridin-2-yl) -3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride

To (RS) -3- {4- [3- (5-chloro-pyridin-2-yl) -ureido]-phenyl } -pyrrolidine-1-carboxylic acid tert-butyl ester (210mg) in THF (4ml) was added hydrogen chloride dropwise to a stirred solution of di-tert-butyl esterA solution in alkane (1.89ml, 4M solution), and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃, the subsequent crystals were collected by filtration, washed with ethyl acetate, and dried in vacuo at 60 ℃ to give (RS) -1- (5-chloro-pyridin-2-yl) -3- (4-pyrrolidin-3-yl-phenyl) -urea hydrochloride (167mg, 94%) as a beige crystalline solid. Ms (isp): 319.1([{³⁷Cl}M+H]⁺)，317.2([{³⁵Cl}M+H]⁺)。

S8

(RS) -5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

a) (RS) -3- {4- [ (5-chloro-pyridine-2-carbonyl) -amino]-phenyl } -pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred suspension of (RS) -3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (200mg, CAS908334-28-1) in DMF (10ml) were added N-methylmorpholine (0.22ml), TBTU (490mg) and 5-chloro-2-pyridinecarboxylic acid (180mg) in that order, and the mixture was stirred at room temperature for 90 minutes. Then, the mixture was diluted with ethyl acetate and washed successively with 1M aqueous hydrochloric acid and with saturated brine. The phases were separated and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (RS) -3- {4- [ (5-chloro-pyridine-2-carbonyl) -amino ] -amino as a white solid]-phenyl } -pyrrolidine-1-carboxylic acid tert-butyl ester (310mg, quantitative). Ms (isp): 421.3([ M + NH ]₄]⁺)，419.2([M+NH₄]⁺)。

b) (RS) -5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride

To (RS) -3- {4- [ (5-chloro-pyridine-2-carbonyl) -amino]-phenyl } -pyrrolidine-1-carboxylic acid tert-butyl ester (310mg) in THF (6ml) was added hydrogen chloride dropwise to a stirred solution of di-tert-butyl esterA solution in alkane (2.9ml, 4M solution), and the mixture was heated at 60 ℃ overnight. The mixture was then cooled to 0 ℃, the subsequent crystals were collected by filtration, washed with diethyl ether, and dried in vacuo at 60 ℃ to give (RS) -5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide hydrochloride as a pale yellow solid. Ms (isp): 304.2([{³⁷Cl}M+H]⁺)，302.3([{³⁵Cl}M+H]⁺)。

S9

(S) -4- [ (S) -1- (4-fluoro-phenyl) -ethoxymethyl]-4, 5-dihydro-Azol-2-ylamines

a)1- ((S) -1-allyloxy-ethyl) -4-fluoro-benzene

To a stirred suspension of sodium hydride (3.14g, 55% dispersion in oil) in anhydrous DMF (180ml) under argon atmosphere was added (S) -1- (4-fluorophenyl) -ethanol (8.41g, CAS 101219-73-2). Allyl bromide (6.6ml) was then added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and then quenched by the addition of water. The mixture was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO)₄) And concentrated in vacuo. The crude product is purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give 1- ((S) -1-allyloxy-ethyl) -4-fluoro-benzene (8.66g, 80%) as a colorless liquid.¹H NMR(300MHz，CDCl3，.δppm)：1.43(d，J＝6.6Hz，3H)，3.84(m，2H)，4.45(q，J＝6.6Hz，1H)，5.15(dd，J₁＝10.5Hz，J₂＝1.8Hz，1H)，5.22(dd，J₁＝17.4Hz，J₂＝1.8Hz，1H)，5.89(m，1H)，7.03(m，2H)，7.29(m，2H)。

b) (S) -3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]-propane-1, 2-diol

AD-MIX-. beta. (62.9g) was stirred at room temperature in t-BuOH/H2O 1: 1(440ml) for 15 minutes, then cooled to 0 ℃. To this solution was added 1- ((S) -1-allyloxy-ethyl) -4-fluoro-benzene (8.00 g). The mixture was stirred at 0 ℃ for 48 hours. The reaction mixture was treated with sodium sulfate and stirred at 0 ℃ for 30 minutes and at room temperature for 1 day. The solution was taken up in ethyl acetateThe extraction was performed twice. The combined organic layers were dried (MgSO)₄) And concentrated in vacuo. The product was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc 1/1 to 0/1) to give (S) -3- [ (S) -1- (4-fluoro-phenyl) -ethoxy as a pale yellow liquid]-propane-1, 2-diol and (R) -3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]An 80: 20 mixture of propane-1, 2-diol (8.59g, 90%).¹H NMR(300MHz，CDCl3，)：1.44(d，J＝6.6Hz，3H)，2.1(b，1H)，2.6(b，OH)，3.39(m，2H)，3.60(m，1H)，3.64(m，1H)，3.83(m，1H)，4.41(q，J＝6.6Hz，1H)，7.03(m，2H)，7.27(m，2H)。

c) (R) -1- (tert-butyl-dimethyl-siloxy) -3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]-propan-2-ol

To (S) -3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]-propane-1, 2-diol and (R) -3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]To a solution of an 80: 20 mixture (8.40g) of-propane-1, 2-diol in tetrahydrofuran (84ml) were added triethylamine (5.74ml) and 4-dimethylaminopyridine (479 mg). The mixture was cooled to 0 ℃ and a solution of tert-butyl (chloro) dimethylsilane (6.21g) in tetrahydrofuran (17ml) was added dropwise. After 2 hours at 0 ℃, the reaction mixture was allowed to stir at room temperature for 16 hours. Water was added, and the mixture was extracted twice with diethyl ether. The combined organic layers were dried (MgSO)₄) And concentrated in vacuo to give (R) -1- (tert-butyl-dimethyl-siloxy) -3- [ (S) -1- (4-fluoro-phenyl) -ethoxy) -as a yellow liquid]-propan-2-ol and (S) -1- (tert-butyl-dimethyl-siloxy) -3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]An 80: 20 mixture of-propan-2-ol (12.6g, 98%). The crude product was used in the next step without further purification.

d) (S) -2- (tert-butyl-dimethyl-siloxy) -1- [ (S) -1- (4-fluoro-phenyl) -ethoxymethyl]-ethylamine

To (R) -1- (tert-butyl-dimethyl-siloxy) -3- [ (S) -1- (4-fluoro-l-fluoroxy) at 0 deg.C-phenyl) -ethoxy]-propan-2-ol and (S) -1- (tert-butyl-dimethyl-siloxy) -3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]To a stirred solution of an 80: 20 mixture of propan-2-ol (12.4g) and triethylamine (6.84ml) in dichloromethane (60ml) was added dropwise a solution of methanesulfonyl chloride (3.52ml) in THF. The mixture was stirred at 0 ℃ for 1 hour, then water and dichloromethane were added. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with brine and MgSO₄And (5) drying. The solvent was evaporated and the product was dried under high vacuum. The resulting crude mesylate product (15.5g) was dissolved in DMF (100ml) and sodium azide (4.94g) was added. The reaction mixture was stirred at 100 ℃ for 16 hours. Then, the reaction was quenched with water, and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude azide product (15.6g) was dissolved in methanol (160ml) and 10% palladium on charcoal (1.6g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The catalyst was removed by filtration through celite, and the filtrate was concentrated in vacuo to give (S) -2- (tert-butyl-dimethyl-siloxy) -1- [ (S) -1- (4-fluoro-phenyl) -ethoxymethyl as a yellow liquid]-ethylamine and (R) -2- (tert-butyl-dimethyl-siloxy) -1- [ (S) -1- (4-fluoro-phenyl) -ethoxymethyl]An 80: 20 mixture of ethylamine (14.4g, 100%) which was used in the next step without further purification.

e)(R) -2-amino-3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]-propan-1-ol

To (S) -2- (tert-butyl-dimethyl-siloxy) -1- [ (S) -1- (4-fluoro-phenyl) -ethoxymethyl at 0 deg.C]-ethylamine and (R) -2- (tert-butyl-dimethyl-siloxy) -1- [ (S) -1- (4-fluoro-phenyl) -ethoxymethyl]To a stirred solution of an 80: 20 mixture of ethylamine (14.4g) in THF (150ml) was added tetrabutylammonium fluoride (22.9ml, 1M solution in THF), and the mixture was stirred at room temperature for 18 h. The solvent was evaporated and the crude product was passed through column chromatography (column: from Separtis)Flash-NH₂(ii) a Elution is carried outPreparation: ethyl acetate) to give (R) -2-amino-3- [ (S) -1- (4-fluoro-phenyl) -ethoxy as a pale yellow liquid]-propan-1-ol and (S) -2-amino-3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]An 80: 20 mixture of propan-1-ol (5.58g, 60%). Ms (isp): 214.4([ M + H)]⁺)。

f)(R) -hydroxy-phenyl-acetic acid (R) -2-amino-3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]-propan-1-ol ester

To (R) -2-amino-3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]-propan-1-ol and (S) -2-amino-3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]To a stirred solution of an 80: 20 mixture of propan-1-ol (2.94g) in isopropanol (3ml) was added a solution of D- (-) -mandelic acid (2.10g) in isopropanol (2 ml). The solvent was evaporated and replaced with ethyl acetate to give white crystals, which were collected by filtration. The crystals were dissolved in hot EtOAc (65ml) at 80 ℃ and the mixture was allowed to cool slowly. Crystals appeared upon reaching a temperature of 70 ℃ and the suspension was then stirred at room temperature for 16 hours. The crystals were collected by filtration and redissolved in hot EtOAc (80ml) at 80 ℃ and the mixture was allowed to cool slowly until crystallisation started, and the resulting suspension was then stirred at room temperature for 16 hours. The crystals were collected by filtration to give pure (R) -hydroxy-phenyl-acetic acid (R) -2-amino-3- [ (S) -1- (4-fluoro-phenyl) -ethoxy as a white solid]-propan-1-ol ester (3.08g, 61%).¹H NMR(300MHz，DMSO，)：1.34(d，J＝6.3Hz，3H)，3.13(m，1H)，3.23(m，1H)，3.37(m，4H)，3.83(m，1H)，4.46(q，J＝6.3Hz，1H)，4.54(s，1H)，7.20(m，5H)，7.35(m，4H)。

g)(S) -4- [ (S) -1- (4-fluoro-phenyl) -ethoxymethyl]-4, 5-dihydro- Azol-2-ylamines

Reacting (R) -hydroxy-phenyl-acetic acid (R) -2-amino-3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]-CA suspension of the-1-alcohol ester in EtOAc was treated with aqueous sodium bicarbonate and the mixture was stirred at room temperature until all solids were dissolved. The phases were separated and the organic layer was MgSO₄And (5) drying. Evaporating the solvent to obtain (R) -2-amino-3- [ (S) -1- (4-fluoro-phenyl) -ethoxy as the free base]-propan-1-ol.

To (R) -2-amino-3- [ (S) -1- (4-fluoro-phenyl) -ethoxy]To a stirred solution of-propan-1-ol (1.40g) in THF (80ml) was added K in sequence₂CO₃(1.82g) and cyanogen bromide (0.83 g). The mixture was stirred at room temperature for 18 hours, then water was added. The mixture was extracted twice with ethyl acetate and the combined organic layers were over MgSO₄Drying and usingFlash-NH₂The silica gel was evaporated. Chromatography (column: from SepartisFlash-NH₂(ii) a Eluent: heptane/ethyl acetate 25: 75) to give the title compound as a white solid, (1.15g, 73%). Ms (isp): 239.0([ M + H ]]⁺)。

S10

5-chloro-pyrimidine-2-carboxylic acid {4- [2- ((S) -2-amino-4, 5-dihydro-Oxazol-4-yl) -ethyl]-phenyl } -amides

In analogy to example S3, the title compound was obtained using 5-chloropyrimidine-2-carboxylic acid (CAS38275-61-5) instead of 4-chlorobenzoic acid in step c). A white solid. Ms (isp): 348.3([{³⁷Cl}M+H]⁺)，346.1([{³⁵Cl}M+H]⁺)。

S11

N- {4- [2- ((S) -2-amino-4, 5-dihydro-Oxazol-4-yl) -ethyl]-phenyl } -4-chloro-benzamide

a) (S) -2, 2-dimethyl-4- [ (E) -2- (4-nitro-phenyl) -ethenyl]- Oxazolidine-3-carboxylic acid tert-butyl ester

To a stirred solution of diisopropylamine (1.81ml) in THF (50ml) cooled to-78 deg.C was added dropwise a solution of n-butyllithium in hexane (8.05ml, 1.6M). The ice bath was removed and the reaction mixture was allowed to warm to 10 ℃ and then cooled to-78 ℃ again. A solution of (4-nitro-benzyl) -diethyl phosphate (2.71g, CAS2609-49-6) in THF (60ml) was then added dropwise and the reaction mixture was stirred at-78 deg.C for 1 hour. Then (R) -4-formyl-2, 2-dimethyl-benzene is added dropwise in 30 minutesA solution of tert-butyl oxazolidine-3-carboxylate (2.50g, CAS95715-87-0) in THF (50ml) and the mixture was then allowed to warm to room temperature over 90 minutes. Then, the mixture was diluted with ethyl acetate and acidified by adding 1N aqueous hydrochloric acid. The mixture was then washed successively with water and with saturated brine. The organic phase was separated and dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (S) -2, 2-dimethyl-4- [ (E) -2- (4-nitro-phenyl) -vinyl as a yellow oil]-Oxazolidine-3-carboxylic acid tert-butyl ester (2.21g, 64%). Ms (ei): 333([ M-CH)₃]⁺)，292([M-C₄H₈]⁺)，277([M-CH₃-C₄H₈]⁺)，57([C₄H₉]⁺)。

b) (S) -4- [2- (4-amino-phenyl) -ethyl]-2, 2-dimethyl- Oxazolidine-3-carboxylic acid tert-butyl ester

To (S) -2, 2-dimethyl-4- [ (E) -2- (4-nitro-phenyl) -ethenyl]-To a stirred suspension of oxazolidine-3-carboxylic acid tert-butyl ester (2.08g) in methanol (140ml) were added ammonium formate (5.66g) and palladium on charcoal (0.51g, 10 wt%) and the mixture was heated at 60 ℃ for 90 min. The mixture was then cooled to room temperature, filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (S) -4- [2- (4-amino-phenyl) -ethyl as a yellow oil]-2, 2-dimethyl-Oxazolidine-3-carboxylic acid tert-butyl ester (1.58g, 82%). Ms (isp): 321.4([ M + H)]⁺)。

c) (S) -4- {2- [4- (4-chloro-benzoylamino) -phenyl]-ethyl } -2, 2-dimethyl- Oxazolidine-3-carboxylic acid Tert-butyl ester

To (S) -4- [2- (4-amino-phenyl) -ethyl]-2, 2-dimethyl-To a stirred solution of tert-butyl oxazolidine-3-carboxylate (20) in THF (4ml) was added 4-chlorobenzoic acid (147mg), N-methylmorpholine (0.27ml) and TBTU (401 mg). The reaction mixture was heated to 50 ℃ and stirred for 16 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (SiO)₂(ii) a Gradient: EtOAc/heptane) to give (S) -4- {2- [4- (4-chloro-benzoylamino) -phenyl as a white solid]-ethyl } -2, 2-dimethyl-Oxazolidine-3-carboxylic acid tert-butyl ester (254mg, 89%). Ms (isp): 478.3([{³⁷Cl}M+NH₄]⁺)，476.3([{³⁵Cl}M+NH₄]⁺)，405.4([{³⁷Cl}M+H-C₄H₈]⁺)，403.2([{³⁵Cl}M+H-C₄H₈]⁺)。

d) N- [4- ((S) -3-amino-4-hydroxy-butyl) -phenyl]-4-chloro-benzamide

To (S) -4- {2- [4- (4-chloro-benzoylamino) -phenyl]-ethyl } -2, 2-dimethyl-To a solution of tert-butyl oxazolidine-3-carboxylate (438mg) in acetonitrile (5ml) were added water (4ml) and trifluoroacetic acid (0.29 ml). The mixture was heated at 80 ℃ for 4.5 hours. The mixture was then cooled to room temperature and poured into 1M aqueous NaOH and extracted twice with EtOAc/THF. The combined organic layers were washed with brine, washed with Na₂SO₄Dried, filtered and concentrated in vacuo to yield N- [4- ((S) -3-amino-4-hydroxy-butyl) -phenyl as a white solid]-4-chloro-benzamide (255mg, 84%). Ms (isp): 321.2([{³⁷Cl}M+H]⁺)，319.2([{³⁵Cl}M+H]⁺)。

e) N- {4- [2- ((S) -2-amino-4, 5-dihydro- Oxazol-4-yl) -ethyl]-phenyl } -4-chloro-benzamide

To N- [4- ((S) -3-amino-4-hydroxy-butyl) -phenyl]To a stirred suspension of-4-chloro-benzamide (250mg) and sodium acetate (124mg) in methanol (10ml) was added dropwise a solution of cyanogen bromide (100mg) in methanol (3 ml). The resulting pale yellow solution was then stirred at room temperature for 16 hours. The reaction mixture was poured into 1N aqueous NaOH and extracted twice with dichloromethane/THF. The combined organic layers were washed with saturated aqueous NaCl and Na₂SO₄Dried, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; eluent: 0% to 100% EtOAc in heptane, then 0% to 30% MeOH in EtOAc) to afford N- {4- [2- ((S) -2-amino-4, 5-dihydro-Oxazol-4-yl) -ethyl]-phenyl } -4-chloro-benzamide (150mg, 56%). Ms (isp): 346.1([{³⁷Cl}M+H]⁺)，344.2([{³⁵Cl}M+H]⁺)。

S12

(R) -2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

In analogy to example S4, the title compound was obtained using (R) -2- (4-bromo-phenyl) -morpholine instead of (S) -2- (4-bromo-phenyl) -morpholine in step b) and 2-chloro-6-methylisonicotinic acid (CAS25462-85-5) instead of 6- (2, 2, 2-trifluoroethoxy) nicotinic acid in step e). Light yellow solid. Ms (isp): 334.1([{³⁷Cl}M+H]⁺)，332.1([{³⁵Cl}M+H]⁺)。

S13

(S) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

a) (S) -2- (4-bromophenyl) morpholine:

the enantiomer of (RS) -2- (4-bromo-phenyl) -morpholine (2.27g, CAS-1131220-82-0) was separated using chiral HPLC (column: Chiralpak IA, 8X32 cm; eluent: n-heptane/ethanol (1: 11) with 0.1% DEA to give:

(S) -2- (4-bromo-phenyl) -morpholine: collected from 7.6 minutes to 9.4 minutes.

Yield 0.97g (42.9%) in 97.4% ee

(R) -2- (4-bromo-phenyl) -morpholine: collected from 9.8 minutes to 13.9 minutes.

Yield 0.99g (43.6%) in 97.4% ee

b) (S) -2- (4-bromophenyl) morpholine-4-carboxylic acid tert-butyl ester

(S) -2- (4-bromo-phenyl) -morpholine (36.3g) and N, N-diisopropylethylamine (31.4ml) in THF (360ml) were treated with di-tert-butyl dicarbonate (39.3 g). The reaction mixture was stirred at room temperature for 17 hours, then concentrated in vacuo, diluted with ethyl acetate, washed with 1M aqueous citric acid (2 × 100ml), dried over magnesium sulfate, filtered and concentrated in vacuo, and the crude material crystallized from hexane to give tert-butyl (S) -2- (4-bromophenyl) morpholine-4-carboxylate (47.1g, 92%) as an off-white solid. Ms (isp): 344.1([ M + H)]⁺)。

c) (S) -2- (4- (diphenylmethyleneamino) phenyl) morpholine-4-carboxylic acid tert-butyl ester

Mixing (S) -2- (4)-bromophenyl) morpholine-4-carboxylic acid tert-butyl ester (47g), diphenylimine (29.9g), BINAP (6.41g) and Pd₂(dba)₃(3.14g) was dissolved in anhydrous and degassed toluene (940ml) under argon and treated with sodium tert-butoxide (18.5 g). The dark brown mixture was stirred at 90 ℃ for 18 hours. The yellow/brown reaction mixture was diluted with toluene (700ml), cooled to room temperature and extracted twice with water. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo. The crude product was diluted with 300ml of hexane, stirred for 1 hour, and filtered, resulting in an orange solid (68g), which was purified by column chromatography (silica gel, 20% ethyl acetate/heptane). The combined and concentrated fractions were suspended in hexane, stirred for 17 hours, filtered and dried in vacuo to give tert-butyl (S) -2- (4- (diphenylmethyleneamino) phenyl) morpholine-4-carboxylate (54.1g, 89%) as a yellow solid. Ms (isp): 443.3([ M + H)]⁺)。

d) (S) -2- (4-aminophenyl) morpholine-4-carboxylic acid tert-butyl ester

A suspension of (S) -tert-butyl 2- (4- (diphenylmethyleneamino) phenyl) morpholine-4-carboxylate (54.1g), ammonium formate (116g) and 5% palladium on charcoal (6.5g) in methanol (930ml) was stirred at 60 ℃ for 2 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate and water. The organic phase was extracted twice with 0.5M aqueous HCl. The combined aqueous phases were basified with 2M aqueous NaOH and extracted twice with dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and dried in vacuo to give tert-butyl (S) -2- (4-aminophenyl) morpholine-4-carboxylate (31.95g, 94%) as an off-white solid. Ms (isp): 279.1([ M + H)]⁺)。

e) (S) -2- (4- (6- (2, 2, 2-trifluoroethoxy) nicotinamido) phenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred suspension of tert-butyl (S) -2- (4-aminophenyl) morpholine-4-carboxylate (1.5g) in THF (75ml) were added N-methylmorpholine (1.78ml), HBTU (3.07g) and 6- (2, 2, 2-trifluoroethoxy) nicotinic acid (1.63g) in that order, and the mixture was stirred inStirred at room temperature for 17 hours. The suspension was diluted with EtOAc and successively with 0.5M aqueous HCl, saturated NaHCO₃The aqueous solution and saturated brine were washed. The organic layer was washed with MgSO₄Dried, filtered and concentrated in vacuo. The crude product was purified by recrystallization from heptane/EtOAc (1: 1) to give tert-butyl (S) -2- (4- (6- (2, 2, 2-trifluoroethoxy) nicotinamido) phenyl) morpholine-4-carboxylate (2.11g, 81%) as a white solid. Ms (isp): 482.1([ M + H)]⁺)。

f) (S) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride

To tert-butyl (S) -2- (4- (6- (2, 2, 2-trifluoroethoxy) nicotinamido) phenyl) morpholine-4-carboxylate (2.11g) in diTo a stirred suspension in an alkane (8ml) was added dropwise hydrogen chloride in dioxaneA solution in alkane (16.7ml, 4M solution) and the mixture was heated at 60 ℃ for 2 hours. The reaction mixture was cooled to room temperature and quenched with diAlkane dilution and the crystalline product was collected by filtration, using Et₂And O washing. The product was dried in vacuo to give (S) -N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide hydrochloride (1.75g, 94%) as a pale yellow solid. Ms (isp): 382.2([ M + H)]⁺)。

S14

(S) -N- (4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide hydrochloride

In analogy to example S4, the title compound was obtained using 2- (trifluoromethyl) isonicotinic acid (CAS131747-41-6) instead of 6- (2, 2, 2-trifluoroethoxy) nicotinic acid in step e). Off-white solid. Ms (isp): 352.3([ M + H)]⁺)。

S15

(S) -1- (4-fluorobenzyl) -3- (4- (morpholin-2-yl) phenyl) urea hydrochloride

a) (S) -2- (4- (3- (4-fluorobenzyl) ureido) phenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (100mg) in DMF (3.5ml) were added triethylamine (62. mu.l) and 1-fluoro-4- (isocyanatomethyl) benzene (58.4. mu.l) in this order, and the mixture was stirred at 60 ℃ for 17 hours. The suspension was cooled to room temperature, then diluted with water and extracted twice with EtOAc. The combined organic phases were washed successively with water and saturated brine. The organic layer was washed with MgSO₄Dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; gradient: EtOAc/heptane) to give tert-butyl (S) -2- (4- (3- (4-fluorobenzyl) ureido) phenyl) morpholine-4-carboxylate (164mg, quantitative) as a white solid. Ms (isp): 374.0([ M + H-C)₄H₈]⁺)。

b) (S) -1- (4-fluorobenzyl) -3- (4- (morpholin-2-yl) phenyl) urea hydrochloride

To a stirred suspension of (S) -tert-butyl 2- (4- (3- (4-fluorobenzyl) ureido) phenyl) morpholine-4-carboxylate (163mg) in THF (9ml) was added dropwise hydrogen chloride in bis (tert-butyl) chloride solutionA solution in alkane (1.42ml, 4M solution) and the mixture was heated at 60 ℃ for 6 hours. Cooling the reaction mixture toAt room temperature, diluted with EtOAc, and the crystalline product collected by filtration, with Et₂And (4) diluting with oxygen. The product was dried in vacuo to give (S) -1- (4-fluorobenzyl) -3- (4- (morpholin-2-yl) phenyl) urea hydrochloride as a white solid (101mg, 73%). Ms (isp): 330.1([ M + H)]⁺)。

S16

(S) -1- (3-cyanophenyl) -3- (4- (morpholin-2-yl) phenyl) urea hydrochloride

In analogy to example S7, the title compound was obtained using 3-isocyanatobenzonitrile (CAS16413-26-6) instead of 1-fluoro-4- (isocyanatomethyl) benzene in step a). Off-white solid. Ms (isp): ms (isp): 323.2([ M + H)]⁺)。

S17

(S) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

The title compound was obtained in analogy to example S4, using 6-chloronicotinic acid (CAS5326-23-8) instead of 6- (2, 2, 2-trifluoroethoxy) nicotinic acid in step e). Off-white solid. Ms (isp): ms (isp): 320.1([{³⁷Cl}M+H]⁺)，318.1([{³⁵Cl}M+H]⁺)。

In vitro functional Activity of TAAR1 agonists on the mouse TAAR 1receptor

Recombinant HEK293 cells expressing mouse TAAR1 were grown in 30ml of medium at 37 ℃ and 5% CO 2/95% air in 250ml Falcon flasks. The cell culture medium contained DMEM high glucose, fetal bovine serum (10%, heat inactivated at 56 ℃ for 30 minutes), geneticin G418 (500. mu.g/ml) and penicillin/streptomycin (1%). When 80-90% were confluent, cells were harvested. The medium was then removed from the flask and the cells were washed once with 5ml PBS. After removal of the wash solution, 5ml trypsin/EDTA solution was added for 5 minutes at 37 ℃. Subsequently, 45ml of the medium was added to 5ml of the separated cell solution, and a total of 50ml was transferred to a 50ml Falcon tube (ref: 2070), which was centrifuged at 1300rpm at room temperature for 3 minutes and the medium was removed. The cell pellet was resuspended in fresh medium and 5X10E5 cells/ml were allowed to settle. Then, cells were plated (100 μ l/well, 50000 cells/well) in 96-well plates (BIOCOAT 6640 from Becton Dickinson) with a multiplex pipette and incubated at 37 ℃ for 20 hours.

cAMP measurement:

the cell culture medium was removed and the cells were washed once with PBS. 50 μ l of PBS with 1mM MIBMX (AMIMED without endotoxin: 8-05F00-1) was added and the cells were allowed to incubate at 37 ℃ and 5% CO 2/95% air for 30 minutes. Then 50 μ l of e.g.20 μ M compound solution or 50 μ l of 50% β -PEA stimulation concentration in PBS with 1mM IBMX (AMIMED without endotoxin) was added and the cells were incubated for a further 30 minutes at 37 ℃ as described above. After incubation, cells were lysed with 50 μ l of a 3 × Detection cocktail solution containing Ru-cAMP, Alexa700-cAMP Ab and lysis buffer (Detection Mix solution) at room temperature under vigorous shaking for at least 60 minutes (better 2 hours). Fluorescence was measured on a NanoScan (IOM reader (ex.456nm, em.630&700 nm).

As shown in the table below, the compounds exhibited EC for mouse TAAR1 in the range of < 0.01 μ M₅₀Value (. mu.M). Work value (% eff.) is relative to phenylethylamine, which has 100% agonist activity.

The antipsychotic-like activity of TAAR1 agonist was additive and synergistic with the commercial antipsychotic drug olanzapine in two animal models indicative of psychosis.

Additive effect of TAAR1 agonist and olanzapine in cocaine-induced exercise testing in mice By using

Activation of TAAR1 was shown to down-regulate dopaminergic neurotransmission, while inhibition of TAAR1 was shown to enhance dopaminergic neurotransmission (Lindemann et al, 2008; Bradaia et al, 2009). Data from cocaine-and L-687414 (benzyloxyamine) -induced hyperlocomotor activity tests in mice suggest that TAAR1 agonists have potential antipsychotic-like activity.

At doses with moderate effect on baseline locomotor activity, S2 significantly antagonized cocaine-induced hyperlocomotor activity in mice at 1 and 3mg/kg per mouth (p.o.). In addition, partial active doses of S2(0.3mg/kg, oral) and olanzapine (0.3mg/kg, oral) completely reversed the excessive exercise induced by cocaine when combined (fig. 1 a). This suggests that S2 may have an additive effect on the marketed antipsychotic drug olanzapine.

It was also observed that while the doses of S1(0.1mg/kg, oral) and olanzapine (0.3mg/kg, oral) partially antagonized cocaine-induced locomotor activity when tested alone, a complete reversal of cocaine-induced hyperlocomotor activity was observed when these compounds were combined (fig. 1 b).

This suggests that S1 has a superimposed effect on the marketed antipsychotic drug olanzapine, supporting its potential as an add-on therapy to the marketed antipsychotic drug.

FIG. 1 shows a schematic view of a

Effect on cocaine-induced locomotion in mice

a) The doses of S1(0.1mg/kg, oral) and olanzapine (0.3mg/kg, oral) that partially antagonize cocaine-induced hyperlocomotor activity when tested alone showed a normalizing effect when combined. P.ltoreq.0.05, p.ltoreq.0.01, p.ltoreq.0.002, relative to the "vehicle (vehicle) and cocaine" groups.

b) The doses of S2(0.3mg/kg, oral) and olanzapine (0.3mg/kg, oral) that partially antagonize cocaine-induced hyperlocomotor activity when tested alone showed a normalizing effect when combined. P.ltoreq.0.05, p.ltoreq.0.01, p.ltoreq.0.002, relative to the "vehicle and cocaine" group.

Synergistic interaction of TAAR1 agonist and olanzapine in L-687414-induced exercise test in mice By using

To illustrate its potential effect on the glutamatergic system, S2(0.00003-1mg/kg per mouth) was tested in mice in an acute procedure of L-687414 (N-hydroxy-3-amino-4-methyl-pyrrolidin-2-one, NMDA receptor antagonist acting at the glycine site) -induced hyperlocomotion, where it dose-dependently antagonizes L-687414 with significance in the dose range of 0.003 to 1mg/kg per mouth (fig. 2).

FIG. 2

Effect of TAAR1 agonists on L-687414-induced locomotion in mice

L-687414-induced movement: s2(0.00003-1mg/kg, oral) completely antagonized L-687414-induced hyperkinetic activity from 0.003 to 1mg/kg (filled circles). P.ltoreq.0.05, p.ltoreq.0.01, p.ltoreq.0.001, relative to the vehicle (open circle).

In addition, a partial active dose of TAAR1 agonist S2(0.001mg/kg, oral; grey bar in FIG. 2) was added to an increasing dose of olanzapine (0-0.1mg/kg, oral). As shown in figure 3, the partial active dose of S2(0.001mg/kg, oral) in combination with an inactive dose of olanzapine (0.02-0.06mg/kg, oral) completely antagonized L-687414-induced motor activity, indicating that the TAAR1 agonist and olanzapine show a synergistic effect in this mouse model indicative of schizophrenia.

FIG. 3

Synergistic effect with olanzapine in mouse L-687414-induced locomotion

L-687414-induced movement: s2(0.001mg/kg, oral) in combination with an increasing dose of olanzapine (0-0.1mg/kg, oral) completely antagonizes L-687414-induced hyperkinetic activity at 0.02 and 0.06mg/kg olanzapine. P.ltoreq.0.05, p.ltoreq.0.01, p.ltoreq.0.001L-687414 + S2 relative to the L-687414 group alone.

Acute effects of TAAR1 agonists on oral glucose tolerance test (oGTT) in conventional male C57B16 mice

Oral glucose tolerance test (oGTT) was performed in C57B16 mice to elucidate the potential anti-diabetic effects of TAAR1 agonists. Male C57BL/6J mice (Charles river laboratories, Lyon, France) were divided into groups by weight, with 8 mice per group. During the night before the animals receive 1g of food, this corresponds to a fasting period of about 10 hours. On the experimental day, animals were treated with TAAR1 agonist or placebo (0.3% Tween 80) 45 minutes prior to oral glucose stimulation at 2 g/kg. The main reading is blood glucose measured with Accu-chekvaviva. Parallel blood samples were taken for insulin determination.

Oral S1 significantly reduced blood glucose excursions at 0.1 and 0.3mg/kg compared to vehicle after glucose stimulation (fig. 4 a). At the same time, insulin fluctuations were significantly lower after TAAR1 agonist administration compared to vehicle treatment (fig. 4 b). No effect on fasting glucose levels was observed with S1. Since metabolic syndrome is highly developed in schizophrenia, it is considered that the antidiabetic effect has a positive effect on schizophrenia patients.

FIG. 4

Effect of S1 on glucose and insulin AUC in ogTT of mice

During oGTT in mice, S1(0.1, 0.3mg/kg, oral) significantly reduced (a) glucose and (b) insulin AUC (0-60 min). Results are shown as mean ± SEM. Statistics: analysis of variance (Anova) was then followed by a Dunett post hoc test (Dunett's post hoc test), p ≦ 0.01, p ≦ 0.001 vs vehicle (Veh) group; n is 8/group.

A number of additional TAAR1 agonists were tested in oGTT (S2-8), with varying levels of efficacy (51-90% compared to β -phenylethylamine), and all showed significant effects in reducing glucose AUC, and reduced insulin AUC were tested (fig. 5-9).

FIG. 5

Effect of S2 on glucose and insulin AUC in ogTT of mice

During oGTT in mice, S2(0.3, 1mg/kg, oral) significantly reduced (a) glucose and (b) insulin AUC (0-60 min). Results are shown as mean ± SEM. Statistics: analysis of variance was then a Dunet post-test,. p.ltoreq.0.001, vs vehicle (Veh) group; n is 8/group.

FIG. 6

Effect of S3 on glucose and insulin AUC in ogTT of mice

During oGTT in mice, S3(1, 3mg/kg, oral) significantly reduced (a) glucose and (b) insulin AUC (0-60 min). Results are shown as mean ± SEM. Statistics: the analysis of variance was then a Dunett post-hoc test, p.ltoreq.0.05, p.ltoreq.0.001, against the vehicle (Veh) group; n is 8/group.

FIG. 7

Effect of S4 on glucose and insulin AUC in ogTT of mice

During oGTT in mice, S4(0.3mg/kg per mouth) significantly reduced (a) glucose and (b) insulin AUC (0-60 min). Results are shown as mean ± SEM. Statistics: the analysis of variance was then a Dunett post-hoc test, p.ltoreq.0.05, p.ltoreq.0.001, against the vehicle (Veh) group; n is 8/group.

FIG. 8

Effect of S5 on glucose AUC in ogTT of mice

During oGTT in mice, S5(30mg/kg, oral) significantly reduced glucose AUC (0-60 min). Results are shown as mean ± SEM. Statistics: analysis of variance was then a Dunett post test,. p.ltoreq.0.001, relative to vehicle group; n is 8/group.

FIG. 9

In oGTT in mice, S6, S7 and S8(10 mg)/kg, oral, each) AUC for glucose Function of

During oGTT in mice, S6(10 and 30mg/kg per mouth), S7(10mg/kg per mouth), and S8(10 and 30mg/kg per mouth) significantly reduced glucose AUC (0-60 min). Results are shown as mean ± SEM. Statistics: the analysis of variance was then a Dunet post-test, p.ltoreq.0.01, p.ltoreq.0.001, against the vehicle group; n is 8/group.

FIG. 10 shows a schematic view of a

Effect of S9, S10 and S11 on glucose AUC in ogTT of mice

During oGTT in mice, a) S9(10mg/kg, oral) and S10(10mg/kg, oral) and b) S11(1 and 3mg/kg, oral) significantly reduced glucose AUC (0-60 min). Results are shown as mean ± SEM. Statistics: the analysis of variance was then a Dunet post-test, p.ltoreq.0.05, p.ltoreq.0.01, p.ltoreq.0.001, relative to the vehicle group; n is 8/group.

FIG. 11

Effect of S12, S13, S14, S15 and S16 on glucose AUC in ogTT of mice

During oGTT in mice, a) S12 and S13(3mg/kg, oral, each) and b) S14, S15 and S16(1mg/kg, oral, each) significantly reduced glucose AUC (0-60 min). Results are shown as mean ± SEM. Statistics: the analysis of variance was then a Dunet post-test, p.ltoreq.0.05, p.ltoreq.0.01, p.ltoreq.0.001, relative to the vehicle group; n is 8/group.

FIG. 12

Effect of S17(0.3 and 1mg/kg, oral) on glucose AUC in oGTT in mice

During oGTT in mice, S17(0.3 and 1mg/kg per mouth) significantly reduced glucose AUC (0-60 min). Results are shown as mean ± SEM. Statistics: the analysis of variance was then a Dunet post-test, p.ltoreq.0.01, p.ltoreq.0.001, against the vehicle group; n is 8/group.

In normal rats, TAAR1 agonists reduced weight gain and normalized the weight gain induced by the antipsychotic drug olanzapine.

Many antipsychotics induce weight gain in patients with schizophrenia. Since weight gain may lead to serious health complications and diseases such as diabetes, it is critical to assess their propensity to alter body weight for promising, newer antipsychotic compounds in animals.

A 14 day treatment regimen with S2 and olanzapine, a clinically used antipsychotic drug known to produce weight gain, was used in female Sprague-Dawley rats. Together with the body weight measurement, the fat mass composition in the animals was determined non-invasively using Magnetic Resonance (MR) relaxation time Measurement (MR) delaxometric.

The results show that the reduction of body weight gain (fig. 13a), fat mass (fig. 14a, 14c) and food intake (table 1) with oral S2 of 3 and 10mg/kg does not induce weight loss when compared to the pre-treatment values compared to vehicle treated animals. No significant effect was detected at 1mg/kg per oral dose (fig. 13b, 14b, table 1). In addition, S2(1mg/kg, oral) in combination with olanzapine (2mg/kg, oral) reduced weight gain, fat mass content and increase in food intake in olanzapine treated rats (fig. 13b, 14b, table 1).

This indicates that S2 does not induce weight gain when administered alone and can inhibit the weight gain induced by the marketed antipsychotic drug olanzapine.

FIG. 13

Effect of S2 on cumulative body weight gain in rats

(a) In female Sprague-Dawley rats, S2 reduced weight gain at 3 and 10mg/kg per mouth, but not at 1mg/kg (compare the linear trend in the S2 group relative to the linear trend in the vehicle group, at 3mg/kg, p ═ 0.0024, and at 10mg/kg, p ═ 0.012). (b) S2(1mg/kg, oral) in combination with olanzapine (2mg/kg, oral) normalized olanzapine-induced weight gain (linear trend olanzapine versus vehicle, p ═ 4.6E-10; S2/olanzapine versus vehicle, p ═ 0.41). Comparison between groups at each time point: t-test, p ≦ 0.05, p ≦ 0.01, p ≦ 0.001, relative to vehicle; # p is less than or equal to 0.05, # p is less than or equal to 0.01, # p is less than or equal to 0.001, relative to olanzapine group; n is 8/group.

FIG. 14

Effect of S2 on fat mass content in rats

S2(1mg/kg, oral) in combination with olanzapine (2mg/kg, oral) normalized olanzapine-induced fat mass increase in female Sprague-Dawley rats. No significant effect of S2 alone was detected when compared to the vehicle group. Dunett test # p ≦ 0.05, # p ≦ 0.01, # p ≦ 0.001, relative to vehicle; # p is less than or equal to 0.05, # p is less than or equal to 0.01, # p is less than or equal to 0.001, relative to olanzapine group; n is 8/group.

TABLE 1

Effect of S2 on cumulative food intake in rats

S2(1mg/kg, oral) in combination with olanzapine (2mg/kg, oral) normalized the increase in food intake induced by olanzapine. A significant decrease in food intake was detected in 10mg/kg of S2-treated rats; n is 8/group.

Olanzapine and compounds of formulae I, I-1, II and II-1 as well as pharmaceutically acceptable salts may be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formulae I, I-1, II and II-1 can be processed with pharmaceutically inert, inorganic or organic carriers to produce pharmaceutical formulations. Lactose, corn starch, cellulose or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active substance, 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, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

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

Medicaments containing olanzapine and a compound of formulae I, I-1, II and II-1 or a pharmaceutically acceptable salt thereof in a primary therapeutically inert carrier are also an object of the present invention, as well as a process for their production, which comprises bringing one or more compounds of formulae I, I-1, II and II-1 together with olanzapine and/or a pharmaceutically acceptable acid addition salt, and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and must, of course, be adjusted to the individual requirements in each particular case. In the case of oral administration, the dosage for adults can vary from about 0.01mg to about 1000mg per day of olanzapine and the compounds of formulae I, I-1, II and II-1 or the corresponding amounts of the pharmaceutically acceptable salts thereof. The daily dose may be administered as a single dose or in divided doses and, in addition, the upper limit may also be exceeded when this is found to be indicated.

Tablet formulation (Wet granulation)

Preparation procedure

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

2. The granules were dried at 50 ℃.

3. Passing the particles through suitable milling equipment.

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

Capsule preparation

Preparation procedure

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

2. Items 4 and 5 were added and mixed for 3 minutes.

3. Fill into suitable capsules.

Olanzapine tablet formulation

Preparation procedure

1. Mix items 1 to 5 and granulate with purified water.

2. The granules were dried at 50 ℃.

3. Passing the particles through suitable milling equipment.

4. Add item 6 and mix for three minutes; pressing on a suitable press.

Combined preparation

Preparation procedure

1. Mix items 1 to 6 and granulate with purified water.

2. The granules were dried at 50 ℃.

3. Passing the particles through suitable milling equipment.

4. Add items 7 and 8 and mix for three minutes; pressing on a suitable press.

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Claims (20)

1. A combination comprising an atypical antipsychotic and a TAAR1 agonist.

2. A combination according to claim 1 comprising olanzapine and a TAAR1 agonist of formula I:

wherein the content of the first and second substances,

R¹is hydrogen, deuterium, tritium, lower alkyl, hydroxy, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, phenyl optionally substituted by halogen, or is phenoxy, benzyl, benzyloxy, -COO-lower alkyl, -O- (CH)₂)_o-O-lower alkyl, NH-cycloalkyl, cycloalkyl or tetrahydropyran-4-yloxy, wherein for n > 1 the substituents may be the same or different;

x is a bond, -CHR-, -CHRCHR' -, -OCH₂-，-NRCHR’，-OCHRCHR’，-CH₂OCHR-，-CH₂CH₂CH₂-，-SCH₂-，-S(O)₂CH₂-，-CH₂SCH₂-，-CH₂N(R)CH₂-, -cycloalkyl-CH₂-or SiRR' -CH₂-；

R/R' may be independently from each other hydrogen, lower alkyl or lower alkyl substituted by halogen;

R²is hydrogen, phenyl or lower alkyl;

y is phenyl, naphthyl, thienyl, pyridyl, cycloalkyl, 1, 2, 3, 4-tetrahydro-naphthalen-2-yl, 2, 3-dihydrobenzo [1, 4] dioxin-6-yl or benzo [1, 3] dioxol-5-yl;

n is 0, 1, 2 or 3;

o is 2 or 3;

or a pharmaceutically suitable acid addition salt thereof,

or a TAAR1 agonist of formula II:

wherein the content of the first and second substances,

r is hydrogen or lower alkyl;

R¹is- (CH)₂)_n-(O)_o-heterocycloalkyl, optionally substituted by lower alkyl, hydroxy, halogen or by- (CH)₂)_p-aryl substitution;

n is 0, 1 or 2;

o is 0 or 1;

p is 0, 1 or 2;

R²is cycloalkyl, heterocycloalkyl, or is aryl or heteroaryl, wherein the aromatic ring is optionally substituted with one or two substituents selected from: lower alkyl, halogen, heteroaryl, CF₃，OCF₃，OCH₂CF₃Lower alkoxy, CH₂-lower alkoxy, lower alkynyl or cyano;

x is a bond, -NR' -, -CH₂NH-，-CHR”-，-(CH₂)_q-O-or- (CH)₂)₂-；

R' is hydrogen or lower alkyl,

r' is hydrogen, lower alkyl, lower alkoxy,

q is 0, 1 or 2;

or a pharmaceutically suitable acid addition salt thereof.

3. A combination according to claim 2 comprising olanzapine and a TAAR1 agonist of formula I-1:

wherein the content of the first and second substances,

R¹is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or halogen, wherein for n ═ 2 the substituents may be the same or different;

x is a bond, -NRCHR ', -CHRCHR ' or-OCHRCHR ';

R/R' may be independently from each other hydrogen, lower alkyl;

n is 1 or 2;

or a TAAR1 agonist of formula II-1:

wherein the content of the first and second substances,

r is hydrogen;

R¹is pyrrolidinyl;

R²is aryl or heteroaryl, wherein the aromatic ring is optionally substituted with halogen;

x is a bond or-NR' -;

r' is hydrogen or lower alkyl,

or a pharmaceutically suitable acid addition salt thereof.

4. A combination according to claims 1-3 comprising olanzapine and a TAAR1 agonist, said TAAR1 agonist being:

s1 ═ 4- ((S) -2-phenyl-butyl) -4, 5-dihydro-Azol-2-ylamines

S2 ═ 4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro-Azol-2-ylamines

S3 ═ 4- (4-chloro-2-trifluoromethyl-phenyl) -4, 5-dihydro-Azol-2-ylamines

S4 ═ 4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Azol-2-ylamines

S5 ═ 3- [ (S) -1- ((S) -2-amino-4, 5-dihydro-Azol-4-ylmethyl) -propoxy]-phenol

S6 ═ 5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl) -amide

S7 ═ 4-chloro-N- (4-pyrrolidin-3-yl-phenyl) -benzamide

S8 ═ 1- (5-chloro-pyridin-2-yl) -3- (4-pyrrolidin-3-yl-phenyl) urea

S9 ═ S) -4- [ (S) -1- (4-fluoro-phenyl) -ethoxymethyl]-4, 5-dihydro-Azol-2-ylamines

S10 ═ 5-chloro-pyrimidine-2-carboxylic acid {4- [2- ((S) -2-amino-4, 5-dihydro-Oxazol-4-yl) -ethyl]-phenyl } -amides

S11 ═ N- {4- [2- ((S) -2-amino-4, 5-dihydro-Oxazol-4-yl) -ethyl]-phenyl } -4-chloro-benzamide

S12 ═ 2-chloro-6-methyl-N- (4- (morpholin-2-yl) phenyl) isonicotinamide

S13 ═ S-N- (4- (morpholin-2-yl) phenyl) -6- (2, 2, 2-trifluoroethoxy) nicotinamide

S14 ═ S-N- (4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide

S15 ═ S) -1- (4-fluorobenzyl) -3- (4- (morpholin-2-yl) phenyl) urea

S16 ═ S) -1- (3-cyanophenyl) -3- (4- (morpholin-2-yl) phenyl) urea and

s17 ═ S) -6-chloro-N- (4- (morpholin-2-yl) phenyl) nicotinamide.

5. The compounds comprised by the formulae I and I-1 according to claims 2 and 3, S2 ═ (S) -4- (3-fluoro-2-methyl-phenyl) -4, 5-dihydro-Oxazol-2-ylamine.

6. A combination according to claims 1-4 comprising olanzapine and a TAAR1 agonist for use in the treatment of schizophrenia and manic episodes associated with bipolar disorder at reduced incidence of metabolic syndrome.

7. A combination according to claim 6 comprising olanzapine and a TAAR1 agonist for use under anti-diabetic efficacy in the treatment of schizophrenia and manic episodes associated with bipolar disorder.

8. A combination according to claim 7 comprising olanzapine and a TAAR1 agonist for use in the treatment of schizophrenia and manic episodes associated with bipolar disorder with anti-diabetic efficacy which results in a reduction of blood glucose fluctuations.

9. A combination according to claim 8 comprising olanzapine and a TAAR1 agonist for use in the treatment of schizophrenia and manic episodes associated with bipolar disorder with anti-diabetic efficacy resulting in reduced fat mass and body weight.

10. Use of a combination according to claims 1-4 comprising olanzapine and a TAAR1 agonist for the treatment of schizophrenia and manic episodes associated with bipolar disorders with reduced incidence of metabolic syndrome.

11. Use of a combination according to claims 1-4 for the preparation of a medicament for the treatment of schizophrenia and manic episodes associated with bipolar disorders with reduced incidence of metabolic syndrome.

12. Use of a combination according to claim 11 for the preparation of a medicament for the treatment of schizophrenia and manic episodes associated with bipolar disorders with anti-diabetic efficacy.

13. Use of a combination according to claim 12 for the preparation of a medicament for the treatment of schizophrenia and manic episodes associated with bipolar disorders with anti-diabetic efficacy which results in a reduction of blood glucose excursions.

14. Use of a combination according to claim 13, wherein the combination comprises olanzapine and a TAAR1 agonist, for the manufacture of a medicament for the treatment of schizophrenia and manic episodes associated with bipolar disorder with anti-diabetic efficacy which results in reduced fat mass and body weight.

15. A method for treating schizophrenia and manic episodes associated with bipolar disorders at a reduced incidence of metabolic syndrome, comprising administering to a person in need thereof an effective amount of a combination comprising an atypical antipsychotic and a TAAR1 agonist.

16. The method for treating schizophrenia and manic episodes associated with bipolar disorder according to claim 15, wherein said reduced incidence of metabolic syndrome results from having anti-diabetic efficacy in reducing blood glucose excursions, fat mass, and body weight, comprising administering to a human in need thereof an effective amount of a combination comprising an atypical antipsychotic and a TAAR1 agonist.

17. The method for treating schizophrenia and manic episodes associated with bipolar disorder according to claim 16 wherein the atypical antipsychotic drug is olanzapine and the TAAR1 agonist is as described in claims 2, 3 and 4.

18. A pharmaceutical composition comprising a combination of an atypical antipsychotic and a TAAR1 agonist as described in claims 2, 3 and 4 together with pharmaceutically acceptable excipients for use in the treatment of schizophrenia and manic episodes associated with bipolar disorder at a reduced incidence of metabolic syndrome.

18. A pharmaceutical composition comprising a combination of an atypical antipsychotic and a TAAR1 agonist as described in claims 2, 3 and 4 and a pharmaceutically acceptable excipient for use in the treatment of schizophrenia and manic episodes associated with bipolar disorder at a reduced incidence of metabolic syndrome, wherein said reduced incidence of metabolic syndrome results from having an anti-diabetic efficacy in reducing glycemic volatility, fat mass and body weight.

19. The invention as described above.