HK1192562B - Substituted benzamide derivatives - Google Patents

Description

Substituted benzamide derivatives

The invention relates to compounds of formula I

Wherein

R¹Is hydrogen, halogen, cyano, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or C (O) NH₂，

Or phenyl optionally substituted by halogen, cyano or lower alkoxy substituted by halogen,

or 2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl, or 6- (trifluoromethyl) pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or 6- (trifluoromethyl) pyrimidin-4-yl,

or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2

R²Is halogen, lower alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, lower alkyl or cyano;

x is a bond, -NR' -, -CH₂NH-or-CHR' -;

r' is hydrogen or lower alkyl;

z is a bond, -CH₂-or-O-;

ar is phenyl or a heteroaryl selected from the group consisting of: 1H-indazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl;

or a pharmaceutically suitable acid addition salt thereof.

The present invention includes all racemic mixtures, all of their corresponding enantiomers and/or optical isomers. Furthermore, the invention also encompasses all tautomeric forms of the compounds of the formula I.

It has now been found that the compounds of formula I have a good affinity for the Trace Amine Associated Receptors (TAARs), especially TAAR 1.

The compounds may be used for the treatment of depression (depression), anxiety disorders (anxiety disorders), bipolar disorder (bipolar disorder), Attention Deficit Hyperactivity Disorder (ADHD), stress-related disorders (stress-related disorder), psychotic disorders (psychogenic disorders) such as schizophrenia (schizophrenia), neurological diseases (neurological disorders) such as Parkinson's disease, neurodegenerative disorders (neurodegenerative disorders) such as Alzheimer's disease, epilepsy (epilepsy), migraine (migraine), hypertension (hypertension), cardiovascular substance abuse (cardiovascular substance abuse) and metabolic disorders (metabolic disorders) such as eating disorders (eating disorders), diabetes (metabolic disorders), obesity (metabolic disorders), circadian rhythm disorders (obesity disorders), metabolic disorders (metabolic disorders) such as eating disorders (eating disorders), metabolic disorders (diabetes), metabolic disorders (obesity disorders), and metabolic disorders (metabolic disorders), stress-related disorders (obesity) and metabolic disorders (metabolic disorders).

Some of the physiological effects reported for compounds that can bind to adrenergic receptors (i.e. cardiovascular effects, hypotension, sedation induction) (WO02/076950, WO97/12874 or EP0717037) may be considered as undesirable side effects in the case of drugs for the treatment of central nervous system diseases as described above. It is therefore desirable to obtain a drug which is selective for the TAAR1 receptor compared to the adrenergic receptor. The objects of the present invention show selectivity for the TAAR1 receptor over the adrenergic receptor, especially good selectivity compared to the human and rat α 1 and α 2 adrenergic receptors.

Classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play an important role as neurotransmitters in the central and peripheral nervous systems [1 ]. Their synthesis and storage, as well as their degradation and resorption upon release, are tightly regulated. Imbalances in biogenic amine levels are known to be responsible for altered brain function in many pathological situations [2-5 ]. The second class of endogenous amine compounds, known as Trace Amines (TAs), significantly overlaps with classical biogenic amines in structure, metabolism, and subcellular localization. TA includes p-tyramine, β -phenylethylamine, tryptamine and octopamine, and they are present in the mammalian nervous system at levels generally lower than classical biogenic amines [6 ].

Their dysregulation is associated with a variety of psychiatric disorders such as schizophrenia and depression [7], and other conditions such as attention deficit hyperactivity disorder, migraine, Parkinson's disease, substance abuse and eating disorders [8, 9 ].

For a long time, TA-specific receptors have only been hypothesized to be based on anatomically discrete high-affinity TA binding sites in the CNS of humans and other mammals [10, 11 ]. Thus, the pharmacological effects of TA are believed to be mediated via the well-known mechanism of classical biogenic amines by: or by causing their release, inhibiting their resorption, or by "cross-reacting" with their receptor systems [9, 12, 13 ]. This view has changed significantly with the recent identification of several members of the new GPCR family, namely the Trace Amine Associated Receptors (TAARs) [7, 14 ]. There are 9 TAAR genes (including 3 pseudogenes) in humans and 16 genes (including 1 pseudogene) in mice. The TAAR genes do not contain introns (with one exception, TAAR2 contains 1 intron) and are located adjacent to each other on the same chromosomal segment. Phylogenetic relationships of the receptor genes, consistent with in-depth GPCR pharmacophore similarity comparisons and pharmacological data, suggest that these receptors form three distinct subfamilies [7, 14 ]. TAAR1 belongs to the first subset of four genes (TAAR1-4) that are highly conserved between humans and rodents. TA activates TAAR1 via G α t. Dysregulation of TA has been shown to contribute to the etiology of a variety of diseases such as depression, psychosis, attention deficit hyperactivity disorder, substance abuse, parkinson's disease, migraine, eating disorders, and metabolic disorders, and thus TAAR1 ligands have a high potential for treatment of these diseases.

Therefore, there is a wide interest in increasing knowledge about trace amine associated receptors.

The references used are:

1Deutch, a.y. and Roth, r.h. (1999) neutransmiters, in fundamental neuroscience (2 nd edition) (zigbee, m.j., Bloom, F.E, Landis, s.c., Roberts, j.l and Squire, l.r. editions), page 193-;

2Wong, M.L. and Licinio, J. (2001) research into a disease modification of a protein kinase inhibitor expression. Nat. Rev. Neurosci.2, 343. 351;

3Carlsson, A. et al (2001) interactionsbetweenomines, glutamate, and GABAinschizophenia: newevidence.annu.rev.pharmacol.toxicol.41, 237-260;

4Tuite, p. and ross, j. (2003) recenterdevelopmental hepatological alteration of parkinson's disease. expertopin. investig. drugs12, 1335-;

5Castellanos, f.x. and Tannock, R. (2002) neurosciention of effort-specific/hypeacetivitdioderder: the peptide of the peptide;

6 Usedin, Earl; sandler, Merton; editors, psychopharmacogenomics series, volume 1: traceaminesandthbrain [ proceedings of the SofastudyGroupathe 14th Nual Meetin of the American collegeof the Neuropsychroalarcollelogy, SanJuan, PuertoRico ] (1976);

7Lindemann, L. and Hoener, M. (2005) Arenaissancentraminesispiredbyachene GPCRfamearly. trends Pharmacol. Sci.26, 274- "281;

8Branchek, T.A. and Blackburn, T.P. (2003) Tracenamerepittostartstfornoveltotherecutics: legend, mythandfact. curr. opin. pharmacol.3, 90-97;

9Premont, r.t. et al (2001) followingthe novel amides, proc.natl.acad.sci.u.s.a.98, 9474-9475;

10Mousseau, D.D. and Butterworth, R.F. (1995) Ahigh-affinity [3H ] tryPtaminobindingsite in human serum.prog.BrainRes.106, 285-291;

11McCormack, j.k. et al (1986) audiographiticlocalizationftynamindingsistingheratherandogcentrorvoussystemj.neurosci.6, 94-101;

12Dyck，L.E.(1989)Releaseofsomeendogenoustraceaminesfromratstriatalslicesinthepresenceandabsenceofamonoamineoxidaseinhibitor.LifeSci.44，1149-1156；

13Parker, e.m. and cubedu, L.X. (1988) compatible effective major, phenylvinylia amino eflux, dopamineupataubrand and diazophenol binding.j. pharmacol. exp. ther.245, 199-210;

14Lindemann, L. et al (2005) Traceramineassatedrepitter for constructing a library of functions of expressing library of genes of noveltoveGprotein-coupledrepitter. genomics85, 372-385.

The present invention relates to novel compounds of formula I and their pharmaceutically acceptable salts, their use for the preparation of medicaments for the treatment of disorders relating to the biological function of trace amine associated receptors, their preparation as well as medicaments based on the compounds according to the invention for the control or prevention of disorders such as depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as parkinson's disease, neurodegenerative disorders such as alzheimer's disease, epilepsy, migraine, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and homeostasis, disorders of body temperature and function, disorders of sleep and circadian rhythm, and cardiovascular disorders.

Preferred indications for use of the compounds of the invention are depression, psychosis, parkinson's disease, anxiety, Attention Deficit Hyperactivity Disorder (ADHD) and diabetes.

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

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

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

As used herein, the term "lower alkyl substituted by halogen" refers to a saturated straight or branched chain group containing 1 to 7 carbon atoms as defined for the term "lower alkyl", wherein at least one hydrogen atom is replaced by a halogen atom. The preferred halogen atom is fluorine. An example of such a group is CF₃，CHF₂，CH₂F，CH₂CF₃Or CH₂CHF₂。

As used herein, the term "lower alkoxy substituted by halogen" refers to an alkoxy group as defined above and wherein one or more hydrogen atoms are replaced by halogen, e.g. OCH₃，OCHF₂，OCH₂F，OCH₂CF₃Or OCH₂CHF₂。

The term "pharmaceutically acceptable acid addition salts" includes salts with inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

One embodiment of the present invention are compounds of formula IA

R¹Is hydrogen, halogen, cyano, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or C (O) NH₂，

Or phenyl optionally substituted by halogen, cyano or lower alkoxy substituted by halogen,

or 2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl, or 6- (trifluoromethyl) pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or 6- (trifluoromethyl) pyrimidin-4-yl,

or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2;

R²is halogen, lower alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, lower alkyl or cyano;

or a pharmaceutically suitable acid addition salt thereof, for example the following compounds:

1- (3-cyano-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

1- (3-cyano-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

(RS) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea

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

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea

1- (3-cyano-5-fluoro-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

1- (3-cyano-4-fluoro-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

(S) -1- (5-cyano-2-methoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea

(R) -1- (5-cyano-2-methoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2-methoxyphenyl) urea

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2-methoxyphenyl) urea

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2- (difluoromethoxy) phenyl) urea

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2- (difluoromethoxy) phenyl) urea

1- (5-cyano-2-fluoro-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-methoxy-phenyl) -urea

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-methoxy-phenyl) -urea

1- (3-cyano-5-fluoro-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-difluoromethoxy-phenyl) -urea

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-difluoromethoxy-phenyl) -urea

(R) -1- (3-cyano-2-fluorophenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea

(R) -1- (3-cyano-4-fluorophenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea

1- (5-cyano-2-difluoromethoxy-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

1- (5-cyano-2-difluoromethoxy-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

(S) -1- (5-cyano-2-ethoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea or

(R) -1- (5-cyano-2-ethoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea.

A further embodiment of the present invention are compounds of the formula IB

Wherein

R¹Is hydrogen, halogen, cyano, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or C (O) NH₂，

Or phenyl optionally substituted by halogen, cyano or lower alkoxy substituted by halogen,

or 2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl, or 6- (trifluoromethyl) pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or 6- (trifluoromethyl) pyrimidin-4-yl,

or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2;

R²is halogen, lower alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, lower alkyl or cyano;

or a pharmaceutically suitable acid addition salt thereof, for example the following compounds:

1- (3-cyano-benzyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

1- (3-cyano-benzyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

(R) -1- (3- (difluoromethoxy) benzyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea or

(S) -1- (3- (difluoromethoxy) benzyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea.

A further embodiment of the present invention are compounds of the formula IC

Wherein

R¹Is hydrogen, halogen, cyano, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or C (O) NH₂，

Or phenyl optionally substituted by halogen, cyano or lower alkoxy substituted by halogen,

or 2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl, or 6- (trifluoromethyl) pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or 6- (trifluoromethyl) pyrimidin-4-yl,

or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2

R²Is halogen, lower alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, lower alkyl or cyano;

or pharmaceutically suitable acid addition salts thereof, for example the following compounds:

(S) -4-chloro-N- (2-chloro-4- (morpholin-2-yl) phenyl) benzamide.

A further embodiment of the invention are compounds of the formula ID

Wherein

R¹Is hydrogen, halogen, cyano, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or C (O) NH₂，

Or phenyl optionally substituted by halogen, cyano or lower alkoxy substituted by halogen,

or 2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl, or 6- (trifluoromethyl)

Pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or is 6- (trifluoromethyl) pyrimidin-4-yl,

or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2

R²Is halogen, lower alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, lower alkyl or cyano;

hetar is selected from the group consisting of: 1H-indazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl;

or pharmaceutically suitable acid addition salts thereof, for example

6-fluoro-1H-indazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

6-fluoro-1H-indazole-3-carboxylic acid ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

1- (4-fluoro-phenyl) -1H-pyrazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

1- (4-fluoro-phenyl) -1H-pyrazole-3-carboxylic acid ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -

2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

(RS) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -H-pyrazole-4-carboxamide

(R) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide

(S) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide

2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

2-chloro-N- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -6-methoxy-isonicotinamide

2-chloro-N- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -6-methoxy-isonicotinamide

(RS) -N- (2-cyano-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide

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

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

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

(S) -1- (3- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

(S) -1- (4- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

(S) -4-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide

(R) -4-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide

(S) -6-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide

(S) -1- (2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

(R) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide

(R) -2-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) isonicotinamide

(R) -6-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) nicotinamide

(R) -1- (4- (difluoromethoxy) phenyl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide

(S) -2-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) isonicotinamide

(S) -6-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) nicotinamide

(S) -1- (4- (difluoromethoxy) phenyl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

(R) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -2-ethoxyisonicotinamide

(R) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -6-ethoxynicotinamide

(R) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxamide

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -2-ethoxyisonicotinamide

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -6-ethoxynicotinamide

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxamide

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -6-cyanopyridinecarboxamide

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

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -5-cyanopyridinecarboxamide

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -5-cyanopyridinecarboxamide

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

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -6-cyanonicotinamide

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-cyanophenyl) -1H-pyrazole-4-carboxamide

(S) -1- (4- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-1,2, 3-triazole-4-carboxamide

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4-cyanophenyl) -1H-pyrazole-4-carboxamide

(S) -4-chloro-6-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide

(S) -2-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methoxyisonicotinamide

(S) -1- (4-cyano-2-fluorophenyl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4-cyano-2-fluorophenyl) -1H-pyrazole-4-carboxamide

(S) -1- (4-cyano-2-fluorophenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

(S) -1- (4-cyanophenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -2-cyano-6-methylisonicotinamide

(S) -2-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methylisonicotinamide

(S) -N4- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide

(S) -2-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methylisonicotinamide

(S) -6-chloro-N4- (3-fluoro-4- (morpholin-2-yl) phenyl) pyridine-2, 4-dicarboxamide

(S) -6-Ethyl-N4- (3-fluoro-4- (morpholin-2-yl) phenyl) pyridine-2, 4-dicarboxamide

(S) -N4- (3-chloro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide

(S) -N4- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide

(S) -N4- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methoxypyridine-2, 4-dicarboxamide

(S) -2-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methoxyisonicotinamide

(S) -N4- (2-chloro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -2-cyano-6-methylisonicotinamide

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -2-cyano-6-methoxyisonicotinamide

(S) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyridin-3-yl) -1H-pyrazole-4-carboxamide

(S) -1- (5-cyanopyrazin-2-yl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (2- (trifluoromethyl) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide

(S) -4-chloro-6-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (5- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide

(S) -5-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-carboxamide

(S) -5-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-carboxamide

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -5- (trifluoromethyl) pyrazine-2-carboxamide or

(S) -6-ethoxy-N- (2-fluoro-4- (morpholin-2-yl) phenyl) nicotinamide.

A further embodiment of the invention are compounds of the formula IE

Wherein

R¹Is hydrogen, halogen, cyano, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or C (O) NH₂，

Or phenyl optionally substituted by halogen, cyano or lower alkoxy substituted by halogen,

or 2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl, or 6- (trifluoromethyl)

Pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or is 6- (trifluoromethyl) pyrimidin-4-yl,

or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2

R²Is halogen, lower alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, lower alkyl or cyano;

hetar is selected from the group consisting of: 1H-indazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl;

or pharmaceutically suitable acid addition salts thereof, for example

1- (6-chloro-pyridin-3-yl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

1- (6-chloro-pyridin-3-yl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

1- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -3- (6-trifluoromethyl-pyridin-3-yl) -urea

1- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -3- (6-trifluoromethyl-pyridin-3-yl) -urea

(RS) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea

(S) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea

(R) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea

(RS) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-chloropyridin-3-yl) urea

(RS) -1- (6-chloro-pyridin-3-yl) -3- (2-chloro-4-pyrrolidin-3-yl-phenyl) -urea

(R) -1- (6-Chloropyridin-3-yl) -3- (2-methyl-4- (morpholin-2-yl) phenyl) urea

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (6- (trifluoromethyl) pyridin-3-yl) urea

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (6- (trifluoromethyl) pyridin-3-yl) urea

1- ((S) -2-chloro-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea

1- ((R) -2-chloro-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5- (trifluoromethyl) pyridin-2-yl) urea

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5- (trifluoromethyl) pyridin-2-yl) urea

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-chloropyridin-2-yl) urea

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-chloropyridin-2-yl) urea

(R) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-cyanopyridin-3-yl) urea

(S) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-cyanopyridin-3-yl) urea

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea or

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea.

Another object of the present invention are the compounds of formula I, wherein Z is a bond or-CH₂-, for example the following compounds

(RS) -1- (6-chloro-pyridin-3-yl) -3- (2-chloro-4-pyrrolidin-3-yl-phenyl) -urea

(RS) -1- (2-chloro-4- (piperidin-3-yl) phenyl) -3- (6-chloropyridin-3-yl) urea or

(RS) -6-chloro-N- (2-chloro-4-piperidin-3-yl-phenyl) -nicotinamide.

A further embodiment of the present invention are compounds of formula I

Wherein

R¹Is hydrogen, halogen, cyano, lower alkyl substituted by halogen, lower alkoxy or is phenyl optionally substituted by halogen;

R²is halogen, lower alkyl or cyano;

x is a bond, -NR' -, -CH₂NH-or-CHR' -;

r' is hydrogen or lower alkyl;

z is a bond, -CH₂-or-O-;

ar is phenyl or heteroaryl selected from the group consisting of: 1H-indazol-3-yl, pyridin-4-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl; or a pharmaceutically suitable acid addition salt thereof.

The compounds of formula I of the present invention and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by the methods described below, which methods comprise:

a) cleaving the N-protecting group from the compound of the formula

To form a compound of formula I

Wherein PG is an N-protecting group selected from the group consisting of-C (O) O-t-butyl, and the other definitions are the same as described above, and,

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

The preparation of the compounds of formula I according to the invention can be carried out sequentially or by convergent routes. The synthesis of the compounds of the present invention is shown in schemes 1-7 below and in the description of 138 specific compounds. The skills required for carrying out the reaction and purification of the resulting product are known to those skilled in the art. Unless indicated to the contrary, the substituents and symbols used in the description of the following methods have the meanings given herein before.

In more detail, the compounds of formula I can be prepared by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions for each reaction step are known to those skilled in the art. The reaction sequence is not limited to the sequence shown in schemes 1 to 7, but the order of the reaction steps may be freely changed according to the raw materials and their respective reactivity. The starting materials are commercially available or can be prepared by methods similar to those given below, by methods described in the references cited in the specification or in the examples, or by methods known in the art.

General procedure

Scheme 1

The substituents are as described above and R²Is F or Cl and R³Is hydrogen, or R²Is hydrogen and R³Is F or Cl.

Step A: alpha-chloroketone 2 can be obtained by homologation of acid chloride 1, comprising successive treatments, first of all treatment with (trimethylsilyl) diazomethane and then with concentrated hydrochloric acid. The reaction was carried out at a temperature of 0 ℃ to room temperature using a mixture of acetonitrile, THF and diethyl ether as a solvent.

Preferred conditions for the first step are that the reactants are allowed to react at room temperature for 30 minutes after mixing at 0-5 c, and that for the second step the reactants are allowed to react at room temperature for 30 minutes after mixing at 0-5 c.

Step B epoxide formation can be accomplished by a step-wise process comprising α -chloroketone 2 by treatment with a reducing agent such as NaBH₄Or LiBH₄In solvents such as MeOH, EtOH, THF, bisReduction of treatment in an alkane, followed by cyclization of α -chlorohydrin by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or cesium carbonate in the same solvent.

Preferred conditions are NaBH₄In ethanol at 5 ℃ to room temperature for 1 hour, followed by treatment with sodium methoxide at room temperature for 16 hours and thenAt 40 ℃ for 1 hour.

Step C: nucleophilic ring-opening can be accomplished by: the epoxide 3 is reacted with 2-aminoethanol,

optionally in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine in an aprotic polar organic solvent such as ether, THF, diAlkane or TBME.

Preferred conditions are the use of an excess of 2-aminoethanol as base in THF for 16 hours at room temperature.

Step D: the selective protection of the amino group of amino alcohol 4 can be achieved by: with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine, in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diethyl etherAlkane, THF or TBME.

Preferred conditions are dichloromethane in the absence of base at room temperature for 16 hours.

Step E: the cyclization can be accomplished by a step-wise process comprising the steps of: with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine via diol 5 in an ethereal solvent such as diethyl ether, diethyl etherTreatment in an alkane, THF or TBME to form a sulfonate ester followed by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in an ethereal solvent such as diethyl ether, diIn alkane, THF or TBMEAnd (4) processing and cyclizing.

Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 ℃ and then allowing to react for 30 minutes at room temperature, after which by-product triethylamine hydrochloride is removed by filtration. The preferred conditions for the second step are that potassium 2-methyl-2-butoxide in THF the reactants are mixed at 0-5 deg.C and then allowed to react at room temperature for 1 hour.

Step F: the C-N bond formation can be carried out by 6-ring-opening benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in a solvent such as bisTreatment in alkanes, DME, THF, toluene, DMF and DMSO is accomplished at elevated temperatures, for example using the palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are catalytic tris (dibenzylideneacetone) dipalladium (0), catalytic (R) - (+) -2,2 '-bis (diphenylphosphino) -1, 1' -binaphthyl and sodium tert-butoxide in bisIn an alkane at 100 ℃ for 1 hour.

Step G: removal of the nitrogen protecting group of 7 can be carried out by hydrogenation with hydrogen at atmospheric or elevated pressure or by using ammonium formate or cyclohexadiene as catalyst for hydrogen source such as PtO₂Pd-C or Raney nickel in a solvent such as MeOH, EtOH, H₂O, twoAlkane, THF, HOAc, EtOAcCH₂Cl₂、CHCl₃Transfer hydrogenation in DMF or mixtures thereof.

Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 60 ℃ for 1 hour.

If desired, racemic mixtures of chiral amines 8 can be separated into their component enantiomers by using chiral HPLC.

Step H: amide bond formation can be achieved by reacting an amine 8 with a carboxylic acid compound 9 in the presence of a coupling agent such as DCC, EDC, TBTU or HATU in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diethyl etherThe coupling reaction in alkane, THF, DME or TBME is complete.

Preferred conditions are TBTU with N-methylmorpholine in THF at 50-60 deg.C for 18-48 hours.

Alternatively, amide bond formation may be by between the amine 8 and the acid chloride compound 9' in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, bisThe coupling reaction in an alkane, THF, DME or TBME in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine is complete.

Preferred conditions are triethylamine in THF for 18 hours at room temperature.

If desired, the acid chloride compound 9' can be isolated from the corresponding carboxylic acid 9 by treatment with oxalyl chloride in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diethyl etherPrepared in situ by treatment in an alkane, THF, DME or TBME in the presence of a catalyst such as DMF.

Preferred conditions are dichloroethane at room temperature for 1 hour.

Step I: removal of the BOCN-protecting group may be carried out with mineral acids such as HCl, H₂SO₄Or H₃PO₄Or organic acids such as CF₃COOH、CHCl₂COOH, HOAc or p-tolueneSulfonic acids in solvents such as CH₂Cl₂、CHCl₃THF, MeOH, EtOH or H₂In O at 0 to 80 ℃.

Preferred conditions are CF₃COOH in aqueous acetonitrile at 80 ℃ for 5 hours or 4NHCl in bisAlkane and THF at 60 ℃ for 16 hours.

If desired, racemic mixtures of the morpholino compounds IC-1 or ID-1 can be separated into their component enantiomers by the use of chiral HPLC.

Scheme 2

The substituents are as described above and R²Is F or Cl and R³Is hydrogen, or R²Is hydrogen and R³Is F or Cl. And Y is a bond or-CH₂-。

Step A: urea formation can be accomplished by a two-step one-pot procedure comprising first converting the amine 8-1 to the corresponding isocyanate 12 followed by reacting the isocyanate with the amine compound 11 in situ.

Isocyanate formation can be accomplished by treating the amine 8-1 with triphosgene, diphosgene, or phosgene in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine or an inorganic base such as sodium carbonate or potassium carbonate.

Preferred conditions for the formation of the isocyanate 12 are triphosgene and sodium carbonate in a mixture of dichloromethane and water at room temperature for 2-3 hours, followed by treatment with the amine 11 in the same solvent mixture at room temperature for 2 hours.

And B: removal of the BOCN-protecting group may be carried out with mineral acids such as HCl, H₂SO₄Or H₃PO₄Or organic acids such as CF₃COOH、CHCl₂COOH, HOAc or p-toluenesulfonic acid in a solvent such as CH₂Cl₂、CHCl₃THF, MeOH, EtOH or H₂In O at 0 to 80 ℃.

Preferred conditions are CF₃COOH in aqueous acetonitrile at 80 ℃ for 3 hours or 4NHCl in bisAlkane and THF at 60 ℃ for 16 hours.

If desired, racemic mixtures of morpholine compounds IA-1, IE-1 or IB-1 may be separated into their component enantiomers by the use of chiral HPLC.

Scheme 3

The substituents are as described above, R²Is Cl, Br or I, and Z is a bond, -CH₂-or O.

Step A: aniline compound 14 can be regioselectively halogenated by reaction with one equivalent of a halogenating agent such as N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide. Examples of suitable anilines 14 include pyrrolidine derivatives in which Z is a bond [ CAS908334-28-1]Wherein Z is-CH₂Piperidine derivative of (1) [ CAS875798-79-1 ]]And morpholine derivatives [ CAS1002726-96-6 ] wherein Z is O]。

The reaction is carried out in an aprotic polar organic solvent such as DMF or NMP.

Preferred conditions are NBS in DMF at room temperature for 15 minutes or NCS in DMF at 70 ℃ for 1 hour.

And B: amide bond formation can be achieved between amine 15 and carboxylic acid compound 9 in the presence of a coupling agent such as DCC, EDC, TBTU or HATU in the presence of an organic base such as trisEthylamine, N, N-diisopropylethylamine or N-methylmorpholine in the presence of a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diethyl etherThe coupling reaction in alkane, THF, DME or TBME is complete.

Preferred conditions are TBTU with N-methylmorpholine in THF at 50-60 deg.C for 18-48 hours.

Alternatively, amide bond formation may be by between the amine 15 and the acid chloride compound 9' in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, bisThe coupling reaction in an alkane, THF, DME or TBME in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine is complete.

Preferred conditions are triethylamine in THF for 18 hours at room temperature.

If desired, the acid chloride compound 9' can be isolated from the corresponding carboxylic acid 9 by treatment with oxalyl chloride in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diethyl etherPrepared in situ by treatment in an alkane, THF, DME or TBME in the presence of a catalyst such as DMF.

Preferred conditions are dichloroethane at room temperature for 1 hour.

And C: removal of the BOCN-protecting group may be carried out with mineral acids such as HCl, H₂SO₄Or H₃PO₄Or organic acids such as CF₃COOH、CHCl₂COOH, HOAc or p-toluenesulfonic acid in a solvent such as CH₂Cl₂、CHCl₃THF, MeOH, EtOH or H₂In O at 0 to 80 ℃.

Preference is given toProvided that CF is₃COOH in aqueous acetonitrile at 80 ℃ for 5 hours or 4NHCl in bisAlkane and THF at 60 ℃ for 16 hours.

If desired, racemic mixtures of the morpholino compounds IC-2 or ID-2 can be separated into their component enantiomers by the use of chiral HPLC.

Scheme 4

The substituents are as described above, R²Is CN and Z is a bond, -CH₂-or O.

Step A: the aromatic nitrile compound 17 can be prepared by reacting the aromatic bromine compound 15-1 with a metal cyanide salt such as potassium cyanide, sodium cyanide or copper (I) cyanide, optionally in the presence of a palladium catalyst.

The reaction is carried out in an aprotic polar organic solvent such as DMF or NMP at elevated temperature.

Preferred conditions are CuCN in NMP at 160 ℃ for 5 hours.

And B: amide bond formation can be effected between the amine 17 and the carboxylic acid compound 9 in the presence of a coupling agent such as DCC, EDC, TBTU or HATU in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diethyl etherThe coupling reaction in alkane, THF, DME or TBME is complete.

Preferred conditions are TBTU with N-methylmorpholine in THF at 50-60 deg.C for 18-48 hours.

Alternatively, amide bond formation may be by between the amine 17 and the acid chloride compound 9' in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, bisThe coupling reaction in an alkane, THF, DME or TBME in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine is complete.

Preferred conditions are triethylamine in THF for 2 hours at room temperature.

If desired, the acid chloride compound 9' can be isolated from the corresponding carboxylic acid 9 by treatment with oxalyl chloride in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diethyl etherPrepared in situ by treatment in an alkane, THF, DME or TBME in the presence of a catalyst such as DMF.

Preferred conditions are dichloroethane at room temperature for 1 hour.

And C: removal of the BOCN-protecting group may be carried out with mineral acids such as HCl, H₂SO₄Or H₃PO₄Or organic acids such as CF₃COOH、CHCl₂COOH, HOAc or p-toluenesulfonic acid in a solvent such as CH₂Cl₂、CHCl₃THF, MeOH, EtOH or H₂In O at 0 to 80 ℃.

Preferred conditions are CF₃COOH in aqueous acetonitrile at 80 ℃ for 5 hours or 4NHCl in bisAlkane and THF at 60 ℃ for 16 hours.

If desired, racemic mixtures of the morpholino compounds IC-3 and ID-3 can be separated into their component enantiomers by the use of chiral HPLC.

Scheme 5

The substituents are as defined above, Z is a bond, -CH₂-or O.

Step A: urea formation can be accomplished by a two-step one-pot procedure comprising first converting the amine 17 to the corresponding isocyanate 19 followed by reacting the isocyanate with the amine compound 11 in situ.

Isocyanate formation can be accomplished by treating the amine 17 with triphosgene, diphosgene, or phosgene in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine or an inorganic base such as sodium carbonate or potassium carbonate.

Preferred conditions for the formation of the isocyanate 19 are triphosgene and sodium carbonate in a mixture of dichloromethane and water at room temperature for 3 hours, followed by treatment with the amine 11 in the same solvent mixture at room temperature for 24-48 hours.

And B: removal of the BOCN-protecting group may be carried out with mineral acids such as HCl, H₂SO₄Or H₃PO₄Or organic acids such as CF₃COOH、CHCl₂COOH, HOAc or p-toluenesulfonic acid in a solvent such as CH₂Cl₂、CHCl₃THF, MeOH, EtOH or H₂In O at 0 to 80 ℃.

Preferred conditions are CF₃COOH in aqueous acetonitrile at 80 ℃ for 4 hours or 4NHCl in bisAlkane and THF at 60 ℃ for 16 hours.

If desired, racemic mixtures of morpholine compounds IA-2 and IE-2 can be separated into their component enantiomers by using chiral HPLC.

Scheme 6

The substituents are as described above.

Step A: the α -haloketone 22 can be obtained by a homologation reaction involving an acyl halide 21[ e.g. hal' = chloride and alkyl = methyl, CAS35675-46-8] treated sequentially as follows: first with (trimethylsilyl) diazomethane, followed by concentrated hydrobromic or hydrochloric acid. The reaction is carried out at a temperature of 0 ℃ to room temperature using a mixture of acetonitrile, THF and hexane as a solvent.

Preferred conditions for the first step are that the reactants are allowed to react at room temperature for 1 hour after mixing at 0-5 c, and for the second step the reactants are allowed to react at room temperature for 30 minutes after mixing at 0-5 c.

Step B epoxide formation can be accomplished by a step-wise process comprising α -haloketone 22 by using a reducing agent such as NaBH₄Or LiBH₄In solvents such as MeOH, EtOH, THF, bisReduction of treatment in an alkane, followed by cyclization of α -halohydrin by treatment with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or cesium carbonate in the same solvent.

Preferred conditions are NaBH₄After 1 hour at 5 ℃ to room temperature in ethanol, treatment with sodium methoxide at room temperature for 16 hours.

Step C: nucleophilic ring-opening can be accomplished by: epoxide 23 is reacted with 2-aminoethanol, optionally in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine, in an aprotic polar organic solvent such as ether, THF, diAlkane or TBME.

Preferred conditions are the use of an excess of 2-aminoethanol as base in THF for 16 hours at room temperature.

Step D: selective protection of the amino group of amino alcohol 24 can be achieved by: with di-tert-butyl carbonate, optionally in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine, in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diethyl etherAlkane, THF or TBME.

Preferred conditions are THF in the absence of base at room temperature for 16 hours.

Step E: the cyclization can be accomplished by a step-wise process comprising the steps of: with one equivalent of methanesulfonyl chloride in the presence of an organic base such as triethylamine, N-diisopropylethylamine or N-methylmorpholine via a diol 25 in an ethereal solvent such as diethyl ether, diethyl etherTreatment in an alkane, THF or TBME to form a sulfonate ester followed by treatment with a non-nucleophilic base such as potassium tert-butoxide or potassium 2-methyl-2-butoxide in an ethereal solvent such as diethyl ether, diTreatment in alkane, THF or TBME for cyclization.

Preferred conditions for the first step are triethylamine in THF mixing the reactants at 0-5 ℃ and then allowing to react for 1 hour at room temperature, after which by-product triethylamine hydrochloride is removed by filtration. The preferred conditions for the second step are that potassium 2-methyl-2-butoxide in THF the reactants are mixed at 0-5 deg.C and then allowed to react for 30 minutes at room temperature.

Step F: the reduction of the nitro group of 26 can be carried out by using hydrogen at atmospheric pressure or elevated pressureBy hydrogenation under pressure or by using ammonium formate or cyclohexadiene as catalyst for the hydrogen source, e.g. PtO₂Pd-C or Raney nickel in a solvent such as MeOH, EtOH, H₂O, twoAlkane, THF, HOAc, EtOAcCH₂Cl₂、CHCl₃Transfer hydrogenation in DMF or mixtures thereof.

Preferred conditions are ammonium formate in the presence of palladium on charcoal in MeOH at 60 ℃ for 1 hour.

Step G: amide bond formation can be achieved by reacting an amine 27 with a carboxylic acid compound 9 in the presence of a coupling agent such as DCC, EDC, TBTU or HATU in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diethyl etherThe coupling reaction in alkane, THF, DME or TBME is complete.

Preferred conditions are TBTU with N-methylmorpholine in THF at 50-60 deg.C for 18-48 hours.

Alternatively, amide bond formation may be by between the amine 27 and the acid chloride compound 9' in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diThe coupling reaction in an alkane, THF, DME or TBME in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine is complete.

Preferred conditions are triethylamine in THF for 2 hours at room temperature.

If desired, the acid chloride compound 9 can be prepared from the corresponding carboxylic acid 9 by reacting oxalyl chloride in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane or an ethereal solvent such as diethyl ether, diethyl etherPrepared in situ by treatment in an alkane, THF, DME or TBME in the presence of a catalyst such as DMF.

Preferred conditions are dichloroethane at room temperature for 1 hour.

Step H: removal of the BOCN-protecting group may be carried out with mineral acids such as HCl, H₂SO₄Or H₃PO₄Or organic acids such as CF₃COOH、CHCl₂COOH, HOAc or p-toluenesulfonic acid in a solvent such as CH₂Cl₂、CHCl₃THF, MeOH, EtOH or H₂In O at 0 to 80 ℃.

Preferred conditions are CF₃COOH in aqueous acetonitrile at 80 ℃ for 4 hours or 4NHCl in bisAlkane and THF at 60 ℃ for 16 hours.

If desired, racemic mixtures of the morpholino compounds IC-4 and ID-4 can be separated into their component enantiomers by the use of chiral HPLC.

Scheme 7

The substituents are as described above and X is NH, R²Is alkyl and Z is O.

Step 4: urea formation can be accomplished by a two-step one-pot procedure comprising first converting the amine 27 to the corresponding isocyanate 29 and then reacting that isocyanate with the amine compound 11 in situ.

Isocyanate formation may be accomplished by treating amine 27 with triphosgene, diphosgene or phosgene in a halogenated solvent such as dichloromethane or 1, 2-dichloroethane in the presence of an organic base such as triethylamine or N, N-diisopropylethylamine or an inorganic base such as sodium carbonate or potassium carbonate.

Preferred conditions for the formation of the isocyanate 29 are triphosgene and sodium carbonate in a mixture of dichloromethane and water at room temperature for 2-3 hours, followed by treatment with the amine 11 in the same solvent mixture at room temperature for 2 hours.

And B: removal of the BOCN-protecting group may be carried out with mineral acids such as HCl, H₂SO₄Or H₃PO₄Or organic acids such as CF₃COOH、CHCl₂COOH, HOAc or p-toluenesulfonic acid in a solvent such as CH₂Cl₂、CHCl₃THF, MeOH, EtOH or H₂In O at 0 to 80 ℃.

Preferred conditions are CF₃COOH in aqueous acetonitrile at 80 ℃ for 3 hours or 4NHCl in bisAlkane and THF at 60 ℃ for 16 hours.

If desired, racemic mixtures of morpholine compounds IA-3 and IE-3 can be separated into their component enantiomers by using chiral HPLC.

Isolation and purification of compounds

Isolation and purification of the compounds and intermediates described herein can be accomplished by any suitable isolation or purification procedure, if desired, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low or high pressure liquid chromatography, or a combination of such procedures. A detailed description of suitable separation and isolation procedures can be obtained by reference to the preparations and examples herein below. However, other equivalent separation or isolation steps may of course be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC. Racemic mixtures of chiral synthetic intermediates can also be separated using chiral HPLC.

Salts of compounds of formula I

The compounds of formula I are basic and can be converted into the corresponding acid addition salts. The conversion is accomplished by treatment with at least a stoichiometric amount of a suitable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and an organic acid, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol, etc., and the acid is added to a similar solvent. The temperature was maintained between 0 ℃ and 50 ℃. The resulting salt precipitates spontaneously or can be removed from solution with a less polar solvent.

Example 1

6-fluoro-1H-indazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

a) 2-chloro-1- (4-bromo-3-fluoro-phenyl) -ethanone

To a stirred solution of 4-bromo-3-fluorobenzoyl chloride (5.6g, CAS695188-21-7) in acetonitrile (30ml) and THF (30ml) at 0-5 deg.C was added dropwise (trimethylsilyl) diazomethane (13.7ml, 2M solution in diethyl ether). The reaction mixture was stirred at room temperature for 30 minutes. TLC analysis showed the reaction was complete. Hydrochloric acid (3.81ml, 37% aqueous solution) was then added dropwise over 10 minutes at 0-5 ℃ and the reaction mixture was stirred at room temperature for an additional 20 minutes. The reaction mixture was poured into EtOAc and successively over Na₂CO₃Aqueous solution, water and saturated brine. The organic layer was then washed with Na₂SO₄Dried above and concentrated in vacuo to afford 2-chloro-1- (4-bromo-3-fluoro-phenyl) -ethanone (5.67g) as a yellow solid which was used in the next step without further purificationThe preparation is used. Ms (ei): 203([{⁸¹Br}M-CH₂Cl]⁺)，201([{⁷⁹Br}M-CH₂Cl]⁺)，175([{⁸¹Br}M-CH₂Cl-CO]⁺)，173([{⁷⁹Br}M-CH₂Cl-CO]⁺)。

b) (RS) -2- (4-bromo-3-fluoro-phenyl) -oxirane

To a stirred solution of 2-chloro-1- (4-bromo-3-fluoro-phenyl) -ethanone (6.16g) in ethanol (100ml) at 5 ℃ was added NaBH portion by portion over 5 minutes₄(788 mg). The reaction mixture was then stirred at room temperature for 1 hour to give a pale yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (562mg) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed a small amount of starting material remained and the reaction mixture was then stirred at 40 ℃ for 1 h. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, then over Na₂SO₄Dried above and concentrated in vacuo to afford (RS) -2- (4-bromo-3-fluoro-phenyl) -oxirane (4.69g) as a yellow oil, which was used in the next step without further purification.

c) (RS) -1- (4-bromo-3-fluoro-phenyl) -2- (2-hydroxy-ethylamino) -ethanol

To a stirred solution of (RS) -2- (4-bromo-3-fluoro-phenyl) -oxirane (4.69g) in THF (11ml) was added 2-aminoethanol (13.2ml) and the mixture was stirred at rt overnight. The reaction mixture was then poured into brine and extracted twice with EtOAc. The combined organic layers were washed with Na₂SO₄Dried on and concentrated in vacuo to afford (RS) -1- (4-bromo-3-fluoro-phenyl) -2- (2-hydroxy-ethylamino) -ethanol (5.37g) as a yellow viscous oil, which was used in the next step without further purification. Ms (isp): 280.2([{⁸¹Br}M+H]⁺)，278.1([{⁷⁹Br}M+H]⁺)。

d) (RS) - [2- (4-bromo-3-fluoro-phenyl) -2-hydroxy-ethyl]- (2-hydroxy-ethyl) -carbamic acid tert-butyl ester

To a stirred solution of (RS) -1- (4-bromo-3-fluoro-phenyl) -2- (2-hydroxy-ethylamino) -ethanol (5.37g) in dichloromethane (60ml) was added Boc₂O (4.00g) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with dichloromethane. The organic layer was successively washed with lM aqueous HCl, saturated NaHCO₃The aqueous solution and saturated brine were washed, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 10% MeOH in dichloromethane) to give (RS) - [2- (4-bromo-3-fluoro-phenyl) -2-hydroxy-ethyl]- (2-hydroxy-ethyl) -carbamic acid tert-butyl ester (3.89g, 45% over 4 steps) as light yellow viscous oil. Ms (isp): 380.1([{⁸¹Br}M+H]⁺)，378.2([{⁷⁹Br}M+H]⁺)。

e) (RS) -2- (4-bromo-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester

To (RS) - [2- (4-bromo-3-fluoro-phenyl) -2-hydroxy-ethyl at 0-5 ℃]A stirred solution of tert-butyl- (2-hydroxy-ethyl) -carbamate (3.88g) and triethylamine (1.71ml) in THF (40ml) was added dropwise to methanesulfonyl chloride (873. mu.l). The reaction mixture was then stirred at room temperature for 30 minutes to give a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride and the filter was washed with THF (6 ml). The filtrate was cooled to 0-5 ℃ and potassium 2-methyl-2-butoxide (9.05ml, 1.7M solution in toluene) was added. The reaction mixture was stirred at room temperature for 1 hour and then poured into water and extracted twice with EtOAc. The combined organic phases were washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to give (RS) -2- (4-bromo-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (1.73g, 47%) as an orange viscous oil. Ms (isp): 306.1([{⁸¹Br}M+H-C₄H₈]⁺)，304.1([{⁷⁹Br}M+H-C₄H₈]⁺)，262.0([{⁸¹Br}M+H-C₄H₈-CO₂]⁺)，260.1([{⁷⁹Br}M+H-C₄H₈-CO₂]⁺)。

f) (RS) -2- [4- (diphenylmethylene-amino) -3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -2- (4-bromo-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (1.57g) and benzophenone imine (1.15ml) in toluene (40ml) was added sodium tert-butoxide (691 mg). The reaction mixture was purged with argon for 10 minutes. (R) - (+) -2,2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (280mg) and tris (dibenzylideneacetone) dipalladium (0) (120mg) were added to the solution, and the reaction mixture was heated to 100 ℃ and stirred for 1 h. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexane) to give (RS) -2- [4- (diphenylmethylene-amino) -3-fluoro-phenyl ] -ethyl acetate]Tert-butyl morpholine-4-carboxylate (2.215g, quantitative) as a yellow viscous oil. Ms (isp): 461.3([ M + H)]⁺)，405.4([M+H-C₄H₈]⁺)，361.3([M+H-C₄H₈-CO₂]⁺)。

g) (RS) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester

To (RS) -2- [4- (diphenylmethylene-amino) -3-fluoro-phenyl]A stirred solution of tert-butyl (2.21g) morpholine-4-carboxylate in methanol (40ml) was added ammonium formate (4.54 g). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. Then 10% palladium on activated carbon (255mg) was added and the reaction mixture was stirred at 60 ℃ for 1 hour. The reaction mixture was then filtered through celite and the filtrate was poured into 1M aqueous NaOH and extracted twice with EtOAc. The combined organic layers were washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to give (RS) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (1.42g, 74%) as a white solid. Ms (isp): 319.2([ M + Na ]]⁺)，297.3([M+H]⁺)，241.2([M+H-C₄H₈]⁺)，197.2([M+H-C₄H₈-CO₂]⁺)。

h) (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester&(-) - (S) -2- (4-amino-3-) Fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester

The enantiomer of (RS) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester was separated using chiral HPLC (column: chiralpak ad, 5 × 50 cm; eluent: 10% isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) to give:

(+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (146mg, light yellow solid), retention time =62 minutes

(-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (153mg, off-white solid) retention time =74 minutes

i) (R) -2- { 3-fluoro-4- [ (6-fluoro-1H-indazole-3-carbonyl) -amino]-phenyl } -morpholine-4-carboxylic acid tert-butyl ester

To a stirred suspension of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (40mg) in THF (6ml) and DMF (2ml) were successively added N-methylmorpholine (0.12ml), TBTU (128mg) and 6-fluoro-1H-indazole-3-carboxylic acid (47mg, CAS129295-30-3) and the mixture was heated at 50 ℃ for 24H and then at 60 ℃ for 18H. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO)₂(ii) a Gradient: heptane/EtOAc) to give (R) -2- { 3-fluoro-4- [ (6-fluoro-1H-indazole-3-carbonyl) -amino]-phenyl } -morpholine-4-carboxylic acid tert-butyl ester (15mg, 24%) as a white solid. Ms (isp): 476.1([ M + NH ]₄]⁺)，459.1([M+H]⁺)，403.1([M+H-C₄H₈]⁺)。

j) 6-amino-1H-indazole-3-carboxylic acid ((R) -2-amino-4-morpholin-2-yl-phenyl) -amide

To a stirred solution of trifluoroacetic acid (38 μ l) in water (1.5ml) was added (R) -2- { 3-fluoro-4- [ (6-fluoro-1H-indazole-3-carbonyl) -amino]-phenyl } -morpholine-a solution of tert-butyl 4-carboxylate (15mg) in acetonitrile (0.5 ml). The reaction mixture was then capped and the mixture was shaken at 80 ℃ for 5 h. The reaction mixture was then cooled to room temperature and poured into 1M aqueous NaOH and the resulting mixture was extracted twice with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. Passing the crude material through flash column chromatography (Flash-NH₂From Separtis; gradient: MeOH/EtOAc/heptane) to give 6-fluoro-1H-indazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide (9mg, 77%) as a white solid. Ms (isp): 359.1([ M + H)]⁺)。

Example 2

6-fluoro-1H-indazole-3-carboxylic acid ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

The title compound was obtained in analogy to example 1 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester in step (i) instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 359.1([ M + H)]⁺)。

Example 3

1- (3-cyano-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

a) (R) -2- {4- [3- (3-cyano-phenyl) -ureido ] -urea]-3-fluoro-phenyl } -morpholineQuinoline-4-carboxylic acid tert-butyl ester

To a stirred solution of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (60mg, example 1h) in dichloromethane (2ml) was added triphosgene (22 mg). A solution of sodium carbonate (43mg) in water (2ml) was then added. The reaction mixture was stirred at room temperature for 2.5 hours. TLC showed all starting material had reacted. 3-aminobenzonitrile (48mg, CAS2237-30-1) was then added and the reaction mixture was stirred at room temperature for an additional 2 hours. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 80% EtOAc in hexanes) to give (R) -2- {4- [3- (3-cyano-phenyl) -ureido [ ]]-3-fluoro-phenyl } -morpholine-4-carboxylic acid tert-butyl ester (95mg, quantitative) as a white solid. Ms (isp): 439.2([ M-H)]^-)。

b)1- (3-cyano-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

To a stirred solution of trifluoroacetic acid (216. mu.l) in water (4.5ml) was added (R) -2- {4- [3- (3-cyano-phenyl) -ureido]-3-fluoro-phenyl } -morpholine-4-carboxylic acid tert-butyl ester (85mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80 ℃ for 3 h. The reaction mixture was then cooled to room temperature and poured into 1M aqueous NaOH and the resulting mixture was extracted twice with EtOAc. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. Passing the crude material through flash column chromatography (Flash-NH₂From Separtis); gradient: heptane/EtOAc/MeOH) to give 1- (3-cyano-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea (45mg, 61%) as a white solid. Ms (isp): 341.1([ M + H)]⁺)。

Example 4

1- (3-cyano-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

The title compound was obtained in analogy to example 3 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester in step (a) instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 341.1([ M + H)]⁺)。

Example 5

(RS) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea

a)1- (4-bromo-3-chlorophenyl) -2-chloroacetone

To a stirred solution of 4-bromo-3-chlorobenzoyl chloride (11g, CAS21900-32-3) in acetonitrile (50ml) and THF (50ml) at 0-5 deg.C was added dropwise (trimethylsilyl) diazomethane (26.0ml, 2M solution in diethyl ether). The reaction mixture was stirred at room temperature for 30 minutes. TLC analysis showed the reaction was complete. Hydrochloric acid (7.22ml, 37% aqueous solution) was then added dropwise over 10 minutes at 0-5 ℃ and the reaction mixture was then stirred at room temperature for another 20 minutes. The reaction mixture was poured into EtOAc and successively over Na₂CO₃Aqueous solution, water and saturated brine. The organic layer was then washed with Na₂SO₄Dried on and concentrated in vacuo to afford 1- (4-bromo-3-chlorophenyl) -2-chloroacetophenone (11.0g, 95%) as a light brown solid, which was used in the next step without further purification. Ms (ei): 221([{⁸¹Br³⁷Cl}M-CH₂Cl]⁺)，219([{⁷⁹Br³⁷Cl/⁸¹Br³⁵Cl}M-CH₂Cl]⁺)，217([{⁷⁹Br³⁵Cl}M-CH₂Cl]⁺)，193([{⁸¹Br³⁷Cl}M-CH₂Cl-CO]⁺)，191([{⁷⁹Br³⁷Cl/⁸¹Br³⁵Cl}M-CH₂Cl-CO]⁺)，189([{⁷⁹Br³⁵Cl}M-CH₂Cl-CO]⁺)。

b) (RS) -2- (4-bromo-3-chlorophenyl) oxirane

To a stirred solution of 1- (4-bromo-3-chlorophenyl) -2-chloroacetone (18.4g) in ethanol (200ml) at 5 ℃ was added NaBH portionwise over 5 minutes₄(2.23 g). The reaction mixture was then stirred at room temperature for 90 minutes to give a pale yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (1.59g) was then added and the reaction mixture was stirred at 50 ℃ for 4 h. TLC analysis showed the reaction was complete. The reaction mixture was then poured into TBME and extracted with saturated brine. The organic layer was washed with Na₂SO₄Dried on and concentrated in vacuo to give (RS) -2- (4-bromo-3-chlorophenyl) oxirane (15.2g) as a brown oil, which was used in the next step without further purification.

c) (RS) -1- (4-bromo-3-chlorophenyl) -2- (2-hydroxyethylamino) ethanol

To a stirred solution of (RS) -2- (4-bromo-3-chlorophenyl) oxirane (15.2g) in THF (40ml) was added 2-aminoethanol (35.1ml) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was then poured into brine and extracted twice with EtOAc. The combined organic layers were washed with Na₂SO₄Dried on and concentrated in vacuo to afford (RS) -1- (4-bromo-3-chlorophenyl) -2- (2-hydroxyethylamino) ethanol (19.0g) as a yellow oil, which was used in the next step without further purification. Ms (isp): 298.1([{⁸¹Br³⁷Cl}M+H]⁺)，296.0([{⁷⁹Br³⁷Cl/⁸¹Br³⁵Cl}M+H]⁺)，293.9([{⁷⁹Br³⁵Cl}M+H]⁺)。

d) (RS) -2- (4-bromo-3-chlorophenyl) -2-hydroxyethyl (2-hydroxyethyl) carbamic acid tert-butyl ester

To a stirred solution of (RS) -1- (4-bromo-3-chlorophenyl) -2- (2-hydroxyethylamino) ethanol (19.0g) in THF (200ml) at 0 deg.C was added Boc₂O (14.1g) and then the mixture was stirred at room temperature overnight. The reaction mixture was then poured into ethyl acetate and extracted successively with 1M aqueous NaOH and saturated brine. The organic phase is washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; MeOH/dichloromethane 1/20) to give tert-butyl (RS) -2- (4-bromo-3-chlorophenyl) -2-hydroxyethyl (2-hydroxyethyl) carbamate (12.7g, 47% over 3 steps) as a yellow oil. Ms (isp): 397.9([{⁸¹Br³⁷Cl}M+H]⁺)，395.9([{⁷⁹Br³⁷Cl/⁸¹Br³⁵Cl}M+H]⁺)，393.9([{⁷⁹Br³⁵Cl}M+H]⁺)，341.9([{⁸¹Br³⁷Cl}M+H-C₄H₈]⁺)，339.9([{⁷⁹Br³⁷Cl/⁸¹Br³⁵Cl}M+H-C₄H₈]⁺)，338.0([{⁷⁹Br³⁵Cl}M+H-C₄H₈]⁺)。

e) (RS) -2- (4-bromo-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl (RS) -2- (4-bromo-3-chlorophenyl) -2-hydroxyethyl (2-hydroxyethyl) carbamate (12.7g) and triethylamine (6.72ml) in THF (150ml) at 0-5 deg.C was added dropwise methanesulfonyl chloride (2.76 ml). The reaction mixture was then stirred at room temperature for 1 hour to give a white suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride and the filter was washed with THF (20 ml). The filtrate was cooled to 0-5 ℃ and potassium 2-methyl-2-butoxide (28.4ml, 1.7M solution in toluene) was added. The reaction mixture was stirred at room temperature for 30 minutes and then poured into EtOAc and extracted successively with dilute aqueous HCl, water and saturated brine. The organic phase is washed with Na₂SO₄Upper dryingAnd concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexane) to give tert-butyl (RS) -2- (4-bromo-3-chlorophenyl) morpholine-4-carboxylate (9.32g, 77%) as a yellow oil. Ms (isp): 324.0([{⁸¹Br³⁷Cl}M+H-C₄H₈]⁺)，321.9([{⁷⁹Br³⁷Cl/⁸¹Br³⁵Cl}M+H-C₄H₈]⁺)，319.8([{⁷⁹Br³⁵Cl}M+H-C₄H₈]⁺)。

f) (RS) -2- (3-chloro-4- (diphenylmethyleneamino) phenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -2- (4-bromo-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (0.50g) and benzophenone imine (253mg) in toluene (5ml) was added sodium tert-butoxide (204 mg). The reaction mixture was purged with argon for 10 minutes. (R) - (+) -2,2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (82.7mg) and tris (dibenzylideneacetone) dipalladium (0) (36.5mg) were added to the solution, and the reaction mixture was heated at 90 ℃ overnight. The reaction mixture was poured into EtOAc and extracted successively with dilute aqueous HCl, water and saturated brine. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in hexane) to give tert-butyl (RS) -2- (3-chloro-4- (diphenylmethyleneamino) phenyl) morpholine-4-carboxylate (639mg, quantitative) as a yellow oil. Ms (isp): 479.1([ {37Cl } M + H)]⁺)，477.1([{³⁵Cl}M+H]⁺)。

g) (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -2- (3-chloro-4- (diphenylmethyleneamino) phenyl) morpholine-4-carboxylic acid tert-butyl ester (0.63g) in methanol (8ml) were added sodium acetate (325mg) and hydroxylamine hydrochloride (202 mg). The reaction mixture was stirred at room temperature for 16 hours and then at 60 ℃ for 5 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% in hexane)EtOAc) to give (RS) -tert-butyl 2- (4-amino-3-chlorophenyl) morpholine-4-carboxylate (345mg, 84%) as a white solid. Ms (isp): 337.2([{³⁷Cl}M+Na]⁺)，335.1([{³⁵Cl}M+Na]⁺)，314.9([{³⁷Cl}M+H]⁺)，313.0([{³⁵Cl}M+H]⁺)，259.1([{³⁷Cl}M+H-C₄H₈]⁺)，257.1([{³⁵Cl}M+H-C₄H₈]⁺)。

h) (RS) -2- (3-chloro-4- (3- (3-cyanophenyl) ureido) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (70mg) in dichloromethane (2ml) was added triphosgene (25 mg). A solution of sodium carbonate (47mg) in water (2ml) was then added. The reaction mixture was stirred at room temperature for 2.5 hours. TLC showed all starting material had reacted. 3-aminobenzonitrile (53mg, CAS2237-30-1) was then added and the reaction mixture was stirred at room temperature for an additional 2 hours. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 30% EtOAc in hexanes) to give (RS) -tert-butyl 2- (3-chloro-4- (3- (3-cyanophenyl) ureido) phenyl) morpholine-4-carboxylate (114mg, quantitative) as an amorphous white solid. Ms (isp): 457.2([{³⁷Cl}M-H]^-)，455.2([{³⁵Cl}M-H]^-)。

i) (RS) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea

To a stirred solution of trifluoroacetic acid (225 μ l) in water (4.5ml) was added a solution of tert-butyl (RS) -2- (3-chloro-4- (3- (3-cyanophenyl) ureido) phenyl) morpholine-4-carboxylate (114mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80 ℃ for 3 h. The reaction mixture was then cooled to room temperature and poured into 1M aqueous NaOH and the resulting mixture was extracted twice with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuoAnd (4) shrinking. Passing the crude material through flash column chromatography (Flash-NH₂From Separtis); gradient: heptane/EtOAc/MeOH) to give (RS) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea (58mg, 72%) as a white solid. Ms (isp): 359.1([{³⁷Cl}M+H]⁺)，357.1([{³⁵Cl}M+H]⁺)。

Examples 6&7

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea & (R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea

The enantiomer of (RS) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea (49mg, example 5) was separated using chiral HPLC (column: ChiralpakAD, 5X50 cm; eluent: 40% ethanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) to give:

(+) - (S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea (27mg, off-white solid)

Retention time =60 minutes. Ms (isp): 359.1([{³⁷Cl}M+H]⁺)，357.1([{³⁵Cl}M+H]⁺)。

(-) - (R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea (26mg, off-white solid)

Retention time =75 minutes. Ms (isp): 359.1([{³⁷Cl}M+H]⁺)，357.1([{³⁵Cl}M+H]⁺)。

Example 8

1- (6-chloro-pyridin-3-yl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

The title compound was obtained in analogy to example 3, using 6-chloropyridin-3-amine (CAS5350-93-6) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 353.1([{³⁷Cl}M+H]⁺)，351.1([{³⁵Cl}M+H]⁺)。

Example 9

1- (6-chloro-pyridin-3-yl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

The title compound was obtained in analogy to example 3 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and 6-chloropyridin-3-amine (CAS5350-93-6) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 353.1([{³⁷Cl}M+H]⁺)，351.1([{³⁵Cl}M+H]⁺)。

Example 10

1- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -3- (6-trifluoromethyl-pyridin-3-yl) -urea

The title compound was obtained in analogy to example 3 using 6- (trifluoromethyl) pyridin-3-amine (CAS106877-33-2) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 385.1([ M + H)]⁺)。

Example 11

1- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -3- (6-trifluoromethyl-pyridin-3-yl) -urea

The title compound was obtained in analogy to example 3 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and 6- (trifluoromethyl) pyridin-3-amine (CAS106877-33-2) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 385.1([ M + H)]⁺)。

Example 12

1- (4-fluoro-phenyl) -1H-pyrazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

The title compound was obtained in analogy to example 1 using 1- (4-fluorophenyl) -1H-pyrazole-3-carboxylic acid (CAS1152535-34-6) instead of 6-fluoro-1H-indazole-3-carboxylic acid in step (i). A white solid. Ms (isp): 385.1([ M + H)]⁺)。

Example 13

1- (4-fluoro-phenyl) -1H-pyrazole-3-carboxylic acid ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

The title compound was obtained in analogy to example 1 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and 1- (4-fluorophenyl) -1H-pyrazole-3-carboxylic acid (CAS1152535-34-6) instead of 6-fluoro-1H-indazole-3-carboxylic acid in step (i). A white solid. Ms (isp): 385.1([ M + H)]⁺)。

Example 14

(RS) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea

The title compound was obtained in analogy to example 5, using 6-chloropyridin-3-amine (CAS5350-93-6) instead of 3-aminobenzonitrile in step (h). Off-white solid. Ms (isp): 371.1([{³⁷Cl}M+H]⁺)，368.9([{³⁷Cl³⁵Cl}M+H]⁺)，367.1([{³⁵Cl}M+H]⁺)。

Example 15

1- (3-cyano-benzyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

Use of 3- (aminomethyl) benzyl in step (a)The title compound was obtained in analogy to example 3, using nitrile (CAS10406-24-3) instead of 3-aminobenzonitrile. Off-white amorphous solid. Ms (isp): 355.2([ M + H)]⁺)。

Example 16

1- (3-cyano-benzyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

The title compound was obtained in analogy to example 3 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and 3- (aminomethyl) benzonitrile (CAS10406-24-3) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 385.1([ M + H)]⁺)。

Example 17

2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

The title compound was obtained in analogy to example 1 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and 1-methyl-3-phenyl-1H-pyrazole-5-carboxylic acid (CAS10250-64-3) instead of 6-fluoro-1H-indazole-3-carboxylic acid in step (i). A white solid. Ms (isp): 381.3([ M + H)]⁺)。

Example 18

(RS) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide

a) (RS) -2- (3-chloro-4- (1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide) phenyl) morpholine-4-carboxylic acid tert-butyl ester Esters

To a stirred suspension of 1- (4-fluorophenyl) -1H-pyrazole-4-carboxylic acid (69mg, CAS138907-81-0) in dichloroethane (2ml) were added oxalyl chloride (67 μ l) and DMF (2 drops). The reaction mixture was stirred at room temperature for 1h and then concentrated in vacuo. The residue was dissolved in THF (1ml) and the resulting solution was added dropwise to a stirred solution of tert-butyl (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylate (80mg, example 5g) and triethylamine (178. mu.l) in THF (2 ml). The reaction mixture was stirred at rt for 2 h. The crude reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 50% EtOAc in heptane) to give (RS) -tert-butyl 2- (3-chloro-4- (1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide) phenyl) morpholine-4-carboxylate (102mg, 80%) as a white solid. Ms (isp): 520.3([{³⁷Cl}M+NH₄]⁺)，518.2([{³⁵Cl}M+NH₄]⁺)，503.1([{³⁷Cl}M+H]⁺)，501.1([{³⁵Cl}M+H]⁺)，447.1([{³⁷Cl}M+H-C₄H₈]⁺)，445.1([{³⁵Cl}M+H-C₄H₈]⁺)。

b) (RS) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide

To a stirred solution of trifluoroacetic acid (200 μ l) in water (4.5ml) was added a solution of tert-butyl (RS) -2- (3-chloro-4- (1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide) phenyl) morpholine-4-carboxylate (100mg) in acetonitrile (3 ml). The reaction mixture was then capped and the mixture was shaken at 80 ℃ for 5 h. Then will beThe reaction mixture was cooled to room temperature and poured into 1M aqueous NaOH and the resulting mixture was extracted twice with EtOAc. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. Passing the crude material through flash column chromatography (Flash-NH₂From Separtis); gradient: MeOH/EtOAc/heptane) to give (RS) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide (77mg, 96%) as a white solid. Ms (isp): 403.1([{⁵⁷Cl}M+H]⁺)，401.0([{³⁵Cl}M+H]⁺)。

Examples 19 and 20

(S) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea & (R) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea

The enantiomer of (RS) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea (42mg, example 14) was separated using chiral HPLC (column: chiralpak ad, 5 × 50 cm; eluent: 40% ethanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) to give:

(+) - (S) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea (14mg, light yellow solid)

Retention time =21 minutes. Ms (isp): 371.1([{³⁷Cl}M+H]⁺)，368.9([{³⁷Cl³⁵Cl}M+H]⁺)，367.1([{³⁵Cl}M+H]⁺)。

(-) - (R) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea (13mg, white solid)

Retention time =30 minutes. Ms (isp): 371.1([{³⁷Cl}M+H]⁺)，368.9([{³⁷Cl³⁵Cl}M+H]⁺)，367.1([{³⁵Cl}M+H]⁺)。

Example 21

(R) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide

The title compound was obtained in analogy to example 1 using 1- (4-fluorophenyl) -1H-pyrazole-4-carboxylic acid (CAS138907-81-0) instead of 6-fluoro-1H-indazole-3-carboxylic acid in step (i). A white solid. Ms (isp): 385.1([ M + H)]⁺)。

Example 22

(S) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide

The title compound was obtained in analogy to example 1 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and 1- (4-fluorophenyl) -1H-pyrazole-4-carboxylic acid (CAS138907-81-0) instead of 6-fluoro-1H-indazole-3-carboxylic acid in step (i). A white solid. Ms (isp): 385.1([ M + H)]⁺)。

Example 23

2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

a) (R) -2- { 3-fluoro-4- [ (2-methyl-5-phenyl-2H-pyrazole-3-carbonyl) -amino]-phenyl } -morpholine-4-carboxylic acid ester Tert-butyl ester

To a stirred suspension of 1-methyl-3-phenyl-1H-pyrazole-5-carboxylic acid (46mg, CAS10250-64-3) in dichloroethane (2ml) were added oxalyl chloride (44 μ l) and DMF (2 drops). The reaction mixture was stirred at room temperature for 1h and then concentrated in vacuo. The residue was dissolved in THF (1ml) and the resulting solution was added dropwise to a stirred solution of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (50mg, example 1h) and triethylamine (118 μ l) in THF (2 ml). The reaction mixture was stirred at rt for 2 h. The crude reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 50% EtOAc in heptane) to give (R) -2- { 3-fluoro-4- [ (2-methyl-5-phenyl-2H-pyrazole-3-carbonyl) -amino]-phenyl } -morpholine-4-carboxylic acid tert-butyl ester (81mg, quantitative) as a white solid. Ms (isp): 503.1([ M + Na)]⁺)，481.3([M+H]⁺)，425.2([M+H-C₄H₈]⁺)。

b) 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide

To a stirred solution of trifluoroacetic acid (124. mu.l) in water (4ml) was added (R) -2- { 3-fluoro-4- [ (2-methyl-5-phenyl-2H-pyrazole-3-carbonyl) -amino]-phenyl } -morpholine-4-carboxylic acid tert-butyl ester (78mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80 ℃ for 4 h. The reaction mixture was then cooled to room temperature and poured into 1M aqueous NaOH and the resulting mixture was extracted twice with EtOAc. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. Passing the crude material through flash column chromatography (Flash-NH₂From Separtis); gradient: EtOAc/heptane) to give 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide (49mg, 79%) as a white solid. Ms (isp): 381.3([ M + H)]⁺)。

Example 24

2-chloro-N- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -6-methoxy-isonicotinamide

The title compound was obtained in analogy to example 23, using 2-chloro-6-methoxyisonicotinic acid (CAS15855-06-8) instead of 1-methyl-3-phenyl-1H-pyrazole-5-carboxylic acid in step (a). A white solid. Ms (isp): 368.1([{³⁷Cl}M+H]⁺)，366.2([{³⁵Cl}M+H]⁺)。

Example 25

2-chloro-N- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -6-methoxy-isonicotinamide

The title compound was obtained in analogy to example 23, using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and using 2-chloro-6-methoxyisonicotinic acid (CAS15855-06-8) instead of 1-methyl-3-phenyl-1H-pyrazole-5-carboxylic acid in step (a). A white solid. Ms (isp): 368.1([{³⁷Cl}M+H]⁺)，366.1([{³⁵Cl}M+H]⁺)。

Example 26

1- (3-cyano-5-fluoro-phenyl) -34(S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

The title compound was obtained in analogy to example 3 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and 5-amino-3-fluorobenzonitrile (CAS210992-28-2) instead of 3-aminobenzonitrile in step (a). Off-white solid. Ms (isp): 359.2([ M + H)]⁺)。

Example 27

1- (3-cyano-4-fluoro-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

The title compound was obtained in analogy to example 3 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and 5-amino-2-fluorobenzonitrile (CAS53312-81-5) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 359.2([ M + H)]⁺)。

Example 28

(RS) -N- (2-cyano-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide

a) (RS) -2- (4-amino-3-bromophenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -2- (4-aminophenyl) morpholine-4-carboxylic acid tert-butyl ester (3.07g, CAS-1002726-96-6) in DMF (30ml) was added NBS (1.96g) and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was then poured into EtOAc and extracted successively with water and saturated brine. The organic layer was washed with Na₂SO₄Dried and then concentrated in vacuo to afford (RS) -tert-butyl 2- (4-amino-3-bromophenyl) morpholine-4-carboxylate (4.0g, quantitative) as a light brown solid, which was used in the next step without further purification. Ms (isp): 359.0([{⁸¹Br}M+H]⁺)，357.0([{⁷⁹Br}M+H]⁺)，303.0([{⁸¹Br}M+H-C₄H₈]⁺)，301.0([{⁷⁹Br}M+H-C₄H₈]⁺)。

b) (RS) -2- (4-amino-3-cyanophenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -2- (4-amino-3-bromophenyl) morpholine-4-carboxylic acid tert-butyl ester (3.76g) in NMP (30ml) was added CuCN (1.77g) and the reaction mixture was then stirred at 160 ℃ for 5 h. The mixture was then cooled to room temperature and poured into EtOAc. The resulting suspension was filtered through sintered glass and the filtrate was extracted successively with water and with saturated brine. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 60% EtOAc in heptane) to give tert-butyl (RS) -2- (4-amino-3-cyanophenyl) morpholine-4-carboxylate (659mg, 21%) as a yellow solid. Ms (isp): 321.2([ M + NH ]₄]⁺)，304.2([M+H]⁺)。

c) (RS) -2- (3-cyano-4- (1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide) phenyl) Morpholine-4-carboxylic acid tert-butyl ester Butyl ester

To a stirred suspension of 1- (4-fluorophenyl) -1H-pyrazole-3-carboxylic acid (52mg, CAS1152535-34-6) in dichloroethane (2ml) were added oxalyl chloride (61. mu.l) and DMF (2 drops). The reaction mixture was stirred at room temperature for 1h and then concentrated in vacuo. The residue was dissolved in THF (1ml) and the resulting solution was added dropwise to a stirred solution of tert-butyl (RS) -2- (4-amino-3-cyanophenyl) morpholine-4-carboxylate (70mg) and triethylamine (161 μ l) in THF (2 ml). The reaction mixture was stirred at rt for 2 h. The crude reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 50% EtOAc in heptane) to give (RS) -tert-butyl 2- (3-cyano-4- (1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide) phenyl) morpholine-4-carboxylate (49mg, 43%) as a white solid. Ms (isp): 514.2([ M + Na ]]⁺)，509.2([M+NH₄]⁺)，492.2([M+H]⁺)，436.2([M+H-C₄H₈]⁺)。

d) (RS) -N- (2-cyano-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide

To a stirred solution of trifluoroacetic acid (84 μ l) in water (4.5ml) was added a solution of tert-butyl (RS) -2- (3-cyano-4- (1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide) phenyl) morpholine-4-carboxylate (41mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80 ℃ for 5 h. The reaction mixture was then cooled to room temperature and poured into 1M aqueous NaOH and the resulting mixture was extracted twice with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. Passing the crude material through flash column chromatography (SiO)₂(ii) a Gradient: 0% to 10% methanol in dichloromethane) to give (RS) -N- (2-cyano-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide (20mg, 61%) as a white solid. Ms (isp): 392.2([ M + H)]⁺)。

Example 29

(S) -N- (2-chloro-4- (morpholin-2-yl)

a) (+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester&(-) - (S) -2- (4-amino-3-chloro) Phenyl) morpholine-4-carboxylic acid tert-butyl ester

The enantiomer of tert-butyl (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylate (2.00g, example 5g) was isolated using chiral HPLC (column: ChiralpakAD, 5X50 cm; eluent: 10% isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) to give:

(+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (894mg, white solid)

Retention time =60 minutes. Ms (isp): 337.2([{³⁷Cl}M+Na]⁺)，335.1([{³⁵Cl}M+Na]⁺)，315.0([{³⁷Cl}M+H]⁺)，313.0([{³⁵Cl}M+H]⁺)，259.2([{³⁷Cl}M+H-C₄H₈]⁺)，257.1([{³⁵Cl}M+H-C₄H₈]⁺)。

(-) - (S) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (934mg, white solid)

Retention time =76 minutes. Ms (isp): 337.1([{³⁷Cl}M+Na]⁺)，335.0([{³⁵Cl}M+Na]⁺)，314.7([{³⁷Cl}M+H]⁺)，313.0([{³⁵Cl}M+H]⁺)，259.0([{³⁷Cl}M+H-C₄H₈]⁺)，257.0([{³⁵Cl}M+H-C₄H₈]+)。

b) (S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide

(-) - (S) -2- (4-amino-3-chlorophenyl) morpholine was used in step (a)The title compound was obtained in analogy to example 18 using tert-butyl-4-carboxylate instead of tert-butyl (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylate and 1- (4-fluorophenyl) -1H-pyrazole-3-carboxylic acid (CAS1152535-34-6) instead of 1- (4-fluorophenyl) -1H-pyrazole-4-carboxylic acid. A white solid. Ms (isp): 403.1([{³⁷Cl}M+H]⁺)，401.1([{³⁵Cl}M+H]⁺)。

Example 30

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide

The title compound was obtained in analogy to example 18 using in step (a) tert-butyl (+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylate (example 29a) instead of tert-butyl (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylate and 1- (4-fluorophenyl) -1H-pyrazole-3-carboxylic acid (CAS1152535-34-6) instead of 1- (4-fluorophenyl) -1H-pyrazole-4-carboxylic acid. A white solid. Ms (isp): 403.1([{³⁷Cl}M+H]⁺)，401.1([{³⁵Cl}M+H]⁺)。

Example 31

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide

The title compound was obtained in analogy to example 18 using (-) - (S) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester in step (a). A white solid.MS(ISP)：403.1([{³⁷Cl}M+H]⁺)，401.1([{³⁵Cl}M+H]⁺)。

Example 32

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide

The title compound was obtained in analogy to example 18 using (+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester in step (a). A white solid. Ms (isp): 403.1([{³⁷Cl}M+H]⁺)，401.1([{³⁵Cl}M+H]⁺)。

Example 33

(RS) -1- (2-cyano-4-morpholin-2-yl-phenyl) -3- (3-cyano-phenyl) -urea

a) (RS) -2- { 3-cyano-4- [3- (3-cyano-phenyl) -ureido]-phenyl } -morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -tert-butyl 2- (4-amino-3-cyanophenyl) morpholine-4-carboxylate (70mg, example 28b) in dichloromethane (2ml) was added triphosgene (25 mg). A solution of sodium carbonate (49mg) in water (2ml) was then added. The reaction mixture was stirred at room temperature for 3 hours. TLC showed all starting material had reacted. 3-aminobenzonitrile (28mg, CAS2237-30-1) was then added and the reaction mixture was stirred at room temperature for another 40 hours. TLC showed the reaction was complete. Mixing the reactionThe mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 100% EtOAc in hexanes) to give (RS) -2- { 3-cyano-4- [3- (3-cyano-phenyl) -ureido []-phenyl } -morpholine-4-carboxylic acid tert-butyl ester (16mg, 16%) as a white solid. Ms (isp): 392.2([ M + H-C)₄H₈]⁺)，348.2([M+H-C₄H₈-CO₂]⁺)。

b) (RS) -1- (2-cyano-4-morpholin-2-yl-phenyl) -3- (3-cyano-phenyl) -urea

To a stirred solution of trifluoroacetic acid (22. mu.l) in water (3ml) was added (RS) -2- { 3-cyano-4- [3- (3-cyano-phenyl) -ureido]-phenyl } -morpholine-4-carboxylic acid tert-butyl ester (13mg) in acetonitrile (1.5 ml). The reaction mixture was then capped and the mixture was shaken at 80 ℃ for 4 h. The reaction mixture was then cooled to room temperature and poured into 1M aqueous NaOH and the resulting mixture was extracted twice with EtOAc. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. Passing the crude material through flash column chromatography (Flash-NH₂From Separtis); gradient: heptane/EtOAc/MeOH) to give (RS) -1- (2-cyano-4-morpholin-2-yl-phenyl) -3- (3-cyano-phenyl) -urea (6mg, 52%) as a light colored solid. Ms (isp): 348.1([ M + H)]⁺)。

Example 34

(S) -4-chloro-N- (2-chloro-4- (morpholin-2-yl) phenyl) benzamide

4-chloro-benzoic acid (CAS 74-1) was used in step (a)1-3) instead of 1- (4-fluorophenyl) -1H-pyrazole-4-carboxylic acid, the title compound was obtained in analogy to example 18. A white solid. Ms (isp): 355.2([{³⁷Cl}M+H]⁺)，353.1([{³⁷Cl³⁵Cl}M+H]⁺)，351.2([{³⁵Cl}M+H]⁺)。

Example 35

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

The title compound was obtained in analogy to example 18 using in step (a) tert-butyl (+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylate (example 29a) instead of tert-butyl (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylate and 6-chloronicotinic acid (CAS5326-23-8) instead of 1- (4-fluorophenyl) -1H-pyrazole-4-carboxylate. A white solid. Ms (isp): 356.2([{³⁷Cl}M+H]⁺)，354.1([{³⁷Cl³⁵Cl}M+H]⁺)，352.2([{³⁵Cl}M+H]⁺)。

Example 36

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

The title compound was obtained in analogy to example 18 using (-) - (S) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 6-chloronicotinic acid (CAS5326-23-8) instead of 1- (4-fluorophenyl) -1H-pyrazole-4-carboxylic acid in step (a). A pale yellow solid. Ms (isp):356.2([{³⁷Cl}M+H]⁺)，354.1([{³⁷Cl³⁵Cl}M+H]⁺)，352.2([{³⁵Cl}M+H]⁺)。

example 37

(RS) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-chloropyridin-3-yl) urea

a) (RS) -2- { 3-bromo-4- [3- (6-chloro-pyridin-3-yl) -ureido]-phenyl } -morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -tert-butyl 2- (4-amino-3-bromophenyl) morpholine-4-carboxylate (100mg, example 28a) in dichloromethane (2ml) was added triphosgene (31 mg). A solution of sodium carbonate (59mg) in water (2ml) was then added. The reaction mixture was stirred at room temperature for 2.5 hours. TLC showed all starting material had reacted. Then a solution of 6-chloropyridin-3-amine (36mg, CAS5350-93-6) in dichloromethane (2ml) was added and the reaction mixture was stirred at room temperature for an additional 2 hours. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 80% EtOAc in heptane) to give (RS) -2- { 3-bromo-4- [3- (6-chloro-pyridin-3-yl) -ureido []-phenyl } -morpholine-4-carboxylic acid tert-butyl ester (47mg, 33%) as an off-white solid. Ms (isp): 515.2([{³⁷Cl⁸¹Br}M+H]⁺)，513.2([{³⁷Cl⁷⁹Br or³⁵Cl⁸¹Br}M+H]⁺)，511.0([{³⁵Cl⁷⁹Br}M+H]⁺)，459.0([{³⁷Cl⁸¹Br}M+H-C₄H₈]⁺)，457.0([{³⁷Cl⁷⁹Br or³⁵Cl⁸¹Br}M+H-C₄H₈]⁺)，454.9([{³⁵Cl⁷⁹Br}M+H-C₄H₈]⁺)。

b) (RS) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-chloropyridin-3-yl) urea

To a stirred solution of trifluoroacetic acid (90. mu.l) in water (6ml) was added (RS) -2- { 3-bromo-4- [3- (6-chloro-pyridin-3-yl) -ureido]-phenyl } -morpholine-4-carboxylic acid tert-butyl ester (46mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80 ℃ for 5 h. The reaction mixture was then cooled to room temperature and poured into 1M aqueous NaOH and the resulting mixture was extracted twice with EtOAc. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. Passing the crude material through flash column chromatography (Flash-NH₂To obtain white Separtis) for purification; gradient: heptane/EtOAc/MeOH) to give (RS) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-chloropyridin-3-yl) urea (25mg, 68%) as an off-white solid. Ms (isp): 415.0([{³⁷Cl⁸¹Br}M+H]⁺)，413.0([{³⁷Cl⁷⁹Br or³⁵Cl⁸¹Br}M+H]⁺)，411.0([{³⁵Cl⁷⁹Br}M+H]⁺)。

Example 38

(RS) -1- (6-chloro-pyridin-3-yl) -3- (2-chloro-4-pyrrolidin-3-yl-phenyl) -urea

a) (RS) -3- (4-amino-3-chlorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 3- (4-aminophenyl) pyrrolidine-1-carboxylate (2.00g, CAS-908334-28-1) in DMF (15ml) was added NCS (1).07g) And the mixture was stirred at 70 ℃ for 1 hour. The reaction mixture was then cooled to room temperature and poured into EtOAc and extracted successively with water and saturated brine. The organic layer was washed with Na₂SO₄Dried and then concentrated in vacuo. The residue is purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 55% EtOAc in hexanes) to give (RS) -3- (4-amino-3-chlorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.16g, 51%) as a yellow oil, which was used in the next step without further purification. Ms (isp): 299.0([{³⁷Cl}M+H]⁺)，297.2([{³⁵Cl}M+H]⁺)，243.0([{³⁷Cl}M+H-C₄H₈]⁺)，241.1([{³⁵Cl}M+H-C₄H₈]+)。

b) (RS) -3- { 3-chloro-4- [3- (6-chloro-pyridin-3-yl) -ureido]-phenyl } -pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -3- (4-amino-3-chlorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (70mg) in dichloromethane (2ml) was added triphosgene (26 mg). A solution of sodium carbonate (50mg) in water (2ml) was then added. The reaction mixture was stirred at room temperature for 1.5 hours. TLC showed all starting material had reacted. 6-Chloropyridin-3-amine (31mg, CAS5350-93-6) was then added and the reaction mixture was stirred at room temperature for an additional 20 hours. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 100% EtOAc in heptane) to give (RS) -3- { 3-chloro-4- [3- (6-chloro-pyridin-3-yl) -ureido]-phenyl } -pyrrolidine-1-carboxylic acid tert-butyl ester (71mg, 67%) as an off-white solid. Ms (isp): 399.2([{³⁷Cl}M+H-C₄H₈]⁺)，397.2([{³⁷Cl³⁵Cl}M+H-C₄H₈]⁺)，395.0([{³⁵Cl}M+H-C₄H₈]⁺)，355.2([{³⁷Cl}M+H-C₄H₈-CO₂]⁺)，353.2([{³⁷Cl³⁵Cl}M+H-C₄H₈-CO₂]⁺)，351.2([{³⁵Cl}M+H-C₄H₈-CO₂]⁺)。

c) (RS) -1- (6-chloro-pyridin-3-yl) -3- (2-chloro-4-pyrrolidin-3-yl-phenyl) -urea

To (RS) -3- { 3-chloro-4- [3- (6-chloro-pyridin-3-yl) -ureido]A stirred suspension of tert-butyl-phenyl } -pyrrolidine-1-carboxylate (68mg) in dichloromethane (6ml) was added to trifluoroacetic acid (92. mu.l) and the reaction mixture was then stirred at room temperature for 34 h. The reaction mixture was then poured into 1M aqueous NaOH and the resulting mixture was extracted twice with EtOAc. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. Passing the crude material through flash column chromatography (Flash-NH₂From Separtis); gradient: heptane/EtOAc/MeOH) to give (RS) -1- (6-chloro-pyridin-3-yl) -3- (2-chloro-4-pyrrolidin-3-yl-phenyl) -urea (9mg, 17%) as an off-white solid. Ms (isp): 355.1([{³⁷Cl}M+H]⁺)，353.1([{³⁷Cl³⁵Cl}M+H]⁺)，351.2([{³⁵Cl}M+H]⁺)。

Example 39

(S) -1- (5-cyano-2-methoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea hydrochloride

a) (S) -2- {4- [3- (5-cyano-2-methoxy-phenyl) -ureido]-3-fluoro-phenyl } -morpholine-4-carboxylic acid tert-butyl ester Esters

Analogously to example 3 step a), (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 1h) was used instead(+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and 3-amino-4-methoxybenzonitrile (CAS 60979-25-1). Ms (isp): 415.1([ M + H-C)₄H₈]⁺)

b) (S) -1- (5-cyano-2-methoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea hydrochloride

To (S) -2- {4- [3- (5-cyano-2-methoxy-phenyl) -ureido]A solution of tert-butyl (3-fluoro-phenyl) -morpholine-4-carboxylate (97mg, 106. mu. mol, Eq: 1.00) in THF (4ml) was added di4M-HCl in alkane (0.773ml, 3.09mmol, Eq: 15). The reaction mixture was stirred at 60 ℃ for 5 h. Ethyl acetate was then added to the cooled mixture and the suspension was filtered and dried under high vacuum to give the title compound as an off-white solid (63mg, 75%). Ms (isp): 369.1([ M + H)]⁺)。

Example 40

(R) -1- (6-Chloropyridin-3-yl) -3- (2-methyl-4- (morpholin-2-yl) phenyl) urea

a) 2-bromo-1- (3-methyl-4-nitrophenyl) ethanone&2-chloro-1- (3-methyl-4-nitrophenyl) ethanone

To a stirred solution of 3-methyl-4-nitrobenzoyl chloride (5.85g, CAS35675-46-8) in acetonitrile (70ml) and THF (70ml) at 0-5 deg.C was added dropwise (trimethylsilyl) diazomethane (16.5ml, 2M solution in hexane). The reaction mixture was stirred at room temperature for 1 hour. TLC analysis showed the reaction was complete. Hydrobromic acid (9.29g) was then added dropwise at 0-5 ℃ and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured into EtOAc and successively over Na₂CO₃Aqueous solution, water and saturated brine. The organic layer was then washed with Na₂SO₄Dried and concentrated in vacuo to give about 1: mixture 1 (6.23g) as a brown solid, which was used in the next step without further purification. Ms (ei): 163.9([ M ]₁-CH2Cl]⁺&[M₂-CH2Br]⁺)。

b) (RS) -2- (3-methyl-4-nitrophenyl) oxirane

To a stirred suspension of a mixture of 2-bromo-1- (3-methyl-4-nitrophenyl) ethanone and 2-chloro-1- (3-methyl-4-nitrophenyl) ethanone (6.23g) in ethanol (100ml) at 5 ℃ was added NaBH stepwise over 5 minutes₄(913 mg). The reaction mixture was then stirred at room temperature for 1 hour to give a dark yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (652mg) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed a small amount of starting material remained and the reaction mixture was then stirred at 40 ℃ for 1 h. The reaction mixture was then poured into EtOAc and extracted with saturated brine. The organic layer was washed with Na₂SO₄It was dried and concentrated in vacuo to give (RS) -2- (3-methyl-4-nitrophenyl) oxirane (4.63g, 94% over 2 steps) as a yellow oil. Ms (ei): 179 (M)⁺)，164([M-CH₃]⁺)，162[M-OH]⁺)，132[M-OH-NO]⁺)，103，77。

c) (RS) -2- (2-hydroxyethylamino) -1- (3-methyl-4-nitrophenyl) ethanol

To a stirred solution of (RS) -2- (3-methyl-4-nitrophenyl) oxirane (4.63g) in THF (15ml) was added 2-aminoethanol (15.5ml) and the mixture was stirred at rt overnight. The reaction mixture was then poured into EtOAc/THF (1: 1) and extracted with saturated brine. The organic layer was washed with Na₂SO₄Dried on and concentrated in vacuo to afford (RS) -2- (2-hydroxyethylamino) -1- (3-methyl-4-nitrophenyl) ethanol (6.84g, quantitative) as a brown oil which was purified without further purificationThe next is used in the next step. Ms (isp): 241.1([ M + H)]⁺)。

d) (RS) -2-hydroxy-2- (3-methyl-4-nitrophenyl) ethyl (2-hydroxyethyl) carbamic acid tert-butyl ester

To a stirred solution of (RS) -2- (2-hydroxyethylamino) -1- (3-methyl-4-nitrophenyl) ethanol (6.84g) in THF (50ml) was added Boc₂O (6.52g) and the mixture was stirred at room temperature overnight. The reaction mixture is then concentrated in vacuo and the residue is purified by flash column chromatography (silica; gradient: heptane/CH)₂Cl₂MeOH) to give tert-butyl (RS) -2-hydroxy-2- (3-methyl-4-nitrophenyl) ethyl (2-hydroxyethyl) carbamate (6.55g, 74% over 2 steps) as a yellow oil. Ms (isp): 385.2([ M + HCOO)^-]^-)。

e) (RS) -2- (3-methyl-4-nitrophenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl (RS) -2-hydroxy-2- (3-methyl-4-nitrophenyl) ethyl (2-hydroxyethyl) carbamate (6.55g) and triethylamine (3.22ml) in THF (50ml) at 0-5 deg.C was added dropwise methanesulfonyl chloride (1.65 ml). The reaction mixture was then stirred at room temperature for 30 minutes to give a yellow suspension. TLC analysis showed a small amount of starting material remained and then further aliquots of triethylamine (0.5ml) and methanesulfonyl chloride (0.2ml) were added. The reaction mixture was stirred at room temperature for a further 20 minutes and then filtered to remove triethylamine hydrochloride, the filter was washed with THF (20 ml). The filtrate was cooled to 0-5 ℃ and potassium 2-methyl-2-butoxide (17.0ml, 1.7M solution in toluene) was added. The reaction mixture was stirred at room temperature for 30 minutes and then poured into EtOAc and extracted successively with water and with saturated brine. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo.

The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexane) to give tert-butyl (RS) -2- (3-methyl-4-nitrophenyl) morpholine-4-carboxylate (2.21g, 36%) as a yellow oil. Ms (isp): 223.1([ M + H-C)₅H₈O₂]⁺)。

f) (RS) -2- (4-amino-3-methylphenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (RS) -2- (3-methyl-4-nitrophenyl) morpholine-4-carboxylic acid tert-butyl ester (2.21g) in methanol (100ml) was added ammonium formate (6.48 g). The reaction mixture was degassed by bubbling argon into the mixture for several minutes. 10% palladium on activated carbon (219mg) was then added and the reaction mixture was stirred at 60 ℃ for 1 hour. The reaction mixture was then filtered through celite and concentrated in vacuo. The residue was taken up in EtOAc and extracted successively with water and with saturated brine. The organic layer was washed with Na₂SO₄Was dried over and concentrated in vacuo to give (RS) -tert-butyl 2- (4-amino-3-methylphenyl) morpholine-4-carboxylate (1.99g, 99%) as a colorless oil. Ms (ei): 292 (M)⁺)，235([M-C₄H₉]⁺)，219([M-C₄H₉O]⁺)，191，136，57([C₄H₉]⁺)。

g) (R) -2- (4-amino-3-methylphenyl) morpholine-4-carboxylic acid tert-butyl ester&(S) -2- (4-amino-3-methylbenzene Yl) morpholine-4-carboxylic acid tert-butyl ester

The enantiomer of (RS) -2- (4-amino-3-methylphenyl) morpholine-4-carboxylic acid tert-butyl ester (1.18g) was separated using chiral HPLC (column: ChiralpakAD, 5X50 cm; eluent: 5% isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) to give:

(+) - (R) -2- (4-amino-3-methylphenyl) morpholine-4-carboxylic acid tert-butyl ester (453mg, yellow oil)

Retention time =120 minutes

(-) - (S) -2- (4-amino-3-methylphenyl) morpholine-4-carboxylic acid tert-butyl ester (464mg, yellow oil)

Retention time =152 minutes

h) (R) -2- (4- (3- (6-Chloropyridin-3-yl) ureido) -3-methylphenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl (+) - (R) -2- (4-amino-3-methylphenyl) morpholine-4-carboxylate (99mg) in dichloromethane (3ml) was added a solution of sodium carbonate (72mg) in water (3 ml). The reaction mixture was cooled to 0 ℃ and triphosgene (37mg) was added. The reaction mixture was then stirred at 0 ℃ for 1 hour. TLC showed all starting material had reacted. 6-Chloropyridin-3-amine (48mg, CAS5350-93-6) was then added and the reaction mixture was stirred at room temperature for an additional hour. TLC showed the reaction was complete. The reaction mixture was poured into dichloromethane and extracted with water. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 70% EtOAc in hexanes) to give tert-butyl (R) -2- (4- (3- (6-chloropyridin-3-yl) ureido) -3-methylphenyl) morpholine-4-carboxylate (106mg, 70%) as an off-white solid. Ms (isp): 449.2([{³⁷Cl}M+H]⁺)，447.2([{³⁵Cl}M+H]⁺)。

i) (R) -1- (6-Chloropyridin-3-yl) -3- (2-methyl-4- (morpholin-2-yl) phenyl) urea

To a stirred solution of trifluoroacetic acid (233 μ l) in water (6ml) was added a solution of tert-butyl (R) -2- (4- (3- (6-chloropyridin-3-yl) ureido) -3-methylphenyl) morpholine-4-carboxylate (104mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80 ℃ for 4 h. The reaction mixture was then cooled to room temperature and poured into 1M aqueous NaOH and the resulting mixture was extracted twice with EtOAc. The organic layer was washed with Na₂SO₄Dried and concentrated in vacuo. Passing the crude material through flash column chromatography (Flash-NH₂From Separtis); gradient: heptane/EtOAc/MeOH) to give (R) -1- (6-chloropyridin-3-yl) -3- (2-methyl-4- (morpholin-2-yl) phenyl) urea (41mg, 51%) as a white solid. Ms (isp): 349.1([{³⁷Cl}M+H]⁺)，347.1([{³⁵Cl}M+H]⁺)。

EXAMPLE 41

(RS) -1- (2-chloro-4- (piperidin-3-yl) phenyl) -3- (6-chloropyridin-3-yl) urea

The title compound was obtained in analogy to example 38, using 3- (4-aminophenyl) -piperidine-1-carboxylic acid tert-butyl ester (CAS875798-79-1) instead of 3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester in step (a). A white solid. Ms (isp): 369.1([{³⁷Cl}M+H]⁺)，367.1([{³⁷Cl³⁵Cl}M+H]⁺)，365.1([{³⁵Cl}M+H]⁺)。

Example 42

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

The title compound was obtained in analogy to example 23 using in step (a) (+) - (R) -2- (4-amino-3-methylphenyl) morpholine-4-carboxylic acid tert-butyl ester (example 40(g)) instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and using 6-chloro-nicotinic acid (CAS5326-23-8) instead of 1-methyl-3-phenyl-1H-pyrazole-5-carboxylic acid. A white solid. Ms (isp): 334.1([{³⁷Cl}M+H]⁺)，332.1([{³⁵Cl}M+H]⁺)。

Example 43

(RS) -6-chloro-N- (2-chloro-4-piperidin-3-yl-phenyl) -nicotinamide

a)(RS) -3- (4-amino-3-chloro-phenyl) -piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained in analogy to example 38 step (a) using 3- (4-aminophenyl) -piperidine-1-carboxylic acid tert-butyl ester (CAS875798-79-1) instead of 3- (4-aminophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester. Yellow solid. Ms (isp): 313.2([{³⁷Cl}M+H]⁺)，311.2([{³⁵Cl}M+H]⁺)，257.1([{³⁷Cl}M+H-C₄H₈]⁺)，255.2([{³⁵Cl}M+H-C₄H₈]⁺)。

b)(RS) -6-chloro-N- (2-chloro-4-piperidin-3-yl-phenyl) -nicotinamide

The title compound was obtained in analogy to example 18 using 6-chloro-nicotinic acid (CAS5326-23-8) instead of 1- (4-fluorophenyl) -1H-pyrazole-4-carboxylic acid and (RS) -3- (4-amino-3-chlorophenyl) -piperidine-1-carboxylic acid tert-butyl ester instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester in step (a). Off-white solid. Ms (isp): 354.3([{³⁷Cl}M+H]⁺)，352.2([{³⁷Cl³⁵Cl}M+H]⁺)，350.2([{³⁵Cl}M+H]⁺)。

Example 44

(R) -1- (5-cyano-2-methoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea hydrochloride

Step a Using (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 1h) and 3-amino-4-methoxybenzonitrile (CAS60979-25-1), with example39 the title compound was obtained analogously. Off-white solid. Ms (isp): 369.1([ M + H)]⁺)。

Example 45

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2-methoxyphenyl) urea

The title compound was obtained in analogy to examples 5(h) - (i) using (+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 3-amino-4-methoxybenzonitrile (CAS60979-25-1) instead of 3-aminobenzonitrile in step (h). A white solid. Ms (isp): 389.1([{³⁷Cl}M+H]⁺)，387.1([{³⁵Cl}M+H]⁺)。

Example 46

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2-methoxyphenyl) urea

The title compound was obtained in analogy to example 5(h) - (i) using (-) - (S) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 3-amino-4-methoxybenzonitrile (CAS60979-25-1) instead of 3-aminobenzonitrile in step (h). A white solid. Ms (isp): 389.1([{³⁷Cl}M+H]⁺)，387.1([{³⁵Cl}M+H]⁺)。

Example 47

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2- (difluoromethoxy) phenyl) urea

The title compound was obtained in analogy to examples 5(h) - (i) using (+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 3-amino-4- (difluoromethoxy) benzonitrile (CAS1211578-67-4) instead of 3-aminobenzonitrile in step (h). A white solid. Ms (isp): 425.1([{³⁷Cl}M+H]⁺)，423.1([{³⁵Cl}M+H]⁺)。

Example 48

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2- (difluoromethoxy) phenyl) urea

The title compound was obtained in analogy to example 5(h) - (i) using (-) - (S) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 3-amino-4- (difluoromethoxy) benzonitrile (CAS1211578-67-4) instead of 3-aminobenzonitrile in step (h). Off-white solid. Ms (isp): 425.1([{³⁷Cl}M+H]⁺)，423.1([{³⁵Cl}M+H]⁺)。

Example 49

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (6- (trifluoromethyl) pyridin-3-yl) urea

The title compound was obtained in analogy to examples 5(h) - (i) using (+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 6- (trifluoromethyl) pyridin-3-amine (CAS106877-33-2) instead of 3-aminobenzonitrile in step (h). A white solid. Ms (isp): 403.1([{³⁷Cl}M+H]⁺)，401.1([{³⁵Cl}M+H]⁺)。

Example 50

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (6- (trifluoromethyl) pyridin-3-yl) urea

The title compound was obtained in analogy to example 5(h) - (i) using (-) - (S) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 6- (trifluoromethyl) pyridin-3-amine (CAS106877-33-2) instead of 3-aminobenzonitrile in step (h). A white solid. Ms (isp): 403.1([{³⁷Cl}M+H]⁺)，401.1([{³⁵Cl}M+H]⁺)。

Example 51

1- ((S) -2-chloro-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea

The title compound was obtained in analogy to example 5(h) - (i) using (-) - (S) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 2- (trifluoromethyl) -5-aminopyrimidine (CAS73418-87-8) instead of 3-aminobenzonitrile in step (h). A white solid. Ms (isp): 404.3([{³⁷Cl}M+H]⁺)，402.3([{^3SCl}M+H]⁺)。

Example 52

1- ((R) -2-chloro-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea

The title compound was obtained in analogy to examples 5(h) - (i) using (+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 2- (trifluoromethyl) -5-aminopyrimidine (CAS73418-87-8) instead of 3-aminobenzonitrile in step (h). Off-white solid. Ms (isp): 404.3([{³⁷Cl}M+H]⁺)，402.3([{³⁵Cl}M+H]⁺)。

Example 53

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5- (trifluoromethyl) pyridin-2-yl) urea

(-) - (S) -2- (4-amino-3-chlorophenyl) morpholine-The title compound was obtained in analogy to examples 5(h) - (i) using tert-butyl 4-carboxylate (example 29a) instead of tert-butyl (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylate and 5- (trifluoromethyl) pyridin-2-amine (CAS74784-70-6) instead of 3-aminobenzonitrile. A white solid. Ms (isp): 403.1([{³⁷Cl}M+H]⁺)，401.1([{³⁵Cl}M+H]⁺)。

Example 54

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5- (trifluoromethyl) pyridin-2-yl) urea

The title compound was obtained in analogy to examples 5(h) - (i) using (+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 5- (trifluoromethyl) pyridin-2-amine (CAS74784-70-6) instead of 3-aminobenzonitrile in step (h). A white solid. Ms (isp): 403.1([{³⁷Cl}M+H]⁺)，401.1([{³⁵Cl}M+H]⁺)。

Example 55

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-chloropyridin-2-yl) urea

The title compound was obtained in analogy to examples 5(h) - (i) using (+) - (R) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylic acid tert-butyl ester and 5-chloropyridin-2-amine (CAS1072-98-6) instead of 3-aminobenzonitrile in step (h)A compound is provided. A white solid. Ms (isp): 371.1([{³⁷Cl}M+H]⁺)，369.1([{³⁷Cl³⁵Cl}M+H]⁺)，367.1([{³⁵Cl}M+H]⁺)。

Example 56

1- (5-cyano-2-fluoro-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

The title compound was obtained in analogy to example 3, using 3-amino-4-fluorobenzonitrile (CAS859855-53-1) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 359.1([ M + H)]⁺)。

Example 57

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-methoxy-phenyl) -urea

a) (R) -2- (4-amino-3-bromophenyl) morpholine-4-carboxylic acid tert-butyl ester

To a stirred solution of (R) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (3.2g, CAS1260220-42-5) in DMF (25ml) was added NBS (2.05g) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then poured into EtOAc and extracted successively with water and with saturated brine. The organic layer was washed with Na₂SO₄Dried and then concentrated in vacuo. The residue is purified by column chromatography (SiO)₂(ii) a Gradient: 0% to 70% EtOAc in heptane) to give (R) -tert-butyl 2- (4-amino-3-bromophenyl) morpholine-4-carboxylate (3.71g, 90%) As an off-white solid. Ms (isp): 359.1([{⁸¹Br}M+H]⁺)，357.0([{⁷⁹Br}M+H]⁺)，303.0([{⁸¹Br}M+H-C₄H₈]⁺)，301.0([{⁷⁹Br}M+H-C₄H₈]⁺)。

b)1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-methoxy-phenyl) -urea

The title compound was obtained in analogy to example 37 using (R) -tert-butyl 2- (4-amino-3-bromophenyl) morpholine-4-carboxylate instead of tert-butyl (RS) -2- (4-amino-3-bromophenyl) morpholine-4-carboxylate and 3-amino-4-methoxybenzonitrile (CAS60979-25-1) instead of 6-chloropyridin-3-amine in step (a). A white solid. Ms (isp): 433.2([{⁸¹Br}M+H]⁺)，431.1([{⁷⁹Br}M+H]⁺)。

Example 58

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-methoxy-phenyl) -urea

The title compound was obtained in analogy to example 57 using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS1260220-43-6) instead of tert-butyl (R) -2- (4-aminophenyl) morpholine-4-carboxylate in step (a). A white solid. Ms (isp): 433.2([{⁸¹Br}M+H]⁺)，431.2([{⁷⁹Br}M+H]⁺)。

Example 59

1- (3-cyano-5-fluoro-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea

The title compound was obtained in analogy to example 3, using 3-amino-5-fluorobenzonitrile (CAS210992-28-2) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 359.1([ M + H)]⁺)。

Example 60

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-difluoromethoxy-phenyl) -urea

The title compound was obtained in analogy to example 57 using 3-amino-4- (difluoromethoxy) -benzonitrile (CAS1211578-67-4) instead of 3-amino-4-methoxybenzonitrile in step (b). A white solid. Ms (isp): 469.1([{⁸¹Br}M+H]⁺)，467.1([{⁷⁹Br}M+H]⁺)。

Example 61

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-difluoromethoxy-phenyl) -urea

The title compound was obtained in analogy to example 57 using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS1260220-43-6) instead of tert-butyl (R) -2- (4-aminophenyl) morpholine-4-carboxylate in step (a) and 3-amino-4- (difluoromethoxy) -benzonitrile (CAS1211578-67-4) instead of 3-amino-4-methoxybenzonitrile in step (b). A white solid. Ms (isp): 469.2([{⁸¹Br}M+H]⁺)，467.1([{⁷⁹Br}M+H]⁺)。

Example 62

(R) -1- (3-cyano-2-fluorophenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea

The title compound was obtained in analogy to example 3 using 3-amino-2-fluorobenzonitrile (CAS873697-68-8) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 359.1([ M + H)]⁺)。

Example 63

(R) -1- (3-cyano-4-fluorophenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea

The title compound was obtained in analogy to example 3, using 5-amino-2-fluorobenzonitrile (CAS53312-81-5) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 359.1([ M + H)]⁺)。

Example 64

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-chloropyridin-2-yl) urea

Use of (-) - (S) -2- (4) in step (h)The title compound was obtained in analogy to examples 5(h) - (i) substituting (example 29a) for tert-butyl (RS) -2- (4-amino-3-chlorophenyl) morpholine-4-carboxylate and 5-chloropyridin-2-amine (CAS1072-98-6) for 3-aminobenzonitrile. A white solid. Ms (isp): 371.1([{³⁷Cl}M+H]⁺)，369.1([{³⁷Cl³⁵Cl}M+H]⁺)，367.1([{³⁵Cl}M+H]⁺)。

Example 65

(R) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-cyanopyridin-3-yl) urea

The title compound was obtained in analogy to example 57 using 5-amino-2-pyridinecarbonitrile (CAS55338-73-3) instead of 3-amino-4-methoxybenzonitrile in step (b). A white solid. Ms (isp): 404.1([{⁸¹Br}M+H]⁺)，402.1([{⁷⁹Br}M+H]⁺)。

Example 66

(S) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-cyanopyridin-3-yl) urea

The title compound was obtained in analogy to example 57 using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS1260220-43-6) instead of tert-butyl (R) -2- (4-aminophenyl) morpholine-4-carboxylate in step (a) and 5-amino-2-pyridinecarbonitrile (CAS55338-73-3) instead of 3-amino-4-methoxybenzonitrile in step (b). A white solid. Ms (isp): 404.1([{⁸¹Br}M+H]⁺)，402.1([{⁷⁹Br}M+H]⁺)。

Example 67

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea

The title compound was obtained in analogy to example 57 using 6-chloro-3-aminopyridine (CAS5350-93-6) instead of 3-amino-4-methoxybenzonitrile in step (b). Off-white solid. Ms (isp): 415.2([{⁸¹Br³⁷Cl}M+H]⁺)，413.0([{⁸¹Br³⁵Cl or⁷⁹Br³⁷Cl}M+H]⁺)，411.1([{⁷⁹Br³⁵Cl}M+H]⁺)。

Example 68

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea

The title compound was obtained in analogy to example 57 using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS1260220-43-6) instead of tert-butyl (R) -2- (4-aminophenyl) morpholine-4-carboxylate in step (a) and 6-chloro-3-aminopyridine (CAS5350-93-6) instead of 3-amino-4-methoxybenzonitrile in step (b). A white solid. Ms (isp): 415.2([{⁸¹Br³⁷Cl}M+H]⁺)，413.1([{⁸¹Br³⁵Cl or⁷⁹Br³⁷Cl}M+H]⁺)，411.1([{⁷⁹Br³⁵Cl}M+H]⁺)。

Example 69

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea

The title compound was obtained in analogy to example 57 using (S) -tert-butyl 2- (4-aminophenyl) morpholine-4-carboxylate (CAS1260220-43-6) instead of tert-butyl (R) -2- (4-aminophenyl) morpholine-4-carboxylate in step (a) and 5-amino-2- (trifluoromethyl) pyrimidine (CAS73418-87-8) instead of 3-amino-4-methoxybenzonitrile in step (b). Off-white solid. Ms (isp): 447.9([{⁸¹Br}M+H]⁺)，446.0([{⁷⁹Br}M+H]⁺)。

Example 70

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea

The title compound was obtained in analogy to example 57 using 5-amino-2- (trifluoromethyl) pyrimidine (CAS73418-87-8) instead of 3-amino-4-methoxybenzonitrile in step (b). Off-white solid. Ms (isp): 447.9([{⁸¹Br}M+H]⁺)，446.1([{⁷⁹Br}M+H]⁺)。

Example 71

1- (5-cyano-2-difluoromethoxy-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 39 using 3-amino-4- (difluoromethoxy) benzonitrile (CAS1211578-67-4) in step a. A white solid. Ms (isp): 407.2([ M + H)]⁺)。

Example 72

1- (5-cyano-2-difluoromethoxy-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea hydrochloride

The title compound was obtained in analogy to example 39 using (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 1h) and 3-amino-4- (difluoromethoxy) benzonitrile (CAS1211578-67-4) in step a. A white solid. Ms (isp): 407.3([ M + H)]⁺)。

Example 73

(S) -1- (5-cyano-2-ethoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea hydrochloride

The title compound was obtained in analogy to example 39 using 3-amino-4-ethoxybenzonitrile (CAS72635-79-1) in step a. Off-white solid. Ms (isp): 383.2([ M + H)]⁺)。

Example 74

(R) -1- (5-cyano-2-ethoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea hydrochloride

The title compound was obtained in analogy to example 39 using (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 1h) and 3-amino-4-ethoxybenzonitrile (CAS72635-79-1) in step a. Off-white solid. Ms (isp): 383.2([ M + H)]⁺)。

Example 75

(S) -1- (3- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

a)1- (3- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxylic acid ethyl ester

(3- (difluoromethoxy) phenyl) hydrazine hydrochloride (4.2g, 19.9 mmol; CAS479581-64-1) was suspended in ethanol (80ml) and cooled to 0 ℃. A solution of ethyl 2-formyl-3-oxopropanoate (2.87g, 19.9 mmol; CAS80370-42-9) in ethanol (40ml) was added and the reaction stirred overnight. The solvent was removed under reduced pressure and the residue was partitioned between sodium bicarbonate solution and ethyl acetate. The organic layers were combined and dried (MgSO)₄) And evaporated to give an orange solid. The solid was suspended in pentane (50ml) and stirred for 90 minutes at 35 ℃. The suspension was cooled in an ice bath for one hour and the solid was filtered and washed with pentane. After drying, 5.12g (91%) of a yellow solid are obtained. Ms (isp): 283.1([ M + H)]⁺)。

b)1- (3- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxylic acid

To a solution of ethyl 1- (3- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxylate (5g, 17.7mmol) in a mixture of THF (100ml), methanol (50ml) and water (50ml) was added lithium hydroxide hydrate (2.23g, 53.1 mmol). The solution was heated to 80 ℃ for 2 h. Most of the organic solvent was removed under reduced pressure. Sodium bicarbonate solution was added and the organic layer was separated. The aqueous layer was made acidic by adding 25% aqueous hydrochloric acid (to acidic pH) and the mixture was extracted twice with ethyl acetate. The organic layers were combined and dried (MgSO)₄) And evaporated to give a solid.

The solid was stirred in a mixture of heptane and ethyl acetate for 2H, filtered and dried to give 1- (3- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxylic acid as an off-white solid (3.5g, 78%) which was used in the next step.

c) (S) -2- (4- (1- (3- (diaminomethoxy) phenyl) -1H-pyrazole-4-carboxamide) -3-aminophenyl) morpholine-4- (iv) Carboxylic acid tert-butyl ester

Tert-butyl (S) -2- (4-amino-3-fluorophenyl) morpholine-4-carboxylate (104mg, 0.35mmol), 1- (3- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxylate (107mg, 0.42mmol), HBTU (200mg, 0.525mmol) and N-methylmorpholine (106mg, 115. mu.l, 1.05mmol) were combined with DMF (4ml) to give a light yellow solution. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into 50ml of water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (20g silica gel, 70 to 50% ethyl acetate in heptane) to give a white solid (110mg, 59%). Ms (isp): 477.1 (100%, [ M-tBu + H ]]⁺)，533.2(30％，[M+H]⁺)。

d) (S) -1- (3- (diaminomethoxy) phenyl) -N- (2-amino-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxylic acid methyl ester Amide hydrochloride

Reacting (S) -2- (4- (1- (3- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxamide) -3-fluorophenyl) morpholine-4-carboxylic acid tert-butyl ester (102mg, 0.2mmol) was dissolved in bis (formamide)Alkane (0.75ml) and HCl in bisSolution in alkane (4M, 0.75ml, 3 mmol). The reaction mixture was stirred at 60 ℃ for 90 minutes. After addition of cooling ether, the solid was filtered off, washed with ether and dried in vacuo at 60 ℃ to give (S) -1- (3- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide hydrochloride (84mg, 91%) as a white solid. Ms (isp): 433.2([ M + H)]⁺)。

Example 76

(S) -1- (4- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

The title compound was obtained in analogy to example 75 using (4- (difluoromethoxy) phenyl) hydrazine hydrochloride instead of (3- (difluoromethoxy) phenyl) hydrazine hydrochloride in step a). A white solid. Ms (isp): 433.3([ M + H)]⁺)。

Example 77

(R) -1- (3- (difluoromethoxy) benzyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea

The title compound was obtained in analogy to example 3 using (3- (difluoromethoxy) phenyl) methylamine (CAS244022-71-7) instead of 3-aminobenzonitrile in step (a). A colorless amorphous solid. Ms (isp): 396.2([ M + H)]⁺)。

Example 78

(S) -1- (3- (difluoromethoxy) benzyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea

The title compound was obtained in analogy to example 3 using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and (3- (difluoromethoxy) phenyl) methylamine (CAS244022-71-7) instead of 3-aminobenzonitrile in step (a). A white solid. Ms (isp): 396.2([ M + H)]⁺)。

Example 79

(S) -4-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide hydrochloride

a)(S) -2- {4- [ (4-cyano-pyridine-2-carbonyl) -amino]-3-fluoro-phenyl } -morpholine-4-carboxylic acid tert-butyl ester

(-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 1h, 70mg, 236. mu. mol, Eq: 1.00), 4-cyanopyridine carboxylic acid (CAS640296-19-1, 45.5mg, 307. mu. mol, Eq: 1.3) and HBTU (134mg, 354. mu. mol, Eq: 1.5) were dissolved in DMF (1.25ml), treated with N-methylmorpholine (71.7mg, 77.9. mu.l, 709. mu. mol, Eq: 3) and washed with brineStir at rt for 17 h. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The solid residue was diluted with a small volume of MeOH and filtered to give 64mg of white solid. Ms (isp): 371.0([ M + H-C)₄H₈]⁺)。

b)(S) -4-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide hydrochloride

To (S) -2- {4- [ (4-cyano-pyridine-2-carbonyl) -amino group]A solution of tert-butyl (3-fluoro-phenyl) -morpholine-4-carboxylate (73mg, 171. mu. mol, Eq: 1.00) in THF (3ml) was added di4M-HCl in alkane (0.642ml, 2.52mmol, Eq: 15). The reaction mixture was stirred at 60 ℃ for 5 h. Ethyl acetate was then added to the cooled mixture and the suspension was filtered and dried under high vacuum to give the title compound as a white solid (53mg, 85%). Ms (isp): 325.2([ M + H)]⁺)。

Example 80

(R) -4-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide hydrochloride

In analogy to example 79, step a), tert-butyl (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylate (example 1h) was used instead of tert-butyl (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylate. A white solid. Ms (isp): 325.2([ M + H)]⁺)

Example 81

(S) -6-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide hydrochloride

In analogy to example 79, step a) 6-cyano-2-pyridinecarboxylic acid (CAS872602-74-9) was used. A white solid. Ms (isp): 325.3([ M + H)]⁺)

Example 82

(S) -1- (2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide

In step a), use is made of (2, 2-difluorobenzo [ d ]][1，3]The title compound was obtained in analogy to example 75, substituting (3- (difluoromethoxy) phenyl) hydrazine hydrochloride for dioxol-5-yl) hydrazine hydrochloride. A pale yellow solid. Ms (isp): 447.2([ M + H)]⁺)。

Example 83

(R) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide hydrochloride

Step a) (R) -2- { 2-amino-4- [ (2-triaminomethyl-pyridine-4-carbonyl) -amino]-phenyl } -morpholine-4-carboxylic acid Tert-butyl ester：

Under N2, 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS 131)747-41-6) (64.4mg, 337. mu. mol, Eq: 1.00) was dissolved in CH2Cl2(1 ml). 1-chloro-N, N2-trimethylpropenylamine (51.8mg, 51.3. mu.l, 388. mu. mol, Eq: 1.15) was added dropwise. After 30 minutes at room temperature, a solution containing (R) -tert-butyl 2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylate (100mg, 337. mu. mol, Eq: 1.00) and ethyldiisopropylamine (109mg, 140. mu.l, 842. mu. mol, Eq: 2.5) in DMF (1.00ml) was added. The resultant was stirred at room temperature for 1 hour. Control by TLC: the reaction was complete. The resultant was extracted with EtOAc and 1M citric acid solution; the organic phase was dried over MgSO 4; filtering; concentrate in vacuo. The crude material was purified by flash chromatography (silica gel, 10g, 10% to 50% EtOAc in heptane). 149mg (82%) of a white foam were obtained. Ms (eic): 468.1([ M-H)]^-)

Step b) analogously to example 79, step b) using two An alkane was used instead of THF and 2h instead of 5h at 60 ℃.Yellow solid. Ms (isp): 370.1([ M + H)]⁺)

(R) and (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl esterThe preparation of (1):

a) (RS) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester

In analogy to (RS) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 1, steps a-g) 4-bromo-2-fluorobenzoyl chloride (CAS151982-51-3) was used instead of 4-bromo-3-fluorobenzoyl chloride.

In being used for(RS) -2- (4-bromo-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl esterThe following alternative steps may be used in step (e) of the preparation of (a):

tert-butyl 2- (4-bromo-2-fluoro-phenyl) -2-hydroxyethyl (2-hydroxyethyl) carbamate (7.385g, 19.5mmol, Eq: 1.00) and triphenylphosphine (6.15g, 23.4mmol, Eq: 1.2) were dissolved in TBME (33ml) under N2. DIAD (5.04g, 4.85ml, 23.4mmol, Eq: 1.2) was added (exotherm) with ice-bath cooling. The yellow solution was stirred at room temperature overnight. The result was a yellow suspension. Control by TLC: the reaction was complete. The solvent was evaporated. TBME was added and the solid was filtered. The filtrate was evaporated. The crude material was purified by flash chromatography (silica gel, 100g, 5% to 40% EtOAc in heptane).

b)(+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester&(-) - (S) -2- (4-amino-2-) Fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester

The enantiomer of (RS) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (5130mg) was separated using chiral HPLC (column: chiralpak ad, 5x50 cm; eluent: 15% isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) to give:

(+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (1780mg, off-white solid), retention time =83 minutes

(-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (2070mg, light yellow solid), retention time =96 minutes

Example 84

(R) -2-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

In analogy to example 83, step a) 2-ethoxy-4-pyridinecarboxylic acid (CAS91940-86-2) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS 131747-41-6). Light yellow foam. Ms (isp): 346.1([ M + H)]⁺)

Example 85

(R) -6-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

In analogy to example 83, step a), 6-ethoxy-3-pyridinecarboxylic acid (CAS97455-65-7) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS 131747-41-6). A white solid. Ms (isp): 346.1([ M + H)]⁺)

Example 86

(R) -1- (4- (difluoromethoxy) phenyl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 83, step a)1- (4-difluoromethoxy-phenyl) -1H-pyrazole-4-carboxylic acid was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS 131747-41-6). A white solid. Ms (isp): 433.3([ M + H)]⁺)

Obtained in analogy to example 75 steps (a-b) using (4- (difluoromethoxy) phenyl) hydrazine hydrochloride instead of (3- (difluoromethoxy) phenyl) hydrazine hydrochloride in step a)1- (4-difluoromethoxy-phenyl) -1H-pyrazole-4-carboxylic acid。

Example 87

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide hydrochloride

Analogously to example 83, step a)(-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. Off-white solid. Ms (isp): 370.1([ M + H)]⁺)

Example 88

(S) -2-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) isonicotinamide hydrochloride

In analogy to example 83, step a) 2-ethoxy-4-pyridinecarboxylic acid (CAS91940-86-2) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. Yellow foam. Ms (isp): 346.1([ M + H)]⁺)

Example 89

(S) -6-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) nicotinamide hydrochloride

In analogy to example 83, step a) 6-ethoxy-3-pyridinecarboxylic acid (CAS97455-65-7) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 346.1([ M + H)]⁺)

Example 90

(S) -1- (4- (difluoromethoxy) phenyl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 86, step a) (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 449.1([ M + H)]⁺)

Example 91

(R) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -2-ethoxyisonicotinamide hydrochloride

In analogy to example 83, step a) 2-ethoxy-4-pyridinecarboxylic acid (CAS91940-86-2) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (+) - (R) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. Light yellow foam. Ms (isp): 362.0([ M + H)]⁺)

(R) and (S) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl esterThe preparation of (1):

a) (RS) -2- (4-amino-2-chloro-phenyl) morpholine-4-carboxylic acid tert-butyl ester

In analogy to (RS) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 1, steps a-g) 4-bromo-2-chlorobenzoyl chloride (CAS21900-55-0) was used instead of 4-bromo-3-fluorobenzoyl chloride.

b)(+) - (R) -2- (4-amino-2-chloro-Phenyl) -morpholine-4-carboxylic acid tert-butyl ester&(-) - (S) -2- (4-amino-2-) Chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester

The enantiomer of (RS) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (1640mg) was separated using chiral HPLC (column: chiralpak ad, 5x50 cm; eluent: 15% isopropanol/heptane; pressure: 18 bar; flow rate: 35 ml/min) giving:

(+) - (R) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (772mg, light yellow solid), retention time =51 min

(-) - (S) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (793mg, light yellow solid), retention time =68 minutes

Example 92

(R) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -6-ethoxynicotinamide hydrochloride

In analogy to example 83, step a) 6-ethoxy-3-pyridinecarboxylic acid (CAS97455-65-7) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (+) - (R) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (prepared as described in example 91) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. Off-white solid. Ms (isp): 362.0([ M + H)]⁺)

Example 93

(R) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxylic acid

Amine hydrochloride

In analogy to example 86, step a), tert-butyl (+) - (R) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylate (prepared as described in example 91) was used instead of tert-butyl (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylate. A white solid. Ms (isp): 449.1([ M + H)]⁺)

Example 94

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -2-ethoxyisonicotinamide hydrochloride

In analogy to example 83, step a) 2-ethoxy-4-pyridinecarboxylic acid (CAS91940-86-2) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (prepared as described in example 91) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. Light yellow foam. Ms (isp): 362.0([ M + H)]⁺)

Example 95

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -6-ethoxynicotinamide hydrochloride

Analogously to example 83, step a), 6-ethoxy-3-pyridinecarboxylic acid (CAS97455-65-7) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester was used (as in example)Prepared as described in example 91) instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 362.0([ M + H)]⁺)

Example 96

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 86, step a) (-) - (S) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (prepared as described in example 91) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 449.1([ M + H)]⁺)

Example 97

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

In analogy to example 79, step a) 6-cyano-2-pyridinecarboxylic acid (CAS872602-74-9) was used instead of 4-cyanopicolinic acid (CAS640296-19-1) and (+) - (R) -2- (4-amino-3-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 29a) was used instead of (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 341.1([ M + H)]⁺)

Example 98

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

In analogy to example 79, step a) 6-cyano-2-pyridinecarboxylic acid (CAS872602-74-9) was used instead of 4-cyanopicolinic acid (CAS640296-19-1) and (-) - (S) -2- (4-amino-3-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 29a) was used instead of (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 341.1([ M + H)]⁺)

Example 99

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -5-cyanopyridinecarboxamide hydrochloride

In analogy to example 79, step a) 5-cyano-2-pyridinecarboxylic acid (CAS53234-55-2) was used instead of 4-cyanopicolinic acid (CAS640296-19-1) and (-) - (S) -2- (4-amino-3-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 29a) was used instead of (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 341.1([ M + H)]⁺)

Example 100

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -5-cyanopyridinecarboxamide hydrochloride

Analogously to example 79, step a), 5-cyanogen was usedYl-2-pyridinecarboxylic acid (CAS53234-55-2) instead of 4-cyanopicolinic acid (CAS640296-19-1) and (-) - (R) -2- (4-amino-3-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 341.1([ M + H)]⁺)

Example 101

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

In analogy to example 79, step a) 6-cyano-3-pyridinecarboxylic acid (CAS70165-31-0) was used instead of 4-cyanopicolinic acid (CAS640296-19-1) and (-) - (S) -2- (4-amino-3-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 29a) was used instead of (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 341.1([ M + H)]⁺)

Example 102

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

In analogy to example 79, step a) 6-cyano-3-pyridinecarboxylic acid (CAS70165-31-0) was used instead of 4-cyanopicolinic acid (CAS640296-19-1) and (+) - (R) -2- (4-amino-3-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 29a) was used instead of (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 341.1([ M + H)]⁺)

Example 103

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-cyanophenyl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 83, step a)1- (4-cyanophenyl) -1H-pyrazole-4-carboxylic acid (CAS1152945-21-5)) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 29a) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 408.2([ M + H)]⁺)

Example 104

(S) -1- (4- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-1,2, 3-triazole-4-carboxamide

a)1- (4- (difluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxylic acid ethyl ester

In a 20mL four-necked flask, 4- (difluoromethoxy) aniline (0.5g, 3.14mmol) and hydrochloric acid (37% in water, 0.54mL, 6.6mmol) were combined with water (5mL) to give a pale yellow solution. Cooled to 0 ℃ using an ice bath, sodium nitrite (217mg, 3.14mmol) was dissolved in water (1ml) and added carefully ensuring that the temperature did not increase above 5 ℃. Sodium azide (204mg, 3.14mmol) was dissolved in water (1ml) and added dropwise to the orange solution, keeping the temperature below 5 ℃. The reaction mixture was cooled at 0-5 ℃ for 1 hour and an orange emulsion was observed. The layers were separated using TBME and the organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-azido-4- (difluoromethoxy) benzene as an orange liquid.

In a 50ml round-bottom flask, 1-azido-4- (difluoromethoxy) benzene (540mg, 2.92mmol) was combined with THF (10ml) and dimethylsulfoxide (0.16ml) to give an orange solution. Ethyl propargionate (858mg, 0.89ml, 8.75mmol), copper (I) iodide (556mg, 2.92mmol) and 2, 6-lutidine (625mg, 0.68ml, 5.83mmol) were then added and the reaction mixture was stirred at room temperature for 2 h. Water and ethyl acetate were added and the layers were separated. The organic layer was washed with 1N hydrochloric acid and brine over MgSO₄Dried and filtered. The filtrate was concentrated in vacuo to give a brown solid, which was adsorbed on silica gel and purified by flash chromatography (20g silica gel, 20% ethyl acetate in heptane) to give 698mg (84%) of a light yellow solid. Ms (isp): 284.2([ M + H)]⁺)。

b)1- (4- (difluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxylic acid

To a solution of ethyl 1- (4- (difluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxylate (600mg, 2.12mmol) in a mixture of THF (7ml), methanol (7ml) and water (7ml) was added lithium hydroxide hydrate (267mg, 6.36 mmol). The solution was heated to 70 ℃ for 3 h. Most of the organic solvent was removed under reduced pressure. Water was added and the solution was extracted with methyl tert-butyl ether to remove non-acid materials. Then 25% aqueous hydrochloric acid was added to achieve an acidic pH. The product was precipitated and the mixture was extracted three times with ethyl acetate. The organic layers were combined and dried (MgSO)₄) And evaporated to give a pale yellow solid (583mg, 99%). Ms (isp): 253.9([ M-H)]⁺)；509.2([2M-H]⁺)。

c) (S) -2- (4- (1- (4- (difluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide) -3-fluorophenyl) Morpholine-4-carboxylic acid tert-butyl ester

1- (4- (difluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxylic acid (68.9mg, 0.27mmol) was suspended in dichloromethane (1.3ml) under argon. 1-chloro-N, N "-trimethylpropenylamine (41.5mg, 41 μ l, 0.31mmol) was then added dropwise and the reaction mixture was stirred at room temperature for 15 minutes to form the acid chloride.

Tert-butyl (S) -2- (4-amino-3-fluorophenyl) morpholine-4-carboxylate (80mg, 0.27mmol) was dissolved in dichloromethane (1.3 ml). Ethyldiisopropylamine (87.2mg, 112. mu.l, 0.675mmol) was added. To this solution, the acid chloride was added dropwise and the reaction mixture was stirred at room temperature for 3 hours.

Extracting the reaction mixture with dichloromethane and ammonium chloride solution; the organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10% to 30% EtOAc in heptane). The solid (100mg) was recrystallized from ethyl acetate/heptane to give a white solid (65mg, 45%). Ms (isp): 478.1 (100%, [ M-tBu + H)]⁺)，534.3(10％，[M+H]⁺)。

d) (S) -1- (4- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-1,2, 3-tris Azole-4-carboxamide hydrochloride

Tert-butyl (S) -2- (4- (1- (4- (difluoromethoxy) phenyl) -1H-1,2, 3-triazole-4-carboxamide) -3-fluorophenyl) morpholine-4-carboxylate (62mg, 0.116mmol) was dissolved in diAlkane (0.6ml) and HCl in bisSolution in alkane (4M, 0.35ml, 1.39 mmol). The reaction mixture was stirred at 60 ℃ for 2 h. After addition of cooling ether, the solid was filtered off, washed with ether and dried in vacuo to give (S) -1- (4- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-1,2, 3-triazole-4-carboxamide hydrochloride (53mg, 97%) as a white solid. Ms (isp): 434.4([ M + H)]⁺)。

Example 105

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4-cyanophenyl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 83, step a)1- (4-cyanophenyl) -1H-pyrazole-4-carboxylic acid (CAS1152945-21-5) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (prepared as described in example 91) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. Yellow solid. Ms (isp): 408.2([ M + H)]⁺)

Example 106

(S) -4-chloro-6-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide hydrochloride

In analogy to example 83, step a) 4-chloro-6-cyano-2-pyridinecarboxylic acid (CAS1060812-13-6) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (example 1 step h) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 359.1([ M + H)]⁺)

Example 107

(S) -2-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methoxyisonicotinamide hydrochloride

In analogy to example 83, step a) 2-cyano-6-methoxy-isonicotinic acid was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. A white solid. Ms (isp): 357.1([ M + H)]⁺)

Preparation of 2-cyano-6-methoxy-isonicotinic acid:

a) 2-cyano-6-methoxyisonicotinic acid methyl ester:

methyl 2-chloro-6-methoxyisonicotinate (CAS42521-10-8) (3.97g, 19.7mmol, Eq: 1.00), zinc cyanide (2.77g, 23.6mmol, Eq: 1.2) and tetrakis-triphenylphosphine-palladium (1.14g, 985. mu. mol, Eq: 0.05) were mixed in DMF (67.5ml) under N2. The resultant was stirred at 160 ℃ for 30 minutes under microwave. Control with LC-MS: the reaction was complete.

The resultant was partitioned between EtOAc and water; extracting; the organic phase was dried over MgSO 4; filtering; concentrate in vacuo. The crude material was purified by flash chromatography (silica gel, 300g, 5% to 30% EtOAc in heptane) to afford 2.48g (66%) of the desired product. A pale yellow solid. Ms (isp): 193.1([ M + H)]⁺)

b) 2-cyano-6-methoxy-isonicotinic acid：

Methyl 2-cyano-6-methoxyisonicotinate (0.433g, 2.25mmol, Eq: 1.00) was dissolved in THF (25.0ml) and methanol (3.03ml) under N2. 1M LiOH (2.82ml, 2.82mmol, Eq: 1.25) in H2O was added at 0 ℃ and the resulting mixture was stirred at 0 ℃ for 30 min. Control by TLC: the reaction was complete. The reaction mixture was acidified with 1 MHCl. The mixture was diluted with H2O and extracted with EtOAc. The organic phase was dried over MgSO 4; filtering; concentrate in vacuo. A pale yellow solid. Ms (eic): 176.8([ M-H)]^-)

Example 108

(S) -1- (4-cyano-2-fluorophenyl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 79, step a)1- (4-cyano-2-fluoro-phenyl) -1H-pyrazole-4-carboxylic acid (CAS1283184-05-3) was used instead of 4-cyanopicolinic acid (CAS640296-19-1) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (prepared in example 83) was used instead of (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) instead of THF, use twoAlkane and the reaction mixture was stirred at room temperature for 2 hours. Then 5ml of diAlkane, the suspension was stirred for 5 minutes, filtered and the solid residue was washed with ether and dried under high vacuum. Off-white solid. Ms (isp): 410.3([ M + H-Cl)]⁺)

Example 109

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4-cyano-2-fluorophenyl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 79, step a)1- (4-cyano-2-fluoro-phenyl) -1H-pyrazole-4-carboxylic acid (CAS1283184-05-3) was used instead of 4-cyanopicolinic acid (CAS640296-19-1) and (-) - (S) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (prepared in example 91) was used instead of (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b), instead of THF, use twoAlkane and the reaction mixture was stirred at room temperature for 2 hours. Then 5ml of diAlkane, the suspension was stirred for 5 minutes, filtered and the solid residue was washed with ether and dried under high vacuum. Off-white solid. Ms (isp): 426.2([ M + H-Cl)]⁺)

Example 110

(S) -1- (4-cyano-2-fluorophenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 79, step a)1- (4-cyano-2-fluoro-phenyl) -1H-pyrazole-4-carboxylic acid (CAS1283184-05-3) was used instead of 4-cyanopicolinic acid (CAS 640296-19-1).

Step b), instead of THF, use twoAlkane and the reaction mixture was stirred at room temperature for 2 hours. Then 5ml of diAlkane, the suspension was stirred for 5 minutes, filtered and the solid residue was washed with ether and dried under high vacuum. Ash ofA white solid. Ms (isp): 410.3([ M + H-Cl)]⁺)

Example 111

(S) -1- (4-cyanophenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 83, step a)1- (4-cyanophenyl) -1H-pyrazole-4-carboxylic acid (CAS1152945-21-5) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 1-H) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester. Yellow solid. Ms (isp): 390.3([ M-H)]⁺)

Example 112

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -2-cyano-6-methylisonicotinamide hydrochloride

In analogy to example 83, step a) 2-cyano-6-methyl-isonicotinic acid was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 91) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 60 ℃ at room temperature for 2 h. The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1M HCl in ether; filtered and dried under high vacuum.

Yellow foam. Ms (isp): 357.1([ M + H)]⁺)

Preparation of 2-cyano-6-methyl-isonicotinic acid:

a) 2-cyano-6-methylisonicotinic acid methyl ester:

methyl 2-chloro-6-methylisonicotinate (CAS3998-90-1) (1.000g, 5.39mmol, Eq: 1.00), zinc cyanide (759mg, 6.47mmol, Eq: 1.2) and tetrakis-triphenylphosphine-palladium (623mg, 539. mu. mol, Eq: 0.1) were mixed in DMF (17ml) under N2. The resultant was stirred at 160 ℃ for 30 minutes under microwave. Control by TLC: the reaction was complete. The resultant was partitioned between EtOAc and water; extracting; the organic phase was dried over MgSO 4; filtering; concentrate in vacuo. The crude material was purified by flash chromatography (silica gel, 100g, 5% to 30% EtOAc in heptane). A purple solid. Ms (isp): 177.2([ M + H ]]⁺)

b) Under N2, methyl 2-cyano-6-methylisonicotinate (0.490g, 2.78mmol, Eq: 1.00) was dissolved in tetrahydrofuran (25ml) and methanol (3.03 ml). 1M LiOH (3.48ml, 3.48mmol, Eq: 1.25) in H2O was added at 0 ℃ and the resulting mass was stirred for 30min at 0 ℃. Control by TLC: the reaction was complete. The reaction mixture was acidified with 1 MHCl. The mixture was diluted with H2O and extracted with EtOAc. The organic phase was dried over MgSO 4; filtering; concentrate in vacuo. Pink solid. Ms (eic): 160.8([ M + H)]⁺)

Example 113

(S) -2-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methylisonicotinamide hydrochloride

In analogy to example 83, step a) 2-cyano-6-methyl-isonicotinic acid (described in example 112) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (prepared as described in example 1-h) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 60 ℃ at room temperature for 2 h. The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum. Yellow gum. Ms (isp): 341.1([ M + H)]⁺)

Example 114

(S) -N4- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide hydrochloride

Obtained as a by-product of example 115 during the deprotection step (step b). The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum. Yellow solid. Ms (isp): 359.1([ M + H)]⁺)

Example 115

(S) -2-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methylisonicotinamide hydrochloride

In analogy to example 83, step a) 2-cyano-6-methyl-isonicotinic acid (described in example 112) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 83) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 60 ℃ at room temperature for 2 h. The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum. Yellow foam. Ms (isp): 341.1([ M + H)]⁺)

Example 116

(S) -6-chloro-N4- (3-fluoro-4- (morpholin-2-yl) phenyl) pyridine-2, 4-dicarboxamide hydrochloride

In analogy to example 83, step a) 2-chloro-6-cyano-4-pyridinecarboxylic acid (CAS1060812-14-7) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 83) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 60 ℃ at room temperature for 2 h.

Formed as a by-product of the deprotection step (step b). The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1M HCl in ether; filtered and dried under high vacuum.

A white solid. Ms (isp): 379.2([ M + H ]]⁺)

Example 117

(S) -6-Ethyl-N4- (3-fluoro-4- (morpholin-2-yl) phenyl) pyridine-2, 4-dicarboxamide hydrochloride

In analogy to example 83, step a) 2-ethyl-6-cyano-4-pyridinecarboxylic acid was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 83) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 60 ℃ at room temperature for 2 h.

Formed as a by-product of the deprotection step (step b). The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum.

A pale yellow solid. Ms (isp): 373.1([ M + H)]⁺)

Preparation of 2-ethyl-6-cyano-4-pyridinecarboxylic acid:

a) 2-ethyl-4- (methoxycarbonyl) pyridine 1-oxide:

methyl 2-chloroisonicotinate (CAS58481-11-1) (1.000g, 5.83mmol, Eq: 1.00) was dissolved in THF (35.0ml) and NMP (4.00ml) under N2. Iron III acetylacetonate (106mg, 291. mu. mol, Eq: 0.05) (red solution) was added. Ethyl magnesium bromide 1M (11.7ml, 11.7mmol, Eq: 2) in THF was added dropwise at 0 ℃. The resultant became dark brown. The resultant was stirred at room temperature for 30 minutes. Control by TLC: the reaction was complete. 50ml of a saturated NH4 Cl-solution and 10ml of water were added. The resultant was extracted. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO 4; filtering; concentrate in vacuo (200 mbar). The crude material was purified by flash chromatography (silica gel, 70g, DCM).

The residue was diluted in DCM (20ml) under N2. m-CPBA (1.51g, 8.74mmol, Eq: 1.50) was added and the resultant was stirred at room temperature overnight. Control by TLC: the reaction was complete. The solvent was evaporated. The crude material was purified by flash chromatography (silica gel, 100g, 35% to 100% EtOAc in heptane; then DCM; then MeOH). Brown oil. Ms (isp): 182.1([ M + H)]⁺)

b) 2-cyano-6-ethyliisonicotinic acid methyl ester:

2-Ethyl-4- (methoxycarbonyl) pyridine 1-oxide (0.165g, 911. mu. mol, Eq: 1.00) was dissolved in acetonitrile (4ml) under N2. Dimethylcarbamoyl chloride (108mg, 92.1. mu.l, 1.00mmol, Eq: 1.1), triethylamine (175mg, 239. mu.l, 1.73mmol, Eq: 1.9) and trimethylsilicononitrile (280mg, 355. mu.l, 2.82mmol, Eq: 3.10) were added and the mixture was stirred at 90 ℃ overnight. The resultant became an orange solution. Control by TLC: the reaction was complete. The resultant was partitioned between water and EtOAc at room temperature. The organic phase was dried over MgSO 4; filtering; concentration in vacuo: 350 mg; NMR: t205185. The crude material was purified by flash chromatography (silica gel, 20g, 5% to 50% EtOAc in heptane). Light yellow oil.

c) 2-ethyl-6-cyano-4-pyridinecarboxylic acid:

2-cyano-6-ethyliisonicotinate (0.233g, 1.23mmol, Eq: 1.00) was diluted in THF (12.1ml) and MeOH (1.46ml) under N2. 1MLiOH (1.53ml, 1.53mmol, Eq: 1.25) in water was added dropwise (over 3 min) at 2-3 ℃. The resulting mixture was stirred at 2-3 ℃ for 30 minutes. Control by TLC: the reaction was complete. The reaction mixture was acidified with 1 MHCl. The mixture was diluted with H2O and extracted with EtOAc. The organic phase was dried over MgSO 4; filtering; concentrate in vacuo. A white solid. Ms (eic): 174.9([ M-H)]^-)

Example 118

(S) -N4- (3-chloro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide hydrochloride

As a byproduct of example 112, the deprotection step (step b) was formed. The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum. Off-white solid. Ms (isp): 375.1([ M + H)]⁺)

Example 119

(S) -N4- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide hydrochloride

In analogy to example 83, step a) 2-cyano-6-methyl-isonicotinic acid (described in example 112) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 1h) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 60 ℃ at room temperature for 2 h.

Formed as a by-product of the deprotection step (step b). The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum.

A pale yellow solid. Ms (isp): 359.1([ M + H)]⁺)

Example 120

(S) -N4- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methoxypyridine-2, 4-dicarboxamide hydrochloride

Formed as a byproduct of the deprotection step (step b) in example 121. The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum.

White foam. Ms (isp): 375.1([ M + H)]⁺)

Example 121

(S) -2-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methoxyisonicotinamide hydrochloride

In analogy to example 83, step a) 2-cyano-6-methoxy-isonicotinic acid (described in example 107) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 1h) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 60 ℃ at room temperature for 2 h.

Formed as the main product of the deprotection step (step b). The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum.

A white solid. Ms (isp): 357.1([ M + H)]⁺)

Example 122

(S) -N4- (2-chloro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide hydrochloride

Formed as a byproduct of the deprotection step (step b) in example 123. The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum.

Yellow solid. Ms (isp): 375.1([ M + H)]⁺)

Example 123

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

In analogy to example 83, step a) 2-cyano-6-methyl-isonicotinic acid (described in example 112) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 29a) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 60 ℃ at room temperature for 2 h.

Formed as the main product of the deprotection step (step b). The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum.

Yellow gum. Ms (isp): 357.1([ M + H)]⁺)

Example 124

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

In analogy to example 83, step a) 2-cyano-6-methoxy-isonicotinic acid (described in example 107) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 29a) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 60 ℃ at room temperature for 2 h. The reaction mixture was extracted with EtOAc/0.5MNa2CO 3; the organic layer was dried over MgSO 4; filtered and concentrated in vacuo. The residue was chromatographed (preparative HPLC) using the following conditions: column GeminiNXC185u110A (100x30mm), eluent a: H2O + 0.1% Et3 NB: gradient 20% B to 100% B over 12 min. Flow rate: 40 ml/min, Room temperature)

The pure fractions were concentrated and the residue was dissolved in ether and acidified with 1MHCl in ether; filtered and dried under high vacuum.

Off-white foam. Ms (isp): 373.0([ M + H)]⁺)

Example 125

(S) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 83, step a)1- (6-trifluoromethyl-pyrazin-2-yl) -1H-pyrazole-4-carboxylic acid was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 1H) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) was continued at 60 ℃ for 3h instead of 2 h. A white solid. Ms (isp): 437.2([M+H]⁺)

Preparation of 1- (6-trifluoromethyl-pyrazin-2-yl) -1H-pyrazole-4-carboxylic acid

a)1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxylic acid ethyl ester:

2-iodo-6- (trifluoromethyl) pyrazine (CAS141492-94-6) (0.137g, 500. mu. mol, Eq: 1.00), ethyl 1H-pyrazole-4-carboxylate (CAS37622-90-5) (70.1mg, 500. mu. mol, Eq: 1.00) and potassium carbonate (138mg, 1.00mmol, Eq: 2) were combined in DMSO (2.4ml) under N2. The orange solution was stirred at 120 ℃ for 1 hour. Control by TLC: the reaction was complete. The resultant was partitioned between water and EtOAc at rt; extracting; the organic layer was washed with water and brine; drying over MgSO 4; filtering; concentrate in vacuo. The crude material was purified by flash chromatography (silica gel, 20g, 5% to 25% EtOAc in heptane).

b)1- (6-trifluoromethyl-pyrazin-2-yl) -1H-pyrazole-4-carboxylic acid:

ethyl 1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxylate (155mg, 542. mu. mol, Eq: 1.00) was dissolved in DMF (9.3ml) and water (9.3ml) under N2. Potassium carbonate (150mg, 1.08mmol, Eq: 2) was added and the resulting mass was stirred at 70 ℃ overnight. Control with LC-MS: Pr/SM: 74/26. Potassium carbonate (150mg, 1.08mmol, Eq: 2) was added and the resulting mass was stirred at 70 ℃ overnight. Control with LC-MS: SM/Pr: 4/96. The resultant was partitioned between 1MK2C03 and EtOAc at room temperature; extracting; the aqueous layer was acidified with 1 MHCl; extraction with EtOAc; the organic phase was dried over MgSO 4; filtering; concentration in vacuo afforded 132mg of an off-white solid.

Example 126

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 83, step a)1- (6-trifluoromethyl-pyrazin-2-yl) -1H-pyrazole-4-carboxylic acid (prepared as described in example 125) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 29a) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) was continued at 60 ℃ for 3h instead of 2 h. A pale yellow solid. Ms (isp): 453.2([ M + H)]⁺)

Example 127

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 83, step a)1- (6-trifluoromethyl-pyrazin-2-yl) -1H-pyrazole-4-carboxylic acid (prepared as described in example 125) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 83) instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 2h with 3h at 60 ℃. A white solid. Ms (isp): 437.2([ M + H)]⁺)

Example 128

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 83, step a)1- (6-trifluoromethyl-pyrazin-2-yl) -1H-pyrazole-4-carboxylic acid (prepared as described in example 125) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-chloro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 91) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) replaced 2h with 3h at 60 ℃. A white solid. Ms (isp): 453.2([ M + H)]⁺)

Example 129

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide hydrochloride

Step a) (S) -tert-butyl 2- (2-fluoro-4- (1H-pyrazole-4-carboxamide) phenyl) morpholine-4-carboxylate:

1H-pyrazole-4-carboxylic acid (CAS37718-11-9) (97.5mg, 844. mu. mol, Eq: 1.00) was dissolved in methanol (6 ml). Tert-butyl (S) -2- (4-amino-2-fluorophenyl) morpholine-4-carboxylate (prepared as described in example 83) (0.250g, 844. mu. mol, Eq: 1.00) was added. 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholine-4-one chloride was added at 0 ℃ over 1 hour(303mg, 1.1mmol, Eq: 1.3) in methanol (5 ml). The resultant was stirred at 50 ℃ for 3 hours. After cooling to room temperature, the solvent was evaporated and the residue was purified by flash chromatography (silica gel, 50g, 10% to 100% EtOAc in heptane). White solid (0.25g, 74%). Ms (eic): 413.2([ M + Na ]]⁺)

Step b) (S) -tert-butyl 2- (2-fluoro-4- (1- (6- (trifluoromethyl) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide) phenyl) morpholine-4-carboxylate:

tert-butyl (S) -2- (2-fluoro-4- (1H-oxazole-4-carboxamide) phenyl) morpholine-4-carboxylate (60mg, 154. mu. mol, Eq: 1.00), 4-chloro-6- (trifluoromethyl) -pyrimidine (CAS37552-81-1) (28mg, 154. mu. mol, Eq: 1.00) were combined in DMSO (2ml) at N2. The orange solution was stirred at 120 ℃ for 1 hour. Control by TLC: the reaction was complete. The resultant was partitioned between water and EtOAc at rt; extracting; the organic layer was washed with water and brine; drying over MgSO 4; filtering; concentrate in vacuo. The crude material was purified by flash chromatography (silica gel, 10g, 15% to 60% EtOAc in heptane). Yellow solid (41 mg). MS: 535.7([ M-H)]^-)

Step c) (S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl tomb) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide hydrochloride: analogous to example 83, step b). A white solid. Ms (isp): 453.2([ M + H)]⁺)

Example 130

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyridin-3-yl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 129, step b) 5-bromo-2- (trifluoromethyl) -pyridine (CAS436799-92-5) was used instead of 4-chloro-6- (trifluoromethyl) -pyrimidine (CAS37552-81-1) and heated at 120 ℃ for 17h (instead of 1 h).

A white solid. Ms (isp): 436.4([ M + H)]⁺)

Example 131

(S) -1- (5-cyanopyrazin-2-yl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 129, step b), 5-bromo-2-pyrazinecarbonitrile (CAS221295-04-1) was used instead of 4-chloro-6- (trifluoromethyl) -pyrimidine (CAS37552-81-1) and the reaction was carried out at room temperature (instead of at 120 ℃).

A white solid. Ms (isp): 394.4([ M + H)]⁺)

Example 132

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (2- (trifluoromethyl) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 129, step b) 4-chloro-2- (trifluoromethyl) -pyrimidine (CAS1514-96-1) was used instead of 4-chloro-6- (trifluoromethyl) -pyrimidine (CAS 37552-81-1). A white solid. Ms (isp): 419.5([ M + H)]⁺)

Example 133

(S) -4-chloro-6-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide hydrochloride

In analogy to example 83, step a) 4-chloro-6-cyano-2-pyridinecarboxylic acid (CAS1060812-13-6) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 83) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

Step b) is as described in step (b) of example 79. A white solid. Ms (isp): 361.1([ M + H)]⁺)

Example 134

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (5- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide hydrochloride

In analogy to example 129, step b) 2-chloro-5- (trifluoromethyl) -pyrazine (CAS799557-87-2) was used instead of 4-chloro-6- (trifluoromethyl) -pyrimidine (CAS 37552-81-1). A white solid. Ms (isp): 435.0([ M + H)]⁺)

Example 135

(S) -5-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine carboxamide hydrochloride

In analogy to example 83, step a) 5-cyano-6-methyl-2-pyridinecarboxylic acid (CAS855916-58-4) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 1h) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

A white solid. Ms (isp): 340.9([ M + H)]⁺)

Example 136

(S) -5-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine carboxamide hydrochloride

In analogy to example 83, step a) 5-cyano-6-methyl-2-pyridinecarboxylic acid (CAS855916-58-4) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 83) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

A white solid. Ms (isp): 340.9([ M + H)]⁺)

Example 137

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -5- (trifluoromethyl) pyrazine-2-carboxamide hydrochloride

In analogy to example 83, step a) 5- (trifluoromethyl) -2-pyrazinecarboxylic acid (CAS1060814-50-7) was used instead of 2- (trifluoromethyl) -4-pyridinecarboxylic acid (CAS131747-41-6) and (-) - (S) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester (described in example 83) was used instead of (+) - (R) -2- (4-amino-2-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester.

A white solid. Ms (isp): 370.9([ M + H)]⁺)

Example 138

(S) -6-ethoxy-N- (2-fluoro-4- (morpholin-2-yl) phenyl) nicotinamide

The title compound was obtained in analogy to example 23, using (-) - (S) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester instead of (+) - (R) -2- (4-amino-3-fluoro-phenyl) -morpholine-4-carboxylic acid tert-butyl ester and using 6-ethoxy-nicotinic acid (CAS97455-65-7) instead of 1-methyl-3-phenyl-1H-pyrazole-5-carboxylic acid in step (a). A white solid. Ms (isp): 346.2([ M + H)]⁺)。

The compounds of formula I and their pharmaceutically useful addition salts possess valuable pharmacological properties. In particular, it has been found that the compounds of the invention have a good affinity for Trace Amine Associated Receptors (TAARs), especially TAAR 1.

These compounds were investigated according to the tests given hereinafter.

Materials and methods

Construction of TAAR expression plasmids and stably transfected cell lines

For constructing expression plasmids, essentially as described by Lindemann et al [14 ]]The coding sequence of human, rat and mouse TAAR1 was amplified from genomic DNA as described. At a molar ratio of 1.5mMMg²⁺The purified PCR product was cloned into pCR2.1-TOPO cloning vector (Invitrogen) using an extended high fidelity PCR system (ExpandhighFidelity PCRSystem) (Roche diagnostics) and following the manufacturer's instructions. The PCR product was subcloned into pIRESneo2 vector (bdceltech, PaloAlto, California) and the expression vector was sequence verified prior to introduction into the cell line.

HEK293 cells (ATCC # CRL-1573) were cultured essentially as described in Lindemann et al (2005). To produce stable transfectionsCell lines HEK293 cells were transfected with pIRESneo2 expression plasmid containing the TAAR coding sequence (described above) with Lipofectamine2000(Invitrogen) according to the manufacturer's instructions and 24 hours post transfection the medium was supplemented with 1mg/ml g418(Sigma, Buchs, switzerland). After a culture period of about 10d, the clones were isolated, expanded and tested for reactivity to trace amines (all compounds purchased from Sigma) with the cAMPBiotrak Enzyme Immunoassay (EIA) system (Amersham) according to the non-acetylated EIA program provided by the manufacturer. Will show stable EC for a culture period of 15 passages₅₀The monoclonal cell line of (3) was used in all subsequent studies.

Radioligand binding assay for rat TAAR1

Membrane preparation and radioligand binding

HEK-293 cells stably expressing rat TAAR1 were subjected to inactivation by heat at 56 ℃ for 30min in DMEM high glucose medium containing fetal bovine serum (10%, heat-inactivated at 56 ℃), penicillin/streptomycin (1%), and 375. mu.g/ml geneticin (Gibco) at 37 ℃ and 5% CO₂And (4) maintaining. Cells were released from flasks using trypsin/EDTA, harvested, and frozen-cold PBS (Ca free)^{2 +}And Mg²⁺) Washed twice, granulated at 1' 000rpm at 4 ℃ for 5min, frozen and stored at-80 ℃. The frozen pellets were suspended in 20ml HEPES-NaOH (20mM, pH7.4) containing 10mM EDTA and homogenized with Polytron (PT6000, Kinematica) at 14' 000rpm for 20 s. The homogenate was centrifuged at 48' 000Xg for 30min at 4 ℃. Thereafter, the supernatant was removed and discarded, and the pellet was resuspended in 20ml HEPES-NaOH (20mM, pH7.4) containing 0.1mM EDTA using Polytron (at 14' 000rpm, 20 s). This procedure was repeated and the final pellet was resuspended in HEPES-NaOH containing 0.1mM EDTA and homogenized using Polytron. Typically, 2ml aliquots of the membrane fraction were stored at-80 ℃. For each new membrane batch, the dissociation constant (Kd) was determined by saturation curve. TAAR1 radioligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Oxazol-2-ylamine (described in WO 2008/098857) is used at a concentration equivalent to the calculated Kd value, which is typically about 2.3nM, resulting in about 0.2% binding of the radioligand and about 85% specific binding of the total binding. Non-specific binding is defined as binding in the presence of 10. mu.M unlabelled ligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Amount of oxazol-2-ylamine. All compounds were tested in duplicate at a wide range of concentrations (10pM to 10 μ M). Test compound (A)μ l/well) were transferred to a 96 deep well plate (TreffLab) and 180 μ l of MgCl-containing solution was added₂(10mM) and CaCl₂(2mM) HEPES-NaOH (20mM, pH7.4) (binding buffer), 300. mu.l radioligand at a concentration of 3.3xKd in nM³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Oxazol-2-ylamine and 500. mu.l of membrane (resuspended at 50. mu.g protein/ml). The 96 deep well plate was incubated at 4 ℃ for 1 hr. The incubation was terminated by rapid filtration through a Unifilter-96 plate (PackardInstrument company) and glass filter GF/C (PerkinElmer) pre-soaked in polyethyleneimine (0.3%) for 1hr and washed 3 times with 1ml cold binding buffer. After addition of 45. mu.l Microscint40(PerkinElmer), the Unifilter-96 plates were sealed and radioactivity was counted after 1hr using a TopCount microplate scintillation counter (packardInstrument company).

Radioligand binding assay against mouse TAAR1

Membrane preparation and radioligand binding

HEK-293 cells stably expressing mouse TAAR1 in the presence of fetal bovine serum (10%, heat-inactivated at 56 ℃ for 30min), penicillin/streptDMEM high glucose medium with elements (1%) and 375. mu.g/ml Geneticin (Gibco) at 37 ℃ and 5% CO₂And (4) maintaining. Cells were released from flasks using trypsin/EDTA, harvested, and frozen-cold PBS (Ca free)²⁺And Mg²⁺) Washed twice, granulated at 1' 000rpm at 4 ℃ for 5min, frozen and stored at-80 ℃. The frozen pellets were suspended in 20ml HEPES-NaOH (20mM, pH7.4) containing 10mM EDTA and homogenized with Polytron (PT6000, Kinematica) at 14' 000rpm for 20 s. The homogenate was centrifuged at 48' 000Xg for 30min at 4 ℃. Thereafter, the supernatant was removed and discarded, and the pellet was resuspended in 20ml HEPES-NaOH (20mM, pH7.4) containing 0.1mM EDTA using Polytron (at 14' 000rpm, 20 s). This procedure was repeated and the final pellet was resuspended in HEPES-NaOH containing 0.1mM EDTA and homogenized using Polytron. Typically, 2ml aliquots of the membrane fraction were stored at-80 ℃. For each new membrane batch, the dissociation constant (Kd) was determined by saturation curve. TAAR1 radioligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Oxazol-2-ylamine (described in WO 2008/098857) is used at a concentration equivalent to the calculated Kd value, which is typically about 0.7nM, resulting in about 0.5% binding of the radioligand and about 70% specific binding of the total binding. Non-specific binding is defined as binding in the presence of 10. mu.M unlabelled ligand³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Amount of oxazol-2-ylamine. All compounds were tested in duplicate at a wide range of concentrations (10pM to 10 μ M). Test compound (A)μ l/well) were transferred to a 96 deep well plate (TreffLab) and 180 μ l of MgCl-containing solution was added₂(10mM) and CaCl₂(2mM) HEPES-NaOH (20mM, pH7.4) (binding buffer)) 300 μ l of radioligand at a concentration of 3.3xKd in nM³[H]- (S) -4- [ (ethyl-phenyl-amino) -methyl]-4, 5-dihydro-Oxazol-2-ylamine and 500. mu.l of membrane (resuspended at 60. mu.g protein/ml). The 96 deep well plate was incubated at 4 ℃ for 1 hr. The incubation was terminated by rapid filtration through a Unifilter-96 plate (PackardInstrument company) and glass filter GF/C (PerkinElmer) pre-soaked in polyethyleneimine (0.3%) for 1hr and washed 3 times with 1ml cold binding buffer. After addition of 45. mu.l Microscint40(PerkinElmer), the Unifilter-96 plates were sealed and radioactivity was counted after 1hr using a TopCount microplate scintillation counter (packardInstrument company).

Compounds show K in mice or rats to TAAR1 as shown in the following table_iValue (. mu.M).

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

The compounds of formula I may be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as those 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 preparation of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

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

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

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

The dosage can vary within wide limits and should of course be adjusted in each particular case to the individual requirements. In the case of oral administration, the dosage for adults may vary within the following ranges: from about 0.01mg to about 1000mg per day of a compound of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose may be administered as a single dose or in divided doses and, in addition, may exceed the upper limit when it is deemed necessary.

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. The particles are passed through a suitable milling apparatus.

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. Add items 4 and 5 and mix for 3 minutes.

3. Filling into suitable capsules.

Claims (22)

1. A compound of formula I

Wherein

R¹Is hydrogen, halogen, cyano, C_1-7Alkyl, C substituted by halogen_1-7-an alkyl group,

C_1-7alkoxy, C substituted by halogen_1-7Alkoxy or C (O) NH₂，

Or C optionally substituted by halogen, cyano or by halogen_1-7Phenyl substituted by alkoxy, or 2, 2-difluorobenzo [ d][1，3]Dioxol-5-yl, or is 6- (trifluoromethyl) pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or is 6- (trifluoromethyl) pyrimidin-4-yl, or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2

R²Is halogen, C_1-7-alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, C_1-7-alkyl or cyano;

x is a bond, -NR' -, -CH₂NH-or-CHR' -;

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

z is a bond, -CH₂-or-O-;

ar is phenyl or a heteroaryl selected from the group consisting of: 1H-indazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl;

and compounds

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -5- (trifluoromethyl) pyrazine-2-carboxamide or

Suitable for pharmaceutical use.

2. A compound of formula IA encompassed by formula I according to claim 1,

wherein

R¹Is hydrogen, halogen, cyano, C_1-7Alkyl, C substituted by halogen_1-7-alkyl radical, C_1-7Alkoxy, C substituted by halogen_1-7Alkoxy or C (O) NH₂，

Or C optionally substituted by halogen, cyano or by halogen_1-7-alkoxy substitutedPhenyl, or is 2, 2-difluorobenzo [ d ]][1，3]Dioxol-5-yl, or 6- (trifluoromethyl) pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or 6- (trifluoromethyl) pyrimidin-4-yl,

or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2;

R²is halogen, C_1-7-alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, C_1-7-alkyl or cyano;

or a pharmaceutically suitable acid addition salt thereof.

3. The compound of any one of claims 1 or 2, wherein the compound is:

1- (3-cyano-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

1- (3-cyano-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

(RS) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea,

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

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (3-cyanophenyl) urea,

1- (3-cyano-5-fluoro-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

1- (3-cyano-4-fluoro-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

(S) -1- (5-cyano-2-methoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea,

(R) -1- (5-cyano-2-methoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea,

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2-methoxyphenyl) urea,

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2-methoxyphenyl) urea,

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2- (difluoromethoxy) phenyl) urea,

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-cyano-2- (difluoromethoxy) phenyl) urea,

1- (5-cyano-2-fluoro-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-methoxy-phenyl) -urea,

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-methoxy-phenyl) -urea,

1- (3-cyano-5-fluoro-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-difluoromethoxy-phenyl) -urea,

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (5-cyano-2-difluoromethoxy-phenyl) -urea,

(R) -1- (3-cyano-2-fluorophenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea,

(R) -1- (3-cyano-4-fluorophenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea,

1- (5-cyano-2-difluoromethoxy-phenyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

1- (5-cyano-2-difluoromethoxy-phenyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

(S) -1- (5-cyano-2-ethoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea, or

(R) -1- (5-cyano-2-ethoxyphenyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea.

4. A compound of formula IB encompassed by formula I in claim 1

Wherein

R¹Is hydrogen, halogen, cyano, C_1-7Alkyl, C substituted by halogen_1-7-alkyl radical, C_1-7Alkoxy, C substituted by halogen_1-7Alkoxy or C (O) NH₂，

Or is optionally coveredHalogen, cyano, or C substituted by halogen_1-7Phenyl substituted by alkoxy, or 2, 2-difluorobenzo [ d][1，3]Dioxol-5-yl, or is 6- (trifluoromethyl) pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or is 6- (trifluoromethyl) pyrimidin-4-yl, or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2;

R²is halogen, C_1-7-alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, C_1-7-alkyl or cyano;

or a pharmaceutically suitable acid addition salt thereof.

5. The compound of formula IB according to any one of claims 1 or 4, wherein the compound is:

1- (3-cyano-benzyl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

1- (3-cyano-benzyl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

(R) -1- (3- (difluoromethoxy) benzyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea, or

(S) -1- (3- (difluoromethoxy) benzyl) -3- (2-fluoro-4- (morpholin-2-yl) phenyl) urea.

6. A compound of formula IC encompassed by formula I in claim 1

Wherein

R¹Is hydrogen, halogen, cyano, C_1-7Alkyl, C substituted by halogen_1-7-alkyl radical, C_1-7Alkoxy, C substituted by halogen_1-7Alkoxy or C (O) NH₂，

Or C optionally substituted by halogen, cyano or by halogen_1-7-alkoxy-substituted phenyl, or2, 2-difluorobenzo [ d ]][1，3]Dioxol-5-yl, or is 6- (trifluoromethyl) pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or is 6- (trifluoromethyl) pyrimidin-4-yl, or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2

R²Is halogen, C_1-7-alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, C_1-7-alkyl or cyano;

or a pharmaceutically suitable acid addition salt thereof.

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

(S) -4-chloro-N- (2-chloro-4- (morpholin-2-yl) phenyl) benzamide.

8. A compound of formula ID encompassed by formula I in claim 1

Wherein

R¹Is hydrogen, halogen, cyano, C_1-7Alkyl, C substituted by halogen_1-7-alkyl radical, C_1-7-Alkoxy, C substituted by halogen_1-7Alkoxy or C (O) NH₂，

Or C optionally substituted by halogen, cyano or by halogen_1-7Phenyl substituted by alkoxy, or 2, 2-difluorobenzo [ d][1，3]Dioxol-5-yl, or is 6- (trifluoromethyl) pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or is 6- (trifluoromethyl) pyrimidin-4-yl, or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2

R²Is halogen, C_1-7-alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, C_1-7-alkyl or cyano;

hetar is selected from the group consisting of: 1H-indazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl;

or a pharmaceutically suitable acid addition salt thereof.

9. The compound of formula ID according to any one of claims 1 and 8, wherein the compound is

6-fluoro-1H-indazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide,

6-fluoro-1H-indazole-3-carboxylic acid ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -amide,

1- (4-fluoro-phenyl) -1H-pyrazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide,

1- (4-fluoro-phenyl) -1H-pyrazole-3-carboxylic acid ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -amide,

2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -amide,

(RS) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide,

(R) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide,

(S) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide,

2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -amide,

2-chloro-N- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -6-methoxy-isonicotinamide,

2-chloro-N- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -6-methoxy-isonicotinamide,

(RS) -N- (2-cyano-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide,

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide,

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-3-carboxamide,

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide,

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-fluorophenyl) -1H-pyrazole-4-carboxamide,

(R) -6-chloro-N- (2-chloro-4- (morpholin-2-yl) phenyl) nicotinamide,

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

6-chloro-N- ((R) -2-methyl-4-morpholin-2-yl-phenyl) -nicotinamide,

(S) -1- (3- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide,

(S) -1- (4- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide,

(S) -4-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide,

(R) -4-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide,

(S) -6-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide,

(S) -1- (2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide,

(R) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide,

(R) -2-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) isonicotinamide,

(R) -6-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) nicotinamide,

(R) -1- (4- (difluoromethoxy) phenyl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide,

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -2- (trifluoromethyl) isonicotinamide,

(S) -2-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) isonicotinamide,

(S) -6-ethoxy-N- (3-fluoro-4- (morpholin-2-yl) phenyl) nicotinamide,

(S) -1- (4- (difluoromethoxy) phenyl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide,

(R) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -2-ethoxyisonicotinamide,

(R) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -6-ethoxynicotinamide,

(R) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxamide,

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -2-ethoxyisonicotinamide,

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -6-ethoxynicotinamide,

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4- (difluoromethoxy) phenyl) -1H-pyrazole-4-carboxamide,

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -6-cyanopyridinecarboxamide,

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -6-cyanopyridinecarboxamide,

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -5-cyanopyridinecarboxamide,

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -5-cyanopyridinecarboxamide,

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -6-cyanonicotinamide,

(R) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -6-cyanonicotinamide,

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (4-cyanophenyl) -1H-pyrazole-4-carboxamide,

(S) -1- (4- (difluoromethoxy) phenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-1,2, 3-triazole-4-carboxamide,

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4-cyanophenyl) -1H-pyrazole-4-carboxamide,

(S) -4-chloro-6-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide,

(S) -2-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methoxyisonicotinamide,

(S) -1- (4-cyano-2-fluorophenyl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide,

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (4-cyano-2-fluorophenyl) -1H-pyrazole-4-carboxamide,

(S) -1- (4-cyano-2-fluorophenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide,

(S) -1- (4-cyanophenyl) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide,

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -2-cyano-6-methylisonicotinamide,

(S) -2-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methylisonicotinamide,

(S) -N4- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide,

(S) -2-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methylisonicotinamide,

(S) -6-chloro-N4- (3-fluoro-4- (morpholin-2-yl) phenyl) pyridine-2, 4-dicarboxamide,

(S) -6-ethyl-N4- (3-fluoro-4- (morpholin-2-yl) phenyl) pyridine-2, 4-dicarboxamide,

(S) -N4- (3-chloro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide,

(S) -N4- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide,

(S) -N4- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methoxypyridine-2, 4-dicarboxamide,

(S) -2-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methoxyisonicotinamide,

(S) -N4- (2-chloro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-2, 4-dicarboxamide,

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -2-cyano-6-methylisonicotinamide,

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -2-cyano-6-methoxyisonicotinamide,

(S) -N- (2-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide,

(S) -N- (2-chloro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide,

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide,

(S) -N- (3-chloro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide,

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide,

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (6- (trifluoromethyl) pyridin-3-yl) -1H-pyrazole-4-carboxamide,

(S) -1- (5-cyanopyrazin-2-yl) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1H-pyrazole-4-carboxamide, (S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (2- (trifluoromethyl) pyrimidin-4-yl) -1H-pyrazole-4-carboxamide,

(S) -4-chloro-6-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) pyridinecarboxamide,

(S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -1- (5- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazole-4-carboxamide,

(S) -5-cyano-N- (2-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine-carboxamide,

(S) -5-cyano-N- (3-fluoro-4- (morpholin-2-yl) phenyl) -6-methylpyridine carboxamide, or

(S) -6-ethoxy-N- (2-fluoro-4- (morpholin-2-yl) phenyl) nicotinamide.

10. A compound of formula IE encompassed by formula I in claim 1

Wherein

R¹Is hydrogen, halogen, cyano, C_1-7Alkyl, C substituted by halogen_1-7-alkyl radical, C_1-7Alkoxy, C substituted by halogen_1-7Alkoxy or C (O) NH₂，

Or C optionally substituted by halogen, cyano or by halogen_1-7Phenyl substituted by alkoxy, or 2, 2-difluorobenzo [ d][1，3]Dioxol-5-yl, or is 6- (trifluoromethyl) pyrazin-2-yl or 5- (trifluoromethyl) pyrazin-2-yl or is 6- (trifluoromethyl) pyrimidin-4-yl, or is 6- (trifluoromethyl) pyridin-3-yl, or is 5-cyanopyrazin-2-yl or is 2- (trifluoromethyl) pyrimidin-4-yl;

n is 1 or 2

R²Is halogen, C_1-7-alkyl or cyano and R³Is hydrogen, or

R²Is hydrogen and R³Is halogen, C_1-7-alkyl or cyano;

hetar is selected from the group consisting of: 1H-indazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl;

or a pharmaceutically suitable acid addition salt thereof.

11. A compound of formula IE according to any one of claims 1 or 10, wherein the compound is

1- (6-chloro-pyridin-3-yl) -3- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

1- (6-chloro-pyridin-3-yl) -3- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -urea,

1- ((R) -2-fluoro-4-morpholin-2-yl-phenyl) -3- (6-trifluoromethyl-pyridin-3-yl) -urea,

1- ((S) -2-fluoro-4-morpholin-2-yl-phenyl) -3- (6-trifluoromethyl-pyridin-3-yl) -urea,

(RS) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea,

(S) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea,

(R) -1- (2-chloro-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea,

(RS) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-chloropyridin-3-yl) urea,

(RS) -1- (6-chloro-pyridin-3-yl) -3- (2-chloro-4-pyrrolidin-3-yl-phenyl) -urea,

(R) -1- (6-chloropyridin-3-yl) -3- (2-methyl-4- (morpholin-2-yl) phenyl) urea,

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (6- (trifluoromethyl) pyridin-3-yl) urea,

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (6- (trifluoromethyl) pyridin-3-yl) urea,

1- ((S) -2-chloro-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea,

1- ((R) -2-chloro-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea,

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5- (trifluoromethyl) pyridin-2-yl) urea,

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5- (trifluoromethyl) pyridin-2-yl) urea,

(R) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-chloropyridin-2-yl) urea,

(S) -1- (2-chloro-4- (morpholin-2-yl) phenyl) -3- (5-chloropyridin-2-yl) urea,

(R) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-cyanopyridin-3-yl) urea,

(S) -1- (2-bromo-4- (morpholin-2-yl) phenyl) -3- (6-cyanopyridin-3-yl) urea,

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea,

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (6-chloro-pyridin-3-yl) -urea,

1- ((S) -2-bromo-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea, or

1- ((R) -2-bromo-4-morpholin-2-yl-phenyl) -3- (2-trifluoromethyl-pyrimidin-5-yl) -urea.

12. A compound of formula I according to claim 1, wherein Z is a bond or-CH₂-。

13. The compound of any one of claims 1 or 12, wherein the compound is

(RS) -1- (6-chloro-pyridin-3-yl) -3- (2-chloro-4-pyrrolidin-3-yl-phenyl) -urea,

(RS) -1- (2-chloro-4- (piperidin-3-yl) phenyl) -3- (6-chloropyridin-3-yl) urea, or

(RS) -6-chloro-N- (2-chloro-4-piperidin-3-yl-phenyl) -nicotinamide.

14. The compound (S) -N- (3-fluoro-4- (morpholin-2-yl) phenyl) -5- (trifluoromethyl) pyrazine-2-carboxamide.

15. A process for the preparation of a compound of formula I as defined in claim 1, which process comprises

a) Dissociating the N-protecting group from the compound of the following formula,

to form the compound of the formula I,

wherein PG is an N-protecting group selected from the group consisting of-C (O) O-t-butyl, and the other definitions are as described in claim 1, and,

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

16. A pharmaceutical composition comprising a compound according to any one of claims 1-14 and a pharmaceutically acceptable carrier and/or adjuvant.

17. A pharmaceutical composition comprising a compound according to any one of claims 1-14 and a pharmaceutically acceptable carrier and/or adjuvant for use in the treatment of neurological diseases, substance abuse, metabolic diseases, eating disorders, and cardiovascular diseases.

18. A pharmaceutical composition comprising a compound according to any one of claims 1-14 and a pharmaceutically acceptable carrier and/or adjuvant for use in the treatment of psychotic disorders, neurodegenerative disorders, hypertension, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm.

19. A pharmaceutical composition comprising a compound according to any one of claims 1-14 and a pharmaceutically acceptable carrier and/or adjuvant for the treatment of depression, anxiety disorders, bipolar disorder, Attention Deficit Hyperactivity Disorder (ADHD), stress-related disorders, schizophrenia, parkinson's disease or alzheimer's disease.

20. The use of a compound according to any one of claims 1-14 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of neurological diseases, psychiatric substance abuse, metabolic disorders, eating disorders, and cardiovascular diseases.

21. The use of a compound according to any one of claims 1-14 for the preparation of medicaments for the therapeutic and/or prophylactic treatment of psychotic disorders, neurodegenerative disorders, hypertension, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm.

22. The use of a compound according to any one of claims 1-14 for the preparation of medicaments for the therapeutic and/or prophylactic treatment of depression, anxiety disorders, bipolar disorder, Attention Deficit Hyperactivity Disorder (ADHD), stress-related disorders, schizophrenia, parkinson's disease or alzheimer's disease.