HK1228379B - Morpholin-pyridine derivatives - Google Patents

Description

Morpholine-pyridine derivatives

The present invention relates to compounds of the formula

in

X is CR or N;

R is hydrogen, halogen or lower alkyl;

L is a bond, -C(O)-, or -C(O)NH-;

Ar is a phenyl group or a five- or six-membered heteroaryl group containing one or two nitrogen atoms;

^R1 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, or cycloalkyl;

n is 0, 1, 2, or 3;

or their pharmaceutically acceptable acid addition salts, all racemic mixtures, all their corresponding enantiomers and/or optical isomers.

It has now been found that the compounds of formula I have good affinity for trace amine associated receptors (TAARs), in particular TAAR1.

The compounds can be used to treat depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse, and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, and the like. homeostasis), disorders of sleep and circadian rhythm, and cardiovascular disorders.

Some physiological effects reported for compounds that can bind to adrenergic receptors (i.e. cardiovascular effects, hypotension, sedation induction) (WO 02/076950, WO 97/12874 or EP 0717 037) may be considered undesirable side effects in the context of drugs intended to treat central nervous system diseases as described above. Therefore, it is desirable to obtain drugs that are selective for TAAR1 receptors compared to adrenergic receptors. The target of the present invention shows selectivity for TAAR1 receptors over adrenergic receptors, in particular good selectivity compared to human and rat α1 and α2 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 reuptake after release, are tightly regulated. Imbalances in biogenic amine levels are known to be responsible for altered brain function in many pathological conditions [2-5]. A second class of endogenous amine compounds, the so-called trace amines (TAs), overlap significantly with the classical biogenic amines in terms of structure, metabolism, and subcellular localization. TAs include p-tyramine, β-phenylethylamine, tryptamine, and octopamine, and are present in the mammalian nervous system at levels generally lower than those of the classical biogenic amines [6].

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

For a long time, the existence of specific receptors for TA was hypothesized based on the presence of anatomically discrete high-affinity TA binding sites in the CNS of humans and other mammals [10, 11]. Consequently, the pharmacological effects of TA were thought to be mediated through the well-known mechanisms of classical biogenic amines, either by causing their release, inhibiting their reuptake, or by "cross-reacting" with their receptor systems [9, 12, 13]. This view has changed significantly with the recent identification of several members of a new family of GPCRs, the trace amine-associated receptors (TAARs) [7, 14]. There are nine TAAR genes (including three pseudogenes) in humans and 16 genes (including one pseudogene) in mice. TAAR genes do not contain introns (with one exception, TAAR2, which contains one intron) and are located adjacent to each other on the same chromosomal segment. The 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 is in the first subclass of four genes (TAAR1-4) that are highly conserved between humans and rodents. TA activates TAAR1 via Gα. Dysregulation of TA has been shown to contribute to the etiology of numerous diseases, such as depression, psychosis, attention deficit hyperactivity disorder, psychotropic substance abuse, Parkinson's disease, migraine, eating disorders, and metabolic diseases, and therefore TAAR1 ligands have high potential for the treatment of these diseases.

Therefore, there is widespread interest in increasing knowledge about trace amine-associated receptors.

References used:

1 Deutch, A.Y. and Roth, R.H. (1999) Neurotransmitters. In Fundamental Neuroscience (2nd ed.) (Zigmond, M.J., Bloom, F.E., Landis, S.C., Roberts, J.L. and Squire, L.R., eds.), pp. 193–234. Academic Press.

2 Wong, M.L. and Licinio, J. (2001) Research and treatment approaches to depression. Nat. Rev. Neurosci. 2, 343-351;

3 Carlsson, A. et al. (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence.Annu.Rev.Pharmacol.Toxicol.41, 237-260;

4 Tuite, P. and Riss, J. (2003) Recent developments in the pharmacological treatment of Parkinson’s disease. Expert Opin. Investig. Drugs 12, 1335-1352;

5 Castellanos, F.X. and Tannock, R. (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat. Rev. Neurosci. 3, 617-628;

6 Usdin, Earl; Sandler, Merton; Editor, Psychopharmacology Series, Volume 1: Trace Amines and the Brain. [Proceedings of a Study Group at the 14th Annual Meeting of the American College of Neuropsychoparmacology, San Juan, Puerto Rico] (1976);

7 Lindemann, L. and Hoener, M. (2005) A renaissance in trace amines inspired by a novel GPCR family. Trends in Pharmacol. Sci. 26, 274-281;

8 Branchek, T.A. and Blackburn, T.P. (2003) Trace amine receptors as targets for novel therapeutics: legend, myth and fact. Curr. Opin. Pharmacol. 3, 90-97;

9 Premont, R.T. et al. (2001) Following the trace of elusive amines. Proc.Natl.Acad.Sci.U.S.A.98, 9474-9475;

10 Mousseau, D.D. and Butterworth, R.F. (1995) A high-affinity[3H]tryptaminebinding site in human brain.Prog.Brain Res.106, 285-291;

11 McCormack, J.K. et al. (1986) Autoradiographic localization of tryptaminebinding sites in the rat and dog central nervous system. J. Neurosci. 6, 94-101;

12 Dyck, L.E. (1989) Release of some endogenous trace amines from rattriatal slices in the presence and absence of a monoamine oxidaseinhibitor. Life Sci. 44, 1149-1156;

13 Parker, E. M. and Cubeddu, L.

14 Lindemann, L. et al. (2005) Trace amine associated receptors formstructurally and functionally distinct subfamilies of novel Gprotein-coupledreceptors. Genomics 85, 372-385.

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

Preferred indications for the use of the compounds of the present invention are depression, psychosis, Parkinson's disease, anxiety disorders, attention deficit hyperactivity disorder (ADHD) and diabetes.

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

As used herein, the term "halogen-substituted lower alkyl" refers to a saturated straight-chain or branched group containing 1 to 7 carbon atoms as defined for the term "lower alkyl", in which at least one hydrogen atom is replaced by a halogen atom. Preferably, the _halogen atom is fluorine. Examples of such groups are _CF3 , _CHF2 , _CH2F , _CH2CF3 or _{CH2CHF2 .}

As used herein, the term "lower alkoxy substituted by halogen" denotes an alkoxy group as defined above, and wherein at least one hydrogen atom is replaced by halogen.

The term "cycloalkyl" denotes a saturated carbocyclic ring containing from 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "five- or six-membered heteroaryl containing one or two N atoms" denotes a cyclic aromatic five- or six-membered ring in which at least one carbon atom is replaced by a nitrogen atom, for example the groups pyridinyl, pyrimidinyl or pyrazolyl.

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 is a compound of formula I, wherein "L" is a bond, for example the following compound

(RS)-N-(4-Chlorophenyl)-6-morpholin-2-yl-pyridin-3-amine

(RS)-N-(4-Bromophenyl)-6-morpholin-2-yl-pyridin-3-amine

(RS)-N-(4-ethoxyphenyl)-6-morpholin-2-yl-pyridin-3-amine

(RS)-N-(3-Chlorophenyl)-6-morpholin-2-yl-pyridin-3-amine

(RS)-N-(4-Fluorophenyl)-6-morpholin-2-yl-pyridin-3-amine

(RS)-6-Morpholin-2-yl-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine

(RS)-N-(6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyrimidin-4-amine

N-(4-Chlorophenyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine

6-[(2S)-Morpholin-2-yl]-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine

N-(5-chloro-2-pyridinyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine

N-(5-Bromo-2-pyridinyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine

6-[(2S)-Morpholin-2-yl]-N-[6-(trifluoromethyl)-3-pyridinyl]pyridin-3-amine

6-[(2S)-Morpholin-2-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine

N-(4-Chlorophenyl)-6-[(2R)-morpholin-2-yl]pyridin-3-amine

6-[(2R)-Morpholin-2-yl]-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine

N-(5-chloro-2-pyridinyl)-6-[(2R)-morpholin-2-yl]pyridin-3-amine

6-[(2R)-morpholin-2-yl]-N-[6-(trifluoromethyl)-3-pyridinyl]pyridin-3-amine

6-[(2R)-morpholin-2-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-5-(trifluoromethyl)pyridin-2-amine

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-6-(trifluoromethyl)pyridin-2-amine

N-(5-Bromo-2-pyridinyl)-6-[(2R)-morpholin-2-yl]pyridin-3-amine

N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-5-(trifluoromethyl)pyridin-2-amine

N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-6-(trifluoromethyl)pyridin-2-amine

(RS)-N-(4-Chlorophenyl)-2-morpholin-2-yl-pyrimidin-5-amine

(RS)-2-Morpholin-2-yl-N-[4-(trifluoromethyl)phenyl]pyrimidin-5-amine

(RS)-5-Chloro-N-(5-chloro-2-pyridinyl)-6-morpholin-2-yl-pyridin-3-amine

(RS)-5-Chloro-6-morpholin-2-yl-N-[5-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine

(RS)-5-Methyl-6-morpholin-2-yl-N-[5-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine

(RS)-N-(5-chloro-2-pyridinyl)-5-fluoro-6-morpholin-2-yl-pyridin-3-amine, or

(RS)-5-Fluoro-6-morpholin-2-yl-N-[5-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine.

A further embodiment of the present invention is a compound of formula I, wherein "L" is -C(O)-, for example the following compound

(RS)-4-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)benzamide

(RS)-3-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)benzamide

(RS)-4-Ethoxy-N-(6-morpholin-2-yl-3-pyridyl)benzamide

(RS)-4-Fluoro-N-(6-morpholin-2-yl-3-pyridinyl)benzamide

(RS)-4-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide

(RS)-N-(6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide

4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]benzamide

3-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]benzamide

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-4-(trifluoromethyl)benzamide

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-2-(trifluoromethyl)pyridine-4-carboxamide

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)benzamide

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide

2-Ethyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]pyrimidine-5-carboxamide

3-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide

4-Chloro-3-cyclopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

4-Chloro-3-methyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Methyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Chloro-1-methyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-5-propyl-pyrazole-3-carboxamide

4-Chloro-1-methyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-5-propyl-pyrazole-3-carboxamide

4-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]benzamide

3-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]benzamide

N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-4-(trifluoromethyl)benzamide

N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-2-(trifluoromethyl)pyridine-4-carboxamide

N-[6-[(2R)-Morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)benzamide

N-[6-[(2R)-Morpholin-2-yl]-3-pyridinyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide

2-Ethyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]pyrimidine-5-carboxamide

3-Isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide

4-Chloro-3-cyclopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

4-Chloro-3-methyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Methyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

(R)-3-Ethyl-4-methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-1H-pyrazole-5-carboxamide

(S)-3-Ethyl-4-methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-1H-pyrazole-5-carboxamide

(R)-6-Methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-2-(trifluoromethyl)pyrimidine-4-carboxamide

(S)-6-Methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-2-(trifluoromethyl)pyrimidine-4-carboxamide

(RS)-4-Chloro-N-(2-morpholin-2-ylpyrimidin-5-yl)benzamide

(RS)-4-Chloro-3-ethoxy-N-(6-morpholin-2-yl-3-pyridinyl)-1H-pyrazole-5-carboxamide

(RS)-4-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide

4-Chloro-3-ethyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

3-Ethyl-4-fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Bromo-3-ethyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide

3-Cyclopropyl-4-fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Bromo-3-cyclopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Chloro-3-ethyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

3-Ethyl-4-fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Bromo-3-ethyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide

3-Cyclopropyl-4-fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Bromo-3-cyclopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

3-Isobutyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Fluoro-3-isobutyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

3-Butyl-4-fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

3-Butyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

5-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxamide

2-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide

3-Isobutyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Fluoro-3-isobutyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

3-Butyl-4-fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

3-Butyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

5-Isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxamide

2-Isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide

4-Chloro-3-ethoxy-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide

4-Chloro-3-ethoxy-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

(RS)-N-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide

(RS)-4-Chloro-N-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide

(RS)-N-(5-Fluoro-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide

(RS)-4-Chloro-N-(5-fluoro-6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide

4-Chloro-3-isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

4-Fluoro-3-isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

(RS)-N-(5-methyl-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide

(RS)-4-Chloro-N-(5-methyl-6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide

4-chloro-3-isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide, or

4-Fluoro-3-isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide.

A further embodiment of the present invention is a compound of formula I, wherein "L" is -C(O)NH-, for example the following compound

(RS)-1-(3-chlorophenyl)-3-(6-morpholin-2-yl-3-pyridyl)urea

(RS)-1-(4-Fluorophenyl)-3-(6-morpholin-2-yl-3-pyridyl)urea

(RS)-1-(6-morpholin-2-yl-3-pyridinyl)-3-[4-(trifluoromethyl)phenyl]urea

(RS)-1-(4-chlorophenyl)-3-(6-morpholin-2-yl-3-pyridyl)urea

1-(3-chlorophenyl)-3-[6-[(2S)-morpholin-2-yl]-3-pyridyl]urea

1-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-[3-(trifluoromethyl)phenyl]urea

1-(3-chlorophenyl)-3-[6-[(2R)-morpholin-2-yl]-3-pyridyl]urea

1-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-[3-(trifluoromethyl)phenyl]urea

(RS)-1-(3-chlorophenyl)-3-(2-morpholin-2-ylpyrimidin-5-yl)urea

(RS)-1-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-3-(3-chlorophenyl)urea

(RS)-1-(3-chlorophenyl)-3-(5-fluoro-6-morpholin-2-yl-3-pyridyl)urea, or

(RS)-1-(3-chlorophenyl)-3-(5-methyl-6-morpholin-2-yl-3-pyridyl)urea.

The preparation of the compound of formula I of the present invention can be carried out in sequence or with a convergent synthesis route. The synthesis of the compound of the present invention is shown in the following schemes 1, 2 and 3 and in the description of 121 specific embodiments. The skills required for carrying out the reaction and purification of the resulting product are known to those skilled in the art. Unless otherwise indicated, the substituents and symbols used in the following method descriptions have the meanings previously given in this article.

In more detail, the compound of formula I can be prepared by the method given below, by the method given in the examples or by a similar method. Suitable reaction conditions for the individual reaction steps are well known to those skilled in the art. The reaction sequence is not limited to the sequence given in schemes 1, 2 and 3, but according to the starting materials and their corresponding reactivity, the order of the reaction steps can be freely changed. Starting materials are commercially available or can be prepared by a method similar to the method given below, prepared by the method described in the references cited in the specification or in the examples, or prepared by methods known in the art.

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

a) the compound of formula 14

Reaction with the compound of formula 15-a

Obtain a compound of formula 16-a

Then deprotect the Boc-group to obtain a compound of formula I

wherein L is -C(O)- and the other substituents are as described above, or

b) the compound of formula 14

Reaction with the compound of formula 15-b

Obtain a compound of formula 16-b

Then deprotect the Boc-group to obtain a compound of formula I

wherein L is -NHC(O)- and the other substituents are as described above, or

c) the compound of formula 8, 9 or 10

Reaction with the compound of formula 11

Obtaining a compound of formula 12

Then deprotect the Boc-group to obtain a compound of formula I

wherein L is a bond and the other substituents are as described above, or

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

General Procedure

Solution 1

The substituents are as described above.

Step A: Conversion of ketone 1 to α-halogenated ketone 3 can be accomplished by treating with a halogenating agent such as chlorine, bromine, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or tetraethylammonium chloride, optionally with an acid such as HBr, HCl, HOAc, p-toluenesulfonic acid as an additive, in a solvent such as _CH2Cl2 , _CHCl3 , _dioxane , THF, acetonitrile at room temperature to elevated temperature.

Preferred conditions are bromine in HBr/HOAc solution at 70°C for 3 hours to form the α-bromoketone 3 (hal=Br).

Step A': Alternatively, α-halogenated ketone 3 can be obtained by a stepwise process involving an acyl halide intermediate. Carboxylic acid 2 can be converted to the corresponding acyl halide by treatment with a halogenating agent such as (COCl) ₂ , SOCl ₂ , PCl ₃ , PBr ₃ or Ph ₃ P·Br ₂ , optionally in a solvent such as CH ₂ Cl ₂ , CHCl ₃ , benzene, or toluene at 0° C. to elevated temperatures. In a second step, the acyl halide intermediate can be treated with (trimethylsilyl)diazomethane followed by concentrated HCl or HBr. The reaction can be carried out using a mixture of acetonitrile, THF, and diethyl ether as a solvent at temperatures between 0° C. and room temperature.

Preferred conditions are (COCl) ₂ in _CH2Cl2 at 0° _C to room temperature for the first step and mixing of the reactants at 0-5°C followed by reaction at room temperature for 30 minutes to form the α-chloroketone 3 (hal=Cl).

Step B: C-N bond formation can be accomplished by nucleophilic substitution with N-benzylaminoethanol to provide α-aminoketone 4. _The reaction can be carried out using a base such as triethylamine, diisopropylethylamine, _K2CO3 , _Na2CO3 , _Cs2CO3 , ^KOtBu _in an aprotic solvent such as DMF, acetonitrile, DMSO _, THF, DME, or dioxane at room temperature to elevated temperatures.

Preferred conditions are _K2CO3 as _base in anhydrous DMF at room temperature.

Step C: Conversion of ketone 4 to diol 5 can be accomplished by treatment with a reducing agent such as _LiBH4 , _NaBH4 , _LiAlH4 , or DIBAL-H in a solvent such as MeOH, EtOH, THF, diethyl ether, or toluene at -78°C to room temperature.

Preferred conditions are _NaBH4 in ethanol at room temperature for 1 hour.

Step D: Cyclization of diol 5 can be accomplished via acid-mediated cationic cyclization or a stepwise approach involving a sulfonate intermediate.

In acid-mediated cationic cyclization, the conversion can be accomplished by treatment _with mineral _acids such as _H2SO4 or _H3PO4 at elevated temperatures.

In a stepwise approach, the conversion can be accomplished by treating the diol 5 with an equivalent of a sulfonylating agent, such as 1-(p-toluenesulfonyl)imidazole, methanesulfonyl chloride, or toluenesulfonyl chloride, or in the presence of an inorganic base such as NaH and ^KO'Bu , or an organic base such as pyridine, triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine, in an ethereal solvent such as diethyl ether, dioxane, THF, or TBME, or using an organic base as solvent at 0° C. to 50° C. The resulting sulfonate can be converted to the morpholine 6 by treatment with a non-nucleophilic base such as sodium hydride, potassium tert-butoxide, or potassium 2-methyl-2-butoxide in an ethereal solvent such as diethyl ether, dioxane, THF, or TBME.

Preferred conditions are a stepwise procedure using NaH as base and 1-(p-toluenesulfonyl)imidazole as sulfonylating agent in THF at room temperature for 16 hours.

Step E: Removal of the benzyl protecting group can be accomplished by hydrogenation catalyzed by a Pd catalyst or by treatment with _{chloroformates} such as _{ClCOOCH2CH2Cl} , ClCOOCH(Cl)Me, _ClCOOCH2Ph , and _ClCOOCH2CCl3 , and optionally with a base such as triethylamine, _{diisopropylethylamine} , and sodium hydroxide, in solvents such as dichloromethane, 1,2-dichloroethane, toluene, THF, diethyl ether, dioxane, TBME, methanol, and ethanol at room temperature to elevated temperatures.

Preferred conditions are using ClCOOCH(Cl)Me in dichloromethane at room temperature for 4 hours followed by MeOH and toluene at reflux temperature for 1 hour.

Step F: Protection of morpholine 7 can be accomplished by treatment with di-tert-butyl carbonate, optionally in the presence of an organic or inorganic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium carbonate, or cesium carbonate, in a halogenated solvent such as dichloromethane or 1,2-dichloroethane or an ethereal solvent such as diethyl ether, dioxane, THF, or TBME.

Preferred conditions are THF in the presence of potassium carbonate as base at room temperature for 2 hours.

Step G: The enantiomers of 8 can be separated using chiral HPLC. Preferred conditions are to use SFC (column: Chiralpak AD-3100 x 4.6 mm ID, 3 um) with 5% to 40% ethanol in _CO2 (0.05% DEA) as the mobile phase.

Option 2

Step A: Coupling of aryl bromide 8, 9, or 10 with arylamine 11 can be accomplished by treatment with a palladium or copper catalyst, a ligand, and a base in solvents such as dioxane, DMF, THF, toluene, DMF, and DMSO at elevated temperature, for example, using a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are catalytic tris(dibenzylideneacetone)dipalladium(0), catalytic 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and _Cs2CO3 in _dioxane at 90°C for 12 hours.

Step B: Removal _of the Boc N-protecting group can be carried out with inorganic acids such as HCl _{, H25O4} , or _H3PO4 or organic acids such as _CF3COOH , _CHCl2COOH , HOAc or p-toluenesulfonic acid in solvents such _{as CH2Cl2} , _CHCl3 , THF, MeOH, EtOH, or _H2O at 0-80°C.

Preferred conditions are _CF3COOH as _the acid in _CH2Cl2 at room temperature for 1 hour.

Option 3

Step A: C-N bond formation can be accomplished by treating bromide 8, 9 or 10 with benzophenone imine in the presence of a palladium or copper catalyst, a ligand and a base in solvents such as dioxane, DME, THF, toluene and DMSO at elevated temperature, for example using a palladium-catalyzed Buchwald-Hartwig reaction.

Preferred conditions are catalytic tris(dibenzylideneacetone)dipalladium(0), catalytic 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and _Cs2CO3 in _dioxane at 90°C for 12 hours.

Step B: Removal of the diphenylmethylene N-protecting group can be accomplished by hydrogenation with hydrogen at normal or elevated pressure or by transfer hydrogenation using ammonium formate or cyclohexadiene as hydrogen source with a catalyst such as _PtO2 , Pd-C or Raneynickel in a solvent such as MeOH, EtOH, _H2O , dioxane, THF, EtOAc, dichloromethane, chloroform, DMF or mixtures thereof.

This transformation can also be carried out by treatment with hydroxylamine hydrochloride along with a base such as sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, in a solvent such as MeOH, EtOH, dioxane, THF, DMF or mixtures thereof.

Preferred conditions are hydroxylamine hydrochloride with sodium acetate in MeOH at room temperature for 1 hour.

Step C: Amide formation can be accomplished by treating the carboxylic acid 15-a with a coupling reagent such as DCC, EDC, TBTU, HBTU or HATU in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in a solvent such as dichloromethane, 1,2-dichloroethane, DMF, DMSO, or an ethereal solvent including diethyl ether, dioxane, THF, DME, or TBME.

Preferred conditions are HATU with N,N-diisopropylethylamine in DMF at room temperature for 16 hours.

Step D: Urea formation can be accomplished by treatment with isocyanate 15-b in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine in a halogenated solvent such as dichloromethane, 1,2-dichloroethane or chlorobenzene.

Preferred conditions are triethylamine as the base in dichloromethane at room temperature.

Step E: Removal of the Boc N-protecting group can be carried out with inorganic acids such as HCl, _H2SO4 , or _H3PO4 or organic acids such as _CF3COOH , _CHCl2COOH , HOAc or _{p -} toluenesulfonic acid in solvents such _{as CH2Cl2} , _CHCl3 , THF, MeOH, EtOH, or _H2O at 0-80°C.

Preferred conditions are _CF3COOH as _the acid in _CH2Cl2 at room temperature for 1 hour.

Isolation and purification of compounds

If desired, the separation and purification of the compounds and intermediates described herein can be accomplished by any suitable separation or purification procedure, such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low pressure or high pressure liquid chromatography, or a combination of these procedures. Specific descriptions of suitable separation and isolation procedures can be obtained by reference to the preparations and examples below in this article. However, other equivalent separation or isolation procedures can certainly also 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

Formula I compound is alkaline and can be converted into corresponding acid addition salt.This conversion is completed by treating with at least stoichiometric amount of suitable acid, and described acid is such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., and organic acid is 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 etc.Typically, free alkali is dissolved in inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol etc., and acid is added in similar solvent.Temperature is maintained between 0 ℃ and 50 ℃.The resulting salt precipitates spontaneously or can be separated out from solution with less polar solvent.

Example 1

(RS)-N-(4-Chlorophenyl)-6-morpholin-2-yl-pyridin-3-amine

a) 2-Bromo-1-(5-bromo-2-pyridyl)ethanone

2-Acetyl-5-bromopyridine (10.0 g, CAS: 214701-49-2) in a HBr/HOAc solution (35% to 39%, 80 mL) was stirred at 70°C for 5 min. _Br₂ (9.6 g) was added dropwise. The reaction was continued at 70°C for 3 h, and TLC analysis showed complete consumption of the starting material. The mixture was cooled to room temperature and filtered through filter paper. The volatiles were removed under reduced pressure, and the residue was further dried under high vacuum to obtain crude 2-bromo-1-(5-bromo-2-pyridyl)ethanone (16.8 g, yield: 93.3%) as a brown oil. The crude product was used in the next step without purification. MS (ESI): 281.9 ([{ ⁸¹ Br}M+H] ⁺ ), 277.9 ([{ ⁷⁹ Br}M+H] ⁺ ).

b) 2-[Benzyl(2-hydroxyethyl)amino]-1-(5-bromo-2-pyridyl)ethanone

To a solution of 2-bromo-1-(5-bromo-2-pyridyl)ethanone (16.8 g) in anhydrous DMF (150 mL) was added _K₂CO₃ (19.5 _g ) portionwise at room temperature. N-benzylaminoethanol (10.2 g, CAS: 104-63-2) was then added dropwise. The reaction was continued at room temperature until TLC analysis indicated completion. The mixture was poured into water (1000 mL) and extracted with EtOAc (2 x 1000 _mL ). The organic layers were combined and dried over _Na₂SO₄ . Volatiles were removed under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether/EtOAc = 10:1 by volume) to give 2-[benzyl(2-hydroxyethyl)amino]-1-(5-bromo-2-pyridyl)ethanone as a light brown oil (9 g, 55% yield).

c)(RS-2-[Benzyl(2-hydroxyethyl)amino]-1-(5-bromo-2-pyridyl)ethanol

At room temperature, NaBH ₍ 540 mg, 14 mmol) was added portionwise to a solution of 2-[benzyl(2-hydroxyethyl)amino]-1-(5-bromo-2-pyridyl)ethanone (4.1 g) in EtOH (40 mL). After TLC analysis showed that the reaction was complete, the reaction was carefully quenched by adding a saturated _NH4Cl aqueous solution (200 mL). EtOH was removed under reduced pressure. The residue was extracted with EtOAc (2x100 mL). The combined organic extracts were dried _{over Na2SO4} and concentrated under reduced pressure. The residue was further dried under high vacuum to provide crude (RS)-2-[benzyl(2-hydroxyethyl)amino]-1-(5-bromo-2-pyridyl)ethanol (3 g, 73%), which was used for the next step without purification. MS(ESI): 352.9([{ ⁸¹ Br}M+H] ⁺ ), 350.9([{ ⁷⁹ Br}M+H] ⁺ ).

d)(RS)-4-Benzyl-2-(5-bromo-2-pyridyl)morpholine

Sodium hydride (60%, 2.7 g) was added portionwise to a solution of (RS)-2-[benzyl(2-hydroxyethyl)amino]-1-(5-bromo-2-pyridyl)ethanol (12 g) in THF (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was cooled to 0°C and 1-(p-toluenesulfonyl)imidazole (7 g, CAS: 2232-08-8) was added portionwise. After 30 minutes, the mixture was warmed to room temperature. Stirring was continued overnight. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, washed with brine, and dried over _Na₂SO₄ . Purification by chromatography (silica gel, petroleum ether:ethyl acetate = 3: ₁ by volume) provided (RS)-4-benzyl-2-(5-bromo-2-pyridyl)morpholine (4 g, yield: 34.5%).

MS (ESI): 335.0 ([{ ⁸¹ Br}M+H] ⁺ ), 333.0 ([{ ⁷⁹ Bt}M+H] ⁺ ).

¹ H NMR (DMSO-d ⁶ ): 8.60(1H), 8.05(1H), 7.42(1H), 7.30(5H), 4.51(1H), 3.97(1H), 3.82 (1H), 3.59(1H), 3.47(1H), 3.07(1H), 2.75(1H), 2.19(1H), 1.91(m, 1H).

e)(RS)-2-(4-bromophenyl)morpholine

A solution of (RS)-4-benzyl-2-(5-bromo-2-pyridyl)morpholine (4.35 g) and 1-chloroethyl chloroformate (2.5 g, CAS: 50893-53-3) in CH ₂ Cl ₂ (50 mL) was stirred at room temperature for 4 h. TLC analysis indicated complete consumption of the starting material. Volatiles were removed under reduced pressure, and the residue was further dried under high vacuum. The residue was dissolved in MeOH (40 mL). The solution was stirred at reflux for one hour. TLC analysis indicated completion of the reaction. Volatiles were removed under reduced pressure, and the residue was further dried under high vacuum to provide (RS)-2-(4-bromophenyl)morpholine (4.35 g, 13 mmol, yield: 100%). The crude product was used directly in the next step.

MS (ESI): 244.9 ([{ ⁸¹ Br}M+H] ⁺ ), 242.9 ([{ ⁷⁹ Br}M+H] ⁺ ).

f)(RS)-tert-Butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate

A solution of K ₂ CO ₃ (5.38 g), di-tert-butyl dicarbonate (3.4 g, CAS: 424-99-5), and (RS)-2-(4-bromophenyl)morpholine (4.35 g, 13 mmol) from the above reaction (step e) in THF (50 mL) was stirred at room temperature for 2 hours. TLC analysis indicated the reaction was complete. Water (200 mL) was added. The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (200 mL). The organic layer was concentrated under reduced pressure. Flash chromatography (silica gel, petroleum ether/EtOAc = 3:1 by volume) gave (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate (3.95 g, 89% yield).

MS(ESI): 344.8([{ ⁸¹ Br}M+H] ⁺ ), 342.8([{ ⁷⁹ Br}M+H] ⁺ ).

¹ H NMR (DMSO-d ⁶ ): 8.69(1H), 8.09(1H), 7.46(1H), 4.45(2H), 4.00(1H), 3.82(1H), 3.63(1H), 2.89(2H), 1.43(9H).

g) (RS)-tert-Butyl 2-[5-(4-chlorophenylamino)-2-pyridyl]morpholine-4-carboxylate

A mixture _of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate (60 mg), 4-chloroaniline (25 mg, CAS: 106-47-8), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 20 mg, CAS: 161265-03-8), tris(dibenzylideneacetone)dipalladium(0) (16 mg, CAS: 51364-51-3) and _Cs2CO3 (170 _mg ) in dioxane (3 mL) was stirred at 90°C under N2 atmosphere for 12 hours. CMS indicated the reaction was complete. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (100 mL). The organic layer was concentrated under reduced pressure to provide crude (RS)-tert-butyl 2-[5-(4-chlorophenylamino)-2-pyridinyl]morpholine-4-carboxylate as a brown oil. The crude product was used in the next step without purification.

h)(RS)-N-(4-chlorophenyl)-6-morpholin-2-yl-pyridin-3-amine

Crude (RS)-tert-butyl 2-[5-(4-chlorophenylamino)-2-pyridinyl]morpholine-4-carboxylate from the above reaction (step g) was dissolved in _CH2Cl2 (3 _mL ) at room temperature. Trifluoroacetic acid (TFA, 1 mL, CAS: 76-05-1) was added. The reaction was continued at room temperature for one hour, and the volatiles were removed under reduced pressure. Purification by preparative HPLC (mobile phase A: _H2O , B: _CH3CN with 0.1% TFA, C18 column) gave (RS)-N-(4-chlorophenyl)-6-morpholin-2-yl-pyridin-3-amine (25 mg) as a light yellow waxy solid.

MS (ESI): 292.1 ([{ ³⁷ Cl}M+H] ⁺ ), 290.1 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 2

(RS)-N-(4-Bromophenyl)-6-morpholin-2-yl-pyridin-3-amine

The title compound was obtained by using 4-bromoaniline (CAS: 106-40-1) in place of 4-chloroaniline in step (g) in a similar manner to Example 1. Pale yellow waxy solid. MS (ESI): 336.0 ([{ ⁸¹ Br}M+H] ⁺ ), 334.1 ([{ ⁷⁹ Br}M+H] ⁺ ).

Example 3

(RS)-N-(4-ethoxyphenyl)-6-morpholin-2-yl-pyridin-3-amine

In a similar manner to Example 1, 4-ethoxyaniline (CAS: 156-43-4) was used instead of 4-chloroaniline in step (g) to obtain the title compound. Pale yellow oil. MS (ESI): 300.2 ([M+H] ⁺ ).

Example 4

(RS)-N-(3-Chlorophenyl)-6-morpholin-2-yl-pyridin-3-amine

The title compound was obtained in a similar manner to Example 1, using 3-chloroaniline (CAS: 108-42-9) instead of 4-chloroaniline in step (g). Pale yellow oil. MS (ESI): 292.0 ([{ ³⁷ Cl}M+H] ⁺ ), 290.0 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 5

(RS)-N-(4-Fluorophenyl)-6-morpholin-2-yl-pyridin-3-amine

In a similar manner to Example 1, 4-fluoroaniline (CAS: 371-40-4) was used instead of 4-chloroaniline in step (g) to obtain the title compound as a pale yellow oil. MS (ESI): 274.1 ([M+H] ⁺ ).

Example 6

(RS)-6-Morpholin-2-yl-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine

The title compound was obtained by analogy to Example 1, using 4-(trifluoromethyl)aniline (CAS: 455-14-1) instead of 4-chloroaniline in step (g). Pale yellow waxy solid. MS (ESI): 324.1 ([M+H] ⁺ ).

Example 7

(RS)-4-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)benzamide

a)(RS)-tert-Butyl 2-[5-(benzhydrylamino)-2-pyridyl]morpholine-4-carboxylate

A mixture of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate (1.0 g), Example 1(f), benzophenone imine (580 mg, CAS: 1013-88-3), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 500 mg, CAS: 161265-03-8), tris(dibenzylideneacetone)dipalladium(0) (265 mg, CAS: 51364-51-3) and Cs ₂ CO ₃ (2.8 g) in dioxane (40 mL) was degassed by bubbling argon through the mixture for several minutes. The reaction mixture was stirred at 90° C. under an Ar atmosphere for 12 hours. TLC analysis indicated that the reaction was complete. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was diluted with water (100 mL). The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (100 mL) and concentrated to dryness. The residue was purified by flash chromatography (silica gel, _CH₂Cl₂ : _MeOH =30:1 by volume) to give tert-butyl (RS)-2-[5-(benzylideneamino)-2-pyridyl]morpholine-4-carboxylate (1.28 g, yield: 99.9%) as a yellow solid.

b) (RS)-tert-Butyl 2-(5-amino-2-pyridyl)morpholine-4-carboxylate

A mixture of tert-butyl (RS)-2-[5-(benzhydrylamino)-2-pyridyl]morpholine-4-carboxylate (1.28 g) from the above reaction (step a), hydroxylamine hydrochloride (320 mg, CAS: 5470-11-1), and NaOAc (2.38 g, CAS: 127-09-3) in methanol (50 mL) was stirred at room temperature for 3 hours. TLC analysis indicated the reaction was complete. The mixture was filtered and concentrated. Purification by flash chromatography (silica gel, _CH₂Cl₂ :MeOH = 100: ₁ to 50:1 by volume) gave tert-butyl (RS)-2-(5-amino-2-pyridyl)morpholine-4-carboxylate (450 mg, 55.4% yield) as a white solid.

MS (ESI): 280.0 ([M+H] ⁺ ).

c) (RS)-tert-Butyl 2-[5-[(4-chlorobenzoyl)amino]-2-pyridyl]morpholine-4-carboxylate

By (RS) -2- (5- amino -2- pyridyl) morpholine -4- carboxylic acid tert-butyl ester (35mg), 4- chlorobenzoic acid (23mg, CAS: 74-11-3), HATU (57mg, CAS: 148893-10-1), and N, N- diisopropylethylamine (DIPEA, 49mg, CAS: 7087-68-5) are dissolved in DMF (1.5mL). The solution is stirred at room temperature until TLC analysis shows that the reaction is complete. The reactant is diluted with water (30mL). The mixture is extracted with ethyl acetate (2x 20mL). The organic layer _merged is dried and concentrated under reduced pressure with _NaSO . Further drying under high vacuum provides crude (RS) -2- [5- [(4- chlorobenzoyl) amino] -2- pyridyl] morpholine -4- carboxylic acid tert-butyl ester, as yellow solid, which is used for the next step without purification.

d)(RS)-4-chloro-N-(6-morpholin-2-yl-3-pyridyl)benzamide

(RS)-tert-Butyl 2-[5-[(4-chlorobenzoyl)amino]-2-pyridinyl]morpholine-4-carboxylate from the above reaction (step c) was dissolved in a mixture of _CH2Cl2 (2 _mL ) and trifluoroacetic acid (1 mL). The solution was stirred at room temperature for one hour until LCMS indicated the reaction was complete. The solution was concentrated under reduced pressure. Purification by preparative HPLC (mobile phase A: _H2O , B: _CH3CN with 0.1% TFA, C18 column) gave (RS)-4-chloro-N-(6-morpholin-2-yl-3-pyridinyl)benzamide (32 mg) as a white solid.

MS (ESI): 320.1 ([{ ³⁷ Cl}M+H] ⁺ ), 318.1 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 8

(RS)-1-(3-chlorophenyl)-3-(6-morpholin-2-yl-3-pyridyl)urea

a) (RS)-tert-Butyl 2-[5-[(3-chlorophenyl)carbamoylamino]-2-pyridinylmorpholine-4-carboxylate

(RS)-2-(5-amino-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester (80 mg), Example 7(b), 3-chlorophenyl isocyanate (44 mg, CAS: 2909-38-8) and triethylamine (90 mg, CAS: 121-44-8) were dissolved in CH ₂ Cl ₂ (1 mL). The solution was stirred at room temperature until TLC analysis showed that the reaction was complete. Water (20 mL) was added. The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. Further drying under high vacuum provided crude (RS)-2-[5-[(3-chlorophenyl)carbamoylamino]-2-pyridyl]morpholine-4-carboxylic acid tert-butyl ester as a yellow oil, which was used in the next step without purification.

b) (RS)-1-(3-chlorophenyl)-3-(6-morpholin-2-yl-3-pyridyl)urea

Tert-butyl (RS)-2-[5-[(3-chlorophenyl)carbamoylamino]-2-pyridinyl]morpholine-4-carboxylate from the above reaction (step a) was dissolved in a mixture of trifluoroacetic acid (0.5 mL) and _CH₂Cl₂ ( ₂ mL). The solution was stirred at room temperature until TLC analysis indicated the reaction was complete. Water (20 mL) was added. The mixture was extracted with ethyl acetate (2 x 20 mL). The aqueous layer was neutralized with saturated aqueous _NaHCO₃ to neutral pH and extracted with _CH₂Cl₂ / _CH₃OH (10: ₁ by volume, 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase A: _H2O , B: _CH3CN with 0.1% TFA, C18 column) to give (RS)-1-(3-chlorophenyl)-3-(6-morpholin-2-yl-3-pyridinyl)urea as a white solid (40 mg).

MS (ESI): 335.1 ([{ ³⁷ Cl}M+H] ⁺ ), 333.1 ([{ ³⁵ Cl}M+H] ⁺ ).

¹ H NMR (Methanol-d ⁴ ): 8.75 (1H), 8.10 (1H), 7.68 (1H), 7.59 (1H), 7.30 (2H), 7.16 (1H), 4.91 (1H), 4.15 (1H), 4.37 (1H), 3.67 (1H), 3.36 (1H), 3.29 (2H).

Example 9

(RS)-1-(4-Fluorophenyl)-3-(6-morpholin-2-yl-3-pyridyl)urea

The title compound was obtained in a similar manner to Example 8, except that 4-fluorophenyl isocyanate (CAS: 1195-45-5) was used in place of 3-chlorophenyl isocyanate in step (a). It was a pale yellow oil. MS (ESI): 317.1 ([M+H] ⁺ ).

Example 10

(RS)-1-(6-morpholin-2-yl-3-pyridinyl)-3-[4-(trifluoromethyl)phenyl]urea

The title compound was obtained in a similar manner to Example 8, except that 4-(trifluoromethyl)phenyl isocyanate (CAS: 1548-13-6) was used in place of 3-chlorophenyl isocyanate in step (a). Pale yellow solid. MS (ESI): 367.1 ([M+H] ⁺ ).

Example 11

(RS)-1-(4-chlorophenyl)-3-(6-morpholin-2-yl-3-pyridyl)urea

The title compound was obtained in a similar manner to Example 8, using 4-chlorophenyl isocyanate (CAS: 104-12-1) instead of 3-chlorophenyl isocyanate in step (a). Off-white solid. MS (ESI): 335.1 ([{ ³⁷ Cl}M+H] ⁺ ), 333.1 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 12

(RS)-3-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)benzamide

The title compound was obtained by using 3-chlorobenzoic acid (CAS: 535-80-8) instead of 4-chlorobenzoic acid in step (c) in a similar manner to Example 7. Pale yellow solid. MS (ESI): 320.1 ([{ ³⁷ Cl}M+H] ⁺ ), 318.1 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 13

(RS)-4-Ethoxy-N-(6-morpholin-2-yl-3-pyridinyl)benzamide

The title compound was obtained by analogy to Example 7, using 4-ethoxybenzoic acid (CAS: 619-86-3) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 328.2 ([M+H] ⁺ ).

Example 14

(RS)-4-Fluoro-N-(6-morpholin-2-yl-3-pyridinyl)benzamide

The title compound was obtained by analogy to Example 7, using 4-fluorobenzoic acid (CAS: 456-22-4) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 302.1 ([M+H] ⁺ ).

Example 15

(RS)-4-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide

The title compound was obtained in a similar manner to Example 7, using 4-chloro-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 1340578-20-2) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 352.1 ([{ ³⁷ Cl}M+H] ⁺ ), 350.1 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 16

(RS)-N-(6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide

The title compound was obtained in a similar manner to Example 7, using 2-(trifluoromethyl)pyridine-4-carboxylic acid (CAS: 131747-41-6) instead of 4-chlorobenzoic acid in step (c). Pale yellow solid. MS (ESI): 353.0 ([M+H] ⁺ ).

Example 17

(RS)-N-(6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyrimidin-4-amine

In analogy to Example 1, in step (g), using 2-(trifluoromethyl)pyrimidin-4-amine (CAS: 672-42-4) instead of 4-chloroaniline, the title compound was obtained. White solid. MS (ESI): 326.2 ([M+H] ⁺ ).

Example 18

N-(4-Chlorophenyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine

a) (2R)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester and (2S)-2-(5-bromo-2-pyridyl)morpholine tert-Butyl 4-phenoxylate

(RS)-tert-Butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate was separated by SFC using the following conditions: Chiralpak AD-3 column (100×4.6 mm ID: 3 μm); ethanol (0.05% DEA) in 5% to 40% _CO₂ as the mobile phase; 3 mL/min flow rate; wavelength: 220 nm. (2S)-tert-Butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate (1.6 g, retention time: 1.421 min) was obtained as the first fraction. (2R)-tert-Butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate (1.6 g, retention time: 1.571 min) was obtained as the second fraction.

b) N-(4-chlorophenyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine

Similar to Example 1, in step (g), (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate was used instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate to react with 4-chloroaniline (CAS: 106-47-8) to obtain N-(4-chlorophenyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine. A waxy solid was obtained. MS (ESI): 292.1 ([{ ³⁷ Cl}M+H] ⁺ ), 290.2 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 19

6-[(2S)-Morpholin-2-yl]-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine

The title compound was obtained by analogy to Example 18, using 4-(trifluoromethyl)aniline (CAS: 455-14-1) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 324.0 ([M+H] ⁺ ).

Example 20

N-(5-chloro-2-pyridinyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine

The title compound was obtained by using 2-amino-5-chloropyridine (CAS: 1072-98-6) in place of 4-chloroaniline in step (b) in analogy to Example 18. White solid. MS (ESI): 293.0 ([{ ³⁷ Cl}M+H] ⁺ ), 291.0 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 21

N-(5-Bromo-2-pyridinyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine

The title compound was obtained by using 2-amino-5-bromopyridine (CAS: 1072-97-5) in place of 4-chloroaniline in step (b) in a similar manner to Example 18. White solid. MS (ESI): 337.0 ([{ ⁸¹ Br}M+H] ⁺ ), 335.0 ([{ ⁷⁹ Br}M+H] ⁺ ).

Example 22

6-[(2S)-Morpholin-2-yl]-N-[6-(trifluoromethyl)-3-pyridinyl]pyridin-3-amine

The title compound was obtained by analogy to Example 18, using 5-amino-2-(trifluoromethyl)pyridine (CAS: 106877-33-2) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 325.1 ([M+H] ⁺ ).

Example 23

6-[(2S)-Morpholin-2-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine

The title compound was obtained by analogy to Example 18, using 2-amino-4-(trifluoromethyl)pyridine (CAS: 106447-97-6) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 325.1 ([M+H] ⁺ ).

Example 24

N-(4-Chlorophenyl)-6-[(2R)-morpholin-2-yl]pyridin-3-amine

Similar to Example 1, in step (g), (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate was used instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate to react with 4-chloroaniline (CAS: 106-47-8) to obtain the title compound. A waxy solid. MS (ESI): 292.1 ([{ ^37Cl }M+H] ⁺ ), 290.1 ([{ ^35Cl }M+H] ⁺ ).

Example 25

6-[(2R)-Morpholin-2-yl]-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine

The title compound was obtained by analogy to Example 24, using 4-(trifluoromethyl)aniline (CAS: 455-14-1) instead of 4-chloroaniline. White solid. MS (ESI): 324.0 ([M+H] ⁺ ).

Example 26

N-(5-chloro-2-pyridinyl)-6-[(2R)-morpholin-2-yl]pyridin-3-amine

The title compound was obtained by analogy to Example 24 using 2-amino-5-chloropyridine (CAS: 1072-98-6) instead of 4-chloroaniline. White solid. MS (ESI): 293.1 ([{ ³⁷ Cl}M+H] ⁺ ), 291.1 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 27

6-[(2R)-morpholin-2-yl]-N-[6-(trifluoromethyl)-3-pyridinyl]pyridin-3-amine

The title compound was obtained by analogy to Example 24 using 5-amino-2-(trifluoromethyl)pyridine (CAS: 106877-33-2) instead of 4-chloroaniline. White solid. MS (ESI): 325.0 ([M+H] ⁺ ).

Example 28

6-[(2R)-morpholin-2-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine

The title compound was obtained by analogy to Example 24 using 2-amino-4-(trifluoromethyl)pyridine (CAS: 106447-97-6) instead of 4-chloroaniline. White solid. MS (ESI): 325.0 ([M+H] ⁺ ).

Example 29

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-5-(trifluoromethyl)pyridin-2-amine

The title compound was obtained by analogy to Example 18, using 2-amino-5-(trifluoromethyl)pyridine (CAS: 74784-70-6) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 325.1 ([M+H] ⁺ ).

Example 30

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-6-(trifluoromethyl)pyridin-2-amine

The title compound was obtained by analogy to Example 18, using 2-amino-6-(trifluoromethyl)pyridine (CAS: 34486-24-3) instead of 4-chloroaniline in step (b). White solid. MS (ESI): 325.0 ([M+H] ⁺ ).

Example 31

4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]benzamide

The title compound was obtained by replacing (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester with (2S)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a) in a similar manner to Example 7. It was obtained as a white solid. MS (ESI): 319.9 ([{ ^37Cl }M+H] ⁺ ), 317.9 ([{ ^35Cl }M+H] ⁺ ).

Example 32

3-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]benzamide

The title compound was obtained by using (2S)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester instead of (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester in step (a) and 3-chlorobenzoic acid (CAS: 535-80-8) instead of 4-chlorobenzoic acid in step (c) in analogy to Example 7. The product was a white solid. MS (ESI): 319.9 ([{ ^37Cl }M+H] ⁺ ), 317.9 ([{ ^35Cl }M+H] ⁺ ).

Example 33

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-4-(trifluoromethyl)benzamide

The title compound was obtained by analogy to Example 7, using (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 4-(trifluoromethyl)benzoic acid (CAS: 455-24-3) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 352.0 ([M+H] ⁺ ).

Example 34

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-2-(trifluoromethyl)pyridine-4-carboxamide

The title compound was obtained by analogy to Example 7, using (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 2-(trifluoromethyl)pyridine-4-carboxylic acid (CAS: 131747-41-6) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 352.9 ([M+H] ⁺ ).

Example 35

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)benzamide

The title compound was obtained by analogy to Example 7, using (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 3-(trifluoromethyl)benzoic acid (CAS: 454-92-2) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 352.0 ([M+H] ⁺ ).

Example 36

N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide

The title compound was obtained by analogy to Example 7, using (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 6-(2,2,2-trifluoroethoxy)nicotinic acid (CAS: 175204-90-7) instead of 4-chlorobenzoic acid in step (c). The product was obtained as a white solid. MS (ESI): 382.9 ([M+H] ⁺ ).

Example 37

2-Ethyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]pyrimidine-5-carboxamide

The title compound was obtained by similarly replacing (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate with (2S)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and replacing 4-chlorobenzoic acid with 2-ethylpyrimidine-5-carboxylic acid (CAS: 72790-16-0) in step (c). The product was a white solid. MS (ESI): 314.0 ([M+H] ⁺ ).

Example 38

3-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

The title compound was obtained by analogy to Example 7, using (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and using 3-isopropylpyrazole-5-carboxylic acid (CAS: 92933-47-6) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 316.0 ([M+H] ⁺ ).

Example 39

4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide

The title compound was obtained by using (2S)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester instead of (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a) in analogy to Example 7, and using 4-chloro-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 1340578-20-2) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 352.1 ([{ ^37Cl }M+H] ⁺ ), 350.1 ([{ ^35Cl }M+H] ⁺ ).

Example 40

4-Chloro-3-cyclopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

The title compound was obtained by analogy to Example 7, using (2S)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester instead of (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester in step (a), and using 4-chloro-3-cyclopropyl-1H-pyrazole-5-carboxylic acid (CAS: 1291275-83-6) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 349.9 ([{ ^37Cl }M+H] ⁺ ), 347.9 ([{ ^35Cl }M+H] ⁺ ).

Example 41

1-(3-chlorophenyl)-3-[6-[(2S)-morpholin-2-yl]-3-pyridyl]urea

The title compound was obtained in a similar manner to Example 8, using (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a). White solid. MS (ESI): 335.0 ([{ ³⁷ Cl}M+H] ⁺ ), 333.0 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 42

1-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-[3-(trifluoromethyl)phenyl]urea

Similar to Example 8, in step (a), the title compound was obtained by replacing (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate with (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate and replacing 3-chlorophenyl isocyanate with 3-(trifluoromethyl)phenyl isocyanate (CAS: 329-01-1). The product was a white solid. MS (ESI): 367.0 ([M+H] ⁺ ).

Example 43

4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

The title compound was obtained by using (2S)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester instead of (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a) in analogy to Example 7, and using 4-chloro-5-(trifluoromethyl)-2H-pyrazole-3-carboxylic acid (CAS: 934758-95-9) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 377.9 ([{ ³⁷ Cl}M+H] ⁺ ), 375.9 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 44

4-Chloro-3-methyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

The title compound was obtained by using (2S)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester instead of (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a) in analogy to Example 7, and using 4-chloro-3-methyl-1H-pyrazole-5-carboxylic acid (CAS: 29400-84-8) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 324.1 ([{ ^37Cl }M+H] ⁺ ), 322.2 ([{ ^35Cl }M+H] ⁺ ).

Example 45

4-Methyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

The title compound was obtained by analogy to Example 7, using (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 4-methyl-1H-pyrazole-3-carboxylic acid (CAS: 82231-51-4) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 288.2 ([M+H] ⁺ ).

Example 46

4-Chloro-1-methyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-5-propyl-pyrazole-3-carboxamide

The title compound was obtained by similarly using tert-butyl (2S)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of tert-butyl (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 4-chloro-1-methyl-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 1248078-41-2) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 366.0 ([{ ^37Cl }M+H] ⁺ ), 364.0 ([{ ^35Cl }M+H] ⁺ ).

Example 47

N-(5-Bromo-2-pyridinyl)-6-[(2R)-morpholin-2-yl]pyridin-3-amine

In analogy to Example 1, in step (g), (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate was used instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate, and 2-amino-5-bromopyridine (CAS: 1072-97-5) was used instead of 4-chloroaniline (CAS: 106-47-8) to obtain the title compound. A waxy solid was obtained. MS (ESI): 337.0 ([{ ^81Br }M+H] ⁺ ), 335.1 ([{ ^79Br }M+H] ⁺ ).

Example 48

4-Chloro-1-methyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-5-propyl-pyrazole-3-carboxamide

The title compound was obtained by analogy to Example 7, using tert-butyl (2R)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of tert-butyl (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 4-chloro-1-methyl-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 1248078-41-2) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 366.2 ([{ ^37Cl }M+H] ⁺ ), 364.2 ([{ ^35Cl }M+H] ⁺ ).

Example 49

N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-5-(trifluoromethyl)pyridin-2-amine

In analogy to Example 1, in step (g), the title compound was obtained by using (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate, and 2-amino-5-(trifluoromethyl)pyridine (CAS: 74784-70-6) instead of 4-chloroaniline (CAS: 106-47-8). It was obtained as a white solid. MS (ESI): 325.2 ([M+H] ⁺ ).

Example 50

N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-6-(trifluoromethyl)pyridin-2-amine

In analogy to Example 1, in step (g), the title compound was obtained by using (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate, and 2-amino-6-(trifluoromethyl)pyridine (CAS: 34486-24-3) instead of 4-chloroaniline (CAS: 106-47-8). It was obtained as a white solid. MS (ESI): 325.2 ([M+H] ⁺ ).

Example 51

4-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]benzamide

In analogy to Example 7, tert-butyl (2R)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate was used instead of tert-butyl (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a). The title compound was obtained as a white solid. MS (ESI): 320.1 ([{ ³⁷ Cl}M+H] ⁺ ), 318.1 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 52

3-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]benzamide

The title compound was obtained by using (2R)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester instead of (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester in step (a) and 3-chlorobenzoic acid (CAS: 535-80-8) instead of 4-chlorobenzoic acid in step (c) in analogy to Example 7. The product was a white solid. MS (ESI): 320.1 ([{ ^37Cl }M+H] ⁺ ), 318.1 ([{ ^35Cl }M+H] ⁺ ).

Example 53

N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-4-(trifluoromethyl)benzamide

The title compound was obtained by analogy to Example 7, using (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 4-(trifluoromethyl)benzoic acid (CAS: 455-24-3) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 352.2 ([M+H] ⁺ ).

Example 54

N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-2-(trifluoromethyl)pyridine-4-carboxamide

The title compound was obtained by analogy to Example 7, using (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 2-(trifluoromethyl)pyridine-4-carboxylic acid (CAS: 131747-41-6) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 353.1 ([M+H] ⁺ ).

Example 55

N-[6-[(2R)-Morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)benzamide

The title compound was obtained by analogy to Example 7, using (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 3-(trifluoromethyl)benzoic acid (CAS: 454-92-2) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 352.1 ([M+H] ⁺ ).

Example 56

N-[6-[(2R)-Morpholin-2-yl]-3-pyridinyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide

The title compound was obtained by analogy to Example 7, using tert-butyl (2R)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of tert-butyl (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 6-(2,2,2-trifluoroethoxy)nicotinic acid (CAS: 175204-90-7) instead of 4-chlorobenzoic acid in step (c). A waxy solid was obtained. MS (ESI): 383.2 ([M+H] ⁺ ).

Example 57

2-Ethyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]pyrimidine-5-carboxamide

The title compound was obtained by analogy to Example 7, using (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 2-ethylpyrimidine-5-carboxylic acid (CAS: 72790-16-0) instead of 4-chlorobenzoic acid in step (c). A waxy solid was obtained. MS (ESI): 314.2 ([M+H] ⁺ ).

Example 58

3-Isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

The title compound was obtained by analogy to Example 7, using (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 3-isopropylpyrazole-5-carboxylic acid (CAS: 92933-47-6) instead of 4-chlorobenzoic acid in step (c). A waxy solid was obtained. MS (ESI): 316.2 ([M+H] ⁺ ).

Example 59

4-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide

The title compound was obtained by using (2R)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester instead of (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a) in analogy to Example 7, and using 4-chloro-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 1340578-20-2) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 352.2 ([{ ^37Cl }M+H] ⁺ ), 350.2 ([{ ^35Cl }M+H] ⁺ ).

Example 60

4-Chloro-3-cyclopropyl-N-[6-[(2R)-morpholin-2-yl].3-pyridinyl]-1H-pyrazole-5-carboxamide

The title compound was obtained by using (2R)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester instead of (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a) in analogy to Example 7, and using 4-chloro-3-cyclopropyl-1H-pyrazole-5-carboxylic acid (CAS: 1291275-83-6) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 350.2 ([{ ^37Cl }M+H] ⁺ ), 348.2 ([{ ^35Cl }M+H] ⁺ ).

Example 61

1-(3-chlorophenyl)-3-[6-[(2R)-morpholin-2-yl]-3-pyridyl]urea

The title compound was obtained in a similar manner to Example 8, using (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a). White solid. MS (ESI): 335.1 ([{ ³⁷ Cl}M+H] ⁺ ), 333.2 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 62

1-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-[3-(trifluoromethyl)phenyl]urea

In a similar manner to Example 8, the title compound was obtained by replacing (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate with (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate and replacing 3-chlorophenyl isocyanate with 3-(trifluoromethyl)phenyl isocyanate (CAS: 329-01-1) in step (a). The product was a white solid. MS (ESI): 367.1 ([M+H] ⁺ ).

Example 63

4-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

The title compound was obtained by using (2R)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester instead of (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a) in analogy to Example 7, and using 4-chloro-5-(trifluoromethyl)-2H-pyrazole-3-carboxylic acid (CAS: 934758-95-9) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 378.1 ([{ ³⁷ Cl}M+H] ⁺ ), 376.1 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 64

4-Chloro-3-methyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

The title compound was obtained by using (2R)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylic acid tert-butyl ester instead of (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a) in analogy to Example 7, and using 4-chloro-3-methyl-1H-pyrazole-5-carboxylic acid (CAS: 29400-84-8) instead of 4-chlorobenzoic acid in step (c). White solid. MS (ESI): 324.1 ([{ ^37Cl }M+H] ⁺ ), 322.1 ([{ ^35Cl }M+H] ⁺ ).

Example 65

4-Methyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

The title compound was obtained by similarly using (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 4-methyl-1H-pyrazole-3-carboxylic acid (CAS: 82231-51-4) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 288.2 ([M+H] ⁺ ).

Example 66

(R)-3-Ethyl-4-methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-1H-pyrazole-5-carboxamide

The title compound was obtained by analogy to Example 7, using (2R)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid (CAS: 957129-38-3) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 316.2 ([M+H] ⁺ ).

Example 67

(S)-3-Ethyl-4-methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-1H-pyrazole-5-carboxamide

The title compound was obtained by analogy to Example 7, using (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid (CAS: 957129-38-3) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 316.2 ([M+H] ⁺ ).

Example 68

(R)-6-Methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-2-(trifluoromethyl)pyrimidine-4-carboxamide

The title compound was obtained by analogy to Example 7, using tert-butyl (2R)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of tert-butyl (RS)-2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 6-methyl-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (CAS: 945717-59-9) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 368.1 ([M+H] ⁺ ).

Example 69

(S)-6-Methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-2-(trifluoromethyl)pyrimidine-4-carboxamide

The title compound was obtained by analogy to Example 7, using (2S)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate instead of (RS)-tert-butyl 2-(5-bromo-2-pyridyl)morpholine-4-carboxylate in step (a), and 6-methyl-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (CAS: 945717-59-9) instead of 4-chlorobenzoic acid in step (c). A white solid was obtained. MS (ESI): 368.1 ([M+H] ⁺ ).

Example 70

(RS)-N-(4-Chlorophenyl)-2-morpholin-2-yl-pyrimidin-5-amine

a) 5-Bromopyrimidine-2-carbonyl chloride

To a solution of 5-bromopyrimidine-2-carboxylic acid (10.0 g, CAS: 37131-87-6) in _CH₂Cl₂ (100 _mL ) was added oxalyl chloride (6.4 g) at room temperature. DMF (0.5 mL) was added. The reaction was continued at room temperature for 5 hours. The mixture was filtered. The filtrate was concentrated under reduced pressure and further dried under high vacuum to give crude 5-bromopyrimidine-2-carbonyl chloride (10.9 g, yield: 100%) as a gray solid, which was used in the next step without purification.

b) 2-Bromo-1-(5-bromopyrimidin-2-yl)ethanone

To a solution of 5-bromopyrimidine-2-carbonyl chloride (10.9 g, 49.5 mmol) in _CH₃CN (200 mL) from step (a) was added dropwise _TMSCHN₂ (2 M, 74.3 mL) in hexanes at 0°C under an _N₂ atmosphere. The solution was stirred at room temperature for 16 hours. A solution of HBr in AcOH (48%, 20 mL) was then added at 0°C. The solution was stirred at room temperature for 3 hours. EtOAc (500 mL) and water (100 mL) were added. The organic layer was washed with brine, dried _{over Na₂SO₄} , and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, petroleum ether:EtOAc = 30/1 to 10/1 by volume) to give 2-bromo-1-(5-bromopyrimidin-2-yl)ethanone (13.8 g, 100% yield) as a yellow oil.

MS(ESI): 282.8({ ⁸¹ Br+ ⁸¹ Br}M+H) ⁺ , 280.8({ ⁷⁹ Br+ ⁸¹ Br}M+H) ⁺ , 278.8({ ⁷⁹ Br+ ⁷⁹ Br}M+H) ⁺ .

c) 2-[Benzyl(2-hydroxyethyl)amino]-1-(5-bromopyrimidin-2-yl)ethanone

To a solution of 2-bromo-1-(5-bromopyrimidin-2-yl)ethanone (13.8 g, 49.5 _mmol ) from step (b) in _CH₃CN (200 mL) was added N-benzylaminoethanol (7.5 g, CAS: 104-63-2) and _K₂CO₃ (13.7 _g ). The mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted with _CH₂Cl₂ (3 x 200 mL). The combined organic layers were dried _{over Na₂SO₄} and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, _CH₂Cl₂ : _MeOH = 200/1 to 50/1 by volume) to give 2-[benzyl(2-hydroxyethyl)amino]-1-(5-bromopyrimidin-2-yl)ethanone (3.3 g, yield: 18.7% total over three steps from step (a)) as a yellow oil.

MS(ESI): 349.9({ ⁷⁹ Br}M+H) ⁺ , 351.9({ ⁸¹ Br}M+H) ⁺ .

d)(RS)-2-[Benzyl(2-hydroxyethyl)amino]-1-(5-bromohexidine-2-yl)ethanol

To a solution of 2-[benzyl(2-hydroxyethyl)amino]-1-(5-bromopyrimidin-2-yl)ethanone (3.3 g) in MeOH (70 mL) was added NaBH ₄ (394 mg) at 0° C. The solution was stirred at room temperature for one hour until TLC analysis indicated consumption of the starting material. The reaction solution was poured into water and extracted with CH ₂ Cl ₂ (2 x 200 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude (RS)-2-[benzyl(2-hydroxyethyl)amino]-1-(5-bromopyrimidin-2-yl)ethanol (3.5 g, 100% yield), which was used in the next step without purification.

e)(RS)-4-Benzyl-2-(5-bromopyrimidin-2-yl)morpholine

To a solution of (RS)-2-[benzyl(2-hydroxyethyl)amino]-1-(5-bromopyrimidin-2-yl)ethanol (3.5 g, 9.93 mmol, directly from step d) in THF (80 mL) was added _Et3N (1.5 g) and methanesulfonyl chloride (1.14 g) at 0°C. The mixture was stirred at room temperature for 2 hours and then filtered. To the filtrate was added a solution of potassium tert-amylate (1.5 g) in THF (20 mL) at 0°C. The mixture was stirred at room temperature for one hour. The reaction solution was poured into EtOAc (500 mL), washed with brine (50 mL), and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, _CH2Cl2 /MeOH = 200/1 to 50/1 _by volume) to give (RS)-4-benzyl-2-(5-bromopyrimidin-2-yl)morpholine (0.5 g, 16% yield from step d in two steps).

MS(ESI): 333.9({ ⁷⁹ Br}M+H) ⁺ , 335.9({ ⁸¹ Br}M+H) ⁺ .

f)(RS)-2-(5-bromopyrimidin-2-yl)morpholine

To a solution of (RS)-4-benzyl-2-(5-bromopyrimidin-2-yl)morpholine (0.5 g) in _CH2Cl2 (10 _mL ) was added 2-chloroethyl chloroformate (643 mg, CAS: 627-11-2). The solution was then stirred at reflux for 4 hours until TLC indicated consumption of the starting material. Volatiles were removed under reduced pressure. The residue was dissolved in methanol (10 mL) and stirred at reflux for one hour. The reaction solution was concentrated under reduced pressure. Further drying under high vacuum gave crude (RS)-2-(5-bromopyrimidin-2-yl)morpholine (365 mg, 100% yield), which was used in the next step without purification.

g) (RS)-tert-Butyl 2-(5-bromopyrimidin-2-yl)morpholine-4-carboxylate

To a solution of (RS)-2-(5-bromopyrimidin-2-yl)morpholine (365 mg, 1.5 mmol) and _K2CO3 (414 _mg ) from step (f) in a mixture of THF (10 mL) and water (5 mL) was added di-tert-butyl dicarbonate (486 mg, CAS: 24424-99-5) at room temperature. The reaction was continued _overnight . The mixture was extracted with _{CH2Cl2 (} 2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , and concentrated under reduced pressure. Purification by flash chromatography (silica gel, _CH2Cl2 /MeOH ₌ 200/1 to 50/1 by volume) gave tert-butyl (RS)-2-(5-bromopyrimidin-2-yl)morpholine-4-carboxylate (300 mg, 58% yield) as a yellow oil.

MS(ESI): 366.0({ ⁷⁹ Br}M+Na) ⁺ , 368.0({ ⁸¹ Br}M+Na) ⁺ , 287.8({ ⁷⁹ Br}MC ₄ H ₈ +H) ⁺ , 289.8({ ⁸¹ Br}MC ₄ H ₈ +H) ⁺ .

h)(RS)-N-(4-chlorophenyl)-2-morpholin-2-yl-pyrimidin-5-amine

To a solution of (RS)-tert-butyl 2-(5-bromopyrimidin-2-yl)morpholine-4-carboxylate (30 mg) and 4-chloroaniline (11 mg, CAS: 106-47-8) in dioxane (1 mL) were added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 15 mg, CAS: 161265-03-8), _Cs2CO3 (85 mg, CAS: 534-17-8), and tris(dibenzylideneacetone)dipalladium(0) (8 mg, CAS: 51364-51-3). _The reaction was carried out at 90°C under an _N2 atmosphere overnight. The solution was diluted with _CH2Cl2 (10 _mL ), washed with brine (20 mL), _dried over _Na2SO4 , and concentrated under reduced pressure. The residue was dissolved in a mixture of _CH2Cl2 (1 _mL ) and TFA (1 mL). The solution was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (mobile phase A: _H2O , B: _CH3CN with 0.1% TFA, C18 column) to give (RS)-N-(4-chlorophenyl)-2-morpholin-2-yl-pyrimidin-5-amine (10 mg, 40% yield over two steps) as a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 8.54 (2H), 7.33 (2H), 7.17 (2H), 4.9 (1H), 4.1 (1H), 3.97 (1H), 3.63 (1H), 3.51 (1H), 3.35-3.23 (2H).

MS(ESI): 290.9({ ³⁵ Cl}M+H) ⁺ , 292.9({ ³⁷ Cl}M+H) ⁺ .

Example 71

(RS)-2-Morpholin-2-yl-N-[4-(trifluoromethyl)phenyl]pyrimidin-5-amine

The title compound was obtained by analogy to Example 70, using 4-(trifluoromethyl)aniline (CAS: 455-14-1) instead of 4-chloroaniline in step (h). White solid. MS (ESI): 325.0 ([M+H] ⁺ ).

Example 72

(RS)-4-Chloro-N-(2-morpholin-2-ylpyrimidin-5-yl)benzamide

a)(RS)-tert-Butyl 2-[5-(benzhydrylamino)pyrimidin-2-yl]morpholine-4-carboxylate

To a solution of (RS)-tert-butyl 2-(5-bromopyrimidin-2-yl)morpholine-4-carboxylate (230 mg) and benzophenone imine (127 mg, CAS: 1013-88-3) in dioxane (10 mL) were added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 116 mg, CAS: 161265-03-8), tris(dibenzylideneacetone)dipalladium(0) (61.3 mg, CAS: 51364-51-3), and _{Cs2CO3 (} 653 mg, CAS: 534-17-8). The reaction was carried out at 90°C under an _N2 atmosphere overnight. The solution was poured into water (100 mL) and extracted with _{CH2Cl2 (} 2 x 150 mL). The combined organic layers were dried over _{Na2SO4 and} concentrated under reduced pressure to give crude (RS)-tert-butyl 2-[5-(benzhydrylamino)pyrimidin-2-yl]morpholine-4-carboxylate (297 mg, yield: 100%), which was used in the next step without purification.

b) (RS)-tert-Butyl 2-(5-aminopyrimidin-2-yl)morpholine-4-carboxylate

To a solution of (RS)-tert-butyl 2-[5-(benzhydrylamino)pyrimidin-2-yl]morpholine-4-carboxylate (297 mg, 0.668 mmol) in MeOH (10 mL) was added sodium acetate (274 mg, CAS: 127-09-3) and hydroxylamine hydrochloride (69.6 mg, CAS: 5470-11-1). The mixture was stirred at room temperature for 2 hours until TLC analysis indicated complete consumption of the starting material. The solution was poured into water (50 mL) and extracted with _{CH2Cl2 (} 2 x 100 mL). The combined organic layers were dried _{over Na2SO4} , concentrated under reduced pressure, and purified by flash chromatography ( _silica gel, _CH2Cl2 /MeOH = 100/1 to 50/1 by volume) to give (RS)-tert-butyl 2-(5-aminopyrimidin-2-yl)morpholine-4-carboxylate (100 mg, yield: 55.6%) as a yellow solid.

MS (ESI): 281.2 (M+H) ⁺ .

c) (RS)-4-chloro-N-(2-morpholin-2-ylpyrimidin-5-yl)benzamide

To a solution of 4-chlorobenzoic acid (16.7 mg, CAS: 74-11-3) in DMF (1 mL) was added HATU (40.3 mg, CAS: CAS: 148893-10-1) and DIPEA (37.2 mg, CAS: 7087-68-5). The mixture was stirred at room temperature for 30 minutes. (RS)-tert-butyl 2-(5-aminopyrimidin-2-yl)morpholine-4 _- carboxylate (27 mg) was added. The reaction was continued at room temperature overnight. The solution was then diluted with _CH2Cl2 (10 _mL ), washed with brine (20 mL), dried over _Na2SO4 , and concentrated under reduced pressure. The residue was dissolved in a mixture _{of CH2Cl2} (1 mL) and trifluoroacetic acid (TFA, 1 mL, CAS: 76-05-1). The solution was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (mobile phase A: _H2O , B: _CH3CN with 0.1% TFA, C18 column) to give (RS)-4-chloro-N-(2-morpholin-2-ylpyrimidin-5-yl)benzamide (8 mg, 26% yield in two steps) as a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 9.24 (2H), 7.98 (2H), 7.57 (2H), 4.97 (1H), 4.21 (1H), 4.02 (1H), 3.73 (1H), 3.54 (1H), 3.73-3.30 (2H).

MS(ESI): 319.0({ ³⁵ Cl}M+H) ⁺ , 321.0({ ³⁷ Cl}M+H) ⁺ .

Example 73

(RS)-1-(3-chlorophenyl)-3-(2-morpholin-2-ylpyrimidin-5-yl)urea

To a solution of (RS)-tert-butyl 2-(5-aminopyrimidin-2-yl)morpholine-4-carboxylate (27 _mg ) in _CH₂Cl₂ (1 mL) was added _Et₃N (19.4 mg, CAS: 121-44-8) and 3-chlorophenyl isocyanate (14.7 mg, CAS: 2909-38-8). The reaction was allowed to proceed overnight at room temperature. The solution was _diluted with _CH₂Cl₂ (10 mL), washed with aqueous citric acid (2 x 20 mL) and brine (20 _mL ), dried over _Na₂SO₄ , and concentrated under reduced pressure. The residue was dissolved in a mixture of _CH₂Cl₂ (1 _mL ) and trifluoroacetic acid (TFA, 1 mL, CAS: 76-05-1). The solution was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (mobile phase A: _H2O , B: _CH3CN with 0.1% TFA, C18 column) to give the title compound (7 mg, 22% yield in two steps) as a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 9.00 (2H), 7.67 (1H), 7.32-7.26 (2H), 7.05 (1H), 4.95 (1H), 4.18 (1H), 4.01 (1H), 3.67 (1H), 3.53 (1H), 3.36-3.30 (2H).

MS(ESI): 334.1({ ³⁵ Cl}M+H) ⁺ , 336.1({ ³⁷ Cl}M+H) ⁺ .

Example 74

(RS)-4-Chloro-3-ethoxy-N-(6-morpholin-2-yl-3-pyridinyl)-1H-pyrazole-5-carboxamide

a) 5-Hydroxy-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of hydrazine monohydrate (3.85 g, 0.077 mol, CAS: 7803-57-8) in toluene (30 mL), acetic acid (15 mL) and dimethyl butynedioate (10 g, 0.07 mol, CAS: 762-42-5) were added. The solution was stirred at room temperature for 3 hours. The mixture was then poured into ice water. The precipitate was collected by filtration and washed with cold water. Further dried under high vacuum to obtain 5-hydroxy-1H-pyrazole-3-methyl formate (7.5 g, 75% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ 12.81 (s, 1H), 10.04 (br, 1H), 5.96 (br, 1H), 3.77 (s, 3H).

b) 5-ethoxy-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of 5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester (4 g, 28.17 mmol) in DMF (25 mL) was added K ₂ CO ₃ (5.83 g, 42.2 mmol) and iodoethane (4.8 g, 31 mmol). The solution was stirred at room temperature for 15 hours. The mixture was then poured into ice water. The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (30 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure. Recrystallization from dichloromethane (10 ml) gave 5-ethoxy-1H-pyrazole-3-carboxylic acid methyl ester (2.2 g, 46% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ 13.13 (s, 1H), 6.23 (s, 1H), 4.11 (d, 2H), 3.81 (s, 3H), 1.28 (m, 3H).

c) 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of 5-ethoxy-1H-pyrazole-3-carboxylic acid methyl ester (2.2 g, 12.94 mmol) in DMF (40 mL) was added N-chlorosuccinimide (2.06 g, 15.53 mmol, CAS: 128-09-6) at 0°C. The mixture was then heated to 50°C. Stirring was continued for 15 hours. The reaction solution was concentrated under reduced pressure to remove approximately 50% of the DMF. The solution was then poured into ice water. The precipitate was collected by filtration and washed with cold water. Further dried under high vacuum to obtain 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid methyl ester (1.65 g, 63% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ 13.44 (br, 1H), 4.24 (d, 2H), 3.85 (s, 3H), 1.32 (t, 3H).

d) 4-Chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid

To a solution of 4-chloro-5-ethoxy-1H-pyrazole-3-methyl formate (1.65 g, 8.06 mmol) in THF (30 mL) was added 1 M NaOH aqueous solution (16.1 mL, 16.1 mmol) at 0 ° C. The solution was then refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured into water. The pH was adjusted to 1 with concentrated HCl. The precipitate was collected by filtration and washed with cold water. Further dried under high vacuum to obtain 4-chloro-5-ethoxy-1H-pyrazole-3-formic acid (1.4 g, 91.5% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ 13.25 (s, 1H), 4.23 (d, 2H), 1.32 (t, 3H).

e)(RS)-4-chloro-3-ethoxy-N-(6-morpholin-2-yl-3-pyridinyl)-1H-pyrazole-5-carboxamide

Analogously to Example 7, using 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid instead of 4-chlorobenzoic acid in step (c), the title compound was obtained as a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 8.91 (d, 1H), 8.26 (dd, 1H), 7.62 (d, 1H), 4.90 (s, 1H), 4.33 (m, 2H), 4.25 (m, 1H), 4.04 (m, 1H), 3.70 (d, 1H), 3.36 (d, 1H), 3.29 (m, 2H), 1.43 (t, 3H).

MS(ESI): 352.1({ ³⁵ Cl}M+H) ⁺ , 354.1({ ³⁷ Cl}M+H) ⁺ .

Example 75

(RS)-4-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide

a) 5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of methyl 5-hydroxy-1H-pyrazole- ₃ -carboxylate (10 g, 70.4 mmol) and _Cs₂CO₃ (25 g, 77.5 mmol) in DMF (100 ml) was added portionwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (16.3 g, 70.4 mmol, CAS: 6226-25-1). The solution was stirred at room temperature overnight. The reaction mixture was carefully poured into 500 ml of ice-water. The precipitate was collected by filtration and washed with cold water. Further drying under high vacuum gave methyl 5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylate (12 g, 76% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ13.41 (s, 1H), 6.43 (s, 1H), 4.86 (m, 2H), 3.84 (s, 3H)

MS (ESI): 225.1 ([M+H] ⁺ ).

b) 4-chloro-5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of 5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-formic acid methyl ester (1.9 g, 8.47 mmol) in DMF (30 mL) was added N-chlorosuccinimide (1.35 g, 10.17 mmol) at 0 ° C. The solution was then stirred at 50 ° C for 15 hours. The reaction solution was concentrated under vacuum to remove 50% of the DMF. The solution was then poured into water. The precipitate was collected by filtration, washed with water, and dried under high vacuum to obtain 4-chloro-5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-formic acid methyl ester (1.9 g, 87% yield) as a white solid.

c) 4-Chloro-5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylic acid

To a solution of 4-chloro-5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylic acid methyl ester (1.9 g, 7.35 mmol) in a mixture of THF (15 mL) and MeOH (15 mL) was added 1 M NaOH aqueous solution (14.7 mL, 14.7 mmol) at 0°C. The solution was then stirred at reflux for 3 hours. The reaction solution was poured into water. The pH was adjusted to about 1 with concentrated HCl solution. The precipitate was collected by filtration, washed with water, and dried under high vacuum to give 4-chloro-5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylic acid (1.5 g, 83% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ 13.91 (br, 1H), 13.56 (s, 1H), 4.91 (m, 2H).

MS(ESI): 245.0({ ³⁵ Cl}M+H) ⁺ , 247.0({ ³⁷ Cl}M+H) ⁺ .

d)(RS)-4-chloro-N-(6-morpholin-2-yl-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5- Formamide

Analogously to Example 7, using 4-chloro-5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylic acid instead of 4-chlorobenzoic acid in step (c), the title compound was obtained as a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 8.90 (d, 1H), 8.26 (dd, 1H), 7.63 (d, 1H), 4.91 (s, 1H), 4.81 (m, 2H), 4.25 (d, 1H), 4.03 (m, 1H), 3.70 (d, 1H), 3.36 (d, 1H), 3.29 (m, 2H).

MS(ESI): 406.1({ ³⁵ Cl}M+H) ⁺ , 408.1({ ³⁷ Cl}M+H) ⁺ .

Example 76

4-Chloro-3-ethyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 4-chloro-3-ethyl-1H-pyrazole-5-carboxylic acid (CAS: 158668-22-5) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS(ESI): 336.0({ ³⁵ Cl}M+H) ⁺ , 338.0({ ³⁷ Cl}M+H) ⁺ .

Example 77

3-Ethyl-4-fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 5-ethyl-4-fluoro-1H-pyrazole-3-carboxylic acid (CAS: 681034-63-9) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 320.0 (M+H) ⁺ .

Example 78

4-Bromo-3-ethyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 4-bromo-5-ethyl-1H-pyrazole-3-carboxylic acid (CAS: 1291177-22-4) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a waxy solid.

MS (ESI): 381.9 ([{ ⁸¹ Br}M+H] ⁺ ), 379.9 ([{ ⁷⁹ Br}M+H] ⁺ ).

Example 79

4-Fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 4-fluoro-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 681034-64-0) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 334.0 (M+H) ⁺ .

Example 80

3-Cyclopropyl-4-fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 5-cyclopropyl-4-fluoro-1H-pyrazole-3-carboxylic acid (CAS: 681034-74-2) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a waxy solid.

MS (ESI): 332.0 (M+H) ⁺ .

Example 81

4-Bromo-3-cyclopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 4-bromo-5-cyclopropyl-2H-pyrazole-3-carboxylic acid (CAS: 1290764-98-5) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 394.0 ([{ ⁸¹ Br}M+H] ⁺ ), 392.0 ([{ ⁷⁹ Br}M+H] ⁺ ).

Example 82

4-Chloro-3-ethyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 4-chloro-3-ethyl-1H-pyrazole-5-carboxylic acid (CAS: 158668-22-5) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS(ESI): 336.1({ ³⁵ Cl}M+H) ⁺ , 338.1({ ³⁷ Cl}M+H) ⁺ .

Example 83

3-Ethyl-4-fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 5-ethyl-4-fluoro-1H-pyrazole-3-carboxylic acid (CAS: 681034-63-9) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 320.2 (M+H) ⁺ .

Example 84

4-Bromo-3-ethyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 4-bromo-5-ethyl-1H-pyrazole-3-carboxylic acid (CAS: 1291177-22-4) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS(ESI): 382.1([{ ⁸¹ Br}M+H] ⁺ ), 380.1([{ ⁷⁹ Bt}M+H] ⁺ ).

Example 85

4-Fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 4-fluoro-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 681034-64-0) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 334.2 (M+H) ⁺ .

Example 86

3-Cyclopropyl-4-fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 5-cyclopropyl-4-fluoro-1H-pyrazole-3-carboxylic acid (CAS: 681034-74-2) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a waxy solid.

MS (ESI): 332.2 (M+H) ⁺ .

Example 87

4-Bromo-3-cyclopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 4-bromo-5-cyclopropyl-2H-pyrazole-3-carboxylic acid (CAS: 1290764-98-5) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 394.0 ([{ ⁸¹ Br}M+H] ⁺ ), 392.0 ([{ ⁷⁹ Br}M+H] ⁺ ).

Example 88

3-Isobutyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 3-isobutyl-1H-pyrazole-5-carboxylic acid (CAS: 92933-49-8) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 330.2 (M+H) ⁺ .

Example 89

4-Fluoro-3-isobutyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

a) 6-Methyl-2,4-dioxo-heptanoic acid ethyl ester

To a solution of sodium ethoxide (7 g, 0.1 mol) in anhydrous ethanol (150 mL) was added diethyl oxalate (15 g, 0.1 mol, CAS: 95-92-1) at 0°C. 4-Methyl-2-pentanone (10 g, 0.1 mol, CAS: 108-10-1) was then added portionwise. The mixture was stirred at 50°C for 20 hours. The solution was cooled to room temperature and used directly in the next step.

b) 5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester

To a solution of 6-methyl-2,4-dioxo-heptanoic acid ethyl ester (0.1 mol) in ethanol (150 mL) from step (a) was added acetic acid (9 g, 0.15 mol) and hydrazine monohydrate (8.1 g, 0.15 mol, CAS: 7803-57-8). The reaction mixture was stirred for 12 hours. The reaction solution was then concentrated under reduced pressure, diluted with water, and extracted twice with ethyl acetate (2 x 300 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered through a thin silica pad, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give 5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (13 g, 68% yield).

MS (ESI): 197.2 (M+H) ⁺ .

c) 4-Fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid ethyl ester

To a solution of ethyl 5-isobutyl-1H-pyrazole-3-carboxylate (5.0 g, 25.5 mmol) in _CH₃CN (300 mL) at 0°C was added 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylate (18.0 g, 51.0 mmol, CAS: 140681-55-6). The solution was then heated to 70°C. Stirring was continued for ₁₅ hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with aqueous HCl (3N, 200 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (20 mL), dried over _Na₂SO₄ , and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane/MeOH = 200/1 to 100/1 by volume) gave ethyl 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylate (1.4 g, 26% yield) as a yellow oil.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ 4.42 (q, 2H), 2.55 (d, 2H), 2.00 (m, 1H), 1.40 (t, 3H), 0.96 (d, 6H).

MS (ESI): 215.1 (M+H) ⁺ .

d) 4-Fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid

To a solution of 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid (1.4 g, 6.54 mmol) in THF/MeOH (V/V=1:1, 20 mL) was added 1 M NaOH aqueous solution (13.1 mL, 13.1 mmol) at 0°C. The solution was then refluxed for 3 hours. The reaction solution was poured into water. The pH was adjusted to about 1 with concentrated HCl. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (20 mL), concentrated under reduced pressure and recrystallized from ethyl acetate (30 mL) to give 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid (1.2 g, 99% yield) as a yellow solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ 2.44 (d, 2H), 1.90 (m, 1H), 0.87 (d, 6H).

MS (ESI): 187.1 (M+H) ⁺ .

e) 4-Fluoro-3-isobutyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a waxy solid.

MS (ESI): 348.2 (M+H) ⁺ .

Example 90

3-Butyl-4-fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 5-butyl-4-fluoro-1H-pyrazole-3-carboxylic acid (CAS: 681034-65-1) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a waxy solid.

MS (ESI): 348.2 (M+H) ⁺ .

Example 91

3-Butyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 5-butyl-1H-pyrazole-3-carboxylic acid (CAS: 92933-48-7) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a waxy solid.

MS (ESI): 330.2 (M+H) ⁺ .

Example 92

5-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxamide

a) 5-Isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester

To a solution of ethyl 4-methyl-3-oxopentanoate (4 g, 21.6 mmol, CAS: 7152-15-0) in ethanol (100 mL) was added acetic acid (1.9 g, 32.4 mmol) and hydrazine monohydrate (1.7 g, 0.032 mol, CAS: 7803-57-8). The reaction mixture was stirred for 12 hours until LCMS analysis showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and diluted with water. The mixture was extracted twice with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered through a thin silica pad, and concentrated under vacuum to obtain ethyl 5-isopropyl-1H-pyrazole-3-carboxylate (2.1 g, 54% yield) as a yellow oil.

MS (ESI): 183.2 (M+H) ⁺ .

b) Ethyl 5-isopropyl-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxylate

To a solution of ethyl 5-isopropyl-1H-pyrazole-3-carboxylate (1 g, 5.5 mmol) in DMF (10 mL) was added 2,2,2-trifluoroethyl iodide (1.7 g, 8.3 mmol, CAS: 353-83-3) and Cs ₂ CO ₃ (2.1 g, 11 mmol). The reaction mixture was stirred at 50° C. for 12 hours. The reaction solution was then concentrated under reduced pressure and diluted with water. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered through a thin silica pad, and concentrated under vacuum. The crude product was purified by silica gel chromatography to give ethyl 5-isopropyl-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxylate (500 mg, 36% yield) as a white solid.

MS (ESI): 265.2 (M+H) ⁺ .

c) 5-Isopropyl-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxylic acid

To a solution of ethyl 5-isopropyl-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxylate (2 g, 7.6 mmol) in MeOH/ _H₂O (V/V = 3:1, 12 mL) was added NaOH (1.2 g, 30.3 mmol). The reaction mixture was stirred at 30°C for 2 hours. The reaction solution was concentrated under reduced pressure and diluted with water. The mixture was acidified to approximately pH = 2 with 2N HCl (30 mL). The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (100 _mL ), dried over _Na₂SO₄ , filtered through a thin pad of silica, and concentrated under reduced pressure. Further drying under high vacuum gave 5-isopropyl-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxylic acid (1.6 g, 89% yield) as a white solid.

¹ H NMR (CDCl ₃ , 400MHz): δ 6.91 (s, 1H), 5.25 (q, 2H), 3.04 (m, 1H), 1.29 (d, 6H).

MS (ESI): 237.2 (M+H) ⁺ .

d) 5-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-2-(2,2,2-trifluoroethyl)pyrazol-3-yl Formamide

Analogously to Example 67, using 5-isopropyl-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 398.2 (M+H) ⁺ .

Example 93

2-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide

a) 5-Hydroxy-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of hydrazine monohydrate (44.8 g, 0.894 mol, CAS: 7803-57-8) in toluene (300 mL), add acetic acid (180 mL) and dimethyl butynedioate (100 mL, 0.813 mol, CAS: 762-42-5). The solution was stirred at room temperature for 3 hours. The mixture was poured into ice water. The precipitation was collected by filtration, washed with cold water, and dried under high vacuum to obtain 5-hydroxy-1H-pyrazole-3-methyl formate (67.5 g, 59% yield), which was a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ 12.81 (bra, 1H), 10.03 (br, 1H), 5.91 (s, 1H), 3.78 (s, 3H).

b) 5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylic acid methyl ester

To a solution of 5-hydroxy-1H-pyrazole- ₃ -methyl carboxylate (10 g, 70.4 mmol) and _CsCO (25 g, 77.5 mmol) in DMF (100 ml) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (16.3 g, 70.4 mmol) in portions. The solution was stirred at room temperature overnight. The reaction mixture was then poured into 500 ml of ice water. The precipitate was collected by filtration, washed with cold water, and dried under high vacuum to give 5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-methyl carboxylate (12 g, 76% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ13.41 (s, 1H), 6.43 (s, 1H), 4.86 (m, 2H), 3.84 (s, 3H)

MS (ESI): 225.1 (M+H) ⁺ .

c) Methyl 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylate

To a solution of methyl 5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylate (12.0 g, 53.4 mmol) _{and CsCO} (52.0 g, 161 mmol) in DMF (100.0 ml) was added 2-bromopropane (7.2 g, 56.0 mmol) in portions. The solution was stirred at room temperature overnight. The reaction solution was then concentrated in vacuo to remove at least 50% of the DMF. The remaining mixture was poured into water. The precipitate was collected by filtration, washed with cold water, and dried under high vacuum to give methyl 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylate (10.3 g, 74% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ 6.45 (s, 1H), 5.35 (m, 1H), 4.82 (q, 2H), 3.83 (s, 3H), 1.371 (d, 6H).

MS (ESI): 267.0 (M+H) ⁺ .

d) 2-Isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid

A solution of methyl 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylate (4.3 g, 16.2 mmol) and NaOH (1.9 g, 48.5 mmol) in MeOH/H O (V/V=3:1, 50.0 ml) was stirred at room temperature overnight. The reaction mixture was acidified to pH=4-5 by adding concentrated HCl (about 5 ml) at 0°C. The solution was poured into 500 ml of ice water. The precipitate was collected by filtration, washed with cold water, and dried under high vacuum to give 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid (3.86 g, 95% yield) as a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ 6.37 (s, 1H), 5.38 (m, 1H), 4.79 (q, 2H), 1.34 (d, 6H).

MS (ESI): 252.9 (M+H) ⁺ .

e) 2-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-5-(2,2,2-trifluoroethoxy)pyrazol- 3-Formamide

Analogously to Example 67, using 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 414.2 (M+H) ⁺ .

Example 94

3-Isobutyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 3-isobutyl-1H-pyrazole-5-carboxylic acid (CAS: 92933-49-8) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 330.2 (M+H) ⁺ .

Example 95

4-Fluoro-3-isobutyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 4-fluoro-5-isobutyl-1H-pyrazole-3-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a waxy solid.

MS (ESI): 348.2 (M+H) ⁺ .

Example 96

3-Butyl-4-fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 5-butyl-4-fluoro-1H-pyrazole-3-carboxylic acid (CAS: 681034-65-1) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a waxy solid.

MS (ESI): 348.2 (M+H) ⁺ .

Example 97

3-Butyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 5-butyl-1H-pyrazole-3-carboxylic acid (CAS: 92933-48-7) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 330.2 (M+H) ⁺ .

Example 98

5-Isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxamide

Analogously to Example 66, using 5-isopropyl-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 398.1 (M+H) ⁺ .

Example 99

2-Isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide

Analogously to Example 66, using 2-isopropyl-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 414.2 (M+H) ⁺ .

Example 100

4-Chloro-3-ethoxy-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS(ESI): 352.1({ ³⁵ Cl}M+H) ⁺ , 354.1({ ³⁷ Cl}M+H) ⁺ .

Example 101

4-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 4-chloro-5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS(ESI): 406.1({ ³⁵ Cl}M+H) ⁺ , 408.0({ ³⁷ Cl}M+H) ⁺ .

Example 102

(RS)-5-Chloro-N-(5-chloro-2-pyridinyl)-6-morpholin-2-yl-pyridin-3-amine

a) 5-Bromo-3-chloro-pyridine-2-carbonyl chloride

To a suspension of 5-bromo-3-chloropyridine-2-carboxylic acid (5.0 g, 21.06 mmol, CAS: 1189513-51-6) in dichloromethane (50 mL) was added oxalyl chloride (3.38 g, 31.6 mmol, CAS: 79-37-8) and DMF (0.1 mL) at room temperature. The reaction was continued for 5 hours. The solution was concentrated under reduced pressure and dried under high vacuum to give crude 5-bromo-3-chloro-pyridine-2-carbonyl chloride (5.4 g, 100% yield) as a yellow solid which was used directly in the next step.

b) 2-Bromo-1-(5-bromo-3-chloro-2-pyridyl)ethanone

To a solution of crude 5-bromo-3-chloro-pyridine-2-carbonyl chloride (5.4 g, 21.06 mmol) in _CH₃CN (100 mL) was added dropwise a solution of (trimethylsilyl)diazomethane (2 M in hexanes, 31.6 mL, 63.2 mmol, CAS: 18107-18-1) at 0-5°C. The mixture was stirred at room temperature overnight. HBr (48% in water, 10 mL) was added at 0-5°C. The solution was stirred for one hour. The reaction solution was poured into water (200 mL). The mixture was extracted with EtOAc (200 mL). The organic layer was washed with brine (100 _mL ), dried over _Na₂SO₄ , and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 100/1 by volume) to give 5-bromo-3-chloro-pyridine-2-carbonyl chloride (5.17 g, 78.3% yield) as a yellow solid.

MS(ESI): 315.8([{ ⁸¹ Br+ ⁸¹ Br}M+H] ⁺ ), 313.8([{ ⁸¹ Br+ ⁷⁹ Br}M+H] ⁺ ), 311.8([{ ⁷⁹ Br+ ⁷⁹ Br}M+H] ⁺ ).

c) 5-Bromo-3-chloro-2-(oxirane-2-yl)pyridine

To a solution of 5-bromo-3-chloro-pyridine-2-carbonyl chloride (5.17 g, 16.5 mmol) in ethanol (100 mL) was added NaBH ₄ (752.4 mg, 19.8 mmol) at 0-5° C. The solution was stirred at room temperature for one hour. K ₂ CO ₃ (2.3 g, 16.5 mmol) was added. The reaction was continued overnight. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure. Further dried under high vacuum to obtain 5-bromo-3-chloro-2-(oxirane-2-yl)pyridine (3.86 g, 100% yield) as a yellow oil, which was used directly in the next step.

MS(ESI): 235.9([{ ⁸¹ Br}M+H] ⁺ ), 233.9([{ ⁷⁹ Br}M+H] ⁺ ).

d) 1-(5-bromo-3-chloro-2-pyridyl)-2-(2-hydroxyethylamino)ethanol

To a solution of 5-bromo-3-chloro-2-(oxirane-2-yl)pyridine (3.86 g, 16.5 mmol) in THF (20 mL) was added ethanolamine (10 mL, CAS: 141-43-5). The solution was stirred at room temperature overnight. The solution was then diluted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure. Further drying under high vacuum gave crude 1-(5-bromo-3-chloro-2-pyridyl)-2-(2-hydroxyethylamino)ethanol (3.0 g, 61.6% yield) as a yellow oil which was used directly in the next step.

e) tert-Butyl N-[2-(5-bromo-3-chloro-2-pyridinyl)-2-hydroxy-ethyl]-N-(2-hydroxyethyl)carbamate

To a solution of 1-(5-bromo-3-chloro-2-pyridyl)-2-(2-hydroxyethylamino)ethanol (3.0 g, 16.5 mmol) in a mixture of THF (30 mL) and water (20 mL) was added di-tert-butyl dicarbonate (3.29 g, 15.22 mmol, CAS: 24424-99-5) and K ₂ CO ₃ (2.8 g, 20.3 mmol). The solution was stirred at room temperature overnight. The reaction solution was diluted with water (50 mL). The mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by column chromatography ( _CH2Cl2 / _MeOH = 100/1 to 50/1 by volume) to give tert-butyl N-[2-(5-bromo-3-chloro-2-pyridinyl)-2-hydroxy-ethyl]-N-(2-hydroxyethyl)carbamate (1.5 g, 37.5% yield) as a yellow oil.

MS(ESI): 295.0([{ ⁷⁹ Br}M-Boc+H] ⁺ ), 296.9([{ ⁸¹ Br}M-Boc+H] ⁺ ), 338.9([{ ⁷⁹ Br}M-56+H] ⁺ ), 340.9([{ ⁸¹ Br}M-56+H] ⁺ ),

f) tert-Butyl 2-(5-bromo-3-chloro-2-pyridyl)morpholine-4-carboxylate

To a solution of tert-butyl N-[2-(5-bromo-3-chloro-2-pyridinyl)-2-hydroxy-ethyl]-N-(2-hydroxyethyl)carbamate (1.5 g, 3.79 mmol) in toluene (20 mL) was added _PPh₃ (1.19 g, 4.55 mmol) and _Et₃N (957 mg, 9.47 mmol) at room temperature. A solution of diisopropyl azodicarboxylate (0.92 g, 4.55 mmol, CAS: 2446-83-5) in toluene (10 mL) was then added at 0-5°C. The solution was stirred at room temperature overnight. The reaction solution was then diluted with ethyl acetate (200 mL). The mixture was washed with _NaHCO₃ (100 mL x 3) and brine (100 mL x ₂ ), dried over _Na₂SO₄ , and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 20/1 to 5/1 by volume) to give tert-butyl 2-(5-bromo-3-chloro-2-pyridinyl)morpholine-4-carboxylate (1.0 g, 70% yield) as a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 8.62 (d, J=2 Hz, 1H), 7.89 (d, J=2 Hz, 1H), 4.89 (d, J=10 Hz, 1H), 4.30-3.8 (m, 3H), 3.76 (m, 1H), 3.13 (br, 2H), 1.49 (s, 9H).

g) (RS)-5-chloro-N-(5-chloro-2-pyridinyl)-6-morpholin-2-yl-pyridin-3-amine

To a solution of tert-butyl _2- (5-bromo-3-chloro-2-pyridyl)morpholine-4-carboxylate (80 mg, 0.211 mmol) and 2-amino-5-chloropyridine (27 mg, 0.211 mmol, CAS: 1072-98-6) in dioxane (1 mL) was added Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 36.7 mg, 0.063 mmol, CAS: 161265-03-8), Cs ₂ CO ₃ (206.2 mg, 0.633 mmol), and tris(dibenzylideneacetone)dipalladium(0) (19.3 mg, 0.021 mmol, CAS: 51364-51-3) under N 2 atmosphere. The mixture was stirred at 80° C. overnight. The solution was then poured into water (100 mL). The mixture was extracted with CH ₂ Cl ₂ (150 mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (1 mL). Trifluoroacetic acid (1 mL) was then added. The solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.5% TFA in CH ₃ CN) to give (RS)-5-chloro-N-(5-chloro-2-pyridyl)-6-morpholin-2-yl-pyridin-3-amine (50 mg) as a white solid.

¹ H NMR (400MHz, methanol-d ⁴ ): δ8.62(dd, 2H), 8.21(s, 1H), 7.64(dd, 1H), 6.87(d, 1H), 5.23(dd, 1H), 4.11(m, 1H), 3.98(m, 1H), 3.67(m, 1H), 3.49(m, 1H), 3.35～3.30(m, 2H).

MS(ESI): 325.1({ ³⁵ Cl}M+H) ⁺ , 327.0({ ³⁷ Cl}M+H) ⁺ .

Example 103

(RS)-5-Chloro-6-morpholin-2-yl-N-[5-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine

The title compound was obtained in a similar manner to Example 102, using 2-amino-5-trifluoromethylpyridine (CAS: 74784-70-6) instead of 2-amino-5-chloropyridine in step (g). White solid. MS (ESI): 361.0 ([{ ³⁷ Cl}M+H] ⁺ ), 359.1 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 104

(RS)-5-Methyl-6-morpholin-2-yl-N-[5-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine

a) 2-Bromo-1-(5-bromo-3-methyl-2-pyridyl)ethanone

A solution of 5-bromo-3-methylpyridine-2-carbonyl chloride (4 g, 17 mmol, CAS: 1114809-24-3) in CH ₃ CN (60 mL) was stirred at 0° C. (Trimethylsilyl)diazomethane (2 M in hexane, 21 mL, 42 mmol, CAS: 18107-18-1) was added. The mixture was stirred at room temperature overnight until TLC analysis showed that the starting material was completely consumed. HBr (12 mL, 48% aqueous solution) was added. The resulting solution was stirred at room temperature overnight. The mixture was treated with saturated NaHCO ₃ aqueous solution to adjust the pH to about 7. The layers were separated. The aqueous layer was extracted with ethyl acetate (200 mL x2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue (4.5 g) was used for the next step without purification.

b) 5-Bromo-3-methyl-2-(oxirane-2-yl)pyridine

A solution of 2-bromo-1-(5-bromo-3-methyl-2-pyridyl)ethanone (4g, 13.7mmol) in EtOH (80mL) was stirred at 0°C. NaBH ₄ (623mg, 16.4mmol) was added. The mixture was stirred at room temperature for 4 hours. K ₂ CO ₃ (945mg, 6.9mmol) was added. The resulting solution was stirred at room temperature overnight. The mixture was diluted with water (300ml). Layered. The aqueous layer was extracted with EtOAc (300mL x 2). The combined organic layers were washed with brine (300mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was used for the next step without purification.

c) 1-(5-Bromo-3-methyl-2-pyridyl)-2-(2-hydroxyethylamino)ethanol

To a stirred solution of 5-bromo-3-methyl-2-(oxirane-2-yl)pyridine (3.5 g, 16.4 mmol) in THF (15 mL) was added 2-aminoethanol (15 mL, CAS: 41-43-5). The mixture was stirred at room temperature overnight. The reaction mixture was then poured into THF/EtOAc (1:1, 200 mL ₎ and washed with brine (100 mL). The organic layer was dried over _Na₂SO₄ and concentrated to give crude 1-(5-bromo-3-methyl-2-pyridinyl)-2-(2-hydroxyethylamino)ethanol (2.6 g, 58% yield) as an oil, which was used in the next step without purification.

MS (ESI): 277.0 ([{ ⁸¹ Br}M+H] ⁺ ), 275.0 ([{ ⁷⁹ Br}M+H] ⁺ ).

d) tert-Butyl N-[2-(5-bromo-3-methyl-2-pyridyl)-2-hydroxy-ethyl]-N-(2-hydroxyethyl)carbamate ester

A mixture of 1-(5-bromo-3-methyl-2-pyridyl)-2-(2-hydroxyethylamino)ethanol (2.6 g, 9.5 mmol, crude), K ₂ CO ₃ (3.0 g, 22 mmol) and (Boc) ₂ O (1.9 g, 7.3 mmol, CAS: 24424-99-5) in THF (30 mL) was stirred at room temperature for 12 hours. The mixture was then diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with water (100 mL) and brine (100 mL) and concentrated under reduced pressure. Purification by silica gel chromatography gave tert-butyl N-[2-(5-bromo-3-methyl-2-pyridyl)-2-hydroxy-ethyl]-N-(2-hydroxyethyl)carbamate (1.31 g, 37% yield) as a light yellow oil.

e) tert-Butyl 2-(5-bromo-3-methyl-2-pyridyl)morpholine-4-carboxylate

A mixture of tert-butyl N-[2-(5-bromo-3-methyl-2-pyridinyl)-2-hydroxy-ethyl]-N-(2-hydroxyethyl)carbamate (1.3 g, 3.5 mmol), _PPh₃ (1.02 g, 4.2 mmol), and _Et₃N (900 mg, 9 mmol) was stirred at 0°C for 10 minutes. Diisopropyl azodicarboxylate (848 mg, 4.2 mmol, CAS: 2446-83-5) was added dropwise. The reaction was continued overnight. The mixture was concentrated under reduced pressure. Purification by flash chromatography on silica gel gave tert-butyl 2-(5-bromo-3-methyl-2-pyridinyl)morpholine-4-carboxylate (600 mg, 48% yield) as an off-white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 8.46 (d, 1H), 7.87 (d, 1H), 4.65 (m, 1H), 4.11 (m, 1H), 3.98 (m, 2H), 3.72 (t, 1H), 3.32 (m, 2H), 2.43 (s, 3H), 1.52 (s, 9H).

MS (ESI): 359.0 ([{ ⁸¹ Br}M+H] ⁺ ), 357.0 ([{ ⁷⁹ Br}M+H] ⁺ ).

f)(RS)-5-methyl-6-morpholin-2-yl-N-[5-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine

Under _N2 atmosphere, a mixture of tert-butyl 2-(5-bromo-3-methyl-2-pyridyl)morpholine-4-carboxylate (60 mg, 0.17 mmol), 2-amino-5-trifluoromethylpyridine (26 mg, CAS:74784-70-6), Xantphos (20 mg, 0.034 mmol, CAS:161265-03-8), _Pd2 (dba) ₃ (16 mg, 0.017 mmol, CAS:51364-51-3) and _{Cs2CO3 (} 166 mg, 0.51 mmol) in dioxane (5 mL) was stirred at 90°C for 12 hours. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (100 mL x2). The combined organic layers were washed with water (100 mL) and concentrated under reduced pressure. The residue was dried under high vacuum.

The residue is then dissolved in dichloromethane (2mL). Triethylamine (0.5ml) is added. The resulting mixture is stirred at room temperature for one hour. Volatiles are removed under reduced pressure. Silica gel chromatography purifies to obtain (RS)-5-methyl-6-morpholine-2-base-N-[5-(trifluoromethyl)-2-pyridyl] pyridine-3-amine (15mg), which is a white solid.

¹ H NMR (400MHz, methanol-d ⁴ ): δ9.05(d, 1H), 8.54(s, 1H), 8.24(d, 1H), 7.89(dd, 1H), 7.01(d, 1H), 5.21(dd, 1 H), 4.17 (m, 1H), 4.04 (m, 1H), 3.60 (m, 2H), 3.41 (m, 1H), 3.34 (m, 1H), 2.50 (s, 3H).

MS (ESI): 339.1 (M+H) ⁺ .

Example 105

4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 4-chloro-5-(2,2,2-trifluoroethoxy)-1H-pyrazole-3-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS(ESI): 406.1({ ³⁵ Cl}M+H) ⁺ , 408.1({ ³⁷ Cl}M+H) ⁺ .

Example 106

4-Chloro-3-ethoxy-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 4-chloro-5-ethoxy-1H-pyrazole-3-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS(ESI): 352.1({ ³⁵ Cl}M+H) ⁺ , 354.1({ ³⁷ Cl}M+H) ⁺ .

Example 107

(RS)-N-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide

a) tert-Butyl 2-[5-(benzylideneamino)-3-chloro-2-pyridyl]morpholine-4-carboxylate

To a solution of tert-butyl _2- (5-bromo-3-chloro-2-pyridyl)morpholine-4-carboxylate (0.4 g, 1.057 mmol) and benzophenone imine (191.3 mg, 1.057 mmol, CAS: 1013-88-3) in dioxane (15 mL) was added Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 183.5 mg, 0.317 mmol, CAS: 161265-03-8), Cs ₂ CO ₃ (1.03 g, 3.17 mmol) and tris(dibenzylideneacetone)dipalladium(0) (96.8 mg, 0.1 mmol, CAS: 51364-51-3) under N 2 atmosphere. The mixture was stirred at 85° C. overnight. The reaction mixture was then filtered. The filtrate was concentrated in vacuo to give crude tert-butyl 2-[5-(benzylideneamino)-3-chloro-2-pyridinyl]morpholine-4-carboxylate (505 mg, 100% yield) as a yellow oil which was used directly in the next step.

b) tert-Butyl 2-(5-amino-3-chloro-2-pyridyl)morpholine-4-carboxylate

To a solution of tert-butyl 2-[5-(benzylideneamino)-3-chloro-2-pyridyl]morpholine-4-carboxylate (505 mg, 1.057 mmol) in methanol (10 mL) were added sodium acetate (433.4 mg, 5.28 mmol) and hydroxylamine hydrochloride (110.2 mg, 1.58 mmol). The mixture was stirred at room temperature for 2 hours. The solution was poured into water (50 mL) and extracted with _{CH₂Cl₂ (} 100 mL×2). The combined organic layers were dried over _Na₂SO₄ , concentrated in _vacuo , and purified by column chromatography ( _CH₂Cl₂ / _methanol = 100/1 to 50/1 by volume) to give tert-butyl 2-(5-amino-3-chloro-2-pyridyl)morpholine-4-carboxylate (270 mg, 81% yield) as a yellow solid.

MS (ESI): 258.0 ([{ ³⁵ Cl}M-56+H] ⁺ ), 314.0 ([{ ³⁵ Cl}M+H] ⁺ ), 316.0 ([{ ³⁷ Cl}M+H] ⁺ ), 336.0 ([{ ³⁵ Cl}M+Na] ⁺ ).

c) (RS)-N-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide

To a solution of 2-(trifluoromethyl)pyridine-4-carboxylic acid (40 mg, 0.21 mmol, CAS: 131747-41-6) in DMF (1 mL) were added HATU (79.7 mg, 0.21 mmol, CAS: 148893-10-1), diisopropylethylamine (73.7 mg, 0.57 mmol), and tert-butyl 2-(5-amino-3-chloro-2-pyridyl)morpholine- ₄ -carboxylate (60 mg, 0.19 mmol). The solution was stirred at room temperature overnight. The reaction mixture was then diluted with _{CH₂Cl₂ (} 50 mL). The solution was washed with brine (50 mL×2), dried over _Na₂SO₄ , and concentrated under vacuum. The residue was dissolved in _CH₂Cl₂ (1 _mL ) and trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum. The residue was purified by prep-HPLC (0.5% trifluoroacetic acid in _CH3CN ) to give (RS)-N-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide (11 mg) as a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 8.95 (d, 1H), 8.90 (d, 1H), 8.50 (d, 1H), 8.34 (s, 1H), 8.15 (m, 1H), 5.28 (dd, 1H), 4.07 (m, 1H), 4.01 (m, 1H), 3.72 (m, 1H), 3.56 (m, 1H), 3.36-3.30 (m, 2H).

MS (ESI): 387.1 ([{ ³⁵ Cl}M+H] ⁺ ), 389.1 ([{ ³⁷ Cl}M+H] ⁺ ).

Example 108

(RS)-4-Chloro-N-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide

Analogously to Example 107, using 4-chloro-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 1340578-20-2) instead of 2-(trifluoromethyl)pyridine-4-carboxylic acid in step (c), the title compound was obtained as a white solid.

MS (ESI): 386.1 ([{ ³⁷ Cl}M+H] ⁺ ), 384.1 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 109

(RS)-1-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-3-(3-chlorophenyl)urea

To a solution of tert-butyl 2-(5-amino-3-chloro-2-pyridyl)morpholine-4-carboxylate (60 mg, 0.19 mmol) in _CH₂Cl₂ (1 _mL ) was added triethylamine (38.4 mg, 0.38 mmol) and ₃ -chlorophenyl isocyanate (29.2 mg, 0.19 mmol, CAS: 2909-38-8). The solution was stirred at room temperature overnight. _The reaction solution was diluted with _CH₂Cl₂ (50 mL), washed with brine (50 mL x 2), dried over _Na₂SO₄ , and concentrated under vacuum. The residue was dissolved in a mixture of _CH₂Cl₂ (1 _mL ) and trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 2 hours. Volatiles were removed under reduced pressure. The residue was purified by preparative HPLC (0.5% trifluoroacetic acid in _CH₃CN ) to give the title compound (20 mg) as a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 8.58 (s, 1H), 8.25 (s, 1H), 7.67 (s, 1H), 7.31-7.27 (m, 2H), 7.08-7.06 (m, 1H), 5.27-5.24 (dd, J=12 Hz, 1H), 4.10-4.00 (m, 1H), 4.99-3.98 (m, 1H), 3.71-3.68 (m, 1H), 3.55-3.54 (m, 1H), 3.36-3.30 (m, 2H).

LCMS for compound RW-04-035-05: MS (ESI): 367.1 ({35Cl}M+H)+, 369.0 ({37Cl}M+H)+.

Example 110

(RS)-N-(5-Chloro-2-pyridinyl)-5-fluoro-6-morpholin-2-yl-pyridin-3-amine

a) 2-Bromo-1-(5-bromo-3-fluoro-2-pyridyl)ethanone

To a solution of 1-(5-bromo-3-fluoropyridin-2-yl)ethanone (5.5 g, 25.2 mmol, CAS: 1160936-52-6) in acetic acid (30 mL) was added hydrobromic acid solution (33 wt % in acetic acid, 30 mL) and pyrrolidone hydrogen tribromide (8.4 g, 26.4 mmol, CAS: 22580-55-8) at room temperature. The solution was stirred at room temperature overnight. The solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate (800 mL). The precipitate was collected by filtration and dried under high vacuum to give 2-bromo-1-(5-bromo-3-fluoro-2-pyridinyl)ethanone (7.52 g, 79% yield) as the HBr salt.

b) 5-Bromo-3-fluoro-2-(oxirane-2-yl)pyridine

To a solution of 2-bromo-1-(5-bromo-3-fluoro-2-pyridyl)ethanone (7.52 g, 20 mmol, HBr salt) in ethanol (140 mL) was added NaBH ₄ (910 mg, 24 mmol) at 0-5° C. The solution was then stirred at room temperature for one hour. Sodium ethoxide (660 mg, 10 mmol) was added. The solution was stirred at room temperature overnight. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , and concentrated in vacuo to give 5-bromo-3-fluoro-2-(oxirane-2-yl)pyridine (4.4 g, 100% yield) as a yellow oil, which was used directly in the next step.

MS(ESI): 219.9([{ ⁸¹ Br}M+H] ⁺ ), 217.9([{ ⁷⁹ Br}M+H] ⁺ ).

c) 1-(5-bromo-3-fluoro-2-pyridyl)-2-(2-hydroxyethylamino)ethanol

To a solution of 5-bromo-3-fluoro-2-(oxirane-2-yl)pyridine (4.8 g, 22.12 mmol) in THF (20 mL) was added 2-aminoethanol (10 mL, CAS: 41-43-5). The solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (200 mL). The organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ , and concentrated in vacuo to give crude 1-(5-bromo-3-fluoro-2-pyridyl)-2-(2-hydroxyethylamino)ethanol (5.0 g, 81% yield) as a yellow solid, which was used directly in the next step.

d) tert-Butyl N-[2-(5-bromo-3-fluoro-2-pyridyl)-2-hydroxy-ethyl]-N-(2-hydroxyethyl)carbamate

To a solution of 1-(5-bromo-3-fluoro-2-pyridyl)-2-(2-hydroxyethylamino)ethanol (5.0 g, 17.9 mmol) in a mixture of THF (50 mL) and _H₂O (30 mL) was added _di -tert-butyl dicarbonate (5.8 g, 26.9 mmol, CAS: 24424-99-5) and _K₂CO₃ (4.9 g, 36 mmol). The solution was stirred at room temperature overnight. The reaction solution was diluted with water (50 mL). _The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over _Na₂SO₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( _CH2Cl2 / _MeOH = 100/1 to 50/1 by volume) to give tert-butyl N-[2-(5-bromo-3-fluoro-2-pyridinyl)-2-hydroxy-ethyl]-N-(2-hydroxyethyl)carbamate (5.2 g, 77% yield) as a yellow oil.

MS (ESI): 278.9 ([{ ⁷⁹ Br}M-Boc+H] ⁺ ), 280.9 ([{ ⁸¹ Br}M-Boc+H] ⁺ ).

e) tert-Butyl 2-(5-bromo-3-fluoro-2-pyridyl)morpholine-4-carboxylate

To a solution of tert-butyl N-[2-(5-bromo-3-fluoro-2-pyridinyl)-2-hydroxy-ethyl]-N-(2-hydroxyethyl)carbamate (5.2 g, 13.7 mmol) in toluene (100 mL) was added _PPh₃ (4.3 g, 16.4 mmol) and _Et₃N (3.46 g, 34.25 mmol) at room temperature. A solution of DIAD (3.32 g, 16.4 mmol) in toluene (30 mL) was then added at 0-5°C. The solution was stirred at room temperature overnight. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with aqueous _NaHCO₃ (100 mL x 3) and brine (100 mL x ₂ ), dried over _Na₂SO₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1 to 5/1 by volume) to give tert-butyl 2-(5-bromo-3-fluoro-2-pyridinyl)morpholine-4-carboxylate (3.2 g, 65% yield) as a white solid.

MS (ESI): 361.0 ([{ ⁷⁹ Br}M+H] ⁺ ), 363.0 ([{ ⁸¹ Br}M+H] ⁺ ).

f)(RS)-N-(5-chloro-2-pyridinyl)-5-fluoro-6-morpholin-2-yl-pyridin-3-amine

To a solution of tert-butyl _2- (5-bromo-3-fluoro-2-pyridyl)morpholine-4-carboxylate (80 mg, 0.221 mmol) and 2-amino-5-chloropyridine (28.4 mg, 0.221 mmol, CAS: 1072-98-6) in dioxane (1 mL) was added Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 38.4 mg, 0.066 mmol, CAS: 161265-03-8), Cs ₂ CO ₃ (216 mg, 0.663 mmol), and tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.022 mmol, CAS: 51364-51-3) under N 2 atmosphere. The mixture was stirred at 80° C. overnight. The solution was then poured into water (100 mL). The mixture was extracted with CH ₂ Cl ₂ (150 mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (1 mL). Trifluoroacetic acid (1 mL) was then added. The solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.5% TFA in CH ₃ CN) to give (RS)-N-(5-chloro-2-pyridyl)-5-fluoro-6-morpholin-2-yl-pyridin-3-amine (44 mg) as a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 8.45 (m, 2H), 8.22 (d, 1H), 7.64 (dd, 1H), 6.88 (d, 1H), 5.12 (m, 1H), 4.12 (m, 1H), 3.98 (m, 1H), 3.67 (m, 1H), 3.48 (m, 1H), 3.33 (m, 1H), 3.31 (m, 1H).

MS (ESI): 308.9 ([{ ³⁵ Cl}M+H] ⁺ ), 310.9 ([{ ³⁷ Cl}M+H] ⁺ ).

Example 111

(RS)-5-Fluoro-6-morpholin-2-yl-N-[5-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine

Analogously to Example 110, using 2-amino-5-trifluoromethylpyridine (CAS: 74784-70-6) instead of 2-amino-5-chloropyridine in step (f), the title compound was obtained as a white solid.

MS (ESI): 343.0 (M+H) ⁺ .

Example 112

(RS)-1-(3-chlorophenyl)-3-(5-fluoro-6-morpholin-2-yl-3-pyridyl)urea

a) tert-Butyl 2-[5-(benzhydrylamino)-3-fluoro-2-pyridyl]morpholine-4-carboxylate

To a solution of tert-butyl _2- (5-bromo-3-fluoro-2-pyridyl)morpholine-4-carboxylate (0.6 g, 1.66 mmol) and benzophenone imine (300 mg, 1.66 mmol, CAS: 1013-88-3) in dioxane (30 mL) was added Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 288 mg, 0.5 mmol, CAS: 161265-03-8), Cs ₂ CO ₃ (1.62 g, 4.98 mmol) and tris(dibenzylideneacetone)dipalladium(0) (152 mg, 0.166 mmol, CAS: 51364-51-3) under N 2 atmosphere. The mixture was stirred at 85° C. overnight. The reaction mixture was then filtered. The filtrate was concentrated under vacuum to give crude tert-butyl 2-[5-(benzhydrylamino)-3-fluoro-2-pyridinyl]morpholine-4-carboxylate (766 mg, 100% yield) as a yellow oil, which was used directly in the next step.

b) tert-Butyl 2-(5-amino-3-fluoro-2-pyridyl)morpholine-4-carboxylate

To a solution of tert-butyl 2-[5-(benzhydrylamino)-3-fluoro-2-pyridyl]morpholine-4-carboxylate (766 mg, 1.66 mmol) in methanol (20 mL) was added sodium acetate (681 mg, 8.3 mmol) and _{hydroxylamine} hydrochloride (173 mg, 2.5 mmol). The mixture was stirred at room temperature for 2 hours. The solution was poured into water (50 mL) and extracted with _{CH₂Cl₂ (} 100 mL×2). The combined organic layers were dried over _Na₂SO₄ , concentrated under vacuum, and purified by column chromatography ( _CH₂Cl₂ / _methanol = 100/1 to 50/1 by volume) to give tert-butyl 2-(5-amino-3-fluoro-2-pyridyl)morpholine-4-carboxylate (350 mg, 71% yield) as a yellow solid.

MS(ESI): 242.0(M-56+H) ⁺ , 298.0(M+H) ⁺ .

c)(RS)-1-(3-chlorophenyl)-3-(5-fluoro-6-morpholin-2-yl-3-pyridyl)urea

To a solution of tert-butyl 2-(5-amino-3-fluoro-2-pyridyl)morpholine-4-carboxylate (70 mg, 0.235 mmol) in dichloromethane (1 mL) was added _Et₃N (48 mg, 0.47 mmol) and ₃ -chlorophenyl isocyanate (36 mg, 0.24 mmol, CAS: 2909-38-8). The solution was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane (50 mL). The solution was then washed with brine (50 mL x 2), dried over _Na₂SO₄ , concentrated under reduced pressure, and dried under high vacuum. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.5% TFA in _CH3CN ) to give (RS)-1-(3-chlorophenyl)-3-(5-fluoro-6-morpholin-2-yl-3-pyridinyl)urea (52 mg) as a white solid.

¹ H NMR (400MHz, methanol-d ⁴ ): δ8.41(s, 1H), 8.06(dd, 1H), 7.67(s, 1H), 7.29(m, 2H), 7.05(m, 1H), 5.13(dd , 1H), 4.12(m, 1H), 3.98(m, 1H), 3.69(m, 1H), 3.51(dd, 1H), 3.35～3.30(m, 2H).

MS (ESI): 351.1 ([{ ³⁵ Cl}M+H] ⁺ ), 353.1 ([{ ³⁷ Cl}M+H] ⁺ ).

Example 113

(RS)-N-(5-Fluoro-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide

To a solution of 2-(trifluoromethyl)pyridine-4-carboxylic acid (57 mg, 0.30 mmol, CAS: 131747-41-6) in DMF (1 mL) was added HATU (112.2 mg, 0.295 mmol, CAS: 148893-10-1), N,N-diisopropylethylamine (104 mg, 0.804 mmol, CAS: 7087-68-5) and tert-butyl 2-(5-amino-3-fluoro-2-pyridyl)morpholine-4-carboxylate (80 mg, 0.27 mmol). The solution was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (50 mL). The solution was then washed with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ , concentrated under reduced pressure, and dried under high vacuum. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.5% TFA in _CH3CN ) to give (RS)-N-(5-fluoro-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide (10 mg) as a white solid.

¹ H NMR (400 MHz, methanol- ^{d 4} ): δ 8.94 (d, 1H), 8.77 (d, 1H), 8.34-8.30 (m, 2H), 8.15 (d, 1H), 5.19 (dd, 1H), 4.14 (m, 1H), 4.06 (m, 1H), 3.71 (m, 1H), 3.55 (m, 1H), 3.36-3.30 (m, 2H).

MS(ESI): 393.0(M+Na) ⁺ , 371.0(M+H) ⁺ .

Example 114

(RS)-4-Chloro-N-(5-fluoro-6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide

The title compound was obtained by analogy with Example 113, using 4-chloro-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 1340578-20-2) instead of 2-(trifluoromethyl)pyridine-4-carboxylic acid. White solid. MS (ESI): 370.0 ([{ ³⁷ Cl}M+H] ⁺ ), 368.0 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 115

4-Chloro-3-isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 4-chloro-5-propan-2-yl-2H-pyrazole-3-carboxylic acid (CAS: 1291271-55-0) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS(ESI): 350.0({ ³⁵ Cl}M+H) ⁺ , 352.0({ ³⁷ Cl}M+H) ⁺ .

Example 116

4-Fluoro-3-isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

a) 4-Fluoro-3-isopropyl-1H-pyrazole-5-carboxylic acid ethyl ester

To a solution of ethyl 3-isopropyl-1H-pyrazole-5-carboxylate (5.0 g, 0.027 mmol, CAS: 78208-72-7) in _CH₃CN (300 mL) at 0°C was added 12.7 g, 35.7 mmol, CAS: 140681-55-6). The solution was then heated to 70°C. Stirring was continued for 15 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with aqueous HCl (3N, 200 mL) and extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried _{over Na₂SO₄} , and concentrated under reduced pressure. Purification by silica gel column chromatography (dichloromethane/MeOH = 200/1 to 100/1 by volume) gave ethyl 4-fluoro-3-isopropyl-1H-pyrazole-5-carboxylate (900 mg, 17% yield) as a yellow oil.

MS(ESI): 223.1(M+Na) ⁺ , 201.1(M+H) ⁺ .

b) 4-Fluoro-3-isopropyl-1H-pyrazole-5-carboxylic acid

To a solution of 4-fluoro-3-isopropyl-1H-pyrazole-5-ethyl formate (900mg, 4.49mmol) in THF/MeOH (10/10mL) was added the 1M NaOH aqueous solution (9mL, 9mmol) at 0°C. The solution was then refluxed for 3 hours. The reaction solution was poured into water. The pH was adjusted to 1 with concentrated HCl. The mixture was extracted with ethyl acetate (100mL x2). The combined organic layer was washed with salt water and concentrated under vacuum. The residue was recrystallized from ethyl acetate (10mL) to obtain 4-fluoro-3-isopropyl-1H-pyrazole-5-formic acid (450mg, 58% yield), which was a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 3.08 (m, 1H), 1.32 (d, 6H).

MS (ESI): 173.1 (M+H) ⁺ .

c) 4-Fluoro-3-isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 66, using 4-fluoro-3-isopropyl-1H-pyrazole-5-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

¹ H NMR (400MHz, methanol-d ⁴ ): δ 8.93 (d, 1H), 8.27 (dd, 1H), 7.59 (d, 1H), 4.87 (m, 1H), 4.24 (dd, 1H), 4.01 (t, 1H), 3.67 (d, 1H), 3.34 (m, 1H), 3.30 (m, 2H), 3.11 (m, 1H). 1.35(d,6H).

MS (ESI): 334.1 (M+H) ⁺ .

Example 117

(RS)-N-(5-methyl-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide

a) tert-Butyl 2-[5-(benzhydrylamino)-3-methyl-2-pyridyl]morpholine-4-carboxylate

To a solution of tert-butyl _2- (5-bromo-3-methyl-2-pyridyl)morpholine-4-carboxylate (0.28 g, 0.78 mmol) and benzophenone imine (156 mg, 0.86 mmol, CAS: 1013-88-3) in dioxane (20 mL) was added Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 90 mg, 0.156 mmol, CAS: 161265-03-8), Cs ₂ CO ₃ (0.77 g, 2.34 mmol) and tris(dibenzylideneacetone)dipalladium(0) (72 mg, 0.078 mmol, CAS: 51364-51-3) under N 2 atmosphere. The mixture was stirred at 90° C. for 12 hours. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine, dried _{over Na2SO4} , and concentrated under reduced pressure. Further drying under high vacuum gave tert-butyl 2-[5-(benzhydrylamino)-3-methyl-2-pyridyl]morpholine-4-carboxylate (360 mg) as a yellow oil, which was used directly in the next step.

b) tert-Butyl 2-(5-amino-3-methyl-2-pyridyl)morpholine-4-carboxylate

To a solution of tert-butyl 2-[5-(benzylideneamino)-3-methyl-2-pyridyl]morpholine-4-carboxylate (360 mg, 0.78 mmol) in methanol (10 mL) was added sodium acetate (250 mg, 2.34 mmol) and _{hydroxylamine} hydrochloride (82 mg, 1.17 mmol). The mixture was stirred at room temperature for 3 hours. The solution was poured into water (50 mL) and extracted with _{CH₂Cl₂ (} 100 mL x 2). The combined organic layers were dried over _Na₂SO₄ , concentrated under vacuum, and purified by column chromatography ( _CH₂Cl₂ / _methanol = 100/1 to 50/1 by volume) to give tert-butyl 2-(5-amino-3-methyl-2-pyridyl)morpholine-4-carboxylate (150 mg, 65% yield) as an off-white solid.

c) (RS)-N-(5-methyl-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide

To a solution of 2-(trifluoromethyl)pyridine-4-carboxylic acid (29 mg, 0.15 mmol, CAS: 131747-41-6) in DMF (1 mL) was added HATU (56 mg, 0.15 mmol, CAS: 148893-10-1), N, N-diisopropylethylamine (52 mg, 0.40 mmol, CAS: 7087-68-5) and tert-butyl 2-(5-amino-3-methyl-2-pyridyl)morpholine-4-carboxylate (40 mg, 0.14 mmol). The solution was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane (50 mL). The solution was then washed with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ , concentrated under reduced pressure, and dried under high vacuum. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure.The residue was purified by preparative HPLC (0.5% TFA in _CH3CN ) to give (RS)-N-(5-methyl-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide (4 mg) as a white solid.

¹ H NMR (400 MHz, methanol-d ⁴ ): δ 8.95 (d, 1H), 8.85 (d, 1H), 8.34 (s, 1H), 8.15 (dd, 1H), 5.13 (dd, 1H), 4.04 (m, 2H), 3.77 (m, 1H), 3.61 (dd, 1H), 3.38-3.30 (m, 2H), 2.49 (s, 3H).

MS (ESI): 367.1 (M+H) ⁺ .

Example 118

(RS)-4-Chloro-N-(5-methyl-6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide

The title compound was obtained by analogy with Example 117, using 4-chloro-5-propyl-1H-pyrazole-3-carboxylic acid (CAS: 1340578-20-2) instead of 2-(trifluoromethyl)pyridine-4-carboxylic acid. White solid. MS (ESI): 366.0 ([{ ³⁷ Cl}M+H] ⁺ ), 364.0 ([{ ³⁵ Cl}M+H] ⁺ ).

Example 119

(RS)-1-(3-chlorophenyl)-3-(5-methyl-6-morpholin-2-yl-3-pyridyl)urea

To a solution of tert-butyl 2-(5-amino-3-methyl-2-pyridyl)morpholine-4-carboxylate (30 mg, 0.1 mmol) in dichloromethane (1 mL) was added _Et₃N (30 mg, 0.3 mmol) and ₃ -chlorophenyl isocyanate (16 mg, 0.1 mmol, CAS: 2909-38-8). The solution was stirred at room temperature overnight. The reaction solution was diluted with dichloromethane (50 mL). The solution was then washed with brine (50 mL x 2), dried over _Na₂SO₄ , concentrated under reduced pressure, and dried under high vacuum. The residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.5% TFA in _CH3CN ) to give (RS)-1-(3-chlorophenyl)-3-(5-methyl-6-morpholin-2-yl-3-pyridinyl)urea (32 mg) as a white solid.

¹ H NMR (400MHz, DMSO-d ⁶ ): δ9.36 (d, 2H), 9.04 (m, 1H), 8.47 (s, 1H), 7.84 (d, 1H), 7.73 (s, 1H), 7.32 (m, 2H), 7.05 (m, 1H) , 4.91 (dd, 1H), 4.00 (m, 1H), 3.89 (m, 1H), 3.58 (m, 2H), 3.27 (d, 1H), 3.15 (m, 1H), 2.35 (s, 3H).

MS (ESI): 347.0 ([{ ³⁵ Cl}M+H] ⁺ ), 349.0 ([{ ³⁷ Cl}M+H] ⁺ ).

Example 120

4-Chloro-3-isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 4-chloro-5-propan-2-yl-2H-pyrazole-3-carboxylic acid (CAS: 1291271-55-0) instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS(ESI): 350.1({ ³⁵ Cl}M+H) ⁺ , 352.1({ ³⁷ Cl}M+H) ⁺ .

Example 121

4-Fluoro-3-isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide

Analogously to Example 67, using 4-fluoro-3-isopropyl-1H-pyrazole-5-carboxylic acid instead of 3-ethyl-4-methyl-1H-pyrazole-5-carboxylic acid, the title compound was obtained as a white solid.

MS (ESI): 334.2 (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 good affinity for trace amine associated receptors (TAARs), in particular TAAR1.

These compounds were investigated according to the test given hereinafter.

Materials and methods

Construction of TAAR expression plasmid and stably transfected cell line

To construct expression plasmids, the coding sequences of human, rat, and mouse TAAR 1 were amplified from genomic DNA essentially as described by Lindemann et al. [14]. The purified PCR product was cloned into the pCR2.1-TOPO cloning vector (Invitrogen) using the Expand High Fidelity PCR System (Roche Diagnostics) with 1.5 mM Mg ²⁺ according to the manufacturer's instructions. The PCR product was subcloned into the pIRESneo2 vector (BD Clontech, Palo Alto, California), and the expression vector was sequence-confirmed before introduction into the cell line.

Essentially as described in Lindemann et al. (2005), HEK293 cells (ATCC #CRL-1573) were cultured. To generate stably transfected cell lines, HEK293 cells were transfected with the pIRESneo2 expression plasmid (described above) containing the TAAR coding sequence and Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions, and 24 hours after transfection, the culture medium was supplemented with 1 mg/ml G418 (Sigma, Buchs, Switzerland). After a culture period of approximately 10 days, clones were isolated, amplified, and assayed for reactivity to trace amines (all compounds purchased from Sigma) using the cAMP Biotrak enzyme immunoassay (EIA) system (Amersham) according to the non-acetylated EIA procedure provided by the manufacturer. Monoclonal cell lines that demonstrated stable EC _50s for 15 passages were used for all subsequent studies.

Radioligand binding assay targeting rat TAAR1

Membrane preparation and radioligand binding

HEK-293 cells stably expressing rat TAAR1 were maintained in DMEM high glucose medium containing fetal bovine serum (10%, heat-inactivated at 56°C for 30 min), penicillin/streptomycin (1%), and 375 μg/ml geneticin (Gibco) at 37°C and 5% _CO2 . Cells were released from the culture flask using trypsin/EDTA, harvested, washed twice with ice-cold PBS (without ^{Ca2 +} and Mg2 ⁺ ), pelleted at 1'000 rpm at 4°C for 5 min, frozen, and stored at -80°C. The frozen pellet was suspended in 20 ml of HEPES-NaOH (20 mM, pH 7.4) containing 10 mM EDTA and homogenized at 14'000 rpm for 20 s using a Polytron (PT 6000, Kinematica). The homogenate was centrifuged at 48'000 x g for 30 min at 4°C. Afterwards, the supernatant was removed and discarded, and the pellet was resuspended in 20 ml of HEPES-NaOH (20 mM, pH 7.4) containing 0.1 mM EDTA using a Polytron (14,000 rpm for 20 s). This procedure was repeated, and the final pellet was resuspended in HEPES-NaOH containing 0.1 mM EDTA and homogenized using a Polytron. Typically, 2 ml aliquots of the membrane fraction were stored at -80°C. For each new membrane batch, the dissociation constant ( _Kd ) was determined using a saturation curve. The TAAR1 radioligand ³ [H] -(S) -4- [(ethyl-phenyl-amino) -methyl] -4,5-dihydro-oxazol-2-ylamine (described in WO 2008/098857) was used at a concentration equivalent to the calculated _K value, which was typically approximately 2.3 nM, resulting in approximately 0.2% binding of the radioligand and specific binding accounting for approximately 85% of total binding. Nonspecific binding was defined as the amount of ³ [H] -(S) -4- [(ethyl-phenyl-amino) -methyl] -4,5-dihydro-oxazol-2-ylamine bound in the presence of 10 μM unlabeled ligand. All compounds were tested in duplicate over a wide concentration range (10 pM to 10 μM). The test compound (20 μl/well) was transferred to a 96-deep-well plate (TreffLab), and 180 μl of HEPES-NaOH (20 mM, pH 7.4) containing _MgCl₂ (10 mM) and _CaCl₂ (2 mM) (binding buffer), 300 μl of the radioligand ³ [H]-(S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine at a concentration of 3.3 x _Kd in nM, and 500 μl of membranes (resuspended at 50 μg protein/ml) were added. The 96-deep-well plate was incubated at 4°C for 1 hour. The incubation was terminated by rapid filtration through a Unifilter-96 plate (Packard Instrument Company) presoaked in polyethyleneimine (0.3%) for 1 hour and washed three times with 1 ml of cold binding buffer and a glass filter GF/C (Perkin Elmer). After adding 45 μl of Microscint 40 (PerkinElmer), the Unifilter-96 plate was sealed and the radioactivity was counted after 1 hr using a TopCount microplate scintillation counter (Packard Instrument Company).

Radioligand binding assay targeting mouse TAAR1

Membrane preparation and radioligand binding

HEK-293 cells stably expressing mouse TAAR1 were maintained in DMEM high glucose medium containing fetal bovine serum (10%, heat-inactivated at 56°C for 30 min), penicillin/streptomycin (1%), and 375 μg/ml geneticin (Gibco) at 37°C and 5% _CO2 . Cells were released from the culture flask using trypsin/EDTA, harvested, washed twice with ice-cold PBS (without Ca2 ⁺ and Mg2 ⁺ ), pelleted at 1'000 rpm at 4°C for 5 min, frozen, and stored at -80°C. The frozen pellet was suspended in 20 ml of HEPES-NaOH (20 mM, pH 7.4) containing 10 mM EDTA and homogenized at 14'000 rpm for 20 s using a Polytron (PT 6000, Kinematica). The homogenate was centrifuged at 48'000 x g for 30 min at 4°C. Afterwards, the supernatant was removed and discarded, and the pellet was resuspended in 20 ml of HEPES-NaOH (20 mM, pH 7.4) containing 0.1 mM EDTA using a Polytron (14,000 rpm for 20 s). This procedure was repeated, and the final pellet was resuspended in HEPES-NaOH containing 0.1 mM EDTA and homogenized using a Polytron. Typically, 2 ml aliquots of the membrane fraction were stored at -80°C. For each new membrane batch, the dissociation constant ( _Kd ) was determined using a saturation curve. The TAAR1 radioligand ³ [H] -(S) -4- [(ethyl-phenyl-amino) -methyl] -4,5-dihydro-oxazol-2-ylamine (described in WO 2008/098857) was used at a concentration equivalent to the calculated _K value, which was typically approximately 0.7 nM, resulting in approximately 0.5% binding of the radioligand and specific binding accounting for approximately 70% of total binding. Nonspecific binding was defined as the amount of ³ [H] -(S) -4- [(ethyl-phenyl-amino) -methyl] -4,5-dihydro-oxazol-2-ylamine bound in the presence of 10 μM unlabeled ligand. All compounds were tested in duplicate over a wide concentration range (10 pM to 10 μM). The test compound (20 μl/well) was transferred to a 96-deep-well plate (TreffLab), and 180 μl of HEPES-NaOH (20 mM, pH 7.4) containing _MgCl₂ (10 mM) and _CaCl₂ (2 mM) (binding buffer), 300 μl of the radioligand ³ [H]-(S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine at a concentration of 3.3 x _Kd in nM, and 500 μl of membranes (resuspended at 60 μg protein/ml) were added. The 96-deep-well plate was incubated at 4°C for 1 hour. The incubation was terminated by rapid filtration through a Unifilter-96 plate (Packard Instrument Company) presoaked in polyethyleneimine (0.3%) for 1 hour and washed three times with 1 ml of cold binding buffer and a glass filter GF/C (Perkin Elmer). After adding 45 μl of Microscint 40 (PerkinElmer), the Unifilter-96 plate was sealed and the radioactivity was counted after 1 hr using a TopCount microplate scintillation counter (Packard Instrument Company).

The compounds showed _K values (μM) against TAAR1 (in μM) in mice or rats as shown in the table below.

The compounds of formula I and pharmaceutically acceptable salts of the compounds of formula I can be used as pharmaceuticals, 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 gelatin capsules, solutions, emulsions or suspensions. However, administration can also be rectally administered, for example in the form of suppositories, or parenterally, for example in the form of injections.

The compound of formula I can be processed with pharmaceutically inert inorganic or organic carriers for the preparation of pharmaceutical preparations. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts etc. can be used as those carriers for tablets, coated tablets, lozenges and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc. However, depending on the nature of the active substance, carriers are usually not required in the case of soft gelatin capsules. Suitable carriers for preparing solutions and syrups are, for example, water, polyols, glycerol, vegetable oils etc. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.

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

Medicaments containing compounds of the formula I or pharmaceutically acceptable salts thereof and therapeutically inert carriers are also an object of the present invention, as are processes for their preparation, which comprise bringing one or more compounds of the formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more further therapeutically valuable substances into a galenic administration form together with one or more therapeutically inert carriers.

The most preferred indications according to the present invention are those involving disorders of the central nervous system, such as the treatment or prevention of 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 specific case to suit individual needs. In the case of oral administration, the dosage for adults can vary in the following range: about 0.01 mg to about 1000 mg per day of a compound of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage can be administered as a single dose or in divided doses, and in addition, the upper limit may also be exceeded when it is deemed necessary.

Tablet preparation (wet granulation)

Preparation procedure

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

2. Dry the granules at 50°C.

3. Pass the granules through suitable grinding equipment.

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

Capsule preparations

Preparation procedure

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

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

3. Fill into suitable capsules.

Claims (13)

1. A compound of the formula in X is CR; R is hydrogen, halogen or C _1-7 alkyl; L is a bond, -C(O)-, or -NHC(O)-; Ar is a phenyl group or a five- or six-membered heteroaryl group containing one or two nitrogen atoms; ^R1 is halogen, _C1-7 alkyl, _C1-7 alkyl substituted by halogen, _C1-7 alkoxy, _C1-7 alkoxy substituted by halogen, or cycloalkyl; n is 0, 1, 2, or 3; or a pharmaceutically acceptable acid addition salt thereof. 2. The compound of formula I according to claim 1, wherein "L" is a bond and the other substituents are as described in claim 1. 3. The compound of formula I according to claim 2, wherein the compound is (RS)-N-(4-Chlorophenyl)-6-morpholin-2-yl-pyridin-3-amine (RS)-N-(4-Bromophenyl)-6-morpholin-2-yl-pyridin-3-amine (RS)-N-(4-ethoxyphenyl)-6-morpholin-2-yl-pyridin-3-amine (RS)-N-(3-Chlorophenyl)-6-morpholin-2-yl-pyridin-3-amine (RS)-N-(4-Fluorophenyl)-6-morpholin-2-yl-pyridin-3-amine (RS)-6-Morpholin-2-yl-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine (RS)-N-(6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyrimidin-4-amine N-(4-Chlorophenyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine 6-[(2S)-Morpholin-2-yl]-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine N-(5-chloro-2-pyridinyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine N-(5-Bromo-2-pyridinyl)-6-[(2S)-morpholin-2-yl]pyridin-3-amine 6-[(2S)-Morpholin-2-yl]-N-[6-(trifluoromethyl)-3-pyridinyl]pyridin-3-amine 6-[(2S)-Morpholin-2-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine N-(4-Chlorophenyl)-6-[(2R)-morpholin-2-yl]pyridin-3-amine 6-[(2R)-Morpholin-2-yl]-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine N-(5-chloro-2-pyridinyl)-6-[(2R)-morpholin-2-yl]pyridin-3-amine 6-[(2R)-morpholin-2-yl]-N-[6-(trifluoromethyl)-3-pyridinyl]pyridin-3-amine 6-[(2R)-morpholin-2-yl]-N-[4-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-5-(trifluoromethyl)pyridin-2-amine N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-6-(trifluoromethyl)pyridin-2-amine N-(5-Bromo-2-pyridinyl)-6-[(2R)-morpholin-2-yl]pyridin-3-amine N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-5-(trifluoromethyl)pyridin-2-amine N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-6-(trifluoromethyl)pyridin-2-amine (RS)-5-Chloro-N-(5-chloro-2-pyridinyl)-6-morpholin-2-yl-pyridin-3-amine (RS)-5-Chloro-6-morpholin-2-yl-N-[5-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine (RS)-5-Methyl-6-morpholin-2-yl-N-[5-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine (RS)-N-(5-chloro-2-pyridinyl)-5-fluoro-6-morpholin-2-yl-pyridin-3-amine, or (RS)-5-Fluoro-6-morpholin-2-yl-N-[5-(trifluoromethyl)-2-pyridinyl]pyridin-3-amine. 4. The compound of formula I according to claim 1, wherein "L" is -C(O)- and the other substituents are as described in claim 1. 5. The compound of formula I according to claim 4, wherein the compound is (RS)-4-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)benzamide (RS)-3-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)benzamide (RS)-4-Ethoxy-N-(6-morpholin-2-yl-3-pyridyl)benzamide (RS)-4-Fluoro-N-(6-morpholin-2-yl-3-pyridinyl)benzamide (RS)-4-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide (RS)-N-(6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide 4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]benzamide 3-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]benzamide N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-4-(trifluoromethyl)benzamide N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-2-(trifluoromethyl)pyridine-4-carboxamide N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)benzamide N-[6-[(2S)-Morpholin-2-yl]-3-pyridinyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 2-Ethyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]pyrimidine-5-carboxamide 3-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide 4-Chloro-3-cyclopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide 4-Chloro-3-methyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Methyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Chloro-1-methyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-5-propyl-pyrazole-3-carboxamide 4-Chloro-1-methyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-5-propyl-pyrazole-3-carboxamide 4-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]benzamide 3-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]benzamide N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-4-(trifluoromethyl)benzamide N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-2-(trifluoromethyl)pyridine-4-carboxamide N-[6-[(2R)-Morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)benzamide N-[6-[(2R)-Morpholin-2-yl]-3-pyridinyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide 2-Ethyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]pyrimidine-5-carboxamide 3-Isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide 4-Chloro-3-cyclopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Chloro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide 4-Chloro-3-methyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Methyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide (R)-3-Ethyl-4-methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-1H-pyrazole-5-carboxamide (S)-3-Ethyl-4-methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-1H-pyrazole-5-carboxamide (R)-6-Methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-2-(trifluoromethyl)pyrimidine-4-carboxamide (S)-6-Methyl-N-(6-(morpholin-2-yl)pyridin-3-yl)-2-(trifluoromethyl)pyrimidine-4-carboxamide (RS)-4-Chloro-3-ethoxy-N-(6-morpholin-2-yl-3-pyridinyl)-1H-pyrazole-5-carboxamide (RS)-4-Chloro-N-(6-morpholin-2-yl-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide 4-Chloro-3-ethyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 3-Ethyl-4-fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Bromo-3-ethyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide 3-Cyclopropyl-4-fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Bromo-3-cyclopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Chloro-3-ethyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 3-Ethyl-4-fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Bromo-3-ethyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-propyl-1H-pyrazole-5-carboxamide 3-Cyclopropyl-4-fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Bromo-3-cyclopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 3-Isobutyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Fluoro-3-isobutyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 3-Butyl-4-fluoro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 3-Butyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 5-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxamide 2-Isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide 3-Isobutyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Fluoro-3-isobutyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 3-Butyl-4-fluoro-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 3-Butyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 5-Isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-2-(2,2,2-trifluoroethyl)pyrazole-3-carboxamide 2-Isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide 4-Chloro-3-ethoxy-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Chloro-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxamide 4-Chloro-3-ethoxy-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide (RS)-N-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide (RS)-4-Chloro-N-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide (RS)-N-(5-Fluoro-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide (RS)-4-Chloro-N-(5-fluoro-6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide 4-Chloro-3-isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide 4-Fluoro-3-isopropyl-N-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide (RS)-N-(5-methyl-6-morpholin-2-yl-3-pyridinyl)-2-(trifluoromethyl)pyridine-4-carboxamide (RS)-4-Chloro-N-(5-methyl-6-morpholin-2-yl-3-pyridinyl)-3-propyl-1H-pyrazole-5-carboxamide 4-chloro-3-isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide, or 4-Fluoro-3-isopropyl-N-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-1H-pyrazole-5-carboxamide. 6. The compound of formula I according to claim 1, wherein "L" is -NHC(O)-. 7. The compound of formula I according to claim 6, wherein the compound is (RS)-1-(3-chlorophenyl)-3-(6-morpholin-2-yl-3-pyridyl)urea (RS)-1-(4-Fluorophenyl)-3-(6-morpholin-2-yl-3-pyridyl)urea (RS)-1-(6-morpholin-2-yl-3-pyridinyl)-3-[4-(trifluoromethyl)phenyl]urea (RS)-1-(4-chlorophenyl)-3-(6-morpholin-2-yl-3-pyridyl)urea 1-(3-chlorophenyl)-3-[6-[(2S)-morpholin-2-yl]-3-pyridyl]urea 1-[6-[(2S)-morpholin-2-yl]-3-pyridinyl]-3-[3-(trifluoromethyl)phenyl]urea 1-(3-chlorophenyl)-3-[6-[(2R)-morpholin-2-yl]-3-pyridyl]urea 1-[6-[(2R)-morpholin-2-yl]-3-pyridinyl]-3-[3-(trifluoromethyl)phenyl]urea (RS)-1-(5-chloro-6-morpholin-2-yl-3-pyridinyl)-3-(3-chlorophenyl)urea (RS)-1-(3-chlorophenyl)-3-(5-fluoro-6-morpholin-2-yl-3-pyridyl)urea, or (RS)-1-(3-chlorophenyl)-3-(5-methyl-6-morpholin-2-yl-3-pyridinyl)urea. 8. A method for preparing a compound of formula I as defined in any one of claims 1 to 7, comprising a) the compound of formula 14 Reaction with the compound of formula 15-a Obtain a compound of formula 16-a Then deprotection of the Boc-group yields a compound of formula I wherein L is -C(O)- and the other substituents are as described in claim 1, or b) the compound of formula 14 Reaction with the compound of formula 15-b Obtain a compound of formula 16-b Then deprotect the Boc-group to obtain a compound of formula I wherein L is -NHC(O)- and the other substituents are as described in claim 1, or c) the compound of formula 8, 9 or 10 8, 9, or 10 Reaction with the compound of formula 11 Obtaining a compound of formula 12 Then deprotect the Boc-group to obtain a compound of formula I wherein L is a bond and the other substituents are as described in claim 1, or If necessary, the obtained compound is converted into a pharmaceutically acceptable acid addition salt. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier and/or adjuvant. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier and/or adjuvant for the treatment of depression, anxiety, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, schizophrenia, neurological disorders, Parkinson's disease, neurodegenerative diseases, Alzheimer's disease, epilepsy, migraine, hypertension, psychotic drug abuse, metabolic diseases, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy expenditure and assimilation disorders, body temperature homeostasis disorders and dysfunctions, sleep and circadian rhythm disorders, and cardiovascular diseases. 11. Compounds according to any one of claims 1 to 7 for use as therapeutically active substances. 12. A compound according to any one of claims 1 to 7 for use as a therapeutically active substance in the treatment of depression, anxiety, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, schizophrenia, neurological disorders, Parkinson's disease, neurodegenerative diseases, Alzheimer's disease, epilepsy, migraine, hypertension, psychotropic substance abuse, metabolic diseases, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy expenditure and assimilation disorders, body temperature homeostasis disorders and dysfunctions, sleep and circadian rhythm disorders, and cardiovascular diseases. 13. The use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of depression, anxiety, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders, schizophrenia, neurological disorders, Parkinson's disease, neurodegenerative diseases, Alzheimer's disease, epilepsy, migraine, hypertension, psychotic drug abuse, metabolic diseases, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy expenditure and assimilation disorders, body temperature homeostasis disorders and dysfunction, sleep and circadian rhythm disorders, and cardiovascular disease.