RU2804638C2 - Pyridinaminpyridones and pyrimidinaminpyridones - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl or a monocyclic 5–6 membered heteroaryl selected from the group consisting of imidazole, pyrazole, thiazole, oxazole and pyrimidine, each optionally substituted with C₁-C₆ alkyl; R² represents a hydrogen atom; R³ is selected from the group consisting of A, phenyl and a monocyclic heteroaryl selected from pyrazole or pyridine, each of said phenyl and heteroaryl rings optionally substituted with one or two R⁴, R⁵, R⁶ and R⁷; R⁴, R⁵, R⁶ and R⁷ are independently selected from halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl and C₁-C₆ haloalkoxy; R⁹ is C₁-C₆ alkyl, with each C₁-C₆ alkyl optionally substituted with one R¹⁰; R¹⁰ is phenyl, the said phenyl optionally substituted with one R¹¹; R¹¹ is halogen; A represents

R¹² represents a hydrogen atom or C₁-C₃haloalkyl; Y is selected from the group consisting of CH₂, NSO₂R⁹ and O; and Z is CH or N. The invention also relates to a pharmaceutical composition for inhibiting Vps34 based on these compounds.

EFFECT: obtaining new compounds and a pharmaceutical composition based on them which can be used in medicine as effective agents for the treatment of prostate cancer.

28 cl, 2 tbl, 69 ex

Description

FIELD OF THE INVENTION

The invention provides new pyridinamine-pyridone and pyrimidinamine-pyridone compounds of formula (I), pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of diseases, including cancer and type II diabetes.

BACKGROUND ART

Enzymes belonging to the phosphatidylinositide 3-kinase (PI3K) family are regulators of several important cellular events. This family consists of three classes, I, II and III, and while the group belonging to class I has been an interesting drug target for many years, class II and III enzymes have been less exploited. Class III PI3K, vacuolar sorting protein 34 (Vps34, PIK3C3), forms a heterodimer with its regulatory subunit p150 (Vps15), and this dimer is involved in several complexes that regulate events associated with vesicular transport, such as autophagy, endocytosis, exocytosis, and micropinocytosis (Amaravadi et al., Clin. Cancer Res., 2011, 17: 654-666; Carpentier et al., 2013, Traffic). This enzyme is responsible for the phosphorylation of phosphatidylinositol (PI) to form phosphatidylinositol (3)-phosphate (PI3P). Binding of this ligand to the PX and FYVE domains leads to the recruitment and delocalization of these effector proteins, resulting in the formation, elongation and movement of vesicles (Backer et al., J. Biochem., 2008, 410: 1-17).

Autophagy is a catabolic process in which cellular components undergo destruction by encapsulation in bilayer membrane vesicles, autophagosomes, which fuse with protease-containing lysosomes. This is a way for the cell to process damaged organelles and misfolded proteins and thereby maintain the functioning of the cell. This pathway is also a way to recycle cell contents to form new structural units (Boya et al., Nat. Cell Biol., 2013, 15: 713-720). Autophagy is a cellular response to stress-related conditions such as nutrient deprivation, acidosis and hypoxia, as well as drug treatment. In view of this, inhibition of autophagy is a means of enhancing the effects of anticancer drugs and desensitizing drug-resistant tumors (Nagelkerke et al., Semin. Cancer Biol., 2014, 31: 99-105). Tumors in the most advanced stages of development show strong activation of the autophagic flux (Leone et al. Trends in Endocrin. Metab., 2013, 24: 209-217). A common marker for studying autophagic flux is the detection of an “autophagic spot” in the autophagosome in the form of lipidated protein LC3 (light chain of microtubule-associated protein 1 (MAP1)). Inhibition of Vps34 results in inhibition of autophagy as measured by LC3 redistribution in the blot (Dowdle et al., Nat. Cell Biol., 2014, 16: 1069-79).

As recently described, deletion of the p150 regulatory subunit results in increased insulin sensitivity in vivo due to decreased internalization of insulin receptors (Nemazanyy, Nature Commun., 2015, 6: 8283). In an animal model with a heterozygous genotype for the kinase dead mutation, this result was confirmed by increased glucose tolerance and increased insulin sensitivity (WO2013076501).

Inhibition of Vps34 could be beneficial in a variety of disease states, including cancer, inflammatory diseases, autoimmune diseases, neurodegenerative disorders, cardiovascular disorders, type II diabetes, and viral infections (reviewed in Rubinsztein et al., Nat. Rev., 2012, 11 : 709-730). Cancers that would benefit from Vps34 inhibition include, but are not limited to, breast cancer such as triple negative breast cancer, bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer , colon cancer, glioma, prostate cancer, ovarian cancer, melanoma and lung cancer, as well as hypoxic tumors. Thus, there is a need for new and potent Vps34 inhibitors.

Previous inventions describing Vps34 inhibitors for use in treating diseases include WO2015150555, WO2015150557, WO2015108861, WO2015108881, WO2012085815, WO2012085244, WO2013190510, Farkas, J. Biol. Chem., 2011, 286(45): 38904-12.

DESCRIPTION OF THE INVENTION

The purpose of this invention is to develop new and potent Vps34 inhibitors. Another aim of the invention is to develop new and potent Vps34 inhibitors that can be used to treat cancer and other diseases such as type II diabetes. According to aspect 1 of the invention there is provided a compound of formula (I),

Where

R ¹ represents phenyl or monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino and N,N-diC ₁ -C ₃ alkylamino;

R ² is selected from hydrogen, C ₁ -C ₃ haloalkyl and C ₁ -C ₃ alkyl;

R ³ is selected from A, phenyl and monocyclic heteroaryl, with each said phenyl and said heteroaryl optionally substituted by one or more of R ⁴ , R ⁵ , R ⁶ and R ⁷ ;

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy , azetidine, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, NHSO ₂ R ⁸ , SO ₂ R ⁹ and hydroxy;

R ⁸ represents C ₁ -C ₃ haloalkyl or C ₁ -C ₃ alkyl;

R ⁹ is selected from R ¹⁰ , C ₁ -C ₆ alkyl, amino, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, wherein each said C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is optionally substituted with one R ¹⁰ and/or one or more halogen atoms;

R ¹⁰ is selected from phenyl, benzyl, monocyclic heteroaryl, C ₃ -C ₆ cycloalkyl, heterocyclyl, each of which is optionally substituted with one or more R ¹¹ ;

R ¹¹ is selected from halogen, C ₁ -C ₃ haloalkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₃ alkyl, amino, NC ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino and C ₁ - C ₃ alkoxyC ₁ -C ₃ alkyl;

A represents

R ¹² is selected from hydrogen atom, halogen, COR ¹³ , C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C 1 -C ₃ alkoxy, C ₁ -C ₃ alkyl, C _{1 -C 6} alkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₃ cyanoalkyl and C ₁ -C ₃ haloalkyl;

R ¹³ is selected from C ₁ -C ₃ alkoxy, N-C ₁ -C ₃ alkylamino, N,N-diC ₁ -C ₃ alkylamino, 1-pyrrolidinyl, 1-piperidinyl and 1-azetidinyl;

Y is selected from CH ₂ , S, SO, SO ₂ , NR ¹⁴ , NCOR ⁹ , NCOOR ¹⁵ , NSO ₂ R ⁹ , NCOCH ₂ R ⁹ , O or bonds;

R ¹⁴ is selected from H, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl and C ₃ -C ₆ cycloalkyl; And

R ¹⁵ is selected from R ¹⁰ , C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, and each said C ₁ -C ₆ alkyl and C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl is optional substituted with one R ¹⁰ and/or one or more halogen atoms; And

Z represents CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 2 of the invention there is provided a compound of formula (I), for example corresponding to aspect 1, where R ² represents a hydrogen atom or C ₁ -C ₃ alkyl.

According to aspect 3 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1 or 2, where R ² represents a hydrogen atom.

According to aspect 4 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-3, where R ¹ represents phenyl or a monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino, N,N- di-C ₁ -C ₃ alkylamino and halogen.

According to aspect 5 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-4, where R ¹ represents phenyl or a monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl and halogen.

According to aspect 6 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-5, where R ³ is selected from

According to aspect 7 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-6, where R ³ is selected from

According to aspect 8 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-5, where R ³ is selected from

Y is selected from CH ₂ , NSO ₂ R ⁹ , O and bond;

R ⁴ is selected from CF ₃ , fluorine, cyclopropyl and methyl;

R ⁵ represents a fluorine atom;

R ⁹ is selected from C ₁ -C ₆ alkyl, phenyl and benzyl, each of which is optionally substituted with one or more halogen atoms; And

R ¹² is selected from hydrogen, methyl, cyclopropyl and CF ₃ . According to aspect 9 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-7, wherein R ³ is selected from

Y is selected from NSO ₂ R ⁹ , CH ₂ and O;

R ⁴ is selected from cyclopropyl, CF ₃ and a chlorine atom;

R ⁵ represents a fluorine atom;

R ⁹ is selected from C ₁ -C ₆ alkyl, phenyl and benzyl, each of which is optionally substituted with one or more halogen atoms; and R ¹² is cyclopropyl or CF ₃ .

According to aspect 10 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-7, where R ³ represents

R ⁹ is selected from C ₁ -C ₆ alkyl, phenyl and benzyl, wherein said phenyl and benzyl group may optionally be substituted by one or more halogen atoms, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -With ₄ cycloalkyl; And

R ¹² is selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl.

According to aspect 11 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-10, where R ¹ is selected from phenyl, pyrimidinyl, oxazolyl, imidazolyl, pyrazolyl and thiazolyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl and C ₁ -C ₆ haloalkyl.

According to aspect 12 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-11, where R ¹ is selected from phenyl, pyrimidinyl, oxazolyl, imidazolyl and thiazolyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl and C ₁ -C ₆ haloalkyl.

According to aspect 13 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-5, where R ³ is selected from A, phenyl, pyridyl, thienyl, furyl, pyrimidinyl and pyrazolyl, each of which is optionally and independently substituted by one or more R ⁴ or R ⁵ .

According to aspect 14 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-8, wherein R ³ is selected from A, phenyl and pyridyl, each of which is optionally and independently substituted with one or more R ⁴ or R ⁵ .

According to aspect 15 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-8, where R ³ is selected from phenyl, pyridyl, morpholinyl, piperidyl, pyrrolidinyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents, selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl.

According to aspect 16 of the invention, there is provided a compound of formula (I), for example corresponding to one of aspects 1-7, wherein R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from fluorine atom, chlorine atom, C ₁ -C ₃ alkyl, C ₁ -C ₃ fluoroalkyl, cyclopropyl and SO ₂ R ⁹ .

According to aspect 17 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-8, aspect 13, aspect 14 or aspect 16, where Y is selected from CH ₂ , O and a bond.

Aspect 18 of the invention provides a compound of formula (I), for example corresponding to one of aspects 1 to 7 or aspect 13, wherein R ¹² is selected from hydrogen, CON(CH ₃ ) ₂ , C ₁ -C ₃ alkyl, CF ₃ and cyclopropyl .

According to aspect 19 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-7, aspect 13, aspect 14 or aspect 16, where R ⁹ is selected from R ¹⁰ , N,N-diC ₁ -C ₃ alkylamino and methoxyC ₁ -C ₃ alkyl, wherein said C ₁ -C ₃ alkyl is possibly substituted by one R ¹⁰ .

According to aspect 20 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-7, aspect 13, aspect 14, aspect 16 or aspect 19, where R ¹⁰ is selected from phenyl, benzyl, pyridyl, imidazolyl, isoxazolyl, oxazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl and tetrahydrofuryl, each of which is optionally substituted with one or more methyl and/or fluorine atoms.

According to aspect 21 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-5, where R ³ is selected from phenyl, pyridyl, pyrrolidinyl and thienyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl; or A;

Y represents CH ₂ , O, NSO ₂ C ₁ -C ₆ alkyl or NSO ₂ benzyl, said benzyl optionally being substituted by one or more halogen atoms; And

R ¹² represents C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

According to aspect 22 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1 to 3, where R ¹ represents phenyl or a monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, amino, N-C ₁ -C ₃ alkylamino, N,N- di-C ₁ -C ₃ alkylamino and halogen;

R ² represents a hydrogen atom;

R ³ represents phenyl or monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl.

According to aspect 23 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1 to 7, where R ¹ represents phenyl or a monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl;

R ² represents a hydrogen atom; And

R ³ represents phenyl or monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl.

According to aspect 24 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-5, wherein R ¹ is selected from phenyl, pyrimidinyl, oxazolyl, imidazolyl or thiazolyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl;

R ² represents a hydrogen atom;

R ³ is selected from phenyl, pyridyl, pyrazolyl, pyrrolidinyl and thienyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₄ cycloalkyl; or A;

Y represents CH ₂ , O, NSO ₂ C ₁ -C ₆ alkyl or NSO ₂ benzyl, said benzyl optionally being substituted by one or more halogen atoms; And

R ¹² represents C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

According to aspect 25 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-7, where R ¹ is selected from phenyl, 4-pyrimidinyl, 2-methylpyrimidin-4-yl, 2-cyclopropyl-pyrimidin-4-yl, 2-oxazolyl, 1-methyl-imidazol-4-yl, 2-methyl-thiazol-4-yl, 3,5-difluorophenyl and

2-methylpyrazol-3-yl;

R ² represents a hydrogen atom; And

R ³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 4-morpholinyl, 3-(trifluoromethyl)morpholin-4-yl, 2-(trifluoromethyl)-piperidin-1-yl, 2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl, 2-(trifluoromethyl)-pyridin-3-yl, 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl, 3-cyclopropyl-morpholin-4-yl, 4-[ (4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl, 2-(trifluoromethyl)-pyrrolidin-1-yl, 2-chloro- 5-fluorophenyl, 3-(trifluoromethyl)-pyrazolin-4-yl, 2-(trifluoromethyl)-pyridin-3-yl, 3-methyl-thien-4-yl, 2-methylphenyl, 1-acetyl-3-trifluoromethyl- piperazin-4-yl, 2-methyl-piperidin-1-yl, 2-cyclopropyl-piperidin-1-yl, 2-methyl-morpholin-4-yl, 2-trifluoromethyl-morpholin-4-yl and 2-cyclopropyl- morpholin-4-yl.

According to aspect 26 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-7, where R ¹ is selected from phenyl, 4-pyrimidinyl, 2-methylpyrimidin-4-yl, 2-cyclopropyl-pyrimidin-4-yl, 2-oxazolyl, 1-methyl-imidazol-4-yl, 2-methyl-thiazol-4-yl and 3,5-difluorophenyl;

R ² represents a hydrogen atom; And

R ³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 4-morpholinyl, 3-(trifluoromethyl)morpholin-4-yl, 2-(trifluoromethyl)-piperidin-1-yl, 2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl, 2-(trifluoromethyl)-pyridin-3-yl, 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl, 3-cyclopropyl-morpholin-4-yl, 4-[ (4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl, 2-(trifluoromethyl)-pyrrolidin-1-yl, 2-chloro- 5-fluorophenyl, 3-(trifluoromethyl)-pyrazolin-4-yl, 2-(trifluoromethyl)-pyridin-3-yl, 3-methyl-thien-4-yl, 2-methylphenyl, 1-acetyl-3-trifluoromethyl- piperazin-4-yl, 2-methyl-piperidin-1-yl, 2-cyclopropyl-piperidin-1-yl, 2-methyl-morpholin-4-yl, 2-trifluoromethyl-morpholin-4-yl and 2-cyclopropyl- morpholin-4-yl.

According to aspect 27 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1 to 7, where R ¹ represents phenyl or a monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl;

R ² represents a hydrogen atom;

R ³ represents phenyl or monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl; And

Z represents CH or N;

or a pharmaceutically acceptable salt thereof.

Aspect 28 of the invention provides a compound of formula (I), for example corresponding to one of aspects 1 to 7, wherein R ¹ is phenyl or pyrimidinyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl , C ₁ -C ₆ haloalkyl or C ₃ -C ₄ cycloalkyl;

R ² represents a hydrogen atom;

R ³ is selected from phenyl, pyridyl and pyrazolyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl; or A;

Y is CH ₂ , O, NSO ₂ -C ₁ -C ₆ alkyl or NSO ₂ -benzyl, said benzyl being optionally substituted with one or more halogen atoms;

R ¹² represents C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; And

Z represents CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 29 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-7, where R ¹ represents phenyl, 3,5-difluorophenyl or 2-methylpyrimidin-4-yl;

R ² represents a hydrogen atom;

R ³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl ]-2-(trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl, 2-(trifluoromethyl)phenyl, 4-methyl-3-pyridyl, 2-(trifluoromethyl)-3 -pyridyl, 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl and 3-cyclopropylmorpholin-4-yl; And

Z represents CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 30 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1 to 7, where R ¹ represents phenyl or a monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl;

R ² represents a hydrogen atom;

R ³ represents phenyl or monocyclic 5-6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl; And

Z represents CH or N;

or a pharmaceutically acceptable salt thereof.

Aspect 31 of the invention provides a compound of formula (I), for example corresponding to one of aspects 1 to 7, wherein R ¹ is phenyl or pyrimidinyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl , C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl;

R ² represents a hydrogen atom;

R ³ is selected from phenyl or pyridyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₃ -C ₄ cycloalkyl; or A;

Y is CH ₂ , O, NSO ₂ -C ₁ -C ₆ alkyl or NSO ₂ -benzyl, said benzyl being optionally substituted with one or more halogen atoms;

R ¹² represents C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; And

Z represents CH or N;

or a pharmaceutically acceptable salt thereof.

Aspect 32 of the invention provides a compound of formula (I), for example corresponding to one of aspects 1 to 7, wherein R ¹ is phenyl, 2-methylpyrimidin-4-yl, oxazol-2-yl, 2-methylthiazol-4-yl, 2-methylpyrazol-3-yl and 1-methylimidazol-4-yl;

R ² represents a hydrogen atom;

R ³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl ]-2-(trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl, 2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl, 2-(trifluoromethyl) -pyridin-3-yl and 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl; And

Z represents CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 33 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-7, wherein R ¹ represents phenyl or 2-methylpyrimidin-4-yl;

R ² represents a hydrogen atom;

R ³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl ]-2-(trifluoromethyl)piperazin-1-yl and 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl; And

Z represents CH or N;

or a pharmaceutically acceptable salt thereof.

According to aspect 34 of the invention there is provided a compound selected from:

4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;

6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H -pyridin-2-one;

6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methyl-pyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2- she;

4-[2-(oxazol-2-ylamino)-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;

4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;

4-[2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;

4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;

6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one;

6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;

4-[2-[(1-methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one and

6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one,

or a pharmaceutically acceptable salt thereof.

According to aspect 35 of the invention, a compound selected from:

4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;

6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H -pyridin-2-one;

6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methyl-pyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2- she;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;

6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one;

6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;

6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one and

6-(3-cyclopropylmorpholin-4-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one,

or a pharmaceutically acceptable salt thereof.

According to aspect 36 of the invention, a compound selected from:

4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;

4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one;

6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H -pyridin-2-one;

6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methyl-pyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2- she;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;

6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one;

4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one;

6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one and

6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one,

or a pharmaceutically acceptable salt thereof.

According to aspect 37 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-5, wherein R ³ is selected from

According to aspect 38 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-5, wherein R ⁴ is selected from chlorine, CF ₃ and methyl; R ⁵ represents C ₁ -C ₃ alkyl such as ethyl; and R ¹² represents a hydrogen atom or CF ₃ .

According to aspect 39 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-5, where Y is selected from CH ₂ , O and NSO ₂ R ⁹ .

According to aspect 40 of the invention there is provided a compound of formula (I), for example corresponding to one of aspects 1-5, wherein R ⁹ is selected from C ₁ -C ₃ alkyl and benzyl, wherein said benzyl is substituted in the meta position with a fluorine atom.

According to one aspect of the invention, a compound of the present invention is provided for use in the treatment or prevention of a disease.

According to one aspect of the invention, a compound of the present invention is provided for use in the treatment of cancer. Typically, said cancer is selected from breast cancer, such as triple negative breast cancer, bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer, glioma, prostate cancer, cancer ovarian, melanoma and lung cancer, as well as hypoxic tumors.

According to one aspect of the invention, a compound of the present invention is provided for use in the treatment of hypoxic tumors.

According to one aspect of the invention, a compound of the present invention is provided for use in the treatment of type II diabetes.

According to one aspect of the invention, a compound of the present invention is provided for use in the treatment of a disease selected from inflammatory diseases, neurodegenerative disorders, cardiovascular disorders, autoimmune diseases and viral infections.

According to one aspect of the invention, there is provided the use of a compound of the present invention for the preparation of a medicament for the treatment of cancer. Typically, said cancer is selected from breast cancer, such as triple negative breast cancer, bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer, glioma, prostate cancer, cancer ovarian, melanoma and lung cancer, as well as hypoxic tumors.

According to one aspect of the invention, a compound of the present invention is provided for the preparation of a medicament for the treatment of hypoxic tumors.

According to one aspect of the invention, there is provided the use of a compound of the present invention for the preparation of a medicament for the treatment of type II diabetes.

According to one aspect of the invention, there is provided the use of a compound of the present invention for the preparation of a medicament for the treatment of a disease selected from inflammatory diseases, neurodegenerative disorders, cardiovascular disorders, autoimmune diseases and viral infections.

According to one aspect of the invention, there is provided a method of treating cancer, comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof. Typically, said cancer is selected from breast cancer, such as triple negative breast cancer, bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer, glioma, prostate cancer, cancer ovarian, melanoma and lung cancer, as well as hypoxic tumors.

According to one aspect of the invention, there is provided a method of treating hypoxic tumors, comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof.

According to one aspect of the invention, a compound of the present invention is provided for use in the treatment of cancer, wherein said cancer treatment further comprises radiation therapy.

According to one aspect of the invention, there is provided a method of treating cancer, comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof, together with radiation therapy.

The compounds of the present invention can also be used for the treatment of cancer in conjunction with radiation therapy and/or surgery. Typically, the use of cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will:

(1) achieving better effectiveness in reducing tumor growth or even eliminating tumors compared with the case of administering each of the agents separately;

(2) ensuring the administration of smaller amounts of chemotherapeutic agents used;

(3) providing chemotherapy treatment that is well tolerated by the patient and has fewer harmful pharmacologic complications than observed with single agent chemotherapy and certain other combination therapies;

(4) providing treatment for a wider range of different types of cancer in mammals, especially in humans;

(5) achieving a higher response rate among treated patients;

(6) providing longer survival times among treated patients compared to standard chemotherapy methods;

(7) ensuring a delay in tumor progression; and/or

(8) obtaining at least the same satisfactory results in terms of efficacy and tolerability as those obtained with the agents used alone as compared to known cases in which other combinations of anticancer agents produce antagonistic effects.

According to one aspect of the invention, there is provided a method of treating type II diabetes, comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof.

According to one aspect of the invention, there is provided a method of treating a disease selected from inflammatory diseases, neurodegenerative disorders, autoimmune diseases and viral infections, comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof.

According to one aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable diluent, carrier and/or excipient.

According to one aspect of the invention, there is provided a pharmaceutical composition containing a therapeutically effective amount of a compound of the present invention and another anticancer agent selected from alkylating agents, antimetabolites, anticancer camptothecin derivatives, anticancer herbal agents, antibiotics, enzymes, platinum coordination complexes, tyrosine kinase inhibitors, hormones , hormone antagonists, monoclonal antibodies, interferons and biological response modifiers.

As used herein, the term “C ₁ -C ₆ alkyl” means saturated hydrocarbon groups, both straight and branched chain, consisting of 1-6 carbon atoms. Examples of C ₁ -C ₆ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 4-methyl-butyl, n-hexyl, 2-ethyl -butyl group. Among straight-chain C ₁ -C ₆ alkyl groups, typical ones are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl groups. Among the branched alkyl groups, mention may be made of isopropyl, isobutyl, sec-butyl, tert-butyl, 4-methylbutyl and 2-ethylbutyl groups.

As used herein, the term “C ₁ -C ₃ alkyl” means saturated hydrocarbon groups, both straight and branched chain, consisting of 1-3 carbon atoms. Examples of C ₁ -C ₃ alkyl groups include methyl, ethyl, n-propyl and isopropyl groups.

As used herein, the term “C ₁ -C ₆ alkoxy” means an O-alkyl group, and “C ₁ -C ₆ alkyl” is used as described above. Examples of C ₁ -C ₆ alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, n-hexoxy, 3-methyl-butoxy groups.

As used herein, the term "C ₁ -C ₃ alkoxy" means the group

O-alkyl, in which case “C ₁ -C ₃ alkyl” is used, as described above. Examples of C ₁ -C ₃ alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy and n-propoxy groups.

As used herein, the term "C ₁ -C ₆ haloalkyl" means saturated hydrocarbon groups, both straight and branched chain, consisting of 1-6 carbon atoms, and in which from 1 to all hydrogen atoms are replaced by halogen atom(s) of various types. or the same type. Examples of C ₁ -C ₆ haloalkyl groups include methyl groups substituted with 1 to 3 halogen atoms, ethyl groups substituted with 1 to 5 halogen atoms, n-propyl or isopropyl groups substituted with 1 to 7 halogen atoms, n-butyl or isobutyl groups, substituted with 1-9 halogen atoms, and sec-butyl or tert-butyl groups substituted with 1-9 halogen atoms.

As used herein, the term "C ₁ -C ₃ haloalkyl" means saturated hydrocarbon groups, both straight and branched chain, consisting of 1 to 3 carbon atoms, and in which from 1 to all hydrogen atoms are replaced by halogen atom(s) of various types. or the same type. Examples of C ₁ -C ₃ haloalkyl groups include methyl substituted with 1 to 3 halogen atoms, ethyl substituted with 1 to 5 halogen atoms, and n-propyl or isopropyl substituted

1-7 halogen atoms.

As used herein, the term "C ₁ -C ₃ haloalkoxy" means saturated alkoxy groups, both straight and branched chain, consisting of 1 to 3 carbon atoms, and in which from 1 to all hydrogen atoms are replaced by halogen atom(s) of various types. or the same type. Examples of C ₁ -C ₃ haloalkoxy groups include a methoxy group substituted with 1 to 3 halogen atoms, an ethoxy group substituted with 1 to 5 halogen atoms, and an n-propoxy or isopropoxy group substituted with 1 to 7 halogen atoms.

As used herein, the term “C ₁ -C ₃ fluoroalkyl” means saturated hydrocarbon groups, both straight and branched chain, consisting of 1 to 3 carbon atoms, and in which from 1 to all hydrogen atoms are replaced by fluorine atom(s). Examples of C ₁ -C ₃ fluoroalkyl groups include methyl substituted with 1-3 fluorine atoms, ethyl substituted with 1-5 fluorine atoms, and n-propyl or isopropyl substituted with 1-7 fluorine atoms.

As used herein, the term “C ₁ -C ₃ fluoroalkoxy” means saturated alkoxy groups, both straight and branched chain, consisting of 1 to 3 carbon atoms, and in which from 1 to all hydrogen atoms are replaced by fluorine atom(s). Examples of C ₁ -C ₃ fluoroalkoxy groups include a methoxy group substituted with 1 to 3 fluorine atoms, an ethoxy group substituted with 1 to 5 fluorine atoms, and an n-propoxy or isopropoxy group substituted with 1 to 7 fluorine atoms.

As used herein, the term “C ₃ -C ₆ cycloalkyl” means a cyclic saturated hydrocarbon group consisting of 3-6 carbon atoms. Examples of C ₃ -C ₆ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term “C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl” means a saturated hydrocarbon group, either straight or branched chain, of 1 to 3 carbon atoms, substituted by an alkoxy group of 1 to 3 carbon atoms. Examples of C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl groups are given below:

As used herein, the term “C ₁ -C ₃ cyanoalkyl” means a straight- or branched-chain cyano(CN) derivative containing one to three carbon atoms, including a carbon atom that forms part of the cyano group. Examples of C ₁ -C ₃ cyanoalkyl groups are given below:

As used herein, the term "N-C ₁ -C ₃ alkylamino" means an amino-containing substituent bearing one C ₁ -C ₃ alkyl group as defined above. Examples of N-C ₁ -C ₃ alkylamino are given below:

As used herein, the term "N,N-diC ₁ -C ₃ alkylamino" means an amino-containing substituent bearing two C ₁ -C ₃ alkyl groups as defined above. Examples of N,N-diC ₁ -C ₃ alkylamino are given below:

As used herein, the term “halogen” means fluorine, chlorine, bromine or iodine. It should be understood that if the substituent is a halogen (or a halogen atom), then it is always associated with a carbon atom.

As used herein, the term “aryl” means a monocyclic aromatic carbocyclic group. Examples of such a group include phenyl.

As used herein, the term “monocyclic aryl” means a monocyclic aromatic carbocyclic group. Examples of monocyclic aryl groups include phenyl.

As used herein, the term “heteroaryl” means a monocyclic or bicyclic aromatic group consisting of carbon atoms in which one to three carbon atoms have been replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur atoms. In a bicyclic aryl, one of the rings may be partially saturated. Examples of such groups include indolinyl, dihydrobenzofuran and 1,3-benzodioxolyl.

As used herein, the term “monocyclic heteroaryl” means a monocyclic aromatic group consisting of carbon atoms in which one to three carbon atoms have been replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur atoms.

Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl.

Examples of bicyclic heteroaryl groups include, but are not limited to, quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuryl, indolyl, indazolyl, benzothiazolyl, pyridopyrimidinyl and isoquinolinyl.

As used herein, the term “heterocyclyl” means a cyclic group consisting of carbon atoms in which one to three carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur atoms. Examples of heterocyclyl groups include, but are not limited to, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and dioxanyl.

Depending on the substituents present in the compounds of formula (I), the compounds can form salts which are within the scope of the present invention. Salts of the compounds of formula (I) suitable for medical use are those where the counterion is pharmaceutically acceptable.

Suitable salts of the invention include those formed by reaction with organic or inorganic acids or bases. In particular, suitable salts formed by reaction with acids according to the invention include salts formed by reaction with mineral acids, with strong organic carboxylic acids, such as alkane carboxylic acids consisting of 1-4 carbon atoms, which are unsubstituted or substituted, for example , a halogen atom, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (C ₁ -C ₄ )alkyl or arylsulfonic acids, which are unsubstituted or substituted, for example , a halogen atom. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic and glutamic acids, lysine and arginine.

Pharmaceutically acceptable salts with bases include ammonium salts, alkali metal salts, for example, potassium and sodium salts, alkaline earth metal salts, for example, calcium and magnesium salts, and salts with organic bases, for example, dicyclohexylamine, N-methyl-D-glucamine, morpholine , thiomorpholine, piperidine, pyrrolidine, with lower mono-, di- or trialkylamines, for example, ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or with lower mono-, di- - or a trihydroxyalkylamine, for example mono-, di- or triethanolamine. In addition, corresponding internal salts can be formed.

The compounds of the invention can be used for prophylaxis and/or treatment as is or in the form of a pharmaceutical composition. Although it is possible to administer the active ingredient as such, it is also possible for it to be present in a pharmaceutical composition. Accordingly, according to the invention there is provided a pharmaceutical composition containing a compound of formula (I) and a pharmaceutically acceptable diluent, excipient and/or carrier. The pharmaceutical compositions of the invention may be in the form of a pharmaceutical composition, which is described below.

Typical compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose for bulking, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents, such as those known in the art; and immediate release tablets, which may contain, for example, microcrystalline cellulose, dibasic calcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactose and/or other excipients, binders, dry fillers, disintegrants, diluents and lubricants, such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum acacia, gum tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like. Delivery of the compounds of formula (I) can also be accomplished through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are typical forms that can be used. Typical compositions include compositions containing the compound(s) of the present invention with rapidly dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. High molecular weight excipients such as celluloses (Avicel) or polyethylene glycols (PEG) may also be included in such compositions. Such compositions may also include a mucosal adhesion promoting excipient such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and release control agents. such as a copolymer based on an acrylic acid polymer (for example, Carbopol 934). For ease of manufacture and use, lubricants, glidants, flavors, colorants and stabilizers may also be added. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. For oral administration in liquid form, the components of the oral drug may be combined with any orally suitable non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.

The compositions of the present invention suitable for oral administration may be presented in the form of discrete units such as capsules, wafers, pills or tablets, each containing a predetermined amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous liquid or non-aqueous liquid, for example, in the form of elixirs, tinctures, suspensions or syrups; or in the form of an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

The tablet may be made by compression or molding, possibly with one or more additional ingredients. Compressed tablets can be prepared in a suitable machine by compressing the active ingredient into a free-flowing form such as powder or granules, possibly mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. Molded tablets can be prepared in a suitable machine by molding a mixture of crushed compound moistened with an inert liquid diluent. It is possible that the tablets may be coated or scored and may be formulated to provide a slow or controlled release of the active ingredient. For example, the compounds of the present invention can be administered in a form suitable for immediate release or sustained release. Immediate release or sustained release can be achieved through the use of suitable pharmaceutical compositions containing the compounds of the present invention, or, especially in the case of sustained release, through the use of devices such as subcutaneous implants or osmotic pumps. The compounds of the present invention can also be administered using liposomes.

Typical compositions in unit dosage form are those that contain the active ingredient at an effective dose, as described above, or an appropriate proportion thereof.

It should be understood that in addition to the ingredients, particularly those mentioned above, the compositions of this invention may include other agents conventionally used in the art, taking into account the type of composition in question, for example, those suitable for oral administration may include flavorings.

These compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical field. Such methods may include the step of combining the active ingredient with a carrier that consists of one or more additional ingredients. The compositions can be prepared by continuously and uniformly combining the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired composition.

The compounds of the present invention can also be administered in liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin), phosphatidylserine, phosphatidylinositol, diphosphatidylglycerol (cardiolipin), or phosphatidylcholine (lecithin).

Compositions for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic agents and solutes to make the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. These compositions may be presented in single-dose or multi-dose containers, such as sealed ampoules and hermetically sealed vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, immediately prior to application. Extemporaneous solutions and suspensions for injection can be prepared from sterile powders, granules and tablets of the type described earlier. Typical compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, suitable non-toxic parenterally acceptable diluents or solvents such as polyethylene glycol, ethanol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid or cremophor.

Typical compositions for nasal, aerosol or inhalation administration include solutions in saline, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability and/or other solubilizing or dispersing agents, for example, agents known in the art technology.

Compositions for rectal administration can be presented in the form of a suppository with typical carriers such as cocoa butter, synthetic glycerol esters (glycerides) or polyethylene glycol. Typically, such carriers are solid at normal temperatures but melt and/or dissolve in the rectum to release the drug.

Compositions for topical administration to the oral cavity, for example, buccally or sublingually, include lozenges containing the active ingredient in a flavored base such as sucrose and gum acacia or tragacanth, and lozenges containing the active ingredient in a base such as gelatin and glycerin or sucrose and gum arabic. Typical compositions for topical administration include a topical carrier such as Plastibase® (polyethylene thickened mineral oil).

The compounds of formula (I) may be administered as a single pharmaceutical agent or in combination with one or more additional therapeutic agents without the combination causing any unacceptable adverse effects. Such a pharmaceutical composition involves administering a single pharmaceutical composition that contains a compound of formula (I) and one or more additional therapeutic agents, and administering a compound of formula (I) and each additional therapeutic agent as part of its own separately administered pharmaceutical composition. For example, a compound of Formula (I) and a therapeutic agent may be administered to a patient together in a single orally administered composition, such as a capsule or tablet, or each agent may be administered in separate dosage compositions.

When compositions are used for separate administration, administration of a compound of formula (I) and one or more additional therapeutic agents can be performed substantially in parallel (eg, simultaneously) or spaced apart in time (eg, sequentially).

The amount of active ingredient required to achieve a therapeutic effect will undoubtedly vary depending on the specific compound, the route of administration, the subject being treated, including the type, species, age, weight, sex and health status of the subject and renal and hepatic function. in a given subject, and the particular disorder or disease being treated, as well as its severity. A physician, veterinarian, or normally trained clinician can readily determine and prescribe the effective amount of a drug needed to prevent, counteract, or delay the progression of the condition.

Oral dosages of the present invention, when used to achieve these effects, will range from about 0.01 mg per kg body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably from 0. 01 mg per kg body weight per day (mg/kg/day) to 10 mg/kg/day and most preferably 0.1 to 5.0 mg/kg/day for an adult. If administered orally, the compositions may be formulated as tablets or other presentation forms prepared in discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0 , 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient, to adjust the dosage of the symptomatic therapy of the patient being treated. Typically, the drug contains from about 0.01 mg to about 500 mg of active ingredient, preferably from about 1 mg to about 100 mg of active ingredient. If administered intravenously, the most preferred doses will be in the range of about 0.1 to about 10 mg/kg/minute when infused at a constant rate. The compounds of the present invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses on a two, three or four times daily basis. In addition, the compounds of the present invention can be administered in intranasal form through topical application together with suitable intranasal excipients or can be administered by transdermal routes using such forms of transdermal skin patches as are well known to those of ordinary skill in the art. If administered in the form of a transdermal delivery system, the dosing will certainly be continuous rather than intermittent throughout the dosing regimen.

RECEIVING CONNECTIONS

The compounds of the present invention can be prepared as the free base or a pharmaceutically acceptable salt thereof by the method described below. In the following description of such methods, it is intended that, where appropriate, suitable protecting groups will be added to and subsequently removed from the various reagents and intermediates in a manner readily apparent to one skilled in the art of organic synthesis. Traditional techniques for the use of such protecting groups, as well as examples of suitable protecting groups, are described, for example, in Protective Groups in Organic Synthesis, edited by TW Greene, PGM Wutz, ^4th edition, Wiley-Interscience, New York, 2006. It is obvious that for an alternative Microwave radiation can be used to heat reaction mixtures.

According to another aspect of the present invention, there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and Z are as defined herein unless otherwise indicated. This method includes:

(1) formation of the corresponding compound of formula (I)

A compound of formula (I) can be prepared (Scheme 1) starting from, for example, a compound of formula (II), where R ^X can be F, OCH ₃ , OS(CH ₃ ) ₃ or OSiR'R''R''' (wherein R', R'' and R''' are independently aryl (such as phenyl) or alkyl (such as methyl or t-butyl)). If R ^X represents F, then conversion to compound (I) can be accomplished by, for example, acid hydrolysis using an aqueous HCl solution. If R ^X is OCH ₃ , then conversion to compound (I) can be accomplished by reaction, for example, with trimethylsilyl iodide in a suitable solvent such as chloroform, or by reaction with HBr in a suitable solvent such as acetic acid, or by reaction with BBr ₃ in a suitable solvent such as dichloromethane. If R ^X is OC(CH ₃ ) ₃ , then conversion to compound (I) can be accomplished by reaction with, for example, trifluoroacetic acid in a suitable solvent such as dichloromethane. If R ^X is OSiR'R''R''', then conversion to compound (I) can be accomplished using, for example, HCl in a suitable solvent such as methanol, or using tetrabutylammonium fluoride in tetrahydrofuran. If enantiomerically pure or enriched compound (II) is used in this reaction, enantiomerically pure or enantiomerically enriched compound (I) is obtained.

The compounds of formula (II) are commercially available or known from the literature, or they are prepared by standard methods known in the art. The compound of formula (I) or (II) can be separated into its enantiomers by standard methods known in the art, for example, by chromatography on a chiral stationary phase.

GENERAL METHODS

All solvents used were of analytical grade, and commercially available anhydrous solvents were routinely used to carry out the reactions. Starting materials were obtained from commercial sources or prepared according to published procedures in the literature. Room temperature means +20-25°C. The compositions of solvent mixtures are given in volume percentages or volume ratios.

Microwave heating was performed in a Biotage Initiator microwave cavity irradiating continuously at 2.45 GHz. Obviously, microwave radiation can be used to heat reaction mixtures.

Normal phase chromatography was performed manually on silica gel 60 (0.040-0.063 mm) from Merck or automated using the ISCO Combiflash® Companion™ system using SiliaSep™ normal phase flash chromatography columns and the specified solvent system.

Nuclear magnetic resonance (NMR) spectra were recorded on an NMR spectrometer at 400 MHz (or higher field) equipped with a suitably configured probe. Spectra were recorded at ambient temperature unless otherwise stated. Chemical shifts are given in ^ppm downfield and upfield relative to the TMS (tetramethylsilane) signal (0.00 ^ppm ). The following reference signals were used: the residual signal of the solvent DMSO-d ₆ δ 2.5, CDCl ₃ δ 7.26, or methanol-d ₄ δ 3.31. The multipletities of resonant signals are denoted as s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet and broadened signals, respectively.

High pressure liquid chromatography (HPLC) was performed on a reverse phase column. A linear gradient was applied using, for example, mobile phase A (aqueous 0.1% NH ₃ solution, or aqueous 0.1% acetic acid solution, or aqueous 0.1% formic acid solution) and B ( acetonitrile or methanol). Mass spectrometry (MS) analyzes were performed in positive ion mode using electrospray ionization (ES+).

Preparative chromatography was performed on a Gilson-PREP GX271 or GX281 using Trilution Ic as software on a reverse phase column. A linear gradient was applied using, for example, mobile phase A (aqueous 0.1% NH ₃ solution, or aqueous 0.1% acetic acid solution, or aqueous 0.1% formic acid solution) and B ( acetonitrile or methanol).

Preparative chiral chromatography for enantiomer separation was performed on a Thar SFC system using supercritical fluid chromatography (SFC) on a chiral stationary phase. A linear gradient was applied using mobile phase A (carbon dioxide) and B (acetonitrile or methanol or ethanol or 2-propanol or any mixtures thereof). Excipients (such as diethylamine or isopropylamine or ammonia or formic acid or TFA) may be used.

Compound names are given using BIOVIA Draw 16.1.

ABBREVIATIONS

Amphos - (4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine;

without - anhydrous;

aq. - water;

BuLi - butyllithium;

DCM - dichloromethane;

DMAc - N,N-dimethylacetamide;

DME - 1,2-dimethoxyethane;

DMF - N,N-dimethylformamide;

DMSO - dimethyl sulfoxide;

EtOAc - ethyl acetate;

EtOH - ethanol;

h - hour(s);

HPLC - high performance liquid chromatography (or high pressure);

KOtBu - potassium tert-butoxide;

LCMS - liquid chromatography combined with mass spectrometry;

MeCN - acetonitrile;

2-MeTHF - 2-methyl-tetrahydrofuran;

MeOH - methanol;

min - minute(s);

NMR - nuclear magnetic resonance;

Pd-118 - [1,1'-bis(di-tert-butylphosphino)ferrocene]-palladium(II) dichloride;

PEPPSI-iPr - [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride;

Pd(OAc) ₂ - palladium(II) acetate;

PdCl ₂ (dppf) - [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II);

quantity - quantitative;

RT - room temperature;

sat. - rich;

TFA - trifluoroacetic acid;

THF - tetrahydrofuran.

EXAMPLES

Example 1

4-(2,6-Dichloro-4-pyridyl)-N-phenyl-pyrimidin-2-amine

2,6-Dichloropyridine-4-carboxylic acid (2.88 g; 15 mmol) was taken up in 1,4-dioxane (75 ml) and oxalyl chloride (1.35 ml; 15.75 mmol) was added. The resulting mixture was stirred at 50°C for 5 minutes, then DMF (3 drops) was added and stirring was continued for 45 minutes. After cooling to RT, PdCl ₂ (PPh ₃ ) ₂ (210 mg; 0.3 mmol), CuI (114 mg; 0.6 mmol), ethynyltrimethylsilane (2.12 ml; 15 mmol) and triethylamine (6.26 ml) were added ; 45 mmol) and the mixture was stirred at RT for 30 min. Phenylguanidinium nitrate (2.97 g; 15 mmol), K ₂ CO ₃ (5.18 g; 37.5 mmol) and 2-ethoxyethan-1-ol (15 ml) were added and the resulting mixture was refluxed overnight . After cooling to RT, the mixture was filtered through a silica gel pad eluting with DCM/MeOH/NH ₃ (100:3:1) to give the product as a black gum. Recrystallization from MeOH gave the product as a solid (3.03 g; 64%). MS ES+ m/z 317 [M+H] ⁺ .

Example 2

4-(2-tert-Butoxy-6-chloro-4-pyridyl)-N-phenyl-pyrimidin-2-amine

4-(2,6-Dichloropyridin-4-yl)-N-phenylpyrimidin-2-amine (3 g; 9.46 mmol), 4A molecular sieves (3 g) and KOtBu (2.65 g; 23.65 mmol ) was transferred to toluene (50 ml) and the resulting mixture was stirred at 90°C for 3 hours. After cooling to RT, water (50 ml), 2 M aq. a solution of HCl (20 ml) and EtOAc (50 ml) and the resulting precipitate was filtered and discarded. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×25 ml). The combined organic extracts were washed with brine, treated with Na ₂ SO ₄ , filtered and concentrated. The resulting residue was transferred to DCM (50 ml) along with activated carbon and the mixture was stirred at RT for 15 min. Filtration through celite and concentration of the filtrate gave the product as a gummy substance (1.5 g; 45%). MS ES+ m/z 355 [M+H] ⁺ .

Example 3

4-[2-tert-Butoxy-6-(2-chlorophenyl)-4-pyridyl]-N-phenyl-pyrimidin-2-amine

4-[2-(tert-Butoxy)-6-chloropyridin-4-yl]-N-phenylpyrimidin-2-amine (650 mg; 1.13 mmol), (2-chlorophenyl)boronic acid (344 mg; 2. 2 mmol), Pd-118 (60 mg; 0.09 mmol) and K ₂ CO ₃ (760 mg; 5.5 mmol) were transferred into a mixture of DME:H ₂ O:EtOH (6:3:1; 15 ml) and the resulting mixture was stirred at 75°C overnight. (2-Chlorophenyl)boronic acid (344 mg; 2.2 mmol) and Pd-118 (60 mg; 0.09 mmol) were added again and the mixture was stirred at 75°C for 4 hours. After cooling to RT, the mixture was concentrated and the resulting residue was taken up in water (20 ml) and EtOAc (50 ml). The mixture was stirred at RT for 10 minutes and then filtered. EtOAc (20 ml) was added to the filtrate and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic extracts were washed with brine, treated with Na ₂ SO ₄ , filtered, concentrated and purified on a silica gel column eluting with 0-50% EtOAc in heptane then preparative HPLC to give the product as solids (140 mg; 18%). MS ES+ m/z 431 [M+H] ⁺ .

Example 4

4-(2-Anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one

To a solution of 4-[2-(tert-butoxy)-6-(2-chlorophenyl)pyridin-4-yl]-N-phenylpyrimidin-2-amine (130 mg; 0.3 mmol) in DCM (8 ml) at At RT, TFA (0.1 ml; 1.35 mmol) was added and the resulting mixture was stirred at RT for 2 hours. TFA (0.1 ml; 1.35 mmol) was added again and stirring was continued for 2 hours. The mixture was concentrated and the resulting residue was taken up in MeOH (10 ml). NH ₄ OH (28% solution; 3 ml) was added and the mixture was stirred at RT for 1 hour. The precipitate was filtered, washed with water, MeOH and dried. The solid was dissolved in boiling pyridine (15 ml) and left to cool to RT. MeOH (10 ml) was added to the cloudy solution with stirring, and after 10 min at RT, the mixture was cooled in the refrigerator for 15 min. The resulting precipitate was filtered off, washed successively with MeOH and pentane and dried to give the product as a solid (30 mg; 25%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 12.15 (s, 1H), 9.77 (s, 1H), 8.62 (d, 1H), 7.79 (d, 2H), 7.69-7.56 (m, 2H), 7.51 (dq, 2H), 7.30 (q, 2H), 7.18 (s, 1H), 6.97 (t, 1H). MS ES+ m/z 375 [M+H] ⁺ .

Example 5

4-[2-tert-Butoxy-6-(3-pyridyl)-4-pyridyl]-N-phenyl-pyrimidin-2-amine

The title compound was prepared as described in Example 3 using (pyridin-3-yl)boronic acid to give the product (435 mg; 97%). MS ES+ m/z 398 [M+H] ⁺ .

Example 6

4-(2-Anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one

The title compound was prepared as described in Example 4 and recrystallized from 2-propanol to give the product as a solid (14 mg; 14%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 12.08 (s, 1H), 9.81 (s, 1H), 9.14 (s, 1H), 8.72-8.58 (m, 2H), 8.31 (d, 1H), 7.82 (d, 2H), 7.68-7.51 (m, 3H), 7.38-7.27 (m, 3H), 6.99 (t, 1H). MS ES+ m/z 342 [M+H] ⁺ .

Example 7

4-[2-tert-Butoxy-6-(4-pyridyl)-4-pyridyl]-N-phenyl-pyrimidin-2-amine

The title compound was prepared as described in Example 3 using (pyridin-4-yl)boronic acid to give the product (100 mg; 64%). MS ES+ m/z 398 [M+H] ⁺ .

Example 8

4-(2-Anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one

The title compound was prepared as described in Example 4 and recrystallized from 2-propanol to give the product as a solid (20 mg; 21%). ^1H NMR (500 MHz, DMSO- _d6 ) δ ^ppm 11.85 (s, 1H), 9.83 (s, 1H), 8.76 (d, 2H), 8.67 (d, 1H), 7.98 (s, 2H ), 7.82 (d, 2H), 7.62 (d, 1H), 7.44-7.24 (m, 3H), 7.00 (t, 1H). MS ES+ m/z 342 [M+H] ⁺ .

Example 9

4-(2-tert-Butoxy-6-morpholino-4-pyridyl)-N-phenyl-pyrimidin-2-amine

4-(2-tert-Butoxy-6-chloro-4-pyridyl)-N-phenyl-pyrimidin-2-amine (190 mg; 0.54 mmol), Pd(OAc) ₂ (8 mg; 0.04 mmol ) and XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (19 mg; 0.03 mmol) were dissolved in toluene (6 ml). Morpholine (185 μl; 2.14 mmol) and KOtBu (180 mg; 1.61 mmol) were added and the resulting mixture was stirred at 100°C overnight. After cooling to RT, EtOAc and brine were added, the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, treated with MgSO ₄ , filtered, concentrated and purified on a silica gel column eluting with 20% EtOAc in heptane to give the product (60 mg; 28%). MS ES+ m/z 406 [M+H] ⁺ .

Example 10

4-(2-Anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one

The title compound was prepared as described in Example 4, yielding the product as a solid (26 mg; 50%). ^1H NMR (400 MHz, DMSO-d ₆ ) δ ^ppm 3.33 (s, 1H), 3.47 (br. s., 4H), 3.65-3.79 (m, 4H), 6.62 (s, 1H), 6.85 (br. s., 1H), 6.97 (t, 1H), 7.31 (t, 2H), 7.42 (s, 1H), 7.82 (d, 2H), 8.58 (d, 1H), 9.72 (s, 1H) . MS ES+ m/z 350 [M+H] ⁺ .

Example 11

4-Benzyloxy-2,6-dichloro-pyridine

A 60% suspension of NaH (945 mg; 24.7 mmol) was added in portions to a solution of 2,4,6-trichloropyridine (4.5 g; 24.7 mmol) in DMF (25 ml) at 0°C. After 20 minutes, phenylmethanol (2.7 g, 24.7 mmol) was added dropwise and the mixture was stirred for 3 hours. Water (30 ml) was added and the precipitate was filtered off. The solid was dissolved in EtOAc, treated with MgSO ₄ , filtered and concentrated to give the product as a solid (5 g; 80%). MS ES+ m/z 254 [M+H] ⁺ .

Example 12

4-Benzyloxy-2-tert-butoxy-6-chloro-pyridine

4-Benzyloxy-2,6-dichloro-pyridine (5 g; 19.7 mmol) and KOtBu (2.2 g; 19.7 mmol) were dissolved in anhydrous 2-MeTHF (25 ml) and the mixture was stirred at 70°C for 2 hours. After cooling to RT, the mixture was filtered, concentrated and purified on a silica gel column eluting with 30% EtOAc in heptane to give the product (4 g; 70%). MS ES+ m/z 292 [M+H] ⁺ .

Example 13

4-Benzyloxy-2-tert-b utoxy-6-[2 -(trifluoromethyl)-1-piperidyl]pyridine

4-Benzyloxy-2-tert-butoxy-6-chloro-pyridine (4 g; 13.7 mmol), 2-(trifluoromethyl)piperidine (2.3 g; 15.1 mmol), PEPPSI-iPr (146 mg; 1.37 mmol) and KOtBu (3.85 g; 34.3 mmol) were taken into 1,4-dioxane (30 ml) and the mixture was stirred at 90°C for 2 hours. After cooling to RT, water and EtOAc were added and the organic layer was separated, filtered, concentrated and purified on a silica gel column eluting with 30% EtOAc in heptane to give the product (4.1 g; 73%). MS ES+ m/z 409 [M+H] ⁺ .

Example 14

2-tert-Butoxy-6-[2-(trifluoromethyl)-1-piperidyl]pyridin-4-ol

A mixture of 4-benzyloxy-2-tert-butoxy-6-[2-(trifluoromethyl)-1-piperidyl]pyridine (3.5 g; 8.57 mmol) and 10% Pd/C (600 mg; 0. 56 mmol) in MeOH and EtOAc were hydrogenated (1.5 bar (150 kPa)) at RT for 2 hours. The mixture was filtered through celite and concentrated to give the product (2.7 g; quant.). MS ES+ m/z 319[M+H] ⁺ .

Example 15

[2-tert-Butoxy-6-[2-(trifluoromethyl)-1-piperidyl]-4-pyridyl]-trifluoromethanesulfonate

2-tert-Butoxy-6-[2-(trifluoromethyl)-1-piperidyl]pyridin-4-ol (2.7 g; 8.48 mmol) and Et ₃ N (1.66 ml; 11.9 mmol) transferred to DCM (20 ml) at 0°C. Trifluoromethylsulfonyl trifluoromethanesulfonate (2.54 ml; 11.9 mmol) was added dropwise over 5 minutes and stirred for 1 hour. The mixture was washed with sat. aq. NaHCO ₃ solution (2 x 20 ml), concentrated and purified on a silica gel column eluting with 20% EtOAc in heptane to give the product (3.5 g; 92%). MS ES+ m/z 451 [M+H] ⁺ .

Example 16

2-tert-Butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-[2-(trifluoromethyl)-1-piperidyl]pyridine

4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.96 g; 11 .7 mmol), [2-tert-butoxy-6-[2-(trifluoromethyl)-1-piperidyl]-4-pyridyl]trifluoromethanesulfonate (3.5 g; 7.77 mmol), KOAc (1.14 g; 11.7 mmol) and PdCl ₂ (dppf) (215 mg; 0.29 mmol) were taken into toluene (10 ml) and stirred at 90°C for 5 hours. After cooling to RT, the mixture was concentrated and the residue was dissolved in EtOAc, washed with water, concentrated and purified on a silica gel column eluting with 0-60% EtOAc in heptane to give the product (2.15 g; 65%). MS ES+ m/z 347 [M+H] ⁺ .

Example 17

N-(4-Chloro-2-pyridyl)-2-methyl-pyrimidin-4-amine

2-Bromo-4-chloro-pyridine (250 mg; 1.25 mmol), 2-methylpyrimidin-4-amine (107 mg; 0.9 mmol), PdCl ₂ (dppf) (14 mg; 0.015 mmol) and dppf (43 mg; 0.07 mmol) was taken up in toluene. A 1 M solution of KOtBu (167 mg; 1.4 mmol) in THF was added and the resulting mixture was stirred at 110°C overnight. Workup and purification by silica gel column chromatography gave the product as a solid (100 mg; 36%). MS ES+ m/z 221 [M+H] ⁺ .

Example 18

4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one

1-[3-tert-Butoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-(trifluoromethyl)piperidine (100 mg; 0.23 mmol), K ₂ CO ₃ (81 mg; 0.59 mmol), N-(4-chloro-2-pyridyl)-2-methyl-pyrimidin-4-amine (52 mg; 0.23 mmol) and PdCl ₂ (dppf) (15 mg; 0.02 mmol) was dissolved in 1,4-dioxane (3 ml) and water (1 ml) and the resulting mixture was stirred at 90°C for 2 hours. After cooling to RT, water and EtOAc were added and the organic layer was separated and concentrated. The residue was dissolved in DCM (3 ml), TFA (0.5 ml; 6.7 mmol) was added and the mixture was stirred at RT for 30 min. The mixture was concentrated, the residue was dissolved in MeOH, filtered and purified by preparative HPLC to give the product as a solid (7 mg; 6%). ^1H NMR (500 MHz, methanol- _d4 ) δ ppm ^1.17-1.33 (m, 1H), 1.54-1.66 (m, 1H), 1.68-1.77 (m, 2H), 1.81 (br d, 3H) , 2.08 (br d, 1H), 2.57 (s, 3H), 3.15-3.29 (m, 1H), 3.86 (br d, 1H), 5.16 (br s, 1H), 6.21-6.27 (m, 2H), 7.17 (dd, 1H), 7.38 (d, 1H), 8.07 (br s, 1H), 8.23 (d, 1H), 8.32 (d, 1H). MS ES+ m/z 431 [M+H] ⁺ .

Example 19

2-Anilino-1H-pyrimidin-6-one

2-Methylsulfanyl-1H-pyrimidin-6-one (5 g; 35.21 mmol) and aniline (3.2 g; 35.21 mmol) were transferred to diglyme (50 ml) and the resulting mixture was stirred at 170°C for 5 hours After cooling to RT, water was added and the resulting precipitate was filtered off, washed with water and dried to give the product as a solid (3 g; 46%). MS ES+ m/z 188 [M+H] ⁺ .

Example 20

4-Chloro-N-phenyl-pyrimidin-2-amine

PCl ₅ (1 g, 5.34 mmol) was added portionwise to a solution of 2-anilino-1H-pyrimidin-6-one (1.5 g, 5.34 mmol) in POCl ₃ (5 ml) and the resulting mixture was stirred at 110 °C overnight. After cooling to RT, ice water was added and the mixture was extracted with EtOAc. The combined organic extracts were treated with Na ₂ SO ₄ , filtered, concentrated and purified on a silica gel column to give the product as a solid (840 mg; 76%). MS ES+ m/z 206 [M+H] ⁺ .

Example 21

4-(2-Anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18 using 4-chloro-N-phenyl-pyrimidin-2-amine to give the product as a solid (11 mg; 8%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm ^1.52 (br s, 1H), 1.70 (br s, 2H), 1.78 (br d, 2H), 2.02 (br d, 1H), 3.09 ( br t, 1H), 4.22 (br s, 1 H), 5.54 (br s, 1H), 6.65 (s, 1H), 6.95-7.04 (m, 2H), 7.31 (t, 2H), 7.44 (d, 1H), 7.83 (d, 2H), 8.60 (d, 1H), 9.72 (s, 1H), 10.47 (brs, 1H). MS ES+ m/z 416 [M+H] ⁺ .

Example 22

4-(4-Benzyloxy-6-tert-butoxy-2-pyridyl)-3-(trifluoromethyl)morpholine

The title compound was prepared as described in Example 13 using 3-(trifluoromethyl)morpholine to give the product as an oil (1 g; 50%). MS ES+ m/z 411 [M+H] ⁺ .

Example 23

2-tert-Butoxy-6-[3-(trifluoromethyl)morpholin-4-yl]pyridin-4-ol

The title compound was prepared as described in Example 14 to give the product (780 mg; 99%). MS ES+ m/z 321 [M+H] ⁺ .

Example 24

[2-tert-Butoxy-6-[3-(trifluoromethyl)morpholin-4-yl]-4-pyridyl]-trifluoromethanesulfonate

The title compound was prepared as described in Example 15, yielding the product as an oil (800 mg; 81%). MS ES+ m/z 453 [M+H] ⁺ .

Example 25

4-[6-tert-Butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-3-(trifluoromethyl)morpholine

The title compound was prepared as described in Example 16 to give the product (270 mg; 33%). MS ES+ m/z 431 [M+H] ⁺ .

Example 26

4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18 using 4-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 -pyridyl]-3-(trifluoromethyl)morpholine to give the product as a solid (6 mg; 6%). ^1H NMR (500 MHz, methanol- _d4 ) δ ^ppm 2.52-2.62 (m, 3H), 3.50-3.69 (m, 2H), 3.70-3.85 (m, 2H), 4.04 (dd, 1H), 4.30 (d, 1H), 5.05-5.19 (m, 1H), 6.34 (t, 2H), 7.20 (dd, 1H), 7.45 (d, 1H), 8.04 (s, 1H), 8.25 (d, 1H) , 8.30-8.40 (m, 1H). MS ES+ m/z 433 [M+H] ⁺ .

Example 27

4-(2-Anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18 using 4-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 -pyridyl]-3-(trifluoromethyl)morpholine and 4-chloro-N-phenyl-pyrimidin-2-amine to give the product as a solid (15 mg; 17%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 3.33-3.38 (m, 1H), 3.53-3.59 (m, 1H), 3.77 (br d, 1H), 4.00 (br dd, 2H), 4.21 (d, 1H), 5.29 (brdd, 1H), 6.71 (s, 1H), 6.96 (s, 1H), 6.98-7.01 (m, 1H), 7.32 (t, 2H), 7.43 (d, 1H) , 7.84 (d, 2H), 8.61 (d, 1H), 9.72 (s, 1H), 10.33-10.82 (m, 1H). MS ES+ m/z 418 [M+H] ⁺ .

Example 28

1-[(4-Fluorophenyl)methylsulfonyl]-3-(trifluoromethyl)piperazine

2-(Trifluoromethyl)-piperazine (2 g; 13 mmol) and triethylamine (TEA; 2.17 ml; 15.6 mmol) were dissolved in DCM (30 ml). (4-fluorophenyl)methanesulfonyl chloride (2.71 g, 13 mmol) was added in small portions at 0° C. and the mixture was stirred at RT overnight. Water (45 ml) was added and the mixture was extracted with DCM (2x 80 ml). The combined organic extracts were washed twice with brine, treated with Na ₂ SO ₄ , filtered and concentrated to give the product as a solid (3.5 g; 83%). MS ES+ m/z 327 [M+H] ⁺ .

Example 29

1-(4-Benzyloxy-6-tert-butoxy-2-pyridyl)-4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazine

A mixture of 1-[(4-fluorophenyl)methylsulfonyl]-3-(trifluoromethyl)piperazine (1.2 g; 3.68 mmol), 4-benzyloxy-2-tert-butoxy-6-chloro-pyridine (1.34 g ; 4.6 mmol), Cs ₂ CO ₃ (2.4 g; 7.35 mmol), XantPhos (206 mg; 0.37 mmol) and Pd(OAc) ₂ (83 mg; 0.37 mmol) in anhydrous degassed 1,4-dioxane (50 ml) was refluxed overnight under argon. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were treated with Na ₂ SO ₄ , filtered, concentrated and purified on a silica gel column eluting with 0-100% EtOAc in heptane to give the product (1.25 g; 58%). MS ES+ m/z 582 [M+H] ⁺ .

Example 30

2-tert-Butoxy-6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]pyridin-4-ol

The title compound was prepared as described in Example 14 to give the product (1.22 g; 96%). MS ES+ m/z 492 [M+H] ⁺ .

Example 31

[2-tert-Butoxy-6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]trifluoromethanesulfonate

The title compound was prepared as described in Example 15 to give the product (700 mg; 45%). MS ES+ m/z 624 [M+H] ⁺ .

Example 32

1-[6-tert-Butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-4-[(4-fluorophenyl)methylsulfonyl] -2-(trifluoromethyl)piperazine

The title compound was prepared as described in Example 16 to give the product (490 mg; 73%). MS ES+ m/z 602 [M+H] ⁺ .

Example 33

6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H -pyridin-2-one

The title compound was prepared as described in Example 18 using 1-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 -pyridyl]-4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazine to give the product as a solid (14 mg; 14%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.85-2.94 (m, 1H), 3.15 (br d, 1H), 3.13-3.14 (m, 1H), 3.17-3.18 (m, 1H) , 3.22 (br t, 1H), 3.27-3.31 (m, 1H), 3.62 (br d, 1 H), 3.89 (br d, 1H), 4.33 (br d, 1H), 4.52 (s, 2H), 5.57 (br s, 1H), 6.31 (s, 1H), 6.65 (br s, 1H), 7.24 (t, 2H), 7.32 (dd, 1H), 7.48 (dd, 2H), 7.62 (br d, 1H ), 8.04 (s, 1H), 8.35 (d, 1H), 8.39 (d, 1H), 10.23 (s, 1H). MS ES+ m/z 604 [M+H] ⁺ .

Example 34

1-Ethylsulfonyl-3-(trifluoromethyl)piperazine

The title compound was prepared as described in Example 28 using ethanesulfonyl chloride to give the product as a solid (3 g; 98%). MS ES+ m/z 247 [M+H] ⁺ .

Example 35

1-(4-Benzyloxy-6-tert-butoxy-2-pyridyl)-4-ethylsulfonyl-2-(trifluoromethyl)piperazine

The title compound was prepared as described in Example 29 using 1-ethylsulfonyl-3-(trifluoromethyl)piperazine to give the product as a solid (2.53 g; 67%). MS ES+ m/z 502 [M+H] ⁺ .

Example 36

2-tert-Butoxy-6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]pyridin-4-ol

The title compound was prepared as described in Example 14 to give the product (1.94 g; 85%). MS ES+ m/z 412 [M+H] ⁺ .

Example 37

[2-tert-Butoxy-6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-trifluoromethanesulfonate

The title compound was prepared as described in Example 15 to give the product (1.56 g; 62%). MS ES+ m/z 544 [M+H] ⁺ .

Example 38

1-[6-tert-Butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-4-ethylsulfonyl-2-(trifluoromethyl)piperazine

The title compound was prepared as described in Example 16 to give the product (1.2 g; 86%). MS ES+ m/z 440 [M+H] ⁺ (boronic acid).

Example 39

6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18 using 1-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 -pyridyl]-4-ethylsulfonyl-2-(trifluoromethyl)piperazine, giving the product as a solid (7 mg; 7%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ppm ^1.24 (t, 3H), 2.50 (br s, 3H), 2.97-3.05 (m, 1H), 3.13 (q, 2H), 3.23- 3.30 (m, 2H), 3.67 (br d, 1 H), 3.95 (br d, 1 H), 4.36 (br d, 1H), 5.63 (br s, 1 H), 6.31 (s, 1H), 6.67 (s, 1H), 7.33 (dd, 1H), 7.63 (d, 1H), 8.04 (s, 1H), 8.35 (d, 1H), 8.39 (d, 1H), 10.23 (s, 1H), 10.66 (br s, 1H). MS ES+ m/z 524 [M+H] ⁺ .

Example 40

4-[2-(Oxazol-2-ylamino)-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18 using 4-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 -pyridyl]-3-(trifluoromethyl)morpholine and N-(4-chloro-2-pyridyl)oxazol-2-amine (Tetrahedron Letters (2012), 53, (24), 3038-3043), giving the product as a solid substances (5 mg; 5%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 3.23-3.31 (m, 1H), 3.40-3.57 (m, 1H), 3.75 (br d, 1H), 3.94-4.04 (m, 2H) , 4.19 (d, 1H), 5.28-5.35 (m, 1H), 6.27 (s, 1H), 6.57 (s, 1H), 7.05-7.10 (m, 1H), 7.29 (br d, 1H), 7.73 ( s, 1H), 8.28-8.35 (m, 2H), 10.84 (br s, 2H). MS ES+ m/z 408 [M+H] ⁺ .

Example 41

N-(4-Chloro-2-pyridyl)-2-methyl-thiazol-4-amine

A mixture of 4-bromo-2-methyl-thiazole (1.5 g; 8.52 mmol), 4-chloropyridin-2-amine (1.3 g; 10.22 mmol) and Cs ₂ CO ₃ (6.92 g ; 21.3 mmol) in 1,4-dioxane (30 ml) was purged with nitrogen for 20 min. Pd ₂ (dba) ₃ (0.389 g, 0.42 mmol) and Xantphos (0.24 g, 0.42 mmol) were added and the resulting mixture was stirred at 90°C for 16 hours. After cooling to RT, the mixture was filtered through celite , concentrated and purified by preparative HPLC to give the product as a solid (600 mg; 31%). ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.15 (s, 1H), 8.15 (d, 1H), 7.37 (s, 1H), 7.03 (d, 1H), 6.85-6.84 (m, 1H), 2.61 (s, 3H). MS ES+ m/z 226 [M+H] ⁺ .

Example 42

4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18 using 4-[6-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 -pyridyl]-3-(trifluoromethyl)morpholine and N-(4-chloro-2-pyridyl)-2-methyl-thiazol-4-amine to give the product as a solid (20 mg; 21%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.62-2.65 (m, 3H), 3.32 (br s, 1H), 3.54 (td, 1H), 3.71-3.80 (m, 1H), 3.93-4.05 (m, 2H), 4.20 (d, 1H), 5.30 (br dd, 1H), 6.22 (s, 1H), 6.53 (s, 1H), 7.08 (dd, 1H), 7.23 (s, 1H), 7.43 (s, 1H), 8.27 (d, 1H), 10.00 (s, 1H), 10.57 (br s, 1H). MS ES+ m/z 438 [M+H] ⁺ .

Example 43

4-Benzyloxy-2 tert-butoxy-6-[2-(trifluoromethyl)phenyl]pyridine

4-Benzyloxy-2-tert-butoxy-6-chloro-pyridine (1.46 g; 5 mmol), [2-(trifluoromethyl)phenyl]boronic acid (950 mg; 5 mmol), K ₂ CO ₃ (1, 73 g; 12.5 mmol) and PdCl ₂ (dppf) (366 mg; 0.5 mmol) were dissolved in 1,4-dioxane (25 ml) and water (5 ml) and the resulting mixture was stirred at 90°C for 2 hours. After cooling to RT, the mixture was diluted with water and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were filtered through Celite, treated with Na ₂ SO ₄ , filtered, concentrated and purified on a silica gel column eluting with 0-80% EtOAc in heptane to give the product as a solid (1.58 g; 79%). MS ES+ m/z 402 [M+H] ⁺ .

Example 44

2-tert-Butoxy-6-[2-(trifluoromethyl)phenyl]pyridin-4-ol

The title compound was prepared as described in Example 14 to give the product (948 mg; 72%). MS ES+ m/z 312 [M+H] ⁺ .

Example 45

[2-tert-Butoxy-6-[2-(trifluoromethyl)phenyl]-4-pyridyl]-trifluoromethanesulfonate

The title compound was prepared as described in Example 15 to give the product (720 mg; 54%). MS ES+ m/z 388 [M-tBu] ⁺ .

Example 46

2-tert-Butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-[2-(trifluoromethyl)phenyl]pyridine

The title compound was prepared as described in Example 16 to give the product (450 mg; 76%). MS ES+ m/z 340 [M+H] ⁺ (boronic acid).

Example 47

4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 18 using 2-tert-butoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-[2 -(trifluoromethyl)phenyl]pyridine to give the product as a solid (10 mg; 9%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ppm ^2.47 (s, 3H), 6.46-6.63 (m, 1H), 6.76-6.82 (m, 1H), 7.30-7.37 (m, 1H), 7.58-7.64 (m, 1H), 7.65-7.68 (m, 1H), 7.71-7.76 (m, 1H), 7.78-7.84 (m, 1H), 7.88-7.93 (m, 1H), 8.03-8.10 (m , 1H), 8.32-8.44 (m, 2H), 10.18-10.31 (m, 1H), 11.25-11.87 (m, 1H). MS ES+ m/z 424 [M+H] ⁺ .

Example 48

4-Chloro-N-(2-methylpyrazol-3-yl)pyridin-2-amine

The title compound was prepared as described in Example 41 using 2-methylpyrazol-3-amine and 2-bromo-4-chloro-pyridine. Purification on a silica gel column eluting with 0-5% MeOH in DCM gave the product as a solid (1.2 g; quant.). MS ES+ m/z 209 [M+H] ⁺ .

Example 49

4-[2-tert-Butoxy-6-[2-(trifluoromethyl)phenyl]-4-pyridyl]-N-(2-methylpyrazol-3-yl)pyridin-2-amine

A mixture of 4-chloro-N-(2-methylpyrazol-3-yl)pyridin-2-amine (58 mg; 0.28 mmol), 2-tert-butoxy-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-6-[2-(trifluoromethyl)phenyl]pyridine (117 mg; 0.28 mmol), K ₂ CO ₃ (77 mg; 0.56 mmol) and PdCl ₂ (dppf) (20 mg; 0.03 mmol) in 1,4-dioxane (2 ml) and water (0.5 ml) was heated and stirred at 90°C for 6 hours. After cooling to RT, the mixture was diluted with water and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, treated with Na ₂ SO ₄ , filtered, concentrated and purified on a silica gel column eluting with 0-6% MeOH in DCM to give the product as a solid (94 mg; 51% yield; 70% purity). MS ES +m/z 468 [M+H] ⁺ .

Example 50

4-[2-[(2-Methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one

TFA (1.05 ml; 14.1 mmol) was added to a solution of 4-[2-tert-butoxy-6-[2-(trifluoromethyl)phenyl]-4-pyridyl]-N-(2-methylpyrazol-3-yl )pyridin-2-amine (94 mg; 0.14 mmol; 70%) in DCM (7 ml) at 0°C and the resulting mixture was stirred at 0°C for 1 hour. The mixture was concentrated, treated with toluene and purified preparative HPLC, yielding the product as a solid (11 mg; 19%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 3.68 (s, 3H), 6.28 (d, 1H), 6.51 (brs, 1H), 6.72 (d, 1H), 7.02-7.11 (m, 2H), 7.34 (d, 1H), 7.65 (d, 1H), 7.71-7.82 (t, 2H), 7.89 (d, 1H), 8.20 (d, 1H), 8.93 (s, 1H), 12.03 (brs , 1H). MS ES+ m/z 412 [M+H] ⁺ .

Example 51

N-[4-[2-tert-Butoxy-6-[2-(trifluoromethyl)phenyl]-4-pyridyl]-2-pyridyl]-2-methyl-thiazol-4-amine

The title compound was prepared as described in Example 49 using N-(4-chloro-2-pyridyl)-2-methyl-thiazol-4-amine to give the product as a solid (145 mg; 60% yield; purity 80%). MS ES+ m/z 485 [M+H] ⁺ .

Example 52

4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 50, yielding the product as a solid (45 mg; 43%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.53-2.65 (m, 3H), 6.48 (br s, 1H), 6.63-6.79 (m, 1H), 7.08 (dd, 1H), 7.26 (s, 1H), 7.43 (s, 1H), 7.66 (d, 1H), 7.72-7.83 (m, 2H), 7.90 (d, 1H), 8.28 (d, 1H), 10.05 (s, 1H), 12.02 (br s, 1H). MS ES+ m/z 429 [M+H] ⁺ .

Example 53

N-[4-(2-tert-Butoxy-6-chloro-4-pyridyl)-2-pyridyl]-2-methyl-pyrimidin-4-amine

A mixture of N-(4-chloro-2-pyridyl)-2-methyl-pyrimidin-4-amine (1.08 g, 4.89 mmol), 4,4,5,5-tetramethyl-2-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.55 g; 6.12 mmol), KOAc (961 mg; 9.79 mmol) and PdCl ₂ (dppf) (358 mg; 0.49 mmol) in 1,4-dioxane (25 ml) was stirred at 100°C overnight. After cooling to RT, 2-tert-butoxy-6-chloro-4-iodo-pyridine (Bioorganic & Medicinal Chemistry Letters (2012), 22 (5), 1940-1943; 1.53 g; 4.89 mmol) was added. K ₂ CO ₃ (1.35 g; 9.79 mmol), PdCl ₂ (dppf) (179 mg; 0.25 mmol) and water (6 ml) and the reaction mixture was heated and stirred at 85°C for 2 h After cooling to RT, water (25 ml) was added and the mixture was extracted with EtOAc. The combined organic extracts were treated with Na ₂ SO ₄ , filtered, concentrated and purified on a silica gel column eluting with 25-100% EtOAc in heptane to give the product as a solid (1.61 g; 80% yield; 90% purity). MS ES+ m/z 370 [M+H] ⁺ .

Example 54

N-[4-[2-tert-Butoxy-6-(4-methyl-3-pyridyl)-4-pyridyl]-2-pyridyl]-2-methyl-pyrimidin-4-amine

The title compound was prepared as described in Example 49 using N-[4-(2-tert-butoxy-6-chloro-4-pyridyl)-2-pyridyl]-2-methyl-pyrimidin-4-amine and (4-methyl-3-pyridyl)boronic acid (1.5 eq.) to give the product as a solid (75 mg; 70%). MS ES+ m/z 427 [M+H] ⁺ .

Example 55

6-(4-Methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 50, yielding the product as a solid (55 mg; 58%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.36-2.41 (m, 3H), 2.48-2.50 (m, 3H), 6.62 (br s, 1H), 6.74 (br s, 1H), 7.37-7.42 (m, 2H), 7.68 (d, 1H), 8.05 (s, 1H), 8.36 (d, 1H), 8.40 (d, 1H), 8.54 (d, 1H), 8.57 (s, 1H) , 10.26 (s, 1Н), 12.06 (brs, 1Н). MS ES+ m/z 371 [M+H] ⁺ .

Example 56

N-[4-[2-tert-Butoxy-6-[2-(trifluoromethyl)-3-pyridyl]-4-pyridyl]-2-pyridyl]-2-methyl-pyrimidin-4-amine

The title compound was prepared as described in Example 49 using N-[4-(2-tert-butoxy-6-chloro-4-pyridyl)-2-pyridyl]-2-methyl-pyrimidin-4-amine and [2-(trifluoromethyl)-3-pyridyl]boronic acid (1.5 eq.) to give the product as a solid (110 mg; 92%). MS ES+ m/z 481 [M+H] ⁺ .

Example 57

4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 50, yielding the product as a solid (50 mg; 54%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.46-2.49 (m, 3H), 6.68 (br s, 1H), 6.83 (br s, 1 H), 7.35 (dd, 1 H), 7.62 (d, 1H), 7.87 (dd, 1H),8.07 (s, 1H),8.19(d, 1H),8.36(d, 1H),8.41 (d, 1H),8.88(d, 1H), 10.29 (s, 1H), 11.71-12.58 (m, 1H). MS ES+ m/z 425 [M+H] ⁺ .

Example 58

N-[4-[2-tert-Butoxy-6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-pyridyl]-2-pyridyl]-2-methyl-pyrimidin-4- amine

The title compound was prepared as described in Example 49 using N-[4-(2-tert-butoxy-6-chloro-4-pyridyl)-2-pyridyl]-2-methyl-pyrimidin-4-amine and 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]boronic acid (1.2 eq.) to give the product as a solid (194 mg; 66%). MS ES+ m/z 498 [M+H] ⁺ .

Example 59

6-[1-Ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 50, giving the product as a solid (2 mg; 1%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm ^1.42-1.46 (m, 3H), 2.48-2.49 (m, 3H), 4.24-4.31 (m, 2H), 6.65-6.67 (m, 1 H), 6.66-6.74 (m, 1H), 7.26-7.31 (m, 1H), 7.61-7.67 (m, 1H), 7.97-8.02 (m, 1H), 8.35 (d, 1H), 8.38-8.41 ( m, 1H), 8.41-8.45 (m, 1H), 8.43-8.43 (m, 1H), 10.31-10.36 (m, 1H). MS ES+ m/z 442 [M+H] ⁺ .

Example 60

4-Chloro-N-(1-methylimidazol-4-yl)pyridin-2-amine

The title compound was prepared as described in Example 41 using 1-methylimidazol-4-amine and 2,4-dichloropyridine and heating the mixture in a microwave reactor at 160°C for 1 hour to obtain the product as a solid ( 0.1 g; 12%). ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.04 (s, 1H), 8.59 (s, 1H), 8.17 (d, 1H), 7.48 (s, 1H), 6.98-6.95 (m, 2H), 3.80 (s, 3H). MS ES+ m/z 209 [M+H] ⁺ .

Example 61

4-[2-tert-Butoxy-6-[2-(trifluoromethyl)phenyl]-4-pyridyl]-N-(1-methylimidazol-4-yl)pyridin-2-amine

The title compound was prepared as described in Example 49 using 4-chloro-N-(1-methylimidazol-4-yl)pyridin-2-amine to give the product as a solid (50 mg; 21% yield; purity 80%). MS ES+ m/z 468 [M+H] ⁺ .

Example 62

4-[2-[(1-Methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 50, yielding the product as a solid (18 mg; 37%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 3.63 (s, 3H), 6.28-6.56 (m, 1H), 6.67 (br s, 1H), 6.93 (d, 1H), 7.18 (s , 1H), 7.28 (d, 1H), 7.35 (s, 1H), 7.65 (d, 1H), 7.70-7.82 (t, 2H), 7.89 (d, 1H), 8.20 (d, 1H), 9.27 ( s, 1H), 11.44-12.43 (m, 1H). MS ES+ m/z 412 [M+H] ⁺ .

Example 63

6-(2-Chlorophenyl)-4-hydroxy-1H-pyridin-2-one

Ethyl 3-oxobutanoate (6.33 ml; 50 mmol) was added dropwise to a 60% suspension of NaH (1.92 g; 50 mmol) in 2-MeTHF (60 ml) at -78°C under nitrogen atmosphere. After 5 minutes, the cooling bath was removed and the mixture was stirred at RT for 20 minutes. The mixture was cooled again to -78°C and a 1.6 M n-BuLi solution (31.25 mL; 50 mmol) was added slowly over 20 min. The resulting solution was stirred at -78°C for 30 minutes. 2-chlorobenzonitrile (6.88 g, 50 mmol) was added in one portion as a solid and the reaction mixture was stirred in a cooling bath of melting ice overnight. The mixture was cooled to 0°C and MeOH (15 ml) was added slowly. The cooling bath was removed, the mixture was stirred at RT for 30 min and then cooled again to 0°C. The mixture was neutralized by slowly adding conc. HCl and the resulting precipitate was filtered, washed with EtOH, pentane and dried to give the product as a solid (11.08 g; 87%). MS ES+ m/z 222 [M+H] ⁺ .

Example 64

2,4-Dichloro-6-(2-chlorophenyl)pyridine

6-(2-Chlorophenyl)-4-hydroxy-1H-pyridin-2-one (5 g; 22.56 mmol) was taken up in POCl ₃ (40 ml) and N,N-dimethylaniline (5.5 ml; 43.4 mmol). The resulting mixture was refluxed overnight. After cooling to RT, the mixture was poured onto ice (600 ml) and stirred at RT for 30 min. The precipitate was filtered off and washed with water. The solid was dissolved in EtOAc (100 ml), treated with Na ₂ SO ₄ , filtered and concentrated to give the product as a solid (7 g; 83%). MS ES+ m/z 258 [M+H] ⁺ .

Example 65

4-Chloro-6-(2-chlorophenyl)-1H-pyridin-2-one

2,4-Dichloro-6-(2-chlorophenyl)pyridine (5.7 g; 22.05 mmol) and KOtBu (6.19 g; 55.12 mmol) were taken up in toluene (75 ml) and the resulting mixture was stirred at 100°C for 2 hours. After cooling to RT, water (40 ml) was added and the organic layer was separated. The aqueous layer was slightly acidified using conc. HCl, and extracted with EtOAc (2×40 ml). The combined organic extracts were washed with brine (50 ml), treated with Na ₂ SO ₄ , filtered and concentrated. The resulting residue was taken up in DCM (30 ml) and TFA (5 ml; 67.3 mmol) was added. The reaction mixture was stirred at RT for 1 hour, concentrated and the resulting residue was taken up in MeOH (25 ml). A 30% NH ₄ OH solution (20 ml) and water (20 ml) were added and the mixture was stirred at RT overnight. The resulting precipitate was filtered off, washed with water, EtOH, pentane and dried to give the product as a solid (4.13 g; 78%). MS ES+ m/z 240 [M+H] ⁺ .

Example 66

6-(2-Chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one

A mixture of N-(4-chloro-2-pyridyl)-2-methyl-pyrimidin-4-amine (132 mg; 0.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (190 mg; 0.75 mmol) and PdCl ₂ (dppf) (22 mg; 0.06 mmol) in 1,4-dioxane (1.5 ml) was stirred in a sealed tube at 100°C for 15 hours. After cooling to RT, 4-chloro-6-(2-chlorophenyl)-1H-pyridin-2-one ( 144 mg; 0.6 mmol), K ₂ CO ₃ (83 mg; 0.6 mmol), PdCl ₂ (dppf) (11 mg; 0.03 mmol), 1,4-dioxane (1 ml) and water ( 0.5 ml) and the resulting mixture was washed with a strong stream of argon, heated and stirred at 85°C for 2 hours. After cooling to RT, water (25 ml) was added and the mixture was extracted with DCM. The combined organic extracts were treated with Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give the product as a solid (20 mg; 9%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ ^ppm 2.48-2.50 (m, 3H), 6.66 (br s, 1H), 6.74 (s, 1H), 7.37 (dd, 1H), 7.46-7.56 (m, 2H), 7.59-7.68 (m, 3H), 8.05 (s, 1H), 8.36 (d, 1H), 8.40 (d, 1H), 10.27 (s, 1H), 11.57-12.34 (m, 1H ). MS ES+ m/z 390 [M+H] ⁺ .

Example 67

Using suitable substitutions of the starting material and, if necessary, adaptations of reaction conditions and the like, the following compound is synthesized:

6-(3-cyclopropylmorpholin-4-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1 H-pyridin-2-one.

Example 68

Biochemical analysis of Vps34

A series of dilutions of the compounds of the invention were prepared in DMSO at a concentration 100 times the final concentration in the assay (n ₁ =n ₀ /3; 10 points). The compounds were then diluted to 4 times the assay concentration in assay buffer (Buffer Q from Life Technologies, PV5125, diluted 5 times, supplemented with 2 mM dithiothreitol (DTT) and 2 mM MnCl ₂ ). 2.5 μl of diluted solutions of compounds were added to the 384-well plate used in the assay, then 2.5 μl of a 16.5 nM solution of the Vps34 enzyme (Life Technologies, PV5126) was added. Pre-incubation of the enzyme and compounds was carried out at RT for 15 min. Then, 5 μl of a substrate mixture containing 20 μM ATP (Life Technologies, PV3227) and 200 μM PI:PS (phosphatidylserine) substrate (Life Technologies, PV5122) in assay buffer was added to the wells containing the compound and enzyme. Mixing was carried out by repeated pipetting. The reaction mixture was incubated at room temperature for 1 hour. Then, 5 μl of stop and detection mixture, prepared as described in the instructions for the Adapta™ Kinase Assay Kit (Life Technologies, PV5099), containing Eu-labeled, was added to quench the reaction. anti-ADP antibody Adapta™ (2.3 nM), ADP indicator Alexa Fluor 647 (9 nM) and EDTA (ethylenediaminetetraacetic acid; 30 mM) in TR-FRET (time-resolved fluorescence resonance energy transfer) buffer. Mixing was carried out by repeated pipetting. The plate used in the assay was then incubated at room temperature for 30 min and measurements were taken using an Artemis microplate reader. The percentage of inhibition due to the compounds was calculated relative to DMSO-treated control samples. To determine the IC ₅₀ values (the concentration causing 50% inhibition), a point-by-point plot of the percentage of inhibition versus the concentration of the compounds was plotted using Dotmatics software.

The example compounds effectively inhibited Vps34 and the assay results are shown in Table 1 (mean IC ₅₀ values in nM; Adapta™).

Example 69

Simultaneous multiparameter analysis of autophagy

To determine the inhibitory effect of the proprietary compounds on autophagy, human osteosarcoma (HOS) cells stably expressing green fluorescent protein (GFP)-tagged LC3 (GFP-LC3) were used. For this purpose, autophagy was activated using the mTOR inhibitor (mammalian target of rapamycin) KU-0063794 at a concentration of 500 nM in the presence of bafilomycin A1 (Sigma-Aldrich) at a concentration of 5 nM. Briefly, cells were seeded overnight in clear-bottom 96-well plates in DMEM (Dulbecco's Modified Eagle's Medium) with high glucose (Hi-Clone, Cat. No. SH30285.01). At the start of the experiment, the medium was removed and replaced with fresh medium containing mTOR inhibitor, bafilomycin A1 and diluent or test compound as indicated. After 6 hours, the medium was removed and the cells were washed twice with ice-cold phosphate buffered saline (PBS) and fixed using 4% paraformaldehyde for 20 minutes at room temperature. Cells were then washed twice with ice-cold PBS, after which nuclear dye Hoechst 33342 was added at a concentration of 1 μg/ml in PBS. After incubation overnight at 4°C, cells were washed once with PBS to remove excess dye, and 100 μl of PBS was added to each well. Images were acquired at 20× magnification, 6 images per well, using an ImageXpress automated microscope (Molecular Devices Inc.) and analyzed using MetaXpress software to identify LC3-GFP foci. Foci area per cell was used to obtain a dose response curve, and IC ₅₀ values were calculated using nonlinear fit in GraphPad Prism software.

The tested compounds from the examples effectively inhibited autophagy in HOS cells. The results of this analysis are shown in Table 2 (mean IC ₅₀ values in µM; HOS-LC3).

Claims (133)

1. Compound of formula (I) , Where R ¹ is phenyl or a monocyclic 5-6 membered heteroaryl selected from the group consisting of imidazole, pyrazole, thiazole, oxazole and pyrimidine, each optionally substituted with C ₁ -C ₆ alkyl; R ² represents a hydrogen atom; R ³ is selected from the group consisting of A, phenyl and a monocyclic heteroaryl selected from pyrazole or pyridine, each of said phenyl and heteroaryl rings being optionally substituted by one or two R ⁴ , R ⁵ , R ⁶ and R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and C ₁ -C ₆ haloalkoxy; R ⁹ represents C ₁ -C ₆ alkyl, with each C ₁ -C ₆ alkyl optionally substituted by one R ¹⁰ ; R ¹⁰ represents phenyl, and said phenyl is optionally substituted by one R ¹¹ ; R ¹¹ represents halogen; A represents R ¹² represents a hydrogen atom or a C ₁ -C ₃ haloalkyl; Y is selected from the group consisting of CH ₂ , NSO ₂ R ⁹ and O; And Z represents CH or N; or a pharmaceutically acceptable salt thereof. 2. The connection according to claim 1, where R ³ is selected from or a pharmaceutically acceptable salt thereof. 3. Connection according to claim 1 or 2, where R ³ is selected from R ⁴ is selected from CF ₃ , fluorine atom and methyl; R ⁵ represents a fluorine atom; And R ⁹ represents C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt thereof. 4. Connection according to any one of paragraphs. 1 or 2, where R ³ is selected from R ⁴ represents CF ₃ or a chlorine atom; R ⁵ represents a fluorine atom; And R ¹² represents CF ₃ ; or a pharmaceutically acceptable salt thereof. 5. Connection according to any one of paragraphs. 1-4, where R ³ represents 6. A compound according to claim 1, wherein R ³ is selected from the group consisting of A, phenyl, pyridyl and pyrazolyl, each of which is optionally and independently substituted with one or two R ⁴ or R ⁵ ; or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1, where R ³ is selected from A, phenyl and pyridyl, each of which is optionally and independently substituted with one or two R ⁴ or R ⁵ ; or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 1, where R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from fluorine atom, chlorine atom, C ₁ -C ₃ alkyl and C ₁ -C ₃ fluoroalkyl; or a pharmaceutically acceptable salt thereof. 9. Connection according to any one of paragraphs. 1, 2 or 7, where R ¹² represents a hydrogen atom or CF ₃ ; or a pharmaceutically acceptable salt thereof. 10. Connection according to any one of paragraphs. 1, 2 7, 8 or 9, where R ¹⁰ represents phenyl. 11. Connection according to any one of paragraphs. 1 or 2, where R ¹ is selected from phenyl, 4-pyrimidinyl, 2-methylpyrimidin-4-yl, 2-oxazolyl, 1-methyl-imidazol-4-yl, 2-methyl-thiazol-4-yl, and 2- methylpyrazol-3-yl; And R ³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 4-morpholinyl, 3-(trifluoromethyl)morpholin-4-yl, 2-(trifluoromethyl)-piperidin-1-yl, 2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl, 2-(trifluoromethyl)-pyridin-3-yl, 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl, 4-[(4-fluorophenyl)methylsulfonyl]-2- (trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl, 2-chloro-5-fluorophenyl, 3-(trifluoromethyl)-pyrazolin-4-yl, 2-(trifluoromethyl)- pyridin-3-yl, 2-methylphenyl, 2-methyl-piperidin-1-yl, 2-methyl-morpholin-4-yl, 2-trifluoromethyl-morpholin-4-yl; or a pharmaceutically acceptable salt thereof. 12. Connection according to any one of paragraphs. 1 or 2, where R ¹ represents phenyl or pyrimidinyl, each of which is optionally substituted with C ₁ -C ₆ alkyl; R ³ is selected from phenyl, pyridyl and pyrazolyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl; or A; Y represents CH ₂ , O, NSO ₂ -C ₁ -C ₆ alkyl or NSO ₂ -benzyl, wherein said benzyl is optionally substituted by one halogen atom; R ¹² represents C ₁ -C ₃ haloalkyl; And Z represents CH or N; or a pharmaceutically acceptable salt thereof. 13. Connection according to any one of paragraphs. 1 or 2, where R ¹ represents phenyl or 2-methylpyrimidin-4-yl; R ³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl ]-2-(trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl, 2-(trifluoromethyl)phenyl, 4-methyl-3-pyridyl, 2-(trifluoromethyl)-3 -pyridyl, 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl; And Z represents CH or N; or a pharmaceutically acceptable salt thereof. 14. Connection according to any one of paragraphs. 1 or 2, where R ¹ represents phenyl or pyrimidinyl, each of which is optionally substituted with one C ₁ -C ⁶ alkyl; R ³ is selected from phenyl or pyridyl, each of which is optionally substituted with one or two substituents selected from halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl; or A; Y represents CH ₂ , O, NSO ₂ -C ₁ -C ₆ alkyl or NSO ₂ -benzyl, wherein said benzyl is optionally substituted by one halogen atom; R ¹² represents C ₁ -C ₃ haloalkyl; And Z represents CH or N; or a pharmaceutically acceptable salt thereof. 15. A compound according to claim 1, where R ¹ represents phenyl, 2-methylpyrimidin-4-yl, oxazol-2-yl, 2-methylthiazol-4-yl, 2-methylpyrazol-3-yl and 1-methylimidazol-4 -il; And R ³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl ]-2-(trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl, 2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl, 2-(trifluoromethyl) -pyridin-3-yl and 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl; or a pharmaceutically acceptable salt thereof. 16. The compound according to claim 1, where R ¹ represents phenyl or 2-methylpyrimidin-4-yl; And R ³ is selected from 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl ]-2-(trifluoromethyl)piperazin-1-yl and 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl; or a pharmaceutically acceptable salt thereof. 17. The connection according to claim 1, where the connection is selected from 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H -pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-(oxazol-2-ylamino)-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(1-methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one and 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one, or a pharmaceutically acceptable salt thereof. 18. The connection according to claim 1, where the connection is selected from 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H -pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one and 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one, or a pharmaceutically acceptable salt thereof. 19. The connection according to claim 1, where the connection is selected from 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H -pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; or a pharmaceutically acceptable salt thereof. 20. The connection according to claim 1, selected from 4-[2-(oxazol-2-ylamino)-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 4-[2-[(2-methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; And 4-[2-[(1-Methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one, or a pharmaceutically acceptable salt thereof. 21. Use of a compound according to any one of paragraphs. 1-19 or a pharmaceutically acceptable salt thereof for inhibiting vacuolar sorting protein 34 (Vps34) in the treatment or prevention of a disease. 22. Use of a compound according to any one of paragraphs. 1-19 or a pharmaceutically acceptable salt thereof for inhibiting Vps34 in the treatment of cancer. 23. Use according to claim 22, wherein said cancer is selected from breast cancer, such as triple negative breast cancer, bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer , glioma, prostate cancer, ovarian cancer, melanoma and lung cancer, as well as hypoxic tumors. 24. Use of the compound according to any one of paragraphs. 1-19 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting Vps34 in the treatment of cancer. 25. Use according to claim 24, wherein said cancer is selected from breast cancer, such as triple negative breast cancer, bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer , glioma, prostate cancer, ovarian cancer, melanoma and lung cancer, as well as hypoxic tumors. 26. A method of inhibiting Vps34 in the treatment of cancer, comprising administering a therapeutically effective amount of a compound according to any one of claims. 1-19 or a pharmaceutically acceptable salt thereof to a patient in need thereof. 27. The method of claim 26, wherein said cancer is selected from breast cancer, such as triple negative breast cancer, bladder cancer, liver cancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, kidney cancer, colon cancer , glioma, prostate cancer, ovarian cancer, melanoma and lung cancer, as well as hypoxic tumors. 28. Pharmaceutical composition for inhibiting Vps34, containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent, carrier and/or excipient.