EA043225B1 - THIAZOL- OR THIADIAZOL-SUBSTITUTED ARYL AND HETEROARYL DERIVATIVES AS VPS34 INHIBITORS - Google Patents

Description

The present invention relates to thiazole- or thiadiazole-substituted aryl and heteroaryl compounds, pharmaceutical compositions containing them, and methods of their use, including the treatment of disorders or diseases associated with the regulation of the Vps34/PI3K III signaling pathway.

State of the art

Vps34 (vascular sorting protein 34) is a class III member of the PI3K (phosphatidylinositol-3-kinase) lipid kinase family and is involved in the regulation of numerous cellular functions. Vps34 is the only PI3 kinase expressed in all eukaryotic cells. It was originally identified in yeast and has been evolutionarily conserved in mammals. In humans, hVPS34 is encoded by the PIK3C3 gene. Vps34 phosphorylates phosphatidylinositol (PI) with the formation of phosphatidylinositol-3phosphate (PI3P) in preautophagosomes or endosomes, which leads to the recruitment of proteins containing the FYVE domain and PX (Hawkins R.T., Stephens L.R., PI3K signaling in inflammation, Biochim. Biophys. Acta ., 2015; 1851:882-897; Okkenhaug K., Signaling by the phosphoinositide 3-kinase family in immune cells, Annu. Rev. Immunol., 2013, 31:675-704; Backer J.M., Biochem. J., 2008 410:1-17). Vps34 associates with Vps15 protein kinase in various protein complexes and plays an important role in membrane traffic and protein sorting cascades. Unlike other PI3Ks, the substrate specificity of Vps34 is limited to phosphatidylinositol. This property distinguishes it from class I and II enzymes, which can be more actively phosphorylated depending on the isoform. PI3P produced by Vps34 is required for autophagosome and phagosome maturation and NOX2-mediated ROS production and therefore plays a key role in autophagy and pathogen uptake and destruction by innate immune cells.

The primary function of Vps34 is to regulate vesicular traffic in endosomes/lysosomes, where it is involved in the recruitment of proteins containing binding motifs to intracellular membranes. Inhibition of Vps34 can lead to impaired lysosomal function, impaired vesicular traffic between late endosomes and lysosomes (Pasquier B., Autophagy, 2015, 11:725-726). Vps34 activity is essential for autophagy in yeast and is significantly involved in this process in mammals. Autophagy is the process of uptake and destruction of cellular components in bilayer membrane vesicles (autophagosomes) and plays an important role in the response to oxidative damage. The interaction of Vps34 with the beclinl autophagy gene is essential for the biosynthesis, maturation, and apoptosis of autophagosomes. Inhibition of this step by Vps34 inhibitors may prevent the formation of autophagy vesicles (Chude C.I. et al. (2017), Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors, Int. J. Mol. Sci., 18(6):1279-1289 ). Vps34 is also involved in amino acid recognition and putatively regulates mTOR in mammalian cell cultures (Goberdhan D.C.I. et al. (2009), Biochem. Soc. Trans., 37(Pt 1):248-252).

Pathological activity of PI3 kinases is observed in many human pathological conditions, including diabetes, diabetes-related cardiovascular disease, polycystic ovary syndrome, cancer, neuroinflammation, and ischemic stroke. As a potential therapy for diabetes, Vps34 inhibition may increase glucose tolerance and insulin sensitivity by reducing hepatic glucose production and stimulating muscle glucose uptake. In vitro, treatment of mitotubules, hepatocytes, and myoblasts with a Vps34 inhibitor activates the AMPK cascade (provides increased levels of pAMPKT ¹⁷² and pACCS ⁷⁹ ), influencing cellular energy homeostasis. In vivo, treatment of mice on an HFD (high fat) diet with a selective Vps34 antagonist has been shown to improve both glucose tolerance and insulin sensitivity (as measured by GTT and ITT assays) (Bilanges, B. et al. (2017)., Vps34 PI 3-Kinase Inactivation Enhances Insulin Sensitivity Through Reprogramming of Mitochondrial Metabolism, Nature Comm., 8(1): article no. 1804). In cancer, Vps34 inhibitors may be useful because, unlike class I and II PI3K enzyme inhibitors, which induce autophagy, inhibition of Vps34 leads to the cessation of autophagy. Autophagy may increase the survival of apoptotic-impaired cancer cells by protecting them from metabolic stress. Inhibition of autophagy and increased susceptibility of apoptosis-resistant cells to metabolic stress could be used as a therapeutic regimen for tumors (Mathew et al. (2007), Role of autophagy in cancer, Nat. Rev. Cancer (12), p. 961- 967; Stein et al (2001), Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment, Endocrine-Related Cancer (8), pp. 237-248. Inhibition of Vps34 may also have a cytoprotective effect under stressful conditions such as ischemia-reperfusion. Inactivation of the Vps34/phosphatidylinositol-3-phosphate kinase (PI3K) III signaling pathway through pharmacological inhibition with 3-methyladenine (3MA) or through transgene expression of dominant-negative Vps34 prevents autophagy and protects dopaminergic neuroblastoma cells (SH-Sy5y) from H2O2 toxicity (Castino et al., 2010,

Inhibition of PI3k Class III-Dependent Autophagy Prevents Apoptosis and Necrosis by Oxidative Stress in Dopaminergic Neuroblastoma Cells, Toxicological Sciences (117), 1, p. 152-162).

Disclosure of invention

In one aspect, a compound of formula I is provided.

where R ¹ represents C6-C14-aryl, 5-10-membered heteroaryl, C3-C6-cycloalkyl or 4-10-membered heterocycloalkyl, and each specified C6-C14-aryl, 5-10-membered heteroaryl, C3-C6 -cycloalkyl or 4-10 membered heterocycloalkyl in R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -CN, -NO2, substituted or unsubstituted C1-C ₆ -alkyl, substituted or unsubstituted C ₂ -C ₆ -alkenyl, substituted or unsubstituted C2-C6-alkynyl, C1-C6-haloalkyl, -OR ^a , -SR ^a , -S(ObR ^a , -NRbRc, -C(O)R ^a , -OC(O )R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ -aryl, substituted or unsubstituted 5-10-membered heteroaryl and substituted or unsubstituted 4- 10-membered heterocycloalkyl;

L represents -S(O) ₂ -, -O-, -C(O)- or -CH2-;

Y ¹ represents CH or N;

R ² is 5-membered heteroaryl or 5-membered heterocycloalkyl, wherein each said 5-membered heteroaryl and 5-membered heterocycloalkyl in R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, - NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -ORd, -SRd, -S(O)2R ^d , - NR ^e R ^f , -C(O)R ^d , -OC(O)R ^d , -C(O)OR ^d , -C(O)NR ^e R ^f , -OC(O)NR ^e R ^f , - NR ^d C(O)R ^e , -NR ^d C(O)OR ^e , substituted or unsubstituted C3-C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ aryl , substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted 4-10 membered heterocycloalkyl; And

R ^a , R ^b , R ^c , Rd, R ^e and R ^f each independently represent H or C _1-4 -alkyl, and if L represents -S(O) ₂ - and Y ¹ represents N, then R ¹ is not 4,4-difluoropiperidin-1-yl;

or a pharmaceutically acceptable salt thereof.

In a preferred embodiment of a compound of formula (I), R1 is C ₆ -C ₁₄ aryl or 4-10 membered heterocycloalkyl;

L represents -S(O) ₂ -, -O-, -C(O)- or -CH2-;

Y ¹ represents CH or N;

R ² is 5-membered heteroaryl, said 5-membered heteroaryl in R ² being unsubstituted or substituted with one or more substituents selected from the group consisting of unsubstituted C1- _C6 alkyl, C1- _C6 haloalkyl, and -NR ^e R ^f ; And

R ^e and R ^f each independently represent H or C _1-4 -alkyl, and if L represents -S(O) ₂ - and Y ¹ represents N, then R ¹ is not 4,4-difluoropiperidine-1 -yl, wherein each heteroaryl contains 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and each heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur, or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of formula (I), R1 is C ₆ -C ₁₄ aryl or 4-10 membered heterocycloalkyl. In some embodiments, R ¹ is phenyl. In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl. In some embodiments, R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, R ¹ is tetrahydrofuranyl. In some embodiments, R ¹ is tetrahydropyranyl. In some embodiments, R ¹ is tetrahydrofuran-3-yl. In other embodiments, R ¹ is tetrahydropyran-4-yl.

In some embodiments of a compound of formula (I), L is -S(O) ₂ -. In some embodiments, L is -O-. In some embodiments, L is -C(O)-. In some embodiments, L is -CH ₂ -. In some embodiments, Y ¹ is CH. In some embodiments, Y ¹ is N.

- 2 043225

In some embodiments of a compound of formula (I), R ² is a 5-membered heteroaryl ring, wherein said 5-membered heteroaryl ring is substituted with one or more substituents selected from the group consisting of C1.6-alkyl, C1.6-haloalkyl, and NR ^e R ^f , where R ^e and R ^f independently represent H or C 1-4 alkyl. In some embodiments, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from the group consisting of C1.6 alkyl, C1.6 haloalkyl, and NR ^e R ^f , where R ^e and R ^f are independently H or C1. ₄ -alkyl. In some embodiments, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from methyl, CF3 and NH ₂ .

In some embodiments, R ² is

NR ^e R ^f

where G ¹ represents S or N;

G ² is CR ³ , S or N;

R ³ is H, C ₁ . ₆ -alkyl or C ₁ . ₆ -haloalkyl; And

R ^e and R ^f are independently H or C ₁ . ₄ alkyl.

In some embodiments, G ¹ is S. In some embodiments, G ¹ is N. In some embodiments, G ² is CR ³ . In some embodiments, R ³ is H. In some embodiments, R ³ is C1-6-alkyl. In other embodiments, R ³ is C1. ₆ -haloalkyl. In some embodiments, G ² is S. In some embodiments, G ² is N. In some embodiments, G ¹ is S and G ² is CR ³ , where R ³ is H, C1-6-αkyl, or C1.6 haloalkyl. In some embodiments, G ¹ is S and G ² is CH. In some embodiments, G ¹ is S and G ² is C1. ₆ -alkyl. In other embodiments, G ¹ is S and G ² is C1.6 haloalkyl. In some embodiments, G ¹ is N and G ² is S. In other embodiments, G ¹ is S and G ² is N. In some of any of the above embodiments, both R ^e and R ^f are H In some of any of the above embodiments, one of R ^e and R ^f is C1. ₄ is alkyl and the other is H. In other embodiments, R ^e and R ^f are both C ₁ . ₄ -alkyl.

Also provided are compounds selected from the group consisting of

- 3 043225

or their pharmaceutically acceptable salts.

In some embodiments, the proposed compound is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

- 4 043225

Also provided are compounds selected from the group consisting of

or their pharmaceutically acceptable salts.

In some embodiments, the proposed compound is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

Also provided are pharmaceutical compositions containing (a) at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient.

In other aspects, methods are provided for treating a disease or medical condition associated with regulation of the Vps34/PI3K III signaling pathway, comprising administering to a subject in need of such treatment an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. containing a compound of formula (I). In some embodiments, the disease or medical condition is diabetes, polycystic ovary syndrome, diabetic cardiovascular disease, cancer, neuroinflammation, or ischemic stroke. In some embodiments of the methods provided herein, the disease or medical condition is cancer, and the cancer is glioblastoma, renal cell carcinoma, or melanoma.

In some aspects, any compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I), is used to treat a disease or medical condition associated with the regulation of the Vps34/PI3K III signaling pathway. In some embodiments, the disease or medical condition is diabetes, polycystic ovary syndrome, diabetic cardiovascular disease, cancer, neuroinflammation, or ischemic stroke. In some embodiments of the uses provided herein, the disease or medical condition is cancer, and the cancer is glioblastoma, renal cell carcinoma, or melanoma.

Also provided is the use of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing at least one compound of formula (I), for the manufacture of a medicament for the treatment of a disease or medical condition associated with the regulation of a signaling pathway. Vps34/PI3K III. In some embodiments, the disease or medical condition is diabetes, polycystic ovary syndrome, diabetic cardiovascular disease, cancer, neuroinflammation, or ischemic stroke. In some embodiments of the uses provided herein, the disease or medical condition is cancer, and the cancer is glioblastoma, renal cell carcinoma, or melanoma.

- 5 043225

In another aspect, methods are provided for interfering with a Vps34/PI3K III signaling pathway in a cell, or modulating, preventing, slowing, reversing, or inhibiting a Vps34/PI3K III signaling pathway in a cell, comprising contacting said cell with an effective amount of at least one compound of the formula ( I) or a salt thereof, and/or at least one pharmaceutical composition containing a compound of formula (I), said contacting being carried out in vitro, ex vivo or in vivo.

Detailed description

The present invention relates to thiazole- or thiadiazole-substituted aryl and heteroaryl compounds, pharmaceutical compositions containing them, and methods of their use, including the treatment of disorders or diseases associated with the regulation of the Vps34/PI3K III signaling pathway.

It should be understood that the present invention is not limited to the specific embodiments described, as these may, of course, vary. It should also be understood that the terminology used herein is only intended to describe specific embodiments and should not be construed as limiting.

As used in this specification and the appended claims, the singular forms include the plural forms, unless the context clearly dictates otherwise. Additionally, it should be noted that the claims may be drafted to exclude any optional element. Thus, the said statement is intended as a preliminary basis for the use of such exclusive terminology as exclusively, only, etc., in relation to the enumeration of the elements of the claims or for the application of a negative limitation.

In the context of this document, the terms including, containing, and including are used in an open, non-limiting sense.

To provide a more concise description, some quantitative expressions presented in this document are not defined by the term approximately. It should be understood that whether the term approximate or not is used, each amount presented herein refers to an actual given value, and also refers to an approximation of a given value that is reasonable to assume based on general knowledge in the art, including equivalents and approximations due to experimental and/or measurement conditions for a given value. If the yield is given as a percentage, then the reported yield refers to the mass of the substance for which the yield is given, relative to the maximum amount of the same substance that can be obtained under specific stoichiometric conditions. Concentrations expressed as a percentage refer to mass ratios unless otherwise indicated.

Unless otherwise stated, all technical and scientific terms used in this document have the same meaning as is generally understood by a person skilled in the art to which this invention pertains. Any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All publications mentioned herein are incorporated herein by reference in relation to the disclosure and description of the methods and/or materials in connection with which these publications are mentioned.

Unless otherwise indicated, the methods and techniques of the proposed embodiments are generally carried out in accordance with standard methods known in the art, as well as in accordance with the methods described in various general and more specific sources, which are cited and discussed in this description. See, for example, Loudon, Organic Chemistry, 4th edition, New York: Oxford University Press, 2002, p. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, Wiley-Interscience, 2001.

The nomenclature used in this document for the names of the compounds in question is presented in the examples. Compound names were generally compiled using commercially available ChemBioDraw Ultra software version 14.0.

It should be understood that certain features of the present invention, which are described in the context of separate embodiments for clarity, may also be presented as a combination within a single embodiment. Conversely, certain features of the present invention, which are described for brevity in the context of one embodiment, may also be presented individually or in any suitable subcombination. All combinations of embodiments relating to the chemical groups represented by the variables are specifically contemplated by the present invention and are described herein as if each and every combination were described separately and explicitly, to the extent that such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of chemical groups listed in the embodiments describing such variables are also specifically contemplated by the present invention and are described herein as if any and each such subcombination of chemical groups were described herein individually and explicitly. .

- 6 043225

Terms.

Unless otherwise indicated, the following terms have the meanings given. Terms for which there is no definition have the meaning known in the art.

The term alkyl refers to a straight or branched monovalent saturated hydrocarbon group, or a combination thereof, containing the specified number of carbon atoms (ie, C ₁ -C ₁₀ means from one to ten carbon atoms). Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl (tBu), pentyl, isopentyl, t -pentyl, hexyl, isohexyl, and groups which, in the light of standard knowledge in the art and the teachings provided herein, are considered equivalent to any of the above examples. In some cases, the alkyl groups are C ₁ .4-alkyl.

Alkenyl in the context of this document refers to an unsaturated linear or branched monovalent hydrocarbon chain, or a combination thereof, containing at least one center of olefinic unsaturation (i.e. containing at least one moiety of the formula C=C) and having the specified number of carbon atoms (t .e C ₂ -C ₁₀ means from two to ten carbon atoms). The alkenyl group may have a cis or trans configuration, or alternatively have an E or Z configuration. Examples of alkenyl include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but -2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, their homologues and isomers, and the like.

Alkynyl in the context of this document refers to an unsaturated linear or branched monovalent hydrocarbon chain, or a combination thereof, containing at least one center of acetylenic unsaturation (i.e. containing at least one moiety of the formula C=C) and having the specified number of carbon atoms (t .e C ₂ -C ₁₀ means from two to ten carbon atoms). Examples of alkynyl include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, propy-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3 -inyl, their homologues and isomers, and the like.

Haloalkyl refers to an alkyl group as described above in which one or more hydrogen atoms of the alkyl group have been replaced by a halo group. Examples of such groups include, without limitation, fluoroalkyl groups such as fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, and the like.

Aryl or Ar refers to a monovalent aromatic carbocyclic group containing 6 to 18 ring carbon atoms, having a single ring (such as that present in the phenyl group) or a ring system containing multiple fused rings (examples of such aromatic ring systems include naphthyl, anthryl, and indanyl ), and said fused rings may or may not be aromatic, provided that the point of attachment is at an atom of the aromatic ring. This term includes, by way of example, phenyl and naphthyl.

Cycloalkyl refers to cyclic hydrocarbon groups containing from 3 to 10 ring carbon atoms, having one or more cyclic rings, including fused, bridged and spiro ring systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like, or multi ring structures such as adamantanyl and the like. In some cases, cycloalkyl is a monocyclic ring. In some cases, cycloalkyl is a 3-6 membered ring.

Cycloalkenyl refers to non-aromatic cyclic hydrocarbon groups containing from 3 to 10 ring carbon atoms, having one or more cyclic rings and having at least one ring unsaturation >C=C<. In some embodiments, the cycloalkenyl contains 1 or 2 centers of ring unsaturation >C=C<. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.

The term heteroaryl refers to a monocyclic, fused bicyclic or fused polycyclic aromatic heterocycle (a ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen and sulfur) having 5 to 12 ring atoms per heterocycle . Such heteroaryl groups contain at least one ring in said ring system that is aromatic, provided that the point of attachment is at an atom of the aromatic ring. In some embodiments, the nitrogen and/or sulfur ring atom(s) in the heteroaryl group are optionally oxidized to form N-oxide (N^O), sulfinyl, or sulfonyl moieties. In some instances, the heteroaryl groups are 5-, 6-, 8-, 9-, or 10-membered ring systems.

Examples of heteroaryls include, but are not limited to, pyrrole, furan, thiophenyl, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, benzofuran, benzothiophene, indazole 7 043225 benzoxazole, indolizine, isoindole, purine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, phenoxazine, phenothiazine , phthalimide, and the like.

Heterocycloalkyl refers to a saturated or partially unsaturated group containing one ring or multiple fused rings, including fused, bridged or spiro ring systems, and containing from 3 to 20 ring atoms, including from 1 to 10 heteroatoms. Said ring atoms are selected from the group consisting of carbon, nitrogen, sulfur or oxygen, wherein in fused ring systems one or more rings may be cycloalkyl, aryl or heteroaryl provided that the point of attachment is on a non-aromatic ring. In some embodiments, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to form N-oxide moieties, -S(O)- or -SO2-. Examples of heterocycloalkyls include, but are not limited to, azetidine, oxetane, tetrahydrofuran, pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine, 1,1-dioxothiomorpholinyl, dihydroindole, indazole, quinolysine, imidazolidine, imidazoline, indoline, 1,2,3,4 -tetrahydroisoquinoline, thiazolidine, and the like. In some cases, heterocycloalkyl groups are 4-, 5-, or 6-membered rings. In some cases, heterocycloalkyl contains a fused phenyl ring.

Halo or halogen refers to fluorine, chlorine, bromine and iodine.

In addition to the description provided herein, the term substituted, as used to modify a particular group or radical, means that one or more hydrogen atoms of a particular group or radical, each independently of the other, are substituted with the same or different groups of substituents as described below. . Substituent groups include, but are not limited to, alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halogen, hydroxyl, nitro, carboxyl, thiol , thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy, and the like. The term unsubstituted means that the specified group has no substituents. The term optionally substituted means that said group is unsubstituted or substituted with one or more substituents. When using the term substituted to describe a structural system, substitution can take place at any position in the system allowed by the valency. If a group or fragment contains more than one substituent, it should be understood that the substituents may be the same or different from each other. In some embodiments, the substituted group or moiety contains from one to five substituents. In some embodiments, the substituted group or moiety contains one substituent. In some embodiments, the substituted group or moiety contains two substituents. In some embodiments, the substituted group or moiety contains three substituents. In some embodiments, the substituted group or moiety contains four substituents. In some embodiments, the substituted group or moiety contains five substituents.

Any formula depicted herein is intended to refer to a compound of a given structural formula, as well as certain variations or forms. For example, a formula given herein includes the racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. In addition, any formula given herein also refers to a hydrate, solvate or polymorph of a given compound, or a mixture thereof.

Any formula provided herein is also intended to refer to the unlabeled and isotopically labeled forms of these compounds. Isotopically labeled compounds have structures depicted by the formulas presented herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine such as ² H, ³ H, ^P C, ¹³ C, ¹⁴ C, ¹⁵ N , ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and ¹²⁵ I, respectively. Such isotopically labeled compounds are suitable for metabolic studies (preferably with ¹⁴ C), reaction kinetics studies (for example with ² H or ³ H), detection or imaging technologies [such as positron emission tomography (PET) or single photon emission computed tomography ( SPECT)], including drug or substrate tissue distribution assays, or for radioactive treatment of patients. In particular, a compound labeled ¹⁸ F or ⁿ C may be particularly preferred for PET or SPECT studies. PET and SPECT studies can be performed as described, for example, in Brooks DJ, Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development, NeuroRx, 2005, 2(2), 226-236, and in the references cited therein. In addition, substitution with heavier isotopes such as deuterium (ie, ² H) may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced doses required. The isotopically labeled compounds of the present invention and their prodrugs can generally be prepared

- 8 043225 methods described in the schemes or in the examples and methods of preparation below, by replacing the reagent without an isotope label with an available reagent with an isotope label.

The nomenclature Ci-j, where j is greater than i, used herein to designate a class of substituents, refers to embodiments of the present invention for which each and all possible numbers of carbon atoms, from i to j, including i and j, are individually implemented. For example, the term C independently refers to embodiments that have one carbon atom (C ₁ ), to embodiments that have two carbon atoms (C ₂ ), and to embodiments that have three carbon atoms (C ₃ ).

In this context, any reference to a disubstituent includes various attachment options when there is more than one such possibility. For example, reference to a di-substituent -A-B-, where AaB, in this context refers to such a di-substituent in which A is attached to the first substituted element and B is attached to the second substituted element, and also refers to such a di-substituent in which A is attached to the second substituted element, and B is attached to the first substituted element.

With respect to any groups described herein that contain one or more substituents, it is of course to be understood that such groups do not contain substituents or substitution methods that are sterically impossible and/or synthetically impossible. In addition, the considered compounds include all stereochemical isomers arising from the substitution of these compounds.

The present invention also includes pharmaceutically acceptable salts of the compounds represented by formula (I), preferably the compounds described above, and specific compounds, examples of which are given herein, as well as pharmaceutical compositions containing such salts, and methods of using these salts.

A pharmaceutically acceptable salt means a free acid or base salt of a compound provided herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See in general S.M. Berge et al., Pharmaceutical Salts, J. Pharm. Sci., 1977, 66, 1-19. Particular pharmaceutically acceptable salts are salts that are pharmacologically effective and suitable for contact with the tissues or body of a subject without undue toxicity, irritation, or allergic reaction. The compound described herein may contain a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one group of each type, and, accordingly, can react with a variety of inorganic or organic bases, as well as inorganic or organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates. , oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, metalsulfonates, propylsulfonates , besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates and mandelates. A list of other suitable pharmaceutically acceptable salts is provided in Remington, Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985.

For a compound of formula (I) which contains a basic nitrogen atom, a pharmaceutically acceptable salt may be prepared by any suitable method known in the art, for example by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid and the like, or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidilic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as mandelic acid, citric acid or tartaric acid, amino acid such as aspartic acid or glutaric acid, aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid, or any compatible mixture of acids, such as those described in the examples provided herein, and any other acid and mixture thereof that are considered equivalents or acceptable substitutes in light of the general level of knowledge in this technology.

- 9 043225

A solvate refers to a complex formed by the combination of solvent molecules with molecules or ions of a solute. The solvent may be an organic compound, an inorganic compound, or a mixture thereof. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. If the solvent is water, then the solvate formed is a hydrate.

Stereoisomer and stereoisomers refer to compounds that have the same order of joining atoms, but a different arrangement of atoms in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers and diastereomers.

Tautomer refers to alternative forms of the molecule that differ only in the electronic bonding of atoms and/or the position of the proton, such as enol-ketone and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing a ring grouping of atoms -N=C(H)-NH- such as pyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles. Those skilled in the art will recognize that other tautomeric ring atom arrangements are possible.

The term or a salt or solvate or stereoisomer thereof should be understood to include all permutations of salts, solvates and stereoisomers, for example a solvate of a pharmaceutically acceptable salt or stereoisomer of the compound in question.

Connections.

The compounds and their salts (such as pharmaceutically acceptable salts) are described in detail herein, including the summary of the invention and the appended claims. Also provided are the use of all compounds described herein, including salts and solvates of the compounds described herein, as well as methods for preparing such compounds. Any compound described herein may also be referred to as a drug compound.

In one aspect, compounds of formula (I) are provided.

where R ¹ represents C6-C14-aryl, 5-10-membered heteroaryl, C3-C6-cycloalkyl or 4-10-membered heterocycloalkyl, and each specified C6-C14-aryl, 5-10-membered heteroaryl, C3-C6 -cycloalkyl or 4-10 membered heterocycloalkyl in R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -CN, -NO2, substituted or unsubstituted C1-C ₆ -αkyl, substituted or unsubstituted C ₂ -C ₆ -alkenyl, substituted or unsubstituted C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -haloαalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C( O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted 5-10 membered heteroaryl, and substituted or unsubstituted 4-10 membered heterocycloalkyl;

L represents -S(O) ₂ -, -O-, -C(O)- or -CH2-;

Y ¹ represents CH or N; And

R ² is 5-membered heteroaryl or 5-membered heterocycloalkyl, wherein each said 5-membered heteroaryl and 5-membered heterocycloalkyl in R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, - NO2, substituted or unsubstituted C1-C6-αalkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl, C1-C6-halogenαalkyl, -OR ^d , -SR ^d , -S(O)2R ^d , -NR ^e R ^f , -C(O)R ^d , -OC(O)R ^d , -C(O)OR ^d , -C(O)NR ^e R ^f , -OC(O)NR ^e R ^f , -NR ^d C(O)R ^e , -NR ^d C(O)OR ^e , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C6-C ₁₄ aryl, substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted 4-10 membered heterocycloalkyl;

R ^a , R ^b , R ^c , R ^d , R ^e and R ^f each independently represent H or C _1-4 -alkyl, and if L represents -S(O) ₂ - and Y ¹ represents N, then R ¹ is not 4,4-difluoropiperidin-1 -yl, or their pharmaceutically acceptable salts.

In some embodiments of formula (I), R ¹ is C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, C ₃ -C ₆ cycloalkyl, or 4-10 membered heterocycloalkyl, each of which is substituted with one or more substituents selected from the group consisting of halogen, -CN, -NO ₂ , substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, C1- C ₆ -haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b In some embodiments,

- 10 043225 formula (I) R ¹ represents C6-C14-aryl, 5-10-membered heteroaryl, C3-C6-cycloalkyl or 4-10-membered heterocycloalkyl, and each specified C6-C14-aryl, 5-10- the membered heteroaryl, C3-C6-cycloalkyl or 4-10-membered heterocycloalkyl in R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -CN, -NO2, C1-C ₆ -alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, -OR ^a , -SR ^a , -S(O) 2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C (O)R ^b , -NR ^a C(O)OR ^b . In some embodiments of Formula (I), R ¹ is C6-C14 aryl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, or 4-10 membered heterocycloalkyl, each said C6-C14 aryl, 5-10 -membered heteroaryl, C3-C6-cycloalkyl or 4-10-membered heterocycloalkyl in R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, - NR ^b R ^c . In some embodiments of Formula (I), R ¹ is C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, C ₃ -C ₆ cycloalkyl, or 4-10 membered heterocycloalkyl, each of which is unsubstituted.

In some embodiments of formula (I), R ¹ is C6 or Cu aryl, 5-6 membered heteroaryl, C5-C6 cycloalkyl, or 5-6 membered heterocycloalkyl, each of which is substituted with one or more substituents selected from the group, consisting of halogen, -CN, -NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , - OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b . In some embodiments of Formula (I), R ¹ is C6 or _C10 aryl, 5-6 membered heteroaryl, _C5 - _C6 cycloalkyl, or 5-6 membered heterocycloalkyl, each said _C6 or C ₁₀ -aryl, 5-6 membered heteroaryl, C5- _C6- cycloalkyl or 5-6 membered heterocycloalkyl in R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, Q-Qalkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , NR ^b R ^c , - C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O) R ^b , -NR ^a C(O)OR ^b . In some embodiments of Formula (I), R ¹ is C6 or _C10 aryl, 5-6 membered heteroaryl, C5- _C6 cycloalkyl, or 5-6 membered heterocycloalkyl, each said _C6 or _C10 -aryl, 5-6 membered heteroaryl, C ₅ -C ₆ -cycloalkyl or 5-6 membered heterocycloalkyl in R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 - C6 haloalkyl, -NR ^b R ^c . In some embodiments of Formula (I), R ¹ is C6 or _C10 aryl, 5-6 membered heteroaryl, C5- _C6 cycloalkyl, or 5-6 membered heterocycloalkyl, each of which is unsubstituted.

In some embodiments of formula (I), R ¹ is C6-C14 aryl, unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C(O) R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , - NR ^a C(O)OR ^b ; substituted or unsubstituted C3- _C6 cycloalkyl, substituted or unsubstituted _C3 - _C6 cycloalkenyl, substituted or unsubstituted _C6 - _C14 aryl, substituted or unsubstituted 5-10-membered heteroaryl, and substituted or unsubstituted 4-10-membered heterocycloalkyl. In some embodiments, R ¹ is phenyl or naphthyl substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6-haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , C3-C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkenyl, C ₆ -C ₁₄ -aryl, 5-10-membered heteroaryl and 4-10-membered heterocycloalkyl. In some embodiments, R ¹ is phenyl. In some embodiments, R ¹ is naphthyl.

In some embodiments, R ¹ is 4-10 membered heterocycloalkyl, unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2 -C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl, C1-C6-haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C (O)OR ^b , substituted or unsubstituted C3-C ₆ -cycloalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ -aryl, substituted or unsubstituted 5-10-membered heteroaryl and substituted or unsubstituted 4-10 membered heterocycloalkyl. In other embodiments, R ¹ is 5-6 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 -alkynyl, C1-C6-haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C( O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , C3-C ₆ - cycloalkyl, C ₃ -C ₆ -cycloalkenyl, C ₆ -C ₁₄ -aryl, 5-10 membered heteroaryl and 4-10 membered heterocycloalkyl. In some embodiments, R ¹ is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,2-dioxothiomorpholinyl, azepinyl, or diazepinyl, each of which is unsubstituted or substituted with one or more substituents selected from groups,

- 11 043225 consisting of halogen, -CN, -NO2, C ₁ -C ₆ -alkyl C ₂ -Cb-alkenyl, C _{2 -Cb} -alkynyl, C1-Cb-haloalkyl, -OR ^a , -SR ^a , -S (O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O )NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C6-C14-aryl, 5-10-membered heteroaryl and 4-10 membered heterocycloalkyl. In some embodiments, R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of C1- _C6 alkyl, _C1 - _C6 -haloalkyl and -NR ^b R ^c , where R ^b and R ^c each independently represent H or C1.4-alkyl. In some embodiments, R ¹ is unsubstituted tetrahydrofuranyl. In some embodiments, R ¹ is tetrahydrofuranyl substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C ₁ -C 6 haloalkyl, -NHC ₁ . ₄ -alkyl, -N(C ₁ . ₄ -alkyl) ₂ and NH2. In some embodiments, R ¹ is unsubstituted tetrahydropyranyl. In some embodiments, R ¹ is tetrahydropyranyl substituted with one or more substituents selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C 6 haloalkyl, -NHC ₁ . ₄ -alkyl, -N(C ₁ . ₄ -alkyl) ₂ and NH2. In some embodiments, R ¹ is tetrahydrofuran-3-yl. In other embodiments, R ¹ is tetrahydropyran-4-yl. In some embodiments, R ¹ is an unsubstituted piperidine. In some embodiments, if Y ¹ is N, then R ¹ is an unsubstituted piperidine.

In some embodiments, L is -S(O) ₂ -. In some embodiments, L is -O-. In some embodiments, L is -C(O)-. In some embodiments, L is -CH2-.

In some embodiments, Y ¹ is CH. In some embodiments, Y ¹ is N.

In some embodiments of Formula (I), R ² is 5-membered heteroaryl or 5-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C1 -C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^d , -SR ^d , -S(OhR ^d , -NReRf, -C(O )R ^d , -OC(O)R ^d , -C(O)OR ^d , -C(O)NR ^e Rf, -OC(O)NR ^e Rf, -NR ^d C(O)R ^e , -NR ^d C(O)OR ^e In some embodiments, R ² is 5-membered heteroaryl or 5-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents selected from the group consisting of _C1.6 -alkyl, C _{1 6} -haloalkyl and NReRf.

In some embodiments of Formula (I), R ² is a 5-membered heteroaryl ring; substituted with one or more substituents selected from C1.6-alkyl, C1.6-haloalkyl and NReRf, where R ^e and Rf are independently H or C1. ₄ -alkyl. In some embodiments, R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6-alkyl, C1.6-haloalkyl, NHC1.4-alkyl, N(C1.4-alkyl)2 and NH2. In some embodiments, R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, NHCH3, NH2. In other embodiments, R ² is a 5-membered heteroaryl ring substituted with an NReRf group, where R ^e and Rf are independently hydrogen or methyl. In other embodiments, R ² is a 5-membered heteroaryl ring substituted with an NH2 group. In some embodiments, R ² is a 5-membered heteroaryl ring substituted with C1.6 haloalkyl. In some embodiments, R ² is a 5-membered heteroaryl ring substituted with trifluoromethyl or difluoroethyl. In some embodiments, R ² is a 5-membered heteroaryl ring substituted with a trifluoromethyl group. In some embodiments, R ² is a 5-membered heteroaryl ring substituted with C1.6 alkyl. In some embodiments, R ² is a 5-membered heteroaryl ring; substituted with C1.6-alkyl and NReRf; where R ^e and Rf are both H. In some embodiments, R ² is a 5-membered heteroaryl ring; substituted C1. ₆ -haloalkyl and NReRf, where both R ^e and Rf are H. In some embodiments, R ² is a 5-membered heteroaryl ring that contains one, two, or three heteroatoms selected from the group consisting of N, S, and O In some embodiments, R ² is a 5-membered heteroaryl ring that contains one or two nitrogen ring members. In some embodiments, R ² is a 5-membered heteroaryl ring that contains a sulfur atom. In some embodiments, R ² is a 5-membered heteroaryl that contains one nitrogen ring member. In some embodiments, R ² is selected from the group consisting of pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl or benzoxazolyl, each of which

- 12 043225 is optionally substituted with one or more substituents selected from C _1-6 alkyl, C _1-6 haloalkyl and NR ^e R ^f . In some embodiments, R ² is a thiazole or thiadiazole, each of which is optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, and NR ^e R ^f In some embodiments, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from methyl, CF3 and NH2. In some embodiments, R ² is thiazolyl substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, and NR ^e R ^f In some embodiments, R ² is 1,3-thiazole substituted with one or more substituents selected from methyl, CF3 and NH ₂ . In some embodiments, R ² is thiadiazolyl substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, and NR ^e R ^f In some embodiments, R ² is 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole or 1,3,4-thiadiazole, each of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, C _1-6 haloalkyl and NR ^e R ^f In some embodiments, R ² is 1,3,4-thiadiazole substituted with one or more substituents selected from methyl, CF3 and NH ₂ .

In some embodiments, R ² is

S or N, G ² is CR ³ , S or N, R ³ is where G ¹ is H, C _1-6 alkyl or

C _1-6 haloalkyl and R ^e and R ^f are independently H or C 1-4 alkyl. In some embodiments, G ¹ is S. In some embodiments, G ¹ is N. In some embodiments, G ² is CR ³ , where R ³ is C 1-6 alkyl or C _1-6 haloalkyl. In some embodiments, G ² is CH. In other embodiments, G ² is CR ³ where R ³ is C1-6 alkyl. In other embodiments, G ² is CR ³ where R ³ is C1-6 haloalkyl. In some embodiments, G ² is S. In some embodiments, G ² is N.

NR ^e R ^f

In some embodiments, R ² is where one of R ^e and R ^f is H and the other is C 1-4 alkyl. In some embodiments, R ^e and R ^f are both C1- _C4 alkyl. In some embodiments, both R ^e and R ^f are H.

NR ^e R ^f

In some embodiments, R ² is where G ¹ is

S, G ² is CR ³ , S or N, R ³ is H, C1-6 alkyl, or C1-6 haloalkyl, and R ^a and R ^b are both H. In some embodiments, G ¹ is N , G ² is CR ³ , S or N; where R ³ is H, C1-6 alkyl, or C _1-6 haloalkyl and both R ^a and R ^b are H.

In some embodiments, R ² is

NR ^e R ^f

or ^N A,

V , where R ³ represents H, C1-6-alkyl or C1-6-haloalkyl and R ^e and R ^f independently represent H or C1-4-alkyl. In some embodiments, R ² is

- 13 043225

NR®R ^f

In some embodiments, R ² is > where G ¹ is

S or N, G ² is CR ³ , R ³ is H, C1-6 alkyl or C1.6 haloalkyl, and both R ^e and R ^f are H. In some embodiments, G ¹ is S or N , G ² is S and R ^e and Rf are each independently H or C1-4 alkyl. In some embodiments, G ¹ is S or N, G ² is N, and R ^e and R ^f are each independently H or C _1-4 alkyl.

NR ^e R ^f

In some embodiments, R ² is where G ¹ is

S or N, G ² is CR ³ , R ³ is H, and R ^a and R ^b are each independently H or C _1-4 alkyl.

In some embodiments, G ¹ is S or N, G ² is CR ³ , where R ³ is C1_6 alkyl and R ^e and Rf are each independently H or C 1-4 alkyl. In some embodiments, G ¹ is S or N, G ² is CR ³ , where R ³ is C1_6 haloalkyl and R ^e and Rf are each independently H or C 1-4 alkyl.

In some embodiments of formula (I), R ¹ is C6-C14-aryl and R ² is 5-membered heteroaryl, where R ¹ is substituted or unsubstituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₂ -C ₆ -alkenyl, substituted or unsubstituted C2-Cb-alkynyl, C1-Cb-haloalkyl, -OR ^a , -SR ^a , -S (O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O )NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C6-C14 -aryl, substituted or unsubstituted 5-10 membered heteroaryl, and substituted or unsubstituted 4-10 membered heterocycloalkyl, and R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, C 1 -C6 haloalkyl, -OR ^d , -SR ^d , -S(O )2R ^d , -NR ^e R ^f , -C(O)R ^d , -OC(O)R ^d , -C(O)OR ^d , -C(O)NR ^e R ^f , -OC(O)NR ^e R ^f , -NR ^d C(O)R ^e , -NR ^d C(O)OR ^e , substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ -aryl, substituted or unsubstituted 5-10-membered heteroaryl and substituted or unsubstituted 4-10-membered heterocycloalkyl.

In some embodiments, R ¹ is 5-10 membered heteroaryl and R ² is 5 membered heteroaryl, where R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO ₂ , substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₂ -C ₆ -alkenyl, substituted or unsubstituted C2-Cb-alkynyl, C1-Cb-haloalkyl, -OR ^a , -SR ^a , -S (O )2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C6-C14 aryl , substituted or unsubstituted 5-10 membered heteroaryl, and substituted or unsubstituted 4-10 membered heterocycloalkyl, and R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^d , -SR ^d , -S(O)2R ^d , -NR ^e R ^f , -C(O)R ^d , -OC(O)R ^d , -C(O)OR ^d , -C(O)NR ^e R ^f , -OC(O)NR ^e R ^f , -NR ^d C(O)R ^e , -NR ^d C(O)OR ^e , substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ -aryl , substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted 4-10 membered heterocycloalkyl.

In some embodiments, R ¹ is C3-C6 cycloalkyl and R ² is 5-membered heteroaryl, where R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C1- _C6 alkyl, substituted or unsubstituted _C2 - _C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted

- 14 043225

4-10 membered heterocycloalkyl, and R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -CN, -NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl , substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^d , -SR ^d , -S(O)2R ^d , -NReRf, -C(O)R ^d , -OC(O)R ^d , -C(O)OR ^d , -C(O)NR ^e Rf, -OC(O)NR ^e Rf, -NR ^d C(O)R ^e , -NR ^d C(O)OR ^e , substituted or unsubstituted C3- _C6 cycloalkyl, substituted or unsubstituted _C3 - _C6 cycloalkenyl, substituted or unsubstituted _C6 - _C14 aryl, substituted or unsubstituted 5-10 membered heteroaryl, and substituted or unsubstituted 4-10 membered heterocycloalkyl.

In some embodiments, R ¹ is 4-10 membered heterocycloalkyl and R ² is 5 membered heteroaryl, where R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , - NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NRbR ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted 5-10 -membered heteroaryl and substituted or unsubstituted 4-10-membered heterocycloalkyl, and R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C1-C6 alkyl, substituted or an unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a C1-C6 haloαalkyl, -OR ^d , -SR ^d , -S(O)2R ^d , -NReRf, -C(O)R ^d , -OC(O)R ^d , -C(O)OR ^d , -C(O)NR ^e Rf , -OC(O)NR ^e R ^f , -NR ^d C(O)R ^e , -NR ^d C( O)OR ^e , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C ₆ cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted 5-10 membered heteroaryl, and substituted or unsubstituted 4- 10-membered heterocycloalkyl.

In some embodiments of formula (I), R ¹ is C6-C14-aryl and R ² is a 5-membered heterocycloalkyl, where R ¹ is substituted or unsubstituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₂ -C ₆ -alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, C ₁ -C ₆ -haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , substituted or unsubstituted C3-C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl , substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted 5-10 membered heteroaryl, and substituted or unsubstituted 4-10 membered heterocycloalkyl, and R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -CN, -NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^d , -SR ^d , - S(O)2R ^d , -NReRf, -C(O)R ^d , -OC(O)R ^d , -C(O)OR ^d , -C(O)NR ^e Rf, -OC(O)NR ^e R ^f , -NR ^d C(O)R ^e , -NR ^d C(O)OR ^e , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C ₆ cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ -aryl, substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted 4-10 membered heterocycloalkyl.

In some embodiments, R ¹ is 5-10 membered heteroaryl and R ² is 5 membered heterocycloalkyl, where R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted 4-10 membered heterocycloalkyl, and R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₂ -C ₆ -alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6-halogenαalkyl, -OR ^d , -SR ^d , -S(O)2R ^d , -NReRf, - C(O)R ^d , -OC(O)R ^d , -C(O)OR ^d , -C(O)NR ^e Rf , -OC(O)NR ^e R ^f , -NR ^d C(O)R ^e , -NR ^d C(O)OR ^e , substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ -aryl, substituted or unsubstituted 5- 10-membered heteroaryl; and substituted or unsubstituted 4-10-membered heterocycloalkyl.

In some embodiments, R ¹ is C3-C6 cycloalkyl and R ² is 5-membered heterocycloalkyl, where R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C1- _C6 alkyl, substituted or unsubstituted _C2 - _C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 haloalkyl, -OR ^a , -SR ^a , -S(O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, replace

- 15 043225 saturated or unsubstituted C ₃ -C ₆ -cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ -aryl, substituted or unsubstituted 5-10-membered heteroaryl and substituted or unsubstituted 4-10-membered heterocycloalkyl, and R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1- C6-haloalkyl, -OR ^d , -SR ^d , -S(O)2R ^d , -NReRf, -C(O)R ^d , -OC(O)R ^d , -C(O)OR ^d , -C( O)NR ^e Rf, -OC(O)NR ^e Rf, -NR ^d C(O)R ^e , -NR ^d C(O)OR ^e , substituted or unsubstituted C3-C ₆ -cycloalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ -aryl, substituted or unsubstituted 5-10-membered heteroaryl and substituted or unsubstituted 4-10-membered heterocycloalkyl.

In some embodiments, R ¹ is 4-10 membered heterocycloalkyl and R ² is 5 membered heterocycloalkyl, where R ¹ is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, -CN, -NO2, substituted or unsubstituted C ₁ -C6 alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, -OR ^a , -SR ^a , -S (O)2R ^a , -NR ^b R ^c , -C(O)R ^a , -OC(O)R ^a , -C(O)OR ^a , -C(O)NR ^b R ^c , -OC(O )NR ^b R ^c , -NR ^a C(O)R ^b , -NR ^a C(O)OR ^b , substituted or unsubstituted C3-C ₆ -cycloalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkenyl, substituted or unsubstituted C ₆ -C ₁₄ -aryl, substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted 4-10 membered heterocycloalkyl, and R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, -CN , -NO ₂ , substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₂ -C ₆ -alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, C ₁ -C ₆ -haloalkyl, -OR ^d , -SR ^d , -S(O)2R ^d , -NR ^e Rf , -C(O)R ^d , -OC(O)R ^d , -C(O)OR ^d , -C(O)NR ^e R ^f , -OC(O)NR ^e R ^f , -NR ^d C(O)R ^e , -NR ^d C(O)OR ^e , substituted or unsubstituted C3-C6-cycloalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkenyl , substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted 5-10 membered heteroaryl, and substituted or unsubstituted 4-10 membered heterocycloalkyl.

In some embodiments, R ¹ is C6-C14-aryl, L is -S(O)2-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1. ₆ -alkylα, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is C6-C ₁₄ -aryl, L is -O-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6- alkyl, C1.6-haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is C6-C14-aryl, L is -C(O)-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1 . ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is C6-C ₁₄ -aryl, L is -CH ₂ -, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6 -alkyl, C1.6-haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1. ₄ -alkyl.

In some embodiments, R ¹ is phenyl or naphthyl, L is -S(O)2-, Y ¹ is CH, and R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1. ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is -O-, Y ¹ is CH, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1. ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is -C(O)-, Y ¹ is CH, and R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1. ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is -CH2-, Y ¹ is CH, and R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1.6 alkyl, C1.6 -haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1. ₄ -alkyl.

In some embodiments, R ¹ is C6-C14-aryl, L is -S(O)2-, Y ¹ is N, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1 . ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is C6-C ₁₄ -aryl, L is -O-, Y ¹ is N, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C ₁ . ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is C6-C ₁₄ -aryl, L is -C(O)-, Y ¹

- 16 043225 is N and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C ₁ . ₆ -alkyl, C _1-6 -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is C6-C ₁₄ -aryl, L is -CH ₂ -, Y ¹ is N, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C _{1- 6} -alkyl, C ₁ . ₆ haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C _1-4 alkyl.

In some embodiments, R ¹ is phenyl or naphthyl, L is -S(O)2-, Y ¹ is N, and R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1. ₆ alkyl, C _1-6 haloalkyl, and NR ^a R ^b , where R ^a and R ^b are independently H or C 1-4 alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is -O-, Y ¹ is N, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1-6 alkyl, C _1-6 - haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C 1-4 alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is —C(O)—, Y ¹ is N, and R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1. ₆ -alkyl, C ₁ . ₆ haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1-4 alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is -CH2-, Y ¹ is N, and R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1.6 alkyl, C1.6 -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C 1-4 alkyl.

In some embodiments, R ¹ is a 5- or 6-membered heterocycloalkyl, L is -S(O)2-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents, selected from C1-6 alkyl, C1-6 haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C 1-4 alkyl. In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L is -O-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6 -alkyl, C1.6-haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1. ₄ alkyl. In some embodiments, R ¹ is a 5- or 6-membered heterocycloalkyl, L is -C(O)-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from from C1.6-alkylα, C1.6-haloalkyl and NR ^a R ^b where R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L is -CH2-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6 -alkyl, C1.6-haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1. ₄ -alkyl.

In some embodiments, R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, L is -S(O)2-, Y ¹ is CH, and R ² is thiazolyl or thiadiazolyl substituted with one or more substituents , selected from C1.6-alkyl, C1.6-haloalkyl and NR ^a R ^b where R ^a and R ^b independently represent H or C1. ₄ -alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, L is -O-, Y ¹ is CH, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1 .6-alkyl, C1.6-haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, L is -C(O)-, Y ¹ is CH, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents, selected from C1.6-alkyl, C1.6-haloalkyl and NR ^a R ^b where R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, L is -CH2-, Y ¹ is CH, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1 . ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C ₁ . ₄ -alkyl.

In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L is -S(O)2-, Y ¹ is N, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from from C1. ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L is -O-, Y ¹ is N, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1. ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C ₁ . ₄ -alkyl. In some embodiments, R ¹ is a 5- or 6-membered heterocycloalkyl, L is -C(O)-, Y ¹ is N, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from from

- 17 043225

C1-b-alkyl, C1-b-haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C _1-4 -alkyl. In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L is -CH2-, Y ¹ is N, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C ₁ _ ₆ -alkyl, C ₁ _ ₆ -haloalkyl and

NR ^a R ^b , where R ^a and R ^b are independently H or C ₁ _ ₄ alkyl.

In some embodiments, R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, L is -S(O)2-, Y ¹ is N, and R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1. ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, L is -O-, Y ¹ is N, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1 . ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, L is -C(O)-, Y ¹ is N, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents, selected from C1. ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1_4-alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, L is -CH2-, Y ¹ is N, R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from C1 .6-alkyl, C1-6 haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1. ₄ -alkyl.

In some embodiments, R ¹ is tetrahydrofuranyl, L is -S(O)2-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6- alkyl, C1.6-haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1_ ₄ -alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, L is -O-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6-alkylα, C1.6 -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1_ ₄ -alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, L is -C(O)-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6-alkyl , C1.6-haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, L is -CH2-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6-alkylα, C1. 6-haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, L is -S(O)2-, Y ¹ is N, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1. ₆ -alkylα, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1_4-alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, L is -O-, Y ¹ is N, R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1. ₆ -αkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, L is -C(O)-, Y ¹ is N, R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1. ₆ -alkylα, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1.4-alkyl. In some embodiments, R ¹ is tetrahydrofuranyl, L is -CH2-, Y ¹ is N, R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1. ₆ -alkyl, C ₁ . ₆ haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C ₁ _ ₄ alkyl.

In some embodiments, R ¹ is tetrahydropyranyl, L is -S(O)2-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1. ₆ -alkyl, C ₁ . ₆ haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C ₁ _ ₄ alkyl. In some embodiments, R ¹ is tetrahydropyranyl, L is -O-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6-alkyl, C1.6 -haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is tetrahydropyranyl, L is —C(O)—, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C ₁ . ₆ -alkyl, C ₁ . ₆ -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C1_4-alkyl. In some embodiments, R ¹ is tetrahydropyranyl, L is -CH2-, Y ¹ is CH, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C _1-6- alkyl, C _1-6 haloalkyl, and NR ^a R ^b , where R ^a and R ^b are independently H or C 1-4 alkyl. In some embodiments, R ¹ is tetrahydropyranyl, L is -S(O)2-, Y ¹ is N, and R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1-6 alkyl , C1.6-haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1-4 alkyl. In some embodiments, R ¹ is tetrahydropyranyl, L is -O-, Y ¹ is N, R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1-6 alkyl, C1-6 -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C 1-4 alkyl. In some embodiments, R ¹ is tetrahydropyranyl, L is -C(O)-, Y ¹ is N, R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1.6-alkylα, C1-6 haloalkyl and NR ^a R ^b , where R ^a and R ^b are independently H or C1-4 alkyl. In some embodiments, R ¹ is tetrahydropyranyl, L is -CH2-, Y ¹ is N, R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from C1-6 alkyl, C1-6 -haloalkyl and NR ^a R ^b , where R ^a and R ^b independently represent H or C 1-4 alkyl.

In some embodiments, R ¹ is phenyl or naphthyl, L is coNR ^e R ^f

Tn ⁴

C) N bout -S(O) ₂ -, Y ¹ is CH and R ² is , where G ¹ is

S or N, G ² is CR ³ , S or N, R ³ is H, C1-6 alkyl or C1-6 haloalkyl, and R ^a and R ^b are independently H or C 1-4 alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is -O-, Y ¹ is CH, and R ² is NR ^e R ^f

G%(

I C J N

- where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C1.6-αkyl or C1.6-haloalkyl and R ^a and R ^b are independently H or C1 . ₄ -alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is

NR ^e R ^f G ¹ ^( is -C(O)-, Y ¹ is CH and R ² is where G ¹ is

S or N, G ² is CR ³ , S or N, R ³ is H, C1-6 alkyl or C1-6 haloalkyl, and R ^a and R ^b are independently H or C 1-4 alkyl.

In some embodiments, R ¹ is phenyl or naphthyl, L is coNR ^e R ^f g^ (j N moi -CH2-, Y ¹ is CH and R ² is > where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C1-6 alkyl, or C 1-6 haloalkyl, and R ^a and R ^b are independently H or C 1-4 alkyl In some embodiments, R ¹ is is phenyl or naphthyl, L is -S(O) ₂ -, Y ¹ is N and R ² is

where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C _1-6 alkyl or C _1-6 haloalkyl, and R ^a and R ^b are independently H or C _1-4 -alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is NR ^e R ^f

From ¹ D\

I C JN is -O-, Y ¹ is N and R ² is ' where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C1-6-alkyl or C1-6 haloalkyl and R ^a and R ^b are independently H or C1-4 alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is —C(O)—, Y ¹ is N, and R ² is NR ^e R*

C ) N is ' where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C ₁ . ₆ -alkyl or C ₁ . ₆ -haloalkyl and R ^a and R ^b are independently H or C ₁ . ₄ -alkyl. In some embodiments, R ¹ is phenyl or naphthyl, L is

NR ^e R ^f

With JN is -CH ₂ -, Y ¹ is N and R ² is ' where G ¹ is

S or N, G ² is CR ³ , S or N, R ³ is H, C1.6 alkyl or C1.6 haloalkyl, and R ^a and R ^b are independently H or C1. ₄ -alkyl.

In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L

NR ^e R ^f g ¹ ^

C ) N is -S(O) ₂ -, Y ¹ is CH and R ² is • where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C1.6-alkyl or C1.6-haloalkyl and R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L is -O-, Y ¹

NR ^e R ^f

G%(

I ( ) N is CH and R ² is ' where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C1.6-alkyl or C1.6-haloalkyl and R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L is -C(O)-, Y ¹ is CH, and R ²

NR ^e R ^f

C ) N is > where G ¹ is S or N, G ² is CR ³ , S or

N, R ³ is H, C1-6 alkyl or C 1-6 haloalkyl; and R ^a and R ^b are independently H or C 1-4 alkyl. In some embodiments, R ¹ is a 5- or 6-membered heterocycle

loalkyl, L is -CH ₂ -, Y ¹ is CH and R ² is where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C1.6- alkyl or C1.6-haloalkul and R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L is

NR®R ^f g^ (JN is -S(O)2-, Y ¹ is N and R ² is where G ¹ is

S or N, G ² is CR ³ , S or N, R ³ is H, C1.6 alkyl or C1.6 haloalkyl, and R ^a and R ^b are independently H or C1. ₄ -alkyl. In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L is -O-, Y ¹ is N

NR ^e R ^f

G ¹ ^ and R ² is ' where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C1-6 alkyl or C1-6 haloalkyl and R ^a and R ^b is independently H or C1-4 alkyl. In some embodiments, R ¹ is a 5- or 6-membered

- 20 043225 heterocycloalkyl, L is -C(O)-, Y ¹ is N and R ² is

NR ^e R ^f UOl ⁴ where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C _1-6 alkyl or C _1-6 haloalkyl and R ^a and R ^b independently represent H or C _1-4 -alkyl. In some embodiments, R ¹ is 5- or 6-membered heterocycloalkyl, L preNR ^e R ^f is -CH ₂ -, Y ¹ is N, and R ² is > where G ¹ is S or N, G ² is CR ³ , S or N, R ³ is H, C1-6 alkyl or C1-6 haloalkyl, and R ^a and R ^b are independently H or C 1-4 alkyl.

In some embodiments of formula (I)

R ¹ is C ₆ -C ₁₄ aryl or 4-10 membered heterocycloalkyl;

L represents -S(O) ₂ - or -O-;

Y ¹ represents CH or N; And

R ² is a 5-membered heteroaryl ring substituted with one or more substituents selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl and NR ^e R ^f ;

R ^e and R ^f independently represent H or C _1-4 -alkyl;

or a pharmaceutically acceptable salt thereof.

Any of the variants or embodiments of R ¹ , R ² , Y1, R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , L, G ¹ , G ² and R ³ proposed herein can be combined with any other variation or embodiment of R ¹ , R ² , Y1, R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , L, G ¹ , G ² and R ³ , as if specifically and in each combination is described separately.

In other embodiments, the compound of formula (I) is selected from the group consisting of compounds from Table. 1.

Table 1

Example No. Structure chemical name 1 V O (R)-5 -(3-morpholino-5 ((tetrahydrofuran-3 yl)sulfonyl)phenyl)thiazol-2-amine 2 V /—NF ₃ C (R)-5 -(3-morpholino-5 ((tetrahydrofuran-3 yl)sulfonyl) phenyl) -4 - (trifluoromethyl)thiazol-2-amine 3 C\1 T b 5-(3-morpholino-5(phenylsulfonyl)phenyl)-1,3,4thiadiazol-2-amine

- 21 043225

4 Q? ate 1 ^ζ ζ 5-(3-morpholino-5(phenylsulfonyl)phenyl)-1,2,4thiadiazol-3-amine 5 h ₂ n > ^N , ϊkjf'° 5-(6-morpholino-4- (phenylsulfonyl)pyridin-2yl)thiazol-2-amine 6 Q, . Η, y^ CHX / ^ζ / ^ζ ο Ο 5-(6-morpholino-4- (phenylsulfonyl)pyridin-2-yl)-4- (trifluoromethyl)thiazol-2-amine 7 Q, . '<Л' ю Η, CHX / ^ζ / /—Ζ C) 4-methyl-5-(6-morpholino-4(phenylsulfonyl)pyridin-2yl)thiazol-2-amine 8 9 Ο' J /ΜΪ 0 5-(6-morpholino-4-phenoxypyridin2-yl)thiazol-2-amine 9 / Ο O^Q » ^ζ ί (K) -4-methyl-5- (3-morpholino-5 ((tetrahydrofuran-3 - yl)sulfonyl)phenyl)thiazol-2-amine 10 νη ₂ \ JHJ ^Μ θ 0^ 0 (K)-4-methyl-5-(3-morpholino-5((tetrahydrofuran-3 yl)oxy)phenyl)thiazol-2-amine eleven Q Ο ^φ rf 4-methyl-5-(3-morpholino-5-phenoxyphenyl)thiazol-2-amine

-22043225

12 ω—< /ABOUT ° \ (K) - (3- (2-amino-4-methylthiazol-5-yl) - morpholinophenyl)(tetrahydrofuran3-yl) methanone 13 νη ₂ 0 (3-(2-amino-4-methylthiazol-5-yl)-5 morpholinophenyl)(phenyl)methanone 14 νη ₂ ί J KJ ^Me 0 5-(3-benzyl-5-morpholinophenyl)-4methylthiazol-2-amine 15 w—( σ'Z^ /O X/° (H)-4-methyl-5-(3-morpholino-5 ((tetrahydrofuran-3 yl)methyl)phenyl)thiazol-2-amine 16 nh ₂ <Ύ jCjMe ° 0 4-methyl-5-(3-morpholino-5((te1rahydro-2H-pyran-4yl)sulfonyl)phenyl)thiazol-2-amine 17 Q o ® nF 4-methyl-5-(3-morpholino-5((te1rahydro-2H-pyran-4yl)oxy)phenyl)thiazol-2-amine

- 23 043225

18 nh ₂ AX/ ^N oCj XT ^me 0 (3-(2-amino-4-methylthiazol-5-yl)-5 morpholinophenyl)(tetrahydro-2Hpyran-4-yl)methanone 19 nh ₂ oCTXT ^me 0 4-methyl-5-(3-morpholino-5((te1rahydro-2H-pyran-4yl)methyl)phenyl)thiazol-2-amine

and their pharmaceutically acceptable salts.

Any formula presented herein, such as formula (I), is intended to refer to compounds having the structures depicted by this structural formula, as well as certain variations or forms thereof. In particular, compounds of any formula provided herein may have asymmetric centers and therefore exist in various enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the given general formula, as well as their mixtures in any ratio, are considered to be included in the scope of the specified formula. Thus, any formula provided herein is intended to refer to the racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. If the connection from the table. 1 is depicted in a certain stereochemical configuration, any alternative stereochemical configuration of this compound is also provided herein, as well as mixtures of stereoisomers of this compound in any ratio. For example, if the connection from the table. 1 has a stereocenter that is in the stereochemical configuration S, then this document also provides an enantiomer of this compound in which the specified stereocenter is in the stereochemical configuration R. In the same way, if the compound from table. 1 has a stereocenter that is in the R configuration, the enantiomer of this compound in the stereochemical configuration S is also provided herein. Mixtures of the compound in the stereochemical configuration S and R are also provided. In addition, some structures may exist as geometric isomers (i.e. cis and trans isomers), tautomers or atropisomers. In addition, any formula given herein also applies to any hydrates, solvates, and amorphous and polymorphic forms of such compounds, as well as mixtures thereof, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvates are hydrates.

The compounds of formula (I) may be prepared and/or formulated in the form of pharmaceutically acceptable salts. In some embodiments, pharmaceutically acceptable salts include acid addition salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or prepared with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, and the like. Such salts may be derived from inorganic or organic acids. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, metalsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates and mandelates. In some embodiments, pharmaceutically acceptable salts are formed by replacing an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or when it is coordinated with an organic base. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- diethylaminoethanol, tromethamine, trimetamine,

- 24 043225 dicyclohexylamine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-ethylglucamine, N-methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, amino acids such as lysine, arginine, histidine, etc. Examples of pharmaceutically acceptable base addition salts include salts derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In some embodiments, the organic non-toxic bases are L-amino acids such as L-lysine and L-arginine, tromethamine, N-ethylglucamine, and N-methylglucamine. Suitable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. A list of other suitable pharmaceutically acceptable salts is provided in Remington, Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985.

For a compound described herein that contains a basic nitrogen atom, a pharmaceutically acceptable salt may be prepared by any suitable method known in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid , nitric acid, boric acid, phosphoric acid, and the like, or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid , valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidilic acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as mandelic acid , citric acid or tartaric acid, amino acid such as aspartic acid or glutaric acid, aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid acid, benzenesulfonic acid or ethanesulfonic acid, or any compatible mixture of acids, such as those described in the examples provided herein, and any other acid and mixture thereof that are considered equivalents or acceptable substitutes in light of the general level of knowledge in this technology.

The proposed embodiments also relate to pharmaceutically acceptable prodrugs of the compounds described herein, as well as methods of treatment using these pharmaceutically acceptable prodrugs. The term prodrug means a precursor of said compound which, after administration to a subject, forms said compound in vivo by a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., exposing the prodrug to physiological pH converts it to a compound of formula (I) ). A pharmaceutically acceptable prodrug is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject. Exemplary methods for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. N. Bundgaard, Elsevier, 1985.

The proposed embodiments also relate to pharmaceutically active metabolites of the compounds described herein and to the use of such metabolites in the methods provided herein. Pharmaceutically active metabolite means the pharmacologically active product of metabolism in the body of the compound described herein, or its salt. Prodrugs and active metabolites of a compound can be determined using standard techniques known or available in the art. For example, see Bertolini et al., J. Med Chem., 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci., 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res., 1995, 34, 220-230; Bodor, Adv. Drug Res., 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

pharmaceutical compositions.

For use in therapy, the pharmaceutical composition of the present invention contains at least one compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions may additionally contain one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable excipient is one that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate the administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, coloring agents, fillers, emulsifiers, or flavor modifying agents. In preferred embodiments, the pharmaceutical compositions according to the present embodiments are sterile.

- 25 043225 compositions. Pharmaceutical compositions can be prepared using compounding techniques known or available to those skilled in the art.

Sterile compositions are also contemplated by the proposed embodiments, including compositions that comply with national and local regulations governing such compositions.

The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, dispersions, or inclusion complexes such as inclusion complexes of cyclodextrins, in suitable pharmaceutical solvents or carriers, or in the form of pills, tablets, lozenges, suppositories, sachets. , dragees, granules, powders, powders for dilution or capsules, together with solid carriers in accordance with standard methods known in the field of obtaining various dosage forms. Pharmaceutical compositions according to the proposed embodiments may be administered by a conventional delivery route such as oral, parenteral, rectal, nasal, topical, or ophthalmic routes, or by inhalation. Preferably the proposed compositions are formulated for intravenous or oral administration.

For oral administration, the compounds according to the proposed embodiments may be presented in solid form such as a tablet or capsule, or as a solution, emulsion or suspension. For oral formulations, the compounds of the preferred embodiments may be formulated to provide a dose of, for example, about 0.01 mg/kg to about 50 mg/kg per day, or about 0.05 mg/kg to about 20 mg/kg per day, or from about 0.1 mg/kg to about 10 mg/kg per day. Tablets for oral administration may contain the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrants, binders, lubricants, sweeteners, flavors, coloring agents and preservatives. Suitable excipients include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Illustrative liquid oral excipients include ethanol, glycerin, water, and the like. Exemplary disintegrants are starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid. Binding agents may include starch and gelatin. The lubricant, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption from the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, the active ingredient(s) may be mixed with a solid, semi-solid or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono- and diglycerides of short chain fatty acids, polyethylene glycol 400 or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups, or may be lyophilized and presented as a dry product for reconstitution with water or other suitable vehicle prior to use. Such liquid compositions may optionally contain pharmaceutically acceptable excipients such as suspending agents (eg, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles such as oil (eg almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (eg methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and optionally flavoring or coloring agents.

The compositions of the present invention may be formulated for rectal administration in the form of suppositories. For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes of administration, the agents according to the proposed embodiments may be presented in sterile aqueous solutions or suspensions buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride solution. Such forms may be presented in unit dosage form, such as ampoules or disposable injection devices, or in multi-dose forms, such as vials, from which the appropriate dose can be drawn, or in solid form, or in the form of a preconcentrate, which can be used to obtain dosage form for injection. Exemplary infusion doses are from about 1 to 1000 μg/kg/min of the agent mixed with a pharmaceutical carrier over a period of minutes to several days.

For nasal, inhalation or oral administration, the pharmaceutical compositions of the present invention may be administered using, for example, a dosage form

- 26 043225 spray also containing a suitable carrier.

For topical application, the compounds according to the proposed embodiments are preferably formulated in the form of creams or ointments, or a similar carrier suitable for topical application. For topical use, the compounds of the present invention may be mixed with a pharmaceutical carrier at a concentration of from about 0.1% to about 10% drug compound relative to the carrier. In another method of administering agents according to the proposed embodiments, a patch dosage form may be used to provide transdermal delivery.

In the context of this document, the terms treat or treatment is an approach to achieve beneficial or desired results, including clinical results. In the context of the present invention, advantageous or desired results include, but are not limited to, reducing the severity or slowing the aggravation of an existing disease, symptom or condition, alleviating a symptom and/or reducing the severity of a symptom, and/or preventing the aggravation of a symptom associated with a pathological condition, stopping development of a disease, symptom or condition, alleviation of the disease, symptom or condition, initiation of regression of the disease, disorder or symptom (in terms of severity or frequency of negative symptoms), or cessation of symptoms of the disease or condition. Advantageous or desired results may also be slowing, stopping or reversing the progression of a disease or condition.

The term subject refers to a mammalian patient in need of such treatment, such as a human. The subject may be a human, or may be a cat, dog, cow, rat, mouse, horse, or other domesticated mammal.

Illustrative pathological conditions or diseases that may be a therapeutic target for modulators of the Vps34/PI3K III signaling pathway include diabetes, polycystic ovary syndrome, diabetic cardiovascular disease, neuroinflammation, ischemic stroke, and cancer, including, but not limited to, glioblastoma. , renal cell carcinoma and melanoma. In some embodiments, the disease or medical condition is cancer, and the cancer is glioblastoma, renal cell carcinoma, or melanoma.

In one aspect, the compounds and pharmaceutical compositions described herein specifically target the Vps34/PI3K III signaling pathway. In some embodiments, these compounds and pharmaceutical compositions may prevent, reverse, slow or suppress the Vps34/PI3K III signaling pathway. In some embodiments, the compounds and pharmaceutical compositions described herein are used to treat or prevent diabetes, polycystic ovary syndrome, diabetic cardiovascular disease, cancer, neuroinflammation, or ischemic stroke. In some embodiments, the disease or medical condition is cancer, and the cancer is glioblastoma, renal cell carcinoma, or melanoma. In some embodiments, the methods of the present invention target diseases associated with the Vps34/PI3K III signaling pathway.

In the methods according to the proposed embodiments, an effective amount of a Vps34-PI3K modulator means an amount sufficient to alter the phosphorylation of components of the Vps34/PI3K III signaling pathway, alter the expression of survival genes regulated by said pathway, improve cell energy balance, initiate apoptosis in transformed cells, and inhibit autophagy. Measurement of one or more of these markers of regulation of the Vps34/PI3K III signaling pathway can be carried out by standard analytical methods, such as those described below, and which are suitable for many conditions, including in vitro assays.

In the methods of treatment according to the proposed embodiments, an effective amount means an amount or dose generally sufficient to achieve the desired therapeutic effect in subjects in need of such treatment. Effective amounts or doses of active compounds according to the proposed embodiments can be determined by standard methods such as modeling, dose escalation studies or clinical trials, taking into account conventional factors such as the method or route of administration or delivery of the drug compound, the pharmacokinetics of the agent, the severity and course of the infectious disease. disease, health status of the subject, pathological condition and weight of the subject, as well as the decision of the attending physician. An exemplary dosage is from about 1 μg to 2 mg of active agent per kilogram of the subject's body weight per day, preferably from about 0.05 to 100 mg/kg/day, or from about 1 to 35 mg/kg/day, or from about 0 ,1 to 10 mg/kg/day. The total dose may be administered as single or divided doses (eg BID, TID, QID).

Once relief of the patient's disease has occurred, the dose may be adjusted to provide preventive or maintenance treatment. For example, depending on the symptoms, the dose or frequency of administration, or both, can be reduced to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if the symptoms are reduced to an appropriate level, then the treatment can be stopped. However, patients may require intermittent treatment on a long-term basis for any recurrence of symptoms. Patients may also need chronic treatment on a long-term basis.

drug combinations.

The compounds of the present invention described herein can be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients for the treatment of diseases or medical conditions associated with the regulation of the Vps34/PI3K III signaling pathway. For example, additional active ingredients are those known or established to be effective in the treatment of diseases or medical conditions associated with the regulation of the Vps34/PI3K III signaling pathway, including those active against another disease-related target, for example, but not limited to anti-cancer drugs with a synergistic mechanism, compounds that treat the symptoms of such disorders, and antioxidants.

For example, additional active ingredients are those known or established to be effective in treating diseases or medical conditions associated with the regulation of the Vps34/PI3K III signaling pathway, including those active against another target associated with the disease, for example, but not limited to them

a) compounds that target various mechanisms of protein folding disorder (such as aggregation and/or reproduction);

b) compounds that treat the symptoms of such disorders (eg dopamine replacement therapy); And

c) drugs that act as neuroprotective agents by a complementary mechanism (eg, those that target autophagy, antioxidants, and adenosine A2A antagonists).

For example, compositions and dosage forms according to the proposed embodiments, as well as methods of treatment, may additionally include other drugs or pharmaceutical preparations, for example, other active agents useful for the treatment or alleviation of diabetes, polycystic ovary syndrome, cardiovascular disease associated with diabetes, neuroinflammation, ischemic stroke, and cancer, including, but not limited to, glioblastoma, renal cell carcinoma, and melanoma. In this regard, compositions and dosage forms of exemplary and specific compounds described herein are useful in the treatment of diabetes, polycystic ovary syndrome, diabetic cardiovascular disease, neuroinflammation, ischemic stroke, and cancer, including, but not limited to, glioblastoma. , renal cell carcinoma and melanoma. Pharmaceutical compositions according to the proposed embodiments may further comprise one or more such active agents, and methods of treatment may further comprise administering an effective amount of one or more such active agents.

In some embodiments, the additional active agent is an anticancer agent, an antidiabetic agent, or a cardiovascular drug. Exemplary anticancer agents include, but are not limited to, alkylating agents (eg, cisplatin, chlorambucil, procarbazine, carmustine), antimetabolites (eg, methotrexate, cytarabine, gemcitabine), antimicrotubulin agents (eg, methotrexate, cytarabine, gemcitabine), antitumor antibiotics ( eg bleomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, mitoxantrone), topoisomerase inhibitors (eg etoposide, doxorubicin), mitotic inhibitors (eg paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinoreblin, colchicine, podophyllotoxin, griseofulvin , glaziovianin), corticosteroids (eg, prednisone, prednisolone, methylprednisolone, dexamethasone), proteasome inhibitors (eg, bortezomib, carfilzomib, salinosporamide A (NPI-0052, MLN9708, CEP-18770, ONX 0912), kinase inhibitors (eg, imatinib mesylate, gefitinib, erlotinib, lapatinib, canertinib, semaxinib, vatalanib, sorafenib, sutent, and leflunomide), histone deacetylase inhibitors (eg, hydroxamic acid suberoylalanide, chidamide, entinostat, mocetinostat, abexinostat, quisinostat, depsipeptide, resminostat, belinostat, CUDC-101 , givinostat, panobinostat, pracinostat, SHP-141, tefinostat, trichostatin A, vorinostat, sulforaphane, pivanex, valproic acid) and antibodies (eg, abciximab, adalimumab, alefacept, alemtuzumab, basiliximab, belimumab, bezlotoxumab, canakinumab, certolizumab pegol, cetuximab , daclizumab, denosumab, efalizumab, golimumab, inflectra, ipilimumab, ixekizumab, natalizumab, nivolumab, olaratumab, omalizumab, palivizumab, panitumumab, pembrolizumab, rituximab, tocilizumab, trastuzumab, secukinumab, ustekinumab). Illustrative antidiabetic agents include, but are not limited to, biguanides (eg, metformin, phenformin, and buformin), sulfonylureas (eg, tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide or glibenclamide, glimepiride, gliclazide, glycopyramide, and gliquidone), meglitinides ( eg, repaglinide and nateglinide), alpha-glucosidase inhibitors (eg, miglitol, acarbose, and voglibose), thiazolidinediones (TZD) (eg, rosiglitazone, pioglitazone, and troglitazone), glucagon-like peptide-1 (GLP-1) antagonists (eg, exenatide, liraglutide, taspoglutide, and lixisenatide

- 28 043225 (Lyxumia)), dipeptidyl peptidase IV (DPP-4) inhibitors (e.g. vildagliptin (Galvus), sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin, septagliptin, teneligliptin and gemigliptin: Zemiglo), selective sodium-dependent glucose transporter 2 (SGLT-2) inhibitors (glycosuretics) (eg, dapagliflozin, canagliflozin, and empagliflozin), insulins (eg, regular insulin (Humulin R, Novolin R), insulin lispro (Humalog), insulin aspart (Novolog), insulin glulisine (Apidra), fast acting insulin zinc (Semilente), isophane insulin, Hagedorn neutral protamine (NPH) (Humulin N, Novolin N), insulin zinc (Lente), long acting insulin zinc (Ultralente), insulin glargine (Lantus) and insulin detemir (Levemir)), amylinomimetics (eg pramlintide), bile acid sequestrants and dopamine agonists. Illustrative cardiovascular drugs include, but are not limited to, anticoagulants (eg, rivaroxaban (Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), heparin (various), and warfarin (Coumadin)), antiplatelet agents, and dual antiplatelet therapy (DAPT). ) (eg, aspirin, clopidogrel (Plavix®), dipyridamole, prazugrel (Effient), and ticagrelor (Brilinta)), angiotensin-converting enzyme (ACE) inhibitors (eg, benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec) , fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik)), angiotensin-2 receptor antagonists (eg, candesartan (Atacand ), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), and valsartan (Diovan)) angiotensin/neprilysin receptor inhibitors (ARNI) (eg, sacubitril/valsartan (Entresto)), beta-adrenergic agents (eg, acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide (Ziac), bisoprolol (Zebeta), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), and sotalol (Betapace)), combined alpha and beta blockers (eg, carvedilol (Coreg) and labetalol hydrochloride (Normodyne, Trandate)), calcium channel blockers (eg, amlodipine (Norvasc, Lotrel), diltiazem (Cardizem, Tiazac), felodipine ( Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), and verapamil (Calan, Verelan)) cholesterol-lowering drugs (eg, statins: atorvastatin (Lipitor), rosuvastatin (Crestor), nicotinic acids: lovastatin (Advicor) and cholesterol uptake inhibitors: ezetimibe/simvastatin (Vytorin)), digistoxins (eg, lanoxin), diuretics (eg, amiloride (Midamor), bumetanide (Bumex), chlorthiazide (Diuril), chlorthalidone (Hygroton), furosemide ( Lasix), hydrochlorothiazide (Esidrix, Hydrodiuril), indapamide (Lozol), and spironolactone (Aldactone)), as well as vasodilators (eg, isosorbide dinitrate (Isordil), nesiritide (Natrecor), hydralazine (Apresoline), nitrates, and minoxidil).

In some embodiments, additional active agents may be antibiotics (e.g., antibacterial or bacteriostatic peptides or proteins), such as those effective against Gram-positive or negative bacteria, liquid preparations, cytokines, immunoregulatory agents, anti-inflammatory agents, complement-activating agents, such as peptides or proteins containing collagen-like domains or fibrinogen-like domains (eg, fiolin), carbohydrate-binding domains, and the like, as well as combinations thereof. Additional active agents include those useful in such compositions and methods and include dopamine therapy drugs, catechin O-methyltransferase inhibitors, monoamine oxidase inhibitors, cognitive impairment correctors (such as acetylcholinesterase inhibitors or memantine), adenosine 2A receptor antagonists, beta inhibitors. secretases or gamma-secretase inhibitors. In specific embodiments, at least one compound according to the proposed embodiments can be combined in a pharmaceutical composition or method of treatment with one or more drugs selected from the group consisting of tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), galantamine ( Reminyl), physostigmine, neostigmine, icopezil (CP-118954, 5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo-[4,5-1]- 1,2benzisoxazol-6-one maleate), ER-127528 (4-[(5,6-dimethoxy-2-fluoro-1-indanone)-2-yl]methyl-1-(3-fluorobenzyl)piperidine hydrochloride), zanapezil (TAK-147; 3-[1-(phenylmethyl)piperidin-4-yl]-1-(2,3,4,5tetrahydro-1H-1-benzazepin-8-yl)-1-propane fumarate), metrifonate (T-588; (-)-R-alpha-[[2(dimethylamino)ethoxy]methyl]benzo[b]thiophene-5-methanol hydrochloride), FK-960 (N-(4-acetyl-1piperazinyl)-p -fluorobenzamide hydrate), TSN-346 (N-methyl-N-2-pyropynyldibenz[b,f]oxepin-10methanamine), SDZ-220-581 ((S)-alpha-amino-5-(phosphonomethyl)-[ 1 ,1'-biphenyl]-3-propionic acid), memantine (Namenda/Exiba) and 1,3,3,5,5-pentamethylcyclohexane-1-amine (Neramexane), tarenflurbil (Flurizan), tramiprosate (Alzhemed), clioquinol , PBT-2 (8-hydroxyquinilone derivative), 1-(2-(2naphthyl)ethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, Huperzine A, posirelin, leuprolide or its derivatives, ispronicline, (3-aminopropyl)(n-butyl)phosphinic acid (SGS-742), N-methyl-5-(3-(5-isopropoxypyridinyl))-4-penten-2-amine (ispronicline), internal salts N -(2hydroxy-3-sulfopropyl)-N-methyl-N-octyl-1-decanaminium (zt-1), salicylates, aspirin, amoxiprin, benorylate, choline magnesium salicylate, diflunisal, faislamin, methyl salicylate, magnesium salicylate, salicyl salicylate, diclofenac, aceclofenac, acemethacin, bromfenac, etodolac, indomethacrine, nabumetone, sulindac, tolmetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen,

- 29 043225 ketoprofen, ketorolac, loxoprofen, naproxen, thiaprofenic acid, suprofen, mefenamic acid, meclofenamic acid, phenylbutazone, azapropazone, metamizole, oxyphenbutazone, sulfinprazone, piroxicam, lornoxicam, meloxicam, tenoxicam , celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, nimesulide, arylalkanoic acids, 2-arylpropionic acids (profens), N-arylanthranilic acids (fenamic acids), pyrazolidin derivatives, oxicams, COX-2 inhibitors, sulfonanilides, essential fatty acids and minozac (2-(4-(4- methyl-6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine dihydrochloride hydrate). Such a combination may serve to increase efficacy, alleviate other symptoms of a disease, reduce one or more side effects, or reduce the required dose of a compound of this invention. Additional active ingredients can be administered in a separate pharmaceutical composition separate from the compound according to the proposed embodiments, or they can be included in the same pharmaceutical composition with the compound according to the proposed embodiments. Additional active ingredients may be administered simultaneously, before or after the administration of the compound of formula (I).

Application methods.

The compounds and pharmaceutical compositions described herein can be used to treat or prevent a disease or condition in an individual. In some embodiments, a method of treating a disease or medical condition associated with regulation of the Vps34/PI3K III signaling pathway is provided, comprising administering to a subject in need of such treatment an effective amount of at least one compound of formula (I) or a compound of Table 1. 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing (a) at least one compound of formula (I), or a compound from table. 1, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient.

In some embodiments, a compound of formula (I) or a compound of Table 1 is provided. 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing (a) at least one compound of formula (I), or a compound from table. 1, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient for the treatment of a disease or medical condition associated with the regulation of the Vps34/PI3K III signaling pathway.

In some embodiments, the proposed use of at least one compound of formula (I), or compounds from table. 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing (a) at least one compound of formula (I), or a compound from table. 1, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient for the manufacture of a medicament for the treatment of a disease or medical condition associated with the regulation of the Vps34/PI3K III signaling pathway.

In some embodiments, a method is provided for interfering with a Vps34/PI3K III signaling pathway in a cell, or modulating, preventing, slowing, reversing, or inhibiting a Vps34/PI3K III signaling pathway in a cell, comprising contacting said cell with an effective amount of at least one compound of the formula (I), or compounds from the table. 1, or its pharmaceutically acceptable salt, and/or at least one pharmaceutical composition containing (a) at least one compound of formula (I), or a compound from the table. 1, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient, said contacting being carried out in vitro, ex vivo or in vivo.

In some embodiments, the disease or medical condition is selected from diabetes, polycystic ovary syndrome, diabetic cardiovascular disease, neuroinflammation, ischemic stroke, and cancer, including, but not limited to, glioblastoma, renal cell carcinoma, and melanoma. In some embodiments, the disease or medical condition is selected from diabetes, polycystic ovary syndrome, diabetic cardiovascular disease, cancer, neuroinflammation, or ischemic stroke. In some embodiments, the disease or medical condition is cancer, and the cancer is glioblastoma, renal cell carcinoma, or melanoma.

Sets.

Also provided are industrial products and kits containing any of the compounds and pharmaceutical compositions provided herein. The product of industrial production may contain a container with a label. Suitable containers include, for example, bottles, vials and test tubes. Containers can be made from various

- 30 043225 materials such as glass or plastic. The container may contain a pharmaceutical composition as provided herein. The label on the container may indicate that the pharmaceutical composition is intended to prevent, treat or suppress the disease or medical condition described herein, and may also indicate instructions for use in vivo or in vitro.

In one aspect, this document provides kits containing a compound or composition described herein and instructions for use. The kits may contain instructions for use in the treatment of a disease or medical condition associated with the regulation of the Vps34/PI3K III signaling pathway in an individual in need thereof. The kit may further comprise any materials or equipment that can be used to administer the compound or composition, such as vials, syringes, or IV infusion bags. The kit may also contain sterile packaging.

General methods of synthesis.

Compounds of the present invention can be prepared in a variety of ways, outlined below and more specifically described in the following examples (eg, in the schemes presented in the examples below). In the following descriptions of the methods, the symbols used in the depicted formulas are to be understood as representing those groups as described above with respect to the formulas of this invention.

If a particular enantiomer of a compound is to be obtained, this can be done from an appropriate mixture of enantiomers using any suitable standard technique for separating or isolating enantiomers. Thus, for example, diastereomeric derivatives can be obtained by reacting a mixture of enantiomers, such as a racemate, and the corresponding chiral compound. The diastereomers can then be separated by any standard means, such as crystallization, and the desired enantiomer can be isolated. In another separation method, the racemate may be separated using chiral high performance liquid chromatography. Alternatively, if a specific enantiomer is desired, it can be obtained using the appropriate chiral intermediate in one of the methods described.

If a particular isomer of a compound is to be obtained, or the reaction product is otherwise to be purified, chromatography, recrystallization, and other standard separation techniques with intermediates or end products may also be used.

Also contemplated are solvates of a compound provided herein, or a pharmaceutically acceptable salt thereof. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and are often formed during the crystallization process. Hydrates are formed if the solvent is water, or alcoholates are formed if the solvent is alcohol.

In some embodiments, the compounds of formula (I) can be synthesized according to scheme A.

Scheme A

where R ¹ , R ² and Y ¹ are as described for formula (I), or as described in any of the options detailed herein; And

X is a halogen.

In some embodiments, the compounds of formula (I) can be synthesized according to scheme B.

Scheme B

where R ¹ , R ² and Y ¹ are as described for formula (I), or as described in any of the options detailed herein; And

X is a halogen.

- 31 043225

In some embodiments, the compounds of formula (I) can be synthesized according to scheme C.

Scheme C

where R ¹ , Y ¹ , R ^a and R ^b are as described for formula (I), or as described in any of the options detailed herein; And

X is a halogen.

Chemical synthesis.

Illustrative chemical compounds suitable for the methods of the present invention are described below with reference to the following specific examples. Those skilled in the art will appreciate that, to prepare the various compounds described herein, the starting materials may be chosen to produce the desired substituents in the reaction scheme, with or without protection, as appropriate, to obtain the desired product. Alternatively, instead of the ultimately required substituent, it may be necessary or desirable to use a suitable group that can be used in the reaction scheme and, if necessary, substituted by the desired substituent. In addition, those skilled in the art will appreciate that the transformations shown in the following schemes may be performed in any order appropriate to the functionality of the particular pendant groups. Each reaction shown in the general schemes is preferably carried out at a temperature from about 0° C. to the boiling point of the organic solvent used.

Examples

The following examples are presented to illustrate but not limit the present invention. Those skilled in the art will recognize that the following synthetic reactions and schemes may be modified by selection of suitable starting materials and reagents to produce other compounds of formula (I). The proposed compounds are obtained by the general methods described above.

The following abbreviations are used in the examples given:

Boc (tert-butyloxycarbonyl),

BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl),

CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate),

DBU (1,8-diazabicyclo[5.4.0]undec-7-ene),

DIPEA (N,N-diisopropylethylamine),

DMF (N,N-dimethylformamide),

DMSO (dimethyl sulfoxide),

DTT (1,4-dithiothreitol),

EGTC (ethylene-bis(oxyethylenenitrile)tetraacetic acid),

HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), mCPBA (meta-chloroperoxybenzoic acid),

MeOH (methanol),

Pd (dppf) Cl ₂ ([1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride),

Pd (OAc) ₂ (palladium (II) acetate),

Pd(PPh ₃ ) ₄ (tetrakis(triphenylphsophine)palladium (0)),

PPh ₃ (triphenylphosphamide),

THF (tetrahydrofuran),

TLC (thin layer chromatography),

Tris-HCl (tris(hydroxymethyl)aminomethane hydrochloride), and

Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene).

- 32 043225

Example 1 (R)-5-(3-morpholino-5-((tetrahydrofuran-3-yl)sulfonyl)phenyl)thiazole-2-amine

Example 1

Scheme 1

Stage 1

Phenylmethanethiol (19.8 g, 0.16 mol) was added to a solution of sodium hydride (7.04 g, 0.18 mol, 60% purity in mineral oil) in DMF (300 ml) at 0°C. The reaction mixture was stirred for 15 min at room temperature and 1,3,5-tribromobenzene (50 g, 0.16 mol) was added. The reaction mixture was stirred for another 2 h at room temperature. The solution was poured into ice water (500 ml) and extracted with ethyl acetate (300 mlx3). The organic extracts were combined, washed with brine (300 mlx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to give benzyl(3,5dibromophenyl)sulfane (50.1 g, 88% yield). The connection was confirmed by LC-MS only: 379.10 (M+Na)+, C ₁₃ H ₁₀ Br ₂ S.

Stage 2

Pd ₂ dba ₃ (5 g) was added to a mixture of benzyl(3,5-dibromophenyl)sulfane (50 g, 0.14 mmol), BINAP (7.9 g, 12.6 mmol), t-BuONa (20.16 g, 0.21 mol), DBU (19.2 g, 0.126 mol) and morpholine (12.2 g, 0.14 mol) in toluene (400 ml) under nitrogen protection. The reaction mixture was heated at 95° C. for 2 hours. The mixture was cooled to room temperature and poured into water (500 ml). The mixture was extracted with ethyl acetate (300 mlx3). The organic extracts were combined, washed with brine (200 mlx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30:1) to give 4-(3-(benzylthio)-5bromophenyl)morpholine (21.3 g, 42% yield) as a yellow solid. The connection was confirmed only by LC-MS: 364.30 (M+H) ⁺ , C ₁₇ H ₁₈ BrNOS.

Stage 3

Anhydrous AlCl ₃ (60.7 g, 0.45 mol) was added to a solution of 4-(3-(benzylthio)-5-bromophenyl)morpholine (33 g, 0.09 mol) in toluene (500 ml). The reaction mixture was heated at 50° C. for 2 hours. The mixture was quenched by carefully adding ice water (500 ml) and extracted with ethyl acetate (500 mlx3). The organic extracts were combined, washed with brine (300 mlx2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give crude 3-bromo-5-morpholinobenzenethiol (21.6 g, 87% yield), which was used for the next reaction without further purification. The connection was confirmed only by LC-MS: 276.22 (M+H) ⁺ , C ₁₀ H ₁₂ BrNOS.

Stage 4

DEAD (9.88 g, 56.7 mmol) was added to a solution of PPh ₃ (14.9 g, 56.7 mmol) in toluene (100 ml) at 0°C. The solution was stirred for 0.5 h at 0° C. room temperature and a solution of (3)-tetrahydrofuran-3-ol (5.0 g, 56.7 mmol) in toluene (10 mL) was added. After stirring for another 0.5 h at 0° C., a solution of 3-bromo-5-morpholinobenzenethiol (15.56 g, 56.75 mmol) in toluene (20 mL) was added. The reaction mixture was stirred for another 1 h at room temperature. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 mlx3). The combined organic layers were washed with brine (200 ml), dried over sodium sulfate and concentrated to give a yellow solid. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give (R)-4-(3-bromo-5-((tetrahydrofuran-3-33 043225 yl)thio)phenyl)morpholine (11, 6 g, 59% yield as a pale yellow oil. The connection was confirmed only by LC-MS: 344.35 (M+H)+, C ₁₄ H ₁₈ O ₂ SBrN.

Stage 5

mCPBA (23.3 g, 0.13 mol) was added portionwise to a solution of (R)-4-(3-bromo-5-((tetrahydrofuran-3yl)thio)phenyl)morpholine (11.6 g, 33.7 mmol) in dichloromethane (250 ml). The mixture was stirred at room temperature for 2 hours. 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (34 .2 g, 0.13 mol) and the resulting mixture was stirred for 0.5 h at room temperature. The reaction mixture was washed with saturated Na ₂ CO ₃ solution (200 mlx3), brine (100 ml), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to give 4-[3-6pom-5-[(3R)tetrahydrofuran-3-yl]sulfonylphenyl]morpholine (5.0 g, 39% yield). ) as a colorless oily substance. The connection was confirmed only by LC-MS: 376.53 (M+H) ⁺ , C ₁₄ H ₁₈ NO ₄ SBr.

Stage 6

4-[3-Bromo-5-[(3R)-tetrahydrofuran-3-yl]sulfonylphenyl]morpholine mixture (680 mg, 1.81 mmol, to prepare), 4,4,5,5-tetramethyl-2 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (689 mg, 2.72 mmol), KOAc (381 mg, 5.43 mmol) and Pd(dppf)Cl ₂ (148 mg, 0.18 mmol) in 1,4-dioxane (20 ml) and DMSO (0.2 ml) were stirred at 100° C. for 1 h under N2 atmosphere. The reaction mixture was poured into water (50 ml) and extracted with dichloromethane (50 mlx3). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100:1) to give 4-[3-[(3R)tetrahydrofuran-3-yl]sulfonyl-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)phenyl]morpholine (400 mg, 52% yield) as an off-white solid.

Stage 7

4-[3-[(3R)-tetrahydrofuran-3-yl]sulfonyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]morpholine mixture (465 mg, 1 .1 mmol), 5-bromothiazol-2-amine (196 mg, 1.1 mmol), Na ₂ CO ₃ (350 mg, 3.3 mmol) and Pd (ddpf) Cl ₂ (90 mg, 0.11 mmol ) in 1,4-dioxane (15 ml) and H ₂ O (2 ml) was stirred at 100°C for 2 h under N2 atmosphere. The reaction mixture was poured into water (50 ml) and extracted with dichloromethane (50 mlx3). The combined organic layers were washed with brine (30 ml), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/methanol=100:1) and preparative TLC to give (R)-5-(3-morpholino-5-((tetrahydrofuran-3-yl)sulfonyl)phenyl)thiazole-2-amine ( 21 mg, 5% yield as an off-white solid.

LC-MS: 396.00 (M+H) ⁺ , C ₁₇ H ₂₁ N ₃ O ₄ S ₂ .

¹ H NMR (DMSO-d6, 400 MHz) δ: 7.61 (s, 1H), 7.32 (s, 2H), 7.26 (s, 1H), 7.18 (s, 1H), 7 .14 (s, 1H), 4.37 (m, 1H), 4.01 (m, 1H), 3.82 (m, 2H), 3.76 (m, 4H), 3.64 (m, 1H), 3.25 (m, 4H), 1.95-2.16 (m, 2H).

Example 2 (R)-5-(3-morpholino-5-((tetrahydrofuran-3-yl)sulfonyl)phenyl)-4-(trifluoromethyl)thiazol2-amine.

Example 2 was synthesized in the same manner as described for Example 1 in Scheme 1, but using 5-bromo-4-(trifluoromethyl)thiazol-2-amine (133 mg, 0.54 mmol) in step 7 to give (R)- 5-(3morpholino-5-((tetrahydrofuran-3-yl)sulfonyl)phenyl)-4-(trifluoromethyl)thiazol-2-amine (71 mg, 28% yield) as an off-white solid.

LC-MS: 464.1 (M+H) ⁺ , C18H20F3N3O4S2.

1H NMR (DMSO-d6, 400 MHz) δ: 7.63 (s, 2H), 7.36 (s, 1H), 7.24 (s, 1H), 7.20 (s, 1H), 4, 28 (m, 1H), 3.98 (m, 1H), 3.81 (m, 2H), 3.76 (m, 4H), 3.65 (m, 1H), 3.25 (m, 4H ), 2.11 (m, 2H).

Example 3 5-(3-morpholino-5-(phenylsulfonyl)phenyl)-1,3,4-thiadiazol-2-amine, trifluoroacetic acid salt.

Vg

Vg

Example 3

Scheme 2

- 34 043225

Stage 1

A mixture of benzenesulfonyl chloride (10 g, 56.7 mmol), sodium sulfite (14.3 g, 0.11 mol) and sodium bicarbonate (9.5 g, 0.11 mol) in water (100 ml) was stirred at 30°C within 2 hours. Water was removed in vacuo. The residue was extracted with methanol (30 mlx3). The organic extracts were combined, concentrated and co-evaporated with dichloromethane twice to give crude sodium benzenesulfinate (11 g, quantitative) as a white solid. The connection was confirmed by LC-MS only: 141.36 (M-Na) ^- , C ₆ H ₅ NaO ₂ S.

Stage 2

Potassium carbonate (1.66 g, 12.0 mmol), 4E molecular sieves (0.5 g) and Cu(OAc) ₂ (1.22 mg, 6.6 mmol) were added successively to a solution of sodium benzenesulfinate (0.98 g, 6.0 mmol) and 3-bromo-5-morpholinophenylboronic acid (2.56 g, 9.0 mmol) in DMSO (20 ml). The reaction mixture was stirred for 2 hours at 45° C. under balloon oxygen. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 mlx3). The organic extracts were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in dichloromethane (20 ml) and washed with 2N. NaOH solution (20 mlx2). The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product (1.03 g, yellow solid) was further triturated with petroleum ether/ethyl acetate (2/1, 20 mL x 2) to give 4-(3-bromo-5-(phenylsulfonyl)phenyl)morpholine (0.4 g, 18% yield) as a pale yellow solid. The connection was confirmed by LC-MS only: 381.69 (M+H)+, C16H16BrNO ₃ S.

Stage 3

A mixture of 4-(3-bromo-5-(phenylsulfonyl)phenyl)morpholine (1 g, 2.62 mmol), Pd(dppf)Cl ₂ (0.2 g, 0.23 mmol) and Pd(OAc) ₂ ( 60 mg, 0.28 mmol) in MeOH/DMF (10/10 ml) was heated overnight at 80° C. in the presence of 20 kg CO. The methanol was removed in vacuo. The residue was poured into water (20 ml) and extracted with ethyl acetate (20 mlx3). The organic extracts were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give methyl ester (0.61 g, 64% yield). A solution of the resulting methyl ester (600 mg, 1.66 mmol) and LiOH-H ₂ O (133 mg, 2.32 mmol) in THF/water (3/3 ml) was stirred for 1 h at 60°C. The THF was removed in vacuo and the aqueous phase was acidified to pH 3-4 with 5% KHSO ₄ . The resulting mixture was extracted with dichloromethane (20 mlx3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated to give crude 3-morpholino-5-(phenylsulfonyl)benzoic acid (0.4 g, 69% yield), which was used for the next reaction without further purification. The connection was confirmed by LC-MS only: 348.18 (M+H) ⁺ , C ₁₇ H ₁₇ NO ₅ S.

Stage 4

3-Morpholino-5-(phenylsulfonyl)benzoic acid (370 mg, 1.07 mmol) was dissolved in POCl ₃ (4 ml) and hydrazinecarbothioamide (194 mg, 2.13 mmol) was added. The reaction mixture was stirred for 30 min at 85°C. The reaction mixture was cooled to room temperature and added to water (40 ml), maintaining the internal temperature below 60°C. The mixture was cooled to room temperature and neutralized to pH 8-9 with sodium carbonate. The resulting precipitate was collected and washed with a mixture of petroleum ether/ethyl acetate (1/2, 20 mlx2). The filter cake was repurified by preparative HPLC to give 5-(3-morpholino-5-(phenylsulfonyl)phenyl)-1,3,4-thiadiazol-2-amine salt with trifluoroacetic acid (45 mg, 10% yield).

LC-MS: 403.1 (M+H) ⁺ , C18H18N ₄ O3S ₂ .

¹ H NMR (DMSO-d6, 400 MHz) δ: 8.03 (d, J=8.4 Hz, 2H), 7.60-7.78 (m, 6H), 7.45 (s, 1H) , 7.41 (s, 1H), 3.75 (m, 4H), 3.27 (m, 4H).

- 35 043225

Example 4 5-(3-morpholino-5-(phenylsulfonyl)phenyl)-1,2,4-thiadiazol-3-amine

Example 4

Scheme 3

Stage 1

Potassium acetate mixture (82 mg, 2.49 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (318 mg, 1.25 mmol), Pd(dppf)Cl ₂ (68 mg, 0.08 mmol) and 4-(3-bromo-5-(phenylsulfonyl)phenyl)morpholine (300 mg, 0.83 mmol, the preparation is described in Scheme 2) in dioxane/DMSO (5/0.05 ml) was heated at 100°C for 1 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 mlx3). The organic extracts were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give 4-(3-(phenylsulfonyl)-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl)morpholine (250 mg, 70% yield). The connection was confirmed by LC-MS only: 429.90 (M+H)+, C ₂₂ H ₂₈ BNO ₅ S.

Stage 2

A mixture of 4-(3-(phenylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (250 mg, 0.58 mmol), 3- bromine-5-chloro-1,2,4-thiadiazole (96 mg, 0.48 mmol), Pd(dppf)Cl ₂ (20 mg, 0.03 mmol) and CsF (146 mg, 0.96 mmol) in a mixture of dioxane/water (10/1 ml) was heated overnight at 80°C. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 mlx3). The organic extracts were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give 4-(3-(3-bromo-1,2,4-thiadiazol-5-yl)-5(phenylsulfonyl)phenyl)morpholine (203 mg, 91% yield. The connection was confirmed only by LC-MS: 466.17 (M+H) ⁺ , C ₁₈ H ₁₆ BrN ₃ O ₃ S ₂ .

Stage 3

LiHMDS (1 M in THF, 1.23 mL, 1.23 mmol) was added to a solution of 4-(3-(3-bromo-1,2,4-thiadiazol-5-yl)5-(phenylsulfonyl)phenyl)morpholine (190 mg, 0.41 mmol) in THF (10 ml) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 h. Water (20 ml) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with saturated NH ₄ Cl solution (10 ml) and extracted with ethyl acetate (30 mlx3). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give 5-(3-morpholino-5(phenylsulfonyl)phenyl)-1,2,4-thiadiazol-3-amine (89 mg, 54% yield). ).

LC-MS: 403.1 (M+H) ⁺ , C ₁₈ H ₁₈ N ₄ O ₃ S ₂ .

¹ H NMR (DMSO-d6, 400 MHz) δ: 8.04 (d, J=7.6 Hz, 2H), 7.72 (m, 2H), 7.64 (m, 2H), 7.59 (s, 1H), 7.53 (s, 1H), 6.95 (s, 2H), 3.76 (m, 4H), 3.29 (m, 4H).

- 36 043225

Example 5 5-(6-morpholino-4-(phenylsulfonyl)pyridin-2-yl)thiazol-2-amine

Example 5 (R=H)

Example 6 (R-CF _a )

Example 7 (R-SND

Scheme 4

Stage 1

Pcb(dba) ₃ (0.17 g, 0.18 mmol) was added to a mixture of 2,6-dichloro-4-iodopyridine (1 g, 3.66 mmol), thiophenol (0.44 g, 4.03 mmol) , Xantphos (0.21 g, 0.37 mmol) and DIPEA (0.94 g, 7.32 mmol) in dioxane (20 ml) under N2 atmosphere. The reaction mixture was heated at 110° C. for 2 hours. The mixture was cooled to room temperature, poured into water (20 ml) and extracted with ethyl acetate (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to give 2,6-dichloro-4-(phenylthio)pyridine (0.78 g, 83% yield) as an off-white solid. The connection was confirmed only by LC-MS: 256.16 (M+H)+, C11H ₇ Cl ₂ NS.

Stage 2

mCPBA (1.84 g, 10.7 mmol) was added portionwise to a solution of 2,6-dichloro-4-(phenylthio)pyridine (0.68 g, 2.67 mmol) in dichloromethane (20 ml). The mixture was stirred for 50 minutes at room temperature. The reaction mixture was washed with saturated Na ₂ CO ₃ solution (10 mlx2), brine (20 ml), dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=60:1) to give 2,6-dichloro-4-(phenylsulfonyl)pyridine (0.69 g, 90% yield). The connection was confirmed by LC-MS only: 287.98 (M+H) ⁺ , C ₁₁ H ₇ Cl ₂ NO ₂ S.

Stage 3

Solution of 2,6-dichloro-4-(phenylsulfonyl)pyridine (0.69 g, 2.40 mmol), morpholine (0.23 g, 2.64 mmol) and DIPEA (0.40 g, 3.13 mmol) in dioxane (20 ml) was heated at 120°C during the night. The reaction mixture was cooled to room temperature and poured into water (100 ml). The mixture was extracted with ethyl acetate (100 mlx3). The organic extracts were combined, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=60:1) to give 4-(6-chloro-4-(phenylsulfonyl)pyridin-2-yl)morpholine (700 mg, 86% yield). The connection was confirmed by LC-MS only: 339.74 (M+H) ⁺ , C ₁₅ H ₁₅ ClN ₂ O ₃ S.

Stage 4

Mixture of 4-(6-chloro-4-(phenylsulfonyl)pyridin-2-yl)morpholine (270mg, 0.80mmol), 5-bromothiazol2-amine (156mg, 0.80mmol), 1.1.1 ,2,2,2-hexamethyldistannan (557 mg, 2.0 mmol) and anhydrous LiCl (33 mg, 0.80 mmol) in 1,4-dioxane (10 ml) were degassed and placed under a protective nitrogen atmosphere. Pd(PPh ₃ ) ₄ (93 mg, 0.08 mmol) was added and the reaction mixture was stirred at 90° C. for 3 h under nitrogen protection. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, concentrated. The crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate=10:1) and preparative TLC to give 5-(6-morpholino-4(phenylsulfonyl)pyridin-2-yl)thiazol-2-amine (Example 5) (29 mg , yield 9%) to a yellow solid.

LC-MS: 403.1 (M+H) ⁺ , C ₁₈ H ₁₈ N ₄ O ₃ S ₂ .

¹ H NMR (DMSO-d6, 400 MHz) δ: 8.07 (d, J=7.6 Hz, 2H), 7.85 (s, 1H), 7.73 (m, 1H), 7.65 (m, 2H), 7.36-7.55 (m, 3H), 6.91 (s, 1H), 3.69 (m, 4H), 3.51 (m, 4H).

Example 6 5-(6-morpholino-4-(phenylsulfonyl)pyridin-2-yl)-4-(trifluoromethyl)thiazol-2-amine.

5-(6-Morpholino-4-(phenylsulfonyl)pyridin-2-yl)-4-(trifluoromethyl)thiazol-2-amine (5 mg, 2% yield) was obtained from 4-(6-chloro-4-(phenylsulfonyl) )pyridin-2-yl)morpholine (203 mg, 0.60 mmol) and 5-bromo-4(trifluoromethyl)thiazol-2-amine (148 mg, 0.60 mmol) in the same manner as Example 5 (Scheme 4 , stage 4).

LC-MS: 468.75 (M-H) ^- , C ₁₉ H ₁₇ F ₃ N ₄ O ₃ S ₂ .

1 H NMR (CDCl ₃ , 400 MHz) δ: 7.95 (d, J=7.6 Hz, 2H), 7.65 (m, 1H), 7.58 (m, 2H), 7.33 (s , 2H), 7.22 (s,

- 37 043225

1H), 7.05 (s, 1H), 3.82 (m, 4H), 3.59 (m, 4H).

Example 7 4-methyl-5-(6-morpholino-4-(phenylsulfonyl)pyridin-2-yl)thiazol-2-amine

4-Methyl-5-(6-morpholino-4-(phenylsulfonyl)pyridin-2-yl)thiazol-2-amine (31 mg, 7% yield) was obtained from 4-(6-chloro-4-(phenylsulfonyl)pyridine -2-yl)morpholine (338 mg, 1.0 mmol) and 5-bromo-4-methylthiazol-2-amine (384 mg, 2.0 mmol) in the same manner as Example 5 (Scheme 4, step 4).

LC-MS: 417.3 (M+H)+, C ₁₉ H ₂₀ N ₄ O ₃ S ₂ .

¹ H NMR (DMSO-d6, 400 MHz) δ: 8.04 (d, J=7.2 Hz, 2H), 7.74 (m, 1H), 7.66 (m, 2H), 7.31 (s, 2H), 6.97 (s, 1H), 6.94 (s, 1H), 3.69 (m, 4H), 3.51 (m, 4H), 2.35 (s, 3H) .

Example 8 5-(6-morpholino-4-phenoxypyridin-2-yl)thiazol-2-amine

Scheme 5

Stage 1

A mixture of 2,6-dichloro-4-iodopyridine (600 mg, 2.20 mmol), phenol (207 mg, 2.20 mmol) and potassium carbonate (455 mg, 3.30 mmol) in DMSO (20 ml) was stirred at 100°С for 3 h under N2 atmosphere. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 mlx3). The combined organic layers were washed with brine (50 mlx2), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether) to give 2,6-dichloro-4-phenoxypyridine (210 mg, 40% yield). The connection was confirmed only by LC-MS: 239.86 (M+H)+, C ₁₁ H ₇ Cl ₂ NO.

Stage 2

Solution of 2,6-dichloro-4-phenoxypyridine (200 mg, 0.84 mmol), morpholine (218 mg, 2.51 mmol) and DIPEA (216 mg, 1.67 mmol) in 1,4-dioxane (6 ml ) was heated overnight at 140° C. under a protective nitrogen atmosphere. The solvent was removed in vacuo. The residue was treated with water (30 ml) and extracted with ethyl acetate (30 mlx3). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1) to give 4-(6-chloro-4-phenoxypyridin-2yl)morpholine (180 mg, 74% yield). The connection was confirmed only by LC-MS: 290.75 (M+H)+, C ₁₅ H ₁₅ ClN ₂ O ₂ .

Stage 3

5-(6-Morpholino-4-phenoxypyridin-2-yl)thiazol-2-amine (15 mg, 10% yield) was obtained from 4-(6-chloro4-phenoxypyridin-2-yl)morpholine (129 mg, 0. 44 mmol, to obtain) and 5-bromothiazol-2-amine (157 mg, 0.88 mmol) in the same way as example 5 (scheme 4, stage 4).

LC-MS: 354.92 (M+H) ⁺ , C ₁₈ H ₁₈ N ₄ O ₂ S.

1H NMR (400 MHz, chloroform-d) 1H NMR (400 MHz, chloroform-d) δ: 7.46-7.34 (m, 3H), 7.22 (t, J=7.4 Hz, 1H) , 7.09 (dd, J=7.5, 1.6 Hz, 2H), 6.48 (d, J=1.7 Hz, 1H), 5.98 (d, J=1.7 Hz, 1H), 5.60-5.31 (m, 2H), 3.83-3.77 (m, 4H), 3.45 (t, J=4.9 Hz, 4H).

biological analysis.

Analytical example 1: Protocol for VPS34.

PI3KC3 kinase (hVPS34) reactions use ATP and produce ADP as a by-product. The formation of ADP is quantified by detecting the luminescence of ADP-Glo. The PI3KC3 kinase (hVPS34) assay was performed by Reaction Biology Corp. (Malvern, Pennsylvania).

The reaction was 3-stage. First, the kinase was reacted with a lipid substrate in the presence of ATP. The reaction was then quenched and the remaining ATP was consumed with the ADP-Glo™ reagent. Finally, ADP was converted to ATP, the amount of which was measured using a luciferase/luciferin reaction. The luminescence was recalculated in μM of produced ADP according to standard ADP curves. Non-linear regression analysis to fit the standard curve and determine IC ₅₀ values was performed using Graphpad Prism software.

Substrate (phosphatidylinositol (PI):phosphatidylserine (PS)) was added to freshly prepared reaction buffer (40 mM Tris-HCl (pH 7.5), 3 μM orthovanadate, 20 mM MgCl ₂ , 2 mM DTT, 0.05% CHAPS, 1 % DMSO). The kinase PI3KC3 (hVPS34) was introduced into the substrate solution with gentle stirring. Compounds were introduced into the kinase reaction mixture in 100% DMSO using acoustic technology

- 38 043225 (Echo550; nanoliter range). The reaction mixture was incubated for 20 min at room temperature. ATP was introduced into the reaction mixture to initiate the reaction. After the mixture was incubated for 60 min at 30°C, the reaction was quenched with ADP-Glo reagent (Promega, ADP Glo kinase assay kit #V9102) and incubated for 40 min at room temperature. Detection mix (Promega, ADP Glo kinase assay kit #V9102) was added and the reaction mixture was incubated for 30 minutes. The luminescence was measured.

IC ₅₀ values for compounds against PI3KC3 kinase (hVPS34) are shown in Table 1. 2.

Analytical Example 2: Protocol for PI3Ka.

PI3Ka inhibition - quantifies the conversion of ATP to ADP as a measure of PI3Ka activity. Active PI3Ka (Life Technologies) in the presence or absence of a PI3Ka inhibitor was reacted with PIP2:PS (Life Technologies), a substrate specifically optimized for use with class I PI3 kinases, and ultrapure ATP (Promega). The conversion of ATP to ADP by PI3Ka was measured from the luminescent signal using the ADP-Glo Promega kinase activity assay. The assay was validated using the published PI3Ka inhibitors LY294002, PI-103, BYL719, and GDC0198, and a DMSO vehicle control.

Compounds were prepared at 100X final concentration using a 12-point 1:3 serial dilution of DMSO with a DMSO control sample as the 12th point. The compound was then diluted in HEPES buffer (25 mM HEPES pH 7.5, 1 mM EGTA, 0.3% CHAPS) before adding to PI3Ka. Active PI3Ka diluted to 0.24 ng/µl (1.1 nM) in (50 mM HEPES pH 7.5, 6 mM MgCl ₂ , 1 mM EGTA, 200 mM NaCl, 0.03% CHAPS, 8 mM DTT) , were incubated with the compound for 0 and 3 hours before starting the reaction. 25 μM PIP2:PS and 60 μM ATP were diluted from the stock solution (25 mM HEPES pH 7.5, 1 mM EGTA, 0.3% CHAPS) and added to initiate the PI3Ka reaction. The reaction time was 30 min. The conversion of ATP to ADP was measured by luminescence counting on a DTX880 tablet reader (Beckman Coulter). The IC ₅₀ values of the compounds were recorded using the GraphPad Prism software. As an analytical method, a 4-parameter non-linear regression curve fitting with a lower fit to validated reference controls of PI3Ka inhibitors and no upper fit (floating upper value) was used.

The IC ₅₀ values of the compounds against PI3Ka are shown in Table 1. 3.

Claims (34)

1. Compound of formula I where R ¹ represents C ₆ -C ₁₄ -aryl or 4-10-membered heterocycloalkyl; L represents -S(O) ₂ -, -O-, -C(O)- or -CH ₂ -; Y ¹ represents CH or N; R ² is 5-membered heteroaryl, wherein said 5-membered heteroaryl in R ² is unsubstituted or substituted with one or more substituents selected from the group consisting of - 39 043225 from unsubstituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl and -NReRf; And R ^e and Rf are each independently H or Cm-alkyl, and if L is -S(O) ₂ - and Y ¹ is N, then R ¹ is not 4,4-difluoropiperidin-1-yl, each heteroaryl containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur and each heterocycloalkyl containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is phenyl. 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is a 5- or 6-membered heterocycloalkyl. 4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. 5. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is tetrahydrofuran-3-yl. 6. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, characterized in that R ¹ is tetrahydropyran-4-yl. 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that L is -S(O) ₂ -. 8. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that L is -O-. 9. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that L is -C(O)-. 10. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that L is -CH2-. 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, characterized in that Y ¹ is CH. 12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, characterized in that Y ¹ is N. 13. The compound according to any one of claims 1 to 12, characterized in that R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from the group consisting of C1.6-alkyl, C1.6-haloalkyl and NReRf, where R ^e and R ^f independently represent H or C1. ₄ -alkyl. 14. A compound according to any one of claims 1 to 13, characterized in that R ² is thiazolyl or thiadiazolyl substituted with one or more substituents selected from the group consisting of methyl, CF3 and NH2. 15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, characterized in that R ² is NR ^e R ^f where G ¹ represents S or N; G ² is CR ³ , S or N; R ³ is H, C ₁ . ₆ -alkyl or C ₁ . ₆ -haloalkyl; And R ^e and Rf are independently H or C ₁ . ₄ -alkyl. 16. A compound according to claim 15 or a pharmaceutically acceptable salt thereof, characterized in that G ¹ is S and G ² is CR ³ . 17. A compound according to claim 16 or a pharmaceutically acceptable salt thereof, characterized in that R ³ is H. 18. A compound according to claim 16 or a pharmaceutically acceptable salt thereof, characterized in that R ³ is C ₁ . ₆ -alkyl. 19. A compound according to claim 16 or a pharmaceutically acceptable salt thereof, characterized in that R ³ is C ₁ . ₆ -haloalkyl. 20. A compound according to claim 15 or a pharmaceutically acceptable salt thereof, characterized in that G ¹ is N and G ² is S. 21. A compound according to claim 15 or a pharmaceutically acceptable salt thereof, characterized in that G ¹ is S and G ² is N. 22. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, characterized in that both R ^e and R ^f are H. - 40 043225 23. The compound according to claim 1, selected from the group consisting of or a pharmaceutically acceptable salt thereof. - 41 043225 24. The compound according to claim 23, characterized in that said compound is selected from the group consisting of nh ₂ or a pharmaceutically acceptable salt thereof. 25. A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. 26. The compound according to claim 25, characterized in that said compound is selected from the group consisting of or a pharmaceutically acceptable salt thereof. 27. Pharmaceutical composition containing (a) at least one compound according to any one of paragraphs.1-26 or its pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable excipient. 28. A method of treating a disease or medical condition associated with the regulation of the Vps34/PI3K III signaling pathway, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27. 29. The method according to claim 28, characterized in that said disease or medical condition is diabetes, polycystic ovary syndrome, cardiovascular disease on the background - 42 043225 diabetes, cancer, neuroinflammation or ischemic stroke. 30. The method of claim 29 wherein said disease or medical condition is cancer and the cancer is glioblastoma, renal cell carcinoma or melanoma. 31. The use of at least one compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for the manufacture of a medicament for the treatment of a disease or medical condition associated with the regulation of the Vps34/PI3K III signaling pathway . 32. Use according to claim 31, wherein said disease or medical condition is diabetes, polycystic ovary syndrome, diabetic cardiovascular disease, cancer, neuroinflammation, or ischemic stroke. 33. Use according to claim 32, wherein said disease or medical condition is cancer and the cancer is glioblastoma, renal cell carcinoma or melanoma. 34. A method of interfering with the Vps34/PI3K III signaling pathway in a cell, comprising contacting said cell with an effective amount of at least one compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, and/or at least one pharmaceutical composition according to claim 27, wherein said contacting is carried out in vitro, ex vivo or in vivo.