Treatment of skin lesions

Abstract

To provide a compound for use in preventing or treating a skin lesion in a subject.SOLUTION: Compounds of Formula (I) and prodrugs, metabolites, tautomers, solvates, and pharmaceutically acceptable salts thereof are provided. Wherein X1, X2 and X3 are independently of each other N or CH, with the proviso that at least two of X1, X2 and X3 are N, Y is N or CH, W is H or F, with the proviso that when W is F, X1, X2 and X3 are N, and and are independently of each other substituted or unsubstituted morpholinyl, and R1 R2 SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compositions used to prevent and treat skin lesions in a subject. [Background technology]

[0002] Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide, with over 1 million cases diagnosed annually in the United States alone (Bowden GT. Nat Rev Cancer. 2004;4:23-35.). NMSC refers to a group of diseases including actinic keratosis (AK), cutaneous squamous cell carcinoma (cSCC), cSCC in situ (cSCCis or Bowen's disease (BD)), and basal cell carcinoma (BCC, also known as basal cell tumor or basal cell carcinoma) (Di Magliano P. et al., Nature Rev. Cancer 2003,3,903-911). cSCC and BCC are the most common forms of NMSC, accounting for over 40% of newly diagnosed cancers (Bowden GT. Nat Rev Cancer. 2004,4,23-35). Although BCC has an extremely low risk of metastasis, these tumors can invade surrounding tissues, resulting in significant disfigurement. BCC is a prominent manifestation in patients with nevoid basal cell carcinoma syndrome (NBCCS). Inherited and acquired mutations in Patched1 (PTCH1), a tumor suppressor gene that regulates the activity of Smoothened (SMO), are key factors in constitutive activation of the Hedgehog (HH) pathway, leading to the development of BCC in NBCCS (Di Magliano P. et al., Nature Rev. Cancer 2003;3,903-911; Merchant AA et al., Clin. Cancer Res. 2010,16,3130-3140). Smo inhibitors and PI3K pathway inhibitors have been shown to delay or prevent the development of resistance observed with treatment with SMO antagonists alone (Buonamici S. et al., Science Transl. Med. 2010,2,51ra70).

[0003] Several studies have demonstrated that PI3K / mTOR signaling may play an important role in the development of NMSC, particularly AK and cSCC (Ayli EE et al., J. Cutaneous Pathology 2008, 35, 273-277). Immunohistochemical (IHC) analysis of human epithelial tumors has shown that mTOR itself, as well as its downstream effectors 4EBP1, S6K, and AKTSer473, are phosphorylated at significantly higher levels in SCC and precancerous actinic keratosis (AK) compared with normal skin (Chen SJ, et al. Br J Dermatol. 2009;160, 442-5). More recently, reverse-phase protein microarray analysis of cSCC and AK revealed that the mTOR pathway is aberrantly activated in precancerous and cancerous tissues compared with normal skin (Einspahr JG, et al. Cancer Prev Res (Phila). 5, 403-13). Thus, a significant upregulation of the PI3K / AKT / mTOR pathway has been observed in cSCC and cSCCis (BD) as well as in AK compared to normal healthy skin. Increased activity of the PI3K / mTOR pathway may already be observed in sun-damaged skin lesions (Ratushny V et al., J. Clin. Investigation 2012, 122, 464-472).

[0004] Low-risk cSCCs of the trunk and extremities can be treated with electrodessication and curettage (ED&C). For invasive cSCCs, surgical excision and Mohs micrographic surgery are the primary treatment options, and these procedures have comparable cure rates in appropriately selected patients. Radiation therapy is typically used as an adjuvant to surgery to improve locoregional control but may also be used as primary treatment for patients who cannot undergo surgical resection. Chemotherapy can be considered as adjuvant therapy in selected, highest-risk cases of cSCC. In particular, evidence suggests that epidermal growth factor receptor (EGFR) inhibitors may be useful adjuvant therapy to surgical treatment. Systemic chemotherapy can be considered for metastatic cSCC.

[0005] Radiation therapy as primary treatment for cSCC is usually reserved for patients who cannot undergo surgical resection. More commonly, radiation therapy is used as an adjuvant to surgery to improve locoregional control. Postoperative radiation therapy is considered for tumors that exhibit perineural invasion or other high-risk features and for tumors with regional metastases.

[0006] A variety of different chemotherapeutic agents have been used to treat metastatic cSCC. While many of these agents have an established role in the chemotherapy of mucosal head and neck squamous cell carcinoma, there is often a lack of high-quality data regarding their use in cSCC. The most common non-targeted agents used in cSCC include cisplatin and carboplatin, 5-FU, and taxanes (Martinez JC et al., Dermatologic Surgery 2004, 30, 679-686).

[0007] In selected, highest-risk cases of cSCC, adjuvant treatment can be considered. Options include oral 5-fluorouracil (5-FU) and epidermal growth factor receptor (EGFR) inhibitors. Treatment must be administered through a cancer treatment center.

[0008] A variety of different chemotherapy agents have been used to treat metastatic cSCC. While many of these agents have an established role in the chemotherapy of mucosal head and neck squamous cell carcinoma, there is often a lack of high-quality data regarding their use in cSCC. The most common non-targeted agents used in cSCC include cisplatin and carboplatin, 5-FU, and taxanes.

[0009] Several treatment modalities exist for precancerous skin lesions, including cSCCis (BD) and actinic keratosis. Topical administration of 5-FU or imiquimod and diclofenac, used to treat precancerous skin lesions, has negative side effects such as skin irritation and severe inflammation, or shows moderate or low efficacy (Kose O. et al., J. Dermatol. Treatment 2008, 19, 159-163). Similarly, liquid nitrogen cryotherapy or curettage-electrocautery can also be used. Risks associated with cryotherapy include transient pain, edema, and blister formation. Hypopigmentation and hair loss are also common and can be permanent, so treatment is generally not recommended for hairy and heavily pigmented individuals.

[0010] Cutaneous lymphoma is slow but treatable (but not curable) and is usually not fatal.

[0011] Cutaneous T-cell lymphoma (CTCL) has variable localized skin involvement and may be accompanied by tumor formation, ulceration, and desquamation complicated by pruritus and infection. Cutaneous B-cell lymphoma (CBCL) is a less common form of cutaneous lymphoma, accounting for approximately 20-25% of all cutaneous lymphomas.

[0012] There are multiple treatments available for cutaneous lymphoma (local or systemic): local treatments include corticosteroids, bexarotene (Targretin), mechlorethamine (Mustalgen and Valchlor), carmustine (BCNU), phototherapy, and conventional topical and whole-skin electron beam radiation therapy; systemic treatments include a variety of targeted biological immunotherapies, HDAC inhibitors, and chemotherapy.

[0013] In conclusion, there remains a need for improved treatments for skin lesions. Summary of the Invention

[0014] It has now unexpectedly been found that compounds of formula (I) are selective and specific inhibitors of mTOR and / or dual PI3K / mTOR inhibitors, and are highly effective in inducing regression of skin lesions, in particular cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK).

[0015] Thus, in a first aspect of the present invention there is provided a compound of formula (I) for use in the prevention or treatment of a skin lesion in a subject: [ka] [In the formula, X 1 , X 2 and X 3 are independently N or CH (provided that X 1 , X 2 and X 3 at least two of which are N), Y is N or CH; W is H or F (provided that if W is F, then X 1 , X 2 and X 3 is N), R 1 and R 2 are independent of each other, (i) morpholinyl of formula (II): [ka] (wherein the arrow indicates a bond in formula (I), R 3 and R 4 are each independently H, C1-C3 alkyl optionally substituted with one or two OH, C1-C2 fluoroalkyl, C1-C2 alkoxy, C1-C2 alkoxyC1-C3 alkyl, CN, or C(O)O-C1-C2 alkyl, or R 3 and R 4 and both represent C1 to C3 alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -forming) or (ii) 1 to 3 R 7 and Z is a saturated 6-membered heterocycle selected from thiomorpholinyl and piperazinyl, optionally substituted with R 7 is independently in each occurrence C1-C3 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxyC1-C3 alkyl, C3-C6 cycloalkyl optionally substituted with one or two OH, or two R 7 a divalent residue -R, the substituents of which together are selected from C1-C3 alkylene, -CH2-O-CH2-, or -O-CH2CH2-O-, optionally substituted with 1 to 4 F; 8 R 9 -forming), However, R 1 and R 2 at least one of which is morpholinyl of formula (II); and prodrugs, metabolites, tautomers, solvates, and pharmaceutically acceptable salts thereof are provided. [Brief explanation of the drawings]

[0016] [Figure 1A]K14-Fyn-Y528F mice were treated with topical application of compound 1* gel (10 mg of compound 1*) in 75 μl of DMSO or 1000 mg of propylene glycol in the control solution (final concentration 1% (w / w)) (Figure 1A, B, and C). The compound 1*-treated cohort included six mice with 20 cSCC lesions (Figure 1B), and the control cohort included six mice with 15 cSCC lesions (Figure 1A). The size of each SCC was measured with a caliper before and weekly after treatment. The gel was applied to the lesions once daily, Monday through Friday. As shown in Figures 1B and 1C, daily topical application of compound 1* gel induced nearly complete regression of all cSCC lesions in the K14-Fyn Y528F model within 4 weeks without significant inflammation or ulceration. Figure 1: Effect of topical application of Compound 1* or vehicle on cSCC lesions in K14-Fyn-Y528F mice. Twelve 6-week-old K14-Fyn-Y528F mice were divided into two cohorts (6 mice each) with 15 cSCC lesions (control group) or 20 cSCC lesions (treatment group). Lesion size was measured using a caliper before treatment initiation (and weekly thereafter) and varied from 4 to 68 mm2 (the range of lesion size in each cohort was initially similar). Each lesion was topically treated (5 times per week for 4 weeks) with daily application of either vehicle (1A) or Compound 1* (1B) (vehicle: 75 μl DMSO mixed with propylene glycol to a total of 1000 mg; Compound 1*: 10 mg Compound 1* dissolved in 75 μl DMSO mixed with propylene glycol to a total of 1000 mg). Different abbreviations indicate the location of individual lesions. The area of ​​each lesion at each time point was normalized to the area at the start (relative tumor area at WK0 (week 0) = 100). In the vehicle group (1A), one individual lesion spontaneously disappeared (left dorsal T2). In the compound-treated group (1B), all 20 individual lesions disappeared upon treatment. The mean ± SEM of the area of ​​cSCC lesions in both groups is compared in 1C and 1D.A significant reduction in lesions in the treated group (50% mean area, p<0.001) occurred already after 5 days. Figure 1A: Vehicle (control) treatment of 6-week-old K14-Fyn-Y528F mice with 15 individual cSCC lesions. [Figure 1B] Figure 1B: Effect of topical application of Compound 1* on 20 cSCC lesions in 6-week-old K14-Fyn-Y528F mice. [Figure 1C] Figure 1C: Treatment of cSCC lesions in K14-Fyn-Y528F mice: Compound 1* vs. vehicle treatment (curve). Vehicle group: n=15, treatment group: n=20. [Figure 1D] Figure 1D: Treatment of cSCC lesions in K14-Fyn-Y528F mice: Comparison of Compound 1* and vehicle treatment (bar graph). Vehicle group: n=15, treatment group: n=20. [Figure 2] Treespot for compound 1*. The human kinome is represented as a circular dendrogram with eight large groups of typical protein kinases and nine groups of atypical protein kinases. Some protein kinase mutants and the lipid kinase panel, which are not part of the human kinome, are also shown. The results are reported as a map (treespot), which allows visualization of compound interactions across the human kinome and the lipid kinase panel. Kinases found to bind to compound 1* are shown as circles, with larger circles indicating higher affinity. [Figure 3] The pharmacokinetic profiles of nine formulations, including compounds of the present invention and controls, were evaluated. A control formulation, Aldara (5% imiquimod), was applied to assess skin penetration variability (local variability within the same animal and inter-subject variability). The stratum corneum was stripped using tape stripping to prevent contamination during biopsy collection. Three duplicate biopsies were taken from each of the nine test formulation application sites at 6, 12, 18, and 24 hours post-treatment. One biopsy was taken from each control site. Five blank samples were also collected. [Figure 4]Pharmacokinetic profiles of three formulations containing the compound of the present invention. Excised pig skin was placed in a climate chamber to control temperature and humidity. Three duplicate biopsies were taken from each application site (20 x 40 mm) at 6, 12, 18, and 24 hours after administration. Prior to biopsy collection, the stratum corneum was removed by tape stripping, and the biopsies consisted of the remaining epidermis and intact dermis. [Figure 5] Pharmacokinetics of 1% Compound 1* in propylene glycol or PEG. Domestic pigs weighing 30-45 kg were anesthetized for 12 hours. Each of the four formulations was applied six times (in duplicate at each of three time points: 6, 9, and 12 hours) to 24 different application sites. At the end of the experiment, the pigs were sacrificed and the stratum corneum was stripped by tape stripping. [Figure 6A]Effects of Compound 1* on SKH1 UV-B-irradiated mice after 24 days of treatment (Figure 6A) and at the end of 24 days of treatment (Figure 6B). Hairless SKH1 mice were irradiated with UV light for 102 days as described below prior to treatment with Compound 1*. NT = untreated, V = vehicle. In vivo topical treatment of actinic keratosis in the SKH1-UVB-induced mouse model was performed with NT or V or Compound 1* (3 mg / mouse / day) using a non-optimized formulation as described for the cSCC mouse model. Photographs of the middorsal area of ​​two selected mice per group are shown (NT: mice 1-1 and 1-4; V: mice 2-3 and 2-6; Compound 1*: mice 3-4 and 3-6). Hairless SKH-1 mice (Charles River Laboratories) were used in all in vivo experiments and fed a standard chow diet. Individually housed (one mouse per cage) SKH-1 mice (6–8 weeks old, weighing 18–20 g) were exposed to UV-B radiation daily for approximately 14–15 weeks in a dedicated cabinet. A medium-wavelength UV-B lamp, T-40.M, from Vilber Lourmat (Eberhardzell, Germany), was used, operating at 280–320 nm with an energy peak at 312 nm. The MED (minimal erythema dose) of this device was set at 0.06 J / cm² / day, which corresponds to approximately 20 minutes of UV-B exposure per day in SKH-1 mice. The UV-B irradiation dose was internally calibrated prior to each experiment to adjust the exposure time. To develop AK lesions and prevent the risk of skin burns, the following stepwise exposure was performed: 0.05 J / cm² / day for 10 days, followed by 0.055 J / cm² / day for 10 days, followed by the MED for up to 102 days. [Figure 6B]Effects of Compound 1* on SKH1 UV-B-irradiated mice after 24 days of treatment (Figure 6A) and at the end of 24 days of treatment (Figure 6B). Hairless SKH1 mice were irradiated with UV light for 102 days as described below prior to treatment with Compound 1*. NT = untreated, V = vehicle. In vivo topical treatment of actinic keratosis in the SKH1-UVB-induced mouse model was performed with NT or V or Compound 1* (3 mg / mouse / day) using a non-optimized formulation as described for the cSCC mouse model. Photographs of the middorsal area of ​​two selected mice per group are shown (NT: mice 1-1 and 1-4; V: mice 2-3 and 2-6; Compound 1*: mice 3-4 and 3-6). Hairless SKH-1 mice (Charles River Laboratories) were used in all in vivo experiments and fed a standard chow diet. Individually housed (one mouse per cage) SKH-1 mice (6–8 weeks old, weighing 18–20 g) were exposed to UV-B radiation daily for approximately 14–15 weeks in a dedicated cabinet. A medium-wavelength UV-B lamp, T-40.M, from Vilber Lourmat (Eberhardzell, Germany), was used, operating at 280–320 nm with an energy peak at 312 nm. The MED (minimal erythema dose) of this device was set at 0.06 J / cm² / day, which corresponds to approximately 20 minutes of UV-B exposure per day in SKH-1 mice. The UV-B irradiation dose was internally calibrated prior to each experiment to adjust the exposure time. To develop AK lesions and prevent the risk of skin burns, the following stepwise exposure was performed: 0.05 J / cm² / day for 10 days, followed by 0.055 J / cm² / day for 10 days, followed by the MED for up to 102 days. [Figure 7]Effect of Compound 1* on SKH1 UV-B-irradiated mice after 17 days of treatment cessation. Hairless SKH1 mice were irradiated as described in Figure 6. Treatment was cessation after 24 days of treatment with 3 mg / mouse / day of Compound 1* using a non-optimized formulation as described for the cSCC mouse model. After 17 days of treatment cessation, photographs of the left flank, mid-dorsal, and right flank were taken for three selected mice in each group (NT: mice 1-4, 1-5, and 1-6; vehicle: mice 2-4, 2-5, and 2-6; Compound 1*: mice 3-4, 3-5, and 3-6). DETAILED DESCRIPTION OF THE INVENTION

[0017] Reference will now be made in detail to the illustrated and further aspects and embodiments of the present invention, examples of which are illustrated in the accompanying structures and formulas. While the present invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to such embodiments. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is not limited in any way to the methods and materials described herein.

[0018] Elements, integers, and properties described in connection with a particular aspect, embodiment, or example of the invention should be understood as applicable to any other aspect, embodiment, or example described herein, unless specifically incompatible. All elements disclosed in this specification (including all accompanying claims, abstracts, and drawings) and / or all steps of any method or process disclosed herein may be combined in any combination, except where at least some of these elements and / or steps are mutually exclusive. The invention is not limited to the details of any of the above embodiments. The scope of the invention extends to every novel one or every novel combination of elements disclosed in this specification (including all accompanying claims, abstracts, and drawings), or every novel one or every novel combination of steps of any method or process disclosed herein.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0020] For purposes of interpreting this specification, the following definitions will be used, and where appropriate, terms used in the singular will also include the plural and vice versa. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0021] The terms "comprising," "having," and "including" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted.

[0022] The terms "individual," "subject," or "patient" are used interchangeably herein. In a preferred embodiment, the subject is a human.

[0023] The term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image, and the term "achiral" refers to a molecule that is superimposable on its mirror image.

[0024] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0025] "Diastereomers" refer to stereoisomers with two or more chiral centers such that the compounds are not mirror images of one another. Diastereomers differ in properties, such as melting points, boiling points, spectral properties, and chemical and biological reactivity. Mixtures of diastereomers can be separated by high-resolution analytical techniques such as electrophoresis and chromatography.

[0026] "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of one another. Stereochemical definitions and conventional techniques used herein generally follow S.P. Parker, Ed., McRaw-Hiff Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore may exist as different stereoisomers. All stereoisomers of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to be part of the present invention. Many organic compounds exist in optically active forms (i.e., having the property of rotating the plane of plane-polarized light). When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l indicating that the compound is levorotatory. Compounds represented by the prefix (+) or d are dextrorotatory. For a particular chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of these isomers are often called enantiomeric or scalenic mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate. The terms "tautomer" or "tautomeric form" refer to structural isomers that differ in energy and can be interconverted via a low energy barrier. For example, proton tautomers include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations.

[0027] As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present invention, particularly an acid addition salt.Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate (mesylate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.Pharmaceutically acceptable salts may include those containing another molecule, such as acetate ion, succinate ion, or other counterion. Counter ions can be any organic or inorganic moiety that stabilizes the charge of the parent compound. Furthermore, pharmaceutically acceptable salts can have multiple charged atoms in their structure. When multiple charged atoms are part of a pharmaceutically acceptable salt, they can have multiple counter ions. Therefore, pharmaceutically acceptable salts can have one or more charged atoms and / or one or more counter ions.

[0028] If the compound of the present invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, or the like; or with an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid (e.g., glucuronic acid or galacturonic acid), an alpha hydroxy acid (e.g., citric acid or tartaric acid), an amino acid (e.g., aspartic acid or glutamic acid), an aromatic acid (e.g., benzoic acid or cinnamic acid), a sulfonic acid (e.g., p-toluenesulfonic acid or ethanesulfonic acid), or the like.

[0029] The phrase "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated with the formulation.

[0030] "Solvate" refers to an association or complex of one or more solvent molecules with a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0031] The term "protecting group" refers to a substituent that is commonly used to block or protect a particular functional group during reaction of other functional groups in a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl, and 9-fluorenylmethyleneoxycarbonyl (Fmoc). For a general description of protecting groups and their uses, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0032] The terms "compounds of the invention" and "compounds of the invention" and "compounds of formula (I)" include their stereoisomers, geometric isomers, tautomers, solvates, pharmaceutically acceptable salts, and solvates of the salts.

[0033] As used herein, the term "skin lesion" refers to a skin lesion that may be a skin cancer, such as non-melanoma skin cancer (NMSC), or a pre-invasive neoplastic skin growth, such as squamous cell carcinoma in situ (cSCCis or Bowen's disease) or actinic keratosis (AK, also known as "actinic keratosis" and "senile keratosis"). Bowen's disease is a neoplastic skin disorder that may be considered an early or intraepithelial form of squamous cell carcinoma. Actinic keratosis is characterized by pre-cancerous patches of thick, scaly, or hardened skin that usually form when the skin is damaged by ultraviolet (UV) radiation from the sun or indoor tanning beds.

[0034] The terms "non-melanoma skin cancer" and "NMSC" are used interchangeably herein. The term "NMSC" refers to a group of diseases that includes actinic keratosis (AK), squamous cell carcinoma (SCC), Bowen's disease (BD), and basal cell carcinoma (BCC).

[0035] The term "field cancerization" refers to precancerous widespread disease, a biological process in which large areas of cells on tissue surfaces or within organs undergo oncogenic changes. This process often occurs due to prolonged exposure to damaging environmental conditions, such as UV radiation. The initial stage of field cancerization involves various molecular lesions, such as acquired genetic mutations and epigenetic changes, across a widespread, multifocal "field" (wide area). The field is affected by asymptomatic (subclinical, nonpalpable) AK lesions, early AK lesions, late AK lesions, and possibly invasive cSCC. The concept of field cancerization provides the rationale for field therapy, which treats the entire field rather than individual lesions. The goal of field therapy is to eliminate asymptomatic lesions as well as clinically apparent lesions and prevent the development of invasive SCC.

[0036] The terms "cutaneous squamous cell carcinoma" and "cSCC" are used interchangeably herein. cSCC is a histologically distinct form of cancer. cSCC arises from the uncontrolled division of epithelial cells or cells that exhibit specific cytological or histoarchitectural characteristics of squamous cell differentiation, such as the presence of keratins, tonofilament bundles, or desmosomes, which are structures involved in cell-cell adhesion.

[0037] The term "treatment" / "treating" as used herein includes (1) preventing or delaying the onset of clinical symptoms of a condition, disease, or condition that develops in a subject who may be suffering from or predisposed to the condition, disease, or condition, but who has not yet experienced or displayed clinical or subclinical symptoms of the condition, disease, or condition; (2) arresting the condition, disease, or condition (e.g., arresting, reducing, or delaying the onset of at least one clinical or subclinical symptom of the disease, or, in the case of maintenance treatment, its recurrence); and / or (3) alleviating the condition (i.e., causing regression of the condition, disease, or condition, or at least one of its clinical or subclinical symptoms). The benefit to a treated patient is statistically significant or at least perceptible to the patient or physician. However, it is understood that when a drug is administered to a patient to treat a disease, the outcome may not always be effective treatment. In one embodiment, the term "treatment" / "treating" as used herein refers to therapeutic treatment. In another embodiment, the terms "treatment" / "treating" as used herein refer to prophylactic treatment.

[0038] The term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. As used herein, the term "mammal" preferably refers to humans.

[0039] As used herein, the term "treatment" with respect to actinic keratosis (AK) includes lesion-directed treatment and broad-field (field) targeted treatment. Lesion-directed treatment can be useful for treating individual, isolated lesions. Other factors to consider when choosing which treatment option include the morphology and age of the lesion, pre-existing skin cancer, and individual patient factors such as age, immune status, cosmesis, pain tolerance, and treatment adherence. Broad-field targeted treatment is indicated when multiple lesions are present on a chronically photodamaged field or when there is a history of multiple lesions. Lesion-directed treatment and broad-field targeted treatment can be used in combination. The advantage of combined treatment is increased therapeutic efficacy, especially in difficult-to-treat cases.

[0040] As used herein, the term "systemic administration" refers to administration of a compound of the present invention such that the compound is widely distributed throughout the body in significant quantities to produce a biological effect, e.g., its desired effect, in the blood and / or to reach its desired site(s) of action via the vascular system. Typical routes of systemic administration include (1) direct introduction of the compound into the vascular system, or (2) oral, intrapulmonary, or intramuscular administration, in which the compound is absorbed, enters the vascular system, and is carried via the blood to one or more desired sites of action.

[0041] As used herein, the terms "oral," "orally," and "oral administration" refer to taking the compounds of the present invention by mouth.

[0042] The term "topical administration" is used in its broadest sense, including administration to surfaces of the body that are generally open to the surrounding environment. This includes not only the skin, but also the nasal and oral cavities and genitalia. Thus, topical administration can include application to the skin, the nasal cavities, the oral cavity (including the nasopharynx), and the genitalia. Topical formulations are available in a variety of forms, including creams, ointments, solutions, lotions, suspensions, pastes, emulsions, foams, and the like. Water-miscible creams are commonly used for moist or weeping lesions, while ointments are generally selected for dry, lichenified, or scaly lesions, or for areas where a more occlusive effect is desired. Lotions are generally useful when minimal application to widespread or hairy areas is desired, or for treating weeping lesions.

[0043] Skin lesions such as cSCC, AK, or cSCCis are usually diagnosed / assessed by physical examination, but can also be confirmed by histological analysis.

[0044] The term "effective amount" refers to an amount of a compound of the present invention that (i) treats or prevents a particular disease, condition, or disorder described herein, (ii) alleviates, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder. In the case of NMSC or its pre-invasive forms, an effective amount of the agent can cause the lesion to regress or disappear. In the treatment of NMSC or its pre-invasive forms, efficacy can be measured, for example, by physically assessing the lesion or by histological analysis.

[0045] As used herein, the term "dual PI3K / mTOR" inhibitor refers to a compound capable of inhibiting type I PI3K kinase activity and mTOR kinase activity at at least 2 μM, preferably at 1 μM.

[0046] The term "prodrug," as used herein, refers to a precursor or derivative form of a compound of the present invention that can be activated or converted into a more active form of the parent compound, which may have improved properties, such as increased solubility, reduced cytotoxicity, or increased bioavailability, compared to the parent compound or drug. Prodrugs of the present invention include, but are not limited to, derivatives of an amino group attached to a pyridine or pyrimidine nucleus in which one or two hydrogens have been replaced with suitable substituents, or R 2 When is piperazin-1-yl, derivatives of the cyclic amino functional group are included. Examples of such prodrugs are compounds acylated with carbonate, sulfate, or phosphoric acid with an amino acid selected from the 20 most commonly occurring naturally occurring L-α-amino acids, compounds acylated with a dipeptide such as L-Ala-L-Ala, and pharmaceutically acceptable salts thereof.

[0047] A "metabolite" is a product produced by metabolism in the body of a particular compound or its salt. Metabolites of a compound can be identified by routine methods known in the art, and their activity can be measured, for example, by tests such as those described herein. Such products can result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. In particular, a morpholine, piperazine, or thiomorpholine ring R 1 and / or R 2 Compounds of formula (I), as defined above, in which any one of the positions is oxygenated or hydroxylated are considered to be metabolites. Additional contemplated metabolic products include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Accordingly, the present invention also relates to metabolites of the compounds of the present invention, including compounds produced by a process comprising contacting a compound of the present invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0048] In a first aspect of the present invention there is provided a compound of formula (I) for use in the prevention or treatment of a skin lesion in a subject: [ka] [In the formula, X 1 , X 2 and X 3 are independently N or CH (provided that X 1 , X 2 and X 3 at least two of which are N), Y is N or CH; W is H or F (provided that if W is F, then X 1 , X 2 and X 3 is N), R 1 and R 2 are independent of each other, (i) morpholinyl of formula (II): [ka] (wherein the arrow indicates a bond in formula (I), R 3 and R 4 are each independently H, C1-C3 alkyl optionally substituted with one or two OH, C1-C2 fluoroalkyl, C1-C2 alkoxy, C1-C2 alkoxyC1-C3 alkyl, CN, or C(O)O-C1-C2 alkyl, or R 3 and R 4 and both represent C1 to C3 alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -forming) or (ii) 1 to 3 R 7 and Z is a saturated 6-membered heterocycle selected from thiomorpholinyl and piperazinyl, optionally substituted with R7 is independently in each occurrence C1-C3 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxyC1-C3 alkyl, C3-C6 cycloalkyl optionally substituted with one or two OH, or two R 7 a divalent residue -R, the substituents of which together are selected from C1-C3 alkylene, -CH2-O-CH2-, or -O-CH2CH2-O-, optionally substituted with 1 to 4 F; 8 R 9 -forming), However, R 1 and R 2 at least one of which is morpholinyl of formula (II); and prodrugs, metabolites, tautomers, solvates, and pharmaceutically acceptable salts thereof are provided.

[0049] In another aspect of the invention, the present invention provides a compound of formula (I) for use in the prevention or treatment of a skin lesion in a subject: [ka] [In the formula, X 1 , X 2 and X 3 are independently N or CH (provided that X 1 , X 2 and X 3 at least two of are N), Y is N or CH, and W is H or F (provided that when W is F, then X 1 , X 2 and X 3 is N), R 1 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, R 2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-thiomorpholinyl.

[0050] Each alkyl moiety, alone or as part of a larger group such as alkoxy, is straight or branched, and is preferably C1-C3 alkyl, more preferably C1-C2 alkyl. Examples include, among others, methyl, ethyl, n-propyl, and prop-2-yl (iso-propyl). Examples of alkoxy specifically include methoxy, ethoxy, n-propoxy, and iso-propoxy. As noted herein, alkoxy may have further substituents, such as halogen atoms, resulting in a haloalkoxy moiety.

[0051] The term "alkoxyalkyl" refers to the moiety R—O—R′, where the R and R′ groups are alkyl groups as defined herein. Examples include methoxymethyl, methoxyethyl, ethoxyethyl, and methoxypropyl.

[0052] Each alkylene moiety is straight-chain or branched, specifically, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-, preferably -CH2-, -CH2-CH2-, or -CH(CH3)-.

[0053] Each haloalkyl moiety, alone or as part of a larger group such as haloalkoxy, is an alkyl group substituted with one or more of the same or different halogen atoms. The haloalkyl moiety has, for example, 1 to 5 halo substituents, or 1 to 3 halo substituents. Examples specifically include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, and 2,2,2-trifluoro-ethyl.

[0054] Each haloalkenyl moiety, alone or as part of a larger group such as haloalkenyloxy, is an alkenyl group substituted with one or more of the same or different halogen atoms. Examples include 2-difluoro-vinyl and 1,2-dichloro-2-fluoro-vinyl. The haloalkenyl moiety has, for example, 1 to 5 halo substituents, or 1 to 3 halo substituents.

[0055] Each cycloalkyl moiety may be monocyclic or bicyclic, and is typically and preferably monocyclic, preferably having from 3 to 6 carbon atoms. Preferred examples of monocyclic cycloalkyl groups specifically include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0056] The term "heterocycle" refers to a saturated or partially unsaturated carbocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring members. Such rings do not have adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Preferred examples specifically include tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, dioxanyl, morpholinyl, oxazolidinyl, and isoxazolidinyl.

[0057] When it is said that a certain group may be substituted, it may preferably have 1 to 3 substituents, and more preferably have 1 to 2 substituents.

[0058] Certain compounds of formula (I) may have one or more chiral centers and such compounds may be provided as pure enantiomers or pure diastereomers, or as mixtures thereof in any ratio. The compounds of the invention also include all tautomeric forms of the compounds of formula (I).

[0059] In a preferred embodiment, the present invention provides compounds of formula (I) as defined herein, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject.

[0060] In another preferred embodiment, the present invention provides a compound of formula (I) for use in the prevention or treatment of a skin lesion in a subject, comprising X 1 , X 2 and X 3 is N.

[0061] In another preferred embodiment, (i) the X 1 and X 2 is N, and the X 3 is CH, or (ii) the X 1 and X 3 is N, and the X 2 is CH, or (iii) said X 2 and X 3 is N, and the X 1 is CH, preferably a tautomer, solvate, or pharmaceutically acceptable salt thereof. 1 and X 2 is N, and the X 3 is CH, or (ii) said X 2 and X 3 is N, and the X 1 is CH, preferably a tautomer, solvate, or pharmaceutically acceptable salt thereof. 1 and X 3 is N, and the X 2is CH, preferably tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0062] In another preferred embodiment, the present invention provides a compound of formula (I), wherein W is H, for use in the prevention or treatment of a skin lesion in a subject.

[0063] In another preferred embodiment, the present invention provides a compound of formula (I), wherein W is F, for use in the prevention or treatment of a skin lesion in a subject.

[0064] In another preferred embodiment, said Y is N, preferably a tautomer, solvate, or pharmaceutically acceptable salt thereof. In another preferred embodiment, said Y is CH, preferably a tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0065] In another preferred embodiment, the R 1 and the R 2 are independent of each other, [ka] Selected from JPEG2026028259000009.jpg155154.

[0066] In another preferred embodiment, the R 1 and the R 2 are independent of each other, [ka] Selected from JPEG2026028259000011.jpg31154.

[0067] In another preferred embodiment, the R 1 and the R 2 are independent of each other, [ka] is selected from.

[0068] In another preferred embodiment, the compound is 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine; 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine; 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine; 4-(Difluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine; 4'-(Difluoromethyl)-2,6-dimorpholino-[4,5'-bipyrimidine]-2'-amine; 4-(Difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine; 4'-(Difluoromethyl)-4,6-dimorpholino-[2,5'-bipyrimidine]-2'-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine; 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4'-(difluoromethyl)-6-morpholino-[4,5'-bipyrimidine]-2'-amine; 5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine; 4'-(Difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5'-bipyrimidine]-2'-amine; (S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine; (S)-4'-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5'-bipyrimidine]-2'-amine; 5-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; (S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine; (S)-4'-(Difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5'-bipyrimidine]-2'-amine; 4-(Difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3R)-3-isopropylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]morpholin-3-yl]methanol; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4-(4-cyclopropylpiperazin-1-yl)-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]morpholin-3-yl]methanol; 4-(Difluoromethyl)-5-[4-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-morpholino-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis[(3S,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3S)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0069] In another preferred embodiment, the compound is 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine; 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine; 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine; 4-(Difluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine; 4'-(Difluoromethyl)-2,6-dimorpholino-[4,5'-bipyrimidine]-2'-amine; 4-(Difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine; 4'-(Difluoromethyl)-4,6-dimorpholino-[2,5'-bipyrimidine]-2'-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine; 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4'-(difluoromethyl)-6-morpholino-[4,5'-bipyrimidine]-2'-amine; 5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine; 4'-(Difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5'-bipyrimidine]-2'-amine; (S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine; (S)-4'-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5'-bipyrimidine]-2'-amine; 5-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; (S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine; (S)-4'-(Difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5'-bipyrimidine]-2'-amine; 4-(Difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis[(3S,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3S)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0070] In another preferred embodiment, the compound is 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine; 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis[(3S,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3S)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0071] In another preferred embodiment, the compound is 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine; 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; 5-[4,6-bis[(3S,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine; 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3S)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine; 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0072] In another preferred embodiment, the compound is 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine; 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0073] In another preferred embodiment, the compound is 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; 4-(Difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine; 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0074] In another preferred embodiment, the compound is 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0075] In another preferred embodiment, the compound is 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0076] In another preferred embodiment, the compound is 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine; 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0077] In another highly preferred embodiment, the compound is 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0078] In another highly preferred embodiment, the compound is 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine; (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine; and 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0079] In another highly preferred embodiment, said compound of formula (I) is 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine.

[0080] In another highly preferred embodiment, the compound of formula (I) is 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0081] In another highly preferred embodiment, the compound of formula (I) is 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine.

[0082] In another highly preferred embodiment, the compound of formula (I) is 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0083] In another highly preferred embodiment, the compound of formula (I) is (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine.

[0084] In another highly preferred embodiment, the compound of formula (I) is (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0085] In another highly preferred embodiment, the compound of formula (I) is 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine.

[0086] In another highly preferred embodiment, the compound of formula (I) is 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0087] In another preferred embodiment, the R 1 and R 2 are, independently of each other, morpholinyl of formula (II). 1 is R 2 In another preferred embodiment, R 1 is R 2 is not equal to.

[0088] In another preferred embodiment, W is H and R 1 and R 2 are, independently of each other, morpholinyl of formula (II). 1 is R 2 In another preferred embodiment, R 1 is R 2 is not equal to.

[0089] In another preferred embodiment, W is F and R 1 and R 2 are, independently of each other, morpholinyl of formula (II). 1 is R 2 In another preferred embodiment, R 1 is R 2 is not equal to.

[0090] In another preferred embodiment, the R 1 and R2 are, independently of each other, morpholinyl of formula (II) and said saturated 6-membered heterocycle Z.

[0091] In another preferred embodiment, W is H and R 1 and R 2 are, independently of each other, morpholinyl of formula (II) and said saturated 6-membered heterocycle Z.

[0092] In another preferred embodiment, W is F and R 1 and R 2 are, independently of each other, morpholinyl of formula (II) and said saturated 6-membered heterocycle Z.

[0093] In another preferred embodiment, in the morpholinyl of formula (II), [ka] R 3 and R 4 are each independently H, C1-C3 alkyl optionally substituted with one or two OH, C1-C2 fluoroalkyl, C1-C2 alkoxy, C1-C2 alkoxyC1-C3 alkyl, CN, or C(O)O-C1-C2 alkyl, or R 3 and R 4 and both represent C1 to C3 alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -form.

[0094] When R3 and R4 together form a divalent residue and are attached to adjacent carbon atoms, a cyclic morpholinyl substituent is formed; when R3 and R4 together form a divalent residue and span the morpholine ring, a bridged morpholinyl substituent is formed; and when R3 and R4 together form a divalent residue and are attached to the same carbon atom of the morpholine, a spiromorpholinyl substituent is formed.

[0095] In one preferred embodiment, R 3 and R 4 and both represent C1 to C3 alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] a divalent residue -R selected from 5 R 6 - to form a bridging morpholinyl substituent.

[0096] In another preferred embodiment, the R 1 and R 2 are, independently of each other, morpholinyl of formula (II), with the proviso that R 3 and R 4 and together form a divalent residue that is a bridging morpholinyl, and R 3 and R 4 and both represent C1 to C3 alkylene, preferably C1 to C2 alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -form.

[0097] In a further preferred embodiment, the morpholinyl of formula (II): [ka] are each independently morpholinyl of formula (II) above (provided that R 3 and R 4 are each independently H, C1-C3 alkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, C1-C2 alkoxy, C1-C2 alkoxyC1-C3 alkyl, CN, or C(O)O-C1-C2 alkyl, or R 3 and R 4 and both represent C1 to C3 alkylene, preferably C1 to C2 alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -form).

[0098] In a further preferred embodiment, the morpholinyls of formula (II) are independently R 3 and R 4 are each independently H or CH3.

[0099] In a further preferred embodiment, the morpholinyls of formula (II) are, independently of each other, morpholinyls of formula (II) (provided that R 3 and R 4 are, independently of one another, C2-C3 alkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, C1-C2 alkoxy, C1-C2 alkoxyC1-C3 alkyl, CN, or C(O)O-C1-C2 alkyl, or R 3 and R 4 and both represent -CH2 or C3 alkylene, preferably -CH2-, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -form).

[0100] In a further preferred embodiment, the morpholinyls of formula (II) are independently [ka] Selected from JPEG2026028259000021.jpg168154.

[0101] In a further preferred embodiment, the morpholinyls of formula (II) are independently [ka] Selected from JPEG2026028259000023.jpg32154.

[0102] In a more preferred embodiment, the heterocycle Z is selected from 1 to 3 R 7 and Z is a saturated 6-membered heterocycle selected from thiomorpholinyl and piperazinyl, optionally substituted with R 7 is independently in each occurrence C1-C3 alkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, C1-C2 alkoxyC1-C3 alkyl, C3-C6 cycloalkyl, or two R 7 a divalent residue -R, the substituents of which together are selected from C1-C3 alkylene, -CH2-O-CH2-, or -O-CH2CH2-O-, optionally substituted with 1 to 4 F; 8 R 9 -form).

[0103] In a further preferred embodiment, the heterocycle Z is [ka] is selected from.

[0104] In another preferred embodiment of the present invention, the R 1 and R 2 are, independently of each other, morpholinyl of formula (II): [ka] (wherein the arrow indicates a bond in formula (I), R 3 and R 4 are each independently H, C1-C3 alkyl optionally substituted with one or two OH, C1-C2 fluoroalkyl, C1-C2 alkoxy, C1-C2 alkoxyC1-C3 alkyl, CN, or C(O)O-C1-C2 alkyl, or R 3 and R 4 and both represent C1 to C3 alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -forms).

[0105] In a further preferred embodiment, the R 1 is the above R 2 and said R 1 and the above R 2 and independently represent morpholinyl of formula (II): [ka] (wherein the arrow indicates a bond in formula (I), R 3 and R 4 are each independently H, C1-C3 alkyl optionally substituted with one or two OH, C1-C2 fluoroalkyl, C1-C2 alkoxy, C1-C2 alkoxyC1-C3 alkyl, CN, or C(O)O-C1-C2 alkyl, or R 3and R 4 and both represent C1 to C3 alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -forms).

[0106] In a further preferred embodiment of the present invention, the R 1 and R 2 are, independently of each other, morpholinyl of formula (II): [ka] (wherein the arrow indicates a bond in formula (I), R 3 and R 4 are each independently H, C1-C3 alkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, C1-C2 alkoxy, C1-C2 alkoxyC1-C3 alkyl, CN, or C(O)O-C1-C2 alkyl, or R 3 and R 4 and both represent C1 to C3 alkylene, preferably C1 to C2 alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -forms).

[0107] In a further preferred embodiment of the present invention, the R 1 is the above R 2 and said R 1 and the R 2is a morpholinyl of formula (II): [ka] (wherein the arrow indicates a bond in formula (I), R 3 and R 4 are each independently H, C1-C3 alkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, C1-C2 alkoxy, C1-C2 alkoxyC1-C3 alkyl, CN, or C(O)O-C1-C2 alkyl, or R 3 and R 4 and both represent C1 to C3 alkylene, preferably C1 to C2 alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -forms).

[0108] In another aspect and preferred embodiment, the present invention provides a compound of formula (I) for use in the prevention or treatment of a skin lesion in a subject: [ka] [In the formula, X 1 , X 2 and X 3 are independently N or CH (provided that X 1 , X 2 and X 3 at least two of are N, Y is N or CH; R 1 and R 2 are, independently of each other, morpholinyl of formula (II): [ka] (wherein the arrow indicates the bond in formula (I)), and R 1 is R 2 and said R 1 and the R 2 At least one of the groups is a morpholinyl group of formula (II): [ka] (In the formula, R 3 and R 4 are, independently of one another, C2-C3 alkyl, CH2OH, CH2CH2OH, CH2F, CHF2, CF3, CH2CF3, C1-C2 alkoxy, C1-C2 alkoxyC1-C3 alkyl, CN, or C(O)O-C1-C2 alkyl, or R 3 and R 4 and both represent -CH2 or C3 alkylene, preferably -CH2-, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] (wherein the arrow indicates the bond in formula (II)), 5 R 6 -forms].

[0109] Preferably, the R 3 and R 4 and both represent -CH2 or C3 alkylene, preferably -CH2-, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or the following structure: [ka] a divalent residue -R selected from 5 R 6 -form.

[0110] In another preferred embodiment, R 1is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and R 2 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-thiomorpholinyl.

[0111] In another preferred embodiment, R 1 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and R 2 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-thiomorpholinyl; and X 1 , X 2 and X 3 is N, as well as tautomers, solvates, and pharmaceutically acceptable salts thereof. Preferably, Y is N or CH and R 1 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and R 2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-thiomorpholinyl, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0112] In a further preferred embodiment, R 1 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and R 2 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-thiomorpholinyl; and X 1 and X 3 is N and X 2 is CH, as well as tautomers, solvates, and pharmaceutically acceptable salts thereof. Preferably, Y is N or CH, and R 1 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and R 2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-thiomorpholinyl, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0113] In a preferred embodiment, R 1 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and R 2 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-thiomorpholinyl; and X 1 and X 2 is N and X 3 is CH, as well as tautomers, solvates, and pharmaceutically acceptable salts thereof. Preferably, Y is N or CH, and R 1 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and R 2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-thiomorpholinyl, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0114] In a preferred embodiment, R 1 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and R 2 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-thiomorpholinyl; and X 2 and X 3 is N and X 1 is CH, as well as tautomers, solvates, and pharmaceutically acceptable salts thereof. Preferably, Y is N or CH, and R 1 is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, or 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, and R 2is 4-morpholinyl, 2-methyl-4-morpholinyl, 3-methyl-4-morpholinyl, octadeuterio-4-morpholinyl, 8-aza-3-oxabicyclo[3.2.1]oct-8-yl, 3-aza-8-oxabicyclo[3.2.1]oct-3-yl, 4-piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-thiomorpholinyl, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0115] In one embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of a skin lesion in a subject, wherein said skin lesion is non-melanoma skin cancer (NMSC), cutaneous lymphoma, or pre-invasive forms thereof.

[0116] In a preferred embodiment of the invention, the skin lesion is a pre-invasive form of non-melanoma skin cancer (NMSC).

[0117] In another preferred embodiment of the invention, the skin lesion is a non-melanoma skin cancer (NMSC).

[0118] In another preferred embodiment of the present invention, the skin lesion is cutaneous lymphoma.

[0119] In a further embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of non-melanoma skin cancer (NMSC) in a subject, wherein said non-melanoma skin cancer is cutaneous squamous cell carcinoma (cSCC) or basal cell carcinoma.

[0120] In a preferred embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of cutaneous squamous cell carcinoma (cSCC) in a subject.

[0121] In a further embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of cutaneous squamous cell carcinoma (cSCC) in a subject, wherein said cutaneous squamous cell carcinoma (cSCC) is invasive cSCC.

[0122] In a further embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of cutaneous squamous cell carcinoma (cSCC) in a subject, wherein said cutaneous squamous cell carcinoma (cSCC) is metastatic cSCC.

[0123] In one embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of basal cell carcinoma in a subject.

[0124] In a further embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of basal cell carcinoma in a subject, wherein the basal cell carcinoma is selected from the group consisting of superficial basal cell carcinoma (also known as "in situ basal cell carcinoma" or "superficial multicentric basal cell carcinoma"), invasive basal cell carcinoma, and nodular basal cell carcinoma.

[0125] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of basal cell carcinoma in a subject, wherein the basal cell carcinoma is superficial basal cell carcinoma (also known as "intraepithelial basal cell carcinoma" or "superficial multicentric basal cell carcinoma").

[0126] In a further preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of basal cell carcinoma in a subject, wherein said basal cell carcinoma is invasive basal cell carcinoma.

[0127] In a further preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of basal cell carcinoma in a subject, wherein said basal cell carcinoma is nodular basal cell carcinoma.

[0128] In one embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of basal cell carcinoma in a subject, wherein the basal cell carcinoma is selected from the group consisting of cystic basal cell carcinoma, cicatricial basal cell carcinoma (also known as "morphea basal cell carcinoma" or "morphea basal cell carcinoma"), micronodular basal cell carcinoma, pigmented basal cell carcinoma, erosive ulcer (also known as "Jacob's ulcer"), pinkus fibroepithelioma, polypoid basal cell carcinoma, pore-like basal cell carcinoma, and aberrant basal cell carcinoma.

[0129] In a further embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of a pre-invasive form of non-melanoma skin cancer (NMSC) in a subject, wherein said pre-invasive form is selected from the group consisting of squamous cell carcinoma in situ (cSCCis, also known as "Bowen's disease"), precancerous actinic keratosis (AK), and long-term ultraviolet damage.

[0130] In a preferred embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of a pre-invasive form of non-melanoma skin cancer (NMSC) in a subject, wherein said pre-invasive form is squamous cell carcinoma in situ (cSCCis, also known as "Bowen's disease").

[0131] In a further preferred embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of a pre-invasive form of non-melanoma skin cancer (NMSC) in a subject, wherein said pre-invasive form is precancerous actinic keratosis (AK).

[0132] In a further preferred embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of a pre-invasive form of non-melanoma skin cancer (NMSC) in a subject, wherein said pre-invasive form is chronic ultraviolet damage.

[0133] In one embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of precancerous actinic keratosis (AK) in a subject, wherein said AK is field cancer.

[0134] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of cutaneous lymphoma in a subject, wherein said cutaneous lymphoma is cutaneous T-cell lymphoma (CTCL) or cutaneous B-cell lymphoma (CBCL).

[0135] In another preferred embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of cutaneous T-cell lymphoma (CTCL) in a subject.

[0136] In another preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of cutaneous lymphoma in a subject, wherein said cutaneous lymphoma is cutaneous B-cell lymphoma (CBCL).

[0137] In one embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of a skin lesion in a subject, wherein said compound of formula (I) is administered topically to the subject.

[0138] In a further embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of a skin lesion in a subject, wherein said skin lesion is non-melanoma skin cancer (NMSC) or a pre-invasive form thereof, and wherein said compound of formula (I) is administered topically to the subject.

[0139] In a further embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of non-melanoma skin cancer (NMSC) or pre-invasive forms thereof in a subject, wherein the non-melanoma skin cancer is cutaneous squamous cell carcinoma (cSCC) or basal cell carcinoma, and wherein the compound of formula (I) is administered topically to the subject.

[0140] In a further preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of non-melanoma skin cancer (NMSC) or its pre-invasive form in a subject, wherein said pre-invasive form is precancerous actinic keratosis (AK), and wherein said compound of formula (I) is administered topically to the subject.

[0141] In one embodiment there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of a skin lesion in a subject, wherein said compound of formula (I) is administered systemically, preferably orally, to the subject.

[0142] In a further embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of a skin lesion in a subject, wherein said skin lesion is non-melanoma skin cancer (NMSC) or a pre-invasive form thereof, and wherein said compound of formula (I) is administered systemically, preferably orally, to the subject.

[0143] In a further embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of non-melanoma skin cancer (NMSC) or pre-invasive forms thereof in a subject, wherein said non-melanoma skin cancer is cutaneous squamous cell carcinoma (cSCC) or basal cell carcinoma, and wherein said compound of formula (I) is administered systemically, preferably orally, to the subject.

[0144] In a further preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of non-melanoma skin cancer (NMSC) or its pre-invasive form in a subject, wherein said pre-invasive form is precancerous actinic keratosis (AK), and wherein said compound of formula (I) is administered systemically, preferably orally, to the subject. In a preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of a skin lesion in a subject, said compound comprising: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof; There is provided a compound of formula (I), wherein said skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

[0145] In a preferred embodiment there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of a skin lesion in a subject, said compound comprising: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof; There is provided a compound of formula (I), wherein said skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

[0146] In a further preferred embodiment, there is provided a compound of formula (I) according to the present invention, which is 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject, and wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL, or AK, preferably cSCC, cSCCis, or AK.

[0147] In a further preferred embodiment there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of cSCC in a subject, said compound comprising: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, and a tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0148] In a further preferred embodiment there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of cSCC in a subject, said compound comprising: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, Provided is a compound of formula (I) selected from (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0149] In a further preferred embodiment, there is provided a compound of formula (I) according to the present invention, wherein the compound is 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject.

[0150] In a preferred embodiment there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of cSCCis in a subject, said compound comprising: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, and a tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0151] In a preferred embodiment there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of cSCCis in a subject, said compound comprising: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, Provided is a compound of formula (I) selected from (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0152] In a further preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein the compound is 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject.

[0153] In a preferred embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of AK in a subject, said compound comprising: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, and a tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0154] In a preferred embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of AK in a subject, said compound comprising: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, Provided is a compound of formula (I) selected from (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0155] In a further preferred embodiment, there is provided a compound of formula (I) according to the present invention, wherein said compound is 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of AK in a subject.

[0156] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of a skin lesion in a subject, said compound being selected from 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof; and said skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL, or AK, preferably cSCC, cSCCis, or AK.

[0157] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in preventing or treating cSCC in a subject, said compound being selected from 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0158] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in preventing or treating cSCCis in a subject, said compound being selected from 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0159] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention for use in the prevention or treatment of AK in a subject, said compound being selected from 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof.

[0160] In a preferred embodiment, there is provided the compound 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject, wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL, or AK, preferably cSCC, cSCCis, or AK.

[0161] In a particularly preferred embodiment, there is provided the compound 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject.

[0162] In a further particularly preferred embodiment, there is provided the compound 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCCis in a subject.

[0163] In a further particularly preferred embodiment, there is provided the compound 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of AK in a subject.

[0164] In a preferred embodiment, there is provided the compound (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject, wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL, or AK, preferably cSCC, cSCCis, or AK.

[0165] In a particularly preferred embodiment, there is provided the compound (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject.

[0166] In a further particularly preferred embodiment, there is provided the compound (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCCis in a subject.

[0167] In a further particularly preferred embodiment, there is provided the compound (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of AK in a subject.

[0168] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, wherein R1 and R2 are each independently morpholinyl of formula (II), for use in the prevention or treatment of a skin lesion in a subject, wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK, as well as tautomers, solvates and pharmaceutically acceptable salts thereof.

[0169] In a preferred embodiment, R 1 and R 2are independently from each other morpholinyl of formula (II) and said saturated 6-membered heterocycle Z, wherein said skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK, as well as tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject.

[0170] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, wherein W is H and R1 and R2 are, independently of each other, morpholinyl of formula (II), for use in the prevention or treatment of a skin lesion in a subject, wherein said skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK, as well as tautomers, solvates and pharmaceutically acceptable salts thereof.

[0171] In a preferred embodiment, W is H and R 1 and R 2 are independently from each other morpholinyl of formula (II) and said saturated 6-membered heterocycle Z, wherein said skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK, as well as tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject.

[0172] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, wherein W is F and R1 and R2 are, independently of each other, morpholinyl of formula (II), for use in the prevention or treatment of a skin lesion in a subject, wherein said skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK, as well as tautomers, solvates and pharmaceutically acceptable salts thereof.

[0173] In a preferred embodiment, W is F and R 1 and R 2 are independently from each other morpholinyl of formula (II) and said saturated 6-membered heterocycle Z, wherein said skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK, as well as tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject.

[0174] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject, wherein R1 and R2 are, independently of each other, morpholinyl of formula (II).

[0175] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject, wherein R1 and R2 are, independently of each other, morpholinyl of formula (II).

[0176] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of AK in a subject, wherein R1 and R2 are, independently of each other, morpholinyl of formula (II).

[0177] In a preferred embodiment, R 1 and R 2 are each independently a morpholinyl of formula (II) and the saturated 6-membered heterocycle Z, as well as tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject.

[0178] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject, wherein W is H and R1 and R2 are, independently of each other, morpholinyl of formula (II).

[0179] In a preferred embodiment, W is H and R 1 and R 2 are each independently a morpholinyl of formula (II) and the saturated 6-membered heterocycle Z, as well as tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject.

[0180] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject, wherein W is F and R1 and R2 are, independently of each other, morpholinyl of formula (II).

[0181] In a preferred embodiment, W is F and R 1 and R 2 are each independently a morpholinyl of formula (II) and the saturated 6-membered heterocycle Z, as well as tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject.

[0182] In a preferred embodiment, R 1 and R 2 are independently from each other morpholinyl of formula (II) and the saturated 6-membered heterocycle Z, as well as tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject.

[0183] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject, wherein W is H and R1 and R2 are, independently of each other, morpholinyl of formula (II).

[0184] In a preferred embodiment, W is H and R 1 and R 2 are independently from each other morpholinyl of formula (II) and the saturated 6-membered heterocycle Z, as well as tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject.

[0185] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject, wherein W is F and R1 and R2 are, independently of each other, morpholinyl of formula (II).

[0186] In a preferred embodiment, W is F and R 1 and R 2 are independently from each other morpholinyl of formula (II) and the saturated 6-membered heterocycle Z, as well as tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject.

[0187] In a preferred embodiment, R 1 and R 2 are independently from each other morpholinyl of formula (II) and the saturated 6-membered heterocycle Z, as well as tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC or cSCCis in a subject.

[0188] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC or cSCCis in a subject, wherein W is H and R1 and R2 are, independently of each other, morpholinyl of formula (II).

[0189] In a preferred embodiment, W is H and R 1 and R 2 are independently from each other morpholinyl of formula (II) and the saturated 6-membered heterocycle Z, as well as tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC or cSCCis in a subject.

[0190] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC or cSCCis in a subject, wherein W is F and R1 and R2 are, independently of each other, morpholinyl of formula (II).

[0191] In a preferred embodiment, W is F and R 1 and R 2 are independently from each other morpholinyl of formula (II) and the saturated 6-membered heterocycle Z, as well as tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC or cSCCis in a subject.

[0192] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, wherein R1 is equal to R2, for use in the prevention or treatment of a skin lesion in a subject, wherein said skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK, as well as tautomers, solvates and pharmaceutically acceptable salts thereof.

[0193] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject, wherein R1 is equal to R2.

[0194] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and its tautomers, solvates and pharmaceutically acceptable salts, for use in the prevention or treatment of cSCCis in a subject, wherein R1 is equal to R2.

[0195] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates, and pharmaceutically acceptable salts thereof, wherein R1 is equal to R2, for use in the prevention or treatment of AK in a subject.

[0196] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, wherein R1 is not equal to R2, for use in the prevention or treatment of a skin lesion in a subject, wherein said skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK, as well as tautomers, solvates and pharmaceutically acceptable salts thereof.

[0197] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in preventing or treating cSCC in a subject, wherein R1 is not equal to R2.

[0198] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and its tautomers, solvates, and pharmaceutically acceptable salts, for use in the prevention or treatment of cSCCis in a subject, wherein R1 is not equal to R2.

[0199] In a preferred embodiment, there is provided a compound of formula (I) according to the present invention, and tautomers, solvates, and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of AK in a subject, wherein R1 is not equal to R2.

[0200] In a further aspect of the present invention, there is provided a method for preventing or treating a skin lesion in a subject, comprising administering to said subject an effective amount of a compound of formula (I) according to the present invention.

[0201] In one embodiment, there is provided a method for preventing or treating a skin lesion in a subject, comprising administering to said subject an effective amount of a compound of formula (I) according to the present invention, wherein said skin lesion is selected from the group consisting of cutaneous lymphoma, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma, squamous cell carcinoma in situ (cSCCis, Bowen's disease), and precancerous actinic keratosis (AK).

[0202] In certain preferred embodiments, there is provided a method for preventing or treating a skin lesion in a subject, comprising administering to said subject an effective amount of a compound of formula (I) according to the present invention, wherein said compound is 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine; 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine; and the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

[0203] In a still further aspect of the present invention, there is provided the use of a compound of formula (I) according to the present invention for preventing or treating a skin lesion in a subject.

[0204] In one embodiment, there is provided a use of a compound of formula (I) according to the present invention for preventing or treating a skin lesion in a subject, wherein said skin lesion is selected from the group consisting of cutaneous lymphoma, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma, squamous cell carcinoma in situ (cSCCis, Bowen's disease), and precancerous actinic keratosis (AK).

[0205] In a particularly preferred embodiment, there is provided the use of a compound of formula (I) according to the invention for preventing or treating a skin lesion in a subject, said compound comprising: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL, or AK, preferably cSCC, cSCCis, or AK.

[0206] In a still further aspect of the present invention there is provided the use of a compound of formula (I) according to the present invention in the manufacture of a medicament for preventing or treating a skin lesion in a subject.

[0207] In one embodiment, there is provided the use of a compound of formula (I) according to the present invention in the manufacture of a medicament for preventing or treating a skin lesion in a subject, wherein said skin lesion is selected from the group consisting of cutaneous lymphoma, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma, squamous cell carcinoma in situ (cSCCis, Bowen's disease), and precancerous actinic keratosis (AK).

[0208] In a particularly preferred embodiment there is provided the use of a compound of formula (I) according to the invention in the manufacture of a medicament for preventing or treating a skin lesion in a subject, said compound comprising: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, and tautomers, solvates, and pharmaceutically acceptable salts thereof, wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL, or AK, preferably cSCC, cSCCis, or AK.

[0209] Most preferred in the present invention are compounds represented by the following formula: (The names of the corresponding structures were generated using ChemDraw Ultra, version 13.0.1 (CambridgeSoft Corp., Cambridge, Massachusetts), as well as lower and higher versions of the same software.)

[0210] Compound 1: [ka] 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine

[0211] Compound 1*: [ka] 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine

[0212] Compound 2: [ka] 4-(Difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine

[0213] Compound 2*: [ka] 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine

[0214] Compound 3: [ka] 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine

[0215] Compound 4: [ka] 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine

[0216] Compound 5: [ka] 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine

[0217] Compound 6: [ka] 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine

[0218] Compound 6*: [ka] 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine

[0219] Compound 7: [ka] 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine

[0220] Compound 7*: [ka] 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine

[0221] Compound 8: [ka] (S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine

[0222] Compound 8*: [ka] 5-[4-[(3S)-3-Methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine

[0223] Compound 9: [ka] (S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine

[0224] Compound 9*: [ka] 5-[4-[(3S)-3-Methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine

[0225] Compound 10: [ka] 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine

[0226] Compound 11: [ka] 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine

[0227] Compound 12: [ka] 4-(Difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine

[0228] Compound 12*: [ka] 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine

[0229] Compound 13: [ka] 4-(Difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine

[0230] Compound 13*: [ka] 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine

[0231] Compound 14: [ka] (S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine

[0232] Compound 15: [ka] (S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine

[0233] Compound 16: [ka] 4-(Difluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine

[0234] Compound 17: [ka] 4'-(Difluoromethyl)-2,6-dimorpholino-[4,5'-bipyrimidine]-2'-amine

[0235] Compound 18: [ka] 4-(Difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine

[0236] Compound 19: [ka] 4'-(Difluoromethyl)-4,6-dimorpholino-[2,5'-bipyrimidine]-2'-amine

[0237] Compound 20: [ka] 4-(Difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine

[0238] Compound 20*: [ka] 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine

[0239] Compound 21: [ka] 4-(Difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine The following compounds are more preferred:

[0240] Compound 21*: [ka] 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine

[0241] Compound 22: [ka] 5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine

[0242] Compound 23: [ka] 5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine

[0243] Compound 24: [ka] 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4'-(difluoromethyl)-6-morpholino-[4,5'-bipyrimidine]-2'-amine

[0244] Compound 25: [ka] 5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine

[0245] Compound 26: [ka] 4'-(Difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5'-bipyrimidine]-2'-amine

[0246] Compound 27: [ka] (S)-4-(Difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine

[0247] Compound 28: [ka] (S)-4'-(Difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5'-bipyrimidine]-2'-amine

[0248] Compound 29: [ka] 5-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine

[0249] Compound 30: [ka] 5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0250] Compound 31: [ka] (S)-4-(Difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine

[0251] Compound 32: [ka] (S)-4'-(Difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5'-bipyrimidine]-2'-amine

[0252] Compound 33: [ka] 4-(Difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0253] Compound 34: [ka] 5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0254] Compound 37: [ka] 5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0255] Compound 38: [ka] 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

[0256] Compound 39: [ka] 5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0257] Compound 40: [ka] 5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0258] Compound 41: [ka] 5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0259] compound 42 [ka] 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine

[0260] Compound 44: [ka] 4-(Difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0261] Compound 45: [ka] 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0262] Compound 46: [ka] 4-(Difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0263] Compound 47: [ka] 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0264] Compound 50: [ka] 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

[0265] Compound 51: [ka] 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

[0266] Compound 52: [ka] 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0267] Compound 53: [ka] 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0268] Compound 54: [ka] 5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0269] Compound 55: [ka] 5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0270] Compound 56: [ka] 5-[4,6-bis[(3R)-3-isopropylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0271] Compound 66: [ka] 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0272] Compound 67: [ka] 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0273] Compound 68: [ka] [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]morpholin-3-yl]methanol

[0274] Compound 69: [ka] 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

[0275] Compound 70: [ka] 5-[4-(4-cyclopropylpiperazin-1-yl)-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0276] Compound 71: [ka] 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0277] Compound 77: [ka] [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]morpholin-3-yl]methanol

[0278] Compound 78: [ka] 4-(Difluoromethyl)-5-[4-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0279] Compound 79: [ka] 4-(Difluoromethyl)-5-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0280] Compound 80: [ka] 4-(Difluoromethyl)-5-[4-morpholino-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

[0281] Compound 82: [ka] 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

[0282] Compound 83: [ka] 5-[4,6-bis[(3S,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine

[0283] Compound 84: [ka] 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine

[0284] Compound 85: [ka] 4-(Difluoromethyl)-5-[4-[(3S)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0285] Compound 86: [ka] 4-(Difluoromethyl)-5-[4-[(3R)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine

[0286] Compound 88: [ka] 4-(Difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine

[0287] Preparation of Compounds of the Invention The compounds of the present invention can be synthesized by synthetic routes that include processes similar to those well known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art.

[0288] In preparing the compounds of the present invention, it may be necessary to protect remote functional groups (e.g., primary or secondary amines) of intermediates. The need for such protection will vary with the nature of the remote functional group and the conditions of the preparation method. Suitable amino-protecting groups include tert-butyloxycarbonyl (BOC), bis-tert-butyloxycarbonyl, or dimethylaminomethylenyl. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0289] Separation method In the methods for preparing the compounds of the present invention, it may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified to the desired degree of homogeneity by methods common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse-phase and normal-phase, high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus, small-scale analytical and preparative thin- or thick-layer chromatography, and small-scale thin-layer and flash chromatography.

[0290] The selection of an appropriate separation method will depend on the properties of the materials used, such as, for example, the presence or absence of polar functional groups in chromatography, the stability of the materials in acidic and basic media in multiphase extraction, etc. A person skilled in the art will use a method that is likely to achieve the desired separation.

[0291] Example The following examples are intended to illustrate the invention without limiting it.

[0292] The chemical reactions described in the examples can be easily adapted to prepare many other lipid kinase inhibitors of the present invention, and alternative methods for preparing the compounds of the present invention are considered to be within the scope of this specification. For example, the synthesis of compounds not exemplified in the present invention can be carried out without hindrance by making modifications that are obvious to those skilled in the art, such as by appropriately protecting interfering groups, using other suitable reagents known in the art other than those described, and / or by making routine changes to reaction conditions. In addition, other reactions disclosed herein or known in the art will be recognized as being applicable to preparing other compounds of the present invention.

[0293] In principle, for the compounds prepared 1H NMR and mass spectra were obtained. In the examples described below, all temperatures are in degrees Celsius (°C) unless otherwise indicated. Reagents were purchased from commercial sources such as Sigma Aldrich, Fluorochem, Acros, Lancaster, TCI, or Maybridge and used without further purification unless otherwise indicated. Reactions described below were generally carried out in anhydrous solvents under a positive pressure of nitrogen or using drying tubes (unless otherwise noted), and reaction flasks were typically equipped with rubber septa for introduction of substrates and reagents via syringe. Glassware was oven-dried. Column chromatography was performed using silica gel from Merck. 1 1 H NMR spectra were recorded on a Bruker instrument operating at 400 MHz. 1 H NMR spectra were obtained for solutions in various deuterated solvents such as CDCl3, (CD3)2SO, CD3OD, or (CD3)2CO. The δ values ​​of the chemical shifts are reported in ppm and corrected to the signal of the deuterated solvent (7.26 ppm for CDCl3) or TMS (0 ppm). 19 F NMR spectra were calibrated against CFCl3 (δ = 0 ppm) as an external standard. 19 The F NMR spectrum is 1 H-decoupled peaks were recorded. The following abbreviations are used when reporting peak multiplicities: s (singlet), d (doublet), t (triplet), m (multiplet), quint (quintet), and br (broad line). Coupling constants, when given, are reported in units of hertz (Hz). MALDI-ToF mass spectra (MS) were obtained on a Voyager-De™ Pro, measured as m / z.

[0294] The following abbreviations are used below: BSA (bovine serum albumin), DMSO (dimethyl sulfoxide), ESI (electrospray ionization), HCl (hydrochloric acid), M (molar), MALDI (matrix-assisted laser desorption / ionization), MS (mass spectrometry), PBS (phosphate-buffered saline), TLC (thin layer chromatography), nd (not determined).

[0295] Example 1 Preparation of Intermediate Compounds and Compounds of the Invention Preparation of intermediate compounds The following methods were used to prepare intermediate compounds used in the preparation of compounds of formula (I).

[0296] Method 1: 8-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chloro-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (i1) [ka] 3-Oxa-8-azabicyclo[3.2.1]octane·HCl (Advanced ChemBlocks Inc., Product No. A-861, 2.00 g, 13.4 mmol, 2.0 equiv.) and N,N-diisopropylethylamine (4.80 mL, 27.6 mmol, 4.1 equiv.) were placed in a flask and dissolved in dichloromethane (20 mL). The flask was placed in an ice bath and the solution was cooled to 0 °C. This solution was then added dropwise to a solution of cyanuric chloride in dichloromethane (20 mL) at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred overnight. Additional dichloromethane (100 mL) was added, and the organic layer was washed with saturated aqueous sodium hydrogen sulfate. The organic layer was then dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Purification by flash chromatography (cyclohexane / ethyl acetate = 4:1) afforded the desired intermediate i1 as a colorless solid (79% yield). 1H NMR(400MHz,CDCl3):δ4.70-4.54(m,4H),3.80-3.58(m,8H),2.14-1.89(m,8H);MS(MALDI):m / z=338.4([M+H] + ).

[0297] Method 1 is also used to prepare the following intermediate compounds i2-i10, as well as intermediates i79-i81 and i90.

[0298] [Table 1] JPEG2026028259000117.jpg208154JPEG2026028259000118.jpg75154

[0299] Method 2: 2,4-Dichloro-6-morpholino-1,3,5-triazine (i11) [ka] A solution of morpholine (17.4 g, 0.200 mol, 2.0 equiv.) was added dropwise to a solution of cyanuric chloride (18.1 g, 0.100 mol, 1.0 equiv.) in dichloromethane (200 mL) at −78° C. over 2 h. The resulting mixture was allowed to warm to 0° C. with stirring and mixed with ice-cold saturated aqueous sodium hydrogen sulfate. The phases were separated, and the organic phase was washed with semi-concentrated brine, dried over sodium sulfate, and evaporated to give the title compound i11 as a colorless solid. 1 H NMR (400MHz, CDCl3): δ3.90-3.86(m,4H),3.77-3.72(m,4H).

[0300] Method 3: 8-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo-[3.2.1]octane (i12) [ka] 3-Oxa-8-azabicyclo[3.2.1]octane·HCl (Advanced ChemBlocks Inc., Product No. A-861, 200 mg, 1.34 mmol, 1.1 equiv.) and N,N-diisopropylethylamine (470 μL, 2.69 mmol, 2.1 equiv.) were placed in a flask and dissolved in ethanol (3 mL). The flask was placed in an ice bath. A solution of compound i11 (300 mg, 1.28 mmol, 1.0 equiv.) in ethanol (2 mL) was added to the above solution at 0 °C. The resulting mixture was stirred overnight while warming to room temperature. Deionized water (20 mL) was added, and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Purification by flash chromatography (cyclohexane / ethyl acetate=9:1→8:2) affords the desired intermediate i12 as a colorless solid (78% yield). 1 H NMR(400MHz,CDCl3):δ4.69-4.56(m,2H),3.86-3.59(m,12H),2.12-1.91(m,4H);MS(MALDI):m / z=312.7([M+H] + ).

[0301] Method 3 is also used to prepare the following intermediate compounds i13-i16, as well as intermediates i87 and i91.

[0302] [Table 2]

[0303] Method 4: (S)-4-(4,6-dichloro-1,3,5-triazin-2-yl)-3-methylmorpholine (i17) [ka] To a solution of cyanuric chloride (450 mg, 2.44 mol, 1.0 equiv.) in dichloromethane (4 mL) was slowly added a solution of (S)-3-methylmorpholine (Activate Scientific, Product No. AS3424, 0.28 mL, 2.44 mol, 1.0 equiv.) and triethylamine (0.35 mL, 2.51 mol, 1.02 equiv.) in dichloromethane (2 mL) at −50° C. The resulting mixture was stirred at −50° C. for 2 h, then warmed to 0° C. with stirring and mixed with ice-cold saturated aqueous sodium hydrogen sulfate. The phases were separated, and the organic phase was washed with brine, dried over sodium sulfate, and evaporated to give the title compound i17 as a colorless solid (95% yield). 1 H NMR (400MHz, CDCl3): δ4.78-4.69(m,1H),4.43-4.39(m,1H),3.98-3.96(m,1H),3.78 -3.76(m,1H),3.67-3.65(m,1H),3.51-3.47(m,1H),3.40-3.37(m,1H),1.36(m,3H).

[0304] Method 5: 8-(4-chloro-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (i18) [ka] 3-Oxa-8-azabicyclo[3.2.1]octane·HCl (Advanced ChemBlocks Inc., Product No. A-861, 383 mg, 2.55 mmol, 1.1 equiv.) and N,N-diisopropylethylamine (1.0 mL, 5.60 mmol, 2.4 equiv.) were placed in a flask and dissolved in ethanol (4 mL). The flask was placed in an ice bath. A solution of compound i17 (580 mg, 2.33 mmol, 1.0 equiv.) in ethanol (2 mL) was added to the above solution at 0 °C. The resulting mixture was stirred for 4 h while warming to room temperature. Deionized water (20 mL) was added, and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Purification by flash chromatography (cyclohexane / ethyl acetate=9:1→8:2) affords the desired intermediate i18 as a colorless solid (88% yield). 1 H NMR (400MHz, CDCl3): δ4.75-4.52(m,3H),4.37-4.24(m,1H),3.95-3.92(m,1H),3.73-3.70(m, 3H),3.64-3.61(m,3H),3.52-3.42(m,1H),3.29-3.17(m,1H),2.11-1.89(m,4H),1.31(m,3H).

[0305] Method 6: tert-Butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (i19) [ka] To a cooled (-50 °C) solution of cyanuric chloride (1.0 g, 5.42 mmol, 1.0 equiv.) in dichloromethane (4 mL), a solution of tert-butyl piperazine-1-carboxylate (Sigma, product no. 343536, 1.02 g, 5.48 mmol, 1.01 equiv.) and triethylamine (0.767 mL, 5.53 mmol, 1.02 equiv.) in dichloromethane (2 mL) was added dropwise. The resulting reaction mixture was stirred at -50 °C for 4 h. A saturated aqueous solution of sodium hydrogen sulfate (10 mL) and dichloromethane (20 mL) were added. The mixture was transferred to a separatory funnel. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogen sulfate (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give pure intermediate i19 (80% yield). 1 H NMR (400MHz, CDCl3): δ3.88-3.85(m,4H),3.53-3.51(m,4H),1.49(m,9H).

[0306] Method 7: tert-Butyl 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (i20) [ka] 3-Oxa-8-azabicyclo[3.2.1]octane·HCl (Advanced ChemBlocks Inc., Product No. A-861, 235 mg, 1.57 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (592 μL, 3.14 mmol, 2.1 equiv.) were placed in a flask and dissolved in ethanol (6 mL). The flask was placed in an ice bath. A solution of compound i19 (500 mg, 1.5 mmol, 1.0 equiv.) in ethanol (2 mL) was added to the above solution at 0 °C. The resulting mixture was stirred overnight while warming to room temperature. Deionized water (10 mL) was added, and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Purification by flash chromatography (cyclohexane / ethyl acetate = 8:2) afforded the desired intermediate i20 as a colorless solid (77% yield). 1 H NMR (400MHz, CDCl3): δ4.68-4.60(m,2H),3.76-3.70(m,6H),3.64-3.62(m,2H),3.47-3.45(m,4H),2.08-1.95(m,4H),1.48(br s,9H);MS(MALDI):m / z=411.8([M+H] + ).

[0307] Method 7 is also used to prepare the following intermediate compound i21.

[0308] [Table 3]

[0309] Method 8: 4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine (i22) and 4,4'-(2-chloropyrimidine-4,6-diyl)dimorpholine (i23) [ka] 2,4,6-Trichloropyrimidine (Manchester Organics, product number Y17832, 11.2 g, 61 mmol, 1.0 equiv.), N,N-diisopropylethylamine (23.3 mL, 134.2 mmol, 2.2 equiv.), and morpholine (11.7 mL, 134.2 mmol, 2.2 equiv.) were placed in a flask and dissolved in ethanol (120 mL). The flask was fitted with a reflux condenser and placed in a preheated oil bath at 100 °C. The reaction mixture was stirred at this temperature for 18 h. After this time, the reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The resulting mixture was dissolved in dichloromethane (100 mL) and washed twice with an aqueous solution of sodium hydrogen sulfate (2 × 80 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure using a rotary evaporator. Products i22 and i23 are isolated by flash chromatography on silica gel (cyclohexane / ethyl acetate = 3:1 to 1:1). The product fractions are pooled and evaporated to give i22 as a colorless powder (13.8 g, 80%) and i23 as a colorless powder (2.2 g, 13% yield).

[0310] 4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine (i22): 1 H NMR(400MHz,CDCl3):δ5.85(s,1H),3.71-3.75(m,12H),3.52-3.55(m,4H);MS(MALDI):m / z:285.4([M+H] + ). 4,4'-(2-chloropyrimidine-4,6-diyl)dimorpholine (i23): 1 H NMR(400MHz,CDCl3):δ5.38(s,1H),3.73-3.76(m,8H),3.52-3.54(m,8H);MS(MALDI):m / z:285.2([M+H] + ).

[0311] Method 9: 8-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chloropyrimidin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (i24) [ka] A solution of 2,4,6-trichloropyrimidine (0.676 mL, 5.88 mmol, 1.0 equiv.), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.76 g, 11.8 mmol, 2.0 equiv.), and N,N-diisopropylethylamine (4.10 mL, 23.5 mmol, 4.0 equiv.) in ethyl acetate (18 volumes) was heated (100 °C) for 16 h. The solvent was then removed under reduced pressure, and the residue was dissolved in dichloromethane (60 volumes) and washed with saturated aqueous sodium hydrogen sulfate (3 x 60 volumes). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (cyclohexane / ethyl acetate = 3:1 to 1:1) on silica gel afforded the desired intermediate i24 as a colorless solid (1.23 g, 78%). 1 H NMR(400MHz,CDCl3):δ5.80(s,1H),4.59(s,2H),4.35(m,2H),3.76(t, 2 J H,H =10.8Hz,4H),3.59(d, 2 J H,H =10.8Hz,4H),2.03(m,8H);MS(MALDI):m / z=337.7([M+H] + ).

[0312] Method 9 is also used to prepare the following intermediate compound i25.

[0313] [Table 4]

[0314] Method 10: 4-(4,6-dichloropyrimidin-2-yl)morpholine (i26) and 4-(2,6-dichloropyrimidin-4-yl)morpholine (i27) [ka] To a solution of 2,4,6-trichloropyrimidine (14.0 mL, 122 mmol, 1.0 equiv.) in ethanol (150 mL) is added dropwise a solution of morpholine (11.2 mL, 256 mmol, 2.1 equiv.) and N,N-diisopropylethylamine (44.6 mL, 256 mmol, 2.1 equiv.) in ethanol (150 mL) at 0 °C. The reaction mixture is stirred overnight at room temperature, and the solvent is removed under reduced pressure. The crude product is extracted with dichloromethane (3 × 100 mL), and the organic phase is washed successively with saturated aqueous sodium hydrogen sulfate (3 × 400 mL). The combined organic layers are dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is purified by flash column chromatography (SiO2, cyclohexane / ethyl acetate = 9:1 to 3:1) to give i26 (5.02 g, 18%) and i27 (16.7 g, 59%), both as colorless solids.

[0315] 4-(4,6-Dichloropyrimidin-2-yl)morpholine (i26): 1 H NMR (400MHz, CDCl3): δ6.56(s,1H),3.78(m,4H)3.74(m,4H). 4-(2,6-Dichloropyrimidin-4-yl)morpholine (i27): 1 H NMR (400MHz, CDCl3): δ6.41(s,1H),3.78(m,4H),3.65(m,4H).

[0316] Method 11: (S)-4-(2-chloro-6-morpholinopyrimidin-4-yl)-3-methylmorpholine (i28) [ka] A solution of i27 (694 mg, 2.97 mmol, 1.0 equiv), (S)-3-methylmorpholine (0.500 mL, 4.46 mmol, 1.5 equiv), and N,N-diisopropylethylamine (1.29 mL, 7.43 mmol, 2.5 equiv) in ethanol (5.0 mL) was heated to reflux for 3 days. The solvent was then removed under reduced pressure. The residue was dissolved in dichloromethane (60 volumes) and washed with saturated aqueous sodium hydrogen sulfate (3 x 60 volumes). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (SiO, cyclohexane / ethyl acetate = 3:1 to 1:1) to afford the title compound (S)-4-(2-chloro-6-morpholinopyrimidin-4-yl)-3-methylmorpholine (i28) as a colorless solid (425 mg, 48%). 1 H NMR(400MHz,CDCl3):δ5.85(s,1H),4.62(dd, 2 J H,H =13.6Hz, 3 J H,H =2.9Hz,1H),4.25(dd, 2 J H,H =13.6Hz, 3 J H,H =2.9Hz,1H),3.93(dd, 2 J H,H =11.4Hz, 3 J H,H =3.8Hz,1H),3.75,(t, 3 J H,H =5.0Hz,4H),3.71(s,1H),3.66(dd, 2 J H,H =11.3Hz, 3 J H,H =3.2Hz,1H),3.53(m,5H),3.23(m,1H),1.26(d, 2 J H,H =11.3Hz,3H);MS(MALDI):m / z=299.4([M+H] + ).

[0317] Method 11 is also used to prepare the following intermediate compound i29.

[0318] [Table 5]

[0319] Method 12: (S)-4-(6-chloro-2-morpholinopyrimidin-4-yl)-3-methylmorpholine (i30) [ka] A solution of (S)-3-methylmorpholine (194 mg, 1.32 mmol, 1.5 equiv), i26 (300 mg, 1.28 mmol, 1.0 equiv), and N,N-diisopropylethylamine (3.0 equiv) in DMF (17 volumes) is heated (130 °C) for 16 hours. The solvent is then removed under reduced pressure. The residue is dissolved in dichloromethane (100 volumes) and washed with saturated aqueous sodium hydrogen sulfate (3 x 100 volumes). The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography (SiO, cyclohexane / ethyl acetate = 5:1) to afford the title compound i30 as a colorless solid (257 mg, 67%). 1 H NMR(400MHz,CDCl3):δ5.84(s,1H),4.18(m,1H),3.94(m,2H),3.71(m,10H),3.53,(dt, 2 J H,H =12.0Hz, 3 J H,H =3.1Hz,1H),3.20(dt, 2 J H,H =12.8Hz, 3 J H,H =3.8Hz,1H),1.27(d, 3 J H,H =6.8Hz,3H);MS(MALDI):m / z=298.4([M] + ).

[0320] Method 14: 8-(4,6-Dichloro-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (i32) [ka] A solution of cyanuric chloride (1.97 g, 10.7 mmol, 1.0 equiv.) in dichloromethane (10 mL) is cooled to -50 °C. A solution of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.60 g, 10.7 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (3.73 mL, 21.4 mmol, 2.0 equiv.) in dichloromethane (40 mL) is added slowly over 5 h. The mixture is stirred at this temperature for an additional 5 h. Dichloromethane (20 mL) and saturated aqueous sodium hydrogen sulfate (50 mL) are then added, and the mixture is allowed to warm to room temperature. The layers are separated, and the organic phase is washed with saturated aqueous sodium hydrogen sulfate (2 x 50 mL). The organic layer is dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The crude product is recrystallized from n-heptane / dichloromethane (20 mL / 13 mL) to give the title compound 8-(4,6-dichloro-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (i32) as a colorless solid (2.47 g, 47%). 1 H NMR(400MHz,CDCl3):δ4.74(m,2H),3.72(d, 3 J H,H =1.5Hz,4H),2.08(m,4H).

[0321] Method 14 is also used to prepare the following intermediate compounds i33 and i34.

[0322] [Table 6]

[0323] Method 15: 9-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chloro-1,3,5-triazin-2-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane (i35) [ka] To a solution of 3,7-dioxa-9-azabicyclo[3.3.1]nonane (184 mg, 0.700 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.170 mL, 0.970 mmol, 1.4 equiv) in 1,4-dioxane (1.0 mL) was added a solution of i32 (100 mg, 0.770 mmol, 1.1 equiv) in 1,4-dioxane (2.0 mL). The resulting mixture was heated to 70 °C for 1 h. Dichloromethane (50 mL) and water (50 mL) were then added. The aqueous layer was extracted with dichloromethane (3 × 50 mL), and the combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated. The crude product is purified by automated flash chromatography (cyclohexane / ethyl acetate = 2:1 to 0:1) on silica gel to give the title compound 9-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chloro-1,3,5-triazin-2-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane (i35) as a colorless solid (192 mg, 77%). 1 H NMR(400MHz,(CD3)2SO):δ4.70(m,1H),4.55(m,2H),4.44(m,1H),4.12(m,4H),3.90(m ,4H),3.72(m,2H),3.64(m,2H),2.08(m,2H),1.97(m,2H);MS(MALDI):m / z=354.3([M] + ).

[0324] Method 16: 9-(4-chloro-6-((R)-3-methylmorpholino)-1,3,5-triazin-2-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane (i36) [ka] To a solution of 3,7-dioxa-9-azabicyclo[3.3.1]nonane (173 mg, 1.27 mmol, 1.05 equiv.) and N,N-diisopropylethylamine (0.50 mL, 2.52 mmol, 2.1 equiv.) in tetrahydrofuran (5 mL) was added a solution of i33 (300 mg, 2.52 mmol, 2.1 equiv.) in 1,4-dioxane (2.0 mL). The resulting mixture was heated (70 °C) for 2 h. Ethyl acetate (20 mL) and saturated aqueous sodium hydrogen sulfate (20 mL) were then added. The phases were separated, and the organic phase was washed with saturated aqueous sodium hydrogen sulfate (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product is purified by automated flash chromatography (SiO2, cyclohexane / ethyl acetate = 2:1 to 0:1) to afford the title compound i36 as a colorless solid (316 mg, 76%). 1 H NMR(400MHz,(CD3)2SO):δ4.55-4.53(m,1H),4.42(m,1H),4.32(m,1H),4.25-4.16(m,1H),4.01-3.97(m,4H),3.87(dd, 3 J H,H =3.8Hz, 2 J H,H =11.2Hz,1H),3.73-3.65(m,5H),3.53(dd, 3 J H,H =3.0Hz, 2 J H,H =11.6Hz,1H),3.38(m,1H),3.15(m,1H),1.20(d, 3 J H,H =6.9Hz,3H).

[0325] Method 16 is also used to prepare the following intermediate compounds i37-i53, intermediate i82 and intermediates i85, i86, i92, i93, i94.

[0326] [Table 7] JPEG2026028259000139.jpg207154JPEG2026028259000140.jpg196154

[0327] Method 17: 9-(4-chloro-6-(3,3-dimethylmorpholino)-1,3,5-triazin-2-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane (i54) [ka] i34 i54 To a solution of 3,7-dioxa-9-azabicyclo[3.3.1]nonane (155 mg, 1.20 mmol, 1.05 equiv.) and N,N-diisopropylethylamine (0.42 mL, 2.40 mmol, 2.1 equiv.) in 1,4-dioxane (5 mL) was added a solution of i34 (300 mg, 1.14 mmol, 1 equiv.) in 1,4-dioxane (1 mL). The resulting mixture was heated (70 °C) for 2 h. Ethyl acetate (20 mL) and saturated aqueous sodium hydrogen sulfate (20 mL) were then added. The phases were separated, and the organic phase was washed with saturated aqueous sodium hydrogen sulfate (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product is purified by automated flash chromatography (SiO2, cyclohexane / ethyl acetate = 2:1 to 0:1) to afford the title compound i54 as a colorless solid (178 mg, 44%). 1 H NMR(400MHz,(CD3)2SO):δ4.32(m,2H),4.05-3.98(m,4H),3.77(m,4H),3.71(m,4H),3.44(m,2H),1.41(s,6H).MS(MALDI):m / z=356.3([M+H] + ).

[0328] Method 17 is also used to prepare the following intermediate compounds i55-i64.

[0329] [Table 8]

[0330] Method 18: 4-(Difluoromethyl)pyridin-2-amine (i65) [ka] Palladium acetate (275 mg, 1.22 mmol, 0.05 equiv.) and 2-dicyclohexylphosphino-2',4',6'-triylpropylbiphenyl (Sigma-Aldrich, product number 638064, 1.17 g, 2.45 mmol, 0.10 equiv.) are dissolved in 1,4-dioxane (10 mL) under a nitrogen atmosphere, and the resulting mixture is stirred at room temperature for 45 min. This solution is then added to a mixture of tert-butyl carbamate (Sigma, Product No. 167398, 4.30 g, 36.7 mmol, 1.5 equiv.), CsCO (15.9 g, 48.8 mmol, 2.0 equiv.), and 2-chloro-4-difluoromethyl-pyridine (Manchester Organics, Product No. U15343, 4.00 g, 24.5 mmol, 1.0 equiv.) in 1,4-dioxane (80 mL) under a nitrogen atmosphere. The resulting reaction mixture is then heated to 90° C. for 3 hours, during which time it turns brown. After this time, the mixture is allowed to cool to room temperature. The mixture is then diluted with ethyl acetate and washed with saturated aqueous ammonium chloride (2×30 mL) and deionized water. The organic layer is dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure. The brown residue is mixed with 4 M HCl in dioxane (50 mL, excess) and methanol (20 mL) and then heated to 80 °C for 45 min. Deionized water is added, and the aqueous layer is washed with ethyl acetate (3x). The aqueous layer is then basified with solid sodium hydroxide to pH = 9. The aqueous layer is extracted with ethyl acetate (3x). The combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The desired product i65 is obtained as a colorless solid, which is used in the next step without further purification (yield 98%). 1 H NMR (400 MHz, CDCl): δ 8.16 (d 2 J H,H =5.2Hz,1H),6.74(d, 2 J H,H =4.8Hz,1H),6.59(s,1H),6.51(t, 2 J H,F =56Hz,1H),4.61(br s,2H); 19F NMR(376MHz,CDCl3):δ-116.0(s,2F).

[0331] Method 19: 5-Bromo-4-(difluoromethyl)pyridin-2-amine (i66) [ka] To a solution of compound i65 (3.00 g, 20.8 mmol, 1.0 equiv) in tetrahydrofuran (60 mL) was added N-bromosuccinimide (3.89 g, 21.9 mmol, 1.05 equiv) in an ice bath at 0 °C. The resulting mixture was stirred overnight while warming to room temperature. Ethyl acetate was added, and the organic layer was washed with aqueous sodium carbonate (8%). The organic phase was then separated and acidified with 3 M aqueous HCl. The aqueous layer was washed with ethyl acetate (3 × 50 mL) and then basified to pH = 10 with solid sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The desired product i66 was obtained as a brown solid, which was used in the next step without further purification (79% yield). 1 H NMR(400MHz,CDCl3):δ8.20(s,1H),6.75(s,1H),6.71(t, 2 J H,F =54Hz,1H);4.62(br s,2H); 19 F NMR(376MHz,CDCl3):δ-118.9(s,2F).

[0332] Method 20: N'-(5-bromo-4-(difluoromethyl)pyridin-2-yl)-N,N-dimethylformimidamide (i67) [ka] To a solution of compound i66 (3.68 g, 16.5 mmol, 1.0 equiv) in tetrahydrofuran (50 mL), N,N-dimethylformamide dimethyl acetal (Manchester Organics, product number 005030, 3.30 mL, 24.8 mmol, 1.5 equiv) was added, and the resulting mixture was stirred at 60 °C for 3 h. The resulting mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (cyclohexane / ethyl acetate = 1:1) on silica gel to give the desired product i67 as a yellow solid (82% yield). 1 H NMR(400MHz,CDCl3):δ8.43(s,1H),8.34(br s,1H),7.17(s,1H),6.73(t, 2 J H,F =54Hz,1H),3.12(s,3H),3.10(s,3H); 19 F NMR(376MHz,CDCl3):δ-118.6(s,2F);MS(MALDI):m / z=278.5([M+H] + ).

[0333] Method 21: N'-(4-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-N,N-dimethylformimidamide (i68) [ka] A solution of compound i67 (1.50 g, 5.39 mmol, 1.0 equiv.) in tetrahydrofuran (5 mL) was slowly added to a solution of 2 M isopropylmagnesium chloride (Sigma, Product No. 230111, 3.10 mL, 6.20 mmol, 1.15 equiv.) in tetrahydrofuran (6 mL) at 0 °C. The resulting brown mixture was stirred at 0 °C for 45 minutes and then at room temperature for 15 minutes. After this time, TLC monitoring (cyclohexane / ethyl acetate = 1:1) indicated complete consumption of the starting material. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Manchester Organics, Product No. W23343, 1.43 mL, 7.00 mmol, 1.3 equiv.) was added, and the mixture was heated to 60 °C for 3 hours. The mixture was then placed in an Erlenmeyer flask, cooled to 0 °C in an ice bath, and quenched with 15% aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Heptane was added, and the organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The desired product i68 was obtained as a brown oil, which was used in the next step without further purification (94% yield). 1 H NMR (400MHz, CDCl3): δ8.66(s,1H),8.51(s,1H),7.34-7.04(m,2H),3.12(s,3H),3.12(s,3H),1.34(s,12H); 19 F NMR(376MHz,CDCl3):δ-115.6(s,2F);MS(MALDI):m / z=326.0([M+H] + ).

[0334] Method 22: 4-(Difluoromethyl)pyrimidin-2-amine (i69) [ka] To a solution of ethyl vinyl ether (4.00 mL, 41.8 mmol, 1.0 equiv.) in a mixture of pyridine (4.10 mL, 50.7 mmol, 1.2 equiv.) and dichloromethane (40 mL) was added a solution of 2,2-difluoroacetic anhydride (Manchester Organics, product no. L24754, 5.90 mL, 50.1 mmol, 1.2 equiv.) in dichloromethane (5 mL) dropwise at -70 °C in a dry ice / isopropanol bath. The resulting solution was allowed to warm to room temperature overnight. The mixture was then washed with deionized water, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give an orange oil.

[0335] Simultaneously, a suspension of guanidine·HCl (Sigma, product no. 50940, 4.80 g, 50.2 mmol, 1.2 equiv.) in ethanol (20 mL) was stirred at room temperature for 1 h. Sodium hydroxide pellets (2.00 g, 50.0 mmol, 1.2 equiv.) were added in one portion to this solution. The resulting suspension was stirred at room temperature overnight.

[0336] The orange oil is diluted with dichloromethane (20 mL) and added dropwise to the ethanol suspension over 1 h. The resulting suspension is stirred at room temperature for 2 h. Dichloromethane is evaporated under reduced pressure. Deionized water (25 mL) is added to the residue. The resulting mixture is stirred vigorously for 2 h and then allowed to stand at room temperature overnight. The resulting solid is filtered off, washed with deionized water (2x) and heptane (1x), and then dried under vacuum. The desired product i69 is obtained as a colorless solid (65% yield). 1 H NMR (400 MHz, CDCl): δ 8.43 (d 2 J H,H =4.8Hz,1H),7.02(br s,2H),6.76(d, 2 J H,H =5.2Hz,1H),6.67(t, 2 J H,F =55Hz,1H); 19 F NMR(376MHz,CDCl3):δ-120.5(s,2F).

[0337] Method 23: 5-Bromo-4-(difluoromethyl)pyrimidin-2-amine (i70) [ka] To a solution of compound i69 (3.00 g, 20.7 mmol, 1.0 equiv) in tetrahydrofuran (90 mL) was added N-bromosuccinimide (3.86 g, 21.7 mmol, 1.0 equiv) portionwise at 0 °C. The resulting reaction mixture was allowed to warm to room temperature overnight. After this time, the solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate (4x), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The desired product i70 was obtained as a yellow solid, which was used in the next step without further purification (98% yield). 1 H NMR(400MHz,(CD3)2SO):δ8.50(s,1H),7.30(br s,2H),6.87(t, 2 J H,F =53Hz,1H); 19 F NMR(376MHz,(CD3)2SO):δ-121.4(s,2F).

[0338] Method 24: N-tert-butylcarboxylate-N-(5-bromo-4-(difluoromethyl)pyrimidin-2-yl)carbamate (i71) [ka] Compound I70 (4.35 g, 19.4 mmol, 1.0 equiv.) and 4-(dimethylamino)pyridine (480 mg, 3.92 mmol, 0.20 equiv.) were dissolved in tetrahydrofuran (50 mL). N,N-Diisopropylethylamine (7.50 mL, 42.1 mmol, 2.2 equiv.) and di-tert-butyl dicarboxylate (9.33 g, 42.7 mmol, 2.2 equiv.) were then added at 0 °C, and the resulting solution was allowed to warm to room temperature overnight. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (cyclohexane / ethyl acetate = 9:1 → 4:1) on silica gel to give the desired product I71 as a colorless solid (85% yield).1 H NMR(400MHz,CDCl3):δ8.92(s,1H),6.73(t, 2 J H,F =53Hz,1H),1.47(s,18H); 19 F NMR(376MHz,CDCl3):δ-120.4(s,2F).

[0339] General Step 1: [ka] A substituted monochloro-triazine or substituted monochloro-pyrimidine (1.0 equiv.), compound i68 (1.1 equiv.), tripotassium phosphate (2.0 equiv.), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]-palladium(II) (Sigma-Aldrich, product number 741825, 0.05 equiv.) were placed in a flask. Under a nitrogen atmosphere, 1,4-dioxane (30 volumes) and deionized water (1.5 volumes) were added, and the resulting mixture was placed directly in an oil bath preheated to 95°C. The reaction mixture was stirred at this temperature for 2 hours. 5M aqueous HCl (20 equiv.) was added. The resulting mixture was heated to 60°C overnight. The pH of the resulting mixture is adjusted to 8-9 by adding 2 M aqueous sodium hydroxide, and the mixture is then extracted with ethyl acetate (3 x 20 volumes). The combined organic layers are dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure. Purification by flash chromatography affords the desired product of formula (I).

[0340] General Procedure 2: [ka] Compound i71 (1.0 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (Manchester Organics, product number M23170, 1.5 equivalents), potassium acetate (3.0 equivalents), and [1,1'-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (Sigma-Aldrich, product number 697230, 0.099 equivalents) were dissolved in 1,4-dioxane (12.5 volumes) under a nitrogen atmosphere. The resulting mixture was heated at 100 °C for 15 minutes (the solution turned black). TLC monitoring (cyclohexane / ethyl acetate = 3:1) showed complete consumption of the starting material.

[0341] To the resulting mixture is added substituted chloro-triazine or chloro-pyrimidine (1.1 equiv.), aqueous potassium carbonate (2 M, 3.0 equiv.), and a premixed solution of triphenylphosphine (0.12 equiv.) and palladium acetate (0.04 equiv.) in tetrahydrofuran (100 vol.). The resulting mixture is heated at 60° C. for 2 hours and then cooled to room temperature.

[0342] 5M aqueous HCl (20 equiv.) is added. The resulting mixture is heated to 60°C overnight. The pH of the resulting mixture is adjusted to 8-9 by adding 2M aqueous sodium hydroxide, and the mixture is then extracted with ethyl acetate (3 x 20 volumes). The combined organic layers are dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure. Purification by flash chromatography gives the desired product.

[0343] Method 27: tert-Butyl N-tert-butoxycarbonyl-N-(5-(4-chloro-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-yl)carbamate (i74) [ka] Intermediate i71 (2.00 g, 4.71 mmol, 1.0 equiv), bis(pinacolato)diboron (1.80 g, 7.09 mmol, 1.5 equiv), KOAc (1.60 g, 16.3 mmol, 3.4 equiv), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (350 mg, 478 μmol, 0.10 equiv) were combined in 1,4-dioxane under a nitrogen atmosphere and heated to 95 °C for 45 min. A precatalyst solution of palladium(II) acetate (43.0 mg, 192 μmol, 0.04 equiv) and triphenylphosphine (148 mg, 564 μmol, 0.12 equiv) in tetrahydrofuran (2 mL) was also prepared and stirred at room temperature for 1 h. This solution was then added to the cooled solution at room temperature, followed by the addition of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine i11 (1.65 g, 7.05 mmol, 1.5 equiv.) and aqueous K2CO3 (2.4 M, 5.90 mL, 14.2 mmol, 3.0 equiv.). The resulting mixture was heated to 55 °C overnight. After this time, the mixture was poured onto aqueous NHCl (15%) and extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (cyclohexane / ethyl acetate = 1:0 to 4:1) on silica gel afforded product i74 as a colorless solid (36% yield).

[0344] 1 H NMR(400MHz,CDCl3):δ9.57(s,1H),7.55(t, 2 J H,F =54Hz,1H),3.99-3.91(m,4H),3.84-3.76(m,4H),1.49(s,18H); 19 F NMR(376MHz,CDCl3):δ-121.0(s,2F).

[0345] Method 32: (E)-4-Ethoxy-1,1-difluoro-but-3-en-2-one (i83) [ka] To a cooled (-70 °C) solution of pyridine (61.5 mL, 760.5 mmol, 1.2 equiv) in dichloromethane (500 mL) was added ethyl vinyl ether (60 mL, 626.5 mmol, 1 equiv), followed by a solution of difluoroacetic anhydride (88.5 mL, 760.5 mmol, 1.2 equiv) in dichloromethane (75 mL). The mixture was then allowed to warm gradually to room temperature overnight. The mixture was transferred to a separatory funnel, and the organic layer was washed with water (6 x 800 mL) until the pH of the aqueous layer was neutral. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to give the desired product i83 as an orange oil (76.7 g, 81%). 1 H NMR(400MHz,(CD3)2SO):δ7.92(d, 3 J H,H =12.5Hz,1H),6.34(t, 2 J H,F =53.6Hz,1H),5.87(d, 3 J H,H =12.5Hz,1H),4.14(q, 3 J H,H =7,1Hz,2H),1.28(t, 3 J H,H =7,1Hz,3H); 19 F NMR(400MHz,(CD3)2SO):δ-127.39(s,2F).

[0346] Method 33: (E)-3-(Difluoromethyl)-5-ethoxy-3-hydroxy-pent-4-enenitrile (i84) [ka] To a cooled (-70 °C) solution of 2.5 M n-butyllithium (102.9 mL, 256.7 mmol, 1 equiv.) in tetrahydrofuran (435 mL) is added acetonitrile (13.4 mL, 256.7 mmol, 1 equiv.). A white suspension forms, which is stirred at -70 °C for 1.5 h. A solution of (E)-4-ethoxy-1,1-difluoro-but-3-en-2-one (i83) (38.5 g, 256.7 mmol, 1 equiv.) in tetrahydrofuran (65 mL) is added to the white suspension (the mixture becomes an orange solution). The mixture is stirred at -70 °C for 1 h and allowed to warm gradually to room temperature. Water (400 mL) is added, followed by ethyl acetate (600 mL). The layers are separated, and the aqueous layer is extracted with ethyl acetate (3 x 600 mL). The combined organic layers are dried over sodium sulfate, and the solvent is evaporated under reduced pressure. Filtration through a short pad of silica gel using a cyclohexane / ethyl acetate (3:1) mixture as eluent gives the desired product i84 as a dark orange oil (43.4 g, 88%). 1 H NMR(400MHz,(CD3)2SO):δ6.66(d, 3 J H,H =12.8Hz,1H),6.20(s,1H),5.79(t, 2 J H,F =55.8Hz,1H),4.75(d, 3 J H,H =12.8Hz,1H),3.74(q, 3 J H,H =7.0Hz,2H),2.88(d, 3 J H,H =16.8Hz,1H),2.81(d, 3 J H,H =16.8Hz,1H),1.21(t, 3 J H,H =7.0Hz,3H); 19 F NMR(400MHz,(CD3)2SO):δ-129.32(d, 2 J F,F =311.2Hz,1F),-130.05(d, 2 J F,F =311.2Hz,1F).

[0347] Method 34: 4-(Difluoromethyl)pyridin-2-amine (i65) [ka] To a solution of (E)-3-(difluoromethyl)-5-ethoxy-3-hydroxy-pent-4-enenitrile (i84) (8.1 g, 42.4 mmol, 1 equiv.) in acetic acid (80 mL) was added O-methylhydroxyamine hydrochloride (Fluorochem, product number 078603) (10.6 g, 127.2 mmol, 3 equiv.). The mixture was stirred at 50 °C for 7 h. The reaction mixture was then cooled to room temperature, and a solution of hydrobromic acid in acetic acid (33%) (14.2 mL, 84.8 mmol, 2 equiv.) was added. The reaction mixture was stirred at 90 °C overnight. The reaction mixture was degassed and placed under nitrogen. The reaction mixture was maintained at room temperature in an ice-water bath, and zinc powder (8.12 g, 127.2 mmol, 3 equiv.) was added portionwise. The reaction mixture was stirred at room temperature for 3 h. The mixture was filtered through a short pad of Celite, and the cake was washed with ethyl acetate. The majority of the solvent is then removed under reduced pressure. 60 mL of aqueous ammonium hydroxide (28%) is added. The aqueous layer is extracted with dichloromethane (3 x 150 mL). The combined organic layers are dried over sodium sulfate. Compound i65 is recrystallized from dichloromethane and heptane as an anti-solvent (solvent exchange on a rotary evaporator). Compound i65 is recovered by filtration as a pale yellow solid (5.12 g, 84%).

[0348] Method 35: 9-[4-chloro-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-3,7-dioxa-9-azabicyclo[3.3.1]nonane (i89) [ka] To a solution of 3-oxa-9-azabicyclo[3.3.1]nonane hydrochloride (176 mg, 1.20 mmol, 1.05 equiv.) and N,N-diisopropylethylamine (0.42 mL, 2.40 mmol, 2.1 equiv.) in 1,4-dioxane (5 mL) was added a solution of i88 (300 mg, 1.14 mmol, 1 equiv.) in 1,4-dioxane (1 mL). The resulting mixture was heated (75 °C) for 3 h. Ethyl acetate (20 mL) and saturated aqueous sodium hydrogen sulfate (20 mL) were then added. The phases were separated, and the organic phase was washed with saturated aqueous sodium hydrogen sulfate (2 x 20 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product is purified by automated flash chromatography (SiO2, cyclohexane / ethyl acetate = 2:1 to 0:1) to afford the title compound i89 as a colorless solid (297 mg, 75%). 1 H NMR(400MHz,(CD3)2SO):δ4.58(m,1H),4.44(m,1H),4.40(m,1H),4.32(m,1H),4.00-3.97(m,4H),3.94-3 .90(m,2H),3.72-3.64(m,6H),2.46(m,1H),1.90-1.70(m,4H),1.53(m,1H).MS(MALDI):m / z=368.0([M+H] + ).

[0349] Preparation of Compounds of the Invention Compound 1: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine (1) [ka] According to general procedure 1, compound 1 is obtained from starting materials i2 and i68 in 73% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.02(s,1H),7.65(t, 2 J H,F =55Hz,1H),6.83(s,1H),4.85(br s,2H),3.89-3.79(m,8H),3.77-3.72(m,8H); 19F NMR(376MHz,CDCl3):δ-115.9(s,2F);MS(MALDI):m / z=393.9([M+H] + ).

[0350] Compound 2: 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine (2) [ka] According to general procedure 2, compound 2 is obtained from starting materials i2 and i71 in 74% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.20(s,1H),7.62(t, 2 J H,F =54Hz,1H),5.97(br s,2H),3.91-3.68(m,16H); 19 F NMR(376MHz,CDCl3):δ-121.5(s,2F);MS(MALDI):m / z=395.2([M+H] + ).

[0351] Compound 3: 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine (3) [ka] According to general procedure 1, compound 3 is obtained from starting materials i1 and i68 in 75% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.04(s,1H),7.71(t, 2 J H,F =55Hz,1H),6.83(s,1H),4.89(br s,2H),4.71-4.64(m,4H),3.79-3.76(m,4H),3.67-3.62(m,4H),2.09-1.98(m,8H); 19F NMR(376MHz,CDCl3):δ-115.4-(-117.3)(m,2F);MS(MALDI):m / z=446.3([M+H] + ).

[0352] Compound 4: 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine (4) [ka] According to general procedure 1, compound 4 is obtained from starting materials i12 and i68 in 57% yield as a colorless solid. 1 H NMR (400MHz, CDCl3): δ9.03(s,1H),7.68(m,1H),6.83(s,1H),4.94(br s,2H),4.70-4.65(m,2H),3.93-3.57(m,12H),2.14-1.92(m,4H); 19 F NMR(376MHz,CDCl3):δ-116.0-(-116.2)(m,2F);MS(MALDI):m / z=420.6([M+H] + ).

[0353] Compound 5: 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine (5) [ka] According to general procedure 2, compound 5 is obtained from starting materials i71 and i12 in 50% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.23(s,1H),7.65(t, 2 J H,F =54Hz,1H),5.66(br s,2H),4.68(m,2H),3.90-3.61(m,12H),2.13-1.92(4H); 19F NMR(376MHz,CDCl3):δ-120.4-(-121.5)(m,2F);MS(MALDI):m / z=420.9([M+H] + ).

[0354] Compound 6: 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine (6) [ka] According to general procedure 1, compound 6 is obtained from starting materials i3 and i68 in 79% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ8.87(s,1H),7.70(t, 2 J H,F =55Hz,1H),6.86(s,1H),5.48(br s,2H),4.73-4.72(m,2H),4.41-4.38(m,2H),3.98(dd,J H,H =11.6,3.8Hz,2H),3.78(d,J H,H =12Hz,2H),3.67(dd,J H,H =12,3.2Hz,2H),3.52(td,J H,H =12,3.0Hz,2H),3.27(td,J H,H =13,3.8Hz,2H),1.33(d, 3 J H,H =6.8Hz,6H); 19 F NMR(376MHz,CDCl3):δ-115.4-(-116.2)(m,2F);MS(MALDI):m / z=421.9([M+H] + ).

[0355] Compound 7: 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine (7) [ka] According to general procedure 2, compound 7 is obtained from starting materials i71 and i3 in 52% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.24(s,1H),7.66(t, 2 J H,F =54Hz,1H),5.77(br s,2H),4.73(br s,2H),4.45-4.32(m,2H),3.98(dd,J H,H =12,3.6Hz,2H),3.78(d,J H,H =12Hz,2H),3.67(dd,J H,H =11,2.8Hz,2H),3.52(td,J H,H =12,2.8Hz,2H),3.27(td,J H,H =13,3.2Hz,2H),1.33(d, 3 J H,H =6.8Hz,6H); 19 F NMR(376MHz,CDCl3):δ-120.5-(-122.7)(m,2F);MS(MALDI):m / z=423.3([M+H] + ).

[0356] Compound 8: (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (8) [ka] According to general procedure 1, compound 8 is obtained from starting materials i13 and i68 in 47% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.03(s,1H),7.70(t, 2 J H,F =55Hz,1H),6.84(s,1H),4.78(br s,2H),4.75(m,1H),4.42-4.38(m,1H),4.00-3.96(m,1H),3.84-3-66(m,10H),3.55-3.50(m,1H),3.30-3.25(m,1H),1.33(d, 3 J H,H =6.8Hz,3H); 19F NMR(376MHz,CDCl3):δ-116.1-(-115.9)(m,2F);MS(MALDI):m / z=408.9([M+H] + ).

[0357] Compound 9: (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine (9) [ka] According to general procedure 2, compound 9 is obtained from starting materials i71 and i13 in 60% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.24(s,1H),7.66(t, 2 J H,F =54Hz,1H),5.67(br s,2H),4.74(m,1H),4.41-4.38(m,1H),4.00-3.97(m,1H),3.90-3.72(m ,9H),3.68-3.36(m,1H),3.56-3.49(m,1H),3.32-3.25(m,1H),1.33(d, 3 J H,H =6.9Hz,3H); 19 F NMR(376MHz,CDCl3):δ-121.3-(-121.6)(m,2F);MS(MALDI):m / z=409.4([M+H] + ).

[0358] Compound 10: 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine (10) [ka] According to general procedure 1, compound 10 is obtained from starting materials i18 and i68 in 42% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.04(s,1H),7.69(t, 2 JH,F =55Hz,1H),6.84(s,1H),4.85(br s,2H),4.71-4.65(m,3H),4.42-4.39(m,1H),3.98-3.95(m,1H),3.79-3.76(m,3H),3. 70-3.65(m,3H),3.56-3.53(m,1H),3.30-3.27(m,1H),2.10-1.99(m,4H),1.33(m,3H); 19 F NMR(376MHz,CDCl3):δ-115.9-(-116.2)(m,2F);MS(MALDI):m / z=434.2([M+H] + ).

[0359] Compound 11: 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine (11) [ka] According to general procedure 2, compound 11 is obtained from starting materials i71 and i18 in 46% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.25(s,1H),7.68(t, 2 J H,F =55Hz,1H),5.81(br s,2H),4.71-4.65(m,3H),4.42-4.38(m,1H),4.00-3.96(m,1H),3.81-3.60(m,6 H),3.55-3.50(m,1H),3.31-3.24(m,1H),2.11-2.00(m,4H),1.37-1.28(m,3H); 19 F NMR(376MHz,CDCl3):δ-121.5-(-121.7)(m,2F);MS(MALDI):m / z=434.6([M+H] + ).

[0360] Compound 12: 4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine (12) [ka] According to general procedure 1, compound 12 is obtained from starting materials i68 and i14 in 86% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.85(s,1H),7.74(t, 2 J H,F =55Hz,1H),6.84(s,2H),6.75(s,1H),3.82-3.70(m,8H),3.69-3.60(m,4H),2.88-2.80(m,4H); 19 F NMR(376MHz,(CD3)2SO):δ-115.4(s,2F);MS(MALDI):m / z=393.8([M+H] + ).

[0361] Compound 13: 4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine (13) [ka] According to general procedure 2, compound 13 is obtained from starting materials i71 and i14 in 55% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.23(s,1H),7.64(t, 2 J H,F =55Hz,1H),5.60(br s,2H),3.83-3.75(m,12H),2.94-2.88(m,4H); 19 F NMR(376MHz,CDCl3):δ-111.4(s,2F);MS(MALDI):m / z=394.1([M+H] + ).

[0362] Compound 14: (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine (14) [ka] According to general procedure 1, compound 14 is obtained from starting materials i21 and i68 in 47% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.02(s,1H),7.67(t, 2 J H,F =56Hz,1H),6.84(s,1H),4.90(br s,2H),4.74(s,1H),4.40(d,J H,H =16Hz,1H),3.98(dd,J H,H =4.0Hz,12Hz,1H),3.91(m,4H),3.78(d,J H,H =12Hz,1H),3.68(dd,J H,H =4.0,12Hz,1H),3.56(t,J H,H =4.0Hz,1H),3.26(dt,J H,H =4.0,12Hz,1H),2.99(t,J H,H =4.0Hz,4H),1.32(d,J H,H =8.0Hz,3H); 19 F NMR(376MHz,CDCl3):δ-115.9(s,2F);MS(MALDI):m / z=407.2([M+H] + ).

[0363] Compound 15: (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine (15) [ka] According to general procedure 2, compound 15 is obtained from starting materials i71 and i21 in 30% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.24(s,1H),7.66(t, 2 J H,F =56Hz,1H),5.69(br s,2H),4.74(s,1H),4.40(d,J H,H =16Hz,1H),4.38(dd,J H,H =4.0,12Hz,1H),3.83(m,4H),3.78(d,JH,H =12Hz,1H),3.68(dd,J H,H =4.0,12Hz,1H),3.54(dt,J H,H =4.0,12Hz,1H),3.28(dt,J H,H =4.0,12Hz,1H),2.92(t,J H,H =8.0Hz,4H),1.33(t,J H,H =8.0Hz,3H); 19 F NMR(376MHz,CDCl3):δ-121.4(s,2F);MS(MALDI):m / z=408.7([M+H] + ).

[0364] Compound 16: 4-(difluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine (16) [ka] According to general procedure 1, compound 16 is obtained from starting materials i22 and i68 in 73% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ8.31(s,1H),7.30(t, 2 J H,F =55Hz,1H),6.85(s,1H),6.04(s,1H),4.73(br s,2H),3.81-3.72(m,12H),3.65-3.59(m,4H); 19 F NMR(376MHz,CDCl3):δ-115.1(s,2F);MS(MALDI):m / z=393.3([M+H] + ).

[0365] Compound 17: 4'-(Difluoromethyl)-2,6-dimorpholino-[4,5'-bipyrimidine]-2'-amine (17) [ka] According to general procedure 2, compound 17 is obtained from starting materials i71 and i22 in 7% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ8.60(s,1H),7.11(t,2 J H,F =55Hz,1H),6.02(s,1H),5.46(br s,2H),3.80-3.74(m,12H),3.64-3.60(m,4H); 19 F NMR(376MHz,CDCl3):δ-119.5(s,2F);MS(MALDI):m / z=394.3([M+H] + ).

[0366] Compound 18: 4-(difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine (18) [ka] According to general procedure 1, compound 18 is obtained from starting materials i23 and i68 in 89% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ8.94(s,1H),7.61(t, 2 J H,F =55Hz,1H),6.83(s,1H),5.50(s,1H),4.74(br s,2H),3.82-3.78(m,8H),3.61-3.57(m,8H); 19 F NMR(376MHz,CDCl3):δ-115.4(s,2F);MS(MALDI):m / z=393.3([M+H] + ).

[0367] Compound 19: 4'-(Difluoromethyl)-4,6-dimorpholino-[2,5'-bipyrimidine]-2'-amine (19) [ka] According to general procedure 2, compound 19 is obtained from starting materials i71 and i23 in 7% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.16(s,1H),7.58(t, 2 J H,F =55Hz,1H),5.75(br s,2H),5.50(s,1H),3.82-3.79(m,8H),3.61-3.58(m,8H);19 F NMR(376MHz,CDCl3):δ-121.1(s,2F);MS(MALDI):m / z=395.3([M+H] + ).

[0368] Compound 20: 4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine (20) [ka] According to general procedure 1, compound 20 is obtained from starting materials i15 and i68 in 77% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.02(s,1H),7.65(t, 2 J H,F =55Hz,1H),6.84(s,1H),4.83(br s,2H),4.23-4.07(m,4H),3.90-3.79(m,4H),3.79-3.71(m,4H),2.71-2.62(m,4H); 19 F NMR(376MHz,CDCl3):δ-116.0(s,2F);MS(MALDI):m / z=410.3([M+H] + ).

[0369] Compound 21: 4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine (21) [ka] According to general procedure 2, compound 21 is obtained from starting materials i71 and i15 in 70% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.21(s,1H),7.60(t, 2 J H,F =54Hz,1H),5.90(br s,2H),4.22-4.06(m,4H),3.91-3.78(m,4H),3.78-3.71(m,4H),2.71-2.62(m,4H); 19F NMR(376MHz,CDCl3):δ-120.5-(-121.5)(m,2F);MS(MALDI):m / z=411.2([M+H] + ).

[0370] Compound 22: 5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine (22) [ka] According to general procedure 1, compound 22 is obtained from starting materials i24 and i68 in 61% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.34(s,1H),7.55(t, 2 J H,F =55Hz,1H),6.76(s,1H),6.60(br s,2H),6.36(s,1H),4.64-4.47(m,4H),3.67-3.49(m,4H),3.56-3.49(m,4H),1.98-1.79(m,8H); 19 F NMR(376MHz,(CD3)2SO):δ-114.9-(-115.2)(m,2F);MS(MALDI):m / z=445.3([M+H] + ).

[0371] Compound 23: 5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine (23) [ka] According to general procedure 1, compound 23 is obtained from starting materials i29 and i68 in 54% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ8.30(s,1H),7.30(t, 2 J H,F=55Hz,1H),6.84(s,1H),6.04(s,1H),4.85(br s,2H),4.62(br s,2H),3.82-3.74(m,6H),3.65-3.56(m,6H),2.09-2.00(m,2H),2.00-1.91(m,2H); 19 F NMR(376MHz,CDCl3):δ-115.2-(-116.2)(m,2F);MS(MALDI):m / z=419.0([M+H] + ).

[0372] Compound 24: 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4'-(difluoromethyl)-6-morpholino-[4,5'-bipyrimidine]-2'-amine (24) [ka] According to general procedure 2, compound 24 is obtained from starting materials i29 and i71 in 72% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.71(s,1H),7.35(s,2H),7.32(t, 2 J H,F =54Hz,1H),6.45(s,1H),4.54(br s,2H),3.71-3.50(m,12H),1.95-1.78(m,4H); 19 F NMR(376MHz,(CD3)2SO):δ-119.2(s,2F);MS(MALDI):m / z=420.6([M+H] + ).

[0373] Compound 25: 5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine (25) [ka] According to general procedure 1, compound 25 is obtained from starting materials i25 and i68 in 57% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.31(s,1H),7.52(t,2 J H,F =55Hz,1H),6.76(s,1H),6.59(br s,2H),6.30(s,1H),4.60-4.50(m,1H),4.44-4.33(m,1H),4.24-4.15(m,1H),4.12-4.04(m,1H),3.9 4-3.83(m,2H),3.74-3.64(m,2H),3.59-3.51(m,2H),3.45-3.35(m,2H),3.14-3.02(m,2H),1.18(t, 3 J H,H =7.2Hz,6H); 19 F NMR(376MHz,(CD3)2SO):δ-113.7-(-115.9)(m,2F);MS(MALDI):m / z=421.1([M+H] + ).

[0374] Compound 26: 4'-(difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5'-bipyrimidine]-2'-amine (26) [ka] According to general procedure 2, compound 26 is obtained from starting materials i25 and i71 in 56% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ8.60(s,1H),7.14(t, 2 J H,F =54Hz,1H),5.98(s,1H),5.48(br s,2H),4.71-4.62(m,1H),4.34-4.23(m,2H),4.08-3.92(m,3H),3.83-3.65(m,4H),3.61-3.49(m,2H),3.25(dt, 2 J H,H =13Hz, 3 J H,H =3.6Hz,2H),1.33-1.27(m,6H); 19 F NMR(376MHz,CDCl3):δ-119.5(s,1F),119.7(m,1F);MS(MALDI):m / z=422.2([M+H] + ).

[0375] Compound 27: (S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine (27) [ka] According to general procedure 1, compound 27 is obtained from starting materials i30 and i68 in 74% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ8.31(s,1H),7.30(t, 2 J H,F =55Hz,1H),6.85(s,1H),6.02(s,1H),4.75(br s,2H),4.35-4.25(m,1H),4.06-3.96(m,2H),3.83-3.69(m,10H),3.58(dt, 2 J H,H =12Hz, 3 J H,H =3.2Hz,1H),3.25(dt, 2 J H,H =13Hz, 3 J H,H =3.8Hz,1H),1.31(d, 3 J H,H =6.8Hz,3H); 19 F NMR(376MHz,CDCl3):δ-114.9-(-115.0)(m,2F);MS(MALDI):m / z=407.1([M+H] + ).

[0376] Compound 28: (S)-4'-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5'-bipyrimidine]-2'-amine (28) [ka] According to general procedure 2, compound 28 is obtained from starting materials i30 and i71 in 53% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ8.60(s,1H),7.13(t, 2 J H,F=54Hz,1H),6.01(s,1H),5.47(br s,2H),4.71-4.63(m,1H),4.31(dd, 2 J H,H =14Hz, 3 J H,H =2.4Hz,1H),3.97(dd, 2 J H,H =11Hz, 3 J H,H =3.4Hz,1H),3.79(t, 3 J H,H =4.6Hz,4H),3.72-3.66(m,2H),3.65-3.58(m,3H),3.58-3.50(m,2H),3.30-3.21(m,1H),1.30(d, 3 J H,H =6.8Hz,3H); 19 F NMR(376MHz,CDCl3):δ-119.7(br s,2F);MS(MALDI):m / z=408.9([M+H] + ).

[0377] Compound 29: 5-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine (29) [ka] According to general procedure 1, compound 29 is obtained from starting materials i68 and i81 in 89% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.03(s,1H),7.69(t, 2 J H,F =55Hz,1H),6.83(s,1H),4.85(br s,2H),4.50-4.24(m,8H),3.28-3.12(m,4H),1.94(br s,4H),1.86-1.71(m,4H); 19 F NMR(376MHz,CDCl3):δ-115.1-(-117.2)(m,2F);MS(MALDI):m / z=446.3([M+H] +).

[0378] Compound 30: 5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (30) [ka] According to general procedure 1, compound 30 is obtained from starting materials i68 and i80 in 63% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.86(s,1H),7.71(t, 2 J H,F =55Hz,1H),6.84(br s,2H),6.76(s,1H),3.81-3.56(m,12H),1.14(s,12H);MS(MALDI):m / z=450.0([M+H] + ).

[0379] Compound 31: (S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine (31) [ka] According to general procedure 1, compound 31 is obtained from starting materials i28 and i68 in 58% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.31(s,1H),7.52(t, 2 J H,F =55Hz,1H),6.74(s,1H),6.59(br s,2H),6.35(s,1H),4.59-4.51(m,1H),4.22-4.14(m,1H),3.91-3.84(m ,1H),3.72-3.50(m,10H),3.44-3.35(m,1H),3.14-3.03(m,1H),1.16(d, 3 J H,H =6.7Hz,3H); 19F NMR(376MHz,(CD3)2SO):δ-113.7-(-115.3)(m,2F);MS(MALDI):m / z=407.1([M+H] + ).

[0380] Compound 32: (S)-4'-(difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5'-bipyrimidine]-2'-amine (32) [ka] According to general procedure 2, compound 32 is obtained from starting materials i28 and i71 in 63% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ8.60(s,1H),7.13(t, 2 J H,F =54Hz,1H),5.99(s,1H),5.46(br s,2H),4.34-4.25(m,1H),4.06-3.97(m,2H),3.82-3.68(m,10H),3.58(dt, 2 J H,H =12Hz, 3 J H,H =3.2Hz,1H),3.26(dt, 2 J H,H =13Hz, 3 J H,H =3.7Hz,1H),1.31(d, 3 J H,H =6.8Hz,3H); 19 F NMR(376MHz,(CD3)2SO):δ-119.5(s,2F);MS(MALDI):m / z=408.7([M+H] + ).

[0381] Compound 33: 4-(difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (33) [ka] According to general procedure 1, compound 33 is obtained from starting materials i68 and i82 in 71% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.87(s,1H),7.74(t, 2 J H,F =55Hz,1H),6.83(br s,2H),6.76(s,1H),4.71-4.62(m,1H),4.45-4.34(m,2H),4.31-4.09(m,1H),3.90 (m,1H),3.71(m,1H),3.55(m,3H),3.38(m,1H),3.13(m,1H),2.55(m,2H),1.20(d, 3 J H,H =6.9Hz,3H),1.19(d, 3 J H,H =6.9Hz,6H);MS(MALDI):m / z=436.1([M+H] + ).

[0382] Compound 34: 5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (34) [ka] According to general procedure 1, compound 34 is obtained from starting materials i68 and i79 in 75% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.86(s,1H),7.71(t, 2 J H,F =55Hz,1H),6.83(br s,2H),6.76(s,1H),4.64-4.46(m,4H),3.60-3.48(m,4H),2.63(m,4H),1.14(m,12H);MS(MALDI):m / z=450.0([M+H] + ).

[0383] Compound 37: 5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (37) [ka] According to general procedure 1, compound 37 is obtained from starting materials i7 and i68 in 39% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.85(s,1H),7.68(t, 3 J H,F =55Hz,1H),6.87(br s,2H),6.74(s,1H),4.51(br s,2H),4.45(br s,2H),4.07-3.93(m,8H),3.79-3.67(m,8H); 19 F NMR(376MHz,(CD3)2SO):δ-115.8(s,2F);MS(MALDI):m / z=478.1([M+H] + ).

[0384] Compound 38: 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine (38) [ka] According to general procedure 1, compound 38 is obtained from starting materials i35 and i68 in 67% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.87(s,1H),7.73(t, 3 J H,F =55Hz,1H),6.87(br s,2H),6.75(s,1H),4.70-4.54(m,2H),4.53-4.43(m,2H),4.05-3.97(m,4H),3.79-3.67(m,4H),3.63-3.55(m,4H)2.00-1.83(m,4H); 19 F NMR(376MHz,(CD3)2SO):δ-115.8(s,1F),-115.9(s,1F);MS(MALDI):m / z=462.1([M+H] + ).

[0385] Compound 39: 5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (39) [ka] According to general procedure 1, compound 39 is obtained from starting materials i4 and i68 in 28% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.78(s,1H),7.70(t, 2 J H,F =55Hz,1H),6.82(br s,2H),6.77(s,1H),3.87-3.75(m,8H),3.45(br s,4H),1.49(s,12H); 19 F NMR(376MHz,(CD3)2SO):δ-114.9-(-115.1)(m,2F);MS(MALDI):m / z=450.1([M+H] + ).

[0386] Compound 40: 5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (40) [ka] According to general procedure 1, compound 40 is obtained from starting materials i6 and i68 in 42% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.90(s,1H),7.82(t, 2 J H,F =55Hz,1H),6.84(br s,2H),6.77(s,1H),4.59-4.43(m,4H),3.82-3.73(m,4H),3.60-3.51(m,4H),1.29(d, 2 J H,H =6.9Hz,12H); 19F NMR(376MHz,(CD3)2SO):δ-114.9-(-115.0)(m,2F);MS(MALDI):m / z=450.2([M+H] + ).

[0387] Compound 41: 5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (41) [ka] According to general procedure 1, compound 41 is obtained from starting materials i5 and i68 in 98% yield as a colorless solid. 1 H NMR(400MHz,CDCl3):δ9.04(s,1H),7.70(t, 2 J H,F =52.0Hz,1H),6.84(s,1H),4.88(br s,2H),4.77-4.72(m,2H),4.41(d, 2 J H,H =12.0Hz,2H),3.98(dd, 2 J H,H =12.0Hz, 3 J H,H =4.0Hz,2H),3.78(d, 2 J H,H =12.0Hz,2H),3.68(dd, 2 J H,H =12.0Hz, 3 J H,H =4.0Hz,2H),3.53(dt, 2 J H,H =12.0Hz, 3 J H,H =4.0Hz,2H),3.28(dt, 2 J H,H =12.0Hz, 3 J H,H =4.0Hz,2H),1.33(d, 2 J H,H =8.0Hz,6H); 19 F NMR(376MHz,CDCl3):δ-115.9(s,1F),-116.0(s,1F);MS(MALDI):m / z=421.7([M+H]+ ).

[0388] Compound 42: 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine (42) [ka] According to general procedure 1, compound 42 is obtained from starting materials i16 and i68 in 35% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.83(s,1H),7.73(t, 2 J H,F =55Hz,1H),6.84(br s,2H),6.76(s,1H),3.85-3.76(m,4H),3.76-3.63(m,8H),3.45(br s,2H),1.49(s,6H); 19 F NMR(376MHz,(CD3)2SO):δ-116(s,2F);MS(MALDI):m / z=422.1([M+H] + ).

[0389] Compound 44: 4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (44) [ka] According to general procedure 1, compound 44 is obtained from starting materials i37 and i68 in 75% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.89(s,1H),7.79(t, 2 J H,F =55Hz,1H),6.83(br s,2H),6.76(s,1H),4.65(br s,1H),4.50(br s,2H),4.37-4.25(m,1H),3.93(dd, 3 J H,H =11Hz, 3 JH,H =3.2Hz,1H),3.79-3.67(m,3H),3.59-3.51(m,3H),3.45-3.36(m,1H),3.22-3.11(m,1H),1.30(d, 3 J H,H =6.7Hz,6H),1.24(d, 3 J H,H =6.7Hz,3H); 19 F NMR(376MHz,(CD3)2SO):δ-115.0(br s,2F);MS(MALDI):m / z=436.1([M+H] + ).

[0390] Compound 45: 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (45) [ka] According to general procedure 1, compound 45 is obtained from starting materials i38 and i68 in 71% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.84(s,1H),7.74(t, 2 J H,F =55Hz,1H),6.83(br s,2H),6.76(s,1H),4.58(br s,1H),4.31-4.19(m,1H),3.93(dd, 2 J H,H =12Hz, 3 J H,H =3.9Hz,1H),3.84-3.81(m,4H),3.76-3.69(m,1H),3.58(dd, 2 J H,H =11Hz, 3 J H,H =3.2Hz,1H),3.46-3.38(m,3H),3.23-3.13(m,1H),1.50(br s,6H),1.23(d, 3 J H,H =6.7Hz,3H); 19F NMR(376MHz,(CD3)2SO):δ-114.8-(-115.5)(m,2F);MS(MALDI):m / z=436.0([M+H] + ).

[0391] Compound 46: 4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (46) [ka] According to general procedure 1, compound 46 is obtained from starting materials i39 and i68 in 67% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.87(s,1H),7.77(t, 2 J H,F =55Hz,1H),6.84(br s,2H),6.76(s,1H),4.67(br s,2H),4.44-4.24(m,2H),3.96-3.83(m,3H),3.75-3.63(m,2H),3.60-3.36(m,5H),3.31(s,3H),3.21-3.04(m,2H),1.23(d, 3 J H,H =6.7Hz,3H); 19 F NMR(376MHz,(CD3)2SO):δ-115.0(br s,2F);MS(MALDI):m / z=452.3([M+H] + ).

[0392] Compound 47: 4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (47) [ka] According to general procedure 1, compound 47 is obtained from starting materials i36 and i68 in 85% yield as a colorless solid. 1H NMR(400MHz,(CD3)2SO):δ8.86(s,1H),7.72(t, 2 J H,F =55Hz,1H),6.84(br s,2H),6.75(s,1H),4.64(br s,1H),4.53-4.42(m,2H),4.37-4.25(m,1H),4.05-3.96(m,4H),3.92-3.84(m,1H), 3.77-3.66(m,5H),3.60-3.52(m,1H),3.44-3.35(m,1H),3.22-3.10(m,1H),1.23(d, 3 J H,H =6.7Hz,3H); 19 F NMR(376MHz,(CD3)2SO):δ-114.9-(-117.1)(m,2F);MS(MALDI):m / z=450.0([M+H] + ).

[0393] Compound 50: 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine (50) [ka] According to general procedure 1, compound 50 is obtained from starting materials i40 and i68 in 52% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.90(s,1H),7.82(t, 2 J H,F =55Hz,1H),6.87(br s,2H),6.76(s,1H),4.55-4.51(m,1H),4.34-4.14(m,3H),4.12-4.25(m,2H),3.92-3.80(m,1H),3.7 6-3.68(m,3H),3.55-3.51(m,1H),3.38(m,1H),3.20-3.13(m,1H),2.68(m,1H),1.78(m,1H),1.20(d, 3 J H,H =6.9Hz,3H); 19F NMR(376MHz,(CD3)2SO):δ-115.0(br s,2F);MS(MALDI):m / z=420.6([M+H] + ).

[0394] Compound 51: 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine (51) [ka] According to general procedure 1, compound 51 is obtained from starting materials i41 and i68 in 36% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.99(s,1H),7.89(t, 2 J H,F =55Hz,1H),6.84(br s,2H),6.77(s,1H),4.69(m,3H),4.37(m,1H),3.91-3.85(m,3H),3.75-3.53(m,4 H),3.42-3.35(m,1H),3.22-3.15(m,1H),3.12-3.08(m,1H),1.85(m,1H),1.24(d, 3 J H,H =6.9Hz,3H); 19 F NMR(376MHz,(CD3)2SO):δ-116.0(br s,2F);MS(MALDI):m / z=420.6([M+H] + ).

[0395] Compound 52: 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (52) [ka] According to general procedure 1, compound 52 is obtained from starting materials i42 and i68 in 44% yield as a colorless solid (1:1 mixture of rotamers). 1 H NMR(400MHz,(CD3)2SO):δ8.89(m,1H),7.77(m,1H),6.84(br s,2H),6.76(s,1H),5.02-4.97(m,1H),4.68-4.66(m,2H),4.31(m,1H),3.89-3.85(m ,1H),3.79-3.57(m,3H),3.57-3.44(m,4H),3.22(m,1H),1.90-1.83(m,2H),1.21(d, 3 J H,H =6.9Hz,3H); 19 F NMR(376MHz,(CD3)2SO):δ-115.5(br s,2F);MS(MALDI):m / z=420.2([M+H] + ).

[0396] Compound 53: 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (53) [ka] According to general procedure 1, compound 53 is obtained from starting materials i43 and i68 in 53% yield as a colorless solid (1:1 mixture of rotamers). 1 H NMR(400MHz,(CD3)2SO):δ8.90(m,1H),7.77(m,1H),6.84(br s,2H),6.76(s,1H),5.02-4.96(m,1H),4.68-4.62(m,2H),3.90(m,1H),3.80(m,1H) ),3.70(m,2H),3.57(m,2H),3.45(m,3H),3.20(m,1H),1.90-1.83(m,2H),1.21(d, 3 J H,H =6.9Hz,3H); 19F NMR(376MHz,(CD3)2SO):δ-115.0(br s,2F);MS(MALDI):m / z=420.2([M+H] + ).

[0397] Compound 54: 5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (54) [ka] According to general procedure 1, compound 54 is obtained from starting materials i8 and i68 in 61% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.87(s,1H),7.77(t, 2 J H,F =55Hz,1H),6.83(br s,2H),6.76(s,1H),4.47(m,4H),3.89-3.81(m,4H),3.51-3.34(m,4H),3.12(m,2H),1.71(m,4H),0.86(m,6H). 19 F NMR(376MHz,(CD3)2SO):δ-115.0(br s,2F);MS(MALDI):m / z=450.3([M+H] + ).

[0398] Compound 55: 5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (55) [ka] According to general procedure 1, compound 55 is obtained from starting materials i9 and i68 in 59% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.74(s,1H),7.65(t, 2 J H,F=55Hz,1H),6.81(br s,2H),6.75(s,1H),3.68(m,8H),3.49(m,4H),2.46-2.38(m,4H),2.25-2.16(m,4H),1.72-1.66(m,4H); 19 F NMR(376MHz,(CD3)2SO):δ-115.5(br s,2F);MS(MALDI):m / z=474.3([M+H] + ).

[0399] Compound 56: 5-[4,6-bis[(3R)-3-isopropylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (56) [ka] According to general procedure 1, compound 56 is obtained from starting materials i10 and i68 in 59% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.87(s,1H),7.76(t, 2 J H,F =55Hz,1H),6.82(br s,2H),6.76(s,1H),4.50(m,2H),4.29(m,2H),4.02-3.84(m,4H),3.40(m,4H),3.08(m,2H),2.34(m,2H),1.02(m,6H),0.77(m,6H); 19 F NMR(376MHz,(CD3)2SO):δ-115.0(br s,2F);MS(MALDI):m / z=478.4([M+H] + ).

[0400] Compound 66: 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (66) [ka] According to general procedure 1, compound 66 is obtained from starting materials i55 and i68 in 61% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.87(s,1H),7.77(t, 2 J H,F =55Hz,1H),6.83(br s,2H),6.76(s,1H),4.46(m,2H),3.81-3.77(m,6H),3.55(m,2H),3.44(m,2H),1.49(s,6H),1.28(d, 3 J H,H =6.9Hz,6H); 19 F NMR(376MHz,(CD3)2SO):δ-115.0(br s,2F);MS(MALDI):m / z=450.4([M+H] + ).

[0401] Compound 67: 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (67) [ka] According to general procedure 1, compound 67 is obtained from starting materials i56 and i68 in 37% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.84(s,1H),7.89(t, 2 J H,F =55Hz,1H),6.85(br s,2H),6.76(s,1H),4.60(m,1H),4.31(m,1H),3.92(m,2H),3.83(m,4H),3.65( m,1H),3.51-3.41(m,5H),3.28(s,3H),3.12(m,1H),1.49(s,3H),1.48(s,3H); 19 F NMR(376MHz,(CD3)2SO):δ-115.5(br s,2F);MS(MALDI):m / z=466.4([M+H] + ).

[0402] Compound 68: [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]morpholin-3-yl]methanol (68) [ka] According to general procedure 1, compound 68 is obtained from starting materials i57 and i68 in 58% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.83(s,1H),7.77(m,1H),6.84(br s,2H),6.76(s,1H),4.91(m,1H),4.35(m,2H),4.05(m,1H),3.97-3.70(m,6H),3.54-3.38(m,5H),3.12(m,1H),1.49(s,3H),1.48(s,3H); 19 F NMR(376MHz,(CD3)2SO):δ-115.5(br s,2F);MS(MALDI):m / z=452.2([M+H] + ).

[0403] Compound 69: 4-(Difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine (69) [ka] According to general procedure 1, compound 69 is obtained from starting materials i54 and i68 in 57% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.83(s,1H),7.69(t, 2 J H,F =55Hz,1H),6.85(br s,2H),6.76(s,1H),4.47-4.37(m,2H),4.01(m,4H),3.80-3.71(m,8H),3.45(m,2H),1.48(s,6H); 19F NMR(376MHz,(CD3)2SO):δ-115.7(br s,2F);MS(MALDI):m / z=464.3([M+H] + ).

[0404] Compound 70: 5-[4-(4-cyclopropylpiperazin-1-yl)-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (70) [ka] According to general procedure 1, compound 70 is obtained from starting materials i58 and i68 in 12% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.82(s,1H),7.72(t, 2 J H,F =55Hz,1H),6.83(br s,2H),6.76(s,1H),3.82(m,4H),3.71(m,4H),3.44(m,2H),2.58(m,4H),1.64(m,1H),1.44(s,6H),0.45(m,2H),0.36(m,2H); 19 F NMR(376MHz,(CD3)2SO):δ-115.4(br s,2F);MS(MALDI):m / z=460.4([M] + ).

[0405] Compound 71: 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (71) [ka] According to general procedure 1, compound 71 is obtained from starting materials i59 and i68 in 42% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.82(s,1H),7.73(t, 2 J H,F=55Hz,1H),6.83(br s,2H),6.76(s,1H),3.88-3.69(m,10H),3.47-3.44(m,4H),3.24(m,3H),2.52-2.45(m,4H),1.44(s,6H); 19 F NMR(376MHz,(CD3)2SO):δ-115.4(br s,2F);MS(MALDI):m / z=478.4([M] + ).

[0406] Compound 77: [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]morpholin-3-yl]methanol (77) [ka] According to general procedure 1, compound 77 is obtained from starting materials i53 and i68 in 31% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.88(s,1H),7.78(t, 2 J H,F =55Hz,1H),6.84(br s,2H),6.76(s,1H),4.96(m,1H),4.73(m,1H),4.58-4.24(m,3H),4.05(m,1H),3.9 0(m,2H),3.72(m,2H),3.59(m,1H),3.51-3.36(m,4H),3.23-3.02(m,2H),1.23(d, 3 J H,H =6.9Hz,3H);MS(MALDI):m / z=438.3([M+H] + ).

[0407] Compound 78: 4-(difluoromethyl)-5-[4-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (78) [ka] According to general procedure 1, compound 78 is obtained from starting materials i85 and i68 in 71% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.90(s,1H),7.82(t, 2 J H,F =55Hz,1H),6.84(br s,2H),6.76(s,1H),4.66(m,1H),4.32(m,3H),4.15-4.11(m,2H),3.92(m,1H) ),3.70(m,3H),3.57(m,1H),3.40(m,1H),3.18(m,1H),1.37(m,6H),1.24(d, 3 J H,H =6.9Hz,3H); 19 F NMR(376MHz,(CD3)2SO):δ-114.9(br s,2F);MS(MALDI):m / z=435.4([M] + ).

[0408] Compound 79: 4-(difluoromethyl)-5-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (79) [ka] According to general procedure 1, compound 79 is obtained from starting materials i86 and i68 in 65% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.91(s,1H),7.82(t, 2 J H,F =55Hz,1H),6.85(br s,2H),6.76(s,1H),4.66(m,1H),4.32(m,3H),4.15-4.11(m,2H),3.92(m,1H) ),3.70(m,3H),3.57(m,1H),3.40(m,1H),3.19(m,1H),1.37(m,6H),1.24(d, 3 J H,H =6.9Hz,3H); 19F NMR(376MHz,(CD3)2SO):δ-114.9(br s,2F);MS(MALDI):m / z=434.3([M] + ).

[0409] Compound 80: 4-(difluoromethyl)-5-[4-morpholino-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine (80) [ka] According to general procedure 1, compound 80 is obtained from starting materials i87 and i68 in 57% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.85(s,1H),7.73(t, 2 J H,F =55Hz,1H),6.84(br s,2H),6.75(s,1H),4.61-4.57(m,2H),3.95(m,2H),3.75-3.65(m,10H),2.48(m,1H),1.88-1.72(m,4H),1.57(m,1H); 19 F NMR(376MHz,(CD3)2SO):δ-115.4(m,2F);MS(MALDI):m / z=434.3([M+H] + ).

[0410] Compound 82: 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine (82) [ka] According to general procedure 1, compound 82 is obtained from starting materials i89 and i68 in 51% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.84(s,1H),7.70(t, 2 J H,F=55Hz,1H),6.85(br s,2H),6.75(s,1H),4.62(m,1H),4.54(m,1H),4.52(m,1H),4.44(m,1H),4.04 -3.92(m,6H),3.75-3.62(m,6H),2.45(m,1H),1.89-1.75(m,4H),1.57(m,1H); 19 F NMR(376MHz,(CD3)2SO):δ-115.7(m,2F);MS(MALDI):m / z=476.2([M+H] + ).

[0411] Compound 83: 5-[4,6-bis[(3S,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (83) [ka] According to general procedure 1, compound 83 is obtained from starting materials i90 and i68 in 56% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.92(s,1H),7.87(t, 2 J H,F =55Hz,1H),6.84(br s,2H),6.77(s,1H),4.32(m,4H),4.14(m,4H),3.70(m,4H),1.39(d, 3 J H,H =6.9Hz,12H); 19 F NMR(376MHz,(CD3)2SO):δ-115.5(br s,2F);MS(MALDI):m / z=448.3([M] + ).

[0412] Compound 84: 4-(Difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine (84) [ka] According to general procedure 1, compound 84 is obtained from starting materials i91 and i68 in 63% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.86(s,1H),7.71(t, 2 J H,F =55Hz,1H),6.87(br s,2H),6.75(s,1H),4.49(m,2H),4.02(m,4H),3.74-3.65(m,12H); 19 F NMR(376MHz,(CD3)2SO):δ-115.6(br s,2F);MS(MALDI):m / z=436.4([M+H] + ).

[0413] Compound 85: 4-(difluoromethyl)-5-[4-[(3S)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (85) [ka] According to general procedure 1, compound 85 is obtained from starting materials i92 and i68 in 52% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.88(s,1H),7.77(t, 2 J H,F =55Hz,1H),6.85(br s,2H),6.76(s,1H),4.70-4.25(m,4H),3.90(m,3H),3.72(m,1H),3.60-3.45(m,4H),3.16(m,2H),1.73(m,2H),1.22(d, 3 J H,H =6.9Hz,3H),0.86(m,3H); 19 F NMR(376MHz,(CD3)2SO):δ-114.9(br s,2F);MS(MALDI):m / z=436.9([M+H] + ).

[0414] Compound 86: 4-(difluoromethyl)-5-[4-[(3R)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine (86) [ka] According to general procedure 1, compound 86 is obtained from starting materials i93 and i68 in 47% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.88(s,1H),7.77(t, 2 J H,F =55Hz,1H),6.85(br s,2H),6.76(s,1H),4.65(m,1H),4.49-4.30(m,3H),3.93-3.82(m,3H),3.72(m,1H), 3.57(m,1H),3.50(m,1H),3.43-3.37(m,2H),3.19-3.14(m,2H),1.73(m,2H),1.22(d, 3 J H,H =6.9Hz,3H),0.86(m,3H); 19 F NMR(376MHz,(CD3)2SO):δ-115.3(br s,2F);MS(MALDI):m / z=436.9([M+H] + ).

[0415] Compound 88: 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine (88) [ka] According to general procedure 1, compound 88 is obtained from starting materials i94 and i68 in 50% yield as a colorless solid. 1 H NMR(400MHz,(CD3)2SO):δ8.82(s,1H),7.71(t, 2 J H,F=55Hz,1H),6.84(br s,2H),6.75(s,1H),4.55(m,1H),4.23(m,1H),3.91(m,1H),3.78(m,2H),3.69(m,3H),3.56(m ,1H),3.50(m,2H),3.41(m,1H),3.16(m,1H),2.50(m,2H),2.26(m,2H),1.73(m,2H),1.21(d, 3 J H,H =6.9Hz,3H); 19 F NMR(376MHz,(CD3)2SO):δ-114.9(br s,2F);MS(MALDI):m / z=446.8([M+H] + ).

[0416] Example 2 In vitro mTOR binding assay and in-cell Western blot In vitro mTOR binding assay N-terminally GST-tagged mTOR (catalog no. PR8683B; 0.45 mg / ml; truncated form (amino acids 1360–2549)), Alexa Fluor® 647-labeled Kinase Tracer 314 (catalog no. PV6087), and LanthaScreen Eu-anti-GST tag antibody (catalog no. PV5594) were purchased from Life Technologies. 1x mTOR kinase buffer consisted of 50 mM HEPES pH 7.5, 5 mM MgCl2, 1 mM EGTA, and 0.01% Pluronic F-127 (Sigma catalog no. P2443-250G).

[0417] Ten-point, four-fold serial dilutions of each compound (highest concentration 10 μmol / L to lowest concentration 40 pmol / L) were tested in duplicate for mTOR binding in a 384-well plate. To perform the LanthaScreen kinase binding assay, 5 μl of test compound concentrated to 3x the final concentration, 5 μl of a 9 nM GST-mTOR / 6 nM Eu-anti-GST antibody mixture, and 5 μl of a 30 nM Tracer 314 solution were mixed together to give final concentrations of 3 nM GST-mTOR, 2 nM Eu-anti-GST antibody, and 10 nM Tracer 314 per well. After a 30-minute incubation at room temperature, time-resolved FRET was measured using a Synergy 4 multimode microplate reader (Biotek Instruments) with the following settings: a 100 μs delay before data collection, a 200 μs data collection time, and 10 measurements per data point. Emission filter: 665 nm / 8 nm set at sensitivity 190, and 620 nm / 10 nm set at sensitivity 130; excitation filter: 340 nm / 30 nm; 400 nm dichroic mirror.

[0418] For data analysis, the average background (mTOR kinase buffer only wells) was subtracted, and the emission ratio was calculated by dividing the signal emitted at 665 nm from the acceptor (Alexa Fluor® 647-labeled Tracer 314) by the signal emitted at 620 nm from the donor (Eu-labeled antibody). The IC of each compound was calculated. 50 Values ​​were determined by plotting emission ratios (on a logarithmic scale) against compound concentration and then fitting sigmoidal dose-response curves of different slopes to the data using GraphPad™ Prism.

[0419] In-cell Western blot A2058 cells were seeded at 20,000 cells per well in a 96-well plate (Perkin Elmer, catalog no. 6005558) and treated with different compounds for 1 hour after 24 hours. Seven different concentrations of each compound were applied to the cells (5 μM, 1.25 μM, 0.625 μM, 0.3125 μM, 0.155 μM, 0.08 μM, and 0.04 μM). Cells were fixed with 4% paraformaldehyde for 30 minutes at room temperature, washed twice with 1% BSA in PBS, permeabilized with 0.1% Triton X-100 in PBS / 1% BSA for 30 minutes at room temperature, and then blocked with 5% goat serum in PBS / 1% BSA / 0.1% Triton X-100 for 30 minutes at room temperature. Cells were stained overnight at 4°C with either rabbit anti-pPKB S473 (1:500; Cell Signaling Technology, Cat. No. 4058) in combination with mouse anti-α-tubulin (1:2000, used for normalization; Sigma, Cat. No. T9026) or rabbit anti-pS6 S235 / S236 (1:500; Cell Signaling Technology, Cat. No. 4856) in combination with mouse anti-α-tubulin (1:2000, used for normalization). After washing three times for 5 minutes with PBS / 1% BSA / 0.1% Triton, cells were treated with secondary antibodies goat anti-mouse IRDye680 (LICOR, Cat. No. 926-68070) and goat anti-rabbit IRDye800 (LICOR, Cat. No. 926-32211) (each diluted 1:500 in PBS / 1% BSA / 0.1% Triton) for 1 hour in the dark with shaking. Cells were washed three times for 5 minutes with PBS / 1% BSA / 0.1% Triton, and plates were scanned using both the 700 nm and 800 nm channels with an Odyssey Infrared Scanning System. Vehicle (0.2% DMSO) was added to the cells as a 0% inhibition control. Wells treated with secondary antibody alone were also included to correct for background staining during data analysis.

[0420] For data analysis, the average background signals from the 700 nm and 800 nm channels were subtracted from each signal in the 700 nm and 800 nm channels, respectively. After normalizing the signals in each channel to 0% inhibition, the ratio of the 800 nm signal to the 700 nm signal was calculated to obtain the values ​​for pPKB S473 or pS6 S235 / S236 normalized to α-tubulin.

[0421] IC of each compound 50 Values ​​are determined by plotting normalized pPBK S473 and pS6 S235 / S236 signals (on a logarithmic scale) versus compound concentration, respectively, and then fitting sigmoidal dose-response curves of different slopes to the data using GraphPad™ Prism.

[0422] [Table 9]

[0423] [Table 10]

[0424] [Table 11]

[0425] [Table 12]

[0426] [Table 13]

[0427] [Table 14]

[0428] [Table 15]

[0429] [Table 16]

[0430] [Table 17]

[0431] [Table 18]

[0432] [Table 19]

[0433] [Table 20] JPEG2026028259000236.jpg107154

[0434] Example 3 A: Kinase binding To test the binding of Compound 1 to PI3K isoforms and related kinases, biochemical assays were performed at DiscoveRx (Fremont, USA) (Table 13, lines 1-7).

[0435] B: Kinase inhibition Compound 1* and the reference compounds were further analyzed for their ability to inhibit the kinase function of PIK3CA and related kinases (Proqinase, Germany) (Table 13, column 3). The lipid kinases PIK3CA, PIK3CB, PIK3CG, PIK3CD, (PI3Kα, β, γ and δδ), PIK3C2A, PIK3C2B, PIK3C2G, PIK3C3, PIK4B were tested by ADP-Glo ​​assay (Promega, USA). The protein kinases mTOR and DNAPK were assayed by radiometric assay. 33 P-γATP assay ( 33 The compounds were tested using the PanQinase® Activity Assay (Proqinase GmbH, Germany). IC values ​​were determined by testing 10 semi-logarithmic concentrations of each compound in the range of 1 x 10-04 M to 3 x 10-09 M in duplicate. 50 Values ​​were measured. Prior to testing, each compound was dissolved in the amount of 100% DMSO indicated on the compound submission form (CSF) to form a 1x10-02 M stock solution. 100 μl of each stock solution was transferred to column 2 of a microtiter plate. The 1x10-02 M stock solution in column 2 of this master plate was then serially diluted semi-logarithmically using 100% DMSO as the solvent. This resulted in 10 different concentrations, with a dilution endpoint of 3x10-07 M / 100% DMSO. Pure DMSO was used as a control. Each compound was diluted with water and then transferred to the assay in 1% DMSO at concentrations ranging from 1x10-04 M to 3x10-09 M.

[0436] To measure the rate of lipid kinase inhibition, an assay was performed in a 96-well half-area microtiter plate. The following solutions were mixed and incubated at 30°C for 40 minutes: 10 μl of ATP solution (50 mM HEPES-NaOH, pH 7.5, 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS, 2 mM DTT, ATP (PIK3C3, 20 μM; PIK3CA, 150 μM, PIK3CB, 300 μM, PIK3CG, 500 μM, PIK3CG, 100 μM), kinase (PK3C3, 25 ng / 25 μl; PIK3CA, 2 25 ng / 25 μl, PIK3CB, 10 25 ng / 25 μl, PIK3CG, 5 25 ng / 25 μl, PIK3CG, 40 25 ng / 25 μl) and substrate (50 or 100 μM, respectively) in 5% DMSO were added to 5 μl of test sample and 10 μl of enzyme / substrate mixture. PIK3C3 assay was further adjusted to 3 mM Assays for PIK3CA / PIK3R1, PIK3CB / PIK3R1, PIK3CD / PIK3R1, and PIK3CG contained 3 mM MgCl. After adding 50 μl of kinase detection reagent per well, the assays were incubated for an additional 60 minutes at room temperature. Signals were measured in luminescence mode on a microplate reader (Victor2, Perkin Elmer, Boston, MA, USA).

[0437] To measure protein kinase activity, reaction mixtures were pipetted into 96-well plates in four steps in the following order: 20 μl assay buffer, 5 μl ATP solution (in HO), 5 μl test compound (in 10% DMSO), and 20 μl enzyme / substrate mix. All protein kinase assays contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl, 3 mM MnCl, 3 μM sodium orthovanadate, 1.2 mM DTT, 50 μg / ml PEG20000, 1 μM ATP, [γ-33P]-ATP (approximately 1.8 × 1006 cpm / well), protein kinase (0.1 nM DNA-PK; 2.4 nM mTOR), and substrate (2 μg / well for DNA-PK and 1 μg / well for mTOR). DNA-PK assays also contained 2.5 μg / ml DNA. These reaction cocktails were incubated at 30°C for 60 minutes. The reactions were stopped with 50 μl of 2% (v / v) H3PO4, the plates were aspirated, and washed twice with 200 μl of 0.9% (w / v) NaCl. 33Pi incorporation was measured using a microplate scintillation counter (Microbeta, Wallac). All assays were performed using a BeckmanCoulter / SAGIAN™ Core System.

[0438] IC of compounds for all kinases tested 50 Values ​​were calculated using Quattro Workflow V3.1.0 (Quattro Research GmbH, Germany).

[0439] To determine the affinity of compound 1* for kinases that showed greater than 50% inhibition by KinomeScan, the dissociation constants (Kd) of compound 1* were determined by dose-response curves using KINOMEscan technology for class I PI3Ks (α, β, γ, and δ), class II PI3K PIK3C2B, class III PI3K PIK3C3 (Vps34), class IV PIKKs mTOR and DNAPK, and the PI4 kinase PIK4B. The smaller the dissociation constant, the higher the affinity of the test compound for the kinase. Kd measurements revealed that compound 1* bound to the ATP site of the PI3K class I family PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ with high affinity (0.002 μM, 0.011 μM, 0.025 μM, and 0.025 μM, respectively) (Table 13, row 2). Weak binding was observed for the class II PIK3CB (Kd: 0.82 μM) and the class III family kinase PIK3C3 (Kd: 0.23 μM). Compound 1* showed high affinity for the class IV PIKK mTOR (Kd: 0.012 μM), but approximately 130-fold weaker binding to another PIKK member, DNAPK (Kd: 1.6 μM), and no binding was observed for the PI4 kinase PIK4B (Kd: >40 μM).

[0440] To explore its selectivity and interactions across the human kinome, compound 1* was tested on KINOMEscan™, developed by DiscoverRx, Inc., which utilizes a proprietary active-site-dependent competitive binding assay to measure the affinity of compounds for the ATP site of protein and lipid kinases. The KINOMEscan assay does not require ATP and therefore represents true thermodynamic interaction affinities, as opposed to IC50 values, which can be dependent on ATP concentration (see http: / / www.discoverx.com / technologies-platforms / competitive-binding-technology / kinomescan-technology-platform#sthash.TRzjYTmK.dpuf for more information).

[0441] In the primary screen, compound 1* was tested against 456 human protein and lipid kinases at a single concentration of 10.0 μM. In these assays, binding of the test compound to the kinases results in a decrease in signal; results from this primary screen are reported as %Ctrl (percent of control), with lower values ​​indicating more potent hits (Figure 2).

[0442] [Table 21]

[0443] Binding assay: 11-point 3-fold serial dilutions of each test compound were prepared in 100% DMSO at a final concentration of 100x, and then diluted to 1x in the assay according to the instructions of DiscoveRx (Fremont, USA) (final DMSO concentration = 2.5%) (Table 13). As shown in Table 13 (column 1), at 10.0 μM compound 1*, strong binding inhibition was observed in the PI3K class I family (PI3Kα, β, γ, and δ), related PI3Kα (PIK3CA) mutants, and mTOR, with some inhibition also observed in class II (PIK3CB, Kd = 0.82 μM). Kd measurements showed that compound 1* bound to the ATP site of the PI3K class I family PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ at 2 nM, 11 nM, 25 nM, and 25 nM, respectively. Compound 1* also exhibited strong binding to the ATP site of mTOR (Kd: 12 nM). Compound 1 inhibited the lipid kinase activity of all recombinant PI3K class I subtypes, including PI3Kα and mTOR mutants, with IC values ​​in the nM range (2–25 nM), without significantly affecting other lipid and protein kinases tested in biochemical assays (Kinomescan (DiscoverX) 456 kinases). 50 It strongly inhibits class II kinases and also inhibits class II kinases to some extent (PIK3CB, Kd = 0.82 μM).

[0444] Kinase assay: We also analyzed the ability of compound 1* to inhibit the kinase function of PIK3CA and related kinases (Proqinase, Germany). The lipid kinases PIK3CA, PIK3CB, PIK3CG, PIK3CD, PIK3C2A, PIK3C2B, PIK3C2G, PIK3C3, and PIK4B were tested by ADP-Glo ​​assay (Promega, USA). The protein kinases mTOR and DNAPK were assayed by radiometric assay. 33 P-γATP assay ( 33 The compounds were tested using the PanQinase® Activity Assay (Proqinase GmbH, Germany). IC values ​​were determined by testing 10 semi-logarithmic concentrations of each compound in the range of 1 x 10-04 M to 3 x 10-09 M in duplicate.50 The values ​​were measured.

[0445] Example 4 The antiproliferative activity of compound 1* was tested in a panel of epidermoid tumor-derived cells. Data show that compound 1* inhibited all cell lines except MC7 cells in the range of 1598 nM to 1485 nM.

[0446] [Table 22]

[0447] All cell lines were obtained under license from the American Type Culture Collection (ATCC) (Manassas, VA, USA). Master and working cell banks (MCB and WCB) were prepared by subculturing in ATCC-recommended medium and freezing according to the ATCC-recommended protocol (www.atcc.org). Assay cell line stocks were prepared from the WCB. MCB, WCB, and assay stocks were prepared within 3, 6, and 9 passages of the ATCC vials, respectively. Solid powders of reference compounds were stored according to the supplier's instructions. Each compound was weighed on a calibrated balance and dissolved in 100% DMSO. DMSO samples were stored at room temperature. On the day of the experiment, compound stocks were diluted 3.16-fold into 100% DMSO to obtain 9-point serial dilutions, which were further diluted 31.6-fold in 20 mM sterile Hepes buffer, pH 7.4. A 5 μl volume was transferred to cells to prepare a test concentration range of 3.16 x 10-5 M to 3.16 x 10-9 M (31.6 μM to 3.16 nM) in duplicate. The final DMSO concentration during incubation was 0.4% in all wells. If a compound showed significant activity, it was further diluted 100-fold and a new dose-response curve was measured in duplicate. Assay stocks were thawed, diluted in their ATCC-recommended medium, and dispensed into 384-well plates at concentrations of 400 to 1600 cells / well in 45 μl of medium, depending on the cell line used. The optimal cell density for each cell line used was used. The plate margins were filled with phosphate-buffered saline. The plated cells were incubated at 37°C in a humidified atmosphere with 5% CO2. After 24 h, 5 μl of compound dilutions were added, and the plates were further incubated for another 72 h. After 72 hours, 25 μl of ATPlite 1Step™ (PerkinElmer) solution was added to each well and shaken for 2 minutes. After 10 minutes of incubation in the dark, luminescence was read on an Envision multimode reader (PerkinElmer).

[0448] Dose-response curves were constructed, and GI50, TGI, and LC50 values ​​were calculated from the dose-response curves. 50) is the drug concentration that produces a 50% reduction in the net increase in cell number upon incubation with the drug compared to the (untreated) control. TGI (complete growth inhibitory concentration) refers to the compound concentration that causes 0% proliferation (maintaining constant cell number throughout the experiment = cytostatic effect). 50% lethal concentration (LC 50 ) is the concentration of drug that results in a 50% decrease in cell number at the end of treatment with the drug compared to the initial cell number, indicating the net loss of cells after treatment due to the toxic effects of the drug.

[0449] Example 5 K14-Fyn Y528F transgenic mice are a model of cSCC that develop precancerous lesions and cSCCs similar to human lesions. (K14-Fyn(Y528F) transgenic mouse skin tumors resemble AK and cSCC and show strong activation of the PDK-1 / mTOR / S6 pathway.) (Zhao L, Li W, Marshall C, Griffin T, Hanson M, Hick R, Dentchev T, Williams E, Werth A, Miller C, Bashir H, Pear W, Seykora JT (2009). Cancer Res;69:9439-9447). Src family tyrosine kinases (SFKs) regulate cell proliferation, and elevated SFK activity is prevalent in human cancers, including cutaneous squamous cell carcinoma (cSCC) and its precursors. Elevated SFK activity in cutaneous cSCC was modeled using K14-Fyn Y528F transgenic mice, which spontaneously develop actinic keratosis, intraepithelial cSCC, and cSCC-like punctate keratotic lesions, scaly plaques, and large tumors, respectively. Lesioned tissues showed elevated levels of activated SFKs, PDK1, STAT3, and ERK1 / 2, whereas Notch1 / NICD protein and transcript levels were decreased. Intraepithelial cSCC and cSCC also showed decreased levels of p53.

[0450] We investigated whether a topically applied PI3K / mTOR inhibitor specifically targeting the PI3K / mTOR pathway could induce regression of cSCC in K14 Fyn Y528F mice by local or systemic (oral) administration (50 mg / kg orally, once daily). Oral administration of 50 mg / kg orally, once daily, is known to provide pharmaceutically significant levels of Compound 1 (Cmax: 2-4 μM).

[0451] Cohorts of 6-week-old K14-Fyn Y528F mice were treated by topical application of 1000 mg of Compound 1* (10 mg of Compound 1*) in 75 μl of DMSO or propylene glycol (1% (w / w) final concentration) (Figure 1B).

[0452] The compound 1*-treated cohort contained six mice with 20 cSCC lesions (Figure 1B), and the control cohort contained six mice with 15 cSCC lesions (Figure 1A). The size of each SCC was measured with a caliper before and weekly after treatment. The size of the cSCC ranged from 4 to 68 mm. 2 The size range of cSCCs in each cohort varied (the range of sizes was similar). The gel was applied to the lesions once daily, Monday through Friday.

[0453] As shown in Figures 1B and 1C, once-daily topical application of compound 1* gel induced near-complete regression of all cSCC lesions in the K14-Fyn Y528F model within 4 weeks without significant inflammation or ulceration. These data strongly suggest that topical application of a potent dual PI3K / mTOR inhibitor may be useful for the treatment of cSCC. The effects of oral administration, as well as histology and IHC, will also be measured.

[0454] Minimally invasive (2-3 mm thick) skin biopsies were collected for histological and immunohistochemical (IHC) analysis of PI3K / mTOR biomarkers (pAKT and pS6) at multiple time points: 1) at the start of oral treatment, 2) after 1 week, and 3) after 3 weeks. Blood concentrations of compound 1* were also measured and analyzed. Biopsies should be taken at less sensitive sites, such as the shoulder, and at nearby sites to ensure comparability (skin has different thicknesses at different body sites). The skin was frozen and analyzed by IHC and extraction, followed by LC / MS analysis of compound 1*. A rough estimate of the drug concentration required to achieve therapeutic effect, depending on potency and physicochemical properties, is approximately 0.1-3 μg per gram of tissue. This procedure was repeated for oral treatment.

[0455] Example 6 Daily oral administration of Compound 1* gel induced near-complete regression of all cSCC lesions in the K14-Fyn Y528F model without significant side effects. Histology and IHC for tumor lesion and circulating biomarkers will be performed, and skin and plasma levels of Compound 1* will be evaluated in a human clinical neoadjuvant trial.

[0456] Example 7 Penetration of the compounds of the present invention through pig skin The assessment of skin permeability is important for the successful development of new products and formulations intended for human use. Furthermore, the assessment of skin permeability is even more important in the assessment of bioequivalence of topical products in the pharmaceutical industry. The more commonly used model for conducting skin permeation studies is ex vivo human or animal skin. With standardization of protocols and methods, available skin models can serve as surrogates for in vivo human skin to evaluate the bioequivalence of topical products. A wide range of animal models have been used as surrogates for human skin to evaluate the skin permeability of substances. This is because pig skin is histologically similar to human skin and has an equivalent stratum corneum thickness of 21–26 μm. Furthermore, the average hair follicle density of pig ear skin is 14–32 / cm compared to human forehead skin.2 20 pieces / cm 2 In addition to being similar to human skin, pig ear skin is readily available and has been widely used in skin permeability studies. Therefore, the use of ex vivo or in vivo pig skin to replicate the permeability of human skin is sufficient and not novel.

[0457] Ex vivo and in vivo models have been established to evaluate the permeability of different drugs, including the compounds of the present invention, in pig skin.This model allows the evaluation of the pharmacokinetic profiles of multiple candidate drugs, including the compounds of the present invention, in one subject, thereby improving comparability and avoiding inter-subject variability.

[0458] In the first study (Figure 3, Table 15), the pharmacokinetic profiles of nine test formulations were evaluated using 80% SBECD at pH 3 or pH 7. Compounds 1* and 3, as 1% test formulations, penetrated ex vivo porcine skin (lower epidermis and dermis) well, even though they dried onto the skin several hours after application. Compared to Aldara, a cream containing 5% TLR7 agonist imiquimod, the intrinsic permeation properties of Compound 1* were estimated to be similar to those of imiquimod, whereas the permeation properties of Compound 3 were slightly lower.

[0459] [Table 23] 1. Application area: 4cm x 2cm = 8cm 2 ; 5.75 μL / cm of applied formulation 2 or 7 mg / cm 2 is equivalent to 46 μL or 56 mg.

[0460] Further studies were conducted to investigate the skin pharmacokinetic profiles of four test formulations on ex vivo pig skin: 1% Compound 1* in 90% propylene glycol (PG) / 10% oleyl alcohol (OA), 1% Compound 1* in 100% PG, 1% Compound 3 in 90% PG / 10% OA, and the control formulation, Aldara (containing 5% imiquimod). The pharmacokinetic profiles are shown in Table 16 and Figure 4. The Compound 1* formulation in 90% PG and 10% OA exhibited the highest skin permeation, followed by Compound 3 in 90% PG and 10% OA. The skin concentrations of Compound 1* in 100% PG alone were lower compared to the formulation containing 10% OA, but were still significantly higher than those of the control formulation, Aldara. The skin pharmacokinetic profile of Compound 3 in 100% PG was comparable to that of Compound 1*. Therefore, neither Compound 1* nor Compound 3 requires the penetration enhancer oleyl alcohol to achieve sufficient skin penetration.

[0461] In conclusion, topical treatment of ex vivo pig skin with Compound 1* and Compound 3 in a 1% experimental formulation containing the standard solvent propylene glycol resulted in high drug concentrations in the lower epidermis and dermis, which were higher than the skin concentrations obtained after topical treatment with the standard product Aldara (containing 5% imiquimod).

[0462] [Table 24] 1. Application area: 4cm x 2cm = 8cm 2 ; 5.75 μL / cm of applied formulation 2 or 7 mg / cm 2 is equivalent to 46 μL or 56 mg.

[0463] In conclusion, topical treatment of ex vivo pig skin with Compound 1* and Compound 3 in a 1% experimental formulation containing the standard solvent propylene glycol resulted in high drug concentrations in the lower epidermis and dermis, which were higher than the skin concentrations obtained after topical treatment with the standard product Aldara (containing 5% imiquimod).

[0464] Thus, formulations of Compound 1* and Compound 3 (1% each in propylene glycol) were tested in ex vivo studies on pig skin and demonstrated superior penetration into the epidermis and dermis compared to Aldara (5% imiquimod). Further studies aimed to determine the skin penetration of the same formulations of Compound 1* and Compound 3 in vivo in pigs. The following formulations were tested: 1% Compound 1* in propylene glycol (PG), 1% Compound 1* in propylene glycol and thickener (PG+TH), 1% Compound 1* in PEG, and imiquimod (Aldara 5% cream) as a control formulation. With the exception of the PEG formulation, significant levels of Compound 1* were found in the epidermis and dermis of live pigs after stripping of the stratum corneum by tape stripping (FIG. 5).

[0465] Example 8 Penetration of the compounds of the present invention through pig skin The hairless (Hr) gene encodes a transcriptional corepressor highly expressed in mammalian skin. In mice, several null and hypomorphic Hr alleles have been identified, resulting in hairlessness in homozygous animals, characterized by alopecia that develops after one cycle of relatively normal hair growth. Mutations in the human ortholog have also been associated with congenital alopecia. While various hairless strains have been developed, the outbred SKH1 mouse is the most widely used in dermatological research. These pigmented, immunocompetent mice facilitate skin manipulation, topical agent application, and UVR exposure, as well as easy visualization of skin reactions. Wound healing, acute photobiological responses, and skin carcinogenesis have been extensively studied and well characterized in SKH1 mice. Furthermore, the tumors induced in these mice resemble human UVR-induced skin malignancies at both the morphological and molecular levels (Benavidesa F, Oberyszynb TM, VanBuskirkc AM, Reeved VE, Kusewitta, DF (2009). The hairless mouse in skin research. J Dermatol Sci. 2009 Jan;53(1):10-18). Indeed, exposure of SKH-1 to UV-B for 20 minutes daily results in actinic keratosis (AK) similar to human AK.

[0466] As shown in Figure 6, topical daily treatment with Compound 1* shows significant effects compared to untreated (NT) or vehicle-treated (V) mice.

[0467] The effect of Compound 1* was lost when treatment was discontinued (Figure 7).

[0468] In summary, UV-induced AK in the SKH-1 mouse model is effectively reduced and prevented by topical daily treatment with compound 1*.

Claims

1. A compound of formula (I) for use in the prevention or treatment of a skin lesion in a subject: 【Chemistry 1】 [In the formula, X １ , X ２ and X ３ are each independently N or CH (provided that X １ , X ２ and X ３ at least two of which are N), Y is N or CH; W is H or F (provided that when W is F, X １ , X ２ and X ３ is N), R １ and R ２ are independent of each other, (iii) morpholinyl of formula (II): 【Chemistry 2】 wherein the arrow indicates a bond in formula (I), R ３ and R ４ are each independently H, C optionally substituted with one or two OH groups; １ ~C ３ Alkyl, C １ ~C ２ Fluoroalkyl, C １ ~C ２ Alkoxy, C １ ~C ２ Alkoxy C １ ~C ３ Alkyl, CN, or C(O)O—C １ ~C ２ alkyl or R ３ and R ４ and C optionally substituted with 1 to 4 F. １ ~C ３ Alkylene, —CH ２ -O-CH ２ -, -CH ２ -NH-CH ２ - or the following structure: 【Transformation 3】 (wherein the arrow indicates the bond in formula (II)), ５ R ６ -forming), or (iv) 1 to 3 R ７ and a saturated 6-membered heterocycle Z selected from thiomorpholinyl and piperazinyl, optionally substituted with R ７ is, independently in each occurrence, C optionally substituted by one or two OH groups; １ ~C ３ Alkyl, C １ ~C ２ Fluoroalkyl, C １ ~C ２ Alkoxy C １ ~C ３ Alkyl, C ３ ~C ６ cycloalkyl or two R ７ C, both of which may be substituted with 1 to 4 F. １ ~C ３ Alkylene, —CH ２ -O-CH ２ -, or -O-CH ２ CH ２ a divalent residue -R selected from -O- ８ R ９ -form), However, R １ and R ２ at least one of which is morpholinyl of formula (II); and prodrugs, metabolites, tautomers, solvates, and pharmaceutically acceptable salts thereof.

2. The R １ and the R ２ But independently of each other, 【Chemistry 4】 【change】 2. A compound of formula (I) for use according to claim 1, selected from:

3. The R １ and R ２ But independently of each other, 【Transformation 5】 3. A compound of formula (I) for use according to claim 1 or 2, selected from:

4. 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine, 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine, 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine, 4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine, 4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyridin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine, 4-(difluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine, 4'-(difluoromethyl)-2,6-dimorpholino-[4,5'-bipyrimidine]-2'-amine, 4-(difluoromethyl)-5-(4,6-dimorpholinopyrimidin-2-yl)pyridin-2-amine, 4'-(difluoromethyl)-4,6-dimorpholino-[2,5'-bipyrimidine]-2'-amine, 4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyridin-2-amine, 4-(difluoromethyl)-5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine, 5-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholinopyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine, 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4'-(difluoromethyl)-6-morpholino-[4,5'-bipyrimidine]-2'-amine, 5-(2,6-bis((S)-3-methylmorpholino)pyrimidin-4-yl)-4-(difluoromethyl)pyridin-2-amine, 4'-(difluoromethyl)-2,6-bis((S)-3-methylmorpholino)-[4,5'-bipyrimidine]-2'-amine, (S)-4-(difluoromethyl)-5-(6-(3-methylmorpholino)-2-morpholinopyrimidin-4-yl)pyridin-2-amine, (S)-4'-(difluoromethyl)-6-(3-methylmorpholino)-2-morpholino-[4,5'-bipyrimidine]-2'-amine, 5-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, 5-[4,6-bis(2,2-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, (S)-4-(difluoromethyl)-5-(2-(3-methylmorpholino)-6-morpholinopyrimidin-4-yl)pyridin-2-amine, (S)-4'-(difluoromethyl)-2-(3-methylmorpholino)-6-morpholino-[4,5'-bipyrimidine]-2'-amine, 4-(difluoromethyl)-5-[4-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine, 5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 5-[4,6-bis[(3R)-3-ethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 5-[4,6-bis(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 5-[4,6-bis[(3R)-3-isopropylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-(methoxymethyl)morpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]morpholin-3-yl]methanol, 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine, 5-[4-(4-cyclopropylpiperazin-1-yl)-6-(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[4-(2-methoxyethyl)piperazin-1-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, [(3R)-4-[4-[6-amino-4-(difluoromethyl)-3-pyridyl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]morpholin-3-yl]methanol, 4-(difluoromethyl)-5-[4-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3S,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-morpholino-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine, 5-[4,6-bis[(3S,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3S)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine, 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine, 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine, 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine, 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine, 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine, 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine 10. The compound of formula (I) for use according to claim 1, selected from: and tautomers, solvates and pharmaceutically acceptable salts thereof.

5. 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, 5-(4,6-bis((S)-3-methylmorpholino)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyrimidin-2-amine, (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, 4-(difluoromethyl)-5-(4-morpholino-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)pyrimidin-2-amine, 4-(difluoromethyl)-5-(4,6-dimorpholino-1,3,5-triazin-2-yl)pyridin-2-amine, and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyrimidin-2-amine, 5-[4,6-bis(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl]pyridin-2-amine, 5-[4,6-bis(3,3-dimethylmorpholin-4-yl)-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 5-[4,6-bis[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 5-[4,6-bis[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,3-dimethylmorpholin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R)-3-(methoxymethyl)morpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1,3,5-triazin-2-yl]pyridin-2-amine, 5-[4,6-bis[(3S,5S)-3,5-dimethylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine, 4-(difluoromethyl)-5-[4-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-6-morpholino-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3S)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R)-3-ethylmorpholin-4-yl]-6-[(3R)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]pyridin-2-amine, 4-(difluoromethyl)-5-[4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1,3,5-triazin-2-yl]pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine, 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine, 5-[4,6-bis[(3S)-3-methylmorpholin-4-yl]-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine, 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyridin-2-amine, 5-[4-[(3S)-3-methylmorpholin-4-yl]-6-morpholino-1,3,5-triazin-2-yl]-4-(trifluoromethyl)pyrimidin-2-amine, 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, 5-(4-morpholino-6-piperazin-1-yl-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine, 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine, 5-(4-morpholino-6-thiomorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyrimidin-2-amine 10. The compound of formula (I) for use according to claim 1, selected from the group consisting of: and tautomers, solvates, and pharmaceutically acceptable salts thereof.

6. 5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine, and (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine, 5-(4,6-dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine 10. The compound of formula (I) for use according to claim 1, selected from: and tautomers, solvates and pharmaceutically acceptable salts thereof.

7. The R １ and R ２ A compound of formula (I) for use according to any one of claims 1 to 6, wherein, independently of each other, is morpholinyl of formula (II).

8. R １ is R ２ 8. A compound of formula (I) for use according to claim 7, wherein

9. R １ is R ２ 8. A compound of formula (I) for use according to claim 7, wherein:

10. A compound of formula (I) for use according to any one of claims 1 to 9, wherein W is H.

11. 11. The compound of formula (I) for use according to any one of claims 1 to 10, wherein the skin lesion is a non-melanoma skin cancer (NMSC), and the non-melanoma skin cancer is a cutaneous squamous cell carcinoma (cSCC) or a basal cell carcinoma.

12. 11. The compound of formula (I) for use according to any one of claims 1 to 10, wherein the skin lesion is a non-melanoma skin cancer (NMSC), and the non-melanoma skin cancer is a cutaneous squamous cell carcinoma (cSCC).

13. 11. The compound of formula (I) for use according to any one of claims 1 to 10, wherein the skin lesion is a non-melanoma skin cancer (NMSC), and the non-melanoma skin cancer is a basal cell carcinoma.

14. 11. A compound of formula (I) for use according to any one of claims 1 to 10, wherein the skin lesion is a pre-invasive form of non-melanoma skin cancer (NMSC), the pre-invasive form being actinic keratosis (AK).

15. 11. A compound of formula (I) for use according to any one of claims 1 to 10, wherein the skin lesion is a pre-invasive form of non-melanoma skin cancer (NMSC), and the pre-invasive form is cSCC in situ (cSCCis).

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