NZ788302A

NZ788302A - Treatment of skin lesions

Info

Publication number: NZ788302A
Application number: NZ788302A
Authority: NZ
Inventors: Florent Beaufils; Doriano Fabbro; Paul Hebeisen; Wuellner Petra Hillmann; John T Seykora; Anton Stuetz
Original assignee: Piqur Therapeutics Ag; The Trustees Of The University Of Pennsylvania
Priority date: 2016-05-18
Filing date: 2017-05-17
Publication date: 2022-05-27

Abstract

The present invention is relates to a compound of formula (I), 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, then X1, X2 and X3 are N; R1 and R2 are independently of each other (i) a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue –R5R6– selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures; wherein the arrows denote the bonds in formula (II); or (ii) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R7; wherein R7 is independently at each occurrence C1-C3alkyl optionally substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxyC1-C3alkyl, C3-C6cycloalkyl; or two R7 substituents form together a bivalent residue –R8R9– selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CH2CH2-O-; with the proviso that at least one of R1 and R2 is a morpholinyl of formula II; and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject. ly of each other (i) a morpholinyl of formula (II) wherein the arrow denotes the bond in formula (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue –R5R6– selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures; wherein the arrows denote the bonds in formula (II); or (ii) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally substituted by 1 to 3 R7; wherein R7 is independently at each occurrence C1-C3alkyl optionally substituted with one or two OH, C1-C2fluoroalkyl, C1-C2alkoxyC1-C3alkyl, C3-C6cycloalkyl; or two R7 substituents form together a bivalent residue –R8R9– selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O-CH2CH2-O-; with the proviso that at least one of R1 and R2 is a morpholinyl of formula II; and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject.

Description

– 1 – TREATMENT OF SKIN S The present invention s to compositions for use in the prevention or treatment of a skin lesion in a subject.

The entire disclosure in the complete specification of our New Zealand Patent Application No. 748930 is by this cross-reference orated into the present specification.

RELATED ART lanoma skin cancer (NMSC) is the most frequent malignancy worldwide, with more than 1 million cases diagnosed each year in the US 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 in situ (cSCCis or Bowen's Disease (BD)) and basal cell carcinoma (BCC, also known as basalioma or basal cell ) (Di Magliano P. et al., Nature Rev. Cancer 2003, 3, 903-911). cSCC and BCC are the most common forms of NMSC and account for greater than 40% of newly diagnosed cancers (Bowden GT. Nat Rev Cancer. 2004, 4, 23–35). gh BCC has a very low metastatic risk, this tumor can cause significant disfigurement by invading surrounding tissues. BCC is a distinctive manifestation in nevoid basal cell carcinoma syndrome (NBCCS) patients. Both inherited and acquired mutations of patched 1 (PTCH1), a tumor-suppressor gene controlling the activity of Smoothened (SMO), are the y cause of the constitutive activation of the Hedgehog (HH) pathway, leading to the emergence of BCCs 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 t the development of resistance which is observed upon treatment with SMO antagonists alone (Buonamici S. et al., Science transl. Med. 2010, 2, 51ra70).

Several studies indicate that PI3K/mTOR signaling may play a al role in NMSC, in particular in the AK and cSCC development (Ayli EE et al., J. Cutaneous ogy 2008, 35, 273-277). Immunohistochemical (IHC) analysis of human epidermal tumors showed that mTOR itself, as well as its downstream ors 4EBP1, S6K, and AKTSer473 are phosphorylated at much higher levels in SCC and precancerous actinic keratosis (AK) than normal skin (Chen SJ, et al. Br J Dermatol. 2009; 160, 442–5). More ly, reverse phase protein microarray analysis of cSCC and AK revealed aberrantly activated mTOR pathways in the pre-cancerous and transformed tissues compared to normal skin (Einspahr JG, et al.

Cancer Prev Res (Phila). 5, 403–13). Thus, significant up-regulation of the PI3K/AKT/mTOR pathway was not only found in cSCC and in cSCCis (BD), but also in AK when compared to normal, healthy skin. Increased PI3K/mTOR pathway activity may already be seen in sun- damaged skin lesions (Ratushny V et al., J. Clin. Investigation 2012, 122, 464-472). sk cSCC on the trunk and extremities can be treated with electrodessication and curettage (ED&C). For invasive cSCC, surgical excision and Mohs micrographic surgery are the primary treatment options; with appropriate patient selection, these techniques have comparable cure rates. Radiation therapy is lly used as an adjuvant to y, to provide improved locoregional control, but it may be used as primary therapy in ts who are unable to undergo surgical excision. Chemotherapy may be considered as adjuvant therapy in select highest-risk cases of cSCC. In particular, emerging evidence suggests that epidermal growth factor receptor (EGFR) inhibitors may be useful adjuncts to surgical treatment. Systemic chemotherapy may be considered for metastatic cSCC.

Radiation therapy as y treatment for cSCC is typically ed for patients who are unable to undergo surgical excision. More frequently, radiation therapy is used as an adjuvant to surgery for improved locoregional control. Postoperative radiotherapy is considered for tumors that exhibit perineural invasion or other high-risk features and for those that involve regional metastasis.

A y of different chemotherapeutic agents have been used to treat atic cSCC. gh many of these agents have an established role in chemotherapy for mucosal head and neck squamous cell carcinoma, high-quality data is frequently lacking for their use in cSCC. Among the most common nontargeted agents used in cSCC are cisplatin and latin, S-FU, and taxanes (Martinez JC et al., Dermatologic y 2004, 30, 679-686).

Adjuvant tion may be considered in selected highest-risk cases of cSCC. Options include oral S-ﬂuorouracil (S-FU) and epidermal growth factor receptor (EGFR) inhibitors. ent should be administered through oncology treatment centers.

A variety of different chemotherapeutic agents have been used to treat metastatic cSCC. gh many of these agents have an established role in chemotherapy for mucosal head and neck squamous cell carcinoma, high-quality data is frequently lacking for their use in cSCC. Among the most common nontargeted agents used in cSCC are cisplatin and latin, S-FU, and taxanes.

Several treatment modalities exist for precancerous skin lesions, including cSCCis (BD) and actinic keratosis. Topical application of S-FU or imiquimod and diclofenac used for the treatment of precancerous skin lesions have negative side effects including skin irritation and _ 3 _ severe inﬂammation or show moderate/low efficacy (Kose O. et al., J. Dermatol. Treatment 2008, 19, 159-163). Similarly, liquid nitrogen cryotherapy or electrocautery and age may be used. The risks associated with cryotherapy include transient pain, edema, and blistering. Hypopigmentation and alopecia are also common and may be permanent, so treatment of hair-bearing areas and in darkly pigmented individuals is generally not recommended.

Cutaneous lymphomas are indolent but treatable (not e) and y not lifethreatening.

Cutaneous T-cell lymphoma (CTCL) has variable limited skin involvement and may be anied by tumor formation, ulceration, and exfoliation, complicated by itching and infections. Cutaneous B-cell lymphomas (CBCL) are a less common version of cutaneous lymphomas, making up about 20-25% of all cutaneous lymphomas.

There are multiple treatments for ous lymphoma (topical or systemic): Topical: Corticosteroids, Bexarotene (Targretin), Mechlorethamine (Mustargen and or), Carmustin (BCNU), Phototherapy, Local and total skin electron beam conventional radiotherapy. Systemic: Various targeted biological immuno-therapies, HDAC inhibitors and chemotherapies In conclusion, there is an ongoing need for ed therapies for skin lesions.

SUMMARY OF THE INVENTION It has now singly been found that the compounds of formula (I) are selective and specific inhibitors of mTOR and/or dual inhibitors of PI3K/mTOR and are highly effective in regressing skin lesions, in particular cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK).

Thus, in a ﬁrst aspect of the invention, there is provided a nd of formula (I), X1J\\X2 F W F l , Wherein _ 4 _ 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, then X1, X2 and X3 are N; R1 and R2 are independently of each other (i) a morpholinyl of formula (II) R3— —R4 l (11) wherein the arrow denotes the bond in formula (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2ﬂuoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)O-C1- Czalkyl; or R3 and R4 form together a bivalent residue —R5R6— ed from C1-C3alkylene ally substituted with 1 to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any ofthe structures A O A. wherein the arrows denote the bonds in formula (II); or (ii) a saturated 6-membered heterocyclic ring Z ed from rpholinyl and piperazinyl, optionally substituted by 1 to 3 R7; n R7 is independently at each occurrence C1-C3alkyl optionally substituted with one or two OH, C1-C2ﬂuoroalkyl, C1- CzalkoxyCl-Cgalkyl, C3-C6cycloalkyl; or two R7 substituents form together a bivalent residue —R8R9— selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2-O-CH2- or -O- CHzCHz-O-; with the proviso that at least one of R1 and R2 is a morpholinyl of formula II; and prodrugs, metabolites, tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subj ect.

DESCRIPTION OF FIGURES K14-Fyn—Y528F mice were treated with a topical application of a gel containing Compound 1* (10 mg of Compound 1*) or g (control) were dissolved in 75 ul of DMSO and then propyleneglycol was added to 1000 mg (ﬁnal tration is 1% (w/w) (Fig. 1A, B and C). The Compound 1* treated cohort contained 6 mice with 20 cSCC lesions (Fig. 1B) while the control cohort contained 6 mice with 15 cSCC lesions (FiglA). The size of each SCC was measured using calipers before treatment and weekly thereafter. Gels were applied to s daily once Mo-Fr. As shown in Fig. 1B and 1C and the once daily topical application of Compound 1* gel induced almost complete regression of all cSCC lesions in the K14-Fyn Y528F model without ent inﬂammation or ulceration within 4 weeks.

Effect of topical application of compound 1* or vehicle on cSCC lesions in K14-Fyn—Y528F mice. 12 of 6-week-old K14-Fyn-Y528F mice were grouped in two s (6 mice each) carrying either 15 cSCC lesion (control group) or 20 cSCC lesions (treatment group). Using Calipers, the size of the lesions was measured before start of treatment (and weekly thereafter) and varied from 4 — 68 mm2 (the size range of the lesions in each cohort was similar at the beginning). The lesions were treated topically by daily application (5X per week for 4 weeks) either with vehicle (1A) or compound 1* (1B); vehicle: 75 ul DMSO mixed with propyleneglycol to a total of 1000 mg, compound 1*: 10 mg of compound 1* dissolved in 75 ul of DMSO mixed with propyleneglycol to a total of 1000 mg. The various abbreviations denote the site of the individual lesions. The areas of each lesion for each time point were normalized to the area at the start (relative tumor area at WKO = 100). In the vehicle group (1A), one of the individual lesion disappeared spontaneously (L back T2). In the compound- treated group (1B), all 20 dual lesion disappeared upon treatment. The mean values :: SEM for the cSCC lesion-areas in both groups are compared in 1C and 1D. Significant reduction (50% mean-area, p<0.001) of the s in the treatement group occurred y after 5 days.

: Vehicle (control) ent of six-week-old n—Y528F mice carrying 15 dual cSCC lesions.

: Effect of topical application of nd 1* on 20 cSCC lesions in six-week- old K14-Fyn-Y528F mice.

: Treatment of cSCC lesions in K14-Fyn—Y528F mice: Comparison of compound 1* versus vehicle ent (Curve). Vehicle: n=15; treated: n=20.

FIG 1D: Treatment of cSCC lesions in K14-Fyn—Y528F mice: Comparison of compound 1* versus vehicle treatment (Bar graph). Vehicle: n=15; treated: n=20.

FIG 2: Treespot of nd 1*. The human kinome is represented as circular phylogenetetic tree with the 8 main groups of typical protein kinases and 9 groups of atypical protein kinases. The mutant ts of some protein kinases are also shown, as well as the _ 6 _ lipid kinase panel, which is not integral part of the human kinome. The results are reported as a map (Treespot), which allows visualizing compound interactions across the human kinome and lipd kinase panel. Kinases found to bind to Compound 1* are marked with circles, where larger circles indicate higher-afﬁnity.

PK proﬁles of nine ations comprising the inventive compounds and control have been assessed. The l formulation Aldara (5 % imiquimod) was applied to detect variations in skin permeability (local variability in the same animal and inter-subject variability). The stratum comeum was removed by tape stripping to avoid contamination during the biopsy extraction. From the application sites dosed with the 9 test ations, 3 replicate biopsies were taken at 6 hours, 12 hours, 18 hours and 24 hours post dose. One biopsy was taken from each control site. Additionally, 5 blank samples were taken.

PK profiles of three formulations sing the inventive compounds. Excised pig skin was placed in a climate chamber to control temperature and humidity. From every application site (20 x 40 mm) three replicate biopsies were taken at 6 hours, 12 hours, 18 hours and 24 hours post dose. Before es were taken the stratum comeum was removed by tape stripping and biopsies consisted of the remaining epidermis and entire dermis.

PK of 1% de1* in either propylene glycol or PEG. A 30-45 kg domestic pig was hetized for a duration of 12 hours. Each of the four formulations were applied 6 times (2 replicates for each of the three time points — 6, 9 and 12 hours) on 24 different application sites At the end of the study the pig was sacriﬁced and m comeum removed by tape stripping.

Effect of de1* on SKH1 UV-B irradiated mice during the 24 day treatment () and at the end of 24 day treatment ().

Hairless SKH1 mice were irradiated as described below for 102 days prior to treatment with del*. NT = Not treated, V=Vehicle. In vivo topical treatment of Actinic Keratosis on VB induced mice model was performed with either NT or V or de1* 3mg/mouse/day using a non-optimized formulation as described for the cSCC mouse model.

Mid dorsal photo on two selected mice by group is shown (NT: mouse 1-1 and mouse 1-4; V: mouse 2-3 and mouse 2-6; de1*: mouse 3-4 and mouse 3-6). ss SKH-1 mice (Charles River Laboratories) were used for all in vivo experiments and they were fed with standard chow. SKH-1 mice (6-8 weeks old, weighting 18-20g) in individual g (one mouse/cage) were UV-B-exposed every single day for about 14-15 weeks in dedicated cabinet. Medium wave UV-B lamps T-40.M were from Vilber Lourmat (Eberhardzell, Germany), and run from 280 to 320 nm with an energy peak at 312 nm. The MED (minimal erythemal dose) of this device was deﬁned at 0.06 J/cmZ/day, which represents about 20 minutes UV-B exposure per day for SKH-l mice. UV-B irradiation dose was internally calibrated before each experiment to adjust irradiation period. To generate AK lesions and to prevent the risk of skin burn, gradual exposure was med as follow: 10 days at 0.05 J/cmZ/day, 10 days at 0.055 J/cmZ/day and then the MED was applied for the up to 102 days.

Effect of del* on SKHl UV-B irradiated mice after discontinuation of treatment for 17 days.

Hairless SKHl mice were irradiated as described in FIG..6. After treatment for 24 days with del* at 3mg/mouse/day using a non-optimized formulation as described for the cSCC mouse model the ent was discontinued. After 17 days of discontinuation of treatment photos of the Left ﬂank, Mid dorsal and Right ﬂank were taken for 3 selected mice per group (NT: mouse l-4 and mouse l-5 and l-6; Vehicle: mouse 2-4 and and mouse 2-5 and mouse 2- 6; del*: mouse 3-4 and mouse 3-5 and mouse 3-6).

DETAILED PTION OF THE INVENTION Reference will now be made in detail to the presented and further aspects and the presented and further embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be bed in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the ion to those ments. One 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 in no way limited to the methods and materials herein described.

Features, integers and teristics, described in ction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features sed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except ations where at least some of such features and/or steps are _ 8 _ mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this speciﬁcation (including any anying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or s so disclosed.

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

For the es of interpreting this speciﬁcation, the following deﬁnitions will apply and whenever 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 e of describing particular ments only and is not intended to be limiting.

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.

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

The term "chiral" refers to molecules, which have the property ofnon-superimposability of the mirror image partner, while the term "achiral" refers to molecules, which are mposable on their mirror image partner.

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.

"Diastereomer" refers to a stereoisomer with two or more centers of chirality in which the compounds are not mirror images of one another. Diastereomers have ent physical properties, 6.g. melting points, boiling points, spectral ties, and chemical and biological reactivities. Mixtures of diastereomers may be ted under high resolution analytical procedures such as electrophoresis and chromatography.

"Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Stereochemical deﬁnitions and conventions used herein generally follow S.P. , Ed., McRaw—Hiﬁ’ Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., ochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may n asymmetric or chiral centers, and therefore exist in different isomeric forms. It is intended that all stereoisomeric forms of the compounds of the _ 9 _ invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the t invention. Many organic compounds exist in optically active forms, z'.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the s D and L, or R and S, are used to denote the absolute conﬁguration of the le about its chiral center(s). The preﬁxes d and l or (+) and (—) are employed to ate the sign of rotation of plane-polarized light by the compound, with (—) or 1 meaning that the compound is tatory. A compound preﬁxed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another.

A speciﬁc stereoisomer may also be referred to as an omer, and a mixture of such isomers is often called an enantiomeric or a scalemic mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a te. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies, which are interconvertible via a low energy barrier. For example, proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine izations.

The phrase "pharmaceutically acceptable salt" as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention, in particular acid addition salts. 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, inate, ﬁlmarate, gluconate, glucuronate, rate, formate, te, glutamate, methanesulfonate (mesylate), ethanesulfonate, benzenesulfonate, p- toluenesulfonate, and pamoate salts. A ceutically acceptable salt may e the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. rmore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have le counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the d pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such WO 98347 _ 10 _ as acetic acid, roacetic acid, maleic acid, succinic acid, mandelic acid, ﬁll’IlElI'lC acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as ic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxico logically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

A "solvate" refers to an association or complex of one or more t molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, panol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.

The term "protecting group" refers to a substituent that is commonly employed to block or protect a particular ﬁanctionality during the reaction of other ﬁanctional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or ts the amino ﬁanctionality in the compound. Suitable amino- protecting groups include acetyl, triﬂuoroacetyl, utoxycarbonyl (BOC), oxycarbonyl and 9-ﬂuorenylmethylenoxycarbonyl . 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.

The terms "compound of this invention" and "compounds of the present invention" and unds of formula (1)” include stereoisomers, ric isomers, tautomers, solvates, pharmaceutically acceptable salts, and so lvates of the salts thereof The term “skin lesion” as used herein refers to a skin lesion which may be a skin cancer, such as non-melanoma skin cancer (NMSC) or a pre-invasive neoplastic skin proliferation, such as cutaneous squamous cell oma in situ (cSCCis or Bowen’s disease) or c keratosis (AK, also called "solar keratosis" and "senile keratosis"). Bowen’s disease is a neoplastic skin disease which can be ered as an early stage or intraepidermal form of squamous cell carcinoma. Actinic keratosis is characterized by pre-cancerous patches of thick, scaly, or crusty skin, which are usually formed when skin gets damaged by ultraviolet (UV) radiation from the sun or indoor tanning beds.

WO 98347 _ 11 _ The terms “non-melanoma skin cancer” and “NMSC” are used herein interchangeably.

The term “NMSC” refers to a group of diseases including actinic sis (AK), us cell carcinoma (SCC), Bowen's Disease (BD) and basal cell carcinoma (BCC).

The term “field cancerization” refers to premalignant ﬁeld defects and is a biological process in which large areas of cells at a tissue surface or within an organ are ed by carcinogenic alterations. The process arises from exposure to an injurious environment, such as UV radiation, often over a lengthy period. The initial step in ﬁeld cancerization is associated with various molecular lesions such as acquired genetic mutations and etic changes, occurring over a widespread, multi-focal "ﬁeld". The ﬁeld is affected by subclinical (nonvisible, nonpalpable) AK lesions, early AK lesions, late AK lesions, and possibly even invasive cSCCs. The concept of ﬁeld cancerization provides the rationale for ﬁeld y, in which the entire ﬁeld - rather than individual lesions - is treated. The goals of ﬁeld therapy are to eliminate not only clinically visible lesions but also subclinical lesions and to prevent the development of invasive SCC.

The terms “cutaneous squamous cell carcinoma” and “cSCC” are used herein interchangeably. cSCC is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of cells of epithelium, or cells showing ular cytological or tissue architectural characteristics of squamous-cell differentiation, such as the ce of keratin, tonoﬁlament bundles, or desmosomes, structures ed in cell-to-cell adhesion.

The terms “treatment"/”treating” as used herein include: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be ed with or predisposed to the state, disorder or condition but does not yet experience or display clinical or nical symptoms of the state, er or condition; (2) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical m thereof); and/or (3) relieving the condition (i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The beneﬁt to a patient to be d is either statistically signiﬁcant or at least tible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment. In one embodiment, the terms “treatment"/”treating” as used herein, refer to a therapeutic treatment.

In another ment, the terms ment"/”treating” as used herein, refer to a prophylactic treatment. _ 12 _ The term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. The term "mammal", as used herein, preferably refers to humans.

With regard to actinic keratosis (AK) the term ment” as used herein comprises lesion-directed and ﬁeld-directed ies. Lesion-directed therapy may be useful in the treatment of discrete, solitary s. Other factors considered when deciding which treatment option to pursue are morphology and duration of lesions, preexisting skin cancer, and individual patient factors such as age, immune status, cosmesis, pain tolerance, and treatment nce. Field-directed therapy is indicated when there are multiple lesions on a chronically amaged ﬁeld or a history of multiple lesions. Lesion-directed and ﬁeld- directed therapies can be used in combination. The advantage of combination therapy is enhanced therapeutic effect, ally in difficult-to-treat case.

As used herein, the term "systemic administration" refers to administration of a compound ing to the invention, such that the nd becomes widely distributed in the body in signiﬁcant amounts and has a biological effect, e. g. its desired effect, in the blood and/or reaches its desired site of action via the vascular system. Typical ic routes of administration include administration by (l) introducing the compound directly into the vascular system or (2) oral, pulmonary, or intramuscular administration wherein the nd is adsorbed, enters the vascular system, and is carried to one or more desired site(s) of action via the blood.

The terms "oral", 'orally", and "oral administration", as used herein, refer to orally ingesting a nd ofthe present invention.

The term "topical administration" is used in its broadest sense to include administration to a surface on the body that is generally open to the surroundings. This includes not only the skin but also the nasal and oral passages and the genitalia. Thus, topical administration can include ation to the skin, application to the nasal passages, application to the oral cavity (including the upper throat), and application to the genitalia. Topical ations have been available in a variety of forms, including , ointments, solutions, lotions, suspensions, pastes, emulsions, foams and the like. Water le creams have generally been employed for moist or weeping lesions, whereas ointments have been generally chosen for dry, licheniﬁed or scaly lesions or where a more occlusive effect has been required. Lotions have generally been useful when minimal application to a large or hair-bearing area has been ed or for the treatment of exudative lesions. _ 13 _ Skin lesions, such as cSCC, AK or cSCCis are usually diagnosed/assessed by physical examination, but can be conﬁrmed by histological analysis.

The expression "effective amoun " means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) ts or delays the onset of one or more symptoms of the particular e, condition, or disorder described herein. In the case of NMSC or pre- invasive forms thereof, the effective amount of the drug may reduce the lesions or make them ear. For therapy ofNMSC or pre-invasive forms thereof, efficacy can be measured, for e, by either physically assessing the lesions or by ogy.

The term “dual PI3K/mTOR” inhibitor as used herein refers to a compound capable of inhibiting a Type I PI3K kinase and mTOR kinase activity by at least 2 uM preferably by at least 1 uM.

The term "prodrug" as used in this application refers to a sor or derivative form of a compound of the invention that may have improved properties such as better solubility, reduced cytotoxicity or increased bioavailability compared to the parent compound or drug and is capable of being activated or converted into the more active parent form. The prodrugs of this invention include, but are not limited to, tives of the amino group connected to the pyridine or pyrimidine nucleus in which one or two hydrogens are replaced by a suitable tuent, or derivatives of the ring amino function if R2 is piperazin-l-yl. Examples of such prodrugs are compounds acylated by an amino acid selected from the 20 most often occurring natural L-alpha-amino acids, acylated by a dipeptide such as L-Ala-L-Ala, by carbonic acid, sulfuric acid or phosphoric acid, as well as pharmaceutically acceptable salts thereof.

A "metabolite" is a product produced through metabolism in the body of a specified compound or salt thereof. lites of a compound may be identiﬁed using routine techniques known in the art and their activities ined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterif1cation, rif1cation, enzymatic ge, and the like, of the administered compound. In particular, compounds of formula (I) as deﬁned hereinbefore, which are oxygenated or hydroxylated at any one position in the morpholine, piperazine or thiomorpholine ring R1 and/or R2 are ered metabolites. Further lites considered are thiomorpholine S-oxides and thiomorpholine S,S-dioxides. Accordingly, the invention is also directed to metabolites of compounds of the invention, including compounds produced _ 14 _ by a s comprising contacting a nd of this invention with a mammal for a period oftime sufﬁcient to yield a metabolic product thereof.

In a ﬁrst aspect of the invention, there is provided a nd of formula (1), X1J\\X2 F W F RJ\X3|1 / \NJ\N H 2 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, then X1, X2 and X3 are N; R1 and R2 are independently of each other (i) a morpholinyl of formula (11) R3— —R4 l (11) wherein the arrow denotes the bond in formula (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2ﬂuoroalkyl, C1-C2alkoxy, lkoxyC1-C3alkyl, CN, or C(O)O-C1- Czalkyl; or R3 and R4 form together a bivalent residue —R5R6— selected from C1-C3alkylene optionally substituted with l to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any ofthe structures A O A. wherein the arrows denote the bonds in formula (II); or (ii) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally tuted by l to 3 R7; wherein R7 is independently at each occurrence C1-C3alkyl optionally substituted with one or two OH, uoroalkyl, C1- CzalkoxyCl-Cgalkyl, C3-C6cycloalkyl; or two R7 substituents form er a bivalent residue _ 15 _ —R8R9— selected from C1-C3alkylene optionally substituted with l to 4 F, -CH2-O-CH2- or -O- with the proviso that at least one of R1 and R2 is a morpholinyl of formula II; and prodrugs, metabolites, tautomers, es and pharmaceutically acceptable salts thereof, for use in the prevention or ent of a skin lesion in a subject.

In another aspect, the invention provides for a compound of formula (1), X1J\\X2 F W F 1 / \NJ\N H 2 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, then X1, X2 and X3 are N; R1 is holinyl, 2-methylmorpholinyl, 3-methylmorpholinyl, octadeuterio morpholinyl, 8-azaoxabicyclo[3.2.l]octyl or 8-oxabicyclo[3.2.l]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, ylmorpholinyl, octadeuterio morpholinyl, 8-azaoxabicyclo[3.2.l]octyl, 3-azaoxabicyclo[3.2.l]octyl, piperazin- l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl; for use in the prevention or treatment of a skin lesion in a subject.

Each alkyl moiety either alone or as part of a larger group such as alkoxy is a straight or branched chain and is preferably C1-C3alkyl, more preferably C1-C2alkyl. Examples include in ular methyl, ethyl, n-propyl and propyl (iso-propyl). Examples of an alkoxy include in particular methoxy, ethoxy, n-propoxy and iso-propoxy. As described , alkoxy may include further substituents such as halogen atoms leading to haloalkoxy moieties.

The term “alkoxyalkyl” refers to an R—O-R’ moiety in which the R and R’ groups are alkyl groups as defined herein. es include methoxymethyl, methoxyethyl, ethoxyethyl and methoxypropyl.

Each alkylene moiety is a straight or branched chain and is, particularly for example, - CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, OI‘ -CH(CH2CH3)-, _ l6 _ preferably -CH2-, -CH2-CH2- or -CH(CH3)—.

Each haloalkyl moiety either alone or as part of a larger group such as haloalkoxy is an alkyl group substituted by one or more of the same or different halogen atoms. Haloalkyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents. Examples include in particular ﬂuoromethyl, diﬂuoromethyl, triﬂuoromethyl, chlorodiﬂuoromethyl and 2,2,2-triﬂuoro-ethyl.

Each haloalkenyl moiety either alone or as part of a larger group such as haloalkenyloxy is an alkenyl group tuted by one or more of the same or ent halogen atoms.

Examples include 2-diﬂuoro-vinyl and l,2-dichloroﬂuoro-vinyl. Haloalkenyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.

Each cycloalkyl moiety can be in mono- or bi-cyclic form, typically and preferably in mono-cyclic form, and preferably contains 3 to 6 carbon atoms. Preferred examples of monocyclic cycloalkyl groups include in particular cyclopropyl, cyclobutyl, entyl and cyclohexyl.

The term "heterocyclic ring" refers to a saturated or partially unsaturated carbocyclic ring containing one to three heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Preferred es include in ular tetrahydrofuranyl, idinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, dioxanyl, morpholinyl, oxazolidinyl and isooxazolidinyl.

Where a group is said to be optionally tuted, preferably there are optionally 1-3 substituents, more ably ally 1-2 substituents.

Certain compounds of formula (I) may contain one or two or more centers of chirality and such compounds may be provided as pure enantiomers or pure diastereoisomers as well as mixtures thereof in any ratio. The compounds of the ion also include all tautomeric forms of the compounds of formula (I).

In a preferred embodiment, the present invention provides for the compound of formula (I) as deﬁned herein and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the tion or ent of a skin lesion in a t.

In another red embodiment, the present invention provides for the compound of formula (I) for use in the prevention or treatment of a skin lesion in a subject, wherein X1, X2 and X3 are N.

In another preferred embodiment, (i) said X1 and said X2 are N, and said X3 is CH; (ii) _ 17 _ said X1 and said X3 are N, and said X2 is CH; or (iii) said X2 and said X3 are N, and said X1 is CH, and preferably tautomers, solvates and pharmaceutically acceptable salts thereof. In another embodiment, (i) said X1 and said X2 are N, and said X3 is CH; or (ii) said X2 and said X3 are N, and said X1 is CH, and preferably tautomers, solvates and pharmaceutically acceptable salts thereof. In another preferred embodiment, said X1 and said X3 are N, and said X2 is CH; and preferably tautomers, solvates and pharmaceutically acceptable salts thereof In another red embodiment, the present invention es for the compound of formula (I) for use in the prevention or treatment of a skin lesion in a subject, wherein W is H.

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

In another red embodiment, said Y is N, and preferably ers, solvates and pharmaceutically acceptable salts thereof In another preferred embodiment, said Y is CH, and preferably tautomers, solvates and ceutically acceptable salts thereof In another preferred embodiment, said R1 and said R2 are independently of each other [:3 [:3 [:1 [in J? 3:3l -rjr ESL, £ij [if TE‘J’ TEL (l in + if In D in +03 [Firm [waif [$3 [$30 E? E? $ [33> [331:0 (:3:+ i l WO 98347 _ 18 _ In D of a] Q 1;} + 1|r + ,L '3 F F ‘3‘ w w [Dr/F, i, r3» o: ilriJ (Mr? [ii iii trig if F 4* FF {I} 1:} Cr l5} [hm Erik” [$117 [$193 HHS“; In another preferred embodiment, said R1 and said R2 are independently of each other selected from [:1 1:1,,” [fr [if (:1: ASL fl”, 1 0 + + i + + + “it 1E LE 38 m m ~ N [f N "H 3 I‘d—:- HN Ma— —N Na— + l‘ T w._r H_r x x In another preferred embodiment, said R1 and said R2 are independently of each other selected from If! .33, g D 1:} D rm; (,1,an L Egg [Mk AL + + l + + + G 9 ti" ‘3 N—I- HN H.3- ‘-._f ‘-._f In another preferred embodiment, said compound is selected from 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyridinamine; 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 inyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3 -oxaazabicyclo [3 .2. l]octanyl)- l ,3 ,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; -(4-(3-oxaazabicyclo [3 .2. l]octan—8-yl)morpho lino- l ,3 ,5 -triazinyl) (diﬂuoromethyl)pyridin—2-amine; 5 -oxaazabicyclo [3 .2. n—8-yl)morpho lino- l ,3 ,5 -triazinyl) (diﬂuoromethyl)pyrimidin—2-amine; -(4,6-bis((S)methylmorpho lino)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyridinamine; -(4,6-bis((S)methylmorpho lino)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyrimidinamine; (diﬂuoromethyl)-5 -(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; (S)(diﬂuoromethyl)-5 -(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazin yl)pyrimidinamine; -(4-(3-oxaazabicyclo [3 .2. l]octan—8-yl)((S)methylmorpho lino)- l ,3 ,5 -triazinyl) WO 98347 _ 20 _ (diﬂuorornethyl)pyridin—2-amine; -(4-(3-oxaazabicyclo [3 .2. 1]octan—8-y1)((S)-3 1morpholino)-1,3 ,5 in—2-yl) (diﬂuorornethyl)pyrimidin—Z-arnine; 4-(diﬂu0romethyl)(4-rn0rpho1in0(piperazin— 1 -y1)- 1 ,3 ,5 -triaziny1)pyridinamine; 4-(diﬂu0romethyl)(4-rn0rpho1in0(piperazin— 1 -y1)- 1 ,3 ,5 -triaziny1)pyrimidinarnine; (S)(diﬂu0rornethy1)-5 -(4-(3 -rnethy1rnorpho1in0)(piperaziny1)- 1 ,3 ,5 -triazin—2- yl)pyridinarnine; (diﬂu0rornethy1)-5 -(4-(3 -rnethy1rnorpho1in0)(piperaziny1)- 1 ,3 ,5 -triazin—2- yl)pyrimidin—2-arnine; 4-(diﬂu0romethyl)(2,6-dirnorpho linopyrirnidiny1)pyridin—2-arnine; ﬂuorornethyl)-2,6-dirn0rpho1in0-[4,5'-bipyrimidin]-2'-amine; 4-(diﬂu0romethyl)(4,6-dirnorpholinopyrimidin-Z-y1)pyridin—2-arnine; 4'-(diﬂuorornethyl)-4,6-dirn0rpho1in0-[2,5'-bipyrimidin]-2'-amine; 4-(diﬂu0romethyl)(4-rn0rph01in0thiornorpholino- 1 ,3 ,5 -triazin—2-y1)pyridinarnine; 4-(diﬂu0romethyl)(4-rn0rph01in0thiornorpholino- 1 ,3 ,5 -triazin—2-y1)pyrirnidin—2-arnine; -(6-(3-oxaazabicyclo [3 .2. 1 ]octan—8-y1)(3 -oxaazabicyclo[3.2.1]octan—8-y1)pyrirnidin— 4-y1)(diﬂuor0rnethyl)pyridinarnine; -(2-(3-oxaazabicyclo [3 .2. 1 ]octany1)rnorpho linopyrirnidiny1) (diﬂuorornethyl)pyridin—2-amine; 2-(3-oxaazabicyclo [3 .2. 1 ]octany1)-4 ’-(diﬂuorornethyl)rn0rph0 lino- [4,5 ’-bipyrirnidin] - 2’-arnine; -(2,6-bis((S)-3 -rnethy1rn0rpho 1in0)pyrimidiny1)(diﬂuoromethyl)pyridin—2-amine; 4'-(diﬂuorornethy1)-2,6-bis((S)-3 -rnethylrnorpholino)- [4,5 '-bipyrirnidin] -2'-arnine; (S)(diﬂu0rornethy1)-5 -(6-(3 -rnethy1rn0rpho1ino)rnorpholinopyrirnidiny1)pyridin amine; (S)-4'-(diﬂu0rornethyl)(3 -rnethylrnorpho 1in0)rn0rpholino- [4,5 '-bipyrirnidin] -2'-arnine; -(4-(8-Oxaazabicyclo[3.2.1]octan—3-y1)(8-oxaazabicyclo[3.2.1]octan—3-y1)-1,3,5- n—2-yl)(diﬂuoromethyl)pyridin—2-arnine; -[4,6-bis(2,2-dimethylmorpho1in—4-y1)-1 ,3 ,5 -triazinyl] (diﬂuorornethyl)pyridin—2- amine; (S)(diﬂu0r0rnethy1)-5 -(2-(3 -rnethy1rn0rpho1ino)rnorpholinopyrirnidiny1)pyridin amlne; (S)-4'-(diﬂuorornethyl)(3-rnethylmorpho1ino)m0rpholino-[4,5'-bipyrirnidin]-2'-arnine; _ 21 _ 4-(diﬂu0romethyl)-5 - [4- [(2S ,6R)-2,6-dirnethy1rnorpho1in—4-y1]—6-[(3 nethylrnorpho lin- 4-y1]-1 ,3 ,5 -triaziny1]pyridinamine; -[4,6-bis[(2R,6S)-2,6-dirnethy1rnorpho1iny1]—1,3 ,5 -triazin—2-y1]—4- (diﬂuorornethyl)pyridin—2-amine; - [4,6-bis(3 xaazabicyclo [3 .3 . 1 ]nonan—9-y1)- 1 ,3 ,5 -triazin—2-y1]—4- (diﬂuorornethyl)pyridin—2-amine; 4-(diﬂuorornethyl)-5 - [4-(3 ,7-dioxaazabicyclo [3 .3. 1]nonan—9-y1)(3 -oxa azabicyclo [3 .2. 1]0ctan—8-y1)-1 ,3 ,5 -triazinyl]pyridinamine; - [4,6-bis(3 ,3 -dirnethylrnorpho 1in—4-y1)- 1 ,3 ,5 -triaziny1] (diﬂuorornethyl)pyridin—2- amine; - [4,6-bis[(3R,5S)—3 ,5 -dirnethy1rnorpho y1] - 1 ,3 ,5 -triazin—2-y1](diﬂuor0methyl)pyridin— 2-amine; - [4,6-bis[(3R)-3 y1m0rpholin—4-y1]—1 ,3 ,5 -triazin—2-y1] (diﬂuorornethyl)pyridin—2- amine; 4-(diﬂu0romethyl)-5 - [4-(3 ,3-dimethy1rnorpho1iny1)rnorpholino-1 ,3 ,5 -triazin—2- yl]pyridinarnine; 4-(diﬂu0romethyl)-5 - [4- S)-3 ,5-dirnethy1morpho1in—4-y1]—6-[(3R)-3 -rnethy1rn0rpho 1in—4- y1]- 1 ,3 ,5 -triazin—2-y1]pyridin—2-amine; 4-(diﬂu0romethyl)-5 - [4-(3 ethy1morpho 1iny1)[(3R)methylmorpholinyl] - 1 ,3 ,5 -triaziny1]pyridin—2-amine; u0romethyl)-5 - [4-[(3R)(methoxymethyl)morpho1iny1] [(3R) methylrnorpho 1iny1] - 1 ,3 ,5 -triaziny1]pyridinarnine; 4-(diﬂuorornethy1)[4-(3,7-dioxaazabicyclo[3 .3 . 1 ]nonan—9-y1)[(3R) methylrnorpho 1iny1] - 1 ,3 ,5 -triaziny1]pyridinarnine; 4-(diﬂu0romethyl)-5 - [4- [(3R)rnethylrnorpholinyl] (3 -oxaazabicyclo [3. 1 .1]heptan— 6-y1)-1 ,3 ,5 -triaziny1]pyridinamine; u0romethyl)-5 - [4- [(3R)rnethylrnorpholinyl] (6-oxa-3 -azabicyclo [3. 1 .1]heptan— 3 -y1)-1 ,3 ,5 -triaziny1]pyridinamine; 4-(diﬂu0romethyl)[4-[(3R)rnethylrnorpholinyl][(1R,4R)0xa-5 - azabicyclo [2 .2. 1]heptan—5 -y1]-1 ,3 ,5 -triazinyl]pyridinamine; 4-(diﬂu0romethyl)[4-[(3R)rnethylrnorpholinyl][(1S,4S)oxa-5 - azabicyclo [2.2. 1]heptan—5 -y1]-1 ,3 ,5 -triazinyl]pyridinamine; - [4,6-bis[(3R)-3 -ethylrnorpholiny1]-1 ,3 ,5 -triazin—2-y1](diﬂuorornethyl)pyridin—2-arnine; _ 22 _ - is(8-0xa-5 -azaspir0 [3 .5 ]nonan—5 -y1)-1,3 ,5 -triazin—2-y1](diﬂuor0rnethyl)pyridin amine; - [4,6-bis[(3R)-3 -isopr0pylmorpho1in—4-y1]—1 ,3 ,5 -triazin—2-y1](diﬂuor0rnethyl)pyridin amine 4-(diﬂu0romethyl)-5 - [4-(3 ,3-dimethy1morpho 1iny1) [(3R,5S)-3 ,5-dimethy1morpho 1in y1]- 1 ,3 ,5 in—2-y1]pyridin—2-amine; 4-(diﬂu0romethyl)-5 - [4-(3 ,3-dirnethy1rnorpho1iny1)[(3R)(rnethoxyrnethy1)rnorpholin- 4-y1]-1 ,3 ,5 -triaziny1]pyridinamine; [(3R)[4- [6-arnin0(diﬂu0r0rnethyl)-3 -pyridy1] (3 ,3 -dirnethy1rnorpho 1iny1)- 1 ,3 ,5 - triazin—Z-yl]morpholin—3 -y1]rnethan01; 4-(diﬂu0romethyl)-5 - [4-(3 ,3-dirnethy1morpho1iny1)(3 ,7-di0xa azabicyclo [3 .3 . 1 ]nonan—9-y1)- 1 ,3 ,5 -triazinyl]pyridinamine; -[4-(4-cyclopropy1piperaziny1)(3 ,3 -dirnethy1rnorpho 1iny1)- 1 ,3 ,5 -triazinyl] (diﬂuorornethyl)pyridin—2-amine; 4-(diﬂuoromethyl)-5 - [4-(3 ,3-dimethy1morpho 1iny1) [4-(2-meth0xyethy1)piperazin— 1 -y1] - 1 ,3 ,5 -triaziny1]pyridin—2-amine; 4-[4- [6-arnin0(diﬂu0r0rnethyl)-3 -pyridy1] [(3R)-3 -rnethy1rn0rpho 1iny1] - 1 ,3 ,5 - triazin—Z-yl]morpholin—3 -y1]rnethan01; 4-(diﬂu0r0rnethyl)-5 - [4- [(3R,5R)-3 ,5 thy1rnorpho 1in—4-y1] [(3R)-3 -rnethy1rn0rpho 1in—4- y1]- 1 ,3 ,5 -triazin—2-y1]pyridin—2-amine; 4-(diﬂu0romethyl)-5 - [4- [(3S,5S)-3 ,5 -dirnethy1rnorpho 1in—4-y1] 3 -rnethy1rn0rpho 1in—4- y1]- 1 ,3 ,5 -triazin—2-y1]pyridin—2-amine; uor0rnethyl)-5 -[4-rn0rph01ino(3-oxaazabicyclo [3 .3 . 1 ]nonan—9-y1)- 1 ,3 ,5 -triazin—2- yl]pyridinarnine; 4-(diﬂuorornethy1)[4-(3,7-dioxaazabicyclo[3 .3 . 1 ]nonan—9-y1)(3-oxa azabicyclo [3 .3 . 1 ]nonan—9-y1)- 1 ,3 ,5 -triazinyl]pyridinamine; - [4,6-bis[(3 S ,5 S)—3 ,5 -dirnethy1rnorpho 1in—4-y1] - 1 ,3 ,5 -triazin—2-y1](diﬂuor0methyl)pyridin— 4-(diﬂu0romethyl)-5 - [4-(3 ,7-dioxaazabicyclo[3.3.1]nonan—9-y1)rn0rpholino-1,3 ,5 - triazin—2-y1]pyridinarnine; 4-(diﬂu0romethyl)-5 - [4- [(3 S)ethy1rnorph01in—4-y1]—6-[(3 nethylrnorpho1in—4-y1]— 1 ,3 ,5 -triaziny1]pyridin—2-amine; 4-(diﬂu0romethyl)-5 - [4- [(3 R)-3 rn0rpho1iny1]—6-[(3 R)-3 -rnethy1rn0rpho 1iny1] - _ 23 _ l ,3 ,5 -triazinyl]pyridinamine; uoromethyl)-5 - [4- [(3 R)methylmorpho linyl] (8-oxa-5 -azaspiro [3 .5 ]nonan-5 -yl)- l ,3 ,5 -triazinyl]pyridinamine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; - [4,6-bis[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] (triﬂuoromethyl)pyridin amine; - [4,6-bis[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] (triﬂuoromethyl)pyrimidin amine; 5 - [4- [(3 S)—3 -methylmorpho yl]morpho lino - l ,3 ,5-triazinyl] (triﬂuoromethyl)pyridinamine; - [4- [(3 S)—3 -methylmorpho linyl]morpho lino - l ,3 ,5-triazinyl] (triﬂuoromethyl)pyrimidinamine; -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; 5 -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; -(4-morpholinothiomorpholino- l ,3 ,5 inyl)(triﬂuoromethyl)pyridinamine; -(4-morpholinothiomorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another red embodiment, said compound is selected from 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyridinamine; uoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3 -azabicyclo [3 .2. l]octanyl)- l ,3 ,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; -(4-(3-oxaazabicyclo [3 .2. l]octan—8-yl)morpho lino- l ,3 ,5 -triazinyl) (diﬂuoromethyl)pyridin—2-amine; -(4-(3-oxaazabicyclo [3 .2. l]octan—8-yl)morpho lino- l ,3 ,5 -triazinyl) (diﬂuoromethyl)pyrimidin—2-amine; -(4,6-bis((S)methylmorpho lino)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyridinamine; -(4,6-bis((S)methylmorpho lino)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyrimidinamine; (S)(diﬂuoromethyl)-5 -(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; (S)(diﬂuoromethyl)-5 -(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazin yl)pyrimidin—2-amine; _ 24 _ -(4-(3-oxaazabicyclo [3 .2. 1]octan—8-y1)((S)-3 -methy1m0rph01ino)-1,3 ,5 -triaziny1) (diﬂuoromethyl)pyridin—2-amine; -(4-(3-oxaazabicyclo [3 .2. 1]octan—8-y1)((S)-3 -methy1m0rph01ino)-1,3 ,5 -triaziny1) (diﬂuoromethyl)pyrimidin—2-amine; 4-(diﬂu0romethyl)(4-m0rph01in0(piperazin— 1 -y1)- 1 ,3 ,5 -triaziny1)pyridinamine; u0romethyl)(4-m0rph01in0(piperazin— 1 -y1)- 1 ,3 ,5 -triaziny1)pyrimidinamine; (S)(diﬂu0r0methy1)-5 -(4-(3-methy1morph01in0)(piperaziny1)- 1 ,3 ,5 -triazin yl)pyridinamine; (diﬂu0r0methy1)-5 -(4-(3-methy1morph01in0)(piperaziny1)- 1 ,3 ,5 -triazin y1)pyrimidinamine; 4-(diﬂu0romethyl)(2,6-dim0rph01in0pyrimidiny1)pyridin—2-amine; 4'-(diﬂuor0methyl)-2,6-dim0rpho1in0-[4,5'-bipyrimidin]-2'-amine; 4-(diﬂu0romethyl)(4,6-dimorpholinopyrimidin-Z-y1)pyridin—2-amine; 4'-(diﬂuor0methyl)-4,6-dim0rpho1in0-[2,5'-bipyrimidin]-2'-amine; 4-(diﬂu0romethyl)(4-m0rph01in0thi0m0rph01ino- 1 ,3 ,5 -triaziny1)pyridinamine; uoromethy1)(4-m0rph01in0thi0m0rph01ino- 1 ,3 ,5 -triaziny1)pyrimidin—2-amine; -oxaazabicyclo [3 .2. 1]octan—8-y1)(3 -oxaazabicyclo [3 .2. 1]octany1)pyrimidin— 4-y1)(diﬂuor0methyl)pyridinamine; -(2-(3-oxaazabicyclo [3 .2. 1]octany1)m0rph0 1inopyrimidiny1) (diﬂuoromethyl)pyridin—2-amine; 2-(3-oxaazabicyclo [3 .2. 1 ]octany1)-4 ’-(diﬂu0r0methy1)morpholino-[4,5 ’-bipyrimidin] - 2’-amine; -(2,6-bis((S)-3 -methy1morph01in0)pyrimidiny1)(diﬂuoromethyl)pyridin—2-amine; 4'-(diﬂu0r0methy1)-2,6-bis((S)methy1morpholino)— [4,5 '-bipyrimidin] -2'-amine; (S)(diﬂu0r0methy1)-5 -methy1m0rph01ino)morpho1in0pyrimidin—4-y1)pyridin amine; (S)-4'-(diﬂu0r0methyl)(3-methy1m0rpholin0)m0rph01ino-[4,5'-bipyrimidin]—2'-amine; -(4-(8-Oxaazabicyclo[3.2.1]octan—3-y1)(8-oxaazabicyc10[3.2.1]octan—3-y1)-1,3,5- triazin—2-y1)(diﬂuoromethyl)pyridin—2-amine; 5 -[4,6-bis(2,2-dimethy1m0rpho1iny1)-1 ,3 ,5 -triaziny1] ﬂuoromethy1)pyridin amine; (S)(diﬂu0r0methy1)-5 -(2-(3-methy1m0rph01ino)morpho1in0pyrimidin—4-y1)pyridin amine; _ 25 _ (S)-4'-(diﬂu0rornethyl)(3 -rnethylrnorpho 1in0)rn0rpholino- [4,5 '-bipyrirnidin] nine; 4-(diﬂu0romethyl)-5 - [4- [(2S ,6R)-2,6-dirnethy1rnorpho1in—4-y1]—6-[(3 R)rnethylrnorpho lin- 4-y1]-1 ,3 ,5 iny1]pyridinamine; -[4,6-bis[(2R,6S)-2,6-dirnethy1rnorpho1iny1]—1,3 ,5 -triazin—2-y1]—4- (diﬂuorornethyl)pyridin—2-amine; - [4,6-bis(3 ,7-dioxaazabicyclo [3 .3 . 1 ]nonan—9-y1)- 1 ,3 ,5 -triazin—2-y1]—4- (diﬂuorornethyl)pyridin—2-amine; 4-(diﬂuorornethyl)-5 - [4-(3 ,7-dioxaazabicyclo [3 .3. 1]nonan—9-y1)(3 - azabicyclo [3 .2. 1]0ctan—8-y1)-1 ,3 ,5 -triazinyl]pyridinamine; 5 - [4,6-bis(3 ,3 -dirnethylrnorpho 1in—4-y1)- 1 ,3 ,5 -triazinyl] (diﬂuorornethyl)pyridin—2- amine; - [4,6-bis[(3R,5S)—3 ,5 -dirnethy1rnorpho 1in—4-y1] - 1 ,3 ,5 -triazin—2-y1](diﬂuor0methyl)pyridin— 2-amine; - [4,6-bis[(3R)-3 y1m0rpholin—4-y1]—1 ,3 ,5 -triazin—2-yl] (diﬂuorornethyl)pyridin—2- amine; 4-(diﬂu0romethyl)-5 - [4-(3 ,3-dimethy1rnorpho1iny1)rnorpholino-1 ,3 ,5 in—2- yl]pyridinarnine; 4-(diﬂu0romethyl)-5 - [4- S)-3 ,5-dirnethy1morpho1in—4-y1]—6-[(3R)-3 -rnethy1rn0rpho 1in—4- y1]- 1 ,3 ,5 -triazin—2-y1]pyridin—2-amine; 4-(diﬂu0romethyl)-5 - [4-(3 ,3-dimethy1morpho 1iny1)[(3R)methylmorpholinyl] - 1 ,3 ,5 -triaziny1]pyridin—2-amine; 4-(diﬂu0romethyl)-5 - [4-[(3R)(methoxymethyl)morpho1iny1] [(3R) rnorpho 1iny1] - 1 ,3 ,5 -triaziny1]pyridinarnine; 4-(diﬂuorornethy1)[4-(3,7-dioxaazabicyclo[3 .3 . 1 ]nonan—9-y1)[(3R) methylrnorpho 1iny1] - 1 ,3 ,5 -triaziny1]pyridinarnine; 4-(diﬂuorornethy1)[4-(3,7-dioxaazabicyclo[3 .3 . 1 ]nonan—9-y1)(3-oxa azabicyclo [3 .3 . 1 ]nonan—9-y1)- 1 ,3 ,5 -triazinyl]pyridinamine; - [4,6-bis[(3 S ,5 S)—3 ,5 -dirnethy1rnorpho 1in—4-y1] - 1 ,3 ,5 -triazin—2-y1](diﬂuor0methyl)pyridin— 2-amine; 4-(diﬂuoromethyl)-5 - [4-(3 ,7-dioxaazabicyclo[3.3.1]nonan—9-y1)rn0rpholino-1,3 ,5 - triazin—2-y1]pyridinarnine; 4-(diﬂu0romethyl)-5 - [4- [(3 S)ethy1rnorph01in—4-y1]—6-[(3 R)rnethylrnorpho1in—4-y1]— 1 ,3 ,5 -triaziny1]pyridin—2-amine; _ 26 _ 4-(diﬂuoromethyl)-5 - [4- [(3 R)ethylmorpho linyl] [(3 R)methylmorpho linyl] - l ,3 ,5 -triazinyl]pyridinamine; 4-(diﬂuoromethyl)-5 - [4- [(3 R)methylmorpho linyl] oxa-5 -azaspiro [3 .5 ]nonan-5 -yl)- l ,3 ,5 -triazinyl]pyridinamine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; - [4,6-bis[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] (triﬂuoromethyl)pyridin amine; - [4,6-bis [(3 S)-3 -methylmorpho yl] - l ,3 ,5 inyl] (triﬂuoromethyl)pyrimidin amine; - [4- [(3 S)—3 -methylmorpho linyl]morpho lino - l ,3 ,5-triazinyl] (triﬂuoromethyl)pyridinamine; - [4- [(3 S)—3 -methylmorpho linyl]morpho lino - l ,3 ,5-triazinyl] (triﬂuoromethyl)pyrimidinamine; 5 -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; -(4-morpholinothiomorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; rpholinothiomorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; and tautomers, solvates and ceutically acceptable salts thereof.

In another preferred embodiment, said compound is selected from 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3 -oxaazabicyclo [3 .2. l]octanyl)- l ,3 ,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; -(4-(3-oxaazabicyclo [3 .2. l]octan—8-yl)morpho lino- l ,3 ,5 -triazinyl) (diﬂuoromethyl)pyridin—2-amine; -(4,6-bis((S)methylmorpho lino)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyrimidinamine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; uoromethyl)(4-morpholino(piperazin- l -yl)- l ,3 ,5 -triazinyl)pyrimidinamine; 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyridinamine; and (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazin yl)pyrimidin—2-amine; - [4,6-bis(3 ,7-dioxaazabicyclo [3 .3 . 1 yl)- 1 ,3 ,5 -triazinyl] _ 27 _ (diﬂuorornethyl)pyridin—2-amine; 4-(diﬂuorornethyl)-5 - [4-(3 ,7-dioxaazabicyclo [3 .3. 1]nonan—9-y1)(3 -oxa azabicyclo [3 .2. 1]0ctan—8-y1)-1 ,3 ,5 -triazinyl]pyridinamine; - [4,6-bis(3 ,3 -dirnethylrnorpho 1in—4-y1)- 1 ,3 ,5 -triazinyl] (diﬂuorornethyl)pyridin—2- amine; - [4,6-bis[(3R,5S)—3 ,5 -dirnethy1rnorpho 1in—4-y1] - 1 ,3 ,5 -triazin—2-y1](diﬂuor0methyl)pyridin— - [4,6-bis[(3R)-3 -rnethy1m0rpholin—4-y1]—1 ,3 ,5 -triazin—2-yl] (diﬂuorornethyl)pyridin—2- amine; 4-(diﬂu0romethyl)-5 - [4-(3 ,3-dimethy1rnorpho1iny1)rnorpholino-1 ,3 ,5 -triazin—2- yl]pyridinarnine; 4-(diﬂu0romethyl)-5 - [4- [(3R,5S)-3 ,5-dirnethy1morpho1in—4-y1]—6-[(3R)-3 -rnethy1rn0rpho 1in—4- y1]- 1 ,3 ,5 -triazin—2-y1]pyridin—2-amine; 4-(diﬂu0romethyl)-5 - [4-(3 ,3-dimethy1morpho 1iny1)[(3R)methylmorpholinyl] - 1 ,3 ,5 -triaziny1]pyridin—2-amine; 4-(diﬂu0romethyl)-5 - [4-[(3R)(methoxymethyl)morpho1iny1] [(3R) methylmorpho1iny1] - 1 ,3 ,5 -triaziny1]pyridinarnine; 4-(diﬂuorornethy1)[4-(3,7-dioxaazabicyclo[3 .3 . 1 ]nonan—9-y1)[(3R) methylrnorpho 1iny1] - 1 ,3 ,5 iny1]pyridinarnine; 4-(diﬂuorornethy1)[4-(3,7-dioxaazabicyclo[3 .3 . 1 ]nonan—9-y1)(3-oxa azabicyclo [3 .3 . 1 ]nonan—9-y1)- 1 ,3 ,5 -triazinyl]pyridinamine; - [4,6-bis[(3 S ,5 S)—3 ,5 -dirnethy1rnorpho 1in—4-y1] - 1 ,3 ,5 -triazin—2-y1](diﬂuor0methyl)pyridin— 2-amine; 4-(diﬂu0romethyl)-5 - [4-(3 xaazabicyclo[3.3.1]nonan—9-y1)rn0rpholino-1,3 ,5 - triazin—2-y1]pyridinarnine; 4-(diﬂu0romethyl)-5 - [4- [(3 S)ethy1rnorph01in—4-y1]—6-[(3 nethylrnorpho1in—4-y1]— 1 ,3 ,5 -triaziny1]pyridin—2-amine; 4-(diﬂu0romethyl)-5 - [4- [(3 R)-3 -ethylrn0rpho1iny1]—6-[(3 R)-3 y1rn0rpho 1iny1] - 1 ,3 ,5 iny1]pyridin—2-amine; 4-(diﬂu0romethyl)-5 - [4- [(3 R)-3 -rnethy1rn0rpho 1iny1] (8-oxa-5 ir0 [3 .5 ]nonan—5 -y1)- 1 ,3 ,5 -triaziny1]pyridin—2-amine; -(4,6-dirn0rpho lino- 1 ,3 ,5 -triazin—2-y1)(triﬂuorornethyl)pyridinarnine; dirn0rpho lino- 1 ,3 ,5 -triazin—2-y1)(triﬂuoromethyl)pyrirnidin—2-arnine; _ 28 _ - is[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] (triﬂuoromethyl)pyridin amine; - [4,6-bis[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] (triﬂuoromethyl)pyrimidin amine; - [4- [(3 S)—3 -methylmorpho linyl]morpho lino - l ,3 ,5-triazinyl] (triﬂuoromethyl)pyridinamine; - [4- [(3 S)—3 -methylmorpho linyl]morpho lino - l ,3 ,5-triazinyl] (triﬂuoromethyl)pyrimidinamine; -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; 5 -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; -(4-morpholinothiomorpholino- l ,3 ,5 inyl)(triﬂuoromethyl)pyridinamine; -(4-morpholinothiomorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another preferred embodiment, said compound is selected from 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 inyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3 -oxaazabicyclo [3 .2. nyl)- l ,3 ,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; -(4-(3-oxaazabicyclo [3 .2. l]octan—8-yl)morpho lino- l ,3 ,5 -triazinyl) (diﬂuoromethyl)pyridin—2-amine; 5 -(4,6-bis((S)methylmorpho lino)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyrimidinamine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; 4-(diﬂuoromethyl)(4-morpholino(piperazin— l -yl)- l ,3 ,5 -triazinyl)pyrimidinamine; 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyridinamine; and (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazin yl)pyrimidin—2-amine; - [4,6-bis(3 ,7-dioxaazabicyclo [3 .3 . 1 ]nonanyl)- 1 ,3 ,5 -triazinyl] (diﬂuoromethyl)pyridin—2-amine; 4-(diﬂuoromethyl)-5 - [4-(3 ,7-dioxaazabicyclo [3 .3 . l ]nonanyl)(3 -oxa azabicyclo [3 .2. n—8-yl)- l ,3 ,5 -triazinyl]pyridin—2-amine; - [4,6-bis(3 ,3 -dimethylmorpho linyl)- l ,3 ,5 -triazinyl] (diﬂuoromethyl)pyridin—2- am1ne; -[4,6-bis[(3R,5S)—3,5-dimethylmorpholinyl]- l ,3 ,5-triazinyl](diﬂuoromethyl)pyridin— _ 29 _ 2-amine; - [4,6-bis[(3R)methylmorpho linyl] - l ,3 ,5 -triazinyl] (diﬂuoromethyl)pyridin—2- amine; 4-(diﬂuoromethyl)-5 - [4-(3 ,3-dimethylmorpholinyl)morpho lino- l ,3 ,5 in yl]pyridinamine; 4-(diﬂuoromethyl)-5 - [4- [(3R,5S)-3 ,5-dimethylmorpho linyl] [(3R)methylmorpho lin yl] - l ,3 ,5 -triazinyl]pyridinamine; 4-(diﬂuoromethyl)-5 - [4-(3 ,3-dimethylmorpho linyl)[(3R)methylmorpholinyl] - l ,3 ,5 -triazinyl]pyridinamine; 4-(diﬂuoromethyl)-5 - [4-[(3R)(methoxymethyl)morpholinyl] [(3R) methylmorpholinyl] - l ,3 ,5 -triazinyl]pyridinamine; 4-(diﬂuoromethyl)[4-(3 ,7-dioxaazabicyclo[3 .3 . l ]nonanyl)[(3R) methylmorpholinyl] - l ,3 ,5 -triazinyl]pyridinamine; 4-(diﬂuoromethyl)[4-(3 ,7-dioxaazabicyclo[3 .3 . l yl)(3 -oxa azabicyclo [3 .3 . l ]nonanyl)- l ,3 ,5 inyl]pyridin—2-amine; - is[(3 S ,5 S)—3 ,5 -dimethylmorpho linyl] - l ,3 ,5 -triazinyl] (diﬂuoromethyl)pyridin— 2-amine; 4-(diﬂuoromethyl)-5 - [4-(3 ,7-dioxaazabicyclo [3 .3 - . l ]nonanyl)morpholino- l ,3 ,5 triazinyl]pyridinamine; 4-(diﬂuoromethyl)-5 - [4- [(3 S)ethylmorpho linyl] [(3R)methylmorpho linyl] - l ,3 ,5 -triazinyl]pyridinamine; 4-(diﬂuoromethyl)-5 - [4- [(3 R)ethylmorpho linyl] [(3 ethylmorpho linyl] - l ,3 ,5 -triazinyl]pyridinamine; uoromethyl)-5 - [4- [(3 R)methylmorpho linyl] (8-oxa-5 -azaspiro [3 .5 ]nonan-5 -yl)- l ,3 ,5 -triazinyl]pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another preferred ment, said compound is selected from 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3 -oxaazabicyclo [3 .2. nyl)- l ,3 ,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; -(4-(3-oxaazabicyclo [3 .2. l]octan—8-yl)morpho lino- l ,3 ,5 -triazinyl) (diﬂuoromethyl)pyridin—2-amine; bis((S)methylmorpho lino)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyrimidinamine; _ 30 _ (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; 4-(diﬂuoromethyl)(4-morpholino(piperazin— l -yl)- l ,3 ,5 -triazinyl)pyrimidinamine; 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyridinamine; and (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazin imidinamine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; - [4,6-bis[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] (triﬂuoromethyl)pyridin amine; - is[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] (triﬂuoromethyl)pyrimidin amine; - [4- [(3 S)—3 -methylmorpho linyl]morpho lino - l ,3 ,5-triazinyl] (triﬂuoromethyl)pyridinamine; 5 - [4- [(3 S)—3 -methylmorpho linyl]morpho lino - l ,3 azinyl] (triﬂuoromethyl)pyrimidinamine; -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; -(4-morpholinothiomorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; 5 -(4-morpholinothiomorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another preferred embodiment, said compound is selected from 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3 -azabicyclo [3 .2. l]octanyl)- l ,3 ,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; -oxaazabicyclo [3 .2. l]octan—8-yl)morpho lino- l ,3 ,5 -triazinyl) (diﬂuoromethyl)pyridin—2-amine; -(4,6-bis((S)methylmorpho lino)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyrimidinamine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; uoromethyl)(4-morpholino(piperazin— l -yl)- l ,3 ,5 -triazinyl)pyrimidinamine; 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyridinamine; and (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazin _ 31 _ yl)pyrimidinamine; and tautomers, solvates and ceutically acceptable salts f.

In another preferred embodiment, said compound is selected from uoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; 5 -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; - [4,6-bis[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] (triﬂuoromethyl)pyridin amine; - is[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] iﬂuoromethyl)pyrimidin amine; 5 - [4- [(3 S)—3 -methylmorpho linyl]morpho lino - l ,3 ,5-triazinyl] (triﬂuoromethyl)pyridinamine; - [4- [(3 S)—3 lmorpho linyl]morpho lino - l ,3 ,5-triazinyl] (triﬂuoromethyl)pyrimidinamine; -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; 5 -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; -(4-morpholinothiomorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; -(4-morpholinothiomorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine. and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another preferred embodiment, said compound is selected from 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; and tautomers, solvates and pharmaceutically acceptable salts f.

In another preferred embodiment, said compound is selected from -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; _ 32 _ - [4,6-bis[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] (triﬂuoromethyl)pyridin amine; - [4,6-bis[(3 S)-3 -methylmorpho linyl] - l ,3 ,5 -triazinyl] (triﬂuoromethyl)pyrimidin amine; - [4- [(3 S)—3 -methylmorpho linyl]morpho lino - l ,3 ,5-triazinyl] oromethyl)pyridinamine; - [4- [(3 S)—3 -methylmorpho linyl]morpho lino - l ,3 ,5-triazinyl] (triﬂuoromethyl)pyrimidinamine; -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; 5 -(4-morpholinopiperazin- l -yl- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine; -(4-morpholinothiomorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; rpholinothiomorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyrimidin—2-amine. and ers, solvates and pharmaceutically acceptable salts thereof.

In another very preferred embodiment, said nd is selected from 5-(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)—6-(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- nyl)(diﬂuoromethyl)pyridinamine; and (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin amine; and tautomers, solvates and pharmaceutically acceptable salts f.

In another very preferred embodiment, said compound is selected from 3-oxaazabicyclo[3 .2. l]octan—8-yl)—6-(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridinamine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin amine; and -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof In another very preferred embodiment, said compound of formula (I) is 4- (diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 inyl)pyrimidinamine.

In another very preferred embodiment, said compound of formula (I) is 4- (diﬂuoromethyl)(4,6-dimorpholino-l,3,5-triazinyl)pyrimidinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof In another very preferred embodiment, said compound of formula (I) is 5-(4-(3-oxa azabicyclo[3 .2. l]octan—8-yl)(3 -azabicyclo[3 .2. 1 ]octan—8-yl)- 1 ,3 ,5-triazinyl) (diﬂuoromethyl)pyridinamine. _ 33 _ In another very preferred embodiment, said compound of formula (I) is 5-(4-(3-oxa azabicyclo[3.2. l]octan—8-yl)(3-oxaazabicyclo[3.2.1]octan—8-yl)-1,3,5-triazinyl) (diﬂuoromethyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another very preferred embodiment, said compound of formula (I) is (S) (diﬂuoromethyl)-5 -(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin amine.

In another very preferred embodiment, said compound of formula (I) is (S) (diﬂuoromethyl)-5 -(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin amine; and tautomers, es and pharmaceutically acceptable salts thereof.

In another very preferred embodiment, said compound of formula (I) is 5-(4,6- dimorpholino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine.

In r very preferred embodiment, said nd of formula (I) is 5-(4,6- dimorpholino-l,3,5-triazinyl)(triﬂuoromethyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof.

In another preferred embodiment, said R1 and R2 are independently of each other a morpholinyl of formula (II). In one red embodiment, said R1 is equal to R2. In another preferred embodiment, said R1 is not equal to R2.

In another preferred embodiment, said W is H, and said R1 and R2 are independently of each other a morpholinyl of formula (II). In one preferred embodiment, said R1 is equal to R2.

In another preferred embodiment, said R1 is not equal to R2.

In r preferred embodiment, said W is F, said R1 and R2 are independently of each other a morpholinyl of a (II). In one preferred ment, said R1 is equal to R2. In another preferred embodiment, said R1 is not equal to R2.

In r preferred embodiment, said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z.

In another preferred ment, said W is H, and said R1 and R2 are independently of each other a morpholinyl of formula (II) and said ted ered heterocyclic ring Z.

In another preferred embodiment, said W is F, and said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z.

In another preferred embodiment, Within said morpholinyl of formula (II) _ 34 _ l (11) R3 and R4 are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2ﬂuoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C1-C2alkyl; or R3 and R4 form together a nt residue —R5R6— selected from C1-C3alkylene optionally substituted with l to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any ofthe structures / \ f \ ; wherein the arrows denote the bonds in formula (II).

In the instance that R3 and R4 together form a bivalent residue and are bound to Vicinal carbon atoms annulated linyl tuents are formed. In the instance that R3 and R4 together form a bivalent e and are spanning across the morpholine ring bridged linyl substituents are formed. In the instance that R3 and R4 together form a nt residue and are bound to the same carbon atom of the morpholine, spiro morpholinyl substituents are formed.

In a preferred embodiment, R3 and R4 form together a bivalent residue —R5R6— selected from C1-C3alkylene optionally substituted with l to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures A O A. and g a bridged morpholinyl substituent.

In another preferred embodiment, said R1 and R2 are independently of each other a morpholinyl of formula (II), wherein R3 and R4 form together a bivalent residue leading to a bridged morpholinyl, n R3 and R4 form together a bivalent residue —R5R6— selected from C1-C3alkylene, preferably C1-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2- O-CH2-, -CH2-NH-CH2-, or any ofthe structures / \ f \ ; wherein the arrows denote the bonds in formula (II).

In a ﬁarther preferred embodiment, said morpholinyl of formula (II) _ 35 _ l (11) is independently of each other a morpholinyl of said formula (II), wherein R3 and R4 are independently of each other H, C1-C3alkyl, CHZOH, CHZCHZOH, CHZF, CHFZ, CF3, CH2CF3, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue —R5R6— selected from lkylene, preferably C1-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any ofthe ures / \ f \ ; n the arrows denote the bonds in formula (II).

In a further preferred embodiment, said morpholinyl of formula (II) is independently of each other a linyl of said formula (II), wherein R3 and R4 are independently of each other H or CH3.

In a further preferred embodiment, said morpholinyl of formula (II) is ndently of each other a morpholinyl of said formula (II), wherein R3 and R4 are independently of each other C2-C3alkyl, CHZOH, CHZCHZOH, CHZF, CHFZ, CF3, CH2CF3, C1-C2alkoxy, C1- CzalkoxyCl-Cgalkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue —R5R6— selected from —CH2— or Cgalkylene, preferably —CH2—, -CH2CF2-, F-, - CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any ofthe ures / \ f \ ; wherein the arrows denote the bonds in formula (II).

In a further preferred embodiment, said morpholinyl of formula (II) is independently of each [i] [i1 [ii [3k 13L I?l + err ESL [ij if" TjrTEL + + + + + + [EM [EU [31’ [:1 [:10 8 + + ‘ $ $ 31> [311:0 [SEEM4: l + ESE ESE ESE ESE 3e;W + + + + l 3¢3¢3¢ 34¢ 34¢ 34¢CIZIFI: Wu, [4:]; £1303 [ik5““ N ljvqyjcy In a further preefeerred embod1rnen,t said morpholinyl of a (II) is independently of each other selected from [:3 ﬁt, r1 £3; [E ESE + + S S l l _ 37 _ ISL ,5..er \E? + 1'r In a further preferred embodiment, said cyclic ring Z is a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and piperazinyl, optionally tuted by l to 3 R7; wherein R7 is independently at each ence C1-C3alkyl, CHZOH, CHZCHZOH, CHZF, CHFZ, CF3, CHZCFg, C1-C2alkoxyC1-C3alkyl, C3-C6cycloalkyl; or two R7 substituents form together a bivalent residue —R8R9— selected from C1-C3alkylene optionally substituted with 1 to 4 F, -CH2- or -O-CH2CH2-O-; In a ﬁarther preferred embodiment, said heterocyclic ring Z is ed from 'a_r ~._x %._x n_x I * Ui‘s I‘ll—1» S Pal—:- I,» i , "-._-" G In another preferred embodiment of the present invention, said R1 and said R2 are independently of each other a morpholinyl of formula (II) l (11) wherein the arrow denotes the bond in a (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2ﬂuoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)O- C1-C2alkyl; or R3 and R4 form together a bivalent residue —R5R6— selected from C1- C3alkylene optionally substituted with l to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures _ 38 _ wherein the arrows denote the bonds in formula (II).

In a further preferred embodiment, said R1 is equal to said R2, and said R1 and said R2 are independently of each other a morpholinyl of formula (II) R3ﬁ 1R4 l (11) wherein the arrow denotes the bond in formula (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally tuted with one or two OH, C1-C2ﬂuoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)O- C1-C2alkyl; or R3 and R4 form er a bivalent residue —R5R6— selected from C1- C3alkylene optionally substituted with l to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures n the arrows denote the bonds in formula (II).

In a further preferred embodiment of the present invention, said R1 and said R2 are independently of each other a morpholinyl of formula (II) R3— —R4 l (11) wherein the arrow s the bond in formula (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl, CHZOH, CHZCHZOH, CHZF, CHFZ, CF3, CH2CF3, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue —R5R6— selected from lkylene, preferably C1-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any ofthe structures A A0 . n the arrows denote the bonds in a (II).

In a further preferred embodiment of the present invention, R1 is equal to R2, and said _ 39 _ R1 and said R2 are a morpholinyl of formula (II) R3— —R4 l (11) wherein the arrow denotes the bond in a (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl, CHZOH, CHZCHZOH, CHZF, CHFZ, CF3, CH2CF3, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form together a nt residue —R5R6— selected from C1-C3alkylene, preferably C1-C2alkylene, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any ofthe structures A O A. wherein the arrows denote the bonds in formula (II).

In another aspect and preferred embodiment, the present invention es for a compound of (I) for use in the tion or treatment of a skin lesion in a subject, #3ng F“ xF % A 8"" “x3” was? {L ”ﬁlm; N” NH2 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; and wherein R1 and R2 are independently of each other a morpholinyl of formula (II) E 7R4 l (11) n the arrow denotes the bond in formula (I); and R1 is not equal to R2, and at least one of said R1 and said R2 are a morpholinyl of formula (II), _ 40 _ l (11) wherein R3 and R4 are independently of each other C2-C3alkyl, CHZOH, CHZCHZOH, CHZF, CHFZ, c123, CHZCFg, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)O-C1-C2alkyl; or R3 and R4 form together a bivalent residue —R5R6— selected from —CH2— or C3all<ylene, preferably —CH2—, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2-O-CH2-, -CH2-NH-CH2-, or any of the structures / \ f \ ; wherein the arrows denote the bonds in formula (11). ably, said R3 and R4 form together a bivalent residue —R5R6— selected from — CH2— or C3all<ylene, preferably —CH2—, -CH2CF2-, -CHFCHF-, -CH2CF2CH2-, -CH2- O-CH2-, -CH2-NH-CH2-, or any ofthe structures A O A In another preferred embodiment, R1 is 4-morpholinyl, 2-methylmorpholinyl, 3- methylmorpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl or 3- oxabicyclo[3.2.l]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl- 4-morpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl, 3-aza oxabicyclo[3.2.l]octyl, 4-piperazin-l-yl, 4-methylpiperazin-l-yl, or morpholinyl.

In another preferred embodiment, R1 is 4-morpholinyl, 2-methylmorpholinyl, 3- methylmorpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl or 3- azaoxabicyclo[3.2.l]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl- 4-morpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl, 3-aza oxabicyclo[3.2.l]octyl, razin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl, and X1, X2 and X3 are N; and ers, solvates and pharmaceutically acceptable salts thereof. Preferably Y is N or CH; R1 is holinyl, 2-methylmorpholinyl, 3-methyl morpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl or 8- oxabicyclo[3.2.l]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl morpholinyl, uteriomorpholinyl, 3-oxabicyclo[3.2.l]octyl, 3-aza oxabicyclo[3.2.l]octyl, 4-piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl; _ 41 _ and tautomers, solvates and pharmaceutically acceptable salts thereof In a further preferred embodiment, R1 is holinyl, ylmorpholinyl, 3- methylmorpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl or 3- oxabicyclo[3.2.l]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl- 4-morpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl, 3-aza oxabicyclo[3.2.l]octyl, 4-piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl, and X1 and X3 are N, and X2 is CH; and tautomers, solvates and pharmaceutically acceptable salts thereof. Preferably Y is N or CH; R1 is 4-morpholinyl, 2-methylmorpholinyl, 3- methylmorpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl or 3- azaoxabicyclo[3.2.l]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl- holinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl, 3-aza oxabicyclo[3.2.l]octyl, 4-piperazin-l-y, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof In a preferred embodiment, R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl morpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl or 3-aza oxabicyclo[3.2.l]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, yl morpholinyl, uteriomorpholinyl, 3-oxabicyclo[3.2.l]octyl, 3-aza oxabicyclo[3.2.l]octyl, 4-piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl, and X1 and X2 are N, and X3 is CH; and tautomers, solvates and pharmaceutically acceptable salts thereof Preferably, Y is N or CH; R1 is 4-morpholinyl, 2-methylmorpholinyl, 3- methylmorpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl or 3- azaoxabicyclo[3.2.l]octyl; and R2 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl- 4-morpholinyl, uteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl, 3-aza oxabicyclo[3.2.l]octyl, 4-piperazin-l-yl, 4-methylpiperazin-l-yl, or morpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof In a preferred embodiment, R1 is 4-morpholinyl, 2-methylmorpholinyl, 3-methyl morpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl or 3-aza yclo[3.2.l]octyl; and R2 is holinyl, 2-methylmorpholinyl, 3-methyl morpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl, 8- oxabicyclo[3.2.l]octyl, 4-piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl, and X2 and X3 are N, and X1 is CH; and tautomers, solvates and pharmaceutically acceptable salts thereof Preferably, Y is N or CH; R1 is 4-morpholinyl, 2-methylmorpholinyl, 3- methylmorpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl or 3- _ 42 _ azaoxabicyclo[3.2.l]octyl; and R2 is 4-morpholinyl, ylmorpholinyl, 3-methyl- 4-morpholinyl, octadeuteriomorpholinyl, 8-azaoxabicyclo[3.2.l]octyl, 3-aza oxabicyclo[3.2.l]octyl, 4-piperazin-l-yl, 4-methylpiperazin-l-yl, or 4-thiomorpholinyl; and tautomers, solvates and pharmaceutically acceptable salts thereof 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 skin lesion is non-melanoma skin cancer (NMSC), a cutaneous lymphoma or a pre-invasive form thereof.

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

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

In another preferred embodiment of the present invention, said skin lesion is a cutaneous lymphoma.

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

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

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 cutaneous us cell carcinoma (cSCC) in a subject, wherein said cutaneous squamous cell carcinoma (cSCC) is an invasive cSCC.

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

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

In a ﬁarther embodiment, there is provided a compound of formula (I) according to the ion for use in the tion or treatment of a basal cell carcinoma in a t, wherein _ 43 _ said 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”), inﬁltrative basal cell carcinoma and nodular basal cell carcinoma.

In a preferred ment, there is provided a compound of a (I) according to the invention for use in the prevention or treatment of a basal cell oma in a subject, wherein said basal cell carcinoma is a superﬁcial basal cell carcinoma (also known as “in situ basal cell carcinoma” or “superﬁcial multicentric basal-cell oma”).

In a further preferred embodiment, there is provided a compound of formula (I) according to the ion for use in the prevention or treatment of a basal cell carcinoma in a subject, wherein said basal cell carcinoma is an inﬁltrative basal cell carcinoma.

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 basal cell carcinoma in a subject, wherein said basal cell carcinoma is a nodular basal cell carcinoma.

In one embodiment, there is provided a compound of formula (1) according to the invention for use in the tion or treatment of a basal cell carcinoma in a subject, wherein said basal cell carcinoma is selected from the group consisting of cystic basal cell oma, cicatricial basal cell carcinoma (also known as “morpheaform basal cell carcinoma” or “morphoeic basal cell carcinoma”), micronodular basal cell carcinoma, pigmented basal cell carcinoma, rodent ulcer (also known as “Jacob’s ulcer”), ﬁbroepithelioma of Pinkus, polypoid basal cell carcinoma, pore-like basal cell carcinoma and aberrant basal cell carcinoma.

In a further embodiment, there is provided a compound of formula (I) according to the invention for use in the tion 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 cutaneous squamous cell carcinoma in situ (cSCCis, also known as “Bowen’s disease”), precancerous actinic keratosis (AK) and chronic UV damage.

In a red ment, there is provided a compound of formula (I) according to the invention for use in the tion or treatment of a vasive form of lanoma skin cancer (NMSC), wherein said pre-invasive form is cutaneous squamous cell carcinoma in situ (cSCCis, also known as “Bowen’s disease”).

In a ﬁlrther preferred embodiment, there is provided a compound of a (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). _ 44 _ In a ﬁarther preferred ment, 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 UV damage.

In one embodiment, there is provided a compound of formula (1) according to the invention for use in the prevention or treatment of precancerous actinic keratosis (AK) in a subject, wherein said AK is a ﬁeld cancerization.

In a preferred embodiment, there is provided a compound of a (I) according to the ion for use in the prevention or ent of a cutaneous lymphoma in a subject, wherein said cutaneous lymphoma is a cutaneous T-cell lymphoma (CTCL) or a cutaneous B- cell ma (CBCL).

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

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

In one embodiment, there is provided a compound of formula (1) according to the invention for use in the prevention or treatment of a skin lesion in a subject, n said compound of formula (I) is administered topically to the subject.

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

In a ﬁarther embodiment, there is provided a compound of formula (I) according to the ion for use in the prevention or ent of a lanoma skin cancer (NMSC) or a pre-invasive form f in a t, wherein said non-melanoma skin cancer is cutaneous squamous cell carcinoma (cSCC) or a basal cell carcinoma and wherein said compound of formula (I) is administered topically to the subject.

In a r preferred embodiment, there is provided a compound of formula (I) according to the invention for use in the prevention or treatment of a lanoma skin cancer (NMSC) or a pre-invasive form thereof in a subject, wherein said pre-invasive form is precancerous actinic keratosis (AK) and wherein said compound of formula (I) is _ 45 _ administered topically to the subject.

In one embodiment, there is provided a compound of formula (I) according to the ion 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.

In a ﬁarther 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 t, wherein said skin lesion is a lanoma skin cancer (NMSC) or a vasive form thereof and wherein said compound of formula (I) is administered systemically, preferably orally to the subject.

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

In a ﬁarther preferred ment, there is provided a compound of formula (I) according to the invention for use in the tion or treatment of a lanoma skin cancer (NMSC) or a pre-invasive form thereof in a subject, wherein said pre-invasive form is cerous 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 a (I) according to the invention, wherein said compound is selected from: 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)—6-(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridinamine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 inyl)pyridin amine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or ent of a skin lesion in a subject, wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

In a preferred embodiment, there is provided a compound of formula (I) ing to the invention, wherein said compound is selected from: uoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)—6-(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- _ 46 _ nyl)(diﬂuoromethyl)pyridin—2-amine; (diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; and ers, solvates and pharmaceutically able 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.

In a further preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein said nd is 5-(4,6-dimorpholino-l,3,5-triazinyl)- 4-(triﬂuoromethyl)pyridin—2-amine; and ers, 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.

In a further preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein said compound is selected from: 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; 3-oxaazabicyclo[3 .2. l]octan—8-yl)—6-(3-oxaazabicyclo[3 .2. nyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC in a subject.

In a further red embodiment, there is provided a compound of formula (I) according to the invention, wherein said compound is selected from: 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; 3-oxaazabicyclo[3 .2. l]octan—8-yl)—6-(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC in a subject.

In a r preferred embodiment, there is provided a nd of formula (I) according to the invention, wherein said compound is 5-(4,6-dimorpholino-l,3,5-triazinyl)- 4-(triﬂuoromethyl)pyridin—2-amine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC in a subject.

In a preferred embodiment, there is provided a compound of formula (I) according to _ 47 _ the invention, wherein said compound is ed from: 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject.

In a preferred embodiment, there is provided a nd of formula (I) according to the ion, wherein said compound is selected from: 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; (diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; and ers, solvates and pharmaceutically acceptable salts thereof, for use in the tion or treatment of cSCCis in a subject.

In a further preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein said compound is 5-(4,6-dimorpholino-l,3,5-triazinyl)- 4-(triﬂuoromethyl)pyridin—2-amine; and tautomers, solvates and ceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject.

In a preferred embodiment, there is provided a nd of formula (I) according to the invention, wherein said compound is selected from: 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; 5-(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment ofAK in a subject.

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein said nd is selected from: _ 48 _ 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)—6-(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridin—2-amine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin—2- amine; and tautomers, solvates and pharmaceutically acceptable salts f, for use in the prevention or treatment ofAK in a subj ect.

In a further preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein said compound is -dimorpholino-l,3,5-triazinyl)- 4-(triﬂuoromethyl)pyridin—2-amine; and tautomers, solvates and ceutically acceptable salts thereof, for use in the prevention or treatment ofAK in a subj ect.

In a preferred embodiment, there is ed a compound of formula (I) according to the invention, wherein said compound is selected from 5-(4-(3-oxaazabicyclo[3.2.l]octan— 8-yl)(3 -oxaazabicyclo [3 .2. l ]octan—8-yl)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyridin amine; and (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpholino-l,3,5-triazin yl)pyridinamine; and tautomers, es 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, , BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein said compound is selected from 5-(4-(3-oxaazabicyclo[3.2.l]octan— 8-yl)(3 -oxaazabicyclo [3 .2. l —8-yl)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyridin amine; and (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpholino-l,3,5-triazin yl)pyridinamine; and tautomers, solvates and ceutically able salts thereof, for use in the prevention or treatment of cSCC in a subject.

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein said compound is selected from 5-(4-(3-oxaazabicyclo[3.2.l]octan— 8-yl)(3 -oxaazabicyclo [3 .2. l ]octan—8-yl)- l ,3 ,5 inyl)(diﬂuoromethyl)pyridin amine; and (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpholino-l,3,5-triazin yl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject.

In a preferred embodiment, there is provided a compound of formula (I) according to the ion, wherein said compound is ed from 5-(4-(3-oxaazabicyclo[3.2.l]octan— 8-yl)(3 -oxaazabicyclo [3 .2. l ]octan—8-yl)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyridin amine; and (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpholino-l,3,5-triazin _ 49 _ yl)pyridinamine; and tautomers, solvates and ceutically acceptable salts thereof, for use in the prevention or ent ofAK in a subject.

In a preferred embodiment, there is provided the compound 3-oxa azabicyclo[3 .2. l]octan—8-yl)(3 -oxaazabicyclo[3 .2. l —8-yl)- l ,3 ,5-triazinyl) (diﬂuoromethyl)pyridinamine; 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.

In a particularly preferred ment, there is provided the compound 5-(4-(3-oxa azabicyclo[3 .2. l]octan—8-yl)(3 -oxaazabicyclo[3 .2. l —8-yl)- l ,3 ,5-triazinyl) (diﬂuoromethyl)pyridinamine; and tautomers, es and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC in a subject.

In a further particularly preferred embodiment, there is provided the compound 5-(4-(3- oxaazabicyclo[3 .2. l]octan—8-yl)(3 -oxaazabicyclo[3 .2. l ]octan—8-yl)- l ,3 ,5-triazin yl)(diﬂuoromethyl)pyridin—2-amine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject.

In a r particularly preferred embodiment, there is provided the compound 5-(4-(3- oxaazabicyclo[3 .2. l]octan—8-yl)(3 -oxaazabicyclo[3 .2. l —8-yl)- l ,3 ,5-triazin yl)(diﬂuoromethyl)pyridin—2-amine; and tautomers, solvates and pharmaceutically able salts thereof, for use in the prevention or treatment ofAK in a subject.

In a preferred embodiment, there is provided the compound (S)(diﬂuoromethyl) (4-(3-methylmorpholino)morpholino-l,3,5-triazinyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or ent of a skin lesion in a subject, wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, ably cSCC, cSCCis or AK.

In a particularly preferred embodiment, there is ed the compound (S) (diﬂuoromethyl)-5 -(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin amine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC in a subject.

In a further particularly preferred embodiment, there is provided the compound (S) (diﬂuoromethyl)-5 -(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin amine; and tautomers, solvates and pharmaceutically able salts thereof, for use in the prevention or treatment of cSCCis in a t.

In a further particularly preferred embodiment, there is provided the compound (S) _ 50 _ (diﬂuoromethyl)-5 -(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin amine; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment ofAK in a subject.

In a red ment, there is provided a compound of formula (I) according to the invention, wherein R1 and R2 are ndently of each other a morpholinyl of formula (II); and tautomers, solvates and pharmaceutically able salts thereof, for use in the prevention or treatment of a skin lesion in a subject, wherein the skin lesion is cSCC, , BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and tautomers, solvates and ceutically 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.

In a preferred embodiment, there is provided a compound of a (I) according to the invention, wherein W is H, and wherein R1 and R2 are independently of each other a linyl of formula (II); 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.

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein W is H, and wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject, n the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

In a preferred embodiment, there is ed a compound of a (I) according to the invention, wherein W is F, and wherein R1 and R2 are independently of each other a morpholinyl of a (II); and ers, 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, , BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein W is F, and wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and _ 51 _ tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a t, wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

In a preferred ment, there is provided a compound of a (I) according to the invention, wherein R1 and R2 are independently of each other a morpholinyl of formula (II); and tautomers, solvates and pharmaceutically acceptable salts f, for use in the prevention or treatment of cSCC in a subject.

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

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

In a preferred embodiment, there is provided a compound of a (I) according to the ion, wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and tautomers, es and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC in a subject.

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

In a preferred embodiment, there is provided a compound of a (I) according to the invention, wherein W is H, and wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and tautomers, solvates and pharmaceutically able salts thereof, for use in the prevention or treatment of cSCC in a subject.

In a preferred embodiment, there is ed a compound of formula (I) ing to the invention, wherein W is F, and wherein R1 and R2 are independently of each other a morpholinyl of formula (II); and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC in a subject. _ 52 _ In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein W is F, and wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and ers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC in a subject.

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and tautomers, solvates and pharmaceutically able salts thereof, for use in the prevention or ent of cSCCis in a subject.

In a preferred embodiment, there is ed a nd of a (I) according to the ion, wherein W is H, and n R1 and R2 are independently of each other a morpholinyl of formula (II); and tautomers, solvates and pharmaceutically able salts thereof, for use in the prevention or treatment of cSCCis in a subject.

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein W is H, and wherein said R1 and R2 are independently of each other a linyl of a (II) and said saturated 6-membered heterocyclic ring Z; and ers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or ent of cSCCis in a t.

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

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein W is F, and wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject.

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC or cSCCis in a subject. _ 53 _ In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein W is H, and wherein R1 and R2 are independently of each other a morpholinyl of formula (II); and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or ent of cSCC or cSCCis in a subject.

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein W is H, and wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC or cSCCis in a subject.

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

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein W is F, and wherein said R1 and R2 are independently of each other a morpholinyl of formula (II) and said saturated 6-membered heterocyclic ring Z; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the tion or treatment of cSCC or cSCCis in a subject.

In a preferred ment, there is provided a compound of formula (I) according to the invention, wherein R1 is equal to R2; 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, ably cSCC, cSCCis or AK.

In a preferred embodiment, there is provided a compound of formula (I) ing to the ion, wherein R1 is equal to R2; and ers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of cSCC in a subject.

In a preferred embodiment, there is provided a compound of formula (I) ing to the invention, wherein R1 is equal to R2; and tautomers, solvates and ceutically acceptable salts thereof, for use in the prevention or treatment of cSCCis in a subject.

In a preferred embodiment, there is provided a nd of a (I) according to the invention, wherein R1 is equal to R2; and tautomers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment ofAK in a subject.

In a preferred embodiment, there is provided a compound of formula (I) according to _ 54 _ the invention, wherein R1 is not equal to R2; and tautomers, solvates and pharmaceutically able salts f, for use in the prevention or treatment of a skin lesion in a t, wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, ably cSCC, cSCCis or AK.

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

In a preferred embodiment, there is provided a compound of formula (I) according to the invention, wherein R1 is not equal to R2; and tautomers, solvates and ceutically able salts thereof, for use in the prevention or treatment of cSCCis in a subject.

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

In a r aspect of the invention, there is provided a method for treating or preventing a skin lesion in a subject, comprising administering an effective amount of a compound of formula (1) according to the invention to said subject.

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

In a ularly preferred embodiment, there is ed a method for treating or preventing a skin lesion in a subject, comprising administering an effective amount of a nd of formula (1) according to the invention to said subject, wherein said compound is selected from: 4-(difluoromethyl)(4,6-dimorpholino-l,3,5-triazinyl)pyrimidinamine; -(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)—6-(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridinamine; (S)(diﬂuoromethyl)(4-(3- morpholino)morpholino-l,3,5-triazinyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof; and wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

In yet a further aspect of the invention, there is provided the use of a compound of formula (I) according to the invention for treating or preventing a skin lesion in a subject. _ 55 _ In one embodiment, there is provided the use of a nd of formula (I) according to the invention for treating or preventing a skin lesion in a subject, wherein said skin lesion is ed from the group consisting of a cutaneous lymphoma, a cutaneous squamous cell carcinoma (cSCC), a basal cell carcinoma, a cutaneous squamous cell carcinoma in situ (cSCCis, Bowen’s disease) and cerous actinic keratosis (AK).

In a particularly preferred embodiment, there is provided the use of a compound of formula (I) ing to the invention for treating or preventing a skin lesion in a t, wherein said compound is selected from: 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; 5-(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)—6-(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridinamine; (diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin amine; -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; and tautomers, solvates and pharmaceutically acceptable salts thereof; and wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

In yet a further aspect of the invention, there is provided the use of a compound of formula (I) according to the ion for the manufacture of a medicament for treating or preventing a skin lesion in a subject.

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

In a particularly preferred embodiment, there is provided the use of a compound of formula (I) according to the invention for the manufacture of a medicament for ng or ting a skin lesion in a subject, wherein said compound is selected from: 4-(diﬂuoromethyl)(4,6-dimorpho lino- l ,3 ,5 -triazinyl)pyrimidinamine; 5-(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)—6-(3-oxaazabicyclo[3 .2. l]octanyl)- l ,3,5- triazinyl)(diﬂuoromethyl)pyridinamine; (S)(diﬂuoromethyl)(4-(3-methylmorpholino)morpho lino- l ,3 ,5 -triazinyl)pyridin amine; _ 56 _ -(4,6-dimorpho lino- l ,3 ,5 -triazinyl)(triﬂuoromethyl)pyridinamine; and tautomers, solvates and ceutically acceptable salts thereof; and wherein the skin lesion is cSCC, cSCCis, BCC, CTCL, CBCL or AK, preferably cSCC, cSCCis or AK.

Most preferred for the present invention are the following compounds shown by formula: (The names of the corresponding structures were produced using ChemDraw Ultra, version 13.0.1 as well as lower and upper software versions thereof, dgeSoft Corp., Cambridge MA).

Compound 1: 4-(diﬂuoromethyl)(4,6-dimorpholino- l ,3 azinyl)pyridinamine Compound 1*: -(4,6-dimorpholino- l ,3 ,5-triazinyl)(triﬂuoromethyl)pyridinamine Compound 2: 4-(diﬂuoromethyl)(4,6-dimorpholino- l ,3 ,5-triazinyl)pyrimidinamine Compound 2*: _ 57 _ -(4 lino - 1 3 5 -triazin—2-y1)(triﬂuoromethyl)pyrimidin—2-amine , 6-dimorpho , , Compound 3: jig“ F N NH2 -(4-(3-oxaazabicyclo[3.2.1]octan—8-y1)(3-oxaazabicyclo[3.2.1]octan—8-y1)-1,3,5- n—Z-yl)(diﬂuoromethyl)pyridinamine Compound 4: NgFFN r~*~%1 N NH2 -(4-(3-oxaazabicyclo[3.2. 1]octan—8-y1)morpholino-1 ,3 ,5-triazin—2-yl) (diﬂuoromethyl)pyridin—2-amine Compound 5: NgNF F N N \N 0d i N/J\NH2 -(4-(3-oxaazabicyclo[3.2. 1]octan—8-y1)morpholino-1 ,3 ,5-triazin—2-yl) _ 58 _ (diﬂuoromethyl)pyrimidin—2-amine Compound 6: -(4,6-bis((S)methy1morph01ino)-1 ,3,5-triazin—2-y1)(diﬂu0r0methyl)pyridinamine Compound 6*: i F -[4,6-bis[(3S)methy1morpho1iny1]—1 ,3,5-triazin—2-yl](triﬂuoromethy1)pyridin amine Compound 7: -(4,6-bis((S)methy1morpho 1in0)- 1 ,3 ,5 -triazin—2-y1)(diﬂuoromethyl)pyrimidinamine nd 7*: (N1.,,, ji/KNF F N N |\N 0Q NANHg -[4,6-bis[(3S)methy1morpho1iny1]—1 ,3,5-triazin—2-yl](triﬂuoromethyl)pyrimidin amine _ 59 _ Compound 8: (S)(diﬂuoromethyl)(4-(3-methy1morpho1in0)m0rph01ino-1 ,3,5-triazin—2-y1)pyridin—2- amine Compound 8*: ,-/‘O‘\, PERT £ijF i/Nhll/ "*«N’f'i \U/v’ Q13} Oxx’ N5” NHE -[4-[(3S)—3-methy1morph01iny1]—6-m0rpholino-1,3,5-triazinyl]—4- (triﬂuoromethyl)pyridinamine Compound 9: N "‘1, NgN F F N N \ N 0Q i NANHZ (S)(diﬂu0romethy1)-5 -(4-(3-methy1m0rpho1ino)morpholino- 1 ,3 ,5 in—2- yl)pyrimidin—2-amine Compound 9*: ,i, F If; vii FxJ/F l/ ,/‘\N:2’f \E‘wch Chm \. <77L_ - [4- [(3 S)—3 -methy1morpho 1iny1]morpho lino -1,3 ,S-triazin-Z-yl] _ 60 _ (triﬂuoromethy1)pyrimidinamine Compound 10: )L / (N N E\ O N/ NH2 -(4-(3-oxaazabicyclo[3.2.1]octanyl)((S)methy1morph01ino)-1,3,5-triazin—2-yl) (diﬂuoromethyl)pyridin—2-amine Compound 11: F F N \N O “Q”i NANH -(4-(3-oxaazabicyclo[3.2.1]octanyl)((S)methy1morph01ino)-1,3,5-triazin—2-yl) (diﬂuoromethyl)pyrimidin—2-amine Compound 12: 4-(diﬂu0romethyl)(4-m0rph01in0(piperazin— 1 -y1)- 1 ,3 ,5 -triaziny1)pyridinamine Compound 12*: -(4-morpholinopiperazin— 1 -y1— 1 ,3 ,5 -triazin—2-y1)(triﬂuoromethyl)pyridinamine _ 61 _ Compound 13: JNLJMJ F F N N \N 0d i N/)\NH2 4-(diﬂuoromethyl)(4-m0rph01in0(piperazin— 1-y1)-1 ,3 ,5 -triazinyl)pyrimidinamine Compound 13*: -(4-morpholinopiperazin— 1 -y1— 1 ,3 ,5 -triazin—2-y1)(triﬂuoromethyl)pyrimidin—2-amine nd 14: (S)(diﬂu0romethy1)-5 -(4-(3-methy1m0rph01in0)(piperaziny1)- 1 ,3 ,5 -triazin—2- yl)pyridinamine Compound 15: _ NKKNF N/kN/ \N _ 62 _ (S)(diﬂu0romethy1)-5 -(4-(3-methy1morph01in0)(piperaziny1)- 1 ,3 ,5 -triazin—2- yl)pyrimidin—2-amine Compound 16: 4-(diﬂu0romethyl)-5 -(2 ,6-dimorpholinopyrimidiny1)pyridin—2-amine Compound 17: 4'-(diﬂuoromethyl)-2,6-dim0rpholino-[4,5'-bipyrimidin]—2'-amine Compound 18: 0Q L N NH2 4-(diﬂu0romethyl)-5 -(4 orpholinopyrimidiny1)pyridin—2-amine Compound 19: bk] F F N EN/ \N 0d 1 NANHZ 4'-(diﬂuoromethyl)-4,6-dim0rpholino-[2,5'-bipyrimidin]—2'-amine Compound 20: _ 63 _ a; FM: / F r , “‘t “,1 s:‘‘‘‘‘‘‘‘‘‘‘‘, r 4-(diﬂu0r0methyl)(4-m0rph01in0thi0morpholino- 1 ,3,5-triazin—2-y1)pyridinamine Compound 20*: i, F N}, N A A, l? r r N S“ “r i ’ ” , " é “NHQ NNNN N -(4-m0rpholin0thi0m0rpholino- 1 ,3 ,5 -triazin—2-y1)(triﬂuoromethy1)pyridinamine Compound 21 : N, “KN? K 3-» 3'an ; U K i x 4"\ N NH; 4-(diﬂuoromethyl)(4-m0rph01in0thiomorpholino- 1 ,3 ,5 -triazin—2-y1)pyrimidin—2-amine Further preferred are the following compounds nd 21*: -(4-m0rph01in0thi0m0rph01ino-1,3 ,5-triazin—2-y1)(triﬂuoromethyl)pyrimidin—2-amine Compound 22: _ 64 _ 3-oxaazabicyclo[3 .2. 1]octan—8-yl)(3 -oxaazabicyclo [3 .2. 1]octan—8-yl)pyrimidin- 4-y1)(diﬂuor0methyl)pyridinamine Compound 23: -(2-(3-oxaazabicyclo[3.2.1]octany1)morpholinopyrimidiny1) (diﬂuoromethyl)pyridin—2-amine Compound 24: N”“‘*N Fax/F ”AN r»"ﬁ*\y”1\ jcx if N U ”N on A ﬁ-i 2-(3-oxaazabicyclo[3.2. 1]octanyl)-4’-(diﬂu0r0methy1)m0rph0lino-[4,5 rimidin]— 2’-amine Compound 25: 1:1,” ‘ >:z N NH2 -(2,6-bis((S)methy1morpho1in0)pyrimidiny1)(diﬂu0romethy1)pyridin—2-amine Compound 26: 4'-(diﬂuoromethyl)-2,6-bis((S)methy1morpholino)—[4,5'-bipyrimidin]-2'-amine Compound 27: _ 65 _ (S)(diﬂu0r0methyl)(6-(3-methy1morph01ino)morpholinopyrimidiny1)pyridin amine Compound 28: F F N N [\N NANHZ (S)-4'-(diﬂu0romethyl)(3-methy1m0rpholino)m0rph01ino-[4,5'-bipyrimidin]—2'-amine Compound 29: -(4-(8-Oxaazabicyclo[3.2.1]octan—3-y1)(8-oxaazabicyclo[3.2.1]0ctan—3-y1)-1,3,5- triazin—Z-yl)(diﬂuor0methyl)pyridinamine Compound 30: _ 66 _ -[4,6-bis(2,2-dimethylmorpho1iny1)-1 ,3 ,5 -triaziny1] ﬂuoromethy1)pyridin—Z-amine Compound 31: (S)(diﬂu0r0methyl)(2-(3-methy1morpho1ino)morpholinopyrimidiny1)pyridin amine Compound 32: (S)-4'-(diﬂu0romethyl)(3-methy1m0rpholino)m0rpholino-[4,5'-bipyrimidin]—2'-amine Compound 33: 4-(diﬂuoromethyl)[4-[(2S,6R)-2,6-dimethy1morpho1iny1]—6-[(3R)methy1morpholin— 4-y1]-1 ,3 ,5 -triaziny1]pyridinamine Compound 34: 11/,O\ NkN F»; \N: 1:, I f xi 2 N34; ix: OCT/é E'-NJ'":NH2 _ 67 _ -[4,6-bis[(2R,6S)-2,6-dimethy1morpho1iny1]—1,3,5-triazin—2-y1]—4- (diﬂuoromethyl)pyridin—2-amine Compound 37: is a F -[4,6-bis(3,7-dioxaazabicyclo[3.3.1]nonan—9-y1)-1,3,5-triazin—2-yl]—4- (diﬂuoromethyl)pyridin—2-amine Compound 38: 4-(diﬂuoromethy1)[4-(3,7-dioxaazabicyclo[3 .3 . 1 ]nonan—9-y1)(3-oxa azabicyclo [3 .2. 1]octany1)- 1 ,3 ,5 -triaziny1]pyridin—2-amine nd 39: -[4,6-bis(3,3-dimethy1morpho1iny1)-1,3,5-triaziny1](diﬂuoromethy1)pyridin amine Compound 40: -[4,6-bis[(3R,5S)—3,5-dimethy1morpholin—4-y1]-1,3 ,5-triazin—2-y1](diﬂuoromethyl)pyridin— _ 68 _ 2-amine Compound 41: -[4,6-bis[(3R)methy1morpho1iny1]—1 ,3,5-triazin—2-yl](diﬂuoromethyl)pyridin—2- amine Compound 42 L F F 4-(diﬂu0romethyl)[4-(3,3-dimethy1morpho1iny1)m0rph01in0- 1 ,3,5-triazin—2- yl]pyridinamine nd 44: 4-(diﬂu0romethyl)[4-[(3R,SS)-3,S-dimethylmorpho1iny1][(3R)methy1m0rpholin—4- y1]- 1 ,3 ,5 -triazin—2-y1]pyridin—2-amine Compound 45: 3f FR ,F ox:,,:;zN,m;1I,J E‘N‘l‘Nw 4-(diﬂu0romethyl)[4-(3,3-dimethy1morpho1iny1)[(3R)methy1m0rpholinyl]- _ 69 _ 1 ,3 ,5 -triaziny1]pyridin—2-amine Compound 46: 4-(diﬂu0romethy1)[4-[(3R)(meth0xymethy1)morpho1iny1][(3R) methylmorpho1iny1] - 1 ,3 ,5 -triaziny1]pyridinamine Compound 47: uoromethy1)[4-(3,7-dioxaazabicyclo[3 .3 . 1 ]nonan—9-y1)[(3R) methylmorpho1iny1] - 1 ,3 ,5 -triaziny1]pyridinamine Compound 50: Hf [I‘J M NH, 4-(diﬂu0romethy1)[4-[(3R)methy1m0rpholiny1](3-oxaazabicyclo[3. 1 .1]heptan— 6-y1)-1 ,3 ,5 -triaziny1]pyridinamine Compound 51: E:]\FF u0romethyl)[4-[(3R)methylm0rpholinyl](6-oxaazabicyclo[3. 1 .1]heptan— _ 70 _ 3 -y1)-1 ,3 ,5 -triaziny1]pyridinamine Compound 52: 4-(diﬂu0romethy1)[4-[(3R)methy1m0rpholiny1][(1R,4R)oxa azabicyclo [2 .2. 1]heptan—5 -y1]-1 ,3 ,5 -triaziny1]pyridin—2-amine Compound 53.° 4-(diﬂuoromethyl)[4-[(3R)methy1morpholinyl][(1S,4S)oxa azabicyclo[2.2.1]heptan—5-yl]—1,3,5-triazinyl]pyridin—Z-amine nd 54: Elk/Jnunl,-N - [4,6-bis[(3R)-3 -ethylmorpho 1iny1] - 1 ,3 ,5 -triazin—2-yl] ﬂuoromethy1)pyridinamine Compound 55: 0:4LEE N NHW - [4,6-bis(8-0xa-5 -azaspir0 [3 .5 ]nonan—5 -y1)-1,3 ,5 -triazin—2-y1](diﬂuor0methyl)pyridin amine _ 71 _ Compound 56: E0»NEW/F MAIN F» 0QNAN/ﬂ,.N - [4,6-bis[(3R)-3 -isopr0pylmorpho1iny1]—1 ,3 ,5 -triazin—2-y1](diﬂuor0methyl)pyridin amine Compound66: NAN F F N NH2 4-(diﬂuor0methyl)[4-(3,3-dimethylmorpho1iny1)[(3R,5S)-3,5-dimethy1morph01in y1]- 1 ,3 ,5 -triazin—2-y1]pyridin—2-amine Compound67: O A F F N N “a ORV/l I, N N H . 4-(diﬂu0romethyl)-5 - [4-(3 ,3-dimethy1morpho1iny1)[(3R)(methoxymethy1)morpholin- 4-y1]-1 ,3 ,5 -triaziny1]pyridinamine Compound 68: [0N3< HO NAN F F g?I z N NH2 [(3R)[4-[6-amin0(diﬂu0romethyl)-3 y1] (3 ,3-dimethy1morpho 1iny1)- 1 ,3 ,5 - _ 72 _ triazin—Z-yl]m0rpholin—3-y1]methan01 Compound 69: F F N ,wa x» I 0,?N N , a N” NH2 4-(diﬂuor0methyl)[4-(3,3-dimethy1morpho1iny1)(3,7-di0xa azabicyclo [3 .3 . 1]nonany1)-1 ,3 ,5 -triaziny1]pyridin—2-amine Compound 70: I, JV F F N {’L‘N pr? AN% V/N “V” N; NH2 -[4-(4-cyclopropy1piperaziny1)(3 ,3-dimethy1morpho 1iny1)- 1 ,3 ,5 -triaziny1]—4- (diﬂuoromethyl)pyridin—2-amine Compound 71 : N “T.

N-ﬁL‘RNF F FT N IR “QWNH/ " M NH, 4-(diﬂu0romethyl)-5 - [4-(3 ,3-dimethy1morpho y1) meth0xyethy1)piperazin— 1 -y1] - 1 ,3 ,5 -triaziny1]pyridin—2-amine Compound 77: H0, @ka p, F, ,F Lkﬁf/ Q, , '3’ W :1 / x, x V N ‘ng [(3R)[4-[6-amin0(diﬂuor0methyl)pyridy1][(3R)—3-methy1morpho 1iny1]— _ 73 _ 1 ,3 ,5 -triaziny1]morpholin—3 -y1]methanol Compound 78: F F (5meN,N AN N H2. 4-(diﬂu0romethyl)[4-[(3R,5R)-3,5-dimethy1morpho1iny1]—6-[(3R)methy1morpholin—4- y1]- 1 ,3 ,5 -triazin—2-y1]pyridin—2-amine nd 79: 4-(diﬂu0r0methy1)[4-[(3S,5S)-3,5-dimethy1morpho1iny1][(3R)methy1morpho1in y1]- 1 ,3 ,5 -triazin—2-y1]pyridin—2-amine Compound 80: NJ’LWF F k» ' @PJ N “a o N NH2 4-(diﬂu0romethyl)[4-m0rph01in0(3-0xaazabicyclo[3.3.1]nonany1)-1,3 ,5-triazin—2- yl]pyridinamine Compound 82: 4-(diﬂuoromethy1)[4-(3,7-dioxaazabicyclo[3 .3 . 1 ]nonan—9-y1)(3-oxa _ 74 _ azabicyclo [3 .3 . 1]nonany1)-1 ,3 ,5 -triaziny1]pyridin—2-amine Compound 83: OVA... » Na; “NH? -[4,6-bis[(3S,5S)-3,5-dimethy1morpholinyl]-1,3,5-triazin—2-y1]—4- (diﬂuoromethyl)pyridin—2-amine Compound 84: 04%, J 4-(diﬂu0r0methyl)[4-(3 ,7-dioxaazabicyclo[3.3.1]n0nan—9-y1)m0rpholino-1,3 ,5- triazin—Z-yl]pyridinamine nd 85: tJed“Exk :; F- N m ,,,,,,, M/‘m‘a x’LEx 1/;in ”in ” "’ 1 J 2‘ N O“-”“‘” NINN“ NHg 4-(diﬂu0r0methyl)[4-[(3S)ethylmorpho1iny1]—6-[(3R)methy1morpholin—4- y1]- 1 ,3 ,5 -triazin—2-y1]pyridin—2-amine Compound 86: _ 75 _ l N "W F“ ”F 1% a, l {/- «NT NM. NM {/ﬁxx; 0., ,J L; ,l: “V N“ MHz 4-(diﬂuoromethyl)[4-[(3R)ethylmorpholinyl][(3R)methylmorpholin yl] - l ,3 ,5 -triazinyl]pyridinamine Compound 88: 4-(diﬂuoromethyl)-5 - [4-[(3R)methylmorpholinyl](8-oxa-5 -azaspiro [3 .5]nonan- -yl)- l riazinyl]pyridinamine Preparation ofcompounds ofthe invention The nds of the invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein. The starting materials are lly available from commercial sources or are readily prepared using s well known to those skilled in the art.

In preparing compounds of the invention, protection of remote ﬁanctionality (e. g., primary or secondary amine) of intermediates may be ary. The need for such protection will vary ing on the nature of the remote ﬁanctionality and the conditions of the preparation methods. 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.

Methods ofseparation In the methods of preparing the compounds of this ion, it may be advantageous to separate reaction products from one another and/or from starting materials. The desired WO 98347 _ 76 _ products of each step or series of steps are separated and/or puriﬁed to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or t mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; high, medium and low pressure liquid tography methods and apparatus; small scale analytical; and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and ﬂash chromatography. ion of riate methods of separation depends on the nature of the materials involved, for example, presence or absence of polar ﬁanctional groups in chromatography, stability of materials in acidic and basic media in hase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation.

EXAMPLES The Examples are intended to illustrate the present invention without restricting it.

The chemical reactions described in the Examples may be readily adapted to prepare a number of other lipid kinase inhibitors of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exempliﬁed compounds according to the invention may be successfully performed by modiﬁcations apparent to those skilled in the art, e.g., by appropriately protecting ering groups, by utilizing other le reagents known in the art other than those described, and/or by making routine modiﬁcations ofreaction ions.

Alternatively, other reactions disclosed herein or known in the art will be ized as having applicability for preparing other compounds of the invention.

As a rule, 1H NMR and mass a have been obtained for the compounds prepared.

In the Examples described below, unless otherwise indicated, all temperatures are set forth in degrees Celsius (0C). Reagents were purchased from commercial suppliers such as Sigma Aldrich, Fluorochem, Acros, Lancaster, TCI or Maybridge, and were used without r puriﬁcation unless otherwise indicated. The reactions set forth below were done lly under a positive pressure of nitrogen or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction ﬂasks were typically ﬁtted with rubber septa for the _ 77 _ introduction of substrates and reagents via syringe. Glassware was oven dried. Column chromatography was performed using Merck silica gel. 1H NMR spectra were recorded on a Bruker instrument operating at 400 MHz. 1H NMR spectra were ed for solutions in various ated solvents such as CDClg, (CD3)2SO, CD301) or (CD3)2CO. The chemical shift a values were reported in ppm and corrected to the signal of the deuterated solvents (7.26 ppm for CDClg) or TMS (0 ppm). 19F NMR spectra were ated relative to CFC13 (5 = 0 ppm) as external standard. 19F NMR spectra were recorded 1H-decoupled. When peak multiplicities are reported, the following abbreviations are used: s et), let), t (triplet), m (multiplet), quint (quintet), br (broadened). Coupling constants, when given, are reported in Hertz (Hz). MALDI-ToF Mass spectra (MS) have been obtained on a Voyager- DeTM Pro measured in m/z.

The following abbreviations are used hereinafter: BSA (bovine serum albumin), DMSO (dimethyl sulfoxide), ESI ronspray 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).

Preparation of Intermediate Compounds and of Compounds of the Invention Preparation ofIntermediate Compounds The following methods were used to prepare the intermediates compounds used to produce nds of formula (1).

Method 1: 8-(4-(3-oxaazabicyclo[3 .2. l]octanyl)chloro- l ,3,5-triazin—2-yl) oxaazabicyclo[3.2.l]octane (i1) N \N m... N N CIANACI (@JJLIVKCI 3-Oxaazabicyclo[3.2.l]octane-HCl (Advanced ChemBlocks Inc, product number A- _ 78 _ 861, 2.00 g, 13.4 mmol, 2.0 eq.) and N,N—diisopropylethylamine (4.80 mL, 27.6 mmol, 4.1 eq.) are charged into a ﬂask and dissolved in romethane (20 mL). The ﬂask is placed in an ice bath and the solution subsequently cooled down to 0 0C. This solution is then added dropwise to a solution of cyanuric chloride in dichloromethane (20 mL) at 0 oC. The resulting reaction mixture is d overnight, while it is allowed to warm up to room temperature. Additional dichloromethane (100 mL) is added and the organic layer is washed with a saturated aqueous on of sodium bisulfate. The organic layer is then dried over ous sodium e, ﬁltered and the t is evaporated under reduced pressure.

Puriﬁcation by ﬂash chromatography (cyclohexane/ethyl acetate 4:1) gives the desired intermediate i1 as a colorless solid (79% yield). 1H NMR (400 MHZ, CDC13)I 8 .54 (m, 4 H), 3.80-3.58 (m, 8 H), 2.14-1.89 (m, 8 H); MS (MALDI): m/z = 338.4 ([M+H]+).

Method 1 is also used for the preparation of the following intermediate compounds i2 to i10, and intermediates i79 to i81 and i90.

Reagent Structure NMR MS o [N] 1H NMR (400 MHz, CDCls): MS (MALDI): i2 E ] NkN 83.78 (m, 8 H), 3.70 (m, m/z= 285.9 pN/QN/ C, 8H). ([M+H]+). 1H NMR (400 MHz, CDClg): 4.75-4.56 (m, 2H), 4.34— 4.30 (m, 2 H), 3.94 (dd, ZJHH o = 12.0 Hz, 3.11,,H = 4.0 Hz, 0 [N] 2H),3.74 (d, ZJHH=12.0HZ, MS(MALDI): i3 [N] 3.63 m/z= 314.4 E NkN 2H), (dd, 2.1%: H IANJLN/ C, 12.0Hz,3JHH=4.0Hz,2H), ([M+H]+). 0Q 3.49 (dt, ZJHH = 12.0 Hz, 3.1111,: 4.0 Hz, 2 H), 3.25 (dt, ZJHH = 12.0 Hz, 3.1111,: 4.0 Hz, 2 H), 1.31 (d, 3.1111,: 8.0 Hz, 6 H). 1H NMR (400 MHz, CDClg): MS (MALDI): i4 8 3.81—3.72 (m, 8 H), 3.43 (s, m/Z = 342.5 4 H), 1.43 (br s, 12 H). ([M+H]+). 1H NMR (400 MHz, CDClg): 8 4.75-4.56 (m, 2 H), 4.34— 4.30 (m, 2 H), 3.94 (dd, ZJHH = 12.0 Hz, 3.1111,: 4.0 Hz, 2 H), 3.74 (d, ZJHH = 12.0 Hz, 2 H), 3.63 MS (MALDI): i5 (dd, 2 JHH _ — 12.0 Hz, m/Z = 3 14.3 3.1111,: 4.0 Hz, 2 H), 3.49 (dt, ([M+H]+).

ZJHH = 12.0 Hz, 3.11,,H = 4.0 Hz, 2 H), 3.25 (dt, ZJHH = 12.0 Hz, 3.1111,: 4.0 Hz, 2 H), 1.31 (d, 3.1111,: 8.0 Hz, 6 H). 1H NMR (400 MHz, CDClg): 8 4.40—4.37 (m, 4 H), 3.74 (d, MS (MALDI): {JHH = 11.6 Hz, 4 H), i6 m/Z = 342.8 3.53 (dd, {JIM = 11.6 Hz, ZJHH = 4.0 Hz, 4 H), 1.26 (d, 3.1111,: 6.9 Hz, 12 H). 1H NMR (400 MHz, CDClg): MS (MALDI): 8 4.53 (br s, 2 H), 4.36 (br s, m/Z = 370.3 2 H), 4.12-4.06 (m, 8 H), +). 3.92—3.83 (m, 8 H).

WO 98347 1H NMR (400 MHz, L. k, (CD3)ZSO).. 5436-421 (111, MS (MALDI): 1 K 4H), 3.85-3.75 (m, 4H), m i8 ,1 2 342.3 Y “xxx; 3.48-3.45 (m, 2H), 3.40—3.34 ([MT). (gm/,1 (m, 2 H), 3.14—3.09 (m, 2 H), 1.72 (m, 4 H), 0.82 (m, 6 H). ,0 1H NMR (400 MHz, MS (MALDDi .401... {N11 (CD3)ZSO): 5364(m, 8H), (“N/km NﬁcLN” "W 2 366-7 i9 A 3351—348 (m, 4H), 2.46- .344 {/“xN/Lm\f 1 + H . 4,0! 2.38 ([M+H] )- (m, 4 H), 2.20-2.16 (m, Ow” 4 H), .66 (111,4 H). 1H NMR (400 MHz, ,0. (CD3)2SO): 5 4.40—4.25 (m, 04, L. MS (MALDD‘ ( x N 2H), 4.20—4.05 , 4.08 110 “WW "W 370-4 41/ NémN (m,2H), 3.95 (m,2H), 3.83 1 + H . ([M+H] )- {,8 ,N,i-8Nfi~1m (m, 4H), 3.08 (m, 2H), 2.30 Owj (m, 2 H), 0.98 (m, 6 H), 0.48 (m,6H). ﬁQK 1H NMR (400 MHz, CDClg): O N MS (MALDI): \f f ,1 54.59—4.31(m, 4H), 3.66- i79 m/z= 342.4 . 11 346 4 2 0 4 H V”? N 0* (m ) (m ) ([M+H]+).

OT) 1.14 (m, 12 H).

«ONL/ 1H NMR (400 MHz, CDClg): ﬁg C MS (MALDI): N 5 3.73-3.64 (m, 8 H), 3.57 (s, i80 m/z= 342.3 / MAN “N” 2 ) 3 1( ) 114( ’1 H, .5 S, 2 H, . S, :4 2% IEtL‘N’ "c: m A1 ([M+H1+). 12 H). _ 8l _ 1H NMR (400 MHz, CDClg): 4.41 (br s, 4 H), 432— 404. MS ): i81 E, 4.16 (m, 4 H), 3.24—3.10 (m, m/Z = 338.4 \Nm'“ H 4 H), 1.99-1.84 (m, 4 H), ([M+H]+) 1.84-1.67 (m, 4 H). 1H NMR (400 MHz, CDClg): )0,» MS (MALDI): 4 5 4.20 (m, 4 H), 4.10 (m, i90 /[ j , m/z= 342.8 \N/ ‘4)! 2N 4 H9 3 66- (m) 4 H: 1 3- 5 (d : ) a fAN.Jimaiam Z ([M+H]+) OVK JHH= 6.9 Hz, 12 H) Method 2: 2,4-dichloromorpholino- l ,3,5-triazine (i1 1) 1:) O .l I...) [,1 N All” _,. NAN CIANACI EI To a on of cyanuric chloride (18.1 g, 0.100 mol, 1.0 eq.) in romethane (200 mL) is dropwise added a solution of morpholine (17.4 g, 0.200 mol, 2.0 eq.) at — 78 0C over 2 hours. The resulting mixture is allowed to warm to 0 CC with stirring and mixed with an ice cold saturated solution of sodium bisulfate in water. The phases are separated and the organic phase is washed with half concentrated brine dried over sodium sulfate and evaporated to yield the title compound i11 as a colorless solid. 1H NMR (400 MHz, CDC13)C 8 3.90- 3.86 (m, 4 H), 3.77-3.72 (m, 4 H).

Method 3: 8-(4-chloromorpholino-l,3,5-triazinyl)oxaazabicyclo- I321 |octane gi12) 1 a) 11 1“ (\N N/ or o\) 3N N/ CI ill i12 3-Oxaazabicyclo[3.2.1]octane-HCl (Advanced ChemBlocks Inc, product number A- 861, 200 mg, 1.34 mmol, 1.1 eq.) and N,N—diisopropylethylamine (470 uL, 2.69 mmol, 2.1 eq.) are charged in a ﬂask and dissolved in ethanol (3 mL). The ﬂask is placed in an ice bath. A solution of compound i11 (300 mg, 1.28 mmol, 1.0 eq.) in ethanol (2 mL) is added to the above solution at 0 CC. The resulting mixture is stirred overnight, while allowing it to warm up to room temperature. Deionized water (20 mL) is added and the s layer is extracted with ethyl acetate (3 x 30 mL). The combined organic layer is dried over anhydrous sodium sulfate, ﬁltered and the solvent is ated under reduced pressure. Puriﬁcation by ﬂash chromatography hexane / ethyl acetate 9:1 —> 8:2) gives the desired intermediate i12 as a colorless solid (78% yield). 1H NMR (400 MHZ, CDC13)I 8 .56 (m, 2 H), 3.86- 3.59 (m, 12 H), 2.12-1.91 (m, 4 H); MS (MALDI): m/z = 312.7 ([M+H]+).

Method 3 is also used for the preparation of the following intermediate nds i13 to i16, and intermediates i87 and i91.

Reagent Structure NMR 1H NMR (400 MHz, CDClg): 5 4.71— {Ox} 4.61 (m, 1H), 4.34-4.31(m, 1H), 3.96- 3.92 (m, 3.79—3.70 (m, 3.65- 113 E ] MEN 1H), 9H), N 3.61 (m, 1H), 3.51—3.45 (m, 1H), 3.29— [AN . 01 3.21 (m, 1H), 1.36-1.30 (d, 3.11,,H = 6.9 Hz, _ 83 _ O 4 ,04. ,/ 0 0+2 J 3851/[/33] 1H NMR (400 MHz, CDClg): 5 379—371 1.14 [N], 31333:; (m, 12 H), 3.46 (m, 4 H), 1.48 (s, 9 H).

H {/33 N“ “N“; ‘01 1H NMR (400 MHz, CDClg): 5 4.12— 84. LN] 115 £ij N434,“ 3.98 (m, 4 H), 3.84—3.70 (m, 4 H), 3.70— H ., 3.62 (m, 4 H), .56 (m, 4 H). if -4N43-4N~¢3-4m saw/3 [30,, ‘3 3,04, “‘5: 1H NMR (400 MHz, CDClg): 5 3.77 (m, i16 L j\ MEN 4 H), 3.68-3.63 (m, 8 H), 3.44 (s, 2 H), H J: L 1.44 (s, 6 H). ( «4N4 4N4: c: 6.).) M‘GNN 3‘14“] 1H NMR (400 MHz, CDClg): 5 4.52 (111, 3:3,, ”NH )1.“ 1 H), 4.43 (m, 1 H), 3.93 (111,2 H), 3.65 (m, i87 W N" \‘N ,1: 10 H), 2.48 (m, 1H), 1.88 — 1.72 (m, 4 H), O 4.

.N“ “N“ C! 4MB;4 1.57 (m, 1 H) ‘3“ 1f” 1H NMR (400 MHz, CDClg): 5 4.44 (m, .44.. 4:91»: '- ‘3’ 191 0MB 313: T 1H), 4.32 (m, 1H), 4.00 (m, 4H), 3.74 — X x O. . 3.65 (m, 12 H); Method 4: (S)—4-(4,6-dichloro-1,3,5-triazinyl)rnethy1morpholine (i17) i] 0 EN1 Cl/leN/N\ + C! [14].) )NL:N CI N Cl To a solution of cyanuric chloride (450 mg, 2.44 mol, 1.0 eq.) in dichloromethane (4 mL) is slowly added a solution of methylmorpholine (Activate Scientiﬁc, product number AS3424, 0.28 mL, 2.44 mol, l.0 eq.) and triethylamine (0.35 mL, 251 mol, 1.02 eq.) in dichloromethane (2 mL) at — 50 CC. The resulting mixture is stirred for 2 hours at — 50 CC, then allowed to warm to 0 CC with stirring and mixed with an ice cold saturated on of sodium bisulfate in water. The phases are separated and the organic phase is washed with brine dried over sodium e and evaporated to yield the title compound i17 as a colorless solid (95% yield). 1H NMR (400 MHz, C 5 4.78-4.69 (m, l H), 4.43-4.39 (m, l H), 3.98-3.96 (m, l H), 3.78-3.76 (m, l H), .65 (m, l H), 3.51-3.47 (m, l H), 3.40-3.37 (m, l H), 1.36 (m, 3 H).

Method 5: 8-(4-chloro((S)methylmorpholino)-l,3,5-triazinyl)oxa azabicyclo[3.2.l]octane (i18) o o {N}, O [N] W * ESE —’ W Cl/kN/ H Cl Q N/ C] i17 i18 3-Oxaazabicyclo[3.2.l]octane-HCl (Advanced ChemBlocks Inc, product number A- 861, 383 mg, 2.55 mrnol, l.l eq.) and N,N—diisopropylethylamine (1.0 mL, 5.60 mmol, 2.4 eq.) are charged in a ﬂask and dissolved in ethanol (4 mL). The ﬂask is placed in an ice bath. A solution of nd i17 (580 mg, 2.33 mmol, 1.0 eq.) in ethanol (2 mL) is added to the above solution at 0 CC. The resulting e is stirred for 4 hours, while allowing it to warm up to room temperature. Deionized water (20 mL) is added and the aqueous layer is extracted with ethyl acetate (3 x 30 mL). The combined organic layer is dried over anhydrous sodium sulfate, ﬁltered and the solvent is evaporated under reduced pressure. Puriﬁcation by _ 85 _ ﬂash chromatography (cyclohexane / ethyl acetate 9:1 —> 8:2) gives the desired intermediate i18 as a colorless solid (88% yield). 1H NMR (400 MHz, CDC13)C 8 4.75-4.52 (m, 3 H), 4.37- 4.24 (m, 1 H), 3.95-3.92 (m, 1 H), 3.73-3.70 (m, 3 H), 3.64-3.61 (m, 3 H), 3.52-3.42 (m, 1 H), .17 (m, 1 H), .89 (m, 4 H), 1.31 (m, 3 H).

Method 6: tert—butyl 4-(4,6-dichloro-1,3,5-triazinyl)piperazinecarboxylate (i19) Oi‘w / 0 xx /»*” \{f 4 L» 5] N/LuN .L _» Ni” “N /J]\- {/i\ ”(Lin ;;4\ Ci N C; c: N 'c: To a cooled (— 50 oC) solution of cyanuric chloride (1.0 g, 5.42 mmol, 1.0 eq.) in dichloromethane (4 mL) is added dropwise a solution of tert—butyl piperazine-l- ylate (Sigma, product number 343536, 1.02 g, 5.48 mmol, 1.01 eq.) and triethylamine (0.767 mL, 5.53 mmol, 1.02 eq.) in dichloromethane (2 mL). The resulting reaction mixture is stirred at — 50 0C for 4 hours. A saturated aqueous solution of sodium bisulfate (10 mL) and dichloromethane (20 mL) are added. The mixture is transferred to a separating . The organic layer is separated, washed with a saturated aqueous solution of sodium ate (20 mL), dried over anhydrous sodium sulfate, ﬁltered and then the solvent is evaporated under d pressure to give pure intermediate i19 (80% yield). 1H NMR (400 MHz,CDC13): 5 3.88-3.85 (m, 4 H), 3.53—3.51 (m, 4 H), 1.49 (m, 9 H).

Method 7: tert—butyl 4-(4-(3-oxaazabicyclo[3.2.1]octanyl)chloro-1,3 ,5-triazin yl)piperazinecarboxylate (i20) ,1 L ,1 N N xix —> x’Lm, N' “N N‘ KN ,14 .....L. ,1, E? 7:, CE" N Ci {1: N N CE (33;? i19 i20 3-Oxaazabicyclo[3.2.1]octane-HCl (Advanced ChemBlocks Inc, product number A- _ 86 _ 861, 235 mg, 1.57 mrnol, 1.0 eq.) and N,N—diisopropylethylamine (592 uL, 3.14 mmol, 2.1 eq.) are charged in a ﬂask and dissolved in ethanol (6 mL). The ﬂask is placed in an ice bath. A solution of compound i19 (500 mg, 1.5 mrnol, 1.0 eq.) in ethanol (2 mL) is added to the above on at 0 CC. The resulting mixture is stirred ght, while allowed to warm up to room temperature. Deionized water (10 mL) is added and the aqueous layer is extracted with ethyl acetate (3 x 30 mL). The combined organic layer is dried over anhydrous sodium sulfate, d and the solvent is evaporated under reduced pressure. Puriﬁcation by ﬂash chromatography (cyclohexane / ethyl acetate 8:2) gave the desired intermediate i20 as a colorless solid (77% yield). 1H NMR (400 MHz, CDC13)C 8 4.68-4.60 (m, 2 H), .70 (m, 6 H), 3.64-3.62 (m, 2 H), 3.47-3.45 (m, 4 H), 2.08-1.95 (m, 4 H), 1.48 (br s, 9 H); MS (MALDI): m/Z = 411.8 ([M+H]+).

Method 7 is also used for the preparation of the following intermediate compound i21.

Reagent Structure NMR MS 1H NMR (400 MHz, CDClg): 8476-461 (m, 1H), 4.35—4.30 031» 01/ (m, 1 H), 3.94 (dd, 2.11111: 12 Hz, 0 1:”? 3.1111,: 4.0 Hz, 1H), 3.76-3.72 MS (MALDI)i 121 [N] If (m, 5 H), 3.65 (dd, ZJHH= 12 Hz, W2: 399-1 H j. 31 :3 31M: 4.0 Hz, 1H), 3.51—3.44 +).

C1}: 3’ N ‘3‘ (m, 5 H), 3.25 (dt, 2.11111: 12 Hz, 3.1111,: 4.0 Hz, 1 H), 1.48 (s, 9 H), 1.30 (d, 3.1111,: 8.0 Hz, 3 H).

Method 8: 4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine (i22) and 4,4'-(2- chloropyrimidine-4,6-diyl)dimorpho line (i23) Cl LN“) If .104 AC! ,1. l. 4hN ‘NN N x. + l. J —* l L + l A A, 5 c: N c: g ‘N" 1 N N ‘1; 01 N N W 05/‘1 lam/,0 1» ......Mo _ 87 _ Trichloropyrimidine (Manchester Organics, product number Y17832, 11.2 g, 61 mmol, 1.0 eq.), N,N—diisopropylethylamine (23.3 mL, 134.2 mmol, 2.2 eq.) and morpholine (11.7 mL, 134.2 mmol, 2.2 eq.) are charged in a ﬂask and dissolved in ethanol (120 mL). The ﬂask is equipped with a reﬂuxed condenser and placed in an oil bath preheated at 100 CC. The on mixture is stirred at this temperature for 18 hours. After this time, the reaction mixture is cooled down to room temperature and volatiles are removed under reduced pressure. The resulting mixture is dissolved in dichloromethane (100 mL) and washed twice with an aqueous solution of sodium bisulfate (2 x 80 mL). The organic layer is dried over anhydrous sodium sulfate, ﬁltered and trated 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 ons are pooled and evaporated to yield i22 as a colorless powder (13.8 g, 80%) and i23 as a colorless powder (2.2 g, 13% yield). 4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine (i22): 1H NMR (400 MHz, CDC13)I 8 5.85 (s, 1 H), 3.71-3.75 (m, 12 H), 3.52-3.55 (m, 4 H); MS (MALDI): m/z: 285.4 ([M+H]+). 4,4'-(2-chloropyrimidine-4,6-diyl)dimorpholine (i23): 1H NMR (400 MHz, CDC13)I 8 5.38 (s, 1 H), 3.73-3.76 (m, 8 H), 3.52-3.54 (m, 8 H); MS (MALDI): m/z: 285.2 ([M+H]+).

Method 9: 8-(4-(3-oxaazabicyclo[3.2.1]octanyl)chloropyrimidinyl)oxa yclo[3.2.1]octane (i24) z” wwwwwww«, 1/ W1 Ci \N/ ":~ N €53»? 115.. g; 5 + l “l M ,JxN \M‘ N. ”ﬁrm. '/ 3"] ca” N' CE Q m «N x” («j/“N” “N/ c: of?J A solution of 2,4,6-trichloropyrimidine (0.676 mL, 5.88 mmol, 1.0 eq.), 3-oxa azabicyclo[3.2.1]octane hydrochloride (1.76 g, 11.8 mrnol, 2.0 eq.), and N,N— diisopropylethylamine (4.10 mL, 23.5 mmol, 4.0 eq.) in ethyl e (18 volumes) is heated for 16 hours (100 oC). Then, the solvent is d under reduced pressure and the residue is dissolved in dichloromethane (60 volumes) and washed with a saturated aqueous sodium bisulfate (3 x 60 s). The organic layer is dried over anhydrous sodium sulfate, ﬁltered and concentrated under reduced pressure. Puriﬁcation by column chromatography on silica _ 88 _ gel (cyclohexane / ethyl acetate 3:1 to 1:1) affords the desired intermediate i24 as a colorless solid (1.23 g, 62%). 1H NMR (400 MHz, CDC13)C 8 5.80 (s, 1H), 4.59 (s, 2 H), 4.35 (m, 2H), 3.76 (021111.11 = 10.8 Hz, 4H), 3.59 (d, ZJHH = 10.8 Hz, 4H), 2.03 (m, 8H); MS ): m/Z = 337.7 ([M+H]+).

Method 9 is also used for the ation of the following ediate compound i25.

Reagent Structure NMR MS 1H NMR (400 MHz, CDC13): MS (MALDI): m/z 85.83 (s, 1H), 4.64-4.57(m, =313.6([M+H]+). f 1 1H), 4.27 (dd, 3.11,), = 2.4 Hz, 11 21H,H = 13.5 Hz, 1H), 420—411 125 [N] 3111 (m, 1H), 3.97-3.87 (m, 3H), '11 N “"‘c1 3.77-3.63 (m, 4 H), 3.56-3.46 (m, V 2 H), 3.26-3.15 (m, 2 H), 1.28 (d, 3.111,H = 3.2 Hz, 3 H), 1.27 (d, 3.111,H = 3.2 Hz, 3 H).

Method 10: 4-(4,6-dichloropyrimidinyl)morpholine (i26) and 4-(2,6-dichloropyrimidin yl oline 1 i27 1 Ci (3} 1 L 0 j L 1 5 1:1 + £1 _. 11 + [L (31/ N’ “o; {)1 («N/1 “N?“ “c: 1:} “2:1 0%,.13 31"“ NWC§ 126 127 To a solution of 2,4,6-trichloropyrimidine (14.0 mL, 122 mmol, 1.0 eq.) in EtOH (150 mL) is added a solution of morpholine (11.2 mL, 256 mmol, 2.1 eq.) and N,N— diisopropylethylamine (44.6 mL, 256 mmol, 2.1 eq.) in EtOH (150 mL) se at 0 CC. 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 x 100 mL) and the organic phase is successively washed with saturated aqueous sodium bisulfate (3 x 400 mL).

The combined organic layers are dried over anhydrous sodium sulfate, ﬁltered and evaporated under reduced pressure. The crude mixture is puriﬁed by ﬂash column chromatography (SiOz, _ 89 _ cyclohexane / ethyl acetate 9:1 to 3:1) to yield i26 (5.02 g, 18%) and i27 (16.7 g, 59%), both as colorless solids. 4-(4,6-dichloropyrimidinyl)morpholine (i26): 1H NMR (400 MHz, CDC13)I 8 6.56 (s, 1 H), 3.78 (m, 4 H) 3.74 (m, 4 H). 4-(2,6-dichloropyrimidinyl)morpholine (i27): 1H NMR (400 MHz, CDClg): 8 6.41 (s, 1 H), 3.78 (m, 4 H), 3.65 (m, 4 H).

Method 11: (S)—4-(2-chloromorpholinopyrimidinyl)methylmorpholine (i28) .0 101, 1 7 L 1 MN/j /O\ N/ 127 + 1 N k ,1 _" 128 M151 , 1 1‘1 .11. ,1: ,1 Cl/ N KCI { N C1 A solution of i27 (694 mg, 2.97 mmol, 1.0 eq.), (S)methylmorpholine (0.500 mL, 4.46 mmol, 1.5 eq.) and isopropylethylamine (1.29 mL, 7.43 mmol, 2.5 eq.) in EtOH (5.0 mL) is heated to reﬂux for 3 days. Then, the solvent is d under reduced pressure.

The residue is dissolved in romethane (60 volumes) and washed with ted aqueous sodium bisulfate (3 X 60 volumes). The organic layer is dried over anhydrous sodium sulfate, ﬁltered and concentrated under reduced re. The crude mixture is puriﬁed by ﬂash chromatography (SiOz, cyclohexane / ethyl acetate 3:1 to 1:1) to afford the title compound (S)(2-chloromorpholinopyrimidinyl)methylmorpholine (i28) as a colorless solid (425 mg, 48%). 1H NMR (400 MHz, CDClg): 8 5.85 (s, 1 H), 4.62 (dd, ZJHH = 13.6 Hz, {JIM = 2.9 Hz, 1 H), 4.25 (dd, ZJHH = 13.6 Hz, {JIM = 2.9 Hz, 1 H), 3.93 (dd, ZJHH = 11.4 Hz, {JIM = 3.8 Hz, 1 H), 3.75, (t, {JIM = 5.0 Hz, 4 H), 3.71 (s, 1 H), 3.66 (dd, ZJHH = 11.3 Hz, {JIM = 3.2 Hz, 1 H), 3.53 (m, 5 H), 3.23 (m, 1 H), 1.26 (d, ZJHH = 11.3 Hz, 3 H); MS (MALDI): m/z = 299.4 ([M+H]+).

Method 11 is also used for the preparation of the following intermediate compound i29.

Reagent Structure NMR MS WO 98347 {”0"} 1H NMR (400 MHz, CDClg): MS (MALDD‘ 334 ”N“ 85.86 (s, 1H), 4.60 (brs, 2H), m 2 309-6 i29 lid 3.80—3.72 (m, 6H), 3.62-3.56 (m, ([M+H]+)- 8! big) RF“N””L”N’; 29; 2H), 3.56-3.50 (m, 4H), 2.08- 0149 1.90 (m, 4 H).

Method 12: (S)(6-chloromorpholinopyrimidinyl)methylmorpho line (i30) ” ,G hN/ + 1 1 wwwwwwwwm» N xN \N/ “‘1; N ‘43? A}. ,1; H 4. J: J): C?“ ‘V “‘31 l/ N N‘ Ci OMNw/rj i26 i30 A solution of (S)methylmorpholine (194 mg, 1.32 mmol, 1.5 eq.), i26 (300 mg, 1.28 mmol, 1.0 eq.) and N,N—diisopropylethylamine (3.0 eq.) in DMF (17 volumes) is heated for 16 hours (130 oC). Then, the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane (100 volumes) and washed with saturated aqueous sodium bisulfate (3 X 100 volumes). The organic layer is dried over anhydrous sodium sulfate, ﬁltered and concentrated under reduced pressure. The crude mixture is d by ﬂash chromatography (8102, cyclohexane/ethyl acetate 5:1) to afford the title nd i30 as a colorless solid (257 mg, 67%). 1H NMR (400 MHz, CDClg): 8 5.84 (s, 1 H), 4.18 (m, 1 H), 3.94 (m, 2 H), 3.71 (m, 10 H), 3.53, (dt, 9H),: 12.0 Hz, 3.611,: 3.1 Hz, 1 H), 3.20 (dt, 9H),: 12.8 Hz, 3.11,,H = 3.8 Hz, 1H), 1.27 (d, 3.11,,H = 6.8 Hz, 3 H); MS (MALDI): m/Z = 298.4 ([Mr).

Method 14: 8-(4,6-dichloro-1,3,5-triazinyl)oxaazabicyclo[3.2.1]octane (i32) .0... w o Ni M‘N/ ijlm é’ix H :4 Ci N Ci /K @392 "N“ (31 A solution of ic chloride (1.97 g, 10.7 mmol, 1.0 eq.) in dichloromethane (10 mL) is cooled to — 50 0C. A solution of 3-oxaazabicyclo[3.2.1]octane hydrochloride (1.60 g, .7 mmol, 1.0 eq.) and N,N—diisopropylethylamine (3.73 mL, 21.4 mmol, 2.0 eq.) in _ 91 _ dichloromethane (40 mL) is slowly added over a period of 5 hours. The mixture is stirred for another 5 hours at this temperature. Then, dichloromethane (20 mL) and saturated aqueous sodium bisulfate (50 mL) are added and the mixture is allowed to warm to room temperature.

The layers are separated and the organic layer is washed with saturated aqueous sodium bisulfate (2 x 50 mL). The organic layer is dried over anhydrous sodium sulfate and the solvent is d under reduced re. The crude mixture is recrystallized from nheptane / dichloromethane (20 mL/ 13 mL) to afford the title compound 8-(4,6-dichlorol ,3,5-triazinyl)oxaazabicyclo[3.2.l]octane (i32) as a colorless solid (2.47 g, 47%). 1H NMR (400 MHz, CDClg): 5 4.74 (m, 2 H), 3.72 (d311,,H = 1.5 Hz, 4 H), 2.08 (m, 4 H).

Method 14 is also used for the preparation of the following intermediate compounds B3 and Reagent Structure NMR 1H NMR (400 MHz, : 5 4.54-4.60 (m, 1 H), 4.20 (dd, 3.11,,H = 2.9 Hz, ZJHH = .909. [ k 14 Hz, 1 H), 3.92 (dd, H = 3.4 Hz, ZJHH = 133 LNMK “1: 12 Hz, 1 H), 3.71 (d, ZJHH = 12 Hz, 1 H), H T: Rf}: 3.57 (dd, , = 3.2 Hz, ZJHH = 12 Hz, 1 H), C“ "N/ m 3.42 (m, 1 H), 3.32 (m, 1 H), 1.27 (d, 3.11111 = 6.9 Hz, 3 H). 1H NMR (400 MHz, (CD3)ZSO): 5 3.88- 134 (Oh [MK {l NM 3.81 (m, 4 H), 3.51 (s, 2 H), 1.46 (s, 6 H). chQNJL c: Method 15: 9-(4-(3-oxaazabicyclo[3 .2. l]octan—8-yl)chloro- l ,3,5-triazinyl)-3,7- dioxaazabicyclo[3 .3 . l ]nonane (i35) ,od, [CL]("f—x Fl 2. ,. ’4 Q Q N T {312/}! > —* «44K: NAN Q4... 1 ii in /,/LL x/ 1N). MC; x H [{WW/‘A‘Nf 01 N C: VJ“, 20 135 o )1 _ 92 _ To a solution of 3,7-dioxaazabicyclo[3.3.l]nonane (184 mg, 0.700 mmol, 1.0 eq.) and isopropylethylamine (0.170 mL, 0.970 mmol, 1.4 eq.) in 1,4-dioxane (1.0 mL) a solution of i32 (100 mg, 0.770 mmol, 1.1 eq.) in oxane (2.0 mL) is added. The resulting mixture is heated for 1 hour at 70 CC. Then, dichloromethane (50 mL) and water (50 mL) are added. The aqueous layer is extracted with dichloromethane (3 x 50 mL), the combined organic layers are dried over anhydrous sodium sulfate and the solvent is evaporated. The crude mixture is puriﬁed by automated ﬂash chromatography on silica gel (cyclohexane / ethyl acetate 2:1 to 0:1) to afford the title compound 9-(4-(3-oxa azabicyclo[3.2.1]octan—8-yl)chloro-1,3 ,5-triazinyl)-3 ,7-dioxaazabicyclo[3 .3 . 1 e (i35) as a colorless solid (192 mg, 77%). 1H NMR (400 MHz, (CD3)ZSO): 8 4.70 (m, 1 H), 4.55 (m, 2 H), 4.44 (m, 1 H), 4.12 (m, 4 H), 3.90 (m, 4 H), 3.72 (m, 2 H), 3.64 (m, 2 H), 2.08 (m, 2 H), 1.97 (m, 2 H); Ms (MALDI): m/Z = 354.3 ([M]+).

Method 16: 9-(4-chloro((R)—3-methylmorpholino)-1,3,5-triazinyl)-3,7-dioxa azabicyclo[3 .3. l]nonane (i36) ,/0\. , “q ,1 ”AL + W“, N1 “N N! “N N/I/ RN ij rzk ,1? ./1 H m” N” c; ........... (31” ., ., N 01 6&1”! i33 6136 To a solution of oxaazabicyclo[3.3.l]nonane (173 mg, 1.27 mmol, 1.05 eq.) and N,N—diisopropylethylamine (0.50 mL, 2.52 mmol, 2.1 eq.) in tetrahydrofuran (5 mL) a solution of B3 (300 mg, 2.52 mrnol, 2.1 eq.) in 1,4-dioxane (2.0 mL) is added. The ing mixture is heated for 2 hours (70 oC). Then, ethyl acetate (20 mL) and saturated aqueous sodium bisulfate (20 mL) are added. The phases are separated and the organic layer is washed with saturated aqueous sodium bisulfate (2 x 20 mL). The organic layer is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude e is puriﬁed by automated ﬂash chromatography (SiOz, cyclohexane / ethyl acetate 2:1 to 0:1) to afford the title compound i36 as a colorless solid (316 mg, 76%). 1H NMR (400 MHz, (CD3)ZSO): 453 (m, 1 H), 4.42 (m, 1 H), 4.32 (m, 1 H), 4.25-4.16 (m, 1 H), 4.01—3.97 (m, 4 H), 3.87 (dd, {JIM = 3.8 Hz, ZJHH = 11.2 Hz, 1 H), 3.73-3.65 (m, 5 H), 3.53 (dd, 3.11,,H = 3.0 Hz, ZJHH = 11.6 Hz, 1 H), 3.38 (m, 1 H), 3.15 (m, 1 H), 1.20 (d, 3.1111,: 6.9 Hz, 3 H).

Method 16 is also used for the preparation of the following intermediate compounds i37 to i53, intermediate i82 and intermediates i85, i86, i92, i93, i94.

Reagent Structure NMR MS 1H NMR (400 MHz, (CD3)280): 5 .50 (m, 1H), 4.44—4.35 (m, 2H), to...1 4.25-4.12(m, 1H), 390— ”GR [WK 3.86 (m, 1H), 375— MS (MALDI): i37 Ami/k $41,, 3.65 (m, 3H), 3.56- m/z=328.2 H 1 {,9 “RN/151.5643, 3.49 (m, 3 H), 3.38 (m, ([M+H]+). amt/K 1H), 3.16(m, 1H), 1.25 (d, {JIM = 6.9 Hz, 6H), 1.19 (d, 3JHH=6.9HZ, 1H NMR (400 MHz, (CD3)280): 5 4.54-4.46 (m, Aim 1H), 4.18-4.13(m, 1H), ,0, [Wk 3.88 (m, 1H), 3.80- i38 i k 214511 3.65 (m, 5H), 3.54 (m, {13/nix/“99944390; 1H), 3.44-3.36 (m, 3 H), 09...? 3.18 (m, 1H), 1.44 (s, 6H), 1.21 (d, {JIM = 6.9 Hz,3H). 1H NMR (400 MHz, 0 (CD3)ZSO): 5 4.65-4.51 (m, 9:3,, [RN/K 2H), 4.31—4.20 (m, 2H), MS ): 139 i WLO ‘13:» «:N 3.66 (m, 3H), 3.69- m/z=344.2 3 {,,1\¥?,,-»11.N¢kmN 3.56 (m, 2H), 3.54— ([M+H]+).

Ow” 3.48 (m, 3H), 3.42- 3.35(m, 2H), 3.31 (s, 3H), 3.21-3.13(m, 2H), 1.21 (d, 3.11,,H = 6.9Hz, 1H NMR (400 MHz, (CD3)ZSO): 5 4.55—4.51 (m, 1H), 4.42-4.35(rn, 2H), 4.12-4.25(rn, 2H), 4.04— 4.07 (m, 1H), 3.86- 3.88 (m, 1H), 3.78- 3.75 (m, 2H), 3.69-3.65 (m, 1H), 3.55-3.51(m, 1H), 3.38(rn, 1H), 3.20— 3.13 (m, 1H), 2.68 (m, 1H), 1.81 (m, 1H), 1.20 (d, 3.611,: 6.9 Hz, 3 H). 1H NMR (400 MHz, (CD3)280): 5 .53 (m, 3H), 4.31-4.15(rn, 1H), .78(rn, 3H), 3.71— 3.53 (m, 4H), 3.42— 3.35 (m, 1H), 3.22— 3.16(rn, 1H), 3.12-3.08 (m, 1H), 1.81 (m, 1H), 1.21 (d, 3.11,,H = 6.9Hz, 1H NMR (400 MHz, (CD3)280): 8 4.95-4.88 (m, 1 H), 4.64 (m, 1 H), MS (MALDI): i42 4.54 (m, 1 H), 4.31— m/Z = 312.2 4.09 (m, 1 H), 3.89- ([M+H]+). 3.85 (m, 1 H), 3.75— 3.73 (m, 1 H), 3.66-3.63 (m, 2H), 3.52 (m, 1H), 3.45—3.32 (m, 3H), 3.18- 3.12(rn, 1H), 1.90— 1.83 (m, 2 H), 1.21 (d, 3.11,,H = 6.9 Hz, 3 H). 1H NMR (400 MHz, (CD3)ZSO): 5 4.94-4.88 (m, 1H), 4.64 (m, 1H), 4.54 (m, 1H), 4.29— 4.12(rn, 1H), 3.89- MS (MALDI): 3.85 (m, 1H), 3.75— i43 m/Z = 312.2 3.73 (m, 2H), 3.66—3.63 ([M+H]+). (m, 2H), 3.52 (m, 1H), 3.45—3.32 (m, 2H), 3.18- n, 1H), 1.90— 1.83 (m, 2 H), 1.21 (d, 3.11,,H =6.9 Hz,3H). 1H NMR (400 MHz, (CD3)ZSO): 8 4.65 (m, 1H), 4.55 (m, 1H), n, 1H), 4.22(rn, I 2H), 3.98 (m, 1H), MS (MALDI): i53 Hey-w,N 2.1 3.86(rn, 2H), 3.63 (m, m/Z = 330.1 2H), 3.55(rn, 1H), 3.49— ([M+H]+). 3.34(rn, 4H), 3.17(rn, 1H), 3.12(rn, 1H), 1.21 (d, 3.11,,H = 6.9Hz, 1H NMR (400 MHz, (CD3)2SO): 5 4.67-4.53 (m, 1H), 4.45-4.34(m, 2H), 4.31—4.09 (m, 1 H), 3.88 (m, 1H), 3.68 (m, MS (MALDI): i82 1H), 3.55 (m, 3H), m/Z = 328.3 3.38 (m, 1H), 3.13(rn, ([M+H]+). 1H), 2.55 (m, 2 H), 1.20 (d, {JIM = 6.9 Hz, 3H), 1.19 (d, 3JHH=6.9 Hz, 1H NMR (400 MHz, (CD3)2SO): 8 4.53 (m, 1H), 4.22 (m, 3H), 4.11 — 4.08 (m, 2H), 3.88(rn, MS (MALDI): i85 1H), 3.66 (m, 3H), m/Z = 328.2 3.54(rn, 1H), 3.36 (m, ([M+H1+) 1H), n, 1H), 1.33 (m, 6H), 1.22 (d, {JIM = 6.9 Hz,3H) 1H NMR (400 MHz, (CD3)2SO): 8 4.55 (m, 22—4.07(rn,5H), 3.88(rn, 1H), 3.70 — MS (MALDI): i86 3.63 (m, 3H), 3.54(rn, m/Z = 328.5 1H), 3.38 (m, 1H), ([M+H]+). 3.19(rn, 1H), 1.33 (m, 6H), 1.21 (d, 3 JHH _ 6.9 Hz,3H) 1H NMR (400 MHz, (CD3)2SO): 54.54 — 4.15 (m, 4H), 3.86 (m, 2H), 3.77 (m, 1H), 3.66 (m, MS (MALDI): 2 H), 3.55 — 3.46 (m, 2 H), m/Z = 328.6 3.38 (m, 1H), 3.14 (m, 2 ([M+H]+).

H), 1.70 (m, 2H), 1.22 (d, 3.11,,H = 6.9 Hz, 3 H), 0.86 (m, 3 H) 1H NMR (400 MHz, SO): 54.54 — 4.15 (m, 4H), 3.86 (m, 2H), 3.77 (m, 1H), 3.66 (m, MS (MALDI): i93 2 H), 3.55 — 3.46 (m, 2 H), m/Z = 328.1 3.38 (m, 1H), 3.14 (m, 2 ([M+H]+).

H), 1.70 (m, 2H), 1.22 (d, H = 6.9 Hz, 3 H), 0.86 (m, 3 H) 1H NMR (400 MHz, (CD3)2SO): 8 4.45 (m, 1H), 4.11(rn, 1H), 3.87 (m, 1H), 3.66(rn, 5H), MS (MALDI): 3.50(rn, 3H), 3.38(rn, i94 m/Z = 340.6 1H), 3.15 (In, 1H), ([M+H]+). 2.44(rn, 2H), 2.21 (m, 2H), 1.70 (m, 2 H), 1.19(d, {JIM = 6.9Hz, Method 17: 9-(4-ch10r0(3,3-dimethylrnorpholino)-1,3,5-triazin—2-yl)-3,7-dioxa azabicyc10[3 .3 . 1 ]nonane (i54) WO 98347 _ 98 _ '11:!5 mg, 1.20 mmol, 1.05 eq.) ) in 1,4-dioxane (5 mL) a solution of B4 (300 mg, 1.14 mol, 1 eq.) in 1,4-dioxane (1 mL) is added. The resulting mixture is heated for 2 hours (70 oC). Then, ethyl acetate (20 mL) and saturated s sodium bisulfate (20 mL) are added. The phases are separated and the organic layer is washed with saturated aqueous sodium bisulfate (2 x 20 mL). The organic layer is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude mixture is d by automated ﬂash chromatography (SiOz, cyclohexane / ethyl acetate 2:1 to 0:1) to afford the title compound i54 as a colorless solid (178 mg, 44%). 1H NMR (400 MHz, (CD3)ZSO): 8 4.32 (m, 2 H), 4.05-3.98 (m, 4 H), 3.77 (m, 4 H), 3.71 (m, 4 H), 3.44 (m, 2 H), 1.41 (s, 6 H). MS (MALDI): m/Z = 356.3 ([M+H]+).

Vlethod 17 is also used for the preparation of the following intermediate nds i55 to i64.

Reagent Structure NMR MS 1H NMR (400 MHz, 50, (CD3)ZSO): 8 4.36 (m, 33/01 2 H), 3.77-3.74 (m, MS (MALDI): i55 [KT/lg” /l,ﬁl\ T5233 6 H), 3.55 (m, 2 H), m/Z = 342.9 3*" N 131/ “a 3.44 (m, 2 H), 1.44 (s, ([M+H] ).

”WK 6 H), 1.26 (d, 3.1111,: 6.9 Hz, 6 H). 1H NMR (400 MHz, 303/ (CD3)ZSO): 5 4.52 (m, i56 3’01» ‘“‘ 13 *3 1 H), 4.20 (m, 1 H), 33 /1 1: Q 3.90 (m, 2 H), 3.77 (m, (2,, if N 0* 4 H), 3.65 (m, 1 H), 3.51-3.41 (m, 5 H), WO 98347 3.28 (s, 3 H), 3.12 (m, 1 H), 1.44 (s, 3 H), 1.43 (s, 3 H). 1H NMR (400 MHz, (CD3)ZSO): 8498(111, 1H), 4.35 (m, 1H), 4.18 (m, 1 H), 4.00 (m, MS (MALDI): 1H), 3.87 (m, 1H), 157 HO 1’ “J m/Z = 344.2 3.81-3.65(rn, 5H), ([M+H]+). 3.51—3.35 (m, 5 H), 3.21-3.04(rn, 1H), 1.44 (s, 3 H), 1.45 (s, 3 H). 1H NMR (400 MHz, (CD3)ZSO): 8 3.77 (m, 4 H), 3.65 (m, 4 H), MS (MALDI): i58 L, j 3.44 (m, 2 H), 2.56 (m, m/Z = 353.0 4 H), 1.64 (m, 1 H), ([M+H]+). 1.44 (s, 6 H), 0.44 (m, 2 H), 0.35 (m, 2 H). 1H NMR (400 MHz, (CD3)ZSO): 8 3.76 (m, 4 H), 3.68 (m, 4 H), MS (MALDI): i59 N 3.47—3.44 (m, 4 H), m/Z = 371.1 3.24 (m, 3 H), 2.52— ([M+H]+). 2.45 (m, 6 H), 1.44 (s, 6 H).

Method 18: 4-(diﬂuoromethy1)pyridinarnine (i65) F F F F 1\—*1 \ / / N C1 N NH2 — 100 — Palladium acetate (275 mg, 1.22 mmol, 0.05 eq.) and 2-dicyclohexylphosphin0- 2',4',6'-triis0pr0pylbiphenyl (Sigma-Aldrich, product number 638064, 1.17 g, 2.45 mmol, 0.10 eq.) are dissolved in 1,4-dioxane (10 mL) under nitrogen atmosphere, and the resulting mixture is allowed to stir at room temperature for 45 minutes. This solution is then added to a mixture of utylcarbamate (Sigma, product number 167398, 4.30 g, 36.7 mmol, 1.5 eq.), CS2C03 (15.9 g, 48.8 mmol, 2.0 eq.) and 2-chlorodiﬂuoromethyl-pyridine ester Organics, t number , 4.00 g, 24.5 mmol, 1.0 eq.) in 1,4-dioxane (80 mL) under nitrogen atmosphere. The resulting reaction mixture is then heated at 90 CC for 3 hours, during which it turned brownish. After this time, the mixture is allowed to cool to room temperature. It is then diluted with ethyl acetate, washed with an aqueous ted solution of ammonium chloride (2 x 30 mL) and deionized water. The organic layer is dried over anhydrous sodium sulfate, ﬁltered and the solvent is evaporated under reduced pressure. The brownish residue is mixed with 4 M HCl in dioxane (50 mL, excess) and methanol (20 mL), and then heated at 80 0C for 45 minutes. Deionized water is added and the aqueous layer is washed with ethyl acetate (3 x). The s layer is then basif1ed to pH = 9, with solid sodium hydroxide. The aqueous layer is extracted with ethyl acetate (3 x). The combined organic layer is dried over anhydrous sodium sulfate, ﬁltered and concentrated to dryness under reduced pressure. The d product i65 is obtained as a colorless solid, which is used in the next step without further purification (98% yield). 1H NMR (400 MHZ, CDC13)I 8 8.16 (d, 9H),: 5.2 Hz, 1 H), 6.74 (d, 9H),: 4.8 Hz, 1 H), 6.59 (s, 1 H), 6.51 (t, ZJHF = 56 Hz, 1 H), 4.61 (br s, 2 H); 19F NMR (376 MHz, CDClg): 5 — 116.0 (s, 2 F).

Method 19: 5-bromo(diﬂuoromethyl)pyridinamine (i66) F F F F \ \ l _, l / / N NH2 NH2 i65 i66 To a solution of compound i65 (3.00 g, 20.8 mmol, 1.0 eq.) in tetrahydrofuran (60 mL) is added N—bromosuccinimide (3.89 g, 21.9 mmol, 1.05 eq.) at 0 0C in an ice bath. The resulting e is stirred ght, while it is d to warm up to room temperature.

Ethyl acetate is added and the organic layer is washed with aqueous sodium carbonate (8%).

WO 98347 2017/025137 — 101 — The organic layer is then separated and acidiﬁed with an aqueous 3 M HCl-solution. The aqueous layer is washed with ethyl e (3 x 50 mL) and then basiﬁed to pH = 10, with solid sodium hydroxide. The aqueous layer is extracted with ethyl acetate (3 x 50 mL). The combined organic layer is dried over anhydrous sodium sulfate, ﬁltered and concentrated to dryness under reduced pressure. The desired product i66 is obtained as a brownish solid, which is used in the next step without further puriﬁcation (79% . 1H NMR (400 MHz, CDC13): 5 8.20 (s, 1 H), 6.75 (s, 1 H), 6.71 (t, ZJHF = 54 Hz, 1 H); 4.62 (br s, 2 H); 19F NMR (376 MHz, CDC13)C 8 — 118.9 (s, 2 F).

Method 20: N'-(5-bromo(diﬂuoromethyl)pyridin—2-yl)-N,N—dimethylformimidamide (i67) F F F F Br Br \ \ I ' N/ N/ / NAle/ i66 i67 To a solution of compound i66 (3.68 g, 16.5 mrnol, 1.0 eq.) in tetrahydrofuran (50 mL) is added N,N—dimethylformamide dimethyl acetal (Manchester cs, product number 005030, 3.30 mL, 24.8 mrnol, 1.5 eq.) and the resulting mixture is stirred at 60 0C for 3 hours.

The mixture is allowed to cool to room temperature and the t is evaporated under reduced pressure. The crude product is puriﬁed by column chromatography on silica gel (cyclohexane / ethyl acetate 1:1) to afford the desired product i67 as a yellowish solid (82% yield). 1H NMR (400 MHz, CDC13)C 8 8.43 (s, 1 H), 8.34 (br s, 1 H), 7.17 (s, 1 H), 6.73 (t, 2.1”: 54 Hz, 1 H), 3.12 (s, 3 H), 3.10 (s, 3 H); 19F NMR (376 MHz, CDC13): 8 — 118.6 (s, 2 F); MS (MALDI): m/Z = 278.5 ([M+H]+).

Method 21: (diﬂuoromethyl)(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolanyl)pyridin yl)-N,N—dimethylformimidamide (i68) F F Q“? F F \ 0’8 \ I l N/ N¢\l\ll/ N/ NAT/ i67 i68 To a 2 M solution of isopropylmagnesium chloride (Sigma, product number 230111, 3.10 mL, 6.20 mmol, 1.15 eq.) in tetrahydrofuran (6 mL) is slowly added a solution of — 102 — compound i67 (1.50 g, 5.39 mrnol, 1.0 eq.) in tetrahydrofuran (5 mL) at 0 oC. The resulting brownish mixture is stirred at 0 CC for 45 minutes and then at room temperature for minutes. After this time, TLC monitoring (cyclohexane / ethyl acetate 1:1) showed te consumption of starting material. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (Manchester Organics, product number W23343, 1.43 mL, 7.00 mrnol, 1.3 eq.) is added and the mixture is heated at 60 CC for 3 hours. The mixture is then placed in an Erlenmeyer ﬂask, cooled to 0 0C with an ice bath and quenched with a 15% aqueous on of ammonium chloride. The layers are separated and the aqueous layer is extracted with ethyl acetate (3 x 40 mL). The combined organic layers are dried over anhydrous sodium sulfate, ﬁltered and the solvent is ated under reduced pressure. Heptane is added and the organic layer is washed with a ted aqueous solution of sodium onate, dried over ous sodium sulfate, ﬁltered and then concentrated to dryness under d pressure.

The d product i68 is obtained as a brownish oil, which is used in the next step without further puriﬁcation (94% yield). 1H NMR (400 MHZ, CDC13)I 8 8.66 (s, 1 H), 8.51 (s, 1 H), 7.34-7.04 (m, 2 H), 3.12 (s, 3 H), 3.12 (s, 3 H), 1.34 (s, 12 H); 19F NMR (376 MHz, CDC13): 5 — 115.6 (s, 2 F); Ms (MALDI): m/Z = 326.0 ([M+H]+).

Method 22: 4-(diﬁuoromethyl)pyrimidinamine (i69) F F o o FWAOJY F N mm... ‘ A F F N NH2 i69 To a solution of ethyl vinyl ether (4.00 mL, 41.8 mmol, 1.0 eq.) in a mixture of pyridine (4.10 mL, 50.7 mmol, 1.2 eq.) and dichloromethane (40 mL), is added dropwise a solution of 2,2-diﬁuoroacetic anhydride (Manchester Organics, (product number L24754, .90 mL, 50.1 mrnol, 1.2 eq.) in dichloromethane (5 mL) at — 70 0C in a dry ice / isopropanol bath. The resulting solution is allowed to warm up to room temperature overnight. The e is then washed with deionized water, dried over anhydrous sodium sulfate, ﬁltered and the solvent is evaporated under reduced pressure to afford an orange oil.

At the same time, a suspension of guanidine-HCl (Sigma, product number 50940, 4.80 g, 50.2 mmol, 1.2 eq.) in ethanol (20 mL) is stirred at room ature for 1 hour. To this solution are added sodium hydroxide pellets (2.00 g, 50.0 mrnol, 1.2 eq.) in one portion. — 103 — The resulting suspension is stirred at room ature overnight.

The orange oil is diluted with dichloromethane (20 mL) and added se over 1 hour to the ethanol suspension. The resulting suspension is stirred at room temperature for 2 hours. Dichloromethane is ated under reduced pressure. Deionized water (25 mL) is added to the residue. The resulting mixture is d vigorously for 2 hours and is then allowed to stand at room temperature overnight. The formed solid is ﬁltered off, washed with deionized water (2 x) and heptane (1 x) and then dried in vacuo. The desired product i69 is obtained as a colorless solid (65% yield). 1H NMR (400 MHz, CDC13)C 8 8.43 (d, 2.7111,: 4.8 Hz, 1 H), 7.02 (br s, 2 H), 6.76 (d, 2.7111,: 5.2 Hz, 1 H), 6.67 (t, 2.11”: 55 Hz, 1 H); 19F NMR (376 MHz, CDClg): 5 — 120.5 (s, 2 F).

Method 23: 5-bromo(diﬂuoromethyl)pyrimidinamine (i70) F F F F \ \ 1 ,1 -—> 1 ,1 N NH2 N NH2 i69 i70 To a solution of nd i69 (3.00 g, 20.7 mrnol, 1.0 eq.) in tetrahydrofuran (90 mL) is added N—bromosuccinimide (3.86 g, 21.7 mmol, 1.0 eq.) portionwise at 0 oC. The reaction mixture is allowed to warm up to room temperature ght. After this time, the solvent is evaporated under reduced pressure. The residue is taken up in ethyl acetate (200 mL), washed with an aqueous saturated solution of sodium carbonate (4 x), dried over anhydrous sodium sulfate, ﬁltered and then concentrated to dryness under reduced re. The desired t i70 is obtained as a yellowish solid, which is used in the next step without ﬁarther puriﬁcation (98% yield). 1H NMR (400 MHz, (CD3)2SO): 8 8.50 (s, 1 H), 7.30 (br s, 2 H), 6.87 (t, ZJHF = 53 Hz, 1 H); 19F NMR (376 MHz, (CD3)2SO):8 — 121.4 (s, 2 F).

Method 24: N—tert—butyl carboxylate-N—(5-bromo(diﬂuoromethyl)pyrimidinyl)- carbamatei71 Br%:NHZ F F i70 i71 — 104 — nd i70 (4.35 g, 19.4 mmol, 1.0 eq.) and 4-(dimethylamino)pyridine (480 mg, 3.92 mrnol, 0.20 eq.) are dissolved in tetrahydrofuran (50 mL). N,N-Diisopropylethyl— amine (7.50 mL, 42.1 mmol, 2.2 eq.) and di-tert—butyl dicarbonate (9.33 g, 42.7 mmol, 2.2 eq.) are then added at 0 CC and the resulting solution is allowed to warm up to room temperature overnight. The solvent is evaporated under reduced pressure. The crude product is puriﬁed by column chromatography on silica gel (cyclohexane / ethyl acetate 9:1 —> 4: 1) to afford the desired product i71 as a colorless solid (85% yield). 1H NMR (400 MHz, CDClg): 5 8.92 (s, 1 H), 6.73 (t, 2.11”: 53 Hz, 1 H), 1.47 (s, 18 H); 19F NMR (376 MHz, CDClg): 5 — 120.4 (s, 2 F). l procedure 1: R2 ‘1 F..... .F 70 ’322 1i, I “F 1 x3 ‘3‘sz x x2 b a “1,3, i g; A 1 [ﬁx + 3 x —, 1 “a i 1 » “it, 3 ~ R X R x c: «.N» N L A g N NH2 i68 (I) Substituted monochloro-triazine or substituted monochloro-pyrimidine (1.0 eq.), compound i68 (1.1 eq.), potassium phosphate tribasic (2.0 eq.) and (2-dicyclohexyl- phosphin0-2 ',4',6 '-triis0pr0pyl—1,1 '-biphenyl) [2-(2 '-amin0-1,1 '-biphenyl)] -palladium(II) (Sigma-Aldrich, product number 741825, 0.05 eq.) are charged in a ﬂask. Under nitrogen atmosphere, oxane (30 volumes) and deionized water (1.5 volume) are added and the resulting mixture is then directly placed into an oil bath pre-heated at 95 CC. The reaction mixture is d at this temperature for 2 hours. A 5 M aqueous HCl—solution (20 eq.) is added. The resulting mixture is heated to 60 oC overnight. The pH of the resulting mixture is adjusted to 8-9 by on of a 2 M aqueous solution of sodium hydroxide, the mixture is then extracted with ethyl e (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 products of structure (I).

WO 98347 — 105 — General procedure 2: FVF \l? FT F R2 t x , ,1. XMXQFVF. , Br [N O B..V/., TE “)6? R1.lLX3.:l / LN ll E N + RV‘xfkca ll t, E.

N” N(Boc)2 N N(Boc)2 N NH2 i71 (1) Compound i71 (1.0 eq.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-di0xaborolane) (Manchester Organics, product number M23170, 1.5 eq.), potassium acetate (3.0 eq.) and [l , l ’-bis(diphenylph0sphino)-ferrocene]-dichloropalladium(II) (Sigma-Aldrich, t number 697230, 0.099 eq.) are dissolved in 1,4-dioxane (12.5 s) under nitrogen atmosphere. The resulting mixture is heated at 100 CC for 15 minutes (solution turned black).

TLC monitoring (cyclohexane / ethyl e 3:1) is used to show complete consumption of starting material.

To the resulting mixture, substituted chloro-triazine or substituted chloro- pyrimidine (1.1 eq.), an aqueous solution of potassium ate (2 M, 3.0 eq.) and a previously mixed solution oftriphenylphosphine (0.12 eq.) and palladium acetate (0.04 eq.) in tetrahydroﬁlran (100 volumes) are added. The resulting mixture is heated at 60 CC for 2 hours and subsequently allowed to cool to room temperature.

A 5 M aqueous HCl—solution (20 eq.) is added. The resulting mixture is heated to 60 oC overnight. The pH of the resulting mixture is adjusted to 8-9 by addition of a 2 M aqueous solution of sodium hydroxide, the e is then extracted with ethyl acetate (3 x 20 volumes). The combined organic layers are dried over anhydrous sodium sulfate, d and the solvent is evaporated under reduced pressure. ation by ﬂash tography affords the desired products.

Method 27: utyl N—tert—butoxycarbonyl-N—(5 -(4-chlor0m0rpholin0- l ,3 ,5 -triazin yl)(diﬂuoromethyl)pyrimidinyl)carbamate (i74) ,0,» (,0, :— f 1 l 7 l t N N a. ,F i l F F l 1 \ / Q A F\ ,,.,F E B!” B 2. N' ”N N “N ‘x [/33 N l / «O, My lib/V; N l l ll, [L k l L 21., 5 l A,“ + ’ c: ‘N‘”"“cz N j N" “c: N” MSW); g N N(Boc)2 ,il g (800)2N N 1 — 106 — i71 i11 i74 Intermediate i71 (2.00 g, 4.71 mmol, 1.0 eq.), bis(pinacolato)diboron (1.80 g, 7.09 mmol, 1.5 eq.), KOAc (1.60 g, 16.3 mmol, 3.4 eq.) and [1,1’- bis(diphenylphosphino)ferrocene]-dichloropalladium(H) (350 mg, 478 umol, 0.10 eq.) are mixed in oxane under en atmosphere and heated at 95 CC for 45 minutes. A pre- catalyst solution of palladium(II) acetate (43.0 mg, 192 umol, 0.04 eq.) and triphenylphosphine 148 mg, 564 umol, 0.12 eq.) in ydrofuran (2 mL) is also prepared and stirred at room temperature for 1 hour. This solution is then added to the cooled above solution at room temperature, followed by the addition of 4-(4,6-dichloro-1,3,5-triazin yl)morpholine i11 (1.65 g, 7.05 mmol, 1.5 eq.) and aqueous KZCOg-solution (2.4 M, 5.90 mL, 14.2 mmol, 3.0 eq.). The resulting mixture is heated at 55 CC ght. After this time, the mixture is poured onto an aqueous NH4Cl-solution (15%) and extracted with ethyl acetate (3 x). The combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Puriﬁcation by column chromatography on silica gel (cyclohexane / ethyl acetate 1:0 to 4: 1) gives product i74 as a colorless solid (36% . 1H NMR (400 MHz, CDCl3)I 8 9.57 (s, 1 H), 7.55 (t, UHF: 54 Hz, 1 H), 3.99-3.91 (m, 4 H), 3.84-3.76 (m, 4 H), 1.49 (s, 15 H); 19F NMR (376 MHz,CDC13): 5 — 121.0 (s, 2 F).

Method 32: (E)ethoxy-1,1-diﬂuoro-buten—2-one (i83) F F f: A. + W6 , . _,.

F, W507? 1., F,,..1..WWOV, O Q 0 To a cooled (-70°C) solution of ne (61.5 mL, 760.5 mmol, 1.2 eq) in dichloromethane (500 mL) is added ethyl vinyl ether (60 mL, 626.5 mmol, 1 eq), followed by a solution of diﬂuoroacetic anhydride (88.5 mL, 760.5 mmol, 1.2 eq) in dichloromethane (75 mL). Then the mixture is slowly warmed to room temperature overnight. The e is transferred into a ting ﬂannel and the organic layer is washed with water (6x800 mL) until the pH of the aqueous layer becomes neutral. The organic layer is dried over sodium sulfate and solvent is removed under reduced pressure to afford the desired product i83 as an orange Oll (76.7 g, 51%). 1H NMR (400 MHz, (CD3)2SO): 5 7.92 (d, 3.111,H = 12.5 Hz, 1H), 6.34 (t, 2.11,,F = 53.6 Hz, 1H), 5.57 (d, 3.11,,H = 12.5 Hz, 1H), 4.14 (q, 3.11,,H = 7,1 Hz, 2H), 1.28 (t, 3.11,,H = 7,1 Hz, 3H); 19F NMR (400 MHz, (CD3)2SO): 5 —127.39 (s, 2F). — 107 — Method 33: (E)(difluoromethyl)ethoxyhydroxy-pentenenitrile (i84) F F 1 . M 1% 6 z m x"14::”TV6 “\l‘x‘“ «48.x F 68/“ F” 11 f 183 i84 To a cooled (-70°C) solution of n-butyl lithium 2.5M (102.9 mL, 256.7 mol, 1 eq) in tetrahydroﬁlran (435 mL) is added itrile (13.4 mL, 256.7 mol, 1 eq). A White suspension is formed and is stirred at -70°C for 1.5 hours. A solution of (E)ethoxy-1,1- diﬂuoro-buten—2-one (i83) (38.5 g, 256.7 mol, 1 eq) in ydrofuran (65 mL) is added to the White suspension re becomes an orange solution). The mixture is stirred at -70°C for 1 hour and slowly warmed to room temperature. Water (400 mL) is added. Then ethyl acetate (600 mL) is added. Layers are separated and aqueous layer is extracted with ethyl acetate (3 X600 mL). Combined organic layers are dried over sodium sulfate and solvent is evaporated under reduced pressure. Filtration on a short pad of silica gel, using a e of cyclohexane/ethyl acetate (3:1) as eluent, gives the desired product i84 as a dark orange oil (434 g, 88%).1H NMR (400 MHz, (CD3)2SO): 5 6.66 (d, 3.111,H = 12.8 Hz, 1H), 6.20 (s, 1H), .79 (t, 2.11,,F = 55.8 Hz, 1H), 4.75 (d, 3.11,,H = 12.8 Hz, 1H), 3.74 (q, 3.11,,H = 7.0 Hz, 2H), 2.88 (d, 3.11,,H = 16.8 Hz, 1H), 2.81 (d, 3.11,,H = 16.8 Hz, 1H), 1.21 (t, 3.11,,H =70 Hz, 3H); 19F NMR (400 MHz, (CD3)2SO): 8 -129.32 (d, 2JRF = 311.2 Hz, 1F), 5 (d, 2.11:; = 311.2 Hz, 1F).

Method 34: 4-(diﬂuoromethyl)pyridin—2-amine (i65) T, F F A OH x (”*9 m. /’”-;:K Ox M// F 5 —- 1 .1N. m. “N182 i84 i65 To a solution of (E)(diﬂuoromethyl)ethoxyhydroxy-pentenenitrile (i84) (8.1 g, 42.4 mol, 1 eq) in acetic acid (80 mL) is added O-methylhydroxylamine hydrochloride ochem, product number ) (10.6 g, 127.2 mrnol, 3 eq). Mixture is stirred at 50°C for 7 hours. Then reaction mixture is cooled down to room temperature and hydrobromic acid in acetic acid (33%) (14.2 mL, 84.8 mol, 2 eq) is added. Reaction mixture is stirred at 90°C — 108 — overnight. Reaction mixture is degassed and placed under nitrogen. Reaction mixture is maintained at room temperature with a water bath with ice while zinc powder (8.12 g, 127.2 mol, 3 eq) is added portionwise. Reaction mixture is stirred 3 h at room temperature.

Mixture is ﬁltered over a short pad of celite and the cake is washed with ethyl acetate. Then the major part of the solvent is removed under d pressure. 60 mL of s ammonium hydroxide (28%) is added. Aqueous layer is extrated with dichloromethane (3x150 mL). Combined organic layers are dried over sodium sulfate. Compound i65 is recrystallized from dichloromethane and heptane as anti-solvent (solvent switch at the p). Compound i65 is collected, as a light yellow solid, by ion (5.12 g, 84%).

Method 35: 9-[4-chloro(3-oxaazabicyclo[3.3.1]nonanyl)-1,3,5-triazinyl]-3,7- dioxaazabicyclo[3 .3 . 1 e (i89) o Q7 / '7 j x; (i‘ml‘Vftlei/“ﬂi i 7 N i /\A j \‘3 r’itfx Nib/\M‘ ,./ “>7 N N”! CRN + N “in {AN) l.l .71. 7N ” »N N c; c: "“N “C: H 73;}?// i88 i89 To a solution of 3-oxaazabicyclo[3.3.1]nonane hydrochloride (176 mg, 1.20 mmol, 1.05 eq.) and N,N—diisopropylethylamine (0.42 mL, 2.40 mmol, 2.1 eq.) in 1,4-dioxane (5 mL) a solution of i88 (300 mg, 1.14 mol, 1 eq.) in 1,4-dioxane (1 mL) is added. The resulting mixture is heated for 3 hours (75 CC). Then, ethyl acetate (20 mL) and saturated aqueous sodium bisulfate (20 mL) are added. The phases are separated and the organic layer is washed with saturated aqueous sodium bisulfate (2 x 20 mL). The organic layer is dried over anhydrous sodium e and the solvent is removed under reduced pressure. The crude mixture is d by automated ﬂash chromatography (SiOz, cyclohexane / ethyl e 2:1 to 0:1) to afford the title compound i89 as a colorless solid (297 mg, 75%). 1H NMR (400 MHz, (CD3)2SO): 8 4.58 (m, 1 H), 4.44 (m, 1 H), 4.40 (m, 1 H), 4.32 (m, 1 H), 4.00-3.97 (m, 4 H), 3.94 — 3.90 (m, 2 H), 3.72 — 3.64 (m, 6 H), 2.46 (m, 1 H), 1.90 — 1.70 (m, 4 H), 1.53 (m, 1 H). MS (MALDI): m/Z = 368.0 ([M+H]+). — 109 — Preparation ofCompounds ofthe Invention Compound 1: luoromethyl)(4,6-dimorpholino-1,3,5-triazinyl)pyridinamine (1) (CR 0 MIN/1“ C? i: F E‘ l 1, 3i/l a“? /’ Riff/i N/ N N \O ,/B \U N /\';:,N F\\€/F /i§-. 4123:] ~~ 4/} if“ ‘x / j‘L “fix Ex [ 131 N C? N 1313 1 N N \ .3 H xx,» \ilEl'l/ Ox x N LNHZ i2 i68 1 According to general procedure 1, compound 1 is obtained from starting materials i2 and i68 in 73% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 8 9.02 (s, l H), 7.65 (t, 2.1”: 55 Hz, 1 H), 6.83 (s, 1 H), 4.85 (br s, 2 H), 3.89-3.79 (m, 8 H), 3.77-3.72 (m, 8 H); 19F NMR (376 MHz, CDClg): 8 — 115.9 (s, 2 F); Ms (MALDI): m/Z = 393.9 ([M+H]+).

Compound 2: 4-(difluoromethyl)(4,6-dimorpho lino- 1 ,3 ,5 -triazinyl)pyrimidin—2- amine (2) ,_.o\ o l i 1 l ,1 t L ,l FIN/F 1 \/\“O F\/F ’N’ N l 1 \..)\ 1 1 1C is, a. F Br//// 0"B‘~-/"*3‘N l TL {7N ,,,,,,,,,,,,,,,,,,,,,,,,,,,. l + 1 N U ,. All [T T A ML 'N/T ;:J~_\ : ;CL\ ,,,,,, i/ N C! E/ N VNCQ» / N N N(Boc)2 N g {“80ij I V é,\/,J UNI/{xNHz i71 i2 2 According to general procedure 2, nd 2 is obtained from starting materials i2 and i71 in 74% yield as a colorless solid. 1H NMR (400 MHZ, CDC13)I 59.20 (s, 1H), 7.62 (t, 2.1”: 54 Hz, 1 H), 5.97 (br s, 2 H), 3.91-3.68(n1, 16 H); 19F NMR (376 MHz, CDClg): 8 — 121.5 (s, 2 F); Ms (MALDI): m/Z = 395.2 ([M+H]+).

Compound 3: 5-(4-(3-oxaazabicyclo[3.2.l]octan—8-yl)(3-oxaazabicyclo[3.2.1]octan— 8-yl)- 1 ,3 ,5 -triazinyl)(diﬂuoromethyl)pyridinamine (3) O .O\ 16:, \‘l 1 Fm F 1’: )1 1 5 9 / \o B r 1 N.” ‘N J, 1] W N’"‘“‘N F“ X? ,1: 11 7.. .2 ,2, )1 /1 l E N N “Cl N N "fl KN N; N" (1w 1N. (159 1. \1t.

“ V N NH2 i1 i68 3 — llO — According to general procedure 1, compound 3 is obtained from starting materials i1 and i68 in 75% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 89.04 (s, 1H), 7.71 (t, ZJHF= 55 Hz, 1 H), 6.83 (s, l H), 4.89 (br s, 2 H), 4.71-4.64 (m, 4 H), 3.79-3.76 (m, 4H), .62 (m, 4H), 2.09-1.98 (m, 8H); 19F NMR (376 MHz, C8—115.4- (— 117.3) (m, 2 F); MS (MALDI): m/z = 446.3 ([M+H]+).

Compound 4: 5-(4-(3-oxaazabicyclo[3 .2. l ]octanyl)morpho lino- l ,3 ,5-triazinyl) (diﬂuoromethyl)pyridin—2-amine (4) / ”o...

N ,4 C? l N N/EQN ﬁO/BW'I/ “611» N/LEN fan/4;: r,» \.N/ «V‘Nl/ MC; KIN/ N WN/ RN? ll f J «Ky/ugh] O J / O L .5, \\ \“ f}! * N/ NH2 i12 i68 4 According to general procedure 1, compound 4 is obtained from starting materials i12 and i68 in 57% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 89.03 (s, 1H), 7.68 (m, l H), 6.83 (s, l H), 4.94 (br s, 2 H), 4.70-4.65 (m, 2 H), 3.93-3.57 (m, 12 H), 2.14- 1.92 (m, 4H); 19F NMR (376 MHz, CDClg): 8— 116.0-(— 116.2) (m, 2F); MS(MALDI): m/Z = 420.6 ([M+H]+).

Compound 5: 5-(4-(3-oxaazabicyclo[3 .2. l]octanyl)morpho lino- l riazinyl) (diﬂuoromethyl)pyrimidin—2-amine (5) _ ,0 ,O\ “ 44" [rﬁ x F». .F l “\le0 FWF l/Nﬁl EN} Brx '/LN l \/o/li3\ 1 N “ “; NJ?“ F‘x/ F l A 1 l ’ L l L ,l A l, N' N(BOC)2 } N N(BOC)2 f 'N“ N C: l N N 0v) 0 T L J /V “M“ ‘NH; i71 i12 5 According to general procedure 2, nd 5 is obtained from starting materials i71 and i12 in 50% yield as a colorless solid. 1H NMR (400 MHZ, CDC13)I 59.23 (s, 1H), 7.65 (t, UHF: 54 Hz, 1 H), 5.66 (br s, 2 H), 4.68 (m, 2 H), 3.90-3.61 (m, 12 H), 2.13- 1.92 (4 H); 19F NMR (376 MHz, CDClg): 8 — 120.4—(—121.5) (m, 2 F); Ms (MALDI): m/Z = 420.9 ([M+H]+). — lll — Compound 6: 5-(4,6-bis((S)methylmorpholino)-l,3,5-triazinyl) (diﬂuoromethyl)pyridin—2-amine (6) .o. J J .0, ” J F~.\ , F , ‘3 3 2 l , N. A” / \b/ ,J/ K /'"x’:: LN) N N JNJ, ““N N N I /////// AL .JL g; ’ N N‘ “Ci ”’A“N"’i‘i‘N’/‘J\ LJ. l N {I } ll O l V/ l O ««««««« xN \NHZ i3 i68 6 According to general procedure 1, compound 6 is obtained from starting materials i3 and i68 in 79% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 8 8.87 (s, 1H), 7.70 (t, UHF: 55 Hz, 1 H), 6.86 (s, l H), 5.48 (br s, 2 H), 4.73-4.72 (m, 2 H), 4.41-4.38 (m, 2 H), 3.98 (dd, JHH= 11.6, 3.8 Hz, 2 H), 3.78 (d, JHH= 12 Hz, 2 H), 3.67 (dd, JHH= 12, 3.2 Hz, 2 H), 3.52 (td, JHH=12, 3.0 Hz, 2 H), 3.27 (td, JHH= 13, 3.8 Hz, 2 H), 1.33 (d, 3.1111,: 6.8 Hz, 6 H); 19F NMR (376 MHz, CDClg): 5 — 115.4-(—116.2) (m, 2 F); Ms ): m/Z = 421.9 ([M+H]+).

Compound 7: 5-(4,6-bis((S)methylmorpholino)-l,3,5-triazinyl) (diﬂuoromethyl)pyrimidin—2-amine11) o o F ,/F \L F\,,,F L 3 L ,l Br l \‘/ J: 4 [ll T F p t J —* 0 \i + —* N i ‘J rt) I.

N" N<Boc>2 N N<Boc)2 (“)7 """"N\\\Cl L/ A)?" ‘N" \z/"JN ov om/ \NH? i71 i3 7 According to general ure 2, compound 7 is ed from starting materials i71 and i3 in 52% yield as a colorless solid. 1H NMR (400 MHZ, I 8 9.24 (s, l H), 7.66 (t, 2J1”: 54 Hz, 1 H), 5.77 (br s, 2 H), 4.73 (br s, 2 H), 4.45-4.32 (m, 2 H), 3.98 (dd, JHH= 12, 3.6 Hz, 2 H), 3.78 (d, JHH= 12 Hz, 2 H), 3.67 (dd, JHH= 11, 2.8 Hz, 2 H), 3.52 (td, JHH= 12, 2.8 Hz, 2 H), 3.27 (td, JHH= 13, 3.2 Hz, 2 H), 1.33 (d, 3JHH= 6.8 Hz, 6 H); 19F NMR (376 MHz, CDClg): 5 — 120.5—(— 122.7) (m, 2 F); Ms (MALDI): m/Z = 423.3 ([M+H]+).

Compound 8: (S)(difluoromethyl)(4-(3-methylmorpholino)morpholino-l,3,5-triazin- 2- l idinamine 8 — 112 _ .4/0 ~ “xx 5 4'0 ~64 L J 95*“? ”‘1 L ,L i + 13"”8‘1‘L” L .. E F F Ni RN in ’/«_ N’ *§N \MM ~ ,4 4 913.; 'g ,,,,,,,, ,1: 4 41% 4fo? 3’ N N C! m / f N N O ”i L o. 41 ll 414 k/ N“ N MHZ i13 i68 8 ing to general procedure 1, compound 8 is obtained from ng materials i13 and i68 in 47% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 89.03 (s, 1H), 7.70 (t, ZJHF= 55 Hz, 1 H), 6.84 (s, 1 H), 4.78 (br s, 2 H), 4.75 (m, 1 H), 4.42-4.38 (m, 1 H), 4.00-3.96 (m, 1H), 3.8466 (m, 10 H), 3.55-3.50 (m, 1H), 3.30-3.25 (m, 1H), 1.33 (d, 3.1111,: 6.8 Hz, 3 H); 19F NMR (376 MHz, CDClg): 5 — 116.1-(—115.9) (n1, 2 F); Ms (MALDI): m/Z = 408.9 ([M+H]+).

Compound 9: (S)-4—(difluoron1ethyl)(4-(3-n1ethylniorpholino)niorpholino-1,3,5-triazin- 2-yl)pyrin1idinan1ine (9) «' . r»; .F Lo F ,1: . lmel LN) Bra E -33 l. l ,L F, F T \N O \U + 1 NJVN 4:7"\ x, 4;“1 IT; VT 4 4; . A, l 44:1 r 14 N N(Boe)2 N N(BOC)2 ‘4 by} “N/ Kc; / g? .N, TL” \‘N J O 0 v4 ,,,,,, lix‘N'A'Nl—iz i71 i13 9 According to general procedure 2, compound 9 is obtained from starting materials i71 and i13 in 60% yield as a colorless solid. 1H NMR (400 MHZ, CDC13)I 59.24 (s, 1H), 7.66 (t, 2J1”: 54 Hz, 1 H), 5.67 (br s, 2 H), 4.74 (m, 1 H), 4.41-4.38 (m, 1 H), 4.00-3.97 (m, 1 H), 3.90-3.72 (m, 9 H), 3.68-3.36 (m, 1 H), .49 (m, 1 H), 3.32-3.25 (m, 1 H), 1.33 (d, 3.1111,: 6.9 Hz, 3 H); 19F NMR (376 MHz, CDClg): 5 — 121.3—(— 121.6) (m, 2 F); Ms (MALDI): m/Z = 409.4 ([M+H]+).

Compound 10: 5-(4-(3-oxaazabicyclo[3.2.1]octanyl)((S)n1ethylniorpholino)- 1 ,3 ,5-triazinyl)(diﬂuoroniethyl)pyridinan1ine (10) (QT Mo.»1 Fm 4F / Elmo \ l‘nN/V,“ 1 j (13 ‘L i i‘ 4“ 6:351 Fx F N N O I; ”5&1 N l .....................................................,. 4 / l 44 4i 1/: I . f , R x \ R xx. (<2 N , N Ci {1/ L N N \"M 13} 1313 \ W? x f, ‘ \g '43];”I i18 i68 10 — 113 — ing to general ure 1, compound 10 is obtained from starting materials i18 and i68 in 42% yield as a colorless solid. 1H NMR (400 MHZ, CDC13)I 59.04 (s, 1H), 7.69 (t, UHF: 55 Hz, 1 H), 6.84 (s, l H), 4.85 (br s, 2 H), 4.71-4.65 (m, 3 H), 4.42-4.39 (m, l H), 3.98-3.95 (m, l H), 3.79-3.76 (m, 3 H), 3.70-3.65 (m, 3 H), 3.56-3.53 (m, l H), 3.30- 3.27 (m, 1 H), 2.10—1.99 (m, 4 H), 1.33 (m, 3 H); 19F NMR (376 MHz, CDClg): 5 — 115.9— 2) (m, 2 F); MS (MALDI): m/z = 434.2 ([M+H]+).

Compound 1 1: 5-(4-(3-oxaazabicyclo[3 .2. l]octanyl)((S)methylmorpholino)- l ,3 ,5 -triazinyl)(diﬂuoromethyl)pyrimidinamine (1 1) 4 ,,o,\ ,,_o F\_.F 7‘10 F\ F l l l ] Br /:lw. :‘X\ .é w: 31 f: F l “f 0 1‘ N l ‘13"? fl! 1 \l N "N(Boc)2 N “N(Boc)2 lf—N \N {7? N N7 \U \ (31 N O\A// Ox? N LXNHQ i71 i18 11 According to general procedure 2, compound 11 is ed from starting materials i71 and i18 in 46% yield as a colorless solid. 1H NMR (400 MHZ, I 8 9.25 (s, 1 H), 7.68 (t, ZJHF= 55 Hz, 1 H), 5.81 (br s, 2 H), 4.71-4.65 (m, 3 H), 4.42-4.38 (m, l H), 4.00- 3.96 (m, l H), 3.81-3.60 (m, 6 H), .50 (m, l H), 3.31-3.24 (m, l H), 2.11-2.00 (m, 4 H), 1.37-1.28 (m, 3 H); 19F NMR (376 MHz, CDClg): 5 — 121.5—(— 121.7) (m, 2 F); Ms (MALDI): m/Z = 434.6 ([M+H]+).

Compound 12: 4-(diﬂuoromethyl)(4-morpholino(piperazin- l -yl)- l ,3 ,5-triazin yl )pﬂidinamine 1 12) "#031 o * J N F1, l 1 NIE/ “NW/lac? , F \ / I, 23/ F F N/“Q'N NQ/B v/QQ; N/QQX‘N / 5 /i« 72% ’1 C‘ ilxN ,/13\ ,"L\ I\ N 13 N x" N \ 6 1L Hit. 1 l l x / xﬁ/ \W/ {I} 'x/ N NH2 i14 i68 12 According to general procedure 1, compound 12 is obtained from starting materials i68 and i14 in 86% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.85 (s, l H), 7.74 (t, UHF: 55 Hz, 1 H), 6.84 (s, 2 H), 6.75 (s, l H), 3.82-3.70 (m, 8 H), 3.69-3.60 (m, 4 H), 2.88-2.80 (m, 4 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 115.4 (s, 2 F); Ms (MALDI): m/Z = 393.8 ([M+H]+). — 114 — Compound 13: 4-(diﬂuoromethyl)(4-morpholino(piperazin- l -yl)- l ,3 azin yl)pyrimidin—2-amine (13) _ -1 |,o /,o,\ 1 11 1 l l.\ l FRI/1F 1 \f? F1\]/,F i 1‘ Bug/.1 1 f} )1 ﬁx ,3, 1’1 1 1:11 F N N N, w’ l 1 ,1 1 * ,1 f? _. 3‘1 f1 1 N” 1; 1 “N“ New» 1 ’I‘ N C' 1 N l "1‘ 11 J 1 l 1/0“11/N‘~"/ HNV/ N ‘NH2 i71 i14 13 According to general procedure 2, compound 13 is obtained from starting materials i71 and i14 in 55% yield as a colorless solid. 1H NMR (400 MHz, CDC13)I 59.23 (s, 1H), 7.64 (t, UHF: 55 Hz, 1 H), 5.60 (br s, 2 H), .75 (m, 12 H), .88 (m, 4 H); 19F NMR (376 MHz, CDClg): 5 — 111.4 (s, 2 F); Ms (MALDI): m/Z = 394.1 ([M+H]+).

Compound 14: (S)(diﬂuoromethyl)(4-(3-methylmorpholino)(piperazin-l-yl)-l,3,5- triazinyl)pyridinamine (14) ,,o ,0. x / 111 11 i ~~~~~~~ fmﬁq 1,13,. 1\[x \T/ F 0 .1 F1 N’ \N V ‘1 ll N’ “N / 1 1 11 ,1 J ‘1 [\il/ mN/ Cl N/ KIT}: {/ N/ \N R? (111‘ HN a; 1,0 / RN13 “/1 “N‘NN’NHz i21 i68 14 According to general procedure 1, compound 14 is obtained from starting materials i21 and i68 in 47% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 8 9.02 (s, l H), 7.67 (t, UHF: 56 Hz, 1 H), 6.84 (s, l H), 4.90 (br s, 2 H), 4.74 (s, l H), 4.40 (d, JHH= 16 Hz, 1 H), 3.98 (dd, JHH= 4.0 Hz, 12 Hz, 1 H), 3.91 (m, 4 H), 3.78 (d, JHH= 12 Hz, 1 H), 3.68 (dd, JHH= 4.0, 12 Hz, 1 H), 3.56 (t, JHH= 4.0 Hz, 1 H), 3.26 (dt, JHH= 4.0, 12 Hz, 1 H), 2.99 (t, JHH= 4.0 Hz, 4 H), 1.32 (d, JHH= 8.0 Hz, 3 H);19F NMR (376 MHz, CDClg): 5 — 115.9 (s, 2 F); Ms (MALDI): m/Z = 407.2 ([M+H]+).

Compound 15: (S)(diﬂuoromethyl)(4-(3-methylmorpholino)(piperazin-l-yl)-l,3,5- triazinyl)pyrimidin—2-amine (15) \I 1’01 1N1 F1 ,1: F. ,F 1. ~ x / 11 #11\ 1 r 1 111«1 , 1.x? 1 1 ,1 """"""_. N 1 1 + * 111 . N11 1 N” N(Boc)2 “N Mace); 1’ N C! N 1 1 T dill T \x‘ OWNX HN\ / xNo NH; — 115 — i71 i21 15 According to general procedure 2, nd 15 is obtained from starting materials i71 and i21 in 30% yield as a colorless solid. 1H NMR (400 MHZ, CDC13)I 59.24 (s, 1H), 7.66 (t, UHF: 56 Hz, 1 H), 5.69 (br s, 2 H), 4.74 (s, l H), 4.40 (d, JHH= 16 Hz, 1 H), 4.38 (dd, JHH= 4.0, 12 Hz, 1 H), 3.83 (m, 4 H), 3.78 (d, JHH=12 Hz, 1 H), 3.68 (dd, JHH= 4.0, 12 Hz, 1H), 3.54 (dt, JHH=4.0, 12 Hz, 1H), 3.28 (dt, JHH=4.0, 12 Hz, 1H), 2.92 (t, JHH = 8.0 Hz, 4 H), 1.33 (t, JHH = 8.0 Hz, 3 H); 19F NMR (376 MHz, CDClg): 8 — 121.4 (s, 2 F); Ms (MALDI): m/Z = 408.7 ([M+H]+).

Compound 16: 4-(diﬂuoromethyl)(2,6-dimorpholinopyrimidinyl)pyridinamine (16) fox, ”0‘11 1 1 11 1 11 E N xxx/N (I) 12/ / 11‘1““? .....“0"83/1‘11 _, N15} F131: 1 .1 1 1. 1 11 1 1,. 1” 11:1" 11 ‘61 ‘11" 1% 1” ‘1 ““11” 1E 111 OxV""" O‘N/‘M NI; MANH2 \‘IE‘E/K/ i22 i68 16 According to general procedure 1, compound 16 is obtained from starting materials i22 and i68 in 73% yield as a ess solid. 1H NMR (400 MHz, CDC13)C 8 8.31 (s, 1H), 7.30 (t, ZJHF= 55 Hz, 1 H), 6.85 (s, l H), 6.04 (s, l H), 4.73 (br s, 2 H), .72 (m, 12 H), 3.65-3.59 (m, 4 H); 19F NMR (376 MHz, CDClg): 8 — 115.1 (s, 2 F); Ms (MALDI): m/Z = 393.3 ([M+H]+).

Compound 17: 4'-(diﬂuoromethyl)-2,6-dimorpholino-[4,5'-bipyrimidin]-2'-amine (17) RN] iNJ F \‘J‘o F‘VF an. xF1 1338 la, 1 /"j~‘:,> i Fx/F 11 I", _"“’ 0 T1 .1 * """""""""""’ . 11, 1 11 1 1 ‘N ‘N(Boc)2 N A\N(Boc)gi ,1 N N 01 f 1N N 1‘ “N o 1 o. 1 k 411 N NHZ i71 i22 17 According to general procedure 2, nd 17 is ed from starting materials i71 and i22 in 7% yield as a colorless solid. 1H NMR (400 MHZ, CDC13)I 8 8.60 (s, 1 H), 7.11 (t, UHF: 55 Hz, 1 H), 6.02 (s, l H), 5.46 (br s, 2 H), 3.80-3.74 (m, 12 H), 3.64-3.60 (m, 4 H); 19F NMR (376 MHz, CDC13): 8 — 119.5 (s, 2 F); Ms (MALDI): m/Z = 394.3 ([M+H]+).

Compound 18: 4-(difluoromethyl)(4,6-dimorpholinopyrimidinyl)pyridinamine (18) — 116 — o ,,.o\.

A 1 j AL FK ,,F L j 1}: ><’ Q I T F F N \‘o‘ B A/%:~ N -------------------------------> A A A A A AL A. A 11“” ”A A‘A O\ / ,x ORV/A» RNA; \NH2 i23 i68 18 According to general procedure 1, nd 18 is obtained from starting materials i23 and i68 in 89% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 8 8.94 (s, 1H), 7.61 (t, UHF: 55 Hz, 1 H), 6.83 (s, l H), 5.50 (s, l H), 4.74 (br s, 2 H), 3.82-3.78 (m, 8 H), 3.61-3.57 (m, 8 H);19F NMR (376 MHz, CDClg): 5 — 115.4 (s, 2 F); Ms (MALDI): m/Z = 393.3 ([M+H]+).

Compound 19: 4'-(diﬂuoromethyl)-4,6-dimorpholino-[2,5'-bipyrimidin]-2'-amine (19) /o,\ ,.o..» A LNA 1 NJ L A 8n»RIF / F / A x' w 11%:OWN; /’ \rN F\,, A , [A _+ + A, A A A A L “N" \N(Boc)2 N(Boc)-2 g" I? N (31 f N N 11/ \N owA o. A k N‘” v NH? i71 i23 19 According to general procedure 2, compound 19 is obtained from starting materials i71 and i23 in 7% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 8 9.16 (s, l H), 7.58 (t, 2J1”: 55 Hz, 1 H), 5.75 (br s, 2 H), 5.50 (s, l H), 3.82-3.79 (m, 8 H), 3.61-3.58 (m, 8 H); 19F NMR (376 MHz, CDC13): 5 — 121.1 (s, 2 F); Ms ): m/Z = 395.3 ([M+H]+).

Compound 20: 4-(difluoromethyl)(4-morpholinothiomorpholino-l,3,5-triazinyl)- pﬂidin-Z-amine (20 1 on o [A A «A F L A F A N A; ‘9 L N” f” \O/ N ’1};fo \wi/‘I’ NEE r’iﬁlﬁ N FLAT/A F l i, W § ,8 A “N/l“N/l‘ c: “N” ” N f” ” N”"’J\N/’i‘“ "A?“ A 1 LA . A A S A \ // ANA» \/ \va \NH2 i15 i68 20 According to general ure 1, compound 20 is obtained from starting materials i15 and i68 in 77% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 8 9.02 (s, l H), 7.65 — 117 — (t, 2.11”: 55 Hz, 1 H), 6.84 (s, 1 H), 4.83 (br s, 2 H), 4.23—4.07 (m, 4 H), 3.90—3.79 (m, 4 H), 3.79—3.71 (m, 4 H), 2.71-2.62 (m, 4 H); 19F NMR (376 MHz, CDClg): 5 — 116.0 (s, 2 F); Ms ): m/Z = 410.3 ([M+H]+).

Compound 21: 4-(diﬂuoromethyl)(4-morpholinothiomorpholino-l,3,5-triazinyl)- pﬂimidinamine (21 1 ._ 1 .11 o 1 1 1 1 l . .1 1 i N' KN. 3 1 N’M’EQN /l\ F»\ F .11 1 -. 1 1 1 1 “N‘ “N’ "c: / “ha/“N“ \("Q-N 1 1 3’. 1‘ 1 1 1. 1 1. ”g N NHg i71 115 21 According to general procedure 2, compound 21 is obtained from ng materials i71 and HS in 70% yield as a colorless solid. 1H NMR (400 MHz, CDC13)289.21(S, 1H), 7.60 (t, 2J1”: 54 Hz, 1 H), 5.90 (br s, 2 H), 4.22-4.06 (m, 4 H), 3.91-3.78 (m, 4 H), 3.78- 3.71 (m, 4 H), 2.71-2.62(n1, 4 H); 19F NMR (376 MHz, CDClg): 5 — 120.5—(— 121.5) (m, 2 F); Ms (MALDI): m/Z = 411.2 ([M+H]+).

Compound 22: 5-(6-(3-oxaazabicyclo[3.2.l]octan—8-yl)(3-oxa azabicyclo [3 .2. l]octanyl)pyrimidinyl)(diﬂuoromethyl)pyridin—2-amine (22) {101...}f’w‘xi ‘ [/01/h\ N11 N11,? Fiﬁ/”F 1:111 A «BK, 11 F F 1,1 O 1 + 1 -~ 1 1. 1 1 N/ 1 E R/x ,1 «MN/1 m} «1:11: ,1 (5:331 \N/ [E o J / § 01V.1 1 N/ \NHZ i24 i68 22 According to general procedure 1, compound 22 is obtained from starting materials i24 and i68 in 61% yield as a colorless solid. 1H NMR (400 MHz, SO): 8 8.34 (s, l H), 7.55 (t, ZJHF = 55 Hz, 1 H), 6.76 (s, l H), 6.60 (br s, 2 H), 6.36 (s, 1 H), .47 (m, 4 H), 3.67—3.49 (m, 4 H), .49 (m, 4 H), 1.98-1.79 (m, 8 H); 19F NMR (376 MHz, (CD3)ZSO): 8 — 114.9-(— 115.2) (m, 2 F);MS (MALDI): m/z = 445.3 ([M+H]+).

Compound 23: 5-(2-(3-oxaazabicyclo[3 .2. l ]octanyl)morpho linopyriniidinyl) — 118 — (diﬂuoromethyl)pyridin—2-amine (23) fo A 1 {0} If \79 Fig/F {11’ If)“ \0 “lg/*1 F F “““““““““““““““““““““““, W g ’XW‘N / x N/ Ci \er5’ N ‘(7NN ,,,,, N15 \ QQV/lVVVVVVVVV l: \\—.,l emf, [ . 131 N LNHZ i29 i68 23 According to general procedure 1, compound 23 is obtained from starting materials i29 and i68 in 54% yield as a ess solid. 1H NMR (400 MHz, CDC13)C 8 8.30 (s, 1 H), 7.30 (t, UHF: 55 Hz, 1 H), 6.84 (s, 1 H), 6.04 (s, 1 H), 4.85 (br s, 2 H), 4.62 (br s, 2 H), 3.82-3.74 (m, 6 H), 3.65-3.56 (m, 6 H), 2.09—2.00 (m, 2 H), 2.00—1.91 (m, 2 H); 19F NMR (376 MHz, CDCl3)C 8 - 115.2 -(-116.2) (m, 2 F); MS (MALDI): m/z = 419.0 ([M+H]+). nd 24: 2-(3-oxaazabicyclo[3.2.1]octanyl)-4’-(diﬂuoromethyl)morpholino- [4,5 ’-bipyrimidin] -2 e (24) ,0», O PJF 23130 FT F \ >4 km}E N 31;”)? 6,8,“ M? + 1%,,in ’ {LY Fwy/F 1* ”ﬁx (PIN if N'/L~ will/‘ ' ’5 i“ N N(BOC)2 N N(BOC)2 ‘N C: ‘N” 2‘ “T 0 O.,\"—/ I \ N' NH2 i71 i29 24 According to general procedure 2, compound 24 is obtained from starting materials i29 and i71 in 72% yield as a colorless solid. 1H NMR (400 MHZ, SO): 8 8.71 (s, l H), 7.35 (s, 2 H), 7.32 (t, ZJHF = 54 Hz, 1 H), 6.45 (s, 1 H), 4.54 (br s, 2 H), 3.71-3.50 (m, 12 H), 1.95-1.78 (m, 4 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 119.2 (s, 2 F); Ms ): m/Z = 420.6 ([M+H]+).

Compound 25: 5-(2,6-bis((S)methylmorpholino)pyrimidinyl) (diﬂuoromethyl)pyridin—2-amine (25) l/ j 1 E,,.o Ml r ,. «1k FWF 1‘ ’ 512% C; 1 1' .L F l/ N N “"0: N” N f” N/“N O i ‘LNx’ 0%, /l l i25 i68 25 According to general procedure 1, compound 25 is obtained from starting materials i25 — 119 — and i68 in 57% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.31 (s, l H), 7.52 (t, ZJHF = 55 Hz, 1 H), 6.76 (s, l H), 6.59 (br s, 2 H), 6.30 (s, l H), 4.60-4.50 (m, l H), 4.44-4.33 (m, l H), 4.24-4.15 (m, l H), .04 (m, l H), 3.94-3.83 (m, 2 H), 3.74-3.64 (m, 2 H), 3.59-3.51 (m, 2 H), .35 (m, 2 H), 3.14-3.02 (m, 2 H), 1.18 (t, 3JHH= 7.2 Hz, 6 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 113.7—(— 115.9) (m, 2 F); Ms (MALDI): m/Z = 421.1 ([M+H1+).

Compound 26: 4'-(difluoron1ethyl)-2,6-bis((S)n1ethylniorpho lino)- [4,5 '-bipyrin1idin] -2 ’- an1ine 1261 F /F OJ [0 1 \\,LO§‘ FMVF 1,, / \ B [Y ,1. F, .F k, N 1: N '*' 1 N,“ ’ MW,,,,,, 1 A, ' 2L ; .11 1 11 1, l N ‘N(Boc)2 N N(Boc)2 1‘ «N ”N" "c: f] N’ N T” N O 2} o 3 'L ,L ‘‘‘‘‘‘ \v N KNHQ i71 i25 26 ing to general procedure 2, compound 26 is obtained from starting materials i25 and i71 in 56% yield as a colorless solid. 1H NMR (400 MHz, C 8 8.60 (s, l H), 7.14 (t, ZJHF = 54 Hz, 1 H), 5.98 (s, l H), 5.48 (br s, 2 H), 4.71-4.62 (m, l H), 4.34-4.23 (m, 2 H), 4.08-3.92 (m, 3 H), 3.83-3.65 (m, 4 H), 3.61-3.49 (m, 2 H), 3.25 (dt, ZJHH = 13 Hz, 3.1111,: 3.6 Hz, 2 H), .27 (m, 6 H); 19F NMR (376 MHz, CDClg): 5 — 119.5 (s, 1 F), 119.7 (m, 1 F); MS (MALDI): m/z = 422.2 ([M+H]+).

Compound 27: (difluoron1ethyl)(6-(3-n1ethylniorpho lino)niorpholinopyrin1idin- 4-yl)pyridin—2-an1ine (27) \Ti j :1“? FLF _,. B ~ ,/r. x ,/ « “Q . F F ' i N "Q: 0 “k L ”Y , 1 111,. :1 l 11 r r) N C! N ‘3‘: V "1’ N O 1 ‘1 , \Nl/ va/ N/ \NHQ i30 i68 27 According to general procedure 1, compound 27 is obtained from starting materials i30 and i68 in 74% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 8 8.31 (s, l H), 7.30 (t, ZJHF = 55 Hz, 1 H), 6.85 (s, l H), 6.02 (s, l H), 4.75 (br s, 2 H), 4.35-4.25 (m, l H), 4.06- 3.96 (m, 2 H), 3.83-3.69 (m, 10 H), 3.58 (dt, 2JHH = 12 Hz, 3.1111, = 3.2 Hz, 1 H), 3.25 (dt, 2.1%: 13 Hz, 3.1111, = 3.8 Hz, 1H), 1.31 (d, 3.1111, = 6.8 Hz, 3 H); 19F NMR (376 MHz, — 120 — CDClg): 5 — 114.9-(— 115.0) (m, 2 F); MS (MALDI): m/z = 407.1 ([M+H]+).

Compound 28: (S)-4'—(difluoromethyl)(3-methylmorpholino)morpho lino-[4,5 ’- bipyrimidin]—2’-amine (28) 1 £101, o {N1 1 171‘? 1 FxT/F N Br .? 1A0 B F\I1F111,1?! i 1 + ”(“181 N 1] RIF N ARN(BoC)2 N/“N(Boc)2 i g” NAN" c: “N { I? 911/ O 3/ NA? "Ni-12 i71 i30 28 According to general procedure 2, compound 28 is ed from starting materials i30 and i71 in 53% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 8 8.60 (s, l H), 7.13 (t, ZJHF = 54 Hz, 1 H), 6.01 (s, 1 H), 5.47 (br s, 2 H), 4.71-4.63 (m, 1 H), 4.31 (dd, ZJHH = 14 Hz, 3.11,,H = 2.4 Hz, 1 H), 3.97 (dd, ZJHH = 11 Hz, 3.11,,H = 3.4 Hz, 1 H), 3.79 (t, 3.11,,H = 4.6 Hz, 4 H), .66 (m, 2 H), 3.65-3.58 (m, 3 H), 3.58-3.50 (m, 2 H), .21 (m, 1 H), 1.30 (d, 3.7111, = 6.8 Hz, 3 H); 19F NMR (376 MHz, CDClg): 8 — 119.7 (br s, 2 F); Ms (MALDI): m/Z = 408.9 ([M+H]+). nd 29: 5-(4-(8-Oxaazabicyclo[3.2.l]octan—3-yl)(8-oxa azabicyclo[3.2.1]octan—3-yl)-1,3,5-triazinyl)(diﬂuoromethyl)pyridinamine (29) 2,1011 /19 RT F1 1, / “90,551,, N’”“\'N 1: 1: + 11 1 —> 11 1 l ”/1 N N N 4 \N/ RN)”, \T/ x: \‘1 1 x ”i Q 1» \Ox, E1 42:31 ’11» “N‘ N 11, NH2 i81 i68 29 According to general procedure 1, compound 29 is obtained from starting materials i68 and i81 in 89% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 89.03 (s, 1H), 7.69 (t, 2.11”: 55 Hz, 1 H), 6.83 (s, 1 H), 4.85 (br s, 2 H), 4.50-4.24 (m, 8 H), 3.28-3.12 (m, 4 H), 1.94 (br s, 4 H), 1.86-1.71(n1,4 H); 19F NMR (376 MHz, CDClg): 5 — 115.1—(—117.2) (n1, 2 F); Ms (MALDI): m/Z = 446.3 ([M+H]+).

Compound 30: 5-[4,6-bis(2,2-dimethylmorpholinyl)-1,3,5-triazinyl] (diﬂuoromethyl)pyridin—2-amine (30) — 12l — ,od 0 it / ‘I\\O,é% ”£33. 3‘ 1 » F F '1“ 1‘ « “1* 11 / $1713» “Ni NN “xxi /A x / ~\ 1'1““ 1 O 11“”11 iii 0““ / 5 “Ni: NH2 i80 i68 30 According to general procedure 1, compound 30 is obtained from starting als i68 and i80 in 63% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.86 (s, 1 H), 7.71 (t, 2.]H,F= 55 Hz, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 3.81-3.56 (m, 12 H), 1.14 (s, 12 H); Ms (MALDI): m/Z = 450.0 ([M+H]+).

Compound 31: (S)(difluoromethyl)(2-(3-methylmorpholino)morpholinopyrimidin- 4-yl)pyridinamine (3 1) ’011 3&1 kid \ﬂ/lg Fl F 1 38/ F F .1 + '1 w » :11 1%,“fo \ NV » NV x?! (3| i/» / r] I]! N O\// “h.” 0\/ ~.,\ N41”, i28 i68 31 According to general procedure 1, compound 31 is obtained from starting materials i28 and i68 in 58% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.31 (s, 1 H), 7.52 (t, ZJHF = 55 Hz, 1 H), 6.74 (s, 1 H), 6.59 (br s, 2 H), 6.35 (s, 1 H), 4.59-4.51 (m, 1 H), 4.22-4.14 (m, 1 H), 3.91-3.84 (m, 1 H), 3.72-3.50 (m, 10 H), 3.44-3.35 (m, 1 H), 3.14-3.03 (m, 1 H), 1.16 (d, 3.1111, = 6.7 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 113.7—(—115.3) (m, 2 F); Ms (MALDI): m/Z = 407.1 ([M+H]+).

Compound 32: (S)-4’-(diﬂuoromethyl)(3-methylmorpholino)morpho lino-[4,5’- bipyrimidin]-2’-amine (32) F F ~~~~~ F F x l (,oxji L 5/; 9 T.1 N Br v'Bx / *3 ./l 1; r? 0 j I} ,, 1F\T_/F, 5 l‘ + Ill ,1 , H N‘ 2'; “N(Boc)2 ‘3” ,A t» K / a i N N N(Boc)2 l/ N” «N c1 l/ ”Si/k N All, \N O (l QV" l1, 7: "N ‘NH2 i71 i28 32 ing to general procedure 2, compound 32 is obtained from starting materials i28 and i71 in 63% yield as a ess solid. 1H NMR (400 MHz, CDC13)C 8 8.60 (s, 1 H), 7.13 — 122 — (t, 2,1,1): = 54 Hz, 1 H), 5.99 (s, 1 H), 5.46 (br s, 2 H), 4.34—4.25 (m, 1 H), 4.06-3.97 (m, 2 H), .68 (m, 10 H), 3.58 (dt, ZJHH = 12 Hz, H = 3.2 Hz, 1 H), 3.26 (dt, ZJHH = 13 Hz, 3.7151, = 3.7 Hz, 1 H), 1.31 (d, 3.7151, = 6.8 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 119.5 (s, 2 F); Ms (MALDI): m/Z = 408.7 ([M+H]+).

Compound 33: 4-(diﬂuoromethyl)[4-[(2S,6R)-2,6-dimethylmorpholinyl][(3R) methylmorpholinyl] - l ,3 ,5 -triazinyl]pyridinamine (33) {Mk 3;!“ c3 RTE: {Mk ‘/ i ”‘l/ N NHZ i82 i68 33 According to general procedure 1, compound 33 is obtained from starting materials i68 and i82 in 71% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.87 (s, l H), 7.74 (t, ZJHF = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.71-4.62 (rn, 1 H), 4.45-4.34 (rn, 2 H), .09 (rn, 1 H), 3.90 (m, 1 H), 3.71 (m, 1 H), 3.55 (m, 3 H), 3.38 (m, 1 H), 3.13 (m, 1 H), 2.55 (m, 2 H), 1.20 (d, 3.1111): 6.9 Hz, 3 H), 1.19 (d, 3JHH= 6.9 Hz, 6 H);MS (MALDI): m/Z = 436.1 ([M+H]+).

Compound 34: 5-[4,6-bis[(2R,6S)-2,6-dimethylmorpholinyl]-l,3,5-triazinyl]—4- (diﬂuoromethyl)pyridin—2-amine (34) ﬁ/Omr 1 [Rx ,.F \[Okr ,. / 4. iN/ .\ “PLO : )2 1. 1‘3 . L if NJVN 0 + ll l ~~~~———,_ N/‘Q‘N RT? \N/“x ./i‘i\ {ﬁj‘x \Na/\N \« /’l‘i‘~ éi‘m ,/~1««: 1 ~ .1 1 N 1 3 i79 i68 34 According to general procedure 1, compound 34 is obtained from starting materials i68 and i79 in 75% yield as a colorless solid. 1H NMR (400 MHz, SO): 8 8.86 (s, l H), 7.71 (t, 2.11”: 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.64-4.46 (m, 4 H), 3.60-3.48 (m, 4 H), 2.63 (m, 4H), 1.14 (m, 12 H);MS (MALDI): m/Z = 450.0 ([M+H]+).

Compound 37: 5-[4,6-bis(3,7-dioxaazabicyclo[3.3.1]nonan—9-yl)-1,3,5-triazinyl] (diﬂuoromethyl)pyridin—2-amine (37) — 123 — O .0 /O\ 1’ \ (56/ i may; 1 \R :3 \N XL“? F\ F R: L / 0/8»T mqa NNAAQN F\««««« F N N + E L .. $1 l 4/ / 1 L 1K x j\ “x ,,/\ N N N‘ t;~~~~ N \t: ,M/N N c: :3 fur”; ll ’ rv-L‘f l \N/ 01/ng / \ N4 0/ A N NH2 g {,1 i7 i68 37 ing to general procedure 1, compound 37 is obtained from starting materials i7 and i68 in 39% yield as a colorless solid. 1H NMR (400 MHz, SO): 8 8.85 (s, l H), 7.68 (t, UHF: 55 Hz, 1 H), 6.87 (br s, 2 H), 6.74 (s, l H), 4.51 (br s, 2 H), 4.45 (br s, 2 H), 4.07—3.93 (m, 8 H), 3.79-3.67 (m, 8 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 115.8 (s, 2 F); Ms (MALDI): m/Z = 478.1 ([M+H]+).

Compound 38: 4-(diﬂuoromethyl)[4-(3 ,7-dioxaazabicyclo[3 .3 . l yl)(3 -oxa- 8-azabicyclo[3 .2. l]octan—8-yl)- l ,3 ,5-triazinyl]pyridin—2-amine (38) “ox , 19:» 33 gyro/‘3‘“. l [L F» F m/INAN N \‘C‘ N1 N ,6 .72?” i]? \‘L "”le "*1 Al Cl BS i68 38 According to general procedure 1, nd 38 is obtained from starting materials i35 and i68 in 67% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.87 (s, l H), 7.73 (t, UHF = 55 Hz, 1 H), 6.87 (br s, 2 H), 6.75 (s, l H), 4.70-4.54 (m, 2 H), 4.53-4.43 (m, 2 H), 4.05-3.97 (m, 4 H), 3.79-3.67 (m, 4 H), 3.63-3.55 (m, 4 H) 2.00-1.83 (m, 4 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 115.8 (s, 1 F), — 115.9 (s, 1 F); Ms (MALDI): m/Z = 462.1 ([M+H]+).

Compound 39: 5-[4,6-bis(3 ,3-dimethylmorpholinyl)- l ,3 ,5-triazinyl] (diﬂuoromethyl)pyridin—2-amine (39) («OxN/K [XOR {Ax ,/ K ,8. ENE/F kill/k ,«K «t F»... ,F N‘ “"N 0 N’ “N ‘ / + 3 /U Ll / l /T\ p /[ ll” (Vim /\ I 1%: N C: N NE lit [:1 N ll O l V kill 07/ “N” NH2 — 124 — i4 i68 39 According to general procedure 1, nd 39 is obtained from starting als i4 and i68 in 28% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.78 (s, l H), 7.70 (t, 2J1”: 55 Hz, 1 H), 6.82 (br s, 2 H), 6.77 (s, l H), 3.87-3.75 (m, 8 H), 3.45 (br s, 4 H), 1.49 (s, 12 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 114.9—(— 115.1) (m, 2 F); Ms (MALDI): m/Z = 450.1 ([M+H]+).

Compound 40: -bis[(3R,5S)-3,5-din1ethylniorpholinyl]-l,3,5-triazinyl]—4- (diﬂuoroniethyl)pyridinan1ine (40) 22 2 1111111W NA?“ 50.3, 2,1 iN F, F 1. 11, 1 “ 1,11 vvvvvvvvvvvvvvvvvvvv~ 1 11 ,1 .

N” “N’ “‘N/ {\L [ ‘N’ “(:1 N f O ~K E /‘ O“k2/‘K i? N/ NH2 i6 i68 40 According to general procedure 1, compound 40 is obtained from starting als i6 and i68 in 42% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.90 (s, l H), 7.82 (t, ZJHF = 55 Hz, 1 H), 6.84 (br s, 2 H), 6.77 (s, l H), 4.59-4.43 (m, 4 H), 3.82-3.73 (m, 4 H), 3.60-3.51 (m, 4 H), 1.29 (d, ZJHH = 6.9 Hz, 12 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 114.9-(— 115.0) (m, 2 F); MS (MALDI): m/z = 450.2 ([M+H]+).

Compound 41: 5-[4,6-bis[(3R)n1ethylniorpholinyl]-l,3,5-triazinyl]—4- (diﬂuoroniethyl)pyridinan1ine (4 1) (N J\ “/0? “”226 FTP LN \ ,1 i«B l 1 F. .1: 2 s.» ~» .1 11 '1 O 2.5,1. 2/ + 11. mm» 1 1 13 2 ‘N N 01 N N 11/ N N O /i E J l ~~~~~ 01 x J» / I}: “/ N "NS-12 i5 i68 41 According to general procedure 1, compound 41 is obtained from starting materials i5 and i68 in 98% yield as a colorless solid. 1H NMR (400 MHz, CDC13)C 8 9.04 (s, l H), 7.70 (t, 2.11117: 52.0 Hz, 1 H), 6.84 (s, 1 H), 4.88 (br s, 2 H), 4.77—4.72 (m, 2 H), 4.41 (d, ZJHH = 12.0 Hz, 2 H), 3.98 (dd, ZJHH = 12.0 Hz, 3.1111, = 4.0 Hz, 2 H), 3.78 (d, ZJHH = 12.0 Hz, 2 H), 3.68 (dd, 2.1111,: 12.0 Hz, 3.1111, = 4.0 Hz, 2 H), 3.53 (dt, ZJHH = 12.0 Hz, 3.1111, = 4.0 Hz, 2 H), 3.28 (dt, ZJHH = 12.0 Hz, 3.1111, = 4.0 Hz, 2 H), 1.33 (d, ZJHH = 8.0 Hz, 6 H); 19F NMR — 125 — (376 MHz, CDClg): 5 — 115.9 (s, 1 F), — 116.0 (s, 1 F); MS ): m/z = 421.7 ([M+H]+).

Compound 42: 4-(diﬂuoromethyl)[4-(3,3-dimethylmorpholinyl)morpholino-l,3,5- triazinyl]pyridinamine (42) 1 ‘( o F F 1 K E) 43/ ‘9 ,,,,,,,,,,, .B 9 )1/ F F N' \“N o W s N! N i N911 * + 1 .1 > I . l 1’ 01 O 3‘1}: N ‘11 (AF/i N/L L 1 / /./ WIEJ/ O ”””””/ N \NH2 i16 i68 42 According to general ure 1, compound 42 is obtained from starting materials i16 and i68 in 35% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.83 (s, l H), 7.73 (t, UHF: 55 Hz, 1 H), 6.84 (br s, 2 H), 6.76 (s, l H), 3.85-3.76 (m, 4 H), 3.76-3.63 (m, 8 H), 3.45 (br s, 2 H), 1.49 (s, 6 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 116 (s, 2 F); Ms (MALDI): m/Z = 422.1 ([M+H]+).

Compound 44: 4-(difluoromethyl)[4-[(3R,5S)-3,5-dimethylmorpholinyl][(3R)—3- morpholinyl] - l ,3 ,5 -triazinyl]pyridinamine (44) 1,0,, LN \071 l \ 7‘9 “(F LN’K a .53 ,9. A F F N/ N 0 / “*1 N’ \N x" L * ,11 .1 1, * ,1 l, .11 .1, f N” \N ‘0: N 11% f" ‘N/ N o\/J\ o.,,/.l\ 11 “*1 WI? RN NH2 i37 i68 44 ing to general procedure 1, compound 44 is obtained from ng materials B7 and i68 in 75% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.89 (s, l H), 7.79 (t, 2.11,): = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.65 (br s, 1 H), 4.50 (br s, 2 H), 4.37—4.25 (m, 1 H), 3.93 (dd, 3.71,], = 11 Hz, 3.7111, = 3.2 Hz, 1 H), 3.79-3.67 (m, 3 H), 3.59— 3.51 (m, 3 H), 3.45—3.36 (m, 1 H), 3.22—3.11 (m, 1 H), 1.30 (d, 3.11,,H = 6.7 Hz, 6 H), 1.24 (d, 3.11,,H = 6.7 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 115.0 (br s, 2 F); Ms (MALDI): m/Z = 436.1 ([M+H]+).

Compound 45: 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)[(3R)—3- methylmorpholinyl] - l ,3 ,5 -triazinyl]pyridinamine (45) — 126 — (.0,NL “xi F if {01 £21,? N,\ «is»: \O”B‘ A“ F ll. ‘‘‘‘‘ N/LTN F‘ ,j/, “‘ .21 ,1 ,1 ~~~~~~~~~~~~~~~~~~~~~~~~~~ 11, ,. ,l l) 1? N C! N Pill i if N T \1 OXV Wig] Oxf/ N/ RNH2 i38 i68 45 According to general procedure 1, compound 45 is obtained from starting materials BS and i68 in 71% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.84 (s, 1 H), 7.74 (t, 2.1”: 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.58 (br s, 1 H), 4.31—4.19 (m, 1 H), 3.93 (dd/.1111, = 12 Hz, 3.7,, = 3.9 Hz, 1 H), 3.84-3.81 (m, 4 H), 3.76-3.69 (m, 1 H), 3.58 (dd, ZJHH = 11 Hz, 3.11,), = 3.2 Hz, 1 H), .38 (m, 3 H), 3.23—3.13 (m, 1 H), 1.50 (br s, 6 H), 1.23 (d, 3.11,, = 6.7 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 114.8-(— 115.5) (m, 2 F); Ms (MALDI): m/Z = 436.0 +).

Compound 46: 4-(difluoromethyl)[4-[(3R)(methoxymethyl)morpholinyl][(3R) methylmorpholinyl] - 1 ,3 ,5 -triazinyl]pyridinamine (46) L,Nk (no ‘ 3/1,? FfF ,NL o, N_,_/E,N ,./<~,O,s, 6,, o, “LN 12., ,1: 1, + ,1'. ,1, ll, ,1, ~~w—> ,1, ,1 ,1, l (I 31 .N. “C: N f} l”; I? N. Mill" 3 O», o,,,,,,,,,, N \N \NHz i39 i68 46 According to general procedure 1, compound 46 is ed from starting materials B9 and i68 in 67% yield as a ess solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.87 (s, 1 H), 7.77 (t, 2J1”: 55 Hz, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 4.67 (br s, 2 H), 4.44-4.24 (m, 2 H), 3.96-3.83 (m, 3 H), 3.75-3.63 (m, 2 H), 3.60-3.36 (m, 5 H), 3.31 (s, 3 H), .04 (m, 2 H), 1.23 (d, 3.7,, = 6.7 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 115.0 (br s, 2 F); MS (MALDI): m/Z = 452.3 ([M+H]+).

Compound 47: 4-(diﬂuoromethyl)[4-(3 ,7-dioxaazabicyclo[3 .3 . 1 ]nonanyl)[(3R)- 3-methylmorpholin—4-yl]—1,3,5-triazinyl]pyridinamine (47) — 127 — o ,0 1ri ”“\1 1 l a NLN ,, \ A, a F F 0 N + \l ,, N} l? 31‘ 1 .Npl u N /‘i\‘N/i\ /‘,:{:/N N C' 11 / “€12“: U j, o )1 N 0 ,2) “N“ “NH? 6"“ ' 0’ i36 i68 47 According to general procedure 1, compound 47 is obtained from starting materials B6 and i68 in 85% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.86 (s, 1 H), 7.72 (t, UHF: 55 Hz, 1 H), 6.84 (br s, 2 H), 6.75 (s, 1 H), 4.64 (br s, 1 H), 4.53-4.42 (m, 2 H), 4.37-4.25 (m, 1 H), 4.05-3.96 (m, 4 H), 3.92-3.84 (m, 1 H), 3.77-3.66 (m, 5 H), 3.60-3.52 (m, 1 H), 3.44—3.35 (m, 1 H), 3.22—3.10 (m, 1 H), 1.23 (d, 3.11,,H = 6.7 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 114.9-(— 117.1) (m, 2 F); MS (MALDI): m/z = 450.0 ([M+H]+).

Compound 50: uoromethyl)[4-[(3R)methylmorpholinyl](3-oxa azabicyclo [3 . l . l]heptan—6-yl)- l ,3 ,5 -triazinyl]pyridinamine (50) [so\2k (.03 Elm.Q \ F"\I,z F M),, ., ,..B., ,/ K1“/x, F\ X? + ”01“) _.......................1. 21/12) //TxN// 3N /» \C‘ HM Nij; 3N /%N”/ em J, 3&3 1 11 l a.) l ,l O‘R"’RM1\§3/ O W/ RN27" \NHQ i40 i68 50 According to general ure 1, compound 50 is obtained from starting materials i40 and i68 in 52% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.90 (s, 1 H), 7.82 (t, ZJHF = 55 Hz, 1 H), 6.87 (br s, 2 H), 6.76 (s, 1 H), 4.55-4.51 (m, 1 H), 4.34-4.14 (m, 3 H), 4.12-4.25 (m, 2 H), 3.92-3.80 (m, 1 H), .68 (m, 3 H), 3.55-3.51 (m, 1 H), 3.38 (m, 1 H), 3.20—3.13 (m, 1 H), 2.68 (m, 1 H), 1.78 (m, 1 H), 1.20 (d, 3.11,,H = 6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 115.0 (br s, 2 F); MS ): m/z = 420.6 ([M+H]+).

Compound 51: 4-(difluoromethyl)[4-[(3R)methylmorpholinyl](6-oxa azabicyclo[3. l .1]heptan—3-yl)-l,3 ,5-triazinyl]pyridin—2-amine (51) — 128 — .0 .50.

L131 K -J/lo} l fig/F l\ ,1. F.» .1: N N 1 NA}; N N A + /\O/B.,qu . l/ N 31261 O ‘1“ 01lily/xiii/hN/RL/[L ‘1? N NH2 i41 i68 51 According to general procedure 1, compound 51 is obtained from starting materials i41 and i68 in 36% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.99 (s, l H), 7.89 (t, ZJHF = 55 Hz, 1 H), 6.84 (br s, 2 H), 6.77 (s, l H), 4.69 (m, 3 H), 4.37 (m, l H), 3.91- 3.85 (m, 3 H), 3.75-3.53 (m, 4 H), .35 (m, l H), 3.22-3.15 (m, l H), 3.12-3.08 (m, l H), 1.85 (m, 1 H), 1.24 (d, 3.11,,H = 6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 116.0 (br s, 2 F); Ms (MALDI): m/Z = 420.6 ([M+H]+).

Compound 52: 4-(diﬂuoromethyl)[4-[(3R)methylmorpholinyl]—6-[( —2-oxa lO azabicyclo [2 .2. l]heptan—5 -yl] - l ,3 ,5 -triazinyl]pyridinamine (52) l,,,o.\K .1 (o. 2:1: ;:><::C‘;fiii . if \1: .1: W. W ,,,,,1 (l, (/ 1 13,.,2\§1,.. 3L1 l? 111211112 142 i68 52 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). 1H NMR (400 MHz, (CD3)2SO): 8 8.89 (m, l H), 7.77 (m, l H), 6.84 (br s, 2 H), 6.76 (s, l H), 5.02-4.97 (m, l H), 4.68-4.66 (m, 2 H), 4.31 (m, l H), 3.89-3.85 (m, l H), 3.79-3.57 (m, 3 H), 3.57-3.44 (m, 4 H), 3.22 (m, 1 H), .83 (m, 2 H), 1.21 (d, 3.11,,H = 6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 115.5 (br s, 2 F); Ms (MALDI): m/Z = 420.2 ([M+H]+). nd 53: uoromethyl)[4-[(3R)methylmorpholinyl][( lS,4S)oxa azabicyclo[2.2. l]heptan—5-yl]— l ,3 ,5-triazinyl]pyridin—2-amine (53) o. .o l \ N /5i\ >EJ‘é in F RT A: F '1“. l‘ O + 11 Z —» . “‘“N/"3‘01 ,. N. 11“ / N” \N' ‘N ’” N N/ ‘ N N NHQ — l29 — i43 i68 53 According to l procedure 1, compound 53 is obtained from starting materials i43 and i68 in 53% yield as a colorless solid (1:1 mixture of rotamers). 1H NMR (400 MHz, SO): 8 8.90 (m, l H), 7.77 (m, l H), 6.84 (br s, 2 H), 6.76 (s, l H), 5.02-4.96 (m, 1 H), 4.68-4.62 (m, 2 H), 3.90 (m, l H), 3.80 (m, l H), 3.70 (m, 2 H), 3.57 (m, 2 H), 3.45 (m, 3 H), 3.20 (m, 1 H), 1.90-1.83 (m, 2 H), 1.21 (d, 3.11,), = 6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 115.0 (br s, 2 F); Ms (MALDI): m/Z = 420.2 ([M+H]+).

Compound 54: 5-[4,6-bis[(3R)ethylmorpholinyl]—l,3,5-triazinyl] romethyl)pyridin—2-amine (54) .O O l13k,7‘ 5.1 F ,F i. 3f? I pk- \ 3.13.“. w N‘ﬁiw F/F 1 N4, “N .15.. 1.. * lJ m l 11. l {5 1;; .NJ Cl N {31: r 'N E/ «x1 0*” OW3‘ " N “:06 ”I? i8 i68 54 According to general procedure 1, compound 54 is obtained from starting materials i8 and i68 in 61% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.87 (s, l H), 7.77 (t, ZJHF = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, l H), 4.47 (m, 4 H), 3.89-3.81 (m, 4 H), 3.51—3.34 (m, 4H), 3.12 (m, 2H), 1.71 (m, 4H), 0.86 (m, 6H). 19F NMR (376 MHz, (CD3)2SO): 5 — 115.0 (br s, 2 F); Ms (MALDI): m/Z = 450.3 ([M+H]+).

Compound 55: 5-[4,6-bis(8-oxaazaspiro[3.5]nonanyl)-l,3,5-triazinyl] (diﬂuoromethyl)pyridin—2-amine (55) {/05 ”65‘ “Ni/b 5!? RIF “Tit/J N ,,B\ . 5 1:. ,. F o x» \ xx N” N \3 ’i:;\, El + NW N \/4 Li j / \:><.:/ e U L E/ *N’ N“ ”01 N N f \N/ “N“ "1/“ O 1 11, o. /1 i ,l x N’ N/ N1 NHg i9 i68 55 According to general procedure 1, compound 55 is obtained from starting materials i9 and i68 in 59% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.74 (s, l H), 7.65 (t, UHF: 55 Hz, 1 H), 6.81 (br s, 2 H), 6.75 (s, l H), 3.68 (m, 8 H), 3.49 (m, 4 H), 2.46- 2.38 (m, 4 H), 2.25-2.16 (m, 4 H), 1.72-1.66 (m, 4 H); 19F NMR (376 MHz, SO): 5 — 115.5 (br s, 2 F); Ms (MALDI): m/Z = 474.3 ([M+H]+). — l30 — Compound 56: 5-[4,6-bis[(3R)isopropylmorpholinyl]- l ,3 azinyl] (diﬂuoromethyl)pyridin—2-amine (56) (0,, o ﬂ FAN/ F / \ :[A 0 , {A x“ 113AL A F F A AN N O ~~~~~/ z , A ” A A —* A A A {@3101 NAN AANAAA Ow/ xNj/ 0%., N/ “NH; i10 i68 56 According to general procedure 1, compound 56 is obtained from starting materials i10 and i68 in 59% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.87 (s, l H), 7.76 (t, UHF: 55 Hz, 1 H), 6.82 (br s, 2 H), 6.76 (s, 1 H), 4.50 (m, 2 H), 4.29 (m, 2 H), 4.02- 3.84 (m, 4 H), 3.40 (m, 4 H), 3.08 (m, 2 H), 2.34 (m, 2 H), 1.02 (m, 6 H), 0.77 (m, 6 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 1150 (br s, 2 F); Ms (MALDI): m/Z = 478.4 ([M+H]+).

Compound 66: 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)[(3R,5S)-3,5- dimethylmorpholinyl] - l ,3 ,5 -triazinyl]pyridinamine (66) A01 ADA N F RNA? N L”! .9 FAT Ngyl‘xN Or‘va./A"\‘§N N4; N F‘m /F l A A * A A ----------------------> A A A A A N N Cl N If: [ N' N N 0 x/K XL KANN/ OAR/AK N/ NHQ i55 i68 66 According to l procedure 1, compound 66 is obtained from starting materials i55 and i68 in 61% yield as a colorless solid. 1H NMR (400 MHz, SO): 8 8.87 (s, l H), 7.77 (t, ZJHF = 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 4.46 (m, 2 H), 3.81-3.77 (m, 6 H), 3.55 (m, 2 H), 3.44 (m, 2 H), 1.49 (s, 6 H), 1.28 (d, 3.11,), = 6.9 Hz, 6 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 115.0 (br s, 2 F); Ms (MALDI): m/Z = 450.4 ([M+H]+).

Compound 67: 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)[(3R)—3- (methoxymethyl)morpholinyl] - l ,3 ,5 -triazinyl]pyridinamine (67) — 131 — ,,o..\ /o,_. 3 \ LC? FEE: l /‘ Ema/Tl» O», NB», 05 0 L1/~"~>:~ {LL F F 1 ‘1 1 + » .1 1 3" N N on N f N "N lmvny/l" "N: , 1 i Oaw j kw, Dav/i , i56 i68 67 According to general procedure 1, compound 67 is obtained from starting materials i56 and i68 in 37% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.84 (s, 1 H), 7.89 (t, ZJHF = 55 Hz, 1H), 6.85 (br s, 2 H), 6.76 (s, 1H), 4.60 (m, 1H), 4.31 (m, 1H), 3.92 (m, 2 H), 3.83 (m, 4 H), 3.65 (m, 1H), 3.51-3.41 (m, 5 H), 3.28 (s, 3 H), 3.12 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3 H); 19F NMR (376 MHz, (CD3)2SO): 5 —115.5 (brs, 2F); MS (MALDI): m/Z = 466.4 ‘).

Compound 68: [(3R)[4-[6-amino(diﬂuoromethyl)pyridyl](3 ,3- dimethylmorpholinyl)- l ,3,5-triazinyl]morpholin—3-yl]methanol (68) l/O'Ml {503,3 , ,/ «1 F. ,F ,2! N #0 ix; N HCL~ N/EKKN :\X\O’KB H0 991‘” Fx /F ix ,1 )1 + 11 “1 W I 1“ 2 .3 - L L 3 N N Cl N [\3 3 N N ow) ELM,» 33 3 x «(Na/“NW i57 i68 68 According to general ure 1, compound 68 is obtained from starting materials i57 and i68 in 58% yield as a ess solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.83 (s, 1 H), 7.77 (m, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 4.91 (m, 1 H), 4.35 (m, 2 H), 4.05 (m, 1 H), 3.97—3.70 (m, 6 H), 3.54-3.38 (m, 5 H), 3.12 (m, 1 H), 1.49 (s, 3 H), 1.48 (s, 3 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 115.5 (br s, 2 F); MS (MALDI): m/z = 452.2 +).

Compound 69: 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)(3,7-dioxa azabicyclo [3 .3 . l ]nonanyl)- l ,3 ,5 -triazinyl]pyridinamine (69) 50L ,,o.\ l.,N,,l<:; 30 F F law/Li: f ‘ / ‘ m L /B\ 3 ,,,,,x /\3_ F..... F ‘3 ‘3 O 3 R + j) ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,. ‘3 ,‘3 F N N Cl N,/\N 2,...MT/(N/ XN/ \ll \ ,j O N / N NH2 0 I 0" i54 i68 69 — l32 — According to general procedure 1, compound 69 is obtained from starting materials i54 and i68 in 57% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.83 (s, 1 H), 7.69 (t, ZJHF = 55 Hz, 1 H), 6.85 (br s, 2 H), 6.76 (s, 1 H), .37 (m, 2 H), 4.01 (m, 4 H), 3.80-3.71 (m, 8 H), 3.45 (m, 2 H), 1.48 (s, 6 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 115.7 (br s, 2 F); Ms (MALDI): m/Z = 464.3 ([M+H]+).

Compound 70: 4-cyclopropylpiperazinyl)(3,3-dimethylmorpholinyl)-1,3,5- triazinyl](diﬂuoromethyl)pyridin—2-amine (70) i l< 1‘0 l: i: N‘ [\N/ui’x £4, >53 , B 4 l4 ix F 0 ~/ N” N ll, “‘5‘: N4! N 1 J ‘L * .21., ~ ,1... j: .4, i, I? N Cl N [El !/ 4T_. \N \U 1:1 2N. l / _./~4/N 4 [z ,,,,,, 7 "1’ N V NH2 i58 i68 70 ing to general procedure 1, compound 70 is obtained from ng materials i58 and i68 in 12% yield as a colorless solid. 1H NMR (400 MHZ, (CD3)2SO): 8 8.82 (s, l H), 7.72 (t, ZJHF = 55 Hz, 1H), 6.83 (br s, 2H), 6.76 (s, 1H), 3.82 (m, 4H), 3.71 (m, 4H), 3.44 (m, 2 H), 2.58 (m, 4 H), 1.64 (m, 1 H), 1.44 (s, 6 H), 0.45 (m, 2 H), 0.36 (m, 2 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 115.4 (br s, 2 F); MS (MALDI): m/z = 460.4 ([M]+).

Compound 71: 4-(difluoromethyl)[4-(3,3-dimethylmorpholinyl)[4-(2- methoxyethyl)piperazin- l -yl] - l ,3 ,5 -triazinyl]pyridinamine (71) .30., o L L '“K I l W/ N”, #0 ENE/F 4\ 1 T7) ‘6 4 .4, 4, 1: N/ N O xf x3, N4,» N 4 1 + l------------W ,1, )1 11 .14 31., l ’" N N “c: ‘N {:11 f” b}; “‘N’ E \1 O/“ «N4 / 4;? \O 4 «N~4/" N/X NH2 i59 i68 71 According to general procedure 1, compound 71 is obtained from starting materials i59 and i68 in 42% yield as a colorless solid. 1H NMR (400 MHZ, (CD3)2SO): 8 8.82 (s, l H), 7.73 (t, UHF: 55 Hz, 1 H), 6.83 (br s, 2 H), 6.76 (s, 1 H), 3.88-3.69 (m, 10 H), 3.47-3.44 (m, 4 H), 3.24 (m, 3 H), 2.52—2.45 (m, 4 H), 1.44 (s, 6 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 1154 (br s, 2 F); Ms ): m/Z = 478.4 ([M]+).

Compound 77: [(3R)[4-[6-amino(diﬂuoromethyl)pyridyl][(3R)—3- — 133 — methylmorpholinyl]—1,3,5-triazinyl]morpholin—3-yl]methanol (77) [ck \ 3 F F l/OX , f, If . “$0 k HO >llo/é 3 HO 3’ F F "1 13.1 * L —* “L 3“" “1) L? x / [213mx N MNHz i53 i68 77 According to general procedure 1, nd 77 is obtained from starting materials i53 and i68 in 31% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.88 (s, 1 H), 7.78 (t, ZJHF = 55 Hz, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 4.96 (m, 1 H), 4.73 (m, 1 H), 4.58- 4.24 (m, 3 H), 4.05 (m, 1 H), 3.90 (m, 2 H), 3.72 (m, 2 H), 3.59 (m, 1 H), .36 (m, 4 H), 3.23-3.02 (m, 2 H), 1.23 (d, 3JHH= 6.9 Hz, 3 H);MS (MALDI): m/z = 438.3 ([M+H]+).

Compound 78: 4-(diﬂuoromethyl)[4-[(3R,5R)-3,5-dimethylmorpholinyl][(3R) methylmorpholinyl] - 1 ,3 ,5 -triazinyl]pyridinamine (78) ,0 {Ca LNNk L\ .. \ﬁlj‘we ij/ F “‘33 1 N k L ‘- "“33 A, 3111 F ”LN” NL 33 + H j _W.. L N! N L”“rx3‘”i“(:1 N N 1 NA NE” ] 3 l 3 31/ (K 3 l 3 V 33 1 N xxx—32 i85 i68 78 ing to general procedure 1, compound 78 is obtained from starting materials i85 and i68 in 71% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.90 (s, 1 H), 7.82 (t, 2J1”: 55 Hz, 1 H), 6.84 (br s, 2 H), 6.76 (s, 1 H), 4.66 (m, 1 H), 4.32 (m, 3 H), 4.15 — 4.11 (m, 2 H), 3.92 (m, 1 H), 3.70 (m, 3 H), 3.57 (m, 1 H), 3.40 (m, 1 H), 3.18 (m, 1 H), 1.37 (m, 6 H), 1.24 (d, 3.11,), = 6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 114.9 (br s, 2 F); Ms (MALDI): m/Z = 435.4 ([M]+).

Compound 79: 4-(difluoromethyl)[4-[(3S,SS)-3,5-dimethylmorpholinyl][(3R) methylmorpholinyl] - 1 ,3 ,5 -triazinyl]pyridinamine (79) —134— 1“”WM/k L Fx XF [’0 98 Nj\ x 1 NE,LN G F + Ll j E N/LN FL ELL/KfL.NAA “81/ “‘N » AL. LL N L E LL l /, l}; g i "f 0‘8“” “N; N112 i86 i68 79 According to general procedure 1, compound 79 is obtained from starting materials i86 and i68 in 65% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.91 (s, l H), 7.82 (t, UHF: 55 Hz, 1 H), 6.85 (br s, 2 H), 6.76 (s, l H), 4.66 (m, 1 H), 4.32 (m, 3 H), 4.15 — 4.11 (m, 2 H), 3.92 (m, 1 H), 3.70 (m, 3 H), 3.57 (m, 1 H), 3.40 (m, l H), 3.19 (m, l H), 1.37 (m, 6 H), 1.24 (d, 3.1111, = 6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 114.9 (br s, 2 F); Ms (MALDI): m/Z = 434.3 ([M]+).

Compound 80: uoromethyl)[4-morpholino(3-oxaazabicyclo[3.3. l]nonan yl)- l ,3 ,5-triazinyl]pyridin—2-amine (80) LNA : F c; Ff LNA L L 831 L L L AirﬁkN N Cl QN 5:?” N j TL :KL .... I 0,; N NH; i87 i68 80 ing to general procedure 1, compound 80 is obtained from starting materials i87 and i68 in 57% yield as a ess solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.85 (s, l H), 7.73 (t, UHF: 55 Hz, 1 H), 6.84 (br s, 2 H), 6.75 (s, l H), 4.61 — 4.57 (m, 2 H), 3.95 (m, 2 H), 3.75 — 3.65 (m, 10 H), 2.48 (m, 1H), 1.88 — 1.72 (m, 4 H), 1.57 (m, 1H); 19F NMR (376 MHz, (CD3)2SO): 8 — 115.4 (m, 2 F); MS (MALDI): m/Z = 434.3 +).

Compound 82: 4-(diﬂuoromethyl)[4-(3 ,7-dioxaazabicyclo[3 .3 . l ]nonanyl)(3- oxaazabicyclo[3 .3 . l ]nonanyl)- l ,3 ,5-triazinyl]pyridin—2-amine (82) — l35 — 0. C1 53’ 9 x U; 1 41,253 NW fro F F \< L?“ 3* >4 A 6 0A [i/Mitala :31 + \ll AL ‘ F1“ ”F N“ “N 5mm“, N”“*‘N A A “N N A A A” /“~ N N c: 11 f“ :N N \l «A 0' 2 i89 i68 82 According to general ure 1, compound 82 is obtained from starting materials i89 and i68 in 51% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.84 (s, 1 H), 7.70 (t, ZJHF = 55 Hz, 1 H), 6.85 (br s, 2 H), 6.75 (s, 1 H), 4.62 (m, 1 H), 4.54 (m, 1 H), 4.52 (m, 1 H), 4.44 (m, 1H), 4.04 — 3.92 (m, 6 H), 3.75 — 3.62 (m, 6 H), 2.45 (m, 1 H), 1.89 — 1.75 (m, 4H), 1.57 (m, 1H); 19F NMR (376 MHz, SO): 8 — 115.7 (m, 2F); Ms (MALDI): m/Z = 476.2 ([M+H]+). nd 83: 5-[4,6-bis[(3S,SS)-3,5-dimethylmorpholinyl]—1,3,5-triazinyl]—4- (diﬂuoromethyl)pyridin—2-amine (83) K a )‘x /i i” F ,F A,» >1”? j :>3 /l\m N “ A / ‘O/ B / 8:3: if N/QN + L {JR F vvvvvvvvvvvvvvvvvvvy. N/QN Fl] A A3. «A Mr ‘N AL {A N [/ N N (31 U N N M {A N W ORV/K x] Ox“ ]\ ” x / \ ] N} Nﬁg i90 i68 83 According to general procedure 1, compound 83 is obtained from starting materials i90 and i68 in 56% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.92 (s, 1 H), 7.87 (t, ZJHF = 55 Hz, 1 H), 6.84 (br s, 2 H), 6.77 (s, 1 H), 4.32 (m, 4 H), 4.14 (m, 4 H), 3.70 (m, 4 H), 1.39 (d, 3.1111, = 6.9 Hz, 12 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 115.5 (br s, 2 F); Ms (MALDI): m/Z = 448.3 ([M 1+).

Compound 84: 4-(diﬂuoromethyl)—5-[4-(3,7-dioxaazabicyclo[3.3.1]nonanyl)—6- morpholino- 1 ,3 ,5 -triazinyl]pyridinamine (84) — 136 — 1,01w 0 A l .. l F“ ”F J? “o A i ii “Raﬁ ”L if N/QN + W /j Nil/imN Pal/F fl: «52L». \“N’ ”N A {A 1. ,1 [SJ/{N N Cl li’N/ ’C—Nq/{N N \H N1 00,”) 3 00;] \“N/ *NHQ i91 i68 84 According to general ure 1, compound 84 is ed from starting materials i91 and i68 in 63% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.86 (s, l H), 7.71 (t, ZJHF= 55 Hz, 1 H), 6.87 (br s, 2 H), 6.75 (s, l H), 4.49 (m, 2 H), 4.02 (m, 4 H), 3.74 — 3.65 (m, 12 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 115.6 (br s, 2 F); Ms (MALDI): m/Z = 436.4 ([M+H]+).

Compound 85: 4-(diﬂuoromethyl)[4-[(3S)ethylmorpholinyl][(3R) methylmorpholinyl] - l ,3 ,5 -triazinyl]pyridinamine (85) o {.0 l RR “‘0 R ”F x A L 1 >4; , x T ‘11” 1 / /~L::\ N “1:. N”’“‘N "’ ll F —+ ”m 11’le F” {/11NX11N11 111‘” CI “51 ., 1’ .;,,N,..JL “£211,111,“ if J 1 O V») OW” N ’LNHE i92 i68 85 According to general procedure 1, compound 85 is obtained from starting materials i92 and i68 in 52% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.88 (s, l H), 7.77 (t, UHF: 55 Hz, 1 H), 6.85 (br s, 2 H), 6.76 (s, l H), 4.70 — 4.25 (m, 4 H), 3.90 (m, 3 H), 3.72 (m, l H), 3.60 — 3.45 (m, 4 H), 3.16 (m, 2 H), 1.73 (m, 2 H), 1.22 (d, 3.1111,; = 6.9 Hz, 3 H), 0.86 (m, 3 H); 19F NMR (376 MHz, (CD3)2SO): 5 — 114.9 (br s, 2 F); Ms (MALDI): m/Z = 436.9 ([M+H]+).

Compound 86: 4-(diﬂuoromethyl)[4-[(3R)ethylmorpholinyl][(3R) methylmorpholinyl] - l ,3 ,5 -triazinyl]pyridinamine (86) f3* “a.A a F *0 ~ [1.0, .. L 72:01 . 71 1’1 * l ,1 WWwwwww,. 1 11.1 N N 1 1‘1ng f” N” “N“ , .21 ,, c: 11 “N“ N X f T 1 0., (l ”N 01 j A A, / W i 51/ N NH2 — 137 — i93 i68 86 According to general procedure 1, compound 86 is obtained from starting materials i93 and i68 in 47% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.88 (s, 1 H), 7.77 (t, UHF: 55 Hz, 1 H), 6.85 (br s, 2 H), 6.76 (s, 1 H), 4.65 (m, 1 H), 4.49 — 4.30 (m, 3 H), 3.93 — 3.82 (m, 3 H), 3.72 (m, 1 H), 3.57 (m, 1 H), 3.50 (m, 1 H), 3.43 — 3.37 (m, 2 H), 3.19 — 3.14 (m, 2 H), 1.73 (m, 2 H), 1.22 (d, 3.11,,H = 6.9 Hz, 3 H), 0.86 (m, 3 H); 19F NMR (376 MHZ, (CD3)2SO): 8 — 115.3 (br s, 2 F); MS (MALDI): m/Z = 436.9 ([M+H]+).

Compound 88: 4-(diﬂuoromethyl)[4-[(3R)methylmorpholinyl](8-oxa azaspiro[3.5]nonan—5-yl)-1,3,5-triazinyl]pyridinamine 88 l\ L 1 ELMO F“. F l x k N 2% 63 ,N/ ,1 0"" ”Q + UK» f/fJX\ ,1, F: 1F jun] ‘33“? 3 ,,,,,, 6 f; N” N $1”me / a?! N “C1 x $41., El. N /, if x; x11 W”) “N/ {El/l 0”“ 2» M / A? 1 N” a 611—12 LA (Bk/1W i94 i68 88 According to general procedure 1, compound 88 is obtained from starting als i94 and i68 in 50% yield as a colorless solid. 1H NMR (400 MHz, (CD3)2SO): 8 8.82 (s, 1 H), 7.71 (t, ZJHF = 55 Hz, 1 H), 6.84 (br s, 2 H), 6.75 (s, 1 H), 4.55 (m, 1 H), 4.23 (m, 1 H), 3.91 (m, 1 H), 3.78 (m, 2 H), 3.69 (m, 3 H), 3.56 (m, 1 H), 3.50 (m, 2 H), 3.41 (m, 1 H), 3.16 (m, 1 H), 2.50 (m, 2 H), 2.26 (m, 2 H), 1.73 (m, 2 H), 1.21 (d, 3.1111,: 6.9 Hz, 3 H); 19F NMR (376 MHz, (CD3)2SO): 8 — 114.9 (br s, 2 F); MS (MALDI): m/z = 446.8 ([M+H]+).

EXAMPLE 2 In vitro mTOR binding assay and l Western Blot In vitro mTOR binding assay N—terminally gged mTOR (Cat. No. B; 0.45 mg/ml; truncated version: amino acids 1360-2549), Alexa Fluor ® 647 labeled kinase Tracer 314 (Cat. No. PV6087), LanthaScreen Eu-anti-GST Tag antibody (Cat. No. ) were purchased from Life Technologies. The 1X mTOR Kinase Buffer consists of50mM HEPES pH 7.5, 5 mM MgC12, 1 mM EGTA, and 0.01% Pluronic F-127 (Sigma Cat. No. P2443-250G). — 138 — A 10-point 4-fold serial dilution (highest concentration at 10 umol/L and lowest concentration at 40 pmol/L) of each compound was tested for mTOR binding in ate in a 384-well plate. To perform the LanthaScreen kinase binding assay 5 ul of the test compounds concentrated 3x the ﬁnal concentration, 5 ul of 9 nM OlV6 nM i—GST antibody mixture and 5 ul of 30 nM Tracer 314 solution were mixed together resulting to a ﬁnal concentration of 3 nM GST-mTOR, 2 nM i-GST antibody and 10 nM Tracer 314 per well. After 30 min incubation at RT, time-resolved FRET was measured with a Synergy 4 multi-mode microplate reader (Biotek Instruments) using the following settings: 100 microsecs delay before data collection, 200 microsecs time for data collection, 10 measurements per data point. Emission ﬁlter: 665 nm/8 nm with sensitivity set to 190 and 620 nm/10 nm with sensitivity set to 130; Excitation ﬁlter: 340 nm/30 nm; Dichroic mirror 400 For data analysis, the mean background (wells with only mTOR kinase buffer) was cted and the emission ratio 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). IC50 values of each compound were determined by plotting the on ratio versus the compound concentrations (in logarithmic scale) and then by ﬁtting a dal dose-response curve with le slope to the data using GraphPadTM Prism.

In-cell Western Blot A2058 cells are plated at 20,000 cells/well in a 96-well plate (Perkin Elmer, Cat. No. 6005558) and 24 hours later treated with different compounds for 1 hour. For each compound 7 different trations are applied on cells (5 uM, 1.25 uM, 0.625 uM, 0.3125 uM, 0.155 uM, 0.08 uM and 0.04 uM). Cells are ﬁxed with 4% paraformaldehyde for 30 minutes at room temperature, washed 2 times with 1% BSA in PBS, permeabilized with 0.1% Triton X- 100 in PBS/1% BSA for 30 minutes at room temperature and blocked with 5% goat serum in PBS/1% BSA/0.1% Triton X-100 for 30 minutes at room temperature. Cells are stained with primary dy either with rabbit anti-pPKB S473 (1 :500; Cell Signaling Technology, Cat.

No. 4058) combined with mouse x-tubulin (1:2000; used for normalization; Sigma, Cat.

No. T9026) or with rabbit anti-pS6 S235/S236 (1 :500; Cell Signaling Technology, Cat.

No.4856) combined with mouse anti-(x-tubulin (1 :2000; used for normalization) over night at 4 CC. After 3 times 5 minutes wash with PBS/1% BSA/0.1% triton cells are treated with the — 139 — secondary dies goat-anti-mouse 80 (LICOR, Cat. No. 926-68070) and goat-anti- rabbit IRDye800 (LICOR, 926-32211) (each diluted 1:500 in PBS/1% BSA/0.1% triton) for 1 hour while shaking in the dark. Cells are washed 3 times 5 minutes with PBS/1% BSA/0.1% triton and plate scanned with the y Infrared Scanning system using both 700 and 800 nm channels. As l for 0% inhibition vehicle (0.2% DMSO) is added to cells. To correct for background staining in the data analysis wells are treated only with secondary antibodies.

For data analysis the mean background signal from channel 700 nm and 800 nm are subtracted from each signal in channel 700 nm and 800 nm, respectively. The signals in each channel are normalized to the 0% inhibition and then signal ratio 800 nm over 700 nm is performed to obtain the values for either pPKB S473 or pS6 S235/S236 normalized to 0L- Tubulin.

IC50 values of each compound are determined by ng the ized pPBK S473 and pS6 S235/S236 signals, respectively, versus the compound concentrations (in logarithmic scale) and then by ﬁtting a sigmoidal dose-response curve with variable slope to the data using GraphPadTM Prism.

Table 1: Comparative biological activities Compound 1 Compound 1* Compound 2 Compound 2* o ,.O,\ O L [J E j ' 3: i1 F j: F F Nb F\\| F N‘ /|jf: N113: F\\EF )NL\//NKL:E hf‘Y/K, G / o / N \ N \N N ,/<,, pN 0K?/\ 7‘\ /k I ] NANHQ N N/ (l3 [1] 0d NHz »;.l.\NH2 WNT NHZ S473 IC50 108 149 34 64 [11M] S235/236 196 340 80 650 IC50 [11M] 8 190 59 199 ICso [nM] Table 2: Comparative biological activities Compound 6 Compound 6* Compound 7 Compound 7* — 140 — 0 ,0L 0 ,,,o,L [1, LL, [1, 11 N ”I N j: x 3] L, F F 55/1 ML 5 L 15 L L N N \ ("A“N" N"x ”\ N N \N N “\N \‘L/g‘N 0Q lN/ 1 l/ NH2 0V) 1N‘A’LML2 0d N/J\NH2 Ox U‘N L\NH2 S473 IC50 155 255 59 118 [11M] 36 215 433 97 224 IC50 [11M] 23 nd 71 11d ICso [nM] Table 3: Comparative ical activities Compound 8 Compound 8 * Compound 9 Compound 9* /,o\ O ,o\ L1 LN,» [N1 LN F NAN REF NJ§N F F F El F flu (AN JEN ANN/“<3 (\NJLN/ \N 0y 0y I §/\N/l\lNfl\T\N N/ NH; 0V1 LLN/L NHZ NANHQ ONLJ \N//'\LNH2 S473 IC50 74 196 35 91 [11M] S235/236 68 90 72 164 IC50 [11M] nd 24 nd ICso [nM] Table 4: Comparative biological activities Compound 12 Compound 12* Compound 13 Compound 13* [i] LNL EJ LLNLL F Fj/ F NdéNF N N {N MEN FL??- 1N% L L L pN' N/ ,1, ,1 Co N E 0Q N N” 5v? NH2 “NJ \NHg NiNHZg‘w/l 1‘N rim-1; S473 IC50 208 302 43 116 [11M] pS6 515 743 150 416 — 141 — S235/236 IC50 [11M] 543 796 1015 2834 ICso [nM] Table 5: Comparative biological activities Compound 16 WO2007/084786 Compound 17 WO2007/084786 {of} 110:: NN pip N F; F N NN/ L N NlNL LN S473 IC50 207 263 90 194 [11M] S235/236 184 277 149 384 IC50 [11M] 179 155 644 ICso [nM] Table 6: Comparative biological activities Compound 18 WO2008/098058 Compound 19 WO2008/098058 Lou ,/OL /O\,_ [N] i 3 [\N'N L REF ,9 ,1 EN.

N)? A NJ NM; ‘NH2 ON NN N N N7i ‘NHg S473 ICso 243 555 78 175 [11M] S235/236 256 665 147 370 IC50 [11M] 31 366 158 1925 ICso [nM] Table 7: Comparative ical activities Compound 20 Compound 20* nd 21 Compound 21* — 142 — FOL} ,,/.0\ Na 0 L j L [l L J L J T “f F L “a F F-\ F N"<N FL/F N"{“N FLJ/F N/LLN N/LLN Ev}? L L ,LN,L,N,,;L 7L l' NATL“: six/l lLN, LNH2“ N s’ r, Nl'l\N'/**'7~LN I sL/j LlNFLNHZ l V l 8.,” LLN» l‘NHg 8-.” \LNFLNHz S473 IC50 146 3 ll 57 343 [11M] S235/236 250 559 216 996 IC50 [11M] 13 118 54 394 ICso [nM] Table 8: Comparative biological activities Compound 25 WO2007/084786 Compound 26 WO2007/084786 [:1 E0] E0] L°1 N F {:1in I: ”HF F F F F F F 9%N N I F3N N \ i F “‘F N N \N FN N \N O 0d { N/JNH2 0d [ N/)\NH2 N/ 0 NH2 N/ NH2 S473 IC50 303 452 87 193 [11M] S235/236 294 553 191 617 IC50 [11M] 32 152 47 287 ICso [nM] Table 9: Comparative biological activities Compound 27 W02007/O84786 Compound 28 /O84786 E1 NEJFF E:I E3 {\N /]N\/V N 1/\N / 0d [ NVKNH2 NH2 QN/I in}: 00»N [NjiNHZ NH2 S473 IC50 614 883 77 290 [11M] pS6 766 1100 146 1027 S235/236 — 143 — IC50 [11M] 65 3 76 23 1253 ICso [nM] Table 10: Comparative biological activities Compound 23 W02007/084786 Compound 24 W02007/084786 r“: to] E0] \ili/ N N N F F Fox NF F F F F F F {1“LN; L L t l \ i? \ “j \ N 0‘59"“) i"N”"‘1 N N N/ \N N N l NANHz I ‘ N/ANH2 @ NHz 0K;N N/ NH2 0g S473 IC50 285 564 84 340 [11M] S235/236 230 562 167 740 IC50 [11M] 40 88 35 121 1C50 [nM] Tablel 1: Comparative biological activities Compound 31 W02007/084786 Compound 32 W02007/084786 0) 01 L01 °1 N N N N fN N/ \ N/ \ N/ \N N/ \N [ (\N {\N (\N O l [ NANHZ ‘ VFW2 N/ 0 NH2 N/ 0 O S473 IC50 146 248 100 191 [11M] S235/236 124 228 387 535 IC50 [11M] 28 293 1 86 1C50 [nM] Table 12: Results of in-cell n Blot and mTOR g In—cell Western blot binding —144— pPKB S473 pS6 236 mTOR Compound 1c50 [nM] 1c50 [nM] 1c50 [nM] 1 108 196 8 2 34 80 59 3 231 105 8 4 178 135 nd 85 135 nd 6 155 215 23 7 59 97 71 8 74 68 10 9 35 72 24 138 93 nd 11 61 96 nd 12 219 407 543 13 37 120 1015 14 349.5 883 nd 49 286 nd 16 207 184 30 17 90 149 155 18 243 256 31 19 78 147 158 146 250 13 21 57 216 54 22 57 216 18 23 285 230 40 24 84 167 35 303 294 32 26 87 191 47 27 614 766 65 28 77 146 23 31 146 124 15 32 100 387 293 WO 98347 —145— 37 533 268 49 38 219 79 nd 39 106 47 1 40 252 160 5 41 436 261 22 42 54 45 3 44 197 87 5 45 234 93 7 46 956 426 36 47 469 176 29 50 1561 407 nd 51 875 352 nd 52 1050 332 nd 53 1318 612 nd 54 354 209 nd 55 942 526 nd 56 >10000 >10000 nd 66 244 139 4 67 787 395 nd 68 682 415 nd 69 244 140 21 70 914 906 nd 71 2337 3141 nd 77 476 nd 78 506 392 38 79 200 136 10 80 94 117 nd 82 329 169 40 83 379 294 32 84 116 146 nd 85 249 241 nd — 146 — 86 231 236 nd 88 271 192 18 EXAMPLE 3 A: Kinase binding In order to test g of de. l to PI3K ms and related kinases, a biochemical assay was performed at DiscoveRX (Fremont, USA) (Table 13, Rows l-7).

B: Kinase inhibition Furthermore, compound 1* and reference compounds were analyzed for their ability to inhibit kinase ﬁanction of PIK3CA and related kinases (Proqinase, Germany) (Column3 of Table 13). Lipid kinases PIK3CA, PIK3CB, PIK3CG, PIK3CD, (PI3K 01, B, y and 58), A, PIK3C2B, PIK3C2G, PIK3C3, PIK4B were tested in an o assay (Promega, USA). Protein kinases mTOR and DNAPK were tested in a etric 33P-yATP assay (33PanQinase® Activity Assay, Proqinase, Germany). IC50 values were measured by testing 10 semi-log concentrations of each compound in the range from 1 x 10-04 M to 3 x 10-09 M, in singlicate. Prior to testing, the nds dissolved to l X 10-02M stock solutions in volumes of 100 % DMSO as stated in the compound submission form (CSF). 100 ul of each stock solution were transferred into column 2 of a microtiter plate. Subsequently, the l x 10-02 M stock solutions in column 2 of the master plate were subjected to a serial, semi-logarithmic dilution using 100 % DMSO as a solvent. This resulted in 10 distinct concentrations, with a dilution endpoint of 3 X 10-07 M/100 % DMSO. Pure DMSO was used as l. Compounds were diluted with water and then transferred into the assay resulting in a 1% DMSO solution in a concentration range of l x 10-04 M to 3 x 10-09 M.

For ing lipid kinase inhibition, assays were performed in 96-well half-area microtiter plates. The following solutions were mixed and incubated for 30°C for 40 minutes: 10 ul ofATP solution (50 mM HEPES-NaOH, pH 7.5, 1 mM EGTA, 100 mM NaCl, 0.03 % CHAPS, 2 mM DTT, ATP (PIK3C3, 20 uM; PIK3CA, 150 uM, PIK3CB 300 uM, PIK3CG 500 uM, PIK3CG 100 uM), kinase (PK3C3, 25 ng/25ul; PIK3CA, 2 25 ng/25ul, PIK3CB 10 ng/25ul, PIK3CG 5 25 ng/25ul, PIK3CG 40 25 l) and substrate (50 or 100 uM, respectively), 5 ul of test sample in 5 % DMSO and 10 ul of enzyme/substrate mixture. The — 147 — assay for PIK3C3 additionally contained 3 mM MnCl2, the assay for PIK3CA/PIK3R1, PIK3CB/PIK3R1, PIK3CD/PIK3R1 and PIK3CG onally contained 3 mM MgCl2. 50 ul kinase detection reagent per well was added followed by an incubation for further 60 minutes at room temperature. Signal was measured with a microplate reader r2, Perkin Elmer, Boston, Ma, USA), in luminescence mode.

For measuring protein kinase ty, the reaction mixture was pipetted into a 96 well plate in four steps in the following order: 20 ul of assay buffer, 5 ul of ATP solution (in H20), 5 ul of test compound (in 10 % DMSO), 20 ul enzyme/substrate mix. The assay for all protein kinases contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 uM Na-orthovanadate, 1.2 mM DTT, 50 ug/ml PEG20000, 1 uM ATP, [y—33P]—ATP (approx. 1.8 x 1006 cpm per well), protein kinase (0.1 nM DNA-PK; 2.4 nM mTOR), and substrate (2 ug/well for DNA-PK and 1 ug/well for mTOR). The DNA-PK assay additionally contained 2.5 ug/ml DNA. The on cocktails were incubated at 30°C for 60 s. The reaction was stopped with 50 ul of 2 % (v/v) H3PO4, plates were aspirated and washed two times with 200 ul 0.9 % (w/v) NaCl. Incorporation of 33Pi was determined with a microplate scintillation counter (Microbeta, Wallac). All assays were performed with a BeckmanCoulter/SAGIANTM Core System.

The compound IC50 values for all kinases tested were calculated using Quattro Workﬂow V3.1.0 (Quattro Research GmbH, Germany).

In order to specify the ies of Compound 1* towards s that showed > 50% tion in the Kinome Scan, dissociation constants (Kd) for Compound 1* were determined from dose-response curves with the KINOMEscan logy for the class I PI3Ks (a, B, y and 8), for the class II PI3K PIK3C2B, for the class III PI3K PIK3C3 (Vps34), for the PIKKs (Class IV) mTOR and DNAPK and for the PI4 kinase PIK4B. The smaller the dissociation constant, the higher is the affinity between test compound and kinase. Determination of Kd revealed that Compound 1* was binding with high affinities to the ATP-site of PI3K Class-I family PI3K0L, PI3KB, PI3Ky and PI3K5 with 0.002 uM, 0.011 uM, 0.025 uM and 0.025 uM, respectively (Table 13, Column 2). Weak binding was observed to Class II PIK3CB (Kd: 0,82 uM), and to the Class III family kinase PIK3C3 (Kd: 0,23 uM). nd 1* showed high afﬁnity to the Class-IV PIKK mTOR (Kd: 0.012 uM) while binding to the other PIKK- member, DNAPK, was about 130-fold weaker (Kd: 1.6 uM) and no binding was observed to the PI4 kinase PIK4B (Kd >40 uM). — 148 — In order to igate its selectivity and interactions across the human kinome, Compound 1* was tested in the scanTM. Developed by DiscoveRX, KINOMEscanTM employs proprietary active-site dependent ition g assays allowing the determination of afﬁnities of compounds to the ATP site of n and lipid kinases. KINOMEscan assays do not require ATP and thereby report true thermodynamic interaction afﬁnities, as opposed to IC50 values, which can depend on the ATP concentration (See more at: http://www.discoverx.com/technologies-platforms/competitive-bindingtechnology /kinomescan—technology—platform#sthash.TszYTmK.dpuf.

In a primary screen, Compound 1* was tested at a single concentration of 10.0 uM t 456 human protein and lipid kinases. In these assays, binding of the test nd to a kinase results in reduction of the signal and the results for the primary screen are reported as %Ctrl (percentage of control), where lower numbers indicate stronger hits (.

Table 13: Binding assay Kinase %inh@ lOuM Kd (uM) assay PIK3CA 100 0.002 0.03 PIK3CA(C420R) 100 nd nd PIK3CA(E542K) 100 nd nd PIK3CA(E545A) 100 nd nd PIK3CA(E545K) 100 nd nd PIK3CA(H1047L) 86 nd nd PIK3CA(H1047Y) 99 nd nd PIK3CA(I800L) 100 nd nd PIK3CA(M l 0431) 87 nd nd PIK3CA(Q546K) 100 nd nd PIK3CB 97 0.011 0.66 PIK3CG 99 0.025 0.71 PIK3CD 97 0.025 0.45 PIK3C2B 59 0.82 nd PIK3C2G 93 n.d. nd PIK3C3 nd 0.23 85 mTOR 100 0.012 0.09 DNAPK nd 1 .6 8.6 PIK4B 5 >40 nd Binding assays: A ll-point 3-fold serial dilution of each test compound was prepared in — 149 — 100% DMSO at 100x ﬁnal test concentration and subsequently diluted to 1X in the assay (ﬁnal DMSO concentration = 2.5%) as described by DiscoveRX (Fremont, USA) (Table 13).

As shown in Table 13 (Column1), a potent inhibition ofbinding at 10.0 uM of Compound 1* was observed for the PI3K Class-I family (P13Ku, B, y and 5), the nt P13Ku (PIK3CA) mutants as well as mTOR and to certain degree also Class-II B with a Kd = 0.82 uM).

Determination of Kd revealed that Compound 1* was binding to the ATP-site ofPI3K Class-I family P13Ku, PI3KB, PI3Ky and PI3K5 with 2 nM, 11 nM, 25 nMM and 25 nM, tively. Also potent binding to the ATP site of mTOR (Kd: 12 nM) was observed.

Compound 1* inhibits potently the lipid kinase activity of all recombinantly produced PI3K Class-I subtpyes including the mutant version of PI3Ku and mTOR with IC50 in the nanomolar range [2 to 25 nM] tand o certain degree also Class-II (PIK3CB with a Kd = 0.82 nM) without ing signiﬁcantly other lipid and protein kinase tested in biochemical assays (456 s of Kinomescan, DiscoverX).

Kinase assay: We also ed Compound 1* for its ability to inhibit kinase ﬁlnction of PIK3CA and d kinases nase, Germany). Lipid kinases PIK3CA, PIK3CB, PIK3CG, PIK3CD, PIK3C2A, PIK3C2B, PIK3C2G, PIK3C3, PIK4B were tested in an ADP- Glo assay (Promega, USA). Protein kinases mTOR and DNAPK were tested in a radiometric 33P-yATP assay (33PanQinase® Activity Assay, Proqinase, Germany). IC50 values were measured by testing 10 semi-log concentrations of each compound in the range from 1 x 10- 04 M to 3 x 10-09 M, in singlicate.

EXAMPLE 4 The anti-proliferative activity of Compound 1* was tested in a panel of cells with epidermoid origin. The data demonstrate that Compound 1* with the ion of the MC7 cells inhibited all cell lines between 1598 nM and 1485 nM.

Table 14: Cell line name Disease 5.50 (nM) RPMl-7951 Malignant melanoma 775 MeWo Malignant melanoma 1043 A375 Malignant ma 1153 CAL 27 Squamous cell carcinoma, tongue 1523 melanotic melanoma, non epithelia ( metastatic site: LOX IMVI lymph node) 572 — 150 — M14 tic melanoma; non epithelial 482 MALME-3M Melanotic melanoma; metastatic site: lung; mix 140 MDA-MB-435 Melanoma 413 -2 Melanoma; metastatic site: skin of thigh; polygonal 411 -28 Melanoma; polygonal 343 -5 Melanoma; atic site: axillary node; stellate 171 UACC-62 Melanotic melanoma; non epithelial 212 A-431 Skin; epidermoid oma 1170 MDA-MB-231 Breast cancer; adenocarcinoma 1430 MDA-MB-361 Breast cancer; adenocarcinoma 1485 CAL-33 HeadNeck - Squamous cell carcinoma, tongue 163 HSC-4 HeadNeck - Squamous cell oma, tongue 680 BICR 31 HeadNeck - Tongue squamous carcinoma 158 BHY HeadNeck (tongue) - Oral squamous cell oma 348 Headneck (tongue) - squamous cell carcinoma, BICR 16 hypopharynx 362 YD-10B HeadNeck - Squamous cell oma, tongue 393 SNU-1041 HeadNeck squamous cell carcinoma, hypopharyngeal 658 HSC-4 HeadNeck - Squamous cell carcinoma, tongue 680 SCC-9 HeadNeck - Squamous cell carcinoma, tongue 682 YD-8 HeadNeck - Squamous cell carcinoma, tongue 1004 All cell lines have been licensed from the American Type Culture Collection (ATCC) Manassas, Virginia (US). Master and working cell banks (MCB and WCB) were prepared by subculturing in ATCC-recommended media and freezing ing to ATCC recommended protocols (www.atcc.org). Cell line stocks for the assays were prepared from the WCB. The MCB, WCBs and assay stocks were prepared within respectively 3, 6 and 9 passages of the ATCC vial. Solid powders of reference compounds were stored as indicated by the supplier. nds were weighed on a calibrated balance and dissolved in 100 % DMSO. DMSO samples were stored at room temperature. At the day of the experiment, the compound stock was diluted in 3.16 fold steps in 100 % DMSO to obtain a t dilution series. This was further d 31.6 times in 20mM sterile Hepes buffer pH 7.4. A volume of 5 ul was transferred to the cells to generate a test concentration range from 3.16X10-5 M to 3.16X10-9 M (31.6 uM to 3.16 nM) in duplicate. The ﬁnal DMSO concentration during incubation was 0.4 % in all wells. If a compound showed extremely potent activity, it was further diluted 100 times and a new dose-response curve in duplicate measured. An assay stock was thawed and diluted in its ATCC recommended medium and dispensed in a 384-well plate, depending on the cell line used, at a concentration of 400 - 1600 cells per well in 45 ul medium. For each used cell line the optimal cell density was used. The margins of the plate were ﬁlled with WO 98347 — l5l — phosphate-buffered saline. Plated cells were incubated in a humidiﬁed atmosphere of 5 % C02 at 37 0C. After 24 hours, 5 ul of compound dilution was added and plates were further incubated for another 72 hours. After 72 hours, 25 ul of ATPlite lStepTM (PerkinElmer) solution was added to each well, and subsequently shaken for 2 minutes. After 10 minutes of incubation in the dark, the luminescence was ed on an Envision multimode reader (PerkinElmer).

Dose response curves were generated and G150, TGI and LC50 values were calculated from the dose response curves. Growth inhibition of 50 % (G150) is the drug concentration resulting in a 50% reduction in the net increase in cell number during the drug incubation as compared to the (untreated) control. TGI (total growth inhibition) stands for the compound concentration causing 0 % growth (keeping the cell number constant during the whole experiment = cytostatic effect). The lethal concentration of 50 % (LC50) is the concentration of drug resulting in a 50% reduction in cell number at the end of the drug treatment as compared to that at the beginning indicating a net loss of cells following treatment due to toxic effects of the drug.

EXAMPLE 5 Kl4-Fyn Y528F transgenic mouse is a model of cSCC that develops pre-cancerous lesions and cSCCs resembling human lesions (Skin tumors in n (Y528F) transgenic mice resemble AK and cSCC and demonstrate strong activation of the PDK—l/mTOlVS6 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 JT (2009), Cancer Res;69:9439-9447. Src , Seykora family tyrosine kinases (SFK) te cell proliferation, and increased SFK activity is common in human carcinomas, including cutaneous squamous cell omas (cSCC) and its precursors. The elevated SFK activity in cutaneous cSCC was modeled using Kl4-Fyn Y528F transgenic mice, which spontaneously form punctate keratotic lesions, scaly plaques, and large tumors resembling actinic keratoses, cSCC in situ, and cSCC, respectively. al tissue showed increased levels of activated SFKs, PDKl, STAT3, and ERKl/2, whereas Notchl/ NICD n and transcript levels were sed. p53 levels also were decreased in cSCC in situ and cSCC.

We asked whether topically d TOR inhibitors speciﬁcally targeting the — 152 — PI3K/mTOR pathway should induce sion of cSCCs in K14 Fyn Y528F mice by either topical or systemic (PO) application (50 mg/kg PO QD). The oral application of 50 mg/kg PO QD is known to produce pharmacological signiﬁcant levels of Compound 1* (Cmax: 2-4 6-week-old s of K14-Fyn Y528F mice were treated with a topical application of a gel containing Compound 1* (10 mg of Compound 1*) or nothing (control) were ved in 75 ul of DMSO and then propyleneglycol was added to 1000 mg (ﬁnal concentration is 1% (w/w) ().

The Compound 1* treated cohort ned 6 mice with 20 cSCC lesions () while the control cohort contained 6 mice with 15 cSCC lesions (). The size of each SCC was measured using calipers before treatment and weekly thereafter. The cSCCs varied from 4- 68 mm2 in size (size range of cSCCs in each cohort was similar. Gels were applied to lesions daily once Mo-Fr.

As shown in and 1C, the once daily topical application of Compound 1* gel induced almost complete regression of all cSCC lesions in the K14-Fyn Y528F model without prominent inﬂammation or ulceration within 4 weeks. These data strongly suggest that topical application of potent dual PI3K/mTOR inhibitors may be useﬁll for treating cSCC. The efﬁcacy ofthe oral application is determined as is the histology and IHC.

For histology and immune-histochemical (IHC) analysis of the PI3K/mTOR biomarker (pAKT and p86), minimally invasive (2-3mm thick) skin biopsies are taken and ed at several time points, such as 1) at start of oral treatment, 2) after 1 week, 3) after 3 weeks, in on to taking and analyzing blood levels of nd 1*. Biopsies are taken at areas of low sensitivity, e.g. on shoulders and must be taken in close neighbourhood in order to ensure comparability (skin has different thickness at different body areas). The skin is frozen and is is done by IHC and extraction, followed by LC/MS analysis of Compound 1*. Rough estimation of drug concentration needed for therapeutic effect, which depends on potency and physicochemical properties, are around 0.1-3 microgram/gram tissue. This procedure will be replicated also during the the peroral treatment.

EXAMPLE 6 Daily oral application of nd 1* gel induced almost complete regression of all cSCC lesions in the n Y528F model without prominent side effects. The histology and — 153 — IHC for the biomarker in tumor lesions and blood is performed and the ment of skin and plasma level of Compound 1* are addressed in clinical neodjuvant study in man.

EXAMPLE 7 Pig skin penetration of the inventive compounds The assessment of aneous permeation is key to the successful development of new products and ations intended for human use. Moreover, it is further important for bioequivalence assessments of locally acting products in the pharmaceutical industry. More commonly used models to t skin-permeation studies are ex vivo human or animal skin.

Through the standardization of protocols and techniques, the available skin models can be useful as surrogate models for in viva human skin to evaluate the bioequivalence of topical products. A wide range of animal models has been used as atives to human skin to evaluate aneous permeation of substances. Since porcine (pig) skin is histologically similar to human skin with a comparable SC thickness of 21—26 um. In addition, the average hair-follicle density in porcine ear skin is 20/cm2 compared to 14—32/cm2 in human forehead skin. As well as being similar to human skin, porcine ear skin is also convenient to obtain and has been widely used in skin-permeation studies. Therefore to mimic human skin penetration the use of pig skin either ex vivo or in vivo is sufﬁcient and predictable.

Ex vivo and in vivo models to assess the penetration of various drug substances including the inventive compounds in the skin of pigs have been established. This model allows to assess the PK proﬁle of several drug candidates including the inventive compounds in one subject, y enhancing comparability and avoiding inter-subj ect variability.

In the ﬁrst study (Fig 3, Table 15) the PK proﬁles of nine test formulations have been assessed using 80% SBECD either at pH3 or pH 7. de1* and de3 as 1% experimental ations penetrated into pig skin (lower epidermis and dermis) to a significant extent ex vivo, despite drying up on the skin after a few hours post application. In comparison with Aldara, a cream containing 5% of the TLR7 agonist imiquimod, the intrinsic penetration properties of de1* were ted to be similar to imiquimod, while those of de3 were slightly lower.

Table 15: Nine formulations comprising ive compounds and one control — 154 — formulation.

Compound Formulation Nominal Applied Applied cone. amount of amount of [mgme] formulationl nd j de 1951311 3 Wm (base, .,,,,,.... 10.01 46 (LL 460.5 (Lg de 1* pH 7 1% (base, w/V) 10.01 46 (LL 460.5 (Lg de 8 pH 3 0.5% (base, W/v) 5.03 46 (LL 231.4 (Lg de 3 pH 3 1% (base, w/v) 10.03 46 (LL 461.4 (Lg de 13 pH 3 0.5% (base, w/V) 5.00 46 (LL 230.0 (Lg de 2* pH 3 0.2% (base, w/v) 1.82 46 (LL 83.7 (Lg de 21 pH 3 0.1% (base, w/v) 0.74 46 (LL 34.0 (Lg de 20 pH 3 0.5% (base, w/V) 4.35 46 (LL 200.1 (Lg de 42 pH 3 0.5% (base, w/V) 5.05 46 (LL 232.3 (Lg Imiquimod 5% cream (Aldara ' 56 mg 2.8 mg MEDA AB, Sweden) 1 Application area 4 cm X 2 cm = 8 cm2 ; applied formulation of 5.75 (LL/cm2 or 7 mg/cmzcorresponding to 46 (LL or 56 mg A further study was performed to investigate the skin PK proﬁle of 4 test formulations in ex vivo pig skin: 1% de1* in a 90% propylene glycol (PG)/10% oleyl alcohol (0A), 1% del* in a 100% PG formulation, 1% de3 in a 90% PG/10% OA formulation and the control ation Aldara (containing 5% imiquimod). The PK proﬁles are presented in Table 16 and in de1* in a 90% PG and 10% 0A formulation showed the highest skin penetration followed by the de3 in 90% PG and 10% 0A. The skin concentration of del* in 100% PG alone was lower compared with the preparation ning 10% CA, but was still much higher than the skin concentration of the control formulation Aldara. The skin PK profile of de3 in 100% PG was comparable to de1*. Thus, both del"< and de3 do not need the penetration enhancer oleyl alcohol for significant skin penetration.

In conclusion, topical treatment of pig skin ex vivo with de1* and de3 in 1% experimental preparations ning the standard solvent propylene glycol resulted in high drug concentrations in the lower epidermis and dermis, which were higher ed to skin concentrations achieved after topical treatment with the standard product Aldara (containing % imiquimod).

SUBSTITUTE SHEET (RULE 26) — 155 — Table 16: Three formulations comprising inventive compounds and one control formulation.

Compound Formulation Nominal Applied d cone. amount of amount of [mg/mL] fcmnulation1 nd W ”W cm 1* 1% de 1* in 90% .0 46 uL 460 ug PG and 10% OA de 1* (100% PG) 1% de 1* in O 46 uL 460 ug 100% PG de 3 1% de 3 in 90% 0 46 ”L 460 ”g PG and 10% 0A Imiquimod (Aldara 5% cream ' 56 mg 2 8 mg MEDA AB, Sweden) 1 Application area 4 cm X 2 cm = 8 cm2 ; applied formulation of 5.75 uL/cm2 0r 7 mg/cmzcorresponding to 46 uL or 56 mg In conclusion, topical treatment of pig skin ex vivo with del* and de3 in 1% experimental preparations containing the rd solvent propylene glycol resulted in high drug trations in the lower epidermis and dermis, which were higher compared to skin concentrations achieved after topical treatment with the standard product Aldara (containing % imiquimod).

Thus, the formulations of del*and de3 (each 1% in propylene glycol) has been tested in a pig skin ex-vz'vo study and high penetration into epidermis and dermis found, superior to Aldara (5% imiquimod). The aim of a ﬁarther study is to measure the skin penetration of the same formulations of del*and de3 in pigs in vivo. The following ations were tested: 0 1% del * in propylene glycol (PG) 0 1% del * ene glycol with thickener (PG + TH) 0 1% del* in PEG 0 Imiquimod as control formulation (Aldara 5% cream) — l56 — Except for the PEG formulation signiﬁcant levels of del * were found after the stratum comeum removed by tape stripping in epidermis and dermis ofthe living pig (.

EXAMPLE 8 Pig skin penetration of the inventive compounds The hairless (Hr) gene encodes a transcriptional co-repressor highly expressed in the mammalian skin. In the mouse, several null and hypomorphic Hr alleles have been identiﬁed resulting in hairlessness in homozygous animals, terized by ia developing after a single cycle of relatively normal hair growth. Mutations in the human ortholog have also been associated with congenital alopecia. gh a variety of hairless strains have been developed, outbred SKHl mice are the most widely used in dermatologic research. These unpigmented and competent mice allow for ready manipulation of the skin, application of topical agents, and exposure to UVR, as well as easy visualization of the cutaneous response. Wound healing, acute photobiologic responses, and skin carcinogenesis have been extensively studied in SKHl mice and are well characterized. In on, tumors induced in these mice resemble, both at the logic and lar levels, UVR induced skin malignancies in man (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). In fact, irradiation of SKH-l for 20 minutes with UV-B per day results in an actinic keratosis (AK) that resembles the AK in human.

As shown in there was a signiﬁcant effect of the topical daily treatment of del * compared to non treated (NT) or vehicle treated (V) mice.

The effect of del * was lost when the ent was discontinued (FIG.. 7).

In summary treatment of AK d by UV in the SKH-l mouse model is effectively d and prevented by the topical daily treatment with del *. — 157 —

Claims

1. A compound of formula (1), X1J\\X2 F W F RJ\X3|1 / \NJ\N H 2 wherein X1, X2 and X3 are, independently of each other, N or CH; with the o 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, then X1, X2 and X3 are N; R1 and R2 are independently of each other 10 (iii)a morpholinyl of formula (11) R3— —R4 l (11) wherein the arrow denotes the bond in a (I); and wherein R3 and R4 are independently of each other H, C1-C3alkyl optionally substituted with one or two OH, C1-C2ﬂuoroalkyl, C1-C2alkoxy, C1-C2alkoxyC1-C3alkyl, CN, or C(O)O-C1- 15 Czalkyl; or R3 and R4 form er a bivalent residue —R5R6— selected from C1-C3alkylene ally substituted with l to 4 F, -CH2-O-CH2-, -CH2-NH-CH2-, or any ofthe structures A O A. wherein the arrows denote the bonds in formula (II); or (iv) a saturated 6-membered heterocyclic ring Z selected from thiomorpholinyl and 20 piperazinyl, optionally substituted by l to 3 R7; wherein R7 is independently at each occurrence lkyl optionally substituted with one or two OH, uoroalkyl, C1- CzalkoxyCl-Cgalkyl, C3-C6cycloalkyl; or two R7 substituents form together a bivalent residue —R8R9— selected from C1-C3alkylene optionally substituted with l to 4 F, -CH2-O-CH2- or -O- CH2CH2-O-; — 158 — with the proviso that at least one of R1 and R2 is a morpholinyl of formula II; and prodrugs, metabolites, ers, solvates and pharmaceutically acceptable salts thereof, for use in the prevention or treatment of a skin lesion in a subject.

2. The compound of formula (I) for use according to claim 1, wherein said R1 and said R2 [:1 [:1 [Sr [in ,er ,rgjl l wrjr ESL £er [:34- Tjj’ TEL ‘lr *0 i if In D in +0 (”rm ringing” + + rig" [$10 E? $ $ [31> (:1:er 1:130i l + 10 l + + + + l — l59 — “3* U H