RU2356901C2 - 2,4-pyrimidindiamine compounds having effect in case of autoimmune disorders - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I)

L¹ is direct bond; L² is direct bond; R² is phenyl group, three times substituted with three groups R⁸; R⁴ is

X represents N; Y is selected from group consisting of O, NH, S, SO and SO₂; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO₂, Z is not the same as Y; R⁵ is selected from group consisting from R⁶, halogen; each R⁶ is independently selected from group consisting of hydrogen, halogen; R⁸ is selected from group consisting from R^a, R^b, R^a substituted with one or several similar or different groups R^a or R^b, -OR^a, -O-CHR^aR^b; each R³⁵ independently on others is selected from group consisting of hydrogen and R³⁵, or in alternative case, two groups R³⁵, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R³⁵ each independently on each other are selected from group consisting from hydrogen and R⁸; each R^a is independently selected from group consisting of hydrogen, (C₁-C₆) alkyl, (C₃-C₈) cycloalkyl; each R^b is suitable group which is independently selected from group consisting of -OR^d, halogen, -CF₃, -C(O)NR^cR^c, and -OC(O)OR^d; each R^c is independently protective group or R^a; each R^d is independently protective group or R^a; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

Description

1. CROSS RELATIONS TO RELATED APPLICATIONS

Pursuant to § 119 (e) part 35 of the United States Code (USC), this application claims priority on the basis of the following applications: registration number 60/491641, filing date July 30, 2003 (patent attorney case number 28575 / US / US / 2); registration number 60/531598, filing date December 19, 2003 (patent attorney's case number 28575 / US / 8) and registration number 60/572256, filing date May 15, 2004 (patent attorney's case number 28575 / US / 9).

2. FIELD OF THE INVENTION

The present invention generally relates to compounds of 2,4-pyrimidinediamines, pharmaceutical compositions containing these compounds, intermediate compounds and synthetic methods for the production of these compounds and methods for using these compounds and compositions in various fields, for example, in the treatment or prevention of autoimmune diseases and (or) symptoms associated with these diseases.

3. BACKGROUND OF THE INVENTION

Crosslinking of Fc receptors, such as, for example, a receptor with high affinity for IgE (FcεRI) and / or a receptor with high affinity for IgG (FcγRI), activates the signaling cascade in mast cells, basophils and other immune cells, resulting in the release of chemical mediators responsible for a number of adverse events. For example, such crosslinking leads to the release of preformed mediators of type I anaphylactic hypersensitivity reactions (immediate reaction), such as histamine, from the accumulation zones in granules by degranulation. It also leads to the synthesis and secretion of other mediators, including leukotrienes, prostaglandins, and platelet activation factors (PAF), which play an important role in the course of inflammatory reactions. Additional mediators that are synthesized and secreted by crosslinking Fc receptors include cytokines and nitric oxide.

The signal cascade or cascades activated by crosslinking Fc receptors, such as, for example, FcεRI and / or FcγRI, consist of a set of cellular proteins. Tyrosine kinases are one of the most important distributors of intercellular signals. An important tyrosine kinase involved in establishing transduction signaling pathways associated with cross-linking of FcεRI and / or FcγRI receptors, as well as other signal transduction cascades, is Syk kinase (for a review, see Valent et al. , 2002, Intl. J. Hematol. 75 (4): 257-362).

Since mediators isolated by crosslinking of the FcεRI and FcγRI receptors are responsible or play an important role in the manifestation of numerous adverse events, it is highly desirable to have compounds capable of inhibiting the signaling cascade or cascades responsible for their isolation. Moreover, in view of the critical role of Syk kinase in the signaling cascade (s) of these and other receptors, the presence of compounds capable of inhibiting Syk kinase is also highly desirable.

4. SUMMARY OF THE INVENTION

One aspect of the present invention is the provision of new compounds of 2,4-pyrimidinediamines, which, as will be described in detail below, exhibit biological activity in a number of ways. These compounds generally consist of a 2,4-pyrimidinediamine "core", which has the following structure and numbering system:

These compounds according to the present invention are replaced at the point of attachment of nitrogen (N2) to the C2 atom to form a secondary amine and can be further substituted at one or more positions: at the point of attachment of nitrogen (N4) to the C4, C5 and / or C6 atom. When substituted at the N4 site, the substituent forms a secondary amine. The substituent at the N2 site, as well as possible substituents at other positions, can greatly differ in nature and physicochemical properties. For example, the substituent (s) may be branched, unbranched or cyclic alkyl, branched, unbranched or cyclic heteroalkyl, mono- or polycyclic heteroaryl, or a combination of these groups. These substitution groups may be further substituted, as described in detail below.

The substituents N2 and / or N4 may be attached directly to the corresponding nitrogen atoms or be separated from the corresponding nitrogen atoms by means of linkers, which may be the same or different. The nature of the linkers can vary widely and can include virtually any combination of atoms or groups suitable for separating one part of a molecule from another. For example, the linker may be an acyclic hydrocarbon bridge (e.g., saturated or unsaturated alkylene, such as methane, ethane, ethene, propane, 1-propene, butane, 1-butene, 2-butene, 1 , 3-butadiene- and the like), a monocyclic or polycyclic hydrocarbon bridge (e.g., 1,2-benzene, 2,3-naphthalene-and the like), a simple acyclic heteroatom bridge or a heteroalkyldiyl bridge (e.g. -O- , -S-, SO-, -NH-, -PH-, -C (O) -, -C (O) NH-, -S (O) -, -S (O) ₂ -, -S (O ) NH-, -S (O) ₂ NH-, -O-CH ₂ -, -CH ₂ -O-CH ₂ -, -O-CH = CH- CH ₂ -, and the like), a monocyclic or polycyclic heteroaryl ny bridge (e.g., [3,4] furan, pyridine, thiophene, piperidine, piperazine, pirazidin-, pyrrolidin, and the like) or combinations of these bridges.

Substituents at positions N2, N4, C5 and / or C6, as well as potential linkers, may subsequently be substituted with one or more identical or different substitution groups. The nature of these substitution groups can vary widely. An unlimited number of examples of suitable substitution groups include branched, unbranched and cyclic alkyls, mono- and polycyclic aryls, branched, unbranched and cyclic heteroalkyls, mono- and polycyclic heteroaryls, halogens, branched, unbranched or cyclic haloalkyls, hydroxyls, tri-oxo, oxo groups, branched, unbranched and cyclic alkoxy groups, branched, unbranched and cyclic haloalkoxy groups, trifluoromethoxy groups, mono- and polycyclic aryl xy groups, mono- and polycyclic heteroaryloxy groups, esters, alcohols, sulfides, thioethers, sulfanyls (thiols), imines, azo groups, azides, amines (primary, secondary and tertiary), nitriles (any isomers), cyanates (any isomers ), thiocyanates (any isomers), nitroso groups, nitro groups, diazo groups, sulfoxides, sulfonyls, sulfonic acids, sulfamides, sulfonamides, sulfamic acid esters, aldehydes, ketones, carboxylic acids, esters, amides, amidines, formadins, amino acids, acetylenes, acetylenes , lactones, lactams, glucosides, gluco nurides, sulfones, ketals, acetals, thioketals, oximes, oxamic acids, esters of oxamic acids, etc., as well as combinations of these groups. Substitutional groups having functional reactivity may be protected or unprotected, as is well known from previous works.

In one illustrative example, the compounds of 2,4-pyrimidinediamines according to the present invention are compounds of structural formula (I):

including their salts, hydrates, solvates and N-oxides, in which:

structural units L ¹ and L ² each independently independently from each other are selected from groups containing a direct link and a linker;

R ² and R ^{4 are} described below ;

R ⁵ is selected from the group consisting of R ⁶ , (C1-C6) alkyl optionally substituted with one or more identical or different R ⁸ groups; (C1-C4) alkanyl optionally substituted with one or more identical or different R ⁸ groups; (C2-C4) alkenyl optionally substituted with one or more identical or different R ⁸ groups, and (C2-C4) alkynyl optionally substituted with one or more same or different R ⁸ groups;

Each of the groups R ⁶ is independently selected from the group consisting of hydrogen, an electronegative group, -OR ^d , -SR ^d , (C1-C3) haloalkyloxy group, (C1-C3) perhaloalkyloxy group, -NR ^c R ^c , halogen , (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CF ₃ , —CH ₂ CF ₃ , —CF ₂ CF ₃ , —CN, —NC, —OCN, —SCN, —NO, —NO ₂ , -N ₃ ,

-S (O) R ^d , -S (O) ₂ R ^d , -S (O) ₂ OR ^d , -S (O) NR ^c R ^c ; -S (O) ₂ NR ^c R ^c , -OS (O) R ^d , -OS (O) ₂ R ^d , -OS (O) ₂ OR ^d , -OS (O) NR ^c R ^c , -OS ( O) ₂ NR ^c R ^c , -C (O) R ^d , -C (O) OR ^d , -C (O) NR ^c R ^c , -C (NH) NR ^c R ^c , -OC (O) R ^d , -SC (O) R ^d , -OC (O) OR ^d , -SC (O) OR ^d , -OC (O) NR ^c R ^c , -SC (O) NR ^c R ^c , -OC (NH ) NR ^c R ^c , -SC (NH) NR ^c R ^c , - [NHC (O)] _n R ^d , - [NHC (O)] _n OR ^d , - [NHC (O)] _n NR ^c R ^c and - [NHC (NH)] _n NR ^c R ^c , (C5-C10) aryl optionally substituted with one or more identical or different R ⁸ groups, phenyl optionally substituted with one or more same or different R ⁸ groups, (C6- C16) arylalkyl optionally substituted with one or more identical or different groups of R ⁸ , 5-10 membered heteroaryl, optionally substituted one more or more same or different R ⁸ groups, and a 6-16 membered heteroarylalkyl optionally substituted with one or more same or different R ⁸ groups;

R ⁸ is selected from the group consisting of R ^a , R ^b , R ^a optionally substituted with one or more identical or different groups R ^a or R ^b , -OR ^a optionally substituted with one or more identical or different groups R ^a or R ^b , -B (OR ^a ) ₂ , -B (NR ^c R ^c ) ₂ , - (CH ₂ ) _m -R ^b , - (CHR ^a ) _m -R ^b , -O- (CH ₂ ) _m -R ^b ,

-S- (CH ₂ ) _m -R ^b , -O-CHR ^a R ^b , -O-CR ^a (R ^b ) ₂ , -O- (CHR ^a ) _m -R ^b ,

-O- (CH ₂ ) _m -CH [(CH ₂ ) _m R ^b ] R ^b , -S- (CHR ^a ) _m -R ^b , -C (O) NH- (CH ₂ ) _m -R ^b ,

-C (O) NH- (CHR ^a ) _m -R ^b , -O- (CH ₂ ) _m -C (O) NH- (CH ₂ ) _m -R ^b ,

-S- (CH ₂ ) _m -C (O) NH- (CH ₂ ) _m -R ^b , -O- (CHR ^a ) _m -C (O) NH- (CHR ^a ) _m -R ^b ,

-S- (CHR ^a ) _m -C (O) NH- (CHR ^a ) _m -R ^b , -NH- (CH ₂ ) _m -R ^b , -NH- (CHR ^a ) _m -R ^b ,

-NH [(CH ₂ ) _m R ^b ], -N [(CH ₂ ) _m R ^b ] ₂ , -NH-C (O) -NH- (CH ₂ ) _m -R ^b ,

-NH-C (O) - (CH ₂ ) _m -CHR ^b R ^b and -NH- (CH ₂ ) _m -C (O) -NH- (CH ₂ ) _m -R ^b ;

each R ^a group is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16 arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each of the R ^b groups is a suitable group that is independently selected from the group consisting of = O, -OR ^d , (C1-C3) haloalkyloxy group,

-OCF ₃ , = S, -SR ^d , = NR ^d , = NOR ^d , -NR ^c R ^c , halogen, -CF ₃ , -CN, -NC, -OCN, -SCN, -NO, -NO ₂ , = N ₂ , -N ₃ , -S (O) R ^d , -S (O) ₂ R ^d , -S (O) ₂ OR ^d , -S (O) NR ^c R ^c , -S (O) ₂ NR ^c R ^c , -OS (O) R ^d , -OS (O) ₂ R ^d , -OS (O) ₂ OR ^d , -OS (O) ₂ NR ^c R ^c , -C (O) R ^d , -C (O) OR ^d , -C (O) NR ^c R ^c , -C (NH) NR ^c R ^c , -C (NR ^a ) NR ^c R ^c , -C (NOH) R ^a , -C ( NOH) NR ^c R ^c , -OC (O) R ^d , -OC (O) OR ^d , -OC (O) NR ^c R ^c , -OC (NH) NR ^c R ^c , -OC (NR ^a ) NR ^c R ^c , - [NHC (O)] _n R ^d , - [NR ^a C (O)] _n R ^d , - [NHC (O)] _n OR ^d , - [NR ^a C (O)] _n OR ^d , - [NHC (O)] _n NR ^c R ^c , - [NR ^a C (O)] _n NR ^c R ^c , - [NHC (NH)] _n NR ^c R ^c and - [NR ^a C (NR ^a )] _n NR ^c R ^c ;

each of the R ^c groups independently represents a protecting group or R ^a , or alternatively, each of the R ^c groups is taken together with the nitrogen atom to which it is attached to form a 5-8 membered cycloheteroalkyl or heteroaryl, which may optionally include one or more identical or different additional heteroatoms and which may optionally be substituted with one or more identical or different R ^a groups or suitable R ^b groups;

each R ^d group independently represents a protecting group or R ^a ;

each index m independently is an integer from 1 to 3; and

each index n independently represents an integer from 0 to 3.

In one application, R ⁵ is F and R ⁶ is hydrogen.

Another aspect of the present invention includes prodrugs of 2,4-pyrimidinediamine compounds. Such prodrugs can be active in their prodrug form or inactive until converted to the active dosage form under certain physiological or other conditions of use. In the prodrugs of the present invention, one or more functional groups of 2,4-pyrimidinediamine compounds are included in the promoieties, which are cleaved from the molecule under the conditions of use, usually by hydrolysis, enzymatic cleavage, or other cleavage mechanism to form functional groups. For example, primary or secondary amino groups may be included in an amide procomponent that cleaves under conditions of use to form a primary or secondary amino group. Thus, the prodrugs of the present invention include special types of protective groups called “progroups” and mask one or more functional groups of 2,4-pyrimidinediamine compounds that cleave under conditions of use to form active drug compounds 2,4 -pyrimidinediamines. Functional groups that make up 2,4-pyrimidinediamine compounds that can be masked by progroups to be included in the procomponent include, but are not limited to: amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, carbonyls , phenols, catechols, diols, alkynes, phosphates, etc. Currently, there are a huge number of progroups suitable for masking these functional groups in order to form procomponents capable of cleaving under conditions of use. All of these progroups, alone or in combination, may be included in the prodrugs of the present invention. Specific examples of procomponents forming primary or secondary amino groups that may be included in the prodrugs of the present invention include, but are not limited to the following groups: amides, carbamates, imines, ureas, phenenyls, phosphorylates, and sulfenyls. Specific examples of sulfonyl group-forming procomponents that may be included in prodrugs of the present invention include, but are not limited to the following groups: thioethers, for example S-methyl derivatives (monothio-, dithio-, oxythio-, aminothioacetals), silyl thioethers, complex thioethers, thiocarbonates, thiocarbamates, asymmetric disulfides, etc. Specific examples of procomponents that result in cleavage of hydroxyl groups that may be included in the prodrugs of the present invention include, but are not limited to, sulfonates, esters and carbonates. Specific examples of carboxy group-forming procomponents that may be included in prodrugs of the present invention include, but are not limited to, esters (including silyl esters, oxamic acid esters and thioethers), amides and hydrazides.

In one illustrative example, the prodrugs of the present invention are compounds of structural formula (I) in which the protective group R ^c and R ^d is a progroup.

In another illustrative example, prodrugs according to the present invention are compounds of structural formula (II):

including their salts, hydrates, solvates and N-oxides, in which:

R ² , R ⁴ , R ⁵ , R ⁶ , L ¹ and L ² represent the groups indicated previously in the description of formula (I);

R ^2b is a progroup;

R ^4b is a progroup or alkyl group, for example methyl, as described further in the examples section.

A further aspect of the present invention includes formulations containing one or more compounds and / or prodrugs of the present invention, as well as an appropriate carrier, excipient or diluent. The exact nature of the carrier, excipient or diluent will depend on the intended use of the composition, from substances used in veterinary practice, to substances used to treat people.

Another aspect of the present invention includes intermediates useful in the synthesis of 2,4-pyrimidinediamine compounds and prodrugs of the present invention. In one example, the intermediates are 4-pyrimidinamines of structural formula (III):

including their salts, hydrates, solvates and N-oxides in which R ⁴ , R ⁵ , R ⁶ and L ² are the groups mentioned previously in the description of structural formula (I); LG is a substituted group, for example, —S (O) ₂ Me, —SMe or halogen groups ( for example , F, Cl, Br, I); and R ^4c represents hydrogen, a progroup, an alkyl group, or another group described herein.

In another example, the intermediates are 2-pyrimidinamines according to structural formula (IV):

including their salts, hydrates, solvates and N-oxides in which R ² , R ⁵ , R ⁶ and L ¹ are the groups mentioned previously in the description of structural formula (I); LG is a substituted group, for example, —S (O) ₂ Me, —SMe or halogen groups ( for example, F, Cl, Br, I).

In yet another example, the intermediates are 4-amino or 4-hydroxy-2-pyrimidinamines in accordance with structural formula (V):

including their salts, hydrates, solvates and N-oxides in which R ² , R ⁵ , R ⁶ and L ¹ are the groups mentioned previously in the description of structural formula (I); R ⁷ represents an amino or hydroxyl group, and R ^2c represents hydrogen or a progroup.

In yet another example, the intermediates are N4-substituted cytosines in accordance with structural formula (VI):

including their salts, hydrates, solvates and N-oxides in which R ⁴ , R ⁵ , R ⁶ and L ² are the groups mentioned previously in the description of structural formula (I), and R ^4c is a group similar to that mentioned in the description formulas (III).

Another aspect of the present invention includes methods for the synthesis of 2,4-pyridinediamine compounds and prodrugs of the present invention. In one example, this method involves the reaction of 4-pyrimidinamine of structural formula (III) with an amine of the formula HR ^2c NL ¹ -R ² , where L ¹ , R ² and R ^2c are the groups indicated previously in the description of structural formula (IV), with the formation of 2,4-pyrimidinediamine of structural formula (I), or a prodrug in accordance with structural formula (II).

In another example, this method involves the reaction of 2-pyrimidinamine of structural formula (IV) with an amine of the formula R ⁴ -L ² -NHR ^4c , in which L ⁴ , R ⁴ and R ^4c are the groups indicated previously in the description of structural formula (III) , with the formation of 2,4-pyrimidinediamine of structural formula (I), or a prodrug in accordance with structural formula (II).

In yet another example, the method involves the reaction of 4-amino-2-pyrimidinamine of structural formula (V) (in which R ⁷ is an amino group) with an amine of formula R ⁴ -L ² -NHR ^4c , in which L ⁴ , R ⁴ and R ^4c represent the groups indicated previously in the description of structural formula (III), with the formation of 2,4-pyrimidinediamine of structural formula (I), or a prodrug in accordance with structural formula (II). Alternatively, 4-amino-2-pyrimidinamine may be reacted with a compound of formula R ⁴ -L ² -LG, in which R ⁴ and L ² are the groups previously described in the description of structural formula (I), and LG is a substituted group.

In yet another example, said method involves a halogenation reaction of 4-hydroxy-2-pyrimidinamine of structural formula (V) (R ⁷ is a hydroxyl group) to form 2-pyrimidinamine of structural formula (IV) followed by reaction of said pyrimidinamine with the corresponding amine as described above .

In another example, said method involves a halogenation reaction of an N4-substituted cytosine of structural formula (VI) to form 4-pyrimidinamine of structural formula (III) followed by reaction of said pyrimidinamine with the corresponding amine as described above.

The 2,4-pyrimidinediamine compounds of the present invention are potent inhibitors of the degranulation of immune cells such as mast cells, basophils, neutrophils and / or eosinophils. Thus, another aspect of the present invention includes methods for regulating and, in particular, inhibiting the degranulation of such cells. The proposed method generally consists in bringing the degranulated cell into contact with a 2,4-pyrimidinediamine compound or prodrug according to the present invention or an acceptable salt, hydrate, solvate, N-oxide of said compounds and / or a combination thereof in an amount sufficient to effectively regulate or inhibit cell degranulation. The specified method can be used in vitro or in vivo as a tactic for the treatment or prevention of diseases characterized by, associated with or associated with cellular degranulation.

Without claiming to be connected with any theory explaining the principle of action, the available biochemical data confirm that the compounds of 2,4-pyrimidinamines have an inhibitory effect on degranulation, at least in part, by blocking or inhibiting the signal transduction cascade (cascades) initiated by crosslinking Fc receptors with a high degree of affinity for IgE (“FcεRI”) receptors and / or IgG (“FcγRI”) receptors. In fact, 2,4-pyrimidinediamine compounds are potent inhibitors of degranulation mediated by both FcεRI and FcγRI receptors. As a consequence, 2,4-pyrimidine compounds can be used to inhibit signaling cascades of these Fc receptors in any type of cell expressing such FcεRI and / or FcγRI receptors, including but not limited to the following cells: macrophages, mast cells, basophils, neutrophils and / or eosinophils.

These methods also allow you to regulate and, in particular, inhibit the processes that occur in the forward direction, which are the result of the activation of such signaling cascades of Fc receptors. Such direct processes include, but are not limited to: FcεRI and / or FcγRI-mediated degranulation, cytokine production and / or production and / or isolation of lipid mediators such as leukotrienes and prostaglandins. Said method generally consists in bringing a cell from the category of the above expressing an Fc receptor into contact with a 2,4-pyrimidinediamine compound or prodrug of the present invention or a corresponding salt, hydrate, solvate, N-oxide of said compounds and / or a combination thereof in an amount sufficient to effectively regulate or inhibit the Fc receptor signaling cascade and / or a direct process affected by the activation of this signaling cascade. This method can be used in vitro or in vivo as a tactic for the treatment or prophylaxis of diseases characterized by, associated with or associated with the signaling cascade of Fc receptors, such as, for example, diseases caused by the release of chemical mediators of granules during degranulation, isolation and / or synthesis of cytokines and / or the isolation and / or synthesis of lipid mediators, such as, for example, leukotrienes and prostaglandins.

Another aspect of the present invention includes methods of treating and / or preventing diseases characterized by, caused by, or associated with the release of chemical mediators by activating Fc receptor signaling cascades, such as, for example, FcεRI and / or FcγRI receptor signaling cascades. These methods can be applied both to animals and to humans. These methods generally consist of administering to an animal or human a 2,4-pyrimidinediamine compound or prodrug of the present invention or an appropriate salt, hydrate, solvate, N-oxide of said compounds and / or a combination thereof in an amount sufficient to effectively treat or prevent the disease. As discussed above, activation of the FcεRI or FcγRI receptor signaling cascade in certain immune cells leads to the isolation and / or synthesis of various chemicals that are pharmacological mediators of a wide range of diseases. Any of these diseases can be treated or prevented in accordance with the methods of the present invention.

For example, in mast cells and basophils, activation of the FcεRI or FcγRI receptor signaling cascade leads to the immediate ( i.e. , within 1-3 min from the moment of receptor activation) release of preformed mediators of atopic and / or type I hypersensitivity reactions (e.g. histamine, proteases such as tryptases, etc.) through a degranulation process. Such atopic and / or type I hypersensitivity reactions include, but are not limited to: anaphylactic reactions to the environment and other allergens (e.g. pollen, insect and / or animal venom, food, medicine, contrast paint, etc.), anaphylactoid reactions, hay fever, allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic dermatitis, eczema, urticaria, dysfunction of the mucous membrane, tissues, as well as a number of gastrointestinal disorders.

Following the immediate release of preformed mediators through degranulation, a number of other chemical mediators are isolated and / or synthesized, including, among others, platelet activating factor (PAF), prostaglandins and leukotrienes (e.g. LTC4), as well as de novo synthesis and isolation of cytokines, such as e.g. TNFα, IL-4, IL-5, IL-6, IL-13, etc. The first of these two processes occurs approximately 3-30 minutes after activation of the receptors; the next - approximately 30 minutes to 7 hours after activation of the receptors. These late-stage mediators are considered partially responsible for the chronic symptoms of the above atopic and type I hypersensitivity reactions and, in addition, are chemical mediators of inflammation and inflammatory diseases (ie osteoarthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel disease , syndrome of increased irritability of the stomach, spastic colitis, etc.), weak scarring (i.e., scleroderma, severe fibrosis, keloid formation s, postoperative scarring, pulmonary fibrosis, vasospasm, migraine, reperfusion injury and post-myocardial infarction) and Sjogren's syndrome. All of these diseases can be treated or prevented in accordance with the methods of the present invention.

Additional diseases that can be treated or prevented using the methods of the present invention include diseases associated with the pathology of basophilic and / or mast cells. Examples of such diseases include, but are not limited to: skin diseases, such as scleroderma, heart diseases, such as myocardial infarction, lung diseases, such as changes or transformations of lung muscles, or chronic obstructive pulmonary disease (COPD), and bowel disease, such as, for example, intestinal inflammation syndrome (spastic colitis).

The 2,4-pyrimidinediamine compounds of the present invention are also potent inhibitors of tyrosine kinase and, in particular, Syk kinase. Thus, another aspect of the present invention includes methods for regulating and, in particular, inhibiting the activity of Syk kinase. The method generally consists in bringing the Syk kinase or cell containing the Syk kinase into contact with the 2,4-pyrimidinediamine compound or prodrug of the present invention or the corresponding salt, hydrate, MES, N-oxide of said compounds and / or their composition in an amount sufficient to effectively regulate or inhibit the activity of Syk kinase. In one example, a Syk kinase is provided as an isolated or recombinant Syk kinase. In another example, the Syk kinase is presented as an endogenous or recombinant Syk kinase expressed by a cell, as, for example, in the case of a mast cell or basophil. The method can be used in vitro or in vivo as a tactic for the treatment or prophylaxis of diseases characterized by, associated with or associated with Syk kinase activity.

Without attempting to confine itself to any one theory explaining the mechanism of action, it is believed that the 2,4-pyrimidinediamine compounds of the present invention have an inhibitory effect on cell degranulation and / or secretion of other chemical mediators mainly due to the inhibition of Syk kinase, which is activated by a homodimer FcεRI receptor gamma chains (see, for example, FIG. 2). This gamma chain homodimer is common to other Fc receptors, including FcγRI, FcγRIII and FcαRI. For all of these receptors, the process of intracellular signal transduction is mediated by a common gamma chain homodimer. The binding and aggregation of these receptors leads to the recruitment and activation of tyrosine kinases, such as, for example, Syk kinases. As a result of these common signaling actions, these 2,4-pyrimidinediamine compounds can be used to regulate and, in particular, inhibit signaling cascades of Fc receptors with gamma chain homodimers, such as, for example, FcεRI, FcγRI, FcγRIII and FcαRI, as well as cell reactions obtained through these receptors.

Syk kinase is known to play a critical role in other signaling cascades. For example, Syk kinase is an effector of B-cell receptor (BCR) signals (Turner et al., 2000, Immunology Today 21: 148-154) and is an essential component of the beta (1), beta (2), and beta (3) signaling pathway ) integrin in neutrophils (Mocsai et al., 2002, Immunity 16: 547-558). Since these 2,4-pyrimidinediamine compounds are potent inhibitors of Syk kinase, they can be used to regulate and, in particular, inhibit any signal cascades in which Syk kinase plays a role, for example, in signaling cascades of Fc receptors, BCR, and integrin as well as cell responses obtained through these receptors. The regulation or inhibition of a particular cell response depends in part on the particular cell type and receptor signaling cascade, as is well known in the literature. Some of the examples of cell responses that can be regulated or inhibited by 2,4-pyrimidinediamine compounds include respiratory burst, cell adhesion, cell degranulation, cell proliferation, cell migration, phagocytosis (e.g. , in macrophages), calcium ion flow (e.g., in mast cells basophils, neutrophils, eosinophils and B-cells), platelet aggregation and cell maturation (for example, in B-cells).

Thus, another aspect of the present invention includes methods for regulating and, in particular, inhibiting signal transduction cascades in which Syk kinase is involved. The method generally consists in bringing the Syk-dependent receptor or cell expressing the Syk-dependent receptor into contact with the 2,4-pyrimidinediamine compound or prodrug of the present invention, or the corresponding salt, hydrate, solvate, N-oxide of said compounds and / or combinations thereof in an amount sufficient to effectively regulate or inhibit the signal transduction cascade. These methods can also be used to regulate and, in particular, inhibit direct processes or cell responses resulting from the activation of a particular Syk-dependent signal transduction cascade. The methods can be used to control any signal transduction cascades in which the role of the Syk kinase is unknown or is established later. The methods can be used in vitro or in vivo as tactics for the treatment or prophylaxis of diseases characterized by, caused by, or associated with the activation of a Syk-dependent signal transduction cascade. Some examples of such diseases include the diseases described previously.

The data obtained as a result of cell analysis, together with data obtained in animals, also confirm that the 2,4-pyrimidinediamine compounds of the present invention can be used to treat or prevent autoimmune diseases and / or symptoms of these diseases. Appropriate methods generally include administering to a patient suffering from an autoimmune disease or at risk of developing an autoimmune disease, 2,4-pyrimidinediamine or a prodrug of the present invention, or an acceptable salt, N-oxide, hydrate, solvate, or a combination thereof, in an amount effective for treating or preventing an autoimmune disease and / or related symptoms. Autoimmune diseases treatable or preventable with 2,4-pyrimidinediamine compounds include diseases often associated with non-anaphylactic hypersensitivity reactions (type II, III and / or IV) and / or diseases mediated at least in part activation of the FcγR signaling cascade in monocytes. Autoimmune diseases of this kind include, but are not limited to, diseases often characterized as autoimmune disorders of a single organ or single cell type, as well as diseases often characterized as including systemic autoimmune disorders. Some examples of diseases that are often characterized as autoimmune disorders of a single organ or a single type of cell include: Hashimoto thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, ophthalmic immune function, pulmonary hypertension, pulmonary arthritis, and pulmonary arthritis bazedov’s disease, biliary primary cirrhosis of the liver, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy. Some examples of diseases often characterized as including systemic autoimmune disorders include systemic erythematous lupus erythematosus, rheumatoid arthritis, Sjogren’s syndrome, Reiter’s syndrome, polymyositis-dermatomyositis, systemic sclerosis, nodosa polyarteritis, multiple sclerosis, and bullous pemphigoid.

5. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the production of IgE under the influence of allergens and the subsequent isolation of preformed and other chemical mediators of mast cells;

Figure 2 illustrates the signal transduction cascade of FcεR1 receptors leading to degranulation of mast cells and / or basophils; and

Figure 3 illustrates the proposed sites of action of compounds that selectively inhibit FcεRI receptor-mediated reverse degranulation, as well as compounds that inhibit FcεRI receptor-mediated degranulation, and ionomycin-induced degranulation.

6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

6.1 Definitions

For the purposes of this text, the following terms have the following meanings.

“ Alkyl ” alone or as part of another compound refers to a saturated or unsaturated monovalent hydrocarbon radical with a branched, unbranched or cyclic structure and a fixed number of carbon atoms ( for example , C1-C6 means the number of carbon atoms from one to six) obtained by the separation of one atom hydrogen from a single carbon atom of the starting alkane, alkene or alkyn. Typical alkyl groups include, but are not limited to: methyl; ethyls, such as ethanyl, ethenyl, ethynyl; propyl, such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en- 1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc .; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1- silt, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1, 3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1,3-dien-1- silt, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc .; and the like. If desired saturation levels are intended, the term “alkanyl,” “alkenyl,” and / or “alkynyl,” as used below, is used. In preferred embodiments, the alkyl groups are (C1-C6) alkyl.

Alkanyl , alone or as part of another compound, refers to saturated alkyl with a branched, unbranched or cyclic structure obtained by separating one hydrogen atom from a single carbon atom of the starting alkane. Typical alkanyl groups include, but are not limited to: methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc .; butanyls such as butan-1-yl, butan-2-yl ( sec- butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl ( tert -butyl), cyclobutane -1-yl, etc .; and the like. In preferred embodiments, the alkanyl groups are (C1-C6) alkanyl.

Alkenyl , alone or as part of another compound, refers to unsaturated alkyl with a branched, unbranched or cyclic structure having at least one carbon-carbon double bond obtained by separating one hydrogen atom from a single carbon atom of the starting alkene. A group may have a cis or trans configuration in the vicinity of the double bond (double bonds). Typical alkenyl groups include, but are not limited to: ethenyl; propenyls, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1- en-1-yl; cycloprop-2-en-1-yl; butenyls, such as, for example, but-1-en-1-yl, but-1-en-2-yl, 2-methylprop-1-en-1-yl, but-2-en-1-yl, but- 2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3- sludge, cyclobuta-1,3-dien-1-yl, etc .; and the like. In preferred embodiments, the alkenyl groups are (C2-C6) alkenyl.

Alkynyl , alone or as part of another compound, refers to an unsaturated alkyl with a branched, unbranched or cyclic structure having at least one carbon-carbon triple bond obtained by the separation of one hydrogen atom from a single carbon atom of the starting alkyne. Typical alkynyl groups include, but are not limited to: ethynyl; propynyls, such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc .; butynyls, such as, for example, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc .; and the like. In preferred embodiments, the alkynyl group is (C2-C6) alkynyl.

“ Alkyldiyl ” alone or as part of another compound refers to a saturated or unsaturated divalent hydrocarbon group with a branched, unbranched or cyclic structure and a fixed number of carbon atoms ( ie, C1-C6 means the number of carbon atoms from one to six) obtained by separation one hydrogen atom from each of the two separate carbon atoms of the starting alkane, alkene or alkyn, or by separating two hydrogen atoms from the single carbon atom of the starting alkane, alkene or al Kina. Two centers of monovalent radicals or each valency of the center of a divalent radical can form bonds with the same or with different atoms. Typical alkyldiyl groups include, but are not limited to: methanediyl; ethyldiyls such as ethane-1,1-diyl, ethane-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropane-1,1-diyl, cyclopropane-1,2- diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-in-1,3-diyl, etc. d .; butyl diyls such as butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, butane-1,4-diyl, butane-2,2-diyl, 2-methyl-propan- 1,1-diyl, 2-methyl-propan-1,2-diyl, cyclobutane-1,1-diyl; cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3- diyl, but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl, 2-methanylidene-propane-1,1-diyl, buta-1,3-diene 1,1-diyl, buta-1,3-diene-1,2-diyl, buta-1,3-diene-1,3-diyl, buta-1,3-diene-1,4-diyl, cyclobut- 1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl, cyclobut-1,3-diene-1,2-diyl, cyclobuta- 1,3-diene-1,3-diyl, but-1-in-1,3-diyl, but-1-in-1,4-diyl, buta-1,3-diin-1,4-diyl and etc .; and the like. If predetermined saturation levels are intended, the terms “alkanyldiyl”, “alkenyldiyl” and / or “alkynyldiyl” are used. If it is assumed that two valencies of the same carbon atom are involved, the term “alkylidene” is used. In preferred embodiments, the alkyldiyl group is a (C1-C6) alkyldiyl. Also preferred are saturated acyclic alkanyldiyl groups in which the centers of the radicals are located at the extreme carbon atoms, for example methanediyl (methane-); ethane-1,2-diyl (ethane-); propane-1,3-diyl (propane-); butane-1,4-diyl (butane-); and the like (also referred to as alkylene, as defined below ).

“ Alkylene- ” alone or as part of another compound refers to an unbranched saturated or unsaturated alkyldiyl group with two extreme centers of monovalent radicals obtained by separating one hydrogen atom from each of their two extreme carbon atoms of an unbranched starting alkane, alkene or alkyn. The designation of a double or triple bond, if it exists, is indicated in square brackets in a separate alkylene group. Typical alkylene groups include, but are not limited to: methane; ethylene groups, such as, for example, ethane, ethene, ethin; propylene groups, such as, for example, propane, prop [1] en-, propa [1,2] diene, prop [1] in-, etc .; butylene groups, such as, for example, butane, but [1] en, but [2] en, buta [1,3] diene, but [1] in, but [2] in, but [ 1,3] diene, etc .; and the like. If preset levels of saturation are assumed, the term “alkane-,” “alkene-” and / or “alkine-” is used. In preferred embodiments, the alkylene- group is (C1-C6) - or (C1-C3) alkylene. Unbranched saturated alkane groups, for example methane, ethane, propane, butane and the like, are also preferred.

“Heteroalkyl” , “heteroalkanyl” , “heteroalkenyl” , “ heteroalkynyl ”, “ heteroalkyldiyl ” and “ heteroalkylene ” themselves or as part of other compounds refer to groups of alkyls, alkanyls, alkenyls, alkynyls, alkyldiyls or alkylenes, respectively, in which one or more carbon atoms are independently replaced by the same or different heteroatoms or heteroatom groups. Typical heteroatoms and / or heteroatomic groups that can replace carbon atoms include, but are not limited to: -O-, -S-, -SO-, -NR'-, -PH-, -S (O) -, - S (O) ₂ -, -S (O) NR'-, -S (O) ₂ NR'- and the like, including combinations thereof, in which each R 'radical is independently a hydrogen atom or a (C1-C6) alkyl group.

“ Cycloalkyl ” and “ heterocycloalkyl ”, independently or as part of another compound, refer to cyclic versions of “alkyl” and “heteroalkyl” groups, respectively. In the case of a heteroalkyl group, the heteroatom may occupy a position in which it is adjacent to the rest of the molecule. Typical cycloalkyl groups include, but are not limited to: cyclopropyl; cyclobutyls, such as cyclobutanyl and cyclobutenyl; cyclopentyls, such as cyclopentanil and cyclopentenyl; cyclohexyls, such as cyclohexanyl and cyclohexenyl; and the like. Typical heterocycloalkyl groups include, but are not limited to: tetrahydrofuranyl ( e.g. tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, etc.), piperidinyl ( e.g. piperidin-1-yl, piperidin-2-yl, etc.). e.), morpholinyl ( e.g. , morpholin-3-yl, morpholin-4-yl, etc.), piperazinyl ( e.g. , piperazin-1-yl, piperazin-2-yl, etc.) and the like. .

“ Acyclic heteroatom bridge ” refers to a divalent bridge in which the backbone atoms are exclusively heteroatoms and / or heteroatomic groups. Typical acyclic heteroatom bridges include, but are not limited to: -O-, -S-, -SO-, -NR'-, -PH-, -S (O) -, -S (O) ₂ -, -S ( O) NR'-, -S (O) ₂ NR'- and the like, including combinations thereof, in which each R 'radical is independently a hydrogen atom or a (C1-C6) alkyl group.

“ Original aromatic ring system ” refers to an unsaturated cyclic or polycyclic ring system having a conjugated π-electronic system. The definition of “starting aromatic ring system” specifically includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenal, tetrahydronaphthalene, etc. . Typical starting aromatic ring systems include, but are not limited to: aceanthrene, acenaphthylene, acefenantrilene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexafen, hexalene, indacene, s- indacene, indane, indene, indena, octacene, octaphene, octalene, oval, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalen, phenanthrene, pycene, pleiaden, pyrene, pyrantren, rubicene, tetrahydronaphthalene, triphenylene and the like, as well as various hydroisomers of these compounds.

“ Aryl ” alone or as part of another compound refers to a monovalent aromatic hydrocarbon group with a fixed number of carbon atoms ( for example , C5-C15 means the number of carbon atoms from 5 to 15) obtained by separating one hydrogen atom from a separate carbon atom of the original aromatic ring system . Typical aryl groups include, but are not limited to: groups derived from aceanthrene, acenaphtylene, acefenanthrene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexafen, hexalene, a-indacene, c-indacene, indane, indene, naphthalene, octene, octaphene, octalene, ovalen, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, pizza, pleiaden, pyrene, pyrantrene, rubicene, triphenylene, trinaphthalene and the like, and also various hydroisomers of these compounds d. In preferred embodiments, the aryl group is (C5-C15) aryl with the most preferred (C5-C10) structure. The most preferred aryls are cyclopentadienyl, phenyl and naphthyl.

“ Arylaryl ” alone or as part of another compound refers to a monovalent hydrocarbon group obtained by separating one hydrogen atom from a separate carbon atom of a ring system in which two or more identical or non-identical starting aromatic ring systems are combined directly with each other via a single bond, in which the number of said direct ring compounds is one less than the number of the involved aromatic ring systems. Typical arylaryl groups include, but are not limited to: biphenyl, triphenyl, phenyl-naphthyl, binaphthyl, biphenyl-naphthyl and the like. If the arylaryl group has a given number of carbon atoms, then this number refers to the carbon atoms that make up each of the original aromatic ring. For example, (C5-C15) arylaryl is an arylaryl group in which each aromatic ring consists of 5-15 carbon atoms, for example biphenyl, triphenyl, binaphthyl, phenylnaphthyl, etc. Preferably, each starting aromatic ring system of the arylaryl group is an independent (C5-C15) aromatic system, more preferably (C5-C10) aromatic system. Also preferred are arylaryl groups in which all of the starting aromatic ring systems are identical, for example, biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

“ Biaryl ” alone or as part of another compound refers to an arylaryl group having two identical starting aromatic ring systems that are connected directly to each other via a single bond. Typical biaryl groups include, but are not limited to: biphenyl, binaphthyl, bianthracil, and the like. Preferably, the aromatic ring systems are (C5-C15) aromatic rings, more preferably (C5-C10) aromatic rings. It is particularly preferred that the biaryl group is biphenyl.

“ Arylalkyl, ” alone or as part of another compound, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or sp ³ carbon atom, is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to: benzyl, 2-phenylethan-1-yl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylene-1-yl, naphthobenzyl, 2- naphthophenylethan-1-yl and the like. For alkyl compounds, the following terms are used: arylalkanyl, arylalkenyl and / or arylalkynyl. In preferred embodiments, the arylalkyl group is a (C6-C21) arylalkyl, for example , an alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is a (C1-C6) structure, and the aryl moiety is a (C5-C15) structure. In the most preferred embodiments, the arylalkyl group has a (C6-C13) structure, for example , the alkanyl, alkenyl or alkynyl fragment of the arylalkyl group has a (C1-C3) structure and the aryl fragment has a (C5-C10) structure.

An “ original heteroaromatic ring system ” refers to an initial aromatic ring system in which one or more carbon atoms are independently replaced by the same or different heteroatoms or heteroatom groups. Typical heteroatoms or heteroatom groups replacing carbon atoms include, but are not limited to: N, NH, P, O, S, S (O), S (O) ₂ , Si, etc. The definition of “parent heteroaromatic ring systems” specifically includes fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, benzodioxane, benzofuran, chromane, chromene, indole, indoline, xanthan etc. The definition of “starting heteroaromatic ring systems” also includes known rings containing common substitution groups, such as, for example, benzopyrone and 1-methyl-1,2,3,4-tetrazole. Benzene rings condensed to form cyclic polyalkylene glycols such as cyclic polyethylene glycol are specifically excluded from the definition of “starting heteroaromatic ring systems”. Typical starting heteroaromatic ring systems include, but are not limited to: acridine, benzimidazole, benzisoxazole, benzodioxane, benzodioxole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotriazole, benzoxaxine, benzoxazole, benzoxazoline, carbazene, chromazole, β-benzene furan, imidazole, indazole, indole, indoline, indolysin, isobenzofuran, isochromen, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline fenazine pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolysin, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanten and the like.

“ Heteroaryl ”, alone or as part of another compound, refers to a monovalent heteroaromatic group with a fixed number of ring atoms ( for example , “5-14 membered” means the number of ring atoms from 5 to 14) resulting from the separation of one hydrogen atom from a separate atom of the original heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to: groups derived from acridine, benzimidazole, benzisoxazole, benzodioxane, benzodiaxole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotriazole, benzoxazine, benzoxazole, benzoxazoline, carbazene, chromazole, β-chromazene , cinnoline, furan, imidazole, indazole, indole, indoline, indolysin, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, provol, perimidine, phenan tridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolisin, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazazole, thiazole, thiazole, thiazole, thiazole, thiazole, thiazole, thiazole as well as various hydroisomers of these compounds. In preferred embodiments, the heteroaryl group is 5-14 membered heteroaryl, while 5-10 membered heteroaryl is most preferred.

“ Heteroaryl-heteroaryl ”, alone or as part of another compound, refers to a monovalent heteroaromatic group obtained by the separation of one hydrogen atom from a separate atom of the ring system in which two or more identical or non-identical starting heteroaromatic ring systems are directly connected to each other by a single bond, in which the number of such direct ring compounds is one less than the number of the involved initial heteroaromatic ring systems. Typical heteroaryl heteroaryl groups include, but are not limited to: bipyridyl, tripyridyl, pyridylpurinyl, bipurinyl, etc. For a given number of atoms, these numbers refer to the number of atoms that make up each of the original heteroaromatic ring systems. For example, a 5-15 membered heteroaryl heteroaryl is a heteroaryl heteroaryl group in which each of the starting heteroaromatic ring systems consists of 5-15 atoms, for example bipyridyl, tripyridyl, etc. Preferably, each parent heteroaromatic ring system is an independent 5-15 membered heteroaromatic system, more preferably a 5-10 membered heteroaromatic system. Also preferred are heteroaryl heteroaryl groups in which all of the parent heteroaromatic ring systems are identical.

“ Bigheroaryl ”, alone or as part of another compound, refers to a heteroaryl-heteroaryl group comprising two identical parent heteroaromatic ring systems directly connected to each other by a single bond. Typical bigheroaryl groups include, but are not limited to: bipyridyl, bipurinyl, biquinolinyl and the like. Preferably, the heteroaromatic ring systems are 5-15 membered heteroaromatic rings, more preferably 5-10 membered heteroaromatic rings.

“ Heteroarylalkyl ”, alone or as part of another compound, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, usually a terminal or or sp ³ carbon atom, is replaced by a heteroaryl group. In the case of alkyl compounds, the terms heteroarylalkanyl, heteroarylalkenyl and / or heteroarylalkynyl are used. In preferred embodiments, the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, for example , the alkanyl, alkenyl or alkynyl fragment of a heteroarylalkyl is alkyl with a structure (C1-C6), and the heteroaryl moiety is a 5-15 membered heteroaryl. In the most preferred embodiments of the invention, heteroarylalkyl is 6-13 membered heteroarylalkyl, for example , the alkanyl, alkenyl or alkynyl fragment of heteroarylalkyl is alkyl with a structure (C1-C3), and the heteroaryl fragment is 5-10 membered heteroaryl.

" Halogen " or " halo " alone or as part of another compound generally refers to fluorine, chlorine, bromine and iodine groups.

" Haloalkyl " alone or as part of another compound refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen. Thus, the term “haloalkyl” means monohaloalkyls, dihaloalkyls, trihaloalkyls, etc., including perhaloalkyls. For example, the term “(C1-C2) haloalkyl” includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.

The above groups may include prefixes and / or suffixes, which are widely used to create additional well-known substituent groups. For example, “alkyloxy” or “alkoxy” refers to a group of the formula —OR ”,“ alkylamine ”refers to a group of the formula —NHR”, and “dialkylamine” refers to a group of the formula —NR ”R”, where each R ”is an independent alkyl. As another example, “haloalkoxy” or “haloalkyloxy” refers to a group of the formula —OR ″ ″, where R ″ ″ is haloalkyl.

A “ protecting group ” refers to a group of atoms which, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, the protecting group may optionally be selectively excluded during the synthesis process. Examples of protective groups can be found in the book. Greene and Watsa "Protective Groups in Organic Chemistry", 3rd edition, 1999, at publ J. Wiley & Sons, New York (Greene and Wuts, Protective Groups in Organic Chemistry, 3 ^rd Ed., 1999, John Wiley & Sons, NY), as well as in the book. Harrison et al., A Brief Review of Synthetic Organic Methods , vols. 1-8, 1971-1996, J. Wiley & Sans, New York (Harrison et al. , Compendium of Synthetic Organic Methods , Vols. 1- 8, 1971-1996, John Wiley & Sons, NY). Typical amino-containing protecting groups include, but are not limited to: formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert -butoxycarbonyl (“BOC”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TEC” "), Trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (" FMOC "), nitroveratryloxycarbonyl (" NVOC ") and the like. Representative hydroxyl protecting groups include, but are not limited to those where the hydroxyl group is acylated or alkylated, such as, for example, benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers ( e.g. , TMS or TIPPS groups) and allyl ethers.

“ Prodrug ” refers to a derivative of the active compound 2,4-pyrimidinediamine (drug), which requires conversion under conditions of use, such as inside the body, in order to isolate the active 2,4-pyrimidinediamine. Prodrugs are often, but not necessarily, pharmacologically inactive until they are converted into active drugs. Prodrugs are usually obtained by masking the functional group that is part of the 2,4-pyrimidinediamine drug to activate the progroup (defined below) to form the procomponent, which then undergoes transformation, such as cleavage, under given conditions of use to isolate the functional group and therefore, the active drug 2,4-pyrimidinediamine. The decomposition of the procomponent can occur spontaneously, as, for example, as a result of a hydrolysis reaction, under the influence of a catalyst or other agent, such as an enzyme, light, acid or base, or as a result of a change or exposure to any physical parameter or environment, for example temperature. The agent may be endogenous (internal) in terms of conditions of use, such as, for example, an enzyme present in the cells for which the prodrug is intended, or acidic conditions in the stomach, or it can be administered exogenously (externally).

A wide variety of progroups and procomponents suitable for masking functional groups in active components containing 2,4-pyrimidinediamine compounds to produce prodrugs are well known in the art. For example, a hydroxyl functional group may be masked as a sulfonate, ester or carbonate procomponent, which may be hydrolyzed in vivo to form a hydroxyl group. An amino-containing functional group can be masked as an amide, carbamate, imine, urea, phenyl, phosphoryl or sulfenyl procomponent, which can be hydrolyzed in vivo to give an amino-containing group. The carboxyl group can be masked as an ester (including silyl esters and thioesters), a pro-component of an amide or hydrazide, which can be hydrolyzed in vivo to give a carboxyl group. The nitrogen protecting group and nitrogen prodrugs may include lower alkyl groups, as well as amides, carbamates, etc. Other representative examples of suitable progroups and their corresponding procomponents are obvious to experts in this field.

“ Progroup ” refers to a type of protecting group which, when used to mask a functional group in an active drug containing 2,4-pyrimidinediamine, converts the drug into a prodrug to form a procomponent. Progroups usually join the functional group of the drug through bonds that can be cleaved under given conditions of use. Thus, the progroup is that part of the procomponent that is cleaved to release a functional group under given conditions of use. As a specific example, an amide-containing procomponent having the formula —NH — C (O) CH ₃ , which contains the progroup —C (O) CH _3, can be cited.

An “ Fc receptor ” refers to a member of a family of cell surface molecule molecules that binds the Fc portion of an immunoglobulin (containing a specific constant region). Each Fc receptor binds a specific type of immunoglobulin. For example, the Fcα receptor (“FcαR”) binds IgA, the FcεR receptor binds IgE, and the FcγR receptor binds IgG.

The FcαR family includes an Ig polymer receptor involved in IgA / IgM epithelial transfer, a mycloid specific RcαRI receptor (also referred to as CD89), an Fcα / µR receptor, and at least two alternative IgA receptors (for a recent review see Monteiro and van de Winkel, 2003, Annual Review of Immunology, Modern Electronic Publications (Monteiro & van de Winkel, 2003, Annu. Rev. Immunol, advanced e-publication)). The FcαRI receptor appears on neutrophils, eosinophils, monocytes / macrophages, dendritic cells and kupferovy cells. FcαRI comprises one alpha chain and an FcR gamma homodimer that carries an activation motif (ITAM) in the cytoplasmic domain and phosphorylates the Syk kinase.

The FcεR family includes two types of receptors: named FcεRI and FcεRII (also known as CD23). FcεRI is a high affinity receptor (binds IgE with an affinity of the order of 10 ¹⁰ M ^-1 ), which is found on mast cells, basophilic and eosinophilic cells that attach monomeric IgE to the cell surface. FcεRI has one alpha chain, one beta chain and the gamma chain homodimer discussed above. FcεRII is a low affinity receptor expressed on mononuclear phagocytes, B lymphocytes, eosinophils and platelets. FcεRII is a single polypeptide chain and does not contain a gamma chain homodimer.

The FcγR family includes three types: named FcγRI (also known as CD64), FcγRII (also known as CD32) and FcγRIII (also known as CD16). FcγRI is a high affinity receptor (binds IgG1 with an affinity of the order of 10 ⁸ M ^-1 ), which is found on mast cells, basophilic, mononuclear, neutrophilic, eosinophilic, dendritic and phagocytic cells, which attaches monomeric IgG to the cell surface. FcγRI includes one alpha chain and a gamma chain dimer, which is part of FcαRI and FcεRI.

FcγRII is a low affinity receptor expressed on neutrophils, monocytes, eosinophils, platelets, and B lymphocytes. FcγRII includes one alpha chain and does not contain the gamma chain homodimer discussed above.

FcγRIII is a low affinity receptor (binds IgG1 with an affinity of the order of 5 × 10 ⁵ M ^-1 ) expressed on NK, eosinophilic, macrophage, neutrophilic cells and mast cells. It forms one alpha chain and a gamma homodimer, which is part of FcαRI, FcεRI and FcγRI.

Experts in this field will agree that the proposed subunit structure and binding properties of these diverse Fc receptors, as well as the cell types expressed by them, are not fully characterized. The above discussion mainly reflects the current state of the question regarding these receptors ( see, for example, Immunobiology: The immune system in a healthy state and in diseases, 5th edition, Janeway et al., 2001, Fig. 9, 30 on page 371 (Immunobiology:. The Immun System in Health & Disease, 5 ^{th Edition, Janeway et al, Eds} , 2001, ISBN 0-8153-3642-x, Figure 9,30 at pp 371.)), and is not intended to restrict the set signaling cascades of receptors that can be regulated by the components described in this application.

" Fc receptor degranulation " or " Fc receptor degranulation" refers to degranulation that is carried out by means of an Fc receptor signal transduction cascade initiated by crosslinking of the Fc receptor.

“ IgE-related degranulation ” or “ Fc ε RI degranulation” refers to degranulation which is carried out by means of an IgE receptor signal transduction cascade initiated by IgE cross-linking linked by FcεR1. Crosslinking can be caused by an allergen-specific IgE or a multivalent binding agent, such as an anti-IgE antibody. In figure 2, mast cells and / or basophilic cells show that the FcεRI signaling cascade leading to degranulation can be divided into two stages: reverse and direct. The reverse stage includes all the processes that occur before the mobilization of calcium ions (shown as “Ca ²⁺ ” in FIG. 2; see also FIG. 3). The direct stage includes the mobilization of calcium ions and all its subsequent direct processes. Compounds that inhibit degranulation by FcεRI can act at any point along the signal transduction cascade mediated by FcεRI. Compounds that selectively inhibit degranulation by FcεRI in the opposite direction act to inhibit this portion of the FcεRI signaling cascade in the opposite direction from the point at which calcium ion mobilization is excited. In cell samples, compounds that selectively inhibit degranulation by FcεRI in the opposite direction interfere with the degranulation of cells, such as mast cells or basophil cells, that are activated or stimulated by an allergen specific for IgE or a binding agent (such as an anti-IgE antibody), but noticeably they do not inhibit degranulation of cells that are activated or stimulated by degranulating agents that bypass the FcεRI signaling pathway, such as, for example, calcium ionophore ionomycin and A23187.

“ IgG-related degranulation ” or “ Fc γ RI degranulation” refers to degranulation which is accomplished by means of a signal transduction cascade initiated by IgG crosslinking coupled by FcγRI. Crosslinking can be caused by an allergen-specific IgG or multivalent binding agent, such as an anti-IgG antibody or antibody fragment. Like the FcεRI signaling cascade, the FcγRI signaling cascade in mast cells and basophilic cells also leads to degranulation, which can be divided into the same two stages: reverse and direct. Like degranulation by FcεRI, compounds that selectively inhibit degranulation by FcγRI in the opposite direction act in the opposite direction from the point at which calcium ion mobilization is excited. In cell samples, compounds that selectively inhibit degranulation by FcγRI in the opposite direction inhibit degranulation of cells, such as mast cells or basophilic cells, that are activated or stimulated by an allergen-specific IgG, or a binding agent (such as an anti-IgG antibody or fragment thereof), but they do not noticeably inhibit degranulation of cells that are activated or stimulated by degranulating agents that bypass the FcγRI signaling pathway, such as, for example, calcium ionophores of ionomycin and A23187.

“ Ionophore- related degranulation” or “ ionophore degranulation ” refers to the degranulation of a cell, such as a mast cell or basophilic cell, that occurs when a calcium ionophore such as ionomycin or A23187 is exposed.

" Syk kinase " refers to the well-known tyrosine kinase of the 72 kDa non-receptor spleen protein (cytoplasmic) expressed in a B cell and other hematopoietic cells. Syk kinase consists of two consecutive consensus Src homology domains 2 (SH2), which bind to phosphorylated tyrosine-based immunoreceptor motifs (“ITAM”), linker domains and catalytic domains (a review of Syk kinase structure and function is given in Sada et al. , 2001, J. Biochem. (Tokyo) 130: 177-186); as well as Turner et al. , 2000, Immunology Today 21: 148-154). Syk kinase has been extensively studied as an effector of B-cell receptor (BCR) signals (see Turner et al. , 2000 above). Syk kinase is also critical for tyrosine phosphorylation of complex proteins that regulate important pathways leading from immunoreceptors, such as Ca ²⁺ mobilization cascades and mitogen activated protein kinases (MAPKs) (see, for example, FIG. 2) and degranulation. Syk kinase also plays a critical role in integrin signaling in neutrophils ( see, for example, Mocsai et al. 2002, Immunity 16: 547-558).

As is customary in this work, the Syk kinase includes the kinase of any animal species, including, but not limited to, humans, monkeys, cows, pigs, rodents, etc., belonging to the Syk family. This group specifically includes isoforms, splice variants, allelic variants, mutants of both natural and artificial origin. The amino acid sequences of such Syk kinases are well known and are available at GENBANK (Genetic Material Bank). Representative examples of mRNA coding of various isoforms of human Syk kinase can be found in GENBANK under the number gi | 21361552 | ref | NM__003177,2 |,

gi | 496899 | emb | Z29630.1 | HSSYKPTK [496899] and

gi | 15030258 | gb | BC011399,1 | BC011399 [15030258], which are incorporated herein by reference.

Experienced practitioners will appreciate that tyrosine kinases belonging to other families may have active sites or binding pockets with a three-dimensional structure similar to that of Syk. As a result of this structural similarity, it is believed that such kinases, referred to in this application as “ Syk simulators ”, can serve as phosphorylation catalysts for substrates that are phosphorylated by Syk kinase. Thus, it becomes clear that such Syk simulators, signal transduction cascades affected by such Syk simulators, and biological reactions from the effects of such Syk simulators and signal cascades dependent on Syk simulators can be regulated and even inhibited with using the 2,4-pyrimidinediamine compounds described in this application.

“ Syk-dependent signaling cascade ” refers to a signal transduction cascade influenced by a Syk kinase. Some examples of such Syk-dependent signaling cascades include FcαRI, FcεRI, FcγRI, FcγRIII, BCR, and integrin signaling cascades.

The term “autoimmune disease” refers to diseases that are often associated with non-anaphylactic hypersensitivity reactions (type II, III and / or IV hypersensitivity reactions), which are mainly the result of the patient’s own humoral and / or cell-mediated immune response to one or more immunogenic a substance of endogenous and / or exogenous nature. Such autoimmune diseases differ from diseases associated with anaphylactic hypersensitivity reactions (type I or mediated IgE).

6.2 Compounds of 2,4-pyrimidinediamine

The compounds of the present invention are generally 2,4-pyrimidinediamine compounds corresponding to structural formula (I):

including their salts, hydrates, solvates and N-oxides, in which:

L ¹ and L ^{2 are} each independently selected from the group consisting of one direct link and one linker;

R ² and R ⁴ are the groups described in the following embodiments of the present invention and examples;

R ^{5 is} selected from the group consisting of R ⁶ , (C1-C6) alkyl optionally substituted with one or more identical or different R ⁸ groups, (C1-C4) alkanyl optionally substituted with one or more identical or different R ⁸ groups, ( C2-C4) alkenyl optionally substituted with one or more identical or different R ⁸ groups, and (C2-C4) alkynyl optionally substituted with one or more identical or different R ⁸ groups;

each R ⁶ radical is independently selected from the group consisting of hydrogen, an electronegative group, —OR ^d , —SR ^d , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, —NR ^c R ^c , halogen, (C1-C3 ) halogenated, (C1-C3) perhalogenated, -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CN, -NC, -OCN, -SCN, -NO, -NO ₂ , -N ₃ ,

-S (O) R ^d , -S (O) ₂ R ^d , -S (O) ₂ OR ^d , -S (O) NR ^c R ^c , -S (O) ₂ NR ^c R ^c , -OS ( O) R ^d , -OS (O) ₂ R ^d , -OS (O) ₂ OR ^d , -OS (O) NR ^c R ^c , -OS (O) ₂ NR ^c R ^c , -C (O) R ^d , -C (O) OR ^d , -C (O) NR ^c R ^c , -C (NH) NR ^c R ^c , -OC (O) R ^d , -SC (O) R ^d , -OC (O ) OR ^d , -SC (O) OR ^d , -OC (O) NR ^c R ^c , -SC (O) NR ^c R ^c , -OC (NH) NR ^c R ^c , -SC (NH) NR ^c R ^c , - [NHC (O)] _n R ^d , - [NHC (O)] _n OR ^d , - [NHC (O)] _n NR ^c R ^c and - [NHC (NH)] _n NR ^c R ^c , (C5-C10) aryl optionally substituted by one or more identical or different R ⁸ groups, phenyl optionally substituted by one or more identical or different R ⁸ groups, (C6-C16) arylalkyl optionally substituted by one or more identical or different R ⁸ groups, 5-10 membered heteroaryl, optional optionally substituted with one or more identical or different R ⁸ groups, and a 6-16 membered heteroarylalkyl optionally substituted with one or more identical or different R ⁸ groups;

R ^{8 is} selected from the group consisting of R ^a , R ^b , R ^a substituted with one or more identical or different groups R ^a or R ^b , -OR ^a substituted with one or more identical or different groups R ^a or R ^b , B (OR ^a ) ₂ , -B (NR ^c R ^c ) ₂ , - (CH ₂ ) _m -R ^b , - (CHR ^a ) _m -R ^b , -O- (CH ₂ ) _m -R ^b , - S- (CH ₂ ) _m —R ^b , —O — CHR ^a R ^b , —O — CR ^a (R ^b ) ₂ ,

-O- (CHR ^a ) _m -R ^b ,

-O- (CH ₂ ) _m -CH [(CH ₂ ) _m R ^b ] R ^b , -S- (CHR ^a ) _m -R ^b , -C (O) NH- (CH ₂ ) _m -R ^b ,

-C (O) NH- (CHR ^a ) _m -R ^b , -O- (CH ₂ ) _m -C (O) NH- (CH ₂ ) _m -R ^b ,

-S- (CH ₂ ) _m -C (O) NH- (CH ₂ ) _m -R ^b , -O- (CHR ^a ) _m -C (O) NH- (CHR ^a ) _m -R ^b ,

-S- (CHR ^a ) _m -C (O) NH- (CHR ^a ) _m -R ^b , -NH- (CH ₂ ) _m -R ^b , -NH- (CHR ^a ) _m -R ^b ,

-NH [(CH ₂ ) _m R ^b ], -N [(CH ₂ ) _m R ^b ] ₂ , -NH-C (O) -NH- (CH ₂ ) _m -R ^b ,

-NH-C (O) - (CH ₂ ) _m -CHR ^b R ^b and -NH- (CH ₂ ) _m -C (O) -NH- (CH ₂ ) _m -R ^b ;

each R ^{a is} independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;

each R ^b represents a suitable group independently selected from the group consisting of = O, -OR ^d , (C1-C3) haloalkyloxy, -OCF ₃ , = S, -SR ^d , = NR ^d , = NOR ^d , -NR ^c R ^c , halogen, —CF ₃ , —CN, —NC, —OCN, —SCN, —NO, —NO ₂ , = N ₂ , —N ₃ ,

-S (O) R ^d , -S (O) ₂ R ^d , -S (O) ₂ OR ^d , -S (O) NR ^c R ^c , -S (O) ₂ NR ^c R ^c , -OS ( O) R ^d , -OS (O) ₂ R ^d , -OS (O) ₂ OR ^d , -OS (O) ₂ NR ^c R ^c , -C (O) R ^d , -C (O) OR ^d , —C (O) NR ^c R ^c , —C (NH) NR ^c R ^c ,

-C (NR ^a ) NR ^c R ^c , -C (NOH) R ^a , -C (NOH) NR ^c R ^c , -OC (O) R ^d , -OC (O) OR ^d , -OC (O) NR ^c R ^c , -OC (NH) NR ^c R ^c , -OC (NR ^a ) NR ^c R ^c , - [NHC (O)] _n R ^d , - [NR ^a C (O)] _n R ^d , - [NHC (O)] _n OR ^d , - [NR ^a C (O)] _n OR ^d , - [NHC (O)] _n NR ^c R ^c , - [NR ^a C (O)] _n NR ^c R ^c , - [NHC (NH)] _n NR ^c R ^c and - [NR ^a C (NR ^a )] _n NR ^c R ^c ;

each R ^c independently represents R ^a or, alternatively, each R ^c is taken together with the nitrogen atom to which it is bonded to form a 5-8 membered cycloheteroalkyl or heteroaryl, which may include one or more identical or different additional heteroatoms and which may be substituted by one or more identical or different groups R ^a or suitable groups R ^b ;

each R ^d independently represents R ^a ;

each m independently represents an integer from 1 to 3; and

each n independently represents an integer 0 to 3.

In compounds of structural formula (I), L ¹ and L ² independently of one another are a direct bond or a linker. Thus, as will be appreciated by those skilled in the art, the substituents R ² and / or R ⁴ can be bonded either directly to their respective nitrogen atoms or alternatively spaced from their respective nitrogen atoms via a linker. The identity of the linker is uncritical, and typical suitable linkers include, but are not limited to, (C1-C6) alkyldiyls, (C1-C6) alkanes and (C1-C6) heteroalkyldiyls, each of which may optionally be substituted with one or more identical or different R ⁸ groups, where R ⁸ corresponds, as previously defined, to structural formula (I). In specific embodiments, L ¹ and L ^{2 are} independently selected from the group consisting of one direct bond, (C1-C3) alkyl diyl optionally substituted with one or more identical or different R ^a groups, suitable R ^b or R ⁹ groups and a 1-3-membered heteroalkyl diyl optionally substituted with one or more identical or different groups R ^a , suitable R ^b or R ⁹ groups, where R ^{9 is} selected from the group consisting of (C1-C3) alkyl, -OR ^a , -C ^{(O) oR a, (C5} -C10) aryl optionally substituted by one or more identical or different Halogen, phenyl optionally substituted by one or more identical or different halogens, 5-10 membered heteroaryl optionally substituted by one or more identical or different halogens and 6 membered heteroaryl optionally substituted by one or more identical or different halogens; and R ^a and R ^b correspond, as previously defined, to structural formula (I). Particular R ⁹ groups that can be used to replace L ¹ and L ² include —OR ^a , —C (O) OR ^a , phenyl, halogenophenyl and 4-halogenophenyl, where R ^a corresponds, as previously defined, to the structural formula (I).

In another specific embodiment of the invention, each of L ¹ and L ^{2 is} independently selected from the group consisting of methane, ethane and propane, each of which may optionally be monosubstituted by the group R ⁹ described above.

In all of the above embodiments, the specific R ^a groups that can be included in the R ⁹ groups are selected from the group consisting of hydrogen, (C1-C6) alkyl, phenyl, and benzyl.

In yet another specific embodiment of the invention, each of L ¹ and L ² represents one direct bond, such that the 2,4-pyrimidinediamine compounds of the present invention correspond to structural formula (Ia):

including their salts, hydrates, solvates and N-oxides in which R ² , R ⁴ , R ⁵ and R ⁶ correspond to those described above in the description of structural formula (I). Further specific uses for the 2,4-pyrimidinediamine compounds of the present invention are set forth below.

In the first example of compounds of structural formula (I) and (Ia) L ¹ , L ² , R ⁵ , R ⁶ , R ⁸ , R ^a ,

, где каждая группа R³¹ независимо от других является метилом или (C1-C6) алкилом, и группа R⁴ является

. X выбирают из группы, состоящей из N и CH, Y выбирают из группы, состоящей из O, S, SO, SO₂, SONR³⁶, NH, NR³⁵ и NR³⁷, Z выбирают из группы, состоящей из O, S, SO, SO₂, SONR³⁶, NH, NR³⁵ и NR³⁷. Каждая из R³⁵ независимо от других выбирается из группы, состоящей из водорода и R⁸, или, в альтернативном случае, две группы R³⁵, связанные с одним и тем же атомом углерода, берутся вместе с образованием оксо (=O), NH или NR³⁸ группы, а две другие R³⁵ группы, каждая независимо одна от другой, выбираются из группы, состоящей из водорода и R⁸. Каждая группа R³⁶ независимо выбирается из группы, состоящей из водорода и (C1-C6) алкила. Каждая группа R³⁷ независимо выбирается из группы, состоящей из водорода и прогруппы. R³⁸ выбирается из группы, состоящей из (C1-C6) алкила и (C5-C14) арила.R ^b , R ^c , R ^d , m and n are as described above, R ² is

where each R ³¹ group, independently of the others, is methyl or (C1-C6) alkyl, and the R ⁴ group is

. X is selected from the group consisting of N and CH, Y is selected from the group consisting of O, S, SO, SO ₂ , SONR ³⁶ , NH, NR ³⁵ and NR ³⁷ , Z is selected from the group consisting of O, S, SO , SO ₂ , SONR ³⁶ , NH, NR ³⁵ and NR ³⁷ . Each of R ^35, independently of the others, is selected from the group consisting of hydrogen and R ⁸ , or, alternatively, two R ³⁵ groups bonded to the same carbon atom are taken together with the formation of oxo (= O), NH or NR ³⁸ groups, and the other two R ³⁵ groups, each independently of one another, are selected from the group consisting of hydrogen and R ⁸ . Each R ³⁶ group is independently selected from the group consisting of hydrogen and (C1-C6) alkyl. Each R ³⁷ group is independently selected from the group consisting of hydrogen and a progroup. R ³⁸ is selected from the group consisting of (C1-C6) alkyl and (C5-C14) aryl.

In particular, Y is O, Z is NH, and X is N. R ⁵ may be halogen and R ⁶ is hydrogen.

, где каждая группа R³¹ независимо от других представляет собой метил или (C1-C6) алкил, и группа R⁴ представляет собой

. В частности, Y представляет собой O, Z является NH и X представляет собой N. R⁵ может быть галогеном и R⁶ представляет собой водород. В одном частном случае Y представляет собой O, Z является NH, X представляет собой N и каждая из групп R³¹ представляет собой метил.In the second example of compounds of structural formula (I) and (Ia) L ¹ , L ² , R ⁵ , R ⁶ , R ⁸ , R ^a , R ^b , R ^c , R ^d , m , n , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , X, Y and Z are as described above, R ² is

where each group R ³¹ independently of the others represents methyl or (C1-C6) alkyl, and the group R ⁴ represents

. In particular, Y is O, Z is NH and X is N. R ⁵ may be halogen and R ⁶ is hydrogen. In one particular case, Y is O, Z is NH, X is N, and each of the R ³¹ groups is methyl.

или

и R⁴ представляет собой

или

и yy является числом от 1 до 6. В частности, Y представляет собой O, Z представляет собой NH и X представляет собой N. R⁵ может быть галогеном, и R⁶ представляет собой водород.In a third example of compounds of structural formula (I) and (Ia) L ¹ , L ² , R ⁵ , R ⁶ , R ⁸ , R ^a , R ^b , R ^c , R ^d , m , n , R ³¹ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , X, Y and Z are as described above, R ² represents

or

and R ⁴ represents

or

and yy is a number from 1 to 6. In particular, Y is O, Z is NH, and X is N. R ⁵ may be halogen, and R ⁶ is hydrogen.

In a fourth example of compounds of structural formula (I) and (Ia) L ¹ , L ² , R ⁵ , R ⁶ , R ⁸ ,

или

и R⁴ представляет собой

или

. Замещение в области фенильного кольца R² может происходить на позициях 2, 3, 4, 5 или 6. В частности, Y представляет собой O, Z представляет собой NH и X представляет собой N. R⁵ может быть галогеном, и R⁶ представляет собой водород.R ^a , R ^b , R ^c , R ^d , m , n , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , X, Y and Z are as described above, R ² represents

or

and R ⁴ represents

or

. Substitution in the region of the phenyl ring R ² may occur at positions 2, 3, 4, 5 or 6. In particular, Y represents O, Z represents NH and X represents N. R ⁵ may be halogen, and R ⁶ represents hydrogen.

. Замещение в области фенильного кольца R² может происходить на позициях 2,3, 2,4, 2,5, 2,6, 3,4, 3,5, 3,6, 4,5, 4,6 или 5,6 при условии исключения следующих соединений:In a fifth example of compounds of structural formula (I) and (Ia) L ¹ , L ² , R ⁵ , R ⁶ , R ⁸ , R ^a , R ^b , R ^c , R ^d , m , n , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , X, Y and Z are as described above, R ² represents a phenyl group twice substituted with two R ^b groups, and R ⁴ represents

. Substitution in the region of the phenyl ring R ² can occur at positions 2,3, 2,4, 2,5, 2,6, 3,4, 3,5, 3,6, 4,5, 4,6 or 5,6 subject to the exclusion of the following compounds:

N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4- pyrimidinediamine;

N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine;

N2- (3,4-dichlorophenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine;

N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- (3-fluoro-4-methoxyphenyl) -5-fluoro-2,4- pyrimidinediamine;

N2- (3,5-dichlorophenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine and

N2- (3-chloro-4-trifluoromethoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4- pyrimidinediamine.

In particular, Y represents O, Z represents NH, and X represents N. R ⁵ may be halogen, and R ⁶ is hydrogen. In certain instances, each of the R ^b groups is independently selected from (C1-C6) alkoxy, (C1-16) alkyl, (C1-C6) perhaloalkyls, halogens, carboxylic acid, carboxylic ester, carboxamides, sulfonamides and imidazoles.

. Замещение в области фенильного кольца R² может происходить на позициях 2,3,4, 2,3,5, 2,3,6, 2,4,5, 2,4,6, 2,5,6, 3,4,5, 3,4,6, 3,5,6 или 4,5,6 при условии исключения следующих соединений:In the sixth example of compounds of structural formulas (I) and (Ia) L ¹ , L ² , R ⁵ , R ⁶ , R ⁸ , R ^a , R ^b , R ^c , R ^d , m , n , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , X, Y, and Z are as described above, R ² represents a phenyl group thrice substituted by three R ^b groups, and R ⁴ represents

. Substitution in the region of the phenyl ring R ² can occur at positions 2,3,4, 2,3,5, 2,3,6, 2,4,5, 2,4,6, 2,5,6, 3,4 , 5, 3,4,6, 3,5,6 or 4,5,6 subject to the exclusion of the following compounds:

N2- (3-chloro-4-methoxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine;

N2- (3-chloro-4-hydroxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine and

N2- (3,5-dimethyl-4-methoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine.

In particular, Y represents O, Z represents NH, and X represents N. R ⁵ may be halogen, and R ⁶ is hydrogen. In certain cases, each of the R ^b groups is independently selected from (C1-C6) alkoxy, (C1-16) alkyl, (C1-C6) perhaloalkyls, halogens, carboxylic acid, carboxylic esters, carboxamides, sulfonamides.

In certain examples, the compounds indicated in US patent applications under registration numbers 10/631029 (filing date July 29, 2003) and 10/355543 (filing date January 31, 2003), respectively, are not included in the compounds included in this application.

, R^6a представляет собой (C5-C10) арил, необязательно замещенный одной или несколькими одинаковыми или различными группами R⁸, или фенил, необязательно замещенный одной или несколькими одинаковыми или различными группами R⁸, и R⁸ представляет собой группу, описанную выше.In a seventh example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , L ^1, and L ^{2 are} as described above, R ² is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more identical or different groups of R ⁸ , (C3-C8) cycloalkyl optionally substituted with one or more identical or different groups of R ⁸ , cyclohexyl optionally substituted with one or more identical or different groups of R ⁸ , 3-8 membered cycloheteroalkyl optionally substituted with one or more the same and and different R ⁸ groups, (C5-C15) aryl optionally substituted with one or more identical or different R ⁸ groups, phenyl optionally substituted with one or more identical or different R ⁸ groups and 5-15 membered heteroaryl optionally substituted with one or several identical or different groups R ⁸ , R ⁴ represents

, R ^6a is (C5-C10) aryl optionally substituted with one or more identical or different R ⁸ groups, or phenyl optionally substituted with one or more same or different R ⁸ groups, and R ⁸ is a group described above.

и

, где каждая из групп R²¹ независимо представляет собой атом галогена или алкил, необязательно замещенный одной или несколькими одинаковыми или различными группами галогена, группы R²² и R²³ каждая в отдельности и независимо друг от друга представляют атом водорода, метильную или этильную группу, необязательно замещенную одной или несколькими одинаковыми или различными группами галогена, и R⁴ представляет собой (C3-C8) циклоалкил, необязательно замещенный одной или несколькими одинаковыми или различными группами R⁸.In the eighth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ² is selected from the group consisting of

and

where each of the groups R ²¹ independently represents a halogen atom or an alkyl optionally substituted with one or more identical or different halogen groups, the groups R ²² and R ²³ each individually and independently represent a hydrogen atom, a methyl or ethyl group, optionally substituted with one or more identical or different halogen groups, and R ⁴ is (C3-C8) cycloalkyl optionally substituted with one or more same or different R ⁸ groups.

или

;In a ninth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ² is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or several identical or different groups of R ⁸ , (C3-C8) cycloalkyl optionally substituted with one or more identical or different groups of R ⁸ , cyclohexyl optionally substituted with one or more identical or different groups of R ⁸ , 3-8-membered cycloheteroalkyl, optionally one or more of the same and or with various R ⁸ groups, (C5-C15) aryl optionally substituted with one or more identical or different R ⁸ groups, phenyl optionally substituted with one or more identical or different R ⁸ groups, and 5-15 membered heteroaryl optionally one or more identical or different groups R ⁸ , R ⁴ represents

or

;

R ³⁵ represents hydrogen or R ⁸ ; and

R ⁴⁵ is (C3-C8) cycloalkyl optionally substituted with one or more identical or different R ⁸ groups.

In the tenth example of compounds of the structural formula

R ^{2 is} selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more identical or different groups of R ⁸ , (C3-C8) cycloalkyl optionally substituted with one or more identical or different groups of R ⁸ , cyclohexyl optionally substituted one or more identical or different groups of R ⁸ , 3-8-membered cycloheteroalkyl, optionally substituted with one or more identical or different groups of R ⁸ , (C5-C15) aryl, optionally substituted with one or more identical sludge and with various groups of R ⁸ , phenyl optionally substituted with one or more identical or different groups of R ⁸ , and a 5-15 membered heteroaryl optionally substituted with one or more identical or different groups of R ⁸ , R ⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyl optionally substituted with one or more identical or different R ⁸ groups, (C3-C8) cycloalkyl optionally substituted with one or more identical or different R ⁸ groups, cyclohexyl optionally substituted with one, and and more identical or different R ⁸ groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more identical or different R ⁸ groups, (C5-C15) aryl optionally substituted with one or more identical or different R ⁸ groups, phenyl optionally substituted with one or more identical or different groups of R ⁸ , and a 5-15 membered heteroaryl, optionally substituted with one or more same or different groups of R ⁸ , and R ⁵⁵ is selected from the group consisting of (C1-C6) alkyl, not optionally substituted with one or more identical or different groups of R ⁸ , (C3-C8) cycloalkyl, optionally substituted with one or more identical or different groups of R ⁸ , cyclohexyl optionally substituted with one or more identical or different groups of R ⁸ , 3-8 membered cycloheteroalkyl optionally substituted with one or more identical or different groups of R ⁸ , (C5-C15) aryl optionally substituted with one or more identical or different groups of R ⁸ , phenyl, optionally substituted with one or more identical or different R ⁸ groups, and a 5-15 membered heteroaryl optionally substituted with one or more same or different R ⁸ groups.

и R⁴ выбирается из группы, состоящей из водорода, (C1-C6) алкила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, (C3-C8) циклоалкила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, циклогексила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, 3-8-членного циклогетероалкила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, (C5-C15) арила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, фенила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, и 5-15-членного гетероарила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸.In an eleventh example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ² is

and R ⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyl optionally substituted with one or more identical or different groups of R ⁸ , (C3-C8) cycloalkyl optionally substituted with one or more identical or different groups of R ⁸ , cyclohexyl optionally substituted with one or more identical or different groups of R ⁸ , a 3-8 membered cycloheteroalkyl, optionally substituted with one or more identical or different groups of R ⁸ , (C5-C15) aryl, optionally substituted with one or more about identical or different R ⁸ groups, phenyl optionally substituted with one or more identical or different R ⁸ groups, and a 5-15 membered heteroaryl optionally substituted with one or more same or different R ⁸ groups.

In a twelfth example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ , L ¹ and

или

, R⁴ выбирается из группы, состоящей из водорода, (C1-C6) алкила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, (C3-C8) циклоалкила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, циклогексила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, 3-8-членного циклогетероалкила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, (C5-C15) арила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, фенила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, и 5-15-членного гетероарила, необязательно замещенного одной или несколькими одинаковыми или различными группами R⁸, и каждая в отдельности группа R³⁵ представляет собой водород или подходящую группу R⁸.L ² correspond to those described above, R ² represents

or

, R ⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyl optionally substituted with one or more identical or different groups of R ⁸ , (C3-C8) cycloalkyl optionally substituted with one or more identical or different groups of R ⁸ , cyclohexyl optionally substituted with one or more identical or different R ⁸ groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more identical or different R ⁸ groups, (C5-C15) aryl optionally substituted with one or more of different in kind or different R ⁸ groups, phenyl optionally substituted with one or more identical or different R ⁸ groups and 5-15 membered heteroaryl optionally substituted with one or more identical or different R ⁸ groups and each R group individually represents ³⁵ hydrogen or a suitable R ⁸ group.

In a thirteenth example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ , L ¹ and

и R³⁵ представляет собой водород или подходящую группу R⁸.L ² correspond to those described above, R ² is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more identical or different groups R ⁸ , (C3-C8) cycloalkyl optionally substituted with one or more identical or different groups R ⁸ , cyclohexyl optionally substituted with one or more identical or different R ⁸ groups, a 3-8 membered cycloheteroalkyl optionally substituted with one or more same or different R ⁸ , (C5-C15) aryl groups optionally substituted with one one or more identical or different groups of R ⁸ , phenyl optionally substituted by one or more identical or different groups of R ⁸ , and a 5-15 membered heteroaryl optionally substituted by one or more identical or different groups of R ⁸ , R ⁴ is

and R ³⁵ represents hydrogen or a suitable R ⁸ group.

, In the fourteenth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ⁴ is a substituted phenyl group substituted by the same or different groups of R ⁸ , and R ² represents

,

where “yy” = from 1 to 6. In one case, the phenyl group R ⁴ is twice or thrice substituted by the same or different R ⁸ groups and, in particular, halogen atoms. In particular, R ⁴ may be substituted at positions 3 and 4 with respect to the point of attachment of the amine N4, in particular, halogen atoms and / or alkoxy groups.

In the fifteenth example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ , L ¹ and

. В одном случае фенильная группа R⁴ является дважды или трижды замещенной одинаковыми или различными группами R⁸ и, в частности, атомами галогена. В частности, R⁴ может замещаться в позициях 3 и 4 относительно присоединения амина N4, в частности, атомами галогена и/или алкокси-группами.L ² correspond to those described above, R ⁴ represents a substituted phenyl group substituted by the same or different groups of R ⁸ , and R ² represents

. In one case, the phenyl group R ⁴ is twice or thrice substituted by the same or different R ⁸ groups and, in particular, halogen atoms. In particular, R ⁴ may be substituted at positions 3 and 4 with respect to the addition of the amine N4, in particular with halogen atoms and / or alkoxy groups.

. В одном случае фенильная группа R⁴ является дважды или трижды замещенной одинаковыми или различными группами R⁸ и, в частности, атомами галогена. В частности, R⁴ может быть замещена в позициях 3 и 4 по отношению к месту присоединения амина N4, в частности атомами галогена и/или алкокси-группами.In a sixteenth example of compounds of structural formulas (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ⁴ is a substituted phenyl group substituted by the same or different groups of R ⁸ , and R ² represents

. In one case, the phenyl group R ⁴ is twice or thrice substituted by the same or different R ⁸ groups and, in particular, halogen atoms. In particular, R ⁴ may be substituted at positions 3 and 4 with respect to the point of attachment of the amine N4, in particular halogen atoms and / or alkoxy groups.

In the seventeenth example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ , L ¹ and

, где R³⁵ представляет собой алкилалкокси-группу и, в частности, представляет собой

. В одном случае фенильная группа R⁴ является дважды или трижды замещенной одинаковыми или различными группами R⁸ и, в частности, атомами галогена. В частности, R⁴ может быть замещена в позициях 3 и 4 по отношению к месту присоединения амина N4 конкретно атомами галогена и/или алкокси-группами.L ² correspond to those described above, R ⁴ represents a substituted phenyl group substituted by the same or different groups of R ⁸ , and R ² represents

where R ³⁵ represents an alkylalkoxy group and, in particular, represents

. In one case, the phenyl group R ⁴ is twice or thrice substituted by the same or different R ⁸ groups and, in particular, halogen atoms. In particular, R ⁴ may be substituted at positions 3 and 4 with respect to the point of attachment of the amine N4 specifically with halogen atoms and / or alkoxy groups.

, где R³⁵ представляет собой алкильную группу и, в частности, является

. В одном случае фенильная группа R⁴ является дважды или трижды замещенной одинаковыми или различными группами R⁸ и, в частности, атомами галогена. В частности, R⁴ может быть замещена в позициях 3 и 4 по отношению к месту присоединения амина N4 конкретно атомами галогена и/или алкокси-группами.In an eighteenth example of compounds of structural formulas (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ⁴ is a substituted phenyl group substituted by the same or different groups of R ⁸ , and R ² represents

where R ³⁵ represents an alkyl group and, in particular, is

. In one case, the phenyl group R ⁴ is twice or thrice substituted by the same or different R ⁸ groups and, in particular, halogen atoms. In particular, R ⁴ may be substituted at positions 3 and 4 with respect to the point of attachment of the amine N4 specifically with halogen atoms and / or alkoxy groups.

и R² представляет собой

и, в частности, замещается в позициях 3 или 4 изоксазолом. Y выбирается из группы, состоящей из O, S, SO, SO₂, SONR³⁶, NH и NR³⁷. Z выбирается из группы, состоящей из O, S, SO, SO₂, SONR³⁶, NH и NR³⁷. Каждый радикал R³⁵ независимо от остальных выбирают из группы, состоящей из водорода иIn a nineteenth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ⁴ is

and R ² represents

and, in particular, is substituted at positions 3 or 4 with isoxazole. Y is selected from the group consisting of O, S, SO, SO ₂ , SONR ³⁶ , NH, and NR ³⁷ . Z is selected from the group consisting of O, S, SO, SO ₂ , SONR ³⁶ , NH, and NR ³⁷ . Each radical R ^35, independently of the others, is selected from the group consisting of hydrogen and

R ⁸ , or alternatively two R ³⁵ groups bonded to the same carbon atom, are taken together to form oxo (= O), NH or NR ³⁸ groups, and each of the remaining two R ³⁵ groups, if present, independently selected from the group consisting of hydrogen and R ⁸ . Each R ³⁶ group is independently selected from the group consisting of hydrogen and (C1-C6) alkyl. Each R ³⁷ group is independently selected from the group consisting of hydrogen and a progroup. R ³⁸ is selected from the group consisting of (C1-C6) alkyl and (C5-C14) aryl.

In certain instances, R ³⁷ is selected from the group consisting of aryl, arylalkyl, heteroaryl, R ^a , R ^b —CR ^a R ^b —OC (O) R ⁸ , —CR ^a R ^b —O — PO (OR ⁸ ) ₂ , -CH ₂ -O-PO (OR ⁸ ) ₂ , -CH ₂ -PO (OR ⁸ ) ₂ , -C (O) -CR ^a R ^b -N (CH ₃ ) ₂ , -CR ^a R ^b -OC ( O) —CR ^a R ^b —N (CH ₃ ) ₂ , —C (O) R ⁸ , —C (O) CF _3, and —C (O) —NR ⁸ —C (O) R ⁸ .

.In one case, Y represents oxygen, Z represents NH and one or more R ³⁵ radicals represent an alkyl group and, in particular, a methyl group. In certain cases, two R ³⁵ radicals form a heme dialkyl moiety, in particular a heme dialkyl moiety located adjacent to NH, as shown in the diagram

.

, где каждый из R³⁵ радикалов соответствует описанным выше и, в частности, является атомом галогена, например фтором, и R² представляет собой замещенную фенильную группу, замещенную одинаковыми или различными группами R⁸. В одном случае фенильная группа R² является дважды или трижды замещенной одинаковыми или различными группами R⁸ и, в частности, атомами галогена. В частности, R² может быть замещена в позициях 3 и 5 относительно места присоединения N2 амина конкретно атомами галогена и/или алкокси-группами.In a twentieth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ⁴ is

where each of R ³⁵ radicals corresponds to those described above and, in particular, is a halogen atom, for example fluorine, and R ² represents a substituted phenyl group substituted by the same or different R ⁸ groups. In one case, the phenyl group R ² is twice or thrice substituted by the same or different groups of R ⁸ and, in particular, halogen atoms. In particular, R ² can be substituted at positions 3 and 5 relative to the point of attachment of the N2 amine specifically by halogen atoms and / or alkoxy groups.

In the twenty-first example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ ,

, где Y и Z соответствуют описанным выше и R² представляет собой

и, в частности, замещается в позициях 3 или 4 изоксазолом. В одном случае тридцать девятого примера относительно R⁴ радикала Y представляет собой NH и Z представляет собой O, например

.L ¹ and L ² correspond to those described above, R ⁴ represents

where Y and Z correspond to those described above and R ² represents

and, in particular, is substituted at positions 3 or 4 with isoxazole. In one case of the thirty-ninth example, relative to R ^{4 of the} radical, Y represents NH and Z represents O, for example

.

In a twenty-second example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ ,

,

или

, где R⁸ и R^c соответствуют описанным выше и R² представляет собой фенильную группу, замещенную в позициях 3 или 4 группой

. В одном случае группы -OR⁸, R⁸ представляет собой атом водорода.L ¹ and L ² correspond to those described above, R ⁴ represents

,

or

where R ⁸ and R ^c correspond to those described above and R ² represents a phenyl group substituted at positions 3 or 4 by a group

. In one case of the group —OR ⁸ , R ⁸ represents a hydrogen atom.

In the twenty-third example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ ,

и R² представляет собой замещенную фенильную группу, которая замещается по крайней мере двумя одинаковыми или различными группами R⁸ в соответствии с описанным выше. Подходящие примеры включают соединения 340, 343, 349, 350 и 351.L ¹ and L ² correspond to those described above, R ⁴ represents

and R ² represents a substituted phenyl group which is substituted by at least two identical or different R ⁸ groups as described above. Suitable examples include compounds 340, 343, 349, 350, and 351.

и R² представляет собой

.In a twenty-fourth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ⁴ is

and R ² represents

.

и R² представляет собой

, где Y и R³⁵ соответствуют описанным выше. Подходящие примеры включают соединения 368, 381, 382, 383 и 384.In a twenty-fifth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ⁴ is

and R ² represents

where Y and R ^{35 are} as described above. Suitable examples include compounds 368, 381, 382, 383, and 384.

In the twenty-sixth example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ ,

, где R³⁵ соответствует описанному выше. Подходящие примеры включают соединения 205 и 206.L ¹ and L ^{2 are} as described above, R ⁴ is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more identical or different groups R ⁸ , (C3-C8) cycloalkyl optionally substituted with one or more identical or different groups of R ⁸ , cyclohexyl optionally substituted with one or more identical or different groups of R ⁸ , a 3-8 membered cycloheteroalkyl optionally substituted with one or more identical or different groups of R ⁸ , (C5-C15) aryl, optionally substituted one or more identical or different groups of R ⁸ , phenyl optionally substituted with one or more identical or different groups of R ⁸ , and a 5-15 membered heteroaryl optionally substituted with one or more identical or different groups of R ⁸ , and R ² represents

where R ³⁵ as described above. Suitable examples include compounds 205 and 206.

и R² представляет собой фенильную группу, замещенную одной или более одинаковыми группами R⁸. Подходящие примеры включают соединения 328, 329, 330, 341, 553, 554, 555, 556, 559 и 560.In a twenty-seventh example of a compound of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ⁴ is

and R ² represents a phenyl group substituted by one or more identical R ⁸ groups. Suitable examples include compounds 328, 329, 330, 341, 553, 554, 555, 556, 559 and 560.

, где Y соответствует описанному выше или является группой NR³⁵ и R³⁵ соответствует описанному выше. Подходящие примеры включают соединения 1070, 1071, 1073, 1074, 1075, 1076, 1078, 1080, 1085, 1091 и 1092.In a twenty-eighth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ^1, and L ^{2 are} as described above, R ⁴ is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or several identical or different groups of R ⁸ , (C3-C8) cycloalkyl optionally substituted by one or more identical or different groups of R ⁸ , cyclohexyl optionally substituted by one or more identical or different groups of R ⁸ , 3-8 membered cycloheteroalkyl, optionally substituted by one or more different in kind or different R ⁸ groups, (C5-C15) aryl optionally substituted with one or more identical or different R ⁸ groups, phenyl optionally substituted with one or more identical or different R ⁸ groups and 5-15 membered heteroaryl optionally substituted with one or more identical or different groups of R ⁸ and R ² represents

where Y is as described above or is a group of NR ³⁵ and R ^{35 is} as described above. Suitable examples include compounds 1070, 1071, 1073, 1074, 1075, 1076, 1078, 1080, 1085, 1091 and 1092.

, где R² представляет собой замещенную фенильную группу или индазол, которые замещаются одной или более одинаковыми или различными группами R⁸, как описано выше. Подходящие примеры включают соединения 1251, 1252, 1253, 1254 и 1255.In a twenty-ninth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ⁴ is

where R ² represents a substituted phenyl group or indazole, which are substituted by one or more identical or different R ⁸ groups, as described above. Suitable examples include compounds 1251, 1252, 1253, 1254 and 1255.

, где каждая из групп R³⁵ независимо соответствует описанным выше и R² представляет собой

. Подходящие примеры включают соединения 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 1281, 1283, 1283, 1284, 1285, 1287, 1288, 1289, 1290 и 1291.In the thirtieth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above, R ⁴ is

where each of the groups R ³⁵ independently corresponds to those described above and R ² represents

. Suitable examples include compounds 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 1281, 1283, 1283, 1284, 1285, 1287, 1288, 1289, 1290 and 1291.

In the thirty-first example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ ,

, где R^z представляет собой водород или низшую алкильную группу, каждая из групп R^x и R^y независимо представляет собой низшую алкильную группу или в совокупности образуют циклоалкил, и R^p представляет собой атом галогена или низшую алкильную группу, и R² соответствует описанному выше. Подходящие примеры включают соединения 402, 403, 407, 408, 409 и 410.L ¹ and L ² correspond to those described above, R ⁴ represents

where R ^z represents hydrogen or a lower alkyl group, each of the groups R ^x and R ^y independently represents a lower alkyl group or together form a cycloalkyl, and R ^p represents a halogen atom or a lower alkyl group, and R ² corresponds to the above . Suitable examples include compounds 402, 403, 407, 408, 409 and 410.

In the thirty-second example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ ,

иL ¹ and L ² correspond to those described above, R ² represents

and

. Каждая из групп R¹¹ и R¹² независимо одна от другой выбирается из группы, состоящей из алкила, алкокси-группы, галогена, галогеналкокси-группы, аминоалкила и гидроксиалкила.R ⁴ represents

. Each of the groups R ¹¹ and R ^{12 is} independently selected from the group consisting of an alkyl, alkoxy group, halogen, haloalkoxy group, aminoalkyl and hydroxyalkyl.

In the thirty-third example of compounds of structural formula (I) and (Ia) R ⁵ , R ⁶ , R ⁸ ,

или

;L ¹ and L ² correspond to those described above, R ² is selected from (C1-C6) alkyl optionally substituted with one or more identical or different groups R ⁸ , (C3-C8) cycloalkyl optionally substituted with one or more identical or different groups R ⁸ , cyclohexyl optionally substituted with one or more identical or different R ⁸ groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more identical or different R ⁸ groups, (C5-C15) aryl optionally substituted with one or several E identical or different groups R ^8, phenyl optionally substituted with one or more identical or different R ⁸ groups and 5-15 membered heteroaryl optionally substituted with one or more identical or different R ⁸ groups,

or

;

или

;R ⁴ represents

or

;

R ⁵ , R ⁶ , R ⁸ , R ^a , R ^b , R ^c , R ^d , m and n are as described above.

Each of the groups R ²¹ , R ²² and R ²³ independently of one another corresponds to those described above and, in particular, is an alkyl group;

Each individual R ²⁸ group represents a halogen or alkoxy group;

R ²⁹ represents (C1-C6) alkyl or (C3-C9) cycloalkyl;

R ³⁰ represents an alkyl group or halogen;

X is selected from the group consisting of N and CH;

Y, Z, R ³⁵ , R ³⁶ , R ³⁷ and R ^{38 are} as described above.

Each of the groups R ⁴⁶ , R ⁴⁷ and R ^{48 is} independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyl, halogen, isoxazole, piperazino group, N-alkyl piperazine, morpholino group and CH ₃ NHC (O ) CH ₂ O-, provided that none of the groups R ⁴⁶ , R ⁴⁷ and R ⁴⁸ is hydrogen and that if one of the groups R ⁴⁶ , R ⁴⁷ or R ⁴⁸ is isoxazole, a piperazino group, N-alkyl piperazine , morpholino group or a group of CH ₃ NHC (O) CH ₂ O-, then the remaining groups R ⁴⁶ , R ⁴⁷ or R ⁴⁸ are hydrogen;

R ⁵⁰ represents an alkyl group or - (CH ₂ ) _q OH;

q is an integer from 1 to 6;

R ⁵² represents an alkyl group or a substituted alkyl group;

p is 1, 2 or 3; and

x = 1-8.

In the thirty-fourth example of compounds of structural formula (I) and (Ia), R ² , R ⁴ , R ⁵ , L ¹ and L ² correspond to those described above in accordance with structures (I) and (Ia), provided that R ^{2 is} not is 3,4,5-trimethoxyphenyl, 3,4,5-tri (C1-C6) alkoxyphenyl or

where R ²¹ , R ²² and R ²³ correspond to the description of the groups R ¹ , R ² and R ³ given in US patent No. 6235746, the description of which is incorporated by reference. In the specific case of this first example, R ²¹ represents hydrogen, a halogen group, straight or branched (C1-C6) alkyl optionally substituted with one or more identical or different R ²⁵ groups, hydroxyl, (C1-C6) alkoxy group optionally substituted one or more identical or different phenyl or R ²⁵ groups, a thiol (-SH), (C1-C6) alkylthio group optionally substituted by one or more identical or different phenyl or R ²⁵ groups, amino (-NH ₂ ), -NHR ²⁶ or -NR ²⁶ R ²⁶ ; each of the groups R ²² and

R ²³ independently from each other are straight or branched (C 1 -C 6) alkyl optionally substituted with one or more identical or different R ²⁵ groups; R ²⁵ is selected from the group consisting of halogen, hydroxyl, (C1-C6) alkoxy group, thiol, (C1-C6) alkylthio group, (C1-C6) alkylamino group and (C1-C6) dialkylamino group ; and each of R ²⁶ groups independently is (C1-C6) alkyl optionally substituted with one or more identical or different phenyl groups or R ²⁵ or —C (O) R ²⁷ group, where R ²⁷ is (C1-C6) alkyl optionally substituted with one or more identical or different phenyl or R ²⁵ groups.

In another specific example, R ²¹ represents a methoxy group optionally substituted by one or more identical or different halogen and / or R ²² groups, and each of R ²³ independently from one another is methyl or ethyl optionally substituted by one or more same or different groups halogen.

In a thirty-fifth example of compounds of structural formula (I) and (Ia), R ⁵ , R ⁶ , R ⁸ , L ¹ and L ^{2 are} as described above;

, R⁴ представляет собой

, R⁵, R⁶, R³⁰, R³⁵ и x соответствуют описанным выше. В определенных примерах x представляет собой число от 2 до 4. В других примерах R³⁵ представляет собой метильную группу. В дополнительных примерах R³⁰ представляет собой хлор, метил или трифторметил. В других дополнительных примерах R⁵ представляет собой фтор и R⁶ представляет собой водород.R ² represents

R ⁴ represents

, R ⁵ , R ⁶ , R ³⁰ , R ³⁵ and x are as described above. In certain examples, x represents a number from 2 to 4. In other examples, R ³⁵ represents a methyl group. In further examples, R ³⁰ is chloro, methyl or trifluoromethyl. In other further examples, R ⁵ is fluoro and R ⁶ is hydrogen.

, R⁵, R⁶ и R⁸ соответствуют описанным выше. В конкретных примерах R⁵ представляет собой атом фтора и R⁶ представляет собой атом водорода. В определенных примерах R² представляет собой дважды или трижды замещенную фенильную группу.In a thirty-sixth example, 2,4-pyrimidinediamine includes compounds according to structure I and I (a), where R ² is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more identical or different R ⁸ groups, (C3-C8) cycloalkyl optionally substituted with one or more identical or different R ⁸ groups, cyclohexyl optionally substituted with one or more identical or different R ⁸ groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more identical or other or different groups of R ⁸ , (C5-C15) aryl optionally substituted by one or more identical or different groups of R ⁸ , phenyl optionally substituted by one or more identical or different R ⁸ groups, and 5-15 membered heteroaryl optionally substituted one or more identical or different groups of R ⁸ . R ⁴ represents

, R ⁵ , R ⁶ and R ^{8 are} as described above. In specific examples, R ⁵ represents a fluorine atom and R ⁶ represents a hydrogen atom. In certain examples, R ² represents a twice or thrice substituted phenyl group.

или

, R⁴ представляет собой

и R⁵, R⁶, R²² и R²³, R⁴⁶, R⁴⁷ и R⁴⁸ соответствуют описанным выше, а каждая из групп R²¹ независимо одна от другой представляет собой алкильную группу. В определенных примерах R⁵ представляет собой атом фтора и R⁶ представляет собой атом водорода.In a thirty-seventh example, the invention relates to compounds of 2,4-pyrimidinediamine in accordance with structural formulas I and I (a), where R ² represents

or

R ⁴ represents

and R ⁵ , R ⁶ , R ²² and R ²³ , R ⁴⁶ , R ⁴⁷ and R ^{48 are} as described above, and each of the groups R ²¹ independently of one another represents an alkyl group. In certain examples, R ⁵ represents a fluorine atom and R ⁶ represents a hydrogen atom.

In a thirty-eighth example, the present invention relates to compounds of 2,4-pyrimidinediamine in accordance with structural formulas I and I (a), where R ² represents

R ⁴ is

или

;

or

;

R ⁵ , R ⁶ , R ⁸ , R ²¹ , R ²³ , R ²⁸ , R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , Y, Z, R ^a , R ^b , R ^c , R ^d , m and n correspond as described above, and X is selected from the group consisting of N and CH. In a specific example, R ²⁸ represents a methoxy group. In another example, R ²³ represents methyl. In specific examples, R ²¹ represents a methyl group. In other examples, each of the R ²⁸ groups is chloro. In further examples, R ²¹ represents a methyl group and at least one group

R ²⁸ represents chlorine. In another example, R ²⁸ represents a methoxy group.

In a thirty-ninth example, the present invention provides pyrimidinediamine compounds in accordance with structural formulas I and I (a), where R ² represents

или

, R⁵, R⁶, R⁸, R²¹, каждый R²⁸, R²⁹, R^a, R^b, R^c, R^d, m и n, X, Y, Z, каждая из групп R³⁵, каждая из групп R³⁶, каждая из групп R³⁷ и R³⁸ соответствуют описанным выше.R ⁴ is

or

, R ⁵ , R ⁶ , R ⁸ , R ²¹ , each R ²⁸ , R ²⁹ , R ^a , R ^b , R ^c , R ^d , m and n, X, Y, Z, each of the groups R ³⁵ , each of R ³⁶ groups, each of R ³⁷ and R ³⁸ groups are as described above.

In certain examples, R ²⁹ represents a tert- butyl group. In other examples, R ²¹ represents a methyl group. In certain examples, each of the R ²⁸ groups is chloro. In a further example, R ²¹ represents a methyl group and at least one of R ²⁸ represents chlorine.

In a fortieth example, the invention relates to compounds of 2,4-pyrimidinediamine in accordance with structural formulas I and I (a), where R ² represents

, R⁵, R⁶, R⁸, R²¹, каждая из групп R²⁸, R^a, R^b, R^c, R^d, m, n, p, X, Y, Z, каждая из групп R³⁵, каждая из групп R³⁶, каждая из групп R³⁷ и R³⁸ соответствуют описанным выше. В конкретных примерах R²¹ представляет собой метильную группу. В других примерах каждая из групп R²⁸ представляет собой хлор. В других дополнительных примерах R²¹ представляет собой метильную группу и по крайней мере одна из групп R²⁸ представляет собой хлор. В еще одном случае p принимает значения 1 или 2.R ⁴ represents

, R ⁵ , R ⁶ , R ⁸ , R ²¹ , each of the groups R ²⁸ , R ^a , R ^b , R ^c , R ^d , m , n , p , X, Y, Z, each of the groups R ³⁵ , each from the groups R ³⁶ , each of the groups R ³⁷ and R ³⁸ correspond to those described above. In specific examples, R ²¹ represents a methyl group. In other examples, each of the R ²⁸ groups is chloro. In other further examples, R ²¹ represents a methyl group and at least one of the R ²⁸ groups represents chlorine. In another case, p takes the values 1 or 2.

, R⁴ представляет собой

или

, R⁵, R⁶, R⁸, R²¹, каждая из групп R²⁸, R^a, R^b, R^c, R^d, m, n, q, X, Y, Z, R³⁵, R³⁶, R³⁷, R³⁸, R⁵⁰ и R⁵² соответствуют описанным выше.In a forty-first example, the invention relates to compounds of 2,4-pyrimidinediamine in accordance with structural formulas I and I (a), where R ² represents

R ⁴ represents

or

, R ⁵ , R ⁶ , R ⁸ , R ²¹ , each of the groups R ²⁸ , R ^a , R ^b , R ^c , R ^d , m , n , q , X, Y, Z, R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ⁵⁰ and R ^{52 are} as described above.

In certain instances, R ⁵⁰ is —CH ₂ CH ₂ —OH or methyl. In another case, R ⁵² represents trifluoromethyl. In yet another case, at least one of the R ²⁸ groups is chloro. In yet another case, R ⁵⁰ represents methyl and at least one of the groups R ²⁸ represents chlorine.

In the forty-second example and in relation to the first forty-first examples, the group R ^{5 of the} pyrimidine ring represents a halogen atom, such as fluorine, and the group R ^{6 of the} pyrimidine ring represents a hydrogen atom.

In the forty-third example, L ¹ and L ² are covalent bonds in the examples described above.

Also specifically described are combinations of the above examples of specific implementations of the present invention from the first to the forty-third.

Those skilled in the art will appreciate that the 2,4-pyrimidinediamine compounds described herein may include functional groups that can be masked by progroups to create prodrugs. Such prodrugs are usually, but not necessarily, pharmacologically inactive until they pass into their active dosage form. Indeed, many of the active 2,4-pyrimidinediamine compounds described in Table 1 include procomponents that are hydrolyzable or otherwise cleaved under the conditions of use. For example, ester groups are usually hydrolyzed by acid catalyzed to give the starting carboxylic acid if they are under acidic conditions of the stomach, or hydrolyzed by base catalysis if they are under basic intestinal or blood conditions. Thus, when administered orally, 2,4-pyrimidinediamines, which include esters, can be considered prodrugs of the corresponding carboxylic acid, regardless of whether the ester form is pharmacologically active. Based on the data in Table 1, numerous 2,4-pyrimidinediamines in accordance with the present invention containing an ester are active in their ester "prodrug" form.

In the prodrugs of the present invention, any functional component present can be masked by the progroup to obtain the prodrugs. Functional groups in 2,4-pyrimidinediamine compounds that can be masked by progroups to be included in the procomponent include, but are not limited to: amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc. In practice, countless progroups are known that are suitable for masking such functional groups to produce procomponents that cleave under preferred conditions of use. All of these progroups, alone or in combination, may be included in the prodrugs of the present invention.

In one illustrative embodiment, the prodrugs of the present invention are compounds according to structural formula (I) in which R ^c and R ^d may be a progroup in addition to the alternative options previously described.

Those skilled in the art will appreciate that many of the compounds and prodrugs of the present invention, as well as various samples of the compounds specifically described and / or illustrated herein, may exhibit tautomerism, conformational isomerism, geometric isomerism and / or optical isomerism. For example, the compounds and prodrugs of the present invention may include one or more chiral centers and / or double bonds and, as a consequence, can exist as stereoisomers, such as, for example, double bond isomers (i.e. geometric isomers), enantiomers and diastereomers and their mixtures, such as racemic mixtures. As another example, the compounds and prodrugs of the present invention can be considered, which may exist in several tautomeric forms, including the enol form, ketoform, and mixtures thereof. As various names, the formulas and structures of the compounds in the specification and applications can represent only one of the possible tautomeric forms, forms of conformational isomerism, optical isomerism or geometric isomerism. It should be understood that the invention includes any tautomeric forms, any forms of conformational isomerism, optical isomerism and / or geometric isomerism of compounds or prodrugs having one or more of the advantages described herein, as well as mixtures of these various different isomeric forms. In cases of limited rotation around the structure of the 2,4-pyrimidinediamine core, the formation of atropic isomers becomes possible, which are also specifically included in the compounds of the present invention.

In addition, specialists in this field should understand that when alternative members are included in lists that, due to valency or for other reasons, cannot be used to replace a specific group, only those members of the list that are suitable to replace a specific group should be used. For example, it is obvious that while all of the listed alternative substituents for R ^b can be used to replace the alkyl group, some of the alternative substituents, such as = O, cannot be used to replace the phenyl group. It should be noted that this refers only to possible combinations of pairs of substituent groups.

The compounds and / or prodrugs of the present invention can be identified according to their chemical structure or chemical name. If the chemical structure and chemical name contradict each other, the chemical structure is crucial in identifying a particular compound.

Depending on the nature of the various substituents of the compound and prodrug, the 2,4-pyrimidinediamine constituting the invention may take the form of salts. Such salts include salts suitable for pharmaceutical use (“pharmaceutically acceptable salts”), salts suitable for veterinary use, etc. Such salts can be obtained from acids or bases, which is well known in practice.

In one embodiment, the salt is pharmaceutically acceptable. Typically, pharmaceutically acceptable salts are those salts that retain a substantial portion of one or more of the desired pharmacological functions of the parent component and which are suitable for administration to humans. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids. Inorganic acids suitable for the formation of pharmaceutically acceptable acid addition salts include, for example, but are not limited to: hydrohalic acids ( e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid acid and the like. Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, for example, but are not limited to: acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic (hexadecanoic) acid, benzoic acid and, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic (B-phenylacrylic acid), mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.) arylsulfonic acids ( e.g. , benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid), cycloalkyl sulfonic acids (e.g. camphorsulfonic acid), 4-methylbicyclo [2,2,2] oct-2-en-1- 1- carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy naphthoic acid, salicylic acid, stearic (octadecanoic) acid, muconic acid and the like.

Pharmaceutically acceptable salts also include salts formed by replacing the proton of the acid present in the parent compound with a metal ion ( e.g. , an alkali, alkaline earth metal or aluminum ion), an ammonium ion or by coordination with an organic base ( e.g. , ethanolamine, diethanolamine, triethanolamine, N methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.).

Compounds of 2,4-pyrimidinediamine according to the present invention, as well as their salts, can be in the form of hydrates, solvates and N-oxides, well known in practice.

6.3 Synthesis methods

The compounds and prodrugs of the subject invention can be synthesized in various ways using commercially available starting materials and / or starting materials prepared by conventional synthetic methods. Various methods that can be used to synthesize the 2,4-pyrimidinediamine compounds and prodrugs of the present invention are described in US Pat. No. 5,958,935, US Patent Application No. 10/355543, filed January 31, 2003 (US Publication US20040029902-A1) , European Patent WO 03/063794, published August 1, 2003, US Patent Application No. 10/631029, filed July 29, 2003, and European Patent WO 2004/014382, published February 19, 2004, the contents of which are incorporated into this application as links. All compounds having structural formulas (I), (Ia) and (II) can be prepared by a simple modification of these methods.

A variety of possible synthetic routes that can be used to synthesize the 2,4-pyrimidinediamine compounds of the present invention are described below in Schemes (I) to (XI). In schemes (I) to (XI), compounds with the same numbers have similar structures. These methods can traditionally be used to synthesize prodrugs corresponding to structural formula (II).

In one embodiment, the compounds may be synthesized from substituted or unsubstituted uracils or thiouracils, as shown below in Scheme (I):

Scheme (I)

In Scheme (I), R ² , R ⁴ , R ⁵ , R ⁶ , L ¹ and L ² correspond to the previous definition of structural formula (I), X is halogen ( e.g. , F, Cl, Br or I), and Y and Y ', each independently from each other, selected from the group consisting of O and S. Starting from scheme (I), uracil or thiouracil 2 is dihalogenated at the 2- and 4-positions using the standard halogenated substance POX ₃ (or another standard halogenated substances) under standard conditions to obtain 2,4-bishalogenopyrimidine 4 . Depending on the substituent R ⁵ in pyrimidine 4, the halide at position C4 is more reactive with electron-donating substances than the halide at position C2. This difference in reactivity can be used to synthesize 2,4-pyrimidinediamines corresponding to structural formula (I) by reacting 2,4-bishalo-pyrimidine 4 with one equivalent of amine 10 producing 4N-substituted-2-halo-4-pyrimidinamine 8 , followed by amine 6 to give 2,4-pyrimidinediamine corresponding to structural formula (I). 2N, 4N-Bis (substituted) -2,4-pyrimidinediamines 12 and 14 can be obtained by reaction of 2,4-bishalogenopyrimidine 4 with an excess of compounds 6 or 10, respectively.

In most cases, as shown in the diagram, the C4 halide is more reactive with respect to electron-donor substances. However, as should be understood by those skilled in the art, the properties of the substituent R ⁵ may alter this reactivity. For example, if R ⁵ is trifluoromethyl, then a 50:50 mixture of 4N-substituted-4-pyrimidinamine 8 and the corresponding 2N-substituted-2-pyrimidinamine is formed as a result of the reaction. Regardless of what R ⁵ represents, the regioselectivity of the reaction can be controlled by selection of a solvent and other synthesis conditions (such as temperature), which is well known from practice.

The reactions illustrated in Scheme (I) can proceed faster if the reaction mixture is microwave heated. In this case, the following conditions can be used: heating to 175 ° C in ethanol for 5-20 minutes in a Smith reactor (manufactured by Personal Chemistry) in a sealed tube (at a pressure of 20 bar).

The starting materials uracil or thiouracil 2 can be purchased commercially or prepared using a standard technique used in organic chemistry. As an example of commercial uracils and thiouracils, which can be used as starting materials for the reactions according to Scheme (I), uracil supplied by Aldrich (catalog number 13.078-8;

CAS registration number 66-22-8); 2-thio-uracil (Aldrich catalog number 11.558-4; CAS registration number 141-90-2); 2,4-dithiouracil (Aldrich catalog number 15,846-1; CAS 2001-93-6 registration number); 5-acetouracil (Chem. Sources Int'l 2000, CAS No. 6214-65-9); 5-azidouracil; 5-aminouracil (Aldrich catalog number 85.528-6; CAS registration number 932-52-5); 5-bromouracil (Aldrich catalog number 85.247-3; CAS 51-20-7); 5- (trans-2-bromovinyl) uracil (Aldrich catalog number 45.744-2; CAS registration number 69304-49-0); 5- (trans-2-chlorovinyl) -uracil (registration number CAS 81751-48-2); 5- (trans-2-carboxyvinyl) uracil; uracil-5-carboxylic acid (2,4-dihydroxypyrimidine-5-carboxylic acid hydrate; Aldrich catalog number 27,770-3; CAS registration number 23945-44-0); 5-chlororacil (Aldrich catalog number 22,458-8; CAS registration number 1820-81-1); 5-cyanouracil (Chem. Sources Int'l 2000; registration number CAS 4425-56-3); 5-ethyluracil (Aldrich catalog number 23,044-8; CAS registration number 4212-49-1); 5-ethenyluracil (CAS registration number 37107-81-6); 5-fluorouracil (Aldrich catalog number 85.847-1; CAS registration number 51-21-8); 5-iodouracil (Aldrich catalog number 85,785-8; CAS registration number 696-07-1); 5-methyluracil (thymine; Aldrich catalog number 13,199-7; CAS registration number 65-71-4); 5-nitrouracil (Aldrich catalog number 85,276-7; registration number CAS 611-08-5); uracil-5-sulfamic acid (Chem. Sources Int'l 2000; registration number CAS 5435-16-5); 5- (trifluoromethyl) uracil (Aldrich catalog number 22.327-1; CAS registration number 54-20-6); 5- (2,2,2-trifluoroethyl) uracil (registration number CAS 155143-31-6); 5- (pentafluoroethyl) uracil (registration number CAS 60007-38-3); 6-aminouracil (Aldrich catalog number A5060-6; CAS registration number 873-83-6); uracil-6-carboxylic acid (orotic acid; Aldrich catalog number 0-840-2; CAS registration number 50887-69-9); 6-methyluracil (Aldrich catalog number D11.520-7; CAS registration number 626-48-2); uracil-5-amino-6-carboxylic acid (5-amino-orotinic acid; Aldrich catalog number 19.121-3; registration number CAS # 7164-43-4); 6-amino-5-nitrosouracil (6-amino-2,4-dihydroxy-5-nitrosopyrimidine; Aldrich catalog number 27.689-8; CAS registration number 5442-24-0); uracil-5-fluoro-6-carboxylic acid (5-fluororic acid; Aldrich catalog number 42.513-3; registration number CAS 00000-00-0); and uracil-5-nitro-6-carboxylic acid (5-nitroorotic acid; Aldrich catalog number 18.528-0; CAS registration number 600779-49-9). Additional 5-, 6-, and 5,6-substituted uracils and / or thiouracils are available from General Intermediates of Canada, Inc., (Edmonton, Alberta, Canada) (www.generalintermediates.com) and / or Interchim ( France) (www.interchim.com) that produce chemicals or can be prepared using standard methods. Below are a large number of links to reference manuals that describe the relevant synthetic methods .

Amines 6 and 10 can be purchased from commercial sources or, alternatively, can be synthesized using standard techniques. For example, the necessary amines can be synthesized from nitro precursors using standard chemical methods. Examples of specific reactions are given in the Examples section. See also Vogel, 1989, Practical Organic Chemistry , Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

It is known from practice that in some cases, amines 6 and 10 and / or substituents R ⁵ and / or R ⁶ on uracil or thiouracil 2 may include functional groups that require protection during synthesis. The specific features of any protective group (s) used will depend on the features of the functional group that needs to be protected, and this will be taken into account by specialists in this field. Guidance on the selection of suitable protecting groups, as well as synthetic strategies for their attachment and removal, can be found, for example, in Green and Watts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley and Sans, New York, 1999 (Greene & Wuts, Protective Groups in Organic Synthesis , 3d Edition, John Wiley & Sons, Inc., New York (1999)) and in the references cited below (“Green and Watts”).

A specific example of the implementation of the reaction according to scheme (I), in which 5-fluorouracil (Aldrich catalog number 32.937-1) is used as starting material, is presented below in scheme (Ia):

Scheme (Ia)

In Scheme (Ia), R ² , R ⁴ , L ¹ and L ² correspond to their previous definition for scheme (I). According to Scheme (Ia), 5-fluorouracil 3 is halogenated with POCl ₃ to give 2,4-dichloro-5-fluoropyridimine 5 , which then reacts with excess amine 6 or 10 to give N2, N4-bis-substituted 5-fluoro-2 4-pyrimidinediamine 11 or 13, respectively. Alternatively, asymmetric 2N, 4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 can be obtained by reaction of 2,4-dichloro-5-fluoropyridimine 5 with one equivalent of amine 10 (to form 2-chloro-N4-substituted -5-fluoro-4-pyrimidinamine 7 ), and then with one or more equivalents of amine 6 .

In another example implementation of compounds of 2,4-pyrimidinediamine according to the present invention can be synthesized from substituted or unsubstituted cytosines shown below in schemes (IIa) and (IIb):

Scheme (IIa)

Scheme (IIb)

In schemes (IIa) and (IIb), R ² , R ⁴ , R ⁵ , R ⁶ , L ¹ , L ² and X correspond to their previous definition for scheme (I), and PG represents a protective group. Based on Scheme (IIa), the exocyclic amine C4 of cytosine 20 is first protected by a suitable PG protecting group to form an N4-protected cytosine 22 . For specific guidance on the protecting groups used in this context, see Vorbrüggen and Ruh-Pohlenz, 2001, Handbook of Nucleoside Synthesis , John Wiley & Sons, NY, pp. 1-631. Protected cytosine 22 is halogenated at position C2 under standard conditions using a standard halogenation reagent to form 2-chloro-4N-protected-4-pyrimidinamine 24 . The reaction with amine 6, followed by deprotection of the exocyclic amine C4 and the reaction with amine 10 , results in the formation of 2,4-pyrimidinediamine corresponding to structural formula (I).

Alternatively, starting from Scheme (IIb), cytosine 20 may be reacted with amine 10 or protected amine 2 1 to give N4-substituted cytosine 23 or 27, respectively. These substituted cytosines can then be halogenated, deprotected (in the case of N4-substituted cytosine 27 ) as described above, and reacted with amine 6 to give 2,4-pyrimidinediamine corresponding to structural formula (I).

Commercially available cytosines that can be used as starting materials in Schemes (IIa) and (IIb) include, but are not limited to: cytosine (Aldrich catalog number 14,201-8; registration number CAS 71-30-7); N ⁴ -acetylcytosine (Aldrich catalog number 37.791-0; CAS registration number 14631-20-0); 5-fluorocytosine (Aldrich catalog number 27.159-4; CAS registration number 2022-85-7) and 5- (trifluoromethyl) cytosine. Other suitable cytosines useful as starting materials in Schemes (IIa) are available from General Intermediates of Canada, Inc. (Edmonton, Alberta, Canada) (www.generalintermediates.com) and / or Interchim (France) (www.interchim.com) or prepared using standard techniques. Below is a large number of links to reference manuals on synthetic methods for their preparation .

In another embodiment, the 2,4-pyrimidinediamine compounds of the subject invention can be synthesized from substituted or unsubstituted 2-amino-4-pyrimidinols, as shown in Scheme (III) below:

Scheme (III)

In Scheme (III), R ² , R ⁴ , R ⁵ , R ⁶ , L ¹ , L ^2, and X correspond to their description in Scheme (I), and Z represents a substituted group, which is discussed in more detail below in connection with Scheme IV. Starting from Scheme (III), 2-amino-4-pyrimidinol 30 reacts with amine 6 (or optionally with protected amine 21 ) to produce N2-substituted-4-pyrimidinol 32 , which is then subjected to halogenation as described above to give N2-substituted-4-halogen-2-pyrimidinamine 34 . Additional deprotection (for example, if protected amine 21 was used in the first step), followed by reaction with amine 10 , leads to the formation of 2,4-pyrimidinediamine corresponding to structural formula (I). Alternatively, pyrimidinol 30 may react with acylating agent 31 .

Suitable and commercially available 2-amino-4-pyrimidinols 30 that can be used as starting materials in Scheme (III) include, but are not limited to: 2-amino-6-chloro-4-pyrimidinol hydrate (Aldrich A4702 catalog number -8; registration number CAS 00000-00-0) and 2-amino-6-hydroxy-4-pyrimidinol (Aldrich catalog number A5040-1; registration number CAS 56-09-7). Other 2-amino-4-pyrimidinols 30 useful as starting materials in Scheme (III) are available from General Intermediates of Canada, Inc. (Edmonton, Alberta, Canada) (www.generalintermediates.com) and / or Interchim (France) (www.interchim.com), or cook using a standard technique. Below is a large number of links to reference manuals on synthetic methods for their preparation .

Alternatively, the 2,4-pyrimidinediamine compounds of the present invention can be synthesized from substituted or unsubstituted 4-amino-2-pyrimidinols, as shown below in Scheme (IV):

Scheme (IV)

In Scheme (IV), R ² , R ⁴ , R ⁵ , R ⁶ , L ¹ and L ² correspond to their designations in Scheme (I), and Z represents a substituted group. Based on Scheme (IV), the C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towards nucleophiles than the C4-amine, so that the reaction with amine 6 leads to the formation of N2-substituted-2,4-pyrimidinediamine 42 . Subsequent reaction with compound 44 , which includes a good substituted group Z or amine 10 , leads to the formation of 2,4-pyrimidinediamine, corresponding to structural formula (I). Compound 44 may include virtually any substitutable group that may be substituted with the C4-amine of an N2-substituted-2,4-pyrimidinediamine 42 . Suitable substituted Z groups include, but are not limited to: halogens, methanesulfonyloxy group (mesyloxy group; "OMs"), trifluoromethanesulfonyloxy group ("OTf") and p- toluenesulfonyloxy group (tosyloxy group; "OTs"), benzenesulfonyloxy group ("besylate") and methanitrobenzenesulfonyloxy group ("nosylate"). Other suitable substituted groups are well known to those skilled in the art.

The substituted 4-amino-2-pyrimidinol used as starting material can be obtained commercially or synthesized using standard procedures. Below is a large number of links to reference manuals on synthetic methods for their preparation .

In yet another embodiment, the 2,4-pyrimidinediamine compounds of the present invention can be prepared from 2-chloro-4-aminopyrimidine or 2-amino-4-chloropyrimidines, as shown in Scheme (V) below:

Scheme (V)

In scheme (V), R ² , R ⁴ , R ⁵ , R ⁶ , L ¹ , L ² and X correspond to those previously described in scheme (I), and Z corresponds to its designation in scheme (IV). Starting from Scheme (V), 2-amino-4-chloropyrimidine 50 reacts with amine 10 to form 4N-substituted-2-pyrimidinamine 52 , which, following a reaction with compound 31 or amine 6 , forms 2,4-pyrimidinediamine, corresponding to structural formula (I). Alternatively, 2-chloro-4-aminopyrimidine 54 may be reacted with compound 44 and then with an amine to give a compound corresponding to structural formula (I).

Examples of commercially available starting materials for use in Scheme (V) include, but are not limited to, pyrimidines 50 and 54, including 2-amino-4,6-dichloropyrimidine (Aldrich catalog number A4860-1; CAS registration number 56-05-3) ; 2-amino-4-chloro-6-methoxypyrimidine (Aldrich catalog number 51,864-6; CAS registration number 5734-64-5); 2-amino-4-chloro-6-methylpyrimidine (Aldrich catalog number 12,288-2; CAS registration number 5600-21-5); and 2-amino-4-chloro-6-methylthiopyrimidine (Aldrich catalog number A4600-5; CAS registration number 1005-38-5). Additional pyrimidine-based starting material is available from General Intermediates of Canada, Inc. (Edmonton, Alberta, Canada) (www.generalintermediates.com) and / or Interchim (France) (www.interchim.com) or cook using a standard technique. Below is a large number of links to reference manuals on synthetic methods for their preparation .

Alternatively, 4-chloro-2-pyrimidinamines 50 can be prepared as shown in scheme (Va) below:

Scheme (Va)

In Scheme (Va), R ⁵ and R ⁶ correspond to their notation in structural formula (I). In Scheme (Va), dicarbonyl 53 reacts with guanidine to give 2-pyrimidinamine 51 . The reaction with peracids such as m-chloroperbenzoic acid, trifluorooracetic acid or a complex of hydrogen peroxide with urea leads to the formation of N-oxide 55 , which is then halogenated to give 4-chloro-2-pyrimidinamine 50 . The corresponding 4-halogen-2-pyrimidinamines can be prepared using suitable halogenating agents.

In yet another embodiment, the 2,4-pyrimidinediamine compounds of the present invention can be prepared from substituted or unsubstituted uridines, as shown in Scheme (VI) below:

Scheme (VI)

In Scheme (VI), R ² , R ⁴ , R ⁵ , R ⁶ , L ¹ , L ^2, and X correspond to their designations in Scheme (I), and the superscript PG represents the protecting group considered in connection with Scheme (IIb). According to Scheme (VI), uridine 60 has a C4 reactive center such that reaction with amine 10 or protected amine 21 leads to the formation of an N4-substituted cytidine 62 or 64, respectively. Deprotection of N4-substituted 62 or 64 with an acid catalyst (when “PG” represents an acid-unstable protecting group) gives N4-substituted cytosine 28 , which can then be halogenated at the C2 position and reacted with amine 6 to give 2 , 4-pyrimidinadiamine corresponding to structural formula (I).

Similarly, cytidines can also be used as starting material, as shown in scheme (VII) below:

Scheme (VII)

In Scheme (VII), R ² , R ⁴ , R ⁵ , R ⁶ , L ¹ , L ^2, and X correspond to their designations in Scheme (I), and the superscript PG represents a protecting group, as indicated above. Starting from scheme (VII), like uridine 60 , cytidine 70 has a C4 reactive center such that reaction with amine 10 or protected amine 21 leads to the formation of N4-substituted cytidine 62 or 64, respectively. These cytidines 62 and 64 are then processed as described above for Scheme (VI) to give 2,4-pyrimidinediamine corresponding to structural formula (I).

Despite the fact that schemes (VI) and (VII) are given as an example with ribosyl nucleosides, it is clear to an expert in this field that the corresponding 2'-deoxyribo- and 2 ', 3'-dideoxyribonucleosides, as well as nucleosides including sugars or sugar analogs other than ribose.

Numerous uridines and cytidines suitable for use as starting material in Schemes (VI) and (VII) are known to those skilled in the art and include, for example, and without limitation 5-trifluoromethyl-2'-deoxycytidine (Chem. Sources, No. ABCR F07669; registration CAS number 66.384-66-5); 5-bromuridine (Chem. Sources Int'l 2000, CAS 957-75-5); 5-iodo-2'-deoxyuridine (Aldrich catalog number 1-775-6; CAS registration number 54-42-2); 5-fluoruridine (Aldrich catalog number 32.937-1; registration number CAS 316-46-1); 5-ioduridine (Aldrich catalog number 85,259-7; CAS registration number 1024-99-3); 5- (trifluoromethyl) uridine (Chem. Sources Int'l 2000; CAS registration number 70-00-8); 5-trifluoromethyl-2'-deoxyuridine (Chem. Sources Int'l 2000; CAS number 70-00-8). Additional uridines and cytidines that can be used as starting material in Schemes (VI) and (VII) are available from General Intermediates of Canada, Inc. (Edmonton, Alberta, Canada) (www.generalintermediates.com) and / or Interchim (France) (www.interchim.com) or cook using a standard technique. Below is a large number of links to reference manuals on synthetic methods for their preparation .

Compounds of 2,4-pyrimidinediamine according to the present invention can also be synthesized from substituted pyrimidines, such as chlorosubstituted pyrimidines, as shown below in schemes (VIII) and (IX):

Scheme (VIII)

Scheme (IX)

In schemes (VIII) and (IX), R ² , R ⁴ , L ¹ , L ² and R ^a correspond to their notation in the structural formula (I), and “Ar” represents an aryl group. Based on scheme (VIII), the reaction of 2,4,6-trichloropyrimidine 80 (catalog number Aldrich T5,620-0; CAS No. 3764-01-0) with amine 6 leads to the formation of a mixture of three compounds: substituted pyrimidine mono, di- and triamines 81, 82 and 83 , which can be separated and isolated by high performance liquid chromatography (HPLC) or other conventional technique. Mono and diamines 81 and 82 may subsequently react with amines 6 and / or 10 to form N2, N4, N6-trisubstituted-2,4,6-pyrimidine triamines 84 and 85, respectively.

N2, N4-bis-substituted-2,4-pyrimidinediamines can be prepared by a method similar to that shown in scheme (VIII) using 2,4-dichloro-5-methylpyrimidine or 2,4-dichloropyrimidine as starting materials. In this case, the monosubstituted pyrimidinamine corresponding to compound 81 is not formed. Instead, the direct formation of N2, N4-bis-substituted-2,4-pyrimidinediamine proceeds.

Based on scheme (IX), 2,4,5,6-tetrachloropyrimidine 90 (Aldrich catalog number 24,671-9; CAS No. 1780-40-1) is reacted with excess amine 6 to give a mixture of three compounds: 91 , 92 and 93 which can be separated and isolated using HPLC or other conventional methods. As shown, N2, N4-bis-substituted-5,6, -dichloro-2,4-pyrimidinediamine 92 then, in the presence of halide C6, can react, for example, with nucleophilic substance 94 to give compound 95 . Alternatively, Compound 92 can be converted to N2, N4-bis-substituted -5-chloro-6-aryl-2,4-pyrimidinediamine 97 using the Suzuki reaction. 2,4-Pyrimidinediamine 95 can be converted to 2,4-pyrimidinediamine 99 by reaction with Bn ₃ SnH.

It will be understood by those skilled in the art that the 2,4-pyrimidinediamines of the present invention synthesized using the methods described above or other well-known methods can also be used as starting materials and / or intermediates for the synthesis of additional compounds 2, 4-pyrimidinediamine of the invention. A specific example is shown below in diagram (X):

Scheme (X)

In Scheme (X), R ⁴ , R ⁵ , R ⁶ , L ^2, and R ^a correspond to their notation in structural formula (I). Each R ^{a ′} independently represents R ^a and may be the same or different from that represented by R ^a . Based on scheme (X), the carboxylic acid or ester 100 can be converted to amide 104 by reaction with amine 102 . In amine 102, R ^{a ′} may be the same or different from R ^a acid or ester 100 . Similarly, carbonate ester 106 can be converted to carbamate 108 .

A second specific example is shown below in diagram (XI):

Scheme (XI)

In Scheme (XI), R ⁴ , R ⁵ , R ⁶ , L ^2, and R ^c correspond to their notation in structural formula (I). Based on scheme (XI), amide 110 or 116 can be converted to amine 114 or 118, respectively, due to a reduction in the content of borane using a complex of borane methyl sulfide 112 . Other suitable reactions for synthesizing 2,4-pyrimidinediamine compounds from the 2,4-pyrimidinediamine starting material are understood by those skilled in the art.

Although many of the synthetic schemes discussed above do not reflect the use of protective groups, it is clear that in some cases, the substituents R ² , R ⁴ , R ⁵ , R ⁶ , L ¹ and / or L ² may include functional groups, requiring protection. The exact properties of the protective group used will depend, inter alia, on the properties of the functional group that needs to be protected and on the conditions of the reaction used in a particular synthetic scheme, which is obvious to those skilled in the art. Guidance on the selection of protecting groups and attachment and removal mechanisms suitable for a particular application can be found, for example, in Greene & Wuts, supra.

Prodrugs corresponding to structural formula (II) can be prepared using the usual modification of the above methods. Otherwise, such prodrugs can be prepared by the reaction of a suitably protected 2,4-pyrimidinediamine corresponding to structural formula (I) with a suitable progroup. The conditions for carrying out such reactions and for deprotecting the reaction product to obtain a prodrug corresponding to formula (II) are well known.

A large number of teaching methods are known in the literature, mainly applicable for the synthesis of both pyrimidines and the starting materials described in schemes (I) - (IX). For specific guidance, the reader may consult the following sources: Brown, DJ, "The Pyrimidines", in The Chemistry of Heterocyclic Compounds, Volume 16 (Weissberger, A., Ed.), 1962, Interscience Publishers, (A Division of John Wiley & Sons), New York (“Brown I”); Brown, DJ, "The Pyrimidines", in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement I (Weissberger, A. and Taylor, EC, Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons) , New York (Brown II "); Brown, DJ, "The Pyrimidines", in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. and Taylor, EC, Ed.), 1985, An Interscience Publication (John Wiley & Sons), New York ( “Brown III”); Brown, DJ, "The Pyrimidines" in The Chemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. and Taylor, EC, Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509 (Brown IV "); Kenner, GW and Todd, A., in Heterocyclic Compounds , Volume 6, (Elderfield, RC, Ed.), 1957, John Wiley, New York, Chapter 7 (Pyrimidines); Paquette, LA, Principles of Modern Heterocyclic Chemistry , 1968, WA Benjamin, Inc., New York, pp. 1-401 (uracil synthesis pp. 313, 315; pyrimidine synthesis pp. 313-316; amino pyrimidine synthesis pp. 315); Joule, JA, Mills, K. and Smith, GF, Heterocyclic Chemistry, 3 ^rd Edition, 1995, Chapman and Hall, London, UK , pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook of Nucleoside Synthesis , John Wiley & Sons, New York, 2001, pp. 1-631 (protection of pyrimidines by acylation pp. 90-91; silylation of pyrimidines pp. 91-93); Joule, JA, Mills, K. and Smith, GF, Heterocyclic Chemistry , 4 ^th Edition, 2000, Blackwell Science, Ltd, Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis , Volumes 1-9 (Trost, BM and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

Those skilled in the art will understand that in Schemes I through XI, nitrogen N4 can be replaced by a group R ^4c , as noted throughout the text of the description of the present invention, as well as in the examples cited.

6.4 Inhibition of Fc receptor signaling cascades

The active 2,4-pyrimidinediamine compounds of the present invention suppress Fc receptor signaling cascades, which leads, inter alia, to cell degranulation. A specific example of this is the inhibition of cascades of FcεRI and / or FcγRI signals by these compounds, resulting in the degranulation of immune cells, such as neutrophilic, eosinophilic cells, mast cells and / or basophilic cells. Both mast cells and basophilic cells play a central role in disorders caused by allergens, including, for example, allergic rhinitis and asthma. Based on figure 1, under the influence of allergens, which, among other things, may be pollen or parasites, allergen-specific IgE antibodies are synthesized by B cells that are activated using IL-4 (or IL-13) and other messengers, for in order to proceed to the synthesis of a specific IgE class antibody. These allergen-specific IgE antibodies bind to FcεRI having a high affinity. After antigen binding, FcεR1-associated IgE antibodies cross-link and the transduction pathway of the IgE receptor signal is activated, which leads to cell degranulation and subsequent isolation and / or synthesis of a variety of chemical mediators, including histamine, proteases (e.g. tryptase and chymase), lipid mediators, such as leukotrienes (e.g. LTC4), platelet activation factors (PAF) and prostaglandins (e.g. PGD2), as well as a series of cytokines including TNF-α, IL-4, IL-13, IL-5, IL-6, IL-8 GMCSF, VEGF and TGF-β. Isolation and / or synthesis of these mediators from mast cells and / or basophilic cells is the cause of early or late responses caused by allergens and is directly related to processes in the forward direction that lead to a prolonged inflammatory state.

The molecular processes in the transduction pathway of the FcεRI receptor signal that cause the release of preformed mediators through degranulation and the isolation and / or synthesis of other chemical mediators are well known and illustrated in FIG. 2. Based on figure 2, FcεRI is a heterotetrameric receptor composed of IgE-binding alpha subunits, beta subunits and two gamma subunits (gamma homodimer). Crosslinking of FcεRI-bound IgE with multivalent binders (including, for example, IgE-specific allergens, or anti-IgE antibodies, or fragments) causes the fast association and activation of the Src-dependent Lyn kinase. Lyn phosphorylates tyrosine-induced immunoreceptor activation motifs (“ITAMS”) on the intercellular beta and gamma subunits, leading to the recruitment of an additional Lyn kinase to the beta subunit and Syk kinase to the gamma homodimer. These receptor-related kinases, which are activated by intra- and intermolecular phosphorylation, phosphorylate other pathway components, such as Btk kinase, LAT, and C-gamma (PLC-gamma) phospholipase. Activated PLC-gamma initiates a pathway that leads to the activation of protein C-kinase and the mobilization of Ca ²⁺ , which is necessary for degranulation. Crosslinking of FcεR1 also activates the three main classes of mitogen activated protein kinases (MAP), i.e., ERK1 / 2, JNK1 / 2 and p38. Activation of these pathways is important in the transcriptional regulation of pro-inflammatory mediators, such as TNF-α and IL-6, as well as leukotriene CA (LTC4) of the lipid mediator.

Although not shown in the figure, it is believed that the FcγRI receptor signaling cascade has several elements in common with the FcεRI receptor signaling cascade. Significantly, like FcεRI, the FcγRI receptor includes a gamma homodimer that phosphorylates and recruits the Syk kinase, as in the case of FcεRI, and activation of the FcγRI receptor signaling cascade leads, among other things, to degranulation. Other Fc receptors that are involved in the gamma homodimer and can be regulated by the active compounds of 2,4-pyrimidinediamine include, but are not limited to, FcαRI and FcγRIII.

The ability of the 2,4-pyrimidinediamine compounds of the present invention to inhibit Fc receptor signaling cascades can be easily determined or confirmed by in vitro assay. Samples convenient for confirming the inhibition of FcεRI-mediated degranulation are described in the Examples section. In one typical sample, cells capable of undergoing FcεRI mediated degranulation, such as mast cells or basophils, are first grown in the presence of IL-4, stem cell factor (SCF), IL-6 and IgE to increase the expression of FcεRI exposed to the test compound 2,4-pyrimidinediamine according to the present invention and stimulated with anti-IgE antibodies (or, alternatively, an IgE-dependent allergen). Following the incubation, the amount of chemical mediator or other chemical reagent isolated and / or synthesized by activation of the FcεRI signaling cascade can be determined using standard methods and can be equated to the amount of mediator or reagent isolated from control cells ( i.e. cells that stimulated but not exposed to the test compound). The concentration of the test compound, which leads to a 50% reduction in the amount of mediator or reagent measured relative to control cells, is equal to the IC _{50 of the} test compound. The origin of the mast cells or basophilic cells used in the sample will depend, in particular, on the preferred use of the compounds, which is obvious to specialists in this field. For example, if the compounds will be used to treat or prevent a specific disease characteristic of humans, a convenient source of mast cells or basophilic cells is a person or other animal, which is considered to be an acceptable or well-known clinical model for a specific disease. Thus, depending on the particular application, mast cells or basophil cells can be obtained from various animal sources from lower mammals such as mice and rats to dogs, sheep and other mammals commonly used in clinical trials and higher mammals such as monkeys , chimpanzees, anthropoids and even humans. Specific examples of cells suitable for in vitro sample preparation include, but are not limited to, rodent or human basophilic cells, rat leukemia basophilic cell lines, mouse main mast cells (such as BMMC mouse bone marrow mast cells), and human umbilical cord mast cells (“CHMC”) or other tissues, such as lung tissue. Methods for isolating and culturing these types of cells are well known or are presented in the Examples section ( see, for example , Demo et al. , 1999, Cytometry 36 (4): 340-348 and one of several patent applications pending simultaneously). , registration number 10 / 053,355, filing date - November 8, 2001, the exposition of which is included in the references to this work). Of course, other types of immune cells that degranulate after activation of the FcεRI signaling cascade can also be used, including, for example, eosinophils.

Those skilled in the art will agree that a quantified neurotransmitter or reagent is not required. The only requirement is that the mediator or reagent is isolated and / or synthesized as a result of the initiation or activation of the Fc receptor signaling cascade. For example, based on Fig. 1, activation of the FcεRI signaling cascade in mast cells and / or basophilic cells leads to numerous phenomena that occur in the forward direction. For example, as a result of the activation of the FcεRI signaling cascade, various preformed chemical mediators and reagents are released instantly (that is, within 1-3 minutes after activation of the receptor) using degranulation. Thus, in one embodiment of the invention, a quantified neurotransmitter or reagent may be characteristic of the granules ( i.e., usually present in the granules, and not in the cytoplasm of the cell). Examples of granule-specific mediators or reagents that can be quantified to determine and / or confirm the activity of the 2,4-pyrimidinediamine compound of the present invention include, but not limited to, granule-specific enzymes, such as hexosaminidase and tryptase, and granule-specific components, such as histamine and serotonin. Samples for quantifying such factors are well known and, in many cases, commercially available. For example, the isolation of tryptase and / or hexosaminidase can be quantified by growing cells with cleavable substrates that fluoresce after cleavage, determining the amount of fluorescence obtained by conventional methods. Such cleavable fluorogenic substrates are commercially available. For example, fluorogenic substrates Z-Gly-Pro-Arg-AMC (where Z = benzyloxycarbonyl and AMC = 7-amino-4-methylcoumarin, manufactured by BIOMOL Research Laboratories, Inc., Plymouth Meeting, PA 19462, Catalog No. P-142 ) and Z-Ala-Lys-Arg-AMC (manufactured by Enzyme Systems Products, a Division of ICN Biomedicals, Inc., Livermore, CA 94550, Catalog No. AMC-246) can be used to quantify the amount of isolated tryptase. The fluorogenic substrate 4-methylumbelliferyl-N-acetyl-β-D-glucosaminide (supplier company: Sigma, St. Louis, MO, Catalog # 69585) can be used to quantify the amount of hexosaminidase released. Histamine isolation can be quantified using a commercially available enzyme-linked immunosorbent assay ELISA, such as ELISA analysis of Immunotech histamine No. IM2015 (Beckman-Coulter, Inc.). Specific methods for quantifying the isolation of tryptase, hexosaminidase and histamine are presented in the Examples section. Each of these samples can be used to determine or confirm the activity of the 2,4-pyrimidinediamine compounds of the present invention.

As shown again in FIG. 1, degranulation is only one of several reactions initiated by the FcεRI signaling cascade. In addition, activation of this signaling pathway leads to de novo synthesis and release of cytokines and chemokines, such as IL-4, IL-5, IL-6, TNF-α, IL-13 and MIP1-α, and the release of lipid mediators such like leukotrienes (e.g. LTC4), platelet activation factors (PAF), and prostaglandins. Therefore, the 2,4-pyrimidinediamine compounds of the present invention can also be evaluated for their activity by quantifying the amount of one or more of these isolated mediators and / or synthesized using activated cells.

In contrast to the granulospecific components considered above, these late phase mediators do not stand out immediately after the activation of the FcεRI signaling cascade. Thus, when quantifying these late stage mediators, measures should be taken to ensure that the culture of the activated cell is grown for a time sufficient to allow synthesis (if necessary) and isolation of a quantifiable mediator. Typically, PAF and lipid mediators, such as leukotriene C4, are released 3-30 minutes after activation of FcεRI. Cytokines and other late-phase mediators are secreted approximately 4-8 hours after FcεRI activation. Growth times corresponding to specific mediators are known to those skilled in the art. Specific guidance and samples are provided in the Examples section.

The amount of specific late-phase mediator selected can be quantified using any standard method. In one embodiment of the present invention, this amount (s) can be quantified using an ELISA assay. An ELISA kit suitable for quantifying isolated TNFα, IL-4, IL-5, IL-6 and / or IL-13 can be obtained, for example, from Biosource International, Inc., Camarillo, CA 93012 (see, for example , catalog numbers Nos. KHC3011, KHC0042, KHC0052, KHC0061 and KHC0132). An ELISA kit convenient for quantification of C4 leukotriene (LTC4) isolated from cells is available from Cayman Chemical Co., Ann Arbor, MI 48108 (see, for example, catalog number 520211).

Typically, the active 2,4-pyrimidinediamine compounds of the present invention will have an IC ₅₀ concentration relative to FcεRI receptor mediated degranulation and / or a mediator release or synthesis level of about 20 μm or less, in accordance with in vitro measurements such as one of the in vitro samples discussed above or in the Examples section. Of course, it will be understood by those skilled in the art that compounds that exhibit low IC ₅₀ values, for example of the order of 10 μm, 1 μm, 100 nM, 10 nM, 1 nM or even lower, are particularly useful.

Those skilled in the art will also agree with the fact that the various mediators discussed above can cause different negative effects or different levels of the same negative effect. For example, the lipid mediator LTC4 is a powerful vasoconstrictor: its potency in terms of narrowing blood vessels is approximately 1000 times greater than the potency of histamine. As another example, in addition to mediating atopic or type I hypersensitivity reactions, cytokines can also be cited, which can also cause tissue transformation and cell proliferation. Thus, despite the possibility of using compounds that inhibit the excretion and / or synthesis of one of the previously considered chemical mediators, specialists in this field will agree that compounds that inhibit the excretion and / or synthesis of most, or even all of the mediators discussed above, are undoubtedly , will find wider application in view of their ability to improve or completely suppress most or even all of the adverse effects caused by individual mediators. For example, compounds that inhibit the release of all three types of mediators — granule-specific mediators, lipids, and cytokines — are effective in treating or preventing the immediate type I hypersensitivity reaction, as well as associated chronic symptoms.

Compounds of the present invention capable of inhibiting the release of more than one type of mediator ( e.g., a granule-specific mediator or a late-phase mediator) can be identified by determining an IC ₅₀ value relative to the model mediator of each class using the various in vitro assays discussed above (or others equivalent in vitro assays). Compounds of the present invention that can suppress mediators of more than one type will typically exhibit IC ₅₀ values of less than 20 μm for mediators of each type tested. For example, a compound with an IC ₅₀ value of 1 μM relative to histamine release (IC ₅₀ ^histamine ) and with an IC ₅₀ value of 1 nM relative to LTC4 leukotriene synthesis and / or isolation

(IC ₅₀ ^LTC4 ) is characterized both by the immediate release of mediators (inherent in granules), and the release of late phase mediators. As another specific example, we can give a compound with IC ₅₀ ^tryptase values of 10 μM, IC ₅₀ ^LTC4 - 1 μM and IC ₅₀ ^IL-4 - 1 μM, which inhibits the instant release of mediators (characteristic of granules), as well as the release of lipid and cytokine mediators . Despite the fact that the above specific examples use the IC _{50 of} one mediator - a representative of each class, experts in this field will agree that the IC ₅₀ values of most or even all mediators that make up one or more classes can also be obtained. For specialists in this field it will be obvious the number (s) and variety (s) of mediators for which data on the IC ₅₀ should be established in the case of a particular connection and application.

Such samples can be used to test the inhibition of signal transduction cascades initiated by other Fc signaling receptors, such as FcαRI, FcγRI and / or FcγRIII with the usual modification. For example, the ability of compounds to inhibit FcγRI signal transduction can be tested using samples similar to those described above, except that the FcγRI signaling cascade is activated, for example, by growing cells with IgG and allergen-specific IgG or an antibody instead of IgE and allergen-specific IgE or antibodies. Suitable cell types, activating reagents and quantification reagents necessary for checking the inhibition of other Fc receptors, such as, for example, Fc receptors that are part of the gamma homodimer, are known to those skilled in the art.

One most useful class of compounds includes 2,4-pyrimidinediamine compounds that inhibit the release of immediate-type granule mediators and late-phase mediators with approximately equivalent IC ₅₀ values. “Approximately equivalent” means that the IC ₅₀ values for the mediator of each type differ from each other by no more than 10 times. Another particularly useful class of compounds includes 2,4-pyrimidinediamine compounds that inhibit the release of immediate-type granule mediators and cytokine mediators with approximately equivalent IC ₅₀ values. In specific embodiments of the present invention, such compounds inhibit the release of the following mediators with approximately equivalent IC ₅₀ values: histamine, tryptase, hexosaminidase, IL-4, IL-5, IL-6, IL-13, TNFα and LTC4. Such compounds are particularly effective, inter alia, for improving or completely eliminating both early and late responses associated with atopic or immediate type I hypersensitivity reactions.

Ideally, the ability to inhibit the release of mediators of all desirable types will be inherent in one compound. However, mixtures of compounds providing the same result can be identified. For example, a first compound that inhibits the release of granule-specific mediators can be used in combination with a second compound that inhibits the release and / or synthesis of cytokine mediators.

In addition to the FcεRI or FcγRI degranulation pathways discussed above, degranulation of mast cells and / or basophilic cells can be caused by other reagents. For example, ionomycin, which is a calcium ionophore that bypasses the transduction mechanism of early FcεRI or FcγRI cell signals, directly triggers a calcium flux that initiates degranulation. As follows from figure 2, activated PLCγ initiates paths leading, inter alia, to the mobilization of calcium ions and subsequent degranulation. As shown in this figure, such Ca ²⁺ mobilization is caused at a later stage in the FcεRI signal transduction path. As noted above and shown in figure 3, ionomycin directly causes the mobilization of Ca ²⁺ and the flow of Ca ²⁺ , which leads to degranulation. Other ionophores that cause degranulation in this manner include A23187. The ability of ionophores, such as ionomycin, to cause degranulation to bypass the early stages of the FcεRI and / or FcγRI signaling cascades allows them to be used as a counter screen to identify active compounds of the present invention that especially affect their activity in degranulation and inhibition by blocking or suppressing the early signaling cascades of FcεRI or FcγRI, as discussed above. Compounds that specifically inhibit such early degranulation mediated by FcεRI or FcγRI receptors inhibit not only degranulation and subsequent rapid release of histamine, tryptase and other components containing granules, but also proinflammatory activation pathways causing TNFα, IL-4, IL -13 and lipid mediators, such as LTC4. Thus, compounds that specifically inhibit such early degranulation mediated by FcεRI or FcγRI receptors block or inhibit not only acute atopic or type I hypersensitivity reactions, but also late responses involving numerous inflammatory mediators.

Compounds of the present invention that suppress the early degranulation mediated by FcεRI and / or FcγRI receptors to the greatest extent possible are degranulation mediated inhibitors mediated by FcεRI and / or FcγRI receptors (having, for example , IC ₅₀ values less than 20 μM relative to excretion granule-specific mediator or component according to in vitro measurements in a sample with cells that are stimulated by the binding reagent IgE or IgG), but slightly inhibit ionophore degranulation. In one embodiment of the present invention, the compounds are considered to be slightly inhibiting ionophore-induced degranulation if the in vitro determined IC ₅₀ value of ionophore-induced degranulation does not exceed 20 μM. Of course, active compounds that exhibit even higher IC ₅₀ values due to ionophore degranulation or do not suppress ionophore degranulation at all are particularly effective. In another embodiment of the present invention, the compounds are considered to be slightly inhibiting ionophore-induced degranulation if they exhibit more than a 10-fold difference in the IC ₅₀ values of the degranulation mediated by FcεRI and / or FcγRI and due to the ionophore degranulation measured in vitro in the sample. Samples that are convenient for determining the IC ₅₀ value due to ionophore degranulation include any of the previously considered degranulation samples, provided that the cells are stimulated or activated by a calcium ionophore, such as ionomycin or A23187 (AG Scientific, San Diego, CA) that causes degranulation, instead of anti IgE antibodies or allergen-specific IgE. Specific tests for evaluating the ability of a particular 2,4-pyrimidinediamine compound of the present invention to inhibit ionophore-induced degranulation are presented in the Examples section.

Those skilled in the art will understand that compounds that exhibit a high degree of selectivity for FcεRI-mediated degranulation find particular use, since such compounds selectively act on the FcεRI cascade and do not affect other degranulation mechanisms. Similarly, compounds that exhibit a high degree of selectivity for degranulation mediated by FcγRI receptors find particular use, since such compounds selectively act on the FcγRI cascade and do not affect other degranulation mechanisms. Compounds that exhibit a high degree of selectivity, generally 10 or more times, are more selective with respect to mediated FcεRI or FcγRI receptor degranulation than to degranulation due to ionophore such as, for example, ionomycin-induced degranulation.

Accordingly, the activity of the 2,4-pyrimidinediamine compounds of the present invention can also be confirmed by biochemical or cellular activity tests of Syk kinase. As shown in FIG. 2, in the FcεRI signaling cascade in mast cells and / or basophilic cells, Syk kinase phosphorylates LAT and PLC-gamma1, which leads, among other things, to degranulation. Any of these activities may be used to confirm the activity of the 2,4-pyrimidinediamine compounds of the present invention. In one embodiment of the present invention, this activity is confirmed by combining the isolated Syk kinase or its active fragment with a 2,4-pyrimidinediamine compound in the presence of a Syk kinase substrate ( for example, a synthetic peptide or protein, if it is known to be phosphorylated with using Syk in the signaling cascade) as a result of the assessment of substrate phosphorylation by Syk kinase. Alternatively, a sample may be prepared using cells that express Syk kinase. Cells can express Syk kinase endogenously (internally) or they can be constructed to express recombinant Syk kinase. Cells can also additionally express Syk kinase substrate. Cells suitable for the preparation of such control samples, as well as methods for creating suitable cells, are obvious to specialists in this field. Specific examples of biochemical or cell samples convenient for confirming the activity of 2,4-pyrimidinediamine compounds are presented in the Examples section.

In general, Syk kinase inhibitors will have IC ₅₀ values relative to Syk kinase activity, such as, for example, the ability of a Syk kinase to phosphorylate a synthetic or endogenous support in vitro or in a cell sample of the order of 20 μM or less. Those skilled in the art will agree that compounds with lower IC _50s , for example of the order of 10 μM, 1 μM, 100 nM, 10 nM, 1 nM or even less, are particularly effective.

6.5 Applications and formulations

As noted previously, the active compounds of the present invention inhibit Fc receptor signaling cascades and, in particular, Fc receptors including a gamma homodimer, such as FcεRI and / or FcγRI signaling cascades, which lead, inter alia, to isolation and / or synthesis chemical mediators from cells through degranulation or other processes. It has also been discussed that active compounds are also effective inhibitors of Syk kinase. Therefore, the active compounds of the present invention can be used under various in vitro, in vivo and ex vivo conditions to regulate or inhibit Syk kinase signaling cascades in which Syk kinase plays the role of Fc receptor signaling cascades and biological responses induced by such signaling cascades. For example, in one embodiment of the present invention, the compounds can be used to inhibit Syk kinase in vitro or in vivo , in fact, in any type of cell expressing the Syk kinase. They can also be used to control signal transduction cascades in which the Syk kinase plays a role. Such Syk-dependent signal transduction cascades include, but are not limited to, signal transduction cascades FcεRI, FcγRI, FcγRIII, BCR, and integrin. The compounds can also be used in vitro or in vivo to regulate and, in particular, suppress cellular or biological reactions caused by such Syk-dependent signal transduction cascades. Such cellular or biological reactions include, but are not limited to, respiratory bursts, cell adhesion, cell degranulation, cell spreading, cell migration, cell aggregation, phagocytosis, cytokine synthesis and secretion, cell maturation, and Ca ²⁺ ion flux. It is significant that these compounds can be used to inhibit Syk kinase in vivo as a therapeutic approach to the treatment or prevention of diseases mediated in whole or in part by Syk kinase activity. Some examples of Syk kinase-mediated diseases that can be treated or prevented with such compounds are discussed in more detail below.

In another embodiment, the active compounds can be used to regulate or inhibit Fc and / or FcεRI and / or FcγRI-mediated degranulation signaling cascades as a therapeutic approach to the treatment or prevention of diseases characterized by, caused by and / or associated with excretion or by the synthesis of chemical mediators of such signaling cascades or degranulation of Fc receptors. Such treatment can be prescribed to animals in veterinary conditions or to people. As an example, diseases that are characterized, caused, or associated with such isolation, synthesis, or degranulation of a mediator, and therefore amenable to treatment or prevention with active compounds, include, but are not limited to: hereditary predisposition to allergic diseases, anaphylactic hypersensitivity, or allergic reactions allergies (e.g., allergic conjunctivitis, allergic rhinitis, atopic asthma, atopic dermatitis, and food allergies), low-grade scarring (i.e., scleroderma, increased fibrosis, keloid formation, postoperative scarring, pulmonary fibrosis, vascular spasm, migraine, reperfusion injury and the post-infarction period), tissue destruction diseases ( e.g. , chronic obstructive pulmonary disease (COPD), cardiobronchitis and post-infarction period), diseases associated with tissue inflammation ( for example , irritable bowel syndrome, spastic colon and inflammatory bowel disease), inflammation and scarring.

In addition to the sheer number of diseases mentioned above, data obtained from cell analysis and animal testing confirm that the 2,4-pyrimidinediamine compounds described in the present invention are also useful in the treatment or prevention of autoimmune diseases, as well as various symptoms associated with such diseases. Types of autoimmune diseases that can be treated or prevented with 2,4-pyrimidinediamine compounds in total include tissue damage disorders resulting from a humoral and / or cell-mediated reaction to immunogens or antigens of an endogenous and / or exogenous nature . Such diseases are often characterized as diseases associated with non-anaphylactic hypersensitivity reactions (for example, type II, III and / or IV).

In accordance with the discussion above, type I hypersensitivity reactions mainly arise from the release of pharmacologically active substances, for example, histamine, mast cells and / or basophils as a result of contact with a specific exogenous antigen. As noted above, such type I reactions play a role in a large number of diseases that include allergic asthma, allergic rhinitis, etc.

Type II hypersensitivity reactions (also known as cytotoxic, cytolytic complement-induced or cell-stimulated hypersensitivity reactions) occur when immunoglobulins react with antigenic components of cells or tissues or with antigen or hapten that are inextricably linked to cells or tissues. Diseases that are typically associated with type II hypersensitivity reactions include, but are not limited to: autoimmune hemolytic anemia, congenital neonatal anemia, and Goodpasture syndrome.

Type III hypersensitivity reactions (also known as hypersensitivity reactions caused by toxic, soluble, or immune complexes) arise from the deposition of soluble circulating antigen-immunoglobulin complexes in vessels or tissues, which is accompanied by acute inflammatory reactions at the site of immunocomplex deposits. Unlimited examples of prototypical diseases resulting from type III reactions include the Arthus reaction, rheumatoid arthritis, serum sickness, systemic erythematous lupus, certain types of glomerulonephritis, multiple sclerosis, and bullous pemphingoid.

Type IV hypersensitivity reactions (often referred to as cellular, cell-mediated, delayed, or tuberculin hypersensitivity reactions) are caused by sensitized T-lymphocytes, which are formed as a result of contact with a specific antigen. Unlimited examples of diseases that involve type IV reactions include contact dermatitis and allograft rejection.

Autoimmune diseases associated with any of the above non-anaphylactic hypersensitivity reactions can be treated or prevented with the 2,4-pyrimidinediamine compounds of the present invention. In particular, these methods can be used to treat or prevent autoimmune diseases, often characterized as autoimmune disorders of a single organ or a single type of cell, which include, but are not limited to: Hashimoto thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of malignant anemia, autoimmune enamel autoimmune orchitis, Goodpasture syndrome, autoimmune thrombocytopenia, metastatic ophthalmia, bulbospinal paralysis, bazedova disease, b primary liver cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membrane glomerulopathy, as well as autoimmune diseases, often characterized by the presence of systemic autoimmune disorders, which include, but are not limited to: systemic erythematous lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, Reiter’s syndrome, dermatomyositis, systemic sclerosis, nodular polyarteritis, multiple sclerosis, and bullous pemphigoid.

Specialists in this field will agree that many of the above autoimmune diseases are associated with serious symptoms, the weakening of the manifestations of which represents significant progress in treatment, even in cases where it is not possible to improve the condition of the underlying disease. Many of these symptoms, as well as the stages of the underlying disease, are the result of activation of the FcγR signaling cascade in monocytes. Since the 2,4-pyrimidinediamine compounds of the present invention are potential inhibitors of such FcγR signaling cascades in monocytes and other cells, the described methods can be used in the treatment and / or prevention of a variety of undesirable symptoms associated with the above autoimmune diseases.

As an example, rheumatoid arthritis (RA) usually causes swelling, pain, loss of mobility and increased sensitivity of damaged joints of the whole body. RA is characterized by the presence of a chronically inflamed synovial membrane densely populated by lymphocytes. The synovial membrane, which usually has a thickness of one cell layer, becomes saturated with cells and takes on a shape similar to lymphoid tissues, including dendritic cells, T, B, and NK cells, macrophages, and plasmocyte clusters. This process, combined with an abundance of immunopathological mechanisms that include the formation of antigen-immunoglobulin complexes, ultimately leads to a violation of the integrity of the joint, which leads to deformation, the final loss of functioning and / or erosion of the joint bone or in the immediate vicinity of the joint. The methods described can be used to treat or alleviate the condition of any particular, several or all of the symptoms of RA. Thus, within the context of RA, treatment methods (described in more general terms below ) are considered that contribute to the alleviation of the manifestation or improvement of the symptoms often associated with RA, regardless of the concomitant success in treating the underlying disease (RA) and / or reducing the amount of circulatory rheumatoid factor ("RF").

Another specific example is systemic erythematic lupus erythematosus (“SLE”), which is often associated with symptoms such as fever, joint pain (arthralgia), arthritis, and serositis (pleurisy or pericarditis). Within the context of the SLE, treatment methods are considered that contribute to alleviating the manifestation or improving the condition of the symptoms often associated with SLE, regardless of the concomitant success in treating the underlying disease (SLE).

Another specific example is multiple sclerosis (MS), the damage from which includes impaired visual acuity of the patient; the development of double vision; impaired mobility, which affects the ability to walk and act with hands; incontinence of the stomach and bladder; spasticity; as well as limited sensitivity (to touch, pain and temperature). Within the context of MS, treatment methods are considered that contribute to the improvement or retardation of the development of a particular or several damaging factors, often associated with MS, regardless of the concomitant success in the treatment of underlying disease (MS).

When used to treat or prevent such diseases, the active compounds may be administered alone, as mixtures of one or more active compounds, or as a mixture or combination with other substances effective in treating such disorders and / or symptoms associated with such diseases. These active compounds are also prescribed in a mixture or combination with substances that are used to treat other disorders or diseases, such as steroids, membrane stabilizers, 5LO inhibitors, leukotriene synthesis and receptor inhibitors, IgE isotype switching inhibitors or IgE synthesis, inclusion of IgG isotype or synthesis IgG, β-agonists, tryptase inhibitors, aspirin, COX inhibitors, methotrexate, anti-TNF drugs, rituxin, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, antihistamines, etc. These active compounds can be prescribed per se (ca alone) as prodrugs or as drugs containing the active compound or prodrug.

Medicines containing the active compounds of the present invention (or prodrugs thereof) can be prepared by conventional mixing, dissolving, granulating, dragee-eluting, emulsifying, encapsulating, entrainment or lyophilization processes. These formulations can be prepared in the usual manner using one or more physiologically acceptable carriers, diluents, excipients or excipients that facilitate the processing of the active compounds into drugs that can be used for pharmaceutical purposes.

The active compound or prodrug can be prepared in the form of pharmaceutical compositions per se or in the form of a hydrate, solvate, N-oxide or a pharmaceutically acceptable salt, as described above. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, while salts that are less soluble than the corresponding free acids and bases can be obtained.

The pharmaceutical compositions of the present invention can take a form convenient for virtually any type of application, including, for example, external, ophthalmic, internal, buccal, systemic, nasal, injectable, transdermal, rectal, vaginal, etc., or a form convenient for appointments in the form of inhalation or insufflation.

For external use, the active compound (s) or prodrug (s) can be prepared in the form of solutions, gels, ointments, creams, suspensions, etc., which is well known in the literature.

Compositions for systemic administration include those that are intended for use in the form of injections, for example, subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injections, as well as those intended for transdermal, through the mucous membrane, internal or pulmonary administration.

Effective injectable preparations include sterile suspensions, solutions or emulsions of the active compound (s) in aqueous or oily solvents. The compositions may also contain formulating substances, such as a suspending agent, a stabilizing agent and / or a dispersing agent. Formulations for injection may be presented in unit dose form, for example, in ampoules or in multi-dose containers, and may contain added preservatives.

Alternatively, the injectable composition may be administered in the form of a powder in which a convenient solvent is added before use to restore the original consistency, including sterile, pyrogen-free water, a buffer, a dextrose solution, etc. To this end, the active compound (s) can be dried using any known technology, such as lyophilization, and returned to its previous form before use.

For use through the mucous membrane in the composition, wetting agents are used that correspond to the existing biological barrier. Such substances are known in the literature.

For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, lozenges, tablets or capsules prepared by conventional methods using pharmaceutically acceptable excipients, such as binders (for example, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or quartz); disintegrants (e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulfate). Tablets can be coated using well-known methods with substances such as, for example, sugars, films or enteric coatings.

Liquid preparations for internal use may take the form of, for example, elixirs, solutions, syrups or suspensions, or may be supplied as a dry product, which is dissolved in water or another convenient solvent before use. Such liquid preparations can be prepared by conventional methods using pharmaceutically acceptable additives, such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or gum); anhydrous solvents (for example, almond oil, oily esters, ethyl alcohol, cremophor ™ or fractionated vegetable oils); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). If necessary, the preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening substances.

As is well known, preparations for internal use can be conveniently prepared to obtain a controlled release of the active compound or prodrug.

For buccal administration, the formulations may be shaped into tablets or lozenges formulated in a conventional manner.

For rectal or vaginal administration, the active compound (s) can be prepared in the form of solutions (for holding enemas), suppositories (suppositories), or ointments containing a suppository base such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation or injection, the active compound (s) or prodrug (s) may conveniently be supplied as aerosols for spraying from pressurized cans or a nebulizer using a convenient compressed liquid, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons carbon dioxide or other suitable gas. If aerosols are used under pressure, the dosage can be determined using a valve to dispense a measured amount of the drug. Capsules and sprays used in an inhaler or blower (for example, capsules and sprays consisting of gelatin) may be formulated to contain a powder mixture of a drug compound and a convenient powder base such as lactose or starch.

A specific example of an aqueous suspension suitable for intranasal administration using commercially available aerosol intranasal devices includes the following ingredients: active compound or prodrug (0.5-20 mg / ml); benzalkonium chloride (0.1-0.2 mg / ml); polysorbate 80 (polyoxyethylene fatty acid ester) (TWEEN® 80; 0.5-5 mg / ml); sodium carboxymethyl cellulose or microcrystalline cellulose (1-15 mg / ml); phenylethanol (1-4 mg / ml) and dextrose (20-50 mg / ml). The pH of the final suspension can be adjusted in the range of about pH 5 to pH 7 at a typical pH of 5.5.

Another specific example of an aqueous suspension suitable for administration of compounds by inhalation, and in particular for such administration of a compound of the present invention, contains 1-20 mg / ml of a compound or prodrug, 0.1-1% (v / v) polysorbate 80 (TWEEN®80), 50 mM citrate and / or 0.9% sodium chloride.

For ophthalmic use, the active compound (s) or prodrug (s) may be formulated as a solution, emulsion, suspension, etc., suitable for ophthalmic use. Many solvents are known in the literature that are convenient for use with compounds used as ophthalmic agents. Specific non-limiting examples are described in US Pat. Nos. 6,261,547; 6197934; 6,056,950; 5,800,807; 5776445; 5,698,219; 5,521,222; 5403841; 5077033; 4882150 and 4738851.

For sustained delivery, the active compound (s) or prodrug (s) may be formulated as a delayed absorption preparation by implantation or intramuscular injection. The active ingredient can be prepared using suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil), or ion exchange resins, or sparingly soluble derivatives, for example sparingly soluble salts. Alternatively, transdermal delivery systems, such as an adhesive disk or sticker, that slowly release the active compound (s) for subcutaneous absorption may be used. To this end, penetration stimulants can be used to improve subcutaneous absorption of the active compound (s). Convenient transdermal patches are described, for example, in US Pat. Nos. 5,407,713; 5352456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5087240; 5008110 and 4921475.

Alternatively, other drug delivery systems may be used. Liposomes and emulsions are well known examples of carrier solvents that can be used to deliver the active compound (s) or prodrug (s). Certain organic solvents may also be used, such as dimethyl sulfoxide (DMSO), although this usually leads to higher toxicity.

Pharmaceutical compositions, if necessary, can be presented in the form of a package or dispensing device, which may contain one or more dosage forms with the active compound (s). This package may contain, for example, metal or plastic foil, such as a blister pack. The packaging or dispenser may be accompanied by instructions for use.

6.6 Effective Dosages

The active compound (s) or prodrug (s) of the present invention or their compositions will generally be used in amounts effective to achieve the intended results, for example, in an amount effective to treat or prevent a particular disease. The compound (s) may be administered therapeutically to achieve a therapeutic result or prophylactically to achieve a prophylactic result. The therapeutic result means the elimination or reduction of the underlying disorder being treated and / or the elimination or alleviation of one or more symptoms associated with the underlying disorder to such an extent that the patient feels an improvement in well-being or condition, even if he continues to suffer from this disorder . For example, administering the active compound to a patient suffering from an allergy provides a therapeutic result not only when the main allergic reaction is eliminated or weakened, but also when the patient experiences a weakening severity or duration of allergy symptoms as a result of exposure to the allergen. As another example, a therapeutic outcome in the case of asthma includes improving breathing after an asthmatic attack or reducing the frequency or severity of asthmatic episodes. The therapeutic outcome also includes a pause or slowdown in the development of the disease, regardless of whether an improvement has occurred.

For prophylactic administration, the compound may be prescribed to a patient at risk of developing one of the previously described diseases. For example, if it is not known whether the patient is prone to an allergic reaction to a particular drug, the compound may be administered prior to prescribing the drug to avoid or reduce the allergic reaction to that drug. Alternatively, prophylactic administration may be used to avoid the patient having symptoms associated with the underlying disorder. For example, a compound may be administered to an allergy sufferer prior to anticipated exposure to an allergen. The compounds can also be prophylactically prescribed to healthy people who are repeatedly exposed to agents associated with one of the above diseases in order to avoid the onset of the disorder. For example, a compound may be administered to a healthy person who is repeatedly exposed to an allergen known for its ability to cause allergies such as latex, with the intention of preventing the development of allergies in that person. Alternatively, the compound may be administered to a patient suffering from asthma prior to engaging in an activity that causes asthmatic attacks in order to reduce their severity or to completely avoid the occurrence of asthmatic episodes.

The amount of compound prescribed depends on many factors, including, for example, specific indicators, method of use, whether the treatment is prophylactic or therapeutic, the severity of the disease, as well as the age and weight of the patient, bioaccumulation of the specific active compound, etc. The accuracy of determining the effective dose is easily determined by a specialist.

Effective doses can initially be estimated using in vitro samples. For example, an initial dose for animals can be formulated so that the concentration of the active compound circulating in the blood or serum is the same or higher than the IC ₅₀ value for a particular compound in accordance with the results of an in vitro sample, such as, for example, in vitro CHMC or BMMC, as well as in other in vitro samples described in the Examples section. The accuracy of the dosage calculation to achieve such circulating concentrations in the blood or serum, taking into account the bioaccumulation of a particular compound, is easily determined by an experienced physician. For further information, the reader can consult the source: Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics , Chapter 1, pp. 1-46, latest edition, Pagamonon Press, as well as the links in this book.

Initial doses can also be estimated from in vivo analysis using, for example, experimental animal models. Experimental animal models used to test the effects of compounds for the treatment or prophylaxis of the various diseases described above are well known in the literature. Useful animal models for investigating hypersensitivity or allergic reactions are described in Foster, 1995, Allergy 50 (21 Suppl): 6-9, discussion 34-38, and Tumas et al. , 2001, J. Allergy Clin. Immunol. 107 (6): 1025-1033. Useful animal models for the study of allergic rhinitis are described in Szelenyi et al. 2000, Arzneimittelforschung 50 (11): 1037-42); Kawaguchi et al. 1994, Clin. Exp. Allergy 24 (3): 238-244) and Sugimoto et al. , 2000, Immunopharmacology 48 (1): 1-7. Useful animal models for the study of allergic conjunctivitis are described in: Carreras et al. 1993, Br. J. Ophthalmol. 77 (8): 509-514; Saiga et al. 1992, Ophthalmic Res. 24 (1): 45-50; and Kunert et al. , 2001, Invest. Ophthalmol. Vis Sci. 42 (11): 2483-2489. Useful animal models for studying systemic mastocytosis are described in: O'Keefe et al. , 1987, J. Vet. Intern. Med. 1 (2): 75-80 and Bean-Knudsen et al. 1989, Vet. Pathol. 26 (1): 90-92. Useful animal experimental models for investigating hyper-IgE syndrome are described in: Claman et al. 1990, Clin. Immunol. Immunopathol. 56 (1): 46-53. Useful animal experimental models for investigating B-cell lymphoma are described in: Hough et al. 1998, Proc. Natl. Acad. Sci. USA 95: 13853-13858 and Hakim et al. , 1996, J. Immunol. 157 (12): 5503-5511. Useful animal experimental models for investigating atopic disorders such as atopic dermatitis, atopic eczema, and atopic asthma are described in: Chan et al. , 2001, J. Invest. Dermatol. 117 (4): 977-983 and Suto et al. , 1999, Int. Arch. Allergy Immunol. 120 (Suppl 1): 70-75. Those of ordinary skill in the art can easily use this information to determine the dosage suitable for human administration. Additional useful experimental animal models are described in the Examples section.

Dose sizes can usually range from about 0.0001, or 0.001, or 0.01 mg / kg / day to about 100 mg / kg / day, but they can be more or less depending, among other factors, on activity compounds, its bioaccumulation, method of administration and various factors described above. Dose size and administration intervals may be individually adjusted to provide plasma levels of the compound (s) sufficient to maintain a therapeutic or prophylactic effect. For example, the compounds may be prescribed once a week, several times a week (for example, every other day), it is once a day or several times a day depending, inter alia, on the method of application, the specific indications of treatment and the decision of the prescribing physician . In cases of topical administration or selective administration, such as topical administration, the effective local concentration of the active compound (s) may not be related to the plasma concentration. Specialists in this field will be able to optimize the effective local dose, without resorting to experimental verification.

Preferably, the compound (s) have a therapeutic or prophylactic effect without causing significant toxicity. The toxicity of the compound (s) can be determined using standard pharmaceutical procedures. The relationship between toxic and therapeutic (or prophylactic) dose effects is the therapeutic index of the drug. Preference should be given to the compound (s) with high therapeutic indices.

In addition to the description of the invention, the following examples are provided illustrating its effect, but not limiting its use.

EXAMPLES

7.1 Compounds of 2,4-pyrimidinediamine

A large number of N4-substituted-N2-monosubstituted-4-pyrimidinediamines were prepared using the methods described in this text. These compounds are shown in table 1.

7.2 The 2,4-pyrimidinediamine compounds of the present invention inhibit FcεRI receptor mediated degranulation

The ability of the 2,4-pyrimidinediamine compounds of the present invention to inhibit IgE-induced degranulation has been demonstrated by various cell assays on cultured human mast cells (CHMC) and / or cells derived from mouse bone marrow (BMMC). Inhibition of degranulation was measured both at low and at high cell population densities using quantitative analysis of the isolation of granule-specific factors: tryptase, histamine, and hexosaminidase. Inhibition of the release and / or synthesis of lipid mediators was evaluated by measuring the release of leukotriene LTC4, and inhibition of the release and / or synthesis of cytokines was observed by quantitative analysis of TNF-α, IL-6 and IL-13; quantitative analysis of tryptase and hexosaminidase was performed using fluorogenic substrates in accordance with the description given in specific examples. Quantification of histamine, TNFα, IL-6, IL-13, and LTC4 was performed using the following commercial ELISA kits: histamine (Immunotech supplier, catalog No. 2015, Beckman Coulter), TNFα (Biosource supplier, catalog No. KHC3011), IL-6 (supplier "Biosource", catalog number KMC0061), IL-13 (supplier "Biosource", catalog number KHC0132) and LTC4 (supplier "Cayman Chemical", catalog number 520211). The protocols for the various analyzes are given below.

7.2.1 Cultivation of human mastocytes and basophils

Human mast cells and basophils were cultured from CD34-negative progenitor cells as described below (see also the methods set forth in U.S. Patent Application Serial No. 10/053355, filed November 8, 2001, which are described in the text of this document by reference).

7.2.1.1 Preparation of a complete culture medium STEMPRO-34

To prepare complete culture medium (CM), STEMPRO-34, 250 ml of STEMPRO-34 ™ serum-free medium (SFM) (supplier company: GibcoBRL, catalog No. 10640) was placed in a filter flask. To the same flask was added 13 ml of the STEMPRO-34 Nutrient Supplement (NS) (supplier company: GibcoBRL, catalog No. 10641) (the preparation process is described in more detail below). The nutritional supplement vessel was rinsed with approximately 10 ml of serum-free medium (SFM) and added to the flask for filtration. After adding 5 ml of L-glutamine (200 mM; supplier company: Mediatech, catalog number MT 25-005-CI) and 5 ml of 100X penicillin / streptomycin (“pen-strep”; HyClone supplier company, catalog number SV30010), the volume was adjusted to 500 ml by the addition of serum-free medium (SFM) and the solution was filtered.

The largest number of variables in the preparation of a complete nutrient medium (CM) contains the method by which the nutrient supplement (NS) is thawed and mixed before being introduced into serum-free medium (SFM). Defrosting a nutritional supplement (NS) must be done in a water bath at 37 ° C with circular stirring without swirling or shaking until completely dissolved. When mixing, it is necessary to monitor whether insoluble lipids remain. If there are any and the solution is not homogeneous, it is necessary to place the additive in the water bath again and continue the mixing process until a homogeneous solution is obtained. Sometimes this component dissolves immediately, sometimes after one or two cycles of mixing, and sometimes it does not dissolve at all. If after one or two hours the nutritional supplement does not change to a uniform solution, it should be discarded and a new one thawed. Do not use NS Nutritional Supplement, which is not uniform after defrosting.

7.2.1.2 Increase in CD34 + cell population

The initial and rather small population of CD34-positive (or CD34 +) cells (1-5 × l0 ⁶ cells) was increased to a relatively high number of CD34-negative progenitor cells (about 2-4 × l0 ⁹ cells) using a nutrient medium and methodology, described below. CD34 + cells (from a single donor) were supplied by Allcells (Berkeley, CA). Due to a certain degree of variation in terms of quality and quantity of CD34 + cells commonly supplied by this company, the resulting cell cultures were placed in a 15 ml conical tube and brought to a volume of 10 ml in complete culture medium before use.

On day 0, viable (refractile) cells were counted, which were then placed in a centrifuge and rotated at a speed of 1200 rpm to pelletize. After this, the cells were re-transferred to a suspension with a density of 275,000 cells / ml in complete culture medium (CM) containing 200 ng / ml recombinant human stem cell factor (SCF) (supplier company: Peprotech, catalog No. 300-07) and 20 ng / ml human flt-3 ligand (supplier company: Peprotech, catalog No. 300-19) (“CM / SCF / flt-3 medium”). On approximately the fourth or fifth day, the culture density was checked by cell counting and the culture was diluted to a density of 275,000 cells / ml with fresh CM / SCF / flt-3 medium. On approximately the seventh day, the culture was transferred into a sterile tube and cell counts were performed. Cells were centrifuged at 1200 rpm and re-suspended in a density of 275,000 cells / ml in fresh CM / SCF / flt-3 medium.

This cycle was repeated starting from day 0, a total of 3 to 5 times during the period of increase in population.

If it is necessary to re-suspend a large number of cultures contained in several flasks, the contents of all flasks were combined in one vessel before cell counting. Thus, they ensured the accuracy of cell counting, as well as a unified approach to the entire population. Before combining the contents, the flask was examined under a microscope for contamination in order to prevent possible contamination of the entire population.

Between the 17th and 24th day, the deterioration of the state of the culture is possible ( i.e., 5 to 10% of the total number of cells die) and the population growth slows down. During this period, cells are monitored daily, because in just a day the culture can completely die. After the onset of its deterioration, the cells are counted, centrifuged at 850 rpm for 15 minutes and re-suspended in a density of 350,000 cells / ml in a complete CM / SCF / flt-3 medium in order to obtain another or two divisions of culture. The cells are monitored daily in order to prevent the death of the culture.

When the percentage of cell death in the culture of the progenitor cells exceeds 15% and a certain amount of degradation products is observed in the culture, CD34-negative progenitor cells are ready for differentiation.

7.2.1.3 Differentiation of CD34-negative progenitor cells into mucosal mast cells

The second phase is performed to convert the grown CD34-negative progenitor cells into differentiated mucosal mast cells. These mucous cultured human mast cells (“CHMS”) are obtained from CD34 + cells isolated from cord blood and processed to produce a large population of CD34-negative progenitor cells, as described above. To obtain CD43-negative progenitor cells, the culture suspension re-cycle was identical to the above, except that the culture was seeded at a density of 425,000 cells / ml and about 15% of the additional nutrient medium was added on the fourth or fifth day without cell counting. In addition, the cytokine composition of the medium was changed so that it contained stem cell factor (200 ng / ml) and the human recombinant IL-6 (200 ng / ml; supplier: Peprotech, catalog No. 200-06), reduced to 100 μm / ml in sterile acetic acid (10 mM) (“CM / SCF / IL-6 medium”).

Phases I and II take about 5 weeks in duration. Cell death and the presence of decomposition products in the culture are visible during the first to third week; in addition, from the second to the fifth week there is a period during which some part of the culture is no longer in suspension, but attached to the surface of the vessel in which the culture is grown.

As during phase I, if necessary, re-suspension of the culture on the seventh day of each cycle, the contents of all flasks were combined in one vessel before counting the cells to ensure uniformity of the entire population. Each flask was pre-checked under a microscope in order to identify contaminants and prevent contamination of the entire population.

When combining the contents of the flasks, approximately 75% of the volume of the flask was poured into a common vessel, leaving about 10 ml in the flask. Then, the flask with the remaining liquid was tapped abruptly in the transverse direction in order to release the cells adhering to the surface. Repeated tapping was carried out at right angles to the first in order to finally move the cells from the place.

Before pouring the remaining liquid into the vessel for counting, the flask was tilted at an angle of 45 degrees for several minutes. Before plating in a volume of 35-50 ml per flask (at a density of 425,000 cells / ml), the cells were centrifuged at 950 rpm for 15 minutes.

7.2.1.4 Differentiation of CD34-negative progenitor cells into connective tissue mast cells

An increased population of CD34-negative progenitor cells was prepared according to the above method and processed to obtain a tryptase / chymase-positive phenotype (connective tissue). In this case, methods similar to those described above for mast cells of the mucous membranes were used, with the exception of adding IL-4 instead of IL-6 to the culture medium. The resulting cells are typical for connective tissue mast cells.

7.2.1.5 Differentiation of CD34-negative progenitor cells into basophils

A multiplied population of CD34-negative progenitor cells was prepared according to the procedure described in section 7.2.1.3 above and used to form an increased basophil population. CD34-negative cells were processed according to a method similar to that described above for mucosal mast cells, except for the addition of IL-3 (20-50 ng / ml) instead of IL-6 in the culture medium.

7.2.2 Activation of CHMC (Cultured Human Mastocytes) Using IgE at Low Cell Density: Tryptase and LTC4 Assays

65 μl of solutions of the prepared compounds or control samples prepared in MT [137 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl _2, 1.0 mM MgCl ₂ , are added to two 96-well round-bottom plates (Costar 3799 model) 5.6 mM glucose, 20 mM Hepes (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid) (pH 7.4), 0.1% bovine serum albumin, (Sigma A4503)], containing 2% MeOH and 1% DMSO. This is followed by the process of pelletizing CHMC cells in a centrifuge (980 rpm, 10 min) and re-suspension in a pre-heated MT medium. Next, 65 μl of cells are poured into each 96-well round-bottom plate. Depending on the degranulation activity of each of the individual CHMC donors, 1000-1500 cells are placed in each well. It is stirred four times, followed by incubation for 1 hour at a temperature of 37 ° C. A solution of 6X anti-IgE [rabbit anti-human IgE rabbit immunoglobulin (1 mg / ml, supplier: Bethyl Laboratories, catalog No. A80-109A) diluted in a ratio of 1: 167 in MT buffer solution was prepared within 1 hour of incubation time] . Cells are stimulated by adding 25 μl of a 6X anti-IgE solution to the appropriate plates. 25 μl of MT was added to control tubes not subject to stimulation. After adding anti-IgE, mix twice. Incubated at 37 ° C for 30 minutes. During a 30-minute incubation, a solution of 20 mM broth with tryptase substrate was diluted [(Z-Ala-Lys-Arg-AMC · 2TFUK; Enzyme Systems Products, # AMC-246)] 1: 2000 in a buffer solution for quantitative tryptase analysis [0 , 1 M Hepes (pH 7.5), 10% w / v. glycerol, 10 μM heparin (Sigma H-4898) 0.01% NaN ₃ ]. The tablets are centrifuged at 1000 rpm for 10 minutes to pelletize the cells. Transfer 25 μl of the supernatant to a 96-well black-bottom plate and add 100 μl of a freshly diluted tryptase substrate solution to each well. Incubated for 30 minutes at room temperature. Using a spectrophotometer to read the tablets, the optical density of the tablets is determined at 355 nm / 460 nm.

Quantitative analysis of leukotriene C4 (LTC4) is also carried out using ELISA kits on properly diluted samples of the supernatant (determined empirically for the cell population of each donor so that the sample measurements are within the standard curve) in accordance with the manufacturer's instructions.

7.2.3 Activation of CHMC with IgE at high cell density: degranulation assays (tryptase, histamine), leukotriene (LTC4) and cytokine (TNFalpha, IL-13)

Cultured human mast cells (CHMCs) are sensitized for 5 days using IL-4 (20 ng / ml), stem cell factor (200 ng / ml), IL-6 (200 ng / ml) and human IgE CP 1035K (company- supplier: Cortx Biochem, 100-500 ng / ml, depending on generation) in conditioned medium (CM). After sensitization, the cells are counted, centrifuged (1000 rpm, 5-10 minutes) and re-turned into a suspension with a density of 1-2 × 10 ⁶ cells / ml in MT buffer solution. Add 100 μl of cell suspension to each well and 100 μl of solutions of the prepared formulations. The final concentration of the medium is 0.5% DMSO. Incubated at 37 ° C (5% CO ₂ ) for 1 hour. After an hour of treatment with reagents, cells stimulate 6X anti-IgE. The tubes with cells are mixed and left plates for incubation at 37 ° C (5% CO ₂ ) for one hour. After incubation for an hour, the cells are centrifuged (10 minutes, 1000 rpm) and 200 μl of the supernatant are taken from each tube, being careful not to touch the pellet. The supernatant tablet is placed on ice. When performing the 7-hour stage (see below), tryptase activity of the supernatant diluted 1: 500 is determined, the cells are resuspended in 240 μl of CM medium,

containing 0.5% DMSO and the corresponding concentration of the compound. CHMC cells are incubated for 7 hours at 37 ° C (5% CO ₂ ). After incubation, the cells are centrifuged (1000 rpm, 10 minutes), 225 μl are taken from each tube and stored at -80 ° C until ELISA analyzes. ELISA is carried out on properly diluted samples (determined empirically for the cell population of each of the donors so that the measurements of the samples are within the standard curve) in accordance with the manufacturer's instructions.

7.2.4 Results

The results of the analysis of low density CHMC populations are shown in Table 1. All values in Table 1 are expressed in IC ₅₀ (in μM). Most of the analyzed compounds had IC ₅₀ values of less than 10 μM, and in many IC ₅₀ values were observed in the submicromolar range. All values in table 1 are expressed in IC ₅₀ (in μM). The sign “-” means that the IC ₅₀ > 10 μm in the absence of any exposure at a concentration of 10 μm, which could be measured. Most of the analyzed compounds had IC ₅₀ values of less than 10 μM, and in many IC ₅₀ values were observed in the submicromolar range. The “+” sign means that

IC ₅₀ <10 μM. Of the compounds analyzed, the values for BMMC were comparable to those observed in the case of CHMC.

7.3 Selective Inhibition of Compounds of 2,4-Pyrimidinediamine According to the Invention of an Inverse IgE Receptor Cascade

To confirm that many of the 2,4-pyrimidinediamine compounds of the invention exhibit their inhibitory ability by blocking or inhibiting the transmission cascade of the initial IgE receptor signals, some of the compounds were tested by ionomycin-induced degranulation method of cell analysis as described below .

7.3.1 Activation of low density CHMC by ionomycin, tryptase assay

Ionomycin-induced mast cell degranulation analysis was performed similarly to the low-density IgE CHMC activation analysis (Section 7.2.2, above ), except that a 6X ionomycin solution [5 mM ionomycin (Signma I-0634) was prepared for 1 hour during incubation. in MeOH (stock solution), diluted 1: 416.7 in MT buffer (final concentration 2 μM)] and cells were stimulated by adding 25 μl of 6X ionomycin solution to the appropriate plates.

7.3.2 Results

The results of ionomycin-induced degranulation assays, presented as IC ₅₀ values (in μM), are shown in Table 1. Of the analyzed active compounds (ie, those that inhibit IgE immunoglobulin-induced degranulation), a significant majority do not inhibit degranulation-induced ionomycin, which confirms the selective inhibition by these active compounds of the cascade of transmission of early (or reverse) IgE receptor signals. In table 1, all values presented are IC ₅₀ (in μM). The sign “-” means that the IC ₅₀ > 10 μm in the absence of any exposure at a concentration of 10 μm, which could be measured. The “+” sign means that IC ₅₀ <10 μM.

7.4 Inhibition of Syk kinase by 2,4-pyrimidinediamine compounds during biochemical analyzes

A number of 2,4-pyrimidinediamine compounds were analyzed to determine the ability to inhibit the phosphorylation of the peptide substrate catalyzed by Syk kinase by biochemical analysis of fluorescence polarization with isolated Syk kinase. In this experiment, the compounds were diluted to 1% DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM MgCl ₂ , 2 mM MnCl ₂ , 1 mM dithiothreitol (DTT), 0.1 mg / ml acetylated bovine gamma globulin ) The compound in 1% DMSO (0.2% DMSO finally) was mixed with adenosine triphosphate / substrate solution at room temperature. Syk kinase (Upstate, Lake Placid NY) was added to the final reaction volume, 20 μl, and the reaction was incubated for 30 minutes at room temperature. Final enzyme reaction conditions: 20 mM HEPES, pH 7.4, 5 mM

MgCl ₂ , 2 mM MnCl ₂ , 1 mM DTT, 0.1 mg / ml acetylated bovine gamma globulin, 0.125 ng Syk kinase, 4 μm ATP (adenosine triphosphate), 2.5 μM peptide substrate (Biotin-EQEDEPEGDYEEVLE-CONH2, supplier: SynPep Corporation). EDTA (10 mM final concentration) / anti-phosphotyrosine antibody (1X final) / phosphopeptide fluorescent label (0.5X final) was added to the phosphopeptide buffer solution to terminate the reaction and obtain a total volume of 40 μl according to the manufacturer's instructions (company Pan Vera Corporation). The plate was incubated for 30 minutes in the dark at room temperature. The tablets were read on a fluorescence polarization apparatus for Tecan tablets "Polarion" (Polarion). Data was recalculated according to the amount of phosphopeptide available on a calibration curve obtained by competing with a competitor of the phosphopeptide provided in the tyrosine kinase assay kit (green) (supplier: Pan Vera Corporation).

These data, shown in table 1, show that most of the studied drugs inhibit the phosphorylation of Syk kinase with IC ₅₀ values in the submicromolar range. The vast majority of the compounds studied inhibit the phosphorylation of Syk kinase with IC ₅₀ values in the micromolar range. In table 1, all values presented are IC ₅₀ (in μM). The sign “-” means that the IC ₅₀ > 10 μm in the absence of any exposure at a concentration of 10 μm, which could be measured. The “+” sign means that IC ₅₀ <10 μM.

Table 1 room
conn. Connection Name physical characteristics LD Tryptase, CHMC, IgE, 3pt LD
Tryptase, CHMC, IgE, 8pt LD
Tryptase, CHMC, Iono, 3pt fp_syk,
11pt 200 (S) -5-Fluoro-N2- (indazol-6-yl) -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4- pyrimidinediamine ¹ H NMR ¹ (DMSO-d6): d 8.08 (d, 1H), 7.95 (s, 1H), 7.58 (d, 1H), 7.40 (m, 1H), 7.25 (m, 3H), 6.94 (m, 1H), 4.80 (m, 1H), 1.40 (s, 3H); LC ² / MS ³ : purity: 96%; MS (mass / charge): 406 (MH +). + 201 (S) -5-Fluoro-N2- (1-methylindazol-6-yl) -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2, 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.17 (d, 1H), 8.08 (s, 1H), 7.80 (s, 1H), 7.52 (m, 1H), 7.32 ( m, 1H), 7.17 (m, 2H), 6.94 (m, 1H), 4.60 (m, 1H), 3.77 (s, 3H), 1.45 (s, 3H); LC / MS: purity: 94%; MS (mass / charge): 420 (MH +). + 202 (S) -N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.01 (d, 1H), 7.28 (m, 2H), 7.20 (s, 2H), 6.95 (m, 1H), 6.58 ( s, 1H), 4.63 (m, 1H), 3.77 (s, 3H), 2.07 (s, 6H), 1.42 (d, 3H); LC / MS: purity: 92%; MS (mass / charge): 393 (MH +). + 203 N4- (3,4-Dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.02 (d, 1H), 6.98 (m, 2H), 6.90 (m, 2H), 6.80 (m, 1H), 6.03 ( s, 1H), 3.72 (s, 2H), 3.60 (s, 6H), 1.05 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 425 (MH +). + + 204 (R) -N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.01 (d, 1H), 7.28 (m, 2H), 7.20 (s, 2H), 6.95 (m, 1H), 6.58 ( s, 1H), 4.63 (m, 1H), 3.77 (s, 3H), 2.07 (s, 6H), 1.42 (d, 3H); LC / MS: purity: 92%; MS (mass / charge): 393 (MH +). + 205 (R) -5-Fluoro-N2- [6- (2-hydroxyethyl) -2,3-dihydropyrrolo [1,2,3-d, e] benzoxazin-8-yl] -N4- (2-methyl-3 -oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (MeOD-d4): d 7.75 (d, 1H), 7.38 (m, 1H), 7.02 (m, 3H), 6.78 (m, 2H), 4.54 ( m, 1H), 4.4 (m, 2H), 4.14 (m, 2H), 3.62 (m, 2H), 3.62 (m, 2H), 2.80 (m, 2H), 1.41 (d, 3H); LC / MS: purity: 93%; MS (mass / charge): 491 (MH +). + 206 N4- (3,4-Dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [6- (2-hydroxyethyl) -2.3 -dihydropyrrolo [1,2,3-d, e] benzoxazin-8-yl] -2,4-pyrimidinediamine ¹ H NMR (MeOD-d4): d 7.62 (d, 1H), 7.04 (s, 1H), 6.98 (m, 2H), 6.75 (m, 1H), 6.59 ( m, 2H), 4.47 (m, 1H), 4.4 (m, 2H), 4.14 (m, 2H), 3.62 (m, 4H), 2.80 (m, 2H), 1.07 (s, 6H); LC / MS: purity: 98%; MS (mass / charge): 491 (MH +). + 207 (R) -N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2, 4-pyrimidinediamine salt of benzenesulfonic acid ¹ H NMR (MeOD-d4): d 7.98 (d, 1H), 7.82 (m, 2H), 7.48 (s, 1H), 7.41 (m, 3H), 7.25 ( dd, 1H), 7.15 (m, 3H), 6.94 (d, 1H), 4.62 (q, 1H), 3.82 (s, 3H), 1.50 (d, 3H) ; LC / MS: purity: 97%; MS (mass / charge): 430 (MH +). + 208 (R) -N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2, 4-pyrimidinediamine salt of methanesulfonic acid ¹ H NMR (MeOD-d4): d 7.98 (d, 1H), 7.48 (s, 1H), 7.25 (dd, 1H), 7.15 (m, 3H), 6.94 ( d, 1H), 4.62 (q, 1H), 3.82 (s, 3H), 2.68 (s, 3H), 1.50 (d, 3H); LC / MS: purity: 98%; MS (mass / charge): 430 (MH +). + 209 (R) -N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2, 4-pyrimidinediamine salt (1S) - (+) - camphorsulfonic acid ¹ H NMR (DMSO-d6): d 8.19 (d, 1H), 7.62 (m, 1H), 7.38 (m, 1H), 7.21 (m, 1H), 7.12 ( m, 2H), 6.91 (d, 1H), 4.62 (q, 1H), 3.82 (s, 3H), 3.40 (q, 1H), 2.91 (m, 1H ), 2.61 (m, 1H), 2.38 (m, 1H), 2.22 (m, 1H), 1.85 (m, 2H), 1.40 (d, 3H), 1.31 (m, 2H), 1.03 (s, 3H), 0.77 (s, 3H); LC / MS: purity: 97%; MS (mass / charge): 430 (MH +). + 210 (R) -5-Fluoro-N2- (1-methylindazol-6-yl) -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2, 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.16 (d, 1H), 8.08 (s, 1H), 7.80 (s, 1H), 7.52 (m, 1H), 7.32 ( m, 1H), 7.17 (m, 2H), 6.94 (m, 1H), 4.60 (m, 1H), 3.77 (s, 3H), 1.45 (s, 3H); LC / MS: purity: 97%; MS (mass / charge): 420 (MH +). + 211 (R) -N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2, 4-pyrimidinediamine hydrochloride salt ¹ H NMR (DMSO-d6): d 8.12 (d, 1H), 7.41 (dd, 1H), 7.22 (m, 3H), 6.97 (m, 1H), 4.61 ( q, 1H), 3.78 (s, 3H), 1.40 (d, 3H); LC / MS: purity: 97%; MS (mass / charge): 430 (MH +). + + 212 (R) -N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2, 4-pyrimidinediamine salt (1R) - (-) - camphorsulfonic acid ¹ H NMR (DMSO-d6): d 8.19 (d, 1H), 7.62 (m, 1H), 7.38 (m, 1H), 7.21 (m, 1H), 7.12 ( m, 2H), 6.91 (d, 1H), 4.62 (q, 1H), 3.82 (s, 3H), 3.40 (q, 1H), 2.91 (m, 1H ), 2.61 (m, 1H), 2.38 (m, 1H), 2.22 (m, 1H), 1.85 (m, 2H), 1.40 (d, 3H), 1.31 (m, 2H), 1.03 (s, 3H), 0.77 (s, 3H); LC / MS: purity: 98%; MS (mass / charge): 430 (MH +). + + 213 (R) -N2- (3-Chloro-4-methoxy-6-methylphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl ) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.17 (s, 1H), 7.98 (d, 1H), 7.43 (m, 1H), 7.32 (m, 1H), 7.15 ( s, 1H), 6.95 (s, 1H), 6.72 (d, 1H), 4.58 (m, 1H), 3.90 (s, 3H), 2.17 (s, 3H), 1.38 (d, 3H); LC / MS: purity: 97%; MS (mass / charge): 444 (MH +). + + 214 (S) -N2- (3-Chloro-4-methoxy-6-methylphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl ) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.17 (s, 1H), 7.98 (d, 1H), 7.43 (m, 1H), 7.32 (m, 1H), 7.15 ( s, 1H), 6.95 (s, 1H), 6.72 (d, 1H), 4.58 (m, 1H), 3.90 (s, 3H), 2.17 (s, 3H), 1.38 (d, 3H); LC / MS: purity: 99%; MS (mass / charge): 444 (MH +). + + - 215 (S) - (3-Chloro-4,6-dimethoxyphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2, 4-pyrimidinediamine 1H NMR (DMSO-d6): d 1.38 (d, 3H), 3.82 (s, 3H), 3.90 (s, 3H), 4.58 (q, 1H), 6.85 ( m, 2H), 7.19 (m, 1H), 7.37 (m, 1H), 7.43 (m, 1H), 7.59 (s, 1H), 8.17 (m, 2H) purity : 99%; MS (mass / charge): 460 (MH +). + + - 216 N2- (3-Chloro-4-methoxy-6-methylphenyl) -N4- (3,4-dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -5- fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.38 (s, 6H), 2.17 (s, 3H), 3.64 (s, 3H), 3.81 (s, 3H), 6.48 (m , 1H), 6.77 (m, 1H), 6.93 (m, 1H), 6.99 (m, 1H), 7.41 (s, 1H), 7.82 (d, 1H) purity: 99%; MS (mass / charge): 444 (MH +). + + - 217 N4- (3,4-Dihydro-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.19 (m, 1H), 8.15 (d, 1H), 7.78 (m, 1H), 7.39 (m, 2H), 6.90 ( m, 1H), 6.47 (m, 1H), 4.07 (m, 2H), 3.22 (m, 2H); LC / MS: purity: 97%; MS (mass / charge): 405 (MH +). + + - 218 N4- (3,4-Dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.18 (s, 6H), 3.81 (s, 2H), 6.77 (m, 1H), 6.93 (m, 1H), 6.99 (m , 1H), 7.38 (m, 2H), 7.63 (m, 1H), 7.71 (m, 1H), 8.12 (s, 1H), 8.22 (m, 2H) purity: 99%; MS (mass / charge): 433 (MH +). + + - 219 5-Fluoro-N2- [3- (oxazol-2-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 4.50 (s, 2H), 6.78 (m, 1H), 7.18 (m, 1H), 7.23 (m, 1H), 7.38 (m , 2H), 7.59 (m, 1H), 7.77 (m, 1H), 8.22 (m, 3H); purity: 99%; MS (mass / charge): 419 (MH +). + + - 220 5-Fluoro-N2- [3- (oxazol-2-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-7-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 4.50 (s, 2H), 6.78 (m, 1H), 7.18 (m, 1H), 7.23 (m, 1H), 7.41 (m , 2H), 7.59 (m, 1H), 7.78 (m, 1H), 8.22 (m, 3H); purity: 97%; MS (mass / charge): 419 (MH +). + + - 221 5-Fluoro-N4- [2- (2-hydroxyethyl) -3-oxo-2H, 4H-benz [1,4] oxazin-6-yl] -N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.98 (m, 1H), 3.58 (m, 2H), 6.78 (m, 1H), 7.18 (m, 1H), 7.38 (m , 3H), 7.57 (m, 1H), 7.79 (m, 1H), 8.22 (m, 2H); purity: 99%; MS (mass / charge): 463 (MH +). + + - 222 N4- (3,4-Dihydro-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.29 (m, 1H), 8.17 (d, 1H), 7.76 (m, 1H), 7.59 (m, 3H), 6.90 ( m, 1H), 6.77 (m, 1H), 6.62 (m, 1H), 4.07 (m, 2H), 3.22 (m, 2H); LC / MS: purity: 90%; MS (mass / charge): 405 (MH +). + + - 223 N4- (3,4-Dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.18 (s, 6H), 3.80 (s, 2H), 6.71 (m, 2H), 6.95 (m, 1H), 7.51 (s , 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H); purity: 95%; MS (mass / charge): 433 (MH +). + + - 224 5-Fluoro-N2- [4- (oxazol-5-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 4.68 (s, 2H), 6.98 (m, 2H), 7.22 (m, 1H), 7.51 (s, 1H), 7.57 (m , 2H), 7.78 (m, 2H), 8.28 (d, 1H), 8.38 (s, 1H); purity: 98%; MS (mass / charge): 419 (MH +). + + - 225 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [4- (oxazol-5-ylphenyl] -2 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.28 (s, 1H), 8.22 (d, 1H), 7.62 (m, 2H), 7.57 (m, 2H), 7.49 ( s, 1H), 7.25 (m, 2H), 6.98 (m, 1H), 4.62 (q, 1H), 1.42 (d, 3H); LC / MS: purity: 88%; MS (mass / charge): 433 (MH +). + + - 226 5-Fluoro-N2- [4- (oxazol-5-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-7-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 4.66 (s, 2H), 6.98 (m, 2H), 7.22 (m, 1H), 7.51 (s, 1H), 7.57 (m , 2H), 7.76 (m, 2H), 8.28 (d, 1H), 8.38 (s, 1H); purity: 92%; MS (mass / charge): 419 (MH +). + + - 227 5-Fluoro-N4- [2- (2-hydroxyethyl) -3-oxo-2H, 4H-benz [1,4] oxazin-6-yl] -N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), 6.98 (m, 2H), 7.22 (m , 2H), 7.51 (s, 1H), 7.57 (m, 2H), 7.76 (m, 2H), 8.28 (d, 1H), 8.38 (s, 1H) purity: 95%; MS (mass / charge): 463 (MH +). + + - 228 N4- (3,4-Dihydro-4-methyl-2H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.29 (s, 1H), 8.15 (d, 1H), 7.76 (m, 1H), 7.57 (m, 3H), 6.88 ( m, 1H), 6.77 (m, 1H), 6.62 (m, 1H), 4.10 (m, 2H), 3.20 (m, 2H), 2.80 (s, 3H); LC / MS: purity: 94%; MS (mass / charge): 419 (MH +). + + - 229 N4- (3,4-Dihydro-4-methyl-2H-benz [1,4] oxazin-7-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.37 (s, 1H), 8.19 (d, 1H), 7.61 (m, 5H), 7.07 (m, 2H), 6.68 ( m, 1H), 4.22 (m, 2H), 3.22 (m, 2H), 2.81 (s, 3H); LC / MS: purity: 94%; MS (mass / charge): 419 (MH +). + + - 230 5-Fluoro-N4- (4-methyl-3-oxo-2H-benz [1,4] oxazin-7-yl) -N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.36 (s, 1H), 8.20 (m, 1H), 8.19 (d, 1H), 7.77 (m, 2H), 7.54 ( m, 2H), 7.37 (s, 1H), 7.25 (m, 1H), 6.97 (m, 1H), 4.58 (s, 2H), 2.97 (s, 3H); LC / MS: purity: 98%; MS (mass / charge): 433 (MH +). - - - 231 5-Fluoro-N4- (4-methyl-3-oxo-2H-benz [1,4] oxazin-6-yl) -N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.34 (s, 1H), 8.20 (m, 1H), 8.17 (d, 1H), 7.71 (m, 2H), 7.54 ( m, 2H), 7.33 (s, 1H), 7.25 (m, 1H), 6.92 (m, 1H), 4.60 (s, 2H), 2.90 (s, 3H); LC / MS: purity: 95%; MS (mass / charge): 433 (MH +). - - - 232 N4- (3,4-Dihydro-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.39 (m, 1H), 8.22 (d, 1H), 7.86 (m, 1H), 7.59 (m, 4H), 6.87 ( m, 2H), 6.52 (m, 1H), 4.09 (m, 2H), 3.23 (m, 2H); LC / MS: purity: 90%; MS (mass / charge): 405 (MH +). + + - 233 N4- (3,4-Dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.37 (s, 1H), 8.19 (d, 1H), 7.82 (m, 1H), 7.63 (m, 2H), 7.50 ( s, 1H), 7.38 (m, 1H), 6.87 (m, 1H), 6.65 (m, 2H), 3.82 (s, 2H), 1.19 (s, 6H); LC / MS: purity: 95%; MS (mass / charge): 433 (MH +). + + - 234 5-Fluoro-N2- [3- (oxazol-5-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-7-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 4.42 (s, 2H), 6.61 (m, 2H), 6.95 (m, 1H), 7.51 (s, 1H), 7.49 (m , 2H), 7.59 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H); purity: 90%; MS (mass / charge): 419 (MH +). + + - 235 5-Fluoro-N4- [2- (2-hydroxyethyl) -3-oxo-2H, 4H-benz [1,4] oxazin-6-yl] -N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), 6.61 (m, 2H), 6.95 (m , 1H), 7.51 (s, 1H), 7.49 (m, 2H), 7.59 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H) purity: 90% MS (mass / charge): 463 (MH +). + + - 236 N4- (3,4-Dihydro-4-methyl-2H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4 pyrimidinediamine 1 H NMR (DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), 6.61 (m, 2H), 6.95 (m , 1H), 7.51 (s, 1H), 7.49 (m, 2H), 7.59 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H) purity: 95%; MS (mass / charge): 419 (MH +). + - 237 N4- (3,4-Dihydro-4-methyl-2H-benz [1,4] oxazin-7-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4 pyrimidinediamine 1 H NMR (DMSO-d6): d 1.93 (m, 2H), 2.82 (s, 3H), 3.58 (m, 2H), 4.62 (m, 1H), 6.61 (m , 2H), 6.95 (m, 1H), 7.51 (s, 1H), 7.49 (m, 2H), 7.59 (m, 2H), 8.20 (d, 1H), 8 38 (s, 1H) purity: 95%; MS (mass / charge): 419 (MH +). + - 238 N4- (3,4-Dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.38 (s, 6H), 3.81 (s, 2H), 6.71 (m, 2H), 6.95 (m, 1H), 7.51 (s , 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H); purity: 99%; MS (mass / charge): 433 (MH +). + + - 239 5-Fluoro-N2- [4- (oxazol-2-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.15 (d 1H), 8.10 (s, 1H), 7.78 (m, 3H), 7.14 (m, 3H), 6.97 (m , 2H); 4.56 (s, 2H); LC / MS: purity: 98%; MS (mass / charge): 419 (MH +). + + - 240 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.25 (m, 1H), 8.22 (d, 1H), 8.12 (m, 1H), 7.77 (m, 2H), 7.34 ( s, 1H), 7.23 (m, 2H), 6.98 (m, 2H), 4.63 (q, 1H), 1.42 (d, 3H); LC / MS: purity: 95%; MS (mass / charge): 433 (MH +). + + - 241 5-Fluoro-N2- [4- (oxazol-2-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-7-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 4.45 (s, 2H), 6.71 (m, 2H), 6.95 (m, 1H), 7.51 (s, 1H), 7.69 (m , 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H); purity: 95%; MS (mass / charge): 419 (MH +). - - 242 5-Fluoro-N4- [2- (2-hydroxyethyl) -3-oxo-2H, 4H-benz [1,4] oxazin-6-yl] -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.25 (d 1H), 8.20 (d, 1H), 8.16 (s, 1H), 7.82 (m, 3H), 7.35 (s , 1H), 7.20 (m, 2H), 6.95 (m, 1H), 4.62 (m, 1H), 3.58 (m, 1H), 1.95 (m, 2H); LC / MS: purity: 99%; MS (mass / charge): 463 (MH +). + + - 243 N4- (2,3-Dihydro-4-methyl-2H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-2-yl) phenyl] -2,4 pyrimidinediamine 1 H NMR (DMSO-d6): d 1.93 (m, 2H), 2.80 (s, 3H), 3.58 (m, 2H), 4.62 (m, 1H), 6.71 (m , 2H), 6.95 (m, 1H), 7.51 (s, 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8 38 (s, 1H) purity: 99%; MS (mass / charge): 419 (MH +). + + - 244 5-Fluoro-N4- (4-methyl-3-oxo-2H-benz [1,4] oxazin-7-yl) -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.18 (d, 1H), 8.14 (s, 1H), 7.82 (d, 2H), 7.56 (m, 2H), 7.40 ( m, 2H), 7.30 (s, 1H), 6.95 (m, 1H), 4.62 (s, 2H), 2.78 (s, 3H); LC / MS: purity: 99%; MS (mass / charge): 433 (MH +). - - 245 5-Fluoro-N4- (4-methyl-3-oxo-2H-benz [1,4] oxazin-6-yl) -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 8.20 (d, 1H), 8.12 (s, 1H), 7.82 (d, 2H), 7.55 (m, 2H), 7.40 ( m, 2H), 7.33 (s, 1H), 6.88 (m, 1H), 4.59 (s, 2H), 2.77 (s, 3H); LC / MS: purity: 98%; MS (mass / charge): 433 (MH +). - - 246 5-Fluoro-N2- [3- (oxazol-5-yl) phenyl] -N4- [3-oxo-2H, 4H-benz [1,4] oxazin-6-yl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 4.45 (s, 2H), 6.78 (m, 1H), 7.18 (m, 1H), 7.38 (m, 3H), 7.57 (m , 1H); 7.79 (m, 1H); 8.22 (m, 2H); purity: 93%; MS (mass / charge): 419 (MH +). + + - 247 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 1.38 (d, 3H), 4.58 (q, 1H), 6.78 (m, 1H), 7.18 (m, 1H), 7.38 ( m, 3H), 7.57 (m, 1H), 7.79 (m, 1H), 8.22 (m, 2H); purity: 90%; MS (mass / charge): 433 (MH +). + + - 248 5-Fluoro-N4- [2- (2-hydroxyethyl) -3-oxo-2H, 4H-benz [1,4] oxazin-7-yl] -N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), 6.88 (m, 2H), 7.22 (m , 3H), 7.57 (m, 2H), 7.79 (m, 2H), 8.22 (m, 2H); purity: 99%; MS (mass / charge): 463 (MH +). + + - 249 5-Fluoro-N4- [2- (2-hydroxyethyl) -3-oxo-2H, 4H-benz [1,4] oxazin-7-yl] -N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), 6.71 (m, 2H), 6.95 (m , 1H), 7.51 (s, 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H) purity: 99%; MS (mass / charge): 463 (MH +). + - - 250 (R) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [3- (oxazol-4-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): dd 1.38 (d, 3H), 4.58 (q, 1H), 6.88 (m, 1H), 7.22 (m, 4H), 7.57 ( m, 1H), 7.99 (m, 2H), 8.12 (m, 2H); purity: 95%; MS (mass / charge): 433 (MH +). + + + 251 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [3- (oxazol-4-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): dd 1.38 (d, 3H), 4.58 (q, 1H), 6.88 (m, 1H), 7.22 (m, 4H), 7.57 ( m, 1H), 7.99 (m, 2H), 8.12 (m, 2H); purity: 99%; MS (mass / charge): 433 (MH +). + + - 252 (R, S) -N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (tetrahydrofurano [2,3] -2H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.18 (s, 6H), 2.25 (m, 2H) 3.75 (t, 2H) 4.58 (q, 1H), 6.52 (d, 1H), 6.92 (dd, 2H), 7.37 (m, 3H), 8.12 (d, 1H); purity: 90%; MS (mass / charge): 406 (MH +). + 253 N4- [3,4-Dihydro-2- (2-hydroxyethyl) -2H, 4H-benz [1,4] oxazin-6-yl] -N2- (3,5-dimethoxyphenyl) -5-fluoro-2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.88 (m, 2H), 2.97 (m, 2H), 3.55 (m, 2H), 3.61 (s, 6H), 4.08 (q, ., 1H), 6.02 (m, 1H), 6.58 (d, 1H), 6.96 (m, 5H), 8.02 (d, 1H); purity: 96%; MS (mass / charge): 442 (MH +). + + - 254 5-Fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 2.62 (d, 3H), 3.32 (s, 2H), 4.37 (s, 2H), 6.60 (m, 1H), 7.22 (m , 3H), 7.37 (m, 1H), 7.43 (m, 1H), 8.02 (m, 1H), 8.22 (d, 1H); purity: 94%; MS (mass / charge): 455 (MH +). + + - 255 N4- [2,3-Dihydro-2- (2-hydroxyethyl) -2H, 4H-benz [1,4] oxazin-6-yl] -N2- (3,5-dimethylphenyl) -5-fluoro-2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.88 (m, 2H), 2.18 (s, 6H), 2.97 (m, 2H), 3.58 (m, 2H), 4.09 (q, ., 1H), 6.19 (m, 1H), 6.42 (m, 1H), 6.58 (m, 1H), 6.81 (m, 2H), 7.22 (s, 2H), 8.02 (d, 1H); purity: 97%; MS (mass / charge): 410 (MH +). + + - 256 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- (3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 3.37 (s, 2H), 3.61 (s, 6H), 6.18 (m, 1H), 6.75 (m, 2H), 7.22 (m , 2H), 7.43 (m, 1H), 8.22 (d, 1H); purity: 98%; MS (mass / charge): 428 (MH +). + + - 257 N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- (3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 3.47 (s, 2H), 3.88 (s, 3H), 7.08 (m, 1H), 7.25 (s, 2H), 7.42 (m , 2H); 7.78 (m, 1H); 8.22 (d, 1H); purity: 99%; MS (mass / charge): 432 (MH +). + + - 258 N4- (3,4-Dihydro-2H, 4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.67 (d, 3H), 3.32 (m, 2H), 4.30 (s, 2H), 4.37 (m, 2H), 6.45 (m , 1H), 6.88 (m, 1H), 6.96 (m, 2H), 7.13 (m, 1H), 7.23 (m, 2H), 8.02 (m, 2H) purity: 92%; MS (mass / charge): 441 (MH +). + + - 259 5-Fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (4-methyl-3-oxo-2H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.62 (d, 3H), 3.11 (s, 3H), 3.32 (s, 2H), 4.37 (s, 2H), 6.60 (m , 1H), 7.22 (m, 3H), 7.37 (m, 1H), 7.43 (m, 1H), 8.02 (m, 1H), 8.22 (d, 1H) purity: 95%; MS (mass / charge): 469 (MH +). + + - 260 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- (4-methyl-3-oxo-2H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 3.11 (s, 3H), 3.32 (s, 2H), 3.58 (s, 6H), 6.18 (m, 1H), 6.75 (m , 2H), 7.32 (m, 3H), 7.63 (m, 2H), 8.22 (d, 1H); purity: 98%; MS (mass / charge): 442 (MH +). + + - 261 N2- (3-Benzothioamide) -5-fluoro-N4- (3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 4.58 (s, 2H), 6.98 (m, 1H), 7.19 (m, 2H), 7.39 (m, 3H), 7.93 (m , 1H); 8.19 (d, 1H); purity: 90%; MS (mass / charge): 411 (MH +). + - 262 N2- (3-Benzothioamide) -5-fluoro-N4- [2- (2-hydroxyethyl) -3-oxo-2H, 4H-benz [1,4] oxazin-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): 1.91 (m, 2H), 3.54 (m, 2H), 4.63 (m, 1H), 6.98 (m, 1H), 7.19 (m, 2H), 7.39 (m, 3H), 7.93 (m, 1H), 8.19 (d, 1H); purity: 93%; MS (mass / charge): 455 (MH +). + - 263 N2- (3,5-Dimethoxyphenyl) -N4- (dioxide-2-methyl-1,1,3-trioxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-2,4- pyrimidinediamine 1 H NMR (DMSO-d6): d 1.42 (d, 3H), 3.63 (s, 6H), 4.69 (q, 1H), 6.14 (s, 1H), 6.92 ( m, 2H), 7.72 (s, 2H), 7.92 (m, 2H), 8.27 (d, 1H); purity: 99%; MS (mass / charge): 474 (MH +). + + 264 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4- pyrimidinediamine 1 H NMR (DMSO-d 6): d 1.42 (d, 3H), 2.18 (s, 6H), 4.72 (q, 1H), 6.64 (m, 1H), 7.21 ( m, 2H), 7.72 (s, 2H), 7.68 (m, 2H), 8.27 (d, 1H); purity: 99%; MS (mass / charge): 442 (MH +). + + 265 5-Fluoro-N2- (indazol-6-yl) -N4- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4- pyrimidinediamine 1 H NMR (DMSO-d6): d 1.42 (d, 3H), 4.79 (q, 1H), 7.23 (m, 1H), 7.60 (m, 1H), 7.77 ( m, 1H), 7.82 (m, 3H), 8.16 (m, 1H), 8.27 (d, 1H); purity: 94%; MS (mass / charge): 454 (MH +). + + 266 5-Fluoro-N4- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -N2- (3,4,5-trimethoxyphenyl) -2, 4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 1.42 (d, 3H), 3.66 (s, 9H), 4.70 (q, 1H), 7.04 (m, 2H), 7.72 ( s, 2H), 7.72 (m, 3H), 8.22 (d, 1H); purity: 96%; MS (mass / charge): 504 (MH +). + + 267 N2- (3,5-Dimethoxyphenyl) -N4- (2,2-dimethyl-1,1,3-trioxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-2,4- pyrimidinediamine LC / MS: retention time 12.32 min, purity: 100%; MS (mass / charge): 488 (MH ⁺ ) + 268 N2- (3,5-Dimethylphenyl) -N4- (2,2-dimethyl-1,1,3-trioxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-2,4- pyrimidinediamine LC / MS: retention time 13.35 min, purity: 99%; MS (mass / charge): 456 (MH +) + 269 N4- (2,2-Dimethyl-1,1,3-trioxo-4H-benzo [thiazin-6-yl) -5-fluoro-2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time 11.28 min, purity: 99%; MS (mass / charge): 518 (MH +) + 270 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 11.69 min, purity: 95%; MS (mass / charge): 442 (MH +) + 271 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 12.12 min, purity: 98%; MS (mass / charge): 410 (MH +) + 272 5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time 10.44 min, purity: 99%; MS (mass / charge): 472 (MH +) + 273 N4- (2,2-Dimethyl-1,1,3-trioxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- (indazol-6-yl) -2,4- pyrimidinediamine LC / MS: retention time 10.49 min, purity: 95%; MS (mass / charge): 468 (MH +) + 274 N4- (2,2-Dimethyl-1,1,3-trioxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- (indazol-5-yl) -2,4- pyrimidinediamine LC / MS: retention time 8.66 min, purity: 96%; MS (mass / charge): 468 (MH +) + 275 N4- (2,2-Dimethyl-1,1,3-trioxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2 4-pyrimidinediamine LC / MS: retention time 10.16 min, purity: 93%; MS (mass / charge): 515 (MH +) + 276 N2- (3-Chloro-4-methoxyphenyl) -N4- (2,2-dimethyl-1,1,3-trioxo-4H-benzo [thiazin-6-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time 12.66 min, purity: 99%; MS (mass / charge): 492 (MH +) + 277 5-Fluoro-N2- (indazol-6-yl) -N4- (2-methyl-3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 9.40 min, purity: 95%; MS (mass / charge): 422 (MH +) + 278 5-Fluoro-N2- (indazol-5-yl) -N4- (2-methyl-3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 8.23 min, purity: 98%; MS (mass / charge): 422 (MH +) + 279 5-Fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (2-methyl-3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 9.51 min, purity: 96%; MS (mass / charge): 469 (MH +) + 280 N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 11.77 min, purity: 97%; MS (mass / charge): 446 (MH +) + 281 5-Fluoro-N2- (3-hydroxyphenyl) -N4- (3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 8.18 min, purity: 99%; MS (mass / charge): 384 (MH +) + + 282 Racemic-5-fluoro-N2- (3-hydroxyphenyl) -N4- (2-methyl-3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 9.11 min, purity: 99%; MS (mass / charge): 398 (MH +) + 283 Racemic-N4- (2,2-dimethyl-1,1,3-trioxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- [3-hydroxyphenyl] -2,4- pyrimidinediamine LC / MS: retention time 9.89 min, purity: 99%; MS (mass / charge): 444 (MH +) + 284 Racemic-5-fluoro-N2- [3-hydroxyphenyl] -N4- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4- pyrimidinediamine LC / MS: retention time 9.33 min, purity: 97%; MS (mass / charge): 430 (MH +) + 285 Racemic-5-fluoro-N2- [3- (N-methylamine) carbonylmethyleneoxyphenyl] -N4- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 9.44 min, purity: 93%; MS (mass / charge): 501 (MH +) + 286 Racemic-N2- (3-chloro-4-methoxyphenyl) -5-fluoro-N4- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) - 2,4-pyrimidinediamine LC / MS: retention time 11.68 min, purity: 95%; MS (mass / charge): 478 (MH +) + 287 5-Fluoro-N4- (3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time 9.49 min, purity: 99%; MS (mass / charge): 458 (MH +) + 288 5-Fluoro-N2- (indazol-5-yl) -N4- (3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 7.28 min, purity: 98%; MS (mass / charge): 408 (MH +) + 289 N2- (3-Chloro-4-methoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-benzo [thiazin-6-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time 12.45 min, purity: 97%; MS (mass / charge): 460 (MH +) + 290 N2- (3,5-Dimethoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time 12.81 min, purity: 99%; MS (mass / charge): 456 (MH +) + 291 N4- (2,2-Dimethyl-3-oxo-4H-benzo [1,4] thiazin-6-yl) -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time 13.44 min, purity: 99%; MS (mass / charge): 424 (MH +) + 292 N4- (2,2-dimethyl-3-oxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time 11.86 min, purity: 99%; MS (mass / charge): 486 (MH +) + 293 N4- (2,2-Dimethyl-3-oxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- (3-hydroxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time 10.39 min, purity: 99%; MS (mass / charge): 412 (MH +) + 294 N4- (2,2-Dimethyl-3-oxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine LC / MS: retention time 10.04 min, purity: 97%; MS (mass / charge): 483 (MH +) + + 295 N4- (2,2-Dimethyl-3-oxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- (indazol-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 10.54 min, purity: 96%; MS (mass / charge): 436 (MH +) + + 296 Racemic-5-fluoro-N2- (3-fluoro-4-methoxyphenyl) -N4- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) - 2,4-pyrimidinediamine LC / MS: retention time 11.91 min, purity: 96%; MS (mass / charge): 462 (MH +) + + 297 N4- (2,2-Dimethyl-1,1,3-trioxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- (3-fluoro-4-methoxyphenyl) -2, 4-pyrimidinediamine LC / MS: retention time 12.11 min, purity: 96%; MS (mass / charge): 476 (MH +) + + 298 Racemic-5-fluoro-N2- (3-fluoro-4-methoxyphenyl) -N4- (2-methyl-3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4- pyrimidinediamine LC / MS: retention time 11.29 min, purity: 98%; MS (mass / charge): 430 (MH +) + + 299 N4- (2,2-Dimethyl-3-oxo-4H-benzo [thiazin-6-yl) -5-fluoro-N2- (3-fluoro-4-methoxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time 12.14 min, purity: 99%; MS (mass / charge): 444 (MH +) + + 300 5-Fluoro-N2- (3-fluoro-4-methoxyphenyl) -N4- (3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 10.56 min, purity: 97%; MS (mass / charge): 415 (MH +) + + 301 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 11.76 min, purity: 98%; MS (mass / charge): 396 (MH +) + + 302 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 10.72 min, purity: 96%; MS (mass / charge): 428 (MH +) + 303 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- (1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 10.06 min, purity: 95%; MS (mass / charge): 460 (MH +) + 304 N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- (1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 10.13 min, purity: 97%; MS (mass / charge): 464 (MH +) + 305 5-Fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 8.40 min, purity: 97%; MS (mass / charge): 487 (MH +) + 306 5-Fluoro-N2- (3,4,5-trimethoxyphenyl) -N4- (1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 9.19 min, purity: 95%; MS (mass / charge): 490 (MH +) + 307 5-Fluoro-N2- (indazol-6-yl) -N4- (1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 8.33 min, purity: 91%; MS (mass / charge): 440 (MH +) + 308 5-Fluoro-N2- (3-hydroxyphenyl) -N4- (1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 8.07 min, purity: 96%; MS (mass / charge): 416 (MH +) + 309 5-Fluoro-N2- (3-fluoro-4-methoxyphenyl) -N4- (1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 9.74 min, purity: 95%; MS (mass / charge): 448 (MH +) + 310 5-Fluoro-N2- (indazol-5-yl) -N4- (1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 7.40 min, purity: 94%; MS (mass / charge): 440 (MH +) + 311 N4- (2,2-Dimethyl-3-oxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- (1-methylindazol-6-yl) -2,4-pyrimidinediamine LC / MS: retention time 10.15 min, purity: 99%; MS (mass / charge): 450 (MH +) + + 312 N4- (2,2-Dimethyl-3-oxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-N2- (indazol-6-yl) -2,4-pyrimidinediamine trifluoroacetate LC / MS: retention time 10.54 min, purity: 100%; MS (mass / charge): 436 (MH +) 313 N2-Chloro-5-fluoro-N4- (3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -4-pyrimidinamine LC / MS: retention time 5.58 min, purity: 95%; MS (mass / charge): 311 (MH +) + 314 Racemic-N2-chloro-5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benzo [1,4] thiazin-6-yl) -4-pyrimidinamine LC / MS: retention time 11.18 min, purity: 95%; MS (mass / charge): 325 (MH +) + 315 N2-Chloro-5-fluoro-N4- (1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -4-pyrimidinamine LC / MS: retention time 10.03 min, purity: 95%; MS (mass / charge): 343 (MH +) - 316 N2-Chloro-N4- (2,2, -dimethyl-3-oxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-4-pyrimidinamine LC / MS: retention time 12.29 min, purity: 95%; MS (mass / charge): 339 (MH +) + 317 Racemic-N2-chloro-5-fluoro-N4- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -4-pyrimidinamine LC / MS: retention time 10.16 min, purity: 96%; MS (mass / charge): 357 (MH +) - 318 N2-Chloro-N4- (2,2-dimethyl-1,1,3-trioxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro-4-pyrimidinamine LC / MS: retention time 10.50 min, purity: 96%; MS (mass / charge): 371 (MH +) + 319 N4- [Benzoxathiazin-3 (4H) -one-6-yl] 2-chloro-5-fluoro-4-pyrimidinamine LC / MS: retention time 6.40 min, purity: 99%; MS (mass / charge): 296 (MH +) + 320 N2-Chloro-N4- (3,3-dimethyl-1,4-benzoxazin-6-yl) -5-fluoropyrimidinamine LC / MS: retention time 12.20 min, purity 99% MS (mass / charge): 309 (MH ⁺ ) + 324 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- (3-trifluoromethoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.57 (br s, 1H), 9.21 (br s, 1H), 8.16 (d, J = 3.6 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.4 Hz , 1H), 6.91 (d, J = 2.1 Hz, 2H), 6.09-6.06 (m, 1H), 3.65 (s, 6H); 19F NMR (282 MHz, DMSO-d6): -57.17, -163.27; LC / MS: purity: 99%; MS (mass / charge): 425 (MH +) + 325 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (3-trifluoromethoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.54 (br s, 1H), 9.12 (br s, 1H), 8.15 (dd, J = 1.8 and 3.6 Hz, 1H ), 7.96 (d, J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.55 (s, 1H), 2.18 (s, 6H); 19F NMR (282 MHz, DMSO-d6): -57.01, -163.96; LC / MS: purity: 99%; MS (mass / charge): 393 (MH +). + 326 5-Fluoro-N2- (indol-6-yl) -N4- (3-trifluoromethoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.83 (br s, 1H), 9.49 (s, 1H), 9.11 (s, 1H), 8.13 (dd, J = 1.2 and 3.3 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 13.2 Hz, 2H), 7.40-7.32 (m , 2H), 7.21-7.16 (m, 2H), 6.99-6.95 (m, 1H), 6.34-6.28 (m, 1H); 19F NMR (282 MHz, DMSO-d6): -57.14, -164.68; LC / MS: purity: 99%; MS (mass / charge): 404 (MH +). + + 327 5-Fluoro-N4- [1- (N-methylamino) carbonylindol-6-yl] -N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.87 (br s, 1H), 9.61 (s, 1H), 9.46-9.43 (m, 1H), 8.08 (d, J = 3.6 Hz, 1H), 8.04-7.98 (m, 1H), 7.40-7.25 (m, 4H), 7.02 (dd, J = 1.8 and 8.4 Hz, 1H), 6.95-6.90 (m, 1H), 6.77-6.70 (m, 2H), 6.38-6.35 (m, 1H), 4.39 (s, 2H), 2.62 (d, J = 4.8 Hz, 3H); 2.48 (d, J = 4.6 Hz, 3H); LC / MS: purity: 96%; MS (mass / charge): 464 (MH +). + 328 N2- (3,5-Dimethoxyphenyl) -N4- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.15 (br s, 1H), 9.11 (s, 1H), 8.07 (d, J = 3.9 Hz, 1H), 7.37 ( s, 2H), 6.89 (d, J = 1.81 Hz, 2H), 6.68 (s, 1H), 6.05 (t, J = 2.1 Hz, 1H), 3.61 ( s, 6H); 2.23 (s, 6H); 19F NMR (282 MHz, DMSO-d6): -163.60; LC / MS: purity: 99%; MS (mass / charge): 369 (MH + 329 N4- (3,5-Dimethylphenyl) -5-fluoro-N2- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.45 (s, 1H), 9.22 (s, 1H), 8.12 (d, J = 3.9 Hz, 1H), 7.68-7, 64 (m, 1H), 7.58-7.54 (m, 1H), 7.33 (s, 2H), 6.71 (s, 2H), 3.69 (s, 3H), 2.23 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 407 (MH +). + 330 N4- (3,5-Dimethylphenyl) -5-fluoro-N4- (3-methyl-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.11 (br s, 1H), 9.94 (br s, 1H), 8.25 (d, J = 4.8 Hz, 1H), 7, 67 (s, 2H), 7.24 (s, 2H), 7.14 (s, 1H), 6.80 (s, 1H), 2.25 (s, 3H), 2.21 (s, 6H ); 19F NMR (282 MHz, DMSO-d6): -61.76, -161.10; LC / MS: purity: 99%; MS (mass / charge): 390 (M +). + 331 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.86 (br s, 1H), 9.42 (br s, 1H), 8.20 (d, J = 4.2 Hz, 1H), 7, 80-7.76 (m, 1H), 7.56-7.51 (m, 1H), 7.18 (s, 2H), 6.94 (s, 1H), 6.59 (s, 1H) 3.74 (s, 3H); 2.15 (s, 6H); LC / MS: purity: 97%; MS (mass / charge): 407 (MH +). + 332 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.59 (br s, 1H), 9.24 (br s, 1H), 8.18 (d, J = 3.3 Hz, 1H), 7, 84-7.68 (m, 1H), 7.61-7.57 (m, 1H), 6.89 (d, J = 2.4 Hz, 3H), 6.06 (t, J = 2, 4 Hz, 1H), 3.77 (s, 3H), 3.61 (s, 6H); 19F NMR (282 MHz, DMSO-d6): -61.85, -163.20; LC / MS: purity: 97%; MS (mass / charge): 439 (MH +). + 333 N2, N4-Bis (3-methoxy-5-trifluoromethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.80 (br s, 1H), 9.72 (s, 1H), 8.25 (d, J = 3.3 Hz, 1H), 7.77- 7.72 (m, 1H), 7.60-7.52 (m, 3H), 6.92 (s, 1H), 6.75 (s, 1H), 3.77 (s, 3H), 3 71 (s, 3H); 19F NMR (282 MHz, DMSO-d6): -61.90, -161.82; LC / MS: purity: 97%; MS (mass / charge): 477 (MH +). + 334 5-Fluoro-N4- (3-methoxy-5-trifluoromethylphenyl) -N2- (3-methyl-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.83 (br s, 1H), 9.72 (br s, 1H), 8.25 (d, J = 3.6 Hz, 1H), 7, 81-7.68 (m, 3H), 7.57-7.52 (m, 1H), 7.06 (s, 1H), 6.96-6.91 (m, 1H), 3.75 ( s, 3H); 2.26 (s, 3H); 19F NMR (282 MHz, DMSO-d6): -61.82, -162.02; LC / MS: purity: 91%; MS (mass / charge): 461 (MH +). + 335 5-Fluoro-N4- (3-methoxy-5-trifluoromethylphenyl) -N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.67 (br s, 1H), 9.24 (br s, 1H), 8.17 (d, J = 3.6 Hz, 1H), 7, 84-7.78 (m, 1H), 7.59 (s, 1H), 6.95-6.87 (m, 3H), 3.74 (s, 3H), 3.59 (s, 6H) ; 19F NMR (282 MHz, DMSO-d6): -61.86, -163.40; LC / MS: purity: 96%; MS (mass / charge): 469 (MH +). + 336 N2- (3-Chloro-4-hydroxy-5-methylphenyl) -5-fluoro-N4- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.56 (s, 1H), 9.09 (s, 1H), 8.61 (s, 1H), 8.14 (d, J = 3.6 Hz, 1H), 7.82-7.77 (m, 1H), 7.57-7.53 (m, 1H), 7.52-7.48 (m, 1H), 7.27-7.23 ( m, 1H), 6.89 (br s, 1H), 3.76 (s, 3H), 2.10 (s, 3H); 19F NMR (282 MHz, DMSO-d6): -61.80, -164.13; LC / MS: purity: 96%; MS (mass / charge): 444 (MH +). + 337 N2- (3,5-Dichlorophenyl) -5-fluoro-N4- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.74 (s, 1H), 9.70 (s, 1H), 8.25 (d, J = 3.6 Hz, 1H), 7.77-7, 71 (m, 3H), 7.55-7.50 (m, 1H), 7.03-7.01 (m, 1H), 6.95-6.93 (m, 1H), 3.79 ( s, 3H); 19F NMR (282 MHz, DMSO-d6): -61.78, -161.76; LC / MS: purity: 96%; MS (mass / charge): 448 (MH +). + 338 N2- [3,5-Bis (hydroxymethylene) phenyl] -5-fluoro-N4- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.11 (br s, 1H), 9.82 (br s, 1H), 8.26 (d, J = 4.2 Hz, 1H), 7, 83-7.79 (m, 1H), 7.57-7.51 (m, 1H), 7.34 (br s, 2H), 6.99-6.94 (m, 2H), 4, 38 (s, 4H); 3.74 (s, 3H); LC / MS: purity: 92%; MS (mass / charge): 439 (MH +). + + 339 N2- (4-Chloro-3,5-dimethylphenyl) -5-fluoro-N4- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.98 (br s, 1H), 9.66 (br s, 1H), 8.24 (d, J = 4.2 Hz, 1H), 7, 76-7.71 (m, 1H), 7.56-7.52 (m, 1H), 7.37 (s, 2H), 6.98-6.95 (m, 1H), 3.75 ( s, 3H); 2.20 (s, 6H); LC / MS: purity: 98%; MS (mass / charge): 442 (MH +). - 340 N2, N4-Bis (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.27 (s, 1H), 9.18 (s, 1H), 8.10 (d, 1H, J = 3.9 Hz), 6.99 (d, 2H , J = 2.1 Hz), 6.92 (d, 2H, J = 2.4 Hz), 6.21 (t, 1H, J = 2.1 Hz), 6.05 (t, 1H, J = 2.4 Hz), 3.68 (s, 6H), 3.62 (s, 6H); LC / MS: purity: 100%; MS (mass / charge): 401 (MH +) + + 341 N2, N4-Bis (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.11 (s, 1H), 8.98 (s, 1H), 8.05 (d, 1H, J = 3.9 Hz), 7.33 (br. s, 2H), 7.24 (broad s, 2H), 6.69 (broad s, 1H), 6.51 (broad s, 1H), 2.25 (broad s, 6H), 2 14 (s, 6H); LC / MS: purity: 100%; MS (mass / charge): 336 (M +). + 342 N2- [3,5-Bis (hydroxymethylene) phenyl] -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.10 (s, 1H), 9.09 (s, 1H), 8.02 (d, 1H, J = 3.9 Hz), 7.44 (s, 2H), 7.28 (d, 1H, J = 3.0 Hz), 7.24 (d, 1H, J = 2.7 Hz), 6.86 (s, 1H), 6.79 (d, 1H, J = 8.7 Hz), 5.05 (t, 2H, J = 6 Hz), 4.39 (d, 4H, J = 5.4 Hz), 4.22 (broad s, 4H) ; LC / MS: purity: 97%; MS (mass / charge): 399 (MH +). + 343 N2- [3,5-Bis (hydroxymethylene) phenyl] -N4- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.19 (s, 1H), 9.15 (s, 1H), 8.08 (d, 1H, J = 3.6 Hz), 7.46 (s, 2H ), 7.01 (d, 2H, J = 2.1 Hz), 6.86 (s, 1H), 6.21 (t, 1H, J = 1.8 Hz), 5.03 (t, 2H , J = 5.4 Hz), 4.38 (d, 4H, J = 5.4 Hz), 3.68 (s, 6H); LC / MS: purity: 86%; MS (mass / charge): 401 (MH +). + + 344 N2- [3,5-Bis (hydroxymethylene) phenyl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.55 (s, 1H), 9.27 (broad d, 1H), 8.97 (s, 1H), 8.04 (d, 1H, 3.6 Hz), 7.44 (d, 2H, J = 1.2 Hz), 7.39 (dd, 1H, J = 2.4 and 8.4 Hz), 7.24 (d, 1H, J = 2 4 Hz), 6.88 (d, 1H, J = 8.7 Hz), 6.85 (br s, 1H), 6.38 (s, 2H), 5.08 (t, 1H, J = 5.6 Hz), 4.93 (t, 1H, J = 5.7 Hz), 4.38 (d, 2H, J = 5.4 Hz), 4.31 (d, 2H, J = 6 Hz), 1.41 (s, 6H); LC / MS: purity: 93%; MS (mass / charge): 440 (MH +). + 345 N2- [3,5-Bis (hydroxymethylene) phenyl] -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.26 (s, 1H), 9.15 (s, 1H), 8.07 (brd, 1H, J = 3.9 Hz), 7.79 ( dd, 1H, J = 2.7 and 9 Hz), 7.74 (d, 1H, J = 2.7 Hz), 7.43 (s, 2H), 7.11 (d, 1H, J = 9 Hz), 6.86 (s, 1H), 5.06 (t, 2H, J = 5.4 Hz), 4.38 (d, 4H, J = 5.4 Hz), 3.84 (s, 3H); LC / MS: purity: 98%; MS (mass / charge): 405 (MH +). + 346 N2- [3,5-Bis (hydroxymethylene) phenyl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.50 (br s, 1H), 9.28 (s, 1H), 8.16 (d, 1H, J = 3.6 Hz), 8.05 ( d, 1H, J = 2.7 Hz), 7.93 (dd, 1H, J = 2.7 and 9.0 Hz), 7.52 (d, 1H, J = 8.7 Hz), 7, 44 (s, 2H), 6.87 (s, 1H), 5.09 (t, 2H, J = 5.7 Hz), 4.41 (d, 4H), J = 5.4 Hz); LC / MS: purity: 97%; MS (mass / charge): 409 (M +). + 347 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -N2- [1- (N-methylaminocarbonyl) indol-6-yl) -5-fluoro-2 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.02 (s, 1H), 10.49 (s, 1H), 9.69 (d, 1H, J = 4.8 Hz), 9.53 (s, 1H), 8.12 (d, 1H, J = 3.6 Hz), 7.52 (d, 1H, J = 8.4 Hz), 7.38 (t, 1H, J = 2.7 Hz) , 7.11 (s, 1H), 6.81 (d, 1H, J = 2.4 Hz), 6.72 (dd, 1H, J = 1.8 and 8.4 Hz), 6.59 ( dd, 1H, J = 2.4 and 8.7 Hz), 6.49 (s, 1H), 5.84 (d, 1H, J = 8.4 Hz), 2.74 (d, 3H, J = 4.5 Hz), 1.31 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 476 (MH +). + 348 N2- (1-Aminocarbonylindol-6-yl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.01 (s, 1H), 10.44 (s, 1H), 9.50 (s, 1H), 8.16 (d, 1H, J = 3.6 Hz ), 8.07 (d, 1H, J = 5.4 Hz), 7.52 (d, 1H, J = 8.4 Hz), 7.38 (t, 1H, J = 2.7 Hz), 6.73 (dd, 1H, J = 1.5 and 8.4 Hz), 6.54 (m, 2H), 5.69 (d, 1H, J = 8.7 Hz), 2.93 (s , 2H); 1.29 (s, 6H); LC / MS: purity: 95%; MS (mass / charge): 462 (MH +) - 349 N2- (4-Chloro-3,5-dimethylphenyl) -N4- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.26 (br s, 1H), 9.20 (s, 1H), 8.10 (d, 1H, J = 3.9 Hz), 7.48 ( s, 2H), 6.94 (d, 2H, J = 2.4 Hz), 6.23 (t, 1H, J = 2.4 Hz), 3.68 (s, 6H), 2.20 ( s, 6H); LC / MS: purity: 92%; MS (mass / charge): 403 (MH +). + 350 N4- (3,5-Dimethoxyphenyl) -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.20 (s, 1H), 9.05 (s, 1H), 8.08 (d, 1H, J = 3.6 Hz), 7.27 (s, 2H), 6.97 (d, 2H, J = 2.1 Hz), 6.51 (s, 1H), 6.21 (t, 1H, J = 1.8 Hz), 3.67 (s, 6H), 2.15 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 369 (MH +). + + - 351 N4- (3,5-Dimethoxyphenyl) -N2- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.16 (s, 1H), 9.96 (s, 1H), 8.05 (d, 1H, J = 3.3 Hz), 7.22 (d, 1H, J = 2.7 Hz), 7.06 (dd, 1H, J = 2.4 and 8.7 Hz), 6.99 (d, 2H, J = 2.1 Hz), 6.65 ( d, 1H, J = 8.7 Hz), 6.20 (t, 1H, J = 2.1 Hz), 4.17 (s, 4H), 3.69 (s, 6H); LC / MS: purity: 91%; MS (mass / charge): 399 (MH +). + 352 N2- (3,5-Dichlorophenyl) -N4- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.82 (br s, 1H), 9.58 (br s, 1H), 8.21 (d, 1H, J = 3.6 Hz), 7, 75 (br s, 2H), 7.04 (t, 1H, J = 1.8 Hz), 6.89 (d, 2H, J = 1.8 Hz), 6.27 (t, 1H, J = 2.1 Hz), 3.67 (s, 6H); LC / MS: purity: 95%; MS (mass / charge): 410 (MH +). + 353 N4- (3,5-Dimethoxyphenyl) -5-fluoro-N2- (3-methyl-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.47 (s, 1H), 9.31 (s, 1H), 8.15 (d, 1H, J = 3.6 Hz), 7.86 (s, 1H), 7.79 (s, 1H), 6.98 (m, 3H), 6.23 (t, 1H, J = 2.4 Hz), 3.68 (s, 6H), 2.27 ( s, 3H); LC / MS: purity: 96%; MS (mass / charge): 423 (MH +). + 354 N2- (3,5-Dichlorophenyl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.56 (s, 1H), 9.28 (s, 1H), 8.11 (d, 1H, J = 3.6 Hz), 7.76 (d, 2H, J = 1.8 Hz), 7.18 (d, 1H, J = 2.4 Hz), 7.13 (dd, 1H, J = 3.6 and 9 Hz), 6.98 (t, 1H, J = 1.8 Hz), 6.82 (d, 1H, J = 8.7 Hz), 4.21 (br s, 4H); LC / MS: purity: 81%; MS (mass / charge): 407 (MH +). + 355 N4- (3,5-Dimethoxyphenyl) -5-fluoro-N2- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.53 (s, 1H), 9.33 (d, 1H, J = 1.5 Hz), 8.16 (d, 1H, J = 3.6 Hz) , 7.65 (d, 1H, J = 2.1 Hz), 6.98 (d, 2H, J = 2.1 Hz), 6.72 (br s, 1H), 6.22 (t, 1H, J = 2.4 Hz), 3.72 (s, 3H), 3.69 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 439 (MH +). + 356 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.47 (s, 1H), 9.23 (s, 1H), 8.09 (d, 1H, J = 3.9 Hz), 7.67 (s, 1H), 7.59 (s, 1H), 7.27 (d, 1H, J = 2.7 Hz), 7.18 (dd, 1H, J = 2.4 and 8.4 Hz), 6, 78 (d, 1H, J = 8.7 Hz), 6.78 (s, 1H), 4.21, br s, 4H), 3.72 (s, 3H); LC / MS: purity: 90%; MS (mass / charge) 473 (MH +). + 357 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.64 (s, 1H), 9.29 (s, 1H), 8.15 (m, 2H), 7.62 (dd, 1H, J = 2.4 and 9 Hz), 7.39 (d, 1H, J = 8.7 Hz), 6.90 (d, 2H, J = 2.4 Hz), 6.09 (t, 1H, J = 1.8 Hz), 3.66 (s, 6H); LC / MS: purity: 97%; MS (mass / charge): 471 (MH +) + + 358 N2- (4-Chloro-3,5-dimethylphenyl) -5-fluoro-N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.90 (br.s, 1H), 9.56 (br.s, 1H), 8.21 (br.s, 1H, J = 3.6 Hz), 8.06 (br s, 1H), 7.57 (dd, 1H, J = 2.4 and 9.0 Hz), 7.43 (d, 1H, J = 9.3 Hz), 7.39 (s, 2H); 7.06 (br s, 1H); 25 (s, 6H); LC / MS: purity: 97%; MS (mass / charge): 473 (MH +). - 359 N2- [3,5-Bis (hydroxymethylene) phenyl] -5-fluoro-N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.60 (s, 1H), 9.32 (s, 1H), 8.16 (d, 2H, J = 3.6 Hz), 7.70 (dd, 1H, J = 2.7 and 9 Hz), 7.47 (s, 2H), 7.40 (d, 1H, J = 9.0 Hz), 6.88 (broad s, 1H), 5, 11 (t, 2H, J = 5.4 Hz); 4.42 (d, 4H, J = 5.4 Hz); LC / MS: purity: 98%; MS (mass / charge): 471 (MH +). + 360 N2- (3,5-Dichlorophenyl) -5-fluoro-N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.76 (s, 1H), 9.72 (s, 1H), 8.25 (d, 1H, J = 3.6 Hz), 8.00 (d, 1H, J = 2.4 Hz), 7.74 (d, 2H, J = 1.8 Hz), 7.58 (dd, 1H, J = 2.4 and 9.0 Hz), 7.44 ( d, 1H, J = 9.0 Hz); 7.04 (t, 1H, J = 1.8 Hz); LC / MS: purity: 98%; MS (mass / charge): 480 (MH +). - 361 5-Fluoro-N2- (3-methoxy-5-trifluoromethylphenyl) -N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.72 (s, 1H), 9.64 (s, 1H), 8.23 (d, 1H, J = 3.6 Hz), 8.07 (d, 1H, J = 2.4 Hz), 7.67 (broad s, 1H), 7.60 (dd, 1H, J = 2.4 and 9.3 Hz), 7.54 (broad s, 1H ), 7.39 (d, 1H, J = 9 Hz), 6.75 (br s, 1H), 3.75 (s, 3H); LC / MS: purity: 97%: MS (mass / charge): 509 (MH +) + 362 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.60 (s, 1H), 9.19 (s, 1H), 8.15 (d, 1H, J = 3.6 Hz), 8.12 (d, 1H, J = 2.4 Hz), 7.60 (dd, 2.4 and 8.7 Hz), 7.40 (d, 1H, J = 9 Hz), 7.22 (s, 2H), 6 56 (s, 1H); 2.18 (s, 6H); LC / MS: purity: 100%; MS (mass / charge): 439 (MH +). + - 363 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.53 (s, 1H), 9.27 (s, 1H), 8.08 (d, 1H, J = 3.6 Hz), 7.93 (d, 1H, J = 2.4 Hz), 7.37 (dd, 1H, J = 2.4 and 9.3 Hz), 7.26 (d, 1H, J = 9 Hz), 7.11 (dd, 1H, J = 2.4 and 8.7 Hz), 6.80 (d, 1H, J = 8.4 Hz), 4.22 (s, 4H); LC / MS: purity: 96%; MS (mass / charge): 469 (MH +). + 364 N4- (3,5-Dimethoxyphenyl) -5-fluoro-N2- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.59 (s, 1H), 9.37 (d, 1H, J = 0.9 Hz), 8.14 (d, 1H, J = 2.4 Hz) 7.38 (dd, 1H, J = 2.7 and 9.3 Hz), 7.27 (d, 1H, J = 9.0 Hz), 6.91 (d, 2H, J = 2.4 Hz), 6.26 (t, 1H, J = 2.4 Hz), 3.69 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 471 (MH +). + 365 5-Fluoro-N2- [2- (N-methylamino) carbonylindol-7-yl] -N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.59 (s, 1H), 9.66 (s, 1H), 9.34 (s, 1H), 8.46 (d, 1H, J = 4.8 Hz), 8.20 (d, 1H, J = 3.6 Hz), 8.10 (d, 1H, J = 2.4 Hz), 7.91 (d, 1H, J = 7.2 Hz) 7.60 (dd, 1H, J = 2.7 and 9 Hz), 7.39 (d, 1H, J = 9.0 Hz), 7.24 (d, 1H, J = 7.5 Hz) 7.06 (d, 1H, J = 1.8 Hz), 6.94 (t, 1H, J = 7.8 Hz), 2.80 (d, 3H, J = 4.8 Hz); LC / MS: purity: 100%; MS (mass / charge): 507 (MH +). + 366 5-Fluoro-N2- (3-methyl-5-trifluoromethyl) -N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.70 (s, 1H), 9.60 (s, 1H), 8.22 (d, 1H, J = 2.4 Hz), 8.07 (d, 1H, J = 2.4 Hz), 7.87 (s, 1H), 7.70 (s, 1H), 7.60 (dd, 1H, J = 2.1 and 9 Hz), 7.41 ( d, 1H, J = 9 Hz), 7.04 (s, 1H), 2.31 (s, 3H); LC / MS: purity: 100%; MS (mass / charge): 493 (MH +). + 367 N2- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.48 (s, 1H), 9.12 (s, 1H), 8.11 (d, 2H, J = 3.6 Hz), 7.59 (dd, 1H, J = 2.4 and 9 Hz), 7.39 (d, 1H, J = 9.3 Hz), 7.22 (d, 1H, J = 2.4 Hz), 6.99 (dd, 1H, J = 2.4 and 8.7 Hz); 6.70 (d, 1H, J = 9 Hz); LC / MS: purity: 96%; MS (mass / charge): 469 (MH +). + + 368 N4- (3,5-Dimethoxyphenyl) -5-fluoro-N2- [2- (N-methylamino) carbonylindol-7-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.70 (s, 1H), 9.31 (s, 1H), 9.28 (s, 1H), 8.43 (d, 1H, J = 4.8 Hz), 8.14 (d, 1H, J = 4.8 Hz), 8.04 (dd, 1H, J = 0.9 and 8.4 Hz), 7.19 (d, 1H, J = 7 5 Hz), 7.03 (d, 1H, J = 2H, J = 2.4 Hz), 6.89 (t, 1H, J = 8.4 Hz), 6.24 (t, 1H, J = 2.4 Hz), 3.69 (s, 6H), 2.80 (d, 3H, J = 4.55 Hz); LC / MS: purity: 91%; MS (mass / charge): 437 (MH +). + + 369 N2- (3-Chloro-5-methoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.57 (s, 1H), 9.35 (s, 1H), 9.27 (s, 1H), 8.10 (d, 1H, J = 3.6 Hz), 7.47 (m, 1H), 7.25 (dd, 1H, J = 2.7 and 8.7 Hz), 7.16 (d, 2H, J = 2.1 Hz), 6, 87 (d, 1H, J = 8.4 Hz), 6.49 (t, 1H, J = 1.8 Hz), 3.66 (s, 3H), 1.40 (s, 6H); LC / MS: purity: 100%; MS (mass / charge): 445 (MH +). + 370 N2- (3-Chloro-5-methoxyphenyl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.31 (s, 1H), 9.21 (s, 1H), 8.08 (d, 1H, J = 3.9 Hz), 7.48 (t, 1H, J = 1.8 Hz), 7.20 (m, 3H), 6.80 (d, 1H, J = 8.4 Hz), 6.49 (t, 1H, J = 2.4 Hz) 4.21 (s, 4H); 3.67 (s, 3H); LC / MS: purity: 95%; MS (mass / charge): 403 (MH +). + 371 5-Fluoro-N4- (3,4-methylenedioxyphenyl) -N2- [2- (N-methylamino) carbonylindol-7-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.27 (s, 1H), 9.25 (s, 2H), 8.43 (d, 1H, J = 4.5 Hz), 8.09 (d, 1H, J = 3.9 Hz), 8.01 (d, 1H, J = 7.8 Hz), 7.51 (d, 1H, J = 2.1 Hz), 7.6 (m, 2H) 7.04 (d, 1H, J = 1.8 Hz), 6.92 (t, 1H, J = 7.8 Hz), 6.84 (d, 1H, J = 8.1 Hz), 6 01 (s, 2H); 2.81 (d, 3H, J = 4.8 Hz); LC / MS: purity: 100%; MS (mass / charge): 421 (MH +). + 372 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- (3,4-methylenedioxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.20 (s, 1H), 9.10 (s, 1H), 8.05 (d, 1H, J = 3.6 Hz), 7.44 (d, 1H, J = 2.1 Hz), 7.16 (dd, 1H, J = 2.1 and 8.4 Hz), 6.93 (d, 2H, J = 2.4 Hz), 6.84 ( d, 1H, J = 8.4 Hz), 6.04 (t, 1H, J = 2.1 Hz), 5.99 (s, 2H), 3.64 (s, 6H); LC / MS: purity: 89%; MS (mass / charge): 385 (MH +). + 373 5-Fluoro-N4- (3,4-methylenedioxyphenyl) -N2- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.49 (s, 1H), 9.30 (s, 1H), 8.10 (d, 1H, J = 3.6 Hz), 9.67 (br. s, 1H), 7.58 (br s, 1H), 7.40 (d, 1H, J = 1.8 Hz), 7.11 (dd, 1H, J = 1.8 and 8.4 Hz ), 6.84 (d, 1H, J = 8.4 Hz), 6.70 (br s, 1H), 6.99 (s, 2H), 3.73 (s, 3H); LC / MS: purity: 97%; MS (mass / charge): 423 (MH +). + 374 5-Fluoro-N4- (3,4-methylenedioxyphenyl) -N2- (3-methyl-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.46 (s, 1H), 9.29 (s, 1H), 8.10 (d, 1H, J = 3.6 Hz), 7.78 (br. s, 1H), 7.39 (d, 1H, J = 2.1 Hz), 7.10 (1H, J = 2.4 and 8.4 Hz), 6.99 (br s, 1H), 6.85 (d, 1H, J = 8.4 Hz), 5.99 (s, 2H), 2.28 (s, 3H); LC / MS: purity: 99%; MS (mass / charge): 407 (MH +). - 375 N2- (3,5-Dichlorophenyl) -5-fluoro-N4- (3,4-methylenedioxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.59 (s, 1H), 9.36 (s, 1H), 8.12 (d, 1H, J = 3.9 Hz), 7.74 (d, 2H, J = 2.1 Hz), 7.30 (d, 1H, J = 2.1 Hz), 7.06 (dd, 1H, J = 2.4 and 8.4 Hz), 6.97 ( t, 1H, 2.1 Hz); 6.88 (d, 1H, J = 8.4 Hz); 6.00 (s, 2H); LC / MS: purity: 94%; MS (mass / charge): 393 (M +). + 376 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (3,4-methylenedioxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.18 (br s, 1H), 9.03 (s, 1H), 8.04 (d, 1H, J = 3.9 Hz), 7.43 ( d, 1H, J = 2.1 Hz), 7.24 (s, 2H), 7.11 (dd, 1H, J = 2.1 and 8.4 Hz), 6.85 (d, 1H, J = 8.4 Hz), 6.50 (br s, 1H), 5.98 (s, 2H), 2.16 (s, 6H); LC / MS: purity: 87%; MS (mass / charge): 353 (MH +). + 377 N2- (4-Chloro-2,5-dimethoxyphenyl) -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 100%; MS (mass / charge): 439 (M +). + 378 N2- (3-Chloro-4-methoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine salt p-toluenesulfonic acid ¹ H NMR (DMSO-d6): d 10.63 (s, 1H), 10.05 (s, 1H), 9.62 (s, 1H), 8.15 (d, 1H, J = 4.8 Hz), 7.66 (broad s, 1H), 7.44 (dd, 2H, J = 1.8 and 8.7 Hz), 7.35 (broad d, 1H, J = 9 Hz), 7.20 (dd, 1H, J = 2.1 and 8.7 Hz), 7.10 (broad.d, 2H, J = 7.5 Hz), 7.02 (d, 1H, J = 9 Hz ), 6.89 (d, 1H, J = 8.4 Hz), 3.78 (s, 3H), 2.28 (s, 3H), 1.39 (s, 6H); LC / MS: purity: 97%; MS (mass / charge): 444 (M for parenteral molecule + H). + 379 N2- (4-Chloro-2,5-dimethoxyphenyl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.24 (s, 1H), 8.05 (d, 1H, J = 3.9 Hz), 7.87 (s, 1H), 7.70 (s, 1H), 7.17 (d, 1H, J = 2.4 Hz), 7.06 (m, 2H), 6.74 (d, 1H, J = 8.7 Hz), 4.21 (s, 4H), 3.79 (s, 3H); 3.54 (s, 3H); LC / MS: purity: 100%; MS (mass / charge): 433 (MH +). + 380 N2- (4-Chloro-2,5-dimethoxyphenyl) -N4- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 100%; MS (mass / charge): 435 (MH +). + 381 N4- (3,5-Dimethoxyphenyl) -5-fluoro-N2- (2-methoxycarbonylbenzofuran-5-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.36 (s, 1H), 8.25 (d, 1H, J = 1.8 Hz), 8.11 (d, 1H, J = 3.9 Hz) 7.57 (m, 3H), 6.99 (m, 2H), 6.26 (t, 1H, J = 2.1 Hz), 3.88 (s, 3H), 3.69 (s, 6H); LC / MS: purity: 92%; MS (mass / charge): 439 (MH +). + + 382 N2- (2-Carboxybenzofuran-5-yl) -N4- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 91%; MS (mass / charge): 425 (MH +). - - 383 N2- (2-Carboxyindol-7-yl) -N4- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.85 (s, 1H), 9.31 (s, 1H), 9.26 (s, 1H), 8.16 (d, 1H, J = 3.6 Hz ), 8.12 (d, 1H, J = 8.1 Hz), 7.22 (d, 1H, J = 8.1 Hz), 7.02 (d, 2H, J = 2.1 Hz), 6.91 (t, 1H, J = 7.8 Hz), 6.25 (s, 1H), 3.70 (br s, 6H); LC / MS: purity: 80%; MC: 424 (MH +) + 384 N4- (3,5-Dimethoxyphenyl) -5-fluoro-N2- [2- (N-2-hydroxyethyl-N-methylamino) carbonylindol-7-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.52 (s, 1H), 9.30 (br s, 1H), 9.27 (s, 1H), 8.14 (d, 1H, J = 3 6 Hz), 8.04 (m, 1H), 7.22 (d, 1H, J = 8.4 Hz), 7.03 (m, 2H), 6.90 9m, 2H), 6.23 (br s, 1H), 3.68 (s, 6H), 3.64 (br s, 4H), 3.20 (s, 3H); LC / MS: purity: 94%; MS (mass / charge): 481 (MH +). + + + 385 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4-methyl-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 7.50 (br s, 1H), 7.30 (m, 2H), 6.91 (brd, 1H, J = 7.2 Hz), 6.73 (m , 5H), 4.49 (s, 2H), 4.31 (s, 4H), 3.60 (s, 3H), 2.92 (d, 3H, J = 4.5 Hz); LC / MS: purity: 97%, MS (mass / charge): 440 (MH +) + + - 386 N4- (3,4-Ethylenedioxyphenyl) -N2- (3,5-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 7.94 (d, 1H, J = 5.1 Hz), 7.50 (broad d, 1H), 6.90 (d, 1H, J = 9 Hz), 6, 83 (s, 1H), 6.73 (m, 3H), 6.62 (d. 1H, 2.4 Hz), 4.31 (m, 4H), 3.80 (s, 3H), 3, 79 (s, 3H); 3.60 (s, 3H); LC / MS: purity: 90%, MS: 413 (MH +). + + - 387 N2- (3,5-Dimethylphenyl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 7.50 (brd, 1H), 7.40 (s, 1H), 7.27 (m, 1H), 6.90 (brd, 1H), 6.81 (m, 1H), 6.77 (d, 2H, J = 2.4 Hz), 6.70 (dd, 1H, J = 2.7 and 8.7 Hz), 4.30 (s, 4H) 3.50 (s, 3H); 2.32 (s, 6H); LC / MS: purity: 94%, MS (mass / charge): 381 (MH +). + - 388 N2- (3,5-Dimethoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N4-methyl-2,4- pyrimidinediamine 1 H NMR (DMSO-d6): d 10.60 (s, 1H), 9.21 (s, 1H), 7.94 (d, 1H, J = 6.0 Hz), 7.01 (d, 2H , J = 1.2 Hz), 6.88 (m, 2H), 6.75 (d, 1H, J = 2.4 Hz), 6.05 (t, 1H, J = 2.4 Hz), 3.60 (s, 6H); 3.41 (s, 3H); 1.34 (s, 6H); LC / MS: purity: 92%, MS (mass / charge): 454 (MH +). - - 389 N4- (3,5-Dimethoxyphenyl) -N2- [2- (N-1,1-dimethyl-2-hydroxyethylamine) carbonylindol-7-yl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.63 (s, 1H), 9.25 (d, 1H, J = 7.8 Hz), 8.14 (d, 1H, J = 3.6 Hz) 8.02 (d, 1H, J = 8.1 Hz), 7.53 (s, 1H), 7.19 (d, 1H, J = 7.5 Hz), 7.14 (s, 1H) 7.04 (s, 2H), 6.89 (t, 1H, J = 7.5 Hz), 6.23 (s, 1H), 4.94 (t, 1H, J = 6.3 Hz) 3.69 (s, 6H); 3.53 (d, 2H, J = 5.4 Hz); 1.33 (s, 6H); LC / MS: purity: 80%; MS (mass / charge): 495 (MH +). + - 390 2-Chloro-N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (CDCl 3): d 7.85 (d, 1H, J = 4.8 Hz), 6.86 (d, 1H, J = 8.4 Hz), 6.73 (d, 1H, J = 2 7 Hz), 6.60 (dd, 1H, J = 2.7 and 8.1 Hz); LC / MS: purity: 100%, MS (mass / charge): 296 (M +). - - - 391 N2- (3,5-Dimethylphenyl) -5-fluoro-N4-methyl-N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 7.95 (d, 1H, J = 6.4 Hz), 7.67 (br s, 1H), 7.21 (s, 2H), 6.96 (s, 1H ), 6.87 (dd, 1H, J = 2.4 and 8.7 Hz), 6.78 (d, 1H, J = 2.4 Hz), 6.72 (s, 1H), 3.55 (s, 3H), 3.32 (s, 3H), 2.30 (s, 6H), 1.53 (s, 6H); LC / MS: purity: 92%, MS (mass / charge): 436 (MH +). + + 392 N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4-methyl-N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -2,4- pyrimidinediamine 1 H NMR (CD3OD): d 7.77 (d, 1H, J = 2.4 Hz), 7.75 (broad d, 1H), 7.34 (dd, 1H, J = 2.7 and 9, 3 Hz), 7.05 (d, 1H, J = 1.8 Hz), 6.95 (m, 3H), 4.62 (s, 3H), 3.83 (s, 3H), 3.51 (s, 3H); 1.48 (s, 6H); LC / MS: purity: 94%, MS (mass / charge): 472 (M +). + + 393 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4-methyl-N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (CD3OD): d 7.78 (d, 1H, J = 8.4 Hz), 7.07 (br s, 1H), 6.96 (br s, 2H), 6.87 (d , 2H, J = 2.4 Hz), 6.10 (t, 1H, J = 2.4 Hz), 3.70 (s, 6H), 3.54 (s, 3H), 3.32 (s , 3H); 1.48 (s, 6H); LC / MS: purity: 97%, MS (mass / charge): 468 (MH +). + + 394 N2- (3-Chloro-4-methoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N4-methyl-2, 4-pyrimidinediamine LC / MS: purity: 93%, MS (mass / charge): 351 (MH +). + + 395 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- (2-methoxycarbonylbenzofuran-5-yl) -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 7.95 (s, 1H), 7.76 (broad d, 1H), 7.54 (s, 1H), 7.49 (broad d, 2H), 6 87 (d, 1H, J = 8.4 Hz), 6.79 (dd, 1H, J = 2.4 and 6.6 Hz), 6.74 (broad d, 1H); LC / MS: purity: 94%, MS (mass / charge): 452 (MH +). + + + 396 N2- (3,5-Dimethylphenyl) -N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 90%; MS (mass / charge): 422 (MH +). + + + 397 N2- (3,5-Dimethoxyphenyl) -N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 94%; MS (mass / charge): 454 (MH +). + + + 398 N4- (3,5-Dimethoxyphenyl) -5-fluoro-N4-methyl-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine LC / MS: purity: 94%, MS (mass / charge): 442 (MH +). + - 399 N4- (3,5-Dimethoxyphenyl) -N2- (3,5-dimethylphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine LC / MS: purity: 92%, MS (mass / charge): 382 (MH +). + + - + 400 N2, N4-Bis (3,5-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.23 (s, 1H), 7.97 (d, 1H, J = 5.1 Hz), 7.01 (d, 2H, J = 1.8 Hz), 6.45 (d, 2H, J = 1.2 Hz), 6.34 (broad t, 1H), 6.05 (broad t, 1H), 3.72 (s, 6H), 3.68 (6H); 3.45 (s, 3H); LC / MS: purity: 95%, MS (mass / charge): 415 (MH +). + - 401 N4- (3,5-Dimethoxyphenyl) -5-fluoro-N2- (2-methoxycarbonylbenzofuran-5-yl) -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO): d 9.70 (s, 1H), 8.13 (s, 1H), 8.04 (d, 1H, J = 3.8 Hz), 7.69 (s, 1H), 7.62 (m, 2H), 6.51 (d, 2H, J = 1.5 Hz), 6.44 (br t, 1H); 3.88 (s, 3H); 3.72 (s, 6H); 3.46 (s, 3H); LC / MS: MS (mass / charge): 453 (MH +), purity: 95%. + + 402 N4- [3-Chloro-4- (methoxycarbonyl-1,1-dimethylmethyleneoxy) phenyl] -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 81%; MS (mass / charge): 459 (MH +) + 403 N2- (3,5-Dimethylphenyl) -N4- [4- (methoxycarbonyl-1,1-dimethylmethyleneoxy) phenyl] -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 80%; MS (mass / charge): 425 (MH +). + 404 N2- (3-Chloro-4-methoxyphenyl) -N4- (3,5-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.00 (s, 1H), 8.08 (d, 1H, J = 6.00 Hz), 7.89 (d, 1H, J = 5.1 Hz), 7.47 (dd, 1H, J = 2.7 and 9.3 Hz), 7.08 (d, 1H, J = 9.0 Hz), 6.53 (d, 2H, J = 1.8 Hz ), 6.46 (t, 1H, J = 2.1 Hz); LC / MS: purity: 92%, 419 (MH +). - - 405 N2- (4-Chloro-3-methoxyphenyl) -N4- (3,5-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.30 (s, 1H), 9.03 (s, 1H), 8.07 (d, 1H, J = 4.2 Hz), 7.48 (d, 1H , J = 2.1 Hz), 7.37 (dd, 1H, J = 2.4 and 8.4 Hz), 7.24 (s, 2H); LC / MS: purity: 91%, MS (mass / charge): 419 (M +). + - 406 N4- (3,5-Dimethoxyphenyl) -5-fluoro-N4-methyl-N2- [2- (N-methylamino) carbonylindol-7-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 11.71 (s, 1H), 9.39 (s, 1H), 8.44 (brd, 1H, J = 4.8 Hz), 8.02 (m , 2H), 7.20 (d, 1H, J = 7.5 Hz), 7.04 (d, 1H, J = 2.1 Hz), 6.93 (t, 1H, J = 7.8 Hz ), 6.47 (d, 2H, J = 2.1 Hz), 6.41 (t, 1H, J = 2.1 Hz), 3.72 (s, 6H), 3.46 (s, 3H ), 2.81 (d, 3H, J = 4.5 Hz); LC / MS: purity: 95%; MS (mass / charge): 450 (M +). + - 407 2-Chloro-N4- [3-chloro-4- (ethoxycarbonyl-1,1-dimethylmethyleneoxy) phenyl] -5-fluoro-4-pyrimidinamine 1 H NMR (DMSO-d6): d 8.07 (d, 1H, J = 2.7 Hz), 7.69 (m, 1H), 7.45 (m, 1H), 6.95 (d, 1H , J = 9 Hz), 6.92 (br s, 1H), 4.28 (q, 2H, J = 6.9 Hz), 1.62 (s, 6H), 1.31 (t, 3H, J = 7.2 Hz); LC / MS: purity: 85%; MS (mass / charge): 388 (M +). + 408 N4- [3-Chloro-4- (ethoxycarbonyl-1,1-dimethylmethyleneoxy) phenyl] -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (CD3OD): d 7.91 (d, 1H, J = 3.6 Hz), 7.74 (d, 1H, J = 2.7 Hz), 7.66 (dd, 1H, J = 2 7 and 8.7 Hz), 6.91 (d, 1H, J = 9 Hz), 6.78 (d, 2H, J = 2.1 Hz), 6.12 (t, 1H, J = 2 , 1 Hz), 4.26 (q, 2H, J = 6.9 Hz), 3.71 (s, 6H), 1.59 (s, 6H), 1.29 (t, 3H, J = 7.2 Hz); LC / MS: purity: 90%; MS (mass / charge): 505 (MH +). + 409 N4- [3-Chloro-4- (hydroxycarbonyl-1,1-dimethylmethyleneoxy) phenyl] -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 13.15 (br s, 1H), 9.38 (s, 1H), 9.18 (s, 1H), 8.10 (d, 1H, J = 3, 9 Hz), 7.93 (s, 1H), 7.84 (dd, 1H, J = 2.7 and 9.3 Hz), 7.77 (d, 1H, J = 2.7 Hz), 6 91 (m, 3H), 6.07 (t, 1H, J = 2.1 Hz), 3.65 (s, 6H), 1.52 (s, 6H); LC / MS: purity: 90%; MS (mass / charge): 477 (MH +). + + - 410 N4- [3-Chloro-4- (ethoxycarbonyl-1,1-dimethylmethyleneoxy) phenyl] -N2- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.36 (s, 1H), 9.17 (s, 1H), 8.08 (d, 1H, J = 3.6 Hz), 7.78 (d, 1H , J = 2.7 Hz), 7.75 (d, 1H, J = 2.1 Hz), 7.70 (dd, 1H, J = 3.0 and 9.3 Hz), 7.44 (dd , 1H, J = 2.7 and 9.0 Hz), 6.99 (d, 1H, J = 9.0 Hz), 6.88 (d, 1H, J = 9.0 Hz), 4.20 (q, 2H, J = 7.2 Hz), 3.78 (s, 3H), 1.52 (s, 6H), 1.20 (t, 3H, J = 6.9 Hz); LC / MS: purity: 93%; MS (mass / charge): 509 (M +). + + + 411 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4-methyl-N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine LC / MS: purity: 91%, MS (mass / charge): 420 (MH +). + + - 412 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4-methyl-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.61 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 9.97 (d, 1H, J = 6.0 Hz ), 7.70 (br.s.d, 1H, J = 4.8 Hz), 7.52 (br.s., 1H, J = 7.8 Hz), 7.38 (d, 1H, J = 8, 1 Hz), 7.33 (s, 1H), 6.79 (m, 3H), 4.24 (s, 4H), 3.44 (s, 3H); LC / MS: purity: 92%, MS (mass / charge): 420 (MH +). + + 413 N4- (3,4-Dimethoxyphenyl) -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.15 (s, 1H), 8.97 (s, 1H), 8.02 (d, 1H, J = 3.9 Hz), 7.24 (m, 4H ), 6.88 (d, 1H, J = J = 8.4 Hz), 6.48 (d, 1H), 3.73 (s, 3H), 3.65 (s, 3H), 2.12 (s, 6H); LC / MS: purity: 97%, MS (mass / charge): 369 (MH +). + + - 414 N2- (3,5-Dimethoxyphenyl) -N4- (3,4-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.17 (s, 1H), 9.05 (s, 1H), 8.03 (d, 1H, J = 3.9 Hz), 7.32 (dd, 2 4 and 8.7 Hz), 7.24 (d, 1H, J = 2.4 Hz), 6.92 (d, 2H, J = 2.4 Hz), 6.85 (d, 1H, 8 4 Hz), 6.03 (t, 1H, J = 2.1 Hz), 3.73 (s, 3H), 3.66 (s, 3H), 3.60 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 401 (MH +). + + - 415 N4- (3,4-Dimethoxyphenyl) -N2- [2- (ethoxycarbonyl) indol-7-yl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.89 (s, 1H), 9.25 (s, 1H), 9.21 (s, 1H), 8.10 (d, 1H, J = 3.9 Hz ), 8.87 (s, 1H), 8.73 (m, 3H), 7.11 (d, 1H, J = 2.1 Hz), 6.88 (m, 2H), 4.32 (q ., 2H, J = 3.9 Hz), 3.76 (s, 3H), 3.66 (s, 3H), 1.34 (q, t, 3H, J = 3.9 Hz); LC / MS: purity: 93%, MS (mass / charge): 452 (M +). + + - 416 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4-methyl-N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.59 (s, 1H), 8.05 (s, 1H), 7.96 (d, 1H), J = 5.7 Hz), 7.80 (br. s, 4H), 7.27 (s, 1H), 6.85 (m, 2H), 6.78 (dd, 1H), 4.52 (s, 4H), 3.41 (s, 3H), 3.31 (s, 3H); LC / MS: purity: 91%, MS (mass / charge): 420 (MH +). + - 417 2-Chloro-N4- (3,4-dimethoxyphenyl) -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (DMSO-d6): d 8.09 (d, 1H, J = 5.4 Hz), 7.02 (d, 1H, J = 2.4 Hz), 6.93 (d, 1H, J = 8.4 Hz), 6.84 (dd, 1H, J = 2.1 and 8.4 Hz), 3.75 (s, 3H), 3.71 (s, 3H); LC / MS: purity: 87%, MS (mass / charge): 298 (M +). - - - - 418 2-Chloro-N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4- (methoxycarbonylmethyl) -4-pyrimidinamine LC / MS: purity: 99%, MS (mass / charge): 354 (M +). - - 419 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.29 (s, 1H), 9.21 (s, 1H), 8.33 (s, 1H), 8.07 (d, 1H, J = 3.0 Hz ), 8.04 (s, 1H), 7.61 (broad dd, 1H), 7.39 (s, 1H), 7.29 (broad dd, 1H, J = 2.7 and 8.4 Hz), 7.25 (m, 3H), 6.76 (d, 1H, J = 8.7 Hz), 3.70 (s, 3H), 3.64 (s, 3H); LC / MS: purity: 98%, MS (mass / charge): 408 (MH +). + + - 420 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- (indol-6-yl) -N4- (methoxycarbonylmethyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.77 (s, 1H), 9.05 (s, 1H), 7.94 (d, 1H, J = 5.7 Hz), 7.70 (s, 1H ), 7.32 (d, 1H, J = 2.8 Hz), 7.19 (d, 1H, J = 1.5 Hz), 7.17 (t, 1H, J = 3 Hz), 6, 82 (m, 3H), 6.28 (d, 1H, J = 2.1 Hz), 4.60 (s, 2H), 4.24 (s, 4H), 3.33 (s, 3H); LC / MS: purity: 99%; MS (mass / charge): 450 (MH +). + - 421 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N2- [2- (N-methylaminocarbonyl) indol-7-yl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 11.66 (s, 1H), 9.27 (s, 1H), 9.22 (s, 1H), 8.41 (brd, 1H, J = 4, 8 Hz), 8.09 (d, 1H, J = 3.3 Hz), 7.99 (d, 1H, J = 7.8 Hz), 7.33 (dd, 1H, J = 2.4 and 8.4 Hz), 7.28 (d, 1H, J = 2.7 Hz), 7.18 (d, 1H, J = 7.5 Hz), 7.03 (d, 1H, J = 2, 1 Hz), 6.89 (m, 2H), 3.75 (s, 3H), 3.66 (s, 3H), 2.80 (d, 3H, J = 4.2 Hz); LC / MS: purity: 91%; MS (mass / charge): 437 (MH +). + - 422 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.36 (s, 1H), 9.24 (s, 1H), 8.33 (s, 1H), 8.07 (d, 1H, J = 3.9 Hz ), 7.75 (d, 2H, J = 6.0 Hz), 7.50 (d, 2H, J = 8.7 Hz), 7.75 (d, 2H, J = 8.7 Hz), 7.47 (s, 1H), 7.26 (m, 2H), 6.92 (d, 1H, J = 9.6 Hz), 3.76 (s, 3H), 3.69 (s, 3H ); LC / MS: purity: 94%; MS (mass / charge): 408 (M +). + + - 423 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.36 (s, 1H), 9.22 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 8.08 (d , 1H, J = 3 Hz), 7.81 (dd, 1H, J = 1.8 and 7.1 Hz), 7.49 (d, 1H, J = 6.9 Hz), 7.31 (m , 4H), 6.79 (d, 1H, J = 8.7 Hz), 3.71 (s, 3H), 3.67 (s, 3H); LC / MS: purity: 98%, MS (mass / charge): 409 (MH +). + + - + 424 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.50 (s, 1H), 9.28 (s, 1H), 8.09 (s and d, 2H, J = 4.5 Hz), 7.76 (m , 4H), 7.28 (m, 3H), 6.93 (d, 1H, J = 8.4 Hz), 3.76 (s, 3H), 3.70 (s, 3H); LC / MS: purity: 89%, MS (mass / charge): 408 (M +). + - 425 N2- (3-Chloro-4-methoxyphenyl) -N4- (3,4-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.17 (s, 1H), 9.08 (s, 1H), 8.02 (d, 1H, J = 3.9 Hz), 7.84 (s, 1H , J = 2.7 Hz), 7.41 (dd, 1H, J = 3.0 and 9.3 Hz), 7.27 (dd, 1H, J = 2.4 and 8.7 Hz), 7 21 (d, 1H, J = 2.4 Hz), 6.97 (d 1H, J = 8.7 Hz), 6.88 (d, 1H, J = 8.7 Hz), 3.77 ( s, 3H), 3.73 (s, 3H), 3.68 (s, 3H); LC / MS: purity: 95%; MS (mass / charge): 405 (M +). + + - 426 N2- [3- (4-Acetylpiperazino) phenyl] -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.13 (s, 1H), 8.99 (s, 1H), 8.02 (d, 1H, J = 4.2 Hz), 7.22 (m, 4H ), 7.03 (m, 1H), 6.77 (d, 1H, J = 8.7 Hz), 6.50 (broad d, 1H, J = 7.2 Hz), 4.21 (broad s, 4H), 3.02 (br.m, 2H), 2.95 (br.m, 2H), 2.02 (s, 3H); LC / MS: purity: 97%, MS (mass / charge): 465 (MH +). + + - 427 N2- [4- (4-Acetylpiperazino) phenyl] -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.07 (s, 1H), 8.92 (s, 1H), 7.98 (d, 1H, J = 3.9 Hz), 7.48 (d, J = 8.7 Hz), 7.33 (d, 1H, J = 2.4 Hz), 7.18 (dd, 1H, J = 2.1 and 8.7 Hz), 6.83 (d, 1H , J = 9.3 Hz), 6.73 (d, 1H, J = 1H, J = 8.7 Hz), 4.23 (br.s, 4H), 3.56 (br.s, 4H) 3.03 (t, 2H, J = 5.1 Hz), 2.97 (t, 2H, J = 5.1 Hz), 2.03 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 465 (MH +). + + - 428 N2- [3- (4-Acetylpiperazino) phenyl] -N4- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.23 (s, 1H), 9.07 (s, 1H), 8.09 (d, 1H, J = 3 Hz), 7.26 (s, 1H), 7.15 (d, 1H, J = Hz), 7.07 (t, 1H, J = 8.4 Hz), 6.97 (d, 2H, J = 2.4 Hz), 6.50 (broad d, 1H, J = 7.5 Hz), 6.18 (d, 1H, J = 2.1 Hz), 5.74 (s, 1H), 3.49 (m, 4H), 3.32 (s, 6H), 2.96 (m, 4H), 2.01 (s, 3H); LC / MS: purity: 98%; MS (mass / charge): 467 (M +). + - 429 N2- [3- (4-Acetylpiperazino) phenyl] -N4- (3,4-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.17 (br s, 1H), 8.99 (s, 1H), 8.02 (d, 1H, J = 3.9 Hz), 7.27 (m , 2H), 7.01 (broad d, 1H, J = 8.4 Hz), 7.00 (t, 1H, J = 8.1 Hz), 6.86 (d, 1H, J = 8, 4 Hz), 6.48 (br.s.d, 1H, J = 9.9 Hz), 6.13 (br.s, 1H), 3.72 (s, 3H), 3.62 (s, 3H) 3.46 (m, 4H); 2.96 (m, 2H); 2.90 (m, 2H); 2.02 (s, 3H); MS (mass / charge): 467 (M +); purity: 99%. + - 430 N2- [4- (4-Acetylpiperazino) phenyl] -N4- (3,4-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.11 (s, 1H), 8.88 (s, 1H), 7.98 (d, 1H, J = 3.9 Hz), 7.46 (d, 2H , J = 9.3 Hz), 7.27 (m, 2H), 6.87 (d, 1H, J = 8.4 Hz), 6.80 (d, 2H, J = 9 Hz), 3, 74 (s, 3H), 3.65 (s, 3H), 3.56 (m, 4H), 3.02 (m, 2H), 2.96 (m, 2H), 2.03 (s, 3H ); LC / MS: purity 90%, MS (mass / charge): 467 (M +). + - 431 N2- [3- (4-Acetylpiperazino) phenyl] -5-fluoro-N4- (3,4- (tetrafluoroethylene-phenoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.62 (s, 1H), 9.19 (s, 1H), 8.14 (m, 1H), 7.62 (dd, 1H, J = 2.7 and 9.6 Hz), 7.39 (d, 1H, J = 9 Hz), 7.23 (d, 1H, J = 8 Hz), 7.16 (s, 1H), 7.07 (t, 1H , J = 2.6 Hz), 6.55 (d, 1H, J = 2.6 Hz), 6.12 (s, 1H), 3.54 (broad s, 4H), 2.02 (s , 3H); LC / MS: purity: 91%; MS (mass / charge): 537 (MH +). + + - 432 N2- [4- (4-Acetylpiperazino) phenyl] -5-fluoro-N4- (3,4- (tetrafluoroethylene dioxiphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.57 (s, 1H), 9.11 (s, 1H), 8.15 (broad d, 1H), 8.10 (d, 1H, J = 3, 3 Hz), 7.57 (broad dd, 1H, J = 9.6 Hz), 7.45 (d, 2H, J = 8.7 Hz), 7.37 (d, 1H, J = 9 Hz ), 6.87 (d, 2H, J = 9.3 Hz), 6.69 (d, 1H, J = 8.7 Hz), 6.47 (d, 1H, J = 8.7 Hz), 3.52 (m, 4H), 2.99 (m, 2H), 2.85 (m, 2H), 2.03 (s, 3H), LC / MS: purity: 88%; MS (mass / charge): 537 (MH +). + - 433 N4- (3,4-Dimethoxyphenyl) -N2- (3,5-dimethylphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.05 (s, 1H), 7.89 (d, 1H, J = 6.0 Hz), 7.31 (s, 2H), 6.93 (d, 1H , J = 2.7 Hz), 6.90 (s, 1H), 6.81 (dd, 1H, J = 2.4 and 8.1 Hz), 6.50 (s, 1H), 3.75 (s, 3H), 3.71 (s, 1H), 3.42 (s, 3H), 2.18 (s, 6H); LC / MS: purity: 95%, MS (mass / charge): 383 (MH +). + - 434 N2- (3,5-Dimethoxyphenyl) -N4- (3,4-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine LC / MS: purity: 96%, MS (mass / charge): 415 (MH +). + - 435 N4- (3,4-Dimethoxyphenyl) -N2- [2- (ethoxycarbonyl) indol-7-yl] -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 11.94 (s, 1H), 9.32 (s, 1H), 8.15 (d, 1H, J = J = 7.5 Hz), 7.97 (d , 1H, J = 6.0 Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.12 (d, 1H, J = 2.1 Hz), 6.96 (m, 3H ), 6.82 (m, 1H), 4.33 (q, 2H, J = 4.2 Hz), 3.76 (s, 3H), 3.72 (s, 3H), 3.46 ( s, 3H); 1.35 (t, 3H, J = 6.9 Hz); LC / MS: purity: 90%; MS (mass / charge): 466 (MH +). + - 436 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N2- (indol-6-yl) -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.85 (s, 1H), 9.07 (s, 1H), 8.03 (s, 1H), 7.87 (d, 1H, J = 8.4 Hz ), 7.34 (d, 1H, J = 8.7 Hz), 7.16 (m, 2H), 6.93 (m, 2H), 6.90 (s, 1H), 6.80 (m , 1H), 6.28 (s, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.44 (s, 3H); LC / MS: purity: 94%, MS (mass / charge): 394 (MH +). + - 437 N2- [4- (4-Acetylpiperazino) phenyl] -N4- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 80%, MS (mass / charge): 467 (MH +). + - 438 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N4-methyl-N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.42 (s, 1H), 8.40 (s, 1H), 8.28 (br s, 1H), 7.93 (d, 1H, J = 8, 7 Hz), 7.58 (broad d, 1H, J = 6.8 Hz), 7.55 (s, 1H), 7.27 (m, 2H), 6.96 (d, 1H, J = 2.4 Hz), 6.92 (m, 1H), 6.81 (dd, 1H, J = 2.1 and 8.4 Hz), 3.75 (s, 3H), 3.75 2 (s , 3H); 3.47 (s, 3H); LC / MS: purity: 80%; MS (mass / charge): 422 (MH +). + + - 439 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N4-methyl-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.50 (s, 1H), 8.62 (d, 1H, J = 3.6 Hz), 8.17 (s, 1H), 7.94 (d, 1H , J = 6.0 Hz), 7.70 (dd, 1H, J = 2.4 Hz), 7.33 (m, 2H), 6.97 (d, 1H, J = 2.4 Hz), 6.92 (d, 1H, J = 8.4 Hz), 6.82 (dd, 1H, J = 2.4 and 8.7 Hz), 3.76 (s, 3H), 3.73 (s , 3H); 3.48 (s, 3H); LC / MS: purity: 80%; MS (mass / charge): 422 (MH +). + + - - 440 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N4-methyl-N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.59 (s, 1H), 8.10 (s, 1H), 7.98 (m, 2H), 7.62 (dd, 1H, J = 2.1 and 6.6 Hz), 7.27 (s, 1H), 6.96 (m, 2H), 6.92 (s, 1H), 6.81 (dd, 2.4 and 8.4 Hz), 6 61 (dd, 1H, J = 2.1 and 6.6 Hz), 5.67 (br s, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3, 45 (s, 3H). + - 441 N2- (3,5-Dimethylphenyl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4- (methoxycarbonylmethyl) -2,4-pyrimidinediamine LC / MS: purity: 91%, MS 9m / e): 439 (MH +). + - 442 N2- (3,5-Dimethoxyphenyl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4- (methoxycarbonylmethyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.14 (s, 1H), 7.97 (d, 1H, J = 5.7 Hz), 6.84 (m, 5H), 6.07 (m, 1H ), 4.62 (s, 2H), 4.24 (s, 3H), 3.68 (br s, 4H), 3.34 (s, 6H); LC / MS: purity: 94%, MS: 471 (MH +). + - 443 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4- (methoxycarbonylmethyl) -N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.40 (s, 1H), 8.40 (s, 1H), 8.00 (d, 1H, J = J = 4.2 Hz), 7.93 (broad s, 1H), 7.60 (m, 1H), 7.57 (s, 1H), 7.27 (m, 2H), 6.83 (m, 3H), 4.63 (s, 2H) 4.23 (s, 4H); 3.51 (s, 3H); LC / MS: purity: 95%, MS (mass / charge): 478 (MH +). + - 444 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4- (methoxycarbonylmethyl) -N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.49 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 8.00 (d, 1H, J = 5.7 Hz ), 7.76 (broad d, 1H, J = 9.6 Hz), 7.51 (broad d, 1H, J = 8.1 Hz), 7.34 (m, 2H), 6.86 (m, 1H), 6.83 (m, 1H), 4.64 (s, 2H), 4.24 (s, 4H), 3.54 (s, 3H); LC / MS: purity: 91%, MS (mass / charge): 478 (MH +). + - 445 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4- (methoxycarbonylmethyl) -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.61 (s, 1H), 8.10 (s, 1H), 8.05 (d, 1H, J = 8.1 Hz), 7.77 (dd, 2H , J = 8.4 Hz), 7.70 (dd, 2H, J = 8.4 Hz), 7.29 (s, 1H), 6.85 (m, 3H), 4.64 (s, 2H ), 4.25 (s, 4H); 3.63 (s, 3H); LC / MS: purity: 92%, MS (mass / charge): 478 (MH +). + - 446 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4- (methoxycarbonylmethyl) -N2- [3- (N-methylamine) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.24 (s, 1H), 7.97 (d, 1H, J = 5.7 Hz), 7.94 (m, 1H), 7.22 (m, 2H ), 7.08 (t, 1H, J = 7.8 Hz), 6.83 (m, 3H), 6.49 (m, 1H), 4.62 (s, 2H), 4.39 (s , 2H), 4.24 (s, 4H), 3.60 (s, 3H), 2.66 (d, 3H, J = 5.1 Hz); LC / MS: purity: 97%, MS (498 (MH +). + - 447 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N4-methyl-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.24 (s, 1H), 7.94 (br s, 1H), 7.90 (d, 1H, J = 5.7 Hz), 7.46 (t , 1H, J = 2.1 Hz), 7.27 (broad d, 1H, J = 9 Hz), 7.10 (t, 1H, J = 5.1 Hz), 6.93 (m, 1H ), 6.79 (dd, 1H, J = 2.7 and 8.7 Hz), 6.45 (dd, 1H, J = 1.8 and 8.1 Hz), 6.12 (m, 1H) 4.38 (s, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 3.42 (s, 3H), 2.4 (brd, 3H); LC / MS: purity: 98%; MS (mass / charge): 442 (MH +). + - 448 N2- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.37 (s, 1H), 9.18 (s, 1H), 8.21 (d, 1H, J = 4.5 Hz), 8.05 (d, 1H , J = 3.6 Hz), 7.72 (m, 2H), 7.22 (m, 2H), 7.20 (m, 3H), 6.80 (broad dd, 1H, J = 2, 1 and 9 Hz), 4.11 (br s, 4H), 2.71 (d, 3H, J = 4.5 Hz); LC / MS: purity: 95%; MS (mass / charge): 430 (MH +). + + - 449 N2- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N4- (3,4-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 8.20 (d, 1H), 8.05 (d, 1H, J = 3.9 Hz), 7.75 (d, 1H, J = 2.7 Hz), 7.66 (dd, 1H, J = 3.0 and 8.7 Hz), 7.32 (dd, 1H, J = 2.4 and 9.0 Hz), 7.23 (s, 1H), 7 , 18 (m, 1H), 6.88 (d, 1H, J = 8.7 Hz), 4.00 (s, 4H), 3.76 (s, 3H), 3.71 (s, 3H) 2.69 (d, 3H, J = 3.6 Hz); LC / MS: purity: 95%; MS (mass / charge): 432 (M +). + - 450 N2- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N4- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 8.15 (d, 1H, J = 4.2 Hz), 7.82 (dd, 1H, J = 2.7 and 9.0 Hz), 7.61 (d , 1H, J = 2.7 Hz), 7.25 (d, 1H, J = 9.0 Hz), 6.96 (t, 2H, J = 2.4 Hz), 6.26 (t, 1H , J = 2.1 Hz), 3.71 (s, 6H), 2.71 (d, 3H, 3.3 Hz); LC / MS: purity: 87%, MS (mass / charge): 432 (M +). + - 451 N4- (3-Chloro-4-methoxyphenyl) -N2- [4-chloro-3- (N-methylamino) carbonylphenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 8.16 (d, 1H, J = 3.9 Hz), 7.70 (d, 1H, J = 2.7 Hz), 7.64 (m, 2H), 7.30 (d, 1H, J = 9.3 Hz), 7.10 (d, 1H, J = 9 Hz), 3.87 (s, 3H), 2.69 (s, 3H); LC / MS: purity: 91%, MS (mass / charge): 536 (M +). + + 452 N4- [3-Chloro-4- (ethoxycarbonyl-1,1-dimethylmethyleneoxy) phenyl] -N2- [4-chloro-3- (N-methylamino) carbonylphenyl] -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.65 (br s, 2H), 8.26 (d, 1H, J = 4.8 Hz), 8.17 (s, 1H), 7.80-7 58 (m, 4H), 7.27 (d, 1H, J = 8.7 Hz), 6.89 (d, 1H, J = 9 Hz), 4.20 (q, 2H, J = 6 9 Hz), 2.71 (d, 3H, J = 4.2 Hz), 1.54 (s, 6H), 1.21 (t, 3H, J = 7.2 Hz); LC / MS: purity: 91%; MS (mass / charge): 536 (M +). + + 453 N2- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4-methyl-4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.69 (s, 1H), 8.28 (d, 1H, J = 4.5 Hz), 7.98 (d, 1H, J = 6.0 Hz), 7.83 (d, 1H, J = 2.4 Hz), 7.66 (dd, 1H, J = 2.7 and 8.7 Hz), 7.29 (d, 1H, J = 9 Hz), 6.84 (m, 2H), 6.76 (dd, 1H, 2.7 and 8.7 Hz), 4.24 (s, 4H), 3.38 (s, 1H), 2.72 (d , 3H, J = 4.2 Hz); LC / MS: purity: 91%; MS (mass / charge): 444 (M +). + - 454 N2- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N4- (3,4-dimethoxyphenyl) -5-fluoro-N4-methyl-4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.50 (s, 1H), 8.26 (d, 1H, J = 4.5 Hz), 7.93 (d, 1H, 6.0 Hz), 7, 87 (d, 1H, J = 2.7 Hz), 7.68 (dd, 1H, J = 2.4 and 5.7 Hz), 7.26 (d, 1H, J = 8.7 Hz), 6.93 (m, 2H), 6.80 (dd, 1H, J = 2.4 and 8.4 Hz), 3.76 (s, 3H), 3.76 (s, 3H), 3.72 (s, 3H), 3.41 (s, 3H), 2.71 (d, 3H, J = 4.5 Hz); LC / MS: purity: 90%; MS (mass / charge): 446 (M +). + - 455 N2- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.71 (s, 1H), 9.87 (s, 1H), 8.26 (d, 1H, J = 4.2 Hz), 8.16 (d, 1H , J = 4.2 Hz), 7.63 (m, 2H), 7.25 (m, 2H), 7.17 (d, 1H, J = 2.1 Hz), 6.90 (d, 1H , J = 8.7 Hz), 2.71 (d, 3H, J = 4.5 Hz), 1.40 (s, 6H); LC / MS: purity: 97%, MS (mass / charge): 471 (M +). + + - 456 N2- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.74 (s, 1H), 10.34 (s, 1H), 10.09 (s, 1H), 8.24 (d, 1H, J = 4.8 Hz ), 8.15 (d, 1H, J = 4.5 Hz), 7.83 (d, 1H, J = 1.5 Hz), 7.44 (dd, 1H, J = 1.8 and 8, 4 Hz), 7.23 (m, 2H), 6.93 (d, 1H, J = 8.4 Hz), 2.71 (d, 3H, J = 4.2 Hz), 1.40 (s , 6H); LC / MS: purity: 94%; MS (mass / charge): 471 (M +). + + + 457 N2- (2,6-Dimethoxypyrid-3-yl) -N4- (3,5-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 8.02 (d, 1H, J = 8.4 Hz), 7.87 (d, 1H, J = 6.4 Hz), 7.76 (s, 1H), 6.41 (m, 3H), 6.32 (d, 1H, J = J = 8.4 Hz), 3.89 (s, 3H), 3.82 (s, 3H), 3.71 (s , 3H); 3.34 (s, 3H); LC / MS: purity: 95%, MS (mass / charge): 416 (MH +). + + + 458 N2- (2,6-Dimethoxypyrid-3-yl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6); d 8.02 (d, 1H, J = 8.4 Hz), 7.82 (d, 1H, J = 6.6 Hz), 7.68 (s, 1H), 6.79 (m, 2H) 6.72 (dd, 1H, J = 2.1 and 8.1 Hz), 6.30 (d, 1H, J = 8.1 Hz), 4.23 (s, 4H), 3.89 ( s, 3H); 3.81 (s, 3H); 3.28 (s, 3H); LC / MS: purity: 97%, MS (mass / charge): 414 (MH +). - - 459 N4- (3,5-Dimethoxyphenyl) -N2- (2,6-dimethoxypyrid-3-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.12 (s, 1H), 7.97 (d, 1H, J = 5.1 Hz), 7.89 (s, 1H), 7.82 (d, 1H , J = 7.8 Hz), 6.95 (s, 1H), 6.28 (d, 1H, J = 7.8 Hz), 6.15 (s, 1H), 3.84 (s, 3H ), 3.83 (s, 3H); 23.64 (s, 6H); LC / MS: purity: 85%, MS (mass / charge): 402 (MH +). + - 460 N2- (2,6-Dimethoxypyrid-3-yl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 93%, MS (mass / charge): 400 (MH +). + - 461 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2-methyl-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 7.72 (d, 1H, J = 5.1 Hz), 6.79 (d, 1H, J = 9.0 Hz), 6.73 (br s, 1H ), 6.66 (brd, 1H), 2.74 (d, 3H, J = 4.5 Hz); LC / MS: purity: 93%, MS (mass / charge): 291 (MH +). - - 462 N2-Dimethyl-N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 7.78 (d, 1H, J = 6.0 Hz), 6.80 (d, 1H, J = 8.4 Hz), 6.75 (d, 1H, J = 2.7 Hz), 6.66 (dd, 1H, J = 1.8 and 8.4 Hz), 4.22 (s, 4H), 3.31 (s, 3H), 3.30 (s , 3H); LC / MS: purity: 95%; MS (mass / charge): 305 (MH +). - - 463 N2- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.45 (s, 1H), 9.24 (s, 1H), 8.11 (m, 2H), 7.89 (d, 1H, J = 2.1 Hz ), 7.54 (dd, 2.1 and 8.7 Hz), 7.20 (m, 3H), 6.82 (d, 1H, J = 8.4 Hz), 4.22 (broad s , 4H); 2.71 (d, 3H, J = 4.5 Hz); LC / MS: purity: 99%, MS (mass / charge): 430 (MH +). + + - 464 N2- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N4- (3,4-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.34 (s, 1H), 10.10 (s, 1H), 8.25 (d, 1H, J = 4.5 Hz), 8.18 (d, 1H , J = 4.8 Hz), 7.81 (s, 1H), 7.41 (d, 1H, J = 8.1 Hz), 7.27 (d, 1H, J = 8.4 Hz), 7.18 (m, 2H), 6.95 (d, 1H, J = 8.7 Hz), 3.75 (s, 3H), 3.68 (s, 3H), 2.71 (d, 3H ); LC / MS: purity: 96%; MS (mass / charge): 432 (MH +). + - 465 N2- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N4- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 100%, MS (mass / charge): 432 (MH +). + - 466 N4- (3-Chloro-4-methoxyphenyl) -N2- [3-chloro-4- (N-methylamino) carbonylphenyl] -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 100%, MS (mass / charge): 436 (MH +). + + - 467 N4- [3-Chloro-4- (ethoxycarbonyl-1,1-dimethylmethyleneoxy) phenyl] -N2- [3-chloro-4- (N-methylamino) carbonylphenyl] -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 95%, MS (mass / charge): 536 (MH +). + + + 468 N2- [3-Chloro-4- (N-methylamino) carbonylphenyl] -5-fluoro-N4- (3-hydroxyphenyl) -2,4-pyrimidinediamine LC / MS: purity: 100%, MS (mass / charge): 388 (MH +). + + - 469 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- (2-hydroxyethyl) -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 7.70 (d, 1H, J = 5.7 Hz), 6.79 (d, 1H, J = 8.7 Hz), 6.74 (d, 1H, J = 2.4 Hz), 6.66 (dd, 1H, J = 2.4 and 8.4 Hz), 6.50 (t, 1H, J = 5.1 Hz), 4.61 (t, 1H , J = 5.4 Hz), 4.22 (s, 4H), 3.47 (q, 2H, J = 6.3 Hz), 3.29 (t, 2H, J = 5.4 Hz) 3.25 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 321 (MH +). - - 470 2-Chloro-N4- [3-chloro-4- (ethoxycarbonyl-1,1-dimethylmethyleneoxy) phenyl] -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (CDCl ₃ ): d 7.87 (d, 1H, J = 7.8 Hz), 7.25 (m, 1H), 6.95 (m, 2H), 4.25 (q, 2H , J = 4.8 Hz), 3.46 (s, 3H), 1.65 (s, 6H), 1.29 (t, 3H, J = 4.8 Hz); LC / MS: purity: 95%, MS (mass / charge): 404 (MH +; Cl37). - + 471 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2-isopropyl-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 7.70 (d, 1H, J = 5.7 Hz), 6.77 (d, 1H, J = 8.7 Hz), 6.37 (d, 1H, J = 2.4 Hz), 6.68 (dd, 1H, J = 2.4 and 8.7 Hz), 6.44 (d, 1H, J = 8.1 Hz), 4.22 (s, 4H ), 3.90 (sept, 1H, J = 7.5 Hz), 3.27 (s, 3H), 1.12 (d, 6H, J = 6.6 Hz); LC / MS: purity: 93%; MS (mass / charge): 319 (MH +). C - - 472 N2- (2,6-Dimethoxypyrid-3-yl) -5-fluoro-N4- (3-hydroxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.39 (s, 1H), 9.52 (s, 1H), 8.20 (d, 1H, J = 5.7 Hz), 7.77 (m, 1H ), 7.08 (m, 1H), 6.59 (m, 1H), 6.45 (d, 1H, J = 8.4 Hz), 6.37 (d, 1H, J = 8.1 Hz ), 3.88 (s, 3H); 3.86 (s, 3H); LC / MS: purity: 89%, MS (mass / charge): 358 (MH +). + - 473 N2- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.71 (s, 1H), 8.16 (d, 1H, J = 4.5 Hz), 8.00 (d, 1H, J = 5.7 Hz), 7.95 (d, 1H, J = 1.8 Hz) 7.53 (dd, 1H, J = 2.1 and 8.4 Hz), 7.29 (d, 1H, J = 8.4 Hz) 6.85 (m, 2H), 6.77 (dd, 1H, J = 2.1 and 8.4 Hz), 4.24 (s, 4H), 3.40 (s, 3H), 2, 71 (d, 3H, J = 3.9 Hz); LC / MS: purity: 100%; MS (mass / charge): 444 (M +). + - 474 N2- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N4- (3,4-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.86 (br s, 1H), 8.18 (d, 1H, J = 4.5 Hz), 8.03 (dd, 1H, J = 1.2 and 6.3 Hz), 7.94 (d, 1H, J = 1.8 Hz), 7.52 (dd, 1H, J = 2.1 and 8.4 Hz), 7.30 (d, 1H, J = 8.4 Hz), 6.99 (d, 1H, J = 2.4 Hz), 6.93 (d, 1H, J = 8.4 Hz), 6.86 (dd, 1H, J = 2.4 and 8.4 Hz), 3.76 (s, 3H), 3.72 (s, 3H), 3.45 (s, 3H), 2.71 (d, 3H, J = 4.5 Hz); LC / MS: purity: 100%; MS (mass / charge): 446 (M +). + - 475 N4- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.11 (s, 1H), 9.83 (s, 1H), 8.30 (d, 1H, J = 4.5 Hz), 8.24 (d, 1H , J = 4.5 Hz), 8.00 (dd, 1H, J = 2.7 and 8.7 Hz), 7.63 (d, 1H, J = 2.4 Hz), 7.36 (d , 1H, J = 8.7 Hz), 6.78 (d, 2H, J = 2.1 Hz), 6.20 (t, 1H, J = 2.1 Hz), 3.67 (s, 6H ), 2.73 (d, 3H, J = 5.4 Hz); LC / MS: purity: 100%; MS (mass / charge): 432 (M +). + + - 476 N4- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.91 (s, 1H), 9.52 (s, 1H), 8.29 (d, 1H, J = 4.8 Hz), 8.19 (d, 1H , J = 4.2 Hz), 8.00 (broad dd, 1H, J = 8.7 Hz), 7.62 (d, 1H, J = 2.1 Hz), 7.38 (d, 1H , J = 9.0 Hz), 7.17 (s, 2H), 6.63 (s, 1H), 2.72 (d, 3H, J = 4.8 Hz), 2.19 (s, 6H ); LC / MS: purity: 95%; MS (mass / charge): 400 (M +). + + - 477 N4- [4-Chloro-3- (N-methylamino) carbonylphenyl] -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.55 (s, 1H), 9.32 (s, 1H), 8.31 (brs, 1H), 8.15 (brs, 1H), 7 99 (m, 2H), 7.79 (m, 1H), 7.39 (d, 1H, J = 9 Hz), 7.29 (m, 2H), 7.14 (m, 1H), 6 49 (brd, 1H, J = 7.8 Hz), 4.36 (s, 2H), 2.72 (s, 3H), 2.64 (s, 3H); LC / MS: purity: 99%, MS (mass / charge): 459 (MH +). + + - 478 N2- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N4- [4-chloro-3- (N-methylamino) carbonylphenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.69 (s, 1H), 8.34 (d, 1H, J = 4.5 Hz), 8.22 (d, 1H, J = 3.6 Hz), 8.17 (d, 1H, J = 4.5 Hz), 7.95 (dd, 1H, J = 2.7 and 8.7 Hz), 7.81 (d, 1H, J = 2.1 Hz ), 7.71 (d, 1H, J = 2.7 Hz), 7.56 (dd, 1H, J = 2.1 and 8.4 Hz), 7.43 (d, 1H, J = 9, 0 Hz), 7.30 (d, 1H, J = 8.4 Hz), 2.73 (d, 6H, J = 4.5 Hz); LC / MS: purity: 100%; MS (mass / charge): 466 (M +). + - 479 N4- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N2- (indol-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.98 (s, 1H), 10.28 (s, 1H), 10.05 (s, 1H), 8.35 (d, 1H, J = 4.2 Hz ), 8.21 (d, 1H, J = 4.8 Hz), 7.86 (broad.d, 1H, J = 8.7 Hz), 7.77 (d, 1H, J = 2.7 Hz ), 7.54 (s, 1H), 7.47 (d, 1H, J = 8.4 Hz), 7.35 (d, 1H, J = 8.7 Hz), 7.30 (m, 1H ), 7.05 (dd, 1H, J = 1.8 and 8.4 Hz), 6.38 (br s, 1H), 2.75 (d, 3H, J = 4.5 Hz), LC / MS: purity: 92%; MS (mass / charge): 411 (M +). + - 480 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-2-methoxy-N4-methyl-4-pyrimidinamine LC / MS: purity: 97%, MS (mass / charge): 292 (M +). - - 481 N4- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.85 (br s, 1H), 9.50 (br s, 1H), 8.22 (m, 2H), 7.89 (m, 2H), 7 33 (d, 1H, J = 9.0 Hz), 6.85 (d, 2H, J = 1.5 Hz), 6.13 (d, 1H, J = 1.8 Hz), 3.66 (s, 1H); 2.74 (d, 3H, J = 4.5 Hz); LC / MS: purity: 98%, MS (mass / charge): 432 (M +). + + - 482 N4- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.01 (s, 1H), 9.65 (s, 1H), 8.24 (d, 1H, J = 4.5 Hz), 7.85 (br s , 1H), 7.35 (d, 1H, J = 8.7 Hz), 7.16 (s, 2H), 6.94 (s, 2H), 6.65 (s, 1H), 2.74 (d, 3H, J = 4.8 Hz), 2.29 (s, 3H), 2.20 (s, 3H); LC / MS: purity: 98%, MS (mass / charge): 400 (M +). + + - 483 N4- [3-Chloro-4- (N-methylamino) carbonylphenyl] -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.82 (br s, 1H), 9.56 (br s, 1H), 8.22 (m, 2H), 7.98 (brd, 1H) , 7.91 (d, 1H, J = 1.5 Hz), 7.82 (broad.d, 1H, J = 8.7 Hz), 7.37 (d, 1H, J = 8.7 Hz) 7.22 (m, 3H), 6.56 (m, 1H), 4.38 (s, 2H), 2.74 (d, 3H, J = 4.5 Hz), 2.64 (d, 3H, J = 4.8Hz); LC / MS: purity: 97%; MS (mass / charge): 459 (M +). + 484 N2- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N4- [3-chloro-4- (N-methylamino) carbonylphenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.69 (s, 1H), 9.60 (s, 1H), 8.25 (m, 3H), 7.85 (m, 3H), 7.36 (m , 3H), 2.75 (d, 3H, J 4.8 Hz), 2.70 (d, 3H, J = 4.5 Hz); LC / MS: purity: 86%, MS (mass / charge): 463 (M +). - 485 N4- [3-Chloro-4- (N-methylamino) carbonylphenyl] -5-fluoro-N2- (indol-6-yl) -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 10.99 (s, 1H), 10.10 (s, 1H), 9.80 (br s, 1H), 8.25 (d, 1H, J = 4, 5 Hz), 8.20 (d, 1H, J = 4.2 Hz), 7.93 (d, 1H, J = 1.8 Hz), 7.83 (broad d, 1H, J = 9, 6 Hz), 7.58 (s, 1H), 7.47 (m, 2H), 7.30 (m, 2H), 7.12 (broad d, 1H, J = 8.1 Hz), 6 38 (s, 1H); LC / MS: purity: 86%; MS (mass / charge): 411 (M +). + + 486 N4- (2-aminopyrid-6-yl) -2-chloro-5-fluoro-4-pyrimidinamine 1 H NMR (CD3OD): d 8.16 (d, 1H, J = 3.6 Hz), 7.46 (m, 2H), 6.32 (dd, 1H, J = 3.9 and 5.1 Hz ); LC / MS: purity: 92%, MS (mass / charge): 240 (M +). - - 487 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (CD3OD): d 7.43 (d, 1H, J = 7.2 Hz), 6.83 (d, 1H, J = 8.4 Hz), 6.78 (d, 1H, J = 2 4 Hz), 6.72 (dd, 1H, J = 2.7 and 8.4 Hz), 4.25 (s, 4H), 3.40 (s, 3H); LC / MS: purity: 100%, MS (mass / charge): 278 (MH +). - - 488 2-Chloro-N4- (3,5-dimethoxyphenyl) -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (CD3OD): d 7.93 (d, 1H, J = 5.4 Hz), 6.46 (s, 3H,), 4.62 (s, 6H), 3.77 (s, 3H) ; LC / MS: purity: 100%, MS (mass / charge): 298 (MH +). + - 489 N2- (2-Ethoxycarbonylindol-7-yl) -5-fluoro-N4- (2-hydroxyethyl) -2,4-pyrimidinediamine 1 H NMR (CD 3 OD): d 7.73 (m, 2H), 7.34 (dd, 1H, J = 1.2 and 8.1 Hz), 7.17 (s, 1H), 7.04 (t , 2H, J = 7.8 Hz), 4.38 (q, 2H, J = 6.9 Hz), 3.69 (t, 2H, J = 5.1 Hz), 3.58 (t, 2H, J = 6.6 Hz); 1.42 (t, 3H, J = 7.2 Hz); LC / MS: purity: 98%, MS (mass / charge): 360 (MH +). - - 490 2-Chloro-N4- (2,6-dimethoxypyrid-5-yl) -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (CD3OD): d 7.89 (d, 1H, J = 5.7 Hz), 7.57 (d, 1H, J = 8.1 Hz), 6.37 (d, 1H, J = 8 , 7 Hz), 3.94 (s, 3H), 3.91 (s, 3H), 3.37 (s, 3H); LC / MS: purity: 97%, MS (mass / charge): 299 (MH +). - - 491 2-Chloro-N4- (3,5-dichloro-4-methoxyphenyl) -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (CD3OD): d 8.02 (d, 1H, J = 5.4 Hz), 7.43 (s, 2H), 3.91 (s, 3H), 3.47 (s, 3H); LC / MS: purity: 89%, MS (mass / charge): 366 (MH +). - - 492 N2- (Bis-2-hydroxyethyl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 7.76 (d, 1H, J = 4.7 Hz), 6.79 (d, 1H, J = 6.3 Hz), 6.75 (d, 1H, J = 2.4 Hz), 6.67 (dd, 1H, J = 2.7 and 9.3 Hz), 4.71 (broad s, 2H), 4.22 (broad s, 4H), 3 57 (br s, 4H); 3.31 (br s, 4H); 3.28 (s, 3H); LC / MS: purity: 97%, MS (mass / charge): 416 (MH +). - - 493 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- [4- (N-methylamino) sulfonyl-3-methoxyphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.58 (s, 1H), 9.29 (s, 1H), 8.11 (d, 1H, J = 3.6 Hz), 7.47 (m, 2H ), 7.42 (broad dd, 1H), 7.27 (d, 1H, J = 2.1 Hz), 7.13 (dd, 1H, J = 2.1 and 8.4 Hz), 6 79 (d, 1H, J = 8.7 Hz), 6.73 (m, 1H), 4.22 (s, 4H), 3.68 (s, 3H), 2.34 (d, 3H, J = 4.8 Hz); LC / MS: purity: 80%; MS (mass / charge): 462 (MH +). + + - 494 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N2- [3-methoxyphenyl-4- (N-methylamino) sulfonyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.57 (s, 1H), 9.33 (s, 1H), 8.11 (d, 1H, J = 3.6 Hz), 7.51 (d, 1H , J = 1.8 Hz), 7.45 (d, 1H, J = 8.4 Hz), 7.34 (dd, 1H, J = 1.8 and 8.7 Hz), 7.24 (m , 2H), 6.90 (d, 1H, J = 9.0 Hz), 6.72 (d, 1H, J = 4.8 Hz), 3.75 (s, 3H), 3.67 (s , 3H), 3.63 (s, 3H), 2.33 (d, 3H, J = 4.8 Hz); LC / MS: purity: 96%; MS (mass / charge): 464 (M +). + + - 495 N4- (3,5-Dimethoxyphenyl) -5-fluoro-N2- [3-methoxyphenyl-4- (methylamino) sulfonyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.64 (s, 1H), 9.37 (s, 1H), 8.16 (brd, 1H), 7.51 (m, 3H), 6.97 (broad s, 2H), 6.71 (broad s, 1H), 6.24 (broad s, 1H), 3.69 (s, 6H), 3.31 (s, 3H), 2, 34 (d, 3H, J = 4.8 Hz); LC / MS: purity: 94%, MS (mass / charge): 464 (M +). + - 496 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3-methoxyphenyl-4- (methylamino) sulfonyl] -2.4 pyrimidinediamine 1 H NMR (DMSO-d6): d 10.62 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.12 (d, 1H, J = 3.9 Hz ), 7.46 (s, 1H), 7.44 (s, 1H), 7.26 (dd, 1H, J = 2.4 and 8.7 Hz), 7.14 (d, 1H, J = 2.4 Hz), 6.90 (d, 1H, J = 8.4 Hz), 6.70 (d, 1H, J = 5.4 Hz), 3.69 (s, 3H), 2.32 (d, 3H, J = 5.1 Hz), 1.41 (s, 6H); LC / MS: purity: 90%; MS (mass / charge): 503 (MH +). + + + 497 N4- (4-Chloro-3-trifluoromethylphenyl) -5-fluoro-N2- [3-methoxyphenyl-4- (methylamino) sulfonyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.88 (s, 1H), 9.72 (s, 1H), 8.26 (m, 2H), 8.18 (d, 1H, J = 4.5 Hz ), 7.65 (d, 1H, J = 8.7 Hz), 7.51 (d, 1H, J = 8.7 Hz), 7.44 (m, 2H), 6.74 (d, 1H , J = 8.4 Hz), 3.72 (s, 3H), 2.34 (d, 3H, J = 5.1 Hz); LC / MS: purity: 97%, MS (mass / charge): 506 (M +). + + - 498 N4- (3-Chloro-4-trifluoromethoxyphenyl) -5-fluoro-N2- [4- (3-methoxyphenyl-N-methylamino) sulfonyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.78 (s, 1H), 9.72 (s, 1H), 8.25 (m, 1H), 8.15 (d, 1H, J = 3.6 Hz ), 7.84 (dd, 1H, J = 2.4 and 9.0 Hz), 7.52 (m, 2H), 7.43 (m, 2H), 6.74 (m, 1H), 3 74 (s, 3H); 2.33 (d, 3H, J = 2.1 Hz); LC / MS: purity: 83%, MS (mass / charge): 522 (M +). + + - 499 5-Fluoro-N4- (3-hydroxyphenyl) -N2- [3-methoxyphenyl-4- (N-methylamino) sulfonyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.57 (s, 1H), 9.38 (s, 1H), 9.31 (s, 1H), 8.13 (d, 1H, J = 3.9 Hz ), 7.51 (m, 1H), 7.47 (m, 2H), 7.21 (d, 1H, J = 1.5 Hz), 7.08 (m, 2H), 6.70 (d , 1H, J = 5.4 Hz), 6.51 (broad dd, 1H, J = 8.1 Hz), 3.31 (s, 3H), 2.30 (d, 3H, J = 2, 4 Hz); LC / MS: purity: 91%; MS (mass / charge): 420 (MH +). + + - 500 N4- (2,6-Dimethoxypyrid-3-yl) -N2, N4-dimethyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 7.66 (d, 1H, J = 5.4 Hz), 7.59 (d, 1H, J = 7.5 Hz), 6.54 (broad d, 1H ), 6.35 (d, 1H, J = 8.4 Hz), 3.85 (s, 3H), 3.83 (s, 3H), 2.71 (d, 3H, J = 3.9 Hz ); LC / MS: purity: 92%, MS (mass / charge): 294 (M +). - - 501 N4- (3,5-Dichloro-4-methoxyphenyl) -N2, N4-dimethyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 7.86 (d, 1H, J = 5.4 Hz), 7.42 (s, 2H), 3.80 (s, 3H), 3.38 (s, 3H ), 2.73 (d, 3H, J = 4.8 Hz); LC / MS: purity: 98%, MS (mass / charge): 331 (M +). - - 502 2-Chloro-5-fluoro-N4- [4- (N-methylamino) sulfonyl-3-methoxyphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.28 (s, 1H), 8.42 (d, 1H, J = 3.0 Hz), 7.71 (d, 1H, J = 1.8 Hz), 7.67 (d, 1H, J = 8.4 Hz), 7.46 (dd, 1H, J = 1.5 and 8.4 Hz), 6.95 (d, 1H, J = 5.4 Hz ), 3.87 (s, 3H), 2.38 (2.38 (d, 3H, J = 4.8 Hz); LC / MS: purity: 80%, MS (mass / charge): 349 (M +2). - - 503 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- [2- (2-hydroxyethyleneoxy) pyrid-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.34 (s, 1H), 9.14 (s, 1H), 8.57 (d, 1H, J = 2.7 Hz), 8.08 (d, 1H , J = 3.0 Hz), 7.98 (dd, 1H, J = 2.7 and 8.7 Hz), 6.91 (d, 2H, J = 1.8 Hz), 6.77 (d , 1H, J = 8.7 Hz), 6.03 (t, 1H, J = 3.6 Hz), 4.23 (t, 2H, J = 4.5 Hz), 3.69 (m, 2H ), 3.65 (s, 3H); 3.62 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 401 (M +). + + - 504 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- [2- (2-hydroxyethyleneoxy) pyrid-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.30 (s, 1H), 9.06 (s, 1H), 8.54 (d, 1H, J = 2.4 Hz), 8.06 (d, 1H , J = 3.6 Hz), 7.94 (dd, 1H, J = 2.7 and 9.0 Hz), 7.20 (d, 2H, J = 0.9 Hz), 6.79 (d , 1H, J = 9.0 Hz), 6.50 (s, 1H), 4.8 (t, 1H, J = 5.7 Hz), 4.23 (t, 2H, J = 5.7 Hz ), 3.70 (q, 2H, = 4.8 Hz), 2.16 (s, 6H); LC / MS: purity: 100%; MS (mass / charge): 369 (M +). + + - 505 N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- [2- (2-hydroxyethyleneoxy) pyrid-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.35 (s, 1H), 9.17 (s, 1H), 8.49 (s, 1H), 8.07 (d, 1H, J = 3.6 Hz ), 7.98 (dd, 1H, J = 2.7 and 9.0 Hz), 7.81 (s, 1H), 7.40 (broad d, 1H, J = 8.7 Hz), 6 98 (d, 1H, J = 8.4 Hz), 6.80 (d, 1H, J = 8.7 Hz), 4.83 (t, 1H, J = 5.7 Hz), 4.24 (t, 1H, J = 4.8 Hz), 3.77 (s, 3H), 3.69 (q, 2H, J = 4.8 Hz); LC / MS: purity: 100%; MS (mass / charge): 406 (MH +). + + - 506 N2-Allyl-N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 7.70 (d, 1H, J = 4.4 Hz), 7.68 (m, 2H), 7.66 (dd, 1H, J = 1.2 and 7, 8 Hz), 5.85 (m, 1H), 5.10 (dd, 1H, J = 1.5 and 16.8 Hz), 5.00 (dd, 1H, J = 1.8 and 12.0 Hz), 4.22 (s, 4H), 3.83 (t, 2H, J = 4.5 Hz), 3.28 (s, 3H); LC / MS: purity: 100%; MS (mass / charge): 317 (MH +). - - 507 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- [4- (N-methylamino) sulfonyl-3-methoxyphenyl] -2,4-pyrimidinediamine LC / MS: purity: 80%, MS (mass / charge): 464 (MH +). + + - 508 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- (3-methylpyrid-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.50 (s, 1H), 9.22 (s, 1H), 8.16 (s, 1H), 8.13 (dd, 1H, J = 0.9 and 6.6 Hz), 8.06 (d, 1H, J = 8.7 Hz), 7.55 (broad dd, 1H, J = 5.7 Hz), 6.94 (d, 2H, J = 1.2 Hz), 6.07 (t, 1H, J = 1.2 Hz), 3.68 (s, 3H), 3.66 (s, 3H), 2.49 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 356 (MH +). + + - 509 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (3-methylpyrid-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.46 (s, 1H), 9.14 (s, 1H), 3.17 (br s, 1H), 8.13 (d, 1H, J = 3, 3 Hz), 8.04 (d, 1H, J = 8.4 Hz), 7.55 (dd, 1H, J = 2.1 and 8.4 Hz), 7.24 (s, 2H), 6 24 (s, 1H); 3.33 (s, 3H); 3.32 (s, 3H); 2.18 (s, 3H); LC / MS: purity: 93%, MS (mass / charge): 324 (MH +). + + - 510 N4- (5-Chloropyrid-2-yl) -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 93%, MS (mass / charge): 376 (MH +). + + - 511 5-Fluoro-N4- (3-hydroxyphenyl) -N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.39 (s, 1H), 9.30 (s, 1H), 9.22 (s, 1H), 8.29 (br s, 1H), 8.14 (s, 1H), 8.11 (d, 1H, J = 3.9 Hz), 7.90 (dd, 1H, J = 1.2 and 9.0 Hz), 7.50 (dd, 1H, J = 1.5 and 6.3 Hz), 7.33 (m, 3H), 7.09 (t, 1H, J = 2.1 Hz), 7.01 (t, 1H, J = 8.1 Hz), 6.45 (dd, 1H, J = 1.5 and 7.8 Hz); LC / MS: purity: 98%; MS (mass / charge): 364 (MH +). + 512 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- [3- (1,2,4-oxadiazol-3-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.54 (s, 1H), 9.26 (s, 1H), 8.18 (s, 1H), 8.10 (d, 1H, J = 2.4 Hz ), 7.83 (broad d, 1H, J = 8.1 Hz), 7.38 (t, 1H, J = 7.8 Hz), 7.27 (m, 2H), 7.13 (broad d, 1H, J = 8.7 Hz), 6.82 (d, 1H, J = 9.0 Hz), 4.22 (s, 4H); LC / MS: purity: 91%, MS (mass / charge): 406 (M +). + - 513 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N2- [3- (1,2,4-oxadiazol-3-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.53 (s, 1H), 9.29 (s, 1H), 8.21 (s, 1H), 8.10 (d, 1H, J = 3.9 Hz ), 7.79 (dd, 1H, J = 1.2 and 8.4 Hz), 7.33 (m, 3H), 7.16 (s, 1H), 6.94 (d, 1H, J = 8.7 Hz), 3.75 (s, 3H), 3.70 (s, 3H); LC / MS: purity: 95%, MS (mass / charge): 407 (MH-). + - 514 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (1,2,4-oxadiazol-3-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.6 (s, 1H), 9.49 (s, 1H), 9.40 (, s, 1H), 8.15 (d, 1H, J = 8.1 Hz), 8.11 (d, 1H, J = 3.9 Hz), 7.85 (broad d, 1H, J = 8.4 Hz), 7.29 (m, 3H), 7.13 ( d, 1H, J = 2.4 Hz), 6.91 (dd, 1H, J = 3.0 and 8.4 Hz), 5.73 (d, 1H, J = 3.6 Hz), 1, 40 (s, 3H); LC / MS: purity: 91%; MS (mass / charge): 446 (M-). + - 515 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N2- [5-methoxycarbonyl-3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.61 (s, 1H), 9.27 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 8.17 (d , 1H, J = 0.9 Hz), 8.12 (d, 1H, J = 3.6 Hz), 8.04 (d, 1H, J = 1.5 Hz), 7.35 (m, 2H ), 7.27 (m, 1H), 6.76 (d, 1H, J = 7.8 Hz), 3.82 (s, 3H), 3.70 (s, 3H), 3.65 (s , 3H); LC / MS: purity: 99%; MS (mass / charge): 466 (MH +). + - 516 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- [5-methoxycarbonyl-3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.64 (s, 1H), 9.23 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 8.19 (s , 1H), 8.12 (d, 1H, J = 3.3 Hz), 8.05 (s, 1H), 7.38 (m, 2H), 7.22 (dd, 1H, J = 2, 7 and 8.7 Hz), 6.70 (d, 1H, J = 8.7 Hz), 5.74 (s, 1H), 4.15 (s, 4H), 3.85 (s, 3H) ; LC / MS: purity: 98%; MS (mass / charge): 464 (MH +). - - 517 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [5-methoxycarbonyl-3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.51 (s, 1H), 9.54 (s, 1H), 9.40 (s, 1H), 8.63 (s, 1H), 8.39 (s , 1H), 8.18 (s, 1H), 8.14 (d, 1H, J = 3.9 Hz), 8.04 (s, 1H), 7.44 (dd, 1H, J = 2, 1 and 8.7 Hz), 7.37 (s, 1H), 6.77 (d, 1H, J = 8.4 Hz), 3.84 (s, 3H), 1.38 (s, 6H) ; LC / MS: purity: 90%; MS (mass / charge): 505 (MH +). - - 518 5-Fluoro-N4- (3-hydroxyphenyl) -N2- [5-methoxycarbonyl-3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.64 (s, 1H), 9.25 (s, 1H), 8.62 (s, 1H), 8.43 (s, 1H), 8.19 (s , 1H), 8.15 (d, 1H, J = 3.9 Hz), 8.05 (s, 1H), 7.38 (s, 2H), 7.36 (s, 2H), 7.13 (s, 1H), 6.98 (t, 1H, J = 8.7 Hz), 6.42 (dd, 1H, J = 2.4 and 6.6 Hz), 3.83 (s, 3H) ; LC / MS: purity: 98%; MS (mass / charge): 422 (M +). + - 519 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- [3- (oxazol-2-yl) -5-trifluoromethylphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.75 (s, 1H), 9.23 (s, 1H), 8.59 (s, 1H), 8.22 (t, 2H, J = 0.9 Hz ), 8.14 (d, 1H, J = 3.9 Hz), 7.69 (s, 1H), 7.40 (s, 1H), 7.31 (d, 1H, J = 2.4 Hz ), 7.19 (dd, 1H, J = 2.7 and 9.0 Hz), 6.72 (d, 1H, J = 8.4 Hz), 4.17 (s, 4H); LC / MS: purity: 92%; MS (mass / charge): 474 (MH +). + - 520 N4- (3,4-Dimethoxyphenyl) -5-fluoro-N2- [3- (oxazol-2-yl) -5-trifluoromethylphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.73 (s, 1H), 9.31 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 8.20 (broad) s, 1H), 8.14 (d, 1H, J = 4.2 Hz), 7.68 (s, 1H), 7.40 (s, 1H), 7.33 (broad dd, 1H, J = 9.0 Hz), 7.23 (br s, 1H), 6.82 (d, 1H, J = 7.5 Hz), 3.71 (s, 3H), 3.68 (s, 3H); LC / MS: purity: 97%; MS (mass / charge): 476 (MH +). + - 521 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) -5-trifluoromethylphenyl] - 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.54 (s, 1H), 9.70 (s, 1H), 9.42 (s, 1H), 8.54 (s, 1H), 8.27 (s , 1H), 8.21 (s, 1H), 8.16 (d, 1H, J = 2.7 Hz), 7.67 (s, 1H), 7.40 (d, 1H), 7.33 (broad dd, 1H, J = 8.4 Hz), 7.17 (d, 1H, J = 2.4 Hz), 6.81 (d, 1H, J = 8.4 Hz), 1.39 (s, 6H); LC / MS: purity: 100%; MS (mass / charge): 515 (MH +). + - 522 5-Fluoro-N4- (3-hydroxyphenyl) -N2- [3- (1,2,4-oxadiazol-3-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.55 (s, 1H), 9.36 (s, 1H), 9.30 (s, 1H), 8.13 (m, 2H), 7.88 (broad) d, 1H, J = 7.8 Hz), 7.38 (t, 1H, J = 7.8 Hz), 7.27 (m, 2H), 7.13 (t, 1H, J = 7, 8 Hz), 7.02 (s, 1H), 6.50 (broad dd, 1H, J = 5.7 Hz); LC / MS: purity: 95%; MS (mass / charge): 364 (M +). + 523 2-Chloro-5-fluoro-N4-methyl-N4- (3,4,5-trimethoxyphenyl) -4-pyrimidinamine 1 H NMR (DMSO-d6): d 8.11 (d, 1H, J = 5.4 Hz), 6.79 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H ), 3.65 (s, 3H); 3.38 (s, 3H); LC / MS: purity: 94%, MS (mass / charge): 329 (MH +). - 524 5-Fluoro-N4- (5-methylisoxazol-3-yl) -N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.45 (s, 1H), 9.59 (s, 1H), 8.33 (s, 1H), 8.21 (d, 1H, J = 2.7 Hz ), 8.18 (s, 1H), 7.83 (broad d, 1H, J = 7.2 Hz), 7.55 (broad d, 1H, J = 8.1 Hz), 7.40 (t, 1H, J = 8.1 Hz), 7.35 (s, 1H, J = 6.92 (s, 1H), 2.29 (s, 3H); LC / MS: purity: 100%, MS (mass / charge): 353 (MH +). + 525 5-Fluoro-N4- (5-methyl-3-phenylisoxazol-4-yl) -N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.33 (s, 1H), 9.06 (s, 1H), 8.23 (s, 1H), 8.14 (br s, 1H), 8.09 (d, 1H, J = 3.6 Hz), 7.66 (m, 3H), 7.43 (m, 4H), 7.32 (s, 1H), 7.24 (t, 1H, J = 7.2 Hz), 2.36 (s, 3H); LC / MS: purity: 85%, MS (mass / charge): 429 (MH +). + 526 5-Fluoro-N4- (1-methyl-3-phenylpyrazol-5-yl) -N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.48 (m, 2H), 8.19 (m, 2H), 8.11 (m, 2H), 7.77 (m, 2H), 7.35 (m 6H); 6.73 (s, 1H); 3.32 (s, 3H); LC / MS: purity: 83%, MS (mass / charge): 428 (MH +). + 527 N2, N4-Bis [3-methoxycarbonyl-5- (oxazol-2-yl) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.89 (s, 1H), 9.83 (s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 8.46 (s , 1H), 8.35 (s, 1H), 8.27 (d, 1H, J = 3.6 Hz), 8.08 (m, 3H), 7.30 (s, 1H), 7.27 (s, 3H); 3.71 (s, 3H); 3.68 (s, 3H); LC / MS: purity: 86%, MS (mass / charge): 531 (MH +). + 528 N2, N4-Bis (3,5-dimethylisoxazol-4-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 8.76 (s, 1H), 8.13 (s, 1H), 7.83 (d, 1H, J = 3.9 Hz), 2.19 (s, 3H ), 2.10 (s, 3H), 2.03 (s, 3H), 1.85 (s, 3H); LC / MS: purity: 91%, MS (mass / charge): 319 (MH +). - 529 N2, N4-Bis [3- (oxazol-2-yl) -5-trifluoromethylphenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.99 (s, 1H), 9.19 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.31 (d , 1H, J = 2.7 Hz), 8.11 (d, 1H, J = 5.1 Hz), 8.05 (s, 1H), 7.79 (s, 1H), 7.61 (s , 1H); 7.31 (s, 1H); 7.27 (s, 1H); LC / MS: purity: 92%, MS (mass / charge): 551 (MH +). + 530 N2 - [(2-tert-Butyl-1,3,4-oxadiazol-5-yl) phenyl] -N4- (3,4-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.43 (s, 1H), 9.23 (s, 1H), 8.25 (s, 1H), 8.08 (d, 1H, J = 3.6 Hz ), 7.93 (broad d, 1H, J = 8.7 Hz), 7.49 (broad d, 1H, J = 7.5 Hz), 7.35 (m, 2H), 7.25 (d, 1H, J = 2.4 Hz), 6.75 (d, 1H, J = 8.7 Hz), 3.70 (s, 3H), 3.66 (s, 3H), 1.37 (s, 9H). + + + 531 N2 - [(2-tert-Butyl-1,3,4-oxadiazol-5-yl) phenyl] -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.45 (s, 1H), 9.19 (s, 1H), 8.25 (t, 1H, J = 1.8 Hz), 8.07 (d, 1H , J = 3.3 Hz), 7.87 (broad d, 1H, J = 2.4 Hz), 7.51 (wide d, 1H, J = 7.8 Hz), 7.40 (m , 2H), 7.16 (dd, 1H, J = 2.4 and 8.7 Hz), 6.70 (d, 1H, J = 9 Hz), 4.15 (m, 4H), 1.37 (s, 9H); LC / MS: purity: 95%; MS (mass / charge): 463 (MH +). + 532 N2 - [(2-tert-Butyl-1,3,4-oxadiazol-5-yl) phenyl] -5-fluoro-N4- (3-hydroxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.45 (s, 1H), 9.28 (s, 1H), 9.23 (s, 1H), 8.24 (s, 1H), 8.11 (d , 1H, J = 3.9 Hz), 8.00 (broad d, 1H, J = 8.1 Hz), 7.50 (d, 1H, J = 7.8 Hz), 7.39 (t , 1H, J = 8.4 Hz), 7.30 (broad d, 1H, J = 8.4 Hz), 7.12 (t, 1H, J = 2.1 Hz), 6.99 (t , 1H, J = 8.4 Hz), 6.43 (dd, 1H, J = 1.8 and 8.4 Hz), 1.38 (s, 9H); LC / MS: purity: 93%; MS (mass / charge): 421 (MH +). + 533 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N4-methyl-2-hydrazine-4-pyrimidinamine 1 H NMR (DMSO-d6): d 7.61 (d, 1H, J = 5.4 Hz), 6.86 (m, 1H), 6.69 (m, 2H), 4.29 (s, 4H ), 3.51 (s, 3H); LC / MS: purity: 90%, MS (mass / charge): 292 (MH +). - 534 N4- (3,5-Dimethylisoxazol-4-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.35 (s, 1H), 8.88 (s, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 8.10 (d , 1H, J = 3.6 Hz), 7.71 (broad d, 1H, J = 7.8 Hz), 7.45 (d, 1H, J = 6.6 Hz), 7.32 (d , 1H, J = 0.9 Hz), 7.29 (t, 1H, J = 8.1 Hz), 2.87 (s, 3H), 2.10 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 367 (MH +). + 535 N4- (3,5-Dimethylisoxazol-4-yl) -5-fluoro-N2- [5-methoxycarbonyl-3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine LC / MS: purity: 85%, MS (mass / charge): 425 (MH +). + 536 N2- (3,5-Dimethyl-4-methoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine salt of p-toluenesulfonic acid 1 H NMR (DMSO-d6): d 11.16 (s, 1H), 10.00 (s, 1H), 9.52 (s, 1H), 8.16 (d, 1H, J = 4.2 Hz ), 7.46 (m, 2H), 7.35 (d, 1H, J = 8.1 Hz), 7.13 (s, 2H), 7.08 (d, 1H, J = 2.4 Hz ), 3.60 (s, 3H), 2.28 (s, 3H), 2.14 (s, 6H), 1.43 (s, 6H); LC / MS: purity: 99%, MS (mass / charge): 439. - 537 N2- (3,5-Dimethyl-4-methoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine salt of benzenesulfonic acid 1 H NMR (DMSO-d6): d 11.19 (s, 1H), 10.52 (s, 1H), 9.65 (s, 1H), 8.19 (d, 1H, J = 4.5 Hz ), 7.56 (m, 2H), 7.44 (d, 1H, J = 8.4 Hz), 7.35 (d, 1H, J = 8.4 Hz), 7.30 (m, 3H ), 7.10 (s, 2H), 3.60 (s, 3H), 2.14 (s, 6H), 1.43 (s, 6H); LC / MS: purity: 93%, MS (mass / charge): 439 (MH +, for parenteral ion). - 538 N2- (3,5-Dimethyl-4-methoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine salt of methanesulfonic acid 1 H NMR (DMSO-d6): d 11.80 (s, 1H), 10.16 (s, 1H), 9.73 (s, 1H), 8.21 (d, 1H, J = 4.2 Hz ), 7.44 (d, 1H, J = 8.4 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.12 (s, 2H), 3.60 (s, 3H ), 2.32 (s, 3H), 2.13 (s, 6H), 1.43 (s, 6H); LC / MS: purity: 97%, MS (mass / charge): 439 (MH +, for parenteral ion). - 539 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (2-trifluoromethyl-3H-benzimidazol-5-yl) -2, 4-pyrimidinediamine salt of p-toluenesulfonic acid 1 H NMR (DMSO-d6): d 10.67 (s, 1H), 10.60 (s, 1H), 10.05 (s, 1H), 8.20 (d, 1H, J = 4.8 Hz ), 7.84 (s, 1H), 7.62 (d, 1H, J = 9 Hz), 7.45 (broad d, 2H, J = 7.8 Hz), 7.23 (d, 1H , J = 8.7 Hz), 7.15 (s, 1H), 7.09 (d, 1H, J = 7.8 Hz), 6.85 (d, 1H, J = 8.7 Hz), 2.28 (s, 3H); 1.38 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 488 (MH +, for parenteral ion). + 540 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (2-trifluoromethyl-3H-benzimidazol-5-yl) -2, 4-pyrimidinediamine salt of benzenesulfonic acid 1 H NMR (DMSO-d6): d 10.66 (s, 1H), 10.20 (s, 1H), 9.90 (s, 1H), 8.17 (d, 1H, J = 4.5 Hz ), 7.88 (s, 1H), 7.57 (m, 3H), 7.48 (d, 1H, J = 8.4 Hz), 7.29 (m, 4H), 7.15 (s , 1H); 6.85 (d, 1H), J = 8.4 Hz); LC / MS: purity: 95%, MS (mass / charge): MH +, for parenteral ion). + 541 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (2-trifluoromethyl-3H-benzimidazol-5-yl) -2, 4-pyrimidinediamine salt of methanesulfonic acid 1 H NMR (DMSO-d6): d 10.67 (s, 1H), 10.45 (s, 1H), 10.19 (s, 1H), 8.23 (d, 1H, J = 5.1 Hz ), 7.80 (s, 1H), 7.62 (d, 1H, J = 8.7 Hz), 7.45 (d, 1H, J = 8.4 Hz), 7.11 (s, 1H ), 6.85 (d, 1H, J = 8.4 Hz), 2.38 (s, 3H), 1.37 (s, 6H); LC / MS: purity: 99%, MS (mass / charge): 488 (MH +, for parenteral ion + 542 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (2-trifluoromethyl-3H-benzimidazol-5-yl) -2, 4-pyrimidinediamine hydrochloride salt 1 H NMR (DMSO-d6): d 10.64 (s, 1H), 9.90 (s, 1H), 9.80 (s, 1H), 8.15 (d, 1H, J = 4.8 Hz ), 7.96 (s, 1H), 7.59 (d, 1H, J = 8.7 Hz), 7.50 (dd, 1H, J = 1.5 and 9.3 Hz), 7.25 (m, 2H); 6.87 (d, 1H, J = 8.4 Hz); LC / MS: purity: 99%, MS (mass / charge): 488 (MH +, for parenteral ion). + 543 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine LC / MS: purity: 98%; MS (mass / charge): 470 (MH +); + + + 544 N4- (2-amino-3-methoxy-pyrid-6-yl) -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 92%; MS (mass / charge): 387 (MH +) + 545 N4- (2-amino-3-methoxypyrid-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine LC / MS: purity: 94%; MS (mass / charge): 417 (MH +) + 546 N4- (2-amino-3-methoxypyrid-6-yl) -5-fluoro-N2- (2-methoxycarbonylbenzofuran-5-yl) -2,4-pyrimidinediamine LC / MS: purity: 82%; MS (mass / charge): 425 (MH +) + 547 N4- (2-amino-3-methoxypyrid-6-yl) -5-fluoro-N2 [3- (N-methylaminocarbonylmethyleneoxy) phenyl] -2,4-pyrimidinediamine LC / MS: purity: 89%; MS (mass / charge): 414 (MH +) + 548 N2- (3,5-Dichloro-4-hydroxyphenyl) -N4- (3,5-dichloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 92%; MS (mass / charge): 465 (MH +) + + 549 N4- (4-Acetyl-2,2-dimethyl-3-oxopyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine LC / MS: purity: 97%; MS (mass / charge): 513 (M +) 550 N4-Acetyl-N4- (2,2-dimethyl-3-oxo-4H-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2, 4-pyrimidinediamine LC / MS: purity: 96%; MS (mass / charge): 513 (M +) 551 N2-Acetyl-N4- (2,2-dimethyl-3-oxo-4H-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2, 4-pyrimidinediamine LC / MS: purity: 95%; 514 (MH +) 552 2, N4-Bis [3-methyl-4- (4-methylpiperazinyl) phenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 99%; MS (m / e): 506 (MH +) 553 N4- (3,5-Dimethylphenyl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.14 (br s, 1H), 9.04 (s, 1H), 8.06 (d, J = 3.9 Hz, 1H), 7.40- 7.36 (m, 2H), 6.95 (s, 2H), 6.67 (s, 1H), 3.58-3.56 (m, 9H), 2.19 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 399 (MH +). + 554 N2- (3-Chloro-4-hydroxy-5-methylphenyl) -5-fluoro-N4- (3,5-dimethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.21 (br s, 1H), 9.04 (br s, 1H), 8.63 (br s, 1H), 8.05 (d, J = 3.6 Hz, 1H), 7.53-7.49 (m, 1H), 7.34-7.30 (m, 2H), 7.24-7.20 (m, 1H), 6, 69 (br s, 1H), 2.22 (s, 6H), 2.09 (s, 3H); LC / MS: purity: 93%; MS (mass / charge): 373 (MH +). + 555 N2- [3,5-Bis (hydroxymethylene) phenyl] -N4- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.11 (s, 2H), 8.06 (d, J = 3.9 Hz, 1H), 7.45 (s, 2H), 7.38 (s, 2H), 6.85 (s, 1H), 6.68 (s, 1H), 4.38-4.34 (m, 4H), 2.22 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 369 (MH +). + 556 N2- (3,5-Dichlorophenyl) -N4- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.76 (br s, 1H), 9.51 (br s, 1H), 8.18 (d, J = 3.9 Hz, 1H), 7, 73-7.69 (m, 2H), 7.29-7.25 (m, 2H), 7.04 (t, J = 1.8 Hz, 1H), 6.75 (s, 1H), 2 25 (s, 6H); LC / MS: purity: 92%; MS (mass / charge): 378 (MH +). + + 557 N4- (3,5-Dimethylphenyl) -5-fluoro-N2- [2- (N-methylamino) carbonylindol-7-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.66 (s, 1H), 9.37 (s, 1H), 9.28 (s, 1H), 8.48-8.40 (m, 1H), 8.13 (d, J = 3.6 Hz, 1H), 7.98-7.88 (m, 1H), 7.33 (s, 2H), 7.22 (d, J = 7.8 Hz , 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.90 (t, J = 8.1 Hz. 1H), 6.71 (s, 1H), 2.80 (d J = 3.0 Hz, 3H); 2.23 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 405 (MH +). - 558 5-Fluoro-N4- (3-methoxy-5-trifluoromethylphenyl) -N2- [2- (N-methylamino) carbonylindol-7-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.57 (s, 1H), 9.65 (s, 1H), 9.40 (s, 1H), 8.39-8.35 (m, 1H), 8.15 (d, J = 3.9 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.57-7 52 (m, 1H), 7.18 (d, J = 7.8 Hz, 1H), 9.98 (d, J = 1.8 Hz, 1H), 6.87-6.80 (m, 2H), 3.70 (s, 3H), 2.74 (d, J = 4.5 Hz, 3H); 19F NMR (282 MHz, DMSO-d6): -61.70, -162.97; LC / MS: purity: 99%; MS (mass / charge): 475 (MH +). + 559 N2- (3,5-Dichloro-4-hydroxyphenyl) -N4- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.49 (s, 1H), 9.21 (s, 1H), 9.19 (s, 1H), 8.08 (d, J = 3.3 Hz, 1H), 7.66 (d, J = 1.5 Hz, 2H), 7.29 (s, 2H), 6.70 (s, 1H), 2.24 (s, 6H); LC / MS: purity: 95%; MS (mass / charge): 394 (MH +). + + 560 N2- (4-Chloro-3,5-dimethylphenyl) -N4- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.17 (s, 1H), 9.13 (s, 1H), 8.07 (d, J = 3.9 Hz, 1H), 7.45 (s, 2H), 7.30 (s, 2H), 6.72 (s, 1H), 2.22 (s, 6H), 2.18 (s, 6H); LC / MS: purity: 93%; MS (mass / charge): 372 (MH +). - 561 N4- [3,4- (Difluoromethylenedioxy) phenyl] -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.53 (s, 1H), 9.13 (s, 1H), 8.17-8.12 (m, 1H), 8.11 (d, J = 3 , 9 Hz, 1H), 7.42 (dd, J = 2.4 and 9.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.00 (s, 2H ), 3.64 (s, 6H); 19F NMR (282 MHz, DMSO-d6): -49.77, -164.19; LC / MS: purity: 93%; MS (mass / charge): 451 (MH +). + 562 N4- [3,4- (Difluoromethylenedioxy) phenyl] -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.54 (s, 1H), 9.22 (s, 1H), 8.12 (d, J = 3.6 Hz, 1H), 8.11-8, 08 (m, 1H), 7.42 (dd, J = 2.1 and 9.0 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 2.1 Hz, 2H), 6.07 (t, J = 2.4 Hz, 1H), 3.65 (s, 6H); 19F NMR (282 MHz, DMSO-d6): -49.69, -163.86; LC / MS: purity: 96%; MS (mass / charge): 421 (MH +). + + 563 N4- [3,4- (Difluoromethylenedioxy) phenyl] -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.51 (s, 1H), 9.13 (s, 1H), 8.11 (d, J = 3.6 Hz, 1H), 8.09-8, 06 (m, 1H), 7.39 (dd, J = 2.1 and 8.7 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H), 7.22 (s, 2H ), 6.53 (s, 1H); 2.16 (s, 6H); 19F NMR (282 MHz, DMSO-d6): -49.67, -164.51; LC / MS: purity: 98%; MS (mass / charge): 389 (MH +). + + 564 N2- (3,5-Dichloro-4-hydroxyphenyl) -N4- [3,4- (difluoromethylenedioxy) phenyl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.59 (s, 1H), 9.45 (br s, 1H), 9.31 (s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 7.85-7.79 (m, 1H), 7.55 (s, 1H), 7.29 (s, 1H); 19F NMR (282 MHz, DMSO-d6): -49.50, -163.68; LC / MS: purity: 96%; MS (mass / charge): 446 (MH +). + 565 N2- (3,5-Dichlorophenyl) -N4- [3,4- (difluoromethylenedioxy) phenyl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.62-9.68 (m, 2H), 8.19 (d, J = 3.6 Hz, 1H), 7.92-7.88 (m, 1H ), 7.71 (s, 1H), 7.70 (s, 1H), 7.38-7.33 (m, 2H), 7.00 (t, J = 1.8 Hz, 1H); 19F NMR (282 MHz, DMSO-d6): -49.51, -162.64; LC / MS: purity: 99%; MS (mass / charge): 430 (MH +). + 566 N2- (4-Chloro-3,5-dimethylphenyl) -N4- [3,4- (difluoromethylenedioxy) phenyl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.84 (s, 1H), 9.51 (s, 1H), 8.18 (s, J = 2.7 Hz, 1H), 7.99 (br. s, 1H), 7.41-7.35 (m, 4H), 2.22 (s, 6H); LC / MS: purity: 94%; MS (mass / charge): 424 (MH +). - 567 N2- (3-Chloro-4-hydroxy-5-methylphenyl) -N4- [3,4- (difluoromethylenedioxy) phenyl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.57 (s, 1H), 9.14 (s, 1H), 8.58 (br s, 1H), 8.05 (d, J = 3.9 Hz, 1H), 7.90 (s, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 1.8 and 8.7 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.14-7.09 (m, 1H), 2.06 (s, 3H); 19F NMR (282 MHz, DMSO-d6): -49.60, -164.34; LC / MS: purity: 97%; MS (mass / charge): 425 (MH +). + 568 N4- [3,4- (Difluoromethylenedioxy) phenyl] -5-fluoro-N2- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.60 (s, 1H), 9.56 (s, 1H), 8.17 (d, J = 3.3 Hz, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 7.41-7.31 (m, 2H), 6.72 (s, 1H), 3.74 (s, 3H ); 19F NMR (282 MHz, DMSO-d6): -49.75, -61.96, -162.93; LC / MS: purity: 93%; MS (mass / charge): 459 (MH +). - 569 N4- [3,4- (Difluoromethylenedioxy) phenyl] -5-fluoro-N2- (3-methyl-5-trifluoromethylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.66 (s, 1H), 9.59 (s, 1H), 8.19 (d, J = 3.6 Hz, 1H), 8.04-7, 97 (m, 1H), 7.84 (br s, 1H), 7.68 (br s, 1H), 7.36 (br s, 2H), 7.03 (s, 1H), 2 29 (s, 3H); 19F NMR (282 MHz, DMSO-d6): -49.63, -61.86, -163.10; LC / MS: purity: 98%; MS (mass / charge): 443 (MH +). + 570 N4- [3,4- (Difluoromethylenedioxy) phenyl] -5-fluoro-N2- [2- (N-methylamino) carbonylindol-7-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.56 (s, 1H), 9.63 (s, 1H), 9.34 (s, 1H), 8.44-8.38 (m, 1H), 8.12 (d, J = 3.6 Hz, 1H), 7.97 (br s, 1H), 7.84-7.78 (m, 1H), 7.38-7.32 (m, 1H), 7.26 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.87 (t, J = 7.8 Hz, 1H); 2.74 (d, J = 3.6 Hz, 3H); 19 NMR (282 MHz, DMSO-d6): -49.66, -163.58; LC / MS: purity: 99%; MS (mass / charge): 457 (MH +). + 571 N4- (3-Chloro-4-methoxyphenyl) -N2- [3,5-dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.28 (s, 1H), 9.03 (s, 1H), 8.15-8.07 (m, 1H), 8.05 (d, J = 3 , 3 Hz, 1H), 7.76-7.72 (m, 2H), 7.68-7.60 (m, 1H), 7.23 (s, 2H), 7.09 (d, J = 9.0 Hz, 1H), 4.10 (s, 2H), 3.83 (s, 3H), 2.69 (d, J = 4.2 Hz, 3H), 2.11 (s, 6H) ; LC / MS: purity: 99%; 461 (MH +). + + 572 N2- [3,5-dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.08 (s, 1H), 8.95 (s, 1H), 8.14-8.06 (m, 1H), 8.00 (d, J = 3 , 6 Hz, 1H), 7.23-7.25 (m, 3H), 7.20-7.14 (m, 1H), 6.78 (d, J = 8.7 Hz, 1H), 4 21 (s, 4H), 4.11 (s, 2H), 2.69 (d, J = 4.5 Hz, 3H), 2.13 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 454 (MH +). + + 573 N4- (3,5-Dimethoxyphenyl) -N2- [3,5-dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.20 (s, 1H), 9.01 (s, 1H), 8.14-8.05 (m, 2H), 7.29 (s, 2H), 7.00-6.96 (m, 2H), 6.24-6.19 (m, 1H), 4.11 (s, 2H), 3.67 (s, 6H), 2.70 (d, J = 4.8 Hz, 3H); 2.12 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 456 (MH +). + + 574 N2- [3,5-dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.59 (s, 1H), 9.32 (s, 1H), 8.95 (s, 1H), 8.11-8.06 (m, 1H), 8.04 (d, J = 3.9 Hz, 1H), 7.34-7.23 (m, 3H), 7.21-7.18 (m, 1H), 6.87 (d, J = 9.0 Hz, 1H), 4.10 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H), 2.11 (s, 6H), 1.40 (s, 6H) ; LC / MS: purity: 95%; MS (mass / charge): 495 (MH +). + + 575 N2- [3,5-dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N4- (3,4-methylenedioxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.15 (s, 1H), 8.96 (s, 1H), 8.12-8.05 (m, 1H), 8.01 (d, J = 3 , 9 Hz, 1H), 7.44-7.40 (m, 1H), 7.25 (s, 2H), 7.15-7.07 (m, 1H), 6.84 (d, J = 8.1 Hz, 1H), 5.98 (s, 2H), 4.11 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H), 2.13 (s, 6H) ; LC / MS: purity: 99%; MS (mass / charge): 440 (MH +). + + 576 2-Chloro-5-fluoro-N4- (2-isopropoxypyrid-5-yl) -N4-methyl-4-pyrimidinamine 1 H NMR (DMSO-d6): d 8.17 (d, J = 2.7 Hz, 1H), 8.14 (d, J = 5.4 Hz, 1H), 7.74 (dd, J = 2 , 7 and 8.7 Hz, 1H), 6.77 (dd, J = 0.6 and 8.7 Hz, 1H), 5.21 (quintet, J = 6.3 Hz, 1H), 3.38 (s, 3H); 1.29 (d, J = 6.3 Hz, 6H); LC / MS: purity: 95%; MS (mass / charge): 298 (MH +). - - 577 N4- (3-Chloro-4-methoxyphenyl) -N2- (3,5-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 7.95 (d, J = 5.7 Hz, 1H), 7.46 (d, J = 2.7 Hz, 1H), 7.28 (dd, J = 2 , 4 and 9.0 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 6.98 (s, 1H), 6.97 (s, 1H), 6.09-6 06 (m, 1H), 3.86 (s, 3H), 3.69 (s, 6H), 3.44 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 419 (MH +). + - 578 N2- (3-Chloro-4-methoxy-5-methylphenyl) -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.41 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.69 (d, J = 2.7 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.28 (dd, J = 2.7 and 8.7 Hz, 1H ), 7.14 (d, J = 8.7 Hz, 1H), 3.87 (s, 3H), 3.68 (s, 3H), 3.42 (s, 3H), 2.19 (s , 3H); LC / MS: purity: 86%; MS (mass / charge): 438 (MH +). + - 579 N4- (3-Chloro-4-methoxyphenyl) -N2- [3,5-dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.24 (s, 1H), 8.16-8.04 (m, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.31-7.24 (m, 3H), 7.15 (d, J = 8.7 Hz, 1H), 4.12 (s, 2H) 3.87 (s, 3H); 3.42 (s, 3H); 2.69 (d, J = 4.8 Hz, 3H); 2.15 (s, 6H); LC / MS: purity: 92%; MS (mass / charge): 475 (MH +). + - 580 N4- (3-Chloro-4-methoxyphenyl) -N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.63 (br s, 1H), 8.02 (d, J = 6.3 Hz, 1H), 8.00-7.97 (m, 1H), 7 50 (d, J = 2.7 Hz, 1H), 7.36-7.34 (m, 1H), 7.33-7.20 (m, 3H), 7.16 (d, J = 9 , 0 Hz, 2H), 6.57-6.52 (m, 1H), 4.41 (s, 2H), 3.87 (s, 3H), 3.44 (s, 3H), 2.64 (d, J = 4.8 Hz, 3H); LC / MS: purity: 94%; MS (mass / charge): 447 (MH +). + - 581 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- (2-isopropoxypyrid-5-yl) -N4-methyl-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.47 (br s, 1H), 8.14 (d, J = 2.7 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H ), 7.71 (dd, J = 3.0 and 8.7 Hz, 1H), 6.96-6.93 (m, 2H), 6.77 (dd, J = 0.6 and 8.7 Hz, 1H), 6.12 (t, J = 2.1 Hz, 1H), 5.21 (quintet, J = 6.3 Hz, 1H), 3.70 (s, 6H), 3.45 ( s, 3H), 1.29 (d, J = 6.3 Hz, 6H); LC / MS: purity: 93%; MS (mass / charge): 414 (MH +). + - 582 5-Fluoro-N4- (2-isopropoxypyrid-5-yl) -N4-methyl-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.53 (s, 1H), 8.14 (d, J = 3.0 Hz, 1H), 8.02-7.93 (m, 2H), 7.70 (dd, J = 2.7 and 8.7 Hz, 1H), 7.37 (t, J = 2.1 Hz, 1H), 7.26-7.20 (m, 1H), 7.13 ( t, J = 8.1 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 6.56-6.50 (m, 1H), 5.22 (quintet, J = 6 , 0 Hz, 1H), 4.40 (s, 2H), 3.44 (s, 3H), 2.64 (d, J = 4.8 Hz, 3H), 1.30 (d, J = 6 , 0 Hz, 6H); LC / MS: purity: 95%; MS (mass / charge): 441 (MH +). + - 583 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (2-isopropoxypyrid-5-yl) -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.42 (s, 1H), 8.14 (d, J = 2.7 Hz, 1H), 8.01 (d, J = 6.6 Hz, 1H), 3.45 (s, 3H), 2.19 (s, 6H), 1.29 (d, J = 6.3 Hz, 6H), 7.70 (dd, J = 2.7 and 8.7 Hz , 1H), 7.24 (s, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.57 (s, 1H), 5.22 (quintet, J = 6.3 Hz , 1H); LC / MS: purity: 96%; MS (mass / charge): 382 (MH +). + - 584 N4- (3-Chloro-4-methoxyphenyl) -N2- (3,5-dimethylphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.09 (s, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.31-7.23 (m, 3H), 7.13 (d, J = 9.0 Hz, 1H), 6.51 (s, 1H), 3.86 (s, 3H), 3.42 (s, 3H); 2.18 (s, 6H); LC / MS: purity: 88%; MS (mass / charge): 387 (MH +). + - 585 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (2-methoxycarbonylbenzofuran-5-yl) -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.45 (s, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.68 (dd, J = 2.1 and 9.0 Hz, 1H), 7.65 (d, J = 0.9 Hz, 1H), 7.63-7.57 (m, 1H), 7 , 54 (d, J = 2.7 Hz, 1H), 7.35 (dd, J = 2.7 and 8.7 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H) 3.95 (s, 3H); 3.94 (s, 3H); 3.51 (d, J = 1.2 Hz, 3H); LC / MS: purity: 91%; MS (mass / charge): 457 (MH +). - - 586 5-Fluoro-N4- (2-isopropoxypyrid-5-yl) -N2- (2-methoxycarbonylbenzofuran-5-yl) -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.39 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 6.3 Hz, 1H), 7.70 (dd, J = 3.0 and 8.7 Hz, 1H), 7.64-7.57 (m, 2H), 7 54 (d, J = 8.7 Hz, 1H), 6.79 (d, 8.7 Hz, 1H), 5.22 (quintet, J = 6.3 Hz, 1H), 3.87 (s, 3H), 3.45 (s, 3H), 1.31 (d, J = 6.3 Hz, 6H), LC / MS: purity: 93%; MS (mass / charge): 452 (MH +). + + 587 N4- (4-Chloro-3-methoxyphenyl) -N2- (3,5-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.44 (br s, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H ), 7.15 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 1.2 Hz, 2H), 6.90 (dd, J = 2.1 and 8.4 Hz , 1H), 6.12-6.08 (m, 1H), 3.82 (s, 3H), 3.69 (s, 6H), 3.49 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 420 (MH +). + + - 588 N4- (4-Chloro-3-methoxyphenyl) -N2- (3,5-dimethylphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.35 (br s, 1H), 8.03 (d, J = 6.0, 1H), 7.41 (d, J = 8.4, 1H), 7.26-7.23 (m, 2H), 7.16 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 2.1 and 8.7 Hz, 1H), 6 58-6.55 (m, 1H); 3.82 (s, 3H); 3.49 (s, 3H); 2.19 (s, 6H); LC / MS: purity: 91%; MS (mass / charge): 387 (MH +). + - 589 N4- (4-Chloro-3-methoxyphenyl) -5-fluoro-N4-methyl-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.34 (s, 1H), 8.00 (d, J = 5.4, 1H), 7.93-8.00 (m, 1H), 7.44 ( t, J = 1.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 1.2 and 8.4 Hz, 1H), 7, 15-7.12 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.87 (dd, J = 2.1 and 9.0 Hz, 1H), 6.47 (dd, J = 2.7 and 7.2 Hz, 1H), 4.39 (s, 2H), 3.82 (s, 3H), 3.48 (s, 3H), 2.64 (d, J = 4.5 Hz, 3H); LC / MS: purity: 98%; MS (mass / charge): 447 (MH +). + + - 590 N4- (4-Chloro-3-methoxyphenyl) -5-fluoro-N2- (indol-5-yl) -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.84 (s, 1H), 9.010 (s, 1H), 7.96 (d, J = 5.4 Hz, 1H), 7.87-7.84 (m , 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.27-7.19 (m, 3H), 7.12 (d, J = 2.1 Hz, 1H), 6 87 (dd, J = 2.4 and 8.7 Hz, 1H), 6.29-6.25 (m, 1H), 3.82 (s, 3H), 3.47 (s, 3H); LC / MS: purity: 97%; MS (mass / charge): 399 (MH +). + + - 591 N4- (4-Chloro-3,5-dimethylphenyl) -N2- (3,5-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.51 (br s, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.19 (s, 2H), 6.93 (d , J = 1.8 Hz, 2H), 6.12 (t, J = 2.4 Hz, 1H), 3.70 (s, 6H), 3.46 (s, 3H), 2.32 (s , 6H); LC / MS: purity: 98%; MS (mass / charge): 418 (MH +). + + - 592 N4- (4-Chloro-3,5-dimethylphenyl) -N2- (3,5-dimethylphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.49 (br s, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.24 (s, 2H), 7.20 (s , 2H), 6.60 (s, 1H), 3.45 (s, 3H), 2.32 (s, 6H), 2.19 (s, 6H); LC / MS: purity: 98%; MS (mass / charge): 386 (MH +). - - 593 N4- (4-Chloro-3,5-dimethylphenyl) -5-fluoro-N4-methyl-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.32 (s, 1H), 7.98 (d, J = 5.7 Hz, 1H), 8.00-7.92 (m, 1H), 7.44 (t, J = 2.1 Hz, 1H), 7.29-7.23 (m, 1H), 7.16 (s, 2H), 7.10 (t, J = 8.1 Hz, 1H) 6.47 (dd, J = 2.4 and 7.8 Hz, 1H), 4.39 (s, 2H), 3.44 (s, 3H), 2.64 (d, J = 4.5 Hz, 3H); 2.32 (s, 6H); LC / MS: purity: 98%; MS (mass / charge): 445 (MH +). + + - 594 N4- (4-Chloro-3,5-dimethylphenyl) -5-fluoro-N2- (indol-5-yl) -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.84 (s, 1H), 8.98 (s, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.84 (s, 1H ), 7.29-7.19 (m, 3H), 7.15 (s, 2H), 6.26 (t, J = 2.1 Hz, 1H), 3.42 (s, 3H), 2 32 (s, 6H); LC / MS: purity: 94%; MS (mass / charge): 397 (MH +). + + + 595 N4- (4-Chloro-3,5-dimethylphenyl) -5-fluoro-N2- (2-methoxycarbonylbenzofuran-5-yl) -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.43 (s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 5.4 Hz, 1H), 7.68-7.61 (m, 2H), 7.55 (d, J = 9.3 Hz, 1H), 7.17 (s, 2H), 3.87 (s, 3H), 3.45 (s, 3H); 2.32 (s, 6H); LC / MS: purity: 97%; MS (mass / charge): 457 (MH +). - - 596 N4- (4-Chloro-3,5-dimethylphenyl) -5-fluoro-N4-methyl-N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.66 (s, 1H), 8.11 (d, J = 0.90 Hz, 1H), 8.04 (d, J = 5.4 Hz, 1H), 7.81 (s, 4H), 7.28 (d, J = 0.6 Hz, 1H), 7.18 (s, 2H), 3.46 (s, 3H), 2.33 (s, 6H ); LC / MS: purity: 89%; MS (mass / charge): 425 (MH +). - - 597 N4- (4-Chloro-3,5-dimethylphenyl) -5-fluoro-N4-methyl-N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.71 (s, 1H), 8.40 (s, 1H), 8.24-8.18 (m, 1H), 8.06 (d, J = 6, 0 Hz, 1H), 7.59-7.53 (m, 2H), 7.34-7.29 (m, 2H), 7.20 (s, 2H), 3.49 (s, 3H), 2.32 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 425 (MH +). + - 598 N4- (4-Chloro-3,5-dimethylphenyl) -5-fluoro-N4-methyl-N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.64 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 5.7 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.49 (s, 1H), 7.19 (s, 2H), 3.46 (s, 3H ), 2.32 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 425 (MH +). + - 599 N4- (4-Chloro-3,5-dimethylphenyl) -5-fluoro-N2- (indol-6-yl) -N4-methyl-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 11.00 (s, 1H), 9.58 (br s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.89 (s , 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.24-7.18 (m, 3H), 7.11 (dd, J = 1.8 and 8.4 Hz, 1H), 6.35-6.31 (m, 1H), 3.47 (s, 3H), 2.33 (s, 6H); LC / MS: purity: 95%; MS (mass / charge): 397 (MH +). + - 600 N4- [3-Chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.94 (br s, 1H), 9.65 (br s, 1H), 8.18 (d, J = 4.2 Hz, 1H), 7.93 -7.84 (m, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 2.7 and 9.0 Hz, 1H), 7.12 ( s, 2H), 6.99 (d, J = 9.0 Hz, 1H), 6.64 (s, 1H), 4.55 (s, 2H), 2.66 (d, J = 4.8 Hz, 3H), 2.18 (s, 6H), LC / MS: purity: 91%; MS (mass / charge): 431 (MH +). + + - 601 N4- [3-Chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -N2- (3,5-dimethoxylphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.52 (br s, 1H), 9.30 (br s, 1H), 8.11 (d, J = 3.9 Hz, 1H), 7.92 -7.85 (m, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 2.7 and 8.7 Hz, 1H), 6.96 ( d, J = 9.0 Hz, 1H), 6.85 (d, J = 1.8 Hz, 2H), 6.10 (t, J = 2.4 Hz, 1H), 4.54 (s, 2H), 3.64 (s, 6H), 2.67 (d, J = 4.5 Hz, 3H); LC / MS: purity: 93%; MS (mass / charge): 463 (MH +). + + - 602 N2- (3-Chloro-4-methoxyphenyl) -N4- [3-chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.45 (br s, 1H), 9.25 (br s, 1H), 8.03 (d, J = 3.3 Hz, 1H), 7.86 -7.78 (m, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.58 (dd, J = 2.7 and 9.3 Hz, 1H), 6.96 (d, J = 9.3 Hz, 1H), 6.93 (d, J = 9.3 Hz, 1H), 4.48 (s, 2H), 3.73 (s, 3H), 2.60 (d, J = 4.5 Hz, 3H); LC / MS: purity: 95%; MS (mass / charge): 467 (MH +). + + - 603 N2- (4-Chloro-3,5-dimethylphenyl) -N4- [3-chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.45 (br s, 1H), 9.2 = 8 (br s, 1H), 8.11 (d, J = 3.9 Hz, 1H), 7 92-7.87 (m, 1H), 7.75 (d, J = 2.4, 1H), 7.68 (dd, J = 2.7 and 9.3 Hz, 1H), 7.40 (s, 2H), 6.99 (d, J = 8.7 Hz, 1H), 4.54 (s, 2H), 2.67 (d, J = 4.2 Hz, 3H), 2.22 (s, 6H); LC / MS: purity: 95%; MS (mass / charge): 464 (MH +). + - - 604 N4- (4-Chloro-3,5-dimethylphenyl) -5-fluoro-N4-methyl-N2- [4- (oxazol-4-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.42 (s, 1H), 8.46-8.43 (m, 1H), 8.39-8.37 (m, 1H), 8.00 (d, J = 5.4 Hz, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H), 7.17 (s, 2H) 3.45 (s, 3H); 2.32 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 424 (MH +). + - 605 N4- [3-Chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N2- (indol-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.80 (s, 1H), 9.26 (s, 1H), 9.07 (s, 1H), 8.06 (s, J = 3.9 Hz, 1H ), 7.93-7.75 (m, 4H), 7.36 (d, J = 8.4 Hz, 1H), 7.22-7.15 (m, 2H), 6.95 (d, J = 8.7 Hz, 1H), 6.33-6.27 (m, 1H), 4.54 (s, 2H), 2.67 (d, J = 4.2 Hz, 3H); LC / MS: purity: 96%; MS (mass / charge): 441 (MH +). + + - 606 N4- (4-Chloro-3-methoxyphenyl) -5-fluoro-N4-methyl-N2- [4- (oxazol-4-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.44 (s, 1H), 8.44 (d, J = 0.90 Hz, 1H), 8.38 (d, J = 0.90 Hz, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7, 41 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.92-6.86 (m, 1H), 3.83 (s, 3H ), 3.49 (s, 3H); LC / MS: purity: 97%; MS (mass / charge): 426 (MH +). + + + 607 N4- (4-Chloro-3-methoxyphenyl) -N2- [4-chloro-3- (N-methylamino) carbonylphenyl] -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.70 (br s, 2H), 8.23-8.18 (m, 1H), 8.15 (d, J = 4.2 Hz, 1H), 7 , 71 (d, J = 2.7 Hz, 1H), 7.54 (dd, J = 2.7 and 9.0 Hz, 1H), 7.45 (dd, J = 2.4 and 8.7 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H), 3.73 (s, 3H), 2.65 (d, J = 4.5 Hz, 3H); LC / MS: purity: 92%; MS (mass / charge): 436 (M +). + + - 608 N4- [3-Chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -N2- [4-chloro-3- (N-methylamino) carbonylphenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.53 (br s, 1H), 9.49 (br s, 1H), 8.28-8.21 (m, 1H), 8.13 (d, J = 3.9 Hz, 1H), 7.93-7.87 (m, 1H), 7.77-7.64 (m, 4H), 7.28 (d, J = 8.7 Hz, 1H ), 6.98 (d, J = 9.0 Hz, 1H), 4.59 (s, 2H), 2.70 (d, J = 4.8 Hz, 3H), 2.67 (d, J = 4.5 Hz, 3H); LC / MS: purity: 94%; MS (mass / charge): 494 (MH +). + - 609 N2- [4-Chloro-3- (N-methylamino) carbonylphenyl] -N4- (4-chloro-3-trifluoromethylphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.84 (s, 1H), 9.59 (s, 1H), 8.35-8.27 (m, 2H), 8.23 (d, J = 3, 9 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.67-7.60 (m, 2H) 7.29 (d, J = 9.0 Hz, 1H); 2.71 (d, J = 4.5 Hz, 3H); LC / MS: purity: 92%; MS (mass / charge): 475 (MH +). + + - 610 N4- (4-Chloro-3,5-dimethylphenyl) -N2- [4-chloro-3- (N-methylamino) carbonylphenyl] -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.55 (s, 1H), 8.30-8.24 (m, 1H), 8.01 (d, J = 6.6 Hz, 1H), 7.86 (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 2.7 and 9.0 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7 16 (s, 2H), 3.42 (s, 3H), 2.72 (d, J = 4.5 Hz, 3H), 2.32 (s, 6H); LC / MS: purity: 98%; MS (mass / charge): 448 (M +). - - 611 N4- (4-Chloro-3-methoxyphenyl) -N2- [3-chloro-4- (N-methylamino) carbonylphenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.57 (s, 1H), 9.54 (s, 1H), 8.19 (d, J = 3.6 Hz, 1H), 8.15-8.08 (m, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 2.4 and 8.7 Hz, 1H), 7.47 (dd, J = 2.45 and 8.7 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 2.72 (d, J = 4.5 Hz, 3H); LC / MS: purity: 99%; MS (mass / charge): 436 (M +). + + - 612 N2- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N4- (4-chloro-3-trifluoromethylphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.83 (s, 1H), 9.65 (s, 1H), 8.33-8.26 (m, 1H), 8.25 (d, J = 3, 6 Hz, 1H), 8.16-8.11 (m, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H) , 7.66 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 1.8 and 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 2.72 (d, J = 4.5 Hz, 3H); LC / MS: purity: 97%; MS (mass / charge): 474 (M +). + + - 613 N4- (4-Chloro-3,5-dimethylphenyl) -N2- [3-chloro-4- (N-methylamino) carbonylphenyl] -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.66 (s, 1H), 8.17-8.09 (m, 1H), 8.05 (d, J = 5.4 Hz, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 2.1 and 8.4 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7 18 (s, 2H), 3.44 (s, 3H), 2.71 (d, J = 4.5 Hz, 3H), 2.32 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 448 (M +). + - 614 N4- [3-Chloro-4- (methoxycarbonyl) methyleneoxyphenyl] -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.28 (s, 1H), 10.05 (s, 1H), 8.26 (d, J = 4.8 Hz, 1H), 7.74 (d, J = 2.7 Hz, 1H), 7.57 (dd, J = 2.7 and 8.7 Hz, 1H), 7.10-7.01 (m, 3H), 6.69 (s, 1H) 4.93 (s, 2H); 3.70 (s, 3H); 2.17 (s, 6H); LC / MS: purity: 98%; MS (mass / charge): 431 (MH +). + + + 615 N4- [3-Chloro-4- (methoxycarbonyl) methyleneoxyphenyl] -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.75 (s, 1H), 9.53 (s, 1H), 8.15 (d, J = 4.5 Hz, 1H), 7.80 (d, J = 2.7 Hz, 1H), 7.66 (dd, J = 2.7 and 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 6.81 (d , J = 2.4 Hz, 1H), 6.14 (t, J = 2.1 Hz, 1H), 4.90 (s, 2H), 3.71 (s, 3H), 3.64 (s , 6H); LC / MS: purity: 98%; MS (mass / charge): 463 (MH +). + + + 616 N4- [3-Chloro-4- (methoxycarbonyl) methyleneoxyphenyl] -N2- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.63 (s, 1H), 9.41 (s, 1H), 8.12 (d, J = 4.2 Hz, 1H), 7.76 (d, J = 2.7 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 2.4 and 9.0 Hz, 1H), 7.44 (dd , J = 2.7 and 8.7 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 4.90 (s, 2H); 3.80 (s, 3H); 3.70 (s, 3H); LC / MS: purity: 92%; MS (mass / charge): 467 (M +). + + + 617 N2- (4-Chloro-3,5-dimethylphenyl) -N4- [3-chloro-4- (methoxycarbonyl) methyleneoxyphenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.64 (s, 1H), 9.45 (s, 1H), 8.14 (d, J = 4.2 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 2.4 and 9.0 Hz, 1H), 7.38 (s, 2H), 7.02 (d, J = 9.0 Hz , 1H); 4.91 (s, 2H); 3.70 (s, 3H); 2.21 (s, 6H); LC / MS: purity: 95%; MS (mass / charge): 465 (M +). + + + 618 N4- [3-Chloro-4- (methoxycarbonyl) methyleneoxyphenyl] -5-fluoro-N2- (indol-5-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.86 (s, 1H), 9.23 (s, 1H), 8.94 (s, 1H), 8.03 (d, J = 3.9 Hz, 1H ), 7.83 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.68 (dd, J = 2.4 and 9.0 Hz, 1H), 7.25 -7.21 (m, 3H), 6.93 (d, J = 9.0 Hz, 1H), 6.27 (t, J = 2.4 Hz, 1H), 4.89 (s, 2H) 3.71 (s, 3H); LC / MS: purity: 95%; MS (mass / charge): 442 (MH +). + + - 619 N4- [3-Chloro-4- (2-hydroxyethylene ethoxy) phenyl] -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.63 (br s, 1H), 9.34 (br s, 1H), 8.11 (d, J = 4.2 Hz, 1H), 7.72 (d, J = 2.7 Hz, 1H), 7.64 (dd, J = 2.7 and 9.0 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6 58 (s, 1H); 4.05 (t, J = 5.1 Hz, 2H); 3.73 (t, J = 5.1 Hz; 2H); 2.16 (s, 6H); LC / MS: purity: 91%; MS (mass / charge): 403 (MH +). + + + 620 N4- [3-Chloro-4- (2-hydroxyethylene ethoxy) phenyl] -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.29 (s, 1H), 9.13 (s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 7.75 (d, J = 2.7 Hz, 1H), 7.71 (dd, J = 2.7 and 8.7 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 6.90 (d , J = 2.1 Hz, 2H), 6.05 (t, J = 2.1 Hz, 1H), 4.89 (t, J = 5.1 Hz, 1H), 4.05 (t, J = 5.1 Hz, 2H), 3.73 (q, J = 5.1 Hz, 2H), 3.63 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 435 (MH +). + + + 621 N4- [3-Chloro-4- (2-hydroxyethylene ethoxy) phenyl] -N2- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.29 (s, 1H), 9.15 (s, 1H), 8.06 (d, J = 3.6 Hz, 1H), 7.74 (d, J = 2.1 Hz, 2H), 7.63 (dd, J = 2.7 and 9.0 Hz, 1H), 7.46 (dd, J = 2.7 and 9.0 Hz, 1H), 7 , 10 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 4.87 (t, J = 5.4 Hz, 1H), 4.05 (t, J = 5 Hz, 2H), 3.78 (s, 3H), 3.74 (q, J = 4.8 Hz, 2H); LC / MS: purity: 100%; MS (mass / charge): 441 (MH +). + + - 622 N2- (4-Chloro-3,5-dimethylphenyl) -N4- [3-chloro-4- (2-hydroxyethyleneoxy) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.31 (s, 1H), 9.18 (s, 1H), 8.08 (d, J = 3.9 Hz, 1H), 7.72 (d, J = 2.7 Hz, 1H), 7.63 (dd, J = 2.4 and 9.0 Hz, 1H), 7.42 (s, 2H), 7.12 (d, J = 9.0 Hz , 1H), 4.87 (t, J = 5.7 Hz, 1H), 4.04 (t, J = 5.1 Hz, 2H), 3.73 (q, J = 5.1 Hz, 2H), 2.20 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 438 (MH +). + + - 623 N4- [3-Chloro-4- (2-hydroxyethylene ethoxy) phenyl] -5-fluoro-N2- (indol-5-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.84 (s, 1H), 9.17 (s, 1H), 8.90 (s, 1H), 8.01 (d, J = 3.9 Hz, 1H ), 7.82-7.76 (m, 2H), 7.67 (dd, J = 3.0 and 9.3 Hz, 1H), 7.25-7.21 (m, 3H), 7, 03 (d, J = 9.0 Hz, 1H), 6.28-6.25 (m, 1H), 4.87 (t, J = 5.4 Hz, 1H), 4.04 (t, J = 5.1 Hz, 2H); 3.73 (q, J = 5.1 Hz, 2H); LC / MS: purity: 100%; MS (mass / charge): 414 (MH +). + + + 624 N4- [3-Chloro-4- (2-hydroxyethylene ethoxy) phenyl] -N2- (4-chloro-3-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.49 (s, 1H), 9.42 (s, 1H), 8.12 (d, J = 3.9 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 2.7 and 9.0 Hz, 1H), 7.40-7.36 (m, 1H), 7.30 (dd, J = 2.7 and 8.4 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 4.06 (t, J = 4.8 Hz, 2H), 3.77-3.71 (m, 2H), 3.66 (s, 3H); LC / MS: purity: 93%; MS (mass / charge): 440 (MH +). + + - 625 N4- [3-Chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N2- (indol-5-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.84 (s, 1H), 9.20 (s, 1H), 8.91 (s, 1H), 8.02 (d, J = 3.9 Hz, 1H ), 7.90-7.82 (m, 2H), 7.73 (dd, J = 2.4 and 9.0 Hz, 1H), 7.26-7.19 (m, 3H), 6, 93 (d, J = 8.7 Hz, 1H), 6.28 (t, J = 2.4 Hz, 1H), 4.52 (s, 2H), 2.67 (d, J = 4.5 Hz, 3H); LC / MS: purity: 98%; MS (mass / charge): 441 (MH +). + + + 626 2-Chloro-N4- (4-chloro-3,5-dimethylphenyl) -5-fluoro-N4-methyl-4-pyrimidinamine 1H NMR (DMSO-d6): d 8.17 (d, J = 5.1 Hz, 1H), 7.23 (s, 2H), 3.38 (s, 3H), 2.32 (s, 6H ); LC / MS: purity: 98%; MS (mass / charge): 301 (MH +). - + 627 2-Chloro-5-fluoro-N4-methyl-N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -4-pyrimidinamine 1 H NMR (DMSO-d6): d 7.94 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 9.6 Hz, 1H), 7.17 (d, J = 9 6 Hz, 1H); 7.05-7.00 (m, 2H); 3.50 (s, 3H); LC / MS: purity: 92%; MS (mass / charge): 368 (MH +). - - 628 2-Chloro-N4- [3,4- (difluoromethylenedioxy) phenyl] -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (DMSO-d6): d 7.82 (d, J = 4.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.90-6.83 (m , 2H); 3.40 (s, 3H); LC / MS: purity: 100%; MS (mass / charge): 318 (MH +). - - 629 N4- (4-Chloro-3-trifluoromethylphenyl) -5-fluoro-N2- (indol-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.86 (s, 1H), 9.67 (s, 1H), 9.14 (s, 1H), 8.44 (dd, J = 2.4 and 9, 0 Hz, 1H), 8.15 (d, J = 3.9 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.77 (s, 1H), 7.51 (d, J = 9.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 2.1 Hz, 1H), 7.14 (dd , J = 1.8 and 8.4 Hz, 1H); 6.34-6.30 (m, 1H); LC / MS: purity: 100%; MS (mass / charge): 422 (MH +). + + - 630 N4- (4-Chloro-3-methoxyphenyl) -5-fluoro-N2- (indol-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 10.85 (s, 1H), 9.35 (s, 1H), 9.04 (s, 1H), 8.10 (d, J = 3.6 Hz, 1H ), 7.79 (s, 1H), 7.62-7.57 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 9, 0 Hz, 1H), 7.19 (t, J = 2.7 Hz, 1H), 7.15 (dd, J = 1.8 and 8.4 Hz, 1H), 6.34-6.30 ( m, 1H); 3.67 (s, 3H); LC / MS: purity: 99%; MS (mass / charge): 384 (MH +). + + - 631 N4- (3-Chloro-4-methoxycarbonylmethyleneoxyphenyl) -5-fluoro-N2- (indol-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.78 (s, 1H), 9.23 (s, 1H), 9.03 (s, 1H), 8.05 (d, J = 3.6 Hz, 1H ), 7.85 (d, J = 2.7 Hz, 1H), 7.79-7.73 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 2.1 and 8.7 Hz, 1H), 7.16 (t, J = 3.0 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6 32-6.28 (m, 1H); 4.88 (s, 2H); 3.71 (s, 3H); LC / MS: purity: 98%; MS (mass / charge): 442 (MH +). + + + 632 N4- [3-Chloro-4- (2-hydroxyethylene ethoxy) phenyl] -5-fluoro-N2- (indol-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.79 (s, 1H), 9.19 (d, J = 1.2 Hz, 1H), 9.01 (s, 1H), 8.04 (d, J = 3.6 Hz, 1H), 7.84 (d, J = 2.7, 1H), 7.79-7.73 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 1.8 and 8.4 Hz, 1H), 7.16 (t, J = 2.4 Hz, 1H), 7.05 (d, J = 9.3 Hz, 1H), 6.32-6.28 (m, 1H), 4.86 (t, J = 5.1 Hz, 1H), 4.04 (t, J = 5.4 Hz, 2H), 3.73 (q, J = 5.1 Hz, 2H); LC / MS: purity: 99%; MS (mass / charge): 414 (MH +). + + - 633 5-Fluoro-N2- [3- (oxazol-2-yl) phenyl] -N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.76 (s, 1H), 9.63 (s, 1H), 8.33-8.29 (m, 1H), 8.22 (d, J = 3, 6 Hz, 1H), 8.16-8.13 (m, 1H), 7.78-7.74 (m, 1H), 7.62 (dd, J = 2.4 and 9.0 Hz, 1H ), 7.58-7.53 (m, 1H), 7.42-7.31 (m, 3H); LC / MS: purity: 92%; MS (mass / charge): 478 (MH +). + - 634 5-Fluoro-N4-methyl-N2- [3- (oxazol-2-yl) phenyl] -N4- [3,4- (tetrafluoroethylenedioxy) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.67 (s, 1H), 8.57 (t, J = 1.8 Hz, 1H), 8.18-8.16 (m, 1H), 8.09 (d, J = 5.7 Hz, 1H), 7.72-7.66 (m, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.54-7.47 ( m, 2H), 7.39-7.32 (m, 3H), 3.53 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 492 (MH +). - + - 635 N2- [3,5-Dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.02 (s, 1H), 8.12-8.06 (m, 1H), 7.88 (d, J = 5.7 Hz, 1H), 7.34 (s, 2H), 6.83 (d, J = 6.9 Hz, 1H), 6.82 (s, 1H), 6.73 (dd, J = 3.0 and 9.0 Hz, 1H) , 4.24 (s, 4H), 4.11 (s, 2H), 3.38 (s, 3H), 2.69 (d, J = 4.8 Hz, 3H), 2.16 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 468 (MH +). + + + 636 N2- [3,5-Dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N4-methyl-N4- [3,4- (tetrafluoroethylene diaxy) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.15 (s, 1H), 8.12-8.05 (m, 1H), 8.02 (d, J = 5.7 Hz, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.55 (dd, J = 0.9 and 2.7 Hz, 1H), 7.48 (d, J = 9.3 Hz, 1H), 7 31 (s, 2H), 7.27 (dd, J = 0.9 and 2.1 Hz, 1H), 4.11 (s, 2H), 3.46 (s, 3H), 2.69 ( d, J = 4.8 Hz, 3H), 2.14 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 540 (MH +). + + + 637 N2- [3,5-Dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N4- [3,4- (tetrafluoroethylene dioxy) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.59 (s, 1H), 9.14 (s, 1H), 8.16-8.08 (m, 3H), 7.61 (dd, J = 2, 7 and 9.0 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.25 (s, 2H), 4.12 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H); 2.15 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 526 (MH +). + - 638 N2- [3,5-Dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (3,5-dimethoxyphenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.07 (s, 1H), 8.13-8.05 (m, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.35 (s, 2H), 6.44 (dd, J = 0.6 and 2.4 Hz, 2H), 6.39 (t, J = 2.4 Hz, 1H), 4.16 (s, 2H) 3.72 (s, 6H); 3.43 (s, 3H); 2.69 (d, J = 4.8 Hz, 3H); 2.16 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 470 (MH +). + + + 639 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (methoxycarbonylmethylene) indol-6-yl] -2.4 pyrimidinediamine 1 H NMR (DMSO-d6): d 10.60 (s, 1H), 9.45 (s, 1H), 9.09 (s, 1H), 8.04 (d, J = 3.6 Hz, 1H ), 7.57 (s, 1H), 7.40-7.33 (m, 2H), 7.31-7.24 (m, 2H), 7.20 (d, J = 3.3 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 3.35 (d, J = 2.4 Hz, 1H), 4.91 (s, 2H), 3.63 (s, 3H), 1.40 (s, 6H); LC / MS: purity: 97%; MS (mass / charge): 491 (MH +). + + - 640 N4- [3-Chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N2- [1- (methoxycarbonylmethylene) indol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.42 (s, 1H), 9.24 (s, 1H), 8.07 (d, J = 3.9 Hz, 1H), 7.92-7.84 (m, 2H), 7.71 (dd, J = 2.7 and 9.3 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H) , 7.29 (dd, J = 1.5 and 8.4 Hz, 1H), 7.20 (d, J = 3.3 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.36 (d, J = 3.3 Hz, 1H), 4.92 (s, 2H), 4.53 (s, 2H), 3.63 (s, 3H), 2.67 ( d, J = 4.5 Hz, 1H); LC / MS: purity: 99%; MS (mass / charge): 514 (MH +). + + - 641 N4- (4-Chloro-3-methoxyphenyl) -5-fluoro-N2- [1- (methoxycarbonylmethylene) indol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.34 (s, 1H), 9.10 (s, 1H), 8.09 (d, J = 3.6 Hz, 1H), 7.62-7.59 (m, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 2.4 and 8.4 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.27-7.22 (m, 2H), 7.20 (d, J = 3.3 Hz, 1H), 6.36 (dd, J = 0.6 and 3 , 0 Hz, 1H), 4.88 (s, 2H), 3.62 (s, 3H), 3.60 (s, 3H); LC / MS: purity: 98%; MS (mass / charge): 457 (MH +). + + + 642 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- [1- (methoxycarbonylmethylene) indol-6-yl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.19 (s, 1H), 9.14 (s, 1H), 8.02 (d, J = 3.9 Hz, 1H), 7.63 (s, 1H ), 7.40-7.31 (m, 2H), 7.30-7.17 (m, 3H), 6.74 (d, J = 9.0 Hz, 1H), 6.35 (d, J = 2.7 Hz, 1H), 4.90 (s, 2H), 4.21 (s, 4H), 3.63 (s, 3H); LC / MS: purity: 93%; MS (mass / charge): 450 (MH +). + + - 643 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (methoxycarbonylmethylene) indol-5-yl] -2.4 pyrimidinediamine 1 H NMR (DMSO-d6): d 10.56 (s, 1H), 9.20 (s, 1H), 8.79 (s, 1H), 8.00 (d, J = 3.6 Hz, 1H ), 7.86 (s, 1H), 7.33 (dd, J = 2.1 and 8.7 Hz, 1H), 7.27-7.16 (m, 4H), 6.83 (d, J = 8.7 Hz, 1H), 6.27 (d, J = 3.0 Hz, 1H), 5.05 (s, 2H), 3.66 (s, 3H), 1.40 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 491 (MH +). + + - 644 N4- [3-Chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N2- [1- (methoxycarbonylmethylene) indol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.22 (s, 1H), 8.96 (s, 1H), 8.03 (d, J = 3.9 Hz, 1H), 7.90-7.72 (m, 4H), 7.28-7.23 (m, 3H), 6.94 (d, J = 8.7 Hz, 1H), 6.32 (d, J = 3.0 Hz, 1H) 5.07 (s, 2H); 4.53 (s, 2H); 3.67 (s, 3H); 2.67 (d, J = 4.5 Hz, 3H); LC / MS: purity: 90%; MS (mass / charge): 514 (MH +). + + - 645 N4- (4-Chloro-3-methoxyphenyl) -5-fluoro-N2- [1- (methoxycarbonylmethylene) indol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.32 (s, 1H), 8.96 (s, 1H), 8.07 (d, J = 3.6 Hz, 1H), 7.84 (s, 1H ), 7.55-7.47 (m, 2H), 7.28-7.17 (m, 4H), 6.29 (d, J = 3.0 Hz, 1H), 5.08 (s, 2H); 3.67 (s, 3H); 3.64 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 457 (MH +). + + - 646 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (methoxycarbonylmethylene) indol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.18 (s, 1H), 8.94 (s, 1H), 8.02 (d, J = 3.0 Hz, 1H), 7.82-7.76 (m, 2H), 7.70 (dd, J = 2.1 and 9.0 Hz, 1H), 7.27-7.21 (m, 3H), 7.03 (d, J = 9.0 Hz, 1H), 6.30 (d, J = 2.7 Hz, 1H), 5.06 (s, 2H), 3.83 (s, 3H), 3.66 (s, 3H); LC / MS: purity: 98%; MS (mass / charge): 456 (MH +). + + - 647 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- [1- (methoxycarbonylmethylene) indol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.18 (s, 1H), 9.99 (s, 1H), 8.16 (d, J-4.5 Hz, 1H), 7.74 (s, 1H ), 7.46-7.18 (m, 3H), 7.34-7.18 (m, 3H), 6.83 (d, J = 8.1 Hz, 1H), 6.46 (d, J = 3.0 Hz, 1H), 5.20 (s, 2H), 4.29 (s, 4H), 3.74 (s, 3H); LC / MS: purity: 92%; MS (mass / charge): 450 (MH +). + + - 648 N4- [3-Chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.25 (s, 1H), 9.07 (s, 1H), 8.04 (d, J = 3.6 Hz, 1H), 7.90-7.83 (m, 3H), 7.77-7.73 (m, 1H), 7.55-7.52 (m, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7, 32-7.26 (m, 1H), 7.16 (d, J = 3.3 Hz, 1H), 6.91 (d, J = 9.3 Hz, 1H), 6.33 (d, J = 3.0 Hz, 1H), 4.62 (s, 4H), 4.52 (s, 2H), 2.67 (d, J = 4.2 Hz, 3H), 2.58 (d, J = 4.5 Hz, 3H); LC / MS: purity: 94%; MS (mass / charge): 513 (MH +). + + - + 649 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.06 (s, 1H), 9.02 (s, 1H), 7.99 (d, J = 3.9 Hz, 1H), 7.88-7.82 (m, 1H), 7.58 (s, 1H), 7.39-7.33 (m, 2H), 7.32-7.25 (m, 2H), 7.16 (d, J = 3 , 3 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 3.3 Hz, 1H), 4.63 (s, 2H), 4, 19 (s, 4H); 2.58 (d, J = 4.2 Hz, 3H); LC / MS: purity: 97%; MS (mass / charge): 449 (MH +). + + - 650 5-Fluoro-N4- [2- (2-hydroxyethylene ethylene) pyrid-5-yl] -N2- [1- (N-methylamino) carbonylmethyleneindol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.26 (s, 1H), 8.98 (s, 1H), 8.51 (s, 1H), 8.07 (dd, J = 2.4 and 9, 0 Hz, 1H), 8.03 (d, J = 3.9 Hz, 1H), 7.98-7.92 (m, 1H), 7.87 (s, 1H), 7.24-7, 14 (m, 3H), 6.76 (d, J = 9.0 Hz, 1H), 6.27 (d, J = 3.0 Hz, 1H), 4.84 (t, J = 5.4 Hz, 1H), 4.72 (s, 2H), 4.25 (t, J = 5.7 Hz, 2H), 3.71 (q, J = 5.7 Hz, 2H), 2.60 ( d, J = 4.5 Hz, 3H); LC / MS: purity: 90%; MS (mass / charge): 452 (MH +). + 651 N4- (3-Chloro-4-trifluoromethoxyphenyl) -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.55 (s, 1H), 9.09 (s, 1H), 8.15-7.99 (m, 2H), 8.02-7.95 (m, 1H), 7.89 (dd, J = 1.5 and 9.6 Hz, 1H), 7.75 (s, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7, 27-7.21 (m, 3H), 6.30 (d, J = 2.7 Hz, 1H), 4.73 (s, 2H), 2.61 (d, J = 4.5 Hz, 3H ); LC / MS: purity: 99%; MS (mass / charge): 510 (MH +). + 652 N4- [3-Chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.88 (s, 1H), 9.70 (s, 1H), 8.12-8.03 (m, 2H), 7.94-7.87 (m, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.69-7.63 (m, 2H), 7.35-7.27 (m, 2H), 7.17 (d , J = 8.7 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.35 (d, J = 3.0 Hz, 1H), 4.77 (s, 2H ), 4.55 (s, 2H), 2.66 (d, J = 4.8 Hz, 3H), 2.61 (d, J = 4.8 Hz, 3H); LC / MS: purity: 97%; MS (mass / charge): 513 (MH +). + + 653 N4- (4-Chloro-3-methoxyphenyl) -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.22 (s, 1H), 9.91 (s, 1H), 8.16 (d, J = 4.8 Hz, 1H), 8.12-8.05 (m, 1H), 7.70-7.66 (m, 1H), 7.52-7.48 (m, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7, 37-7.28 (m, 3H), 7.16-7.10 (m, 1H), 6.35 (d, J = 2.7 Hz, 1H), 4.79 (s, 2H), 3 63 (s, 3H); 2.62 (d, J = 4.5 Hz, 3H); LC / MS: purity: 97%; MS (mass / charge): 456 (MH +). + 654 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 10.21 (s, 1H), 9.94 (s, 1H), 8.16-8.03 (m, 2H), 7.79-7.74 (m, 1H), 7.65-7.58 (m, 2H), 7.37-7.30 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.05 (d , J = 8.7 Hz, 1H), 6.37 (d, J = 3.0 Hz, 1H), 4.78 (s, 2H), 3.84 (s, 3H), 2.61 (d , J = 4.5 Hz, 3H); LC / MS: purity: 97%; MS (mass / charge): 456 (MH +). + 655 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-5-yl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 10.19 (br s, 1H), 10.04 (br s, 1H), 8.12-8.03 (m, 2H), 7.66-7, 61 (m, 1H), 7.36-7.30 (m, 2H), 7.27-7.09 (m, 3H), 6.78 (d, J = 8.4 Hz, 1H), 6 38 (d, J = 2.7 Hz, 1H), 4.79 (s, 2H), 4.23 (s, 4H), 2.61 (d, J = 4.2 Hz, 3H); LC / MS: purity: 99%; MS (mass / charge): 449 (MH +). + 656 N4- [3-Chloro-4- (N-methylamino) carbonylphenyl] -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.46 (s, 1H), 9.07 (s, 1H), 8.24-8.17 (m, 1H), 8.11 (d, J = 3, 0 Hz, 1H), 8.00-7.94 (m, 1H), 7.94-7.86 (m, 2H), 7.77 (s, 1H), 7.31-7.22 (m , 4H), 6.33 (d, J = 3.3 Hz, 1H), 4.73 (s, 2H), 2.73 (d, J = 4.8 Hz, 3H), 2.60 (d , J = 4.8 Hz, 3H); LC / MS: purity: 99%; MS (mass / charge): 482 (MH +). + 657 2-Chloro-5-fluoro-N4- (2-methoxypyrid-5-yl) -N4-methyl-4-pyrimidinamine 1 H NMR (DMSO-d6): d 8.21 (d, J = 3.0 Hz, 1H), 8.15 (d, J = 5.7 Hz, 1H), 7.78 (dd, J = 2 7 and 8.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 3.86 (s, 3H), 3.38 (s, 3H); LC / MS: purity: 95%; MS (mass / charge): 269 (MH +). - - 658 2-Chloro-N4- (4-chloro-3-trifluoromethylphenyl) -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (DMSO-d 6): d 8.25 (d, J = 5.4 Hz, 1H), 7.97-7.94 (m, 1H), 7.78-7.72 (m, 2H) 3.45 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 341 (MH +). - - 659 2-Chloro-N4- (4-chloro-3-methoxyphenyl) -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (DMSO-d6): d 8.18 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.24 (s, 1H), 6.96 (d, J = 8.7 Hz, 1H), 3.82 (s, 1H), 3.31 (s, 3H); LC / MS: purity: 99%; MS (mass / charge): 303 (MH +). - - 660 2-Chloro-N4- (3-chloro-4-methoxyphenyl) -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (DMSO-d6): d 8.14 (d, J = 5.4 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 2 4 and 8.7 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 3.36 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 303 (MH +). - - 661 2-Chloro-N4- [3-chloro-4- (N-methylamino) carbonylmethyleneoxyphenyl] -5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (DMSO-d6): d 8.15 (d, J = 5.4 Hz, 1H), 7.94-7.87 (m, 1H), 7.58 (d, J = 2.4 Hz , 1H), 7.32 (dd, J = 2.4 and 8.7 Hz, 1H), 7.02 (d, J = 9.0 Hz, 1H), 4.60 (s, 2H), 3 36 (s, 3H); 2.66 (d, J = 4.8 Hz, 3H); LC / MS: purity: 90%; MS (mass / charge): 360 (MH +). - - 662 N4- (3-Chloro-4-trifluoromethoxyphenyl) -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.22 (s, 1H), 9.88 (s, 1H), 8.22 (d, J = 3.9 Hz, 1H), 8.14 (d, J = 2.7 Hz, 1H), 8.02-7.95 (m, 1H), 7.84-7.78 (m, 1H), 7.49 (d, J = 8.1 Hz, 1H) 7.45-7.37 (m, 2H), 7.27 (d, J = 2.7 Hz, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.18 ( d, J = 8.4 Hz, 1H), 6.41 (d, J = 3.3 Hz, 1H), 4.70 (s, 2H), 2.58 (d, J = 4.5 Hz, 3H); LC / MS: purity: 91%; MS (mass / charge): 509 (MH +). + + - 663 N4- (4-Chloro-3-methoxyphenyl) -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 10.13 (s, 1H), 9.90 (s, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.91 (d, J = 3.9 Hz, 1H), 7.49-7.34 (m, 4H), 7.23 (d, J = 3.3 Hz, 1H), 7.17 (d, J = 8.4 Hz , 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 3.0 Hz, 1H), 4.62 (s, 2H), 3.52 (s , 3H); 2.51 (d, J = 4.5 Hz, 3H); LC / MS: purity: 97%; MS (mass / charge): 456 (MH +). + - 664 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 10.21 (s, 1H), 10.04 (s, 1H), 8.14 (d, J = 5.1 Hz, 1H), 7.98-7.92 (m, 1H), 7.84 (d, J = 2.7 Hz, 1H), 7.60 (dd, J = 2.4 and 8.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.39 (s, 1H), 7.30 (d, J = 3.3 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7 01 (d, J = 9.0 Hz, 1H), 6.43 (d, J = 3.0 Hz, 1H), 4.70 (s, 2H), 3.82 (s, 3H), 2 58 (d, J = 4.5 Hz, 3H); LC / MS: purity: 96%; MS (mass / charge): 455 (MH +). + + - 665 N4- [3-Chloro-4- (N-methylamino) carbonylphenyl] -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.50 (s, 1H), 9.19 (s, 1H), 8.28-8.20 (m, 1H), 8.12 (d, J = 3, 3 Hz, 1H), 7.97-7.84 (m, 3H), 7.53 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.32-7, 25 (d, J = 3.3 Hz, 1H), 6.35 (d, J = 3.0 Hz, 1H), 4.63 (s, 2H), 2.74 (d, J = 4.5 Hz, 3H); 2.58 (d, J = 4.5 Hz, 3H); LC / MS: purity: 96%; MS (mass / charge): 482 (MH +). + - 666 2-Chloro-N4- (3-chloro-4-methoxyphenyl) -5-fluoro-4-pyrimidinamine 1 H NMR (DMSO-d6): d 9.94 (s, 1H), 8.28 (dd, J = 0.6 and 3.6 Hz, 1H), 7.75 (d, J = 2.1 Hz , 1H), 7.58 (dd, J = 2.4 and 8.7 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 3.84 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 288 (M +). - - 667 5-Fluoro-N2- [3- (oxazol-2-yl) phenyl] -N4- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.38 (s, 1H), 9.28 (s, 1H), 8.28 (s, 1H), 8.14-8.10 (m, 2H), 7 87 (d, J = 7.2 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.34-7.27 (m, 2H), 7.06 (s, 2H); 3.70 (s, 6H); 3.63 (s, 3H); LC / MS: purity: 98%; MS (mass / charge): 438 (MH +). + 668 N4- (3,4-Ethylenedioxyphenyl) -5-fluoro-N2- (2,3,4-trimethoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.10 (s, 1H), 7.96 (d, J = 3.9 Hz, 1H), 7.75 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 2.4 Hz, 1H), 6.74-6.64 (m , 2H), 4.25-4.18 (m, 4H), 3.77 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H); LC / MS: purity: 99%; MS (mass / charge): 429 (MH +). + 669 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (2,3,4-trimethoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.26 (s, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.86 (s, 1H), 7.81 (d, J = 2.7 Hz, 1H), 7.54 (dd, J = 2.4 and 9.0 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.03 (d , J = 9.0 Hz, 1H), 6.70 (d, J = 9.3 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.74 (s , 3H); 3.73 (s, 3H); LC / MS: purity: 96%; MS (mass / charge): 435 (MH +). - 670 N4- (4-Chloro-3-methoxyphenyl) -5-fluoro-N2- (2,3,4-trimethoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 816 (d, J = 4.8 Hz, 1H), 7.56-7.51 (m, 1H), 7.36-7.24 (m, 4H), 6 74 (d, J = 9.3 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H) ; LC / MS: purity: 95%; MS (mass / charge): 436 (MH +). - 671 N4- (3-Chloro-4-trifluoromethoxyphenyl) -5-fluoro-N2- (2,3,4-trimethoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 8.20 (d, J = 4.5 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.73-7.66 (m , 1H), 7.45 (d, J = 9.6 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 9.0 Hz, 1H ), 3.78 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H); LC / MS: purity: 95%; MS (mass / charge): 490 (MH +). + 672 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (2,3,4-trimethoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.73 (s, 1H), 10.44 (s, 1H), 8.21 (d, J = 4.8 Hz, 1H), 7.43-7.32 (m, 1H), 7.27-7.13 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 9.6 Hz, 1H) 3.77 (s, 3H); 3.76 (s, 3H); 3.74 (s, 3H); 1.41 (s, 6H); LC / MS: purity: 98%; MS (mass / charge): 470 (MH +). + 673 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine salt of benzenesulfonic acid 1 H NMR (DMSO-d6): d 11.14 (s, 1H), 9.98 (s, 1H), 9.63 (s, 1H), 8.17 (d, J = 3.9 Hz, 1H ), 7.62-7.52 (m, 3H), 7.36-7.25 (m, 4H), 6.87 (s, 2H), 3.66 (s, 6H), 3.61 ( s, 3H); 1.43 (s, 6H). + + 674 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine salt of methanesulfonic acid 1 H NMR (DMSO-d6): d 11.13 (s, 1H), 9.95 (s, 1H), 9.62 (s, 1H), 8.18 (d, J = 3.9 Hz, 1H ), 7.56 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.88 (s, 2H), 3.66 (s, 6H ), 3.61 (s, 3H), 2.33 (s, 3H), 1.43 (s, 6H). + + 675 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine salt of p-toluenesulfonic acid 1H NMR (DMSO-d6): d 11.12 (s, 1H), 9.89 (s, 1H), 9.57 (s, 1H), 8.17 (d, J = 3.9 Hz, 1H ), 7.57 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.89 (s, 2H), 3.66 (s, 6H), 3.61 (s, 3H), 2.28 (s, 3H ), 1.43 (s, 6H). + + 676 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- 4-hydroxybenzenesulfonic acid pyrimidinediamine salt 1 H NMR (DMSO-d6): d 11.12 (s, 1H), 9.81 (s, 1H), 9.53 (s, 1H), 8.16 (d, J = 4.2 Hz, 1H ), 7.58 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.7 Hz, 1H), 6.90 (s, 2H), 6.64 (d, J = 8.7 Hz, 2H), 3.66 (s, 6H), 3.61 (s, 3H), 1.43 (s, 6H ) + + 677 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine salt of 2,4,6-trimethylbenzenesulfonic acid 1 H NMR (DMSO-d6): d 11.10 (s, 1H), 9.72 (s, 1H), 9.47 (s, 1H), 8.15 (d, J = 4.2 Hz, 1H ), 7.62-7.56 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.91 (s, 2H), 6.72 (s, 2H), 3 66 (s, 6H), 3.61 (s, 3H), 2.48 (s, 6H), 2.16 (s, 3H), 1.43 (s, 6H). + 678 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine salt of 0.5 pyridin-3-sulfonic acid 1 H NMR (DMSO-d6): d 11.08 (s, 2H), 9.46 (s, 2H), 9.30 (s, 2H), 8.91 (s, 1H), 8.70 (d , J = 5.4 Hz, 1H), 8.37 (dd, J = 1.5 and 7.8 Hz, 1H), 8.13 (d, J = 3.6 Hz, 2H), 7.80 -7.74 (m, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.97 (s, 4H) 3.66 (s, 12H); 3.60 (s, 6H); 1.43 (s, 12H). + + 679 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- p-ethylbenzenesulfonic acid pyrimidinediamine salt 1 H NMR (DMSO-d6): d 11.08 (s, 1H), 9.44 (s, 1H), 9.26 (s, 1H), 8.13 (d, J = 3.3 Hz, 1H ), 7.63 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 6.97 (s, 2H), 3.65 (s, 6H), 3.59 (s, 3H), 2.57 (q, J = 7.8 Hz, 2H), 1.42 (s, 6H), 1.15 (t, J = 7.8 Hz, 3H). + + 680 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine salt of 0.5 1,2-ethanedisulfonic acid 1 H NMR (DMSO-d6): d 11.08 (s, 2H), 9.54 (s, 2H), 9.35 (s, 2H), 8.14 (d, J = 3.9 Hz, 2H ), 7.60 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.95 (s, 4H), 3.66 (s, 12H ), 3.60 (s, 6H), 2.62 (s, 4H), 1.43 (s, 12H). + + 681 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine salt of (1R) -10-camphorsulfonic acid 1 H NMR (DMSO-d6): d 11.11 (s, 1H), 9.83 (s, 1H), 9.54 (s, 1H), 8.17 (d, J = 3.9 Hz, 1H ), 7.57 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.99 (s, 2H), 3.66 (s, 6H ), 3.61 (s, 3H), 2.86 (d, J = 14.7 Hz, 1H), 2.67 (t, J = 9.9 Hz, 1H), 2.38 (d, J = 14.7 Hz, 1H), 2.22 (dt, J = 3.6 and 18.0 Hz, 1H), 1.93 (t, J = 4.5 Hz, 1H), 1.89-1 75 (m, 2H), 1.43 (s, 6H), 1.30-1.23 (m, 2H), 1.08 (t, J = 6.9 Hz, 1H), 1.04 ( s, 3H); 0.74 (s, 3H). + + 682 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine salt of (1S) -10-camphorsulfonic acid 1 H NMR (DMSO-d6): d 11.08 (s, 1H), 9.55 (s, 1H), 9.36 (s, 1H), 8.14 (d, J = 3.9 Hz, 1H ), 7.60 (d, J = 8.7 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.94 (s, 2H), 3.66 (s, 6H ), 3.60 (s, 3H), 2.85 (d, J = 14.7 Hz, 1H), 2.68 (t, 11.4 Hz, 1H), 2.36 (d, J = 14 , 7 Hz, 1H), 2.28-2.17 (m, 1H), 1.92 (t, J = 4.8 Hz, 1H), 1.89-1.74 (m, 2H), 1 43 (s, 6H), 1.26 (q, J = 10.8 Hz, 2H), 1.05 (s, 3H), 0.74 (s, 3H). + + 683 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (N-methylamino) carbonylmethyleneindol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 11.04 (s, 1H), 9.08-8.90 (m, 2H), 8.07 (d, J = 3.3 Hz, 1H), 7.99 -7.89 (m, 1H), 7.81-7.96 (m, 1H), 7.70-7.64 (m, 1H), 7.29-7.20 (m, 4H), 6 29 (d, J = 3.0 Hz, 1H), 4.73 (s, 2H), 2.61 (d, J = 4.5 Hz, 3H), 1.42 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 491 (MH +). + + 684 N2- (4-Chloro-3,5-dimethylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine salt of p-toluenesulfonic acid 1 H NMR (DMSO-d6): d 11.13 (s, 1H), 9.68 (s, 1H), 9.46 (s, 1H), 8.17 (d, J = 3.6 Hz, 1H ), 7.51-7.35 (m, 6H), 7.09 (d, J = 8.4 Hz, 2H), 2.28 (s, 3H), 2.22 (s, 6H), 1 43 (s, 6H). + 685 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine hydrochloride salt 1 H NMR (DMSO-d6): d 11.31 (s, 1H), 9.89 (s, 1H), 9.66 (s, 1H), 8.18 (d, J = 4.5 Hz, 1H ), 7.55 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.89 (s, 2H), 3.65 (s, 6H ), 3.61 (s, 3H), 1.43 (s, 6H). + + 686 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- (3,5-dichloro-4-hydroxyphenyl) -5-fluoro-2, 4-pyrimidinediamine 1 H NMR (DMSO- d 6): d 11.07 (s, 1H), 9.32 (s, 1H), 9.27 (s, 1H), 8.13 (d, J = 3.3 Hz, 1H), 7.63 (s, 2H), 7.45 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 1.43 (s, 6H); LC / MS: purity: 92%; MS (mass / charge): 467 (MH ⁺ ). + + 687 N2, N4-Bis (3-oxo-2,2,4-trimethyl-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO- d 6): d 9.49 (br s, 2H), 8.18 (d, J = 3.3 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H) 3.34 (s, 3H); 3.33 (s, 3H); 1.44 (s, 6H); 1.41 (s, 6H); LC / MS: purity: 98%; MS (mass / charge): 509 (MH ⁺ ). + 688 N2, N4-Bis (2,2-dimethyl-4-carbomethoxymethyl-3-oxo-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO- d 6): d 9.55 (s, 1H), 9.49 (s, 1H), 8.19 (d, J = 2.7 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 4.81 (s, 2H), 4.80 (s, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 1.48 (s, 6H), 1.45 (s, 6H); LC / MS: purity: 97%; MS (mass / charge): 625 (MH +). - 689 5-Fluoro-N4- (3-oxo-2,2,4-trimethyl-5-pyrid [1,4] oxazin-6-yl) -N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine 1 H NMR (DMSO- d 6): d 9.42 (s, 1H), 9.13 (s, 1H), 8.14 (d, J = 3.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz. 1H), 7.03 (s, 2H), 3.66 (s, 6H), 3.60 (s, 3H), 1.44 (s, 6H); LC / MS: purity: 97%; MS (mass / charge): 485 (MH ⁺ ). + 690 N4- (2,2-Dimethyl-4-carbomethoxymethyl-3-oxo-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2, 4-pyrimidinediamine 1 H NMR (DMSO- d 6): d 9.46 (s, 1H), 9.15 (s, 1H), 8.15 (d, J = 3.6 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.04 (s, 2H), 4.80 (s, 2H), 3.67 (s, 6H), 3.66 (s, 3H), 3.60 (s, 3H), 1.47 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 543 (MH ⁺ ). + 691 N4- (2,2-Dimethyl-4-carbomethoxymethyl-3-oxo-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N4-carbomethoxymethyl-N2- (3,4,5-trimethoxyphenyl ) -2,4-pyrimidinediamine 1 H NMR (DMSO- d 6): d 9.27 (s, 1H), 8.22 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H) 6.98 (s, 2H), 6.81 (dd, J = 3.3 and 8.4 Hz, 1H), 4.83 (s, 2H), 4.63 (s, 2H), 3, 72 (s, 6H), 3.63 (s, 3H), 3.59 (s, 3H), 3.57 (s, 3H), 1.47 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 615 (MH +). + 692 N2- [3,5-Dimethoxy-4- (2- (N-morpholino) ethyloxy) phenyl] -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6 -yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO- d 6): d 11.04 (s, 1H), 9.14 (s, 1H), 9.09 (s, 1H), 8.11 (d, J = 3.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.02 (s, 2H), 3.87 (t, J = 6.0 Hz, 2H), 3.65 (s, 6H), 3.58-3.53 (m, 4H), 2.58 (t, J = 6.0 Hz, 2H), 2, 47-2.42 (m, 4H); 1.42 (s, 6H); LC / MS: purity: 96%; MS (mass / charge): 570 (MH +). + + 693 N2, N4-Bis (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 11.07 (s, 1H), 10.91 (s, 1H), 9.27 (s, 1H), 9.12 (s, 1H), 8.13 (d , J = 3.3 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 1.43 (s, gH), 1.39 (s, 6H); LC / MS: purity: 99%; MS (mass / charge): 481 (MH +). + 694 N4- (3-Chloro-4-methoxyphenyl) -N2- (1-ethylindazol-5-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.36 (s, 1H), 10.21 (s, 1H), 8.24 (d, 1H, J = 4.9 Hz), 7.92 (s, 1H ), 7.83 (s, 1H), 7.74 (d, 1H, J = 2.6 Hz), 7.65 (d, 1H, J = 9.1 Hz), 7.54 (calculated dd , 1H, J = 2.3 and 9.1 Hz), 7.38 (dd, 1H, J = 1.8 and 9.1 Hz), 7.09 (d, 1H, J = 9.1 Hz) 4.40 (qt, 2H, J = 7.0 Hz), 3.83 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz). LC / MS: retention time: 9.30 min; purity: 97%; MS (mass / charge): 414 (MH +). + + - 695 N4- (3,4-Dichlorophenyl) -N2- (1-ethylindazol-5-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.28 (s, 1H), 10.02 (s, 1H), 8.28 (d, 1H, J = 4.7 Hz), 8.02 (d, 1H, J = 2.3 Hz), 7.94 (s, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 7.66 (d, 1H, J = 9.1 Hz), 7.52 (d, 1H, J = 8.8 Hz), 7.42 (dd, 1H, J = 2.3 and 8.8 Hz), 4.41 (qt, 2H, J = 7.0 Hz), 1.38 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 12.41 min; purity: 99%; MS (mass / charge): 418 (MH +). - - 696 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -N2- (1-ethylindazol-5-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.77 (s, 1H), 10.39 (s, 1H), 10.21 (s, 1H), 8.22 (d, 1H, J = 5.3 Hz), 7.89 (s, 2H), 7.61 (d, 1H, J = 8.8 Hz), 7.37 (d, 1H, J = 8.8 Hz), 7.20 (dd, 2H, J = 2.3 and 8.2 Hz), 6.81 (d, 1H, J = 8.2 Hz), 4.39 (sq.t, 2H, J = 7.0 Hz), 1, 37 (s, 6H), 1.36 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 8.77 min; purity: 97%; MS (mass / charge): 448 (MH +). + + + + 697 N2- (1-Ethylindazol-5-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.42 (s, 1H), 10.29 (s, 1H), 8.26 (d, 1H, J = 4.9 Hz), 7.89 (s, 2H), 7.63 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.2 Hz), 7.37 (d, 1H, J = 9.0 Hz) , 7.31-7.23 (m, 1H), 7.19 (dd, 1H, J = 8.8 and 11.8 Hz), 4.41 (qt, 2H, J = 7.0 Hz ), 3.60 (s, 3H), 1.37 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 9.09 min; purity: 98%; MS (mass / charge): 398 (MH +). + + - 698 N4- (3-Chloro-4-methoxyphenyl) -N2- (1-ethylindazol-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.44 (s, 1H), 10.40 (s, 1H), 8.32 (d, 1H, J = 4.9 Hz), 7.92 (s, 1H), 7.78 (calc, 2H, J = 2.6 Hz), 7.67 (d, 1H, J = 8.5 Hz), 7.58-7.52 (dt, 1H, J = 2.6 and 9.1 Hz), 7.16 (d, 1H, J = 8.8 Hz), 7.10 (d, 1H, J = 9.1 Hz), 4.11 (sq. , 2H, J = 7.0 Hz), 3.83 (s, 3H), 1.25 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 10.83 min; purity: 96%; MS (mass / charge): 414 (MH +). + + - 699 N4- (3,4-Dichlorophenyl) -N2- (1-ethylindazol-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.92 (s, 1H), 9.78 (s, 1H), 8.27 (d, 1H, J = 4.1 Hz), 8.08 (calc. d, 1H, J = 2.6 Hz), 7.93 (s, 1H), 7.91 (s, 1H), 7.76 (dt, 1H, J = 2.6 and 8.1 Hz), 7.62 (d, 1H, J = 8.5 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.23 (d, 1H, J = 8.5 Hz), 4, 14 (qt, 2H, J = 7.0 Hz); 1.29 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 14.02 min; purity: 98%; MS (mass / charge): 418 (MH +). + + 700 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -N2- (1-ethylindazol-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.75 (s, 1H), 10.18 (s, 2H), 8.25 (d, 1H, J = 4.7 Hz), 7.94 (s, 1H), 7.84 (s, 1H), 7.63 (d, 1H, J = 8.5 Hz), 7.27-7.17 (m, 3H), 6.86 (d, 1H, J = 8.5 Hz), 4.14 (sq.t, 2H, J = 7.0 Hz), 1.38 (s, 6H), 1.28 (t, 3H, J = 7.0 Hz). LC / MS: retention time: 9.07 min; purity: 98%; MS (mass / charge): 448 (MH +). + + + 701 N2- (1-Ethylindazol-6-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.18 (s, 2H), 8.26 (d, 1H, J = 4.7 Hz), 7.93 (s, 1H), 7.90 (s, 1H), 7.62 (d, 1H, J = 8.5 Hz), 7.50-7.46 (m, 1H), 7.30-7.27 (m, 1H), 7.19-7 , 13 (m, 2H), 4.09 (sq. T, 2H, J = 7.0 Hz), 3.60 (s, 3H), 1.27 (t, 3H, J = 7.0 Hz) . LC / MS: retention time: 10.82 min; purity: 99%; MS (mass / charge): 397 (MH +). + + 702 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (1 -n- propylindazol-5-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.39 (s, 1H), 10.26 (s, 1H), 8.26 (d, 1H, J = 4.7 Hz), 7.92 (s, 1H), 7.82 (s, 1H), 7.75 (d, 1H, J = 2.7 Hz), 6.66 (d, 1H, J = 9.1 Hz), 7.54 (dt, 1H, J = 2.3 and 9.1 Hz), 7.08 (d, 1H, J = 9.1 Hz), 4.33 (t, 2H, J = 7.0 Hz), 3.83 ( s, 3H), 1.82 (q, 2H, J = 7.03 Hz), 0.81 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 10.32 min; purity: 98%; MS (mass / charge): 427 (MH +). + 703 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (1 -n- propylindazol-5-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.21 (s, 1H), 9.93 (s, 1H), 8.26 (d, 1H, J = 4.4 Hz), 8.01 (d, 1H, J = 2.6 Hz), 7.94 (s, 1H), 7.87 (s, 1H), 7.69 (dd, 1H, J = 1.8 and 8.8 Hz), 7, 65 (d, 1H, J = 9.1 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J = 9.1 Hz), 4.34 ( t, 2H, J = 7.0 Hz), 1.83 (square t, 2H, J = 7.0 Hz), 0.82 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 13.49 min; purity: 98%; MS (mass / charge): 432 (MH +). + 704 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (1 -n- propylindazol-5-yl) -2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.75 (s, 1H), 10.21 (s, 2H), 8.26 (d, 1H, J = 4.9 Hz), 7.94 (s, 1H), 7.83 (s, 1H), 7.63 (d, 1H, J = 8.8 Hz), 7.27-7.17 (m, 3H), 6.86 (d, 1H, J = 8.8 Hz), 4.06 (t, 2H, J = 7.0 Hz), 1.72 (qt, 2H, J = 7.0 Hz), 1.38 (s, 6H), 0.71 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 8.27 min; purity: 96%; MS (mass / charge): 462 (MH +). + + 705 5-Fluoro-N4- (4-fluoro-3-methoxyphenyl) -N2- (1 -n- propylindazol-5-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.46 (s, 1H), 10.35 (s, 1H), 8.28 (d, 1H, J = 4.9 Hz), 7.90 (s, 1H), 7.87 (s, 1H), 7.63 (d, 1H, J = 9.1 Hz), 7.43 (dd, 1H, J = 2.3 and 8.8 Hz), 7, 27-7.22 (m, 1H), 7.14 (dd, 1H, J = 1.8 and 11.1 Hz), 4.34 (t, 2H, J = 7.0 Hz), 3.60 (s, 3H), 1.82 (qt, 2H, J = 7.0 Hz), 0.81 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 10.03 min; purity: 99%; MS (mass / charge): 411 (MH +). + 706 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (1 -n- propylindazol-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.51 (s, 1H), 10.44 (s, 1H), 8.33 (d, 1H, J = 4.9 Hz), 7.96 (s, 1H), 7.77 (d, 1H, J = 2.6 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.55 (dd, 1H, J = 2.6 and 8 , 8 Hz), 7.16 (dd, 1H, J = 2.6 and 8.8 Hz), 4.03 (t, 2H, J = 7.0 Hz), 3.83 (s, 3H), 1.68 (qt, 2H, J = 7.0 Hz); 0.68 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 11.82 min; purity: 99%; MS (mass / charge): 427 (MH +). + + 707 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (1 -n- propylindazol-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.15 (s, 1H), 10.02 (s, 1H), 8.30 (d, 1H, J = 4.4 Hz), 8.06 (d, 1H, J = 2.6 Hz), 7.93 (s, 1H), 7.89 (s, 1H), 7.73 (dd, 1H, J = 2.6 and 8.5 Hz), 7, 65 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 8.8 Hz), 7.21 (d, 1H, J = 8.8 Hz), 4.07 ( t, 2H, J = 7.0 Hz), 1.71 (sq. t, 2H, J = 7.0 Hz), 0.72 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 14.82 min; purity: 98%; MS (mass / charge): 433 (MH +). + + 708 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (1 -n- propylindazol-6-yl) -2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.77 (s, 1H), 10.37 (s, 1H), 10.16 (s, 1H), 8.21 (d, 1H, J = 5.3 Hz), 7.89 (s, 1H), 7.87 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz), 7.37 (dd, 1H, J = 1.8 and 8.8 Hz), 7.20 (d, 1H, J = 8.8 Hz), 8.87 (d, 1H, J = 8.8 Hz), 4.31 (t, 2H, J = 7 , 0 Hz), 1.81 (qt, 2H, J = 7.0 Hz), 1.36 (s, 6H), 0.79 (t, 2H, J = 7.0 Hz); LC / MS: retention time: 9.97 min; purity: 99%; MS (mass / charge): 462 (MH +). + + 709 5-Fluoro-N4- (4-fluoro-3-methoxyphenyl) -N2- (1 -n- propylindazol-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.40 (s, 1H), 10.37 (s, 1H), 8.33 (d, 1H, J = 5.0 Hz), 7.96 (s, 1H), 7.84 (s, 1H), 7.64 (d, 1H, J = 8.5 Hz), 7.47 (dt, 1H, J = 1.8 and 8.5 Hz), 7, 26-7.22 (m, 2H), 7.15 (dd, 1H, J = 11.8 and 8.8 Hz), 4.02 (t, 2H, J = 7.0 Hz), 3.55 (s, 3H), 1.68 (qt, 2H, J = 7.0 Hz), 0.69 (t, 3H, J = 7.0 Hz); LC / MS: retention time: 11.72 min; purity: 100%; MS (mass / charge): 411 (MH +). + 710 N2- (1 -n- Butylindazol-5-yl) -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.40 (s, 1H), 10.27 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.75 ( d, 1H, J = 2.3 Hz), 7.65 (d, 1H, J = 9.1 Hz), 7.54 (dd, 1H, J = 2.3 and 9.1 Hz), 7, 39 (d, 1H, J = 9.1 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.36 (t, 2H, J = 7.3 Hz), 3.83 ( s, 3H), 1.78 (q, 2H, J = 7.3 Hz), 1.22 (calculated hex, 2H, J = 7.3 Hz), 0.86 (t, 3H, J = 7 , 3 Hz), LC / MS: retention time: 12.69 min; purity: 99%; MS (mass / charge): 442 (MH +). + 711 N2- (1 -n- Butylindazol-5-yl) -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.43 (s, 1H), 10.20 (s, 1H), 8.32 (d, 1H, J = 4.7 Hz), 8.00 (d, 1H, J = 2.3 Hz), 7.95 (s, 1H), 7.83 (s, 1H), 7.67 (d, 2H, J = 8.8 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J = 2.3 and 8.8 Hz), 4.38 (t, 2H, J = 7.3 Hz), 1.79 ( q, 2H, J = 7.3 Hz), 1.23 (calculated hex, 2H, J = 7.3 Hz), 0.87 (t, 3H, J = 7.3 Hz), LC / MS : retention time: 15.87 min; purity: 98%; MS (mass / charge): 446 (MH +). + 712 N2- (1 -n- Butylindazol-5-yl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.75 (s, 1H), 10.28 (s, 1H), 10.05 (s, 1H), 8.19 (d, 1H, J = 4.9 Hz), 7.89 (s, 2H), 7.60 (d, 1H, J = 9.1 Hz), 7.38 (d, 1H, J = 9.1 Hz), 7.20 (dd, 1H, J = 1.8 and 9.1 Hz), 7.16 (s, 1H), 6.86 (d, 1H, J = 9.1 Hz), 4.35 (t, 2H, J = 7 , 3 Hz), 1.77 (q, 2H, J = 7.3 Hz), 1.36 (s, 6H), 1.20 (calculated hex, 2H, J = 7.3 Hz), 0, 86 (t, 3H, J = 7.3 Hz), LC / MS: retention time: 11.06 min; purity: 97%; MS (mass / charge): 476 (MH +). + + 713 N2- (1 -n- Butylindazol-5-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.42 (s, 1H), 10.29 (s, 1H), 8.27 (d, 1H, J = 4.9 Hz), 7.89 (s, 1H), 7.87 (s, 1H), 7.63 (d, 1H, J = 8.8 Hz), 7.43 (dd, 1H, J = 2.3 and 8.8 Hz), 7, 36 (dd, 1H, J = 1.8 and 9.1 Hz), 7.28-7.23 (m, 1H), 7.13 (dd, 1H, J = 11.3 and 9.1 Hz) , 4.37 (t, 2H, J = 7.3 Hz), 3.60 (s, 3H), 1.78 (q, 2H, J = 7.3 Hz), 1.22 (calculated hex, 2H, J = 7.3 Hz), 0.86 (t, 3H, J = 7.3 Hz), LC / MS: retention time: 12.60 min; purity: 99%; MS (mass / charge): 426 (MH +). + + 714 N2- (1 -n- Butylindazol-6-yl) -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.27 (s, 2H), 8.30 (d, 1H, J = 4.7 Hz), 7.94 (s, 1H), 7.82 (s, 1H), 7.77 (d, 1H, J = 2.6 Hz), 7.65 (d, 1H, J = 8.8 Hz), 7.56 (dd, 1H, J = 2.6 and 8 8 Hz), 7.16 (d, 1H, J = 8.8 Hz), 7.11 (d, 1H, J = 8.8 Hz), 4.06 (t, 2H, J = 7.3 Hz), 3.83 (s, 3H), 1.64 (q, 2H, J = 7.3 Hz), 1.08 (calculated hex, 2H, J = 7.3 Hz), 0.78 ( t, 3H, J = 7.3 Hz), LC / MS: retention time: 14.10 min; purity: 96%; MS (mass / charge): 442 (MH +). + 715 N2- (1 -n- Butylindazol-6-yl) -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.21 (s, 1H), 10.09 (s, 1H), 8.32 (d, 1H, J = 4.4 Hz), 8.05 (d, 1H, J = 2.3 Hz), 7.94 (s, 1H), 7.86 (s, 1H), 7.72 (d, 1H, J = 8.8 Hz), 7.66 (d, 1H, J = 8.8 Hz), 7.55 (d, 1H, J = 8.8 Hz), 7.20 (d, 1H, J = 8.8 Hz), 4.11 (t, 2H, J = 7.3 Hz), 1.66 (q, 2H, J = 7.3 Hz), 1.12 (calculated hex, 2H, J = 7.3 Hz), 0.79 (t, 3H, J = 7.3 Hz), LC / MS: retention time: 16.86 min; purity: 96%; MS (mass / charge): 446 (MH +). + 716 N2- (1 -n- Butylindazol-6-yl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.77 (s, 1H), 10.40 (s, 1H), 10.36 (s, 1H), 8.29 (d, 1H, J = 4.9 Hz), 7.94 (s, 1H), 7.81 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.23 (s, 2H), 7.18 ( d, 1H, J = 8.8 Hz), 6.85 (d, 1H, J = 8.8 Hz), 4.10 (t, 2H, J = 7.3 Hz), 1.67 (q. , 2H, J = 7.3 Hz), 1.38 (s, 6H), 1.09 (calculated hex, J = 2H, J = 7.3 Hz), 0.78 (t, 3H, J = 7.3 Hz), LC / MS: retention time: 12.49 min; purity: 96%; MS (mass / charge): 476 (MH +) + + 717 N2- (1 -n- Butylindazol-6-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.42 (s, 1H), 10.37 (s, 1H), 8.33 (d, 1H, J = 4.7 Hz), 7.96 (s, 1H), 7.84 (s, 1H), 7.64 (d, 1H, J = 8.8 Hz), 7.50-7.46 (m, 1H), 7.27-7.22 (m , 1H), 7.16 (calc. T, 1H, J = 11.8 and 8.8 Hz), 4.06 (t, 2H, J = 7.3 Hz), 3.54 (s, 3H) 1.65 (q, 2H, J = 7.3 Hz), 1.08 (calculated hex, 2H, J = 7.3 Hz), 0.78 (t, 3H, J = 7.3 Hz) ), LC / MS: retention time: 14.23 min; purity: 97%; MS (mass / charge): 425 (MH +). + 718 N4- (3-Chloro-4-methoxyphenyl) -N2- [1- (cyclohexylmethyl) indazol-5-yl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.19 (s, 1H), 10.03 (s, 1H), 8.22 (d, 1H, J = 4.9 Hz), 7.90 (s, 1H), 7.84 (s, 1H), 7.76 (d, 1H, J = 2.6 Hz), 7.62 (d, 1H, J = 9.1 Hz), 7.56 (dd, 1H, J = 2.6 and 9.1 Hz), 7.39 (dd, 1H, J = 1.8 and 9.1 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.20 (d, 2H, J = 7.0 Hz), 3.83 (s, 3H), 1.89-1.86 (m, 3H), 1.60 (br s, 3H), 1 48-1.44 (br s, 2H), 1.13-0.96 (m, 5H), LC / MS: retention time: 13.78 min; purity: 98%; MS (mass / charge): 481 (MH +). + 719 N2- [1- (Cyclohexylmethyl) indazol-5-yl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.69 (s, 1H), 9.38 (s, 1H), 8.17 (d, 1H, J = 3.8 Hz), 8.07 (calc. d, 1H, J = 2.6 Hz), 7.92 (s, 1H), 7.88 (s, 1H), 7.78 (d, 1H, J = 8.8 Hz), 7.58 ( d, 1H, J = 9.1 Hz), 7.49-7.44 (m, 2H), 4.19 (d, 2H, J = 7.3 Hz), 1.91-1.84 (m , 1H), 1.62 (m, 3H), 1.49-1.45 (m, 2H), 1.15-0.96 (m, 5H), LC / MS: retention time: 17.23 min ; purity: 96%; MS (mass / charge): 485 (MH +). + 720 N2- [1- (Cyclohexylmethyl) indazol-5-yl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4 pyrimidinediamine ¹ H, 7.90 (s, 1H), 7.84 (s, 1H), 7.62 (d, 1H, J = 9.1 Hz), 7.37 (dd, 1H, J = 2.3; and 8.8 Hz), 7.23 (dd, 1H, J = 2.3 and 9.1 Hz), 7.17 (s, 1H), 6.84 (d, 1H, J = 9.1 Hz) , 4.19 (d, 2H, J = 7.3 Hz), 1.91-1.84 (m, 1H), 1.62 (br s, 3H), 1.47-1.38 (m , 2H), 1.36 (s, 6H), 1.13-0.96 (m, 5H), LC / MS: retention time: 11.95 min; purity: 96%; MS (mass / charge): 516 (MH +). + 721 N2- [1- (Cyclohexylmethyl) indazol-5-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.31 (s, 1H), 10.13 (s, 1H), 8.25 (d, 1H, J = 4.9 Hz), 7.89 (s, 1H), 7.87 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.43 (dd, 1H, J = 2.6 and 8.8 Hz), 7, 36 (dd, 1H, J = 1.8 and 9.1 Hz), 7.29-7.25 (s, 1H), 7.12 (dd, 1H, J = 8.8 and 11.4 Hz) , 4.21 (d, 2H, J = 7.3 Hz), 3.61 (s, 3H), 1.91-1.84 (m, 1H), 1.62 (br s, 3H), 1.48-1.44 (m, 2H), 1.16-0.96 (m, 5H), LC / MS: retention time: 13.82 min; purity: 98%; MS (mass / charge): 465 (MH +). + 722 N4- (3-Chloro-4-methoxyphenyl) -N2- [1- (cyclohexylmethyl) indazol-6-yl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.12 (s, 2H), 8.26 (d, 1H, J = 4.7 Hz), 7.93 (s, 1H), 7.85 (s, 1H), 7.78 (d, 1H, J = 2.6 Hz), 7.63 (d, 1H, J = 8.8 Hz), 7.58 (dd, 1H, J = 2.6 and 8 8 Hz), 7.19 (d, 1H, J = 8.8 Hz), 7.11 (d, 1H, J = 8.8 Hz), 3.90 (d, 2H, J = 7.3 Hz), 3.82 (s, 3H), 1.74-1.71 (m, 1H), 1.53 (br s, 3H), 1.37-1.33 (m, 2H), 1 08-1.02 (m, 3H), 0.82-0.78 (m, 2H), LC / MS: retention time: 15.24 min; purity: 91%; MS (mass / charge): 481 (MH +). + + 723 N2- [1- (Cyclohexylmethyl) indazol-6-yl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.05 (s, 1H), 9.91 (s, 1H), 8.29 (d, 1H, J = 4.1 Hz), 8.05 (d, 1H, J = 2.3 Hz), 7.92 (s, 1H), 7.90 (s, 1H), 7.73 (dd, 1H, J = 2.3 and 8.8 Hz), 7, 63 (d, 1H, J = 8.8 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.21 (d, 1H, J = 8.8 Hz), 3.93 ( d, 2H, J = 7.3 Hz), 1.78-1.74 (m, 1H), 1.54 (br s, 3H), 1.40-1.35 (m, 2H), 1 13-1.03 (m, 3H), 0.88-0.81 (m, 2H), LC / MS: retention time: 17.78 min; purity: 91%; MS (mass / charge): 485 (MH +). - 724 N2- [1- (Cyclohexylmethyl) indazol-6-yl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.73 (s, 1H), 10.07 (s, 1H), 10.01 (s, 1H), 8.22 (d, 1H, J = 4.7 Hz), 7.91 (s, 1H), 7.86 (s, 1H), 7.60 (d, 1H, J = 8.8 Hz), 7.26 (dd, 1H, J = 2.3 and 8.5 Hz), 7.22-7.19 (calc., 2H), 6.85 (d, 1H, J = 8.5 Hz), 3.93 (d, 2H, J = 7, 3 Hz), 1.78-175 (m, 1H), 1.52 (br s, 3H), 1.38 (s, 6H), 1.36-1.32 (m, 2H), 1, 09-1.03 (m, 3H), 0.88-0.82 (m, 2H), LC / MS: retention time: 13.52 min; purity: 95%; MS (mass / charge): 516 (MH +). + 725 N2- [1- (Cyclohexylmethyl) indazol-6-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.24 (s, 2H), 8.29 (d, 1H, J = 4.7 Hz), 7.95 (s, 1H), 7.86 (s, 1H), 7.63 (d, 1H, J = 8.8 Hz), 7.49 (dd, 1H, J = 2.3 and 8.8 Hz), 7.28-7.24 (m, 1H ), 7.19-7.12 (m, 2H), 3.91 (d, 2H, J = 7.3 Hz), 3.55 (s, 3H), 1.75-1.73 (m, 1H), 1.54 (br s, 3H), 1.37-1.33 (m, 2H), 1.09-1.03 (m, 3H), 0.84-0.79 (m, 2H), LC / MS: retention time: 15.18 min; purity: 96%; MS (mass / charge): 465 (MH +). + 726 N4- (3-Chloro-4-methoxyphenyl) -N2- [1- (cyclobutylmethyl) indazol-5-yl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.40 (s, 1H), 10.26 (s, 1H), 8.26 (d, 1H, J = 5.3 Hz), 7.91 (s, 1H), 7.81 (s, 1H), 7.75 (d, 1H, J = 2.6 Hz), 7.68 (d, 1H, J = 9.1 Hz), 7.55 (dd, 1H, J = 2.6 and 2.6 and 8.8 Hz), 7.38 (d, 1H, J = 8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.39 (d, 2H, J = 7.0 Hz), 3.83 (s, 3H), 2.80 (m, 1H), 1.94-1.74 (m, 6H), LC / MS : retention time: 12.08 min; purity: 99%; MS (mass / charge): 455 (MH +). + 727 N2- [1- (Cyclobutylmethyl) indazol-5-yl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.32 (s, 1H), 10.06 (s, 1H), 8.29 (d, 1H, J = 4.7 Hz), 8.00 (s, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 7.68 (d, 2H, J = 8.8 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.41 (d, 1H, J = 8.8 Hz), 4.40 (d, 2H), 2.86-2.76 (m, 1H), 1.96-1.75 (m , 6H). LC / MS: retention time: 15.32 min; purity: 98%; MS (mass / charge): 458 (MH +). + 728 N2- [1- (Cyclobutylmethyl) indazol-5-yl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.79 (s, 1H), 10.40 (s, 1H), 10.25 (s, 1H), 8.23 (d, 1H, J = 4.9 Hz), 7.88 (s, 1H), 7.86 (s, 1H), 7.64 (d, 1H, J = 8.8 Hz), 7.37 (d, 1H, J = 9.1 Hz), 7.21 (s, 1H), 7.18 (s, 1H), 6.86 (d, 1H, J = 9.1 Hz), 4.37 (d, 1H, J = 7.0 Hz), 2.83-2.74 (m, 1H), 1.93-1.70 (m, 6H), 1.36 (s, 6H), LC / MS: retention time: 10.57 min; purity: 97%; MS (mass / charge): 488 (MH +). + 729 N2- [1- (Cyclobutylmethyl) indazol-5-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.48 (s, 1H), 10.36 (s, 1H), 8.29 (d, 1H, J = 5.3 Hz), 7.88 (s, 1H), 7.86 (s, 1H), 7.67 (d, 1H, J = 8.0 Hz), 7.43 (dd, 1H, J = 2.3 and 8.0 Hz), 7, 35 (dd, 1H, J = 1.8 and 8.8 Hz), 7.26-7.23 (m, 1H), 7.14 (dd, 1H, J = 9.1 and 11.8 Hz) 4.40 (d, 2H, J = 7.0 Hz), 3.60 (s, 3H), 1.95-1.71 (m, 6H), LC / MS: retention time: 12.16 min ; purity: 99%; MS (mass / charge): 437 (MH +). + 730 N4- (3-Chloro-4-methoxyphenyl) -N2- [1- (cyclobutylmethyl) indazol-6-yl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.35 (s, 2H), 8.31 (d, 1H, J = 4.7 Hz), 7.94 (s, 1H), 7.86 (s, 1H), 7.78 (d, 1H, J = 2.3 Hz), 7.66 (d, 1H, J = 8.8 Hz), 7.57 (dd, 1H, J = 2.3 and 8 8 Hz), 7.16 (d, 1H, J = 8.8 Hz), 7.12 (d, 1H, J = 8.8 Hz), 4.09 (d, 2H, J = 7.3 Hz), 3.83 (s, 3H), 2.69-2.59 (m, 1H), 1.86-1.56 (m, 6H), LC / MS: retention time: 13.56 min; purity: 97%; MS (mass / charge): 454 (MH +). + 731 N2- [1- (Cyclobutylmethyl) indazol-6-yl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.27 (s, 1H), 10.16 (s, 1H), 8.30 (d, 1H, J = 4.4 Hz), 7.99 (d, 1H, J = 2.3 Hz), 7.88 (s, 1H), 7.85 (s, 1H), 7.67 (dd, 1H, J = 2.3 and 8.8 Hz), 7, 60 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.13 (d, 1H, J = 8.8 Hz), 4.07 ( d, 2H, J = 7.0 Hz), 2.66-2.56 (m, 1H), 1.83-1.56 (m, 6H), LC / MS: retention time: 16.25 min; purity: 96%; MS (mass / charge): 458 (MH +). + 732 N2- [1- (Cyclobutylmethyl) indazol-6-yl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.81 (s, 1H), 10.63 (s, 1H), 10.55 (s, 1H), 8.33 (d, 1H, J = 5.3 Hz), 7.94 (s, 1H), 7.81 (s, 1H), 7.64 (d, 1H, J = 8.8 Hz), 7.24-7.21 (m, 2H), 7.17 (d, 1H, J = 8.5 Hz), 6.86 (d, 1H, J = 8.5 Hz), 4.12 (d, 2H, J = 7.0 Hz), 2, 71-2.61 (m, 1H), 1.85-1.59 (m, 6H), 1.38 (s, 6H), LC / MS: retention time: 12.01 min; purity: 97%; MS (mass / charge): 488 (MH +). + 733 N2- [1- (Cyclobutylmethyl) indazol-6-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.67 (s, 1H), 10.58 (s, 1H), 8.38 (d, 1H, J = 5.3 Hz), 7.96 (s, 1H), 7.85 (s, 1H), 7.66 (d, 1H, J = 8.5 Hz), 7.48 (dd, 1H, J = 2.3 and 8.5 Hz), 7, 23-7.11 (m, 3H), 4.07 (d, 2H, J = 7.0 Hz), 3.51 (s, 3H), 2.67-2.57 (m, 6H). LC / MS: retention time: 13.67 min; purity: 98%; MS (mass / charge): 439 (MH +). + 734 N4- (3-Chloro-4-methoxyphenyl) -N2- [1- (cyclopropylmethyl) indazol-5-yl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.05 (s, 1H), 9.91 (s, 1H), 8.31 (d, 1H, J = 5.2 Hz), 7.96 (s, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.72 (d, 1H, J = 8.8 Hz), 7.60 (d, 1H, J = 8.8 Hz), 7.43 (d, 1H, J = 9.1 Hz), 7.14 (d, 1H, J = 8.8 Hz), 4.31 (d, 2H, J = 7.0 Hz) 3.48 (s, 3H), 1.33 (m, 1H), 0.58-0.40 (m, 4H), LC / MS: retention time: 13.98 min; purity: 98%; MS (mass / charge): 439 (MH +). + 735 N2- [1- (Cyclopropylmethyl) indazol-5-yl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.39 (s, 1H), 10.14 (s, 1H), 8.31 (d, 1H, J = 4.7 Hz), 8.05 (d, 1H, J = 2.3 Hz), 7.98 (s, 1H), 7.89 (s, 1H), 7.73 (d, 1H, J = 9.1 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.45 (dd, 1H, J = 2.3 and 8.8 Hz), 4.32 (d, 2H, J = 7.0 Hz), 1.34- 1.24 (m, 1H), 0.54-0.44 (m, 4H), LC / MS: retention time: 13.89 min; purity: 96%; MS (mass / charge): 444 (MH +). + 736 N2- [1- (Cyclopropylmethyl) indazol-5-yl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.85 (s, 1H), 10.46 (s, 1H), 10.29 (s, 1H), 8.23 (d, 1H, J = 5.3 Hz), 7.95 (s, 1H), 7.94 (s, 1H0, 7.71 (d, 1H, J = 9.1 Hz), 7.42 (dd, 1H, J = 2.3 and 9.1 Hz), 7.27 (d, 1H, J = 8.5 Hz), 7.25 (s, 1H), 6.95 (d, 1H, J = 8.5 Hz), 4.32 (d, 2H, J = 7.0 Hz), 1.38 (s, 6H), 1.34-1.24 (m, 1H), 0.54-0.44 (m, 4H), LC / MS: retention time: 9.65 min; purity: 96%; MS (mass / charge): 474 (MH +). + + 737 N2- [1- (Cyclopropylmethyl) indazol-5-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.43 (s, 1H), 10.27 (s, 1H), 8.31 (d, 1H, J = 4.3 Hz), 7.95 (s, 1H), 7.94 (s, 1H), 7.71 (d, 1H, J = 9.1 Hz), 7.48 (dd, 1H, J = 2.3 and 8.8 Hz), 7, 41 (dd, 1H, J = 2.3 and 9.1 Hz), 7.31-7.29 (m, 1H), 7.30 (dd, 1H, J = 8.8 and 11.1 Hz) 4.32 (d, 2H, J = 7.0 Hz), 3.65 (s, 3H), 1.33-1.17 (m, 1H), 0.55-0.46 (m, 4H ), LC / MS: retention time: 11.01 min; purity: 98%; MS (mass / charge): 423 (MH +). + 738 N4- (3-Chloro-4-methoxyphenyl) -N2- [1- (cyclopropylmethyl) indazol-6-yl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.28 (s, 2H), 8.31 (d, 1H, J = 4.3 Hz), 7.95 (s, 1H), 7.96 (s, 2H), 7.87 (s, 1H), 7.79 (d, 1H, J = 2.6 Hz), 7.69 (d, 1H, J = 8.8 Hz), 7.58 (dd, 1H, J = 2.6 and 9.1 Hz), 7.19 (dd, 1H, J = 1.8 and 8.8 Hz), 7.11 (d, 1H, J = 9.1 Hz), 4.32 (d, 2H, J = 6.7 Hz), 3.84 (s, 3H), 1.33-1.17 (m, 1H), 0.55-0.46 (m, 4H) LC / MS: retention time: 12.54 min; purity: 98%; MS (mass / charge): 440 (MH +). + 739 N2- [1- (Cyclopropylmethyl) indazol-6-yl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.21 (s, 1H), 10.10 (s, 1H), 8.32 (d, 1H, J = 4.3 Hz), 8.04 (d, 1H, J = 2.6 Hz), 7.93 (s, 1H), 7.91 (s, 1H), 7.71 (dd, 1H, J = 2.6 and 8.8 Hz), 7, 65 (d, 1H, J = 8.8 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.20 (d, 1H, J = 8.8 Hz), 4.32 ( d, 2H, J = 6.7 Hz), 1.33-1.17 (m, 1H), 0.55-0.46 (m, 4H), LC / MS: retention time: 15.18 min; purity: 95%; MS (mass / charge): 444 (MH +). + 740 N2- [1- (Cyclopropylmethyl) indazol-6-yl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.82 (s, 1H), 10.22 (s, 1H), 10.16 (s, 1H), 8.31 (d, 1H, J = 4.7 Hz), 8.00 (d, 1H, J = 0.8 Hz), 7.97 (s, 1H), 7.34 (d, 1H, J = 8.8 Hz), 7.35-7, 27 (m, 3H), 6.92 (d, 1H, J = 8.5 Hz), 4.32 (d, 2H, J = 7.0 Hz), 1.36 (s, 6H), 1, 33-1.17 (m, 1H), 0.55-0.45 (m, 2H), 0.35-0.30 (m, 2H), LC / MS: retention time: 10.93 min; purity: 96%; MS (mass / charge): 474 (MH +). + + 741 N2- [1- (Cyclopropylmethyl) indazol-6-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.23 (s, 2H), 8.31 (d, 1H, J = 4.9 Hz), 7.95 (s, 1H), 7.91 (s, 1H), 7.65 (d, 1H, J = 8.8 Hz), 7.48 (dd, 1H, J = 2.3 and 8.8 Hz), 7.29-7.24 (m, 1H ), 7.20-7.13 (m, 3H), 4.09 (d, 2H, J = 6.7 Hz), 3.65 (s, 3H), 1.33-1.17 (m, 1H), 0.55-0.46 (m, 2H), 0.35-0.30 (m, 2H), LC / MS: retention time: 12.54 min; purity: 98%; MS (mass / charge): 423 (MH +). + 742 N4- (3-Chloro-4-methoxyphenyl) -N2- (1-cyclohexylindazol-5-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.35 (s, 1H), 10.20 (s, 1H), 8.24 (d, 1H, J = 5.3 Hz), 7.92 (s, 1H), 7.81 (s, 1H), 7.74 (d, 1H, J = 2.6 Hz), 7.71 (d, 1H, J = 8.1 Hz), 7.55 (dd, 1H, J = 2.6 and 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 8.8 Hz), 7.09 (d, 1H, J = 8.1 Hz), 4.56-4.53 (m, 1H), 3.82 (s, 3H), 1.91-1.82 (m, 6H), 1.72-1.68 (m, 1H), 1, 51 -1.46 (m, 2H), 1.31-1.23 (m, 1H), LC / MS: retention time: 13.04 min; purity: 98%; MS (mass / charge): 467 (MH +). + + 743 N2- (1-Cyclohexylindazol-5-yl) -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.26 (s, 1H), 9.99 (s, 1H), 8.23 (d, 1H, J = 4.9 Hz), 7.96 (s, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.66 (d, 1H, J = 8.1 Hz), 7.61 (calculated s, 1H), 7, 45 (d, 1H, J = 9.1 Hz), 7.34 (d, 1H, J = 9.1 Hz), 4.53-4.49 (m, 1H), 1.87-1.78 (m, 6H), 1.67-1.63 (m, 1H), 1.46-1.42 (m, 2H), 1.27-1.18 (m, 1H), LC / MS: time retention: 16.43 min; purity: 97%; MS (mass / charge): 472 (MH +). + 744 N2- (1-Cyclohexylindazol-5-yl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.80 (s, 1H), 10.36 (s, 1H), 10.15 (s, 1H), 8.21 (d, 1H, J = 4.9 Hz), 7.89 (s, 1H), 7.86 (s, 1H), 7.64 (d, 1H, J = 9.4 Hz), 7.36 (dd, 1H, J = 2.3 and 8.8 Hz), 7.18 (d, 1H, J = 2.3 Hz), 6.86 (d, 1H, J = 9.4 Hz), 4.53-4.49 (m, 1H ), 1.89-1.82 (m, 6H), 1.72-1.68 (m, 1H), 1.52-1.43 (m, 2H), 1.36 (s, 6H), 1.29-1.23 (m, 1H), LC / MS: retention time: 11.44 min; purity: 96%; MS (mass / charge): 502 (MH +). + + 745 N2- (1-Cyclohexylindazol-5-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.26 (s, 1H), 10.07 (s, 1H), 8.22 (d, 1H, J = 5.0 Hz), 7.90 (s, 1H), 7.89 (s, 1H), 7.67 (d, 1H, J = 8.8 Hz), 7.44 (dd, 1H, J = 8.5 Hz), 7.34 (dd, 1H, J = 1.8 and 8.8 Hz), 7.28-7.24 (m, 1H), 7.15 (dd, 1H, J = 8.8 and 11.1 Hz), 4.53 -4, 49 (m, 1H), 3.59 (s, 3H), 1.91-1.84 (m, 6H), 1.72-1.68 (m, 1H), 1.52-1 43 (m, 2H), 1.31-1.23 (m, 1H), LC / MS: retention time: 13.11 min; purity: 98%; MS (mass / charge): 451 (MH +). + 746 N4- (3-Chloro-4-methoxyphenyl) -N2- (1-cyclohexylindazol-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.21 (s, 1H), 10.19 (s, 1H), 8.28 (d, 1H, J = 4.9 Hz), 7.95 (s, 1H), 7.86 (d, 1H, J = 2.6 Hz), 7.84 (s, 1H), 7.66 (d, 1H, J = 8.5 Hz), 7.59 (dd, 1H, J = 2.6 and 9.1 Hz), 7.21 (dd, 1H, J = 1.8 and 8.5 Hz), 7.06 (d, 1H, J = 9.1 Hz), 4.19-4.06 (m, 1H), 3.80 (s, 3H), 1.83-1.74 (m, 6H), 1.65-1.62 (m, 1H), 1, 29-1.15 (m, 3H), LC / MS: retention time: 14.39 min; purity: 97%; MS (mass / charge): 465 (MH +). + 747 N2- (1-Cyclohexylindazol-6-yl) -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.05 (s, 1H), 9.88 (s, 1H), 8.29 (d, 1H, J = 4.9 Hz), 8.11 (d, 1H, J = 2.6 Hz), 7.93 (s, 1H), 7.92 (s, 1H), 7.78 (dd, 1H, J = 2.6 and 8.8 Hz), 7, 64 (d, 1H, J = 8.5 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.22 (dd, 1H, J = 1.7 and 8.5 Hz), 4.19-4.06 (m, 1H), 1.85-1.77 (m, 6H), 1.65-1.62 (m, 1H), 1.29-1.13 (m, 3H) ), LC / MS: retention time: 17.10 min; purity: 94%; MS (mass / charge): 472 (MH +). + 748 N2- (1-Cyclohexylindazol-6-yl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.76 (s, 1H), 10.25 (s, 1H), 10.18 (s, 1H), 8.24 (d, 1H, J = 4.9 Hz), 7.94 (s, 1H), 7.83 (s, 1H), 7.63 (d, 1H, J = 8.5 Hz), 7.31-7.22 (m, 3H), 6.80 (d, 1H, J = 8.5 Hz), 4.23-4.12 (m, 1H), 1.85-1.77 (m, 6H), 1.65-1.62 ( m, 1H), 1.38 (s, 6H), 1.29-1.13 (m, 3H), LC / MS: retention time: 12.78 min; purity: 94%; MS (mass / charge): 502 (MH +). + 749 N2- (1-Cyclohexylindazol-6-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.02 (s, 1H), 9.95 (s, 1H), 8.26 (d, 1H, J = 4.3 Hz), 7.93 (s, 2H), 7.83 (s, 1H), 7.63 (d, 1H, J = 8.8 Hz), 7.55 (dd, 1H, J = 2.6 and 8.8 Hz), 7, 31-7.28 (m, 1H), 7.18 (d, 1H, J = 8.8 Hz), 7.12 (dd, 1H, J = 8.8 and 11.4 Hz), 4.11 -4.00 (m, 1H), 3.49 (s, 3H), 1.82-1.75 (m, 6H), 1.65-1.62 (m, 1H), 1.29-1 13 (m, 3H), LC / MS: retention time: 14.35 min; purity: 94%; MS (mass / charge): 452 (MH +). + 750 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (3-methylindazol-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 12.23 (s, 1H), 9.53 (s, 1H), 9.36 (s, 1H), 8.14 (d, 1H, J = 3.5 Hz), 8.10 (d, 1H, J = 2.7 Hz), 7.88 (s, 1H), 7.86 (dd, 1H, J = 2.7 and 8.8 Hz), 7, 47 (d, 2H, J = 8.8 Hz), 7.16 (dd, 1H, J = 1.8 and 8.8 Hz), 2.36 (s, 3H). LC / MS: retention time: 12.62 min; purity: 94%; MS (mass / charge): 404 (MH +). + + 751 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (3-methylindazol-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.62 (s, 1H), 9.63 (s, 1H), 9.44 (s, 1H), 8.13 (d, 1H, J = 41 Hz ), 7.84 (s, 1H), 7.50 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H, J = 2.3 and 8.5 Hz), 7.31 (d, 1H, J = 2.3 Hz), 7.24 (dd, 1H, J = 1.8 and 8.8 Hz), 6.89 (d, 1H, J = 8.5 Hz), 2 41 (s, 3H), 1.39 (s, 6H), LC / MS: retention time: 8.78 min; purity: 92%; MS (mass / charge): 434 (MH +). + + 752 N4- (3-Chloro-4-methoxyphenyl) -N2- (1,3-dimethylindazol-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.49 (s, 1H), 10.43 (s, 1H), 8.33 (d, 1H, J = 5.3 Hz), 7.77 (d, 1H, J = 2.6 Hz), 7.67 (d, 1H, J = 1.2 Hz), 7.62 (d, 1H, J = 8.8 Hz), 7.55 (dd, 1H, J = 2.6 and 8.8 Hz), 7.10 (d, 1H, J = 8.8 Hz), 7.09 (d, 1H, J = 8.8 Hz), 3.83 (s, 3H), 3.67 (s, 3H), 2.41 (s, 3H), LC / MS: retention time: 11.19 min; purity: 94%; MS (mass / charge): 413 (MH +). + + 753 N4- (3,4-Dichlorophenyl) -N2- (1,3-dimethylindazol-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.65 (s, 1H), 9.50 (s, 1H), 8.22 (d, 1H, J = 3.5H), 8.12 (d, 1H , J = 2.3 Hz), 7.91 (d, 1H, J = 1.8 Hz), 7.79 (dd, 1H, J = 2.3 and 8.8 Hz), 7.52 (dd , 2H, J = 2.3 and 8.8 Hz), 7.18 (dd, 1H, J = 1.8 and 8.8 Hz), 3.69 (s, 3H), 2.39 (s, 3H ), LC / MS: retention time: 13.96 min; purity: 97%; MS (mass / charge): 418 (MH +). + + 754 N2- (1,3-Dimethylindazol-6-yl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.72 (s, 1H), 10.25 (s, 2H), 8.26 (d, 1H, J = 4.9 Hz), 7.72 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.25 (dd, 1H, J = 2.3 and 8.5 Hz), 7.22 (calculated s, 1H), 7.14 (dd, 1H, J = 2.3 and 8.5 Hz), 6.87 (d, 1H, J = 8.5 Hz), 3.37 (s, 3H), 2.40 (s , 3H), 1.38 (s, 6H), LC / MS: retention time: 9.77 min; purity: 94%; MS (mass / charge): 448 (MH +). + + + 755 N2- (1,3-Dimethylindazol-6-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.14 (s, 2H), 8.28 (d, 1H, J = 3.7 Hz), 7.79 (d, 1H, J = 1.8 Hz) 7.57 (d, 1H, J = 8.5 Hz), 7.48 (dd, 1H, J = 2.3 and 8.5 Hz), 7.31-7.26 (m, 1H), 7.17 (dd, 1H, J = 8.8 and 11.4 Hz), 7.10 (dd, 1H, J = 1.8 and 8.8 Hz), 3.66 (s, 3H), 3 60 (s, 3H); 2.41 (s, 3H). LC / MS: retention time: 11.36 min; purity: 99%; MS (mass / charge): 397 (MH +). + + 756 N4- (3-Chloro-4-methoxyphenyl) -N2- (1,6-dimethylindazol-5-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.44 (s, 1H), 9.89 (s, 1H), 8.21 (d, 1H, J = 5.6 Hz), 7.97 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.46 (d, 1H, J = 8.5 Hz), 6.91 ( d, 1H, J = 8.5 Hz), 4.00 (s, 3H), 3.75 (s, 3H), 2.32 (s, 3H). LC / MS: retention time: 9.25 min; purity: 93%; MS (mass / charge): 413 (MH +). + 757 N4- (3,4-Dichlorophenyl) -N2- (1,6-dimethylindazol-5-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.34 (s, 1H), 9.70 (s, 1H), 8.24 (d, 1H, J = 4.7 Hz), 7.97 (s, 1H), 7.87 (s, 1H), 7.68 (s, 1H), 7.58 (s, 1H), 7.55 (d, 1H, J = 8.5 Hz), 7.37 ( d, 1H, J = 8.5 Hz), 4.01 (s, 3H), 2.32 (s, 3H). LC / MS: retention time: 11.58 min; purity: 91%; MS (mass / charge): 417 (MH +). + 758 N2- (1,6-Dimethylindazol-5-yl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.70 (s, 1H), 10.51 (s, 1H), 8.16 (d, 1H, J = 4.9 Hz), 7.95 (s, 1H), 7.74 (s, 1H), 7.55 (s, 1H), 7.17 (d, 1H, J = 8.5 Hz), 6.69 (d, 1H, J = 8.5 Hz), 4.00 (s, 3H), 2.34 (s, 3H), 1.31 (s, 6H). LC / MS: retention time: 8.24 min; purity: 96%; MS (mass / charge): 448 (MH +). + + 759 N2- (1,6-Dimethylindazol-5-yl) -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.42 (s, 1H), 9.84 (s, 1H), 8.18 (d, 1H, J = 3.9 Hz), 7.96 (s, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 7.45 (d, 1H, J = 8.5 Hz), 7.20 (m, 1H), 6.97 ( m, 1H), 4.02 (s, 3H), 3.55 (s, 3H), 2.33 (s, 3H). LC / MS: retention time: 9.33 min; purity: 96%; MS (mass / charge): 397 (MH +). + 760 N4- (3,4-Dichlorophenyl) -N2- (2-ethylindazol-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.25 (s, 1H), 10.06 (s, 1H), 8.36 (d, 1H, J = 1.8 Hz), 8.30 (d, 1H, J = 4.4 Hz), 8.03 (d, 1H, J = 2.3 Hz), 7.86 (s, 1H), 7.82 (dd, 1H, J = 2.6 and 8 8 Hz), 7.66 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.14 (dd, 1H, J = 1.8 and 8.8 Hz), 4.42 (sq. t, 2H, J = 7.3 Hz), 1.50 (t, 3H, J = 7.3 Hz), LC / MS: retention time: 12, 85 min; purity: 94%; MS (mass / charge): 418 (MH +). + + 761 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -N2- (2-ethylindazol-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.57 (s, 1H), 9.51 (s, 1H), 9.30 (s, 1H), 8.21 (s, 1H), 8.12 ( d, 1H, J = 4.1 Hz), 8.07 (s, 1H), 7.51 (d, 1H, J = 9.1 Hz), 7.40 (d, 1H, J = 2.3 Hz), 7.27 (dd, 1H, J = 2.3 and 8.8 Hz), 7.11 (dd, 1H, J = 1.8 and 9.1 Hz), 6.89 (d, 1H , J = 8.8 Hz), 4.39 (sq.t, 2H, J = 7.3 Hz), 1.45 (t, 3H, J = 7.3 Hz), 1.40 (s, 6H ), LC / MS: retention time: 9.58 min; purity: 93%; MS (mass / charge): 448 (MH +). + + - 762 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2 -n- propylindazol-5-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.14 (s, 1H), 9.82 (s, 1H), 8.25 (d, 1H, J = 4.4 Hz), 8.22 (s, 1H), 8.06 (d, 1H, J = 2.3 Hz), 7.83 (s, 1H), 7.74 (dd, 1H, J = 2.3 and 9.1 Hz), 7, 57 (d, 1H, J = 9.1 Hz), 7.50 (d, 1H, J = 9.1 Hz), 7.27 (dd, 1H, J = 2.3 and 9.1 Hz), 4.34 (t, 2H, J = 7.33 Hz), 1.91 (sextet, 2H, J = 7.3 Hz), 0.83 (t, 3H, J = 7.3 Hz), LC / MS: retention time: 12.80 min; purity: 92%; MS (mass / charge): 432 (MH +). + + 763 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (2 -n- propylindazol-5-yl) -2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.77 (s, 1H), 10.33 (s, 1H), 10.07 (s, 1H), 8.20 (d, 1H, J = 5.3 Hz), 8.15 (s, 1H), 7.81 (s, 1H), 7.54 (d, 1H, J = 9.1 Hz), 7.23-7.18 (m, 3H), 6.86 (d, 1H, J = 9.1 Hz), 4.32 (t, 2H, J = 7.3 Hz), 1.90 (sextet, 2H, J = 7.3 Hz), 1, 36 (s, 6H), 0.82 (t, 3H, J = 7.3 Hz), LC / MS: retention time: 9.08 min; purity: 98%; MS (mass / charge): 462 (MH +). + + 764 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (2 -n- propylindazol-6-yl) -2,4- pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.56 (s, 1H), 9.29 (s, 1H), 9.09 (s, 1H), 8.17 (d, 1H, J = 0.8 Hz), 8.13 (d, 1H, J = 0.8 Hz), 8.09 (d, 1H, J = 3.8 Hz), 7.48 (d, 1H, J = 9.1 Hz) , 7.41 (d, 1H, J = 2.3 Hz), 7.29 (dd, 1H, J = 2.3 and 9.1 Hz), 7.12 (dd, 1H, J = 2.3 and 8.8 Hz), 6.88 (d, 1H, J = 8.8 Hz), 4.30 (t, 2H, J = 7.33 Hz), 1.87 (sextet, 2H, J = 7 , 3 Hz), 1.40 (s, 6H), 0.82 (t, 3H, J = 7.3 Hz), LC / MS: retention time: 10.48 min; purity: 97%; MS (mass / charge): 462 (MH +). + + 765 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2 -n- propylindazol-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.93 (s, 1H), 9.67 (s, 1H), 8.28 (s, 1H), 8.24 (d, 1H, J = 4.1 Hz), 8.05 (d, 1H, J = 2.3 Hz), 7.91 (s, 1H), 7.88 (dd, 1H, J = 2.6 and 8.8 Hz), 7, 61 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.15 (d, 1H, J = 8.8 Hz), 4.28 ( t, 2H, J = 7.3 Hz), 1.90 (sextet, 2H, J = 7.3 Hz), 0.86 (t, 3H, J = 7.3 Hz), LC / MS: retention time : 13.66 min; purity: 91%; MS (mass / charge): 432 (MH +). + + 766 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (1-methylindazol-6-yl) -2,4-pyrimidinediamine salt DL-camphor-1-sulfonic acid 1 H NMR (DMSO-d6): d 10.69 (s, 1H), 10.09 (s, 1H), 9.88 (s, 1H), 8.21 (d, 1H, J = 4.7 Hz ), 7.91 (d, 1H, J = 0.8 Hz), 7.83 (s, 1H), 7.61 (d, 1H, J = 8.5 Hz), 7.29 (dd, 1H , J = 2.3 and 8.5 Hz), 7.17 (dd, 1H, J = 2.3 and 8.5 Hz), 7.13 (d, 1H, J = 2.3 Hz), 6 85 (d, 1H, J = 8.5 Hz), 3.80 (s, 3H), 2.87 (d, 1H, AB qt, J = 14.6 Hz), 2.26-2 , 18 (m, 1H), 1.92 (br t, 1H, J = 4.7 Hz), 1.88-1.83 (m, 2H), 1.38 (s, 6H), 1, 32-1.21 (, 2H), 1.03 (s, 3H), 0.73 (s, 3H). LC / MS: retention time: 9.53 min; purity: 94%; MS (mass / charge): 434 (MH +). + + - 767 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (1-methylindazol-6-yl) -2,4-pyrimidinediamine salt ethanesulfonic acid ¹ H NMR (DMSO-d6): d 10.70 (s, 1H), 10.22 (s, 1H), 10.00 (s, 1H), 8.24 (d, 1H, J = 4.9 Hz), 7.92 (d, 1H, J = 0.8 Hz), 7.80 (s, 1H), 7.63 (d, 1H, J = 8.8 Hz), 7.28 (dd, 1H, J = 2.3 and 8.8 Hz), 7.16 (d, 1H, J = 1.8 and 8.5 Hz), 7.11 (d, 1H, J = 2.3 Hz), 6, 84 (d, 1H, J = 8.5 Hz), 3.80 (s, 3H), 2.46 (qt, 1H, J = 7.3 Hz), 1.38 (s, 6H ), 1.06 (t, 3H, J = 7.3 Hz), LC / MS: retention time: 9.52 min; purity: 97%; MS (mass / charge): 434 (MH +). + + - 768 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (1-methylindazol-6-yl) -2,4-pyrimidinediamine salt p-hydroxybenzenesulfonic acid ¹ H NMR (DMSO-d6): d 10.69 (s, 1H), 10.17 (s, 1H), 9.92 (s, 1H), 8.21 (d, 1H, J = 4.7 Hz), 7.92 (d, 1H, J = 0.8 Hz), 7.81 (s, 1H), 7.62 (d, 1H, J = 8.5 Hz), 7.38 (td, 2H, J = 2.6 and 8.8 Hz), J = 7.28 (dd, 1H, J = 2.3 and 8.5 Hz), 7.16 (d, 1H, J = 1.8 and 8.5 Hz), 7.11 (d, 1H, J = 2.3 Hz), 6.84 (d, 1H, J = 8.5 Hz), 6.64 (td, 2H, J = 2, 6 and 8.8 Hz), 3.81 (s, 3H), 1.37 (s, 6H), LC / MS: retention time: 9.51 min; purity: 97%; MS (mass / charge): 434 (MH +). + + - 769 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (1-methylindazol-6-yl) -2,4-pyrimidinediamine salt benzenesulfonic acid ¹ H NMR (DMSO-d6): d 10.70 (s, 1H), 10.28 (s, 1H), 10.00 (s, 1H), 8.22 (d, 1H, J = 4.9 Hz), 7.94 (d, 1H, J = 0.8 Hz), 7.78 (s, 1H), 7.64 (d, 1H, J = 8.8 Hz), 7.60-7, 56 (m, 2H), 7.33-7.26 (m, 4H), 7.15 (d, 1H, J = 1.8 and 8.5 Hz), 7.10 (d, 1H, J = 2.3 Hz), 6.84 (d, 1H, J = 8.5 Hz), 3.82 (s, 3H), 1.37 (s, 6H), LC / MS: retention time: 9.51 min; purity: 97%; MS (mass / charge): 434 (MH +). + + - 770 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (1-methylindazol-6-yl) -2,4-pyrimidinediamine salt of hydrochloric acid ¹ H NMR (DMSO-d6): d 10.74 (s, 1H), 10.21 (s, 2H), 8.26 (d, 1H, J = 4.9 Hz), 7.92 (d, 1H, J = 0.8 Hz), 7.82 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.27 (dd, 1H, J = 2.3 and 8 5 Hz), 7.21 (d, 1H, J = 2.3 Hz), 7.18 (dd, 1H, J = 1.8 and 8.5 Hz), 6.86 (d, 1H, J = 8.8 Hz), 3.79 (s, 3H), 1.38 (s, 6H), LC / MS: retention time: 9.52 min; purity: 98%; MS (mass / charge): 434 (MH +). + + - 771 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- (2-methoxyethyl) indazol-5-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.18 (s, 1H), 9.91 (s, 1H), 8.21 (d, 1H, J = 4.7 Hz), 7.98 (d, 1H, J = 2.3 Hz), 7.90 (s, 1H), 7.81 (s, 1H), 7.66 (calculated d, 1H, J = 8.8 Hz), 7.60 ( d, 1H, J = 9.1 Hz), 7.46 (d, 1H, J = 9.1 Hz), 7.37 (dd, 1H, J = 2.3 and 8.8 Hz), 4, 48 (t, 2H, J = 5.2 Hz), 3.69 (t, 2H, J = 5.2 Hz), 3.12 (s, 3H, LC / MS: retention time: 12.23 min; purity: 91%; MS (mass / charge): 448 (MH +). + + - 772 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (2-methoxyethyl) indazol-5-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.45 (s, 1H), 10.33 (s, 1H), 8.27 (d, 1H, J = 4.9 Hz), 7.93 (s, 1H), 7.81 (d, 1H, J = 1.5 Hz), 7.74 (d, 1H, J = 2.3 Hz), 7.65 (d, 1H, J = 8.8 Hz) 7.54 (dd, 1H, J = 2.3 and 9.1 Hz), 7.37 (dd, 1H, J = 2.6 and 9.1 Hz), 7.10 (d, 1H, J == 8.8 Hz), 4.52 (t, 2H, J = 5.2 Hz), 3.83 (s, 3H), 3.73 (t, 2H, J = 5.2 Hz), 3 16 (s, 3H), LC / MS: retention time: 12.23 min; purity: 91%; MS (mass / charge): 448 (MH +). + + - 773 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (2-methoxyethyl) indazol-5-yl] -2 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.78 (s, 1H), 10.35 (s, 1H), 10.19 (s, 1H), 8.21 (d, 1H, J = 4.9 Hz), 7.90 (s, 1H), 7.87 (s, 1H), 7.60 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 8.8 Hz), 7.21 (dd, 1H, J = 1.8 and 8.5 Hz), 7.17 (s, 1H), 6.87 (d, 1H, J = 8.5 Hz ), 4.51 (t, 2H, J = 5.3 Hz), 3.71 (t, 3H, J = 5.3 Hz), 3.16 (s, 3H), 1.36 (s, 6H ), LC / MS: retention time: 8.53 min; purity: 91%; MS (mass / charge): 478 (MH +). + + - 774 5-Fluoro-N4- (4-fluoro-3-methoxyphenyl) -N2- [1- (2-methoxyethyl) indazol-5-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.19 (s, 1H), 9.93 (s, 1H), 8.20 (d, 1H, J = 4.7 Hz), 7.90 (s, 2H), 7.61 (d, 1H, J = 8.8 Hz), 7.44 (dd, 1H, J = 2.6 and 8.8 Hz), 7.37 (dd, 1H, J = 2 , 0 and 8.8 Hz), 7.29-7.26 (m, 1H), 7.13 (dd, 1H, J = 8.8 and 11.1 Hz), 4.53 (t, 2H, J = 5.3 Hz), 3.73 (t, 3H, J = 5.3 Hz), 3.62 (s, 3H), 3.17 (s, 3H), LC / MS: retention time: 9 60 min; purity: 95%; MS (mass / charge): 427 (MH +). + + - 775 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- (2-methoxyethyl) indazol-6-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.08 (s, 1H), 9.96 (s, 1H), 8.26 (d, 1H, J = 4.4 Hz), 8.03 (d, 1H, J = 2.3 Hz), 7.91 (d, 1H, J = 0.8 Hz), 7.82 (s, 1H), 7.70 (dd, 1H, J = 2.3 and 8 8 Hz), 7.60 (d, 1H, J = 8.8 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.19 (dd, 1H, J = 1.8 and 8.8 Hz), 4.24 (t, 2H, J = 5.3 Hz), 3.61 (t, 3H, J = 5.3 Hz), 3.06 (s, 3H), LC / MS: retention time: 13.66 min; purity: 93%; MS (mass / charge): 448 (MH +). + + - 776 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (2-methoxyethyl) indazol-6-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.02 (br s, 2H), 8.24 (d, 1H, J = 4.7 Hz), 7.95 (d, 1H, J = 0.8 Hz), 7.83 (s, 1H), 7.79 (d, 1H, J = 2.6 Hz), 7.63 (d, 1H, J = 8.8 Hz), 6.59 (dd, 1H, J = 2.6 and 9.1 Hz), 7.21 (dd, 1H, J = 1.8 and 8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.25 (t, 2H, J = 5.3 Hz), 3.82 (s, 3H), 3.63 (t, 3H, J = 5.3 Hz), 3.09 (s, 3H), LC / MS: retention time: 10.93 min; purity: 96%; MS (mass / charge): 443 (MH +). + + - 777 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (2-methoxyethyl) indazol-6-yl] -2 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.71 (s, 1H), 10.18 (br s, 2H), 8.20 (d, 1H, J = 4.9 Hz), 7.91 ( d, 1H, J = 0.8 Hz), 7.75 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.23-7.15 (m, 3H), 6.81 (d, 1H, J = 8.8 Hz), 4.24 (t, 2H, J = 5.3 Hz), 3.61 (t, 3H, J = 5.3 Hz), 3, 06 (s, 3H), 1.33 (s, 6H), LC / MS: retention time: 9.59 min; purity: 96%; MS (mass / charge): 479 (MH +). + + - 778 5-Fluoro-N4- (4-fluoro-3-methoxyphenyl) -N2- [1- (2-methoxyethyl) indazol-6-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.92 (br s, 2H), 8.23 (d, 1H, J = 4.4 Hz), 7.94 (d, 1H, J = 0.8 Hz), 7.91 (s, 1H), 7.59 (d, 1H, J = 8.5 Hz), 7.48 (dd, 1H, J = 2.6 and 8.8 Hz), 7, 34-7.30 (m, 1H), 7.21 (dd, 1H, J = 1.8 and 8.8 Hz), 7.15 (dd, 1H, J = 8.8 and 11.1 Hz) 4.24 (t, 2H, J = 5.3 Hz), 3.64 (t, 3H, J = 5.3 Hz), 3.61 (s, 3H), 3.06 (s, 3H) LC / MS: retention time: 10.93 min; purity: 96%; MS (mass / charge): 427 (MH +). + - 779 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (1-methylethyl) indazol-5-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.39 (s, 1H), 10.27 (s, 1H), 8.26 (d, 1H, J = 4.9 Hz), 7.93 (s, 1H), 7.81 (d, 1H, J = 1.4 Hz), 7.74 (d, 1H, J = 2.3 Hz), 6.67 (d, H, J = 9.1 Hz) 7.54 (dd, 1H, J = 2.3 and 9.1 Hz), 7.37 (dd, 1H, J = 1.8 and 8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.94 (q, 1H, J = 6.7 Hz), 3.83 (s, 3H), 1.476 (d, 6H, J = 6.7 Hz), LC / MS: retention time: 10.94 min; purity: 97%; MS (mass / charge): 427 (MH +). + 780 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- (1-methylethyl) indazol-5-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.20 (s, 1H), 9.91 (s, 1H), 8.26 (d, 1H, J = 4.7 Hz), 8.02 (d, 1H, J = 2.3 Hz), 7.94 (s, 1H), 7.86 (s, 1H), 7.68 (d, 1H, J = 8.8 Hz), 7.66 (d, 1H, J = 9.1 Hz), 7.50 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J = 1.8 and 9.1 Hz), 4.95 ( q, 1H, J = 6.7 Hz), 1.47 (d, 6H, J = 6.7 Hz), LC / MS: retention time: 13.92 min; purity: 97%; MS (mass / charge): 432 (MH +). + 781 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (1-methylethyl) indazol-5-yl] -2 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.76 (s, 1H), 10.32 (s, 1H), 10.11 (s, 1H), 8.19 (d, 1H, J = 5.3 Hz), 7.90 (s, 1H), 7.89 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 8.8 Hz), 7.19 (d, 2H, J = 8.9 Hz), 6.87 (d, 1H, J = 8.8 Hz), 4.91 (q, 1H, J = 6 4 Hz), 1.44 (d, 6H, J = 6.4 Hz), 1.36 (s, 6H), LC / MS: retention time: 9.60 min; purity: 96%; MS (mass / charge): 462 (MH +). + 782 5-Fluoro-N4- (4-fluoro-3-methoxyphenyl) -N2- [1- (1-methylethyl) indazol-5-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.35 (s, 1H), 10.21 (s, 1H), 8.25 (d, 1H, J = 4.9 Hz), 7.90 (s, 1H), 7.88 (s, 1H), 7.65 (d, 1H, J = 8.1 Hz), 7.43 (dd, 1H, J = 2.3 and 8.8 Hz), 7, 35 (dd, 1H, J = 1.8 and 8.8 Hz), 7.26-7.22 (m, 1H), 7.14 (dd, 1H, J = 8.8 and 11.1 Hz) 4.95 (q, 1H, J = 6.4 Hz), 3.59 (s, 3H), 1.46 (d, 6H, J = 6.4 Hz), LC / MS: retention time: 10 96 min; purity: 96%; MS (mass / charge): 411 (MH +). + 783 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (1-methylethyl) indazol-6-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.10 (s, 2H), 8.25 (d, 1H, J = 4.7 Hz), 7.93 (s, 1H), 7.86 (s, 1H), 7.78 (d, 1H, J = 2.3 Hz), 7.64 (d, 1H, J = 8.8 Hz), 7.56 (dd, 1H, J = 2.3 and 8 8 Hz), 7.18 (d, 1H, J = 8.8 Hz), 7.10 (d, 1H, J = 8.9 Hz), 4.45 (q, 1H, J = 6, 4 Hz), 3.82 (s, 3H), 1.35 (d, 6H, J = 6.4 Hz), LC / MS: retention time: 12.26 min; purity: 97%; MS (mass / charge): 427 (MH +). + 784 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- (1-methylethyl) indazol-6-yl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.06 (s, 1H), 9.93 (s, 1H), 8.30 (d, 1H, J = 4.3 Hz), 8.06 (d, 1H, J = 2.3 Hz), 7.93 (s, 2H), 7.76 (dd, 1H, J = 2.3 and 8.8 Hz), 7.64 (d, 1H, J = 8 , 8 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.21 (dd, 1H, J = 1.8 and 8.8 Hz), 4.55 (q, 1H, J = 6.4 Hz), 1.38 (d, 6H, J = 6.4 Hz), LC / MS: retention time: 15.20 min; purity: 97%; MS (mass / charge): 432 (MH +). + 785 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (1-methylethyl) indazol-6-yl] -2 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.76 (s, 1H), 10.14 (s, 2H), 8.24 (d, 1H, J = 4.9 Hz), 7.93 (s, 1H), 7.88 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz), 7.27-7.16 (m, 3H), 6.88 (d, 1H, J = 8.8 Hz), 4.50 (q, 1H, J = 6.4 Hz), 1.37 (d, 6H, J = 6.4 Hz), 1.35 (s, 6H). LC / MS: retention time: 10.91 min; purity: 97%; MS (mass / charge): 462 (MH +). + 786 (S) -N4- [2-Methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl] -5-fluoro-N2- [1- (1-methylethyl) indazol-6- il] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.77 (s, 1H), 10.14 (s, 1H), 9.93 (s, 1H0, 8.22 (d, 1H, J = 4.7 Hz) ), 7.93 (s, 1H), 7.92 (s, 1H), 7.60 (d, 1H, J = 8.5 Hz), 7.27 (dd, 1H, J = 2.3 and 8.5 Hz), 7.21-7.16 (m, 2H), 6.90 (d, 1H, J = 8.5 Hz), 4.65 (qt, 1H, J = 6.7 Hz), 4.49 (q, 1H, J = 6.4 Hz), 1.41 (d, 3H, J = 6.7 Hz), 1.36 (d, 6H, J = 6.4 Hz) LC / MS: retention time: 10.30 min; purity: 95%; MS (mass / charge): 448 (MH +). + 787 N2- [1- (3-Acetyloxypropyl) indazol-5-yl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.17 (s, 1H), 9.90 (s, 1H), 8.21 (d, 1H, J = 4.7 Hz), 7.97 (d, 1H , J = 2.3 Hz), 7.90 (dd, 1H, J = 2.3 and 8.8 Hz), 7.59 (d, 1H, J = 8.8 Hz), 7.47 (d , 1H, J = 8.8 Hz), 7.38 (dd, 1H, J = 2.0 and 8.8 Hz), 4.41 (d, 2H, J = 6.7 Hz), 3.88 (t, 2H, J = 6.4 Hz), 2.07 (q, 2H, J = 6.7 Hz), 1.89 (s, 3H). + + - 788 N2- [1- (3-Acetyloxypropyl) indazol-5-yl] -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 10.32 (s, 1H), 10.19 (s, 1H), 8.24 (d, 1H, J = 5.3 Hz), 7.93 (s, 1H ), 7.85 (s, 1H), 7.74 (d, 1H, J = 2.3 Hz), 7.63 (d, 1H, J = 8.8 Hz), 7.54 (dd, 1H , J = 2.3 and 9.1 Hz), 7.40 (dd, 1H, J = 2.3 and 8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4 45 (t, 2H, J 6.7 Hz), 3.93 (t, 2H, J = 6.4 Hz), 3.83 (s, 3H), 2.11 (q, 2H, J = 6 7 Hz), 1.93 (s, 3H). + + - 789 N2- [1- (3-Acetyloxypropyl) indazol-5-yl] -5-fluoro-N4- (4-fluoro-3-methoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.31 (s, 1H), 10.15 (s, 1H), 8.24 (d, 1H, J = 4.7 Hz), 7.91 (s, 2H ), 7.61 (d, 1H, J = 8.8 Hz), 7.44 (dd, 1H, J = 2.3 and 8.8 Hz), 7.38 (dd, 1H, J = 1, 8 and 9.1 Hz), 7.27-7.25 (m, 1H), 7.15 (dd, 1H, J = 8.8 and 11.1 Hz), 4.45 (t, 2H, J = 6.7 Hz), 3.92 (t, 2H, J = 6.4 Hz), 3.62 (s, 3H), 2.11 (calculated q, 2H, J = 6.4 Hz), 1.93 (s, 3H). + + - 790 N2- [1- (3-Acetyloxypropyl) indazol-6-yl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.96 (s, 1H), 9.83 (s, 1H), 8.27 (d, 1H, J = 4.1 Hz), 8.09 (d, 1H , J = 2.3 Hz), 7.94 (s, 1H), 7.92 (s, 1H), 7.75 (dd, 1H, J = 2.3 and 8.8 Hz), 7.63 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.23 (dd, 1H, J = 1.8 and 8.8 Hz), 4 , 20 (t, 2H, J = 6.7 Hz), 3.83 (t, 2H, J = 6.4 Hz), 2.02 (calculated q, 2H, J = 6.4 Hz), 1 89 (s, 3H). + + - 791 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-hydroxypropyl) indazol-6-yl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.68 (s, 1H), 9.84 (s, 1H), 9.74 (s, 1H), 8.18 (d, 1H, J = 4.4 Hz ), 7.90 (s, 1H), 7.56 (s, 1H), 7.58 (d, 1H, J = 8.8 Hz), 7.32-7.24 (m, 3H), 6 85 (d, 1H, J = 8.8 Hz), 4.20 (t, 2H, J = 6.7 Hz), 3.29 (t, 2H, J = 6.4 Hz), 1.87 (qr, 2H, J = 6.7 Hz), 1.38 (s, 6H). + + - 792 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (3-methoxypropyl) indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.42 (s, 1H), 10.30 (s, 1H), 8.26 (d, 1H, J = 5.2 Hz), 7.93 (s, 1H ), 7.82 (d, 1H, J = 1.8 Hz), 7.74 (d, 1H, J = 2.3 Hz), 7.60 (d, 1H, J = 9.1 Hz), 7.53 (dd, 1H, J = 2.3 and 9.1 Hz), 7.38 (dd, 1H, J = 1.8 and 9.1 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.40 (t, 2H, J = 6.7 Hz), 3.83 (s, 3H), 3.23 (t, 2H, J = 6.4 Hz), 3.17 (s, 3H), 2.02 (calc. q, 2H, J = 6.7 Hz). + + - + 793 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- (3-methoxypropyl) indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.36 (s, 1H), 10.13 (s, 1H), 8.30 (d, 1H, J = 5.0 Hz), 8.01 (d, 1H , J = 2.3 Hz), 7.95 (s, 1H), 7.86 (s, 1H), 7.68 (dd, 1H, J = 2.3 and 8.8 Hz), 7.61 (d, 1H, J = 9.1 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J = 1.8 and 9.1 Hz), 4 41 (t, 2H, J = 6.7 Hz), 3.19 (s, 3H), 3.24 (t, 2H, J = 6.4 Hz), 2.03 (q, 2H, J = 6.7 Hz). + + - 794 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-methoxypropyl) indazol-5-yl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.77 (s, 1H), 10.42 (s, 1H), 10.27 (s, 1H), 8.23 (d, 1H, J = 4.3 Hz ), 7.90 (s, 1H), 7.88 (s, 1H), 7.56 (d, 1H, J = 8.8 Hz), 7.37 (dd, 1H, J = 1.8 and 8.8 Hz), 7.21 (calculated d, 2H, J = 9.1 Hz), 6.87 (d, 1H, J = 9.1 Hz), 4.39 (t, 2H, J = 6.7 Hz), 3.21 (t, 2H, J = 6.4 Hz), 3.17 (s, 3H), 2.00 (calculated q, 2H, J = 6.7 Hz), 1 36 (s, 6H). + + - 795 (S) -5-Fluoro-N2- [1- (3-methoxypropyl) indazol-5-yl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6- il) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.73 (s, 1H), 10.32 (s, 1H), 10.15 (s, 1H), 8.17 (d, 1H, J = 4.9 Hz ), 7.85 (s, 1H), 7.83 (s, 1H), 7.51 (d, 1H, J = 8.8 Hz), 7.33 (dd, 1H, J = 2.1 and 9.1 Hz), 7.16 (dd, 2H, J = 2.3 and 9.1 Hz), 6.84 (d, 1H, J = 8.8 Hz), 4.60 (sq. 1H, J = 6.7 Hz), 4.34 (t, 2H, J = 6.7 Hz), 3.17 (t, 2H, J = 6.4 Hz), 3.12 (s, 3H) 1.95 (q, 2H, J = 6.7 Hz); 1.36 (d, 3H, J = 6.7 Hz). + + - 796 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (3-methoxypropyl) indazol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.16 (s, 2H), 8.27 (d, 1H, J = 4.7 Hz), 7.95 (d, 1H, J = 0.8 Hz), 7.80 (s, 1H), 7.78 (d, 1H, J = 8.8 Hz), 7.65 (d, 1H, J = 2.3 and 9.1 Hz), 7.58 (dd , 1H, J = 2.3 and 9.1 Hz), 7.20 (dd, 1H, J = 1.8 and 8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz) , 4.15 (t, 2H, J = 6.7 Hz), 3.82 (s, 3H), 3.13 (t, 2H, J = 6.7 Hz), 3.12 (s, 3H) , 1.89 (qrt, 2H, J = 6.7 Hz). + + - 797 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- (3-methoxypropyl) indazol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 10.13 (s, 1H), 10.02 (s, 1H), 8.31 (d, 1H, J = 4.1 Hz), 8.06 (d, 1H , J = 2.3 Hz), 7.95 (s, 1H), 7.87 (s, 1H), 7.74 (dd, 1H, J = 2.3 and 8.8 Hz), 7.65 (d, 1H, J = 8.5 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.22 (d, 1H, J = 8.5 Hz), 4.17 (t , 2H, J = 6.7 Hz), 3.17 (t, 2H, J = 6.7 Hz), 3.12 (s, 3H), 1.91 (calculated q, 2H, J = 6, 7 Hz). + + - 798 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-methoxypropyl) indazol-6-yl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.73 (s, 1H), 9.92 (s, 2H), 8.21 (d, 1H, J = 4.7 Hz), 7.92 (s, 1H ), 7.89 (s, 1H), 7.58 (d, 1H, J = 8.8 Hz), 7.29-7.24 (m, 3H), 6.85 (d, 1H, J = 8.5 Hz), 4.17 (t, 2H, J = 6.7 Hz), 3.14 (qrt, 2H, J = 6.4 Hz), 3.13 (s, 3H) 1.92 (calc. Q, 2H, J = 6.4 Hz); 1.38 (s, 6H). + + + 799 (S) -5-Fluoro-N2- [1- (3-methoxypropyl) indazol-6-yl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6- il) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.76 (s, 1H), 10.11 (s, 2H), 8.23 (d, 1H, J = 4.7 Hz), 7.94 (s, 1H ), 7.86 (s, 1H), 7.62 (d, 1H, J = 8.5 Hz), 7.28-7.19 (m, 3H), 6.88 (d, 1H, J = 8.5 Hz), 4.64 (sq.t, 1H, J = 6.7 Hz), 4.17 (t, 2H, J = 6.7 Hz), 3.16 (calculated sq.t., 2H, J = 6.7 Hz), 3.13 (s, 3H), 1.91 (calculated q, 2H, J = 6.7 Hz), 1.41 (d, 3H, J = 6.7 Hz). + + - 800 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (2-trifluoromethyl-1H-benzimidazol-5-yl) -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 10.17 (s, 1H), 8.20 (d, 1H, J = 4.9 Hz), 7.85 (s, 1H), 7.69 (d, 1H , J = 2.3 Hz), 7.61 (d, 1H, J = 8.8 Hz), 7.59 (dd, 1H, J = 2.3 and 8.8 Hz), 7.39 (dd , 1H, J = 2.0 and 8.8 Hz), 7.04 (d, 1H, J = 9.1 Hz), 3.76 (s, 3H). + + + + 801 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2-trifluoromethyl-1H-benzimidazol-5-yl) -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.84 (s, 1H), 9.70 (s, 1H), 8.19 (d, 1H, J = 4.1 Hz), 8.05 (d, 1H , J = 2.3 Hz), 7.96 (s, 1H), 7.75 (dd, 1H, J = 2.3 and 8.8 Hz), 7.60 (d, 1H, J = 9, 1 Hz), 7.47-7.43 (m, 2H). + + + + 802 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (2-trifluoromethyl-1H-benzimidazol-5-yl) -2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.71 (s, 1H), 10.26 (s, 1H), 10.21 (s, 1H), 8.22 (d, 1H, J = 4.9 Hz ), 7.88 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz), 7.49 (dd, 1H, J = 2.3 and 8.8 Hz), 7.24 (s, 1H), 7.22 (s, 1H), 6.86 (d, 1H, J = 8.8 Hz), 1.36 (s, 6H). + + - + 803 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- (2-trifluoromethyl-1H-benzimidazol-5-yl ) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.71 (s, 1H), 10.27 (s, 1H), 10.22 (s, 1H), 8.22 (d, 1H, J = 4.9 Hz ), 7.93 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.46 (dd, 1H, J = 2.3 and 8.8 Hz), 7.24 (s, 1H), 7.21 (s, 1H), 6.89 (d, 1H, J = 8.8 Hz), 4.66 (qt, 1H, J = 6.7 Hz), 1 40 (d, 3H, J = 6.7 Hz). + + - 804 N2- (3-amino-1-methylindazol-5-yl) -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.13 (s, 1H), 9.94 (s, 1H), 8.17 (d, 1H, J = 4.9 Hz), 7.76 (s, 1H ), 7.75 (d, 1H, J = 2.3 Hz), 7.61 (dd, 1H, J = 2.3 and 9.1 Hz), 7.44 (s, 2H), 7.05 (d, 1H, J = 9.1 Hz), 3.80 (s, 3H), 3.79 (s, 3H). + + 805 N2- (3-amino-1-methylindazol-5-yl) -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.17 (s, 1H), 9.90 (s, 1H), 8.21 (d, 1H, J = 4.7 Hz), 7.97 (d, 1H , J = 2.3 Hz), 7.90 (dd, 1H, J = 2.3 and 8.8 Hz), 7.59 (d, 1H, J = 8.8 Hz), 7.47 (d , 1H, J = 8.8 Hz), 7.38 (dd, 1H, J = 2.0 and 8.8 Hz), 4.41 (d, 2H, J = 6.7 Hz), 3.88 (t, 2H, J = 6.4 Hz), 2.07 (q, 2H, J = 6.7 Hz), 1.89 (s, 3H). + 806 N2- (3-amino-1-methylindazol-5-yl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.75 (s, 1H), 10.46 (s, 1H), 10.40 (s, 1H), 8.22 (d, 1H, J = 4.9 Hz ), 7.79 (s, 1H), 7.54 (dd, 1H, J = 2.3 an d8.8 Hz), 7.48 (d, 1H, J = 9.1 Hz), 7.28 (calc. broads, 1H), 7.22 (dd, 1H, J = 2.3 and 9.1 Hz), 6.54 (d, 1H, J = 8.8 Hz), 3.84 ( s, 3H); 1.34 (s, 6H). + + 807 (S) -N2- (3-amino-1-methylindazol-5-yl) -5-fluoro-N4- (2-methyl-3-oxo-4H-benz [1,4] oxazin-6-yl) - 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.76 (s, 1H), 10.38 (s, 1H), 10.28 (s, 1H), 8.20 (d, 1H, J = 5.3 Hz ), 7.80 (s, 1H), 7.53 (d, 1H, J = 9.1 Hz), 7.48 (d, 1H, J = 9.1 Hz), 7.27 (s, 1H ), 7.25 (s, 1H), 6.87 (d, 1H, J = 9.1 Hz), 4.63 (qt, 1H, J = 6.7 Hz), 3.83 (s , 3H), 1, 38 (d, 3H, J = 6.7 Hz). + + 808 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.53 (s, 1H), 9.40 (s, 1H), 8.14 (d, 1H, J = 3.8 Hz), 8.13 (s, 1H ), 7.86 (d, 1H, J = 2.6 Hz), 7.72-7.67 (m, 2H), 7.59 (d, 1H, J = 8.8 Hz), 7.11 (d, 1H, J = 9.1 Hz), 3.83 (s, 3H), 2.72 (s, 3H). + + - + 809 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.93 (s, 2H), 8.28 (d, 1H, J = 4.8 Hz), 8.12 (d, 1H, J = 2.6 Hz), 8.07 (s, 1H), 7.81 (dd, 1H, J = 2.3 and 9.1 Hz), 7.66 (s, 2H), 7.56 (d, 1H, J = 8, 8 Hz), 2.75 (s, 3H). + + - + 810 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) -2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.70 (s, 1H), 9.56 (s, 1H), 9.40 (s, 1H), 8.21 (s, 1H), 8.12 (d , 1H, J = 3.8 Hz), 7.79 (dd, 1H, J = 2.3 and 9.1 Hz), 7.55 (d, 1H, J = 8.8 Hz), 7.52 (s, 1H), 7.31 (dd, 1H, J = 2.3 and 8.8 Hz), 6.88 (d, 1H, J = 8.8 Hz), 2.72 (s, 3H) 1.39 (s, 6H). + + - + 811 (S) -5-Fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl ) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.69 (s, 1H), 9.58 (s, 1H), 9.42 (s, 1H), 8.23 (s, 1H), 8.12 (d , 1H, J = 3.5 Hz), 7.74 (dd, 1H, J = 2.3 and 8.8 Hz), 7.57 (d, 1H, J = 9.1 Hz), 7.53 (d, 1H, J = 2.3 Hz), 7.29 (dd, 1H, J = 2.3 and 8.8 Hz), 6.91 (d, 1H, J = 8.8 Hz), 4 64 (qt, 1H, J = 6.7 Hz), 2.71 (s, 3H), 1.42 (d, 3H, J = 6.7 Hz). + + - + 812 N2- (1,3-Dimethylindazol-6-yl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.06 (s, 1H), 9.53 (s, 1H), 9.44 (s, 1H), 8.16 (d, 1H, J = 3.5 Hz ), 7.83 (s, 1H), 7.53 (d, 1H, J = 8.5 Hz), 7.45 (d, 1H, J = 8.8 Hz), 7.30 (d, 1H , J = 8.5 Hz), 7.15 (dd, 1H, J = 2.3 and 8.8 Hz), 3.67 (s, 3H), 2.33 (s, 3H), 1.36 (s, 6H). + 813 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3-methyl-1H-indazol-6-yl) - 2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 12.21 (s, 1H), 11.02 (s, 1H), 9.30 (s, 1H), 9.12 (s, 1H), 8.11 (d , 1H, J = 3.5 Hz), 7.90 (s, 1H), 7.69 (d, 1H, J = 8.5 Hz), 7.43 (d, 1H, J = 8.5 Hz ), 7.33 (d, 1H, J = 8.8 Hz), 7.19 (d, 1H, J = 8.8 Hz), 2.34 (s, 3H), 1.36 (s, 6H ) + 814 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-methoxypropyl) indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), 8.12 (d, 1H, J = 3.5 Hz ), 8.05 (s, 1H), 7.84 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.50 (d, 1H, J = 8.8 Hz ), 7.46 (d, 1H, J = 8.8 Hz), 7.35 (d, 1H, J = 8.8 Hz), 4.37 (t, 2H, J = 6.4 Hz), 3.22 (t, 2H, J = 6.4 Hz), 3.19 (s, 3H), 2.00 (qs, 2H, J = 6.4 Hz), 1.42 (s, 6H ) + 815 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- [3- (N-phthalimidopropyl)] indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.36 (s, 1H), 10.25 (s, 1H), 8.21 (d, 1H, J = 4.9 Hz), 7.85 (s, 1H ), 7.79-7.75 (m, 5H), 7.67 (d, 1H, J = 2.3 Hz), 7.63 (d, 1H, J = 8.8 Hz), 7.49 (dd, 1H, J = 2.3 and 8.8 Hz), 7.32 (dd, 1H, J = 1.8 and 9.1 Hz), 7.03 (d, 1H, J = 8.8 Hz), 4.39 (t, 2H, J = 6.7 Hz), 3.75 (s, 3H), 3.57 (t, 2H, J = 6.7 Hz), 2.12 (calc. q, 2H, J = 6.7 Hz). + 816 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- [3- (N-phthalimidopropyl)] indazol-5-yl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 10.24 (s, 1H), 9.99 (s, 1H), 8.23 (d, 1H, J = 4.7 Hz), 7.95 (d, 1H , J = 2.0 Hz), 7.87 (s, 1H), 7.80 (s, 1H), 7.78-7.73 (m, 4H), 7.64 (d, 1H, J = 9.1 Hz), 7.45 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 9.1 Hz), 4.41 (t, 2H, J = 6.7 Hz), 3.57 (t, 2H, J = 6.7 Hz), 2.12 (calculated q, 2H, J = 6.7 Hz). - 817 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- [3- (N-phthalimidopropyl)] indazole-5- il] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.78 (s, 1H), 10.45 (s, 1H), 10.32 (s, 1H), 8.24 (d, 1H, J = 4.9 Hz ), 7.88 (s, 1H), 7.87 (s, 1H), 7.84-7.77 (m, 4H), 7.65 (d, 1H, J = 8.8 Hz), 7 37 (dd, 1H, J = 1.8 and 9.1 Hz), 7.20 (d, 1H, J = 8.8 Hz), 6.86 (d, 1H, J = 9.1 Hz) 4.43 (t, 2H, J = 6.7 Hz), 3.60 (t, 2H, J = 6.7 Hz), 2.16 (calculated q, 2H, J = 6.7 Hz) 1.32 (s, 6H). + 818 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [1- [3- (N-phthalimidopropyl)] indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.80 (s, 1H), 10.44 (s, 1H), 10.30 (s, 1H), 8.24 (d, 1H, J = 5.3 Hz ), 7.89 (s, 1H), 7.87 (s, 1H), 7.82-7.77 (m, 4H), 7.67 (d, 1H, J = 8.8 Hz), 7 37 (dd, 1H, J = 1.8 and 9.1 Hz), 7.22 (dd, 1H, J = 1.8 and 8.8 Hz), 7.18 (s, 1H), 6, 89 (d, 1H, J = 8.8 Hz), 4.59 (qt, 1H, J = 6.7 Hz), 4.44 (t, 2H, J = 6.7 Hz), 3, 60 (t, 2H, J = 6.7 Hz), 2.16 (calculated q, 2H, J = 6.7 Hz), 1.35 (d, 3H, J = 6.7 Hz). + 819 N2- [1- [3- (N-Acetylamino) propyl] indazol-5-yl] -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.22 (s, 1H), 10.05 (s, 1H), 8.21 (d, 1H, J = 4.9 Hz), 7.92 (s, 1H ), 7.90 (m, 1H), 7.86 (s, 1H), 7.75 (d, 1H, J = 2.3 Hz), 7.64 (d, 1H, J = 9.1 Hz ), 7.57 (dd, 1H, J = 2.3 and 8.8 Hz), 7.39 (dd, 1H, J = 1.8 and 8.8 Hz), 7.09 (d, 1H, J = 8.8 Hz), 4.37 (t, 2H, J = 7.0 Hz), 3.83 (s, 3H), 3.02 (sq.t, 2H, J = 7.0 Hz) 1.92 (calc. Q, 2H, J = 7.0 Hz); 1.78 (s, 3H). + + 820 N2- [1- [3- (N-Acetylamino) propyl] indazol-5-yl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.51 (s, 1H), 9.23 (s, 1), 8.10 (d, 1H, J = 3.8 Hz), 8.04 (d, 1H , J = 2.3 Hz), 7.95 (s, 1H), 7.82 (m, 2H), 7.74 (dd, 1H, J = 2.0 and 9.1 Hz), 7.51 (d, 1H, J = 9.1 Hz), 7.44 (d, 1H, J = 9.1 Hz), 7.43 (dd, 1H, J = 1.8 and 9.1 Hz), 4 30 (t, 2H, J = 6.7 Hz), 2.95 (qt, 2H, J = 6.7 Hz), 1.87 (calculated q, 2H, J = 7.0 Hz) 1.73 (s, 3H). + 821 N2- [1- [3- (N-Acetylamino) propyl] indazol-5-yl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) - 5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.77 (s, 1H), 10.38 (s, 1H), 10.18 (s, 1H), 8.21 (d, 1H, J = 4.9 Hz ), 7.90 (s, 3H), 7.61 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H, J = 2.0 and 9.1 Hz), 7.21 (d, 1H, J = 8.5 Hz), 7.18 (s, 1H), 6.89 (d, 1H, J = 8.5 Hz), 4.36 (t, 2H, J = 7, 0 Hz), 2.99 (calculated q.t., 2H, J = 6.7 Hz), 1.92 (calculated q, 2H, J = 6.7 Hz), 1.78 (s, 3H) 1.36 (s, 6H). + 822 N2- [1- [3- (N-Acetylamino) propyl] indazol-5-yl] -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl ) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 11.05 (s, 1H), 9.18 (s, 1H), 9.15 (s, 1H), 8.07 (d, 1H), 3.5 Hz) 8.01 (s, 1H), 7.80 (d, 1H, J = 6.3 Hz), 7.79 (s, 1H), 7.52 (d, 1H, J = 8.5 Hz) 7.48-7.40 (m, 2H), 7.31 (d, 1H, J = 8.5 Hz), 4.29 (t, 2H, J = 7.0 Hz), 2.94 ( qt, 2H, J = 6.4 Hz), 1.86 (qt, 2H, J = 7.0 Hz), 1.72 (s, 3H), 1.37 (s, 6H). + + 823 N2- [1- (3-Aminopropyl) indazol-5-yl] -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.25 (s, 1H), 10.21 (s, 1H), 8.21 (d, 1H, J = 4.8 Hz), 7.97 (br s , 2H), 7.88 (s, 1H), 7.84-7.78 (m, 2H), 7.70 (d, 1H, J = 2.6 Hz), 9.08 (d, 1H, J = 9.1 Hz), 7.49 (dd, 1H, J = 2.6 and 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 8.8 Hz), 7, 06 (d, 1H, J = 8.8 Hz), 4.43 (t, 2H, J = 6.7 Hz), 3.79 (s, 3H), 2.76-2.70 (m, 2H ), 2.05 (calc. Q, 2H, J = 6.7 Hz). + 824 N2- [1- (3-Aminoporopyl) indazol-5-yl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.01 (s, 1H), 9.77 (s, 1H), 8.24 (d, 1H, J = 3.1 Hz), 8.06 (d, 1H , J = 2.6 Hz), 7.96 (s, 1H), 7.95 (s, 1H), 7.90-7.85 (m, 2H), 7.75 (d, 1H, J = 8.5 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.47 (dd, 1H, J = 2, 0 and 9.1 Hz), 4.43 (t, 2H, J = 6.7 Hz), 2.81-2.77 (m, 2H), 2.14-2.04 (calculated q, 2H , J = 6.7 Hz). + 825 N2- [1- (3-Aminopropyl) indazol-5-yl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.77 (s, 1H), 10.35 (s, 2H), 8.20 (d, 1H, J = 5.0 Hz), 7.94 (br s , 2H), 7.94 (s, 1H), 7.86 (s, 1H), 7.82-7.79 (m, 1H), 7.62 (d, 1H, J = 9.1 Hz) , 7.34 (dd, 1H, J = 1.8 and 9.1 Hz), 7.21 (br.s, 1H), 7.15 (dd, 1H, J = 1.8 and 8.8 Hz ), 6.86 (d, 1H, J = 8.8 Hz), 4.42 (t, 2H, J = 6.7 Hz), 2.76-2.67 (m, 2H), 2.03 (calc. q, 2H, J = 6.7 Hz), 1.32 (s, 6H). + 826 (S) -N2- [1- (3-Aminopropyl) indazol-5-yl] -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6- il) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.78 (s, 1H), 10.30 (s, 2H), 8.18 (d, 1H, J = 4.9 Hz), 7.93 (br s , 2H), 7.91 (s, 1H), 7.87 (s, 1H), 7.83-7.80 (m, 1H), 7.63 (d, 1H, J = 8.8 Hz) , 7.36 (dd, 1H, J = 1.8 and 8.8 Hz), 7.21 (br.s, 1H), 7.17 (dd, 1H, J = 2.3 and 8.5 Hz ), 6.88 (d, 1H, J = 8.5 Hz), 4.61 (qt, 1H, J = 6.7 Hz), 4.42 (t, 2H, J = 6.7 Hz) ), 2.76-2.67 (m, 2H), 2.03 (calc. Q, 2H, J = 6.7 Hz), 1.36 (d, 3H, J = 6.7 Hz). + 827 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (3-hydroxypropyl) indazol-5-yl] -2,4-pyrimidinediamine salt of p-toluenesulfonic acid 1 H NMR (DMSO-d6): d 10.39 (s, 1H), 10.03 (s, 1H), 8.20 (d, 1H, J = 5.3 Hz), 7.95 (s, 1H ), 7.80 (d, 1H, J = 1.8 Hz), 7.74 (d, 1H, J = 2.6 Hz), 7.64 (d, 1H, J = 8.8 Hz), 7.54 (dd, 1H, J = 2.6 and 9.1 Hz), 7.46 (d, 2H, J = 8.1 Hz), 7.38 (dd, 1H, J = 2.1 and 9.1 Hz), 7.10 (d, 2H, J = 8.1 Hz), 7.07 (d, 1H, J = 8.8 Hz), 4.42 (t, 2H, J = 6, 7 Hz), 3.82 (s, 3H), 3.37 (t, 2H, J = 6.7 Hz), 2.27 (s, 3H), 1.94 (calculated q, 2H, J = 6.7 Hz). + - 828 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (3-hydroxypropyl) indazol-5-yl] -2,4-pyrimidinediamine salt of bis-p-toluenesulfonic acid 1 H NMR (DMSO-d6): d 10.63 (s, 1H), 10.23 (s, 1H), 8.24 (d, 1H, J = 5.5 Hz), 7.97 (s, 1H ), 7.76 (d, 1H, J = 1.8 Hz), 7.72 (d, 1H, J = 2.4 Hz), 7.66 (d, 1H, J = 9.1 Hz), 7.52 (dd, 1H, J = 2.6 and 8.8 Hz), 7.47 (d, 4H, J = 8.1 Hz), 7.35 (dd, 1H, J = 1.8 and 8.8 Hz), 7.10 (d, 4H, J = 8.1 Hz), 7.07 (d, 1H, J = 9.1 Hz), 4.43 (t, 2H, J = 6, 7 Hz), 3.82 (s, 3H), 3.38 (t, 2H, J = 6.4 Hz), 2.27 (s, 6H), 1.95 (calculated q, 2H, J = 6.7 Hz). + + - 829 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (3-hydroxypropyl) indazol-5-yl] -2,4-pyrimidinediamine salt of benzenesulfonic acid 1 H NMR (DMSO-d6): d 10.38 (s, 1H), 10.02 (s, 1H), 8.19 (d, 1H, J = 4.7 Hz), 7.95 (s, 1H ), 7.80 (s, 1H), 7.74 (s, 1H), 7.65-7.58 (m, 4H), 7.38 (d, 1H, J = 9.1 Hz), 7 , 29 (s, 3H), 7.07 (d, 1H, J = 8.8 Hz), 4.42 (t, 2H, J = 6.7 Hz), 3.82 (s, 3H), 3 37 (t, 2H, J = 6.4 Hz), 1.95 (calc. Q, 2H, J = 6.7 Hz). + + + 830 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (3-hydroxypropyl) indazol-5-yl] -2,4-pyrimidinediamine salt of bis-benzenesulfonic acid 1H NMR (DMSO-d6): d 10.29 (s, 1H), 9.95 (s, 1H), 8.19 (d, 1H, J = 5.1 Hz), 7.94 (s, 1H ), 7.81 (d, 1H, J = 1.8 Hz), 7.75 (d, 1H, J = 2.6 Hz), 7.65-7.53 (m, 7H), 7.39 (dd, 1H, J = 2.0 and 8.8 Hz), 7.31-7.26 (m, 5H), 7.07 (d, 1H, J = 8.8 Hz), 4.42 ( t, 2H, J = 6.7 Hz), 3.82 (s, 3H), 3.37 (t, 2H, J = 6.4 Hz), 1.95 (calculated q, 2H, J = 6 , 7 Hz). + + - 831 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (3-hydroxypropyl) indazol-5-yl] -2,4-pyrimidinediamine hydrochloride salt 1 H NMR (DMSO-d6): d 10.36 (s, 1H), 10.25 (s, 1H), 8.21 (d, 1H, J = 5.3 Hz), 7.87 (s, 1H ), 7.77 (d, 1H, J = 1.5 Hz), 7.69 (d, 1H, J = 2.1 Hz), 7.57 (d, 1H, J = 9.1 Hz), 7.49 (dd, 1H, J = 2.3 and 8.8 Hz), 7.33 (dd, 1H, J = 2.0 and 9.1 Hz), 7.03 (d, 1H, J = 8.8 Hz), 4.36 (t, 2H, J = 6.7 Hz), 3.78 (s, 3H), 3.32 (t, 2H, J = 6.7 Hz), 1.89 (calc. q, 2H, J = 6.7 Hz). + + - 832 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- [3- (N-methylsulfonylamine) propyl] indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.60 (s, 1H), 10.52 (s, 1H), 8.30 (d, 1H, J = 5.6 Hz), 7.95 (s, 1H ), 7.81 (d, 1H, J = 1.8 Hz), 7.73 (d, 1H, J = 2.3 Hz), 7.69 (d, 1H, J = 9.1 Hz), 7.52 (dd, 1H, J = 2.3 and 8.8 Hz), 7.37 (dd, 1H, J = 2.0 and 8.8 Hz), 7.10 (broad s, 1H) 7.09 (d, 1H, J = 9.1 Hz), 4.42 (t, 2H, J = 6.7 Hz), 3.83 (s, 3H), 2.95 (calc. 2H), 2.86 (s, 3H), 2.00 (calc. Q, 2H, J = 6.7 Hz). + + - 833 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- [3- (N-methylsulfonylamino) propyl] indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.53 (s, 1H), 9.25 (s, 1H), 8.11 (d, 1H, J = 3.8 Hz), 8.04 (d, 1H , J = 2.3 Hz), 7.97 (br s, 1H), 7.83 (s, 1H), 7.73 (d, 1H, J = 2.3 and 8.8 Hz), 7 53 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.8 Hz), 7.43 (dd, 1H, J = 2.3 and 8.8 Hz) 7.02 (t, 1H, J = 5.3 Hz), 4.34 (t, 2H, J = 7.0 Hz), 2.89 (qt, 2H, J = 6.4 Hz) 1.96 (calc. Q, 2H, J = 7.0 and 6.7 Hz); 2.86 (s, 3H). + + - 834 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- [3- (N-methylsulfonylamino) propyl] indazole-5 -yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.74 (s, 1H), 10.24 (s, 1H), 9.98 (s, 1H), 8.21 (d, 1H, J = 4.3 Hz ), 7.93 (s, 1H), 7.90 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz), 7.38 (dd, 1H, J = 1.8 and 9.1 Hz), 7.22 (dd, 1H, J = 1.8 and 8.8 Hz), 7.17 (s, 1H), 7.09 (calc., 1H, J = 5.3 Hz), 6.89 (d, 1H, J = 8.8 Hz), 4.40 (t, 2H, J = 7.0 Hz), 2.91 (calculated qt, 2H, J = 6 7 Hz), 2.86 (s, 3H), 1.98 (calc. Q, 2H, J = 6.7 Hz), 1.37 (s, 6H). - + - 835 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [1- (3- (N-methylsulfonylamino) propyl ) indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.80 (s, 1H), 10.42 (s, 1H), 10.25 (s, 1H), 9.98 (s, 1H), 8.22 (d , 1H, J = 4.9 Hz), 7.92 (s, 1H), 7.90 (d, 1H, J = 1.5 Hz), 7.64 (d, 1H, J = 8.8 Hz ), 7.38 (dd, 1H, J = 2.0 and 9.1 Hz), 7.24-7.19 (m, 3H), 7.09 (t, 1H, J = 5.3 Hz) 6.91 (d, 1H, J = 8.8 Hz), 4.65 (qt, H, J = 6.7 Hz), 4.41 (t, 2H, J = 7.0 Hz) 2.92 (sr, 2H, J = 6.7 Hz), 2.86 (s, 3H), 2.00 (sr, 2H, J = 6.7 Hz), 1, 40 (d, 3H, J = 6.7 Hz). + + - 836 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1- [3- (N-methylsulfonylamino) propyl] indazole -5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.11 (s, 1H), 9.25 (s, 1H), 9.24 (s, 1H), 8.11 (d, 1H, J = 3.0 Hz ), 8.07 (s, 1H), 7.85 (s, 1H), 7.58 (d, 1H, J = 8.5 Hz), 7.54 (d, 1H, J = 9.1 Hz ), 7.48 (d, 1H, J = 9.1 Hz), 7.36 (d, 1H, J = 8.5 Hz), 7.06 (t, 1H, J = 6.7 Hz), 4.39 (t, 2H, J = 6.7 Hz), 2.93 (qt, 2H, J = 6.7 Hz), 2.85 (s, 3H), 1.98 (calc. , 2H, J = 6.7 Hz), 1.42 (s, 6H). + + - 837 N2- (3-amino-1-methylindazol-5-yl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.17 (s, 1H), 10.22 (s, 1H), 10.13 (s, 1H), 8.25 (d, 1H, J = 4.4 Hz ), 7.92 (s, 1H), 7.58 (d, 1H, J = 9.1 Hz), 7.50 (d, 1H, J = 9.1 Hz), 7.34 (d, 1H , J = 8.5 Hz), 3.86 (s, 3H), 1.39 (s, 3H). + + 838 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-hydroxypropyl) indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.22 (s, 1H), 10.22 (s, 1H), 10.09 (s, 1H), 8.25 (d, 1H, J = 4.4 Hz ), 7.90 (s, 2H), 7.57 (d, 1H, J = 9.3 Hz), 7.41-7.35 (m, 3H), 4.40 (t, 2H, J = 6.7 Hz), 3.35 (t, 2H, J = 6.4 Hz), 1.93 (pure q, 2H, J = 6.7 Hz), 1.40 (s, 6H). + + 839 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-methoxypropyl) indazol-6-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.10 (s, 1H), 9.46 (s, 1H), 9.27 (s, 1H), 8.19 (d, 1H, J = 3.5 Hz ), 8.01 (s, 1H), 7.87 (s, 1H), 7.65 (d, 1H, J = 8.5 Hz), 7.54 (d, 1H, J = 8.8 Hz ), 7.35 (d, 1H, J = 8.5 Hz), 7.29 (d, 1H, J = 8.8 Hz), 4.19 (t, 2H, J = 6.7 Hz), 3.16 (t, 2H, J = 6.4 Hz), 3.13 (s, 3H), 1.94 (calculated q, 2H, J = 6.7 Hz), 1.42 (s, 3H ) + + 840 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- [3- (N-trifluoromethylsulfonylamino) propyl] indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.47 (br s, 1H), 9.28 (s, 1H), 9.17 (s, 1H), 8.07 (d, 1H, J = 3, 8 Hz), 8.04 (s, 1H), 7.84 (s, 1H), 7.79 (d, 1H, J = 2.6 Hz), 7.64 (dd, 1H, J = 2, 3 and 9.1 Hz), 7.52 (d, 1H, J = 8.8 Hz), 7.49 (d, 1H, J = 9.1 Hz), 7.07 (d, 1H, J = 8.8 Hz), 4.45 (t, 2H, J = 7.0 Hz), 3.82 (s, 3H), 3.19 (t, 2H, J = 7.0 Hz), 2.06 (calc. q, 2H, J = 7.0 Hz). + 841 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- [3- (N-trifluoromethylsulfonylamino) propyl] indazol-5-yl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 10.48 (s, 1H), 10.28 (s, 1H), 9.55 (t, 1H, J = 5.2 Hz), 8.32 (d, 1H , J = 4.9 Hz), 8.00 (d, 1H, J = 2.0 Hz), 7.98 (s, 1H), 7.85-7.81 (m, 1H), 7.70 -7.65 (m, 2H), 7.52 (d, 1H, J = 8.8 Hz), 7.42 (dd, 1H, J = 2.0 and 9.1 Hz), 4.45 ( t, 2H, J = 6.7 Hz), 3.19 (calc. qt, 2H, J = 6.7 Hz), 2.06 (calc. q, 2H, J = 6.7 Hz). + 842 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- [3- (N-trifluoromethylsulfonylamino) propyl] indazole-5 -yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 10.63 (s, 1H), 9.46 (br s, 1H), 9.28 (s, 1H), 9.06 (s, 1H), 8.12 (s, 1H), 8.05 (d, 1H, J = 3.8 Hz), 7.80 (s, 1H), 7.47 (calculated d, 2H, J = 9.1 Hz), 7 29 (dd, 1H, J = 2.0 and 8.8 Hz), 7.20 (d, 1H, J = 2.0 Hz), 6.89 (d, 1H, J = 8.8 Hz) , 4.37 t, 2H, J = 6.7 Hz), 3.15 (m, 2H), 2.02 (calculated q, 2H, J = 6.7 Hz), 1.39 (s, 6H ) + 843 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [1- [3- (N-trifluoromethylsulfonylamino) propyl ] indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.74 (s, 1H), 9.88 (s, 1H), 9.68 (s, 1H), 9.49 (t, 1H, J = 6.7 Hz ), 8.13 (d, 1H, J = 4.7 Hz), 8.01 (s, 1H), 7.87 (s, 1H), 7.56 (d, 1H, J = 9.1 Hz ), 7.43 (d, 1H, J = 9.1 Hz), 7.26 (d, 1H, J = 8.5 Hz), 7.21 (s, 1H), 6.90 (d, 1H , J = 8.5 Hz), 4.64 (sq.t, 1H, J = 6.7 Hz), 4.40 (t, 2H, J = 6.7 Hz), 3.17 (sq.t , 2H, J = 6.77 Hz), 2.03 (calc. 2H, J = 6.7 Hz), 1.43 (d, 3H, J = 6.7 Hz). + 844 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1- [3- (N-trifluoromethylsulfonylamino) propyl] indazole -5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 11.10 (s, 1H), 9.46 (br s, 1H), 9.23 (s, 1H), 9.19 (s, 1H), 8.11 (dd, 1H, J = 0.9 and 3.5 Hz), 8.07 (s, 1H), 7.86 (s, 1H), 7.59 (d, 1H, J = 8.5 Hz) 7.53 (d, 1H, J = 9.1 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.35 (d, 1H, J = 8.5 Hz), 4 , 39 (t, 2H, J = 7.0 Hz), 3.17 (calc. T, 2H, J = 7.0 Hz), 2.03 (calc., 2H, J = 7.0 Hz), 1.42 (s, 6H). - 845 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) - 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.11 (s, 1H), 9.68 (s, 1H), 9.42 (s, 1H), 8.20 (d, 1H, J = 3.5 Hz ), 8.13 (s, 1H), 7.73 (dd, 1H, J = 1.8 and 9.1 Hz), 7.63 (d, 1H, J = 8.5 Hz), 7.57 (d, 1H, J = 9.1 Hz), 7.39 (d, 1H, J = 8.5 Hz), 2.73 (s, 3H), 1.42 (s, 6H). + + + 846 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (2-trifluoromethyl-1H-benzimidazol-5-yl) - 2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 13.56 (br s, 1H), 11.07 (s, 1H), 9.43 (s, 1H), 9.20 (s, 1H), 8.16 (d, 1H, J = 3.5 Hz), 8.13 (s, 1H), 7.73 (dd, 1H, J = 1.8 and 9.1 Hz), 7.61 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 9.1 Hz), 7.36 (d, 1H, J = 8.5 Hz), 1.42 (s, 6H). + + + 847 N4- (3-Chloro-4-methoxyphenyl) -N2- [1- (3- (diethylphosphonamido) propyl] indazol-5-yl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.27 (s, 1H), 9.16 (s, 1H), 8.07 (d, 1H, J = 3.5 Hz), 8.03 (s, 1H ), 7.82 (s, 1H), 7.79 (d, 1H, J = 2.3 Hz), 7.65 (dd, 1H, J = 2.3 and 8.5 Hz), 7.53 (d, 1H, J = 8.5 Hz), 7.47 (d, 1H, J = 9.1 Hz), 7.08 (d, 1H, J = 9.1 Hz), 4.91 (dt , 1H, JHH = 6.7 and J2PH = 11.0 Hz), 4.35 (t, 2H, J = 6.7 Hz), 3.84 (calculated qt, 4H, JHH = 6.7 and J3PH = 11.0 Hz), 3.84 (s, 3H), 2.73 (m, 2H), 1.92 (calculated q, 2H, J = 6.7 Hz), 1.15 (t , 6H, J = 7.0 Hz). + 848 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (3-pivalamidopropyl) indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.42 (s, 1H), 10.29 (s, 1H), 8.26 (d, 1H, J = 4.9 Hz), 7.93 (s, 1H ), 7.83 (s, 1H), 7.74 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.55-7.47 (m, 2H), 7 39 (d, 1H, J = 9.1 Hz), 7.09 (d, 1H, J = 8.8 Hz), 4.35 (t, 2H, J = 7.0 Hz), 3.82 (s, 3H), 3.06 (rt, 2H, J = 6.4 Hz), 1.94 (rt, 2H, J = 6.7 Hz), 1.06 (s, 9H). + 849 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- (3-pivalamidopropyl) indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.55 (s, 1H), 9.28 (s, 1H), 8.15 (dd, 1H, J = 1.2 and 3.7 Hz), 8.09 (d, 1H, J = 1.5 Hz), 8.00 (s, 1H), 7.87 (s, 1H), 7.79 (dd, 1H, J = 1.8 and 9.1 Hz) 7.54-7.44 (m, 4H), 4.33 (t, 2H, J = 6.7 Hz), 3.04 (qt, 2H, J = 6.4 Hz), 1, 94 (qr, 2H, J = 6.7 Hz), 1.06 (s, 9H). + 850 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-pivalamidopropyl) indazol-5-yl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.74 (s, 1H), 10.21 (s, 1H), 9.89 (s, 1H), 8.18 (d, 1H, J = 4.4 Hz ), 7.93 (s, 1H), 7.88 (s, 1H), 7.56 (d, 1H, J = 8.5 Hz), 7.46 (t, 1H, J = 5.6 Hz ), 7.37 (d, 1H, J = 9.1 Hz), 7.23 (d, 1H, J = 9.1 Hz), 7.17 (s, 1H), 6.88 (d, 1H , J = 8.8 Hz), 4.33 (t, 2H, J = 6.4 Hz), 3.02 (qt, 2H, J = 6.7 Hz), 1.92 (calculated q , 2H, J = 6.7 Hz), 1.37 (s, 6H), 1.05 (s, 9H). + 851 5-Fluoro- (S) -N4- (2-methyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -N2- [1- (3-pivalamidopropyl) indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.80 (s, 1H), 10.42 (s, 1H), 10.28 (s, 1H), 8.22 (d, 1H, J = 4.4 Hz ), 7.90 (s, 2H), 7.59 (d, 1H, J = 8.8 Hz), 7.47 (m, 1H), 7.38 (d, 1H, J = 8.8 Hz ), 7.22 (calc, d, 2H, J = 8.8 Hz), 6.91 (d, 1H, J = 8.8 Hz), 4.64 (qt, 1H, J = 6, 7 Hz), 4.34 (t, 2H, J = 6.7 Hz), 3.03 (qt, 2H, J = 6.7 Hz), 1.95 (calculated q, 2H, J = 7.0 Hz), 1.40 (d, 3H, J = 6.7 Hz), 1.05 (s, 9H). + 852 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-pivalamidopropyl) indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), 8.12 (d, 1H, J = 3.5 Hz ), 7.84 (s, 1H), 7.82 (s, 1H), 7.59 (d, 1H, J = 8.8 Hz), 7.48-7.43 (m, 3H), 7 36 (d, 1H, J = 8.5 Hz), 4.32 (t, 2H, J = 6.7 Hz), 3.02 (sq.t, 2H, J = 6.7 Hz), 1 92 (qr., 2H, J = 6.7 Hz), 1.42 (s, 6H), 1.05 (s, 9H). + 853 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- [3- (N-succinimidopropyl)] indazol-5-yl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.28 (s, 1H), 9.17 (s, 1H), 8.07 (d, 1H, J = 3.5 Hz), 7.82 (s, 1H ), 7.78 (d, 1H, J = 2.0 Hz), 7.66 (dd, 1H, J = 2.0 and 8.5 Hz), 7.52 (d, 1H, J = 9, 1 Hz), 7.46 (d, 1H, J = 9.1 Hz), 7.09 (d, 1H, J = 8.5 Hz), 4.33 (t, 2H, J = 6.3 Hz ), 3.84 (s, 3H), 3.38 (t, 2H, J = 6.3 Hz), 2.54 (s, 2H), 2.48 (s, 2H), 2.02 (q , 2H, J = 6.3 Hz). + + 854 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- [3- (N-succinimidopropyl)] indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.55 (s, 1H), 9.28 (s, 1H), 8.16 (d, 1H, J = 3.5 Hz), 8.08 (d, 1H , J = 2.3 Hz), 8.01 (s, 1H), 7.88 (s, 1H), 7.80 (dd, 1H, J = 2.3 and 8.8 Hz), 7.56 (d, 1H, J = 8.8 Hz), 7.51-7.46 (m, 2H), 4.35 (t, 2H, J = 6.7 Hz), 3.40 (t, 2H, J = 7.0 Hz), 2.55 (s, 2H), 2.48 (s, 2H), 2.03 (calculated q, 2H, J = 7.0 Hz). + - 855 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- [3- (N-succinimidopropyl)] indazole-5- il] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.73 (s, 1H), 10.38 (s, 1H), 10.25 (s, 1H), 8.18 (d, 1H, J = 3.9 Hz ), 7.85 (s, 1H), 7.83 (s, 1H), 7.56 (d, 1H, J = 9.1 Hz), 7.32 (d, 1H, J = 8.8 Hz ), 7.14 (d, 2H, J = 9.1 Hz), 6.84 (d, 1H, J = 8.8 Hz), 4.30 (t, 2H, J = 7.0 Hz), 3.34 (t, 2H, J = 6.7 Hz), 2.50 (s, 2H), 2.42 (s, 2H), 1.98 (calculated q, 2H, J = 7.0 Hz ), 1.31 (s, 6H). + + 856 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [1- [3- (N-succinimidopropyl)] indazol-5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.82 (s, 1H), 10.52 (s, 1H), 10.42 (s, 1H), 8.24 (d, 1H, J = 4.9 Hz ), 7.92 (s, 1H), 7.87 (s, 1H), 7.63 (d, 1H, J = 8.8 Hz), 7.37 (dd, 1H, J = 1.0 and 8.8 Hz), 7.20 (d, 2H, J = 8.8 Hz), 6.91 (d, 1H, J = 9.1 Hz), 4.65 (sq.t, 1H, J = 6.7 Hz), 4.36 (t, 2H, J = 6.7 Hz), 3.39 (t, 2H, J = 6.7 Hz), 2.55 (s, 2H), 2.48 (s, 2H), 2.01 (calc. q, 2H, J = 6.7 Hz), 1.39 (d, 3H, J = 6.7 Hz). + + 857 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1- [3- (N-succinimidopropyl)] indazole- 5-yl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 11.10 (s, 1H), 9.23 (s, 1H), 9.19 (s, 1H), 8.12 (d, 1H, J = 3.5 Hz ), 8.06 (s, 1H), 7.57 (d, 1H, J = 8.8 Hz), 7.53-7.46 (m, 2H), 7.36 (d, 1H, J = 8.8 Hz), 4.33 (t, 2H, J = 7.0 Hz), 3.39 (t, 2H, J = 6.7 Hz), 2.54 (s, 2H), 2.48 (s, 2H), 2.02 (calc. q, 2H, J = 7.0 Hz), 1.42 (s, 6H). + + 858 N4- (3-Chloro-4-methoxyphenyl) -N2- [1- [3- (2,6-dioxopiperidino] propyl) indazol-5-yl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.26 (s, 1H), 10.08 (s, 1H), 8.22 (d, 1H, J = 4.3 Hz), 7.92 (s, 1H ), 7.85 (s, 1H), 7.74 (d, 1H, J = 2.0 Hz), 7.62 (d, 1H, J = 8.8 Hz), 7.57 (dd, 1H , J = 2.3 and 8.8 Hz), 7.39 (dd, 1H, J = 2.0 and 8.3 Hz), 7.09 (d, 1H, J = 8.8 Hz), 4 35 (t, 2H, J = 7.0 Hz), 3.83 (s, 3H), 3.67 (t, 2H, J = 7.0 Hz), 2.53 (t, 4H, J = 6.7 Hz), 1.96 (q, 2H, J = 7.0 Hz), 1.76 (q, 2H, J = 6.7 Hz). + + 859 N4- (3,4-Dichlorophenyl) -N2- [1- [3- (2,6-dioxopiperidino) propyl] indazol-5-yl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.05 (s, 1H), 9.77 (s, 1H), 8.23 (d, 1H, J = 5.1 Hz), 8.03 (s, 1H ), 7.92 (s, 1H), 7.91 (s, 1H), 7.73 (d, 1H, J = 8.8 Hz), 7.61 (d, 1H, J = 8.8 Hz ), 7.51 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.8 Hz), 4.35 (t, 2H, J = 6.7 Hz), 3.67 (t, 2H, J = 6.7 Hz), 2.53 (t, 4H, J = 6.4 Hz), 1.97 (q, 2H, J = 6.4 Hz), 1, 75 (calc. Q, 2H, J = 6.7 Hz). + + 860 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -N2- [1- [3- (2,6-dioxopiperidino] propyl) indazol-5-yl ] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.76 (s, 1H), 10.34 (s, 1H), 10.16 (s, 1H), 8.21 (d, 1H, J = 4.3 Hz ), 7.89 (s, 2H), 7.59 (d, 1H, J = 8.5 Hz), 7.37 (dd, 1H, J = 1.5 and 8.5 Hz), 7.21 (d, 1H, J = 8.8 Hz), 7.19 (s, 1H), 6.88 (d, 1H, J = 8.8 Hz), 4.35 (t, 2H, J = 7, 0 Hz), 3.66 (t, 2H, J = 7.0 Hz), 2.53 (t, 4H, J = 7.0 Hz), 1.95 (q, 2H, J = 7.0 Hz ), 1.76 (calc. Q, 2H, J = 7.0 Hz), 1.36 (s, 6H). + + 861 (S) -N2- [1- [3- (2,6-dioxopiperidino] propyl) indazol-5-yl] -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1 , 4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.78 (s, 1H), 10.49 (s, 1H), 10.44 (s, 1H), 8.21 (d, 1H, J = 4.9 Hz ), 7.85 (s, 1H), 7.82 (s, 1H), 7.56 (d, 1H, J = 8.8 Hz), 7.31 (d, 1H, J = 8.8 Hz ), 7.17 (s, 1H), 7.16 (d, 1H, J = 8.8 Hz), 6.86 (d, 1H, J = 8.8 Hz), 4.59 (qt , 1H, J = 6.7 Hz), 4.29 (t, 2H, J = 6.7 Hz), 3.61 (t, 2H, J = 7.0 Hz), 2.47 (t, 4H , J = 7.0 Hz), 1.90 (q, 2H, J = 7.0 Hz), 1.71 (calculated q, 2H, J = 6.7 Hz), 1.35 (d, 3H , J = 6.7 Hz). + + 862 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- [1- [3- (2,6-dioxopiperidino] propyl) indazole-5 -yl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), 8.12 (d, 1H, J = 3.2 Hz ), 8.05 (s, 1H), 7.84 (s, 1H), 7.58 (d, 1H, J = 8.2 Hz), 7.48 (s, 2H), 7.36 (d , 1H, J = 8.2 Hz), 4.32 (t, 2H, J = 7.3 Hz), 3.66 (t, 2H, J = 7.3 Hz), 2.45 (t, 2H , J = 7.3 = 6.7 Hz), 4.29 (t, 2H, J = 6.7 Hz), 3.61 (t, 2H, J = 7.0 Hz), 2.47 (t , 4H, J = 7.0 Hz), 1.90 (q, 2H, J = 7.0 Hz), 1.71 (calculated q, 2H, J = 6.7 Hz), 1.35 (d , 3H, J = 6.7 Hz). + + 863 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2-trifluoromethyl-1H-benzimidazol-5-yl) -2,4-pyrimidinediamine hydrochloride salt 1 H NMR (DMSO-d6): d 10.33 (s, 1H), 10.23 (s, 1H), 8.32 (d, 1H, J = 4.7 Hz), 8.03 (d, 1H , J = 2.0 Hz), 7.90 (s, 1H), 7.74 (d, 1H, J = 2.0 Hz), 7.69 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.45 (dd, 1H, J = 2.0 and 8.8 Hz). + + 864 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2-trifluoromethyl-1H-benzimidazol-5-yl) -2,4-pyrimidinediamine salt of ethanesulfonic acid 1 H NMR (DMSO-d6): d 10.11 (s, 1H), 9.92 (s, 1H), 8.27 (d, 1H, J = 4.4 Hz), 8.06 (d, 1H , J = 2.0 Hz), 7.94 (s, 1H), 7.76 (d, 1H, J = 2.0 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J = 2.0 and 8.8 Hz), 2.42 (qt, 2H, J = 7, 3 Hz), 1.05 (t, 3H, J = 7.3 Hz). - + 865 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2-trifluoromethyl-1H-benzimidazol-5-yl) -2,4-pyrimidinediamine salt of benzenesulfonic acid 1 H NMR (DMSO-d6): d 10.25 (s, 1H), 10.04 (s, 1H), 8.29 (d, 1H, J = 4.4 Hz), 8.03 (s, 1H ), 7.91 (s, 1H), 7.73-7.26 (m, 2H), 7.58-7.43 (m, 4H), 7.29-7.27 (m, 3H). - + 866 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2-trifluoromethyl-1H-benzimidazol-5-yl) -2,4-pyrimidinediamine salt of p-toluenesulfonic acid 1H NMR (DMSO-d6): d 10.30 (s, 1H), 10.08 (s, 1H), 8.30 (d, 1H, J = 4.7 Hz), 8.03 (d, 1H , J = 2.0 Hz), 7.90 (s, 1H), 7.71 (d, 2H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.47-7.43 (m, 3H), 7.10 (d, 2H, J = 8.8 Hz), 2.26 (s, 3H). - + 867 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) -2,4-pyrimidinediamine salt of benzenesulfonic acid 1 H NMR (DMSO-d6): d 9.77 (s, 1H), 9.74 (s, 1H), 8.25 (d, 1H, J = 3.8 Hz), 8.14 (d, 1H , J = 2.3 Hz), 8.12 (s, 1H), 7.81 (dd, 1H, J = 2.3 and 8.8 Hz), 7.66 (d, 2H, J = 9, 1 Hz), 7.59-7.52 (m, 3H), 7.33-7.27 (m, 3H), 2.74 (s, 3H). + + 868 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) -2,4-pyrimidinediamine salt of p-toluenesulfonic acid 1 H NMR (DMSO-d6): d 9.78 (s, 1H), 9.74 (s, 1H), 8.25 (d, 1H, J = 3.8 Hz), 8.14 (d, 1H , J = 2.3 Hz), 8.12 (s, 1H), 7.81 (dd, 1H, J = 2.3 and 8.8 Hz), 7.66 (d, 2H, J = 9, 1 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.46 (d, 2H, J = 8.2 Hz), 7.10 (d, 2H, J = 8.2 Hz ), 2, 74 (s, 3H). + + 869 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) -2,4-pyrimidinediamine hydrochloride salt 1 H NMR (DMSO-d6): d 9.93 (s, 2H), 8.28 (d, 1H, J = 3.8 Hz), 8.12 (d, 1H, J = 2.3 Hz), 8.07 (s, 1H), 7.81 (dd, 1H, J = 1.8 and 8.8 Hz), 7.66 (d, 2H, J = 8.8 Hz), 7.56 (d , 1H, J = 8.8 Hz), 2.75 (s, 3H). + + 870 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) -2,4-pyrimidinediamine salt of ethanesulfonic acid 1 H NMR (DMSO-d6): d 9.75 (s, 2H), 9.72 (s, 1H), 8.24 (d, 1H, J = 3.8 Hz), 8.14 (d, 1H , J = 2.0 Hz), 8.12 (s, 1H), 7.82 (d, 1H, J = 8.8 Hz), 7.66 (d, 2H, J = 8.5 Hz), 7.53 (d, 1H, J = 8.8 Hz), 2.74 (s, 3H), 2.40 (sq.t, 2H, J = 7.3 Hz), 1.05 (t, 3H , J = 7.3 Hz). + + 871 N4- (3-Chloro-4-methoxyphenyl) -N2- [1- (3-ethoxypropyl) indazol-5-yl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.37 (s, 1H), 10.23 (s, 1H), 8.25 (d, 1H, J = 5.3 Hz), 7.92 (s, 1H ), 7.83 (s, 1H), 7.74 (d, 1H, J = 2.6 Hz), 7.59 (d, H, J = 8.8 Hz), 7.53 (dd, 1H , J = 2.3 and 8.5 Hz), 7.38 (dd, 1H, J = 1.8 and 8.8 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4 40 (t, 2H, J = 6.7 Hz), 3.83 (s, 3H), 3.31 (q, 2H, J = 6.7 Hz), 3.26 (t, 2H, J = 6.7 Hz), 2.01 (calc. Q, 2H, J = 6.7 Hz), 1.06 (t, 3H, J = 6.7 Hz). + + 872 N4- (3,4-Dichlorophenyl) -N2- [1- (3-ethoxypropyl) indazol-5-yl] -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 10.27 (s, 1H), 10.02 (s, 1H), 8.28 (d, 1H, J = 4.7 Hz), 8.02 (d, 1H , J = 2.3 Hz), 7.95 (s, 1H), 7.87 (s, 1H), 7.68 (d, 1H, J = 8.8 Hz), 7.60 (d, 1H , J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.42 (dd, 1H, J = 2.3 and 8.8 Hz), 4.41 (t , 2H, J = 6.4 Hz), 3.32 (qt, 2H, J = 6.7 Hz), 3.27 (t, 2H, J = 6.4 Hz), 2.02 (q , 2H, J = 6.4 Hz), 1.07 (t, 3H, J = 6.7 Hz). + 873 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -N2- [1- (3-ethoxypropyl) indazol-5-yl] -5-fluoro-2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.76 (s, 1H), 10.36 (s, 1H), 10.19 (s, 1H), 8.22 (d, 1H, J = 5.3 Hz ), 7.90 (s, 2H), 7.55 (d, 1H, J = 9.1 Hz), 7.37 (dd, 1H, J = 1.8 and 8.8 Hz), 7.20 (d, 1H, J = 8.8 Hz), 7.18 (s, 1H), 6.87 (d, 1H, J = 8.8 Hz), 4.39 (t, 2H, J = 6, 7 Hz), 3.31 (qt, 2H, J = 7.0 Hz), 3.25 (t, 2H, J = 6.7 Hz), 1.99 (calculated q, 2H, J = 6.7 Hz), 1.36 (s, 6H), 1.07 (t, 3H, J = 7.0 Hz). + + 874 (S) -N2- [1- (3-Ethoxypropyl) indazol-5-yl] -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6- il) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.79 (s, 1H), 10.40 (s, 1H), 10.24 (s, 1H), 8.22 (d, 1H, J = 5.3 Hz ), 7.90 (d, 1H, J = 1.8 Hz), 7.88 (s, 1H), 7.57 (d, 1H, J = 9.1 Hz), 7.37 (dd, 1H , J = 1.8 and 9.1 Hz), 7.22 (dd, 2H, J = 1.8 and 8.5 Hz), 6.89 (d, 1H, J = 8.5 Hz), 4 65 (sq.t, 1H, J = 7.0 Hz), 4.40 (t, 2H, J = 6.7 Hz), 3.29 (sq.t, 2H, J = 7.0 Hz) , 3.25 (t, 2H, J = 6.7 Hz), 2.00 (calculated q, 2H, J = 6.7 Hz), 1.40 (d, 3H, J = 7.0 Hz) 1.07 (t, 3H, J = 7.0 Hz). + + 875 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- [1- (3-ethoxypropyl) indazol-5-yl] -5-fluoro -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), 8.11 (d, 1H, J = 3.5 Hz ), 8.05 (s, 1H), 7.84 (s, 1H), 7.58 (d, 1H, J = 8.5 Hz), 7.42 (d, 2H, J = 8.8 Hz ), 7.35 (d, 1H, J = 8.5 Hz), 4.37 (t, 2H, J = 6.7 Hz), 3.32 (qt, 2H, J = 7.0 Hz ), 3.28 (t, 2H, J = 6.7 Hz), 2.02 (calc. 2H, J = 6.7 Hz), 1.42 (s, 6H), 1.07 (t , 3H, J = 7.0 Hz). + + 876 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.32 (s, 1H), 9.63 (s, 1H), 8.19 (d, 1H, J = 4.1 Hz), 8.06 (d, 1H , J = 8.5 Hz), 7.52 (d, 1H, J = 8.5 Hz), 6.91 (s, 2H), 3.88 (s, 3H), 3.64 (s, 6H ), 3.61 (s, 3H). + + 877 N4- (2-Chloro-3-methoxypyrid-6-yl) -N2- (3,4-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.84 (s, 1H), 9.23 (s, 1H), 8.15 (d, 1H, J = 8.8 Hz), 8.14 (d, 1H , J = 3.5 Hz), 7.55 (d, 1H, J = 9.1 Hz), 6.90 (d, 1H, J = 2.3 Hz), 6.08 (d, 2H, J = 2.3 Hz), 3.88 (s, 3H), 3.65 (s, 3H). + 878 N2- (3-Chloro-4-methoxyphenyl) -N4- (2-chloro-3-methoxypyrid-6-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.83 (s, 1H), 9.26 (s, 1H), 8.14 (d, 1H, J = 3.5 Hz), 8.01 (d, 1H , J = 9.1 Hz), 7.80 (d, 1H, J = 2.6 Hz), 7.59 (d, 1H, J = 9.1 Hz), 7.43 (dd, 1H, J = 2.6 and 9.1 Hz), 7.03 (d, 1H, J = 9.1 Hz), 3.88 (s, 3H), 3.78 (s, 3H). - 879 N4- (2-Chloro-3-methoxypyrid-6-yl) -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.79 (s, 1H), 9.15 (s, 1H), 8.13 (d, 1H, J = 3.5 Hz), 8.08 (dd, 1H , J = 2.3 and 8.8 Hz), 7.57 (d, 1H, J = 8.8 Hz), 7.22 (s, 2H), 6.53 (s, 1H), 3.82 (s, 3H); 2.19 (s, 6H). H +). + + 880 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.84 (s, 1H), 9.32 (s, 1H), 8.14 (d, 1H, J = 3.5 Hz), 8.12 (d, 1H , J = 8.8 Hz), 7.96 (sq.t, 1H, J = 4.7 Hz), 7.60 (d, 1H, J = 8.8 Hz), 7.37 (calculated with , 1H), 7.23 (d, 1H, J = 8.2 Hz), 7.13 (t, 1H, J = 8.2 Hz), 6.48 (dd, 1H, J = 2.3 and 8.2 Hz), 4.37 (s, 2H), 3.87 (s, 3H), 2.61 (d, 3H, J = 4.7 Hz). + + 881 2-Chloro-N4- (2-chloro-3-methoxypyrid-6-yl) -5-fluoro-4-pyrimidinamine 1 H NMR (DMSO-d6): d 8.33 (d, 1H, J = 8.8 Hz), 8.12 (d, 1H, J = 2.3 Hz), 7.65 (br s, 1H ), 7.38 (d, 1H, J = 8.8 Hz), 3.94 (s, 3H). 882 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- (indazol-6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 10.99 min; purity: 93%; MS (mass / charge): 386 (MH ⁺ ). + 883 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- (2-trifluoromethyl-1H-benzimidazol-5-yl) -2,4-pyrimidinediamine LC / MS: retention time: 11.74 min; purity: 97%; MS (mass / charge): 454 (MH ⁺ ). + 884 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) -2,4-pyrimidinediamine LC / MS: retention time: 7.71 min; purity: 93%; MS (mass / charge): 400 (MH ⁺ ). + 885 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- (1-methylindazol-6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 12.20 min; purity: 93%; MS (mass / charge): 400 (MH ⁺ ). + 886 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- (1-methylindazol-5-yl) -2,4-pyrimidinediamine LC / MS: retention time: 10.79 min; purity: 94%; MS (mass / charge): 400 (MH ⁺ ). - 887 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- (1-ethylindazol-6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 12.97 min; purity: 95%; MS (mass / charge): 414 (MH ⁺ ). + 888 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- (1-isopropylindazol-6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 13.86 min; purity: 92%; MS (mass / charge): 428 (MH ⁺ ). + 889 N4- (2-Chloro-3-methoxypyrid-6-yl) -N2- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine LC / MS: retention time: 11.84 min; purity: 94%; MS (mass / charge): 445 (MH ⁺ ). + 890 N2- [1- [3- (N-Acetylamino) propyl] indazol-5-yl] -N4- (2-chloro-3-methoxypyrid-6-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 9.42 min; purity: 95%; MS (mass / charge): 485 (MH ⁺ ). + 891 N4- (2-Chloro-3-methoxypyrid-6-yl) -N2- [1- [3- (N-cyclopropanecarbonylamino) propyl] indazol-5-yl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 10.30 min; purity: 95%; MS (mass / charge): 511 (MH ⁺ ). + 892 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- [1- (3-pivalamidopropyl) indazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 11.73 min; purity: 99%; MS (mass / charge): 527 (MH ⁺ ). + 893 N4- (2-Chloro-3-methoxypyrid-6-yl) -5-fluoro-N2- [1- [3- (N-isobutyrylamino) propyl] indazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 10.71 min; purity: 97%; MS (mass / charge): 514 (MH ⁺ ). + 894 N4- (3,4-Dichlorophenyl) -N2- (1,2-dimethylbenzimidazol-5-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 9.44 min; purity: 100%; MS (mass / charge): 418 (MH ⁺ ). + 895 N4- (3-Chloro-4-methoxyphenyl) -N2- (1,2-dimethylbenzimidazol-5-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 7.66 min; purity: 96%; MS (mass / charge): 413 (MH ⁺ ). + 896 N2- (1,2-Dimethylbenzimidazol-5-yl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4- pyrimidinediamine LC / MS: retention time: 7.09 min; purity: 99%; MS (mass / charge): 448 (MH ⁺ ). + + 897 (S) -N2- (1,2-Dimethylbenzimidazol-5-yl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) - 2,4-pyrimidinediamine LC / MS: retention time: 6.52 min; purity: 97%; MS (mass / charge): 434 (MH ⁺ ). + + + 898 N2- (1,2-Dimethylbenzimidazol-5-yl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-Fluoro-2, 4-pyrimidinediamine LC / MS: retention time: 7.85 min; purity: 91%; MS (mass / charge): 449 (MH ⁺ ). + + + 899 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- (2-hydroxyethyl) -2-methylbenzimidazol-5-yl) -2,4-pyrimidinediamine LC / MS: retention time: 8.77 min; purity: 97%; MS (mass / charge): 448 (MH ⁺ ). + + 900 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (2-hydroxyethyl) -2-methylbenzimidazol-5-yl) -2,4-pyrimidinediamine LC / MS: retention time: 7.06 min; purity: 93%; MS (mass / charge): 443 (MH ⁺ ). + 901 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (2-hydroxyethyl) -2-methylbenzimidazol-5-yl ) -2,4-pyrimidinediamine LC / MS: retention time: 6.50 min; purity: 97%; MS (mass / charge): 478 (MH ⁺ ). + + 902 (S) -5-Fluoro-N2- [1- (2-hydroxyethyl) -2-methylbenzimidazol-5-yl) -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazine -6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 5.99 min; purity: 94%; MS (mass / charge): 464 (MH ⁺ ). + + 903 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (2-hydroxyethyl) -2-methylbenzimidazole-5 -yl) -2,4-pyrimidinediamine LC / MS: retention time: 6.89 min; purity: 97%; MS (mass / charge): 479 (MH ⁺ ). + + 904 N4- (3,4-Dichlorophenyl) -N2- (2,3-dihydro-1-methyl-2-oxobenzimidazol-5-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 10.32 min; purity: 100%; MS (mass / charge): 420 (MH ⁺ ). - - 905 N4- (3-Chloro-4-methoxyphenyl) -N2- (2,3-dihydro-1-methyl-2-oxobenzimidazol-5-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 8.24 min; purity: 96%; MS (mass / charge): 415 (MH ⁺ ). + + 906 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -N2- (2,3-dihydro-1-methyl-2-oxobenzimidazol-5-yl) - 5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 7.53 min; purity: 97%; MS (mass / charge): 450 (MH ⁺ ). + + 907 (S) -N2- (2,3-dihydro-1-methyl-2-oxobenzimidazol-5-yl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4 ] oxazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 7.00 min; purity: 98%; MS (mass / charge): 436 (MH ⁺ ). + + 908 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- (2,3-dihydro-1-methyl-2-oxobenzimidazol-5-yl ) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 8.19 min; purity: 94%; MS (mass / charge): 451 (MH ⁺ ). + + 909 5-Fluoro-N2- (2-methyl-3H-benzimidazol-5-yl) -N4- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl ) -2,4-pyrimidinediamine LC / MS: retention time: 7.11 min; purity: 94%; MS (mass / charge): 468 (MH ⁺ ). + + 910 5-Fluoro-N4- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) -N2- (2-trifluoromethyl-1H-benzimidazol-5-yl ) -2,4-pyrimidinediamine LC / MS: retention time: 10.29 min; purity: 98%; MS (mass / charge): 521 (MH ⁺ ). + + 911 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (1-methyl-2-trifluoromethylbenzimidazol-5-yl) -2,4-pyrimidinediamine LC / MS: retention time: 14.28 min; purity: 97%; MS (mass / charge): 472 (MH ⁺ ). + 912 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (1-methyl-2-trifluoromethylbenzimidazol-5-yl) -2,4-pyrimidinediamine LC / MS: retention time: 11.38 min; purity: 91%; MS (mass / charge): 467 (MH ⁺ ). + 913 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -N2- (1-methyl-2-trifluoromethylbenzimidazol-5-yl) -2,4-pyrimidinediamine LC / MS: retention time: 10.21 min; purity: 94%; MS (mass / charge): 502 (MH ⁺ ). + 914 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- (1-methyl-2-trifluoromethylbenzimidazol-5-yl ) -2,4-pyrimidinediamine LC / MS: retention time: 9.66 min; purity: 93%; MS (mass / charge): 488 (MH ⁺ ). + 915 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- (1-methyl-2-trifluoromethylbenzimidazol-5-yl) -2,4- pyrimidinediamine LC / MS: retention time: 11.48 min; purity: 91%; MS (mass / charge): 503 (MH ⁺ ). + 916 N4- (3,4-Dichlorophenyl) -5-fluoro- [1- (2-hydroxyethyl) -2-trifluoromethylbenzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 12.15 min; purity: 96%; MS (mass / charge): 502 (MH ⁺ ). + 917 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro- [1- (2-hydroxyethyl) -2-trifluoromethylbenzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 9.90 min; purity: 94%; MS (mass / charge): 497 (MH ⁺ ). + 918 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro- [1- (2-hydroxyethyl) -2-trifluoromethylbenzimidazol-5-yl] - 2,4-pyrimidinediamine LC / MS: retention time: 9.08 min; purity: 96%; MS (mass / charge): 532 (MH ⁺ ). + + 919 (S) -5-Fluoro- [1- (2-hydroxyethyl) -2-trifluoromethylbenzimidazol-5-yl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6 -yl) -2,4-pyrimidinediamine LC / MS: retention time: 8.67 min; purity: 92%; MS (mass / charge): 518 (MH ⁺ ). + + 920 N4- (3,4-Dichlorophenyl) -5-fluoro- [1- (2-hydroxymethyl) -2-trifluoromethylbenzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 14.96 min; purity: 97%; MS (mass / charge): 486 (MH ⁺ ). + + 921 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro- [1- (2-hydroxymethyl) -2-trifluoromethylbenzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 12.21 min; purity: 98%; MS (mass / charge): 481 (MH ⁺ ). + + 922 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro- [1- (2-hydroxymethyl) -2-trifluoromethylbenzimidazol-5-yl] - 2,4-pyrimidinediamine LC / MS: retention time: 10.93 min; purity: 96%; MS (mass / charge): 516 (MH ⁺ ). + 923 (S) -5-Fluoro- [1- (2-hydroxymethyl) -2-trifluoromethylbenzimidazol-5-yl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6 -yl) -2,4-pyrimidinediamine LC / MS: retention time: 10.43 min; purity: 92%; MS (mass / charge): 502 (MH ⁺ ). + 924 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- [1- (2-hydroxymethyl) -2-trifluoromethylbenzimidazol-5-yl ] -2,4-pyrimidinediamine LC / MS: retention time: 12.25 min; purity: 98%; MS (mass / charge): 517 (MH ⁺ ). + 925 N2- (1,2-Benzisoxazol-5-yl) -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 9.63 min; purity: 100%; MS (mass / charge): 386 (MH ⁺ ). + 926 N2- (1,2-Benzisoxazol-5-yl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4- pyrimidinediamine LC / MS: retention time: 8.48 min; purity: 100%; MS (mass / charge): 421 (MH ⁺ ). + 927 (S) -N2- (1,2-Benzisoxazol-5-yl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) - 2,4-pyrimidinediamine LC / MS: retention time: 8.11 min; purity: 100%; MS (mass / charge): 407 (MH ⁺ ). + 928 N2- (1,2-Benzisoxazol-5-yl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine LC / MS: retention time: 9.57 min; purity: 100%; MS (mass / charge): 422 (MH ⁺ ). + 929 Racemic-N2- (1,2-benzisoxazol-5-yl) -5-fluoro- (2-methyl-1,1,3-trioxo-2H, 4H-benzo [1,4] thiazin-6-yl) - 2,4-pyrimidinediamine LC / MS: retention time: 9.69 min; purity: 95%; MS (mass / charge): 455 (MH ⁺ ). + 930 N2- (1,2-Benzisoxazol-5-yl) -N4- (2,2-dimethyl-1,1,3-trioxo-4H-benzo [1,4] thiazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine LC / MS: retention time: 10.13 min; purity: 97%; MS (mass / charge): 470 (MH ⁺ ). + 931 Racemic-N2- (1,2-benzisoxazol-5-yl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] thiazin-6-yl) -2, 4-pyrimidinediamine LC / MS: retention time: 9.21 min; purity: 96%; MS (mass / charge): 423 (MH ⁺ ). + 932 N4- (3,4-Dichlorophenyl) -N2- (1-ethyl-2-methylbenzimidazol-5-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 10.09 min; purity: 99%; MS (mass / charge): 432 (MH ⁺ ). - 933 N4- (3-Chloro-4-methoxyphenyl) -N2- (1-ethyl-2-methylbenzimidazol-5-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 8.64 min; purity: 92%; MS (mass / charge): 427 (MH ⁺ ). + 934 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -N2- (1-ethyl-2-methylbenzimidazol-5-yl) -5-fluoro-2, 4-pyrimidinediamine LC / MS: retention time: 7.91 min; purity: 99%; MS (mass / charge): 462 (MH ⁺ ). + 935 (S) -N2- (1-Ethyl-2-methylbenzimidazol-5-yl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl ) -2,4-pyrimidinediamine LC / MS: retention time: 7.72 min; purity: 95%; MS (mass / charge): 448 (MH ⁺ ). + + 936 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -N2- (1-ethyl-2-methylbenzimidazol-5-yl) -5-fluoro- 2,4-pyrimidinediamine LC / MS: retention time: 8.48 min; purity: 96%; MS (mass / charge): 463 (MH ⁺ ). + 937 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- (3-hydroxypropyl) -2-trifluoromethylbenzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 12.33 min; purity: 97%; MS (mass / charge): 516 (MH ⁺ ). + + 938 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (3-hydroxypropyl) -2-trifluoromethylbenzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 9.85 min; purity: 94%; MS (mass / charge): 511 (MH ⁺ ). + 939 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-hydroxypropyl) -2-trifluoromethylbenzimidazol-5-yl ] -2,4-pyrimidinediamine LC / MS: retention time: 9.04 min; purity: 96%; MS (mass / charge): 546 (MH ⁺ ). + + 940 (S) -5-Fluoro-N2- [1- (3-hydroxypropyl) -2-trifluoromethylbenzimidazol-5-yl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazine -6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 8.49 min; purity: 95%; MS (mass / charge): 532 (MH ⁺ ). + + 941 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-hydroxypropyl) -2-trifluoromethylbenzimidazole-5 -yl] -2,4-pyrimidinediamine LC / MS: retention time: 9.85 min; purity: 93%; MS (mass / charge): 547 (MH ⁺ ). + + 942 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1-methyl-2- (4-morpholino) benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 9.49 min; purity: 97%; MS (mass / charge): 489 (MH ⁺ ). + + + 943 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1-methyl-2- (4-morpholino) benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 7.79 min; purity: 93%; MS (mass / charge): 484 (MH ⁺ ). + + 944 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1-methyl-2- (4-morpholino) benzimidazole-5- il] -2,4-pyrimidinediamine LC / MS: retention time: 7.20 min; purity: 99%; MS (mass / charge): 519 (MH ⁺ ). + + + 945 (S) -5-Fluoro-N2- [1-methyl-2- (4-morpholino) benzimidazol-5-yl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 6.78 min; purity: 90%; MS (mass / charge): 505 (MH ⁺ ). + + 946 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- [1-methyl-2- (4-morpholino) benzimidazole- 5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 7.86 min; purity: 96%; MS (mass / charge): 520 (MH ⁺ ). + + 947 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1- (3-hydroxypropyl) -2-methylbenzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 9.65 min; purity: 95%; MS (mass / charge): 462 (MH ⁺ ). + 948 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1- (3-hydroxypropyl) -2-methylbenzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 8.28 min; purity: 90%; MS (mass / charge): 457 (MH ⁺ ). + 949 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-hydroxypropyl) -2-methylbenzimidazol-5-yl ] -2,4-pyrimidinediamine LC / MS: retention time: 7.70 min; purity: 96%; MS (mass / charge): 492 (MH ⁺ ). + 950 (S) -5-Fluoro-N2- [1- (3-hydroxypropyl) -2-methylbenzimidazol-5-yl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazine -6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 7.22 min; purity: 90%; MS (mass / charge): 478 (MH ⁺ ). + 951 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- [1- (3-hydroxypropyl) -2-methylbenzimidazole-5 -yl] -2,4-pyrimidinediamine LC / MS: retention time: 7.97 min; purity: 94%; MS (mass / charge): 493 (MH ⁺ ). + + 952 N2- [1- [3- ( N- Acetylamino) propyl] -2-methylbenzimidazol-5-yl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6- il) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 7.89 min; purity: 97%; MS (mass / charge): 533 (MH ⁺ ). + + 953 N2- [1- [3- ( N- Acetylamino) propyl] -2-methylbenzimidazol-5-yl] -N4- (2,2-dimethyl-3-oxo-4H-5-pyrido [1,4] oxazine- 6-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 8.09 min; purity: 97%; MS (mass / charge): 534 (MH ⁺ ). + + 954 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1-methyl-2- (4-morpholinomethyl) benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 10.04 min; purity: 96%; MS (mass / charge): 503 (MH ⁺ ). + + 955 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1-methyl-2- (4-morpholinomethyl) benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 9.29 min; purity: 93%; MS (mass / charge): 498 (MH ⁺ ). + 956 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1-methyl-2- (4-morpholinomethyl) benzimidazole-5- il] -2,4-pyrimidinediamine LC / MS: retention time: 8.09 min; purity: 94%; MS (mass / charge): 533 (MH ⁺ ). + 957 (S) -5-Fluoro-N2- [1-methyl-2- (4-morpholinomethyl) benzimidazol-5-yl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 7.55 min; purity: 98%; MS (mass / charge): 519 (MH ⁺ ). + + 958 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- [1-methyl-2- (4-morpholinomethyl) benzimidazole- 5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 8.34 min; purity: 98%; MS (mass / charge): 534 (MH ⁺ ). + 959 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [2- (4-morpholinomethyl) -1H-benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 9.12 min; purity: 95%; MS (mass / charge): 489 (MH ⁺ ). + 960 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [2- (4-morpholinomethyl) -1H-benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 8.10 min; purity: 97%; MS (mass / charge): 484 (MH ⁺ ). + 961 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [2- (4-morpholinomethyl) -1H-benzimidazol-5-yl ] -2,4-pyrimidinediamine LC / MS: retention time: 7.70 min; purity: 93%; MS (mass / charge): 519 (MH ⁺ ). + + 962 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- [2- (4-morpholinomethyl) -1H-benzimidazole-5 -yl] -2,4-pyrimidinediamine LC / MS: retention time: 7.93 min; purity: 95%; MS (mass / charge): 520 (MH ⁺ ). + + 963 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [2-methyl-1- [3- ( N- methylsulfonylamino) propyl ] benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 8.01 min; purity: 95%; MS (mass / charge): 569 (MH ⁺ ). + 964 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- [2-methyl-1- [3- ( N- methylsulfonylamino ) propyl] benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 8.36 min; purity: 95%; MS (mass / charge): 570 (MH ⁺ ). + + 965 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- {1-methyl-2 - [(methylsulfonyl) methyl] benzimidazol-5-yl} -2,4-pyrimidinediamine LC / MS: retention time: 10.63 min; purity: 94%; MS (mass / charge): 496 (MH ⁺ ). + 966 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- {1-methyl-2 - [(methylsulfonyl) methyl] benzimidazol-5-yl} -2,4-pyrimidinediamine LC / MS: retention time: 9.10 min; purity: 95%; MS (mass / charge): 491 (MH ⁺ ). + 967 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- {1-methyl-2 - [(methylsulfonyl) methyl] benzimidazole-5 -yl} -2,4-pyrimidinediamine LC / MS: retention time: 9.22 min; purity: 91%; MS (mass / charge): 525 (MH ⁺ ). + + 968 (S) -5-Fluoro-N2- {1-methyl-2 - [(methylsulfonyl) methyl] benzimidazol-5-yl} -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4 ] oxazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 8.62 min; purity: 91%; MS (mass / charge): 512 (MH ⁺ ). + + 969 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- {1-methyl-2 - [(methylsulfonyl) methyl] benzimidazole -5-yl} -2,4-pyrimidinediamine LC / MS: retention time: 9.14 min; purity: 94%; MS (mass / charge): 527 (MH ⁺ ). + + 970 N4- (3,4-Dichlorophenyl) -N2- [2- ( N , N- diethylaminomethyl) -1-methylbenzimidazol-5-yl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 9.42 min; purity: 91%; MS (mass / charge): 489 (MH ⁺ ). + 971 N4- (3-Chloro-4-methoxyphenyl) -N2- [2- ( N , N- diethylaminomethyl) -1-methylbenzimidazol-5-yl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 7.76 min; purity: 94%; MS (mass / charge): 485 (MH ⁺ ). + 972 N2- [2- ( N , N- diethylaminomethyl) -1-methylbenzimidazol-5-yl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) - 5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 7.56 min; purity: 94%; MS (mass / charge): 519 (MH ⁺ ). + + 973 (S) -N2- [2- ( N , N- diethylaminomethyl) -1-methylbenzimidazol-5-yl] -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4 ] oxazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 7.21 min; purity: 97%; MS (mass / charge): 505 (MH ⁺ ). + + 974 N2- [2- ( N , N- diethylaminomethyl) -1-methylbenzimidazol-5-yl] -N4- (2,2-dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl ) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 7.51 min; purity: 97%; MS (mass / charge): 520 (MH ⁺ ). + + 975 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [2- (4-morpholino) -1H-benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 8.89 min; purity: 90%; MS (mass / charge): 475 (MH ⁺ ). + + 976 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [2- (4-morpholino) -1H-benzimidazol-5-yl ] -2,4-pyrimidinediamine LC / MS: retention time: 7.76 min; purity: 96%; MS (mass / charge): 505 (MH ⁺ ). + + 977 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- [2- (4-morpholino) -1H-benzimidazole-5 -yl] -2,4-pyrimidinediamine LC / MS: retention time: 8.05 min; purity: 926%; MS (mass / charge): 506 (MH ⁺ ). + + 978 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [2- (4-morpholino) -1H-benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 8.03 min; purity: 92%; MS (mass / charge): 470 (MH ⁺ ). + 979 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [1-methyl-2- (4-methyl-1-piperazino) -1H-benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 8.12 min; purity: 98%; MS (mass / charge): 502 (MH ⁺ ). 980 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- [1-methyl-2- (4-methyl-1-piperazino) -1H-benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 7.34 min; purity: 96%; MS (mass / charge): 497 (MH ⁺ ). 981 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [1-methyl-2- (4-methyl-1-piperazino) -1H-benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 6.99 min; purity: 97%; MS (mass / charge): 532 (MH ⁺ ). 982 (S) -5-Fluoro-N2- [1-methyl-2- (4-methyl-1-piperazino) -1H-benzimidazol-5-yl] -N4- (2-methyl-3-oxo-2H, 4H -benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine LC / MS: retention time: 6.62 min; purity: 97%; MS (mass / charge): 518 (MH ⁺ ). 983 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- [1-methyl-2- (4-methyl-1- piperazino) -1H-benzimidazol-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 7.05 min; purity: 96%; MS (mass / charge): 533 (MH ⁺ ). 984 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 -pyrimidinediamine salt of benzenesulfonic acid ¹ H NMR (DMSO-d6): d 11.22 (1H, s), 9.79 (1H, s), 9.62 (1H, s), 8.27 (1H, d, J = 3.9 Hz), 8.08 (1H, d, J = 4.5 Hz), 7.68-7.64 (3H, m), 7.47 (1H, d, J = 8.7 Hz), 7, 42-7.31 (5H, m), 7.22 (1H, t, J = 8.1 Hz), 6.63 (1H, dd, J = 8.1 Hz, J = 2.4 Hz), 4.47 (2H, s), 2.74 (3H, d, J = 4.5 Hz), 1.52 (6H, s); purity: 100%; MS (mass / charge): 468 (MH +). + + + 985 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 -pyrimidinediamine salt of p-toluenesulfonic acid ¹ H NMR (DMSO-d6): d 11.23 (1H, s), 9.91 (1H, s), 9.70 (1H, s), 8.29 (1H, d, J = 3.9 Hz), 8.06 (1H, m), 7.65-7.61 (1H, m), 7.55 (1H, d, J = 8.1 Hz), 7.48 (1H, d, J = 8.1 Hz), 7.33-7.18 (5H, m), 6.66 (1H, d, J = 7.5 Hz), 4.48 (2H, s), 2.75 (3H d, J = 3.6 Hz), 2.38 (3H, s), 1.53 (6H, s); purity: 100%; MS (mass / charge): 468 (MH +). + + + 986 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 -pyrimidinediamine hydrochloride salt ¹ H NMR (DMSO-d6): d 11.18 (1H, s), 9.54 (2H, s), 8.26 (1H, s), 8.05 (1H, s), 7.70-7.66 (1H, m), 7.47 (1H, d, J = 8.4 Hz), 7.40 (1H, s), 7.34 (1H, d, J = 9 Hz ), 7.20 (1H, t, J = 7.9 Hz), 6.61 (1H, d, J = 7.5 Hz), 4.47 (2H, s), 2.75 (3H, d , J = 3.3 Hz); 1.53 (6H, s); purity: 100%; MS (mass / charge): 468 (MH +). + + 987 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 -pyrimidinediamine bis-hydrochloride salt ¹ H NMR (DMSO-d6): d 11.18 (1H, s), 9.50 (2H, br s), 8.25 (1H, d, J = 3.3 Hz), 8.06 ( 1H, m), 7.74-7.67 (1H, m), 7.47 (1H, d, J = 8.4 Hz), 7.41 (1H, s), 7.37 (1H, d , J = 8.1 Hz), 7.20 (1H, t, J = 7.9 Hz), 6.59 (1H, d, J = 8.1 Hz), 4.47 (2H, s), 2.74 ((3H, d, J = 3.6 Hz), 1.53 (6H, s); purity: 100%; MS (mass / charge): 468 (MH +). + + 988 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 -pyrimidinediamine salt of nitric acid ¹ H NMR (DMSO-d6): d 11.19 (1H, s), 9.58 (1H, broad s), 9.52 (1H, s), 8.25 (1H, d, J = 3 6 Hz), 8.06 (1H, m), 7.70-7.66 (1H, m), 7.47 (1H, d, J = 8.7 Hz), 7.40 (1H, s ), 7.34 (1H, d, J = 8.1 Hz), 7.21 (1H, t, J = 8.1 Hz), 6.61 (1H, d, J = 7.5 Hz), 4.47 (2H, s), 2.74 (3H, d, J = 3.6 Hz), 1.53 (6H, s); purity: 100%; MS (mass / charge): 468 (MH +). + + 989 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 -pyrimidinediamine salt of bis-nitric acid ¹ H NMR (DMSO-d6): d 11.21 (1H, s), 9.64 (1H, broad s), 9.54 (1H, s), 8.26 (1H, d, J = 3 6 Hz), 8.07 (1H, m), 7.67 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.7 Hz), 7.39 ( 1H, s), 7.34 (1H, d, J = 7.8 Hz), 7.21 (1H, t, J = 8.2 Hz), 6.62 (1H, d, J = 8.4 Hz), 4.47 (2H, s), 2.74 (3H, d, J = 4.5 Hz), 1.53 (6H, s); purity: 95%; MS (mass / charge): 468 (MH +). + + 990 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 -pyrimidinediamine salt of methanesulfonic acid ¹ H NMR (DMSO-d6): d 11.24 (1H, s), 9.79 (1H, broad s), 9.63 (1H, s), 8.27 (1H, d, J = 3 , 9 Hz), 8.07 (1H, m), 7.64 (1H, d, J = 8.4 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.36 ( 1H, s), 7.32 (1H, d, J = 7.5 Hz), 7.22 (1H, t, J = 7.9 Hz), 6.64 (1H, d, J = 8.7 Hz), 4.47 (2H, s), 2.74 (3H, d, J = 4.5 Hz), 2.42 (3H, s), 1.53 (6H, s); purity: 100%; MS (mass / charge): 468 (MH +). + + 991 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 -pyrimidinediamine salt (1S) - (+) - camphorsulfonic acid ¹ H NMR (DMSO-d6): d 11.25 (1H, s), 9.72 (1H, broad s), 9.59 (1H, s), 8.27 (1H, d, J = 3 6 Hz), 8.07 (1H, m), 7.65 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.7 Hz), 7.37 ( 1H, s), 7.33 (1H, d, J = 8.7 Hz), 7.21 (1H, t, J = 8.1 Hz), 6.62 (1H, dd, J = 8.1 Hz, J = 2.4 Hz), 4.47 (2H, s), 2.96 (1H, d, J = 14.7 Hz), 2.78 (1H, m), 2.74 (3H, d, J = 4.5 Hz), 2.47 (1H, d, J = 14.7 Hz), 2.33 (2H, dt, J = 18.9 Hz, J = 3.75 Hz), 2 03 (1H, t, J = 4.5 Hz), 1.98-1.90 (1H, m), 1.98 (1H, d, J = 17.7 Hz), 1.53 (6H, c), 1.40 (1H, d, J = 11.1 Hz), 1.33 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 0.84 (3H, c) purity: 100%; MS (mass / charge): 468 (MH +). + + 992 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 -pyrimidinediamine salt of (+) - camphorsulfonic acid ¹ H NMR (DMSO-d6): d 11.21 (1H, s), 9.63 (1H, broad s), 9.54 (1H, s), 8.26 (1H, d, J = 3 6 Hz), 8.07 (1H, m), 7.67 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.7 Hz), 7.39 ( 1H, s), 7.34 (1H, d, J = 8.1 Hz), 7.21 (1H, t, J = 8.1 Hz), 6.61 (1H, dd, J = 8.1 Hz, J = 1.8 Hz), 4.47 (2H, s), 2.95 (1H, d, J = 14.4 Hz), 2.78 (1H, m), 2.74 (3H, d, J = 4.5 Hz), 2.45 (1H, d, J = 14.4 Hz), 2.36 (1H, t, J = 3.6 Hz), 2.30 (1H, t, J = 4 Hz), 2.03 (1H, t, J = 4.5 Hz), 2.00-1.94 (1H, m), 1.92 (1H, d, J = 18 Hz), 1 , 53 (6H, s), 1.39 (1H, d, J = 9.9 Hz), 1.33 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 0 84 (3H, s); purity: 100%; MS (mass / charge): 468 (MH +). + + - 993 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (1-methylindazol-6-yl) -2,4-pyrimidinediamine salt p-toluenesulfonic acid ¹ H NMR (DMSO-d6): d 10.78 (1H, s), 10.11 (1H, br s), 9.89 (1H, br s), 8.29 (1H, d, J = 4.8 Hz), 8.01 (1H, s), 7.95 (1H, s), 7.70 (1H, d, J = 8.7 Hz), 7.55 (2H, d, J = 8.1 Hz), 7.40 (1H, d, J = 8.4 Hz), 7.29-7.18 (4H, m), 6.95 (1H, d, J = 8.7 Hz ), 3.91 (3H, s), 2.38 (3H, s), 1.49 (6H, s); purity: 100%; MS (mass / charge): 434 (MH +); Anal Est. for C ₂₉ H ₂₈ FN ₇ O ₅ C: C, 57.51; H, 4.66; N, 16.19; C, 5.29; Found: C, 57.63; H, 4.65; N, 16.07; C, 4.95. + + + 994 N2- (3-Chloro-4-methoxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine salt of p-toluenesulfonic acid ¹ H NMR (DMSO-d6): d 10.73 (1H, s), 9.65 (1H, s), 9.41 (1H, s), 8.20 (1H, d, J = 4.2 Hz), 7.71 (1H, s), 7.54 (2H, d, J = 8.1 Hz), 7.43 (1H, s), 7.35 (1H, dd, J = 8.4 Hz, J = 2.4 Hz), 7.23-7.17 (3H, m), 7.00 (1H, d, J = 8.4 Hz), 3.76 (3H, s), 2, 38 (3H, s), 2.25 (3H, s), 1.50 (6H, s); purity: 100%; MS (mass / charge): 458 (MH +); Anal. for C ₂₉ H ₂₉ ClFN ₅ O ₆ C: C, 55.28; H, 4.64; N, 11.11; C, 5.09; Found: C, 55.37; H, 4.74; N, 11.11; C, 4.59. + + + + 995 N2- (3-Chloro-4-hydroxy-5-methylphenyl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.19 (1H, d, J = 1.5 Hz), 9.05 (1H, s), 8.64 (1H, s), 8.10 (1H, d, J = 3.9 Hz), 7.62 (1H, d, J = 2.7 Hz), 7.36 (1H, d, J = 1.8 Hz), 7.31 (1H, m) , 7.27 (1H, d, J = 2.7 Hz), 6.87 (1H, d, J = 8.4 Hz), 4.31 (4H, s), 2.22 (3H, s) ; LC / MS: purity: 96.98%; MS (mass / charge): 403 (MH +). + + + 996 N2- (3-Chloro-4-hydroxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.16 (1H, s), 9.27 (1H, s), 9.15 (1H, s), 8.67 (1H, s), 8.19 ( 1H, d, J = 3.6 Hz), 7.64 (2H, m), 7.42 (1H, d, J = 8.4 Hz), 7.29 (1H, d, J = 2.7 Hz), 2.22 (3H, s), 1.53 (6H, s); LC / MS: purity: 97.69%; MS (mass / charge): 444 (M +). + + - 997 N2- (3,5-Dimethyl-4-methoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.16 (1H, s), 9.23 (1H, s), 9.11 (1H, s), 8.19 (1H, d, J = 3.6 Hz), 7.69 (1H, d, J = 8.1 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.33 (2H, s), 3.68 (3H, s) 2.23 (6H, s); 1.53 (6H, s); LC / MS: purity: 99%; MS (mass / charge): 439 (MH +). + + - + 998 N2- (3,5-Dimethyl-4-methoxyphenyl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.06 (1H, s), 9.85 (1H, s), 8.25 (1H, d, J = 4.8 Hz), 7.33 (1H, d, J = 2.4 Hz), 7.24 (2H, s), 7.20 (1H, d, J = 2.7 Hz), 6.91 (1H, d, J = 8.4 Hz) 4.32 (4H, s); 3.71 (3H, s); 2.25 (6H, s); LC / MS: purity: 96.69%; MS (mass / charge): 397 (MH +). + + - 999 N2- (3-Chloro-4-methoxy-5-methylphenyl) -N4- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.88 (2H, br s), 8.26 (1H, d, J = 4.2 Hz), 7.64 (1H, s), 7.41 ( 1H, s), 7.30-7.28 (1H, m), 7.25-7.20 (1H, m), 6.92 (1H, d, J = 10.2 Hz), 4.32 (4H, s), 3.79 (3H, s), 2.29 (3H, s); LC / MS: purity: 94.81%; MS (mass / charge): 417 (MH +). + + + 1000 N4- (3,4-Dihydro-2,2-dimethyl-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.15 (1H, s), 9.08 (1H, s), 8.09 (1H, d, J = 3.6 Hz), 8.04 (1H, d, J = 4.5 Hz), 7.45-7.42 (2H, m), 7.17 (1H, t, J = 8.4 Hz), 7.01 (1H, d, J = 2 4 Hz), 6.95 (1H, d, J = 8.4 Hz), 6.65 (1H, d, J = 8.7 Hz), 6.53 (1H, d, J = 9.3 Hz), 5.88 (1H, s), 4.44 (2H, s), 3.07 (2H, s), 2.74 (3H, d, J = 4.2 Hz), 1.34 ( 6H, c); purity: 96.6%; MS (mass / charge): 453 (M). + 1001 N2- (3-Chloro-4-methoxy-5-methylphenyl) -N4- (3,4-dihydro-2,2-dimethyl-4H-benz [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.59 (1H, br s), 8.17 (1H, d, J = 4.2 Hz), 7.65 (1H, s), 7.46 ( 1H, s), 6.94-6.86 (2H, m), 6.68 (1H, d, J = 8.7 Hz), 3.77 (3H, s), 3.08 (2H, s ), 2.27 (3H, s), 1.34 (6H, s); purity: 94.5%; MS (mass / charge): 444 (M). + 1002 N4- (3,4-Dihydro-2,2-dimethyl-4H-benz [1,4] oxazin-6-yl) -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 9.06 (2H, s), 8.09 (1H, d, J = 3.6 Hz), 7.03 (1H, dd, J = 6.9 Hz, J = 1.8 Hz), 6.95 (1H, dd, J = 8.1 Hz, J = 2.7 Hz), 6.63 (1H, d, J = 8.7 Hz), 6.11 (1H, s), 5.82 (1H, s), 3.71 (6H, s), 3.07 (2H, s), 1.34 (6H, s); purity 95.9%; MS ((mass / charge): 426 (M). + 1003 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3-isopropylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.17 (1H, s), 9.27 (1H, s), 9.24 (1H, s), 8.21 (1H, d, J = 3.6 Hz), 7.67 (1H, m), 7.61 (1H, d, J = 9 Hz), 7.52 (1H, s), 7.44 (1H, d, J = 8.7 Hz) , 7.19 (1H, t, J = 7.65 Hz), 6.85 (1H, d, J = 7.8 Hz), 2.82 (1H, m), 1.53 (6H, s) 1.25 (6H, d, J = 6.9 Hz); purity 97.7%; MS (mass / charge): 423 (MH +). + + 1004 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (2-methylphenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 11.23 (1H, s), 10.12 (1H, s), 9.39 (1H, s), 8.27 (1H, d, J = 4.8 Hz), 7.52 (1H, d, J = 6.9 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.34-7.16 (4H, m), 2, 30 (3H, s); 1.50 (6H, s); purity 97.9%; MS (mass / charge): 395 (MH +). + - 1005 2-Chloro-5-fluoro-N4-methyl-N4- (3-oxo-2,2,4-trimethyl-5-pyrid [1,4] oxazin-6-yl) -4-pyrimidinamine 1 H NMR (DMSO-d6): d 8.43 (1H, d, J = 5.1 Hz), 7.57 (1H, d, J = 8.4 Hz), 7.15 (1H, dd, J = 8.1 Hz, J = 0.9 Hz), 3.59 (3H, s), 3.30 (3H, s), 1.55 (6H, s); purity 97.2%; MS (mass / charge): 352 (MH +). + - 1006 2-Chloro-5-fluoro-N4- (3-oxo-2,2,4-trimethyl-5-pyrid [1,4] oxazin-6-yl) -4-pyrimidinamine 1 H NMR (DMSO-d6): d 10.35 (1H, s), 8.47 (1H, d, J = 3.3 Hz), 7.62 (1H, d, J = 8.7 Hz), 7.58 (1H, d, J = 8.4 Hz), 3.45 (3H, s), 1.55 (6H, s); purity 96%; MS (mass / charge): 338 (MH +). - - 1007 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4- pyrimidinediamine 1 H NMR (DMSO-d6): d 11.14 (1H, s), 9.24 (1H, s), 9.19 (1H, s), 8.21 (1H, d, J = 3.3 Hz ), 7.76 (1H, d, J = 8.7 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.12 (2H, s), 3.75 (6H, s ), 3.69 (3H, s), 1.52 (6H, s); purity 96%; MS (mass / charge): 471 (MH +) + + - + 1008 N2- (3-Chloro-4-ethoxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 10.67 (1H, s), 9.40 (1H, s), 9.20 (1H, s), 8.16 (1H, d, J = 3.9 Hz), 7.74 (1H, d, J = 3 Hz), 7.45 (1H, d, J = 2.7 Hz), 7.36 (1H, dd, J = 8.7 Hz, J = 2.4 Hz), 7.25 (1H, d, J = 2.4 Hz), 6.98 (1H, d, J = 8.7 Hz), 3.94 (2H, q, J = 7 , 2 Hz), 2.24 (3H, s), 1.50 (6H, s), 1.41 (3H, t, J = 6.9 Hz); purity 97%; MS (mass / charge): 472 (MH +). + + + + 1009 N2- (3-Chloro-4-methoxy-5-methylphenyl) -5-fluoro-N4- (3-oxo-2,2,4-trimethyl-5-pyrid [1,4] oxazin-6-yl) - 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.62 (1H, s), 9.41 (1H, s), 8.27 (1H, s), 7.80 (1H, s), 7.73 (1H d, J = 8.7 Hz), 7.48 (1H, d, J = 8.7 Hz), 7.43 (1H, s), 3.78 (3H, d, J = 2.4 Hz ), 2.92 (3H, s), 1.55 (6H, d, J = 2.4 Hz); purity 97%; MS (mass / charge): 473 (MH +). + + - 1010 N2- (3-Chloro-4-ethoxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.18 (1H, s), 9.41 (1H, s), 9.38 (1H, s), 8.23 (1H, d, J = 3.6 Hz ), 7.74 (1H, d, J = 2.7 Hz), 7.61 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.1 Hz), 7.41 (1H, d, J = 2.1 Hz), 3.95 (2H, q, J = 7.2 Hz), 2.27 (3H, s), 1.53 (6H, s) 1.42 (3H, t, J = 6.9 Hz); purity 99%; MS (mass / charge): 473 (MH +). + - 1011 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-2-yl) phenyl] -2,4 pyrimidinediamine 1 H NMR (DMSO-d6): d 10.74 (1H, s), 9.56 (1H, s), 9.49 (1H, s), 8.21-8.19 (2H, m), 7 89 (2H, d, J = 9 Hz), 7.84 (2H, d, J = 9 Hz), 7.37 (1H, d, J = 0.6 Hz), 7.33 (1H, dd , J = 8.1 Hz, J = 2.4 Hz), 7.26 (1H, d, J = 2.7 Hz), 7.02 (1H, d, J = 8.7 Hz), 1, 53 (6H, s); purity 96%; MS (mass / charge): 447 (MH +). + + - + 1012 5-Fluoro-N2- [3- (oxazol-2-yl) phenyl] -N4- [3-oxo-2,2,4-trimethyl-5-pyrid [1,4] oxazin-6-yl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.76 (1H, s), 9.74 (1H, s), 8.41 (1H, s), 8.32 (1H, d, J = 3.6 Hz ), 8.25 (1H, s), 7.89-7.83 (2H, m), 7.64 (1H, d, J = 7.8 Hz), 7.48 (1H, d, J = 7.8 Hz), 7.44 (1H, s), 7.36 (1H, d, J = 7.2 Hz), 3.42 (3H, s), 1.54 (6H, s); purity 96%. + + - 1013 5-Fluoro-N2- [4- (oxazol-2-yl) phenyl] -N4- [3-oxo-2,2,4-trimethyl-5-pyrid [1,4] oxazin-6-yl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.76 (1H, s), 9.73 (1H, s), 8.31 (1H, d, J = 3.6 Hz), 8.21 (1H, d , J = 0.9 Hz), 7.92 (2H, d, J = 9.3 Hz), 7.88 (2H, d, J = 9.6 Hz), 7.76 (1H, d, J = 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.38 (1H, d, J = 0.9 Hz), 3.44 (3H, s), 1, 57 (6H, s); purity 96%; MS (mass / charge): 462 (MH +). + - 1014 N2- [3-Chloro-4-ethoxycarbonylmethyleneoxy-5-methylphenyl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.69 (1H, s), 9.43 (1H, s), 9.27 (1H, s), 8.17 (1H, d, J = 3.6 Hz ), 7.76 (1H, d, J = 2.7 Hz), 7.46 (1H, d, J = 2.4 Hz), 7.36 (1H, dd, J = 9 Hz, J = 2 , 7 Hz), 7.24 (1H, d, J = 2.4 Hz), 6.99 (1H, d, J = 8.4 Hz), 4.58 (2H, s), 4.28 ( 2H, q, J = 7.2 Hz), 2.27 (3H, s), 1.50 (6H, s), 1.33 (3H, t, J = 6.9 Hz); purity 95.6%; MS (mass / charge): 530 (MH +). + + + 1015 5-Fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- [3-oxo-2,2,4-trimethyl-5-pyrid [1,4] oxazin-6-yl] -2,4 pyrimidinediamine 1 H NMR (DMSO-d6): d 9.58 (1H, s), 9.42 (1H, s), 8.25 (1H, d, J = 3.3 Hz), 8.06 (1H, broad) .s), 7.88 (1H, d, J = 8.4 Hz), 7.49 (2H, m), 7.36 (1H, d, J = 7.5 Hz), 7.20 (1H , t, J = 8.1 Hz), 6.56 (1H, dd, J = 8.4 Hz, J = 2.4 Hz), 4.46 (2H, s), 3.44 (3H, s ), 2.74 (3H, d, J = 4.8 Hz), 1.55 (6H, s); purity 97.2%; MS (mass / charge): 482 (MH +). + + - 1016 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4 pyrimidinediamine 1 H NMR (DMSO-d6): d 10.67 (1H, s), 9.53 (1H, s), 9.38 (1H, s), 8.47 (1H, s), 8.20 (1H d, J = 3.6 Hz), 8.04 (1H, s), 7.78 (1H, m), 7.58 (1H, s), 7.41 (1H, dd, J = 8, 7 Hz, J = 2.4 Hz), 7.35 (2H, d, J = 4.8 Hz), 7.29 (1H, d, J = 2.4 Hz), 6.89 (1H, d , J = 8.7 Hz), 1.49 (6H, s); purity 96%; MS (mass / charge): 447 (MH +). + + - + 1017 5-Fluoro-N2- [3- (oxazol-5-yl) phenyl] -N4- [3-oxo-2,2,4-trimethyl-5-pyrid [1,4] oxazin-6-yl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.65 (1H, s), 9.57 (1H, s), 8.47 (1H, s), 8.29 (1H, d, J = 3.6 Hz ), 8.12 (1H, s), 8.84 (1H, d, J = 8.1 Hz), 7.74 (1H, m), 7.62 (1H, s), 7.43-7 32 (3H, m); 3.42 (3H, s); 1.54 (6H, s); purity 96.4%; MS (mass / charge): 462 (MH +). + + - 1018 N2- [3-Chloro-4-cyclopentyloxy-5-methylphenyl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.68 (1H, s), 9.41 (1H, s), 9.20 (1H, s), 8.16 (1H, d, J = 3.6 Hz ), 7.73 (1H, d, J = 2.7 Hz), 7.45 (1H, d, J = 2.4 Hz), 7.36 (1H, dd, J = 9 Hz, J = 2 , 7 Hz), 7.24 (1H, d, J = 2.4 Hz), 6.98 (1H, d, J = 8.7 Hz), 4.65 (1H, m), 2.23 ( 3H, s), 2.0-1.6 (8H, m), 1.50 (6H, s); purity 98.3%; MS (mass / charge): 512 (MH +). + + - 1019 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N4-methyl-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.72 (1H, s), 9.65 (1H, s), 8.71 (1H, s), 8.27 (1H, t, J = 1.2 Hz ), 8.09 (1H, dd, J = 5.4 Hz, J = 0.9 Hz), 7.82 (1H, dd, J = 8.1 Hz, J = 0.9 Hz), 7, 60 (1H, d, J = 8.4 Hz), 7.48-7.43 (2H, m), 7.05-6.97 (2H, m), 6.87 (1H, d, J = 2.1 Hz), 3.56 (3H, s), 1.51 (6H, s); purity 97.3%; MS (mass / charge): 461 (MH +). + + - 1020 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4 pyrimidinediamine 1 H NMR (DMSO-d6): d 10.75 (1H, s), 9.56 (1H, s), 9.49 (1H, s), 8.43 (1H, s), 8.20 (1H d, J = 3.9 Hz), 7.83 (2H, d, J = 8.7 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.53 (1H, s ), 7.33-7.28 (2H, m), 7.02 (1H, d, J = 8.4 Hz), 1.52 (6H, s); purity 97.4%; MS (mass / charge): 447 (MH +). + + - 1021 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N4-methyl-N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.72 (1H, s), 9.72 (1H, s), 8.20 (1H, d, J = 0.9 Hz), 8.11 (1H, d , J = 5.7 Hz), 7.89 (4H, s), 7.38 (1H, d, J = 0.9 Hz), 7.07-6.97 (2H, m), 6.87 (1H, d, J = 2.7 Hz), 3.54 (3H, s), 1.52 (6H, s); purity 97.1%; MS (mass / charge): 461 (MH +). + + + 1022 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N4-methyl-N2- [3- (N-methylamine) carbonylmethyleneoxyphenyl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.70 (1H, s), 9.38 (1H, s), 8.05 (2H, d, J = 5.4 Hz), 7.55 (1H, m ), 7.37 (1H, d, J = 8.4 Hz), 7.20 (1H, t, J = 7.8 Hz), 7.03 (1H, d, J = 8.4 Hz), 6.97 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 6.85 (1H, d, J = 2.1 Hz), 6.57 (1H, dd, J = 7 , 8 Hz, J = 2.1 Hz), 4.49 (2H, s), 3.51 (3H, s), 2.74 (3H, d, J = 4.5 Hz), 1.50 ( 6H, c); purity 96.8%; MS (mass / charge): 481 (MH +). + + - 1023 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N4-methyl-N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 10.71 (1H, s), 9.55 (1H, s), 8.50 (1H, s), 8.37 (1H, s), 8.08 (1H d, J = 5.7 Hz), 7.68 (1H, d, J = 8.1 Hz), 7.66 (1H, s), 7.43-7.34 (2H, m), 7 05-6.97 (2H, m); 6.87 (1H, d, J = 2.4 Hz); 3.55 (3H, s); 1.51 (6H, s); purity 95.6%; MS (mass / charge): 461 (MH +). + + - 1024 5-Fluoro-N4-methyl-N2- [4- (oxazol-2-yl) phenyl] -N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.71 (1H, s), 8.20 (1H, d, J = 0.9 Hz), 8.10 (1H, d, J = 6 Hz), 7, 90 (4H, s), 7.38 (1H, d, J = 0.6 Hz), 7.27 (1H, s), 7.09 (2H, s), 3.59 (3H, s), 3.34 (3H, s); 1.52 (6H, s); purity 97.4%; MS (mass / charge): 475 (MH +). + + 1025 5-Fluoro-N4-methyl-N2- [3- (oxazol-2-yl) phenyl] -N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.65 (1H, s), 8.72 (1H, d, J = 1.8 Hz), 8.27 (1H, d, J = 0.6 Hz), 8.08 (1H, d, J = 6 Hz), 7.83-7.79 (1H, m), 7.60 (1H, d, J = 7.2 Hz), 7.47 (1H, d , J = 7.8 Hz), 7.43 (1H, d, J = 0.9 Hz), 7.28 (1H, s), 7.07 (2H, s), 3.62 (3H, s ), 3.35 (3H, s), 1.51 (6H, s); purity 97.3%; MS (mass / charge): 475 (MH +). + + 1026 5-Fluoro-N4-methyl-N2- [4- (oxazol-5-yl) phenyl] -N4- (2,2,4-trimethyl-3-oxo-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.60 (1H, s), 8.44 (1H, s), 8.07 (1H, d, J = 6 Hz), 7.88 (2H, d, J = 8.4 Hz), 7.65 (2H, d, J = 8.7 Hz), 7.57 (1H, s), 7.27 (1H, s), 7.08 (2H, s), 3.58 (3H, s), 3.34 (3H, s), 1.52 (6H, s); purity 98.61%; MS (mass / charge): 475 (MH +). + - 1027 N2- (3-Chloro-4-cyclopentyloxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.18 (1H, s), 9.38 (1H, s), 9.35 (1H, s), 8.22 (1H, d, J = 3.6 Hz ), 7.74 (1H, d, J = 2.4 Hz), 7.61 (1H, d, J = 8.7 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 2.7 Hz), 4.67 (1H, m), 2.26 (3H, s), 2.00-1.60 (8H, m), 1.53 (6H, s); purity 94.95%; MS (mass / charge): 513 (MH +). + - 1028 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 11.18 (1H, s), 9.60 (1H, s), 9.37 (1H, s), 8.38 (1H, s), 8.27 (2H , m), 7.93 (1H, d, J = 8.4 Hz), 7.71 (1H, d, J = 8.7 Hz), 7.60 (1H, d, J = 8.1 Hz ), 7.44-7.34 (3H, m), 1.53 (6H, s); purity 95%; MS (mass / charge): 448 (MH +). + + - 1029 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-4-yl) phenyl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.17 (1H, s), 9.45 (1H, s), 9.31 (1H, s), 8.54 (2H, dd, J = 9.9 Hz , J = 0.9 Hz), 8.24 (1H, d, J = 3.6 Hz), 8.10 (1H, s), 7.78-7.72 (2H, m), 7.42 -7.29 (3H, m); 1.52 (6H, s); purity 96.4%; MS (mass / charge): 448 (MH +). + + - 1030 5-Fluoro-N4-methyl-N2- [3- (oxazol-4-yl) phenyl] -N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -2 4-pyrimidinediamine 1H NMR (DMSO-d6): d 9.47 (1H, s), 8.59 (1H, s), 8.51 (1H, s), 8.41 (1H, s), 8.05 (1H d, J = 5.4 Hz), 7.66 (1H, d, J = 7.5 Hz), 7.41-7.32 (2H, m), 7.27 (1H, s), 7 07 (2H, s), 3.60 (3H, s), 3.35 (3H, s), 1.51 (6H, s); purity 97.4%; MS (mass / charge): 475 (MH +). + + 1031 N2- (3,5-Dimethyl-4-methoxyphenyl) -5-fluoro-N4-methyl-N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.11 (1H, s), 8.00 (1H, J = 5.7 Hz), 7.42 (2H, s), 7.24 (1H, s), 7.05 (2H, s), 3.68 (3H, s), 3.55 (3H, s), 3.33 (3H, s), 2.25 (6H, s), 1.51 (6H , from); purity 97.84%; MS (mass / charge): 466 (M). + - 1032 N2- (3-Chloro-4-cyclopentyloxy-5-methylphenyl) -5-fluoro-N4-methyl-N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) - 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.49 (1H, s), 8.07 (1H, dd, J = 6 Hz, J = 1.5 Hz), 7.81 (1H, d, J = 2 , 7 Hz), 7.47 (1H, d, J = 2.4 Hz), 7.27 (1H, s), 7.07 (2H, s), 4.69 (1H, m), 3, 61 (3H, s), 3.33 (3H, s), 2.29 (3H, s), 2.0-1.6 (8H, m), 1.51 (6H, s); purity 96.15%; MS (mass / charge): 540 (M). - - 1033 N2- (3,5-Dimethyl-4-methoxyphenyl) -5-fluoro-N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.49 (1H, d, J = 0.9 Hz), 9.15 (1H, s), 8.21 (1H, d, J = 3.6 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.45 (1H, d, J = 8.4 Hz), 7.35 (2H, s), 3.69 (3H, s), 3.43 (3H, s); 2.23 (6H, s); 1.54 (6H, s); purity 98.82%; MS (mass / charge): 453 (M). + + + 1034 N2- (3-Chloro-4-cyclopentyloxy-5-methylphenyl) -5-fluoro-N4- (3-oxo-2,2,4-trimethylbenz [1,4] oxazin-6-yl) -2,4- pyrimidinediamine 1 H NMR (DMSO-d6): d 9.63 (1H, s), 9.40 (1H, s), 8.26 (1H, d, J = 3.6 Hz), 7.78 (1H, d , J = 2.4 Hz), 7.72 (1H, d, J = 8.4 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 2.4 Hz), 4.68 (1H, m), 3.41 (3H, s), 2.26 (3H, s), 1.95-1.60 (8H, m), 1.54 (6H, s); purity 96%; MS (mass / charge): 527 (MH +). + - 1035 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-2-yl) phenyl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.23 (1H, s), 9.70 (1H, s), 9.53 (1H, s), 8.27 (1H, d, J = 3.6 Hz ), 8.20 (1H, d, J = 0.9 Hz), 7.90 (2H, d, J = 9.3 Hz), 8.86 (2H, d, J = 9.5 Hz), 7.55 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.37 (1H, J = 0.9 Hz), 1.56 ( 6H, c); purity 96%; MS (mass / charge): 448 (MH +). - 1036 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-4-yl) phenyl] -2,4 pyrimidinediamine 1 H NMR (DMSO-d6): d 10.65 (1H, s), 9.41 (1H, d, J = 1.2 Hz), 9.32 (1H, s), 8.50 (1H, d , J = 0.6 Hz), 8.47 (1H, s), 8.17 (1H, d, J = 3.9 Hz), 8.08 (1H, s), 7.78 (1H, d , J = 8.7 Hz), 7.43 (1H, dd, J = 8.7 Hz, J = 2.4 Hz), 7.39-7.27 (3H, m), 6.88 (1H d, J = 8.7 Hz), 1.49 (6H, s); purity 98.9%; MS (mass / charge): 447 (MH +). + + + 1037 N2- [3-Chloro-5-methyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.19 (1H, s), 9.43 (2H, s), 8.24 (1H, d, J = 7.8 Hz), 8.18 (1H, d , J = 4.5 Hz), 7.78 (1H, d, J = 2.4 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 2.4 Hz), 4.32 (2H, s), 2.79 (3H, d, J = 4.8 Hz), 2, 29 (3H, s); 1.53 (6H, s); purity 97.6%; MS (mass / charge): 516 (MH +). + - 1038 N2- (3,5-Dimethyl-4-ethoxycarbonylmethyleneoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.18 (1H, s), 9.26 (1H, s), 9.16 (1H, s), 8.19 (1H, d, J = 3.3 Hz ), 7.68 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.33 (2H, s), 4.49 (2H, s ), 4.28 (2H, q, J = 7.2 Hz), 2.23 (6H, s), 1.52 (6H, s), 1.33 (3H, t, J = 7.2 Hz); purity 97.9%; MS (mass / charge): 511 (MH +). + - 1039 N2- (3-Chloro-4-isopropoxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.72 (1H, s), 9.68 (1H, s), 9.44 (1H, s), 8.20 (1H, d, J = 3.6 Hz ), 7.70 (1H, d, J = 2.1 Hz), 7.42 (1H, d, J = 2.4 Hz), 7.35 (1H, dd, J = 8.7 Hz, J = 2.4 Hz), 7.24 (1H, d, J = 2.4 Hz), 6.98 (1H, d, J = 8.4 Hz), 4.36 (1H, quint, J = 6 , 0 Hz), 2.23 (3H, s), 1.50 (6H, s), 1.32 (6H, d, J = 6.3 Hz); purity 96.9%; MS (mass / charge): 486 (MH +). + + 1040 N2- (3-Chloro-4-isopropoxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.17 (1H, s), 9.37 (1H, s), 9.35 (1H, s), 8.22 (1H, d, J = 3.0 Hz ), 7.74 (1H, d, J = 2.7 Hz), 7.61 (1H, d, J = 8.7 Hz), 7.45 (1H, d, J = 8.7 Hz), 7.41 (1H, d, J = 2.7 Hz), 4.36 (1H, quint, J = 6.0 Hz), 2.25 (3H, s), 1.52 (6H, s), 1.33 (6H, d, J = 6.3 Hz); purity 97.3%; MS (mass / charge): 487 (MH +). - + 1041 N2- [3,5-Dimethyl-4- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5 -fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.18 (1H, s), 9.28 (1H, s), 9.18 (1H, s), 8.19 (2H, d, J = 3.6 Hz ), 7.68 (1H, d, J = 8.4 Hz), 7.45 (1H, d, J = 8.7 Hz), 7.34 (2H, s), 4.22 (2H, s ), 2.79 (3H, d, J = 4.5 Hz), 2.23 (6H, s), 1.52 (6H, s); purity 98%; MS (mass / charge): 496 (MH +). + + + 1042 N2- (3-Chloro-4-ethoxycarbonylmethyleneoxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.19 (1H, s), 9.42 (2H, s), 8.23 (1H, d, J = 3.6 Hz), 7.76 (1H, d , J = 2.4 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.42 (1H, d, J = 2.1 Hz), 4.60 (2H, s), 4.27 (2H, q, J = 7.2 Hz), 2.29 (3H, s), 1.52 (6H, s) 1.33 (3H, t, J = 7.2 Hz); purity 98.4%; MS (mass / charge): 531 (MH +). - - 1043 N2- [3-Chloro-4- [N- (2,3-dihydroxypropyl) amino] carbonylmethyleneoxy-5-methylphenyl] -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4 ] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.17 (1H, s), 9.42 (1H, s), 9.40 (1H, s), 8.23 (1H, d, J = 3.6 Hz ), 7.98 (1H, t, J = 5.7 Hz), 7.78 (1H, d, J = 2.7 Hz), 7.61 (1H, d, J = 8.7 Hz), 7.47 (1H, d, J = 8.4 Hz), 7.34 (1H, d, J = 1.8 Hz), 4.94 (1H, broad s), 4.67 (1H, broad) c), 4.36 (2H, s), 3.67 (1H, t, J = 6.3 Hz), 3.26-3.17 (1H, m), 2.3 (3H, s) 1.53 (6H, s); purity 97.3%; MS (mass / charge): 576 (MH +). + + - 1044 N2- [3,5-Dimethyl-4- (N-cyclopentylamino) carbonylmethyleneoxyphenyl] -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5 -fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.18 (1H, s), 9.27 (1H, s), 9.17 (1H, s), 8.19 (1H, d, J = 3.6 Hz ), 8.03 (1H, d, J = 7.8 Hz), 7.67 (1H, d, J = 8.7 Hz), 7.45 (1H, d, J = 8.7 Hz), 7.34 (2H, s), 4.23 (1H, m), 4.21 (2H, s), 2.23 (6H, s), 1.91 (2H, m), 1.76 (2H m) 1.60 (4H, m); 1.52 (6H, s); purity 98%; MS (mass / charge): 550 (MH +). - - - 1045 N4- (2,2-Difluoro-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine hydrochloride salt 1 H NMR (DMSO-d6): d 12.12 (1H, s), 9.95 (1H, s), 9.58 (1H, s), 8.26 (1H, d, J = 3.6 Hz ), 8.06 (1H, d, J = 4.2 Hz), 7.65 (1H, d, J = 2.1 Hz), 7.61 (1H, d, J = 2.4 Hz), 7.41 (1H, s), 7.35 (1H, d, J = 8.7 Hz), 7.30 (1H, d, J = 9.0 Hz), 7.21 (1H, t, J = 7.8 Hz), 6.61 (1H, d, J = 8.1 Hz), 4.43 (2H, s), 2.73 (3H, d, J = 4.5 Hz); 100% purity; MS (mass / charge): 475 (MH +). + + - 1046 N4- (2,2-Difluoro-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine methanesulfonic acid salt 1 H NMR (DMSO-d6): d 12.05 (1H, s), 9.81 (1H, s), 9.38 (1H, s), 8.24 (1H, d, J = 3.6 Hz ), 8.04 (1H, d, J = 4.2 Hz), 7.66 (1H, dd, J = 10.5 Hz, J = 1.5 Hz), 7.51 (1H, d, J = 1.8 Hz), 7.43 (1H, s), 7.36-7.29 (2H, m), 7.19 (1H, t, J = 7.8 Hz), 6.59 (1H d, J = 10.5 Hz), 4.42 (2H, s), 2.73 (3H, d, J = 4.5 Hz), 2.39 (3H, d, J = 0.6 Hz ); 100% purity; MS (mass / charge): 475 (MH +). + + - 1047 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (indazol-6-yl) -2,4-pyrimidinediamine salt of methanesulfonic acid 1 H NMR (DMSO-d6): d 10.74 (1H, s), 10.11 (1H, s), 9.82 (1H, s), 8.26 (1H, d, J = 4.5 Hz ), 8.05 (1H, s), 7.88 (1H, s), 7.71 (1H, d, J = 8.4 Hz), 7.45 (1H, dd, J = 9.0 Hz , J = 2.7 Hz), 7.31 (1H, dd, J = 8.7 Hz, J = 1.5 Hz), 7.24 (1H, d, J = 2.4 Hz), 6, 97 (1H, d, J = 8.7 Hz), 2.43 (3H, s), 1.48 (6H, s); 100% purity; MS (mass / charge): 420 (MH +). - + - 1048 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (indazol-6-yl) -2,4-pyrimidinediamine hydrochloride salt 1 H NMR (DMSO-d6): d 10.73 (1H, s), 9.282 (1H, s), 9.60 (1H, s), 8.24 (1H, d, J = 4.2 Hz), 8.02 (2H, s), 7.67 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 8.7 Hz), 7.36-7.33 (2H , m), 6.98 (1H, d, J = 8.7 Hz), 1.49 (6H, s); purity 99.3%; MS (mass / charge): 420 (MH +). + + - 1049 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- (1-ethylindazol-6-yl) -5-fluoro-2,4- pyrimidinediamine 1 H NMR (DMSO-d6): d 11.21 (1H, s), 9.56 (1H, s), 9.40 (1H, s), 8.29 (1H, d, J = 3.6 Hz ), 8.11 (1H, s), 7.96 (1H, s), 7.71 (1H, d, J = 7.2 Hz), 7.64 (1H, d, J = 9.0 Hz ), 7.46 (1H, d, J = 8.4 Hz), 7.36 (1H, dd, J = 8.7 Hz, J = 1.5 Hz), 4.25 (2H, q, J = 7.2 Hz), 1.53 (6H, s), 1.41 (3H, t, J = 7.2 Hz); 100% purity; MS (mass / charge): 449 (MH +). + + - 1050 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- (1-isopropylindazol-6-yl) -5-fluoro-2,4- pyrimidinediamine 1 H NMR (DMSO-d6): d 11.22 (1H, s), 9.56 (1H, s), 9.41 (1H, s), 8.29 (1H, d, J = 3.3 Hz ), 8.15 (1H, s), 7.96 (1H, s), 7.70 (1H, d, J = 8.4 Hz), 7.63 (1H, d, J = 8.4 Hz ), 7.46 (1H, d, J = 8.7 Hz), 7.35 (1H, dd, J = 8.7 Hz, J = 1.2 Hz), 4.63 (1H, quint, J = 6.6 Hz), 1.53 (6H, s), 1.49 (6H, d, J = 6.3 Hz); purity 97.67%; MS (mass / charge): 463 (MH +). + + - 1051 2-Chloro-N4- (3,4-dihydro-2,2-dimethyl-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-4-pyrimidinamine 1 H NMR (DMSO-d6): d 9.84 (1H, s), 8.35 (1H, d, J = 3.3 Hz), 7.09 (1H, d, J = 8.1 Hz), 7.06 (1H, d, J = 8.1 Hz), 6.79 (1H, s), 3.23 (2H, s), 1.36 (6H, s); purity 96.73%; MS (mass / charge): 310 (MH +). - - 1052 N4- (3,4-Dihydro-2,2-dimethyl-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (1-methylindazol-6-yl) -2, 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.50 (1H, s), 8.94 (1H, s), 8.21 (1H, d, J = 3.6 Hz), 8.17 (1H, s ), 7.93 (1H, s), 7.63 (1H, d, J = 8.7 Hz), 7.35 (1H, d, J = 1.5 Hz), 7.30 (1H, d , J = 7.8 Hz), 7.01 (1H, d, J = 8.4 Hz), 6.72 (1H, s), 3.92 (3H, s), 3.24 (2H, d , J = 2.4 Hz), 1.37 (6H, s); purity 98.07%; MS (mass / charge): 421 (M2H +). + + + 1053 N4- (3,4-Dihydro-2,2-dimethyl-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.29 (1H, s), 8.83 (1H, s), 8.15 (1H, d, J = 3.6 Hz), 8.03 (1H, m ), 7.47 (1H, t, J = 2.1 Hz), 7.40 (1H, d, J = 7.5 Hz), 7.34 (1H, d, J = 6.9 Hz), 7.20 (1H, t, J = 8.4 Hz), 7.02 (1H, d, J = 8.1 Hz), 6.67 (1H, s), 6.56 (1H, dd, J = 7.8 Hz, J = 2.1 Hz), 4.46 (2H, s), 3.23 (2H, d, J = 2.1 Hz), 2.75 (3H, d, J = 4 5 Hz), 1.36 (6H, s); purity 96.2%; MS (mass / charge): 454 (MH +). + + - 1054 N2- [3-Chloro-4- (N-methylamino) carbonylphenyl] -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.19 (1H, s), 9.70 (1H, s), 9.52 (1H, s), 8.28 (1H, d, J = 2.4 Hz ), 8.21 (1H, d, J = 5.1 Hz), 7.97 (1H, s), 7.62-7.57 (2H, m), 7.50 (1H, d, J = 9.0 Hz), 7.34 (1H, d, J = 8.4 Hz), 2.81 (3H, d, J = 3.6 Hz), 1.53 (6H, s); purity 99.5%; MS (mass / charge): 472 (MH +). + + - 1055 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- (3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 11.12 (1H, s), 9.25 (1H, s), 9.12 (1H, s), 8.17 (1H, d, J = 3.3 Hz ), 7.64 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 2.4 Hz), 7.10 (1H, dd, J = 9.0 Hz, J = 2.4 Hz), 6.76 (1H, d, J = 9.0 Hz), 4.26 (4H, m), 1, 53 (6H, s); purity 96.9%; MS (mass / charge): 439 (MH +). + + - 1056 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1-methylindazol-6-yl] -2,4- pyrimidinediamine hydrochloride salt 1 H NMR (DMSO-d6): d 11.23 (1H, s), 9.88 (1H, s), 9.28 (1H, s), 8.33 (1H, d, J = 3.6 Hz ), 8.02 (1H, s), 7.98 (1H, s), 7.66 (2H, t, J = 8.4 Hz). 7.45 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 8.4 Hz, J = 1.5 Hz), 3.93 (3H, s), 1, 53 (6H, s); 100% purity; MS (mass / charge): 435 (MH +). + + - 1057 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1-methylindazol-6-yl] -2,4- pyrimidinediamine salt of p-toluenesulfonic acid 1 H NMR (DMSO-d6): d 11.23 (1H, s), 9.81 (2H, s), 8.32 (1H, d, J = 3.9 Hz), 8.02 (1H, s ), 7.98 (1H, s), 7.67 (2H, t, J = 8.7 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.44 (1H, d , J = 8.4 Hz), 7.31 (1H, dd, J = 8.4 Hz, J = 0.9 Hz), 7.19 (2H, d, J = 8.4 Hz), 3, 94 (3H, s), 2.38 (3H, s), 1.52 (6H, s); purity 98.8%; MS (mass / charge): 435 (MH +). + + - 1058 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [1-methylindazol-6-yl] -2,4- pyrimidinediamine salt of methanesulfonic acid 1 H NMR (DMSO-d6): d 11.22 (1H, s), 9.76 (1H, s), 9.72 (1H, s), 8.31 (1H, d, J = 3.3 Hz ), 8.04 (1H, s), 7.97 (1H, s), 7.67 (2H, d, J = 8.4 Hz), 7.45 (1H, d, J = 8.1 Hz ), 3.32 (1H, d, J = 8.4 Hz), 3.93 (3H, s), 2.41 (3H, s), 1.53 (6H, s); purity 99%; MS (mass / charge): 435 (MH +). + + - 1059 N2- (3,5-Dimethyl-4-methoxyphenyl) -5-fluoro-N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.13 (s, 6H), 3.58 (s, 3H), 4.62 (s, 2H), 7.22 (s, 2H), 7.33 (d , J = 9.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 3.6 Hz, 1H), 9.01 (s, 1H ), 9.15 (s, 1H); 11.13 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d - 163.82; LC / MS: retention time: 10.29 min; purity: 97.75%; MS (mass / charge): 411.18 (MH +) + 1060 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (3-hydroxy-2-methylphenyl) -2,4-pyrimidinediamine ¹ H NMR (CDCl 3): d 1.45 (s, 6H), 2.13 (s, 3H), 6.78 (m, 3H), 6.90 (d, J = 7.5 Hz, 1H) 7.04 (t, J = 8.1 Hz, 1H), 7.27 (s, 1H), 7.74 (d, J = 5.1 Hz, 1H), 7.91 (s, 1H) 9.09 (s, 1H); 10.86 (s, 1H); 19 F NMR (282 MHz, CDCl 3): d 162.90; LC / MS: retention time: 8.06 min; purity: 97.47%; MS (mass / charge): 410.21 (MH +). + 1061 5-Fluoro-N2- (3-methoxy-2-methylphenyl) -N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 1.99 (s, 3H), 3.79 (s, 3H), 4.60 (s, 2H), 6.54 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 2.4 and 8.1 Hz, 1H), 7.12 (t, J = 8.4 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 3.9 Hz, 1H), 8.73 (s, 1H), 9.23 ( s, 1H); 11.08 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 164.15; LC / MS: retention time: 8.97 min; purity: 99.74%; MS (mass / charge): 397.13 (MH +). + 1062 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (3-methoxy-2-methylphenyl) -2,4-pyrimidinediamine ¹ H NMR (CDCl 3): d 1.49 (s, 6H), 2.12 (s, 3H), 3.95 (s, 3H), 6.71 (dd, J = 2.1 and 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 7.26 (m, 3H), 7.66 (d, J = 4.2 Hz, 1H), 7.93 (s, 1H), 11.04 (s, 1H); 19 F NMR (282 MHz, CDCl 3): d - 163.27; LC / MS: retention time: 9.36 min; purity: 99.94%; MS (mass / charge): 424.18 (MH +). + 1063 5-Fluoro-N2- (3-hydroxy-2-methylphenyl) -N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (CDCl 3): d 2.02 (s, 3H), 4.48 (s, 2H), 6.72 (m, 2H), 6.82 (m, 1H), 6.96 (t, J = 8.1 Hz, 1H), 7.25 (m, 1H), 7.79 (d, J = 4.8 Hz, 1H); LC / MS: retention time: 7.10 min; purity: 77.55%; MS (mass / charge): 383.14 (MH +). + 1064 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3-hydroxy-2-methylphenyl) -2,4- pyrimidinediamine ¹ H NMR (CDCl 3): d 1.41 (s, 6H), 2.04 (s, 3H), 6.61 (t, J = 4.5 Hz, 1H), 6.94 (m, 3H) 7.58 (d, J = 8.7 Hz, 1H); 7.77 (d, J = 3.9 Hz, 1H); 19F NMR (282 MHz, CDCl3): d 165.40; LC / MS: retention time: 7.83 min; purity: 99.01%; MS (mass / charge): 411.19 (MH +). + 1065 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3-methoxy-2-methylphenyl) -2,4- pyrimidinediamine ¹ H NMR (CDCl 3): d 1.57 (s, 6H), 2.19 (s, 3H), 3.88 (s, 3H), 6.79 (dd, J = 2.1 and 7.2 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 7.17 (m, 2H), 7.70 (d, J = 8.7 Hz, 1H), 7.85 ( d, J = 3.6 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 161.49; LC / MS: retention time: 10.92 min; purity 85.56%; MS (mass / charge): 425.17 (MH +). + 1066 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3-methoxycarbonylmethyleneoxy-2-methylphenyl] -2,4-pyrimidinediamine ¹ H NMR (CDCl 3): d 1.49 (s, 6H), 2.26 (s, 3H), 3.80 (s, 3H), 4.84 (s, 2H), 6.69 (dd, J = 2.4 and 8.4 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.98 ( d, J = 8.1 Hz, 1H), 7.19 (t, J = 8.1 Hz, 1H), 7.26 (s, 1H), 7.46 (s, 1H), 7.72 ( s, 1H), 7.79 (d, J = 4.8 Hz, 1H), 11.04 (s, 1H); 19 F NMR (282 MHz, CDCl 3): d 162.94; LC / MS: retention time: 9.21 min; purity: 99.68%; MS (mass / charge): 482.20 (MH +). + 1067 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [2-methyl-3- (N-methylamino) carbonylmethyleneoxyphenyl] -2 4-pyrimidinediamine ¹ H NMR (CDCl 3): d 1.50 (s, 6H), 2.25 (s, 3H), 2.93 (d, J = 4.8 Hz, 3H), 4.57 (s, 2H) 6.82 (m, 4H), 6.97 (t, J = 8.1 Hz, 1H), 7.19 (m, 2H), 7.40 (s, 1H), 7.54 (s, 1H), 7.81 (d, J = 4.2 Hz, 1H); LC / MS: retention time: 8.08 min; purity: 99.78%; MS (mass / charge): 481.21 (MH +). + 1068 5-Fluoro-N2- [2-methyl-3- (N-methylamino) carbonylmethyleneoxyphenyl] -N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2.4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 2.08 (s, 3H), 2.66 (d, J = 4.5 Hz, 3H), 4.46 (s, 2H), 4.58 (s, 2H), 6.65 (dd, J = 1.8 and 7.2 Hz, 1H), 7.04 (m, 2H), 7.15 (d, J = 8.7 Hz, 1H), 7, 47 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 4.2 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 8.54 ( s, 1H), 8.96 ((s, 1H), 11.05 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 164.59; LC / MS: retention time: 7, 60 min; purity: 76.95%; MS (mass / charge): 454.14 (MH +). + 1069 N2- (3,5-Dimethyl-4-hydroxyphenyl) -5-fluoro-N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 2.09 (s, 6H), 4.62 (s, 2H), 7.05 (s, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.89 (br., 1H), 8.07 (d, J = 3.6 Hz, 1H), 9.03 (s , 1H); 9.36 (s, 1H); 11.15 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d - 163.98; LC / MS: retention time: 7.9 min; purity: 77.84%; MS (mass / charge): 397.17 (MH +). + 1070 N2- [3- (4-Ethoxycarbonylpiperazino) phenyl] -5-fluoro-N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (CDCl 3): d 1.14 (t, J = 7.2 Hz, 3H), 3.00 (t, J = 5.1 Hz, 4H), 3.46 (t, J = 5, 1 Hz, 4H), 4.00 (q, J = 7.2 Hz, 2H), 4.47 (s, 2H), 6.55 (dd, J = 1.8 and 8.4 Hz, 1H ), 6.90 (dd, J = 1.2 and 7.8 Hz, 1H), 6.98 (t, J = 2.1 Hz, 1H), 7.04 (d, J = 8.7 Hz , 1H), 7.08 (t, J = 8.4 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 3.9 Hz, 1H ); 19 F NMR (282 MHz, CDCl 3): d 164.67; LC / MS: retention time: 11.64 min; purity: 96.15%; MS (mass / charge): 509.21 (MH +). + 1071 N2- [3- (4-Acetylpiperazino) phenyl] -5-fluoro-N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (CDCl 3): d 2.01 (s, 3H), 3.02 (t, J = 5.1 Hz, 2H), 3.08 (t, J = 5.1 Hz, 2H), 3 , 50 (t, J = 5.1 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 4.50 (s, 2H), 6.66 (dd, J = 2, 4 and 8.4 Hz, 1H), 6.87 (t, J = 2.4 Hz, 1H), 6.92 (ddd, J = 0.9, 2.1 and 7.8 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 7.14 (t, J = 8.1 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7, 80 (d, J = 4.8 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 161.72; LC / MS: retention time: 9.23 min; purity: 73.82%; MS (mass / charge): 479.27 (MH +). + 1072 N2- [4- (4-Ethoxycarbonylpiperazino) phenyl] -5-fluoro-N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 1.20 (t, J = 7.2 Hz, 3H), 2.99 (t, J = 5.1 Hz, 4H), 3.49 (t, J = 5.1 Hz, 4H), 4.05 (q, J = 7.2 Hz, 2H), 4.63 (s, 2H), 6.83 (d, J = 9.3 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H), 8, 06 (d, J = 3.6 Hz, 11H), 9.01 (s, 1H), 9.14 (s, 1H), 11.13 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 164.19; LC / MS: retention time: 10.49 min; purity: 92.43%; MS (mass / charge): 509.27 (MH +). + 1073 5-Fluoro-N2- (3-morpholinophenyl) -N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 2.98 (t, J = 5.1 Hz, 4H), 3.69 (t, J = 5.1 Hz, 4H), 4.62 (s, 2H) 6.50 (d, J = 7.2 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7 , 18 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 3, 6 Hz, 1H), 9.09 (s, 1H), 9.21 (s, 1H), 11.13 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.12; LC / MS: retention time: 9.27 min; purity: 94.96%; MS (mass / charge): 438.23 (MH +). + 1074 5-Fluoro-N2- [3- (4-methylpiperazino) phenyl] -N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 2.85 (s, 3H), 2.90 (m, 2H), 3.23 (m, 4H), 3.67 (m, 2H), 4.63 ( s, 2H), 6.57 (dd, J = 2.1 and 8.4 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 7.20 (s, 1H), 7.28 (m, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 3 , 3 Hz, 1H), 9, 13 (s, 1H), 9.26 (s, 1H), 11.15 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.86; LC / MS: retention time: 6.70 min; purity: 85.78%; MS (mass / charge): 451 (MH +). + 1075 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.42 (s, 6H), 3.00 (t, 4H), 3.45 (t, J = 4.8 Hz, 4H), 4.04 (q, J = 7.2 Hz, 2H), 6.51 (d, J = 9.3 Hz, 1H), 7.03 (t, J = 8.1 Hz, 1H), 7.18 (s, 1H), 7.20 (d, J = 6.6 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 3.3 Hz, 1H), 9.14 (s, 1H), 9.25 (s, 1H), 11.09 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.08; LC / MS: retention time: 12.30 min; purity: 87.49%; MS (mass / charge): 537.33 (MH +). + 1076 N2- [3- (4-Acetylpiperazino) phenyl] -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4 pyrimidinediamine ¹ H NMR (CDCl 3): d 1.46 (s, 6H), 2.06 (s, 3H), 3.08 (t, J = 5.1 Hz, 2H), 3.13 (t, J = 5.1 Hz, 2H), 3.54 (t, J = 5.1 Hz, 2H), 3.65 (t, J = 5.1 Hz, 2H), 6.67 (dd, J = 2, 4 and 8.4 Hz, 1H), 6.94 (t, J = 2.1 Hz, 1H), 7.01 (ddd, J = 0.9, 1.8 and 7.8 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 7.18 (t, J = 8.1 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7, 84 (d, J = 4.5 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 162.20; LC / MS: retention time: 9.92 min; purity: 92.80%; MS (mass / charge): 507.31 (MH +). + 1077 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4 pyrimidinediamine ¹ H NMR (DMSO-d6): d 1.20 (t, J = 7.2 Hz, 3H), 1.43 (s, 6H), 3.03 (t, 4H), 3.50 (t, 4H), 4.05 (q, J = 7.2 Hz, 2H), 6.88 (d, J = 9.3 Hz, 2H), 7.38 (d, J = 8.4 Hz, 1H ), 7.45 (d, J = 9.9 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 3.9 Hz, 1H), 9.24 (s, 1H); 9.44 (s, 1H); 11.12 (s, 1H); LC / MS: retention time: 10.90 min; purity: 91.64%; MS (mass / charge): 537.30 (MH +). + 1078 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 1.42 (s, 6H), 3.00 (t, J = 4.8 Hz, 4H), 3.69 (t, J = 4.8 Hz, 4H) 6.51 (dd, J = 7.5 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 3, 6 Hz, 1H), 9.17 (s, 1H), 9.31 (s, 1H), 11.09 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.98; LC / MS: retention time: 10.81 min; purity: 98.57%; MS (mass / charge): 466.27 (MH +). + 1079 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [2-methyl-3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 1.39 (s, 6H), 2.08 (s, 3H), 2.65 (d, J = 4.8 Hz, 3H), 4.45 (s, 2H), 6.64 (dd, J = 2.7 and 6.6 Hz, 1H), 7.04 (m, 2H), 7.15 (d, J = 8.4 Hz, 1H), 7, 48 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 3.9 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 8.56 ( s, 1H), 8.98 (s, 1H), 11.01 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 164.69; LC / MS: retention time: 8.73 min; purity: 96.88%; MS (mass / charge): 482.26 (MH +). + 1080 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4 pyrimidinediamine ¹ H NMR (CDCl 3): d 1.42 (s, 6H), 2.77 (s, 3H), 3.20 (m, 4H), 3.30 (m, 4H), 6.61 (d, J = 6.9 Hz, 1H), 6.92 (t, J = 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.13 (m, 2H) 7.70 (d, J = 8.7 Hz, 1H); 7.81 (d, J = 4.2 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 162.81; LC / MS: retention time: 8.54 min; purity: 83.90%; MS (mass / charge): 479.38 (MH +). + 1081 (S) -N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) - 2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 1.45 (d, J = 6.6 Hz, 3H), 3.77 (s, 3H), 4.73 (q, J = 6.6 Hz, 1H ), 6.99 (d, J = 9.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.48 (m, 2H), 7.80 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 3.6 Hz, 1H), 9.21 (s, 1H), 9.26 (s, 1H), 11.09 (s, 1H ); 19F NMR (282 MHz, DMSO- d6 ): d - 163.36; LC / MS: retention time: 11.59 min; purity: 97.70%; MS (mass / charge): 431.16 (MH +). + + 1082 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -N2- (3,4,5-trimethoxyphenyl) - 2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 1.45 (d, J = 6.9 Hz, 3H), 3.59 (s, 3H), 3.65 (s, 6H), 4.72 (q. , J = 6.6 Hz, 1H), 7.02 (s, 2H), 7.32 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H ), 8.11 (d, J = 3.3 Hz, 1H), 9.10 (s, 1H), 9.17 (s, 1H), 11.07 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d 162.83; LC / MS: retention time: 10.07 min; purity: 90.75%; MS (mass / charge): 457.22 (MH +). + + 1083 N2, N4-Bis (3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 4.46 (s, 2H), 4.52 (s, 2H), 6.76 (d, J = 9.3 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 7.18 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 2.4 and 8.7 Hz, 1H), 8.00 (d, J = 3.6 Hz, 1H), 8.94 (s, 1H), 9.29 (s, 1H), 10.58 (s, 1H), 10, 63 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 164.54; LC / MS: retention time: 7.32 min; purity: 85.68%; MS (mass / charge): 423.13 (MH +). + + + 1084 (S) -N2- (3,5-Dimethylphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2, 4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 1.44 (d, J = 6.9 Hz, 3H), 2.17 (s, 6H), 4.72 (q, J = 6.9 Hz, 1H ), 6.52 (s, 1H), 7.22 (s, 2H), 7.35 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H ), 8.11 (d, J = 3.6 Hz, 1H), 9.09 (s, 1H), 9.16 (s, 1H), 11.08 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d - 163.48; LC / MS: retention time: 12.47 min; purity: 96.01%; MS (mass / charge): 395.14 (MH +). - + 1085 N2- [3- (4-Acetylpiperazino) phenyl] -N4-cyclobutyl-5-fluoro-2,4-pyrimidinediamine ¹ H NMR (CDCl 3): d 1.82 (m, 2H), 2.03 (m, 2H), 2.15 (s, 3H), 2.46 (m, 2H), 3.20 (m, 4H), 3.63 (t, J = 5.1 Hz, 2H), 3.78 (t, J = 5.1 Hz, 2H), 4.58 (m, J = 8.1 Hz, 1H) , 5.26 (d, J = 6.6 Hz, 1H), 6.58 (dd, J = 1.8 and 8.1 Hz, 1H), 7.01 (dd, J = 1.5 and 7 8 Hz, 1H), 7.19 (t, J = 8.1 Hz, 1H), 7.28 (br. 1H), 7.34 (t, J = 2.1 Hz, 1H), 7, 74 (d, J = 3.3 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 168.16; LC / MS: retention time: 8.93 min; purity: 84.56%; MS (mass / charge): 385.77 (MH +). + - 1086 N2- (5-tert-Butylpyrazol-3-yl) -5-fluoro-N4- (3-oxo-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO-d6): d 1.29 (s, 9H), 4.64 (s, 2H), 5.59 (s, 1H), 7.10 (d, 1H), 7.47 ( d, J = 6.6 Hz, 1H), 8.24 (d, 1H), 10.02 (s, 1H), 10.40 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d 162.59; LC / MS: retention time: 10.51 min; purity: 78.44%; MS (mass / charge): 399.24 (MH +). + - 1087 N4-Cyclobutyl-N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.78-1.87 (m, 2H), 1.96-2.03 (m, 2H), 2.32 (s, 6H), 2.44-2.53 ( m, 2H), 4.56 (m, J = 7.8 Hz, 1H), 5.26 (d, J = 7.8 Hz, 1H), 6.67 (s, 1H), 7.23 ( s, 2H), 7.34 (br., NH, 1H); 7.72 (d, J = 2.7 Hz, 1H); 19F NMR (282 MHz, CDCl3): d 168.35; LC / MS: retention time: 13.76 min; purity: 80.20%; MS (mass / charge): 287.35 (MH +). + + - 1088 N4-Cyclobutyl-N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.71-1.86 (m, 2H), 1.93-2.06 (m, 2H), 2.43-2.53 (m, 2H), 3.81 ( s, 6H), 4.60 (m, J = 7.8 Hz, 1H), 5.31 (d, 1H), 6.16 (t, J = 2.1 Hz, 1H), 6.84 ( d, J = 2.1 Hz, 2H), 7.57 (br. NH, 1H), 7.72 (d, J = 3.6 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 167.56; LC / MS: retention time: 12.44 min; purity: 87.82%; MS (mass / charge): 319.32 (MH +). + + - 1089 N4-Cyclobutyl-5-fluoro-N2- (3-methoxy-5-trifluoromethylphenyl) -2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.75-2.04 (m, 4H), 2.43-2.53 (m, 2H), 3.85 (s, 3H), 4.58 (m, J = 7.8 Hz, 1H), 5.32 (d, J = 6.6 Hz, 1H), 6.76 (s, 1H), 7.18 (t, J = 2.1 Hz, 1H), 7 52 (broad s, NH, 1H); 7.76 (s, 2H); 19 F NMR (282 MHz, CDCl 3): d 167.20, -63.67; LC / MS: retention time: 13.22 min; purity: 82.74%; MS (mass / charge): 357.19 (MH +). + + - 1090 N4- (5-tert-Butyl-1H-pyrazol-3-yl) -5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine LC / MS: retention time: 11.58 min .; purity: 90.45%; MS (mass / charge): 412.33 (MH +). + + - 1091 N2- [3- (4-Acetylpiperazino) phenyl] -N4- (5-tert-butyl-1H-pyrazol-3-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.20 (s, 9H), 2.04 (s, 3H), 3.06 (t, J = 5.4 Hz, 2H), 3.11 (t, J = 5 , 1 Hz, 2H), 3.53 (t, J = 5.1 Hz, 2H), 3.63 (t, J = 5.1 Hz, 2H), 6.10 (s, 1H), 6, 57 (m, 1H), 6.96 (s, 1H), 7.13 (m, 2H), 7.82 (d, J = 3.9 Hz, 1H); LC / MS: retention time: 8.84 min; purity: 90.18%; MS (mass / charge): 453.27 (MH +). + + - 1092 (S) -N2- (5-tert-Butyl-1H-pyrazol-3-yl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-5-pyrid [1,4] oxazine -6-yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.30 (s, 9H), 1.47 (d, J = 6.6 Hz, 3H), 4.74 (q, J = 6.3 Hz, 1H) 5.60 (s, 1H), 7.09 (d, J = 9.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 3.9 Hz, 1H), 10.02 (s, 1H), 10.39 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d 162.62; LC / MS: retention time: 11.61 min; purity: 88.68%; MS (mass / charge): 413.17 (MH +). + + - 1093 N2- (3,5-Dimethyl-4-methoxyphenyl) -5-fluoro- [3- (N-2-imidazolin-2-yl) aminophenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.16 (s, 6H), 3.61 (s, 4H), 3.64 (s, 3H), 6.98 (d, J = 11 Hz, 1H), 7.00 (s, 1H), 7.23 (s, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.75 (d, J = 6.6 Hz, 1H), 8.19 (d, J = 4.5 Hz, 1H), 8.29 (s, 2H), 9.57 (s, 1H), 9.89 (s, 1H), 10.82 (s, 1H ); 19F NMR (282 MHz, DMSO- d6 ): d 162.53; LC / MS: retention time: 7.49 min; purity: 83.77%; MS (mass / charge): 422 (MH +). + + - + 1094 5-Fluoro-N2- (3-fluoro-4-methoxyphenyl) -N4- [3- (N-2-imidazolin-2-yl) aminophenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 3.63 (s, 4H), 3.79 (s, 3H), 6.96 (d, J = 9.3 Hz, 1H), 7.04 (t, J = 9.3 Hz, 1H), 7.28 (m, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.63 (dd, J = 2.1, 13.8 Hz , 1H), 7.68 (d, J = 9.6 Hz, 1H), 7.80 (s, 1H), 8.18 (d, J = 4.2 Hz, 1H), 8.27 (s , 1H); 9.56 (s, 1H); 9.75 (s, 1H); 10.72 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.96, -134.40; LC / MS: retention time: 6.99 min; purity: 81.44%; MS (mass / charge): 412 (MH +). + - 1095 N2- (3,5-Dimethylphenyl) -5-fluoro-N4- [3- (N-2-imidazolin-2-yl) aminophenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.20 (s, 6H), 3.60 (s, 4H), 6.92 (s, 1H), 6.98 (m, 1H), 7.22 (s , 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 8.21 (d , J = 4.2 Hz, 1H), 8.26 (s, 2H), 9.60 (s, 1H), 9.86 (s, 1H), 10.80 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.49; LC / MS: retention time: 7.91 min; purity: 81.26%; MS (mass / charge): 392 (MH +). + - 1096 N2- (3,5-Dimethoxyphenyl) -5-fluoro-N4- [3- (N-2-imidazolin-2-yl) aminophenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 3.62 (s, 4H), 3.66 (s, 6H), 6.13 (t, J = 2.1 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 1.5, 8.4 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.71 (d , J = 8.1 Hz, 1H), 7.93 (s, 1H), 8.20 (d, J = 3.9 Hz, 1H), 8.26 (s, 2H), 9.61 (s , 1H); 9.81 (s, 1H); 10.86 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.22; LC / MS: retention time: 7.49 min; purity: 80.65%; MS (mass / charge): 424 (MH +). + - - 1097 5-Fluoro-N4- [3- (N-2-imidazolin-2-yl) aminophenyl] -N2- (3-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 3.01 (t, J = 4.5 Hz, 4H), 3.60 (s, 4H), 3.70 (t, J = 4.5 Hz, 4H), 6.51 (dd, J = 2.1, 8.4 Hz, 1H), 6.90 (dd, J = 1.5, 7.8 Hz, 1H), 7.05 (t, J = 8, 1 Hz, 1H), 7.29 (m, 3H), 7.64 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 8.12 (d, J = 3, 6 Hz, 1H); 9.20 (s, 1H); 9.48 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.75; LC / MS: retention time: 6.28 min; purity: 87.59%; MS (mass / charge): 449 (MH +). - - 1098 N2- [3- (4-Ethoxycarbonylpiperazino) phenyl] -5-fluoro-N4- [3- (N-2-imidazolin-2-yl) aminophenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.20 (t, J = 7.2 Hz, 3H), 3.02 (t, J = 5.4 Hz, 4H), 3.47 (t, J = 5 4 Hz, 4H), 3.60 (s, 4H), 4.05 (q, J = 7.2 Hz, 2H), 6.53 (dd, J = 1.5, 8.4 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H), 7.30 (m, 3H), 7.66 (d, J = 8.7 Hz, 1H), 7.99 (s, 1H), 8.12 (d, J = 3.6 Hz, 1H), 9.19 (s, 1H), 9.48 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.72; LC / MS: retention time: 9.11 min; purity: 94.51%; MS (mass / charge): 520.34 (MH +). - - 1099 5-Fluoro-N4- [3- (N-2-imidazolin-2-yl) aminophenyl] -N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 3.30 (m, 4H), 3.62 (s, 4H), 6.84 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8 4 Hz, 1H), 7.80 (s, 1H), 8.09 (d, J = 3.3 Hz, 1H), 8.27 (s, 1H), 9.06 (s, 1H), 9.44 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.72; LC / MS: retention time: 2.86 min; purity: 84.74%; MS (mass / charge): 462.37 (MH +). - - 1100 5-Fluoro-N4- [3- (N-2-imidazolin-2-yl) aminophenyl] -N2- [4- (4-methoxycarbonylpiperazino) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 3.00 (t, J = 5.1 Hz, 4H), 3.50 (t, J = 4.5 Hz, 4H), 3.61 (s, 7H), 6.84 (d, J = 9.0 Hz, 2H), 6.91 (dd, J = 1.5, 7.5 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H ), 7.52 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 9.11 (s, 1H), 9.44 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 164.62; LC / MS: retention time: 6.94 min; purity: 86.06%; MS (mass / charge): 506 (MH +). - - 1101 N4- (5-tert-Butyl-1H-pyrazol-3-yl) -N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.28 (t, J = 7.2 Hz, 3H), 1.31 (s, 9H), 3.13 (t, J = 5.1 Hz, 4H), 3, 60 (t, J = 5.4 Hz, 4H), 4.15 (q, J = 7.2 Hz, 2H), 6.35 (s, 1H), 6.61 (m, 1H), 7 , 03 (s, 1H), 7.18 (m, 2H), 7.73 (br, 1H), 7.90 (d, J = 3.3 Hz, 1H), 8.20 (br, 1H); 19 F NMR (282 MHz, CDCl 3): d 166.45; LC / MS: retention time: 12.52 min; purity: 86.92%; MS (mass / charge): 483.37 (MH +). + - 1102 N2- [4- (4-Acetylpiperazino) phenyl] -N4- (5-tert-butyl-1H-pyrazol-3-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 8.02 min; purity: 94.49%; MS (mass / charge): 453.29 (MH +). + + - 1103 N4- (5-tert-Butyl-1H-pyrazol-3-yl) -5-fluoro-N2- [4- (4-methoxycarbonylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 10.38 min; purity: 97.48%; MS (mass / charge): 469.35 (MH +). + + - 1104 N4- (5-tert-Butyl-1H-pyrazol-3-yl) -5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 1.26 (s, 9H), 2.61 (m, 7H), 3.00 (m, 4H), 6.30 (br., 1H), 6.86 ( d, J = 8.4 Hz, 2H), 7.48 (d, J = 9.3 Hz, 2H), 7.97 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d 165.44; LC / MS: retention time: 6.04 min; purity: 90.75%; MS (mass / charge): 425 (MH +). + + - 1105 N2- [4- (4-Acetylpiperazino) phenyl] -5-fluoro-N4- [3- (N-2-imidazolin-2-yl) aminophenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.04 (s, 3H), 2.97 (t, J = 4.8 Hz, 2H), 3.04 (t, J = 4.8 Hz, 2H), 3.57 (m, 4H), 3.61 (s, 4H), 6.84 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.3 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 1H), 7, 79 (s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 9.04 (s, 1H), 9.40 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 164.70; LC / MS: retention time: 7.00 min; purity: 93%; MS (mass / charge): 490.32 (MH +). - - 1106 N2- [3- (4-Acetylpiperazino) phenyl] -5-fluoro-N4- [3- (N-2-imidazolin-2-yl) aminophenyl] -2,4-pyrimidinediamine LC / MS: retention time: 7.31 min; purity: 84.11%; MS (mass / charge): 490.34 (MH +). - - 1107 N4-Cyclobutyl-N2- [2- (ethoxycarbonyl) indol-7-yl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.42 (t, J = 7.2 Hz, 3H), 1.63-2.06 (m, 4H), 2.27-2.36 (m, 2H), 4 41 (q, J = 7.2 Hz, 2H), 5.17 (d, J = 6.0 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7, 14 (d, 1H), 7.22 (m, 2H), 7.28 (broad, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 3.6 Hz, 1H); 10.68 br. 1H); 19 F NMR (282 MHz, CDCl 3): d 168.82; LC / MS: retention time: 10.65 min; purity: 82.48%; MS (mass / charge): 370.20 (MH +). + + 1108 N4-Cyclobutyl-5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.73-2.05 (m, 4H), 2.40-2.50 (m, 2H), 3.20 (t, J = 4.8 Hz, 4H), 3 88 (t, J = 4.8 Hz, 4H), 4.60 (m, J = 7.8 Hz, 1H), 5.14 (d, J = 6.3 Hz, 1H), 6.57 (dd, J = 2.4, 8.1 Hz, 1H), 6.97 (dd, J = 1.8, 7.5 Hz, 1H), 7.06 (br., NH, 1H), 7 19 (t, J = 8.1 Hz, 1H); 7.35 (t, J = 2.4 Hz, 1H); 7.75 (d, J = 3.0 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 168.89; LC / MS: retention time: 10.09 min; purity: 92.98%; MS (mass / charge): 344.32 (MH +). + + - 1109 N4-Cyclobutyl-N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.29 (t, J = 6.9 Hz, 3H), 1.71-2.02 (m, 4H), 2.41-2.51 (m, 2H), 3 , 18 (t, J = 5.1 Hz, 4H), 3.64 (t, J = 5.1 Hz, 4H), 4.17 (q, J = 6.9 Hz, 2H), 4, 59 (m, J = 8.1 Hz, 1H), 5.16 (d, J = 7.8 Hz, 1H), 6.58 (dd, J = 2.4, 8.1 Hz, 1H), 6.97 (dd, J = 1.8, 8.1 Hz, 1H), 7.09 (br. NH, 1H), 7.18 (t, J = 8.1 Hz, 1H), 7.37 (t, J = 2.1 Hz, 1H); 7.74 (d, J = 2.7 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 168.46; LC / MS: retention time: 10.05 min; purity: 89.70%; MS (mass / charge): 415.32 (MH +). + - 1110 N4-Cyclobutyl-5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.65-1.74 (m, 2H), 1.85-1.95 (m, 2H), 2.19-2.33 (m, 2H), 2.71 ( s, 3H), 3.15 (t, 4H), 3.32 (t, J = 4.8 Hz, 4H), 4.36 (m, J = 8.1 Hz, 1H), 6.80 ( d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.3 Hz, 2H), 7.55 (d, J = 4.2 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d: 167.73; LC / MS: retention time: 6.03 min; purity: 90.91%; MS (mass / charge): 357.33 (MH +). + - 1111 N4-Cyclobutyl-N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.31 (t, 3H), 1.50-2.04 (m, 4H), 2.41-2.50 (m, 2H), 3.08 (t, J = 4.8 Hz, 4H), 3.64 (t, J = 5.1 Hz, 4H), 4.17 (q, 2H), 4.52 (m, J = 7.8 Hz, 1H), 5.18 (d, J = 6.6 Hz, 1H), 6.90 (d, J = 9.0 Hz, 2H), 7.07 (br. 1H), 7.45 (d, J = 9.0 Hz, 2H); 7.70 (d, J = 3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): d 168.85; LC / MS: retention time: 10.73 min; purity: 83.62%; MS (mass / charge): 415.34 (MH +). + - 1112 N2- [3- (4-Acetylpiperazino) phenyl] -N4- (3-cyclopropyl-1H-pyrazol-5-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 9.04 min; purity: 87.21%; MS (mass / charge): 437.32 (MH +). + + + 1113 N4- (3-Cyclopropyl-1H-pyrazol-5-yl) -5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 0.54-0.64 (m, 2H), 0.76-0.86 (m, 2H), 1.74 (m, 1H), 2.42 (s, 3H) 2.76 (br. 4H), 3.17 (t, J = 4.8 Hz, 4H), 5.90 (br. 1H), 6.82 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 3.6 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 167.69; LC / MS: retention time: 5.97 min; purity: 76.80%; MS (mass / charge): 409.22 (MH +). + + - 1114 N4- (3-Cyclopropyl-1H-pyrazol-5-yl) -5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine LC / MS: retention time: 8.57 min; purity: 88.76%; MS (mass / charge): 396.24 (MH +). + + - 1115 N4- (3-Cyclopropyl-1H-pyrazol-5-yl) -N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 0.67 (m, 2H), 0.88 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H), 1.85 (m, 1H ), 3.06 (m, 4H), 3.48 (m, 4H), 4.05 (q, J = 7.1 Hz, 2H), 6.52 (d, J = 8.1 Hz, 1H), 7.07 (m, 1H), 7.20 (m, 2H); LC / MS: retention time: 11.80 min; purity: 79.43%; MS (mass / charge): 467.30 (MH +). + + 1116 N4- (3-Cyclopropyl-1H-pyrazol-5-yl) -N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 0.62 (m, 2H), 0.90 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 1.84 (m, J = 3.9 Hz, 1H), 3.08 (br., 4H), 3.44 (br., 4H), 4.05 (q, J = 6.9 Hz, 2H), 6.12 ( broad., 1H), 6.93 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 4.2 Hz , 1H); 9.37 (br. 1H); 10.71 (br. 1H); 11.49 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 171.17; LC / MS: retention time: 9.23 min; purity: 94.89%; MS (mass / charge): 467.29 (MH +). + + 1117 2-Chloro-5-fluoro-N4- (3,4-dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -4-pyrimidinamine 1H NMR (DMSO-d6): d 3.40 (t, J = 4.5 Hz, 2H), 4.10 (t, J = 4.5 Hz, 2H), 6.92 (d, J = 8 , 4 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 8.27 (d, J = 3.6 Hz, 1H), 9.80 (br., 1H); 19F NMR (282 MHz, DMSO-d6): d 152.34; LC / MS: retention time: 9.69 min; purity: 93.93%; MS (mass / charge): 282.12 (MH +). - - 1118 N4- (1-tert-Butoxycarbonylazetidin-3-yl) -5-fluoro-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.45 (s, 9H), 3.18 (t, J = 4.8 Hz, 4H), 3.89 (m, 4H), 3.96 (m, 2H), 4.28 (m, 2H), 4.69 (m, 1H), 6.93 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.3 Hz, 2H), 7.66 (d, J = 3.6 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d - 163.92; LC / MS: retention time: 9.28 min; purity: 100%; MS (mass / charge): 445.25 (MH +). + + 1119 N2- [4- (4-Acetylpiperazino) phenyl] -N4- (1-tert-butoxycarbonylazetidin-3-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.46 (s, 9H), 2.16 (s, 3H), 3.15 (p, J = 5.1 Hz, 4H), 3.64 (t, J = 5 , 1 Hz, 2H), 3.78 (t, J = 5.1 Hz, 2H), 3.91 (dd, J = 5.4, 9.9 Hz, 2H), 4.30 (dd, J = 7.8, 9.6 Hz, 2H), 4.70 (m, 1H), 6.91 (d, J = 9.3 Hz, 2H), 7.38 (d, J = 9.3 Hz , 2H); 7.72 (d, J = 3.6 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 166.44; LC / MS: retention time: 8.48 min; purity: 91.50%; MS (mass / charge): 486.32 (MH +). + - 1120 N2- [3- (4-Acetylpiperazino) phenyl] -N4- (1-tert-butoxycarbonylazetidin-3-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.45 (s, 9H), 2.16 (s, 3H), 3.21 (m, 4H), 3.64 (m, 2H), 3.78 (m, 2H) ), 3.99 (dd, J = 4.8, 9.0 Hz, 2H), 4.30 (dd, J = 7.8, 9.3 Hz, 2H), 4.74 (m, 1H) 6.75 (d, J = 5.1 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 7.19 (m, 1H), 7.26 (m, 1H) 7.69 (d, J = 42 Hz, 1H); 19 F NMR (282 MHz, CDCl 3): d 162.80; LC / MS: retention time: 11.04 min; purity: 93.28%; MS (mass / charge): 486.31 (MH +). - - 1121 N4- (3-Cyclopropyl-1H-pyrazol-5-yl) -5-fluoro-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine LC / MS: retention time: 7.80 min; purity: 96.17%; MS (mass / charge): 396.22 (MH +). + + - 1122 N4- (1-tert-Butoxycarbonylazetidin-3-yl) -N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 10.44 min; purity: 82.19%; MS (mass / charge): 516.26 (MH +). + - 1123 N4- (Azetidin-3-yl) -5-fluoro-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.12 min; purity: 88.18%; MS (mass / charge): 345.21 (MH +). - + 1124 N2- [4- (4-Acetylpiperazino) phenyl] -N4- (azetidin-3-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 2.33 min; purity: 92.29%; MS (mass / charge): 386.25 (MH +). - - 1125 N4- (Azetidin-3-yl) -N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 7.44 min; purity: 85.69%; MS (mass / charge): 416 (MH +). - - 1126 N4- (Azetidin-3-yl) -5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.85 min; purity: 100%; MS (mass / charge): 345.24 (MH +). - + 1127 N2- [3- (4-Acetylpiperazino) phenyl] -N4- (azetidin-3-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 3.10 min; purity: 88.30%; MS (mass / charge): 386.28 (MH +). + - 1128 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 3.00 (t, J = 4.8 Hz, 4H), 3.38 (t, 2H), 3.72 (t, J = 4.8 Hz, 4H), 4.08 (t, J = 4.2 Hz, 2H), 6.50 (br, 1H), 6.82 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 9.3 Hz, 2H), 7.99 (d, J = 3, 6 Hz, 1H), 8.65 ((br. 1H), 8.92 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 164.78; LC / MS: retention time: 8 12 min; purity: 99.30%; MS (mass / charge): 424.25 (MH +). + - 1129 N4- (1-tert-Butoxycarbonylazetidin-3-yl) -N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 11.35 min; purity: 86.05%; MS (mass / charge): 516.32 (MH +). - 1130 N4- (Azetidin-3-yl) -N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 8.39 min; purity: 96.94%; MS (mass / charge): 416 (MH +). - 1131 N4- (Azetidin-3-yl) -5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 1.20 min; purity: 96.44%; MS (mass / charge): 358.24 (MH +). - 1132 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4 pyrimidinediamine 1H NMR (DMSO-d6): d 3.38 (t, 2H), 4.08 (t, J = 4.5 Hz, 2H), 6.52 (br., 1H), 6.78 (d, J = 8.1 Hz, 1H), 7.27 (m, 3H), 7.50 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 8.01 (s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 8.38 (s, 1H), 8.82 (s, 1H), 9.35 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.94; LC / MS: retention time: 9.32 min; purity: 100%; MS (mass / charge): 406.18 (MH +). + 1133 2-Chloro-N4-cyclobutyl-5-fluoro-N4-methyl-4-pyrimidinamine 1 H NMR (CDCl 3): d 1.68-1.76 (m, 2H), 2.17-2.25 (m, 4H), 3.14 (d, J = 3.0 Hz, 3H), 4 79 (m, J = 8.4 Hz, 1H); 7.85 (d, J = 6.0 Hz, 1H); 19F NMR (282 MHz, CDCl3): d -150.50; LC / MS: retention time: 13.83 min; purity: 96.47%; MS (mass / charge): 216.10 (MH +). - 1134 N2- [4- (4-Acetylpiperazino) phenyl] -N4- (3,4-dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.03 (s, 3H), 2.97 (t, J = 5.1 Hz, 2H), 3.03 (t, J = 5.1 Hz, 2H), 3.39 (t, 2H), 3.56 (t, 4H), 4.08 (t, J = 4.2 Hz, 2H), 6.51 (s, 1H), 6.84 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 9 , 0 Hz, 2H), 7.99 (d, J = 3.6 Hz, 1H), 8.67 (br. 1H), 8.95 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 164.68; LC / MS: retention time: 7.60 min; purity: 99.34%; MS (mass / charge): 465.30 (MH +). + + 1135 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 2.99 (t, J = 5.4 Hz, 4H), 3.39 (t, 2H), 3.49 (t, 4H), 4.04 (q, J = 7.2 Hz, 2H), 4.08 (t, J = 4.8 Hz, 2H), 6.51 (s, 1H) 6.84 (d, J = 9.3 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7 49 (d, J = 9.0 Hz, 2H), 7.99 (d, J = 3.6 Hz, 1H), 8.68 (br. 1H), 8.95 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 164.66; LC / MS: retention time: 9.61 min; purity: 94.88%; MS (mass / charge): 495.31 (MH +). + + 1136 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.99 (t, J = 5.1 Hz, 4H), 3.39 (t, 2H), 3.69 (t, J = 4.8 Hz, 4H), 4.08 (t, J = 4.2 Hz, 2H), 6.50 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 8 , 1 Hz, 1H), 7.19 (m, 3H), 8.04 (d, J = 3.6 Hz, 1H), 8.74 (s, 1H), 9.02 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.64; LC / MS: retention time: 9.03 min; purity: 98.67%; MS (mass / charge): 424.26 (MH +). + + 1137 N2- [3- (4-Acetylpiperazino) phenyl] -N4- (3,4-dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.03 (s, 3H), 2.98 (t, J = 4.8 Hz, 2H), 3.05 (t, J = 4.8 Hz, 2H), 3.39 (t, 2H), 3.53 (t, J = 5.4 Hz, 4H), 4.08 (t, 2H), 6.50 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 8.4 Hz, 1H), 7.21 (m, 3H), 8.04 (d, J = 3.6 Hz, 1H), 8.75 (s, 1H); 9.03 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.60; LC / MS: retention time: 8.22 min; purity: 100%; MS (mass / charge): 465.25 (MH +). + + 1138 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.20 (t, J = 7.2 Hz, 3H), 3.01 (t, J = 4.8 Hz, 4H), 3.41 (t, 2H), 3.46 (t, J = 4.8 Hz, 4H), 4.08 (t, 2H), 6.50 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 8.4 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.25 (t, 1H), 8.04 (d, J = 3 6 Hz, 1H); 8.73 (s, 1H); 9.02 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.61; LC / MS: retention time: 10.46 min; purity: 98.68%; MS (mass / charge): 495.25 (MH +). + + 1139 N4-Cyclobutyl-5-fluoro-N4-methyl-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.56-1.69 (m, 2H), 2.07-2.27 (m, 4H), 3.07 (t, J = 4.5 Hz, 4H) , 3.12 (d, J = 3.0 Hz, 3H), 3.73 (t, J = 4.5 Hz, 4H), 4.76 (m, J = 8.4 Hz, 1H), 6 92 (d, J = 9.0 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 7.97 (d, J = 7.2 Hz, 1H), 9.36 (broad., 1H); 19F NMR (282 MHz, DMSO- d6 ): d 157.25; LC / MS: retention time: 9.50 min; purity: 100%; MS (mass / charge): 358.23 (MH +). + - 1140 N2- [4- (4-Acetylpiperazino) phenyl] -N4-cyclobutyl-5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.59-1.69 (m, 2H), 2.03 (s, 3H), 2.10-2.27 (m, 4H), 3.03 (t, J = 4.5 Hz, 2H), 3.11 (d, J = 3.0 Hz, 5H), 3.56 (t, 4H), 4.76 (m, J = 7.5 Hz, 1H) 6.93 (d, J = 9.0 Hz, 2H), 7.45 (d, J = 9.0 Hz, 2H), 7.96 (d, J = 7.2 Hz, 1H), 9 26 (broad s, 1H); LC / MS: retention time: 8.75 min; purity: 100%; MS (mass / charge): 399.28 (MH +). + - 1141 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 2.23 (s, 3H), 3.03 (t, 4H), 3.29 (m, 4H), 3.38 (t, 2H), 4.08 (t , J = 4.5 Hz, 2H), 6.50 (br., 1H), 6.81 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 9.0 Hz, 2H), 7.98 (d, J = 3.6 Hz, 1H) 8.64 (br. 1H); 8.90 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 164.86; LC / MS: retention time: 5.58 min; purity: 100%; MS (mass / charge): 437 (MH +). + + - 1142 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.20 (s, 3H), 2.41 (t, 4H), 3.03 (t, 4H), 3.38 (t, 2H), 4.08 (t , J = 4.8 Hz, 2H), 6.50 (m, 2H), 6.91 (d, J = 7.8 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H ), 7.20 (m, 3H), 8.03 (d, J = 3.6 Hz, 1H), 8.72 (s, 1H), 8.99 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.72; LC / MS: retention time: 6.32 min; purity: 99.99%; MS (mass / charge): 437 (MH +). + + - 1143 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4 pyrimidinediamine 1 H NMR (DMSO-d6): d 3.53 (t, J = 4.2 Hz, 2H), 4.16 (t, J = 4.2 Hz, 2H), 6.84 (d, J = 8 , 7 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.35 (s, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7, 56 (dt, J = 1.2, 8.1 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 8.32 (d, J = 3.3 Hz, 1H), 8.44 (s, 1H), 10.35 (br. 2H); 19F NMR (282 MHz, DMSO- d6 ): d 161.96; LC / MS: retention time: 9.54 min; purity: 98.01%; MS (mass / charge): 406.18 (MH +). + + - 1144 N4- (3-Cyclopropyl-1H-pyrazol-5-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 0.61-0.66 (m, 2H), 0.86 (m, 2H), 1.81 (m, 1H), 6.41 (br., 1H), 7.35 (m, 2H), 7.52 (d, J = 7.5 Hz, 1H), 7.86 (s, 1H), 8.04 (s, 1H), 8.19 (m, 2H ), 9.34 (s, 1H); 9.60 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d - 163.42; LC / MS: retention time: 9.50 min; purity: 98.57%; MS (mass / charge): 378.20 (MH +). + + - + 1145 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 3.49 (t, 2H), 3.61 (s, 3H), 3.69 (s, 6H), 4.14 (t, J = 4.5 Hz, 2H ), 6.94 (d, J = 7.8 Hz, 1H), 7.07 (s, 2H), 7.14 (d, 1H), 8.20 (d, J = 3.6 Hz, 1H ), 9.75 (s, 1H); LC / MS: retention time: 8.80 min; purity: 100%; MS (mass / charge): 429.45 (MH +). + + - + 1146 N2- (3-Chloro-4-methoxyphenyl) -N4- (3,4-dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 3.39 (s, 2H), 3.78 (s, 3H), 4.08 (t, J = 3.9 Hz, 2H), 6.54 (br, 1H), 6.95 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H) 7.46 (dd, J = 2.4, 9.0 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 3.3 Hz, 1H); 8.80 (s, 1H); 9.16 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.72; LC / MS: retention time: 10.31 min; purity: 99.90%; MS (mass / charge): 403.06 (MH +). + - 1147 N4-Cyclobutyl-5-fluoro-N4-methyl-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.56-1.68 (m, 2H), 2.10-2.26 (m, 4H), 2.21 (s, 3H), 2.44 (t, 4H), 3.02 (t, J = 4.8 Hz, 4H), 3.05 (d, J = 2.7 Hz, 3H), 4.74 (m, J = 7.8 Hz, 1H) 6.82 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 6.6 Hz, 1H), 8 79 (broad s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 159.83; LC / MS: retention time: 6.35 min; purity: 95.87%; MS (mass / charge): 371.21 (MH +). + + - + 1148 N4-Cyclobutyl-N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.56-1.69 (m, 2H), 2.07-2.27 (m, 4H) , 3.06 (t, J = 4.8 Hz, 4H), 3.11 (d, J = 3.0 Hz, 3H), 3.50 (t, 4H), 4.05 (q, J = 7.2 Hz, 2H), 4.76 (m, J = 8.4 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 7.43 (d, J = 8 , 7 Hz, 2H), 7.97 (d, J = 7.5 Hz, 1H), 9.33 (br. 1H); LC / MS: retention time: 11.06 min; purity: 96.72%; MS (mass / charge): 429.45 (MH +). + + - 149 N4-Cyclobutyl-5-fluoro-N4-methyl-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.57-1.70 (m, 2H), 2.13-2.24 (m, 4H), 3.07 (t, J = 4.8 Hz, 4H) , 3.11 (d, J = 3.3 Hz, 3H), 3.73 (t, J = 4.5 Hz, 4H), 4.78 (m, J = 8.7 Hz, 1H), 6 , 57 (m, 1H), 7.08 (m, 2H), 7.24 (m, 1H), 7.98 (d, J = 6.9 Hz, 1H), 9.19 (br., 1H ); LC / MS: retention time: 10.46 min; purity: 97.98%; MS (mass / charge): 358.34 (MH +). + - 1150 N2- [3- (4-Acetylpiperazino) phenyl] -N4-cyclobutyl-5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.66-1.78 (m, 2H), 2.15 (s, 3H), 2.22 (m, 4H), 3.17 (d, J = 2.7 Hz , 3H), 3.22 (m, 4H), 3.62 (t, J = 4.8 Hz, 2H), 3.77 (t, J = 5.1 Hz, 2H), 4.85 (m , J = 8.4 Hz, 1H), 6.58 (dd, J = 2.4, 8.1 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 8.1 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.53 (br. 1H), 7.75 (d, J = 6.9 Hz , 1H); 19F NMR (282 MHz, CDCl3): -157.20; LC / MS: retention time: 9.37 min; purity: 87.43%; MS (mass / charge): 399.56 (MH +). + - 1151 N4-Cyclobutyl-5-fluoro-N4-methyl-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1 H NMR (CDCl 3): d 1.63-1.77 (m, 2H), 2.21 (m, 4H), 2.45 (s, 3H), 2.72 (t, J = 4.8 Hz , 4H), 3.13 (d, J = 3.9 Hz, 3H), 3.32 (t, J = 4.8 Hz, 4H), 4.84 (m, J = 8.7 Hz, 1H ), 6.56 (dd, J = 2.4, 8.1 Hz, 1H), 6.82 (br., 1H), 7.00 (d, J = 8.1 Hz, 1H), 7, 17 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 6.6 Hz, 1H); 19F NMR (282 MHz, CDCl3): -158.30; LC / MS: retention time: 7.27 min; purity: 87.72%; MS (mass / charge): 371.20 (MH +). + + - 1152 N4-Cyclobutyl-N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.60-1.70 (m, 2H), 2.13-2.28 (m, 4H) , 3.08 (t, J = 5.1 Hz, 4H), 3.12 (d, J = 3.3 Hz, 3H), 3.50 (t, 4H), 4.05 (q, J = 7.2 Hz, 2H), 4.79 (m, J = 9.0 Hz, 1H), 6.59 (d, J = 6.9 Hz, 1H), 7.09 (m, 2H), 7.27 (s, 1H); 7.99 (d, J = 6.9 Hz, 1H); 9.27 (br. 1H); LC / MS: retention time: 11.92 min; purity: 99.18%; MS (mass / charge): 429.22 (MH +). + - 1153 N2- (2-Aminocarbonyl-5-benzoxy-4-methoxyphenyl) -N4-cyclobutyl-5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.69-1.78 (m, 2H), 2.28 (m, 4H), 3.36 (d, J = 3.3 Hz, 3H), 3.90 (s, 3H), 4.94 (m, 1H), 5.30 (s, 2H), 7.12 (s, 1H), 7.35-7.48 (m, 6H), 9.04 ( d, J = 9.0 Hz, 1H); LC / MS: retention time: 11.25 min; purity: 98.01%; MS (mass / charge): 435.22 (M-16). - - 1154 N2- (4-Benzamidophenyl) -N4-cyclobutyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.62-1.74 (m, 2H), 2.02-2.15 (m, 2H), 2.23-2.31 (m, 2H), 4, 50 (m, J = 8.1 Hz, 1H), 7.46-7.68 (m, 8H), 7.84 (d, J = 3.6 Hz, 1H), 7.92 (td, J = 1.2, 6.6 Hz, 2H), 8.99 (s, 1H), 10.07 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d 167.01; LC / MS: retention time: 9.59 min; purity: 94.19%; MS (mass / charge): 378.50 (MH +). + - 1155 N4-Cyclopentyl-5-fluoro-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.54 (m, 4H), 1.70 (m, 2H), 1.94 (m, 2H), 2.98 (t, J = 4.8 Hz, 4H ), 3.70 (t, J = 4.8 Hz, 4H), 4.30 (q, J = 6.9 Hz, 1H), 6.80 (d, J = 9.0 Hz, 2H) , 7.22 (d, J = 6.9 Hz, 1H), 7.55 (d, J = 9.3 Hz, 2H), 7.76 (d, J = 3.6 Hz, 1H), 8 74 (broad s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 167.62; LC / MS: retention time: 8.98 min; purity: 99.38%; MS (mass / charge): 358.18 (MH +). + - 1156 N2- [4- (4-Acetylpiperazino) phenyl] -N4-cyclopentyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.54 (m, 4H), 1.70 (m, 2H), 1.93 (m, 2H), 2.02 (s, 3H), 2.94 (t , J = 4.8 Hz, 2H), 3.01 (t, J = 5.1 Hz, 2H), 3.54 (t, 4H), 4.30 (q, J = 6.9 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 9.0 Hz, 2H) 7.76 (d, J = 3.9 Hz, 1H); 8.76 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 167.53; LC / MS: retention time: 8.28 min; purity: 98.08%; MS (mass / charge): 399.20 (MH +). + - 1157 N4-Cyclopentyl-5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.54 (m, 4H), 1.70 (m, 2H), 1.93 (m, 2H), 2.21 (s, 3H), 2.44 (t , 4H), 3.01 (t, 4H), 4.30 (q, J = 6.3 Hz, 1H), 6.79 (d, J = 8.7 Hz, 2H), 7.22 ( d, J = 6.3 Hz, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 3.0 Hz, 1H), 8.72 (br. , 1H); 19F NMR (282 MHz, DMSO- d6 ): d 167.68; LC / MS: retention time: 5.53 min; purity: 83.38%; MS (mass / charge): 371.08 (MH +). + - 1158 N4-Cyclopentyl-5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.52 (m, 4H), 1.71 (m, 2H), 1.93 (m, 2H), 3.03 (t, J = 4.8 Hz, 4H ), 3.72 (t, J = 4.8 Hz, 4H), 4.36 (m, 1H), 6.45 (d, J = 9.6 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.42 (s, 1H), 7.80 (d, J = 3.6 Hz, 1H); 8.84 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 166.77; LC / MS: retention time: 9.54 min; purity: 90.50%; MS (mass / charge): 358.20 (MH +). + - 1159 N2- [3- (4-Acetylpiperazino) phenyl] -N4-cyclopentyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.53 (m, 4H), 1.71 (m, 2H), 1.94 (m, 2H), 2.03 (s, 3H), 3.02 (t , J = 5.1 Hz, 2H), 3.08 (t, J = 4.8 Hz, 2H), 3.55 (t, 4H), 4.36 (q, J = 6.6 Hz, 1H), 6.47 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 8.1 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H) , 7.30 (d, J = 7.2 Hz, 1H), 7.44 (s, 1H), 7.80 (d, J = 3.6 Hz, 1H), 8.84 (br. 1H) ; 19F NMR (282 MHz, DMSO- d6 ): d 166.76; LC / MS: retention time: 8.60 min; purity: 97.49%; MS (mass / charge): 399.48 (MH +). + - 1160 N4-Cyclopentyl-5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 6.49 min; purity: 79.17%; MS (mass / charge): 371.23 (MH +). + - 1161 N4-Cyclopentyl-N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 10.76 min; purity: 77.07%; MS (mass / charge): 429.50 (MH +). + - 1162 N4-Cyclohexyl-5-fluoro-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.14 (m, 1H), 1.31 (m, 4H), 1.64 (d, 1H), 1.75 (m, 2H), 1.90 (m , 2H), 2.98 (t, J = 4.8 Hz, 4H), 3.71 (t, J = 4.8 Hz, 4H), 3.86 (m, 1H), 6.80 (d , J = 9.3 Hz, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 3.9 Hz, 1H); 8.74 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 167.70; LC / MS: retention time: 9.48 min; purity: 100%; MS (mass / charge): 372.45 (MH +). + - 1163 N2- [4- (4-Acetylpiperazino) phenyl] -N4-cyclohexyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.31 (m, 5H), 1.64 (d, 1H), 1.75 (m, 2H), 1.90 (m, 2H), 2.02 (s , 3H), 2.94 (t, J = 4.8 Hz, 2H), 3.01 (t, J = 5.1 Hz, 2H), 3.55 (m, 4H), 3.86 (m , 1H), 6.82 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H ), 7.76 (d, J = 3.9 Hz, 1H), 8.75 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 167.64; LC / MS: retention time: 8.62 min; purity: 99.89%; MS (mass / charge): 413.44 (MH +). + - 1164 N4-Cyclohexyl-5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.31 (m, 5H), 1.64 (d, 1H), 1.75 (m, 2H), 1.90 (m, 2H), 2.21 (s , 3H), 2.46 (t, J = 4.8 Hz, 4H), 3.01 (t, J = 4.8 Hz, 4H), 3.85 (m, 1H), 6.79 (d , J = 9.0 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 3.9 Hz, 1H); 8.72 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 167.78; LC / MS: retention time: 6.09 min; purity: 99.06%; MS (mass / charge): 385.20 (MH +). + - + 1165 N4-Cyclohexyl-N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.31 (m, 5H), 1.64 (d, 1H), 1.76 (m, 2H ), 1.90 (m, 2H), 2.97 (t, J = 4.8 Hz, 4H), 3.48 (t, 4H), 3.86 (m, 1H), 4.04 (q ., J = 7.2 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 6.9 Hz, 1H), 7.55 (d, J = 9.3 Hz, 2H), 7.76 (d, J = 3.9 Hz, 1H), 8.75 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 167.63; LC / MS: retention time: 10.75 min; purity: 98.19%; MS (mass / charge): 443.19 (MH +). + + 1166 N4-Cyclohexyl-5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.27 (m, 5H), 1.63 (d, 1H), 1.76 (m, 2H), 1.87 (m, 2H), 3.04 (t , J = 4.8 Hz, 4H), 3.72 (t, J = 4.8 Hz, 4H), 3.90 (m, 1H), 6.46 (dd, J = 2.1, 7, 8 Hz, 1H), 7.03 (t, J = 8.4 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.24 (m, 2H), 7.80 (d, J = 3.9 Hz, 1H); 8.78 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 166.81; LC / MS: retention time: 10.22 min; purity: 99.24%; MS (mass / charge): 372.15 (MH +). + - 167 N2- [3- (4-Acetylpiperazino) phenyl] -N4-cyclohexyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.31 (m, 5H), 1.61 (m, 1H), 1.76 (m, 2H), 1.87 (m, 2H), 2.03 (s , 3H), 3.04 (t, 2H), 3.09 (t, 2H), 3.56 (t, 4H), 3.90 (m, 1H), 6.48 (d, J = 9, 0 Hz, 1H), 7.04 (t, J = 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.25 (m, 2H), 7.80 (d, J = 3.6 Hz, 1H), 8.80 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 166.78; LC / MS: retention time: 9.31 min; purity: 93.22%; MS (mass / charge): 413.19 (MH +). + - 1168 N4-Cyclohexyl-5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.14 (m, 1H), 1.31 (m, 4H), 1.63 (d, 1H), 1.76 (m, 2H), 1.86 (m , 2H), 2.26 (s, 3H), 3.09 (t, 4H), 3.32 (t, 4H), 3.88 (m, 1H), 6.45 (d, J = 6, 9 Hz, 1H), 7.01 (t, J = 8.1 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.24 (m, 2H), 7.80 (d, J = 3.9 Hz, 1H); 8.76 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 166.84; LC / MS: retention time: 7.16 min; purity: 96.05%; MS (mass / charge): 385.27 (MH +). + - 1169 N4-Cyclohexyl-N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.19 (t, J = 6.9 Hz, 3H), 1.31 (m, 5H), 1.62 (d, 1H), 1.76 (m, 2H ), 1.87 (m, 2H), 3.05 (t, J = 4.8 Hz, 4H), 3.49 (t, 4H), 3.90 (m, 1H), 4.05 (q ., J = 7.2 Hz, 2H), 6.48 (d, J = 4.5 Hz, 1H), 7.03 (t, J = 8.1 Hz, 1H), 7.16 (d, J = 6.6 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 7.28 (s, 1H), 7.80 (d, J = 3.9 Hz, 1H) 8.80 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 166.76; LC / MS: retention time: 11.50 min; purity: 85.32%; MS (mass / charge): 442.95 (MH +). + - 1170 N2- (4-Benzamidophenyl) -N4-cyclopentyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.57 (m, 4H), 1.72 (m, 2H), 1.96 (m, 2H), 4.32 (q, J = 7.5 Hz, 1H), 7.29 (d, J = 6.3 Hz, 1H), 7.46-7.69 (m, 7H), 7.81 (d, J = 3.9 Hz, 1H), 7, 92 (d, J = 9.6 Hz, 2H), 8.97 (s, 1H), 10.05 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d 166.85; LC / MS: retention time: 10.15 min; purity: 97.75%; MS (mass / charge): 392.16 (MH +). + - 1171 N2- (2-Aminocarbonyl-5-benzoxy-4-methoxyphenyl) -N4-cyclopentyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.60 (m, 4H), 1.74 (m, 2H), 1.96 (m, 2H), 3.85 (s, 3H), 4.43 (q, ., J = 6.9 Hz, 1H), 5.24 (s, 2H), 7.06 (s, 1H), 7.31-7.50 (m, 6H), 8.53 (d, J = 7.2 Hz, 1H); 8.70 (d, J = 6.9 Hz, 1H); 19F NMR (282 MHz, DMSO-d6): d - 155.92; LC / MS: retention time: 11.18 min; purity: 96.52%; MS (mass / charge): 435.16 (M-16). + - 1172 N2- [4- (N-Acetyl-N-methylamino) phenyl] -N4-cyclopentyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.55 (m, 4H), 1.71 (m, 2H), 1.94 (m, 2H), 3.09 (s, 3H), 3.31 (s , 3H), 4.32 (q, J = 7.2 Hz, 1H), 7.13 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 3.9 Hz, 1H), 9.14 (s, 1H); 19 F NMR (282 MHz, DMSO-d6): d 166.12; LC / MS: retention time: 8.34 min; purity: 97.77%; MS (mass / charge): 344.13 (MH +). + - 1173 N4-Cyclopentyl-5-fluoro-N2- [3- (N-2-imidazolin-2-yl) aminophenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.55 (m, 4H), 1.71 (m, 2H), 1.93 (m, 2H), 3.62 (s, 4H), 4.31 (q, ., J = 6.6 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.84 (s, 2H), 8.22 (s, 1H), 9.23 (s, 1H), 10.54 (broad, 1H); 19F NMR (282 MHz, DMSO- d6 ): d — 165.78; LC / MS: retention time: 5.71 min; purity: 92.06%; MS (mass / charge): 356.17 (MH +). - - 1174 N2- (4-Benzamidophenyl) -N4-cyclohexyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.33 (m, 5H), 1.65 (d, 1H), 1.78 (m, 2H), 1.92 (m, 2H), 3.88 (m , 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.46-7.69 (m, 7H), 7.81 (d, J = 3.9 Hz, 1H), 7 92 (d, J = 6.6 Hz, 2H), 8.99 (s, 1H), 10.05 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d 166.98; LC / MS: retention time: 10.79 min; purity: 94.61%; MS (mass / charge): 406.43 (MH +). - + - + 1175 N2- (2-Aminocarbonyl-5-benzoxy-4-methoxyphenyl) -N4-cyclohexyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.36 (m, 5H), 1.65 (d, 1H), 1.79 (m, 2H), 1.88 (m, 2H), 3.85 (s , 3H), 4.05 (m, 1H), 5.24 (s, 2H), 7.06 (s, 1H), 7.31-7.50 (m, 6H), 8.44 (d, J = 7.5 Hz, 1H); 8.70 (d, J = 6.9 Hz, 1H); 19F NMR (282 MHz, DMSO-d6): d 156.00; LC / MS: retention time 11.66 min; purity: 98.19%; MS (mass / charge): 449.43 (M-16). + - 1176 N2- [4- (N-Acetyl-N-methylamino) phenyl] -N4-cyclohexyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.32 (m, 5H), 1.64 (d, 1H), 1.74 (m, 2H), 1.90 (m, 2H), 3.09 (s , 3H), 3.32 (s, 3H), 3.88 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.5 Hz , 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 3.9 Hz, 1H), 9.15 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 166.21; LC / MS: retention time: 8.97 min; purity: 100%; MS (mass / charge): 358.18 (MH +). + - 1177 N4-Cyclohexyl-5-fluoro-N2- [3- (N-2-imidazolin-2-yl) aminophenyl] -2,4-pyrimidinediamine LC / MS: retention time: 6.42 min; purity: 86.49%; MS (mass / charge): 370.47 (MH +). - - 1178 N2, N4-Bis [3- (oxazol-2-yl) phenyl] -5-fluoro-2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 7.22 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 9.3 Hz, 2H), 7.40 (t, J = 8 , 1 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 8.11 (d, 2H), 8.18 (d, J = 3.6 Hz, 1H), 8.24 ( t, J = 1.8 Hz, 1H), 8.29 (t, 1H), 9.48 (s, 1H), 9.60 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.99; LC / MS: retention time: 11.53 min; purity: 95.22%; MS (mass / charge): 415.02 (MH +). - - 1179 N4-Cyclobutyl-5-fluoro-N4-methyl-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.53-1.71 (m, 2H), 2.11-2.32 (m, 4H), 3.16 (d, J = 3.6 Hz, 3H) , 4.89 (m, J = 8.4 Hz, 1H), 7.36 (d, J = 0.9 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7 57 (m, 2H), 8.06 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 0.9 Hz, 1H), 8.57 (t, J = 1, 8 Hz, 1H); 9.68 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 156.69; LC / MS: retention time: 11.99 min; purity: 95.24%; MS (mass / charge): 340.18 (MH +). + - 1180 (S) -N4- (1-Benzylpyrrolidin-3-yl) -5-fluoro-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.83 (m, 1H), 2.16 (m, 1H), 2.40 (dd, J = 5.1, 9.3 Hz, 1H), 2.58 (m, 2H), 2.89 (dd, J = 7.2, 9.3 Hz, 1H), 2.99 (t, J = 4.8 Hz, 4H), 3.58 (d, J = 1.8 Hz, 2H), 3.72 (t, J = 4.8 Hz, 4H), 4.41 (m, 1H), 6.78 (d, J = 9.0 Hz, 2H), 7 , 22 (m, 1H), 7, 22 (m, 1H), 7.29 (d, 4H), 7.35 (d, J = 6.6 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 3.9 Hz, 1H), 8.73 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 167.51; LC / MS: retention time: 5.99 min; purity: 99.07%; MS (mass / charge): 449 (MH +). + - 1181 (S) -N2- [4- (4-Acetylpiperazino) phenyl] -N4- (1-benzylpyrrolidin-3-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.81-1.87 (m, 1H), 2.03 (s, 3H), 2.14-2.23 (m, 1H), 2.40 (dd, J = 5.7, 9.6 Hz, 1H), 2.56 (m, 2H), 2.89 (dd, J = 7.2, 9.3 Hz, 1H), 2.95 (t, J = 5.1 Hz, 2H), 3.02 (t, J = 5.1 Hz, 2H), 3.55 (m, 4H), 3.58 (s, 2H), 4.41 (m, 1H ), 6.81 (d, J = 9.0 Hz, 2H), 7.22 (m, 1H), 7.29 (d, 4H), 7.35 (d, J = 6.3 Hz, 1H ), 7.51 (d, J = 9.3 Hz, 2H), 7.78 (d, J = 3.9 Hz, 1H), 8.75 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 167.42; LC / MS: retention time: 5.81 min; purity: 97.77%; MS (mass / charge): 490.27 (MH +). + - 1182 (S) -N4- (1-Benzylpyrrolidin-3-yl) -5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 1.17 min; purity: 95.41%; MS (mass / charge): 462.15 (MH +). - -

1183 (S) -N4- (1-Benzylpyrrolidin-3-yl) -N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.83 (m, 1H), 2.17 (m, 1H), 2.40 (dd, J = 5.1, 9.0 Hz, 1H), 2.56 (m, 2H), 2.89 (dd, J = 7.2, 9.0 Hz, 1H), 2.98 (t, J = 5.1 Hz, 4H), 3.49 (t, J = 5.1 Hz, 4H), 3.58 (d, J = 1.8 Hz, 2H), 4.05 (q, J = 7 , 2 Hz, 2H), 4.44 (m, 1H), 6.80 (d, J = 9.0 Hz, 2H), 7.22 (m, 1H), 7.28 (d, 4H), 7.35 (d, J = 6.6 Hz, 1H), 7.50 (d, J = 9.3 Hz, 2H), 7.77 (d, J = 3.9 Hz, 1H), 8, 75 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 167.41; LC / MS: retention time: 7.42 min; purity: 95.27%; MS (mass / charge): 520.22 (MH +). + - 1184 (S) -N4- (1-Benzylpyrrolidin-3-yl) -5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine LC / MS: retention time: 6.81 min; purity: 100%; MS (mass / charge): 449 (MH +). + - 1185 (S) -N2- [3- (4-Acetylpiperazino) phenyl] -N4- (benzylpyrrolidin-3-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.82-1.88 (m, 1H), 2.02 (s, 3H), 2.16-2.26 (m, 1H), 2.37 (dd, J = 5.7, 9.0 Hz, 1H), 2.56 (m, 2H), 2.92 (dd, J = 6.9, 9.0 Hz, 1H), 3.03 (t, J = 5.1 Hz, 2H), 3.10 (t, J = 5.1 Hz, 2H), 3.56 (m, 4H), 3.58 (s, 2H), 4.53 (m, 1H ), 6.47 (d, J = 8.4 Hz, 1H), 7.02 (t, J = 8.1 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.21 (m, 1H), 7.28 (d, 4H), 7.46 (m, 2H), 7.82 (d, J = 3.9 Hz, 1H), 8.87 (br. 1H ); 19F NMR (282 MHz, DMSO- d6 ): d 166.63; LC / MS: retention time: 6.43 min; purity: 94.97%; MS (mass / charge): 490.40 (MH +). + - 1186 (S) -N4- (1-Benzylpyrrolidin-3-yl) -5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 2.79 min; purity: 97.87%; MS (mass / charge): 462 (MH +). + - 1187 (S) -N4- (1-Benzylpyrrolidin-3-yl) -N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.18 (t, J = 7.2 Hz, 3H), 1.82 (m, J = 6.5 Hz, 1H), 2.19 (m, 1H), 2.37 (dd, J = 5.7, 9.0 Hz, 1H), 2.56 (m, 2H), 2.91 (dd, J = 7.2, 9.0 Hz, 1H), 3 06 (t, J = 5.1 Hz, 4H), 3.51 (t, J = 5.1 Hz, 4H), 3.58 (s, 2H), 4.04 (q, J = 7 , 2 Hz, 2H), 4.55 (m, 1H), 6.46 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 7, 07 (d, J = 7.5 Hz, 1H), 7.22 (m, 1H), 7.27 (m, 4H), 7.47 (m, 2H), 7.82 (d, J = 3 9 Hz, 1H); 8.86 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 166.66; LC / MS: retention time: 8.25 min; purity: 97.24%; MS (mass / charge): 520.41 (MH +). + - 1188 N4-Cyclobutyl-5-fluoro-N2- [3-chloro-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.61-1.73 (m, 2H), 2.01-2.14 (m, 2H), 2.25-2.33 (m, 2H), 2, 29 (s, 3H), 2.55 (m, 4H), 2.91 (t, 4H), 4.47 (m, J = 8.1 Hz, 1H), 7.03 (d, J = 8 , 7 Hz, 1H), 7.43 (dd, J = 2.7, 9.0 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.84 (d, J = 3.6 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 9.08 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 166.50; LC / MS: retention time: 11.07 min; purity: 93.70%; MS (mass / charge): 391.10 (MH +). + 1189 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine bis-p-toluenesulfonic acid salt 1 H NMR (DMSO-d6): d 2.28 (s, 6H), 2.86 (d, J = 4.8 Hz, 3H), 2.92 (m, 2H), 3.13 (q, J = 10.8 Hz, 2H), 3.49 (m, 4H), 3.74 (d, J = 13.2 Hz, 2H), 4.15 (t, J = 4.2 Hz, 2H) 6.66 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 8.4 Hz, 4H), 7 , 17 (m, 4H), 7.45 (d, J = 8.1 Hz, 4H), 8.19 (d, J = 3.6 Hz, 1H), 9.42 (br. 1H), 9 51 (br. 1H); 9.95 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.24; LC / MS: retention time: 1.60 min; purity: 98.21%; MS (mass / charge): 436.77 (MH +). + + 1190 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine bis hydrochloride salt 1 H NMR (DMSO-d6): d 2.81 (d, J = 4.5 Hz, 3H), 3.08 (m, 4H), 3.48 (d, J = 11.7 Hz, 2H), 3.55 (t, 2H), 3.72 (d, J = 11.7 Hz, 2H), 4.18 (t, J = 4.2 Hz, 2H), 6.65 (d, J = 9 , 0 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.41 (m, 2H), 8.30 (d, J = 3.3 Hz, 1H), 10.45 (br. 1H), 10.59 (br. 1H), 10, 72 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.32; LC / MS: retention time: 1.51 min; purity: 100%; MS (mass / charge): 437.08 (MH +). + + 1191 N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -N4-cyclohexyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.14 (m, 1H), 1.33 (m, 4H), 1.63 (d, 1H), 1.74 (m, 2H), 1.90 (m , 2H), 2.21 (s, 3H), 2.45 (m, 4H), 2.88 (t, 4H), 3.89 (m, 1H), 7.01 (d, J = 8, 7 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.39 (dd, J = 2.4, 8.4 Hz, 1H), 7.81 (d, J = 3.9 Hz, 1H), 8.03 (d, J = 2.1 Hz, 1H), 9.05 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 166.45; LC / MS: retention time: 1.57 min; purity: 96.83%; MS (mass / charge): 419.15 (MH +). + + 1192 N2- [4- (4-Acetylpiperazino) phenyl] -N4-cyclobutyl-5-fluoro-2,4-pyrimidinediamine bis hydrochloride salt 1 H NMR (DMSO-d6): d 1.65-1.76 (m, 2H), 2.04 (s, 3H), 2.08-2.26 (m, 4H), 3.10 (t, 2H), 3.17 (t, 2H), 3.58 (t, 4H), 4.43 (m, J = 7.8 Hz, 1H), 7.02 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 5.1 Hz, 1H), 9.10 (br, 1H), 10.02 (br ., 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.88; LC / MS: retention time: 15.12 min; purity: 97.62%; MS (mass / charge): 385.16 (MH +). + 1193 N4-Cyclohexyl-5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine salt of bis-p-toluenesulfonic acid 1 H NMR (DMSO-d6): d 1.24 (m, 4H), 1.37 (q, 1H), 1.62 (d, 1H), 1.76 (d, 2H), 1.85 ( d, 2H), 2.28 (s, 6H), 2.86 (d, J = 3.9 Hz, 3H), 2.92 (d, 2H), 3.15 (m, 2H), 3, 52 (d, 2H), 3.80 (d, 3H), 7.00 (d, J = 9.3 Hz, 2H), 7.09 (d, J = 7.8 Hz, 4H), 7, 36 (d, J = 9.3 Hz, 2H), 7.45 (d, J = 8.1 Hz, 4H), 8.01 (d, J = 6.0 Hz, 1H), 8.94 ( broad 1H), 9.53 (broad 1H), 9.92 (broad 1H); 19F NMR (282 MHz, DMSO- d6 ): d 162.18; LC / MS: retention time: 1.52 min; purity: 99.98%; MS (mass / charge): 384.89 (MH +). + 1194 N4-Cyclohexyl-5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine bis hydrochloride salt 1 H NMR (DMSO-d6): d 1.33 (m, 5H), 1.61 (d, 1H), 1.77 (d, 2H), 1.87 (d, 2H), 2.79 (d , J = 4.8 Hz, 3H), 3.09 (m, 4H), 3.47 (d, 2H), 3.78 (d, 2H), 3.83 (m, 1H), 7.01 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 8.10 (d, J = 5.4 Hz, 1H), 9.08 (d , J = 8.1 Hz, 1H), 10.46 (br. 1H), 10.91 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 161.93; LC / MS: retention time: 1.55 min; purity: 99.46%; MS (mass / charge): 385.20 (MH +)., + 1195 N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -N4-cyclopentyl-5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 1.55 (m, 4H), 1.71 (m, 2H), 1.98 (m, 2H), 2.31 (s, 3H), 2.57 (m , 4H), 2.91 (t, 4H), 4.30 (q, J = 6.9 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 7.36 ( d, J = 6.9 Hz, 1H), 7.43 (dd, J = 2.7, 9.0 Hz, 1H), 7.82 (d, J = 3.9 Hz, 1H), 8, 07 (d, J = 2.4 Hz, 1H); 9.08 (br. 1H); 19F NMR (282 MHz, DMSO- d6 ): d 166.32; LC / MS: retention time: 13.47 min; purity: 87.25%; MS (mass / charge): 405.47 (MH +). + 1196 N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -N4- (3-cyclopropyl-1H-pyrazol-5-yl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 0.69 (m, 2H), 0.91 (m, 2H), 1.87 (m, 1H), 2.22 (s, 3H), 2.46 (m , 4H), 2.90 (t, 4H), 6.31 (br., 1H), 7.04 (d, J = 9.0 Hz, 1H), 7.51 (br., 1H), 7 79 (s, 1H), 8.02 (s, 1H), 9.14 (broad, 1H), 9.52 (broad, 1H), 12.07 (broad, 1H); 19F NMR (282 MHz, DMSO- d6 ): d 164.15; LC / MS: retention time: 1.65 min; purity: 92.40%; MS (mass / charge): 443.15 (MH +). + 1197 N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -N4- (3,4-dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 2.21 (s, 3H), 2.45 (t, 4H), 2.88 (t, 4H), 3.39 (m, 2H), 4.09 (t , J = 4.2 Hz, 2H), 6.53 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H ), 7.12 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 2.7, 8.7 Hz, 1H), 7.84 (d, J = 2.7 Hz , 1H), 8.04 (d, J = 3.6 Hz, 1H), 8.80 (s, 1H), 9.20 (s, 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.49; LC / MS: retention time: 1.60 min; purity: 98.82%; MS (mass / charge): 471.12 (MH +). + + 1198 N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -N4-cyclobutyl-5-fluoro-2,4-pyrimidinediamine bis hydrochloride salt 1 H NMR (DMSO-d6): d 1.67-1.76 (m, 2H), 2.11-2.18 (m, 2H), 2.25-2.31 (m, 2H), 2, 82 (d, J = 4.5 Hz, 3H), 3.02-3.20 (m, 4H), 3.35 (m, 2H), 3.48 (m, 2H), 4.44 (m , J = 7.5 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.40 (dd, J = 2.4, 8.7 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 4.8 Hz, 1H), 8.79 (br. 1H), 10.09 (br. 1H), 10.60 (broad. 1H); 19F NMR (282 MHz, DMSO- d6 ): d - 163.03; LC / MS: retention time: 10.61 min; purity: 93.48%; MS (mass / charge): 391 (MH +). + 1199 N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -N4-cyclohexyl-5-fluoro-2,4-pyrimidinediamine bis hydrochloride salt 1 H NMR (DMSO-d6): d 1.17 (m, 1H), 1.36 (m, 4H), 1.63 (d, 1H), 1.78 (m, 2H), 1.86 (m , 2H), 2.83 (d, J = 4.8 Hz, 3H), 3.00-3.20 (m, 4H), 3.34 (m, 2H), 3.48 (m, 2H) 3.87 (m, 1H), 7.16 (d, J = 8.7 Hz, 1H), 7.36 (dd, J = 2.4, 9.0 Hz, 1H), 7.96 ( d, J = 2.4 Hz, 1H) 8.03 (d, J = 5.1 Hz, 1H), 8.41 (br 1H), 10.05 (br 1H), 10.50 (br . 1H); LC / MS: retention time: 14.78 min; purity: 90.99%; MS (mass / charge): 419.39 (MH +). + + 1200 N4-Cyclopentyl-5-fluoro-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 9.70 min; purity: 89.34%; MS (mass / charge): 385 (MH +). + 1201 N4-Cyclohexyl-5-fluoro-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 11.34 min; purity: 94.34%; MS (mass / charge): 399.24 (MH +). + + 1202 N4- (3-Cyclopropyl-1H-pyrazol-5-yl) -5-fluoro-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 10.35 min; purity: 96.72%; MS (mass / charge): 423 (MH +). + + 1203 N4- (3,4-Dihydro-2H, 4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -2 4-pyrimidinediamine LC / MS: retention time: 10.77 min; purity: 93.79%; MS (mass / charge): 451 (MH +). + + 1204 5-Fluoro-N4-isopropyl-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 3.64 min; purity: 95.29%; MS (mass / charge): 345 (MH +). + 1205 N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -5-fluoro-N4-isopropyl-2,4-pyrimidinediamine LC / MS: retention time: 5.14 min; purity: 92.47%; MS (mass / charge): 379 (MH +). + 1206 5-Fluoro-N4-isopropyl-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 1.99 min; purity: 93.17%; MS (mass / charge): 359 (MH +). + - 1207 N4-Cyclobutyl-5-fluoro-N2- [4- (4-methylpiperazino) -3-trifluoromethylphenyl] -2,4-pyrimidinediamine LC / MS: retention time: 15.09 min; purity: 94.19%; MS (mass / charge): 425 (MH +). + 1208 N4-Cyclopentyl-5-fluoro-N2- [4- (4-methylpiperazino) -3-trifluoromethylphenyl] -2,4-pyrimidinediamine LC / MS: retention time: 15.32 min; purity: 92.83%; MS (mass / charge): 439.30 (MH +). + 1209 N4-Cyclohexyl-5-fluoro-N2- [4- (4-methylpiperazino) -3-trifluoromethylphenyl] -2,4-pyrimidinediamine LC / MS: retention time: 15.74 min; purity: 95.26%; MS (mass / charge): 453 (MH +). + 1210 5-Fluoro-N4-isopropyl-N2- [4- (4-methylpiperazino) -3-trifluoromethylphenyl] -2,4-pyrimidinediamine LC / MS: retention time: 7.29 min; purity: 88.24%; MS (mass / charge): 413.05 (MH +). + 1211 N4- (3-Cyclopropyl-1H-pyrazol-5-yl) -5-fluoro-N2 - [(4-methylpiperazino) -3-trifluoromethylphenyl] -2,4-pyrimidinediamine LC / MS: retention time: 8.27 min; purity: 94.19%; MS (mass / charge): 477 (MH +). + 1212 2-chloro-5-fluoro-N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -4-pyrimidinamine LC / MS: retention time: 9.57 min; purity: 90.78%; MS (mass / charge): 301.19 (MH +). - 1213 2-chloro-N4- (1-ethoxycarbonylpiperidin-4-yl) -5-fluoro-4-pyrimidinamine LC / MS: retention time: 10.29 min; purity: 94%; MS (mass / charge): 303.04 (MH +). - 1214 5-Fluoro-N4-isopropyl-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 4.63 min; purity: 97.16%; MS (mass / charge): 345.41 (MH +). - 1215 N4-tert-Butyl-5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 2.80 min; purity: 97.03%; MS (mass / charge): 359 (MH +). - 1216 N4-tert-Butyl-5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 7.81 min; purity: 94.56%; MS (mass / charge): 359.23 (MH +). - 1217 N4-tert-Butyl-N2- [3-chloro-4- (4-methylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 10.53 min; purity: 93.25%; MS (mass / charge): 393 (MH +). + 1218 N4-tert-Butyl-5-fluoro-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 4.35 min; purity: 87.23%; MS (mass / charge): 373.26 (MH +). + 1219 5-Fluoro-N2- [4- (4-methylpiperazino) phenyl] -N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine LC / MS: retention time: 1.30 min; purity: 95.14%; MS (mass / charge): 456.63 (MH +). - 1220 N4-Cyclobutyl-5-fluoro-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 9.16 min; purity: 93.00%; MS (mass / charge): 371.26 (MH +). + 1221 5-Fluoro-N2- [3- (4-methylpiperazino) phenyl] -N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine LC / MS: retention time: 1.40, 1.71 min; purity: 95%; MS (mass / charge): 456.30 (MH +). - 1222 N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -5-fluoro-N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine LC / MS: retention time: 1.44, 1.74 min; purity: 97%; MS (mass / charge): 490.11 (MH +). - 1223 5-Fluoro-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine LC / MS: retention time: 1.46, 2.03 min; purity: 100%; MS (mass / charge): 470.29 (MH +). + 1224 5-Fluoro-N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -N2- [3-trifluoromethyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 1.46, 2.70 min; purity: 97%; MS (mass / charge): 524.23 (MH +). - 1225 N4- (1-Ethoxycarbonylpiperidin-4-yl) -5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 6.13 min; purity: 95.45%; MS (mass / charge): 458 (MH +). + 1226 N4- (1-Ethoxycarbonylpiperidin-4-yl) -5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 9.94 min; purity: 97%; MS (mass / charge): 458.27 (MH +). + 1227 N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -N4- (1-ethoxycarbonylpiperidin-4-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 14.71 min; purity: 98.79%; MS (mass / charge): 492 (MH +). + 1228 N4- (1-Ethoxycarbonylpiperidin-4-yl) -5-fluoro-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 9.26 min; purity: 97.16%; MS (mass / charge): 472 (MH +). + 1229 N4- (1-Ethoxycarbonylpiperidin-4-yl) -5-fluoro-N2- [4- (4-methylpiperazino) -3-trifluoromethylphenyl] -2,4-pyrimidinediamine LC / MS: retention time: 15.48 min; purity: 97.96%; MS (mass / charge): 526 (MH +). + 1230 N4-Cyclobutyl-N2- [2- (4-ethylpiperazino) pyrid-5-yl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 5.52 min; purity: 94.98%; MS (mass / charge): 372 (MH +). + 1231 N4-Cyclopentyl-N2- [2- (4-ethylpiperazino) pyrid-5-yl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 6.27 min; purity: 90.61%; MS (mass / charge): 386.36 (MH +). + 1232 N4-Cyclohexyl-N2- [2- (4-ethylpiperazino) pyrid-5-yl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 6.83 min; purity: 97.62%; MS (mass / charge): 400 (MH +). + 1233 N4-tert-Butyl-5-fluoro-N2- [4- (4-methylpiperazino) -3-trifluoromethylphenyl] -2,4-pyrimidinediamine LC / MS: retention time: 15.37 min; purity: 96.00%; MS (mass / charge): 427 (MH +). + 1234 N2- [2- (4-Ethylpiperazino) pyrid-5-yl] -5-fluoro-N4-isopropyl-2,4-pyrimidinediamine LC / MS: retention time: 1.44, 1.80 min; purity: 96%; MS (mass / charge): 360.28 (MH +). + 1235 N4-Cyclobutyl-5-fluoro-N2- [3-hydroxymethyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 1.82 min; purity: 90%; MS (mass / charge): 387.14 (MH +). - 1236 N4-tert-Butyl-N2- [2- (4-ethylpiperazino) pyrid-5-yl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 4.27 min; purity: 100%; MS (mass / charge): 374.18 (MH +). - 1237 N2- [2- (4-Ethylpiperazino) pyrid-5-yl] -5-fluoro-N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine LC / MS: retention time: 1.27 min; purity: 99.58%; MS (mass / charge): 471.73 (MH +). - 1238 N4- (1-Ethoxycarbonylpiperidin-4-yl) -N2- [2- (4-ethylpiperazino) pyrid-5-yl] -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 7.03 min; purity: 94.74%; MS (mass / charge): 473 (MH +). - 1239 N4-Cyclobutyl-5-fluoro-N2- [2- (4-methylpiperazino) -3-methylpyrid-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 9.65 min; purity: 97.08%; MS (mass / charge): 372.11 (MH +). - 1240 N4-Cyclopentyl-5-fluoro-N2- [2- (4-methylpiperazino) -3-methylpyrid-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 10.50 min; purity: 91.36%; MS (mass / charge): 385.85 (MH +). + 1241 N4-Cyclohexyl-5-fluoro-N2- [2- (4-methylpiperazino) -3-methylpyrid-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 9.22 min; purity: 93.96%; MS (mass / charge): 400.11 (MH +). + 1242 5-Fluoro-N4-isopropyl-N2- [2- (4-methylpiperazino) -3-methylpyrid-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 4.21 min; purity: 91.67%; MS (mass / charge): 360.15 (MH +). + 1243 N4-Cyclobutyl-5-fluoro-N2- [3-hydroxymethyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine bis hydrochloride salt LC / MS: retention time: 1.43, 1.85 min; purity: 94%; MS (mass / charge): 387.05 (MH +). + 1244 5-Fluoro-N2- [2- (4-methylpiperazino) -3-methylpyrid-5-yl] -N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine LC / MS: retention time: 7.05 min; purity: 95.56%; MS (mass / charge): 471.26 (MH +). - 1245 N4-Cyclobutyl-5-fluoro-N2- [2- (4-methylpiperazino) -4-methylpyrid-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 9.37 min; purity: 92.45%; MS (mass / charge): 371.99 (MH +). - 1246 N4-Cyclopentyl-5-fluoro-N2- [2- (4-methylpiperazino) -4-methylpyrid-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 10.12 min; purity: 95.69%; MS (mass / charge): 386.09 (MH +). - 1247 N4-Cyclohexyl-5-fluoro-N2- [2- (4-methylpiperazino) -4-methylpyrid-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 10.35 min; purity: 92.30%; MS (mass / charge): 400.13 (MH +). + 1248 5-Fluoro-N4-isopropyl-N2- [2- (4-methylpiperazino) -4-methylpyrid-5-yl] -2,4-pyrimidinediamine LC / MS: retention time: 6.77 min; purity: 84.20%; MS (mass / charge): 359.97 (MH +). - 1249 5-Fluoro-N2- [2- (4-methylpiperazino) -4-methylpyrid-5-yl] -N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine LC / MS: retention time: 1.48, 2.77 min; purity: 98%; MS (mass / charge): 471.22 (MH +). - 1250 5-Fluoro-N4- (1-hydroxymethylcyclopent-1-yl) -N2- [3-methyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine LC / MS: retention time: 11.16 min; purity: 99.47%; MS (mass / charge): 415.57 (MH +). + 1251 N4- (5-amino-1,2,4-triazol-3-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine LC / MS: purity: 93.2%; MS (mass / charge): 374.52 (MH +, 100). + 1252 N4- (3-amino-1,2,4-triazol-5-yl) -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO): d 8.71 (d, 1H, J = 4.5 Hz), 7.75 (s, 1H), 7.53 (s, 2H), 7.21 (s, 1H) 6.61-6.74 (m, 2H); 5.83 (br s, 2H); 2.43 (s, 6H); LC / MS: purity: 88.8%; MS (mass / charge): 315.24 (MH +, 100). - 1253 N4- (5-amino-1,2,4-triazol-3-yl) -N2- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 92.8%; MS (mass / charge): 351.09 (MH +, 100). - 1254 N4- (5-amino-1,2,4-triazol-3-yl) -N2- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 93.2%; MS (mass / charge): 355.23 (MH +, 100). - 1255 N4- (5-amino-1,2,4-triazol-3-yl) -5-fluoro-N2- (indazol-6-yl) -2,4-pyrimidinediamine LC / MS: purity: 94.3%; MS (mass / charge): 327.14 (MH +, 100). + + 1256 N4 - [(2,3-Dihydro-1,4-benzodioxan-2-yl) methyl] -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.09 (br s, 1H), 9.12 (br s, 1H), 8.13 (d, 1H, J = 5.1 Hz), 7.17 ( s, 2H), 6.74-6.87 (m, 5H), 4.29-4.50 (m, 2H), 3.98 (dd, 1H, 6.3, 11.4 Hz), 3 59-3.80 (m, 2H); 2.23 (s, 6H); LC / MS: purity: 97.8%; MS (mass / charge): 379.14 (M-, 100). + 1257 N4 - [(2,3-Dihydro-1,4-benzodioxan-2-yl) methyl] -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine LC / MS: purity: 97.4%; MS (mass / charge): 438.13 (M-, 100). + 1258 N4 - [(2,3-Dihydro-1,4-benzodioxan-2-yl) methyl] -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.13 (s, 1H), 9.05 (br s, 1H), 8.19 (d, 1H, J = 4.8 Hz), 6.79-6, 86 (m, 6H), 6.24 (m, 1H), 4.29-4.49 (m, 2H), 4.00 (dd, 1H, 6.9, 11.4 Hz), 3.62 -3.79 (m, 8H); LC / MS: purity: 96.7%; MS (mass / charge): 411.10 (M-, 100). + 1259 N2- (3-Chloro-4-methoxyphenyl) -N4 - [(2,3-dihydro-1,4-benzodioxan-2-yl) methyl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.22 (s, 1H), 9.11 (br s, 1H), 8.12 (d, 1H, J = 5.1 Hz), 7.70 (d, 1H, J = 2.4 Hz), 7.35 (dd, 1H, J = 2.7, 9.0 Hz), 7.08 (d, 1H, J = 9.0 Hz), 6.78- 6.87 (m, 4H), 4.28-4.49 (m, 2H), 3.99 (dd, 1H, 6.9, 11.7 Hz), 3.59-3.84 (m, 5H); LC / MS: purity: 96.4%; MS (mass / charge): 415.07 (M-, 100). + 1260 N4 - [(2,3-Dihydro-1,4-benzodioxan-2-yl) methyl] -5-fluoro-N2- (indazol-6-yl) -2,4-pyrimidinediamine LC / MS: purity: 95.0%; MS (mass / charge): 391.10 (M-, 100). + 1261 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (4-methoxycarbonylphenyl) -2,4-pyrimidinediamine LC / MS: purity: 100%; MS (mass / charge): 405.09 (M-, 100). - 1262 N2- [4- (N-Carboxymethyleneamino) carbonylphenyl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 100%; MS (mass / charge): 450.11 (M-) - 1263 (S) -5-Fluoro-N2- (4-methoxycarbonylphenyl) -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.74 (s, 1H), 9.95 (s, 1H), 9.80 (s, 1H), 8.18 (d, 1H, J = 4.2 Hz) 7.20-7.79 (m, 6H), 6.96 (d, 1H, J = 9.3 Hz), 4.66 (q, 1H, J = 6.6 Hz), 3.78 (s, 3H), 1.45 (d, 3H, J = 6.6 Hz); LC / MS: purity: 96.8%; MS (mass / charge): 422.12 (M-, 100). + 1264 (S) -N2- [4- (N-Carboxymethyleneamino) carbonylphenyl] -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2 4-pyrimidinediamine ¹ H NMR (DMSO): d 10.75 (s, 1H), 9.88 (s, 1H), 9.63 (m, 1H), 8.19 (d, 1H, J = 4.5 Hz) , 7.19-7.75 (m, 6H), 6.98 (d, 1H, J = 8.7 Hz), 4.67 (q, 1H, J = 6.9 Hz), 3.89 (d, 1H, 5.7 Hz), 1.44 (d, 3H, J = 6.9 Hz); LC / MS: purity: 91.2%; MS (mass / charge): 465.21 (M-, 100). - 1265 (R) -N2- (4-Aminocarbonylphenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine LC / MS: purity: 95.5%; MS (mass / charge): 407.17 (M-, 100). + 1266 (R) -5-Fluoro-N2- (4-methoxycarbonylphenyl) -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.74 (s, 1H), 9.95 (s, 1H), 9.80 (s, 1H), 8.18 (d, 1H, J = 4.2 Hz) 7.20-7.79 (m, 6H), 6.96 (d, 1H, J = 9.3 Hz), 4.66 (q, 1H, J = 6.6 Hz), 3.78 (s, 3H), 1.45 (d, 3H, J = 6.6 Hz); LC / MS: purity: 98.5%; MS (mass / charge): 422.17 (M-, 100). + 1267 (R) -N2- [4- (N-Carboxymethyleneamino) carbonylphenyl] -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2 4-pyrimidinediamine ¹ H NMR (DMSO): d 10.75 (s, 1H), 9.88 (s, 1H), 9.63 (m, 1H), 8.19 (d, 1H, J = 4.5 Hz) , 7.19-7.75 (m, 6H), 6.98 (d, 1H, J = 8.7 Hz), 4.67 (q, 1H, J = 6.9 Hz), 3.89 (d, 1H, 5.7 Hz), 1.44 (d, 3H, J = 6.9 Hz); LC / MS: purity: 87.5%; MS (mass / charge): 465.21 (M-, 100). - 1268 N2, N4-Bis [4- (N-tert-butoxycarbonylamino) methylene phenyl] -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 100%; MS (mass / charge): 537.34 (M-, 100). + 1269 N2, N4-Bis (4-aminomethylene phenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO): d 9.25 (br s, 1H), 9.09 (br s, 1H), 8.05 (d, 1H, J = 2.4 Hz), 7.69 (d , 2H, J = 8.7 Hz), 7.56 (d, 2H, J = 8.7 Hz), 7.04-7.40 (m, 4H), 3.67 (s, 3H), 3 61 (s, 3H); 3.35 (br s, 4H); LC / MS: purity: 95.5%; MS (mass / charge): 337.18 (M-, 100) + + + + 1270 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [4- (N-methoxycarbonylmethyleneamino) carbonylphenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.21 (s, 2H), 8.33 (m, 1H), 8.33 (d, 1H, J = 4.5 Hz), 8.10 (d, 1H, J = 2.4 Hz), 7.59-7.83 (m, 6H), 3.99 (m, 2H), 3.65 (s, 3H); LC / MS: purity: 100%; MS (mass / charge): 462.11 (M-, 100). + 1271 (S) -5-Fluoro-N2- [4- (N-methoxycarbonylmethyleneamino) carbonylphenyl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2 4-pyrimidinediamine ¹ H NMR (DMSO): d 10.77 (s, 1H), 9.93 (br s, 1H), 8.77 (m, 1H), 8.20 (d, 1H, J = 4.5 Hz), 7.21-7.75 (m, 6H), 6.97 (d, 1H, J = 8.4 Hz), 4.66 (q, 1H, J = 6.6 Hz), 3 97 (m, 2H); 3.64 (s, 3H); 1.44 (d, 3H; J = 6.6 Hz); LC / MS: purity: 96.7%; MS (mass / charge): 481.16 (MH +, 100). + - 1272 (R) -5-Fluoro-N2- [4- (N-methoxycarbonylmethyleneamino) carbonylphenyl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2 4-pyrimidinediamine ¹ H NMR (DMSO): d 10.77 (s, 1H), 9.93 (br s, 1H), 8.77 (m, 1H), 8.20 (d, 1H, J = 4.5 Hz), 7.21-7.75 (m, 6H), 6.97 (d, 1H, J = 8.4 Hz), 4.66 (q, 1H, J = 6.6 Hz), 3 97 (m, 2H); 3.64 (s, 3H); 1.44 (d, 3H; J = 6.6 Hz); LC / MS: purity: 100%; MS (mass / charge): 481.39 (MH +, 100). + - 1273 N2, N4-Bis [3- (N-tert-butoxycarbonylamino) methylene phenyl] -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO): d 9.43 (s, 1H), 9.22 (s, 1H), 9.08 (d, 1H, J = 3.6 Hz), 7.24-7.72 ( m, 7H), 7.15 (t, 1H, J = 7.8 Hz), 6.94 (d, 1H, J = 7.5 Hz), 6.78 (d, 1H, J = 7.5 Hz), 4.08 (m, 4H), 1.39 (s, 18H); LC / MS: purity: 95.8%; MS (mass / charge): 537.16 (M-, 100). + 1274 N2, N4-Bis (3-aminomethylene phenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO): d 9.24 (s, 1H), 8.35 (s, 1H), 8.01-8.07 (m, 2H), 6.73-7.71 (m, 7H ), 3.69 (s, 2H); 3.61 (s, 2H); LC / MS: purity: 100%; MS (mass / charge): 337.21 (M-, 100). + + 1275 N2- [3- (N-tert-butoxycarbonylamino) methylene phenyl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: purity: 93.5%; MS (mass / charge): 476.19 (M-, 100). + + 1276 (S) -N2- [3- (N-tert-Butoxycarbonylamino) methylene phenyl] -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.61 (s, 1H), 9.30 (s, 1H), 9.04 (s, 1H), 8.03 (d, 1H, J = 3.9 Hz) 7.22-7.54 (m, 5H), 7.10 (t, 1H, J = 7.5 Hz), 6.92 (d, 1H, J = 7.5 Hz), 4.64 ( q, 1H, J = 6.6 Hz), 4.01 (m, 2H), 1.44 (d, 3H, J = 6.6 Hz), 1.39 (s, 9H); LC / MS: purity: 95.1%; MS (mass / charge): 493.28 (M-, 100). + + 1277 (R) -N2- [3- (N-tert-Butoxycarbonylamino) methylene phenyl] -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) ¹ H NMR (DMSO): d 10.61 (s, 1H), 9.30 (s, 1H), 9.04 (s, 1H), 8.03 (d, 1H, J = 3.9 Hz) 7.22-7.54 (m, 5H), 7.10 (t, 1H, J = 7.5 Hz), 6.92 (d, 1H, J = 7.5 Hz), 4.64 ( q, 1H, J = 6.6 Hz), 4.01 (m, 2H), 1.44 (d, 3H, J = 6.6 Hz), 1.39 (s, 9H); LC / MS: purity: 92.2%; MS (mass / charge): 493.28 (M-, 100). + + 1278 N2- (3-Aminomethylene phenyl) -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine ¹ H NMR (DMSO): d 9.60 (br s, 1H), 9.31 (s, 1H), 8.16 (d, 1H, J = 3.6 Hz), 8.12 (d, 1H, J = 2.7 Hz), 6.81-7.88 (m, 6H), 3.70 (s, 2H); LC / MS: purity: 96.4%; MS (mass / charge): 376.11 (M-, 100). + + 1279 (S) -N2- (3-aminomethylene phenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine ¹ H NMR (DMSO): d 9.30 (s, 1H), 9.08 (s, 1H), 8.05 (m, 1H), 6.76-7.60 (m, 8H), 4, 63 (q, 1H, J = 6.9 Hz), 3.64 (s, 2H), 1.43 (d, 3H, J = 6.9 Hz); LC / MS: purity: 100%; MS (mass / charge): 393.20 (M-, 100). + + 1280 (R) -N2- (3-aminomethylene phenyl) -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl-2,4-pyrimidinediamine ¹ H NMR (DMSO): d 9.30 (s, 1H), 9.08 (s, 1H), 8.05 (m, 1H), 6.76-7.60 (m, 8H), 4, 63 (q, 1H, J = 6.9 Hz), 3.64 (s, 2H), 1.43 (d, 3H, J = 6.9 Hz); LC / MS: purity: 98.5%; MS (mass / charge): 393.20 (M-, 100). + + 1281 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4 pyrimidinediamine ¹ H NMR (DMSO): d 10.69 (s, 1H), 10.18 (br s, 1H), 8.25 (d, 1H, J = 4.5 Hz), 8.12-8, 17 (m, 2H), 7.73 (d, 1H, J = 8.1 Hz), 7.62 (d, 1H, J = 7.5 Hz), 7.21-7.39 (m, 4H ), 6.76 (d, 1H, J = 8.4 Hz), 1.38 (s, 6H); LC / MS: purity: 100%; MS (mass / charge): 445.14 (M-, 100). + + - 1282 (S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.69 (s, 1H), 9.98 (br s, 2H), 8.22 (d, 1H, J = 2.4 Hz), 8.16 (m, 1H), 7.21-7.75 (m, 6H), 6.78 (d, 1H, J = 8.4 Hz), 4.62 (q, 1H, J = 6.9 Hz), 1 42 (d, 3H, J = 6.9 Hz); LC / MS: purity: 97.3%; MS (mass / charge): 431.15 (M-, 100). + + - 1283 (R) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.69 (s, 1H), 9.98 (br s, 2H), 8.22 (d, 1H, J = 2.4 Hz), 8.16 (m, 1H), 7.21-7.75 (m, 6H), 6.78 (d, 1H, J = 8.4 Hz), 4.62 (q, 1H, J = 6.9 Hz), 1 42 (d, 3H, J = 6.9 Hz); LC / MS: purity: 94.9%; MS (mass / charge): 431.15 (M-, 100). + + - 1284 N4- (2,2-Difluoro-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4 pyrimidinediamine ¹ H NMR (DMSO): d 12.05 (s, 1H), 10.05 (s, 1H), 9.95 (s, 1H), 8.27 (m, 1H), 8.25 (d, 1H, J = 4.5 Hz), 8.14 (s, 1H), 7.32-7.75 (m, 6H), 7.13 (d, 1H, J = 9.0 Hz); LC / MS: purity: 98.0%; MS (mass / charge): 453.12 (M-, 100). + + - 1285 N4- (4-amino-3,4-dihydro-2H-1-benzopyran-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine LC / MS: purity: 87.8%; MS (mass / charge): 417.18 (M-, 100). + + - 1286 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (N-methoxycarbonylmethyleneamino) carbonylphenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.71 (s, 1H), 9.91 (br s, 1H), 8.73 (m, 1H), 1.19 (d, 1H, J = 4.5 Hz), 7.19-7.74 (m, 6H), 6.94 (d, 1H, J = 8.4 Hz), 3.97 (m, 2H), 3.64 (s, 3H), 1.38 (s, 6H); LC / MS: purity: 97.5%; MS (mass / charge): 493.22 (M-, 100). + + - + 1287 N4- (4-N-tert-butoxycarbonylamino-3,4-dihydro-2H-1-benzopyran-6-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4 pyrimidinediamine LC / MS: purity: 89.3%; MS (mass / charge): 517.26 (M-, 100). + - 1288 N4- (4-N-tert-butoxycarbonylamino-3,4-dihydro-2H-1-benzopyran-6-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4 pyrimidinediamine LC / MS: purity: 96.6%; MS (mass / charge): 516.90 (M-, 100). + + + 1289 N4- (4-N-tert-butoxycarbonylamino-3,4-dihydro-2H-1-benzopyran-6-yl) -5-fluoro-N2- [4- (oxazol-2-yl) phenyl] -2,4 pyrimidinediamine LC / MS: purity: 87.2%; MS (mass / charge): 517.54 (M-, 100). + + 1290 5-Fluoro-N4- (4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl) -N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine LC / MS: purity: 100%; MS (mass / charge): 518.16
(M-, 100). + + - 1291 5-Fluoro-N4- (4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl) -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ¹ H NMR (DMSO): d 10.40 (s, 1H), 10.25 (s, 1H), 8.26 (d, 1H, J = 4.8 Hz), 8.15 (s, 1H) 7.65-7.83 (m, 4H), 7.50 (d, 1H, J = 2.7 Hz), 7.40 (dd, 1H, J 2.7, 8.4 Hz), 7 32 (s, 1H), 6.81 (d, 1H, J = 8.7 Hz), 4.59 (t, 1H, J = 5.1 Hz), 4.20-4.24 (m, 2H), 1.70-2, 10 (m, 2H); LC / MS: purity: 94.0%; MS (mass / charge): 418.03 (M-, 100). + + - 1292 (R, S) -N4- [4-amino-3,4-dihydro-2H-1-benzopyran-6-yl] -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2 4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.25 (s, 1H), 9.19 (s, 1H), 8.35 (s, 1H), 8.05 (d, J = 3.6 Hz, 1H ), 7.99 (m, 1H), 7.20-7.63 (m, 5H), 6.62 (d, J = 8.7 Hz, 1H), 3.86-4.20 (m, 3H), 1.75-2.0 (m, 2H); LC / MS: purity: 91.8%; MS (mass / charge): 419.3 (MH +). + + - 1293 (R, S) -N4- [4-amino-3,4-dihydro-2H-1-benzopyran-6-yl] -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2 4-pyrimidinediamine LC / MS: purity: 98.0%; MS (mass / charge): 419.2 (MH +). + 1294 (R, S) -N4- [4-amino-3,4-dihydro-2H-1-benzopyran-6-yl] -5-fluoro-N2- [4- (oxazol-2-yl) phenyl] -2 4-pyrimidinediamine LC / MS: purity: 93.5%; MS (mass / charge): 419.3 (MH +). + 1295 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- [N- (N-methylamino) carbonylmethylene] aminocarbonylphenyl] - 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.73 (s, 1H), 9.97 (s, 1H), 9.87 (s, 1H), 8.53 (m, 1H), 8.19 (d , J = 4.2 Hz, 1H), 7.66-7.83 (m, 5H), 7.24-7.27 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 3.78 (d, J = 5.7 Hz, 2H), 2.58 (d, J = 4.5 Hz, 3H), 1.41 (s, 6H); purity 98.2%; MS (mass / charge): 494.3 (MH +). + + - 1296 (S) -5-Fluoro-N2- [4- [N- (N-methylamino) carbonylmethylene] aminocarbonylphenyl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6 -yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.85 (s, 1H), 10.21 (s, 1H), 9.98 (s, 1H), 8.58 (m, 1H), 8.22 (d , J = 4.5 Hz, 1H), 7.68-7.79 (m, 6H), 7.43 (m, 1H), 7.23 (m, 1H), 6.95 (d, J = 9.0 Hz, 1H), 4.65 (q, J = 6.3 Hz, 1H), 3.79 (m, 2H), 2.58 (d, J = 4.5 Hz, 3H), 1.43 (d, J = 6.3 Hz, 3H); LC / MS: purity: 100%; MS (mass / charge): 480.3 (MH +). + + - 1297 N4- (2,2-Difluoro-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- [N- (N-methylamino) carbonylmethylene] aminocarbonylphenyl] - 2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 12.11 (s, 1H), 9.87 (s, 1H), 9.81 (s, 1H), 8.53 (m, 1H), 8.20 (d , J = 3.9 Hz, 1H), 7.67-7.78 (m, 6H), 7.54 (dd, J = 2.4, 8.7 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 3.79 (d, J = 6.0 Hz, 2H), 2.58 (d, J = 4.2 Hz, 1H); LC / MS: purity: 97.8%; MS (mass / charge): 502.3 (MH +). + - 1298 (R, S) -N4- [4- (N-tert-butoxycarbonyl) amino-3,4-dihydro-2H-1-benzopyran-6-yl] -5-fluoro-N2- [4- [N- ( N-methylamino) carbonylmethylene] aminocarbonylphenyl] -2,4-pyrimidinediamine LC / MS: purity 97%; MS (mass / charge): 566.4 (MH +). + - 1299 (R, S) -N4- [4-amino-3,4-dihydro-2H-1-benzopyran-6-yl] -5-fluoro-N2- [4- [N- (N-methylamino) carbonylmethylene] aminocarbonylphenyl ] -2,4-pyrimidinediamine LC / MS: purity: 93.5%; MS (mass / charge): 466.3 (MH +). + + - + 1300 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [4- [N- (N-methylamino) carbonylmethylene] aminocarbonylphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.84 (s, 1H), 9.81 (s, 1H), 8.54 (m, 1H), 8.24 (d, J = 3.9 Hz, 1H ), 8.10 (d, J = 2.4 Hz, 1H), 7.68-7.81 (m, 6H), 7.56 (d, J = 9.0 Hz, 1H), 3.79 (d, J = 6.0 Hz, 2H); 2.58 (d, J = 3.9 Hz, 3H); LC / MS: purity: 100%; MS (mass / charge): 463.2 (MH +). + + - 1301 N4- (3,4-Dichlorophenyl) -5-fluoro-N4-methyl-N2- [4- [N- (N-methylamino) carbonylmethylene] aminocarbonylphenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.75 (s, 1H), 8.50 (m, 1H), 8.12 (d, J = 4.8 Hz, 1H), 7.63-7.79 (m, 7H), 7.34 (dd, J = 2.4, 9.6 Hz, 1H), 3.78 (d, J = 4.8 Hz, 2H), 3.09 (s, 3H) 2.58 (d, J = 4.5 Hz, 3H); LC / MS: purity: 94.1%; MS (mass / charge): 477.2 (MH +). + + - 1302 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- [N- (2-methoxycarbonylethyl) aminocarbonyl] phenyl] - 2,4-pyrimidinediamine 1H NMR (DMSO-d6): d 10.71 (s, 1H), 9.93 (br s, 2H), 8.32 (m, 1H), 8.19 (d, J = 4.8 Hz , 1H), 7.61-7.69 (m, 4H), 7.22-7.25 (m, 2H), 6.94 (d, J = 6.93 Hz, 1H), 3.60 ( s, 3H), 3.44 (q, J = 6.9 Hz, 2H), 2.57 (t, J = 6.9 Hz, 2H), 1.41 (s, 6H); LC / MS: purity: 97.5%; MS (mass / charge): 509.3 (MH +). + + + 1303 (S) -5-Fluoro-N2- [4- [N- (2-methoxycarbonylethyl) aminocarbonyl] phenyl] -N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6 -yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 10.83 (s, 1H), 10.32 (s, 1H), 10.13 (s, 1H), 8.39 (m, 1H), 8.25 (d , J = 4.8 Hz, 1H), 7.62-7.72 (m, 4H), 7.35 (s, 1H), 7.21 (dd, J = 2.4, 8.7 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.66 (q, J = 6.9 Hz, 1H), 3.59 (s, 3H), 3.43 (m , 2H), 2.57 (t, J = 7.6 Hz, 2H), 1.43 (d, J = 6.9 Hz, 3H); LC / MS: purity: 90.1%; MS (mass / charge): 495.3 (MH +). + + - 1304 N4- (2,2-Difluoro-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- [N- (2-methoxycarbonylethyl) aminocarbonyl] phenyl] - 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 12.15 (s, 1H), 9.85 (m, 2H), 8.31 (m, 1H), 8.20 (d, J = 4.2 Hz, 1H ), 7.70-7.78 (m, 5H), 7.50 (d, J = 9.6 Hz, 1H), 7.27 (d, J = 9.90 Hz, 1H), 3.59 (s, 3H); 3.42 (m, 2H); 2.56 (t, J = 6.9 Hz, 2H); LC / MS: purity: 88.5%; MS (mass / charge): 517.3 (MH +). + + - 1305 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [4- [N- (2-methoxycarbonylethyl) aminocarbonyl] phenyl] -2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.82 (s, 1H), 9.77 (s, 1H), 8.36 (m, 1H), 8.24 (d, J = 3.9 Hz, 1H ), 8.11 (d, J = 2.4 Hz, 1H), 7.65-7.79 (m, 5H), 7.56 (d, J = 8.7 Hz, 1H), 3.60 (s, 3H), 3.47 (q, J = 6.6 Hz, 2H), 2.57 (t, J = 6.6 Hz, 1H); purity 90.9%; MS (mass / charge): 478.2 (MH +). + + + 1306 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- [4- [N- (2-methoxycarbonylethyl) aminocarbonyl] phenyl] -N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.94 (s, 1H), 8.41 (m, 1H), 8.16 (d, J = 5.7 Hz, 1H), 7.64-7.75 (m, 6H), 7.36 (dd, J = 2.4, 8.7 Hz, 1H), 3.59 (s, 3H), 3.50 (s, 3H), 3.45 (m, 2H), 2.57 (t, J = 7.6 Hz, 2H); LC / MS: purity: 88.5%; MS (mass / charge): 492.2 (MH +). + + - 1307 N2- [4- [1- (tert-Butoxycarbonylamino) methylenecarbonylamino] methylphenyl] -N4- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 10.59 (s, 1H), 9.29 (s, 1H), 9.01 (s, 1H), 8.12 (m, 1H), 8.03 (d , J = 3.6 Hz, 1H), 7.56 (d, J = 9.0 Hz, 2H), 7.27 (dd, J = 2.1, 8.4 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 4.16 (d , J = 5.4 Hz, 2H), 3.54 (d, J = 5.4 Hz, 2H), 1.39 (s, 6H), 1.38 (s, 9H); LC / MS: purity: 90.1%; MS (mass / charge): 566.5 (MH +). + + + 1308 (S) -N2- [4- [1- (tert-Butoxycarbonylamino) methylenecarbonylamino] methylphenyl] -5-fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6 -yl) -2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 10.63 (s, 1H), 9.29 (s, 1H), 9.00 (s, 1H), 8.13 (m, 1H), 8.03 (d , J = 3.6 Hz, 1H), 7.29-7.57 (m, 3H), 7.21 (d, J = 2.1 Hz, 1H), 7.05 (d, J = 9, 0 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.65 (q, J = 7.5 Hz, 1H), 4.16 (d, J = 5.7 Hz, 2H), 3.53 (d, J = 6.3 Hz, 2H), 1.43 (d, J = 6.6 Hz, 3H), 1.38 (s, 9H); LC / MS: purity: 90.1%; MS (mass / charge): 552.4 (MH +). + + + 1309 N2- [4- [1- (tert-Butoxycarbonylamino) methylenecarbonylamino] methylphenyl] -N4- (2,2-difluoro-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.52 (s, 1H), 9.08 (s, 1H), 8.13 (m, 1H), 8.09 (d, J = 3.3 Hz, 1H ), 7.46-7.62 (m, 4H), 7.23 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.92 (m, 1H), 4.18 (d, J = 5.7 Hz, 2H), 3.54 (d, J = 5.7 Hz, 2H), 1.37 (s, 9H); LC / MS: purity: 93.1%; MS (mass / charge): 574.4 (MH +). + + - 1310 N2- [4- [1- (tert-Butoxycarbonylamino) methylenecarbonylamino] methylphenyl] -N4- (3,4-dichlorophenyl) -5-fluoro-2,4-pyrimidinediamine 1 H NMR (DMSO-d 6): d 9.56 (s, 1H), 9.28 (s, 1H), 8.12-8.17 (m, 3H), 7.51-7.81 (m, 4H), 7.14 (d, J = 8.7 Hz, 2H), 6.93 (m, 1H), 4.20 (d, J = 6.3 Hz, 2H), 3.54 (d, J = 6.6 Hz, 2H); 1.38 (s, 9H); LC / MS: purity: 94.1%; MS (mass / charge): 535.3 (MH +). + + + 1311 N2- [4- [1- (tert-Butoxycarbonylamino) methylenecarbonylamino] methylphenyl] -N4- (3,4-dichlorophenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine 1 H NMR (DMSO-d6): d 9.31 (s, 1H), 8.15 (m, 1H), 8.04 (d, J = 5.4 Hz, 1H), 7.55-7.66 (m, 4H), 7.30 (m, 1H), 7.08 (d, J = 8.7 Hz, 2H), 6.94 (m, 1H), 4.18 (d, J = 6, 3 Hz, 2H), 3.54 (d, J = 6.3 Hz, 2H), 3.46 (s, 3H), 1.38 (s, 9H); LC / MS: purity: 90.1%; MS (mass / charge): 549.3 (MH +). + - 1312 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- [4- [N- (2-methoxycarbonylethyl) aminocarbonyl] phenyl ] -2,4-pyrimidinediamine LC / MS: retention time: 3.67 min (9 min. Method); purity: 95.3%; MS (mass / charge): 496.3 (MH +). + + 1313 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (4-methoxycarbonylphenyl) -2,4-pyrimidinediamine LC / MS: retention time: 4.45 min (9 min. Method); purity: 97.3%; MS (mass / charge): 439.3 (MH +). + 1314 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3-methoxycarbonylpyrid-2-yl) -2,4- pyrimidinediamine LC / MS: retention time: 4.00 min (9 min. Method); purity: 95.1%; MS (mass / charge): 440.4 (MH +). + 1315 N2- (4-Aminocarbonylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 3.28 min (9 min. Method); purity: 98.1%; MS (mass / charge): 424.3 (MH +). + 1316 N2- (2-Aminocarbonylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 3.98 minutes (9 minutes method); purity: 90.1%; MS (mass / charge): 424.5 (MH +). + - 1317 N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- (indazol-6-yl) -2,4-pyrimidinediamine salt of methanesulfonic acid LC / MS: retention time: 8.50 min (20 min. Method); purity: 98.8%; MS (mass / charge): 420.1 (MH +). 1318 N4- (2,2-Difluoro-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine methanesulfonic acid salt LC / MS: retention time: 9.69 min (20 min method); purity: 98.4%; MS (mass / charge): 475.3 (MH +). 1319 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 3.17 min (7 min. Method); purity: 97.5%; MS (mass / charge): 460.3 (MH +). + 1320 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (4- [2- [N, N-diethylamine] ethyleneaminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.64 min (7 min. Method); purity: 100%; MS (mass / charge): 487.3 (MH +). + + 1321 N2- (4-Aminocarbonylphenyl) -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 2.86 min (7 min. Method); purity: 100%; MS (mass / charge): 488.3 (MH +). + + 1322 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (4-methoxycarbonylphenyl) -2,4-pyrimidinediamine LC / MS: retention time: 4.02 min (7 min. Method); purity: 98.4%; MS (mass / charge): 403.3 (MH +). + 1323 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (4- [N-tert-butoxycarbonylaminomethylene] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 3.83 min (7 min. Method); purity: 92.3%; MS (mass / charge): 474.3 (MH +). + 1324 N2- (4-Aminomethylene phenyl) -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 2.53 min (7 min. Method); purity: 96.6%; MS (mass / charge): 374.2 (MH +). + 1325 N4- (3-Chloro-4-methoxyphenyl) -5-fluoro-N2- (4- [N- [N-methyl] aminocarbonylmethylene] aminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.81 min (7 min. Method); purity: 100%; MS (mass / charge): 459.3 (MH +). + 1326 2-Chloro-5-fluoro-N4- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -4-pyrimidinamine LC / MS: retention time: 2.79 min (7 min. Method); purity: 100%; MS (mass / charge): 339.2 (MH +). - 1327 N4- [4-Aminocarbonylphenyl] -2-chloro-5-fluoro-4-pyrimidinamine LC / MS: retention time: 2.40 min (7 min. Method); purity: 100%; MS (mass / charge): 267.1 (MH +). - 1328 5-Fluoro-N2- (3-hydroxyphenyl) -N4- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.44 min (7 min. Method); purity: 94.9%; MS (mass / charge): 412.3 (MH +). + 1329 N2- (3,5-Dichloro-4-hydroxyphenyl) -5-fluoro-N4- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 9.92 min (20 min. Method); purity: 95.0%; MS (mass / charge): 482.0 (MH +). + 1330 N2- (3-Chloro-4-methoxyphenyl) -5-fluoro-N4- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 3.13 min (7 min. Method); purity: 95% MS (mass / charge): 460.3 (MH +). + + + 1331 N2- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N4- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -2, 4-pyrimidinediamine LC / MS: retention time: 2.80 min (7 min. Method); purity: 92.2%; MS (mass / charge): 495.3 (MH +). + + 1332 5-Fluoro-N2, N4-bis (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.77 min (7 min. Method); purity: 100%; MS (mass / charge): 511.4 (MH +). + + 1333 N2- (4-Aminocarbonylphenyl) -5-fluoro-N4- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.48 min (7 min. Method); purity: 97.6%; MS (mass / charge): 439.3 (MH +). - - 1334 N4- (4-Aminocarbonylphenyl) -5-fluoro-N2- (3-hydroxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.10 min (7 min. Method); purity: 100%; MS (mass / charge): 340.2 (MH +). + + 1335 N4- (4-Aminocarbonylphenyl) -N2- (3,5-dichloro-4-hydroxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 8.72 min (20 min. Method); purity: 93.0%; MS (mass / charge): 410.0 (MH +). + + 1336 N4- (4-Aminocarbonylphenyl) -N2- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 2.79 min (7 min. Method); purity: 100%; MS (mass / charge): 388.3 (MH +). + + 1337 N4- (4-Aminocarbonylphenyl) -N2- (2,2-dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 2.50 min (7 min. Method); purity: 100%; MS (mass / charge): 423.3 (MH +). + + + 1338 N4- (Aminocarbonylphenyl) -5-fluoro-N2- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.52 min (7 min. Method); purity: 94.4%; MS (mass / charge): 439.3 (MH +). + + 1339 N2, N4-Bis (4-aminocarbonylphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 2.26 min (7 min. Method); purity: 100%; MS (mass / charge): 367.3 (MH +). - - 1340 N4- (2,2-Dimethyl-3-oxo-4H-N4-oxo-5-pyrido [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl) - 2,4-pyrimidinediamine LC / MS: retention time: 3.48 min (7 min. Method); purity: 97.4%; MS (mass / charge): 487.3 (MH +). + + 1341 N2- (4-Aminocarbonylphenyl) -5-fluoro-N4- (4- [3-methyl-1,2,4-oxadiazol-5-yl] methyleneoxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.72 min (7 min. Method); purity: 95.8%; MS (mass / charge): 436.3 (MH +). + + + 1342 5-Fluoro-N2- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -N4- (4- [3-methyl-1,2,4-oxadiazol-5-yl] methyleneoxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.99 min (7 min. Method); purity: 95.1%; MS (mass / charge): 508.4 (MH +). + + 1343 N2- (4- [2- [N, N-Diethylamine] ethyleneaminocarbonyl] phenyl) -5-fluoro-N4- (4- [3-methyl-1,2,4-oxadiazol-5-yl] methyleneoxyphenyl) -2 4-pyrimidinediamine LC / MS: retention time: 2.58 min (7 min. Method); purity: 97.8%; MS (mass / charge): 535.4 (MH +). + + + 1344 N2- (3,5-Dichloro-4-hydroxyphenyl) -5-fluoro-N4- (4- [3-methyl-1,2,4-oxadiazol-5-yl] methyleneoxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time: 3.33 min (7 min. Method); purity: 95.0%; MS (mass / charge): 477.2 (MH +). + - + 1345 N2- (3-Chloro-5-methoxyphenyl) -5-fluoro-N4- (4- [3-methyl-1,2,4-oxadiazol-5-yl] methyleneoxyphenyl) -2,4-pyrimidinediamine LC / MS: retention time: 3.35 min (7 min. Method); purity: 96.4%; MS (mass / charge): 457.3 (MH +). - + 1346 N2- (4-Aminocarbonylphenyl) -N4- (3,4-dichlorophenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine LC / MS: retention time: 3.86 minutes (7 minutes method); purity: 100%; MS (mass / charge): 406.2 (MH +). + 1347 N2- (4- [2- [N, N-Diethylamino] ethyleneaminocarbonyl] phenyl) -N4- (3,4-dichlorophenyl) -5-fluoro-N4-methyl-2,4-pyrimidinediamine LC / MS: retention time: 3.31 min (7 min. Method); purity: 100%; MS (mass / charge): 505.3 (MH +). + 1348 N4- (3,4-Dichlorophenyl) -5-fluoro-N2- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -N4-methyl-2,4-pyrimidinediamine LC / MS: retention time: 4.16 min (7 min. Method); purity: 95.8%; MS (mass / charge): 480.2 (MH +). + 1349 N2- (4-Aminocarbonylphenyl) -N4- (cyclopentyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 2.26 min (7 min. Method); purity: 100%; MS (mass / charge): 316.3 (MH +). - 1350 N4- (Cyclopentyl) -N2- (4- [2- (N, N-diethylamino] ethyleneaminocarbonyl) phenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 2.09 min (7 min. Method); purity: 97.3%; MS (mass / charge): 415.4 (MH +). - + 1351 N4- (Cyclopentyl) -5-fluoro-N2- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 2.62 min (7 min. Method); purity: 100%; MS (mass / charge): 388.3 (MH +). + + 1352 N2- (4-Aminocarbonylphenyl) -N4- (4-chloro-3-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 3.13 min (7 min. Method); purity: 96.4%; MS (mass / charge): 388.3 (MH +). + 1353 N2- (4-Aminocarbonyl-3-chlorophenyl) -N4- (3-chloro-4-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 2.91 min (7 min. Method); purity: 89.5%; MS (mass / charge): 422.2 (MH +). + + 1354 N2- (4-Aminocarbonyl-3-chlorophenyl) -N4- (4-chloro-3-methoxyphenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 3.14 min (7 min. Method); purity: 95.0%; MS (mass / charge): 422.2 (MH +). + + 1355 N4- (4-Chloro-3-methoxyphenyl) -N2- (4- [2- [N, N-diethylamino] ethyleneaminocarbonyl] phenyl) -5-fluoro-2,4-pyrimidinediamine LC / MS: retention time: 2.80 min (7 min. Method); purity: 95.6%; MS (mass / charge): 487.4 (MH +). + + 1356 N4- (4-Chloro-3-methoxyphenyl) -5-fluoro-N2- (4- [N- [methoxycarbonylmethylene] aminocarbonyl] phenyl) -2,4-pyrimidinediamine LC / MS: retention time: 3.45 min (7 min. Method); purity: 94.6%; MS (mass / charge): 460.3 (MH +). + + 1357 N2- (4-Aminocarbonylphenyl) -5-fluoro-N4-phenyl-2,4-pyrimidinediamine LC / MS: retention time: 2.58 min (7 min. Method); purity: 100%; MS (mass / charge): 424.3 (MH +). + + 1358 5-Fluoro-N2- (3-hydroxyphenyl) -N4- (4- [3-methyl-1,2,4-oxadiazol-5-yl] methyleneoxyphenyl) -2,4-pyrimidinediamine hydrochloride salt LC / MS: retention time: 2.72 min (7 min. Method); purity: 89.9%; MS (mass / charge): 409.3 (MH +). ¹ NMR - nuclear magnetic resonance;
² LC - liquid chromatography;
³ MS - mass spectrometry

7.5 The effectiveness of compounds in the treatment of autoimmunity

An evaluation of the in vivo efficacy of individual 2,4-pyridinediamine compounds in relation to autoimmune diseases was obtained using the Arthus reverse passive reaction, which is a model of severe tissue damage mediated by an antigen-antibody pair, as well as several models of diseases associated with autoimmunity and inflammation. These models are similar in that an antibody to a specific antigen mediates an inflammatory disease caused by the immune complex (IC) and associated tissue destruction. Deposition of IC in certain anatomical regions (central nervous system (CNS) in the case of experimental autoimmune encephalomyelitis (EAE) and the synovial membrane in the case of collagen-induced arthritis (CIA)) leads to the activation of cells expressing surface receptors FcγR and FcεR, mainly mast cells, macrophages and neutrophils, which leads to the release of the cytokine and chemotaxis of neutrophils. The activation of the inflammatory response is responsible for the forward response of nerve endings, including edema, hemorrhage, neutrophil infiltration, and the release of pro-inflammatory mediators. In the case of autoimmune disorders, the consequences of these events provoked by IC are difficult to establish; however, many researchers have shown that inhibition of FcγR receptor signaling pathways in these animal models led to a significant decrease in the development of the disease and its severity.

7.5.1 Efficacy of compounds in the Arthus reaction in mice

The efficacy (in vivo) of compounds 810, 944, 994, and 1007 for inhibiting IC-triggered inflammatory cascades was demonstrated by reversing the passive Arthus reaction in mice (RPA reaction).

7.5.1.1 Model

Acute inflammatory tissue injury mediated by the immune complex (IC) is part of many different human autoimmune diseases, including vasculitis syndrome, serum sickness, systemic erythematous lupus erythematosus (SLE), rheumatoid arthritis, Goodpasture syndrome and glomerulonephritis. The classic experimental model of IC-mediated tissue damage is Arthus's reverse passive response. The model of this reaction is a convenient in vivo method for studying localized inflammation provoked by immune complexes in the absence of systemic effects. Subcutaneous injection of antibodies (Ab) specific for albumin in chicken eggs (anti-OVA rabbit IgG immunoglobulin), followed by intravenous injection of (IV) antigens (Ag), namely chicken albumin (egg albumin, OVA), causes circulatory immune deposition complexes and an immediate inflammatory reaction characterized by edema, neutrophil infiltration and hemorrhage at the injection site. Some aspects of the mouse RPA model are similar to the inflammatory response of patients with rheumatoid arthritis, SLE, and glomerulonephritis.

7.5.1.2 Study Protocol

In this model, the test compounds are administered at specific points in time before the introduction of antibodies and antigens. A solution of rabbit anti-OVA immunoglobulin IgG (50 μg in 25 μl / mouse) is administered subcutaneously, followed by an intravenous injection of albumin obtained from chicken eggs (20 mg / kg body weight) in a solution containing 1% Evans blue dye. The degree of swelling and hemorrhage is measured in the skin of the back of C57BL / 6 mice using Evans blue dye as an indicator of local tissue damage. Purified polyclonal rabbit IgG immunoglobulin was used as a control.

The time interval between the administration of the test compounds and the antibody / antigen complex depends on the pharmacokinetic (FC) properties of each individual compound. Four hours after the induction of the Arthus reaction, the mice were euthanized and a tissue sample was taken to evaluate edema. This model allows you to quickly track in vivo activity of most inhibitors.

7.5.1.3 Results

All tested compounds were administered orally.

The drug 994, when administered in an amount of 100 mg / kg 90 minutes before administration of the antibody / antigen, when tested in C57Bl6 mice, showed the dependence of the inhibition of edema formation on the administered dose (75%).

Compounds 1007 and 810 showed effective inhibition of edema development by 89.4% and 81.3%, respectively, when administered in an amount of 1.0 mg / kg 30 minutes before exposure to the antibody / antigen.

Compound 1007 showed 64.3%, 78.7%, 98.1% and 99.8% inhibition of edema formation at a dose of 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg and 5 mg / kg when taken in 30 minutes, respectively. The test results of the compounds are presented in table 2.

table 2
Generalized Arthus Reverse Passive Response (RPA) Results in Mice % inhibition of control excipient Satellite: during administration Exposure = sedation time + 4 hours In vitro Potency (CHMC IgE) Title
connections Connection number Dose (mg / kg) Premedication Time (h) Swelling size ± SEM * Plasma Concentration ± SEM (ng / ml) Plasma Concentration ± SEM (ng / ml) 994 one hundred 75.0 ± 6.2 78.6 ± 26.4 44.2 ± 8.9 0,047 1007 one 0.5 89.4 ± 2.2 3 0.5 86.3 ± 7.9 10 0.5 97.8 ± 1.1 thirty 0.5 88.2 ± 5.7 1007 0.1 0.5 64.3 ± 11.2 24.4 ± 9.6 BLQ 0.5 0.5 78.7 ± 6.3 73.1 ± 14.5 BLQ one 0.5 98.1 ± 0.8 90.0 ± 11.0 2.3 ± 0.9 5 0.5 99.8 ± 0.2 398.0 ± 30.2 19.8 ± 15.7 810 0.1 0.5 69.5 ± 19.6 0.5 0.5 60.9 ± 9.6 one 0.5 81.3 ± 8.4 5 0.5 92.1 ± 3.1 944 2 one 39.3 ± 13.8 NA 4.3 ± 4.2 5 one 48.4 ± 12.0 NA 3.5 ± 5.3 fifteen one 56.1 ± 9.2 NA 29.7 ± 25.9 944 0.5 5 -16.0 ± 17.3 22.1 ± 52.4 3.4 ± 9.1 0.5 fifteen 8.3 ± 13.4 1074.0 ± 492.3 85.1 ± 161.9 * Standard error

7.5.2 Efficacy of compounds in mouse modeling of arthritis induced by anti-collagen antibodies

In vivo, the effectiveness of the compounds against autoimmune diseases can be demonstrated in a model of arthritis induced by anti-collagen antibodies (CAIA) in mice.

7.5.2.1 Model

Collagen-induced arthritis (CIA) in rodents is often used as one of the experimental models in the case of tissue damage mediated by the immune complex (IC). The administration of type II collagen to mice or rats leads to an immune response, which is characterized by the presence of inflammatory damage to the cartilage and bones of the peripheral joints, which is accompanied by a tumor of the surrounding tissues. CIA is often used to evaluate the effectiveness of compounds that can potentially be used as medications for the treatment of rheumatoid arthritis and other chronic inflammatory conditions.

Over the past years, a new CIA modeling technology has emerged, based on the use of antibodies to collagen antotype II to induce antibody-mediated CIA. The advantages of this method are as follows: a short period of time required to induce the disease (the disease develops within 24-48 hours after intravenous (IV) injection of antibodies); arthritis can be induced in both CIA-susceptible and CIA-resistant mouse breeds; and in addition, the procedure is ideal for quickly checking the performance of anti-inflammatory therapeutic drugs.

The Arthrogen-CIA® monoclonal antibody mixture (supplier: Chemicon International Inc.), which induces arthritis, is intravenously administered to Balb / c mice (2 mg / mouse) on day 0. Forty-eight hours later, 100 μl LPS ^* is administered intraperitoneally ^. (25 mcg). On the fourth day, claw swelling may occur. On the fifth day, one or both legs (especially the hind legs) begin to redden and swell. On the sixth day and for the next 1-2 weeks, the redness and swelling of the legs will persist. In the course of the study, the clinical characteristics of inflammation are recorded in order to assess the intensity of paw edema. The severity of the occurrence of arthritis is recorded as the sum of the points characterizing the condition of both hind legs of each animal (the maximum possible number of points is 8). The degree of inflammation of the damaged legs is assessed by measuring the diameter of the legs. Also keep track of changes in body weight.

Treatment of animals begins with the induction of arthritis, starting from day zero. The experimental and control compounds are administered one (q.d.) or two (b.i.d.) once a day orally (PO) depending on previously established pharmacokinetic properties.

At the end of the study (1-2 weeks after inducing arthritis), the mice were euthanized, paws were cut off at the site of the distal tibia using guillotine scissors and weighed. The average ± standard error (SD) of the averaged characteristics for each group is determined every day based on the clinical indicators of each individual animal, and at the end of the study, the weight of the hind legs for each experimental group is calculated and recorded. A histopathological evaluation of the legs is also obtained.

7.5.2.2 Results

A reduction in inflammation and swelling should be apparent in animals treated with the compounds of the present invention, and the progression of arthritis should occur more slowly. Compound treatment (b.i.d.) should significantly reduce clinical arthritis compared to animals that were given only vehicle.

7.5.3 The efficacy of compounds in the treatment of collagen-induced arthritis in rats

In vivo, the efficacy of the compounds of the present invention in relation to autoimmune diseases was demonstrated in a rat collagen-induced arthritis (CIA) model.

7.5.3.1 Model Description

Rheumatoid arthritis (RA) is characterized by chronic inflammation of the joints, which ultimately leads to irreversible destruction of the cartilage. The synovial tissues of patients suffering from RA contain a large amount of IC with immunoglobulin IgG. Despite ongoing debate about the role of these complexes in the etiology and pathology of this disease, communication of IC with hematopoietic cells is carried out using FcγR receptors.

CIA is a widely recognized animal model of RA, the result of which is chronic inflammatory synovitis, characterized by pannus formation and joint degradation. In this model, subcutaneous administration of native type II collagen emulsified with incomplete Freund's adjuvant leads to the development of inflammatory arthritis within 10 or 11 days and subsequent destruction of the joints in the period from 3 to 4 weeks.

7.5.3.2 Study Protocol

On day 0, a group of syngenetic rats of the LOU strain were immunized with native type II CII / IFA collagen (University of California, Los Angeles, project manager E. Brahn). From the day onset of arthritis (day 10), a total of 59 rats can be treated with either a control vehicle or a compound of the present invention using one of four dosages (1, 3, 10 and 30 mg / kg, qd orally )

7.5.3.3 Results

The hind limbs were assessed daily using a standardized method based on the degree of joint inflammation. Upon completion of the study (day 28), you can get clear digital x-rays of the hind limbs. These limbs can also be analyzed for histopathological changes. Quantitative measurement of IgG antibodies to native collagen CII can be carried out using enzyme-linked immunosorbent assay ELISA with four repetitions.

Although the present invention has been described using some details to facilitate understanding, it is understood that certain changes and modifications are permitted within the scope of the following claims. Accordingly, the described examples should be considered as illustrative and not limiting, and the present invention is not limited to the details given, but can be modified within the scope and equivalents of the following claims.

All references to literature and patents made in the text of this application are included as a reference for any purpose.

Claims (41)

1. The compound 2,4-pyrimidinediamine corresponding to the structural formula:

including its pharmaceutically acceptable salts,
where L ¹ is a direct bond;
L ² is a direct bond;
R ² is a phenyl group thrice substituted by three R ⁸ groups;
R ⁴ is

X represents N;
Y is selected from the group consisting of O, NH, S, SO, and SO ₂ ;
Z is selected from the group consisting of O and NH; provided that Y is selected from the group consisting of NH, S, SO, and SO ₂ , then Z is not the same as Y;
R ⁵ is selected from the group consisting of R ⁶ and halogen;
each R ^{6 is} independently selected from the group consisting of hydrogen, halogen;
R ⁸ is selected from the group consisting of R ^a , R ^b , R ^a substituted with one or more identical or different groups R ^a or R ^b , —OR ^a and —O — CHR ^a R ^b ;
each R ^{35 is} independently selected from the group consisting of hydrogen and
R ⁸ , or alternatively, two R ³⁵ groups attached to the same carbon atom are taken together with the formation of an oxo group (= O) and the remaining two R ³⁵ groups are each independently selected from the group consisting of hydrogen and R ⁸ ;
each R ^{a is} independently selected from the group consisting of hydrogen, (C1-C6) alkyl and (C3-C8) cycloalkyl;
each R ^b is a suitable group that is independently selected from the group consisting of —OR ^d , halogen, —CF ³ , —C (O) NR ^c R ^c and —OC (O) OR ^d ;
each R ^c independently is R ^a ;
each R ^{d is} independently R ^a ;
provided that
N2- (3-chloro-4-methoxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine;
N2- (3-chloro-4-hydroxy-5-methylphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine; and
N2- (3,5-dimethyl-4-methoxyphenyl) -N4- (2,2-dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-2, 4-pyrimidinediamine are excluded. 2. The compound of the structural formula:

and its pharmaceutically acceptable salts, in which:
R ² is selected from the group consisting of (C1-C6) alkyl, phenyl optionally substituted with one or more identical or different groups of R ⁸ , a 5-6 membered cycloheteroalkyl containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, optionally fused to a benzene ring and optionally substituted with one or more identical or different R ⁸ groups;
R ⁴ is selected from the group consisting of hydrogen, a 5-6 membered cycloheteroalkyl containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, optionally fused to a benzene ring and optionally substituted with one or more identical or different R ⁸ groups, and A 5-6 membered heteroaryl containing 1-2 heteroatoms selected from nitrogen, oxygen and sulfur optionally substituted with one or more identical or different R ⁸ groups;
R ⁸ is selected from the group consisting of R ^a , R ^b substituted with one or more identical or different groups R ^a or R ^b ,
-OR ^a and -O- (CH ₂ ) _m -R ^b ;
each R ^{a is} independently selected from the group consisting of hydrogen, (C1-C6) alkyl, a 5-membered heteroaryl containing 2 heteroatoms selected from nitrogen and oxygen, fused to a benzene ring;
each R ^b is a suitable group that is independently selected from the group consisting of = O, —OR ^d , —NR ^c R ^c , halogen and —C (O) NR ^c R ^c ;
each R ^c independently is R ^a ,
each R ^{d is} independently R ^a ;
R ⁵⁵ is selected from the group consisting of (C1-C6) alkyl and
each index m is independently an integer from 1 to 3. 3. The compound of the structural formula:

and its pharmaceutically acceptable salts in which:
R ² represents

R ⁴ is selected from the group consisting of hydrogen, a 5-6 membered cycloheteroalkyl containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, optionally fused to a benzene ring and optionally substituted with one or more identical or different R ⁸ groups, and A 5-6 membered heteroaryl containing 1-2 heteroatoms selected from nitrogen, oxygen and sulfur optionally substituted with one or more identical or different R ⁸ groups; and
R ⁸ is selected from the group consisting of R ^a , R ^b , R ^a substituted by one or more identical or different groups R ^a or R ^b ,
OR ^a substituted by one or more identical or different groups R ^a
or R ^b , - (CH ₂ ) _m -R ^b , - (CHR ^a ) _m -R ^b ,
O (CH ₂ ) _m -R ^b ;
each R ^{a is} independently selected from the group consisting of hydrogen and (C1-C6) alkyl;
each R ^b is a suitable group that is independently selected from the group consisting of = O, -OR ^d , (C1-C3) haloalkyloxy, -NR ^c R ^c , halogen, -C (O) R ^b , C (O) OR ^d and
-C (O) NR ^c R ^c ;
each R ^c independently is R ^a ;
each R ^{d is} independently R ^a ;
each index m is independently an integer from 1 to 3. 4. The compound 2,4-pyrimidinediamine selected from the group consisting of
N ₄ - [(2,3-Dihydro-1,4-benzodioxan-2-yl) methyl] -N2- (3,5-dimethylphenyl) -5-fluoro-2,4-pyrimidinediamine;
N4 - [(2,3-dihydro-1,4-benzodioxan-2-yl) methyl] -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4-pyrimidinediamine;
N4 - [(2,3-dihydro-1,4-benzodioxan-2-yl) methyl] -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine;
N2- (3-Chloro-4-methoxyphenyl) -N4 - [(2,3-dihydro-1,4-benzodioxan-2-yl) methyl] -5-fluoro-2,4-pyrimidinediamine;
N4 - [(2,3-Dihydro-l, 4-benzodioxan-2-yl) methyl] -5-fluoro-N2- (indazol-6-yl) -2,4-pyrimidinediamine. 5. The compound 2,4-pyrimidinediamine selected from the group consisting of
N4- (3,4-Dihydro-2,2-dimethyl-4H-benz [l, 4] oxazin-6-yl) -5-fluoro-N2- [3- (N-methylamino) carbonylmethyleneoxyphenyl] -2,4 -pyrimidinediamine;
N2- (3-Chloro-4-methoxy-5-methylphenyl) -N4- (3,4-dihydro-2,2-dimethyl-4H-benz [1,4] oxazin-6-yl) -5-fluoro- 2,4-pyrimidinediamine and
N4- (3,4-Dihydro-2,2-dimethyl-4H-benz [1,4] oxazin-6-yl) -N2- (3,5-dimethoxyphenyl) -5-fluoro-2,4-pyrimidinediamine. 6. The compound of 2,4-pyrimidinediamine structural formula:

and its pharmaceutically acceptable salts, in which:
R ² represents

;
R ⁴ represents

;
R ⁵ represents a fluorine atom;
R ⁶ represents a hydrogen atom;
Y is selected from the group consisting of O, S, SO; and NR ³⁷ ;
Z is selected from the group consisting of O, SO, SO ₂ , NH and NR ³⁷ , provided that Z is not the same as Y;
each of R ^{35 is} independently selected from the group consisting of hydrogen and R ⁸ , or alternatively, two R ³⁵ attached to the same carbon atom are taken together with the formation of an oxo group (= O), and the other two groups R ³⁵ each independently from one another are selected from the group consisting of hydrogen and R ⁸ ;
R ⁸ is selected from the group consisting of R ^a , R ^b , R ^a substituted by one or more identical or different groups R ^a or R ^b ,
—OR ^a substituted with one or more identical or different groups R ^a or R ^b - (CH ₂ ) _m —R ^b , —O— (CH ₂ ) _m —R ^b and
-O-CR ^a (R ^b ) ₂ ;
each R ^{a is} independently selected from the group consisting of hydrogen, (C1-C6) alkyl;
each R ^b is a suitable group that is independently selected from the group consisting of = O, —OR ^d , —NR ^c R ^c , halogen, —C (O) OR ^d ; -C (O) OR ^d , -C (O) NR ^with R ^s ;
each R ^{c is} independently R ^a ;
each R ^{d is} independently R ^a ;
each index m is independently an integer from 1 to 3; and
R ³⁷ is selected from the group consisting of hydrogen and a progroup selected from the group consisting of R ^a R ^b and —CR ^a R ^b —O — C (O) R ⁸ . 7. The compound according to claim 6, in which Y represents oxygen, Z represents NH and one or more R ³⁵ represents an alkyl group. 8. The compound according to claim 6, in which R ⁴ represents

. 9. The compound according to claim 6, in which R ⁴ represents

. 10. The compound according to claim 6, in which Y represents oxygen, Z represents NH. 11. The compound 2,4-pyrimidinediamine selected from the group consisting of
N4- (3,4-Dihydro-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ,
N4- (3,4-Dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine,
5-Fluoro-N2- [3- (oxazol-2-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine,
5-Fluoro-N2- [3- (oxazol-2-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-7-yl) -2,4-pyrimidinediamine,
5-Fluoro-N4- [2- (2-hydroxyethyl) -3-oxo-2H, 4H-benz [1,4] oxazin-6-yl] -N2- [3- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine,
N4- (3,4-Dihydro-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine ,
N4- (3,4-Dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine,
5-Fluoro-N2- [4- (oxazol-5-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine,
(S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [4- (oxazol-5-ylphenyl] -2 4-pyrimidinediamine,
5-Fluoro-N2- [4- (oxazol-5-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-7-yl) -2,4-pyrimidinediamine,
5-Fluoro-N4- [2- (2-hydroxyethyl) -3-oxo-2H, 4H-benz [1,4] oxazin-6-yl] -N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine,
N4- (3,4-Dihydro-4-methyl-2H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4 -pyrimidinediamine,
N4- (3,4-Dihydro-4-methyl-2H-benz [1,4] oxazin-7-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4 -pyrimidinediamine,
5-Fluoro-N4- (4-methyl-3-oxo-2H-benz [1,4] oxazin-7-yl) -N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine ,
5-Fluoro-N4- (4-methyl-3-oxo-2H-benz [1,4] oxazin-6-yl) -N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine ,
N4- (3,4-Dihydro-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine ,
N4- (3,4-Dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine,
5-Fluoro-N2- [3- (oxazol-5-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-7-yl) -2,4-pyrimidinediamine,
N4- (3,4-Dihydro-4-methyl-2H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4 -pyrimidinediamine,
N4- (3,4-Dihydro-4-methyl-2H-benz [1,4] oxazin-7-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4 -pyrimidinediamine,
N4- (3,4-Dihydro-3,3-dimethyl-2H, 4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine,
5-Fluoro-N2- [4- (oxazol-2-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -2,4-pyrimidinediamine,
(S) -5-Fluoro-N4- (2-methyl-3-oxo-2H, 4H-benz [1,4] oxazin-6-yl) -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine,
5-Fluoro-N2- [4- (oxazol-2-yl) phenyl] -N4- (3-oxo-2H, 4H-benz [1,4] oxazin-7-yl) -2,4-pyrimidinediamine,
5-Fluoro-N4- [2- (2-hydroxyethyl) -3-oxo-2H, 4H-benz [1,4] oxazin-6-yl] -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine,
N4- (2,3-Dihydro-4-methyl-2H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [4- (oxazol-2-yl) phenyl] -2,4 -pyrimidinediamine,
5-Fluoro-N4- (4-methyl-3-oxo-2H-benz [1,4] oxazin-7-yl) -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ,
5-Fluoro-N4- (4-methyl-3-oxo-2H-benz [1,4] oxazin-6-yl) -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine ,
N4- (2,2-Dimethyl-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4 -pyrimidinediamine,
N4- (2,2-Difluoro-3-oxo-4H-benz [1,4] oxazin-6-yl) -5-fluoro-N2- [3- (oxazol-2-yl) phenyl] -2,4 -pyrimidinediamine,
N4- (4-N-tert-butoxycarbonylamino-3,4-dihydro-2H-1-benzopyran-6-yl) -5-fluoro-N2- [3- (oxazol-5-yl) phenyl] -2,4 -pyrimidinediamine,
N4- (4-N-tert-butoxycarbonylamino-3,4-dihydro-2H-1-benzopyran-6-yl) -5-fluoro-N2- [4- (oxazol-5-yl) phenyl] -2,4 -pyrimidinediamine,
N4- (4-H-tert-Butoxycarbonylamino-3,4-dihydro-2H-1-benzopyran-6-yl) -5-fluoro-N2- [4- (oxazol-2-yl) phenyl] -2,4 -pyrimidinediamine,
5-Fluoro-N4- (4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl) -N2- [4- (oxazol-5-yl) phenyl] -2,4-pyrimidinediamine,
5-Fluoro-N4- (4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl) -N2- [4- (oxazol-2-yl) phenyl] -2,4-pyrimidinediamine. 12. The compound of 2,4-pyrimidinediamine structural formula:

and its pharmaceutically acceptable salts, in which:
R ² represents

where Y represents O, S, NH,
NR ³⁷ ; or NR ³⁵ ;
R ⁴ is a 3-6 membered cycloheteroalkyl containing 1-2 ring heteroatoms, optionally fused to a pyridine or benzene ring, and optionally substituted with one or more identical or different R ⁸ groups;
R ⁵ represents a fluorine atom;
R ⁶ represents a hydrogen atom;
R ⁸ is selected from the group consisting of R ^a , R ^b , R ^a substituted by one or more identical or different groups R ^a or R ^b , -OR ^a , substituted by one or more identical or different groups R ^a or R ^b and -O (CH ₂ ) _m -R ^b ;
each R ^{a is} independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl;
each R ^b is a suitable group that is independently selected from the group consisting of = O, —OR ^d , —NR ^c R ^c , halogen,
- C (O) R ^d and -C (O) OR ^b ;
each R ^{c is} independently a protecting group selected from the group consisting of formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl, tert-butoxycarbonyl;
each R ^{d is} independently R ^a ;
each index m is independently an integer from 1 to 3;
R ³⁵ represents hydrogen or R ⁸ ;
R ³⁶ represents hydrogen or alkyl; and
R ³⁷ is selected from the group consisting of hydrogen and a progroup selected from the group consisting of R ^a , R ^b , —CR ^a R ^b —OC (O) R ⁸ and
- C (O) R ⁸ . 13. The compound 2,4-pyrimidinediamine selected from the group consisting of:
N4- (1-tert-Butoxycarbonylazetidin-3-yl) -5-fluoro-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine,
N2- [4- (4-Acetylpiperazino) phenyl] -N4- (1-tert-butoxycarbonylazetidin-3-yl) -5-fluoro-2,4-pyrimidinediamine,
N2- [3- (4-Acetylpiperazino) phenyl] -N4- (1-tert-butoxycarbonylazetidin-3-yl) -5-fluoro-2,4-pyrimidinediamine,
N4- (1-tert-Butoxycarbonylazetidin-3-yl) -N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine,
N4- (Azetidin-3-yl) -5-fluoro-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine,
N2- [4- (4-Acetylpiperazino) phenyl] -N4- (azetidin-3-yl) -5-fluoro-2,4-pyrimidinediamine,
N4- (Azetidin-3-yl) -N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine,
N4- (Azetidin-3-yl) -5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine,
N2- [3- (4-Acetylpiperazino) phenyl] -N4- (azetidin-3-yl) -5-fluoro-2,4-pyrimidinediamine,
N4- (1-tert-Butoxycarbonylazetidin-3-yl) -N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine,
N4- (Azetidin-3-yl) -N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine,
N4- (Azetidin-3-yl) -5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine,
(S) -N4- (1-Benzylpyrrolidin-3-yl) -5-fluoro-N2- (4-morpholinophenyl) -2,4-pyrimidinediamine,
(S) -N2- [4- (4-Acetylpiperazino) phenyl] -N4- (1-benzylpyrrolidin-3-yl) -5-fluoro-2,4-pyrimidinediamine,
(S) -N4- (1-Benzylpyrrolidin-3-yl) -5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine,
(S) -N4- (1-Benzylpyrrolidin-3-yl) -N2- [4- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine,
(S) -N4- (1-Benzylpyrrolidin-3-yl) -5-fluoro-N2- (3-morpholinophenyl) -2,4-pyrimidinediamine,
(S) -N2- [3- (4-Acetylpiperazino) phenyl] -N4- (benzylpyrrolidin-3-yl) -5-fluoro-2,4-pyrimidinediamine,
(S) -N4- (1-Benzylpyrrolidin-3-yl) -5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine,
(S) -N4- (1-Benzylpyrrolidin-3-yl) -N2- [3- (4-ethoxycarbonylpiperazino) phenyl] -5-fluoro-2,4-pyrimidinediamine
and its pharmaceutically acceptable salts. 14. A compound selected from the group consisting of:
5-Fluoro-N2- [4- (4-methylpiperazino) phenyl] -N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine,
5-Fluoro-N2- [3- (4-methylpiperazino) phenyl] -N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine,
N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -5-fluoro-N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine,
5-Fluoro-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine,
5-Fluoro-N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -N2- [3-trifluoromethyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine,
N4- (1-Ethoxycarbonylpiperidin-4-yl) -5-fluoro-N2- [4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine,
N4- (1-Ethoxycarbonylpiperidin-4-yl) -5-fluoro-N2- [3- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine,
N2- [3-Chloro-4- (4-methylpiperazino) phenyl] -N4- (1-ethoxycarbonylpiperidin-4-yl) -5-fluoro-2,4-pyrimidinediamine,
N4- (1-Ethoxycarbonylpiperidin-4-yl) -5-fluoro-N2- [3-methyl-4- (4-methylpiperazino) phenyl] -2,4-pyrimidinediamine,
N4- (1-Ethoxycarbonylpiperidin-4-yl) -5-fluoro-N2- [4- (4-methylpiperazino) -3-trifluoromethylphenyl] -2,4-pyrimidinediamine,
N2- [2- (4-Ethylpiperazino) pyrid-5-yl] -5-fluoro-N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine,
N4- (1-Ethoxycarbonylpiperidin-4-yl) -N2- [2- (4-ethylpiperazino) pyrid-5-yl] -5-fluoro-2,4-pyrimidinediamine,
5-Fluoro-N2- [2- (4-methylpiperazino) -3-methylpyrid-5-yl] -N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine,
5-Fluoro-N2- [2- (4-methylpiperazino) -4-methylpyrid-5-yl] -N4- (1,2,2,6,6-pentamethylpiperidin-4-yl) -2,4-pyrimidinediamine,
or its pharmaceutically acceptable salts. 15. The compound of 2,4-pyrimidinediamine structural formula:

and its pharmaceutically acceptable salts, in which:
R ² is selected from the group consisting of phenyl optionally substituted with 1-3 identical or different R ⁸ groups, a 5-6 membered heteroaryl containing 2 heteroatoms selected from nitrogen and oxygen, and optionally fused with benzene;
R ⁴ represents

;
R ⁵ represents a fluorine atom;
R ⁶ represents a hydrogen atom; and
R ⁸ is selected from the group consisting of R ^a , R ^b , R ^a substituted with one or more identical or different groups R ^a or R ^b —OR ^a and —O— (CH ₂ ) _m —R ^b ;
each R ^{a is} independently selected from the group consisting of hydrogen and (C1-C6) alkyl;
each R ^b is a suitable group that is independently selected from the group consisting of = O, —OR ^d and —OC (O) NR ^c R ^c ;
each R ^c independently is R ^a ;
each R ^{d is} independently R ^a ;
each index m is independently an integer from 1 to 3. 16. The compound according to clause 15, in which R ² represents

and each R ⁴⁶ , R ⁴⁷ and R ^{48 is} independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyl, halogen, isoxazole, piperazino, N-alkyl piperazine, morpholino, and CH ₃ NHC (O) CH ₂ O-, when provided that none of the groups R ⁴⁶ , R ⁴⁷ and R ⁴⁸ is hydrogen and that if one of the groups R ⁴⁶ , R ⁴⁷ or R ⁴⁸ is isoxazole, piperazino, N-alkyl piperazine, morpholino or CH ₃ NHC (O) CH ₂ O-, then the remaining groups R ⁴⁶ , R ⁴⁷ or R ⁴⁸ are hydrogen. 17. The compound according to clause 15, in which
R ² is selected from the group consisting of

and

; and
each of the groups R ²¹ , R ²² and R ²³ independently of one another is a C1-C4 alkyl group. 18. The compound according to 17, in which each of the groups R ²² and R ²³ or R ²¹ and R ²² or R ²¹ ,
R ²² and R ²³ is a methyl group. 19. The compound of 2,4-pyrimidinediamine structural formula:

and its pharmaceutically acceptable salts, in which:
R ² is

or

R ⁴ is selected from the group consisting of

and

R ⁵ represents a fluorine atom;
R ⁶ represents a hydrogen atom;
R represents, consisting of R ^a ;
R ²¹ represents a C1-C4 alkyl group;
R ²³ represents a C1-C4 alkyl group;
each R ²⁸ individually represents a halogen or a C1-C4 alkoxy group;
R ²⁹ represents (C1-C6) alkyl;
each R ^{a is} independently selected from the group consisting of hydrogen and (C1-C6) alkyl. 20. The compound according to claim 19, in which R ²⁸ is a methoxy group. 21. The compound according to claim 19, in which R ²¹ is a methyl group. 22. The compound according to claim 19, in which each R ²⁸ is chlorine. 23. The compound according to claim 19, in which R ²¹ is a methyl group and R ²⁸ is chlorine. 24. The compound of 2,4-pyrimidinediamine of the structural formula:

and its pharmaceutically acceptable salts, in which:
R ² is

or

;
R ⁴ is selected from the group consisting of

and

R ⁵ represents a fluorine atom;
R ⁶ represents a hydrogen atom;
R ⁸ is selected from the group consisting of R ^a R ^b , R ^a substituted with one or more identical or different groups R ^a or R ^b , —OR ^a , —NH— (CH ₂ ) _m —R ^b ;
R ²¹ represents a C1-C4 alkyl group;
each R ²⁸ individually is halogen or C1-C4 alkoxy;
X is selected from the group consisting of N and CH;
Y is selected from the group consisting of O and NH;
Z is selected from the group consisting of O and NH, provided that Z is not the same as Y;
each R ^{35 is} independently selected from the group consisting of hydrogen and
R ^a , or in the alternative case, two R ³⁵ attached to the same carbon atom are taken together with the formation of an oxo group (= O), and the other two groups
R ³⁵ each independently from one another are selected from the group consisting of hydrogen and R ⁸ ;
each R ^{a is} independently selected from the group consisting of hydrogen, (C1-C6) alkyl, a 5-6 membered cycloheteroalkyl containing 1-2 heteroatoms in the ring selected from nitrogen, oxygen and sulfur;
each R ^b is a suitable group that is independently selected from the group consisting of = O, —NR ^c R ^c , halogen, —CF ³ ,
-S (O) ₂ NR ^c R ^c ;
each R ^{c is} independently R ^a , or in the alternative case, each R ^c is taken together with the nitrogen atom to which it is attached, with the formation of a 5-6 membered cycloheteroalkyl containing 1-2 heteroatoms in a cycle selected from nitrogen and oxygen, and which may optionally be substituted with one or more identical or different R ^a groups or suitable R ^b groups;
each R ^{d is} independently R ^a ;
each index m is independently an integer from 1 to 3;
R ⁵⁰ represents a C1-C4 alkyl group or - (CH ₂ ) _q OH;
q is a goal number from 1 to 6; and
R ⁵² represents an alkyl group or a substituted R ⁸ alkyl group. 25. The compound according to paragraph 24, in which R ²¹ represents a methyl group. 26. The compound according to paragraph 24, in which each R ²⁸ represents chlorine. 27. The compound according to paragraph 24, in which R ²¹ represents a methyl group and R ²⁸ represents chlorine. 28. The compound of claim 24, wherein R ⁵⁰ is —CH ₂ CH ₂ OH. 29. The compound of claim 24, wherein R ⁵² is trifluoromethyl. 30. The compound according to paragraph 24, in which R ⁵⁰ represents a methyl group. 31. The compound according to paragraph 24, in which each R ²⁸ represents chlorine. 32. The compound according to paragraph 24, in which R ⁵⁰ represents a methyl group and R ²⁸ represents chlorine. 33. The compound of 2,4-pyrimidinediamine of the structural formula:

and its pharmaceutically acceptable salts, in which:
R ² represents

R ⁴ represents cycloalkyl;
R ⁵ represents a fluorine atom;
R ⁶ represents a hydrogen atom;
R ²¹ represents an alkyl group; and
R ³⁰ represents an alkyl group or halogen. 34. The compound of claim 33, wherein R ²¹ is a methyl group. 35. The compound according to claim 1, in which
R ⁴ is

. 36. The compound according to claim 1, in which
R ² represents

and R ⁴ represents

R ³¹ represents a (C1-C6) alkyl group. 37. The compound according to clause 36, in which
R ⁴ is

. 38. The compound according to clause 36, in which Y represents O, Z represents NH and X represents N. 39. The compound representing N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4] oxazin-6-yl) -5-fluoro-N2- (3,4,5-trimethoxyphenyl ) -2,4-pyrimidinediamine or a pharmaceutically acceptable salt thereof. 40. A pharmaceutical composition having an effect on autoimmune disorders, comprising an effective amount of a compound according to any one of claims 1 to 39 as an active ingredient and a pharmaceutically acceptable carrier, diluent, excipient or excipient. 41. The use of a compound according to any one of claims 1 to 39 for the manufacture of a medicament for the treatment of autoimmune diseases.

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