Compositions and methods for inhibition of the jak pathway

[0001] The disclosure relates to compounds useful in modulating the JAK pathway, inhibiting one or more JAK kinases, and treating conditions in which the modulation of the JAK pathway or inhibition of JAK kinases, in particular JAK3, is therapeutically useful.

Background [0002] JAnus (or JAK) kinases are a family of cytoplasmic protein tyrosine kinases, including JAK1, JAK2, JAK3 and TYK2. Each JAK kinase is selective for some cytokine receptors, although many JAK kinases may be affected by a particular cytokine or signaling pathway. Studies suggest that JAK3 binds to the typical gamma chain (s) of various cytokine receptors. In particular, JAK3 selectively binds to receptors and is part of the cytokine signaling pathway for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. JAK1 kinase interacts with, inter alia, receptors for IL-2, IL-4, IL-7, IL-9 and IL-21 cytokines, while JAK2 interacts with, inter alia, receptors for IL9 and TNF-α. After binding of certain cytokines to their receptors (e.g. IL-2, IL-4, IL-7, IL-9, IL15 and IL-21), receptor oligomerization occurs, which leads to cytoplasmic tails of related JAK kinases associated with them, bringing proximity and facilitates the transphosphorylation of tyrosine residues on JAK kinase. This transphosphorylation leads to the activation of JAK kinase.

[0003] Phosphorylated JAK kinases bind various signal transducing and activating transcription (Stat) proteins. These STAT proteins, which are DNA binding proteins, activated by phosphorylation of tyrosine residues, play the role of both signaling molecules and transcription factors, and ultimately bind to specific DNA sequences found within the promoters of cytokine responsive gene (Leonard et al. ( 2000) J. Allergy Clin. Immunol. 105: 877-888). JAK / STAT signaling has been associated with mediation in the transmission of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection (allograft), rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid and hematological cancers such as leukemia and lymphoma. For a review of the pharmaceutical intervention of the JAK / STAT pathway, see Frank (1999), Mol. Med. 5: 432: 456 and Seidel et al. (2000), Oncogene 19: 2645 -. 2656.

[0004] In particular, JAK3 has been indicated in many biological processes. For example, proliferation and survival of murine mast cells induced by IL-4 and IL-9, which have been shown to be dependent on JAK3 and gamma chain signaling (Suzuki et al. (2000) Blood, 96: 2172-2180). Having a key role in IgE receptor-mediated mast cell degranulation responses (Malaviya et al. (1999),

- 2 Biochem. Biophys. Res. Commun. 257: 807-813), inhibition of JAK3 kinase has been shown to prevent type I hypersensitivity reactions, including anaphylaxis (Malaviya et al. (1999), J. Biol Chem 274: 27028-27038). Inhibition of JAK3 has also been shown to lead to suppression of the immune system in allograft rejection (Kirken, (2001), Transpl. Proc. 33: 3268-3270). Kinases, especially JAK3 kinases, have also been indicated in a mechanism involved in the early and late stages of rheumatoid arthritis (Muller-Ladner et al. (2000), J. Immunol. 164: 3894-3901); familial amyotrophic lateral sclerosis (Trieu et al., (2000), Biochem Biophys. Res. Commun. 267: 22-25); leukemia (Sudbeck et al. (1999), Clin. Cancer Res. 5: 1569-1582), fungal granuloma, T cell lymphoma (Nielsen et al. (1997), Prac. Natl. Acad. Sci. USA 94: 6764-6769); and abnormal cell growth (Yu et al. (1997), J. Immunol. 159: 5206-5210; CatlettFalcone et al. (1999), Immunity 10: 105-115).

[0005] JAK kinases, including JAK3, are expressed in large amounts in primary leukemia cells in children with acute lymphoblastic leukemia, the most common form of cancer in children, and studies correlated the activation of STAT in some cells and signals regulating apoptosis (Demoulin et al. (1996), Mol. Cell. Biol. 16: 4710-6; Jurlander et al. (1997), Blood. 89: 4146-52; Kaneko et al. (1997), Clin. Exp. Immun. 109: 185-193; and Nakamura i collaborators, (1996), J. Biol. Chem. 271: 19483-8). They are also known to be important for lymphocyte differentiation, activity and survival. JAK3 in particular plays a key role in the activity of lymphocytes, macrophages and mast cells. Given the importance of JAK kinases, in particular JAK3, compounds that modulate the JAK pathway, including those selective for JAK3, may be useful in the treatment of diseases or conditions involving lymphocytes, macrophages or mast cells (Kudlacz et al., (2004) Am J. Transplant 4: 51-57; Changelian (2003) Science 302: 875-878). Conditions in which action directed to the JAK pathway or modulation of JAK kinases, in particular JAK3, are considered therapeutically useful, include leukemia, lymphoma, transplant rejection (e.g. pancreatic islet transplant rejection, bone marrow transplant use (e.g., disease graft-anti-host), autoimmune diseases (e.g. diabetes) and inflammation (e.g. asthma, allergic reactions). Conditions that may benefit from JAK3 inhibition are discussed in more detail below.

[0006] Because of the many conditions that are considered to benefit from treatments involving the modulation of JAK pathways, it is immediately obvious that new compounds that modulate JAK pathways and methods of using these compounds should provide important therapeutic benefits to a wide range of patients. New 2,4-pyrimidinediamine compounds are provided herein for use in the treatment of conditions [diseases] in which activities directed to the JAK pathway or inhibition of JAK kinases, in particular JAK3, are therapeutically useful.

[0007] WO 2008 118822 discloses compositions and methods for inhibiting the JAK pathway.

SUMMARY [0008] The disclosure relates to compounds, pharmaceutical compositions containing these compounds, and those compounds for use in the treatment of [disease] conditions in which modulation of the JAK pathway or inhibition of the JAK kinase, particularly JAK2, JAK3, or both, will be therapeutically useful.

[0009] One embodiment of the invention disclosed herein includes a compound of formula I, a salt thereof, or a pharmaceutical composition comprising the compound:

<img file="PL2389372T3_D0001.tif" />

^v FROM² N K 'i

wherein:

X and Y are each independently O, S, S (O), SO2 or NR¹;

each R¹ is independently, at each occurrence, H, optionally substituted C1-6alkyl, C (O) -C1-6alkyl, CO2-C1-6alkyl or R⁵⁰; each R⁵⁰ is C (R⁹) 2-OR¹⁰ or C (R⁹) 2-SR¹⁰;

each R⁹ is independently, at each occurrence, H, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C7-16arylalkyl; or alternatively, two Rs⁹, together with the carbon to which they are attached, form an optionally substituted C3-8cycloalkyl or optionally substituted 3-8 membered heteroalicyclic; R¹⁰ means R^and or -P (O) (OR¹¹) 2; each R¹¹means independently, in each occurrence, R^andor a monovalent cationic group; or two R¹¹together with the atoms to which they are attached form a 4-8 membered cyclic phosphate group, or two Rs¹¹ together they represent a divalent cationic group;

ring A is C6-10aryl or 5-10 membered heteroaryl;

each R² means independently, in each case, H, R^e, R^b, R^esubstituted with one or more of the same or different R^and and / or R^b, -OR^e substituted with one or more of the same or different R^and and / or R^b, -SR^e substituted with one or more of the same or different R^and and / or R^b, -C (O) R^esubstituted with one or more of the same or different R^and and / or R^b, -N (R^and) R^ewhere R^e is substituted by one or more of the same or different R^and and / or R^b, -S (O) 2R^e substituted with one or more of the same or different R^and and / or

<img file="PL2389372T3_D0002.tif" />

- 4 C (O) N (R^and) - (C (R^and) 2) m^b, -N (R^and) -C (O) -N (R^and) - (C (R^and) 2) m^b, -N (R^and) -C (O) - (C (R^and) 2) mC (R^and) (R^b) 2 or -N (R^and) - (C (R^and) 2) mC (O) -N (R^and) - (C (R^and) 2) m^b;

each R^and means independently, in each case of occurrence, H, deuterium,

C1-6alkyl, C3-8cycloalkyl, C4-11cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclicyl, 4-11 membered heteroalicyclicalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;

each R^b means independently, in each occurrence, = O, -OR^and,

-O- (C (R^and) 2) m -OR^and, haloC1-3alkyloxy, = S, -SR^and, = NR^and, = NOR^and, -N (R^c) 2, halo, -CF3,

-CN, -NC, -OCN, -SCN, -NO, -NO2, = N2, -N3, -S (O) R^and, -S (O) 2R^and, -SO3R^and,

-S (O) N (R^c)2,

-OS (O) R^and, -OS (O) 2R^and, -OSO3R^and, -OS (O) 2N (R^c) 2, -C (O) R^and, -CO2R^and, -C (O) N (R^c)2,

-C (NR^and) -N (R^c) 2, -C (NOH) -R^and, -C (NOH) -N (R^c) 2, -OC (O) R^and, -OC (O) OR^and,

-OC (O) N (R^c) 2, -OC (NH) -N (R^c) 2, -OC (NO^and) -N (R^c) 2, - [N (R^and) C (O)] nR^and,

- [N (R^and) C (O)] nOR^and, - [N (R^and) C (O)] n N (R^c) 2 or - [N (R^and) C (NR^and)] N N (R^c)2;

each R^c means independently, in each occurrence, R^andor, alternatively, two Rs^c is considered together with the nitrogen atom to which they are attached to form a 3 to 10-membered heteroalicyclic or 5-10 membered heteroaryl which may optionally contain one or more of the same or different additional heteroatoms and which is optionally substituted with one or more than the same or different group R^and and / or R^d;

each R^d means = O, -OR^and, haloC1-3alkyloxy, C1-6alkyl, = S, -SR^and, = NR^and, = NOR^and,

-N (R^and) 2, halo, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, = N2, -N3, -S (O) R^and, -S (O2) R^and, -SO3R^and, -S (O) N (R^and) 2, -S (O) 2N (R^and) 2, -OS (O) R^and, -OS (O) 2R^and, -OSO3R^and, -OS (O) 2N (R^and) 2, -C (O) R^and, -CO2R^and, -C (O) N (R^and) 2, -C (NR^and) N (R^and) 2, -C (NOH) R^and, -C (NOH) N (R^and)2,

-OCO2R^and, -OC (O) N (R^and) 2, -OC (NO^and) N (R^and)2^, - [N (R^and) C (O)] nR^and, - (C (R^and) 2) n OR^and, -N (R^and) S (O) 2 R^and, -C (O) -C1-6haloalkyl, -S (O) 2C1-6haloalkyl, -OC (O) R^and, -O (C (R^and) 2) m-OR^and, -S (C (R^and) 2) m-OR^and, -N (R^and) C1-6haloalkyl, -P (O) (OR^and) 2, -N (R^and) - (C (R^and) 2) m-OR^and,

- [N (R^and) C (O)] nOR^and, - [N (R^and) C (O)] n N (R^and) 2, - [N (R^and) C (NR^and)] N (R^and) 2 or -N (R^and) C (O) C16haloalkil; or two R^d, considered together with the atom or atoms to which they are attached, forming a 3-10 membered, partially or fully saturated, mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R^and;

each R^e means independently, in each occurrence, C 1-6 alkyl,

C3-8cycloalkyl, C4-11 cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclic, 4-11 membered heteroalicyclicalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;

- 5 p is 0, 1, 2, 3 or 4;

each m is 1, 2 or 3;

each n is 0, 1, 2 or 3;

or two groups of R², considered together with the atom or atoms to which they are attached, forming a 4-10 membered, partially or fully saturated, mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R^and and / or R^b;

FROM¹ and Z² are each independently CH, CR² or N;

R³ is H, optionally substituted C1-6alkyl or R⁵⁰;

_R4 is H, optionally substituted C1-6alkyl or R⁵⁰; and

R⁵ is halo, -CN, optionally substituted C1-6alkyl, alkynyl, hydroxy, optionally substituted C1-6alkoxy, nitro, -N (R^and) 2, -C (O) N (R^and)₂, -WHAT₂R^and or -C (O) R^and.

[0010] Also disclosed herein is a method of inhibiting JAK kinase activity, comprising contacting a JAK kinase with an amount of a compound effective to inhibit JAK kinase activity, wherein the compound has formula I as described herein. Contact may occur in vitro or in vivo.

[0011] Another embodiment is a compound described herein, of formula I for use in a method of treating T cell mediated autoimmune disease, comprising administering to a patient suffering from such an autoimmune disease an amount of a compound effective to treat an autoimmune disease.

[0012] Another embodiment is a compound of formula I as described herein, for use in a method of treating allograft rejection in a transplant recipient, comprising administering to the recipient an amount of the compound effective to treat or prevent rejection. Administration in this context may include contacting the transplanted organ with the compound or pharmaceutical composition described herein prior to transplantation and / or in parallel with administration of the transplant recipient.

[0013] Still another embodiment is a compound of formula I as described herein for use in a method of treating a type IV hypersensitivity reaction, including administering to the subject an amount of a compound effective to treat or prevent a hypersensitivity reaction.

[0014] Another embodiment is a compound of formula I as described herein for use in a method of treating an eye disease or disorder, including administering to the subject an amount of the compound effective to treat or prevent an eye disease or disorder.

[0015] Another embodiment is a compound of formula I as described herein for use in a method of inhibiting the signal transduction cascade in which a role plays

JAK3 kinase, including contacting the cell expressing the receptor involved in such a signal transduction cascade with a compound.

[0016] Another embodiment is a compound of formula I as described herein for use in a method of treating a disease mediated by JAK kinase, including administering to the subject an amount of a compound effective to treat or prevent the disease mediated by JAK kinase.

[0017] Another embodiment of the invention is a pharmaceutical formulation comprising a compound of formula I described herein. Therapy using the 2,4-pyrimidinediamine compounds and the pharmaceutical formulations described herein can be used alone, or can be used in combination with or adjunct to other immunosuppressive therapies.

[0018] Also disclosed herein is a kit comprising a compound of formula I as described herein, a prodrug thereof, or a pharmaceutical composition containing the given compound, packaging, and instructions for use.

[0019] Also disclosed herein is a unit dose preparation containing a compound of formula I as described herein, a prodrug thereof, or a pharmaceutical composition containing a compound of formula I.

[0020] We also disclose methods of using compounds for screening with respect to other agents used for the treatment or prevention of JAK kinase mediated disease.

[0021] A more detailed description for these and other embodiments of the invention is provided below.

DETAILED DESCRIPTION

Overview [0022] The invention includes compounds of formula I and compositions and compounds for use in the treatment of [disease] conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3, are therapeutically useful. Formulations, their use as screening agents (for screening) and other utilities have also been described.

Terms [0023] As used herein, the following words and phrases are intended to have the meanings given below, except where the context in which they are used indicates otherwise or are clearly defined to mean something else.

[0024] The symbol "-" means a single bond, "=" means a double bond, "=" means a triple bond. The symbol '^%' refers to the group with the double bond as occupying each of the positions at the end of the double bond to which the symbol is attached; that is, the geometry, E- or Z-, of the double bond is ambiguous and both isomers are to be included. If the group is removed from the parent pattern, the symbol is used at the end of the bond that was theoretically split to separate the group from

- 7 of its parent structural formula.

[0025] If the chemical formulas are depicted or described, unless explicitly stated otherwise, all carbon atoms are treated as substituted with hydrogen atoms, according to the valence of four. For example, nine hydrogen atoms are present in the structure on the left in the diagram below. The nine hydrogen atoms are represented on the right-hand structure. Sometimes a particular atom in a structure is represented in the summary formula as having a hydrogen or hydrogen substitution (clearly defined hydrogen), for example, -CH2CH2-. It should be understood by one of ordinary skill in the art that the descriptive techniques mentioned herein are commonly used in the field of chemistry to provide brevity and simplicity in the description of complex structures.

<img file="PL2389372T3_D0003.tif" />

[0026] In the application, some ring structures genetically represented will be described in words. For example, in the scheme below, if ring A is used to describe phenyl, up to four hydrogen atoms in ring A are present (when R is not H).

y [0027] If the R group is represented as "variable" on a ring system, such as in the group:

<img file="PL2389372T3_D0004.tif" />

then, unless otherwise specified, the R substituent may be located at any atom in the condensed bicyclic ring system, with the exception of the atom carrying the bond with the symbol as long as a stable structure is formed.

In the example described, the R group may be on an atom in a 5-membered or 6-membered ring system of an indolyl ring.

[0028] If there are more than one such "variable" groups, for example as in the formulas:

<img file="PL2389372T3_D0005.tif" />

- 8 where there are two groups, namely R and a bond indicating attachment to the parent structure; then, unless otherwise specified, these "variable" groups may be located at any atom in the ring system, again assuming that each replaces the depicted, default or explicitly defined hydrogen atom in the ring system and a chemically stable compound can be formed by such arrangement .

[0029] If the R group is represented as being in a ring system containing saturated carbon atoms, such as in the formula:

<img file="PL2389372T3_D0006.tif" />

where, in this example, y can be more than one, assuming that each is currently replacing a depicted, implied or explicitly defined ring hydrogen atom; then, unless otherwise specified, two R groups may be located on the same carbon atom. A simple example is if R is a methyl group; there may be geminal dimethyl at the carbon in the ring ("ring" carbon atom). In another example, two R groups on the same carbon atom, together with the same carbon atom, can form a ring, thereby forming a spirocyclic ring structure ("spirocyclic" group). Using the previous example in which the two Rs form, e.g. a piperidine ring in a spirocyclic cyclohexane system, as in the formula:

<img file="PL2389372T3_D0007.tif" />

[0030] "Alkyl" in the broadest sense is intended to include linear, branched, or cyclic hydrocarbon structures, and combinations thereof. Alkyl groups may be fully saturated with one or more unsaturation units, but not aromatic. Generally, alkyl groups are defined by a subscript, or a fixed integer or a range of integers. For example, "C₈alkyl "includes n-octyl, iso-octyl, 3-octynyl, cyclohexenylethyl, cyclohexylethyl, and the like; where the subscript "8" means that all groups defined by this term have a fixed number of carbon atoms eight. In another example, the term "C_1-6alkyl "refers to alkyl groups having from one to six carbon atoms and depending on any unsaturations, branches and / or rings, the corresponding number of hydrogen atoms. Examples of groups C_1-6alkyl include methyl, ethyl, vinyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, isobutenyl, pentyl, pentynyl, hexyl, cyclohexyl, hexenyl, and the like. If an alkyl residue containing a certain number of carbon atoms is named generically, all geometric isomers containing this number of carbon atoms are intended to be encompassed by the present invention. For example, "propyl" or "C₃alkyl "each includes n-propyl, c-propyl, propenyl, propynyl and isopropyl. Cycloalkyl means a subgroup of an alkyl group and includes cyclic hydrocarbon groups containing from three to thirteen carbon atoms. Examples of the cycloalkyl group include c-propyl, c-butyl,

- 9 c-pentyl, norbornyl, norbornenyl, c-hexenyl, adamantyl and the like. As mentioned, alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof) - it is intended to include, e.g., cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Alkyl with a certain number of carbon atoms can be called using a more specific, but still general geometric constraint, for example, "C_3-6 cycloalkyl ", which means only cycloalkyl containing between 3 to 6 carbon atoms are to be included in this particular definition. Unless otherwise specified, alkyl groups, either alone or as part of another group, e.g. -C (O) alkyl, contain from one to twenty carbon atoms, which means group C_1-20alkyl group. In the example "-C (O) alkyl," where no carbon number limit was defined, the -C (O) alkyl group carbonyl is not included in the carbon number because "alkyl" is generally designated. But if specific restrictions on carbon are given, e.g., "optionally substituted C_1-20 alkyl ', where the optional substitution includes the' oxo 'carbon of any of the carbonyls formed by such an' oxo 'substitution is included in the carbon number because it was part of the original carbon limit. However, referring again to "optionally substituted C_1-20 alkyl "if the optional substitution includes carbon containing groups, for example -CH₂WHAT₂H, two carbon atoms in this group are not included in C_1-20alkyl carbon restrictions.

[0031] If the carbon number limit is given at the beginning of a term which itself consists of two terms, the carbon number limit is understood to be cumulative for both terms. For example, for the term "C7-14arylalkyl," the parts of both "aryl" and "alkyl" of the term are covered by the number of carbon atoms, a maximum of 14 in this example, but additional substituent groups on them are not included in the number of atoms, unless they contain coal from the group of designated carbons, as in the "oxo" example above. Similarly, if a limitation on the number of atoms is given, for example, "6-14 membered heteroarylalkyl," both parts of "heteroaryl" and "alkyl" are included in the limitation of the number of atoms, but additional groups of substituents on them are not included in the number of atoms, unless they contain they are coal from the group of designated coals. In another example, "C 4-10 cycloalkylalkyl" means a cycloalkyl attached to the parent structure through an alkylene, alkylidene or alkylidine subunit; in this example the group is limited to 10 carbon atoms including the alkylene, alkylidene or alkylidine subunit. As another example, the "alkyl" portion, e.g. "C7-14arylalkyl" is intended to include alkylene, alkylidene or alkylidine, unless otherwise stated, e.g. as in the terms "C7-14arylalkylene" or "C6-10arylCH2CH2-." [0032] "Alkylene" refers to a simple, branched and cyclic (and combination thereof), divalent radical consisting only of carbon and hydrogen, non-unsaturated and having from one to ten carbon atoms, for example methylene, ethylene, propylene, n-butylene and the like. Alkylene, like alkyl, refers to the same residues as alkyl, but having two attachment points and, in particular, fully saturated. Examples of alkylene include ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), dimethylpropylene (-CH2C (CH3) 2CH2-), cyclohexane-1,4-diyl and the like.

[0033] "Alkyliden" refers to straight, branched and cyclic (and combinations thereof)

- an unsaturated divalent radical consisting only of carbon and hydrogen atoms having from two to ten carbon atoms, for example ethylidene, propylidene, n-butylidene, and the like. Alkyliden, like alkyl, refers to the same residues as alkyl, but having two attachment points and, in particular, at least one double unsaturation unit. Examples of alkylidene include vinylidene (-CH = CH-), cyclohexylvinylidene (-CH = C (C₆H₁₃) -), cyclohexene-1,4-diyl and the like.

[0034] "Alkylidines" refers to a simple, branched and cyclic (and combination thereof) unsaturated divalent radical consisting only of carbon and hydrogen atoms, having from two to ten carbon atoms, for example, propylid-2-ynyl, n-butylide 1ynyl, and the like. Alkylidines, like alkyl, refer to the same residue as alkyl, but having two attachment points and, in particular, at least one unsaturation unit of the triple bond.

[0035] Each of the above radicals, "alkylene", "alkylidene" and "alkylidin", if optionally substituted, may contain an alkyl substitution which itself may contain unsaturation. For example, 2- (2-phenylethynyl-but-3-enyl) -naphthalene (IUPAC name) contains a n-butylid-3-ynyl radical with a vinyl substituent at the 2-position of the radical. Combinations of alkyls and carbon-containing substitutions for them are limited to thirty carbon atoms.

[0036] "Alkoxy" refers to an O-alkyl group wherein alkyl is as defined herein. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, cyclohexyloxy, cyclohexenyloxy, cyclopropylmethyloxy and the like.

[0037] "Haloalkyloxy" refers to an -O-alkyl group where alkyl is as defined herein, and, further, alkyl is substituted with one or more halogens. For example, the haloC 1-3 alkyloxy group includes -OCF₃, -OCF2H, -OCHF2, -OCH2CH2Br, -OCH2CH2CH2I, -OC (CH₃) 2Br, -OCH2Cl and the like.

[0038] "Acyl" refers to the groups -C (O) H, -C (O) alkyl, -C (O) aryl and -C (O) heterocyclyl.

[0039] "α-amino acids" refers to naturally occurring and commercially available α-amino acids, and their optical isomers. Typical natural and commercially available α-amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine, methocaine, homocysteine phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. "Α-amino acid side chain" refers to a radical present at the α-carbon atom of an α-amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine) etc.

[0040] "Amino" refers to the NH2 group.

[0041] "Amide" refers to the group -C (O) NH2 or -N (H) acyl.

[0042] "Aryl" (sometimes referred to as "Ar") refers to a monovalent aromatic carbocyclic group, unless otherwise specified, from 6 to 15 carbon atoms having a single

- a ring (e.g., phenyl) or multiple condensed rings (e.g. naphthyl or anthryl), which condensed rings may or may not be aromatic (e.g. 2-benzoxazolinone, 2H-1,4-benzoxazin-3 (4H ) -on-7-yl, 9,10-dihydrophenantrenyl, indanyl, tetralinyl and fluorenyl, and the like) provided that the point of attachment is through the atom of the aromatic part of the aryl group and the aromatic part at the point of attachment contains only carbon atoms in the aromatic ring . If any part of the aromatic ring contains a heteroatom, the group is heteroaryl and non-aryl. Aryl groups are monocyclic, bicyclic, tricyclic and tetracyclic.

[0043] "Arylene" refers to aryl which has at least two groups attached thereto. In a more specific example, the term "phenylene" refers to the divalent phenyl ring radical. Thus, phenylene may have more than two attached groups, but is defined by a minimum of two non-hydrogen groups attached to it.

[0044] "Arylalkyl" refers to a residue in which the aryl moiety is attached to the parent structure through one of the alkylene, alkylidene or alkylidine radicals. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl and the like. If specified as "optionally substituted" both the aryl and the corresponding alkylene, alkylidene or alkylidino part of the arylalkyl group may be optionally substituted. For example, "C_7-11arylalkyl "refers to arylalkyl, limited to eleven total carbon atoms, e.g., phenylethyl, phenylvinyl, phenylpentyl and naphthylmethyl are all examples of the" C₇.₁₁arylalkyl. "

[0045] "Aryloxy" refers to an -O-aryl group in which aryl is as defined herein, including, for example, phenoxy, naphthoxy, and the like.

[0046] "Carboxy," "carboxy" or "carboxylate" refers to -CO₂H or its salt.

[0047] "Carboxylic ester" or "carboxyester" or "ester" refers to the group -CO₂alkyl, -CO₂aryl or -CO₂heterocyclyl.

[0048] "Carbonate" refers to the -OCO2-alkyl, -OCO2-aryl or -OCO2heterocyclyl group.

[0049] "Carbamate" refers to the -OC (O) NH2, -N (H) carboxyl group or ester

-N (H) carboxylic acid.

[0050] "Cyano" or "nitrile" refers to the group -CN.

[0051] "Formyl" refers to the specific acyl group -C (O) H.

[0052] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0053] "Haloalkyl" and "haloaryl" generally refer to alkyl and aryl radicals that are substituted with one or more halogen atoms, respectively. For example, "dihaloaryl", "dihaloalkyl", "trihaloaryl", etc., refer to aryl and alkyl substituted with multiple halogen atoms, but not necessarily many of the same halogen; thus 4-chloro-3-fluorophenyl is a dihaloaryl group.

[0054] "Heteroalkyl" refers to an alkyl in which one or more, but not all, carbons have been replaced with a heteroatom. The heteroalkyl group has linear or branched geometry. For example, "2-6 membered heteroalkyl" means a group that may contain no more than 5 carbon atoms, because at least one of the maximum 6 atoms must be a heteroatom and the group is linear or branched. Also, for the purposes of the invention, the heteroalkyl group always starts with a carbon atom, that is, although the heteroalkyl may contain one or more heteroatoms, the attachment point to the parent molecule is not a heteroatom. A 2-6 membered heteroalkyl group includes, for example, -CH2XCH3,

-CH2CH2XCH3, -CH2CH2XCH2CH3, -C (CH2) 2XCH2CH3 and the like, wherein X is O, NH, NC1-6 alkyl and S (O) 0-2, for example.

[0055] "Perhalo" as a modifier means that the group thus modified has all available hydrogen atoms replaced by halogens. An example would be "perhaloalkyl." Perhaloalkyls include -CF₃, -CF₂CF₃, perchloroethyl and the like.

[0056] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0057] "Heteroatom" refers to O, S, N, or P.

[0058] "Heterocyclyl" in the broadest sense of the word includes aromatic and non-aromatic ring systems, and in particular refers to a stable three to fifteen membered ring radical which consists of carbon atoms and from one to five heteroatoms. For the purposes of the invention, the heterocyclic radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems as well as spirocyclic systems; and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclic radical may be optionally oxidized to varying degrees of oxidation. In a specific example, group S (O)_0-2-, relates to -S- (sulfide), -S (O) - (sulfoxide) and -SO bonds₂- (sulfone). For convenience, nitrites, in particular, but without limitation, which are defined as ring aromatic nitrogen, are intended to include the corresponding forms of their N-oxides, although they are not specifically mentioned in the specific example. Thus, for a compound having, for example, a pyridyl ring; the corresponding pyridyl-N-oxide is intended to be included in the compounds disclosed herein. In addition, ring nitrogen atoms may be optionally quaternized. "Heterocycle" includes heteroaryl and heteroalicyclic, that is, the heterocyclic ring may be partially or fully saturated or aromatic. Thus, a term such as "heterocyclylalkyl" includes heteroalicycloalkyl and heteroarylalkyl. Examples of heterocyclyl radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenynylinyl, phenothiazinyl, chininylin, chininzynyl, chinylzinyl , tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidinyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,

- 13, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, diazabicycloheptane, diazapan, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphosphololyl and oxadiazolyl.

[0059] "Heteroaryl" refers to an aromatic group having from 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms. Heteroaryl groups have at least one aromatic ring component, but heteroaryls may be fully unsaturated or partially unsaturated. If any aromatic ring in the group has a heteroatom, then the group is heteroaryl, even, for example, if the other aromatic rings in the group do not have heteroatoms. For example, 2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -on-7-yl, indolyl and benzimidazolyl are "heteroaryls". Heteroaryl groups may have a single ring (e.g., pyridinyl, imidazolyl or furyl) or multiple condensed rings (e.g., indolizinyl, quinolinyl, benzimidazolyl or benzothienyl), where the fused rings may or may not be aromatic and / or contain a heteroatom provided that the point of attachment to the parent molecule is via the atom of the aromatic part of the heteroaryl group. In one embodiment, the nitrogen and / or sulfur atom (s) of the heteroaryl ring are optionally oxidized to obtain N-oxide (NO), sulfinyl or sulfonyl moieties. The phosphorus containing compounds described herein, in the heterocyclic ring or not, include oxidized forms of phosphorus. Heteroaryl groups are monocyclic, bicyclic, tricyclic and tetracyclic compounds.

[0060] "Heteroaryloxy" refers to -O-heteroaryl.

[0061] "Heteroarylene" generally refers to any heteroaryl that has at least two groups attached thereto. According to a more specific example, "pyridylene" refers to a divalent radical on the pyridyl ring. Thus, pyridylene may contain more than two attached groups, but is defined by a minimum of two non-hydrogen groups attached to it.

[0062] "Heteroalicyclic" refers specifically to a non-aromatic heterocyclyl radical. Heteroalicyclic may contain unsaturation but is not aromatic. As mentioned, aryls and heteroaryls are attached to the parent structure via an aromatic ring. Thus, e.g., 2H-1,4-benzooxazin-3 (4H) -on-4-yl is heteroalicyclic while 2H-1,4-benzooxazin-3 (4H) -on-7-yl is aryl. In another example, 2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -on-4-yl is heteroalicyclic, while 2H-pyrido [3,2b] [1,4] oxazine-3 (4H) -on-7-yl is heteroaryl.

[0063] "Heterocyclylalkyl" refers to a heterocyclic group bonded to the parent structure through, e.g., an alkylene linker, for example (tetrahydrofuran-3-yl) methyl or (pyridin-4-yl) methyl

<img file="PL2389372T3_D0008.tif" />

[0064] "Heterocyclyloxy" refers to an -O-heterocyclic group.

[0065] "Nitro" refers to the group -NO₂.

[0066] "Oxo" refers to an oxygen radical with a double bond, = O.

[0067] "Oxy" refers to the radical -O · (also designated as O), i.e. the oxygen radical with a single bond. For example, N-oxides are nitrogen atoms having an oxygen radical.

[0068] If a group together with its binding structure is marked as being associated with two partners; that is, a divalent radical, for example, -OCH2-, then it should be understood that one of these two partners can be linked to a group at one particular end, and the other partner is necessarily linked to the other end of this divalent group, unless explicitly stated otherwise. In other words, divalent radicals should not be interpreted as limited to the designated orientation, for example, "-OCH2-" is intended to mean not only "-OCH2-" as drawn, but also "-CH2O-".

[0069] "Optional" or "optionally" means that the event or circumstance described subsequently may or may not occur, and that the description includes cases where said event or circumstance occurs and cases where it does not occur. One skilled in the art will understand that with respect to any molecule described as containing one or more optional substituents, only synthetically feasible compounds are to be included. "Optionally substituted" refers to all subsequent modifiers within the term, for example, the term "optionally substituted arylC 1-8 alkyl" optionally substitution may occur in both the "C 1-8 alkyl" portion and the "aryl" portion as the arylC 1-8 alkyl group. Also, for example, optionally substituted alkyl includes optionally substituted cycloalkyl groups. The term "substituted" when used to modify a particular group or radical means that one or more hydrogen atoms of the specified group or radical, independently of each other, have been replaced by the same or different substituent groups as defined below. Thus, if a group is defined as "optionally substituted," the definition is intended to include a group that is substituted by one or more radicals defined below, and a group if it is not so substituted.

[0070] Substituent groups for the substitution of one or more hydrogen atoms (any two hydrogen atoms on one carbon atom may be replaced by = O, = NR⁷⁰, = N-OR⁷⁰, = N2 or = S) with saturated carbon atoms in the specified group or radical are, unless otherwise specified, -R⁶⁰, hello, = O, -OR⁷⁰, -SR⁷⁰, -N (R⁸⁰) 2, perhaloalkyl, -CN, -OCN, -SCN, - NO, -NO2, = N2, -N3, -SO2R⁷⁰, -SOs'M +, -SO3R⁷⁰, -OSO2R⁷⁰, -OSO3 M, -OSO3R⁷⁰,

- 15 -P (O) (O^-) 2 (M +) 2, -P (O) (O ')₂M²+, -P (O) (OR⁷⁰) O'M +, -P (O) (OR⁷⁰) 2, -C (O) R⁷⁰, -C (S) R⁷⁰,

-C (NR⁷⁰) R⁷⁰, -CO2'M +, -CO2R⁷⁰, -C (S) OR⁷⁰, -C (O) N (R⁸⁰) 2, -C (NR⁷⁰) (R⁸⁰)₂, -OC (O) R⁷⁰,

-OC (S) R⁷⁰, -OCO2^-M +, -OC2R⁷⁰, -OC (S) OR⁷⁰, -NR⁷⁰C (O) R⁷⁰, -NR⁷⁰C (S) R⁷⁰, -NR⁷⁰CO2^-M +

-NR⁷⁰CO 2 R⁷⁰, -NR⁷⁰C (S) OR⁷⁰, -NR⁷⁰C (O) N (R⁸⁰) 2, -NR⁷⁰C (NR⁷⁰) R⁷⁰ and

-NR⁷⁰C (NR⁷⁰) N (R⁸⁰) 2, where R⁶⁰ is C1-6 alkyl, 3 to 10 membered heterocyclyl, 3 to 10 membered heterocyclylC₁.₆alkyl, C._6-10aryl or C.₆.₁₀aryl₁.₆alkyl; each R⁷⁰ means independently in each case the occurrence of hydrogen or R⁶⁰; each R⁸⁰ means independently in each case the occurrence of R⁷⁰ or alternatively, two Rs⁸⁰ those taken together with the nitrogen atom to which they are attached form a 3- to 7-membered heteroalicyclic which optionally contains from 1 to 4 same or different additional heteroatoms selected from the group consisting of O, N and S, of which N optionally has H or C substitution₁-C₃alkyl; and each M + is a counterion with one positive charge. Each M + is independently for each occurrence, e.g., alkali metal ions such as K +, Na +, Li +;

+ 60 2 + 2 + ammonium ion such as + N (R)₄; or alkaline earth ion such as [Ca]₀,₅ [Mg]₀,₅ or [Ba² +] 0.5 ("subscript 0.5 means, for example, that one of these counterions for such divalent alkaline earth metal ions can be ionized to form a compound of the invention and another typical counterion, such as chloride, or two ionized compounds can serve as counterions for such divalent alkaline earth metal ions or a doubly ionized compound can serve as counterions for such divalent alkaline earth metal ions). As specific examples, -N (R⁸⁰) 2 is intended -NH2, -NH-alkyl,

-NH-pyrrolidin-3-yl, A-pyrrolidinyl, A-piperazinyl, 4.Y-methyl-piperazin-1-yl, A-morpholinyl and the like.

[0071] Substituent groups for the replacement of hydrogen on unsaturated carbon atoms in groups containing unsaturated carbons are, unless otherwise specified, -R⁶⁰, hello, -O'M +, -OR⁷⁰, -SR⁷⁰, -S "M +, -N (R⁸⁰) 2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO₂, -N3, -SO2R⁷⁰,

-SOfYl ', -SO3R⁷⁰, -OSO2R⁷⁰, -OSOfYf, -OSO3R⁷⁰, -POr (Yl)₂, -PO3^-2M²+, -P (O) (OR⁷⁰) O 'M +, -P (O) (OR⁷⁰) 2, -C (O) R⁷⁰, -C (S) R⁷⁰, -C (NR⁷⁰) R⁷⁰, -CO2^-M +, -CO2R⁷⁰, -C (S) OR⁷⁰, -C (O) NR⁸⁰R⁸⁰, -C (NR⁷⁰) N (R⁸⁰) 2, -OC (O) R⁷⁰, -OC (S) R⁷⁰, -OCO2^-M +, -OCO2R⁷⁰,

-OC (S) OR⁷⁰, -NR⁷⁰C (O) R⁷⁰, -NR⁷⁰C (S) R⁷⁰, -NR⁷⁰CO2^-M +, -NR⁷⁰CO 2 R⁷⁰, -NR⁷⁰C (S) OR⁷⁰,

-NR⁷⁰C (O) N (R⁸⁰) 2, -NR⁷⁰C (NR⁷⁰) R⁷⁰ and -NR⁷⁰C (NR⁷⁰) N (R⁸⁰) 2, in which R⁶⁰, R⁷⁰, R⁸⁰ and M + are as previously defined, provided that in the case of substituted alkene or alkyne, the substituents are not -O'M +, -OR⁷⁰, -SR⁷⁰, or -S'M +.

[0072] Substituent groups for the replacement of hydrogen at nitrogen atoms in groups containing such nitrogen atoms are, unless otherwise specified, -R⁶⁰, -O'M +, -OR⁷⁰, -SR⁷⁰,

-S "M +, -N (R⁸⁰) 2, perhaloalkyl, -CN, -NO, -NO₂, -S (O) 2R⁷⁰, -SOfYl ', -SO3R⁷⁰, -OS (O) 2R⁷⁰,

-OSOfYf, -OSO3R⁷⁰, -PO3^2-(M +) 2, -PO3^2-M²+, -P (O) (OR⁷⁰) O'M +, -P (O) (OR⁷⁰) (OR⁷⁰),

- 16 -C (O) R⁷⁰, -C (S) R⁷⁰, -C (NR⁷⁰) R⁷⁰, -CO2R⁷⁰, -C (S) OR⁷⁰, -C (O) NR⁸⁰R⁸⁰, -C (NR⁷⁰) NR⁸⁰OR⁸⁰,

-OC (O) R⁷⁰, -OC (S) R⁷⁰, -OCO2R⁷⁰, -OC (S) OR⁷⁰, -NR⁷⁰C (O) R⁷⁰, -NR⁷⁰C (S) R⁷⁰,

-NR⁷⁰CO 2 R⁷⁰, -NR⁷⁰C (S) OR⁷⁰, -NR⁷⁰C (O) N (R⁸⁰) 2, -NR⁷⁰C (NR⁷⁰) R⁷⁰ and -NR⁷⁰C (NR⁷⁰) N (R⁸⁰) 2, in which R⁶⁰, R⁷⁰, R⁸⁰ and M + are as previously defined.

[0073] In one embodiment, the group that is substituted has 1, 2, 3 or 4 substituents, 1, 2 or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0074] It is understood that in all substituted groups, polymers obtained by defining substituents with further substituents for them (for example, substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group which is further substituted with a substituted aryl group, etc.) are not intended to be included here. In this case, when the language allows such multiple substitutions, the maximum number of such substitution iterations is three.

[0075] "Sulfonamide" refers to the group -SO₂NH₂, -N (H) SO₂H, -N (H) SO₂alkyl, -N (H) SO₂aryl, or -N (H) SO₂heterocyclyl.

[0076] "Sulfonyl" refers to the group -SO₂H, -SO₂alkyl, -SO₂aryl, or -SO₂heterocyclyl.

[0077] "Sulfanyl" refers to the group: -SH, -S-alkyl, -S-aryl, or -S-heterocyclyl.

[0078] "Sulfinyl" refers to the group: -S (O) H, -S (O) alkyl, -S (O) aryl or -S (O) heterocyclyl.

[0079] "Suitable leaving group" is defined as the term understood by one of ordinary skill in the art; that is, a group at the carbon atom, where after the reaction a new bond is formed, carbon loses the group as a result of the formation of a new bond. A typical example using a suitable leaving group is a nucleophilic substitution reaction, e.g., at³ hybridized carbon (SN2 or SN1), e.g. when the leaving group is a halide, such as bromide, the regent may be benzyl bromide. Another typical example of such a reaction is a nucleophilic aromatic substitution (SNAr) reaction. Another example is the insertion reaction (e.g., via a transition metal) for binding between the aromatic reaction partner with the leaving group, followed by reductive coupling. The "appropriate leaving group" is not limited to such mechanistic restrictions. Examples of suitable leaving groups include halogens, optionally substituted aryl or alkyl sulfonates, phosphonates, azides and -S (O) 0-2R, where R is, for example, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl. Those skilled in the art of organic synthesis will readily determine suitable leaving groups to perform the desired reaction in another reaction.

[0080] "Stereoisomer" and "stereoisomers" refer to compounds that have the same atomic connections but different arrangement of atoms in space. Stereoisomers include cistrans isomers, E and Z isomers, enantiomers and diastereomers. The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R) - or (5) -, or ( D) - or (L) - for amino acids. The invention is intended to include

- all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R) - and (S) - isomers, or (D) - and (L) - isomers can be obtained using chiral synthons, chiral reagents, or separated by conventional techniques such as: formation of diastereomeric salts or complexes that can be separated, for example, by crystallization; by forming diastereometric derivative compounds that can be separated, for example, by crystallization, the selective reaction of one enantiomer with an enantiomer-specific reagent, for example, enzymatic oxidation or reduction, followed by separation of modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand, or in the presence of a chiral solvent. It will be understood that if the desired enantiomer is converted to another chemical entity via one of the separation procedures described above, a further step may be required to release the desired enantiomer form. Alternatively, a particular enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another by asymmetric transformation. For a mixture of enantiomers enriched in a specific enantiomer, the main enantiomeric component can be further enriched (which will be accompanied by a decrease in yield) by recrystallization.

[0081] If the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that these compounds include E and Z geometric isomers.

[0082] "Tautomer" refers to alternative forms of the molecule that differ only in the electronic bonding of atoms and / or in the proton position, such as enolketone and imino-enamine tautomers or tautomeric forms of heteroaryl groups containing -N = C (H) -NH - ring atom system such as pyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles. One of ordinary skill in the art will recognize that other arrangements of tautomeric ring atoms are possible and contemplated herein.

[0083] "Para" for the purposes of the invention, refers to the position of a substituent on a phenyl or six membered heteroaryl ring relative to another substituent on the ring; the relative position is 1,4-substitution. That is, starting from one substituent attached to the first atom of a six-membered ring, counting the carbon atoms including the first atom, another substituent at the atom of the six-membered ring, the relative orientation of the substituents around the six-membered ring is "para". For example, compound L, shown below, has a "para" to N2 methyl group of pyrimidinediamine, compound M also has a "para" methyl group.

<img file="PL2389372T3_D0009.tif" />

[0084] The term "patient" or "subject" refers to mammals and other animals, in particular humans. Thus, these methods can be used for both human treatment and veterinary applications. In one embodiment, the patient or subject is a mammal. In another embodiment, the patient or subject is human.

[0085] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound, which salts are derived from various organic and inorganic counterions, well known in the art, and include, by way of example only, salts of sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like ; and if the molecule contains basic functional groups, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate and the like. Pharmaceutically acceptable acid addition salts are those salts that retain the biological effectiveness of the free bases, formed by acid partners who are not biologically or otherwise undesirable, e.g. inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, acid malonic, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutically acceptable base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Examples of salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary amines, secondary and tertiary, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, and triethylamine. tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Examples of organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. (See, for example, SM Berge, et al., "<a href="http://scholar.google.com/scholar?q=%22Pharmaceutical+Salts%2C%22">Pharmaceutical Salts</a>", J. Pharm Sci, 1977; 66: 1-19).

[0086] "Pharmaceutically effective amount" and "therapeutically effective amount" refer to an amount of a compound sufficient to treat a particular disorder or disease or one or more of its symptoms and / or prevent the occurrence of the disease or disorder. The amount of relationship

19 which constitutes the "therapeutically effective amount" will vary depending on the relationship, the condition and severity of the disease, the age of the patient being treated, and the like. A therapeutically effective amount can be routinely determined by a person skilled in the art.

[0087] "Prodrug" refers to compounds that are transformed in vivo to form a parent compound, for example, by hydrolysis in the intestine or enzymatic transformation in the blood. Typical examples include, but are not limited to, ester and amide forms of a compound having an active form with a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the invention include, but are not limited to, alkyl esters (e.g., having from about one to about six carbon atoms) in which the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and aralkyl esters such as, but not limited to, benzyl. Examples of pharmaceutically acceptable amides of the compounds of the invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example, having from about one to about six carbon atoms). Amides and esters of compounds of the invention can be prepared according to conventional methods. A comprehensive discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," volume 14 of the ACS series Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0088] "Metabolite" refers to a breakdown product, or end product of a compound or a salt thereof, produced by metabolism or biotransformation in the animal or human body; for example, by biotransformation to a more polar molecule, such as oxidation, reduction or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics" 8^-me ed., Pergamon Press, Gilman et al. (ed.), 1990).

[0089] The metabolite of the compound described herein, or a salt thereof, may itself be a biologically active compound in the body. If the prodrug described herein meets these criteria, that is, it forms the described biologically active compound in vivo, the "metabolite" is intended to include those compounds in which loss of the progroup is not considered, but rather all other compounds that are formed under conditions in vivo after administration of a compound of the invention that retains the biological activity described herein. Thus, one aspect discloses 2,4-pyrimidinediamine compounds, in particular a metabolite of a compound described herein is contemplated herein. For example, the biologically active metabolite is detected unexpectedly, that is, no prodrug design per se was performed. In other words, biologically active compounds internally formed as a result of practicing the methods of the invention are contemplated and disclosed herein. "Solvate" refers to a complex formed by combining solvent molecules with solute molecules or ions. The solvent may be an organic, inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide and water. The compounds described herein may exist in unsolvated as well as solvated forms, with

- with or without pharmaceutically acceptable solvents such as water, ethanol and the like. The solvated forms of the compounds disclosed herein are contemplated and included in the invention, at least in general terms.

[0090] "Treat" or "treatment," as used herein, refers to the treatment of a disease or condition of interest in mammals, preferably humans, exhibiting the disease or condition of interest, and includes:

(i) preventing disease or condition prior to its occurrence in mammals, in particular if such a mammal is predisposed to a disease state but has not yet been diagnosed with it;

(ii) inhibiting the disease or condition, for example, arresting or slowing its development;

(iii) relieving the disease or condition, e.g., causing regression of the disease or condition or symptoms thereof, or (iv) stabilizing the disease or condition.

[0091] As used herein, the terms "disease" and "condition" may be used interchangeably or may be different, in particular that the disease or condition may not have a known causative agent (since the etiology has not yet been developed ) and therefore have not yet been recognized as a disease, but only as an undesirable condition or syndrome in which a set of more or less specific symptoms has been identified by doctors.

[0092] Similarly, it should be understood that the above definitions are not intended to include unacceptable substitution patterns (e.g., fluoro-substituted methyl). Such unacceptable substitution patterns are readily recognized by one of ordinary skill in the art.

Compounds and Compositions [0093] Disclosed herein are new 2,4-pyrimidinediamine compounds, prodrugs of compounds, methods for making compounds, and methods for using these compounds in the treatment of conditions [diseases] in which the targeting of the JAK pathway or modulation, including inhibition of JAK kinases , in particular JAK3, are therapeutically useful. These conditions include, but are not limited to, leukemia, lymphoma, transplant rejection (e.g. islet transplant rejection, heart transplant rejection, kidney transplant rejection, liver transplant rejection, lung transplant rejection), bone marrow transplant applications (e.g. graft versus host disease), autoimmune diseases (e.g. diabetes) and inflammation (e.g. asthma, reactions allergic, eye disorders). Given the incidence and severity of these diseases and conditions, new treatments are needed.

compounds

[0094] The compounds and salts thereof described herein are generally pyrimidine-2,4-diamines substituted at the 5-position with different groups; substituted on the 2-amine with various, optionally substituted aromatic groups; and substituted at 4-amine with one of benzo [d] oxazol-2 (3H) -one, 1H-benzo [d] imidazol-2 (3H) -one, benzo [d] thiazol-2 (3H) -one, benzo [d] [1,3] dithiol-2-one, benzo [d] [1,3] oxatiol-2-one, benzo [d] [1,3] dioxol-2-one, [1,3] oxatiolo [4,5-b] pyridin-2-one, thiazolo [5,4-b] pyridin-2 (1H) -one, oxazolo [5,4b] pyridin-2 (1H) -one, [1,3] oxatiolo [5,4-b] pyridin-2-one, thiazolo [4,5-b] pyridin-2 (3H) -one, oxazolo [4,5-b] pyridin-2 (3H) -one, [1 , 3] dioxolo [4,5-b] pyridin-2-one, [1,3] dithiolo [4,5b] pyridin-2-one, 1H-imidazo [4,5-b] pyridin-2 (3H) -one, [1,3] oxatiolo [4,5-b] pyrazin-2-one, thiazolo [5,4-b] pyrazin-2 ( 3H) -one, oxazolo [5,4-b] pyrazin-2 (3H) -one, [1,3] dioxolo [4,5b] pyrazin-2-one, [1,3] dithiolo [4,5- b] pyrazin-2-one and 1H-imidazo [4,5-b] pyrazin-2 (3H) -one; each optionally substituted with one or more groups containing prodrug moieties as described herein. In addition to the groups described above, the N2- and N4-amines of the pyrimidinediamine system may also have optionally substituted alkyl groups and / or prodrug groups.

[0095] More specifically, exemplary disclosed compounds are described with reference to formula I:

<img file="PL2389372T3_D0010.tif" />

wherein:

X and Y are each independently O, S, S (O), SO2 or NR¹;

each R¹ is independently, at each occurrence, H, optionally substituted C1-6alkyl, C (O) -C1-6alkyl, CO2-C1-6alkyl or R⁵⁰;

each R⁵⁰ is -C (R⁹) 2-OR¹⁰ or -C- (R⁹) 2S-R¹⁰; each R⁹ is independently, at each occurrence, H, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C7-16arylalkyl; or alternatively, two Rs⁹, together with the carbon to which they are attached, form an optionally substituted C3-8cycloalkyl or optionally substituted 3-8 membered heteroalicyclic; R¹⁰ means R^and or -P (O) (OR¹¹)₂; each R¹¹ means independently, in each occurrence, R^and or a monovalent cationic group; or two R¹¹, together with the atoms to which they are attached form a 4-8 membered cyclic phosphate group, or two Rs¹¹ together they represent a divalent cationic group; ring A is C6-10aryl or 5-10 membered heteroaryl;

each R² means independently, in each case, H, R^e, R^b, R^esubstituted with one or more of the same or different R^and and / or R^b, -OR^esubstituted with one or more of the same or different R^and and / or R^b, -SR^esubstituted with one or more of the same or different R^and and / or R^b, -C (O) R^e

- 22 substituted by one or more of the same or different R^and and / or R^b, -N (R^and) R^ewhere R^e is substituted by one or more of the same or different R^and and / or

R^b, -S (O) 2R^e substituted with one or more of the same or different R^and and / or

R^b, -B (OR^and) 2, -B (N (R^c)2)2,

- (C (R^and) 2) m^b,

-O- (C (R^and) 2) m^b, (C (R^b) 2) m

-N (R^and) - (C (R^and) 2) m^b,

O- (CH2) m-CH ((CH2) m^b) R

-S- (C (R^and) 2) m^b, -Obb (C (R^and) 2) m^b, -O- (C (R^and) 2) mC (O) N (R^and) - (C (R^and) 2) m^b, -N ((C (R^and) 2) m^b) C (O) N (R^and) - (C (R^and) 2) m^b, -N (R^and) -C (O) -N (R^and) - (C (R^and) 2) m^b, C (R^and) (R^b) 2 or

-C (O) N (R^and)) 2, -S- (C (R^and) 2) mN (R^and) -C (O) - (C (R^and) 2) each R^and means independently, in each occurrence, H, deuterium, C16alkyl, C3-8cycloalkyl, C4-11cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclicalkyl, 4-11 membered heteroalicyclicalkyl, 5-11 15 membered heteroaryl or 6-16 membered heteroarylalkyl;

each R^b means independently, in each occurrence, = O, -OR^and, -O (C (R^and) 2) m-OR^and, haloC1-3alkyloxy, = S, -SR^and, = NR^and, = NOR^and, -N (R^c) 2, halo, -CF3, -CN,

-NC, -OCN, -SCN, -NO, -NO2, = N2, -N3, -S (O) R^and, -S (O) 2R^and, -SO3R^and, -S (O) N (R^c)2,

-OS (O) R^and, -OS (O) 2R^and, -OSO3R^and, -OS (O) 2N (R^c) 2, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, -C (NR^and) -N (R^c) 2, -C (NOH) -R^and, -C (NOH) -N (R^c) 2, -OC (O) R^and, -OC (O) OR^and,

-OC (O) N (R^c) 2, -OC (NH) -N (R^c) 2, -OC (NO^and) -N (R^c) 2, - [N (R^and) C (O)] nR^and,

- [N (R^and) C (O)] nOR^and, - [N (R^and) C (O)] n N (R^c) 2 or - [N (R^and) C (NR^and)] N N (R^c)2;

each R^c means independently, in each occurrence, R^andor, alternatively, two Rs^c are considered together with the nitrogen atom to which they are attached to form a 3 to 10-membered heteroalicyclic or 5-10 membered heteroaryl which may optionally contain one or more of the same or different additional heteroatoms and which is optionally substituted with one or more than the same or different group R^and and / or R^d;

each R^d means = O, -OR^and, haloC1-3alkyloxy, C1-6alkyl, = S, -SR^and, = NR^and, = NOR^and,

-N (R^and) 2, halo, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, = N2, -N3, -S (O) R^and, -S (O2) R^and, -SO3R^and, -S (O) N (R^and) 2, -S (O) 2N (R^and) 2, -OS (O) R^and, -OS (O) 2R^and, -OSO3R^and, -OS (O) 2N (R^and) 2, -C (O) R^and, -CO2R^and, -C (O) N (R^and) 2, -C (NR^and) N (R^and) 2, -C (NOH) R^and, -C (NOH) N (R^and)2,

-OCO2R^and, -OC (O) N (R^and) 2, -OC (NO^and) N (R^and) 2, - [N (R^and) C (O)] nR^and, - (C (R^and) 2) n OR^and, -N (R^and) S (O) 2 R^and, -C (O) -C1-6haloalkyl, -S (O) 2C1-6haloalkyl, -OC (O) R^and, -O (C (R^and) 2) m-OR^and, -S (C (R^and) 2) m-OR^and, -N (R^and) C1-6haloalkyl, - P (O) (OR^and) 2, -N (R^and) - (C (R^and) 2) m-OR^and, - [N (R^and) C (O)] nOR^and, - [N (R^and) C (O)] n N (R^and) 2, - [N (R^and) C (NR^and)] N N (R^and) 2 or -N (R^and) C (O) C1-6haloalkil; or two R^d, considered together with the atom or atoms to which they are attached, forming a 3-10 membered, partially or fully saturated, mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R^and;

- 23 each R^e means independently, in each occurrence, C1-6alkyl, C3-8cycloalkyl, C4-11 cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclicalkyl, 4-11 membered heteroalicyclicalkylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;

p is 0, 1, 2, 3 or 4; each m is 1, 2 or 3; each n is 0, 1, 2 or 3;

or two groups of R², considered together with the atom or atoms to which they are attached, forming a 4-10 membered, partially or fully saturated, mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R^and and / or R^b;

FROM¹ and Z² are each independently CH, CR² or N;

R³ is H, optionally substituted C1-6alkyl or R⁵⁰;

_R4 is H, optionally substituted C1-6alkyl or R⁵⁰; and

R⁵ is halo, -CN, optionally substituted C1-6alkyl, alkynyl, hydroxy, optionally substituted C1-6alkoxy, nitro, -N (R^and) 2, -C (O) N (R^and)₂, -WHAT₂R^and or -C (O) R^and.

[0096] In one embodiment, the compounds of structural formula I are compounds wherein ring A is phenyl or pyridyl substituted with one or more groups. In one embodiment, ring A is phenyl, with at least one para group relative to N4 pyrimidinediamine. In another embodiment, ring A is pyridyl with at least one para group relative to N4 pyrimidinediamine. In a particular embodiment, ring A is pyridin-3-yl (where N4 of the pyrimidinediamine is in the 3-yl position) with at least one para group relative to N4 of the pyrimidinediamine. In another more particular embodiment, ring A is pyridin-2-yl (where N4 of the pyrimidinediamine is in the 2-yl position) with at least one para group relative to N4 of the pyrimidinediamine. In other embodiments, meta groups may replace or multiply the para group pool in the embodiments described above. In all of the above embodiments, the groups at the para and / or meta positions may contain nitrogen, for example an optionally substituted amine, directly attached to ring A, or, in some embodiments, attached to ring A by alkylene. Such optionally substituted amines include those defined by -N (R^c) 2 with respect to formula I. In a specific embodiment, the optionally substituted amine is attached to ring A with C1-6alkylene. In an even more particular embodiment, the optionally substituted amine is attached to ring A with C1-3alkylene and the amine, -N (R^c) 2 with respect to formula I, is itself substituted with the group -N (R^c)₂.

[0097] As mentioned, some of the compounds disclosed herein have structural formula I, where

- ring A is phenyl substituted with one or more R groups². Thus, in one embodiment, the disclosed compounds have formula IA:

<img file="PL2389372T3_D0011.tif" />

wherein the variables are as described in relation to formula I, and furthermore: X and Y are each independently O or NR¹; each R¹ is H, optionally substituted with C_1-6alkyl or

R⁵⁰; each of R^2a, R^2b, R^2c and R^2d means independently, in each occurrence, as defined for R²; and R⁵ is halo, -CN, optionally substituted with C_1-6alkyl, nitro, N (R^and) 2, -C (O) N (R^and) 2, -CO2R^and or -C (O) R^and.

[0098] One embodiment is a compound of structural formula IA, wherein X and Y are each independently NR¹. In a more particular embodiment, X and Y are each independently NH or NC 1-6 alkyl. In an even more particular embodiment, X and Y are each independently NH or NCH3. In one embodiment where X and Y are defined more precisely as mentioned, R⁵ is halo or C1-6alkyl; FROM¹ is CH, C-halo or C-optionally substituted C 1-6 alkyl; and Z² means CH. In a particular embodiment, R^2c and R^2d are H; and R⁵ is F or CH3. In an even more particular embodiment, each of R^2a and R^2b is independently, in each occurrence, H, C 1-6 alkyl, -OR^and, -OCF3 ,, -SR^and, -N (R^c) 2, halo, -OCF2H,

-OCH2F, -CF3, -CN, -S (O) 2R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, or - [N (R^and) C (O)] nR^and; and one of R^2a and R^2b is not H. In another more particular embodiment, each of _R^2a_{and R}^2b means independently, in each case of H, -N (R^c) 2, halo, -CF3,

-CN, S (O) 2N (R^c) 2, -S (O) 2R^and, -C (O) R^and, -CO2R^and, or -C (O) N (R^c) 2. In another particular embodiment, R^2a is H, halo or cyano; and R^2b means halo, -CF3, -CN,

-S (O) 2 N (R^c) 2, -S (O) 2R^and, -C (O) R^and, -CO2R^and, or -C (O) N (R^c) 2. In another particular embodiment, R^2a is halo, -CF3, -CN, -S (O) 2N (R^c) 2, -S (O) 2R^and, -C (O) R^and, -CO2R^and, or -C (O) N (R^c) 2; and R^2b means H, halo or cyano.

[0099] In another embodiment, a compound of structural formula IA is disclosed wherein one of X and Y is O and the other is NR¹. In a specific embodiment, the compound is one of formula IA1 or IA2:

<img file="PL2389372T3_D0012.tif" />

where R^2d is H; R⁵ is halo or C1-6alkyl; FROM¹ is CH, C-halo or C-optionally substituted C 1-6 alkyl; and Z² means CH.

[0100] A further embodiment is a compound of the structural formula IA1 or IA2, wherein R⁵ is F or CH₃. In a particular embodiment, each of R^2a, R^2b and R^2cis independently, in each case, C 1-6 alkyl, -OR^and, -OCF3, -SR^and,

-N (R^c) 2, halo, -OCF2H, -OCH2F, -CF3, -CN, -S (O) 2N (R^c) 2, -S (O) 2R^and, -C (O) R^and, -CO2R^and,

-C (O) N (R^c) 2, - (C (R^and) 2) m^b, -N (R^and) -S (O) 2 R^and or - [N (R^and) C (O)] nR^and. In another more particular embodiment, R^2a, R^2b and R^2c are each independently C 1-6 alkyl, OR^and, -OCF3, halo, -CF3 or -CN. In one embodiment, R^2a is CH3; R^2bmeans halo; and R^2c means CH3. In another embodiment, R^2a is CH3; R^2bis CH3; and R^2c means hello. In another embodiment, R^2a is CH3; R^2bis CH3; and R^2c means CH3. In a particular embodiment, R^2a is CH3; R^2b is CH3 and R^2c is CH3, R⁵ means CH₃.

[0101] Another embodiment is a compound of the structural formula IA1, where R⁵means CH₃, and each of R^2a, R^2b and R^2c is independently, in each case, C 1-6 alkyl, haloC 1-6 alkyl, -OR^and, -OCF3, -SR^and, -N (R^c) 2, halo, -OCF2H, -OCH2F,

-CN, -S (O) 2N (R^c) 2, -S (O) 2R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, - (C (R^and) 2) m^b, -N (R^and) -S (O) 2 R^andor - [N (R^and)WHAT)]_nR^and. In another more particular embodiment, R^2a, R^2b and R^2care each independently C 1-6 alkyl, -OR^and, -OCF3, halo, -CF3 or -CN. In one

2b

2c, embodiment R^2a is CH3; R^2b means halo; and R^2c means CH3. In another embodiment, R^2a is CH3; R^2b is CH3; and R^2c means hello. In the next one

2b

2c, an embodiment of each of R^2a, R^2b and R^2c is independently, in each occurrence, C 1-6 alkyl or haloC 1-6 alkyl. In another embodiment, each of R

2a _R^2b_{and R}^2c means independently, in each occurrence, C 1-6 alkyl. In a particular embodiment, R^2a is CH3; R^2b is CH3 and R^2c means CH₃.

[0102] Another embodiment is a compound of the structural formula IA1 or IA2, where R^2b is H; R⁵ is F or CH3. In a particular embodiment, each of

2c

2c _R^2a_{and R}^2c is independently, in each occurrence, H, C 1-6 alkyl, -OR^and, -OCF

3,

-SR^and, -N (R^c) 2, halo, -OCF2H, -OCH2F, -CF3, -CN, -S (O) 2R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c)2,

-N (R^and) -S (O) 2 R^and, -C (R^and) 2-N (R^c) 2 or - [N (R^and) C (O)] nR^and; and one of R^2a and R^2c is not H. In another embodiment, each of R^2a and R^2c is independently, in each occurrence, H, C 1-6 alkyl, -OR^and, -OCF3, halo, -CF3, -C (R^and) 2-N (R^c) 2 or -CN. In the next one

- 26 embodiment of R^2a is -CF3 or -CH3; and R^2c means halo or -CH3. In another embodiment, R^2a is H, -CH3, -CF3, -OR^and or -OCF3; and R^2c is -C (R^and) 2 N (R^c)2.

[0103] Another embodiment is a compound of the structural formula IA1 or IA2, where R^2c is H; and R⁵ is F or CH3. In one particular embodiment, each of R^2a and R^2b is H, C 1-6 alkyl, -OR^and, -OCF2H, -OCH2F, -OCF3, -SR^and, -N (R^c) 2, hello,

-S (O) 2 R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, -C (R^and) 2-N (R^c) 2 or -CF3, -CN, -S (O) 2N (R^c) 2, [N (R^and) C (O)] nR^and; and one of R^2a and R^2b is not H. In another embodiment, each of R^2a and R^2b is H, C 1-6 alkyl, -OR^and, -OCF3, halo, -N (R^c) 2, -CF3, -C (R^and) 2-N (R^c) 2 or -CN. In another embodiment, R^2b is -CF3 or -CH3; and R^2a means halo or -CH3. In another embodiment, R^2a is H, -CH3, -CF3, -OR^and or -OCF3; and R^2b means

-N (R^c) 2 or -C (R^and) 2-N (R^c) 2. In yet another embodiment, R^2a is -N (R^c) 2 or -C (R^and) 2-N (R^c) 2; and R^2b is H, -CH3, -CF3, -OR^and or -OCF3.

[0104] A yet further embodiment is a compound of the structural formula IA1 or IA2, where R^2c and R^2d are H, and R⁵ is F or CH₃; R^2a and R^2b are considered together with the carbons to which they are attached to form a 4-10 membered, partially or fully saturated, mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R^andand / or R^b. In one embodiment, this is a 5-membered ring, and in a more particular embodiment, the 5-membered ring is cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine or tetrahydrofuran; optionally substituted with one or more R^and and / or R^b. In a specific embodiment, the 5-membered ring is pyrrolidine, and in an even more particular embodiment the compounds have formula IA3:

<img file="PL2389372T3_D0013.tif" />

where R^b means OH, Ci_-6alkyl, -CO₂C_1-6alkyl, -C (O) Ci_₆alkyl or -S (O)₂C_1-6alkyl. In another embodiment, R^2a and R^2b are considered together with the carbons to which they are attached to form a 6, 7 or 8 membered, partially or fully saturated monocyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R^and and / or R^b. In one embodiment, when the ring is 6-membered, the ring is cyclohexane, morpholine, piperidine, dioxane, oxathiazine or piperazine; optionally substituted with one or more R's^and and / or R^b. In another embodiment, when the ring is 7-membered, the ring is cycloheptane, cycloheptene, azepane, tetrahydroazepine or diazepane; optionally substituted with one or more R's^and and / or R^b. In yet another embodiment, when the ring is 8 membered, the ring is cyclooctane,

- cyclooctene, azokan, hexahydroazocin, diazokan or hexahydrodiazocin; optionally substituted with one or more R's^and and / or R^b. For each of the above embodiments, where R^2a and R^2b are considered together with the carbons to which they are attached to form a 5, 6, 7 or 8 membered, partially or fully saturated monocyclic ring, there is a more specific embodiment where it occurs after 0, 1, 2 or 3 of each of R^and and R^band R^and is C1-6alkyl; and each R^b means independently, in each occurrence, = O, -OR^and, haloC1-3alkyloxy, -SR^and, -N (R^c) 2, halo, -CF3, -CN, -S (O) 2R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, or -C (R^and) 2-N (R^c) 2. For example, in one embodiment there is at least one R^bwhich means = O; and optionally R^andwhich is optionally substituted C1-6alkyl. Specific examples of compounds of formula IA3 include, but are not limited to, compounds such as IV-2, IV-10, IV-14 to IV-16, IV-18 to IV-34, and IV-50 (see Table IV).

[0105] Some embodiments include compounds wherein ring A is other than phenyl. In a specific embodiment, ring A is pyridine or pyridazine. As shown in Formula I, and with respect to this embodiment, pyridine or pyridazine may have different regiochemical configurations and attachment points to the parent molecule. One embodiment of the compounds of structural formula I are compounds of formula IB:

<img file="PL2389372T3_D0014.tif" />

where the variables are defined in the same way as for those of formula I, and in addition: Q¹ and Q² each, independently, N or CR², provided that at least one of Q¹ and Q²is N; X and Y are each independently O or NR¹; each R¹ is independently, at each occurrence, H, optionally substituted C1-6alkyl or R⁵⁰; p is 0, 1, 2 or 3; and R⁵ is halo, -CN, optionally substituted C 1-6 alkyl, nitro, -N (R^and) 2, -C (O) N (R^and) 2, -CO2R^and or -C (O) R^and.

[0106] One embodiment of the compounds of structural formula IB is the compound of formula IB1 or IB2:

<img file="PL2389372T3_D0015.tif" />

where each of R^2a, R^2b, R^2c and R^2d (when present) means independently, in each occurrence, as defined for R².

[0107] One embodiment is a compound of the structural formula IB1 or IB2, wherein X and Y are each independently, NR¹. In a particular embodiment, X and Y are each independently NH or NC 1-6 alkyl. In an even more particular embodiment, X and Y are each independently NH or NCH3. In one embodiment, where X and Y are defined more precisely as mentioned, R⁵ is halo or C16alkyl; FROM¹ is CH, C-Halo or C-optionally substituted C 1-6 alkyl; and Z² means CH. In another embodiment, R^2a and R^2d are H; and R⁵ is F or CH3. In another embodiment, each of R^2b and R^2c is independently, in each case, the occurrence of H, C 1-6 alkyl, -OR^and, -OCH2F, -OCF3, -SR^and, -N (R^c) 2, halo, -OCF2H, -CF3, -CN,

-S (O) 2 R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, -C (R^and) 2-N (R^c) 2 or - [N (R^and) C (O)] nR^and; and one of R^2b and R^2c is not H. In another such embodiment, each of R^2b and R^2c is independently, in each occurrence, H, C 1-6 alkyl, -N (R^c) 2, halo, -CF3, -CN,

-S (O) 2 R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, or -C (R^and) 2-N (R^c) 2. In another embodiment, R^2b is H, halo, -CF3, -CN or -CH3; and R^Zc is -N (R^c) 2, -S (O) 2R^and, C (O) N (R^c) 2 or -C (R^and) 2-N (R^c)2.

[0108] A further embodiment is a compound of the structural formula IB1 or IB2, wherein X is O and Y is NR¹. In one embodiment, R⁵ is halo or C1-6alkyl; FROM¹ is CH, C-halo or C-optionally substituted C 1-6 alkyl; and Z² means CH. In another embodiment, R^2a and R^2d are H; and R⁵ is F or CH3. In a particular embodiment, each of R^2b and R^2c is independently, in each case, the occurrence of H, C 1-6 alkyl, -OR^and, -OCF3, -SR^and, -N (R^c) 2, halo, -OCF2H, -OCH2F,

-CF3, -CN, -S (O) 2R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, -C (R^and) 2-N (R^c) 2 or - [N (R^and) C (O) n NR^and; and one of R^2b and R^2c is not H. In another embodiment, each of R^2b and R^2cis independently, in each occurrence, H, C 1-6 alkyl, -N (R^c) 2, halo, -CF3,

-CN, -S (O) 2R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, or -C (R^and) 2-N (R^c) 2. In a more particular embodiment, R^2b is H, halo, -CF3, -CN or -CH3; and R^2c is -N (R^c)2,

-S (O) 2 R^and, -C (O) N (R^c) 2 or -C (R^and) 2-N (R^c) 2. In another embodiment, R^2b is H, halo, -CF3, -CN or -CH3; and R^2c is -N (R^c) 2 or -C (R^and) 2-N (R^c)2.

[0109] Another embodiment is a compound of the structural formula IB1 or IB2, wherein X is O; Y is NR¹; FROM¹ is CH, C-halo or C-optionally substituted C 1-6 alkyl; FROM² is CH; R^2a and R^2d are H; and R⁵ is F or CH3, R^2b and R^2cconsidered together with the carbons to which they are attached to form a 4-10 membered, partially or fully saturated, mono or bicyclic ring, optionally containing one or more heteroatoms, and optionally substituted with one or more R^and and / or R^b. In one embodiment, the ring is a 5, 6, 7 or 8 membered, partially or fully saturated monocyclic ring optionally substituted with one or more R^and and / or R^b. In one embodiment, the 5, 6, 7 or 8 membered, partially or fully saturated, monocyclic ring is cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine, piperidine, dioxane, oxathiazine, piperazine, cyclo .

Cycloheptene, azepane, tetrahydroazepine, diazepane, cyclooctane, cyclooctene, azokan, hexahydroazocine, diazokan or hexahydrodiazocin; optionally substituted with one or more R's^and and / or R^b. For each of the above embodiments, where R^2b and R^2c are considered together with the carbons to which they are attached to form a 5, 6, 7 or 8 membered, partially or fully saturated monocyclic ring, there is a more specific embodiment where it occurs after 0, 1, 2 or 3 of each of R^and and R^band R^and is C1-6alkyl; and each R^b means independently, in each occurrence, = O, -OR^and, haloC1-3alkyloxy, -SR^and, -N (R^c) 2, halo, -CF3, -CN, -S (O) 2R^and, -C (O) R^and, -CO2R^and,

-C (O) N (R^c) 2 or -C (R^and) 2-N (R^c) 2. For example, in one embodiment there is at least one R^bwhich means = O; and optionally R^andwhich is optionally substituted C1-6alkyl. In this embodiment, compounds such as IV-45, IV-46 and IV-47 are included (see Table IV).

[0110] Another embodiment of the compounds of structural formula IB is a compound of formula IB3:

<img file="PL2389372T3_D0016.tif" />

each with R^2a, R^2b and R^2c means independently, in each occurrence, as defined for R².

[0111] One embodiment is a compound of structural formula IB3, wherein X is O and Y is NR¹. In one embodiment, R⁵ is halo or C1-6alkyl; FROM¹ is CH, C-halo or C-optionally substituted C 1-6 alkyl; and Z² means CH. In another embodiment, R^2a is H; and R⁵ is F or CH3. In a particular embodiment, each of R^2b and R^2c is independently, in each case, the occurrence of H, C 1-6 alkyl, -OR^and, -OCF3, -SR^and, -N (R^c) 2, halo, -OCF2H, -OCH2F, -CF3, -CN,

2b

-S (O) 2 R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, -C (R^and) 2-N (R^c) 2 or - [N (R^and) C (O)] nR^and; and one of R² and R^2c is not H. In another embodiment, each of R^2b and R^2c is independently, in each occurrence, H, C 1-6 alkyl, -N (R^c) 2, halo, -CF3, -CN, -S (O) 2R^and,

-C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, or -C (R^and) 2-N (R^c) 2. In a more particular embodiment, R^2b is H, halo, -CF3, -CN or -CH3; and R^2c is -N (R^c) 2, -S (O) 2R^and, -C (O) N (R^c) 2 or -C (R^and) 2-N (R^c) 2. In another embodiment, R^2b is H, halo, -CF3, -CN or -CH3; and R^2c is -N (R^c) 2 or -C (R^and) 2-N (R^c)2.

[0112] Another embodiment is a compound of structural formula IB3, wherein X is O; Y is NR¹; FROM¹ is CH, C-halo or C-optionally substituted C 1-6 alkyl; FROM² is CH; R^2c and R^2d are H; and R⁵ is F or CH₃, R^2b and R^2c are considered together with the carbons to which they are attached to form a 4-10 membered, partially or fully saturated, mono or bicyclic ring, optionally containing one

- 30 or more heteroatoms and optionally substituted with one or more R^andand / or R^b. In one embodiment, the ring is a 5, 6, 7 or 8 membered, partially or fully saturated monocyclic ring optionally substituted with one or more R^and and / or R^b. In one embodiment, the 5, 6, 7 or 8 membered, partially or fully saturated, monocyclic ring is cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine, piperidine, dioxane, oxathiazine, piperazine, cyclo , cycloheptene, azepane, tetrahydroazepine, diazepane, cyclooctane, cyclooctene, azokan, hexahydroazocine, diazokan or hexahydrodiazocin; optionally substituted with one or more R's^and and / or R^b. For each of the above embodiments, where R^2b and R^2c are considered together with the carbons to which they are attached to form a 5, 6, 7 or 8 membered partially or fully saturated monocyclic ring, there is a more specific embodiment where it occurs after 0, 1, 2 or 3 of each of R^and and R^b, and R^and is C1-6alkyl; and each R^b means independently, in each occurrence, = O, -OR^and, haloC1-3alkyloxy, -SR^and, -N (R^c) 2, halo, -CF3, -CN, -S (O) 2R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2 or -C (R^and) 2-N (R^c)2.

[0113] Another embodiment is a compound of structural formula I, wherein ring A is indazole, benzooxazole , pyrazolopyridine or isoxozolopyridine; X is O; Y is NR¹; R⁵ is halo or C1-6alkyl; FROM¹ is CH, C-halo or C-optionally substituted C 1-6 alkyl; FROM² is CH; and each R² is independently, in each occurrence, H, C 1-6 alkyl, -OR^and, -OCF3, -SR^and, -N (R^c) 2, halo, -OCF2H, -OCH2F, -CF3, -CN, -S (O) 2R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2 or - [N (R^and) C (O)] nR^and.

[0114] Another embodiment of the compounds of structural formula I is a compound of formula II:

<img file="PL2389372T3_D0017.tif" />

where the variables are defined in the same way as for those of formula I, and in addition: two with R² combine to form ring B; ring B, together with the two phenyl ring atoms to which it is attached, forms a 5, 6 or 7-membered ring, optionally containing 1, 2 or 3 heteroatoms independently selected from N (R^c), O and S; R^and is C1-6alkyl; and each R^bmeans independently, in each occurrence, = O, -OR^and, haloC1-3alkyloxy, -SR^and, -N (R^c) 2, halo, -CF3, -CN, -S (O) 2R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, or -C (R^and) 2-N (R^c) 2. In one more particular embodiment, Z¹ is CH, C-halo or

C-optionally substituted C1-6alkyl. To further supplement the description of the B ring, the examples of the B rings mean, apart from the unsaturation unit between the two phenyl ring atoms, only for the sake of simplifying the nomenclature, cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine,

- 31 piperidine, dioxane, oxathiazine, piperazine, cycloheptane, cycloheptene, azepane, tetrahydroazepine, diazepane, cyclooctane, cyclooctene, azokan, hexahydroazocine, diazocane or hexahydrodiazocin. That is, for example, if ring B is described as "cyclohexane", then the compound would be one of formula IIa:

<img file="PL2389372T3_D0018.tif" />

[0115] In another example, if ring B is described as "cycloheptene" then the compound would be one of the formulas IIb, IIc, IId or IIe:

<img file="PL2389372T3_D0019.tif" />

<img file="PL2389372T3_D0020.tif" />

[0116] A further embodiment is a compound of formula IA1, wherein R^2d is H; R⁵ is halo or C1-6alkyl; FROM¹ is CH, C-halo or C-optionally substituted C 1-6 alkyl;

FROM² is CH; and each of R^2a, R^2b and R^2c is independently, in each occurrence, C 1-6 alkyl, -OR^and, -OCF3, -SR^and, -N (R^c) 2, halo, -OCF2H, -OCH2F, -CF3, -CN,

- 32 -S (O) 2R^and, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, - (C (R^and) 2) m^b or - [N (R^and) C (0)] nR^and, provided that one of R^2a, R^2b and R^2c is -N (R^c) 2, -C (O) N (R^c) 2 or - (C (R^and) 2) m^b. In a particular embodiment, R⁵ is F or CH3. In another embodiment, one of R^2a, R^2b and R^2c is -N (R^c) 2. In another embodiment, one of R^2a, R^2b and R^2c means - (C (R^and)₂)_m-R^b. In a particular embodiment, R⁵ is F or CH3. In a particular embodiment, one of R^2a, R^2b and R^2c which means -N (R^c) 2 means:

<img file="PL2389372T3_D0021.tif" />

<img file="PL2389372T3_D0022.tif" />

<img file="PL2389372T3_D0023.tif" />

or

<img file="PL2389372T3_D0024.tif" />

optionally substituted with one or more same or different R groups^and and / or R^b. In a particular embodiment, one of R^2a, R^2b and R^2c which means - (C (R^and)₂)_m-R^b, means even more precisely -C (R^and) 2-N (R^c) 2. In an even more particular embodiment, one of R^2a , R^2b and R^2c which means -C (R^and) 2-N (R^c) 2 means:

<img file="PL2389372T3_D0025.tif" />

<img file="PL2389372T3_D0026.tif" />

<img file="PL2389372T3_D0027.tif" />

optionally substituted with one or more same or different R groups^and and / or R^b.

[0117] In one embodiment, at least one R group² means a group that increases water solubility, i.e., a group that has a hydrophilic nature sufficient to cause an improvement or increase in the water solubility of the compound in which it is contained compared to an analog of the compound that does not contain the group. The hydrophilic character can be achieved by, for example, incorporating functional groups that ionize under the conditions of use to form charged moieties (e.g. carboxylic acids, sulfonic acids and salts, phosphoric acids and salts, amines, etc.); groups that contain solid charges (e.g., quaternary ammonium groups); and / or heteroatoms or heteroatomic groups. For example, -O- (C (R^and) 2) m^b, -S- (C (R^and)2)_m-R^b, -O- (C (R^b) 2) m^and, -N (R^and) - (C (R^and) 2) m^b, -O- (CH2) m-CH ((CH2) mR^b) R^b, -C (O) N (R^and) - (C (R^and) 2) m,

-R^b and -N ((C (R^and) 2) m^b) 2. More specific examples include -O-Ci_₆alkylene-R^b, -S-C16alkylene-R^b, -O-C 1-6 alkylene-R^and where R^and is heterocyclyl, -N (R^and) -C1-6alkileno-R^b, -O-C16alkylene-CH ((CH₂)_1-2R^b) R^b, -C (O) N (R^and) -C1-6alkileno-R^b and -N ((C (Ra) 2)_1-3R^b) 2. Even more specific examples include -O-C 1-4 alkylene-R^b, -S-C1.₄alkylene-R^b, -O-C 1-4 alkylene-R^andwhere R^and is heterocyclyl, -N (H) -C 1-4 alkylene-R^b, -OC₁.₄alkylene-CH ((CH₂)₁.₂R^b) R^b,

-C (O) N (H) -C_1-4alkylene-R^b and -N ((CH2) 1-3R^b) 2. In another particular example, according to the formula given above, for water solubility groups, the water solubility group is an amino acid attached to the molecule through an amino acid nitrogen bond. In a more specific example, the group increasing the water solubility is an α-amino acid or derivative thereof attached to the parent ring, e.g. ring A and / or at Z¹ or Z², through the nitrogen-mediated α-amino acid, for example -N (H) C (R^and) 2-R^bwhere R^b means -CO2R^and or -C (O) N (R^c)₂. In another particular embodiment, the water solubilizing group is morpholino, piperidinyl, NC₁.₆alkylpiperidinyl, piperazinyl, NC₁₆alkylpiperazinyl, pyrrolidinyl, NC₁.₆alkylpyrrolidinyl, diazepinyl, NC₁.₆alkylazepinyl, homopiperazinyl, NC_1-6alkyl homopiperazinyl, imidazoyl, and the like. In another example, the group increasing the water solubility is that with the above-mentioned rings attached to the parent molecule by means of an alkylene, alkylidene, alkylidine linker. In a particular embodiment, the water solubilizing group is one of the above-mentioned rings attached to the parent molecule via C_1-6alkylene, where one or two of the alkylene carbons are, independently, replaced by one of O, S or NH, but not when any two of the above-mentioned heteroatoms are adjacent to each other in the linker. Other solubilizing groups are well known and include, for example, hydrophilic groups, such as alkyl or heteroalicyclic groups, substituted with one or more amines,

- 34 alcohol, carboxylic acid, phosphoric acid, sulfoxide, carbohydrate, sugar alcohol, amino acid, thiol, polyol, ether, thioether and quaternary ammonium salt. [0118] For each of the above embodiments of compounds of the structural formulas I, IA, IA1, IA2, IA3, IB, IB1, IB2, IB3 and II, there is another embodiment where R¹ is H or R⁵⁰; R⁵⁰ means -CH2OP (O) (OR¹¹) 2; and each R¹¹ means independently, in each occurrence, R^and or a monovalent cationic group; or two R¹¹, together with the atoms to which they are attached form a 4-8 membered cyclic phosphate group, or two Rs¹¹ together they represent a divalent cationic group. Also, for each of these embodiments, there is a more specific embodiment where each R¹¹ is independently, in each occurrence, H, t-butyl, or a pharmaceutically acceptable cation such as HOCH₂CH₂N (CH₃)₃+, Na +, Li + or K +.

[0119] As mentioned, 2,4-pyrimidinediamine compounds and prodrugs, as well as their salts, may also exist in the form of hydrates, solvates and N-oxides, as is well known in the art. One embodiment is a pharmaceutically acceptable salt form of the compound of formula I. Pharmaceutically acceptable salts of the invention may be prepared by conventional solutions such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent such as water which is removed under reduced pressure. pressure, by freeze-drying, or exchanging anions of an existing salt with another anion on a suitable ion exchange resin. The invention includes within its scope solvates of 2,4-pyrimidinediamine compounds, and salts and hydrates thereof, for example, hydrated formate salt.

[0120] In a further embodiment, the specification discloses compounds selected from Table IIV, or a pharmaceutically acceptable salt thereof. Many of the compounds described herein have been obtained as both a parent compound and at least one salt form. Some specific salts obtained, with respect to the assays of Tables I-IV, include the calcium salt: compound 1-517; monocholine salt: compound 1-414; bischoline salt: compound 1-531; formate salt: compounds 1-7 and I-9, I-46, I-47, I-49, I-127, I-128, I-132, I-134, I-137, I-138, I140, I-153 to I-158, I-165 to I-169, I-172 to I-190, I-201 to I-239, I-241, I-271, I-272, I-423, I- 433, I-438 to I-442, I-445, I-446, I-455 to I-457, I-460, I-463 to I-468, I-470, I-473, I-486,

I-487, I-494, I-498, I-499 to I-504, I-513 to I-515, I-518, I-519, I-527, I-530, II-4, II- 5, II-6,

II- 8, II-9, II-11, II-12, II-42, II-43, II-48, II-49, II-53, II-55 to II-70, II-79, II- 151, III-12, III14, IV-3, IV-10, IV-11, IV-14, IV-17, IV-18, IV-19, IV-21, IV-31, IV-32 and IV- 60 to I-62; formate salt, compounds II-3, II-46, II-47, II-51, II-52 and II-54; monotrifluoroacetate salt, compounds I-16, I-27, I-28, I-36 to I-38, I-59 to I-95, I-106 to I-109, I-115, I-129, I- 130, I-131, I-135, I-136, I-141, I-142, I-145, I-149, I-159, I-160 to I-164, I-171, I-191, I-192, I-193,

I-195 to I-200, I-242, I-244 to I-247, I-249 to I-254, I-256 to I-262.1-264 to I-269, I-273, I- 274, I-403, I-404, I-419 to I-422, I-427 to I-432, I-447 to I-449, I-452 to I-454, I-458, I-469, I-474 to I-477, I-488 to I-492, I-507, I-508, I-520, I-521, I-529, I-535, II-7, IV-12, IV- 13, IV-15, IV-16, IV-22 to IV-30, IV-33, IV-34, IV-51, IV-52, IV-53, IV-54, IV-59 and IV-64; di-trifluoroacetate salt, compounds I-120 to I-123, I-255, I-263, I-270, I-426, I-459, II-17, II-19, II-38, II-45, II -71, II-74, II-76, II-77, II-87, II-100, II-101, II-102, II-150 and IV-20; benzenesulfonic acid salt, compound I-393; p-toluenesulfonic acid salt: compound I409; sulfuric acid salt: compound I-411; the hydrochloride salt, compounds I-133 and I-412; the dihydrochloride salt, compound II-44; disodium salt, compounds I-33, I-358, I-407, I-451, I-528, I-536 and 1-538; magnesium salt: compound I-526; mesylate salt: compound I-410; and monosodium salt: compounds I-413, I-436 and I-437.

[0121] As will be appreciated by one skilled in the art, the formulas include other salt forms in addition to those specifically described herein. Similarly, one of ordinary skill in the art will understand that the presently disclosed formulas include solvates such as hydrates.

<td colspan="9">Table I_R2f Η Η</td>

<td>Orga.</td><td>X</td><td>Y</td><td>FROM¹</td><td>R⁵</td><td>R^2a</td><td>R^2b</td><td>R^2c</td><td>R^2d</td>

<td>I-1</td><td>ABOUT</td><td>NH</td><td>CH</td><td>CH3</td><td>C (O) H</td><td>H</td><td>H</td><td>H</td>

<td>I-2</td><td>ABOUT</td><td>NH</td><td>CH</td><td>CH3</td><td>C (O) NH2</td><td>H</td><td>H</td><td>H</td>

<td>I-3</td><td>ABOUT</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>C (O) NH2</td><td>H</td><td>H</td>

<td>I-4</td><td>ABOUT</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>C (O) H</td><td>H</td><td>H</td>

<td>I-5</td><td>ABOUT</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td></td><td>H</td><td>H</td>

<td>I-6</td><td>ABOUT</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>· κφ -</td><td>H</td><td>H</td>

<td>I-7</td><td>ABOUT</td><td>N- (n-propyl)</td><td>CH</td><td>CH3</td><td>S (O) 2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-9</td><td>ABOUT</td><td>N- (isopropyl)</td><td>CH</td><td>CH3</td><td>S (O) 2CH3</td><td>H</td><td>H</td><td>H</td>

<td>Orga.</td><td>X</td><td>Y</td><td>FROM¹</td><td>R⁵</td><td>R^2a</td><td>R^2b</td><td>R^2c</td><td>R^2d</td>

<td>I-16</td><td>ABOUT</td><td>NH</td><td>CH</td><td>CH3</td><td>S (O) 2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-17</td><td>ABOUT</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>S (O) 2CH3</td><td>H</td><td>H</td>

<td>I-20</td><td>ABOUT</td><td>NH</td><td>CH</td><td>F</td><td>S (O) 2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-21</td><td>ABOUT</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>S (O) 2CH3</td><td>H</td><td>H</td>

<td>I-22</td><td>NH</td><td>NH</td><td>CH</td><td>CH3</td><td>S (O) 2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-23</td><td>NH</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>S (O) 2CH3</td><td>H</td><td>H</td>

<td>I-26</td><td>ABOUT</td><td>NH</td><td>CH</td><td>CH3</td><td>CN</td><td>H</td><td>H</td><td>H</td>

<td>I-27</td><td>ABOUT</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CN</td><td>H</td><td>H</td>

<td>I-28</td><td>NH</td><td>NH</td><td>CH</td><td>CH3</td><td>CN</td><td>H</td><td>H</td><td>H</td>

<td>I-29</td><td>NH</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CN</td><td>H</td><td>H</td>

<td>I-33</td><td>ABOUT</td><td>NCH2OP (O) (OH) 2</td><td>CH</td><td>CH3</td><td>S (O) 2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-36</td><td>NCH ​​3</td><td>NCH ​​3</td><td>CH</td><td>CH3</td><td>S (O) 2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-41</td><td>NCH ​​3</td><td>NCH ​​3</td><td>CH</td><td>F</td><td>S (O) 2 Me</td><td>H</td><td>H</td><td>H</td>

<td>I-44</td><td>ABOUT</td><td>NH</td><td>CH</td><td>F</td><td>CN</td><td>H</td><td>H</td><td>H</td>

<td>I-45</td><td>ABOUT</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>CN</td><td>H</td><td>H</td>

<td>I-46</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>morfolin-4-yl</td><td>H</td><td>H</td><td>H</td>

<td>I-47</td><td>O</td><td>NH</td><td>CH</td><td>F</td><td>morfolin-4-yl</td><td>H</td><td>H</td><td>H</td>

<td>I-48</td><td>NH</td><td>O</td><td>CH</td><td>CH3</td><td>morfolin-4-yl</td><td>H</td><td>H</td><td>H</td>

<td>I-49</td><td>NCH3</td><td>O</td><td>CH</td><td>CH3</td><td>morfolin-4-yl</td><td>H</td><td>H</td><td>H</td>

<td>I-59</td><td>NCH3</td><td>O</td><td>CH</td><td>F</td><td>S(O)2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-60</td><td>NCH3</td><td>O</td><td>CH</td><td>F</td><td>H</td><td>S(O)2CH3</td><td>H</td><td>H</td>

<td>I-65</td><td>NCH3</td><td>O</td><td>CH</td><td>CH3</td><td>S(O)2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-66</td><td>NCH3</td><td>O</td><td>CH</td><td>CH3</td><td>H</td><td>S(O)2CH3</td><td>H</td><td>H</td>

<td>I-69</td><td>O</td><td>NCH3</td><td>CH</td><td>CH3</td><td>S(O)2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-70</td><td>O</td><td>NCH3</td><td>CH</td><td>CH3</td><td>H</td><td>S(O)2CH3</td><td>H</td><td>H</td>

<td>I-77</td><td>O</td><td>NCH3</td><td>CH</td><td>F</td><td>S(O)2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-78</td><td>O</td><td>NCH3</td><td>CH</td><td>F</td><td>H</td><td>S(O)2CH3</td><td>H</td><td>H</td>

<td>I-100</td><td>NH</td><td>O</td><td>CH</td><td>CH3</td><td>S(O)2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-101</td><td>NH</td><td>O</td><td>CH</td><td>CH3</td><td>H</td><td>S(O)2CH3</td><td>H</td><td>H</td>

<td>I-106</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCF3</td><td>H</td><td>H</td><td>H</td>

<td>I-107</td><td>O</td><td>NH</td><td>CH</td><td>F</td><td>OCF3</td><td>H</td><td>H</td><td>H</td>

<td>I-108</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCF3</td><td>H</td><td>H</td>

<td>I-109</td><td>O</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>OCF3</td><td>H</td><td>H</td>

<td>I-110</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>?-N^Z N-v ^x \_t \</td><td>H</td><td>H</td>

<td>I-111</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>R R</td><td>H</td><td>H</td>

<td>I-115</td><td>O</td><td>NH</td><td>CH</td><td>F</td><td>och</td><td>OCH3</td><td>OCH3</td><td>H</td>

<td>I-116</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCF2H</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-117</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>S(O)2CF3</td><td>H</td><td>H</td>

<td>I-118</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>S(O)2CF3</td><td>H</td><td>H</td><td>H</td>

<td>I-119</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>OCH3</td><td>OCH3</td><td>H</td>

<td>I-120</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>ΝΝθ</td><td>H</td><td>H</td>

<td>I-121</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>Λ®</td><td>H</td><td>H</td>

<td>I-122</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>_vco</td><td>H</td><td>H</td>

<td>I-123</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td></td><td>H</td><td>H</td>

<td>I-124</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>morfolin-4-yl</td><td>OCF3</td><td>H</td><td>H</td>

<td>I-125</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CO2CH3</td><td>H</td><td>H</td>

<td>I-126</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CO2H</td><td>H</td><td>H</td>

<td>I-127</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>⁰ 9 ^u H</td><td>H</td><td>H</td>

<td>I-128</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>O</td><td>H</td><td>H</td>

<td>I-129</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>C(O)CH3</td><td>H</td><td>H</td>

<td>I-130</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>C(O)CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-131</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CN</td><td>CH3</td><td>H</td><td>H</td>

<td>I-132</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>C(O)N(CH3)2</td><td>H</td><td>H</td>

<td>I-133</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>C(O)N(H)CH3</td><td>H</td><td>H</td>

<td>I-134</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>I-135</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>C(O)N(H)Ph</td><td>H</td><td>H</td>

<td>I-136</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>pirolidyn-1-yl</td><td>C(O)NH2</td><td>H</td><td>H</td>

<td>I-137</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>C(O)N(H)CH2CH3</td><td>H</td><td>H</td>

<td>I-138</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>⁰ r-, H</td><td>H</td><td>H</td>

- 4i -

<td>I-i39</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>⁰ 1 N</td><td>H</td><td>H</td>

<td>I-i40</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>I-141</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>C(O)NH2</td><td>H</td><td>H</td>

<td>I-i42</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>A* H</td><td>H</td><td>H</td>

<td>I-143</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>I-144</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>° r-, H</td><td>H</td><td>H</td>

<td>I-145</td><td>O</td><td>NC(O)CH2CH3</td><td>CH</td><td>CH3</td><td>H</td><td>C(O)NH2</td><td>H</td><td>H</td>

<td>I-146</td><td>O</td><td>NCH2OP(O)(O-Z-Bu)2</td><td>CH</td><td>CH3</td><td>H</td><td>C(O)NH2</td><td>H</td><td>H</td>

<td>I-147</td><td>O</td><td>NCH2OP(O)(OH)2</td><td>CH</td><td>CH3</td><td>H</td><td>C(O)NH2</td><td>H</td><td>H</td>

<td>I-148</td><td>O</td><td>NCH2OP(O)(ONa)2</td><td>CH</td><td>CH3</td><td>H</td><td>C(O)NH2</td><td>H</td><td>H</td>

<td>I-149</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>⁰ Γ-, H</td><td>H</td><td>H</td>

<td>I-150</td><td>O</td><td>NCH₂OP(O)(OH)₂</td><td>CH</td><td>CH3</td><td>H</td><td>° Γ-H</td><td>H</td><td>H</td>

<td>I-151</td><td>O</td><td>NCH₂OP(O)(ONa)₂</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>I-152</td><td>O</td><td>NCH₂OP(O)(O-t-Bu)₂</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>I-153</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>Cl</td><td>H</td><td>H</td>

<td>I-154</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>CH3</td><td>H</td><td>H</td>

<td>I-155</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>SCH3</td><td>H</td><td>H</td>

<td>I-156</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td> ^-ⁿO-</td><td>C(O)NH₂</td><td>H</td><td>H</td>

<td>I-157</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td> 0 0</td><td>H</td><td>H</td><td>H</td>

<td>I-158</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>H</td><td>H</td><td>H</td>

<td>I-159</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>CO₂CH3</td><td>H</td><td>H</td>

<td>I-160</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CF3</td><td>H</td><td>H</td>

<td>I-161</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>OCF3</td><td>H</td><td>H</td>

<td>I-162</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>H</td><td>CF3</td><td>H</td>

<td>I-163</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCF3</td><td>F</td><td>H</td><td>H</td>

<td>I-164</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>CH3</td><td>H</td><td>H</td>

<td>I-165</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>OCH2CH2OCH3</td><td>H</td><td>H</td>

<td>I-166</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>izopropyl</td><td>H</td><td>H</td>

<td>I-167</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>CF3</td><td>H</td><td>H</td>

<td>I-168</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>OCH2CH3</td><td>H</td><td>H</td>

<td>I-169</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-170</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>CO2H</td><td>H</td><td>H</td>

<td>I-171</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>C(O)N(H)CH2CH3</td><td>H</td><td>H</td>

<td>I-172</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>Cl</td><td>H</td><td>H</td>

<td>I-173</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>H</td><td>H</td><td>H</td>

<td>I-174</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>I-175</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Br</td><td>H</td><td>H</td><td>H</td>

<td>I-176</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>Cl</td><td>H</td><td>CH3</td>

<td>I-177</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>N(H)C(O)CH3</td><td>H</td><td>H</td>

<td>I-178</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>CH3</td><td>H</td><td>H</td>

<td>I-179</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>OCH₂-cykloheksyl</td><td>H</td><td>H</td>

<td>I-180</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCF3</td><td>Cl</td><td>H</td><td>H</td>

<td>I-181</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>Cl</td><td>H</td><td>H</td>

<td>I-182</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH2CH3</td><td>Cl</td><td>H</td><td>H</td>

<td>I-183</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>H</td><td>H</td>

<td>I-184</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>H</td><td>Cl</td><td>H</td>

<td>I-185</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Br</td><td>H</td><td>Cl</td><td>H</td>

<td>I-186</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>H</td><td>F</td><td>H</td>

<td>I-187</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>H</td><td>CN</td><td>H</td>

<td>I-188</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>Br</td><td>H</td><td>H</td>

<td>I-189</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Br</td><td>H</td><td>CF3</td><td>H</td>

<td>I-190</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-191</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td> \/</td><td>H</td><td>H</td>

<td>I-192</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td></td><td>H</td><td>H</td>

<td>I-193</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>H</td><td>F</td>

<td>I-194</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>OCH2CH3</td><td>H</td><td>H</td>

<td>I-195</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCH₂-cyklobutyl</td><td>H</td><td>H</td>

<td>I-196</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCH₂-izopropyl</td><td>H</td><td>H</td>

<td>I-197</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCH₂CH₂-izopropyl</td><td>H</td><td>H</td>

<td>I-198</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>CF3</td><td>H</td><td>H</td>

<td>I-199</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>H</td><td>CH3</td><td>H</td>

<td>I-200</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td>OCH3</td><td>F</td>

<td>I-201</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td></td><td>H</td><td>H</td>

<td>I-202</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>ΣΖ</td><td>H</td><td>H</td>

<td>I-203</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td></td><td>H</td><td>H</td>

<td>I-204</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>Aa</td><td>H</td><td>H</td>

<td>I-205</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>Λχ</td><td>H</td><td>H</td>

<td>I-206</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>1 Ph H</td><td>H</td><td>H</td>

<td>I-207</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>I-208</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>I-209</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>I-210</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>I-211</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td></td><td>H</td><td>H</td><td>H</td>

<td>I-212</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td></td><td>H</td><td>H</td><td>H</td>

<td>I-213</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Ph -A^JH</td><td>H</td><td>H</td><td>H</td>

<td>I-214</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td></td><td>H</td><td>H</td><td>H</td>

<td>I-215</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td></td><td>H</td><td>H</td><td>H</td>

<td>I-216</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>k</td><td>H</td><td>H</td><td>H</td>

<td>I-217</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>kx-°</td><td>H</td><td>H</td><td>H</td>

<td>I-218</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>H</td><td>H</td><td>H</td>

<td>I-219</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>C(O)N(H)Ph</td><td>H</td><td>H</td>

<td>I-220</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH</td><td>H</td><td>H</td><td>H</td>

<td>I-221</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>C(O)N(H)Ph</td><td>H</td><td>H</td>

<td>I-222</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>CO2H</td><td>H</td><td>H</td>

<td>I-223</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>A^ H</td><td>H</td><td>H</td>

<td>I-224</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH2CH(CH3)2</td><td>H</td><td>CF3</td><td>H</td>

<td>I-225</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH₂-cyklopropyl</td><td>H</td><td>CF3</td><td>H</td>

<td>I-226</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>O-cyklobutyl</td><td>H</td><td>CF3</td><td>H</td>

<td>I-227</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH₂-cyklobutyl</td><td>H</td><td>CF3</td><td>H</td>

<td>I-228</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCD3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-229</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>C(O)CH3</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-230</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>F</td><td>CF3</td><td>H</td>

<td>I-231</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-232</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>γΥ H</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-233</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-234</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td></td><td>H</td><td>OCH3</td><td>H</td>

<td>I-235</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td></td><td>H</td><td>OCH3</td><td>H</td>

<td>I-236</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-237</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>H</td><td>CF2H</td><td>H</td>

<td>I-238</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>H</td><td>CH2F</td><td>H</td>

<td>I-239</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>S(O)2CH3</td><td>CH3</td><td>H</td><td>H</td>

<td>I-240</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>morfolin-4-yl</td><td>H</td><td>F</td><td>H</td>

<td>I-241</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Ąl/ Yi—</td><td>H</td><td>F</td><td>H</td>

<td>I-242</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>S(O)2CH3</td><td>F</td><td>H</td><td>H</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>I-244</td><td>O</td><td>NH</td><td>CCH 3</td><td>CH3</td><td>S(O)2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-245</td><td>O</td><td>NH</td><td>CCH 3</td><td>CH3</td><td>S(O)2CH3</td><td>F</td><td>H</td><td>H</td>

<td>I-246</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>O</td><td>H</td><td>H</td><td>H</td>

<td>I-247</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>O</td><td>H</td><td>H</td>

<td>I-249</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>S(O)2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-250</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>S(O)2CH3</td><td>F</td><td>H</td><td>H</td>

<td>I-251</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>OCH</td><td>H</td><td>CF3</td><td>H</td>

<td>I-252</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>C(O)N(CH3)2</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-253</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td> 0</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-254</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>0 ?νΊ</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-255</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>^{7 V}N N— X ⁷</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-256</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>0 Ho</td><td>H</td><td>H</td><td>H</td>

<td>I-257</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>0 /fi</td><td>H</td><td>H</td>

<td>I-258</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-259</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>H</td><td>CH3</td><td>H</td>

<td>I-260</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>C(O)N(CH3)2</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-261</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td> 0</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-262</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td> 0</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-263</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>0 /—\ J?—Ν N—</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-264</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>OCD3</td><td>H</td><td>H</td>

<td>I-265</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>Cl</td><td>OCH</td><td>CH</td><td>H</td>

<td>I-266</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OCD3</td><td>H</td><td>CH</td><td>H</td>

<td>I-267</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OCH</td><td>C(O)N(CH3)2</td><td>H</td><td>H</td>

<td>I-268</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td> 0</td><td>H</td><td>H</td>

<td>I-269</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td> 0</td><td>H</td><td>H</td>

<td>I-270</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OCH</td><td>&gt;-N N— V</td><td>H</td><td>H</td>

<td>I-271</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CF2H</td><td>OCH</td><td>H</td><td>H</td>

<td>I-272</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>H</td><td>OCH</td><td>H</td><td>H</td>

<td>I-273</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OCH</td><td>H</td><td>CF2H</td><td>H</td>

<td>I-274</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OCH</td><td>H</td><td>CHF</td><td>H</td>

<td>I-275</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>F</td><td></td><td>H</td><td>H</td>

<td>I-276</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CF3</td><td></td><td>H</td><td>H</td>

<td>I-277</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>fo;</td><td>H</td><td>H</td>

<td>I-278</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>l/</td><td>H</td><td>H</td>

<td>I-279</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>!-o;</td><td>H</td><td>H</td>

<td>I-280</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-281</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>l/ \l—</td><td>H</td><td>H</td>

<td>I-282</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>^N—</td><td>F</td><td>H</td>

<td>I-283</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td></td><td>Cl</td><td>H</td><td>H</td>

<td>I-284</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>&gt; ?—Ν N—</td><td>Cl</td><td>H</td><td>H</td>

<td>I-285</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>l/</td><td>CF3</td><td>H</td><td>H</td>

<td>I-286</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>oksazol-5-yl</td><td>H</td><td>H</td><td>H</td>

<td>I-287</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Br</td><td>H</td><td>H</td><td>H</td>

<td>I-288</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>Br</td><td>H</td><td>H</td>

<td>I-289</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>pirydyn-4-yl</td><td>H</td><td>H</td><td>H</td>

<td>I-290</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>pirydyn-3-yl</td><td>H</td><td>H</td><td>H</td>

<td>I-291</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>pirydyn-3-yl</td><td>H</td><td>H</td>

<td>I-292</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH2CH2OCH3</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-293</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>⁰ Λ H</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-294</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CN</td><td>F</td><td>H</td><td>H</td>

<td>I-295</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CN</td><td>pyrrol-1-yl</td><td>H</td><td>H</td>

<td>I-296</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-297</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-298</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td> &lt;-0 ⁷</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-299</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td> (-0</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-300</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Y°^N^Z \</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-301</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-302</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>H</td><td>CH3</td><td>H</td>

<td>I-303</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>CN</td><td>H</td><td>H</td>

<td>I-304</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH(OH)CF3</td><td>H</td><td>H</td><td>H</td>

<td>I-305</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH2CO2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-306</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>0 H</td><td>H</td><td>H</td><td>H</td>

<td>I-307</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCH2C(O)NH2</td><td>H</td><td>H</td>

<td>I-308</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>N(H)C(O)Ph</td><td>H</td><td>H</td>

<td>I-309</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>N(CH3)C(O)CH3</td><td>H</td><td>H</td>

<td>I-310</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CN</td><td>pirolidyn-1-yl</td><td>H</td><td>H</td>

<td>I-311</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCF2H</td><td>H</td><td>H</td>

<td>I-312</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCF2H</td><td>H</td><td>H</td><td>H</td>

<td>I-313</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH2CH3</td><td>OCF2H</td><td>H</td><td>H</td>

<td>I-314</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>OCF2H</td><td>H</td><td>H</td>

<td>I-315</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>⁰ Λ H</td><td>H</td><td>H</td><td>H</td>

<td>I-316</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>C(O)NH2</td><td>N⁷ \l—</td><td>H</td><td>H</td>

<td>I-317</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>⁰ 1</td><td>H</td><td>H</td>

<td>I-318</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>O_v5^nh &lt;-NH )</td><td>H</td><td>H</td>

<td>I-319</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH2C(O)NH2</td><td>H</td><td>H</td><td>H</td>

<td>I-320</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td> 0</td><td>H</td><td>H</td><td>H</td>

<td>I-321</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>0 /-\ Jy—N N— V ^-⁷</td><td>H</td><td>H</td><td>H</td>

<td>I-322</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>1 0 Λ</td><td>H</td><td>H</td>

<td>I-323</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>C(O)NH2</td><td>V 0 1</td><td>H</td><td>H</td>

<td>I-324</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OC(CH3)2C(O)NH2</td><td>H</td><td>H</td>

<td>I-325</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>''NH</td><td>CH3</td>

<td>I-326</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH2C(O)N(CH3)2</td><td>H</td><td>H</td><td>H</td>

<td>I-327</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CN</td><td>morfolin-4-yl</td><td>H</td><td>H</td>

<td>I-328</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>OCH3</td><td>CH3</td>

<td>I-329</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>pirydyn-4-yl</td><td>H</td><td>H</td>

<td>I-330</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>pirydyn-4-yl</td><td>H</td><td>H</td>

<td>I-331</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH2OH</td><td>Ąl/ Yl—</td><td>H</td><td>H</td>

<td>I-332</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>piperazyn-1-yl</td><td>H</td><td>H</td>

<td>I-333</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td> /\ ^NH^^NV/^N^_O</td><td>H</td><td>H</td>

<td>I-334</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OC(CH3)2CN</td><td>H</td><td>H</td>

<td>I-335</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OC(CH3)2C(O)NH2</td><td>H</td><td>H</td><td>H</td>

<td>I-336</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>CO2CH3</td><td>H</td><td>H</td>

<td>I-337</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>H</td><td>H</td><td>H</td>

<td>I-338</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>morfolin-4-yl</td><td>H</td><td>H</td>

<td>I-339</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CN</td><td>tiomorfolin-4-yl</td><td>H</td><td>H</td>

<td>I-340</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>Y \l—</td><td>H</td><td>H</td>

<td>I-341</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CN</td><td>Y Yl—</td><td>H</td><td>H</td>

<td>I-342</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OC(CH3)2CN</td><td>H</td><td>H</td><td>H</td>

<td>I-343</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>^X' O</td><td>H</td><td>H</td>

<td>I-344</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>/w^x—⁷ 0</td><td>H</td><td>H</td>

<td>I-345</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>νΑΆ</td><td>H</td><td>H</td><td>H</td>

<td>I-346</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td> /—\ \° '—' 0</td><td>H</td><td>H</td><td>H</td>

<td>I-347</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>OCF2H</td><td>H</td><td>H</td>

<td>I-348</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>OCF2H</td><td>Cl</td><td>H</td>

<td>I-349</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>H</td><td>H</td>

<td>I-350</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-351</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>CH3</td><td>H</td><td>H</td>

<td>I-352</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-353</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>H</td><td>OCF2H</td><td>H</td>

<td>I-354</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>CF3</td><td>H</td><td>H</td>

<td>I-355</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>/-butyl</td><td>H</td><td>/-butyl</td><td>H</td>

<td>I-356</td><td>O</td><td>NCH2OP(O)(O-t-Bu)2</td><td>CH</td><td>CH3</td><td>OCH3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-357</td><td>O</td><td>NCH2OP(O)(OH)2</td><td>CH</td><td>CH3</td><td>OCH3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-358</td><td>O</td><td>NCH2OP(O)(ONa)2</td><td>CH</td><td>CH3</td><td>OCH3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-359</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>H</td><td>F</td><td>H</td>

<td>I-360</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>H</td><td>CF3</td><td>H</td>

<td>I-361</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>F</td><td>H</td><td>H</td>

<td>I-362</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>F</td><td>H</td><td>H</td>

<td>I-363</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>CH3</td><td>H</td><td>H</td>

<td>I-364</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>CH3</td><td>H</td><td>H</td>

<td>I-365</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>CH3</td><td>CH3</td><td>H</td>

<td>I-366</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>OCF3</td><td>H</td><td>H</td>

<td>I-367</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>SCF3</td><td>H</td><td>H</td>

<td>I-368</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>H</td><td>H</td><td>H</td>

<td>I-369</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>OCH3</td><td>CH3</td><td>H</td>

<td>I-370</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>C(O)NH2</td><td>H</td><td>CF3</td><td>H</td>

<td>I-371</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>izopropyl</td><td>OCH3</td><td>izopropyl</td><td>H</td>

<td>I-372</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>O-izopropyl</td><td>H</td><td>CF3</td><td>H</td>

<td>I-373</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CN</td><td>OCH</td><td>H</td><td>H</td>

<td>I-374</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>F</td><td>CH</td><td>H</td>

<td>I-375</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OCF3</td><td>F</td><td>H</td><td>H</td>

<td>I-376</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>F</td><td>OCF3</td><td>H</td><td>H</td>

<td>I-377</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OCF3</td><td>Cl</td><td>H</td><td>H</td>

<td>I-378</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>Cl</td><td>H</td><td>OCF3</td><td>H</td>

<td>I-379</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td><td>OCF3</td><td>H</td>

<td>I-380</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OCH</td><td>CN</td><td>H</td><td>H</td>

<td>I-381</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>F</td><td>OCH</td><td>F</td><td>H</td>

<td>I-382</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>H</td><td>&lt;ν2ρ</td><td>H</td><td>H</td>

<td>I-383</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CN</td><td>Cl</td><td>CH2CH3</td><td>H</td>

<td>I-384</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OCH2CH2OCH3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-385</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>OCF2H</td><td>CH</td><td>H</td>

<td>I-386</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OC(CH)2C(O)NH</td><td>F</td><td>H</td><td>H</td>

<td>I-387</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>OCF2H</td><td>H</td><td>H</td>

<td>I-388</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>F</td><td>OCF2H</td><td>F</td><td>H</td>

<td>I-389</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>OC(CH3)₂C(O)NH₂</td><td>CH3</td><td>H</td>

<td>I-390</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCF₂H</td><td>CH3</td><td>H</td><td>H</td>

<td>I-391</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>OC(CH3)₂C(O)NH₂</td><td>H</td><td>H</td>

<td>I-392</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OC(CH3)₂C(O)NH₂</td><td>CH3</td><td>H</td><td>H</td>

<td>I-393</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-394</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>Cl</td><td>CH3</td><td>H</td>

<td>I-395</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>OC(CH3)₂C(O)NH₂</td><td>F</td><td>H</td>

<td>I-396</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH(OCH3)CF3</td><td>H</td><td>H</td><td>H</td>

<td>I-397</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OC(CH3)₂CN</td><td>CH3</td><td>H</td><td>H</td>

<td>I-398</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>F</td><td>H</td><td>H</td>

<td>I-399</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Cl</td><td>F</td><td>H</td><td>H</td>

<td>I-400</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>Cl</td><td>H</td><td>H</td>

<td>I-401</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>H</td><td>OCF₂H</td><td>H</td>

<td>I-402</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OC(CH3)₂C(O)NH₂</td><td>H</td><td>F</td><td>H</td>

<td>I-403</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-404</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>\ Ό—&lt; NY</td><td>H</td><td>H</td>

<td>I-405</td><td>O</td><td>NCH2OP(O)(O-Z-Bu)2</td><td>CH</td><td>CH3</td><td>CH3</td><td>CH3</td><td>CH3</td><td>H</td>

<td>I-406</td><td>O</td><td>NCH2OP(O)(OH)2</td><td>CH</td><td>CH3</td><td>CH3</td><td>CH3</td><td>CH3</td><td>H</td>

<td>I-407</td><td>O</td><td>NCH2OP(O)(ONa)2</td><td>CH</td><td>CH3</td><td>CH3</td><td>CH3</td><td>CH3</td><td>H</td>

<td>I-408</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>F</td><td>F</td><td>H</td>

<td>I-409</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>CF3</td><td>H</td>

<td>I-410</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>CF3</td><td>H</td>

<td>I-411</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>CF3</td><td>H</td>

<td>I-412</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>CF3</td><td>H</td>

<td>I-413</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>CF3</td><td>H</td>

<td>I-414</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>CF3</td><td>H</td>

<td>I-415</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>CF3</td><td>F</td><td>H</td>

<td>I-416</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OC(CH3)2CN</td><td>H</td><td>F</td><td>H</td>

<td>I-417</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OC(CH3)2CN</td><td>F</td><td>H</td><td>H</td>

<td>I-418</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCF2H</td><td>Cl</td><td>H</td><td>H</td>

<td>I-419</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>izopropyl</td><td>H</td><td>H</td>

<td>I-420</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>/-butyl</td><td>H</td><td>H</td>

<td>I-421</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td>H</td><td>H</td>

<td>I-422</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH₂O-izopropyl</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-423</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Ύ^οη</td><td>H</td><td>OCH3</td><td>H</td>

<td>I-424</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OH</td><td>Cl</td><td>H</td>

<td>I-425</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OH</td><td>H</td><td>H</td>

<td>I-426</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>Y N</td><td>H</td><td>H</td>

<td>I-427</td><td>O</td><td>NH</td><td>CCH3</td><td>CH3</td><td>OCH3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-428</td><td>O</td><td>NH</td><td>CCH3</td><td>CH3</td><td>OCH3</td><td>H</td><td>CH3</td><td>H</td>

<td>I-429</td><td>O</td><td>NH</td><td>CCH3</td><td>CH3</td><td>H</td><td>OCH3</td><td>CH3</td><td>H</td>

<td>I-430</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>OCH3</td><td>H</td><td>CH3</td><td>H</td>

<td>I-431</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>H</td><td>OCH3</td><td>CH3</td><td>H</td>

<td>I-432</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>CH3</td><td>H</td>

<td>I-433</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCF2H</td><td>CH2F</td><td>H</td>

<td>I-434</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CN</td><td>OCF2H</td><td>H</td>

<td>I-435</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td>OCF2H</td><td>H</td>

<td>I-436</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>CH3</td><td>CH3</td><td>H</td>

<td>I-437</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>F</td><td>CH3</td><td>H</td>

<td>I-438</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td>CF2H</td><td>H</td>

<td>I-439</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td>CH2F</td><td>H</td>

<td>I-440</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-441</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCD3</td><td>CF3</td><td>H</td>

<td>I-442</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCF2H</td><td>CF2H</td><td>H</td>

<td>I-443</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>pirydyn-4-yl</td><td>CH3</td><td>H</td><td>H</td>

<td>I-444</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>pirydyn-3-yl</td><td>CH3</td><td>H</td><td>H</td>

<td>I-445</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>C(O)CH3</td><td>H</td><td>CF3</td><td>H</td>

<td>I-446</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>"l^OH</td><td>H</td><td>CF3</td><td>H</td>

<td>I-447</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCD3</td><td>H</td><td>H</td>

<td>I-448</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCD3</td><td>Cl</td><td>H</td>

<td>I-449</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>,/A-⁷</td><td>H</td><td>H</td>

<td>I-450</td><td>O</td><td>NCH2OP(O)(O-/-Bu)2</td><td>CH</td><td>CH3</td><td>CH3</td><td>F</td><td>CH3</td><td>H</td>

<td>I-451</td><td>O</td><td>NCH2OP(O)(ONa)2</td><td>CH</td><td>CH3</td><td>CH3</td><td>F</td><td>CH3</td><td>H</td>

<td>I-452</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>OCH3</td><td>CH3</td><td>H</td>

<td>I-453</td><td>O</td><td>NH</td><td>CCH3</td><td>CH3</td><td>OCH3</td><td>OCH3</td><td>CH3</td><td>H</td>

<td>I-454</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>OCH3</td><td>OCH3</td><td>CH3</td><td>H</td>

<td>I-455</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td></td><td>Cl</td><td>H</td>

<td>I-456</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td>H</td><td>F</td>

<td>I-457</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Y H</td><td>H</td><td>CF3</td><td>H</td>

<td>I-458</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>OCH3</td><td>Cl</td><td>H</td>

<td>I-459</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>u&gt;</td><td>CH3</td><td>H</td>

<td>I-460</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>CF3</td><td>H</td>

<td>I-461</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>CF3</td><td>H</td>

<td>I-462</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>CF3</td><td>H</td>

<td>I-463</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Υν_Ο</td><td>H</td><td>CF3</td><td>H</td>

<td>I-464</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td></td><td>H</td><td>CF3</td><td>H</td>

<td>I-465</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>Η</td><td>H</td><td>CF3</td><td>H</td>

<td>I-466</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>H</td><td>H</td><td>F</td>

<td>I-467</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>F</td><td>F</td>

<td>I-468</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>F</td>

<td>I-469</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>CF3</td><td>H</td>

<td>I-470</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>H</td><td>F</td><td>H</td><td>H</td>

<td>I-471</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>pirydyn-4-yl</td><td>F</td><td>H</td><td>H</td>

<td>I-472</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>pirydyn-3-yl</td><td>F</td><td>H</td><td>H</td>

<td>I-473</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>CF3</td><td>H</td>

<td>I-474</td><td>O</td><td>NH</td><td>CCH</td><td>CH</td><td>CH</td><td>H</td><td>CH</td><td>H</td>

<td>I-475</td><td>O</td><td>NH</td><td>CCH</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td>

<td>I-476</td><td>O</td><td>NH</td><td>CCH</td><td>CH</td><td>CH</td><td>F</td><td>CH</td><td>H</td>

<td>I-477</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>F</td><td>F</td><td>F</td><td>F</td>

<td>I-478</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CN</td><td>H</td><td>OCF2H</td><td>H</td>

<td>I-479</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td><td>CF3</td><td>H</td>

<td>I-480</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>F</td><td>H</td><td>F</td><td>F</td>

<td>I-481</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>F</td><td>F</td><td>H</td><td>F</td>

<td>I-482</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>pirydyn-4-yl</td><td>H</td><td>H</td>

<td>I-483</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>pirydyn-3-yl</td><td>H</td><td>H</td>

<td>I-484</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>F</td><td>pirydyn-4-yl</td><td>H</td><td>H</td>

<td>I-485</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>OCH3</td><td>OCH3</td><td>H</td>

<td>I-486</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>pirydyn-4-yl</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-487</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>pirydyn-3-yl</td><td>OCH3</td><td>H</td><td>H</td>

<td>I-488</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>CH3</td><td>H</td><td>CH3</td><td>H</td>

<td>I-489</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>CH3</td><td>CH3</td><td>CH3</td><td>H</td>

<td>I-490</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>CH3</td><td>F</td><td>CH3</td><td>H</td>

<td>I-491</td><td>O</td><td>NH</td><td>CCH3</td><td>CH3</td><td>OCH3</td><td>F</td><td>CH3</td><td>H</td>

<td>I-492</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>OCH3</td><td>F</td><td>CH3</td><td>H</td>

<td>I-493</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>F</td>

<td>I-494</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>pirydyn-4-yl</td><td>H</td><td>H</td>

<td>I-495</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCF2H</td><td>H</td><td>Cl</td><td>H</td>

<td>I-496</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCH3</td><td>Cl</td><td>H</td>

<td>I-497</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>H</td><td>Cl</td><td>H</td>

<td>I-498</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CF3</td><td>H</td><td>H</td><td>OCH3</td>

<td>I-499</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>CH3</td>

<td>I-500</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td>

<td>I-501</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>H</td><td>H</td><td>CH3</td>

<td>I-502</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>Et</td>

<td>I-503</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH2CH3</td><td>H</td><td>H</td><td>H</td>

<td>I-504</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH2CH3</td><td>H</td><td>H</td>

<td>I-505</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>F</td><td>pirydyn-3-yl</td><td>H</td><td>H</td>

<td>I-506</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>pirydyn-3-yl</td><td>H</td><td>H</td>

<td>I-507</td><td>O</td><td>NH</td><td>CCH3</td><td>CH3</td><td>H</td><td>F</td><td>OCH3</td><td>F</td>

<td>I-508</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>H</td><td>F</td><td>OCH3</td><td>F</td>

<td>I-509</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>6-Cl-pirydyn-3-yl</td><td>H</td><td>H</td>

<td>I-510</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td></td><td>H</td><td>H</td>

<td>I-511</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>i-O&lt;o ^-N —N \</td><td>H</td><td>H</td>

<td>I-512</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td></td><td>H</td><td>H</td>

<td>I-513</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>CH3</td><td>F</td>

<td>I-514</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td>H</td><td>F</td>

<td>I-515</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>H</td><td>H</td><td>F</td>

<td>I-516</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCF2H</td><td>H</td><td>CH3</td><td>H</td>

<td>I-517</td><td>O</td><td>NCH2OP(O)(OH)2</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td>

<td>I-518</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>H</td><td>H</td><td>CF3</td><td>CH</td>

<td>I-519</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>C(O)CH</td><td>H</td><td>H</td><td>F</td>

<td>I-520</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>H</td><td>H</td><td>H</td><td>Cl</td>

<td>I-521</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td><td>H</td><td>Cl</td>

<td>I-522</td><td>O</td><td>NH</td><td>CCl</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>Cl</td>

<td>I-523</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td></td><td>H</td><td>H</td><td>F</td>

<td>I-524</td><td>O</td><td>NCH2OP(O)(O-Z-Bu)2</td><td>CCl</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td>

<td>I-525</td><td>O</td><td>NCH2OP(O)(OH)2</td><td>CCl</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td>

<td>I-526</td><td>O</td><td>NCH2OP(O)(OH)2</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td>

<td>I-527</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>I</td><td>CH</td><td>H</td>

<td>I-528</td><td>O</td><td>NCH2OP(O)(ONa)2</td><td>CCl</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td>

<td>I-529</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>OCH</td><td>CH</td><td>OCH</td><td>H</td>

<td>I-530</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td><td>F</td>

<td>I-531</td><td>O</td><td>NCH2OP(O)(OH)2</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>CH</td><td>H</td>

<td>I-532</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td>CF3</td><td>F</td>

<td>I-533</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>H</td><td>H</td><td>F</td>

<td>I-534</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>CH3</td><td>CH3</td><td>F</td>

<td>I-535</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>OCH3</td><td>CH3</td><td>CH3</td><td>H</td>

<td>I-536</td><td>O</td><td>NCH2OP(O)(OH)2</td><td>CCH3</td><td>CH3</td><td>OCH3</td><td>H</td><td>CH3</td><td>H</td>

<td>I-537</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>CH3</td><td>F</td><td>H</td>

<td>I-538</td><td>O</td><td>NCH2OP(O)(ONa)2</td><td>CH</td><td>CH3</td><td>OCH3</td><td>F</td><td>CH3</td><td>H</td>

- 72 Tabela II

R^2b

<img file="PL2389372T3_D0028.tif" />

<td>Związ.</td><td>X</td><td>Y</td><td>Z¹</td><td>R⁵</td><td>R^2a</td><td>R^2b</td><td>R^2c</td><td>R^2d</td>

<td>II-1</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>-N(CH3)2</td><td>H</td>

<td>II-2</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>nⁿCv^n_R</td><td>H</td>

<td>II-3</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>1 -metylo-1,4-diazepan-4-yl</td><td>H</td>

<td>II-4</td><td>O</td><td>N-(w-propyl)</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-5</td><td>O</td><td>N-(n-propyl)</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>Ν N—/</td><td>H</td>

<td>II-6</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>4-metylopiperydyn-1 -yl</td><td>H</td>

<td>II-7</td><td>O</td><td>N-(izopropyl)</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-8</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>/—\ 0 )—N cf₃</td><td>H</td>

<td>II-9</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>/—\ 0 &gt;—N^{K x}f 0—</td><td>H</td>

<td>II-10</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>piperazyn-1-yl</td><td>H</td>

<td>II-11</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>X -ty N N—/</td><td>H</td>

<td>II-12</td><td>O</td><td>NH</td><td>CH</td><td>co K u</td><td>H</td><td>H</td><td>?—N NH^k \/</td><td>H</td>

<td>II-13</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-14</td><td>O</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-15</td><td>NH</td><td>NH</td><td>CH</td><td>CH</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-16</td><td>NH</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-17</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>H</td><td>H</td><td>morfolin-4-yl</td><td>H</td>

<td>II-18</td><td>O</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>H</td><td>morfolin-4-yl</td><td>H</td>

<td>II-19</td><td>NH</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>H</td><td>morfolin-4-yl</td><td>H</td>

<td>II-20</td><td>NCH</td><td>NCH</td><td>CH</td><td>CH</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-21</td><td>NCH</td><td>NCH</td><td>CH</td><td>F</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-22</td><td>O</td><td>NCH</td><td>CH</td><td>CH</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-23</td><td>NCH</td><td>O</td><td>CH</td><td>CH</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-24</td><td>O</td><td>NCH</td><td>CH</td><td>F</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-25</td><td>NH</td><td>O</td><td>CH</td><td>CH</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-26</td><td>O</td><td>NH</td><td>CH</td><td>CH</td><td>H</td><td>CH</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-27</td><td>NH</td><td>NH</td><td>CH</td><td>CH</td><td>H</td><td>CH</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-28</td><td>O</td><td>NH</td><td>CH</td><td>co K u</td><td>H</td><td>co K u</td><td>R Ά R</td><td>H</td>

<td>II-29</td><td>O</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>CH3</td><td>R Yn^NR</td><td>H</td>

<td>II-30</td><td>O</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>CH3</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-31</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>s Ά s</td><td>H</td>

<td>II-32</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>R R</td><td>H</td>

<td>II-33</td><td>O</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>H</td><td>R \ V^NR</td><td>H</td>

<td>II-34</td><td>O</td><td>NH</td><td>CH</td><td>F</td><td>H</td><td>H</td><td>R R</td><td>H</td>

<td>II-35</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>-N(H)-1 -metylopiperydyn-4-yl</td><td>H</td>

<td>II-36</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>-N(H)-piperydyn-4-yl</td><td>H</td>

<td>II-37</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>A®</td><td>H</td>

<td>II-38</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>θ</td><td>H</td>

<td>II-39</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CF3</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-40</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td>s s</td><td>H</td>

<td>II-41</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>s/ N N—/ 0^-</td><td>H</td>

<td>II-42</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>II-43</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>S(O)2CH3</td><td>H</td>

<td>II-44</td><td>O</td><td>NH</td><td>CH</td><td>co K u</td><td>H</td><td>H</td><td>K</td><td>s? “Λ NH y</td><td>H</td>

<td>II-45</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td colspan="2">-C(O)-piperazyn-1 -yl</td><td>H</td>

<td>II-46</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>W</td><td>K.</td><td>H</td>

<td>II-47</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>Vn^</td><td> &gt;&gt;</td><td>H</td>

<td>II-48</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td colspan="2">b^NCC^N^A</td><td>H</td>

<td>II-49</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td colspan="2"></td><td>H</td>

<td>II-50</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td></td><td>L ^NH</td><td>H</td>

<td>II-51</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td colspan="2">&gt;-Ά^νη</td><td>H</td>

<td>II-52</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td>b^NCC</td><td></td><td>H</td>

<td>II-53</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td>b&lt;X</td><td>Ά /° 'z</td><td>H</td>

<td>II-54</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td> ^-^Ν3^Νγ</td><td>H</td>

<td>II-55</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>)—N N—^K \/</td><td>H</td>

<td>II-56</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>&gt;—N N—&lt; &gt;</td><td>H</td>

<td>II-57</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>λΎ o )—N N— cf₃</td><td>H</td>

<td>II-58</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>⁰\ / \ 11 N N-P-0 \ \ / 1 \^x—⁷ JD ^x—</td><td>H</td>

<td>II-59</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>4,4-difluoropiperydyn-1-yl</td><td>H</td>

<td>II-60</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>4,4-dimetylopiperydyn-1 -yl</td><td>H</td>

<td>II-61</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td>b^NS^NH</td><td>H</td>

<td>II-62</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td></td><td>H</td>

<td>II-63</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td></td><td>H</td>

<td>II-64</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td></td><td>H</td>

<td>II-65</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td></td><td>H</td>

<td>II-66</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td>H£^nh</td><td>H</td>

<td>II-67</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td></td><td>H</td>

<td>II-68</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td></td><td>H</td>

<td>II-69</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td>&lt;=-c.</td><td>H</td>

<td>II-70</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>&gt; 9 (—N\__Z^N \</td><td>H</td>

<td>II-71</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>pirolidyn-1-yl</td><td>H</td>

<td>II-72</td><td>O</td><td>NH</td><td>CCH3</td><td>CH3</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-73</td><td>O</td><td>NH</td><td>CCH3</td><td>CH3</td><td>H</td><td>H</td><td>morfolin-4-yl</td><td>H</td>

<td>II-74</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>-N(H)CH₂-cyklopropyl</td><td>H</td>

<td>II-75</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-76</td><td>O</td><td>NH</td><td>CF</td><td>CH3</td><td>H</td><td>H</td><td>morfolin-4-yl</td><td>H</td>

<td>II-77</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>Br</td><td>H</td><td>H</td>

<td>II-79</td><td>O</td><td>NCH3</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>-N(H)S(O)2CH3</td><td>H</td>

<td>II-80</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>\ N—</td><td>H</td>

<td>II-81</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>II-82</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td> &gt;</td><td>H</td>

<td>II-83</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H N .CF₃</td><td>H</td>

<td>II-84</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>0 N-^Z b^NC7</td><td>H</td>

<td>II-85</td><td>O</td><td>NH</td><td>CH</td><td>CF3</td><td>H</td><td>H</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-86</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>H N. .0. / /-&lt;7 ϊ</td><td>H</td>

<td>II-87</td><td>O</td><td>NH</td><td>CH</td><td>CD κ ω</td><td>H</td><td>H</td><td>/ Η Μ</td><td>H</td>

<td>II-88</td><td>O</td><td>NH</td><td>CH</td><td>CD κ ω</td><td>H</td><td>H</td><td>ί ⁿQ ΗΝ—</td><td>H</td>

<td>II-89</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td> \ '^Ν_</td><td>H</td>

<td>II-90</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td> \ '^Ν_b&lt;3</td><td>H</td>

<td>II-91</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>ρ4 X</td><td>H</td>

<td>II-92</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>NⁿQ ΗΝ—</td><td>H</td>

<td>II-94</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>ΗΝ^, bO t&gt;</td><td>H</td>

<td>II-95</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>'"l· '—' Ph</td><td>H</td>

<td>II-96</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>Η H l\L .l\L</td><td>H</td>

<td>II-97</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>Η H i-O Ϊ</td><td>H</td>

<td>II-98</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>Η H N_x /Ν, , Ph i-o Ϊ</td><td>H</td>

<td>II-99</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>)—NH b'—⁷ Ph</td><td>H</td>

<td>II-100</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>bO o</td><td>H</td>

<td>II-101</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>bO o</td><td>H</td>

<td>II-102</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>/χ/γ^ b^NCT o</td><td>H</td>

<td>II-103</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>W Ο</td><td>H</td>

<td>II-104</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>NH &lt;1&gt;^Η</td><td>H</td>

<td>II-105</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>^!Ά \—⁷ Ph</td><td>H</td>

<td>II-106</td><td>O</td><td>NH</td><td>CH</td><td>co κ ω</td><td>H</td><td>H</td><td> '—⁷ Ph</td><td>H</td>

<td>II-107</td><td>O</td><td>NH</td><td>CH</td><td>co κ ω</td><td>H</td><td>H</td><td>)—NH £&gt;</td><td>H</td>

<td>II-108</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td> ^^nh</td><td>H</td>

<td>II-109</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>u</td><td>s 7-n^ns</td><td>H</td>

<td>II-110</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CF3</td><td>1 -etylopiperazyn-4-yl</td><td>H</td>

<td>II-111</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-112</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td> &gt; ^k \/</td><td>H</td>

<td>II-113</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td>&gt; AO ^K \/</td><td>H</td>

<td>II-114</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>F</td><td>1 -etylopiperazyn-4-yl</td><td>H</td>

<td>II-115</td><td>O</td><td>NH</td><td>CH</td><td>K u</td><td>H</td><td>CN</td><td>s 7-n^ns</td><td>H</td>

<td>II-116</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>Cl</td><td>1 -metylopiperazyn-4-yl</td><td>H</td>

<img file="PL2389372T3_D0029.tif" />

<td>II-126</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>κ ( Ν Ir</td><td>H</td>

<td>II-127</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>?—N N—</td><td>H</td>

<td>II-128</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>&gt; -O &gt;—N N—⁷' \. ./</td><td>H</td>

<td>II-129</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>?—N N—^K \_/ X X X X X</td><td>H</td>

<td>II-130</td><td>O</td><td>NH</td><td>CH</td><td>co κ ω</td><td>H</td><td>H</td><td>&gt; ?—N NH^K \_Z X X X X X</td><td>H</td>

<td>II-131</td><td>O</td><td>NH</td><td>CH</td><td>CD K ω</td><td>H</td><td>H</td><td>&gt; (—N NH</td><td>H</td>

<td>II-132</td><td>O</td><td>NH</td><td>CH</td><td>CD K ω</td><td>H</td><td>H</td><td>^K \/</td><td>H</td>

<td>II-133</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>l.^N—</td><td>H</td>

<td>II-134</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>?— N _c 0 X s Sl</td><td>H</td>

<td>II-135</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>) N O k V_R/ X J·* X</td><td>H</td>

<td>II-136</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>1 -izopropylopiperazyn-4-yl</td><td>H</td>

<td>II-137</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td></td><td>H</td>

<td>II-138</td><td>O</td><td>NH</td><td>CH</td><td>co K u</td><td>H</td><td>H</td><td></td><td> \</td><td>H</td>

<td>II-139</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td>)-O</td><td>R</td><td>H</td>

<td>II-140</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCH3</td><td colspan="2">OCH3</td><td>H</td>

<td>II-141</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCH3</td><td colspan="2">OCH3</td><td>H</td>

<td>II-142</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td colspan="2">OCH2CH2OH</td><td>H</td>

<td>II-143</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>CH3</td><td>H</td><td colspan="2">1 -metylopiperazyn-4-yl</td><td>H</td>

<td>II-144</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td colspan="2">OCH(CH3)2</td><td>H</td>

<td>II-145</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td colspan="2">OCH2CH2OCH3</td><td>H</td>

<td>II-146</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td colspan="2">OC(CH3)2C(O)NH2</td><td>H</td>

<td>II-147</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CF3</td><td colspan="2">OCH3</td><td>H</td>

<td>II-148</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td colspan="2">OCH2CH2CH2OH</td><td>H</td>

<td>II-149</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>H</td><td colspan="2">OCH2CH2CH2OCH3</td><td>H</td>

<td>II-150</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>Cl</td><td colspan="2"></td><td>H</td>

<td rowspan="2">II-151</td><td rowspan="2">O</td><td rowspan="2">NH</td><td rowspan="2">CH</td><td rowspan="2">CH3</td><td rowspan="2">H</td><td rowspan="2">H</td><td colspan="2">⁰ 1—1</td><td rowspan="2">H</td>

<td></td><td>'N^ H</td>

<td>II-152</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>OCH3</td><td colspan="2">H</td><td>H</td>

<td>II-153</td><td>O</td><td>NH</td><td>CH</td><td>CH3</td><td>H</td><td>CH3</td><td colspan="2">CH3</td><td>H</td>

<td>Związ.</td><td>Y</td><td>R³</td><td>R^a lub R^b</td>

<td>III-1</td><td>NH</td><td>H</td><td>H</td>

<td>III-2</td><td>NH</td><td>H</td><td>OH</td>

<td>III-3</td><td>NH</td><td>H</td><td>CO₂-t-Bu</td>

<td>III-4</td><td>NH</td><td>H</td><td>CH3</td>

<td>III-5</td><td>NH</td><td>H</td><td>CH2CH3</td>

<td>III-6</td><td>NH</td><td>H</td><td>«-propyl</td>

<td>III-7</td><td>NH</td><td>H</td><td>CH₂-cyklopropyl</td>

<td>III-8</td><td>NH</td><td>H</td><td>CH₂-izopropyl</td>

<td>III-9</td><td>NH</td><td>H</td><td>CH₂-CH₂-izopropyl</td>

<td>III-10</td><td>NH</td><td>H</td><td>CH₂-cyklopentyl</td>

<td>III-11</td><td>NH</td><td>H</td><td>CH₂-(bicyklo[2.2.1]hept-5-en-2-yl)</td>

<td>III-12</td><td>NH</td><td>H</td><td>C(O)CH3</td>

<td>III-13</td><td>NC(O)-/-Bu</td><td>C(O)-/-Bu</td><td>C(O)-/-Bu</td>

<td>III-14</td><td>NH</td><td>H</td><td>S(O)2CH3</td>

<td colspan="2">Tabela IV H Η H</td>

<td>Związ.</td><td></td>

<td>IV-1</td><td>-jCCbo</td>

<td>IV-2</td><td> 0</td>

<td>]V-3</td><td></td>

<td>IV-4</td><td>V»</td>

<td>|V-5</td><td>μΟΟ</td>

<td>IV-0</td><td></td>

<td>IV-7</td><td>ίΓ^^Ν' Z^NH</td>

<td>IV-B</td><td>_xX^._nq</td>

<td>JV-9</td><td></td>

<td>IV-10</td><td>-νθΡ</td>

<td colspan="2">Tabela IV</td>

<td>0N H</td><td>Η H</td>

<td>Związ.</td><td></td>

<td>IV-u</td><td>Λ V</td>

<td>IV-12</td><td>HN r</td>

<td>IV-13</td><td></td>

<td>IV-14</td><td></td>

<td>IV-] 5</td><td>μθ5"</td>

<td>]V-16</td><td>π°^ί^u HO</td>

<td>IV-17</td><td>μΟ3&lt;</td>

<td>IV-l(t</td><td></td>

<td colspan="2">Tabela IV Η Η Η</td>

<td>Związ.</td><td></td>

<td>IV-19</td><td></td>

<td>ΐν-2ΰ</td><td>_Χχό⁷</td>

<td>ΐν-21</td><td>Oj</td>

<td>]V-22</td><td>&lt; Η</td>

<td>IV-23</td><td></td>

<td>ΙΥ-24</td><td>οχ Η</td>

<td>IV-25</td><td>οχ Η</td>

<td>IV-26</td><td>&lt; Η</td>

<td>rv-2?</td><td></td>

<td>IV-28</td><td>bX&gt;°</td>

<td colspan="2">Tabela IV</td>

<td>0η Η</td><td>H Η</td>

<td>Związ.</td><td></td>

<td>IV-29</td><td></td>

<td>ΙΥ-30</td><td></td>

<td>[V-3l</td><td>οΤ</td>

<td>ΐν-32</td><td></td>

<td>IV-33</td><td>ΟΤ”</td>

<td>IV-34</td><td> \ ,0 07</td>

<td>ΙΥ-35</td><td>Ο&gt;</td>

<td>JY-36</td><td>Ο&gt;·'</td>

<td>IV-37</td><td></td>

<td>ΙΥ-38</td><td>ΟΧ</td>

<td colspan="2">Tabela IV</td>

<td>0O=&lt; N H</td><td>ΟΧ· Η H</td>

<td>Związ.</td><td>J®“^(RZ)p</td>

<td>JV-39</td><td>ΧΟΟ</td>

<td>rv-4o</td><td>xx</td>

<td>IV-4I</td><td>XV</td>

<td>IV-42</td><td>_va&gt;</td>

<td>IV-43</td><td>χθ4^Ν</td>

<td>IVX4</td><td>-Λν</td>

<td>IV-45</td><td></td>

<td>IVXń</td><td></td>

<td>rv-47</td><td>xx H</td>

<td>IV4S</td><td>γΠγΑι "-J ν H</td>

<td colspan="2">Tabela IV H H H</td>

<td>Związ.</td><td>Y*V^R!|»</td>

<td>IV-49</td><td>H n H iT * yy</td>

<td>IV-50</td><td>X«X°</td>

<td>IV-5I</td><td>XX</td>

<td>lV-52</td><td>XZ</td>

<td>IV-53</td><td>χο</td>

<td>IV&lt;4</td><td>χο</td>

<td>IV-55</td><td>(Τ'</td>

<td>lV-56</td><td>oh yio</td>

<td>[V-57</td><td>χο</td>

<td>IY-58</td><td>n</td>

<td colspan="2">Tabela IV</td>

<td>Η</td><td>Η Η</td>

<td>ZWiąz.</td><td></td>

<td>IV-59·</td><td>97 F</td>

<td>IV-6(ł</td><td> 99</td>

<td>IV-ÓI</td><td> 97</td>

<td>IV-62</td><td> 99</td>

<td colspan="2">Tabela IV</td>

<td>Η</td><td>Η Η</td>

<td>Zwi until.</td><td></td>

<td>IV-63</td><td>r ^ N vV F</td>

<td>(V-64</td><td>νΥ F TFA</td>

Prodrugs [0122] Those skilled in the art will appreciate that the 2,4-pyrimidinediamine compounds described herein may contain functional groups that can be masked with progroups to form prodrugs. Such prodrugs are usually, but need not be, pharmacologically inactive until converted to the active form of the drug. In fact, many of the 2,4-pyrimidinediamine compounds described in the invention contain pro-moieties that can be hydrolyzed or otherwise cleaved under the conditions of use. For example, ester groups are usually subjected to acid-catalyzed hydrolysis to give the parent carboxylic acid after exposure to acidic conditions in the stomach, base-catalyzed hydrolysis, after exposure to alkaline conditions in the intestine or blood. Thus, when administered to an individual orally, 2,4-pyrimidinediamine compounds that contain ester moieties can be regarded as prodrugs of the corresponding carboxylic acid, regardless of whether the ester form is pharmacologically active.

[0123] The mechanism by which the progroup (s) metabolize is not critical and may be caused, for example, by hydrolysis under acidic conditions in the stomach as described above, and / or by enzymes present in the gastrointestinal tract and / or tissues or body organs. Indeed, the progroup (s) can be chosen to metabolize in a specific place in the body. For example, many esters are cleaved under the acidic conditions of the stomach. Prodrugs intended to be chemically cleaved in the stomach for the active 2,4-pyrimidinediamine compound may utilize progroups, including such esters. Alternatively, the progroups may be designed to be metabolized in the presence of enzymes such as esterases, amidases,

- 93 lipolases and phosphatases, including ATPases and kinases, etc. Progroups including metabolizable bonds and vivo are well known and include, for example and not as limitation, ethers, thioethers, silylethers, silylthioethers, esters, thioesters, carbonates, thiocarbonates , carbamates, thiocarbamates, ureas, thioureas and carboxamides. In some cases, a "precursor" group that is oxidized by oxidative enzymes such as, for example, liver cytochrome P450 may be selected to metabolize the group.

[0124] In prodrugs, any available functional moiety can be masked with a progroup to produce a prodrug. Functional groups within 2,4-pyrimidinediamine compounds that can be masked with progroups for inclusion in the pro-moiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols) and carboxyls. A wide range of progroups as well as the corresponding pro-groups obtained, suitable for masking functional groups in 2,4-pyrimidinediamine active compounds for the production of prodrugs are well known in the art. For example, a hydroxyl functional group can be masked as a sulfonate, ester or carbonate pro-moiety that can be hydrolyzed and in vivo to form a hydroxyl group. The amine functional group can be masked as an amide, carbamate, imino, urea, phosphenyl, phosphoryl or sulfenyl grouping which can hydrolyze and vivo to provide the amino group. The carboxy group may be masked in the form of an ester grouping (including silyl esters and thioesters), amide or hydrazide, which may be hydrolyzed and vivo to provide the carboxyl group. Other specific examples of relevant progroups and their respective groupings will be apparent to those skilled in the art. All of these progroups, alone or in combinations, can be included in prodrugs.

[0125] In some 2,4-pyrimidinamine compounds, the progroup (s) may be attached to any available primary or secondary amine, including, for example, the nitrogen atom N2 2,4-pyrimidinediamine, nitrogen atom N4 2,4- pyrimidinediamine and / or a primary or secondary nitrogen contained in the substituent at 2.4-pyrimidinediamine.

[0126] As noted above, the identity of the progroup is not critical, provided that it can be metabolized under the conditions of use desired, e.g. under acidic conditions found in the stomach and / or by enzymes found in vivo to produce biologically active groups, e.g. 2,4-pyrimidinediamines, as described herein. Thus, those skilled in the art will appreciate that the progroup may include almost any known or later discovered hydroxyl protecting group, amine or thiol. Non-limiting examples of suitable protecting groups can be found, for example, in Protective Groups in Organic Synthesis, Greene and Wuts, 2nd Edition, John Wiley &amp; Sons, New York, 1991 (especially pages 10-142 (alcohols, 277-308 (thiols ) and 309-405 (amines), herein referred to as "Gree" &amp; Wu / s ").

[0127] A particularly useful progroup used in the exemplary disclosed compounds is -CH2OP (OH) 2 as well as its esters, mixed acid esters and their salts. In some embodiments, the -CH2OP (OH) 2 progroup is attached through a nitrogen atom,

- 94 ring or not, to the parent molecule. There can be more than one such group. Hence one of the embodiments is a compound of formula I,

<img file="PL2389372T3_D0030.tif" />

or its solvate, where A, X, Y, Z¹, FROM², R², R³, R⁴, R⁵ and p are as described above, and at least one of R¹ (when present), R³ and R⁴ means R⁵⁰; where R⁵⁰means -CH2OP (O) (OR¹¹) 2; each R¹¹ is independently, in each case, H, C 1-6 alkyl or a monovalent cationic group, or two R¹¹, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group

<img file="PL2389372T3_D0031.tif" />

where each R⁵⁵ is independently, at each occurrence, H, optionally substituted C1-6alkyl, optionally substituted 3-8 membered heteroalicyclic, optionally substituted C6-14aryl, optionally substituted C7-20arylalkyl, optionally substituted 514 membered heteroaryl or optionally substituted 6-15 membered heteroarylalkyl; z is 0, 1, 2 or 3; or two R¹¹ together they represent a divalent organic or inorganic cationic group, exemplary inorganic divalent cationic groups include those selected from Ba²⁺, Bi²⁺, Ca²⁺, Cu²⁺, Mg²⁺, Ni²⁺, Sr²⁺ and Zn²⁺.

[0128] A further embodiment of the compounds disclosed herein includes compounds o

<img file="PL2389372T3_D0032.tif" />

or solvates thereof, where A, Z¹, FROM², R², R³, R⁴, R⁵ and p are as described above, and at least one of R¹, R³ and R⁴ means R⁵⁰; where R⁵⁰ means - 95 CH2OP (O) (OR¹¹) 2; each R¹¹ is independently, in each case, H, C1-6alkyl or a monovalent cationic group, or two R's¹¹, together with the atoms to which they are attached, form a 5 or 6 membered cyclic phosphate group, where CH2OP (O) (OR¹¹) 2 means

<img file="PL2389372T3_D0033.tif" />

or two R¹¹ together they represent a pharmaceutically acceptable divalent cationic group, including, for example, those selected from Ca²⁺, Mg²⁺ and Zn²⁺.

[0129] A further embodiment is a compound of formula IV

<img file="PL2389372T3_D0034.tif" />

or its solvate, where A, Z¹, FROM², R², R⁵ and p are as described above and R⁵⁰ means -CH2OP (O) (OR¹¹) 2; each R¹¹ is independently, in each case, the occurrence of H, C 1-6 alkyl, Li⁺, K⁺, HOCH2CH2N (CH3) 3⁺, Na⁺ or NH4⁺; or two R¹¹ together they represent a divalent cationic group selected from Ca²⁺, Mg²⁺ and Zn²⁺.

[0130] A further embodiment is a compound of formula V

<img file="PL2389372T3_D0035.tif" />

or its solvate, where A, Z¹, FROM², R², R⁵ and p are as described above, and each R¹¹ means independently, in each case, the occurrence of H, / -butyl, Li⁺,

HOCH₂CH₂N (CH₃)₃⁺, K⁺, Na⁺ or NH₄⁺; or two R¹¹ together they represent a divalent cationic group selected from Ca²⁺, Mg²⁺ and Zn²⁺.

[0131] Without wishing to be bound by any particular theory of action, it is believed that the -CH2OP (O) (OR)¹¹) 2, e.g. according to formula V, are metabolized into the form of active compounds, via the corresponding intermediate hydroxymethylamine, illustrated below:

<img file="PL2389372T3_D0036.tif" />

[0132] Such hydroxymethylamine compounds, although they can usually be isolated under controlled conditions, are known to be unstable under physiological conditions and various pH ranges in which they hydrolyze in vivo to give formaldehyde and the active drug substance. Based on this observation, compounds such as those of formula V include hydroxymethyl progroups that can be metabolized in vivo, for example by acidic conditions in the stomach and / or by enzymes present in the digestive tract or other organs and / or tissues or fluids within the body to obtain the active substance, 2,4-pyrimidinediamine.

[0133] In addition, amino and thio analogs of these hydroxymethylamines are expected to be similarly unstable under physiological conditions, and will also hydrolyze in vivo to give the active 2,4-pyrimidinediamine drug. Accordingly, compounds of the invention include those corresponding thiol compounds. Compounds of the invention include those in which the primary amine, thiol and hydroxy groups are masked with "protecting" groups, which are removed under physiological conditions of use, giving the corresponding hydroxymethyl, thiomethyl and aminomethyl compounds, i.e., thanks to these "protecting groups" of these compounds they will also be suitable prodrugs.

[0134] The suitability of any particular program for the desired mode of administration can be confirmed in biochemical assays. For example, if a prodrug is to be administered by injection into a specific tissue or organ and the identity of individual enzymes expressed in the tissue or organ is known, the specific prodrug may be tested for metabolism in biochemical assays with isolated enzyme (enzymes). Alternatively, a particular prodrug can be tested for metabolism to the active 2,4-pyrimidinediamine compound in tissue and / or organ extracts. The use of tissue and / or organ extracts may be particularly convenient when the identities of the enzymes expressed in the target tissues or organs are unknown or in cases where isolated enzymes are not conveniently available. Those skilled in the art will be able to easily select progroups with metabolic properties (such as kinetics) suitable for specific applications using such in vitro assays. Certain prodrugs can also be tested for adequate metabolism in animal models in vitro.

[0135] Compounds of the invention bearing the -CH2OP (O) (OR¹¹) 2 can

Synthesize, e.g. as below for compounds of formula V.

<img file="PL2389372T3_D0037.tif" />

[0136] Typically, the NH proton on the oxazolidinone ring can be selectively alkylated with a suitable phosphonate reagent, where LG is a suitable leaving group to form compounds of the invention, in this case formula V. Further description of the method for preparing progroups of formula -CH2OP (O) ( OR¹¹) 2 as described herein is specifically defined in US Patent 7,449,458, entitled "Pyrimidinodiamine Prodrugs and their Uses." [0137] One skilled in the art will recognize that compounds of the invention may exhibit the phenomenon of tautomerism, conformational isomerism, geometric isomerism and / or optical isomerism. For example, the compounds of the invention and their prodrugs may contain one or more chiral centers and / or double bonds, and may consequently occur as stereoisomers such as double bond isomers (such as geometric isomers), enantiomers, diasteromers and mixtures thereof, such as racemic mixtures. As another example, the compounds of the invention may exist in several tautomeric forms, including enol form, ketone form, and mixtures thereof. Since the various names of the compounds, formulas and drawings of the compounds in the description and claims may represent only one of the potential tautomeric, conformational isomeric, optical isomeric, or geometric isomeric forms, it will be understood that the invention encompasses all tautomeric, conformational isomeric, optical isomeric and / or geometric isomeric compounds described herein, as well as mixtures of these various, different isomeric forms. In cases of reduced rotation, e.g. around the core structure of 2,4-pyrimidinediamine, atropisomers are also possible, and they are also specifically included in the compounds of the invention. By definition, the compounds included in the description are, with the exception of isomeric forms, chemically stable and suitable for isolation.

[0138] As understood by one of ordinary skill in the art, some atoms exist in more than one isotopic form. For example, hydrogen occurs as a prot (¹H), deuter (²H) and tritium

12 13 (H) and carbon occurs naturally as three different isotopes, C, C and C. Thus, the presently disclosed formulas include compounds having one or more different isotope forms of certain elements, including hydrogen and carbon. In one example of the disclosure, the presently disclosed compounds are presented in isotopically enriched form. In particular examples, compounds of formula I are enriched in deuterium relative to protium.

[0139] Deuterium has a natural abundance of about 0.015%. Accordingly, for each of about

6500 hydrogen atoms occurring in nature account for one deuterium atom. The compounds disclosed herein are enriched in deuterium in one or more positions. Thus,

The deuterium-containing compounds of the invention have deuterium in one or more positions (as the case may be) with an abundance greater than 0.015%.

[0140] In one embodiment, the compound of formula (I) in the position indicated as having deuterium, has a minimum isotopic enrichment factor of at least 2000 (30% incorporation of deuterium), on each atom designated as deuterium in the compound, or at least 3000 ( 45% deuterium incorporation).

[0141] In other embodiments, the compound of formula (I) has an isotopic enrichment factor for each designated deuterium atom, at least 3500 (52.5% deuterium incorporation in each designated deuterium atom), at least 4000 (60% deuterium incorporation) , at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutical Compositions [0142] Another embodiment of the invention is a pharmaceutical composition comprising a compound as described in any of the embodiments above. The pharmaceutical compositions described herein can be prepared using conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, sealing or lyophilizing processes. The compositions can be formulated conventionally using one or more physiologically acceptable carriers, diluents, excipients or excipients that facilitate processing of the active compounds into preparations which can be used pharmaceutically.

[0143] The 2,4-pyrimidinediamine compound may be formulated into pharmaceutical compositions per se or in the form of a hydrate, solvate, N-oxide, or pharmaceutically acceptable salt as described herein. Typically, such salts are usually more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases can also be prepared.

[0144] One embodiment is a pharmaceutical formulation comprising a compound of formula I as described herein and at least one pharmaceutically acceptable excipient, diluent, preservative, stabilizer, or a mixture thereof.

[0145] The compounds may be provided in a variety of formulations and doses. The compounds may be provided in a pharmaceutically acceptable form, including one where the compound may be formulated in pharmaceutical compositions per se, or in the form of a hydrate, solvate, N-oxide or a pharmaceutically acceptable salt as described herein. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases can also be formed. It should be understood that reference to a compound, a 2,4-pyrimidinediamine compound, or "active" when discussing the formulation is also intended to

- 99 assumptions include, where appropriate, known to those skilled in the art, the formulation of prodrugs that are covered by Formula I.

[0146] In one embodiment, the compounds are provided as non-toxic pharmaceutically acceptable salts, as previously mentioned. Suitable pharmaceutically acceptable salts of the compounds described herein include acid addition salts, such as those formed with hydrochloric acid, fumaric acid, p-toluenesulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Salts of amino groups may also include quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group, such as alkyl, alkenyl, alkynyl, or a substituted alkyl moiety. In addition, if the disclosed compound contains an acidic moiety, its suitable pharmaceutically acceptable salts may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.

[0147] Pharmaceutical compositions for the administration of 2,4-pyrimidinediamine compounds may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. Pharmaceutical compositions may, for example, be obtained by uniformly and intimately bringing into association the active ingredient with a liquid carrier, a finely divided solid carrier or both, and then, if necessary, forming the product to the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired therapeutic effect.

[0148] 2,4-Pyrimidinediamine compounds can be administered by the oral, parenteral (e.g. intramuscular, intraperitoneal, intravenous, ICV, injection or infusion into the cerebellospinal reservoir, subcutaneous injection, or implant), inhalation nasal spray, vaginally, rectally, sublingually, into the urethra (e.g. suppositories for the urethra) or local routes of administration (e.g., gel, ointment, cream, aerosol, etc.) and can be formulated, alone or in combination, in appropriate unit dose preparations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, excipients and media suitable for each route of administration. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats and monkeys, the compounds described herein may be effective in humans.

[0149] The administration of the compounds described herein, or a pharmaceutically acceptable salt thereof, in pure form or in a suitable pharmaceutical composition may be carried out by any of the accepted modes of administration or by using agents that serve similar purposes. Thus, administration can be, for example, oral, nasal, parenteral (intravenous, intramuscular or subcutaneous), topical, transdermal, intravaginal, intravesical, into the cerebellospinal reservoir, rectal, in solid, semi-solid, lyophilized powder, or liquid form dosage forms such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions or aerosols, or the like, preferably in unit dosage forms

- 100 suitable for simple administration of accurate doses.

[0150] For topical administration, the compounds described herein can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Such formulations may be included in a patch or other transdermal delivery system or formulation, e.g., formulation from ingredients intended specifically to aid transport of the compound through the skin into body tissues.

[0151] Systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection) as well as those intended for transdermal, transmucosal, oral or pulmonary administration.

[0152] Useful injectable formulations include sterile suspensions, solutions or emulsions of the active compound (s) in aqueous or oily vehicles. The compositions may also contain formulating agents such as suspending, stabilizing and / or dispersing agents. Injectable formulations may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, and may contain added preservatives.

[0153] Alternatively, injectable formulations may be provided in the form of a powder for reconstitution prior to use with a suitable vehicle, including, but not limited to, sterile pyrogen-free water, buffer, and dextrose solution. To this end, the active compound (s) may be dried by any technique known in the art, such as lyophilization, and reconstituted before use.

[0154] For mucosal administration, penetrants appropriate to the barrier to be permeable are used in the formulation. Such penetrants are known in the art.

[0155] For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared using conventional solutions with pharmaceutically acceptable excipients, such as binding agents (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); greases (e.g. magnesium stearate, talc or silica); disintegrators (e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulfate). The tablets can be coated by methods well known in the art, for example, sugars, membranes or enteric coatings. In addition, pharmaceutical compositions containing a compound of the invention in a form suitable for oral use may also include, for example, pastilles, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents, including sweetening agents, flavoring agents, coloring agents and

- 101 preservatives to provide pharmaceutically representative and tasty preparations. The tablets contain the compound of the invention in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents (e.g., corn starch or alginic acid); binding agents (e.g. starch, gelatin or acacia); and lubricants (e.g. magnesium stearate, stearic acid or talc). The tablets can be left uncoated or can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained effect over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. They can also be coated using the techniques described in US Patent Nos. 4,256,108; 4,166,452; and 4,265, 874 to form osmotic therapeutic tablets for controlled release. Pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions.

[0156] Liquid formulations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or may be present as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid preparations may be prepared using conventional solutions with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated food fats); emulsifying agents (e.g. lecithin or acacia); carriers other than water (e.g., almond oil, oily esters, ethyl alcohol, cremophore ™ or fractionated vegetable oils); and preservatives (e.g. methyl- or propyl-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.

[0157] Formulations for oral administration may be suitably formulated to provide controlled release of the active compound as is well known.

[0158] For buccal administration, the compositions may take the form of tablets or lozenges formulated using a conventional means.

[0159] For intranasal administration or administration by inhalation or insufflation, the compound of the invention may conveniently be provided in the form of an aerosol spray pressurized from packages or a nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorinated hydrocarbons, carbon dioxide or other suitable gas). In the case of a pressurized aerosol, the unit dose may be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator (for example, capsules and cartridges containing gelatin) can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0160] The pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions. This suspension may be formulated according to a known state

Techniques using the appropriate dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable, diluent or solvent. Acceptable substrates and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride. The 2,4-pyrimidinediamine compounds can also be administered in the form of suppositories for rectal or urethral administration. For rectal and vaginal routes of administration, the active compound (s) may be formulated as solutions (for retention infusions), suppositories or ointments containing conventional suppository bases, such as cocoa butter or other glycerides. In particular embodiments, the compounds may be formulated in the form of suppositories for the urethra, for example, for use in the treatment of fertility conditions, in particular in men (e.g., for the treatment of testicular dysfunction).

[0161] The disclosed 2,4-pyrimidinediamine compounds can be used to prepare a composition or a medicament, including medications suitable for rectal or urethral administration. Also particularly contemplated are methods of making the compositions, including the disclosed 2,4-pyrimidinediamine compounds, in a form suitable for rectal or urethral administration, including suppositories.

[0162] For topical use, creams, ointments, jellies, gels, solutions, suspensions, etc., containing 2,4-pyrimidinediamine compounds can be used. In some embodiments, the 2,4-pyrimidinediamine compounds can be formulated for topical administration with polyethylene glycol (PEG). These formulations may optionally contain additional pharmaceutically acceptable ingredients, such as diluents, stabilizing agents, and / or adjuvants. In particular embodiments, topical formulations are formulated for the treatment of allergic diseases and / or skin conditions, including psoriasis, contact dermatitis, and atopic dermatitis, among others described herein.

[0163] The 2,4-pyrimidinediamine compounds disclosed herein can be used to prepare a composition or a medicament, including medications suitable for topical administration. Accordingly, methods of making compositions comprising 2,4-pyrimidinediamine compounds in a form suitable for topical administration are specifically contemplated herein.

[0164] The disclosed 2,4-pyrimidinediamine compounds can also be delivered using any of a variety of inhalation devices and methods known in the art, including, for example, US Patent No. 6,241,969; U.S. Patent No. 6,060,069; U.S. Patent No. 6,238,647; U.S. Patent No. 6,335,316; U.S. Patent No. 5,364,838; U.S. Patent No. 5,672,581; WO96 / 32149; WO95 / 24183; U.S. Patent No. 5,654,007; U.S. Patent No. 5,404,871; U.S. Patent No. 5,672,581; U.S. Patent No. 5,743,250; U.S. Patent No. 5,419,315; U.S. Patent No. 5,558,085; WO98 / 33480; U.S. Patent No. 5,364,833; U.S. Patent No. 5,320,094; U.S. Patent No. 5,780,014; U.S. Patent No. 5,658,878; 5,518,998; 5,506,203; U.S. Patent No. 5,661,130; U.S. Patent No.

- 103 5,655,523; U.S. Patent No. 5,645,051; U.S. Patent No. 5,622,166; U.S. Patent No. 5,577,497; U.S. Patent No. 5,492,112; U.S. Patent No. 5,327,883; U.S. Patent No. 5,277,195; U.S. Patent Application. 20010041190; U.S. Patent Application. 20020006901; and US patent application. 20020034477.

[0165] Among those devices that can be used to administer specific examples of 2,4-pyrimidinediamine compounds are those well known in the art, such as metered dose inhalers, liquid nebulizers, dry powder inhalers, nebulizers, thermal evaporators and the like. Other suitable technology for the administration of specific 2,4-pyrimidinediamine compounds includes the production of aerosols by electrohydrodynamic atomization.

[0166] Furthermore, the inhalation device is preferably practical in the sense that it is easy to use, small enough to be worn comfortably, capable of delivering multiple doses and durable. Some specific examples of commercially available inhalation devices are Turbohaler (Astra, Wilmington, DE), Rotahaler (Glaxo, Research Triangle Park, NC), Diskus (Glaxo, Research Triangle Park, NC), Ultravent nebulizer (Mallinckrodt), Acorn II nebulizer (Marquest Medical Products, Totowa, NJ), a Ventolin metered dose inhaler (Glaxo, Research Triangle Park, NC), and the like. In one embodiment, the 2,4-pyrimidinediamine compounds can be delivered via a dry powder inhaler or sprayer.

[0167] Those skilled in the art will recognize that the formulation of the 2,4-pyrimidinediamine compounds, the amount of formulation provided, and the duration of administration of a single dose depend on the type of device used for inhalation as well as other factors. For some aerosol delivery systems, such as nebulizers, the frequency of administration and the length of time the system is activated will depend mainly on the concentration of 2,4-pyrimidinediamine compounds in the aerosol. For example, shorter administration periods may be used at higher concentrations of 2,4-pyrimidinediamine compounds in the nebulization solution. Devices such as metered dose inhalers can produce higher aerosol concentrations and can be operated for shorter periods of time, providing the desired amount of a 2,4-pyrimidinediamine compound, in some embodiments. Devices such as dry powder inhalers provide the active agent until a given charge of agent is ejected from the device. In this type of inhaler, the amount of 2,4-pyrimidinediamine compounds in a given amount of powder determines the dose delivered in a single administration. The 2,4-pyrimidinediamine formulation is selected to obtain the desired particle size in the selected inhalation device.

[0168] Formulations of 2,4-pyrimidinediamine compounds for administration from a dry powder inhaler may typically contain a finely divided dry powder containing 2,4-pyrimidinediamine compounds, but the powder may also contain a bulking agent, buffer, carrier, excipient, other additive, or the like . Additives may be included in the dry powder formulation of 2,4-pyrimidinediamine compounds, for example, to dilute the powder required for delivery from a particular powder inhaler, to facilitate formulation processing, to provide beneficial properties of the formulation powder

To facilitate the dispersion of the powder from the inhalation device, to stabilize the formulation (e.g., antioxidants or buffers), to provide a taste of the formulation, or the like. Typical additives include mono-, di- and polysaccharides, sugar alcohols and other polyols, such as, for example, lactose, glucose, raffinose, melesitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch or combinations thereof; surfactants such as sorbitols, diphosphatidylcholine or lecithin; and similar.

[0169] Examples of 2,4-pyrimidinediamine compounds disclosed herein may also be suitable for administration by inhalation. For example, the 2,4-pyrimidinediamine compounds disclosed herein can be used to prepare a composition or a medicament, including medicaments, for inhalation. Accordingly, the disclosure includes methods for making compositions, including the 2,4-pyrimidinediamine compounds disclosed herein, in a form suitable for administration, including administration by inhalation. For example, a dry powder formulation may be prepared using a variety of solutions, using conventional techniques such as those described in any of the abovementioned publications and expressly incorporated herein by reference, and, for example, Baker, et al., US Patent No. 5, 700.904. Particles in the range suitable for maximum deposition in the lower respiratory tract can be made by micronizing, milling or the like. A liquid formulation can be prepared by dissolving one or more of the 2,4-pyrimidinediamine compounds disclosed herein in a suitable solvent, such as water, at a suitable pH, including buffers or other excipients.

[0170] For ocular administration, a compound of the invention may be formulated as a solution, emulsion, suspension, etc., suitable for ocular administration. Ocular administration generally relies on the topical effect of the formulation on the eye, but also includes injection into the eye, if necessary. A number of vehicles suitable for ocular administration are known in the art. Specific, non-limiting examples are described in U.S. Patent No. 6,261,547; U.S. Patent No. 6,197,934; U.S. Patent No. 6,056,950; U.S. Patent No. 5,800,807; U.S. Patent No. 5,776,445; U.S. Patent No. 5,698,219; U.S. Patent No. 5,521,222; U.S. Patent No. 5,403,841; U.S. Patent No. 5,077,033; U.S. Patent No. 4,882,150; and U.S. Patent No. 4,738,851.

[0171] Typically, formulations for ocular administration contain a pharmaceutically effective amount of the 2,4-pyrimidinediamine compound disclosed herein, such as from about 0.0001% to about 1.0% by weight (w / w). In some formulations, the effective amount of the compound is 0.0003% to about 0.1% (w / w), such as from about 0.003% to about 0.5% (w / w), or from about 0, 01% to about 0.03% (w / w).

[0172] In some examples, the ophthalmic composition comprising the 2,4-pyrimidinediamine compound disclosed herein for ocular administration includes a tonicity adjusting agent, buffer, or both. In some examples of ophthalmic compositions, the tonicity adjusting agent is a simple carbohydrate or sugar alcohol. How is it

Known to those skilled in the art, tonicity adjusting agents may be used in the compositions of the invention to adjust the tonicity of the composition, preferably those of normal tears. Examples of suitable tonicity adjusting agents include, without limitation, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, carbohydrates such as glucose, fructose, galactose, polyols such as sugar alcohols, including, by way of example, mannitol, sorbitol, xylitol , lactitol, isomalt, maltitol and their combinations. Buffer-containing compositions contain, in some examples, phosphate, citrate, or both.

[0173] In one aspect, compositions intended for ocular administration of the 2,4-pyrimidinediamine compounds disclosed herein, optionally include a surfactant, stabilizing polymer, or both. Surfactants are used in some compositions to help provide higher concentrations of the 2,4-pyrimidinediamine compound administered. Such surfactants can act to dissolve the compound. Exemplary surfactants include polysorbate, poloxamer, polyoxyl 40 stearate, polyoxylated castor oil, tyloxapol, triton and sorbitan monolaurate. In some embodiments, the surfactant is selected from Triton X114, tyloxapol and combinations thereof. In yet another embodiment, the compositions for ocular administration, the stabilizing polymer is 974p carbomer.

[0174] For sustained release, the compounds of the invention may be formulated as a depot (storage formulation) for administration by implantation or intramuscular injection. The active ingredient may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins or as sparingly soluble derivatives (e.g. as sparingly soluble salt). Alternatively, transdermal delivery systems produced in the form of an adhesive disk or patch that slowly releases the active compound (s) for absorption through the skin may be used. To this end, penetration enhancers may be used to facilitate the penetration of the active compound through the skin. Suitable transdermal patches are described, for example, in US Pat. No. 5,407,713; U.S. Patent No. 5,352,456; U.S. Patent No. 5,332,213; U.S. Patent No. 5,336,168; U.S. Patent No. 5,290,561; U.S. Patent No. 5,254,346; U.S. Patent No. 5,164,189; U.S. Patent No. 5,163,899; U.S. Patent No. 5,088,977; U.S. Patent No. 5,087,240; U.S. Patent No. 5,008,110; and U.S. Patent No. 4,921,475.

[0175] Alternatively, other pharmaceutical delivery systems can be used. Well known examples of delivery vehicles that can be used to deliver the active compound (s) or prodrug (s) are liposomes and emulsions. Some organic solvents such as dimethyl sulfoxide (DMSO) can be used, although usually at the cost of greater toxicity.

[0176] The pharmaceutical compositions may, if desired, be in a package or

- a dosing device which may contain one or more unit dosage forms containing the active compound (s). The packaging may, for example, comprise metal or plastic foil, such as blister packaging. The packaging or dispensing device may be accompanied by administration instructions.

[0177] Another embodiment is a kit comprising a compound, prodrug or pharmaceutical composition as described in any of the above embodiments. Embodiments of the kit are described in more detail below.

Methods [0178] The invention provides 2,4-pyrimidinediamine compounds, and pharmaceutical compositions thereof, as described herein, for use in treating the [disease] conditions described herein. The invention also discloses the use of compounds of the invention in the manufacture of a medicament for the treatment of [disease] conditions in which an effect directed on the JAK pathway or inhibition of JAK kinases, in particular JAK3, is therapeutically useful. These include conditions in which lymphocytes, macrophages or mast cells are involved. Conditions in which action directed to the JAK pathway or inhibition of JAK kinases, in particular JAK3, are therapeutically useful, include leukemia, lymphoma, transplant rejection (e.g. islet transplant rejection), bone marrow transplant application (e.g. transplant disease anti-host), autoimmune diseases (e.g. rheumatoid arthritis, etc.), inflammation (e.g., asthma, etc.) and other conditions, as described in more detail below.

[0179] In another embodiment, the compounds of the invention may be for use in methods practiced as a therapeutic approach for the treatment of the disease conditions described herein. Thus, in a specific embodiment, the 2,4-pyrimidinediamine compounds (and the various forms described herein, including pharmaceutical formulations containing the compounds (in various forms)) can be used to treat the conditions described herein in animal patients, including people. The methods generally include administering to the subject an amount of a compound described herein, or a salt, prodrug, hydrate or N-oxide thereof, effective in treating the condition. In one embodiment, the subject is a non-human mammal, including, but not limited to, cattle, horses, cats, dogs, rodents or primates. In another embodiment, the subject is human.

[0180] As noted above, numerous conditions can be treated using the 2,4-substituted pyrimidinediamine compounds described herein. The patient's "treat" or "treatment" of a disease as used herein refers to (1) preventing the occurrence of a disease in a patient who is predisposed or not yet showing symptoms of the disease; (2) inhibiting the disease or arresting its development; or (3) relieving or causing regression of the disease. As is well known in the art, "treatment" is an approach to obtain beneficial or desired results, including clinical results. For the purposes of the invention, the beneficial or desired results may include one or more, but not limited to,

- 107 reducing or alleviating one or more symptoms, reducing the degree of the disease, including disease, a stabilized (i.e. not worsening) disease, including disease, preventing the spread of the disease, delaying or slowing down the disease, including disease, progression, improvement or amelioration of the condition, including disease, condition, and remission (whether partial or total), whether detectable or undetectable. Compounds that are relatively strong compared to the entire class as such and can be administered in low doses, preferably topically, although this is not necessary, thus minimizing adverse systemic effects, are preferred.

[0181] The compounds described herein are potent and selective inhibitors of JAK kinases and are particularly selective for JAK3-containing cytokine signaling pathways. As a result of this action, the compounds can be used in a variety of in vitro, in vivo and ex vivo contexts to regulate or inhibit JAK kinase activity, signaling cascades in which JAK kinases play a role, and biological responses made by such signaling cascades. For example, in one embodiment, the compounds can be used to inhibit JAK kinases, either in vitro or in vivo, in almost any cell type expressing JAK kinase, such as in hematopoietic cells in which, for example, mainly expressed is JAK3. They can also be used to regulate signal transduction cascades in which JAK kinases, in particular JAK3, play a role. Such JAK-dependent signal transduction cascades include, but are not limited to, signaling cascades of cytokine receptors that bind to a common gamma chain, such as, for example, IL-4, IL-7, IL-5, IL-9, IL-15 and IL-21 or IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, receptor signaling cascades. The compounds can also be used in in vitro or in vivo tests to regulate, and in particular inhibit, cellular or biological responses affected by JAK-dependent signal transduction cascades. Such cellular or biological responses include, but are not limited to, IL-4 / ramos CD23 enhancement and IL-2 mediated T cell proliferation. More importantly, the compounds can be used to inhibit JAK kinases in vivo, as a therapeutic approach for treating or preventing diseases mediated, in whole or in part, by JAK kinase activity (herein referred to as "JAK kinase mediated diseases"). Non-limiting examples of JAK kinase mediated diseases that can be treated or prevented by the disclosed compounds include, but are not limited to, the following: allergies; asthma; autoimmune diseases; including systemic autoimmune disorders, transplant rejection (e.g., kidneys, heart, lungs, liver, pancreas, skin; host versus graft reaction (HVGR) and graft versus host reaction (GVHR)), rheumatoid arthritis and amyotrophic lateral sclerosis; autoimmune diseases mediated by T cells such as multiple sclerosis, psoriasis and Sjogren's syndrome; and Type II inflammatory diseases such as vasculitis (including vasculitis, arteritis, atherosclerosis, coronary artery disease); central nervous system diseases such as stroke; respiratory diseases such as bronchiolitis obliterans and primary pulmonary hypertension; permanent, delayed type IV hypersensitivity reactions; and malignant haematopoietic malignancies such as leukemia

- 108 and lymphomas.

[0182] One embodiment is a compound for use in a method as described below, wherein the compound is a compound of formula I, or in a more specific embodiment, a compound of formula IA, IA1, IA2, IA3, IB, IB1, IB2, IB3 and / or II, or in an even more particular embodiment, the type described in the description. Briefly, the methods described below relate to a compound of formula I, but are also intended to include the corresponding methods of the various sub-types and types of compounds and compositions.

[0183] One embodiment is a compound for use in a method of inhibiting JAK kinase activity, comprising contacting a JAK kinase with an amount of a compound effective to inhibit JAK kinase activity, wherein the compound is a compound of formula I:

<img file="PL2389372T3_D0038.tif" />

X and Y are each independently O, S, S (O), SO2 or NR¹;

each R¹ is independently, at each occurrence, H, optionally substituted C1-6alkyl, C (O) -C1-6alkyl, CO2-C1-6alkyl or R⁵⁰;

each R⁵⁰ is -C (R⁹) 2-OR¹⁰ or -C- (R⁹) 2S-R¹⁰; each R⁹ is independently, at each occurrence, H, optionally substituted C1-6alkyl, optionally substituted C6-10aryl, or optionally substituted C7-16arylalkyl; or alternatively, two Rs⁹, together with the carbon to which they are attached, form an optionally substituted C3-8cycloalkyl or optionally substituted 3-8 membered heteroalicyclic; R¹⁰ means R^and or -P (O) (OR¹¹)₂; each R¹¹ means independently, in each occurrence, R^and or a monovalent cationic group; or two R¹¹, together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group, or two Rs¹¹ together they represent a divalent cationic group; ring A is C6-10aryl or 5-10 membered heteroaryl;

each R² means independently, in each case, H, R^e, R^b, R^esubstituted with one or more of the same or different R^and and / or R^b, -OR^esubstituted with one or more of the same or different R^and and / or R^b, -SR^esubstituted with one or more of the same or different R^and and / or R^b, -C (O) R^esubstituted with one or more of the same or different R^and and / or R^b, -N (R^and) R^ewhere R^e is substituted with one or more of the same or different R^and and / or

- 109^b, -S (O) 2R^e substituted with one or more of the same or different R^and and / or R^b, --B (OR^and) 2, -B (N (R^c) 2) 2, - (C (R^and) 2) m^b, -O- (C (R^and) 2) m^b, -S- (C (R^and) 2) m^b,

-N (R^and) - (C (R^and) 2) m^b, -O- (CH2) m-CH ((CH2) m^b) R^b, -C (O) N (R^and) -O- (C (R^b) 2) m^and,

2m (C (R^and) 2) m^b,

-O- (CR^and) 2) mC (O) N (R^and) - (R^and) 2) m^b,

-N ((C (R^and) 2) m^b)2,

-S- (C (R^and)2)

2m

C (O) N (R^and) - (C (R^and) 2) m^b, -N (R^and) -C (O) -N (R^and) - (C (R^and) 2) m^b, -N (R^and) -C (O) - (C (R^and) 2) mC (R^and) (R^b) 2 or -N (R^and) - (C (R^and) 2) mC (O) -N (R^and) - (C (R^and) 2) m^b;

each R^and means independently, in each occurrence, H, deuterium, C16alkyl, C3-8cycloalkyl, C4-11cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclicalkyl, 4-11 membered heteroalicyclicalkyl, 5-11 15 membered heteroaryl or 6-16 membered heteroarylalkyl;

each R^b means independently, in each case, = O, -OR^and, -O (C (R^and) 2) m, -OR^and, haloC1-3alkyloxy, = S, -SR^and, = NR^and, = NOR^and, -N (R^c) 2, halo, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, = N2, -N3, -S (O) R^and, -S (O) 2R^and, -SO3R^and, -S (O) N (R^c) 2, OS (O) R^and, -OS (O) 2R^and, -OSO3R^and, -OS (O) 2N (R^c) 2, -C (O) R^and, -CO2R^and, -C (O) N (R^c) 2, C (NR^and) -N (R^c) 2, -C (NOH) -R^and, -C (NOH) -N (R^c) 2, -OC (O) R^and, -OC (O) OR^and, OC (O) N (R^c) 2, -OC (NH) -N (R^c) 2, -OC (NO^and) -N (R^c) 2, - [N (R^and) C (O)] "R^and, [N (R^and) C (O)] "OR^and, - [N (R^and) C (O)] 'N (R^c) 2 or - [N (R^and) C (NR^and)] '- N (R^c)2;

each R^c means independently, in each occurrence, R^andor, alternatively, two Rs^c are considered together with the nitrogen atom to which they are attached to form a 3 to 10-membered heteroalicyclic or 5-10 membered heteroaryl which may optionally contain one or more of the same or different additional heteroatoms and which is optionally substituted with one or more than the same or different group R^and and / or R^d;

each R^d means = O, -OR^and, haloC1-3alkyloxy, C1-6alkyl, = S, -SR^and, = NR^and, = NOR^and, N (R^and) 2, halo, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, = N2, -N3, -S (O) R^and, -S (O2) R^and, -SO3R^and, -S (O) N (R^and) 2, -S (O) 2N (R^and) 2, -OS (O) R^and, -OS (O) 2R^and, -OSO3R^and, -OS (O) 2N (R^and) 2, -C (O) R^and, -CO2R^and, -C (O) N (R^and) 2, -C (NR^and) N (R^and) 2, -C (NOH) R^and, -C (NOH) N (R^and) 2, OCO2R^and, -OC (O) N (R^and) 2, -OC (NO^and) N (R^and) 2, - [N (R^and) C (O)] "R^and, - (C (R^and) 2) "- OR^and, -N (R^and) S (O) 2 R^and, -C (O) -C1-6haloalkyl, -S (O) 2C1-6haloalkyl, -OC (O) R^and, -O (C (R^and) 2) m-OR^and, S (C (R^and) 2) m-OR^and, -N (R^and) C1-6haloalkyl, - P (O) (OR^and) 2, -N (R^and) - (C (R^and) 2) m-OR^and, [N (R^and) C (O)] "OR^and, - [N (R^and) C (O)] 'N (R^and) 2, - [N (R^and) C (NR^and)] 'N (R^and) 2 or -N (R^and) C (O) C16haloalkil; or two R^d, considered together with the atom or atoms to which they are attached, combine to form a 3-10 membered, partially or fully saturated, mono or bicyclic ring, optionally containing one or more heteroatoms, and optionally substituted with one or more R^and;

each R^e means independently, in each occurrence, C1-6alkyl, C38cycloalkyl, C4-11 cycloalkylalkyl, C6-10aryl, C7-16arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclicalkyl, 4-11 membered heteroalicyclicalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;

p is 0, 1, 2, 3 or 4;

- 110 each m is 1, 2 or 3; each n is 0, 1, 2 or 3;

or two groups of R², considered together with the atom or atoms to which they are attached, combine to form a 4-10 membered, partially or fully saturated, mono or bicyclic ring, optionally containing one or more heteroatoms, and optionally substituted with one or more R^and and / or R^b;

FROM¹ and Z² are each independently CH, CR² or N;

R³ is H, optionally substituted C1-6alkyl or R⁵⁰;

_R4 is H, optionally substituted C1-6alkyl or R⁵⁰; and

R⁵ is halo, -CN, optionally substituted C1-6alkyl, alkynyl, hydroxy, optionally substituted C1-6alkoxy, nitro, -N (R^and) 2, -C (O) N (R^and) 2, -CO2R^and or C (O) R^and.

[0184] In another embodiment, the invention provides a compound for use in a method of inhibiting JAK kinase activity, comprising contacting an JAK kinase with an amount of compound effective to inhibit JAK kinase activity, wherein the compound has formula I as described herein. In some embodiments of the methods described herein, the method is carried out in vivo.

[0185] Also disclosed herein is a method of inhibiting JAK kinase activity, comprising contacting in vitro JAK3 kinase with an amount of a compound effective to inhibit JAK kinase activity, wherein the compound is a compound of formula I as described herein.

[0186] In a specific embodiment, the compounds may be used to treat and / or prevent organ and / or tissue rejection in transplant recipients (ie, to treat and / or prevent allograft rejection). Allogeneic transplants may be rejected by cell mediated or humoral immune responses of the recipient to transplant antigens (histocompatibility) present on donor cell cell membranes. The strongest antigens are regulated by a complex of genetic loci called group A (HLA) human leukocyte antigens. Together with ABO blood group antigens, they are the main human transplant antigens.

[0187] Rejections after transplantation can generally be divided into three categories: acute, appearing hours to several days after transplantation; acute, appearing days to several months after transplantation; and chronic, appearing months to years after transplantation.

[0188] Hyperacute rejection is mainly caused by the production of host antibodies that attack the graft tissues. In the reaction of hyperacute rejection, antibodies are observed in vascular transplant very quickly after transplantation. Soon after, blood clotting occurs, which leads to ischemia, ultimately necrosis and death. Transplant infarction does not respond to known immunosuppressive treatments. Because HLA antigens can be identified in vitro, pre-transplant screening is used for

- 111 significantly reducing hyperacute rejection. As a consequence of such screening, acute rejection is now relatively rare.

[0189] Acute rejection is thought to be mediated by the accumulation of antigen-specific cells in transplant tissue. T cell-mediated immune response to these antigens (i.e., HVGR or GVHR) is an essential mechanism for acute rejection. The accumulation of these cells causes damage to the graft tissue. Both CD4 + helper T cells and cytotoxic CD8 + T cells are thought to be involved in the process and that the antigen is presented by donor and host dendritic cells. CD4 + T helper cells help recruit other effector cells such as macrophages and eosinophils for transplantation. Cascades of signal transduction of T cell activation signal (for example, cascades CD28, CD40L and CD2) are used.

[0190] Acute cell-mediated rejection can be reversed in many cases by intensification of immunotherapy. After successful inversion, severely damaged parts of the graft heal by fibrosis and the remainder of the graft looks normal. After resolution of acute rejection, the doses of immunosuppressants may be reduced to very low levels.

[0191] Chronic rejection, which is a particular problem in kidney transplants, often progresses cumulatively, despite increased immunosuppressive therapy. It is thought to be caused in large part by Type IV cell mediated hypersensitivity. The pathological profile differs from that of acute rejection. Arterial endothelium is associated mainly with excessive proliferation, which can gradually close the lumen of the vessel, leading to ischemia, fibrosis, thickened intima and atherosclerotic lesions. Chronic rejection is mainly caused by the progressive destruction of the graft vasculature and resembles the process of slow vasculitis.

[0192] In Type IV hypersensitivity, CD8 cytotoxic T cells and CD4 helper T cells recognize intracellular or extracellularly synthesized antigen when complexed with MHC or class I or class II molecules, respectively. Macrophages act as antigen presenting cells and release IL-1, which promotes helper T cell proliferation. T-helper cells release interferon gamma and IL-2, which together regulate delayed hypersensitivity reactions mediated by macrophage activation and T-cell mediated immunity. In the event of organ transplantation, cytotoxic T cells destroy the transplant cell in contact.

[0193] Because JAK kinases play a critical role in T cell activation, the 2,4-pyrimidinediamine compounds described herein can be used to treat and / or prevent many aspects of transplant rejection and are particularly useful in the treatment and / or prevention rejection reactions that are mediated, at least in part, by T cells, such as HVGR or GVHR. The 2,4-pyrimidinediamine compounds can also be used to treat and / or prevent chronic rejection in transplant recipients and, in particular in renal transplant recipients. The compound can also be administered to tissues or an organ prior to transplantation of the recipient's tissue or organ

- 112 transplants.

[0194] In another embodiment, the invention provides a compound for use in a method of treating an autoimmune disease mediated by T cells, comprising administering to a patient suffering from such an autoimmune disease an amount of a compound effective to treat this autoimmune disease, wherein the compound is a compound of formula I as described here. In some embodiments of the methods, the autoimmune disease is multiple sclerosis (MS), psoriasis or Sjogren's syndrome.

[0195] The 2,4-pyrimidinediamine compounds described herein can be used in therapy alone, or they can be used in combination with or in addition to other conventional immunosuppressive therapies, such as, for example, the following: mercaptopurine; corticosteroids such as prednisone; methylprednisolone and prednisolone; alkylating agents such as cyclophosphamide; calcineurin inhibitors such as cyclosporin, sirolimus and tacrolimus; inosine monophosphate dehydrogenase (IMPDH) inhibitors such as mycophenolate, mycophenolate mofetil and azathioprine; and agents designed to suppress cellular immunity leaving the recipient's humoral immune response intact, including various antibodies (e.g., anti-lymphocyte globulin (ALG), anti-thymocyte globulin (ATG), anti-T cell monoclonal antibodies (OKT3)) and irradiation. These different agents can be used according to their standard or typical dosages, as specified in the required prescription information accompanying commercially available drug forms (see also required prescription information in The Physician's Desk Reference of 2006). Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the AZASAN brand; mercaptopurine is currently available from Salix Pharmaceuticals, Inc. under the PURINETHOL brand; prednisone and prednisolone are currently available from Roxane Laboratories, Inc .; methyl prednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the brand name RAPAMUNE; tacrolimus is currently available from Fujisawa under the PROGRAF brand; ciclosporin is currently available from Novartis under the SANDIMMUNE brand and from Abbott under the GENGRAF brand; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the brand name CELLCEPT and from Novartis under the brand MYFORTIC; azathioprine is currently available from Glaxo Smith Kline under the IMURAN brand; and antibodies are currently available from Ortho Biotech under the ORTHOCLONE brand, from Novartis under the name SIMULECT (basiliximab) and from Roche under the brand ZENAPAX (daclizumab).

[0196] In another embodiment of the invention, the 2,4-pyrimidinediamine compounds may be used in combination or in addition with a Syk kinase inhibitor. Syk kinase is a tyrosine kinase known to play a key role in Fcy receptor signaling as well as in other signaling cascades, such as those regarding B cell receptor signaling (Turner et al. (2000), Immunology Today 21: 148-154) and integrins beta (1), beta (2), and beta (3) in neutrophils (Mocsavi et al. (2002), Immunity 16: 547-558). For example, Syk kinase plays a decisive role in high affinity IgE receptor signaling in mast cells, which leads to the activation and subsequent release of many chemical mediators that cause allergic attacks. However, in

Unlike JAK kinases, which are involved in the regulation of pathways associated with delayed or mediated cell type IV hypersensitivity reactions, Syk kinase allows the regulation of pathways involved in direct, IgE-mediated type I hypersensitivity reactions. Some compounds that affect the Syk pathway may affect or may not affect the JAK pathways.

[0197] Suitable Syk inhibitory compounds are described, for example, in serial number 10 / 355,543 filed January 31, 2003 (Publication No. 2004/0029902); WO 03/063794, Serial No. 10 / 631,029 filed July 29, 2003 (Publication No. 2007/0060603); WO 2004/014382; serial number 10/903 263 filed on July 30, 2004 (publication no. 2005/0234049); PCT / US2004 / 24716 filed July 30, 2004 (WO005 / 016893); serial number 10 / 903,870 filed on July 30, 2004 (publication no. 2005/0209224); PCT / US2004 / 24920 filed July 30, 2004; serial number 60 / 630,808 filed on November 24, 2004; serial number 60 / 645,424 filed on January 19, 2005; and serial number 60 / 654,620, filed February 18, 2005. The 2,4-pyrimidinediamine and Syk inhibitory compounds described herein can be used alone or in combination with one or more conventional methods of treating rejection as described above.

[0198] In a specific embodiment, the 2,4-pyrimidinediamine compounds can be used to treat or prevent these diseases in patients who do not initially respond (are resistant) or who become unresponsive to treatment with a Syk inhibiting compound or one of the other current treatments for the disease. The 2,4-pyrimidinediamine compounds may also be used in combination with the Syk inhibiting compound in refractory or non-responsive patients. Suitable Syk inhibiting compounds with which 2,4-pyrimidinediamine compounds can be administered are provided above.

[0199] In another embodiment, the invention provides a compound for use in a method of treating an T-cell mediated autoimmune disease, comprising administering to a patient suffering from such an autoimmune disease an amount of a compound, wherein the compound is a compound of Formula I, in combination with or in addition to a compound which inhibits Syk kinase with IC₅₀ of at least 10 μΜ, effective in the treatment of autoimmune disease.

[0200] In another embodiment, the invention provides a compound for use in a method of treating allogeneic, acute or chronic transplant rejection in a transplant recipient, comprising administering to the recipient an amount of compound, wherein the compound is a compound of Formula I effective in treating or preventing rejection . In another embodiment, the compound is intended for use by administration to a tissue or organ, prior to or simultaneously with tissue or organ transplantation in a transplant recipient. In another embodiment, the compound is for administration to a tissue or organ and a patient. In a specific embodiment, the allograft rejection is mediated by HVGR or GVHR. In another embodiment, the allograft organ is a kidney, heart, liver or lung. In another embodiment, in which the allograft organ is a kidney,

- 114 heart, liver or lung, the compound is intended for use by administration in combination with or as an adjunct to another immunosuppressive drug. In a more specific embodiment, the immunosuppressant is ciclosporin, tacrolimus, sirolimus, IMPDH inhibitor, mycophenolate, mycophenolate mofetil, anti-T-cell antibody or OKT3.

[0201] The 2,4-pyrimidinediamine compounds described herein are cytokine moderators of IL-4 signaling. Consequently, 2,4-pyrimidinediamine compounds can slow down the type I hypersensitivity reaction. Thus, in a particular embodiment, 2,4-pyrimidinediamine compounds can be used to treat such reactions, and hence related diseases mediated by them or caused by such hypersensitivity reactions (e.g. allergies) prophylactically. For example, an allergy sufferer may take one or more JAK selective compounds described herein before expected allergen exposure to delay the onset or development or eliminate the allergic response completely.

[0202] When used for the treatment or prevention of such diseases, the 2,4-pyrimidinediamine compounds can be used by administration alone, as a mixture of one or more 2,4-pyrimidinediamine compounds, or in a mixture or combination with other agents useful for treating such diseases and / or symptoms associated with such diseases. The 2,4-pyrimidinediamine compounds can also be used by administration as a mixture or in combination with agents useful for treating other disorders or ailments, such as steroids, membrane stabilizers, 5lipoxygenase (5LO) inhibitors, leukotriene and receptor synthesis inhibitors, and IgE isotype switching inhibitors or IgE synthesis, IgG isotype switching or IgG synthesis, β-agonists, tryptase inhibitors, aspirin, cyclooxygenase (COX) inhibitors, methotrexate, anti-TNF drugs, rituximab, PD4 inhibitors, P38 inhibitors, PDE4 inhibitors and antihistamines, to name a few. The 2,4-pyrimidinediamine compounds can be used by administration per se in the form of prodrugs or as pharmaceutical compositions containing the active compound.

[0203] In another embodiment, the invention provides a compound for use in a method of treating a type IV hypersensitivity reaction, comprising administering to the subject an amount of a compound effective to treat or prevent a hypersensitivity reaction, wherein the compound is a compound of formula I described herein. In one embodiment, the way is practiced prophylactically. In some embodiments, the compound is used by administration prior to allergen exposure.

[0204] In another embodiment, the invention provides a compound for use in a method of inhibiting a signal transduction cascade in which JAK3 kinase plays a role, including contacting a cell expressing a receptor associated with such a signal cascade with a compound, wherein the compound is a compound of formula I described herein .

[0205] In another embodiment, the invention provides a compound for use in a method of treating JAK kinase mediated disease, comprising administering to the patient an amount of compound effective to

[0206] treating or preventing a JAK kinase mediated disease, wherein the compound is a compound of formula I described herein.

[0207] In another embodiment, the invention provides a compound for use in a method of treating a JAK kinase mediated disease, wherein the JAK mediated disease is HVGR or GVHR, comprising administering to the subject an amount of a compound effective to treat or prevent the JAK kinase mediated disease, wherein the compound is the compound of formula I described herein

[0208] In another embodiment, the compound of formula I is for use in the treatment of eye disorders using an effective amount of the compound. In one aspect of the disclosed method of treating ophthalmic disorders, administration of one or more of the disclosed 2,4-pyrimidinediamine compounds is effective in increasing the volume of secreted tears compared to the volume of secreted tears without treatment, thereby alleviating the symptoms of dry eye syndrome. In one aspect, the volume of tears secreted is increased in five days, such as in less than four days, and in some examples less than two days. In one embodiment, the volume of secreted tears is increased by at least about 25% relative to the initial secretion of tears over two days of initial treatment with the disclosed 2,4-pyrimidinediamine compound. In other embodiments, tear secretion is increased by at least about 30%, such as at least 50% relative to the initial tear secretion in less than two days. An increase in tear secretion, after administration of the compound, leads, in some cases, to a volume of tear secretion comparable to normal tear secretion. Typically, the disclosed compounds, when used to treat eye disorders topically, are administered at least once a day and typically at most twice a day.

[0209] As mentioned, another embodiment provides a compound for use in a method of treating an ocular disease and / or disorder that comprises administering to a patient an amount of a compound effective to treat an ocular disease and / or disorder wherein the compound is a compound of formula I described herein Eye diseases and disorders include, but are not limited to, dry eye syndrome, uveitis, allergic conjunctivitis, glaucoma and rosacea (ophthalmic). Dry eye syndrome (DES), otherwise known as dry keratitis (keratoconjunctivitis sicca) (KCS), keratitis sicca, dryness syndrome or xerophthalmia, is an eye disease caused by reduced tear secretion or increased tear film evaporation commonly found in humans and some animals. Uveitis or ciliary body inflammation refers to the middle layer of the eye ('uveitis'), and can commonly be used to refer to any inflammatory process related to the inside of the eye. Allergic conjunctivitis is inflammation of the conjunctiva (the membrane covering the white part of the eye) due to allergies. Glaucoma refers to a group of diseases that affect the optic nerve and are associated with the loss of retinal ganglion cells in a characteristic pattern, i.e. a type of optic neuropathy. Increased intraocular pressure is a significant risk factor for glaucoma (over 22 mmHg or 2.9 kPa), and inflammatory processes, e.g. uveitis, can cause this increase in intraocular pressure. Rosacea is a chronic disease

- inflammatory, characterized by facial erythema, but may affect the eyes. As already mentioned, the compounds described herein can be used to treat inflammatory responses. Without wishing to be bound by theory, it is believed that the compounds described herein are effective in treating these eye disorders because of, at least in part, their JAK inhibitory activity.

[0210] The active compounds described herein typically inhibit the JAK / Stat pathway. The activity of a particular compound as an JAK kinase inhibitor can be assessed in vitro or in vivo. In some embodiments, the activity of a particular compound can be tested in a cellular assay. Suitable tests include assays that determine inhibition or phosphorylation activity or ATPase activity of JAK kinase. Thus, a compound is thought to inhibit JAK kinase activity if it inhibits JAK phosphorylation or ATPase activity of IC kinase₅₀ about 20 μΜ or less.

[0211] "Cell proliferative disorder" refers to a disorder characterized by abnormal cell proliferation. The proliferative disorder does not imply any restriction on the rate of cell growth, but merely indicates a loss of normal control that affects cell growth and division. Thus, in some embodiments, proliferative disorder cells may have the same cell division rates as normal cells, but do not respond to signals that limit such growth. The "cell proliferative disorder" includes cancer or tumor that is abnormal tissue growth. Cancer refers to any of a variety of malignant tumors characterized by cell proliferation that have the ability to invade surrounding tissues and / or metastasize to new areas of colonization.

[0212] "Hematopoietic neoplasm" refers to a cell proliferative disorder derived from cells of hematopoietic (hematopoietic) lines. In general, hematopoiesis is a physiological process in which undifferentiated cells or stem cells develop into different cells found in peripheral blood. In the early stages of development, hematopoietic stem cells, typically found in the bone marrow, undergo a number of cell divisions to form multipotent progenitor cells that are involved in two major developmental pathways: the lymphoid and myeloid lines. Involved myeloid progenitor cells differentiate into three major branches covering erythroid, megakaryocyte and granulocyte / monocyte development pathways. An additional pathway leads to the formation of dendritic cells that are involved in antigen presentation. The erythroid line leads to red blood cells, while the megakaryocytic line leads to platelets. The involved cells of the granulocyte / monocyte line are separated into granulocyte or monocyte development pathways, the first pathway leads to the formation of neutrophils, eosinophils, and basophils, and the second pathway leads to blood monocytes and macrophages.

[0213] The involved progenitor cells from the lymphoid line develop into the B cell pathway, T cell pathway, or non-T / B cell pathway. It turns out that, as in the myeloid line, the additional lymphoid pathway leads to the formation of dendritic cells involved in antigen presentation. The B progenitor cell develops into the B (pre-B) precursor cell, which differentiates into B cells responsible for

- 117 production of immunoglobulins. T cell progenitor cells differentiate into precursor T cells (pre-T), based on the effects of some cytokines, develop into cytotoxic or helper / suppressor T cells involved in cell mediated immunity. The non-T / B cell pathway leads to natural killer (NK) cells. Hematopoietic cell neoplasms may include cells of any phase of hematopoiesis, including hematopoietic stem cells, multipotent progenitor cells, oligopotential involved progenitor cells, precursor cells, and mature differentiated cells. Categories of hematopoietic tumors may generally adhere to the descriptions and diagnostic criteria used by those skilled in the art (see e.g. International Classification of Disease and Related Health Problems (ICD 10), World Health Organization (2003). Haematopoietic neoplasms can also be characterized by molecular features such as cell surface markers and gene expression profiles, cellular phenotype exhibited by abnormal cells, and / or chromosomal aberrations (e.g. deletions, translocations, insertions, etc.) characteristic of some hematopoietic malignancies such as the Philadelphia chromosome found in chronic myelogenous leukemia. Other classifications include National Institute Cancer Working Formulation (Cancer, 1982, 49: 2112-2135) and Revised European-American Lymphoma Classification (REAL).

[0214] "Lymphoid tumor" refers to a cell proliferative disorder, including cells of the lymphatic system of hematopoiesis. Lymphoid neoplasms can arise from hematopoietic stem cells as well as involved lymphoid progenitor cells, precursor cells and end-differentiated cells. These neoplasms can be divided based on the phenotypic features of the abnormal cells or the differentiated disease state from which the abnormal cells originate. The subdivisions include, but are not limited to, B cell cancers, T cell cancers, NK cell cancers, and Hodgkin's lymphoma.

[0215] "Myeloid cancer" refers to a proliferative disorder of myeloid hematopoiesis cells. Tumors can arise from hematopoietic stem cells, involved bone marrow progenitor cells, precursor cells, and end-differentiated cells. Bone marrow neoplasms can be divided based on the phenotypic features of the abnormal cells or the differentiated disease state from which the abnormal cells originate. The subdivisions include, but are not limited to, myeloproliferative diseases, myelodysplastic / myeloproliferative diseases, myelodysplastic syndromes, acute myelogenous leukemia and acute biphenotypic leukemia.

[0216] Generally, cell proliferative disorders that can be treated using the compounds disclosed herein refer to any disorder characterized by abnormal cell proliferation. These include various cancers and cancers, benign and malignant tumors, with or without metastasis. The specific properties of tumors, such as tissue invasiveness or metastasis, may be targeted by the methods described herein. Cell proliferative disorders include many cancers, including, among others

- 118 others, breast cancer, ovarian cancer, kidney cancer, gastrointestinal cancer, kidney cancer, bladder cancer, pancreatic cancer, squamous cell lung cancer, and adenocarcinoma. More specifically, in relation to specific tissues, organs and areas of the body, Heart: sarcoma (vascular sarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; Lungs: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chest wall chondromatosis, endothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet cell adenoma, glucagonoma, gastrinoma, carcinoid, carcinoma, VIP tumor) Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibrosis), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, smooth myoma); Genitourinary tract: kidney cancer (adenocarcinoma, Wilms tumor [immature], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transient cancer, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, germ cell carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatous tumors, lipoma); Livers: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bones: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous sarcoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, string, osteocharcoma, osteocharoma , osteomas and multicellular tumors; Nervous system: skulls (osteoma, hemangioma, granuloma, jaundice, Paget's disease of bone (osteitis deformans), meninges (meningioma, meningioma, glioblastoma), brain (astrocytoma, medulloblastoma, glioblastoma, ependymoma, multiforme glioblastoma, oligoma, neuroma, retinoblastoma, congenital tumors), neurofibroma of the spinal cord, meningioma, glioma, sarcoma); gynecological: uterine cancer (endometrial cancer), cervical cancer (cervical cancer, precancerous dysplasia of the cervix), ovaries (ovarian cancer [ovarian cystic adenocarcinoma, ovarian cystic adenocarcinoma, unclassified cancer], granuloma cells of the follicle , reproduction, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, angular sarcoma (rhabdomyosarcoma), fallopian tube carcinoma; Hematological: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin disease [malignant lymphoma]; Skins: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, skin fibroma,

- 119 keloids, psoriasis; and Adrenal areas: neuroblastoma. The term "cancer cell" as used herein includes cells affected by any of the above-mentioned [disease states].

[0217] In some embodiments, the cell proliferative disorder being treated is a hematopoietic cancer that is abnormal growth of hematopoietic cells. Malignant neoplasms of the hematopoietic system can have their genesis in pluripotent stem cells, multipotent progenitor cells, oligopotential involved progenitor cells, precursor cells and terminal differentiated cells involved in hematopoiesis. Some hematological malignancies are thought to be derived from hematopoietic stem cells that have the ability to self-renew. For example, cells capable of developing specific subtypes of acute myeloid leukemia (AML) after transplantation display surface markers of hematopoietic stem cell cells, implicating hematopoietic stem cells as a source of leukemia cells. Blast cells that do not have the characteristic markers of hematopoietic stem cell cells appear unable to form a tumor after transplantation (Blaire et al., 1997, Blood, 89: 3104-3112). The origin of stem cells of some hematopoietic malignancies also finds support in the observation that specific chromosomal aberrations associated with specific types of leukemia can be found in normal hematopoietic cell lines as well as leukemia blast cells. For example, t (9q34; 22q11) reciprocal translocation associated with approximately 95% of chronic myelogenous leukemia cases appears to be present in myeloid, erythroid and lymphoid lineage cells, suggesting that chromosomal aberration arises in hematopoietic stem cells. A subgroup of cells in some types of CML presents the phenotype of the cell marker of hematopoietic stem cells.

[0218] Hematopoietic neoplasms, although often derived from stem cells, involved progenitor cells or more terminally differentiated developmental cells may also be a source of some leukemias. For example, the forced expression of a Bcr / Ab1 fusion protein (associated with chronic lymphocytic leukemia) in typical progenitor marrow cells or granulocyte / macrophage progenitor cells causes a leukemia-like condition. In addition, some chromosomal aberrations associated with leukemia subtypes are not present in the population of cells with the hematopoietic stem cell marker phenotype, but are present in the population of cells presenting markers of the more diverse state of the [pathological] hematopoietic pathway (Turhan et al., 1995, Blood 85: 2154- 2161). Thus, while involved progenitor cells and other differentiated cells may have only limited cell division, leukemia cells may have acquired the ability to grow unregulated, in some cases mimicking the properties of hematopoietic stem cell renewal (Passegue et al., Proc. Natl. Acad. Sci. USA, 2003, 100: 11842-9).

[0219] In some embodiments, the hematopoietic neoplasm being treated is a lymphoid neoplasm in which abnormal cells originate from and / or display the characteristic phenotype of lymphoid line cells. Lymphoid neoplasms can be divided into B cell cancers, T cell cancers and NK cell cancers, and Hodgkin's lymphoma. B cell tumors can be further divided into precursor B cell tumors and mature / peripheral B cell tumors. Exemplary B-cell precursor tumors are lymphoblastic leukemia / lymphoma (from B-precursor acute lymphoblastic leukemia), while exemplary mature / peripheral B-cell tumors are chronic lymphocytic leukemia / small lymphocytic lymphoma, B cell lymphocytic lymphoma, lymphoma lymphoma B-spinal marginal lymphoma from B cells, hair cell leukemia, multiple myeloma / plasmacytoma, extra-node marginal lymphoma associated with the MALT mucosa, marginal nodal B cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, large B mediastinal lymphoma, primary pleural lymphoma and Burk's lymphoma. The compounds disclosed herein are particularly useful in the treatment of T cell and NK cell tumors that have been further divided into T cell precursor tumors and mature (peripheral) T cell tumors. An example of cancer from T cell precursors is lymphoblastic lymphoma from T cell precursors / leukemia (acute lymphoblastic leukemia from T cell precursors), while examples of mature (peripheral) T cell cancers are T cell proliferating leukemia, large granular T lymphocytic leukemia, aggressive NK cell leukemia, adult T cell leukemia / lymphoma (HTLV-1), nasal NK / T cell lymphoma, intestinal enteropathy T-cell lymphoma, hepatosplenic T cell lymphoma, T cell lymphoma in the subcutaneous tissue, fungal granuloma / Sezary syndrome, anaplastic large cell lymphoma, T-line or nullcell, primary skin type, peripheral lymphoma T cells, unspecified, T cell lymphoma, angioimmunoblastic, anaplastic large cell lymphoma, T-line or null-cell, primary systemic type. The third representative of lymphoid cancers is Hodgkin's lymphoma, also referred to as Hodgkin's disease. Exemplary diagnoses of this class that can be treated with compounds include, but are not limited to, Hodgkin lymphoma predominantly lymphocyte type, and various classic forms of Hodgkin's disease, examples of which are Hodgkin's lymphoma nodular sclerosis (grade 1 and 2), classic Hodgkin's lymphoma rich in lymphocytes, mixed cellular Hodgkin's lymphoma, and Hodgkin's lymphoma low in lymphocytes type. In various embodiments, each of the lymphoid tumors that are associated with abnormal JAK activity can be treated using compounds that inhibit JAK kinases.

[0220] In some embodiments, the hematopoietic cancer being treated is leukemia. This group includes a large class of cell proliferative disorders, including or displaying the characteristic phenotype of myeloid line cells. Myeloid neoplasms can be divided into myeloproliferative diseases, myelodysplastic diseases

- 121 / myeloproliferative, myelodysplastic syndromes, myeloid and acute leukemia. Examples of myeloproliferative diseases are chronic lymphocytic leukemia (e.g., Philadelphia chromosome positive (t (9; 22) (qq34; q11)), chronic neutrophilic leukemia, chronic eosinophilic leukemia / hypereosinophilic syndrome, chronic idiopathic fibrosis, polycythemia and idiopathic thrombocytemia. Examples of myelodysplastic / myeloproliferative diseases are chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia and early childhood myelomonocytic leukemia. Examples of myelodysplastic syndromes are refractory anemia, with ringed sideroblasts and without ringed sideroblasts, refractory cytopenia (myelodysplastic syndrome) with multilinear dysplasia, refractory anemia (myelodysplastic syndrome) with excess blasts, mellodysplastic syndrome and 5q syndrome. In various embodiments, any of the hematopoietic tumors that are associated with abnormal JAK activity can be treated using JAK kinase inhibiting compounds.

[0221] In some embodiments, JAK inhibitory compounds can be used to treat acute myeloid leukemia (AML), which is a large class of myeloid tumors having their own subdivisions of disorders. These disorders include, but are not limited to, AML with recurrent cytogenetic translocations, AML with multilinear dysplasia, and other AML not elsewhere classified. Exemplary AMLs with recurrent cytogenetic translocations include, but are not limited to, AML zt (8: 21) (q22; q22), AML1 (CBF-alpha) / ETO, acute promyelocytic leukemia (AML zt (15, 17), (q22, q11 - 12) and PML / RAR-alpha variants), AML with abnormal bone marrow eosinophils (inv (16) (p13q22) or t (16; 16) (p13; q11) CBFb / MYH11X) and AML z11q23 (MLL) abnormalities. Exemplary AML with multilinear dysplasia are those that are associated with or without prior myelodysplastic syndrome. Other acute myeloid leukemia not classified in any definable group include, minimally differentiated AML, AML without puberty, AML with maturation, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, acute megakaryocytic leukemia, acute basophilic leukemia and acute basophilic leukemia and acute basophilic leukemia. bone marrow.

[0222] One possibility for determining such inhibition is to detect the effect of 2,4-pyrimidinediamine compounds on the activation of further gene products. In the Ramos / IL4 assay, B cells were stimulated by interleukin-4 (IL-4) cytokines, which leads to activation of the JAK / Stat pathway through phosphorylation of JAK, JAK1 and JAK3 family kinases, which in turn phosphorylate and activate Stat transcription factor. 6. One of the genes enhanced by activated Stat-6 is the CD23 receptor with low affinity for IgE. To study the effect of inhibitors (e.g., 2,4-substituted pyrimidinediamine compounds described herein) on JAK1 and JAK3 kinases, human Ramos B cells were stimulated with human IL-4. 20 to 24 hours after stimulation, cells were stained for increased CD23 expression and analyzed using FACS. A decrease in the amount of CD23 present relative to control conditions indicates that the test compound actively inhibits the JAK kinase pathway. An example of this type designation is described in more detail in Example 2.

[0223] The activity of the compounds described herein can be further characterized by determining the effect of the 2,4-pyrimidinediamine compounds described herein on the proliferative response of primary human T cells. In this assay, primary human T cells derived from peripheral blood and pre-activated by stimulation T cell receptor and CD28, proliferate in culture in response to the interleukin-2 (IL-2) cytokine. This proliferative response is dependent on the activation of JAK1 and JAK3 tyrosine kinases, which phosphorylate and activate the Stat-5 transcription factor. Primary human T cells are incubated with 2,4-pyrimidinediamine compounds in the presence of IL-2 for 72 hours, and intracellular ATP concentrations were measured at the assay endpoint to assess cell viability. A reduction in cell proliferation compared to control conditions indicates inhibition of the JAK kinase pathway.

[0224] The activity of the compounds described herein can be further characterized by assessing the effect of the 2,4-pyrimidinediamine compounds described herein on A549 lung epithelial cells and U937 cells. A549 lung epithelial cells and U937 cells enhance surface expression of ICAM-1 (CD54) in response to a variety of different stimuli. Thus, by using ICAM-1 expression as a reading, the effect of test compounds in different signal transduction pathways can be assessed in the same cell type. Stimulation of IL-1e by the IL-1e receptor activates the TRAF6 / NFkB pathway, which enhances ICAM-1 expression. IFNy induces ICAM-1 enhancement, by activation of the JAK1 / JAK2 pathway. The enhancement of ICAM-1 expression can be quantified by flow cytometry, which calculates the compound dose curve and EC50 values.

[0225] Active compounds as described herein generally inhibit the JAK kinase pathway, having an IC 50 in the range of about 1 mM or less, as measured in the assays described herein. Of course, those skilled in the art will recognize that a compound that exhibits lower IC50S (on the order of, for example, 100 μΜ, 75 μΜ, 50 μΜ, 40 μΜ, 30 μΜ, 20 μΜ, 15 μΜ, 10 μΜ, 5 μΜ, 1 μΜ, 500 nM, 100 nM, 10 nM, 1 nM and even less) may be particularly useful in therapeutic applications. In cases where cell-specific activity is desired, the compound may be tested for activity with the desired cell type and counteracted for inactivity against other cell types. The desired degree of "inactivity" in these countermeasures, or the desired ratio of activity to inactivity, may vary in different situations and may be selected by the user.

[0226] Active 2,4-pyrimidinediamine compounds also typically inhibit IL-4 stimulated CD23 expression in B cells, having an IC50 in the range of about 20 μΜ or less, typically in the range of about 10 μΜ, 1 μΜ, 500 πΜ, 100 nM , 10 nM, 1 nM, or even less. A suitable assay that can be used is the assay described in Example 2, "Assay for B-Cell Line Stimulated with IL-4." In some embodiments, the active 2,4-pyrimidinediamine compounds have an IC50 less than or equal to 5 μΜ, greater than 5 μΜ, but less than 20 μΜ, greater than 20 μΜ, or greater than 20 μΜ, but less than 50 μΜ in the designation described in Example 2.

[0227] In addition, active 2,4-pyrimidinediamine compounds typically inhibit activity

- 123 human primary T cells, having IC₅₀ in the range of about 20 μΜ or less, typically in the range of about 10 μΜ, 1 μΜ, 500 nM, 100 nM, 10 nM, 1 nM, or even less. IC₅₀relative to human primary T cells can be determined in a standard assay and in vitro with isolated human primary T cells. A suitable assay that can be used is the assay described above, "Primary Human T-cell Proliferation Assay Stimulated with IL-2." In some embodiments 2,4-pyrimidinediamine active compounds have IC₅₀ less than or equal to 5 μM, greater than 5 μM but less than 20 μM, greater than 20 μM, or greater than 20 μM but less than 50 μM in the assay described above.

[0228] Active 2,4-pyrimidinediamine compounds also typically inhibit ICAM1 (CD54) expression induced by IFNγ exposure in U937 or A549 cells, having IC₅₀ in the range of about 20 μM or less, typically in the range of about 10 μM, 1 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even less. IC₅₀ with respect to ICAM (CD54) expression in cells stimulated with IFN? can be determined in a functional cell assay with the isolated A549 or U937 cell line. Active 2,4-pyrimidinediamine compounds typically have ICs₅₀ of less than or equal to 20 μM, greater than 20 μM, or greater than 20 μM but less than 50 μM in the assay.

Utility of compounds as research tools [0229] One skilled in the art will understand that certain crystalline protein-ligand complexes, in particular JAK ligand complexes and corresponding structure coordinates from X-ray structural analysis can be used to obtain new structural information useful for understanding the kinase biological activity as described here. Also, key structural features of the proteins described above, and especially the shape of the ligand binding site, are useful in methods of designing or identifying selective kinase modulators and in determining the structures of other proteins with similar features. Such protein-ligand complexes having the compounds described herein as their ligand component form an aspect of the invention.

[0230] Also, one of ordinary skill in the art will recognize that such crystals of appropriate X-ray quality can be used as part of the method for identifying a candidate representative capable of binding and modulating kinase activity. Such methods can be characterized by the following aspects: a) introducing into a suitable computer program information defining the kinase ligand binding domain in a conformation (e.g. coordinates determined from the X-ray structure obtained from crystals of appropriate X-ray quality as described above), whereby the computer program creates a model of three-dimensional ligand binding domain structures, b) introducing the three-dimensional model of the candidate representative structure into the computer program, c) applying the candidate representative model to the domain model binding ligand, id) assessing whether the candidate representative's model spatially matches the ligand binding domain. Ad aspects do not have to be conducted in the order listed above. Such methods may further include: rational drug design using a three-dimensional structure model and selection of a potential candidate representative in combination with modeling

- 124 computer.

[0231] In addition, one of ordinary skill in the art will appreciate that such methods may further entail: the use of a candidate representative so defined that it spatially matches the ligand binding domain in kinase modulation biological activity assays and determining whether that candidate representative modulates kinase activity in this mark. These methods may also include administering a representative of the candidate who, according to the assay, modulates kinase activity, to a mammal suffering from a [disease state] that can be treated by kinase modulation such as described above.

[0232] In addition, one of ordinary skill in the art will recognize that the compounds described herein can be used in a method of assessing the ability of a candidate representative to attach to a molecule or molecular complex containing a kinase ligand binding domain. This method can be characterized by the following aspects: a) creating a computer model of the kinase binding pocket using structural coordinates obtained from the appropriate x-ray quality kinase crystals, b) using computational algorithms to perform the fitting operation between the test medium and the computer model of the binding pocket, and c) analyzing the results of the matching operations for quantifying the connection between the examined the center and the computer model of the binding pocket.

Utility of compounds as screening agents [0233] For the use of compounds described herein in the screening method for candidate candidates that bind to, for example, JAK protein, the protein bound to the carrier, the compound described herein is added to the assay. Alternatively, the compound described herein has been linked to a carrier, e.g., via a linker that does not overly affect biological activity, and a protein has been added. Classes of candidate representatives among which new binders may be sought include specific antibodies, unnatural binders identified in screening of chemical library libraries, peptide analogs, etc. Screening studies for candidates with low toxicity to human cells are particularly important. A wide range of assays can be used for this purpose, including in vitro protein-protein binding assays, electrophoretic mobility shift assays, protein binding immunotests, functional tests (phosphorylation tests, etc.), and the like.

[0234] Binding determination of a candidate representative, for example, JAK proteins, can be achieved using several solutions. In one example, a candidate representative (compound described herein) is labeled, for example, with a fluorescent or radioactive moiety and the binding is determined directly. For example, this can be accomplished by attaching all or part of the JAK protein to a solid support, adding a labeled member (e.g., a compound described herein in which at least one atom has been replaced with a detectable isotope), washing out excess reagent, and determining whether the amount of label is present in solid support. Various blocking and washing steps can be used as is known in the art. "Tagged" means that the relationship is

- 125 directly or indirectly labeled with something that provides a detectable signal, e.g., a radioisotope, fluorescent label, enzyme, antibodies, particles such as magnetic particles, a chemiluminescent label or specific binding molecules, etc. Specific binding molecules include pairs such as biotin and streptavidin, digoxin and anti-digoxin, etc. For specifically binding partners, the complementary partner would be labeled with a molecule suitable for detection according to known procedures as described above. The label may directly or indirectly provide a detectable signal.

[0235] In some embodiments, only one of these components is labeled. For example, the JAK protein can be labeled at tyrosine positions using¹²⁵And, or using fluorophores. Alternatively, more than one component may be labeled with different markers; using¹²⁵And for proteins, for example, and a fluorophore for candidate representatives.

[0236] The compounds described herein can also be used as screening competitors to find additional potential drugs. The terms "candidate bioactive agent" or "drug candidate" or their grammatical equivalents as used herein include any particle, e.g., protein, oligopeptide, small organic particle, polysaccharide, polynucleotide, etc., which are subjected to testing for their bioactivity. They may be able to directly or indirectly change the cell proliferative phenotype or the expression of the cell proliferation sequence, including both the nucleic acid and protein sequences. In other cases, the change in cell proliferation of binding protein and / or activity is screened. When protein binding or activity is screened, in some embodiments, molecules already known to bind to that particular protein are excluded. Exemplary embodiments of the assays include representatives of candidates that do not bind the target protein in its endogenous native state, herein referred to as "exogenous" agents. In one example, exogenous agents further exclude antibodies to JAK proteins.

[0237] Candidate representatives may include many chemical classes, however, typically these are organic molecules with a molecular weight greater than about 100 daltons and less than about 2500 daltons. Candidate representatives include the functional groups necessary for structural interaction with proteins, especially hydrogen bonding and lipophilic binding, and typically contain at least an amino, carbonyl, hydroxyl, ether or carboxyl group, for example at least two chemical functional groups. Candidate representatives often include cyclic carbon or heterocyclic and / or aromatic structures or polyaromatic structures substituted with one or more of the above functional groups. Candidate representatives can also be found among biomolecules, including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, their derivatives, structural analogues or combinations thereof.

[0238] Candidate representatives are obtained from a variety of sources including synthetic or natural compound libraries. For example, numerous agents are available for random and directed synthesis of a wide variety of organic compounds and

- 126 biomolecules, including the expression of random oligonucleotides. Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts are available or can be easily prepared. Additionally, libraries and compounds made naturally or synthetically can be easily modified by the use of conventional chemical, physical and biochemical agents. Known pharmacological agents can be subjected to targeted or random chemical modifications, such as acylation, alkylation, esterification, amidation, to produce structural analogues.

[0239] In one example, binding of a candidate representative is determined using competitive binding assays. In this example, the competitive agent is a binding moiety known to bind to a JAK protein, such as an antibody, peptide, binding partner, ligand, etc. In some circumstances, there may be a competitive binding such as between the candidate representative and the binding residue, with the residue binding replacing the representative of the candidate.

[0240] In some embodiments, the representative of the candidate is labeled. If present, the candidate representative or competitor, or both, are first added to, for example, JAK protein, for a time sufficient to allow binding. Incubations can be carried out at any temperature that ensures optimal activity, typically in the range of 4 ° C to 40 ° C. Incubation times are selected for optimal activity, but can also be optimized to facilitate rapid and high throughput screening. Excess reagent is usually removed or washed away. The second component is then added followed by the presence or absence of the labeled component to determine binding.

[0241] In one example, a competitive agent is added first followed by the representative of the candidate. Replacing a competitive representative means that the candidate representative has bound to the JAK protein and hence, is able to bind to the JAK protein and potentially modulate its activity. In this embodiment, each component may be marked. Thus, for example, if a competitor is labeled, the presence of the label in the washing solution indicates replacement by the agent. Alternatively, if a candidate representative is tagged, the presence of the tag in the substrate indicates a replacement.

[0242] In an alternative embodiment, a representative of the candidate is added first during incubation and washing, then a competitive agent is added. The lack of binding of a competitive agent may indicate that the candidate representative is bound to the JAK protein with higher affinity. Thus, if the candidate representative is labeled, the presence of the tag on the carrier, in combination with no binding of the competitive representative, may indicate that the candidate representative is capable of binding to the JAK protein.

[0243] It can be advantageous to determine the JAK protein binding site. This can be done using different solutions. In one embodiment, after

By identifying the JAK protein as associated with the candidate representative, the JAK protein is fragmented or modified, and tests are repeated to identify the components necessary for binding.

[0244] Modulation is tested by screening representatives of candidates capable of modulating the activity of the JAK protein, including the steps of combining the candidate representative with the JAK protein as above, and determining changes in the biological activity of the JAK protein. Thus, in this embodiment, the representative of the candidate should both combine (although not necessarily have to) and alter its biological or biochemical activity, as defined above. The methods include both in vitro screening methods and in vivo screening methods for cells to determine changes in cell viability, morphology, and the like.

[0245] Alternatively, differential screening can be used to identify drug candidates that bind to a native JAK protein but cannot bind to a modified JAK protein.

[0246] A variety of other reagents may be used in the screening assays. These reagents include salts, neutral proteins, e.g., albumin, detergents, etc., and can be used to facilitate optimal protein-protein binding and / or to reduce non-specific or side reactions. Reagents that improve test efficiency such as protease inhibitors, nuclease inhibitors, antibacterial agents, etc. can also be used. The component mixture can be added in any order that leads to the required bonding.

Methods of administration [0247] The compounds of the invention described herein, or compositions thereof, will generally be used in an amount effective to achieve the intended result, eg, an amount effective to treat or prevent the particular condition being treated. The compound (s) can be used therapeutically to achieve therapeutic benefit or prophylactically to obtain preventive benefit. A therapeutic benefit is the elimination or amelioration of a given disorder being treated and / or the removal or amelioration of one or more of the symptoms associated with a given disorder such that the patient finds an improvement in well-being or condition, regardless of the fact that the patient may still be affected by the disorder. . For example, administering a compound to a patient suffering from an allergy provides therapeutic benefit not only when the underlying allergic response is eliminated or ameliorated, but also when the patient reports a reduction in the severity or duration of allergy-related symptoms after exposure to the allergen. In another example, the therapeutic benefit in the context of asthma includes improving breathing after an asthmatic attack or reducing the frequency or severity of asthmatic episodes. In another specific example, the therapeutic benefit in the context of transplant rejection includes the ability to alleviate acute transplant rejection, such as, for example, HVGR or GVHR, or the ability to extend the time interval between the occurrence of acute transplant rejection and / or the onset of chronic

- 128 rejections. The therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is occurring.

[0248] The amount of compound administered will depend on a variety of factors, including, for example, the particular condition being treated, the form of administration, the severity of the condition being treated, the age and weight of the patient, and the bioavailability of the particular active compound. Determining the effective dosage is within the skill of the skilled person.

[0249] As known to those skilled in the art, the preferred dose of 2,4-pyrimidinediamine compounds will also depend on the age, body weight, general health, and severity of the subject being treated. It may be necessary to adjust the dose to the subject's sex and / or lung capacity of the subject if administered by inhalation. Dosage may also be adjusted for people suffering from more than one condition and for those who have additional conditions affecting lung capacity and the ability to breathe properly, for example, bronchitis, emphysema, pneumonia and infections respiratory system. The dosage and frequency of administration of the compounds or their prodrugs will also depend on whether these compounds are formulated for the treatment of acute episodes of the disease or the preventive treatment of the disorder. For example, acute episodes of allergic diseases, including allergy-related asthma, associated with transplant rejection, etc. The practitioner will be able to determine the optimal dose for a particular individual.

[0250] For prophylactic administration, the compound may be administered to a patient at risk of developing one of the previously described conditions. For example, if it is not known if the patient is allergic to a particular drug, the compound may be for administration prior to drug administration to avoid or ameliorate the allergic reaction to the drug. Alternatively, prophylactic administration can be used to avoid symptoms in a patient diagnosed with the disorder. For example, the compound may be administered to an allergy sufferer prior to expected allergen exposure.

[0251] The compounds may also be used for prophylactic administration to healthy subjects who are repeatedly exposed to agents known to cause the above-described diseases to prevent the occurrence of the disorder. For example, the compound may be for administration to a healthy individual who is repeatedly exposed to an allergen known to cause allergies, such as latex, to prevent the subject from developing allergies. Alternatively, the compound may be for administration to a patient suffering from asthma before participating in an activity that induces asthma attacks to reduce the severity or completely avoid an asthmatic episode.

[0252] In the context of transplant rejection, the compound may serve for administration while the patient does not exhibit acute rejection reactions to avoid rejection and / or before clinical indications of chronic rejection appear. The compound may be for systemic administration to a patient, as well as administration to tissues or an organ prior to transplantation of the patient's tissue or organ.

[0253] The amount of compound to be administered will depend on a number of factors, in

Including, for example, the particular indication being treated, the form of administration, whether prophylactic or therapeutic benefit is desired, the severity of the indication being treated, and the age and weight of the patient, the bioavailability of the particular active compound, etc. Determining the effective dosage is within the skill of the skilled person.

[0254] Effective dosages can be estimated initially from in vitro assays. For example, an initial dosage for use in animals can be formulated to achieve a concentration of active compound in peripheral blood or serum that is equal to or greater than IC₅₀ given compound as measured in an in vitro assay. The calculation of dosages for achieving such concentrations in peripheral blood or serum, taking into account the bioavailability of a particular compound, is within the skill of those in the art. To read the guidelines, readers are referred to Fingl &amp; Woodbury, "General Principles," in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest issue, Pergamagon Press and references cited therein.

[0255] Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful in testing the efficacy of compounds for treating or preventing the various diseases described above are well known in the art. Suitable animal models for hypersensitivity or allergic reactions are described in Foster, (1995), Allergy 50 (21Suppl): 6-9, discussion 34-38 and Tumas et al. (2001), J. Allergy Clin. Immunol. 107 (6): 1025-1033. Suitable animal models 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. Suitable animal models 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 i collaborators, (2001), Invest. Ophthalmol. Vis. Sci. 42 (11): 2483-2489. Suitable animal models of 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. Suitable animal models of hyper-IgE syndrome are described in Claman et al. (1990), Clin. Immunol. Immunopathol. 56 (1): 46-53. Suitable animal models of 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. Suitable animal models of atopic disorders, such as atopic dermatitis, atopic eczema syndrome 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. Suitable animal models of transplant rejection, such as HVGR models, are described in O'Shea et al. (2004), Nature Reviews Drug Discovery 3: 555-564; CetkovicCurlje &amp; Tibbles, (2004), Current Pharmaceutical Design 10: 1767-1784 and Chengelian et al. (2003) Science 302: 875-878. Skilled artisans can routinely adapt such information to determine dosages suitable for administration to humans.

[0256] Dosage amounts will typically range from about 0.0001 or 0.001 or

- 130 0.01 mg / kg / day to about 100 mg / kg / day, but may be higher or lower, depending on other factors, compound activity, bioavailability, form of administration and various factors discussed above. The dose amount and interval can be individually adjusted to provide plasma levels of the compound (s) that are sufficient to maintain the therapeutic or prophylactic effect. For example, the compounds can be administered once a week, several times a week (e.g. every other day), once a day or several times a day, depending on, inter alia, the form of administration, the particular indication being treated and the opinion of the prescribing physician. For local or selective uptake, such as local topical administration, the effective local concentration of the active compound (s) may not be related to plasma concentrations. Skilled artisans will be able to optimize effective topical dosages without undue experimentation.

[0257] Preferably, the compound (s) provides therapeutic or prophylactic benefits without causing significant toxicity. Toxicity of the compound (s) can be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effects is the therapeutic index. Compound (s) with high therapeutic indices are preferred.

[0258] The above disclosure regarding dosage requirements for 2,4-substituted pyrimidinediamine compounds is relevant for the doses required for prodrugs, with the knowledge obvious to one of ordinary skill in the art that the amount of prodrug (s) administered also depends on a number of factors, including, for example , bioavailability of a particular prodrug (s), and the rate and efficiency of conversion into the active drug for the chosen route of administration. Determining the effective dose of the prodrug (s) for a particular use and form of administration is within the skill of one of ordinary skill in the art.

[0259] Effective dosages can be estimated initially based on in vitro activity and metabolism assays. For example, an initial dosage of the prodrug for use in animals can be formulated to achieve a concentration of the active compound metabolite in peripheral blood or serum that is equal to or greater than IC₅₀ of a given compound as measured in an in vitro assay, such as in vitro CHMC or ΒΜΜί and other in vitro assays described in US Application Serial Number 10 / 355,543 filed January 31, 2003 (US2004 / 0029902A1), International Application Serial Number PCT / US03 / 03022 filed January 31, 2003 (WO 03/063794), US application serial number 10 / 631,029 filed July 29, 2003, international application serial number PCT / US03 / 24087 (WO2004 / 014382), US application serial number 10 / 903,263 filed on July 30, 2004, and international application serial number PCT / US2004 / 24716 (WO2005 / 016893). The calculation of dosages for achieving such concentrations in peripheral blood or serum, taking into account the bioavailability of a particular prodrug, is within the skill of those in the art. To read the guidelines, readers are referred to Fingl &amp; Woodbury, "General Principles," in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, p. 1-46, latest issue, Pagamonon Press and references cited therein.

[0260] Also disclosed herein are kits for the administration of 2,4-pyrimidinediamine, a prodrug thereof, or pharmaceutical formulations comprising a compound that may contain a dose amount of at least one 2,4-pyrimidinediamine or a composition containing at least one 2,4-pyrimidinediamine as disclosed herein. The kits may further contain appropriate packaging and / or instructions for use of the compound. The kits may also contain a means for delivering at least one 2,4-pyrimidinediamine, or compositions containing at least one 2,4-pyrimidinediamine, such as an inhaler, metering spray (e.g., nasal sprays), an injection syringe, or a pressure pack for capsules , tablets, suppositories, or other device as described herein. The kit may also provide a compound and reagents for preparing a composition for administration. The composition may be in dry or lyophilized form or in the form of a solution, especially in the form of a sterile solution. If the composition is in dry form, the reagent may contain a pharmaceutically acceptable diluent for preparing a liquid formulation. The kit may include a device for administering or dispensing the composition, including, but not limited to, syringes, pipettes, transdermal patch or inhaler.

[0261] Kits may contain other therapeutic compounds for use in combination with the compounds described herein. In one embodiment, the therapeutic agents are immunosuppressive or antiallergic compounds. These compounds may be provided in separate form or in a mixture with the compounds of the invention.

[0262] Kits will contain appropriate instructions for the preparation and administration of the compositions, side effects of the compositions, and any other relevant information. The instructions may be in any suitable form, including, without limitation, printed matter, video cassette, computer readable disk, optical disk.

[0263] We disclose herein a kit that contains a compound of formula I or a prodrug thereof, packaging, and instructions for use.

[0264] Disclosed herein is a kit that comprises a pharmaceutical formulation comprising a compound of formula I or a prodrug thereof and at least one pharmaceutically acceptable excipient, diluent, preservative, stabilizer, and mixtures thereof, packaging and instructions for use.

[0265] Disclosed herein is a kit for treating a subject that suffers from or is susceptible to the conditions described herein, comprising a container containing a dose amount of 2,4-pyrimidinediamine or a composition as disclosed herein and instructions for use. The container may be arbitrarily known in the art and suitable for oral, intravenous, topical, rectal, urethral or inhalation storage and delivery.

[0266] Kits that contain sufficient doses of 2,4-pyrimidinediamine or a composition can also be provided to provide effective treatment to a subject for a longer period, such as for a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks or more.

[0267] One skilled in the art will appreciate that the above-described embodiments

132 can be used together in any suitable combination to generate additional embodiments that are not explicitly specified above, and that such embodiments are considered to be part of the invention.

Synthesis of Compounds [0268] The 2,4-pyrimidinediamine compounds described herein can be synthesized by a number of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods. Suitable exemplary methods that can be routinely adapted to the synthesis of 2,4-pyrimidinediamine compounds and the prodrugs described herein can be found in US Patent No. 5,958,935. Specific examples describing the synthesis of numerous 2,4-pyrimidinediamine compounds and prodrugs, as well as intermediates, are therefore described in US Patent No. 10 / 355,543, filed January 31, 2003 (US2004 / 0029902A1). Suitable exemplary methods that can be routinely used and / or adapted for the synthesis of active 2,4-substituted pyrimidinediamine compounds can also be found in International Application Serial Number PCT / US03 / 03022 filed January 31, 2003 (WO 03/063794), US Application Number serial 10 / 631,029 filed July 29, 2003, international application serial number PCT / US03 / 24087 (WO2004 / 014382), US application serial number 10 / 903,263 filed July 30, 2004, and international application serial number PCT / US2004 / 24716 (WO2005 / 016893). All compounds described herein (including prodrugs) can be obtained by routine adjustment of these methods.

[0269] Specific exemplary synthetic methods for the 2,4-substituted pyrimidinediamines described herein are also described in Example 1, below. Those skilled in the art will also be able to easily adapt these examples to the synthesis of additional 2,4-substituted pyrimidinediamines as described herein.

[0270] Many exemplary synthetic routes that can be used to synthesize 2,4-pyrimidinediamine compounds described herein are shown in Schemes (I) (VII) below. These methods can be routinely adapted to the synthesis of the 2,4-substituted pyrimidinediamine compounds described herein. After each reaction stage, the product can be purified or, depending on the chemistry, can be used in the next stage without purification.

[0271] For example, the compounds can be synthesized from substituted or unsubstituted uracils as illustrated in Scheme (I) below. In the diagram (I), ring A, R⁵, (R²) p, X, Y, Z¹, and Z² are as defined here. According to scheme (I), uracil A-1 is dihalogenated in positions 2 and 4 using a standard halogenating agent such as POCl3 (or other standard halogenating agent) under standard conditions to give 2,4-dichloropyrimidine A-2. Depending on the R substituent⁵, in pyrimidinediamine-2 chloride at the C4 position is more reactive to nucleophiles than chloride at the C2 position. This differential reactivity can be used to synthesize 2,4-pyrimidinediamines I by first reacting 2,4-dichloro-pyrimidinamine A-2 with one equivalent of amine A-3 to give 4N-133 substituted-2-chloro-4-pyrimidinamine A-4, then amine A-5 to give 2,4-pyrimidinediamine of formula A-6 (compounds of formula I where each R³ and R⁴ means H). Compounds of formula I may be obtained in which either or both of the NH groups on C2 and C4 pyrimidines are substituted, e.g. by alkylation of NH groups.

<img file="PL2389372T3_D0039.tif" />

[0272] Typically, the C4 halide is more reactive to nucleophiles as illustrated in the scheme. However, as recognized by those skilled in the art, the identity of the substituent R⁵ can change this reactivity. For example, when R⁵ is trifluoromethyl, a 50:50 mixture of 4N-substituted-4-pyrimidinamine A-4 and the corresponding 2N-substituted-2-pyrimidinamine is obtained. The regioselectivity of this reaction can also be controlled by adjusting the solvent and other synthetic conditions (such as temperature) as is well known in the art.

[0273] The reactions shown in Scheme (I) may be faster if the reaction mixtures are heated by microwave radiation. During such heating, the following conditions can be used: heating to 175 ° C in ethanol for 5-20 minutes in a Smith reactor (Personal Chemistry, Uppsala, Sweden) in a sealed tube (at 20 bar pressure).

[0274] Starting materials in the form of uracil A-1 can be purchased from commercial sources or obtained using standard organic chemistry techniques. Commercially available uracils that can be used as substrates in Scheme (I) include, for example, and not limiting, uracil (Aldrich # 13,078-8; CAS Registry 66-22-8); 5-bromouracil (Aldrich # 85,247-3; CAS Registry 51-20-7; 5-fluorouracil (Aldrich # 85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich # 85,785-8; CAS Registry 696 -07-1); 5-nitrouracil (Aldrich # 85,276-7; CAS Registry 611-08-5); 5- (trifluoromethyl) -uracil (Aldrich # 22,327-1; CAS Registry 54-20-6). Additional 5-substituted uracils are available from General Intermediates of Canada, Inc., Edmonton, CA and / or Interchim, Cedex, France, or can be made using standard techniques. The links in the Myriad manual teaching the appropriate synthesis methods are provided infra.

[0275] Amines A-3 and A-5 may be purchased from commercial sources or alternatively may be synthesized using standard techniques. For example, suitable amines can be used

- 134 synthesize from nitro precursors using standard chemistry. Specific examples of reactions are provided in the Examples chapter. See also Vogel, 1989, Practical Organic Chemistry, Addison Wesley Longman, Ltd. and John Wiley &amp; Sons, Inc.

[0276] Those skilled in the art will recognize that in some cases, the amines A-3 and A-5 and / or the X substituent on uracil A-1 may contain functional groups that require protection during synthesis. The exact identity of any protecting group (s) will depend on the identity of the functional group being protected and will be apparent to those skilled in the art. Directions for choosing the appropriate protecting groups, as well as synthetic strategies for their attachment and removal, can be found, for example, in Greene &amp; Wuts.

[0277] Thus, a protecting group refers to a group of atoms that, when bound to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, the protecting group can be selectively removed as needed during the course of the synthesis. Examples of protecting groups can be found in Green &amp; Wuts and in Harrison et al., Compendium of Synthetic Organic Methods, vol. 1-8, 1971/96, John Wiley &amp; Sons, New York. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES" ), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated to form acetate and benzoate esters or alkylated to form benzyl and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups ) and allyl ethers.

[0278] A particular embodiment of Scheme (I) using 5-fluorouracil (Aldrich # 32,937-1) as starting material is illustrated in Scheme (Ia) below. In the diagram (Ia), ring A, (R²) p, X, Y, Z¹, and Z² mean as defined previously for Scheme (I). Compound A-10, 2N, 4N-disubstituted-5-fluoro-2,4-pyrimidinediamine can be obtained by reacting 2,4-dichloro-5-fluoropyrimidine A-8 (commercially available or obtained from A-7 as shown, e.g. starting with uracil and conducting its dehydrohalogenation, e.g. POCl3) with, optimally, one equivalent of amine A-3 to give 2-chloro-N4-substituted-5-fluoro-4-pyrimidinamine A-9, followed by reaction with one or more equivalents of amine A-5, typically between about 1.1 equivalents A-5 and about 2 equivalents A-5.

- 135 -

<img file="PL2389372T3_D0040.tif" />

[0279] Although many of the synthesis schemes discussed above do not illustrate the use of protecting groups, those skilled in the art recognize that in some cases, some substituents, such as, for example, R² and / or other groups may include functionalities that require security. The exact identity of the protecting group used will depend, among other things, on the identity of the functional group being protected and the reaction conditions employed in the given synthetic scheme and will be apparent to those skilled in the art. Guidelines for selecting protecting groups and their attachment and removal for a particular application can be found, for example, in Greene &amp; Wuts.

[0280] The prodrugs described herein may be prepared by routine modification of the methods described above. Alternatively, such prodrugs can be obtained by reacting an appropriately protected 2,4-pyrimidinediamine with an appropriate reagent to add the desired progroup. Conditions for carrying out such reactions and deprotecting the product to obtain the prodrug described herein are well known.

[0281] Myriad references teaching generally useful methods for synthesizing pyrimidines, as well as starting materials described in Scheme (I) - (VII), are known in the art. To read the specific recommendations of the reader, refer to Brown, DJ, "The Pyrimidines", in The Chemistry of Heterocyclic Compounds. Volume 16 (Weissberger, A., Ed.), 1962, Interscience Publishers, (A Division of John Wiley &amp; Sons), New York ("Brown I"); Brown D. J., "The Pyrimidines", in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C, ed.), 1970, WileyInterscience, (A Division of John Wiley &amp; Sons), New York (Brown II "); Brown, DJ, "The Pyrimidines", in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. and Taylor, E. C, ed.), 1985, An Interscience Publication (John Wiley &amp; Sons), New York ("Brown III"); Brown D. J., "The Pyrimidines" in The Chemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. and Taylor, E. C, ed.), 1994, John Wiley &amp; Sons, Inc., New York, pp. 1-1509 (Brown IV "); Kenner, GW and Todd, A., in Heterocyclic

- 136 Association, Volume 6, (Elderfield, R. C, 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 (synthesis of uracil p. 313, 315; synthesis of pyrimidinediamine p. 313-316; synthesis of amino pyrimidinediamine p. 315); Joule, JA, Mills, K. and Smith, GF, Heterocyclic Chemistry, 3rd Edition, 1995, Chapman and Hall, London, UK, pp. 1-516; Vorbmggen, H. and Ruh-Pohlenz, C, Handbook of Nucleoside Synthesis, John Wiley &amp; 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, 4th Edition, 2000, Blackwell Science, Ltd, Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Vol. 1-9 (Trost, BM and Fleming, I., ed.), 1991, Pergamon Press, Oxford, UK.

EXAMPLES [0282] The invention is better understood by reference to the following examples, which are not intended to be limiting. Any synthesis methods that are functionally equivalent are within the scope of the disclosure. Various modifications to the embodiments described herein will be apparent to those skilled in the art from the foregoing description and accompanying figures.

[0283] One embodiment of the invention is a compound of the formula I as described in the following examples.

[0284] In the examples below, as well as throughout the application, the following abbreviations have the following meanings. If not specified, the terms have their generally accepted meanings.

<td>TFA</td><td>= trifluoroacetic acid</td><td>mmol</td><td>= millimole</td>

<td>MeOH</td><td>= methanol</td><td>nM</td><td>= nanomolar</td>

<td>EtOAc</td><td>= ethyl acetate</td><td>DMSO</td><td>= dimethyl sulfoxide</td>

<td>i-PrOH</td><td>= isopropanol</td><td>mL or mL</td><td>= milliliter</td>

<td>EtOH</td><td>= ethanol</td><td>mg</td><td>= milligram</td>

<td>s</td><td>= singlet</td><td>canine</td><td>= pounds in inches²</td>

<td>d</td><td>= doublet</td><td>N</td><td>= normal</td>

<td>t</td><td>= triplet</td><td>uM</td><td>= micromolar</td>

<td>q</td><td>= quartet</td><td>rpm</td><td>= revolutions / minute</td>

<td>m</td><td>= multiplet</td><td>rt</td><td>= room temperature</td>

<td>dd</td><td>= doublet of doublets</td><td>aq.</td><td>= watery</td>

<td>year</td><td>= wide</td><td>μΐ</td><td>= microliter</td>

<td>MS</td><td>= mass spectrum</td><td>FBS</td><td>= bovine serum</td>

fetal

137 -

<td>MS</td><td>= mass spectrometry</td><td>LCMS</td><td colspan="2">= chromatography</td>

<td>(ES)</td><td>(Electrospray)</td><td></td><td>liquid spectrometer mass</td><td>that</td>

<td>RP-HPLC</td><td colspan="2">= FACS high performance chromatography reverse phase liquid</td><td>= flow cytometry</td><td></td>

<td>Example 1:</td><td>Synthesis of pyrimidine-2,4-diamines</td><td></td><td></td><td></td>

Synthesis of 5- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one:

[0285] Into a vial with 5-aminobenzo [d] oxazol-2 (3H) -one (300.1 mg, 2.0 mmol) and 2,4-dichloro5-methylpyrimidine (423.8 mg, 2.6 mmol) , MeOH (8 ml) and H were added₂O (2 ml). The cloudy mixture was stirred at room temperature for 64 h. The precipitate from the reaction mixture was collected by filtration, washed with EtOAc (3 mL × 2), and then dried in vacuo.

5- (2-Chloro-5-methyl-pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one was obtained as an off-white solid: 394 mg (71% yield); ¹H NMR (300 MHz, DMSO) δ 11.68 (br s, 1H), 8.62 (s, 1H), 7.94 (d, J = 0.8, 1H), 6.97 (d, J = 2.0, 1H), 6.82 (d, J = 8.1, 1H), 6.74 (dd, J = 2.0, 8.1, 1H), 2.15 (s, 3H) ; LCMS (M +) m / z 277.10.

Synthesis of N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diamine: (I-16) [0286] Into a vial with 5- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one (138.3 mg, 0.5 mmol) and 3- (methylsulfonyl) benzenamine hydrochloride ( 207.7 mg, 1.0 mmol), z-PrOH (10 mL) was added followed by TFA (116 µL, 1.5 mmol). The vial was sealed, and the reaction mixture was stirred at 85-90 ° C for 40 h. The solvent was removed in vacuo, and the crude product was purified by RP-HPLC.

N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diamine was obtained as the mono-trifluoroacetate salt: off-white solid, 129 mg (49% yield); ¹H NMR (300 MHz, DMSO) δ 11.60 (s, 1H), 9.43 (s, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 8.11 (br d, J = 7.5.1H), 7.96 (d, J = 0.8.1H), 7.49-7.33 (m, 4H), 7.27 (d, J = 8.5 , 1H), 3.13 (s, 3H), 2.16 (s, 3H); LCMS (M +) m / z 412.47.

Synthesis of 5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-benzo [d] imidazol-2 (3H) -one:

[0287] Into a vial with 5-amino-1H-benzo [d] imidazol-2 (3H) -one (298.3 mg, 2.0 mmol) and 2,4-dichloro-5-fluoropyrimidine (434.1 mg, 2 , 6 mmol), MeOH (8 mL) and H were added₂O (2 ml). The cloudy solution was stirred at room temperature for 3 days. The precipitate from the reaction mixture was collected by filtration and washed with EtOAc (3 mL × 2), and then dried under vacuum. 5- (2-Chloro-5-fluoropyrimidin-4-ylamino) -1H-benzo [d] imidazol2 (3H) -one was obtained as an off-white solid: 390.3 mg (70% yield);¹H NMR (300 MHz, DMSO) δ 10.69 (s, 1H), 10.63 (s, 1H), 9.87 (s, 1H), 8.27 (d, J = 3.6.1H) , 7.35 (d, J = 1.9, 1H), 7.18 (dd, J = 1.9, 8.3.1H), 6.93 (d, J = 8.3.1H); LCMS (M +) m / z 279.80.

- 138 Synthesis of 4- (5-nitropyridin-2-yl) morpholine:

[0288] In a round bottom flask, morpholine (5.4 mL, 61.5 mmol) was added to a solution in dichloromethane (125 mL) 2-bromo-5-nitropyridine (5 g, 24.6 mmol). The reaction was heated to reflux for 4 h, then cooled to room temperature. The solution was sequentially washed with a saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried (Na₂SO₄), filtered, and the solvent removed in vacuo. 4- (5-nitropyridin-2-yl) morpholine obtained, yellow solid: 4.9 g (95% yield);¹H NMR (300 MHz, DMSO) δ 8.95 (d, J = 2.7.1H), 8.22 (dd, J = 2.7, 9.1.1H), 6.92 (d, J = 9.6, 1H), 3.74 -3.65 (m, 8H); LCMS (M +) m / z 210.34.

Synthesis of 6-morpholinopyridine-3-amine:

[0289] To a solution in EtOH (250 mL) 4- (5-nitropyridin-2-yl) morpholine (4.9 g, 23.4 mmol) was added 10% Pd on activated carbon, 500 mg. Hydrogenation was performed in a Parr flask at room temperature at 40 psi for 2 h. The solids were filtered off and the filtrate was collected. The solvent was removed in vacuo. 6-morpholinopyridin-3-amine was obtained as a purple solid: 3.7 g (88% yield);¹H NMR (300 MHz, DMSO) δ 7.64 (d, J = 2.7.1H), 6.96 (dd, J = 2.7, 8.8.1H), 6.65 (d, J = 8.8, 1H), 4.63 (s, 2H), 3.72-3.69 (m, 4H), 3.21-3.18 (m, 4H); LCMS (M +) m / z 180.08.

Synthesis of N4- (benzimidazolin-2-one-5-yl) -N2 - ((2-morpholinyl) pyridin-5-yl) -5-fluoropyrimidine-2,4-diamine: (II-19) [0290] Into a vial with 5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-benzo [J] imidazol-2 (3H) onone (27.6 mg, 0.1 mmol) and 6-morpholinopyridine-3-amine ( 35.8 mg, 0.2 mmol), iPrOH (2 mL) was added followed by TFA (10 µL, 0.13 mmol). The vial was sealed, and the cloudy solution was stirred at 95 ° C for 2 days. The solvent was removed in vacuo, and the crude product was purified by RP-HPLC. N4- (benzimidazolin-2-one-5-yl) -N2 - ((2-morpholinyl) pyridin-5-yl) -5-fluoropyrimidine-2,4-diamine was obtained as a pale orange solid, as the di-trifluoroacetate salt: 51, 1 mg (79% yield); ¹H NMR (300 MHz, DMSO) δ 10.61 (s, 2H), 9.79 (br s, 1H), 9.55 (br s, 1H), 8.31 (s, 1H), 8.13 (d, J = 4,4,1H), 7.92 (br d, J = 8,8,1H), 7,22 (d, J = 8,1,1H), 7.18 (s, 1H ), 7.10 (br d, J = 8.8, 1H), 6.89 (d, J = 8.1, 1H), 3.78-3.75 (m, 4H), 3.50- 3.47 (m, 4H); LCMS (M +) m / z 423.00.

Synthesis of 6- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [J] oxazol-2 (3H) -one:

[0291] Into a vial with 6-aminobenzo [d] oxazol-2 (3H) -one (1.0 g, 6.7 mmol) and 2,4-dichloro-5-methylpyrimidine (1.4 g, 8.7 mmol) , MeOH solvents (20 ml) and H were added₂O (5 ml). The cloudy mixture was stirred at room temperature for 2 days. The precipitate from the reaction mixture was collected by filtration, washed with H₂O (3 mL × 2) and EtOAc (3 mL × 2), and then dried under vacuum.

6- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [J] oxazol-2 (3H) -one was obtained as a light beige solid: 1.59 g (86% yield); ¹H NMR (300 MHz, DMSO) δ 11.59 (s,

1H), 8.87 (s, 1H), 7.99 (s, 1H), 7.56 (s, 1H), 7.28 (d, J = 8.3.1H), 7.06 (d , J = 8,3,1H), 2.14 (s,

3H).

- 139 Synthesis of N4- (benzo [d] oxazol-2 (3H) -on-6-yl) -N2 - ((3-morpholinyl) phenyl) -5-methylpyrimidine-2,4-diamine: (I-48) [0292] Into a vial with 6- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [d | oxazol-2 (3H) -one (27.7 mg, 0.1 mmol) and 3-morpholinobenzeneamine (26 , 7 mg, 0.15 mmol), i-PrOH (2 mL) was added followed by TFA (10 µL, 0.13 mmol). The vial was sealed, and the solution was stirred at 95 ° C for 2 days. The solvent was removed in vacuo, and the crude product was purified by RP-HPLC.

N4- (benzo [d] oxazol-2 (3H) -on-6-yl) -N2 - ((3-morpholinyl) phenyl) -5-methylpyrimidine-2,4-diamine was obtained as a light beige solid: 32.9 mg ( 78% efficiency); ¹H NMR (300 ΜΙ Iz, DMSO) δ 11.57 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.90 (s, 1H), 7.81 ( s, 1H), 7.37 (d, J = 8.33.1H), 7.27 (s, 1H), 7.14 (d, J = 8.3, 1H), 7.07-7, 01 (m, 2H), 6.58-6.50 (m, 1H), 3.683.65 (m, 4H), 2.95-2.92 (m, 4H), 2.14 (s, 3H) ; LCMS (Μ +) m / z 419.03.

Synthesis of N4- (benzooxazolin-2-one-5-yl) -N2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine: (II-13) [ 0293] Into the vial with 5- (2-chloro-5-methylpyrimidin-4-ylamino) benzo [J] oxazol-2 (3H) -one (27.7 mg, 0.5 mmol) and 6- (4-methylpiperazine -1-yl) pyridine-3-amine (38.4 mg, 1.0 mmol), i-PrOH (2 mL) was added followed by TFA (10 µL, 0.13 mmol). The vial was sealed, and the reaction mixture was stirred at 85 ° C for 2 days. Solvents were removed in vacuo, and the crude product was purified by RP-HPLC. The purified compound (as the trifluoroacetate salt) was dissolved in MeOH-H₂O (1: 4.2 ml) and passed through a PL-HCO column₃-MP-SPE, washed with the same solvents (1 ml). The filtrate was collected and the solvent was removed by lyophilization. received

N4- (benzooxazolin-2-one-5-yl) -N2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine as a purple solid, 23.1 mg (53% yield); ¹HW (300 \ IIIz, DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30-8.28 (m, 2H), 7.87-7.84 (m, 2H), 7.46-7.28 (m, 2H), 7.22 (d, J = 8.5.1H), 6.71 (d, J = 9.1.1H), 3.40- 3.37 (m, 4H, coincides with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H), 2.11 (s, 3H); LCMS (Μ +) m / z 433.52.

Synthesis of N4- (benzimidazolin-2-one-5-yl) -N2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] 5-fluoropyrimidine-2,4-diamine: (II-16) [0294] Into the vial of

5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-benzo [J] imidazol-2 (3H) -one (28.0 mg,

0.1 mmol) and 6- (4-methylpiperazin-1-yl) pyridine-3-amine (38.4 mg, 0.2 mmol), iPrOH (2 mL) was added followed by TFA (10 PL, 0.13 mmol). The vial was sealed, and the solution was stirred at 85 ° C for 2 days. The solvent was removed in vacuo, and the crude product was purified by RP-HPLC. The purified compound (as the trifluoroacetate salt) was dissolved in MeOH-H₂O (1: 4, 2 ml) and passed through a PL-HCO column₃-MP-SPE, washed with the same solvents (1 ml). The filtrate was collected and the solvent removed by lyophilization.

- N4- (benzimidazolin-2-one-5-yl) -N2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-fluoropyrimidine-2,4-diamine is obtained as a purple solid: 26.2 mg (60% yield); ¹H NMR (300 MHz, DMSO) δ 10.56 (s, 1H), 10.52 (s, 1H), 9.16 (s, 1H), 8.85 (s, 1H), 8.27 (br d, J = 2.3, 1H), 8.00 (br d, J = 3.8, 1H), 7.84 (dd, J = 2.3, 9.1, 1H), 7.30 ( dd, J = 1.7, 8.2, 1H), 7.17 (d, J = 1.7, 1H), 6.86 (d, J = 8.2, 1H), 6.73 (d , J = 9.1, 1H), 3.40-3.37 (m, 4H, coincides with H₂O), 2.44-2.41 (m, 4H), 2.25 (s, 3H); LCMS (M +) m / z 436.50.

Synthesis of 6- (5-methyl-2- (6- (4-methylpiperazin-1-yl) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3 #) -one: (II-25 ) [0295] Into the vial of

5- (2-chloro-5-fluoropyrimidin-4-ylamino) -1H-benzo [d] imidazol-2 (3H) -one (28.0 mg,

0.1 mmol) and 6- (4-methylpiperazin-1-yl) pyridine-3-amine (38.4 mg, 0.2 mmol), iPrOH (2 ml) was added followed by TFA (10 µL, 0, 13 mmol). The vial was sealed, and the solution was stirred at 85 ° C for 2 days. The solvent was removed in vacuo, and the crude product was purified by RP-HPLC. The purified compound (as the trifluoroacetate salt) was dissolved in MeOH-H₂O (1: 4, 2 ml) and passed through a PL-HCO column₃-MP-SPE, washed with the same solvents (1 ml). The filtrate was collected and the solvent removed by lyophilization.

6- (5-methyl-2- (6- (4-methylpiperazin-1-yl) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3 #) - he was obtained as a purple body solid: 26.2 mg (60% yield); ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.97 (s, 1H), 9.49 (s, 1H), 8.15 (s, 1H), 7.82 (s , 1H), 7.65 (d, J = 11.7, 2H), 7.21 (d, J = 8.8, 1H), 7.05 (d, J = 8.4, 1H), 6 , 89 (d, J = 8.9, 1H), 4.34-4.31 (m, 4H), 3.09-3.07 (m, 4H), 2.85 (s, 3H), 2 , 13 (s, 3H).

[0296] The following compounds were prepared similarly to the above examples or by the methods described herein or known to those skilled in the art.

I-1: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-formylphenyl) -5-methylpyrimidine-2,4-diamine [0297] MS (ES) 363.02 (M + H), 361.18 (MH); ¹H NMR (300 MHz, DMSO) δ 10.47 (s, 1H), 9.75 (s, 1H), 7.94 (t, J = 6.3, 2H), 7.70 (m, 3H) , 7.55 (d, J = 7.5, 1H), 7.41 (d, J = 7.9, 3H), 7.24 (t, J = 7.9, 1H), 2.16 ( s, 3H) ppm.

I-2: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-aminocarbonylphenyl) -5-methylpyrimidine-2,4-diamine [0298] MS (ES) 376 , 99 (M + H), 375.11 (MH); ¹H NMR (300 MHz, DMSO) δ 11.66 (s, 1H), 10.36 (s, 1H), 9.61 (s, 1H), 7.93 (m, 2H), 7.76 (s , 1H), 7.63 (d, J = 7.9, 1H), 7.54 (d, J = 7.6, 1H), 7.42 (m, 1H), 7.25 (dd, J = 7.4, 14.7, 1H), 2.14 (s, 3H) ppm.

I-3: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (4-aminocarbonylphenyl) -5-methylpyrimidine-2,4-diamine [0299] MS (ES) 377 , 12 (M + H), 375.04 (MH); ¹H NMR (300 MHz, DMSO) δ 11.78 (s, 1H),

10.40 (s, 1H), 9.61 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.70 (d, J = 8.6, 2H) , 7.51 (d, J = 8.6,

- 141 2H), 7.33 (s, 1H), 2.14 (s, 3H) ppm.

I-4: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (4-formylphenyl) -5-methylpyrimidine-2,4-diamine [0300] MS (ES) 363.02 (M + H), 361.01 (MH); ¹H NMR (300 MHz, DMSO) δ 10.27 (s, 1H), 9.43 (s, 1H), 8.04 - 7.85 (m, 2H), 7.73 (t, J = 9, 6, 1H), 7.57 (d, J = 8.7, 2H), 7.31 (s, 1H), 7.24 (s, 1H), 2.16 (s, 3H) ppm.

I-5: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-methyl-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3 .1] nonan-3-yl) phenyl) -5-methylpyrimidine-2,4-diamine MS (ES) 514.25 (M + H), 512.32 (MH); ¹H NMR (300 MHz, DMSO) δ 8.92 (s, 1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.61 - 7.37 (m, 3H), 7 , 32 (s, 1H), 7.20 (d, J = 8.6, 1H), 7.06 (s, 1H), 6.94 (s, 1H), 3.50 (m, 3H), 2.97 (m, 4H), 2.77 (d, J = 5.0, 4H), 2.59 (d, J = 11.9, 2H), 2.26 (s, 3H), 2, 12 (s, 3H), 2.07 (m, 2H), 1.48 (m, 2H), 0.92 (d, J = 8.0, 9H) ppm.

I-6: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-fluoro-4- (1,5,7-trimethyl-3,7-diazabicyclo [3.3 .1] nonan-3-yl) phenyl) -5-methylpyrimidine-2,4-diamine MS (ES) 518.22 (M + H), 516.30 (MH); ¹H NMR (300 MHz, DMSO) δ 9.20 (s, 1H), 9.14 (m, 1H), 8.40 (s, 1H), 7.85 (s, 2H), 7.63 (s , 2H), 7.42 - 7.25 (m, 1H), 7.14 (m, 1H), 7.06 6.81 (m, 1H), 3.51 - 3.04 (m, 4H) , 2.67 (d, J = 27.5, 4H), 2.08 (m, 6H), 1.41 (m, 2H), 0.91 (d, J = 5.2, 9H) ppm.

I-7: N4- (3-n-propylbenzo [d] oxazol-2 (3H) -on-5-yl) -N2 - ((3-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diamine [0303] ¹H NMR (300 MHz, DMSO) δ 9.41 (s, NH), 8.50 (s, NH), 8.14 (s, 1H), 8.09 - 7.86 (m, 2H), 7 , 64 - 7.23 (m, 6H), 3.68 (t, J = 4.7, 2H), 3.07 (s, 3H), 2.11 (s, 3H), 1.63 (tq , J = 4.4, 9.8, 2H), 0.81 (t, J = 7.6, 3H).

I-9: N4- (3-isopropylbenzo [d] oxazol-2 (3H) -on-5-yl) -N2 - ((3-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diamine [0304] ¹H NMR (300 MHz, DMSO) δ 9.39 (s, NH), 8.43 (s, NH), 8.13 (m, 2H), 8.07-7.85 (m, 2H), 7 , 51 (m, 2H), 7.42 - 7.17 (m, 2H), 4.43-4.34 (m, 1H), 3.05 (s, 3H), 2.11 (s, 3H ), 1.39 (d, J = 6.9, 6H).

I-16: N2 - ((3-methylsulfonyl) phenyl) -N4- (2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) -5-methylpyrimidine-2,4-diamine [0305] ¹H NMR (300 MHz, DMSO) δ 11.50 (s, 1H), 9.40 (s, 1H), 8.39 (s, 1H), 8.17 (s, 1H), 8.05 (d , J = 7.5, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.38-7.32 (m, 3H), 7.02 (d, J = 8 , 4, 1H), 3.10 (s, 3H), 2.11 (s, 3H).

I-17: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (4-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diamine [0306] LCMS (M + ) m / z 411.95; ¹H NMR (300 MHz, DMSO) δ 11.76 (s, 1H), 10.05 (br s,

1H), 9.20 (br s, 1H), 7.98 (s, 1H), 7.80 (d, J = 9.0, 2H), 7.71 (d, J = 9.0, 2H ), 7.37 (d, J = 9.0,

- 142 1H), 7.31 -7.28 (m, 2H), 3.16 (s, 3H), 2.20 (s, 3H).

I-20: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-methylsulfonyl) phenyl) -5-fluoropyrimidine-2,4-diamine [0307] LCMS (M + ) m / z 416.37; ¹H NMR (300 MHz, DMSO) δ 11.68 (br s, 1H), 9.66 (s, 1H), 9.45 (s, 1H), 8.23 ​​(s, 1H), 8.18 ( d, J = 3.7, 1H), 8.08 (d, J = 9.1, 1H), 7.54 - 7.37 (m, 4H), 7.24 (d, J = 8.6 , 1H), 3.16 (s, 3H).

I-21: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (4-methylsulfonyl) phenyl) -5-fluoropyrimidine-2,4-diamine [0308] LCMS (M + ) m / z 415.92; ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.84 (s, 1H),

9.56 (s, 1H), 8.21 (d, J = 3.4, 1H), 7.92 (d, J = 8.9, 2H), 7.73 (d, J = 8.9 , 2H), 7.47 (br d, J = 8.6, 1H), 7.41 (br s, 1H), 7.33 (d, J = 8.6, 1H), 3.16 (s , 3H).

I-22: N4- (benzimidazolin-2-one-5-yl) -N2- (3-methylsulfonyl) phenyl-5-methylpyrimidine-2,4-diamine LCMS (M +) m / z 411.04; ¹H NMR (300 MHz, DMSO) δ 10.71 (s, 1H), 10.67 (s, 1H), 10.18 (br s, 1H), 9.46 (br s, 1H), 8.02 - 7.82 (m, 3H), 7.57 (d, J = 7.0, 1H), 7.39 (dd, J = 8.0, 8.0, 1H), 7.17 - 7, 02 (m, 2H), 6.96 (d, J = 8.0, 1H), 3.14 (s, 3H), 2.19 (s, 3H).

I-23: N4- (benzimidazolin-2-one-5-yl) -N2- (4-methylsulfonyl) phenyl-5-fluoropyrimidine-2,4-diamine LCMS (M +) m / z 414.94; ¹H NMR (300 MHz, DMSO) δ 10.69 (s, 1H), 10.63 (s, 1H), 9.79 (s, 1H), 9.49 (s, 1H), 8.15 (d , J = 3.8, 1H), 7.89 (d, J = 8.5, 2H), 7.68 (d, J = 8.5, 2H), 7.27 (d, J = 8, 2, 1H), 7.19 (s, 1H), 6.96 (d, J = 8.2, 1H), 3.14 (s, 3H).

I-26: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-cyanophenyl) -5-methylpyrimidine-2,4-diamine [0311] LCMS (M +) m / z 359.06; ¹H NMR (300 MHz, DMSO) δ 11.64 (s, 1H), 10.07 (br s, 1H), 9.34 (br s, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.69 - 7.66 (m, 1H), 7.51 - 7.3 (m, 2H), 7.33 (d, J = 8.3, 1H), 7.28 - 7.16 (m, 2H), 2.19 (s, 3H).

I-27: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (4-cyanophenyl) -5-methylpyrimidine-2,4-diamine [0312] LCMS (M +) m / z 359.47; ¹H NMR (300 MHz, DMSO) δ 11.09 (br s, 1H), 9.64 (s, 1H), 8.51 (s, 1H), 8.30 (s, 1H), 7.98 ( s, 1H), 7.88 (d, J = 8.8, 2H), 7.58 (d, J = 8.8, 2H), 7.38 (s, 1H), 7.32 (s, 1H), 2.16 (s, 3H).

I-28: N4- (benzimidazolin-2-one-5-yl) -N2- (3-cyanophenyl) -5-methylpyrimidine-2,4-diamine LCMS (M +) m / z 358.02; ¹H NMR (300 MHz, DMSO) δ 10.67 (s, 2H), 10.43 (s, 1H), 9.55 (s, 1H), 7.97 (d, J = 11.6, 2H) , 7.71 (d, J = 8.1, 1H), 7.47 - 7.36 (m, 2H), 7.18-6.92 (m, 3H), 2.19 (s, 3H) .

I-29: N4- (benzimidazolin-2-one-5-yl) -N2- (4-cyanophenyl) -5-methylpyrimidine-2,4-diamine

143 [0314] LCMS (M +) m / z 358.50; ¹H NMR (300 MHz, DMSO) δ 10.75 (s, 1H), 10.68 (s, 1H), 10.08 (br s, 1H), 9.24 (br s, 1H), 7.93 (s, 1H), 7.73 (d, J = 8.7, 2H), 7.55 (d, J = 8.7, 2H), 7.10 - 7.08 (m, 2H), 7 , 00 (d, J = 8.7, 1H), 2.18 (s, 3H).

I-33: N4- (3-phosphorylmethylbenzo [d] oxazol-2 (3H) -on-5-yl) -N2 - ((3-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diamine [0315] LCMS (M +) m / z 522.40; ¹H NMR (300 MHz, D2O) δ 7.68 (br s, 2H), 7.59 (br d, J = 6.7, 1H), 7.40 - 7.21 (m, 4H), 7, 06 (d, J = 8.5, 1H), 5.38 (d, J = 5.7, 2H), 3.06 (s, 3H), 2.01 (s, 3H).

I-36: N4- (1,3-dimethylbenzimidazolin-2-one-5-yl) -N2 - ((3-methylsulfonyl) phenyl) -5-methylpyrimidine-2,4-diamine [0316] LCMS (M +) m / from 439.01; ¹H NMR (300 MHz, DMSO) δ 10.37 (br s, 1H), 9.62 (br s, 1H), 7.95 - 7.90 (m, 3H), 7.56 (d, J = 7.6, 1H), 7.34-7.39 (m, 2H), 7.25 - 7.18 (m, 2H), 3.40 (s, 3H), 3.26 (s, 3H) , 3.09 (s, 3H), 2.21 (s, 3H).

I-41: N4- (1,3-dimethylbenzimidazolin-2-one-5-yl) -N2 - ((3-methylsulfonyl) phenyl) -5-fluoropyrimidine-2,4-diamine [0317] LCMS (M +) m / from 442.95; ¹H NMR (300 MHz, DMSO) δ 9.60 (s, 1H), 9.44 (s, 1H), 8.20 (s, 1H), 8.16 (d, J = 3.7, 1H) , 8.09 (br d, J = 6.0, 1H), 7.57 (s, 1H), 7.46 - 7.42 (m, 2H), 7.38 (br d, J = 8, 3, 1H), 7.14 (d, J = 8.3, 1H), 3.38 (s, 3H), 3.32 (s, 3H), 3.13 (s, 3H).

I-44: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-cyanophenyl) -5-fluoropyrimidine-2,4-diamine [0318] LCMS (M +) m / z 362.96; ¹H NMR (300 MHz, DMSO) δ 9.72 (s, 1H), 9.70 (br s, 1H), 9.51 (s, 1H), 8.27 (s, 1H), 8.19 ( d, J = 3.8, 1H), 7.81 (d, J = 9.4, 1H), 7.47 - 7.21 (m, 5H).

I-45: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (4-cyanophenyl) -5-fluoropyrimidine-2,4-diamine [0319] LCMS (M +) m / z 362.95; ¹H NMR (300 MHz, DMSO) δ 11.84 (br s, 1H), 9.86 (s, 1H), 9.55 (s, 1H), 8.20 (d, J = 3.7, 1H ), 7.88 (d, J = 8.8, 2H), 7.65 (d, J = 8.8, 2H), 7.44-7.41 (m, 2H), 7.31 (d , J = 8.4, 1H).

I-46: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2 - ((3-morpholinyl) phenyl) -5-methylpyrimidine-2,4-diamine [0320] LCMS ( M +) m / z 419.10; ¹H NMR (300 MHz, DMSO) δ 11.62 (br s, 1H), 8.87 (s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 7.91 ( s, 1H), 7.38 - 7.34 (m, 2H), 7.24 (d, J = 8.2, 1H), 7.16 (d, J = 8.2, 1H), 7, 01 (dd, J = 8.2, 8.2, 1H), 6.47 (d, J = 8.2, 1H), 3.65 - 3.62 (m, 4H), 2.91 - 2 , 88 (m, 4H), 2.13 (s, 3H).

I-47: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2 - ((3-morpholinyl) phenyl) -5-fluoropyrimidine-2,4-diamine [0321] LCMS (M +) m / z 423.07; ¹H NMR (300 MHz, DMSO) δ 11.92 (br s, 1H), 9.39 (s, 1H),

9.12 (s, 1H), 8.12 (d, J = 3.7, 1H), 7.47 - 7.45 (m, 2H), 7.29 - 7.23 (m, 2H), 7.18 (d, J = 8.1,

- 144 1H), 7.06 (dd, J = 8.1, 8.1, 1H), 6.52 (d, J = 8.2, 1H), 3.68 - 3.65 (m, 4H ), 2.97-2.94 (m, 4H).

I-48: N4- (benzo [d] oxazol-2 (3H) -on-6-yl) -N2 - ((3-morpholinyl) phenyl) -5-methylpyrimidine-2,4-diamine [0322] ¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.97 (s, 1H), 8.46 (s, 1H), 7.90 (s, 1H), 7.81 (s , 1H), 7.37 (d, J = 8.3, 1H), 7.27 (s, 1H), 7.14 (d, J = 8.3, 1H), 7.07 - 7.01 (m, 2H), 6.58 - 6.50 (m, 1H), 3.68 - 3.65 (m, 4H), 2.95 - 2.92 (m, 4H), 2.14 (s , 3H); LCMS (M +) m / z 419.03.

I-49: N4- (3-methylbenzo [d] oxazol-2 (3H) -on-6-yl) -N2 - ((3-morpholinyl) phenyl) -5-methylpyrimidine-2,4-diamine [0323] ¹H NMR (300 MHz, DMSO) δ 9.00 (br s, 1H), 8.50 (br s, 1H), 8.90 (s, 1H), 7.88 (s, 1H), 7.44 (d, J = 8.2, 1H), 7.25 - 7.22 (m, 2H), 7.15 (d, J = 8.2, 1H), 7.05 (dd, J = 8, 2, 8.2, 1H), 6.58 - 6.51 (m, 1H), 3.67 - 3.64 (m, 4H), 3.39 (s, 3H), 2.93 - 2, 90 (m, 4H), 2.15 (s, 3H); LCMS (M +) m / z 433.11.

I-59: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) -5-fluoropyrimidine-2,4-diamine [0324 ] ¹H NMR (300 MHz, DMSO) δ 9.66 (s, 1H), 9.53 (s, 1H), 8.19 (s, 1H), 8.15 (d, J = 3.7, 1H) , 8.02 (d, J = 8.8, 1H), 7.99 (s, 1H), 7.54 - 7.36 (m, 3H), 7.19 (d, J = 8.5, 1H), 3.34 (s, 3H), 3.12 (s, 3H).

I-60: N2- (4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) -5-fluoropyrimidine-2,4-diamine [0325] ¹H NMR (300 MHz, DMSO) δ 9.79 (s, 1H), 9.56 (s, 1H), 8.16 (d, J = 3.7, 1H), 7.97 (s, 1H) , 7.88 (d, J = 8.9, 2H), 7.70 (d, J = 8.8, 2H), 7.45 (s, 1H), 7.22 (d, J = 8, 5, 1H), 3.34 (s, 3H), 3.12 (s, 3H).

I-65: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) -5-methylpyrimidine-2,4-diamine [0326 ] ¹H NMR (300 MHz, DMSO) δ 10.09 (s, 1H), 9.34 (s, 1H), 7.94-7.87 (m, J = 10.1, 3H), 7.66 ( s, 1H), 7.51 (d, J = 7.8, 1H), 7.43 (t, J = 7.8, 1H), 7.34 (d, J = 10.1, 1H), 7.22 (d, J = 8.4, 1H), 3.35 (s, 3H), 3.09 (s, 3H), 2.15 (s, 3H).

I-66: N2 - ((4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) -5-methylpyrimidine-2,4-diamine [0327 ] ¹H NMR (300 MHz, DMSO) δ 10.24 (s, 1H), 9.35 (s, 1H), 7.95 (s, 1H), 7.82-7.61 (m, 5H), 7 , 35 (d, J = 8.3, 1H), 7.27 (d, J = 8.3, 1H), 3.36 (s, 3H), 3.13 (s, 3H), 2.16 (s, 3H).

I-69: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-5-yl) -5-methylpyrimidine-2,4-diamine [0328 ] ¹H NMR (300 MHz, DMSO) δ 10.23 (s, 1H), 9.44 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H),

7.84 (d, J = 8.2, 1H), 7.51 (d, J = 7.7, 1H), 7.44-7.39 (m, 2H), 7.32 (d, J = 8.6, 1H), 7.23 (d, J = 8.6, 1H), 3.20 (s, 3H), 3.06 (s, 3H), 2.16 (s, 3H).

- 145 I-70: N2 - ((4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-5-yl) -5-methylpyrimidine-2,4-diamine [0329] ¹H NMR (300 MHz, DMSO) δ 10.16 (s, 1H), 9.30 (s, 1H), 7.96 (s, 1H), 7.74 (d, J = 8.9, 2H) , 7.65 (d, J = 8.9, 2H), 7.48 (s, 1H), 7.38 (d, J = 8.6, 1H), 7.28 (d, J = 8, 6, 1H), 3.25 (s, 3H), 3.12 (s, 3H), 2.16 (s, 3H).

I-77: N2 - ((3-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-5-yl) -5-fluoropyrimidine-2,4-diamine [0330 ] ¹H NMR (300 MHz, DMSO) δ 9.64 (s, 1H), 9.56 (s, 1H), 8.16 (s, 2H), 7.99 (d, J = 8.9, 1H) , 7.65 (s, 1H), 7.51 - 7.33 (m, 3H), 7.28 (d, J = 8.8, 1H), 3.27 (s, 3H), 3.09 (s, 3H).

I-78: N2 - ((4-methylsulfonyl) phenyl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-5-yl) -5-fluoropyrimidine-2,4-diamine [0331 ] ¹H NMR (300 MHz, DMSO) δ 9.80 (s, 1H), 9.59 (s, 1H), 8.18 (d, J = 3.6, 1H), 7.86 (d, J = 8.8, 2H), 7.70 (s, 1H), 7.66 (d, J = 6.3, 2H), 7.39-7.30 (m, 2H), 3.28 (s, 3H), 3.11 (s, 3H).

I-100: N2 - ((3-methylsulfonyl) phenyl) -N4- (2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) -5-methylpyrimidine-2,4-diamine;

I-101: N2 - ((4-methylsulfonyl) phenyl) -N4- (2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) -5-methylpyrimidine-2,4-diamine;

I-106: N4- (benzooxazolin-2-one-5-yl) -N2- (3-trifluoromethoxyphenyl) 5-methylpyrimidine-2,4-diamine trifluoroacetate salt;

I-107: N4- (benzooxazolin-2-one-5-yl) -N2- (3-trifluoromethoxyphenyl) 5-fluoropyrimidine-2,4-diamine trifluoroacetate salt;

I-108: N4- (benzooxazolin-2-one-5-yl) -N2- (4-trifluoromethoxyphenyl) 5-methylpyrimidine-2,4-diamine trifluoroacetate salt;

I-109: N4- (benzooxazolin-2-one-5-yl) -N2- (4-trifluoromethoxyphenyl) 5-fluoropyrimidine-2,4-diamine trifluoroacetate salt;

I-110: N4- (benzooxazolin-2-one-5-yl) -N2- [3-trifluoromethyl-4- (4-ethylpiperazin-1-yl) phenyl] -5-methylpyrimidine-2,4-diamine [0332 ] LCMS (m / z): 514 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 11.51 (s, 1H), 9.22 (s, 1H), 8.38 (s, 1H), 7.94 (s, 1H), 7.87 (m, 2H), 7.33-7.18 (m, 4H), 2.80 (s, 4H), 2.49 (br s, 6H), 2.09 (s, 3H), 1.04 (t, 3H, J = 6.3 Hz).

I-111: N4- (benzooxazolin-2-one-5-yl) -N2- [3-methyl-4- (4-methylpiperazin-1-yl) phenyl] -5-methylpyrimidine-2,4-diamine [0333] LCMS (m / z): 458 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 8.67 (s, 1H), 8.27 (s,

1H), 7.80 (s, 1H), 7.31 (m, 4H), 7.19 (d, 1H, J = 9.3 Hz), 6.69 (d, 1H, J = 8.7 Hz), 3.94 (s,

1H), 3.80 (s, 1H), 3.30 (d, 1H, J = 10.2 Hz), 3.21 (d, 1H, J = 8.7 Hz), 3.15 (s, 1H), 2.92 d,

1H, J = 10.5 Hz), 2.57 (s, 3H), 2.07 (s, 3H), 2.04 (d, 1H, J = 9.6 Hz), 1.99 (d, 1H, J = 10.8

Hz), 2.00 (s, 3H), 1.88 (d, 1H, J = 10.8 Hz).

- 146 I-115: N4- (benzooxazolin-2-one-5-yl) -N2- (3,4,5-trimethoxyphenyl) -5-fluoropyrimidine-2,4-diamine [0334] LCMS (m / z): 428 (Μ + H); ¹H WR (DMSO 300 Μ ^): δ 11.61 (s, 1H), 9.70 (s, 1H), 9.38 (s, 1H), 8.11 (d, 1H, J = 4.2 Hz), 7.44 (dd, 1H, J = 1.8 and 8.7 Hz), 7.34 (d, 1H, J = 1.8 Hz), 7.19 (d, 1H, J = 8 , 4 Hz), 6.93 (s, 2H), 3.58 (s, 3H), 3.57 (s, 6H).

I-116: N2- (3- (difluoromethoxy) -4-methoxyphenyl) -N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -5-methylpyrimidine-2,4-diamine [0335] LCMS : purity: 96.68%; MS (m / e): 430.24 (Μ + H);¹H WR (300 Ylllz, DMSO) δ 11.33 (br, 1H), 8.92 (s, 1H), 8.29 (s, 1H), 7.84 (s, 1H), 7.55 (s , 1H), 7.46 (d, J = 8.7, 1H),

7.30 (d, J = 8.7, 1H), 7.29 (s, 1H), 7.18 (d, J = 9.0, 1H), 6.92 (d, J = 8.7 , 1H), 6.81 (t, J = 75, 1H), 3.73 (s, 3H), 2.08 (s, 3H); ¹⁹FW (282 Ylllz, DMSO) δ - 96.44 (d, J = 73).

I-117: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (4-trifluoromethylsulfonyl) phenyl-5-methyl-pyrimidine-2,4-diamine LCMS: purity: 91.03%; MS (m / e): 466.14 (Μ + H);¹H WR (300 \ IIIz, DMSO) δ 11.62 (s, 1H), 10.02 (s, 1H), 8.59 (s, 1H), 8.00 (d, J = 9.0, 2H ), 7.98 (d, J = 4.2, 1H), 7.78 (d, J = 8.7, 2H), 7.28 (s, 3H), 2.13 (s, 3H); ¹⁹FW (282 µLz, DMSO) δ - 94.87.

I-118: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-trifluoromethylsulfonyl) phenyl-5-methyl-pyrimidine-2,4-diamine LCMS: purity: 100%; MS (m / e): 466.14 (Μ + H);¹HW (300 Ylllz, DMSO) δ

11.56 (s, 1H), 9.64 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.30 (d, J = 7.2, 1H) , 7.94 (s, 1H), 7.56 (t, J = 7.8, 1H), 7.51 (t, J = 7.2, 1H), 7.30 (m, 2H), 7 , 22 (d, J = 9.0, 1H), 2.11 (s, 3H); ¹⁹FW (282 ΜΙ Iz, DMSO) δ - 94.39.

I-119: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3,4,5-trimethoxy) phenyl-5-methylpyrimidine-2,4-diamine [0338] LCMS: purity: 99.98%; MS (m / e): 424.28 (Μ + H);¹H WR (300 Μ ^, DMSO) δ

11.56 (s, 1H), 9.07 (br, 1H), 8.59 (br, 1H), 7.84 (s, 1H), 7.31 (d, J = 9.1, 2H) , 7.18 (d, J = 8.4, 1H), 6.95 (s, 2H), 3.56 (s, 3H), 3.52 (s, 6H), 2.09 (s, 3H) ).

I-120: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2 - ((4- (1,4-diazabicyclo [3.2.2] nonan-4-yl) -3-methyl ) phenyl) -5-methylpyrimidine-2,4-diamine MS (ES) 472.13 (Μ + H); ¹H WR (CD3OD, 300 ΜΗς) 8.37 (m, 2H), 7.78-6.95 (m, 7H), 3.59-3.42 (m, 9H), 2.42-2.21 (m, 4H), 2.13 (s, 3H), 2.11 (s, 3H).

I-121: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (4- (8-methyl-8-azabicyclo [3.2.1] octane-3-ylamino) phenyl) - 5-methylpyrimidine-2,4-diamine MS (ES) 472.12 (Μ + H); ¹H WR (CD3OD, 300 Μΐυ 8,40 (m, 2H), 7,63-6,40 (m, 9H), 3,95-3,53 (m, 4H), 2,81 (s, 3H), 2,66-2,15 (m, 7H), 2,13 (s, 3H).

I-122 N4-(benzo[d]oksazol-2(3H)-on-5-ylo)-N2-((4-(dihydro-1H-pirydo[1,2-a]pirazyn2(6H,7H,8H,9H,9aH)-ylo)-3-metylo)fenylo)-5-metylopirymidyno-2,4-diamina;

- 147 [0341] MS (ES) 486,17 (M+H); ¹H NMR (CD3OD, 300 MHz) 8,35 (m, 2H), 7,71 (m, 1H), 7,298-6,85 (m, 6H), 3,48 (m, 3H), 3,25-2,78 (m, 6H), 2,16 (s, 3H), 2,09 (s, 3H), 2,03-1,51 (m, 6H).

1- 123: N4-(benzo[d]oksazol-2(3H)-on-5-ylo)-N2-(4-(8-metylo-2,8-diazabicyklo[3.2.1]oktan2- ylo)fenylo)-5-metylopirymidyno-2,4-diamina [0342] MS (ES) 458,10 (M+H); ¹H NMR (CD3OD, 300 MHz) 8,41 (brs, 2H), 7,68 (s, 1H), 7,40-6,74 (m, 8H), 4,02 (brs, 2H), 3,59 (m, 2H), 3,17 (m, 2H), 2,87 (s, 3H), 2,29-2,15 (m, 4H), 2,13 (s, 3H).

I-124: N4-(benzo[d]oksazolin-2(3H)-on-5-ylo)-5-metylo-N2-[3-(morfolin-4-ylo)-4-trifluorometoksyfenylo]-2,4-pirymidynodiamina [0343] ¹H NMR (DMSO d6, 300 MHz): δ 11,53 (s, 1H), 9,10 (s, 1H), 8,37 (s, 1H), 7,88 (s, 1H), 7,47 (s, 1H), 7,32-7,18 (m, 3H), 7,00 (d, 1H, J = 8,7 Hz), 4,09 (q, 1H, J = 5,4 Hz), 3,58 (s, 3H), 3,15 (d, 2H, J= 5,1 Hz), 2,69 (s, 3H), 2,08 (s, 3H); LCMS (m/z): 503 (M+H).

1-125: ester metylowy kwasu 4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzoesowego [0344] ¹H NMR (DMSO, 300 MHz): δ 9,30 (s, 1H), 8,41 (s, 1H), 8,22 - 8,31 (m, 1H), 8,17 (s, 1H), 7,91 (s, 1H), 7,67 - 7,78 (m, 2H), 7,54 - 7,65 (m, 1H), 7,30 - 7,40 (m, 2H), 7,25 (d, J = 8,3 Hz, 1H), 3,29 - 3,40 (m, 3H) 2,09 (s, 3H) ppm; MS (ES) 392 (M+H).

I-126: kwas 4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2yloamino]benzoesowy [0345] ¹H NMR (DMSO, 300 MHz): δ 9,26 (s, 1H), 8,53 (d, J = 4,4 Hz, 1H), 8,41 (br. s., 1H), 8,34 (d, J= 8,3 Hz, 2H), 8,14 (s, 1H), 7,90 (s, 1H), 7,68 (m, 2H), 7,44 - 7,52 (m, 1H), 7,27 - 7,38 (m, 1H), 2,04 - 2,15 (m, 3H) ppm; MS (ES) 378 (M+H).

I-127: N-(2-dietyloaminoetylo)-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzamid [0346] MS (ES) 476 (M+H)

I-128: 5-{2-[4-(3-dietyloaminopirolidyno-1-karbonylo)fenyloamino]-5-metylopirymidyn-4yloamino}-3H-benzooksazol-2-on [0347] MS (ES) 502 (M+H)

I-129: 5-[2-(4-acetylofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0348] ¹H NMR (DMSO-d6) δ: 9,31 (s, 1H), 8,38 (s, 1H), 8,20 - 8,33 (m, 1H), 8,18 (s, 1H),

7,88 (s, 1H), 7,66 - 7,79 (m, 2H), 7,52 - 7,69 (m, 1H), 7,32 - 7,42 (m, 2H), 7,25 (d, J = 8,2 Hz, 1H), 2,23 (s, 3H) 2,09 (s, 3H) ppm; MS (ES) 376 (M+H);

I-130: 5-[2-(3-acetylofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0349] ¹H NMR (DMSO, 300 MHz): δ 11,69 (s, 1H), 10,37 (br. s., 1H), 9,60 (br. s., 1H), 7,90 (d, J= 7,4 Hz, 2H), 7,71 (d, J= 8,0 Hz, 1H), 7,62 (d, J= 7,7 Hz, 1H), 7,29 - 7,43 (m, 1H), 7,14

- 148 - 7,27 (m, 4H), 2,39 (s, 3H), 2,14 (s, 3H) ppm; MS (ES) 376 (M+H).

I-131: 2-metylo-5-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2yloamino]benzonitryl [0350] ¹H NMR (DMSO, 300 MHz): δ 11,66 (s, 1H), 10,50 (br. s., 1H), 9,66 (br. s., 1H), 7,93 (d, J= 3,6 Hz, 2H), 7,45 (dd, J= 8,5, 1,7 Hz, 1H), 7,30 (d, J= 8,3 Hz, 2H), 7,07-7,22 (m, 2H), 2,35 (s, 3H), 2,13 (s, 3H) ppm; MS (ES) 373 (M+H).

1- 132: N,N-dimetylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn2- yloamino]benzamid [0351] MS (ES) 405 (M+H)

I-133: N-metylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2yloamino]benzamid [0352] ¹H NMR (DMSO, 300 MHz): δ 11,92 (s, 1H), 10,90 (s, 1H), 10,03 (s, 1H), 8,52-8,28 (m, 1H), 7,95 (s, 1H), 7,67 (d, J= 8,6, 2H), 7,45 (d, J= 8,6, 2H), 7,34 (s, 1H), 7,25 (s, 2H),

2.72 (s, 3H), 2,15 (s, 3H); ppm; MS (ES) 391 (M+H).

I-134: sól mrówczanowa N-cyklopropylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5iloamino)pirymidyn-2-yloamino]benzamidu

I-135: 4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]N-fenylobenzamid [0353] ¹H NMR (DMSO, 300 MHz): δ 11,79 (s, 1H), 10,49 - 10,22 (m, 1H), 10,05 (s, 1H), 9,71 - 9,38 (m, 1H), 7,95 (s, 1H), 7,79 (d, J = 8,7, 1H), 7,73 (d, J = 7,6, 1H), 7,62 (d, J= 8,7, 1H), 7,39 - 7,22 (m, 5H), 7,12 - 7,02 (m, 1H), 2,15 (s, 3H) ppm; MS (ES) 453 (M+H).

1- 136: 4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]2- pirolidyn-1-ylobenzamid [0354] ¹H NMR (DMSO, 300 MHz): δ 11,73 (s, 1H), 10,29 (s, 1H), 9,62 (s, 1H), 7,97 (s, 1H),

7.73 (s, 1H), 7,49 - 7,11 (m, 2H), 7,00 - 6,52 (m, 2H), 3,13 - 2,80 (m, 4H), 2,32-1,97 (m, 3H), 1,85 - 1,54 (m, 4H) ppm; MS (ES) 446 (M+H).

I-137: N-etylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzamid [0355] ¹H NMR (DMSO, 300 MHz): δ 11,64 (s, 1H), 9,32 (s, 1H), 8,47 (s, 1H), 8,18 (s, 1H),

7,89 (d, J= 9,8, 1H), 7,70 (d, J= 8,8, 2H), 7,61 (d, J= 8,8, 2H), 7,45 - 7,15 (m, 3H), 3,30 3,18 (m, 2H), 2,10 (s, 3H), 1,08 (t, J= 7,2, 2H) ppm; MS (ES) 405 (M+H).

I-138: sól kwasu mrówkowego N-cyklobutylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzamidu [0356] MS (ES) 431 (M+H)

1- 139: N-izopropylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn2- yloamino]benzamid

- 149 [0357] ¹H NMR (DMSO, 300 MHz): δ 11,64 (s, 1H), 9,31 (s, 1H), 8,47 (s, 1H), 7,91 (s, 2H), 7,66 (dd, J= 8,8, 22,3, 4H), 7,33 (s, 1H), 7,29 - 7,21 (m, 2H), 4,18 - 3,93 (m, 1H), 2,10 (s, 3H), 1,12 (d, J= 6,6, 6H) ppm; MS (ES) 419 (M+H).

I-140: sól mrówczanowa N-cyklopropylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5iloamino)pirymidyn-2-yloamino]benzamidu

I-141: sól kwasu trifluorooctowego 2-chloro-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzamidu [0358] ¹H NMR (DMSO, 300 MHz): δ 11,89 - 11,38 (m, 1H), 10,43 - 10,06 (m, 1H), 9,77 9,20 (m, 1H), 7,93 (s, 1H), 7,67 (s, 1H), 7,58 - 7,36 (m, 1H), 7,29 (m, 2H), 7,20 (m, 2H), 2,13 (s, 3H) ppm; MS (ES) 410/412 (M+H).

I-142: sól kwasu trifluorooctowego N-cyklopropylo-4-[5-metylo-4-(2-okso-2,3dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzamidu

I-143: N-cyklopropylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzamid [0359] ¹H NMR (DMSO, 300 MHz): δ 11,62 (s, 1H), 9,27 (s, 1H), 8,41 (s, 1H), 8,14 (s, 1H),

7,90 (s, 1H), 7,65 (m, 3H), 7,29 (m, 3H), 3,33 (s, 3H), 2,87 - 2,61 (m, 1H), 0,59 (m, 4H) ppm; MS (ES) 417 (M+H).

I-144: N-cyklobutylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzamid;

1- 145: 4-[5-metylo-4-(2-okso-3-propionylo-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn2- yloamino]benzamid [0360] MS (ES) 433 (M+H)

I-146: (5-(2-(4-karbamoilofenyloamino)-5-metylopirymidyn-4-yloamino)-2-oksobenzo[d]oksazol-3(2H)-ilo)metylofosforan di-tert-butylu [0361] ¹H NMR (DMSO, 300 MHz): δ 9,38 (s, 1H), 8,50 (s, 1H), 8,31 (s, 1H), 7,95 (s, 1H), 7,76 (dd, J = 8,7, 26,3, 5H), 7,36 (s, 2H), 7,12 (s, 1H), 5,63 (d, J = 11,1, 2H), 2,12 (s, 3H),

1,31 (s, 18H) ppm; MS (ES) 599 (M+H).

I-147: dwuwodorofosforan (5-(2-(4-karbamoilofenyloamino)-5-metylopirymidyn-4-yloamino)-2-oksobenzo[d]oksazol-3(2H)-ilo)metylu [0362] MS (ES) 487 (M+H)

I-148: (5-(2-(4-karbamoilofenyloamino)-5-metylopirymidyn-4-yloamino)-2-oksobenzo[d]oksazol-3(2H)-ilo)metylofosforan sodowy [0363] MS (ES) 487 (M+H)

I-150: dwuwodorofosforan(5-(2-(4-(cyklobutylokarbamoilo)fenyloamino)-5-metylopirymidyn-4-yloamino)-2-oksobenzo[d]oksazol-3(2H)-ilo)metylu [0364] MS (ES) 541 (M+H)

- 150 I-151: (5-(2-(4-(cyklobutylokarbamoilo)fenyloamino)-5-metylopirymidyn-4-yloamino)-2oksobenzo[d]oksazol-3(2H)-ilo)metylofosforan sodowy [0365] MS (ES) 541 (M+H)

I-152: (5-(2-(4-(cyklobutylokarbamoilo)fenyloamino)-5-metylopirymidyn-4-yloamino)-2oksobenzo[d]oksazol-3(2H)-ilo)metylofosforan di-tert-butylu [0366] MS (ES) 653 (M+H).

I-153: 5-[2-(4-chloro-3-trifluorometylofenyloamino)-5-metylopirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0367] ¹H NMR (300 MHz, DMSO) δ 9,49 (s, 1H), 8,46 (s, 1H), 8,20 (s, 1H), 8,14 (s, 1H), 7,92 (s, 2H), 7,42 (d, J= 8,8, 1H), 7,26 (m, 2H), 2,09 (s, 3H) ppm; MS (ES) 435/437 (M+H);

I-154: 5-[5-metylo-2-(4-metylo-3-trifluorometylofenyloamino)pirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0368] ¹H NMR (DMSO-d6) δ: 11,71 (s, 1H), 10,59 (br. s., 1H), 9,68 (br. s., 1H), 7,94 (s, 1H), 7,72 (s, 1H), 7,53 (d, J = 8,3 Hz, 1H), 7,25 (d, J = 8,5 Hz, 2H), 7,08 - 7,20 (m, 2H), 2,32 (br. s., 3H), 2,13 (s, 3H) ppm; MS (ES) 416 (M+H);

I-155: 5-[5-metylo-2-(4-metylosulfanylo-3-trifluorometylofenyloamino)pirymidyn-4-yloamino]-3H-benzooksazol-2-on [0369] ¹H NMR (DMSO, 300 MHz): δ 9,35 (s, 1H), 8,42 (s, 1H), 8,05 (s, 1H), 7,90 (s, 2H),

7,32 (s, 2H), 7,23 (d, J= 6,6, 2H), 2,43 (s, 3H), 2,08 (s, 3H) ppm; MS (ES) 448 (M+H).

1- 156: 4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]2- (4-metylo-piperydyn-1-ylo)benzamid [0370] MS (ES) 474 (M+H)

I-157: 5-[2-(3-cyklopentanosulfonylofenyloamino)-5-metylopirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0371] ¹H NMR (DMSO, 300 MHz): δ 9,39 (s, 1H), 8,40 (s, 1H), 8,15 (m, 2H), 7,91 (s, 1H), 7,29 (m, 3H), 2,81 (m, 1H), 2,09 (s, 3H), 1,92 - 1,64 (m, 4H), 1,68 - 1,38 (m, 4H) ppm; MS (ES) 466 (M+H).

I-158: 5-[5-metylo-2-(3-trifluorometylofenyloamino)pirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0372] ¹H NMR (DMSO, 300 MHz): δ 9,38 (s, 1H), 8,42 (s, 1H), 8,29 (s, 1H), 8,07 (s, 1H), 7,88 (d, J = 16,6, 2H), 7,41 - 7,16 (m, 3H), 7,11 (s, 1H), 2,09 (s, 3H) ppm; MS (ES) 402 (M+H).

I-159: ester metylowy kwasu 2-metylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5iloamino)pirymidyn-2-yloamino]benzoesowego [0373] MS (ES) 406 (M+H)

I-160: 5-[5-metylo-2-(4-trifluorometylofenyloamino)pirymidyn-4-yloamino]-3H- 151 benzooksazol-2-on [0374] ¹H NMR (DMSO-d6) δ: 11,75 (s, 1H), 10,16 (br. s., 1H), 9,23 - 9,61 (m, 1H), 7,93 (s, 1H), 7,61 - 7,78 (m, 2H), 7,44 - 7,63 (m, 3H), 7,16 - 7,40 (m, 2H), 2,13 (s, 3H) ppm; MS (ES) 402 (M+H);

I-161: 5-[5-metylo-2-(4-trifluorometoksy-3-trifluorometylofenyloamino)pirymidyn-4-yloamino]-3H-benzooksazol-2-on [0375] MS (ES) 486 (M+H)

I-162: sól trifluorooctanowa 5-[2-(3-fluoro-5-trifluorometylofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-onu [0376] ¹H NMR (DMSO, 300 MHz): δ 11,65 (s, 1H), 10,32 - 10,20 (m, 1H), 9,40 - 9,28 (m, 1H), 7,95 (s, 1H), 7,81 - 7,66 (d, 1H), 7,57 (s, 1H), 7,33 - 7,06 (m, 4H), 2,13 (s, 3H) ppm; MS (ES) 420 (M+H).

I-163: 5-[2-(4-fluoro-3-trifluorometoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0377] MS (ES) 436 (M+H).

I-164: sól kwasu trifluorooctowego 5-[5-metylo-2-(4-metylo-3-trifluorometylofenyloamino)pirymidyn-4-yloamino]-3H-benzooksazol-2-onu, [0378] Aby zapoznać się z ¹H NMR zob. I-154; MS (ES) 413 (M+H).

I-165: 5-{2-[4-(2-metoksyetoksy)-3-trifluorometylofenyloamino]-5-metylopirymidyn-4-yloamino}-3H-benzooksazol-2-on [0379] ¹H NMR (DMSO, 300 MHz): δ 11,67 - 11,58 (m, 1H), 9,65 - 9,56 (m, 1H), 9,06-8,94 (m, 1H), 7,86 (m, 2H), 7,23 (d, J = 8,0, 1H), 7,19 - 7,05 (m, 1H), 6,97 (d, J = 8,7, 2H), 6,83 (m, 1H), 4,10 - 3,99 (m, 2H), 3,60 (m, 2H), 3,28 (s, 3H), 2,10 (s, 3H) ppm; MS (ES) 476 (M+H).

I-166: 5-[2-(4-izopropylo-3-metylofenyloamino)-5-metylopirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0380] MS (ES) 390 (M+H)

I-167: 5-[2-(3-chloro-4-trifluorometylofenyloamino)-5-metylopirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0381] ¹H NMR (DMSO-d6) δ: 11,79 (s, 1H), 10,96 (br. s., 1H), 9,73 (br. s., 1H), 8,00 (s, 1H), 7,87 (s, 1H), 7,61 (d, J= 8,8 Hz, 1H), 7,28 - 7,45 (m, 2H), 7,10 - 7,26 (m, 2H), 2,14 (s, 3H) ppm; MS (ES) 436 (M+H);

I-168: 5-[2-(4-etoksy-3-trifluorometylofenyloamino)-5-metylopirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0382] MS (ES) 446 (M+H)

I-169: 5-[2-(3,5-bistrifluorometylofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzo- 152 oksazol-2-on [0383] MS (ES) 470 (M+H)

I-170: kwas 2-metylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzoesowy [0384] MS (ES) 392 (M+H)

I-171: N-etylo-2-metylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzamid [0385] MS (ES) 419 (M+H)

I-172: 5-[2-(4-chlorofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0386] ¹H NMR (DMSO, 300 MHz): δ 9,16 (s, 1H), 8,37 (s, 1H), 8,23 (s, 1H), 7,87 (s, 1H), 7,67 (d, J = 8,9, 1H), 7,43 - 7,20 (m, 2H), 7,14 (d, J = 8,9, 1H), 2,08 (s, 3H) ppm; MS (ES) 368 (M+H).

I-173: 5-[2-(3-chlorofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0387] MS (ES) 368 (M+H)

I-174: 5-(5-metylo-2-fenyloaminopirymidyn-4-yloamino)-3H-benzooksazol-2-on [0388] ¹H NMR (DMSO-d6) δ: 11,93 (s, 1H), 10,81 (s, 1H), 9,85 (s, 1H), 7,90 (s, 1H), 7,40 (d, J = 8,0 Hz, 2H), 7,26 - 7,32 (m, 2H), 7,11 - 7,23 (m, 3H), 6,98 - 7,08 (m, 1H), 2,13 (s, 3H) ppm; MS (ES) 334 (M+H);

I-175: 5-[2-(3-bromo-fenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0389] MS (ES) 412/414 (M+H)

I-176: 5-[2-(4-chloro-2,5-dimetylofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0390] MS (ES) 396/398 (M+H)

I-177: N-{4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]-2-trifluorometylofenylo}acetamid [0391] MS (ES) 459 (M+H)

I-178: 5-[2-(3,4-dimetylofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2on [0392] ¹H NMR (DMSO-d6) δ: 11,78 (s, 1H), 10,11 (br. s., 1H), 9,65 (br. s., 1H), 7,84 (s, 1H), 7,26 - 7,36 (m, 1H), 7,15 - 7,24 (m, 3H), 6,90 - 7,13 (m, 2H), 2,12 (m, 6H), 1,97 (s, 3H) ppm; MS (ES) 362 (M+H);

I-179: 5-[2-(4-cykloheksylometoksy-3-trifluorometylofenyloamino)-5-metylopirymidyn-4yloamino]-3H-benzooksazol-2-on [0393] ¹H NMR (DMSO, 300 MHz): δ 11,72 (s, 1H), 10,32 (s, 1H), 9,77 (s, 1H), 7,86 (s, 1H),

- 153 7,56 (s, 2H), 7,32 - 7,02 (m, 3H), 2,48 (m, 2H), 2,13 (s, 3H), 1,73 (s, 5H), 1,37-0,90 (m, 6H) ppm; MS (ES) 514 (M+H).

I-180: 5-[2-(4-chloro-3-trifluorometoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0394] MS (ES) 452/454 (M+H)

I-181: 5-[2-(4-chloro-3-metoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0395] ¹H NMR (DMSO, 300 MHz): δ 11,72 (s, 1H), 10,01 (s, 1H), 9,40 (s, 1H), 7,87 (s, 1H),

7.22 (d, J = 8,3, 3H), 7,17 - 7,01 (m, 1H), 3,55 (s, 3H), 2,12 (s, 3H) ppm; MS (ES) 398/400 (M+H).

I-182: 5-[2-(4-chloro-3-etoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0396] ¹H NMR (DMSO, 300 MHz): δ 11,76 (s, 1H), 10,24 (s, 1H), 9,56 (s, 1H), 7,90 (s, 1H), 7,24 (m, 4H), 7,00 (d, J= 10,6, 1H), 3,59 (m, 2H), 2,13 (s, 3H), 1,18 (t, J= 6,9, 3H) ppm; MS (ES) 412/414 (M+H).

I-183: 5-[2-(4-fluoro-3-metoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0397] ¹H NMR (DMSO, 300 MHz): δ 11,75 (s, 1H), 10,25 - 10,08 (s br, 1H), 9,63 - 9,49 (s br, 1H), 7,86 (s, 1H), 7,19 (m,, 5H), 3,55 (s, 3H), 2,13 (s, 3H) ppm; MS (ES) 382 (M+H);

I-184: 5-[2-(3,5-dichlorofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2on [0398] MS (ES) 402/404 (M+H)

I-185: 5-[2-(3-bromo-5-chlorofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0399] MS (ES) 448 (M+H)

I-186: 5-[2-(3-chloro-5-fluorofenyloamino)-5-metylopirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0400] ¹H NMR (DMSO-d6) δ: 11,69 (s, 1H), 10,25 (br. s., 1H), 9,50 (br. s., 1H), 7,94 (s, 1H),

7.23 - 7,44 (m, 3H), 7,06 - 7,23 (m, 2H), 6,93 (d, J = 8,3 Hz, 1H), 2,13 (s, 3H) ppm; MS (ES) 386 (M+H);

I-187: 3-chloro-5-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2yloamino]benzonitryl [0401] MS (ES) 393/395 (M+H)

I-188: 5-[2-(4-bromo-3-trifluorometylofenyloamino)-5-metylopirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0402] MS (ES) 482/484 (M+H);

- 154 I-189: 5-[2-(3-bromo-5-trifluorometylofenyloamino)-5-metylopirymidyn-4-yloamino]-3Hbenzooksazol-2-on [0403] MS (ES) 480/482 (M+H);

I-190: N-cyklobutylo-2-metylo-4-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]benzamid [0404] MS (ES) 445 (M+H);

I-191: 5-{2-[3-chloro-4-(2-morfolin-4-yloetoksy)fenyloamino]-5-metylopirymidyn-4-yloamino}-3H-benzooksazol-2-on [0405] ¹H NMR (DMSO, 300 MHz): δ 11,57 (s, 1H), 9,02 (s, 1H), 8,40 (s, 1H), 8,11 (s, 1H), 7,84 (d, J= 6,3, 1H), 7,37 (d, J= 9,1, 1H), 7,30 - 7,19 (m, 1H), 6,96 (d, J= 9,1, 1H), 6,69 6,40 (m, 1H), 4,26 - 4,00 (m, 2H), 3,63 (m, 4H), 3,02 - 2,81 (m, 2H), 2,87 - 2,60 (m, 4H), 2,07 (s, 3H) ppm; MS (ES) 497/499 (M+H);

I-192: 5-{5-metylo-2-[4-(2-morfolin-4-yloetoksy)fenyloamino]pirymidyn-4-yloamino}-3Hbenzooksazol-2-on [0406] ¹H NMR (DMSO, 300 MHz): δ 9,02 (s, 1H), 8,47 (s, 1H), 8,13 (s, 1H), 7,82 (s, 1H), 7,49 (d, J = 9,0, 2H), 7,41 - 7,26 (m, 2H), 7,21 (d, J = 8,5, 1H), 6,76 (d, J = 9,0, 2H), 4,09 (t, J= 5,3, 2H), 3,76 - 3,59 (m, 4H), 3,01 (t, J= 5,2, 2H), 2,81 (s, 4H), 2,07 (s, 3H) ppm; MS (ES) 463 (M+H);

I-193: 5-[2-(2,4-difluoro-5-metoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0407] ¹H NMR (DMSO, 300 MHz): δ 11,70 (s, 1H), 9,82 (s, 1H), 9,54 (s, 1H), 7,84 (s, 1H), 7,45 (t, J= 10,8, 1H), 7,32 - 7,21 (m, 1H), 7,18 (d, J = 5,1, 2H), 3,57 (s, 3H), 2,12 (s, 3H) ppm; MS (ES) 400 (M+H);

I-194: 5-[2-(3-chloro-4-etoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0408] ¹H NMR (DMSO, 300 MHz): δ 11,73 (s, 1H), 10,16 (s, 1H), 9,67 (s, 1H), 7,86 (s, 1H),

7,53 (s, 1H), 7,22 (m, 3H), 7,08 - 6,88 (m, 1H), 4,10 - 3,82 (m, 2H), 2,07 (s, 3H), 1,44 - 1,06 (m, 3H) ppm; MS (ES) 412/414 (M+H);

I-195: 5-[2-(4-cyklobutylometoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0409] ¹H NMR (DMSO, 300 MHz): δ 11,81 (s, 1H), 10,20 (s, 1H), 9,74 (s, 1H), 7,81 (s, 1H), 7,35 - 7,10 (m, 4H), 6,82 (d, J = 8,8, 2H), 3,87 (d, J = 6,8, 2H), 2,78 - 2,59 (m, 1H), 2,12 (s, 3H), 2,09 - 1,96 (m, 2H), 1,85 (m, 4H) ppm; MS (ES) 418 (M+H);

I-196: 5-[2-(4-izobutoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2on [0410] ¹H NMR (DMSO, 300 MHz): δ 11,81 (s, 1H), 10,25 (s, 1H), 9,70 (s, 1H), 7,81 (s, 1H),

7,24 (m, 3H), 6,81 (m, 2H), 3,66 (m, 2H), 2,10 (s, 3H), 1,97 (m, 1H), 0,94 (m, 6H) ppm; MS

- 155 (ES) 406 (M+H);

I-197: 5-{5-metylo-2-[4-(3-metylobutoksy)fenyloamino]pirymidyn-4-yloamino}-3H-benzooksazol-2-on [0411] ¹H NMR (DMSO, 300 MHz): δ 11,81 (s, 2H), 10,19 (s, 1H), 9,69 (s, 1H), 7,82 (s, 1H), 7,35 - 7,14 (m, 4H), 6,82 (d, J = 8,9, 2H), 3,91 (t, J = 6,6, 2H), 2,11 (s, 3H), 1,88-1,63 (m, 1H), 1,56 (q, J = 6,6, 2H), 0,90 (d, J = 6,6, 6H) ppm; MS (ES) 420 (M+H);

I-198: sól kwasu trifluorooctowego 5-[2-(3-chloro-4-trifluorometylofenyloamino)-5metylopirymidyn-4-yloamino]-3H-benzooksazol-2-onu, [0412] ¹H NMR (DMSO, 300 MHz): δ 11,80 (s, 1H), 11,07 (s, 1H), 9,81 (s, 1H), 7,98 (s, 1H), 7,83 (s, 1H), 7,59 (d, J = 8,8, 1H), 7,43 - 7,25 (m, 2H), 7,20 (s, 1H), 7,12 (d, J = 8,5, 1H), 2,13 (s, 3H) ppm; MS (ES) 436/438 (M+H);

I-199: 5-[2-(3-fluoro-5-metylofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0413] ¹H NMR (DMSO, 300 MHz): δ 11,74 (s, 1H), 10,32 (s, 1H), 9,70 (s, 1H), 7,92 (s, 1H),

7,31 (d, J= 8,5, 1H), 7,18 (d, J = 9,6, 2H), 6,96 (s, 1H), 6,62 (d, J = 10,0, 1H), 2,13 (s, 3H), 2,10 (s, 3H) ppm; MS (ES) 366 (M+H);

I-200: 5-[2-(2,4-difluoro-3-metoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0414] ¹H NMR (DMSO-d6) δ: 11,84 (s, 1H), 10,33 (s, 1H), 9,77 (s, 1H), 7,89 (s, 1H), 7,55 6,94 (m, 5H), 3,82 (s, 3H), 2,12 (s, 3H).ppm; MS (ES) 400 (M+H);

I-201: 5-(2-(4-(1-(azetydyn-1-ylo)etylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0415] C23H24N6O2. MS (ESI) m/z 417,01 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,91 (s, 1H, NH), 8,30 (s, 1H, NH), 8,17 (s, 1H, NH), 7,75 (s, 1H, ArH), 7,65-7,52 (m, 2H, ArH), 7,38-7,27 (m, 2H, ArH), 7,22 (s, 1H, ArH), 7,01 (t, J= 8,3, 1H, ArH), 6,78 (d, J= 8,5, 1H, ArH), 3,63-2,85 (m, 5H, CH, 2CH2), 2,05 (s, 3H, CH3), 1,95 - 1,75 (m, 2H, CH2), 1,05 (d, J=

6,6, 3H, CH3).

I-202: 5-(2-(4-(1-(cyklopropyloamino)etylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0416] C23H24N6O2. MS (ESI) m/z 417,03 (M+1)⁺.

I-203: 5-(5-metylo-2-(4-(1-(pirolidyn-1-ylo)etylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0417] C24H26N6O2. MS (ESI) m/z 431,12 (M+1)⁺.

I-204: 5-(5-metylo-2-(4-(1-morfolinoetylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0418] C24H26N6O3. MS (ESI) m/z 447,13 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,80 (s,

- 156 1H, NH), 8,21 (s, 1H, NH), 8,12 (s, 1H, NH), 7,77 (s, 1H, ArH), 7,64 (d, J = 2,5, 1H, ArH), 7,55 (d, J = 8,5, 2H, ArH), 7,16 (dd, J = 9,6, 2,3, 1H, ArH), 6,99 (d, J = 8,5, 2H, ArH), 6,79 (d, J = 8,6, 1H, ArH), 3,63-3,23 (m, 5H, CH, 2CH2), 2,31-2,18 (m, 4H, 2CH2), 2,07 (s, 3H, CH3), 1,22 (d, J = 6,7, 3H, CH3).

1-205: 5-(2-(4-(1-(3-(dietyloamino)pirolidyn-1-ylo)etylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0419] C28H35N7O2. MS (ESI) m/z 502,19 (M+1)⁺.

I-206: 5-(2-(4-(1-(benzyloamino)etylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0420] C27H26N6O2. MS (ESI) m/z 467,03 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,32 (s, 1H, NH), 8,15 (s, 1H, NH), 7,33-7,15 (m, 13H, ArH), 4,22 (s, 2H, CH2), 3,48 (m, 1H, CH), 1,84 (s, 3H, CH3), 1,22 (d, J = 6,6, 3H, CH3).

I-207: 5-(2-(4-(1-(izopropyloamino)etylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0421] C23H26N6O2. MS (ESI) m/z 419,04 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,13 (s, 1H, NH), 8,35 (s, 1H, NH), 8,27 (s, 1H, NH), 7,86 (s, 1H, ArH), 7,65 (d, J = 8,4, 2H, ArH), 7,42 (s, 1H, ArH), 7,32 (d, J = 8,7, 1H, ArH), 7,27 - 7,16 (m, 3H, ArH), 4,16 (m, 1H, CH), 2,08 (s, 3H, CH3), 1,42 (m, 5H, 2CH2, CH), 1,11 (d, J = 6,3, 3H, CH3).

1-208: 5-(5-metylo-2-(3-(1-(propyloamino)etylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0422] C23H26N6O2. MS (ESI) m/z 419,06 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,03 (s, 1H, NH), 8,33 (s, 1H, NH), 8,24 (s, 1H, NH), 7,86 (s, 1H, ArH), 7,60-7,53 (m, 2H, ArH), 7,37 (d, J = 1,7, 1H, ArH), 7,31 (dd, J = 8,6, 2,1, 1H, ArH), 7,20 (d, J = 8,6, 1H, ArH), 7,16 - 7,06 (m, 1H, ArH), 6,88 (d, J= 7,5, 1H, ArH), 3,54 (m, 1H, CH), 2,34 (m, 2H, CH2), 2,08 (s, 3H, CH3), 1,40 (m, 2H, CH2), 1,27 (d, J = 6,6, 3H, CH3), 0,79 (t, J = 7,4, 3H, CH3).

I-209: 5-(2-(3-(1-(izopropyloamino)etylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0423] C23H26N6O2. MS (ESI) m/z 419,05 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,04 (s, 1H, NH), 8,34 (s, 1H, NH), 8,24 (s, 1H, NH), 7,86 (s, 1H, ArH), 7,67-7,48 (m, 2H, ArH), 7,42-7,03 (m, 4H, ArH), 6,90 (d, J= 7,6, 1H, ArH), 3,71 (m, 1H, CH), 2,66-2,42 (m, 1H, CH), 2,34 (m, 2H, CH2), 2,08 (s, 3H, CH3), 1,27 (d, J = 6,6, 3H, CH3), 0,95 (m, 6H, 2CH3).

I-210: 5-(2-(3-(1-(izopropyloamino)etylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0424] C23H24N6O2. MS (ESI) m/z 417,04 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,92 (s, 1H, NH), 8,32 (s, 1H, NH), 8,15 (s, 1H, NH), 7,86 (s, 1H, ArH), 7,51 (d, J = 9,5, 2H, ArH),

7,31 (d, J = 7,0, 2H, ArH), 7,21 (d, J = 9,2, 1H, ArH), 7,05 (t, J = 7,8, 1H, ArH), 6,83 (d, J =

7,6, 1H, ArH), 3,47 (m, 1H, CH), 2,07 (s, 3H, CH3), 1,90 - 1,74 (m, 1H, CH), 1,13 (d, J = 6,6, 3H, CH3), 0,21 (m, 4H, 2CH2).

- 157 I-211: 5-(2-(3-(1-(azetydyn-1-ylo)etylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0425] C23H24N6O2. MS (ESI) m/z 417,03 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,94 (s, 1H, NH), 8,33 (s, 1H, NH), 8,18 (s, 1H, NH), 7,85 (s, 1H, ArH), 7,54-7,43 (m, 2H, ArH), 7,31 (s, 1H, ArH), 7,28-7,23 (m, 2H, ArH), 7,02 (t, J= 7,8, 1H, ArH), 6,74 (d, J= 7,5, 1H, ArH),

3,53 (m, 1H, CH), 2,98 (m, 4H, 2CH2), 2,04 (s, 3H, CH3), 1,95 - 1,78 (m, 2H, CH2), 0,95 (d, J = 6,6, 3H, CH3).

I-212: 5-(5-metylo-2-(3-(1-(pirolidyn-1-ylo)etylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0426] C23H26N6O2. MS (ESI) m/z 431,12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,94 (s, 1H, NH), 8,33 (s, 1H, NH), 8,17 (s, 1H, NH), 7,85 (s, 1H, ArH), 7,50 (d, J = 8,3, 2H, ArH), 7,25-7,15 (m, 3H, ArH), 7,03 (t, J= 7,8, 1H, ArH), 6,79 (d, J= 10,5, 1H, ArH), 3,51 (m, 1H, CH), 2,98 (m, 4H, 2CH2), 2,54-2,38 (m, 4H, 2CH2), 2,07 (s, 3H, CH3), 1,67-1,51 (m, 4H, 2CH2), 0,95 (d, J= 6,6, 3H, CH3).

I-213: 5-(2-(3-(1-(benzyloamino)etylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0427] C27H26N6O2. MS (ESI) m/z 467,04 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,99 (s, 1H, NH), 8,31 (s, 1H, NH), 8,19 (s, 1H, NH), 7,86 (s, 1H, ArH), 7,61 (s, 1H, ArH), 7,55 (s, 1H, ArH), 7,35 (s, 1H, ArH), 7,31 - 7,20 (m, 5H, ArH), 7,18 (m, 1H, ArH), 7,15 (m, 1H, ArH), 7,09 (t, J = 7,9, 1H, ArH), 6,89 (d, J = 7,5, 1H, ArH), 3,58 (m, 1H, CH), 3,55 (s, 2H, CH2), 2,08 (s, 3H, CH3), 1,23 (d, J = 6,6, 3H, CH3).

I-214: 5-(2-(3-(1-(3-(dietyloamino)pirolidyn-1-ylo)etylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0428] C28H35N7O2. MS (ESI) m/z 502,12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,96 (s, 1H, NH), 8,33 (s, 1H, NH), 8,18 (s, 1H, NH), 7,85 (s, 1H, ArH), 7,53-7,44 (m, 2H, ArH), 7,33 (s, 1H, ArH), 7,26 (d, J = 1,8, 1H, ArH), 7,23 (s, 1H, ArH), 7,04 (t, J= 7,9, 1H, ArH), 6,76 (d, J= 7,6, 1H, ArH), 3,57-3,40 (m, 1H, CH), 2,76 (dd, J = 14,5, 7,3, 4H, 2CH2), 2,35 (d, J= 5,8, 3H, CH2, CH), 2,21 (d, J = 8,3, 1H, CH), 2,07 (s, 3H, CH3), 1,98-1,84 (m, 2H, CH2), 1,78 1,62 (m, 1H, CH), 1,16 (d, J = 6,3, 3H, CH3), 1,01 (m, 6H, 2CH3).

1-215: 5-(5-metylo-2-(3-(1-(piperydyn-1-ylo)etylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0429] C25H28N6O2. MS (ESI) m/z 444,95 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,22 (s, 1H, NH), 8,35 (s, 1H, NH), 8,21 (s, 1H, NH), 7,96 (d, J = 7,9, 1H, ArH), 7,89 (s, 1H, ArH),

7.46- 7,38 (m, 2H, ArH), 7,37 - 7,30 (m, 1H, ArH), 7,27 (d, J = 7,6, 1H, ArH), 7,22 (s, 1H, ArH), 7,18 (s, 1H, ArH), 3,57-3,45 (m, 1H, CH), 2,52-2,40 (m, 4H, 2CH2), 2,09 (s, 3H, CH3),

1.46- 1,36 (m, 6H, 3CH2), 1,15 (d, J= 6,7, 3H, CH3).

I-216: 5-(2-(3-(1-(dietyloamino)etylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on

- 158 [0430] 24H28N6O2. MS (ESI) m/z 433,07 (Μ+1)+.

I-217: 5-(5-metylo-2-(3-(1-morfolinoetylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0431] C24H26N6O3. MS (ESI) m/z 447,06 (Μ+1)+.

I-218: N-cyklobutylo-4-(5-metylo-4-(2-okso-2,3-dihydrobenzo[d]oksazol-5-iloamino)pirymidyn-2-yloamino)-2-(trifluorometylo)benzamid [0432] C24H21F3N6O3. MS (ESI) m/z 499,07 (Μ+1)+. ¹H WR (300 \lllz, DMSO) δ 11,66 (s, 1H, NH), 10,17 (s, 1H, NH), 8,54 (s, 1H, NH), 8,52 (s, 1H, NH), 7,93 (s, 1H, ArH), 7,85 (s, 1H, ArH), 7,74 (d, J= 9,9, 1H, ArH), 7,29 (dd, J= 13,6, 8,1, 2H, ArH), 7,23-7,14 (m, 2H, ArH), 4,28 (m, 1H, CH), 2,16-2,09 (m, 2H, CH2), 2,13 (s, 3H, CH3), 2,02-1,82 (m, 2H, CH2), 1,67-1,60 (m, 2H, CH2).

I-219: 4-(5-metylo-4-(2-okso-2,3-dihydrobenzo[d]oksazol-5-iloamino)pirymidyn-2-yloamino)-N-fenylo-2-(trifluorometylo)benzamid [0433] C26H19F3N6O3. MS (ESI) m/z 521,10 (Μ+1)+.

I-220: N-cyklopropylo-2-metoksy-4-(5-metylo-4-(2-okso-2,3-dihydrobenzo[d]oksazol-5iloamino)pirymidyn-2-yloamino)benzamid [0434] C23H22N6O4. MS (ESI) m/z 446,46 (Μ+1)+. ¹H W (300 \lllz, DMSO) δ 11,72 (s, 1H, NH), 10,06 (s, 1H, NH), 9,61 (s, 1H, NH), 7,87 (s, 1H, ArH), 7,33-6,99 (m, 4H, ArH), 6,93 (d, J = 8,2, 1H, ArH), 6,59 (d, J = 9,7, 1H, ArH), 3,54 (m, 3H, CH3), 2,48 (m, 1H, CH), 2,12 (s, 3H, CH3), 1,37-1,20 (m, 4H, 2CH2).

1- 221: 2-metoksy-4-(5-metylo-4-(2-okso-2,3-dihydrobenzo[d]oksazol-5-iloamino)pirymidyn2- yloamino)-N-fenylobenzamid [0435] C26H22N6O4. MS (ESI) m/z 482,49 (Μ+1)+.

I-222: kwas 4-(5-metylo-4-(2-okso-2,3-dihydrobenzo[d]oksazol-5-iloamino)pirymidyn-2yloamino)-2-(trifluorometylo)benzoesowy [0436] C20H14F3N5O4. MS (ESI) m/z 446,01 (Μ+1)+.

I-223: N-cyklopropylo-4-(5-metylo-4-(2-okso-2,3-dihydrobenzo[d]oksazol-5-iloamino)pirymidyn-2-yloamino)-2-(trifluorometylo)benzamid [0437] C23H19F3N6O4. MS (ESI) m/z 485,08 (Μ+1)+.

I-224: -(2-(3-izobutoksy-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0438] C23H22F3N5O3. MS (ESI) m/z 474,06 (Μ+1)+. ¹H W (300 \lllz, DMSO) δ 9,31 (s, 1H, NH), 8,40 (s, 1H, NH), 7,92 (s, 1H, NH), 7,61 (s, 1H, ArH), 7,54 (s, 1H, ArH), 7,34 7,22 (m, 2H, ArH), 7,18 (d, J = 8,4, 2H, ArH), 6,61 (s, 1H, ArH), 3,56 (d, J = 6,6, 2H, CH2), 2,09 (s, 3H, CH3), 1,97-1,81 (m, 1H, CH), 0,87 (d, J = 6,6, 6H, 2CH3).

I-225: 5-(2-(3-(cyklopropylometoksy)-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn- 159 4-yloamino)benzo[d]oksazol-2(3H)-on [0439] C23H20F3N5O3. MS (ESI) m/z 472,05 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,27 (s, 1H, NH), 8,13 (s, 1H, NH), 7,92 (s, 1H, NH), 7,60 (s, 1H, ArH), 7,53 (s, 1H, ArH), 7,31 7,21 (m, 2H, ArH), 6,72 (s, 2H, ArH), 6,45-6,13 (m, 1H, ArH), 3,76-3,62 (m, 2H, CH2), 2,48 (m, 1H, CH), 2,09 (s, 3H, CH3), 0,52 (d, J = 7,2, 2H, CH3), 0,22 (d, J = 5,9, 2H, CH3).

I-226: 5-(2-(3-cyklobutoksy-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4yloamino)-benzo[d]oksazol-2(3H)-on [0440] C23H20F3N5O3. MS (ESI) m/z 472,09 (M+1)⁺.

I-227: 5-(2-(3-(cyklobutylometoksy)-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0441] C24H22F3N5O3. MS (ESI) m/z 486,11 (M+1)⁺.

I-228: 5-(2-(3-[deuterowany]metoksy-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0442] C20H13D3F3N5O3. MS (ESI) m/z 435,13 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,42 (s, 1H, NH), 8,13 (s, 1H, NH), 7,91 (s, 1H, NH), 7,57 (d, J = 7,1, 2H, ArH), 7,30-7,13 (m, 4H, ArH), 6,62 (s, 1H, ArH), 2,08 (s, 3H, CH3).

I-229: 5-(2-(3-acetylo-5-metoksyfenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0443] C21H19N5O4. MS (ESI) m/z 406,12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,19 (s, 1H, NH), 8,39 (s, 1H, NH), 8,21 (s, 1H, NH), 7,90 (s, 1H, ArH), 7,75 (s, 1H, ArH), 7,66 (s, 1H, ArH), 7,33-7,26 (m, 2H, ArH), 7,19-7,16 (m, 1H, ArH), 6,90 (s, 1H, ArH), 3,64 (s, 3H, CH3), 2,37 (s, 3H, CH3), 2,08 (s, 3H, CH3).

I-230: 5-(2-(3-chloro-4-fluoro-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0444] C19H12ClF4N5O2. MS (ESI) m/z 453,96 (M+1)⁺.

I-231: 5-(2-(3-(1-(izopropyloamino)etylo)-5-metoksyfenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0445] C24H28N6O3. MS (ESI) m/z 449,13 (M+l)⁺.

I-232: 5-(2-(3-metoksy-5-(1-(propyloamino)etylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0446] C24H28N6O3. MS (ESI) m/z 449,07 (M+1)⁺.

1-233: 5-(2-(3-(1-(cyklopropyloamino)etylo)-5-metoksyfenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0447] C24H26N6O3. MS (ESI) m/z 447,20 (M+1)⁺.

I-234: 5-(2-(3-metoksy-5-(1-(pirolidyn-1-ylo)etylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on

- 160 [0448] C2sH28N6O3. MS (ESI) m/z 461,12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,25 (s, 1H, NH), 8,30 (s, 1H, NH), 8,21 (s, 1H, NH), 7,90 (s, 1H, ArH), 7,33-7,11 (m, 2H, ArH), 6,99-6,69 (m, 3H, ArH), 6,47 (s, 1H, ArH), 3,79 (q, J = 7,7, 1H, CH), 3,71 (s, 3H, CH3), 2,13 (s, 3H, CH3), 2,54-2,06 (m, 8H, 4CH2), 1,44 (s, 3H, CH3).

I-235: 5-(2-(3-(1-(azetydyn-1-ylo)etylo)-5-metoksyfenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0449] C24H26N6O3. MS (ESI) m/z 447,42 (M+1)⁺.

I-236: 5-(2-(3-metoksy-5-(1-(metyloamino)etylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0450] C22H24N6O3. MS (ESI) m/z 421,14 (M+1)⁺.

I-237: 5-(2-(3-(difluorometylo)-5-metylofenyloamino)-5-metylopirymidyn-4yloamino)benzo-[d]oksazol-2(3H)-on [0451] C20H17F2N5O2. MS (ESI) m/z 398,08 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,17 (s, 1H, NH), 8,40 (s, 1H, NH), 8,11 (s, 1H, NH), 7,88 (s, 1H, 0ArH), 7,60 (d, J= 13,3, 2H, ArH), 7,30-7,20 (m, 3H, ArH), 6,78 (s, 1H, ArH), 6,71 (t, J= 61,7, 2H, CH), 2,10 (s, 3H, CH3), 2,08 (s, 3H, CH3).

I-238: 5-(2-(3-(fluorometylo)-5-metylofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0452] C20H18FN5O2. MS (ESI) m/z 380,08 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,04 (s, 1H, NH), 8,37 (s, 1H, NH), 8,11 (s, 1H, NH), 7,87 (s, 1H, ArH), 7,45 (d, J = 8,4, 2H, ArH), 7,34-7,18 (m, 3H, ArH), 6,65 (s, 1H, ArH), 5,12 (d, J= 53,3, 2H, CH2), 2,47 (s, 3H, CH3), 2,08 (s, 3H, CH3).

I-239: 5-(5-metylo-2-(4-metylo-3-(metylosulfonylo)fenyloamino)pirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0453] ¹H NMR (300 MHz, DMSO) δ 11,63 (s, 1H), 9,34 (s, 1H), 8,40 (s, 1H), 8,18 (d, J =

1,7, 1H), 8,05 (dd, J= 8,4, 1,9, 1H), 7,93 (s, 1H), 7,44 (dd, J= 8,6, 1,9, 1H), 7,39 (s, 1H), 7,26 (d, J= 8,6, 1H), 7,22 (d, J= 8,4, 1H), 3,16 (s, 3H), 2,56 (s, 3H), 2,15 (s, 3H); LRMS (M+) m/z 426,01.

I-240: 5-(2-(3-fluoro-5-morfolinofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0454] ¹H NMR (300 MHz, DMSO) δ 11,60 (s, 1H), 9,09 (s, 1H), 8,47 (s, 1H), 7,92 (s, 1H),

7.32 (br s, 1H), 7,26 - 7,23 (m, 2H), 7,16 (d, J= 12,1, 1H), 6,96 (s, 1H), 6,27 (d, J= 12,1, 1H), 3,67 - 3,64 (m, 4H), 2,97 - 2,94 (m, 4H), 2,14 (s, 3H); LRMS (M+) m/z 437,05.

I-241: 5-(2-(3-fluoro-5-(4-metylopiperazyn-1-ylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0455] ¹H NMR (300 MHz, DMSO) δ 11,60 (s, 1H), 9,04 (s, 1H), 8,44 (s, 1H), 7,92 (s, 1H),

7.33 (s, 1H), 7,30 - 7,22 (m, 2H), 7,18 (d, J= 12,1, 1H), 6,95 (s, 1H), 6,27 (d, J = 12,1, 1H),

- 161 3,08 - 3,04 (m, 4H), 2,56 - 2,53 (m, 4H, z nakładaniem na piki DMSO), 2,35 (s, 3H), 2,14 (s, 3H); LRMS (M+) m/z 450,06.

I-242: 5-(2-(4-fluoro-3-(metylosulfonylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0456] ¹H NMR (300 MHz, DMSO) δ 11,69 (s, 1H), 10,14 (s, 1H), 9,36 (s, 1H), 8,00-7,91 (m, 3H), 7,41 (t, J= 9,3, 1H), 7,34 - 7,21 (m, 3H), 3,31 (s, 3H), 2,19 (s, 3H); LRMS (M+) m/z 429,99.

I-244: 7-metylo-5-(5-metylo-2-(3-(metylosulfonylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0457] ¹H NMR (300 MHz, DMSO) δ 11,63 (s, 1H), 10,01 (s, 1H), 9,18 (s, 1H), 8,01 (d, J =

7.3, 1H), 7,96 - 7,94 (m, 2H), 7,54 (d, J = 8,0, 1H), 7,44 (t, J = 8,0, 1H), 7,13 (br s, 2H), 3,14 (s, 3H), 2,33 (s, 3H), 2,18 (s, 3H); LRMS (M+) m/z 426,01.

1-245: 5-(2-(4-fluoro-3-(metylosulfonylo)fenyloamino)-5-metylopirymidyn-4-yloamino)-7metylobenzo[d]oksazol-2(3H)-on [0458] ¹H NMR (300 MHz, DMSO) δ 11,62 (s, 1H), 10,08 (br s, 1H), 9,26 (br s, 1H), 8,05 8,00 (m, 1H), 7,93 - 7,90 (m, 2H), 7,37 (t, J = 9,3, 1H), 7,13 (s, 1H), 7,11 (s, 1H),3,30 (s, 3H), 2,32 (s, 3H), 2,18 (s, 3H); LRMS (M+) m/z 444,01.

I-246: 5-(5-metylo-2-(3-(pirolidyno-1-karbonylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0459] ¹H NMR (300 MHz, DMSO) δ 11,78 (s, 1H), 10,19 (s, 1H), 9,71 (s, 1H), 7,94 (s, 1H), 7,66 (s, 1H), 7,50 (d, J = 8,7, 1H), 7,37 - 7,24 (m, 5H), 3,46 (t, J = 6,5, 2H), 3,26 (t, J= 6,5, 2H), 2,20 (s, 3H), 1,90 - 1,77 (m, 4H); LRMS (M+) m/z 431,06.

I-247: 5-(5-metylo-2-(4-(pirolidyno-1-karbonylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0460] ¹H NMR (300 MHz, DMSO) δ 11,81 (s, 1H), 10,13 (s, 1H), 9,62 (s, 1H), 7,95 (s, 1H),

7,53 - 7,50 (m, 2H), 7,45 - 7,36 (m, 3H), 7,29 (br s, 1H), 7,24 (dd, J= 8,4, 2,0, 1H), 3,48 (t, J=

6.4, 2H), 3,39 (t, J= 6,4, 2H), 2,20 (s, 3H), 1,92 - 1,82 (m, 4H); LRMS (M+) m/z 431,05.

I-249: 7-fluoro-5-(5-metylo-2-(3-(metylosulfonylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0461] ¹H NMR (300 MHz, DMSO) δ 12,03 (s, 1H), 10,03 (br s, 1H), 9,16 (br s, 1H), 8,08 (s, 1H), 8,04 - 8,02 (m, 2H), 7,58 - 7,50 (m, 3H), 7,19 (d, J= 1,7, 1H), 3,17 (s, 3H), 2,19 (s, 3H); LRMS (M+) m/z 430,03.

I-250: 7-fluoro-5-(2-(4-fluoro-3-(metylosulfonylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0462] ¹H NMR (300 MHz, DMSO) δ 12,01 (s, 1H), 10,06 (br s, 1H), 9,20 (br s, 1H), 8,05 8,00 (m, 3H), 7,49 - 7,41 (m, 2H), 7,20 (d, J= 1,5, 1H), 3,31 (s, 3H), 2,18 (s, 3H); LRMS (M+) m/z 448,01.

- 162 I-251: 7-fluoro-5-(2-(3-metoksy-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0463] ¹H NMR (300 MHz, DMSO) δ 12,03 (s, 1H), 10,00 (br s, 1H), 9,31 (br s, 1H), 8,01 (br s, 1H), 7,51 (s, 1H), 7,44 (s, 1H), 7,38 (d, J = 12,3, 1H), 7,15 (s, 1H), 6,86 (s, 1H), 3,76 (s, 3H), 2,18 (s, 3H); LRMS (M+) m/z 450,05.

I-252: 3-metoksy-N,N-dimetylo-5-(5-metylo-4-(2-okso-2,3-dihydrobenzo[d]oksazol-5iloamino)pirymidyn-2-yloamino)benzamid [0464] ¹H NMR (300 MHz, DMSO) δ 11,75 (s, 1H), 10,18 (br s, 1H), 9,71 (br s, 1H), 7,95 (s, 1H),7,31 (d, J = 8,5, 1H), 7,24 (br s, 1H), 7,21 (br d, J = 8,5, 1H), 7,10 (s, 1H), 7,05 (s, 1H),

6,64 (s, 1H), 3,68 (s, 3H), 2,98 (s, 3H), 2,84 (s, 3H), 2,19 (s, 3H); LRMS (M+) m/z 435,04.

I-253: 5-(2-(3-metoksy-5-(pirolidyno-1-karbonylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0465] ¹H NMR (300 MHz, DMSO) δ 11,77 (s, 1H), 10,30 (br s, 1H), 9,78 (br s, 1H), 7,96 (s, 1H), 7,30 (d, J = 8,4, 1H), 7,25 (br s, 1H), 7,22 (br d, J = 8,4, 1H), 7,17 (s, 1H), 7,11 (br s, 1H), 6,76 (br s, 1H), 3,69 (s, 3H), 3,45 (t, J= 6,5, 2H), 3,27 (t, J= 6,5, 2H), 2,20 (s, 3H), 1,91 1,75 (m, 4H); LRMS (M+) m/z 461,09.

I-254: 5-(2-(3-metoksy-5-(morfolino-4-karbonylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0466] ¹H NMR (300 MHz, DMSO) δ 11,72 (s, 1H), 10,07 (br s, 1H), 9,57 (br s, 1H), 7,95 (s, 1H), 7,31 (d, J= 8,4, 1H), 7,25 - 7,18 (m, 3H), 7,06 (s, 1H), 6,63 (s, 1H), 3,78 - 3,28 (m, 8H, nałożone), 3,68 (s, 3H, nałożone), 2,19 (s, 3H); LRMS (M+) m/z 477,10.

I-255: 5-(2-(3-metoksy-5-(4-metylopiperazyno-1-karbonylo)fenyloamino)-5metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0467] ¹H NMR (300 MHz, DMSO) δ 11,75 (s, 1H), 10,42 (br s, 1H), 10,07 (br s, 1H), 9,64 (br s, 1H), 8,00 (s, 1H), 7,31 (d, J = 8,4, 1H), 7,25 - 7,21 (m, 3H), 7,06 (s, 1H), 6,68 (s, 1H), 4,01 - 3,01 (m, 8H, nałożone), 3,67 (s, 3H, nałożone), 2,86 (s, 3H), 2,19 (s, 3H); LRMS (M+) m/z 490,10.

I-256: 5-(5-metylo-2-(3-(morfolino-4-karbonylo)fenyloamino)pirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0468] ¹H NMR (300 MHz, DMSO) δ 11,78 (s, 1H), 10,30 (s, 1H), 9,71 (s, 1H), 7,96 (s, 1H),

7.54 - 7,51 (m, 2H), 7,37 - 7,31 (m, 2H), 7,25 - 7,23 (m, 2H), 7,12 (d, J= 7,6, 1H), 3,62 - 3,26 (m, 8H), 2,20 (s, 3H); LRMS (M+) m/z 447,09.

I-257: 5-(5-metylo-2-(4-(morfolino-4-karbonylo)fenyloamino)pirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0469] ¹H NMR (300 MHz, DMSO) δ 11,83 (s, 1H), 10,38 (s, 1H), 9,71 (s, 1H), 7,98 (s, 1H),

7.55 - 7,52 (m, 2H), 7,39 (d, J= 8,5, 1H), 7,33 - 7,30 (m, 3H), 7,25 (br d, J = 8,5, 1H), 3,63 3,51 (m, 8H), 2,20 (s, 3H); LRMS (M+) m/z 447,03.

- 163 I-258: 5-(2-(4-metoksy-3-metylofenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0470] ¹H NMR (300 MHz, DMSO) δ 11,84 (s, 1H), 10,06 (s, 1H), 9,79 (s, 1H), 7,83 (s, 1H), 7,35 (d, J= 8,2, 1H), 7,27 - 7,23 (m, 2H), 7,17 - 7,14 (m, 2H), 6,91 (br d, J= 8,2, 1H), 3,79 (s, 3H), 2,18 (s, 3H), 2,01 (s, 3H); LRMS (M+) m/z 378,05.

I-259: 5-(2-(3-metoksy-5-metylofenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0471] ¹H NMR (300 MHz, DMSO) δ 11,72 (s, 1H), 9,85 (s, 1H), 9,39 (s, 1H), 8,15 (d, J =

4,4, 1H), 7,47 (dd, J = 8,6, 1,5, 1H), 7,39 - 7,27 (m, 4H), 6,87 (d, J = 8,6, 1H), 3,78 (s, 3H), 2,06 (s, 3H); LRMS (M+) m/z 378,05.

I-260: 2-metoksy-N,N-dimetylo-5-(5-metylo-4-(2-okso-2,3-dihydrobenzo[d]oksazol-5iloamino)pirymidyn-2-yloamino)benzamid [0472] ¹H NMR (300 MHz, DMSO) δ 11,80 (s, 1H), 9,99 (s, 1H), 9,68 (s, 1H), 7,87 (s, 1H), 7,38 (br d, J = 8,9, 1H), 7,30 (d, J = 8,6, 1H), 7,25 - 7,20 (m, 3H), 7,06 (d, J = 8,9, 1H), 3,80 (s, 3H), 2,99 (s, 3H), 2,71 (s, 3H), 2,18 (s, 3H); LRMS (M+) m/z 435,11.

I-261: 5-(2-(4-metoksy-3-(pirolidyno-1-karbonylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0473] ¹H NMR (300 MHz, DMSO) δ 11,82 (s, 1H), 9,81 (br s, 1H), 9,50 (br s, 1H), 7,87 (s, 1H), 7,40 (br d, J= 8,8, 1H), 7,31 (d, J = 2,9, 1H), 7,27 - 7,22 (m, 3H), 7,05 (d, J = 8,8, 1H), 3,80 (s, 3H), 3,46 (t, J= 6,6, 2H), 3,05 (t, J = 6,6, 2H), 2,17 (s, 3H), 1,92 - 1,74 (m, 4H); LRMS (M+) m/z 461,11.

I-262: 5-(2-(4-metoksy-3-(morfolino-4-karbonylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0474] ¹H NMR (300 MHz, DMSO) δ 11,75 (s, 1H), 9,88 (br s, 1H), 9,52 (br s, 1H), 7,87 (s, 1H), 7,45 (dd, J = 8,7, 1,9, 1H), 7,33 - 7,22 (m, 4H), 7,04 (d, J = 8,7, 1H), 3,81 (s, 3H), 3,65 3,08 (m, 8H), 2,18 (s, 3H); LRMS (M+) m/z 477,10.

I-263: 5-(2-(4-metoksy-3-(4-metylopiperazyno-1-karbonylo)fenyloamino)-5metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0475] ¹H NMR (300 MHz, DMSO) δ 11,77 (s, 1H), 9,96 (br s, 1H), 9,59 (br s, 1H), 7,91 (s, 1H), 7,53 (br d, J = 8,7, 1H), 7,34 - 7,25 (m, 4H), 7,07 (d, J= 8,7, 1H), 4,60 - 3,10 (m, 8H, nałożone), 3,83 (s, 3H, nałożone), 2,89 (br s, 3H), 2,18 (s, 3H); LRMS (M+) m/z 490,10.

I-264: 5-(2-(3-metylo-4-trideuterometoksyfenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0476] ¹H NMR (300 MHz, DMSO) δ 11,83 (s, 1H), 9,99 (s, 1H), 9,78 (s, 1H), 7,81 (s, 1H),

7,35 (d, J = 9,0, 1H), 7,27 - 7,24 (m, 2H), 7,17 - 7,14 (m, 2H), 6,91 (br d, J = 9,0, 1H), 2,18 (s, 3H), 2,02 (s, 3H); LRMS (M+) m/z 381,10.

1-265:

5-(2-(3-chloro-4-metoksy-5-metylofenyloamino)-5-metylopirymidyn-4- 164 yloamino)benzo[d]oksazol-2(3H)-on [0477] ¹H NMR (300 MHz, DMSO) δ 11,74 (s, 1H), 9,89 (br s, 1H), 9,57 (br s, 1H), 7,92 (s, 1H), 7,48 (s, 1H), 7,36 (d, J= 8,3, 1H), 7,24 - 7,18 (m, 3H), 3,71 (s, 3H), 2,18 (s, 3H), 2,14 (s, 3H); LRMS (M+) m/z 411,97.

I-266: 5-(2-(3-metylo-5-trideuterometoksyfenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0478] ¹H NMR (300 MHz, DMSO) δ 11,77 (s, 1H), 9,93 (br s, 1H), 9,72 (br s, 1H), 7,90 (s, 1H), 7,35 (d, J = 8,3, 1H), 7,25 - 7,22 (m, 2H), 6,84 (s, 1H), 6,81 (s, 1H), 6,50 (s, 1H), 3,43 (s, 3H), 2,19 (s, 3H), 2,12 (s, 3H); LRMS (M+) m/z 381,10.

I-267: 2-metoksy-N,N-dimetylo-4-(5-metylo-4-(2-okso-2,3-dihydrobenzo[d]oksazol-5iloamino)pirymidyn-2-yloamino)benzamid [0479] ¹H NMR (300 MHz, DMSO) δ 11,75 (s, 1H), 10,49 (s, 1H), 9,74 (s, 1H), 7,92 (s, 1H),

7,30 - 7,14 (m, 3H), 7,04 (d, J = 8,8, 1H), 7,03 (app s, 2H), 3,45 (s, 3H), 2,92 (s, 3H), 2,70 (s, 3H), 2,14 (s, 3H).

I-268: 5-(2-(3-metoksy-4-(pirolidyno-1-karbonylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0480] ¹H NMR (300 MHz, DMSO) δ 11,74 (s, 1H), 10,33 (s, 1H), 9,66 (s, 1H), 7,90 (s, 1H),

7.30 - 7,17 (m, 3H), 7,05 (d, J = 5,9, 1H), 7,04 (app s, 2H), 3,46 (s, 3H), 3,38 (t, J= 6,5, 2H), 3,03 (t, J= 6,5, 2H), 2,14 (s, 3H), 1,79 (dt, J = 18,9, 6,5, 4H).

I-269: 5-(2-(3-metoksy-4-(morfolino-4-karbonylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0481] ¹H NMR (300 MHz, DMSO) δ 11,71 (s, 1H), 10,26 (s, 1H), 9,65 (s, 1H), 7,89 (s, 1H),

7.31 - 7,16 (m, 3H), 7,07 (d, J = 8,5, 1H), 7,06 (app s, 2H), 3,57 (br s, 4H), 3,47 (br s, 2H),

3.45 (s, 3H), 3,08 (br s, 2H), 2,14 (s, 3H).

I-270: 5-(2-(3-metoksy-4-(4-metylopiperazyno-1-karbonylo)fenyloamino)-5metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0482] ¹H NMR (300 MHz, DMSO) δ 11,75 (s, 1H), 10,30 (s, 1H), 9,95 (s, 1H), 9,48 (s, 1H), 7,94 (s, 1H), 7,29 - 7,04 (m, 6H), 3,44 (s, 3H), 2,82 (s, 3H), 2,13 (s, 3H).

I-271: 5-(2-(3-(difluorometylo)-4-metoksyfenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0483] ¹H NMR (300 MHz, DMSO) δ11,59 (s, 1H), 9,16 (s, 1H), 8,54 (s, 1H), 7,84 (s, 1H), 7,71 (d, J= 11,0, 2H), 7,31 (d, J = 8,4, 1 H), 7,31 (s, 1H), 7,20 (d, J = 8,4, 1H), 6,94 (t, J =

55,4, 1H), 6,93 (s, 1H), 3,76 (s, 3H), 2,08 (s, 3H).

I-272: 5-(2-(4-metoksyfenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)on [0484] ¹H NMR (300 MHz, DMSO) δ 11,61 (s, 1H), 8,93 (s, 1H), 8,49 (s, 1H), 7,80 (s, 1H),

7.46 (d, J= 8,9, 2H), 7,31 (d, J = 9,0, 2H), 7,30 (s, 1H), 7,21 (d, J = 9,0, 1H), 6,74 (d, J= 8,9,

- 165 2H), 3,67 (s, 3H), 2,07 (s, 3H).

I-273: 5-(2-(3-(difluorometylo)-5-metoksyfenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0485] ¹H NMR (300 MHz, DMSO) δ 11,66 (s, 1H), 10,12 (s, 1H), 9,56 (s, 1H), 7,89 (s, 1H), 7,29 - 7,11 (m, 5H), 6,76 (t, J = 55,9, 1H), 6,73 (s, 1H), 3,62 (s, 3H), 2,13 (s, 3H).

I-274: 5-(2-(3-(fluorometylo)-5-metoksyfenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0486] ¹H NMR (300 MHz, DMSO) δ 11,70 (s, 1H), 10,17 (s, 1H), 9,68 (s, 1H), 7,88 (s, 1H), 7,28 (d, J = 8,6, 1H), 7,18 (s, 1H), 7,16 (d, J = 8,6, 1H), 7,02 (s, 1H), 6,98 (s, 1H), 6,64 (s, 1H), 5,25 (s, 1H), 5,09 (s, 1H), 3,60 (s, 3H), 2,13 (s, 3H).

I-275: N2-[4-(4,4-difluoropiperydynylo)-3-fluoro]fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0487] ¹H NMR (300 MHz, DMSO) δ 11,56 (s, 1H), 9,06 (s, 1H), 8,39 (s, 1H), 7,85 (s, 1H),

7,64 (d, J = 15,3, 1H), 7,25 (m, 3H), 7,18 (d, J = 10,8, 1H), 6,88 (t, J = 9,4, 1H), 2,99 (t, 4H), 2,08 (s, 3H), 2,08 (m, 4H); ¹⁹F NMR (282 MHz, DMSO) δ 111,68, - 138,03; LCMS: czystość: 97,23%; MS (m/e): 471,27 (M+H).

I-276: N2-[4-(4,4-difluoropiperydynylo)-3-trifluorometylo]fenylo-5-metylo-N4-(2-okso-2,3dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0488] ¹H NMR (300 MHz, DMSO) δ 11,51 (s, 1H), 9,28 (s, 1H), 8,44 (s, 1H), 7,95 (s, 1H),

7,88 (s, 1H), 7,80 (d, 1H), 7,36 (d, J= 8,4, 1H), 7,27 (m, 2H), 7,19 (d, J= 9,3, 1H), 2,88 (t, 4H), 2,09 (s, 3H), 2,03 (m, 4H); ¹⁹F NMR (282 MHz, DMSO) δ - 75,78; LCMS: czystość: 89,60%; MS (m/e): 521,31 (M+H).

I-277: N2-[3-chloro-4-(4,4-difluoropiperydynylo)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0489] ¹H NMR (300 MHz, DMSO) δ 11,53 (s, 1H), 9,05 (s, 1H), 8,37 (s, 1H), 7,85 (m, 2H), 7,37 (d, J = 9,0, 1H), 7,23 (m, 3H), 6,99 (d, J = 9,0, 1H), 2,95 (t, J = 5,1, 4H), 2,08 (s, 3H), 2,08 (m, 4H); LCMS: czystość: 93,39%; MS (m/e): 487,23 (M+H).

I-278: N2-[3-chloro-4-(4-etylopiperazyno)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0490] ¹H NMR (300 MHz, DMSO) δ 11,55 (br, 1H), 9,02 (s, 1H), 8,37 (s, 1H), 7,83 (d, J =

6,6, 2H), 7,37 (d, J = 9,0, 1H), 7,22 (m, 3H), 6,93 (d, J= 9,6, 1H), 2,87 (s, 4H), 2,08 (s, 3H), 1,03 (t, J= 6,9, 3H); LCMS: czystość: 89,90%; MS (m/e): 480,29 (M+H).

I-279: N2-[4-(4,4-difluoropiperydynylo)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0491] ¹H NMR (300 MHz, DMSO) δ 11,58 (br, 1H), 8,73 (s, 1H), 8,25 (s, 1H), 7,80 (s, 1H),

7,46 (d, J = 7,8, 2H), 7,32 (d, J= 9,9, 2H), 7,20 (d, J = 7,8, 1H), 6,79 (d, J = 8,1, 2H), 3,16 (m, 4H), 2,06 (s, 3H), 2,03 (m, 4H); ¹⁹F NMR (282 MHz, DMSO) δ - 111,17; LCMS:

- 166 czystość: 97,36%; MS (m/e): 453,23 (M+H).

I-280: N2-(3,5-dimetoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)2,4-pirymidynodiamina [0492] ¹H NMR (300 MHz, DMSO) δ 11,51 (s, 1H), 8,89 (s, 1H), 8,33 (s, 1H), 7,85 (s, 1H), 7,29 (s, 1H), 7,27 (d, J= 11,1, 1H), 7,17 (d, J= 9,3, 1H), 6,89 (d, J= 2,1, 2H), 5,96 (s, 1H),

3,56 (s, 6H), 2,08 (s, 3H); LCMS: czystość: 91,13%; MS (m/e): 394,24 (M+H).

I-281: N2-[3-fluoro-4-(4-metylopiperazyno)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0493] ¹H NMR (300 MHz, DMSO) δ 11,65 (s, 1H), 9,57 (br, 1H), 7,86 (s, 1H), 7,49 (d, 1H), 7,27 (d, J = 7,2, 1H), 7,20 (m, 2H), 7,07 (d, 1H), 6,98 (t, J = 9,0, 1H), 3,48 (d, J = 10,5, 2H), 3,34 (d, J = 12,0, 2H), 3,20 (d, 2H), 2,93 (d, J= 12,3, 2H), 2,86 (s, 3H), 2,12 (s, 3H); LCMS: czystość: 82,99%; MS (m/e): 450,26 (M+H).

I-282: N2-[3,5-difluoro-4-(4-metylopiperazyno)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro1.3- benzooksazol-5-ilo)-2,4-pirymidynodiamina [0494] ¹H NMR (300 MHz, DMSO) δ 11,62 (s, 1H), 9,77 (br, 1H), 9,53 (br, 1H), 9,03 (br, 1H), 7,90 (s, 1H), 7,28 - 7,13 (m, 5H), 3,43 (d, J= 11,1, 2H), 3,24 (d, J= 12,3, 2H), 3,15 (br, 4H), 2,84 (d, J = 3,6, 3H), 2,11 (s, 3H); LCMS: czystość: 92,64%; MS (m/e): 468,29 (M+H).

I-283: N2-[4-chloro-3-(4-etylopiperazyno)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0495] ¹H NMR (300 MHz, DMSO) δ 9,07 (s, 1H), 8,35 (s, 1H), 8,12 (s, 1H), 7,88 (s, 1H),

7,51 (s, 1H), 7,35 - 7,18 (m, 4H), 7,08 (d, J= 9,0, 1H), 2,72 (br, 4H), 2,42 (br, 4H), 2,36 (q, J = 7,2, 2H), 2,09 (s, 3H), 1,02 (t, J= 7,2, 3H); LCMS: czystość: 94,40%; MS (m/e): 480,28 (M+H).

I-284: N2-[4-chloro-3-(3,4,5-trimetylopiperazyno)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro1.3- benzooksazol-5-ilo)-2,4-pirymidynodiamina [0496] ¹H NMR (300 MHz, DMSO) δ 11,57 (s, 1H), 9,05 (s, 1H), 8,35 (s, 1H), 8,10 (s, 1H),

7.87 (s, 1H), 7,32 (m, 3H), 7,20 (d, J = 8,7, 1H), 7,13 (d, J = 8,4, 1H), 2,09 (s, 3H), 1,23 (br, 6H); LCMS: czystość: 80,46%; MS (m/e): 494,32 (M+H).

I-285: 5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-N2-[3-(4propylopiperazyno)-4-trifluorometylo]fenylo-2,4-pirymidynodiamina [0497] ¹H NMR (300 MHz, DMSO) δ 11,52 (s, 1H), 9,28 (s, 1H), 8,40 (s, 1H), 7,97 (s, 1H),

7.88 (s, 2H), 7,28 (m, 3H), 7,19 (d, J = 9,3, 1H), 2,94 (br, 8H), 2,09 (s, 3H), 1,60 (br, 2H), 0,90 (t, J = 7,2, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 75,43; LCMS: czystość: 95,71%; MS (m/e): 528,37 (M+H).

I-286: 5-metylo-N2-[3-(1,3-oksazol-5-ilo)]fenylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol5-ilo)-2,4-pirymidynodiamina [0498] ¹H NMR (300 MHz, DMSO) δ 11,57 (s, 1H), 10,03 (br, 1H), 9,49 (br, 1H), 8,32 (s,

- 167 1H), 7,88 (s, 1H), 7,80 (s, 1H), 7,40 (m, 2H), 7,32 (m, 2H), 7,22 (s, 2H), 7,12 (d, J= 9,3, 1H),

2,15 (s, 3H); LCMS: czystość: 95,22%; MS (m/e): 401,23 (M+H).

I-287: N2-(3-bromo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4pirymidynodiamina [0499] ¹H NMR (300 MHz, DMSO) δ 11,59 (s, 1H), 9,30 (s, 1H), 8,54 (s, 1H), 7,96 (s, 1H),

7,88 (s, 1H), 7,45 (d, J = 8,1, 1H), 7,23 (m, 2H), 7,05 (t, J = 7,8, 1H), 6,96 (m, 2H), 2,10 (s, 3H); LCMS: czystość: 97,81%; MS (m/e): 412,11 (M+H).

I-288: N2-(4-bromo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4pirymidynodiamina [0500] ¹H NMR (300 MHz, DMSO) δ 11,61 (s, 1H), 9,14 (s, 1H), 8,37 (s, 1H), 7,86 (s, 1H), 7,62 (d, J = 9,0, 2H), 7,26 (m, 5H), 2,09 (s, 3H); LCMS: czystość: 98,23%; MS (m/e): 412,12 (M+H).

I-289: 5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-N2-[3-(pirydyn-4ylo)]fenylo-2,4-pirymidynodiamina [0501] ¹H NMR (300 MHz, DMSO) δ 11,52 (s, 1H), 8,58 (d, 2H), 7,99 (br, 1H), 7,89 (s, 1H),

7,56 (m, 2H), 7,49 (m, 2H), 7,42 (d, 1H), 7,19 (m, 2H), 7,07 (d, 1H), 2,15 (s, 3H); LCMS: czystość: 94,63%; MS (m/e): 411,24 (M+H).

I-290: 5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-N2-[3-(pirydyn-3ylo)]fenylo-2,4-pirymidynodiamina [0502] ¹H NMR (300 MHz, DMSO) δ 11,54 (s, 1H), 8,62 (s, 1H), 8,53 (d, 1H), 7,84 (m, 3H), 7,39 (m, 4H), 7,18 (m, 2H), 7,01 (d, 1H), 2,15 (s, 3H); LCMS: czystość: 86,04%; MS (m/e): 411,24 (M+H).

I-291: 5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-N2-[4-(pirydyn-3ylo)]fenylo-2,4-pirymidynodiamina [0503] ¹H NMR (300 MHz, DMSO) δ 11,73 (s, 1H), 8,88 (s, 1H), 8,55 (d, 1H), 8,11 (d, 1H),

7,88 (s, 1H), 7,60 (m, 5H), 7,33 (d, 1H), 7,26 (m, 2H), 2,16 (s, 3H); LCMS: czystość: 94,74%; MS (m/e): 411,21 (M+H).

I-292: N2-[4-metoksy-3-(2-metoksyetoksy)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0504] ¹H NMR (300 MHz, DMSO) δ 11,52 (s, 1H), 8,73 (s, 1H), 8,26 (s, 1H), 7,83 (s, 1H),

7,31 (d, J= 2,4, 3H), 7,17 (d, J = 9,3, 1H), 7,13 (d, J = 8,1, 1H), 6,72 (d, J = 9,0, 1H), 3,69 (t, J= 4,8, 2H), 3,66 (s, 3H), 3,50 (d, J= 4,2, 2H), 3,26 (s, 3H), 2,07 (s, 3H); LCMS: czystość: 95,38%; MS (m/e): 438,08 (M+H).

I-293: N2-[3-(cyklopropyloaminokarbonylometoksy)-4-metoksy]fenylo-5-metylo-N4-(2okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0505] ¹H NMR (300 MHz, DMSO) δ 11,69 (s, 1H), 9,86 (br, 1H), 9,54 (br, 1H), 7,92 (s,

1H), 7,75 (s, 1H), 7,23 (s, 3H), 6,98 (d, 1H), 6,89 (d, J= 9,6, 2H), 4,26 (s, 2H), 3,74 (s, 3H),

- 168 2,64 (p, J= 3,9, 1H), 2,13 (s, 3H), 0,62 (q, J = 6,0, 2H), 0,44 (q, J= 2,7, 2H); LCMS: czystość: 96,56%; MS (m/e): 477,28 (M+H).

I-294: N2-(3-cyjano-4-fluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0506] ¹H NMR (300 MHz, DMSO) δ 11,19 (br, 1H), 9,42 (s, 1H), 8,47 (s, 1H), 8,25 (dd, J =

2,7, 5,7, 1H), 7,90 (s, 1H), 7,72 (m, J = 4,5, 1H), 7,34 - 7,17 (m, 4H), 2,10 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 135,29; LCMS: czystość: 94,39%; MS (m/e): 377,18 (M+H).

I-295: N2-[3-cyjano-4-(1H-pirol-1-ilo)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0507] ¹H NMR (300 MHz, DMSO) δ 9,54 (s, 1H), 8,49 (s, 1H), 8,33 (d, J = 2,4, 1H), 7,93 (s, 1H), 7,79 (d, J = 8,7, 1H), 7,36 (d, J = 8,7, 1H), 7,28 (s, 1H), 7,25 (d, J = 8,4, 1H), 7,20 (d, J = 9,6, 1H), 7,07 (s, 2H), 6,25 (s, 2H), 2,11 (s, 3H); LCMS: czystość: 94,01%; MS (m/e): 424,23 (M+H).

I-296: N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0508] ¹H NMR (300 MHz, DMSO) δ 9,30 (s, 1H), 8,41 (s, 1H), 7,90 (s, 1H), 7,58 (d, 2H), 7,24 (s, 1H), 7,18 (m, 2H), 6,62 (s, 1H), 3,64 (s, 3H), 2,09 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 77,41; LCMS: czystość: 95,05%; MS (m/e): 432,21 (M+H).

I-297: N2-(4-metoksy-3-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0509] ¹H NMR (300 MHz, DMSO) δ 11,15 (br, 1H), 9,04 (s, 1H), 8,33 (s, 1H), 7,90 (s, 1H), 7,85 (s, 1H), 7,81 (d, J= 8,7, 1H), 7,28 (s, 1H), 7,27 (d, J = 6,3, 1H), 7,17 (d, J = 9,0, 1H), 7,03 (d, J= 9,0, 1H), 3,78 (s, 3H), 2,08 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 76,81; LCMS: czystość: 96,38%; MS (m/e): 432,19 (M+H).

I-298: N2-{4-metoksy-3-[(pirydyn-4-ylo)metoksy]}fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0510] ¹H NMR (300 MHz, DMSO) δ 11,51 (br, 1H), 8,76 (s, 1H), 8,52 (d, J = 6,0, 2H), 8,27 (s, 1H), 7,82 (s, 1H), 7,43 (s, 1H), 7,33 (d, J= 8,4, 1H), 7,32 (s, 1H), 7,28 (d, J = 5,1, 2H),

7,16 (m, 2H), 6,78 (d, J= 8,7, 1H), 4,81 (s, 2H), 3,71 (s, 3H), 2,07 (s, 3H); LCMS: czystość: 93,03%; MS (m/e): 471,25 (M+H).

I-299: N2-{4-metoksy-3-[(pirydyn-3-ylo)metoksy]}fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0511] ¹H NMR (300 MHz, DMSO) δ 11,52 (s, 1H), 8,81 (br, 1H), 8,51 (s, 1H), 8,50 (d, J =

7,2, 1H), 7,83 (s, 1H), 7,72 (d, J= 7,5, 1H), 7,46 (s, 1H), 7,38 (d, J= 3,9, 1H), 7,32 (s, 2H),

7,16 (d, J= 8,7, 2H), 6,77 (d, J= 8,7, 1H), 4,80 (s, 2H), 3,68 (s, 3H), 2,07 (s, 3H); LCMS: czystość: 91,60%; MS (m/e): 471,23 (M+H).

I-300:

N2-{4-metoksy-3-[2-(dimetyloamino)etoksy]}fenylo-5-metylo-N4-(2-okso-2,3- 169 dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0512] ¹H W (300 ΜΙ Iz, DMSO) δ 8,72 (s, 1H), 8,25 (s, 1H), 7,82 (s, 1H), 7,33 (s, 2H),

7,31 (d, J = 10,2, 1H), 7,16 (d, J = 8,7, 1H), 7,13 (d, J= 11,1, 1H), 6,72 (d, J = 9,0, 1H), 3,74 (t, J= 5,7, 2H), 3,66 (s, 3H), 2,16 (s, 6H), 2,07 (s, 3H); LCMS: czystość: 98,92%; MS (m/e): 451,26 (Μ+H).

I-301: N2-[3,5-bis(trifluorometylo)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0513] ¹H WR (300 \lHz, DMSO) δ 11,52 (s, 1H), 10,04 (br, 1H), 8,99 (br, 1H), 8,18 (s, 2H), 7,96 (s, 1H), 7,48 (s, 1H), 7,20 (m, 3H), 2,14 (s, 3H); ¹⁹F W (282 \lllz, DMSO) δ 77,91; LCMS: czystość: 96,63%; MS (m/e): 470,18 (Μ+H).

I-302: N2-(3,5-dimetylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)2,4-pirymidynodiamina [0514] ¹H WR (300 \lHz, DMSO) δ 11,71 (s, 1H), 9,79 (br, 1H), 9,59 (br, 1H), 7,83 (s, 1H), 7,30 (d, J = 9,6, 1H), 7,20 (s, 2H), 6,98 (s, 2H), 6,65 (s, 1H), 2,14 (s, 3H), 2,05 (s, 6H); LCMS: czystość: 96,82%; MS (m/e): 362,17 (Μ+H).

I-303: N2-(4-cyjano-3-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0515] ¹H WR (300 Ylllz, DMSO) δ 11,55 (br, 1H), 9,98 (s, 1H), 8,56 (s, 1H), 8,27 (s, 1H), 8,03 (d, J = 8,1, 1H), 7,97 (s, 1H), 7,84 (d, J = 9,3, 1H), 7,26 (s, 1H), 7,23 (s, 2H), 2,12 (s, 3H); ¹⁹F W (282 ΜΗ/, DMSO) δ - 77,44; LCMS: czystość: 93,84%; MS (m/e): 427,16 (Μ+H).

I-304: N2-[3-(1-hydroksy-2,2,2-trifluoroetylo)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0516] ¹H WR (300 \1Ilz, DMSO) δ 11,69 (s, 1H), 10,00 (br, 1H), 9,49 (br, 1H), 7,85 (s, 1H), 7,56 (d, J = 8,1, 1H), 7,41 (s, 1H), 7,29 - 7,12 (m, 4H), 6,81 (s, 1H), 4,92 (q, 1H), 2,14 (s, 3H); ¹⁹F W (282 \lllz, DMSO) δ - 92,60 (d, J= 6); LCMS: czystość: 96,71%; MS (m/e): 432,14 (Μ+H).

I-305: N2-(3-metoksykarbonylometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0517] ¹H WR (300 ΜΗ/, DMSO) δ 11,54 (s, 1H), 8,98 (s, 1H), 8,33 (s, 1H), 7,86 (s, 1H), 7,35 (s, 1H), 7,31 (s, 2H), 7,22 (s, 1H), 7,20 (d, J = 4,8, 1H), 6,99 (t, J = 8,1, 1H), 6,35 (d, J= 8,1, 1H), 4,56 (s, 2H), 3,67 (s, 3H), 2,09 (s, 3H); LCMS: czystość: 90,78%; MS (m/e): 422,18 (Μ+H).

I-306: 5-metylo-N2-(3-metyloaminokarbonylometoksy)fenylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0518] ¹H W (300 \lllz, DMSO) δ 10,63 (br, 1H), 8,99 (s, 1H), 8,30 (s, 1H), 7,89 (d, 1H),

7,86 (s, 1H), 7,39 (s, 1H), 7,33 (d, 2H), 7,24 (d, J= 8,1, 1H), 7,18 (d, J= 9,0, 1H), 7,01 (t, J=

- 170 8.1, 1H), 6,38 (d, J= 8,1, 1H), 4,26 (s, 2H), 2,63 (d, J= 4,5, 3H), 2,09 (s, 3H); LCMS: czystość: 95,80%; MS (m/e): 421,21 (M+H).

I-307: N2-(4-aminokarbonylometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0519] ¹H NMR (300 MHz, DMSO) δ 11,58 (br, 1H), 8,79 (s, 1H), 8,26 (s, 1H), 7,81 (s, 1H),

7,52 (d, J= 8,7, 2H), 7,45 (s, 1H), 7,35 (d, 2H), 7,31 (s, 1H), 7,20 (d, J= 8,4, 1H), 6,75 (d, J =

8,7, 2H), 4,31 (s, 2H), 2,07 (s, 3H); LCMS: czystość: 90,97%; MS (m/e): 407,20 (M+H).

I-308: 5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-N2-(4fenylokarbonyloamino)fenylo-2,4-pirymidynodiamina [0520] ¹H NMR (300 MHz, DMSO) δ 10,06 (s, 1H), 8,94 (s, 1H), 8,30 (s, 1H), 7,90 (d, J =

7.2, 2H), 7,85 (s, 1H), 7,60 (d, J = 9,0, 2H), 7,51 (m, 6H), 7,36 (d, J= 8,4, 1H), 7,31 (s, 1H), 7,20 (d, J = 8,1, 1H), 2,09 (s, 3H); LCMS: czystość: 98,33%; MS (m/e): 453,21 (M+H).

I-309: N2-[4-(N-acetylo-N-metylo)amino]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0521] ¹H NMR (300 MHz, DMSO) δ 10,93 (br, 1H), 9,11 (s, 1H), 8,34 (s, 1H), 7,86 (s, 1H), 7,67 (d, J = 8,4, 2H), 7,29 (d, 2H), 7,22 (d, J = 8,1, 1H), 7,04 (d, J = 8,7, 2H), 3,07 (s, 3H), 2,09 (s, 3H), 1,72 (s, 3H); LCMS: czystość: 95,99%; MS (m/e): 405,22 (M+H).

I-310: N2-[3-cyjano-4-(pirolidyn-1-ylo)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0522] ¹H NMR (300 MHz, DMSO) δ 10,12 (br, 1H), 8,86 (s, 1H), 8,30 (s, 1H), 7,83 (d, J = 6,0, 2H), 7,52 (d, J = 9,0, 1H), 7,25 (s, 1H), 7,18 (t, J = 8,4, 2H), 6,64 (d, J = 9,3, 1H), 3,40 (t, 4H), 2,07 (s, 3H), 1,90 (t, 4H); LCMS: czystość: 96,09%; MS (m/e): 428,20 (M+H).

I-311: N2-(4-difluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0523] ¹H NMR (300 MHz, DMSO) δ 10,48 (br, 1H), 9,04 (s, 1H), 8,32 (s, 1H), 7,85 (s, 1H),

7,65 (d, J= 9,3, 2H), 7,28 (d, 2H), 7,20 (d, J= 9,3, 1H), 7,02 (t, J= 75, 1H), 6,93 (d, J = 9,0, 2H), 2,08 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 96,76 (d, J= 73); LCMS: czystość: 97,82%; MS (m/e): 400,16 (M+H).

I-312: N2-(3-difluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0524] ¹H NMR (300 MHz, DMSO) δ 10,54 (br, 1H), 9,18 (s, 1H), 8,36 (s, 1H), 7,88 (s, 1H), 7,61 (s, 1H), 7,43 (d, J= 8,1, 1H), 7,27 (d, 2H), 7,18 (d, J= 8,7, 1H), 7,12 (t, J= 8,4, 1H), 6,99 (t, J= 75, 1H), 6,58 (d, J = 9,0, 1H), 2,09 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 96,98 (d, J = 73); LCMS: czystość: 97,94%; MS (m/e): 400,16 (M+H).

I-313: N2-(4-difluorometoksy-3-etoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0525] ¹H NMR (300 MHz, DMSO) δ 9,02 (s, 1H), 8,35 (s, 1H), 7,87 (s, 1H), 7,51 (s, 1H),

- 171 7,28 (d, J= 7,2, 2H), 7,21 (s, 1H), 7,16 (d, J= 8,7, 1H), 6,90 (d, J = 9,0, 1H), 6,83 (t, J= 75, 1H), 3,65 (q, J= 6,6, 2H), 2,08 (s, 3H), 1,18 (t, J= 6,9, 3H); ¹⁹F NMR (282 MHz, DMSO) δ 96,43 (d, J= 76); LCMS: czystość: 96,55%; MS (m/e): 444,16 (M+H).

I-314: N2-(3-chloro-4-difluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0526] ¹H NMR (300 MHz, DMSO) δ 9,27 (s, 1H), 8,44 (s, 1H), 7,98 (d, J = 2,4, 1H), 7,88 (s, 1H), 7,43 (d, J = 9,0, 1H), 7,23 (s, 3H), 7,11 (d, J = 9,0, 1H), 7,03 (t, J= 72, 1H), 2,09 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 97,27 (d, J= 73); LCMS: czystość: 97,47%; MS (m/e): 434,12 (M+H).

I-315: N2-[3-(cyklopropyloaminokarbonylometoksy)]fenylo-5-metylo-N4-(2-okso-2,3dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0527] ¹H NMR (300 MHz, DMSO) δ 11,66 (s, 1H), 9,82 (br, 1H), 9,48 (br, 1H), 8,04 (d, J =

4,2, 1H), 7,84 (s, 1H), 7,25 (s, 3H), 7,09 (d, J = 7,5, 1H), 7,05 (s, 2H), 6,56 (d, J = 9,0, 1H), 4,28 (s, 2H), 2,65 (p, J= 3,0, 1H), 2,14 (s, 3H), 0,62 (q, J = 4,8, 2H), 0,46 (q, J= 2,7, 2H); LCMS: czystość: 91,36%; MS (m/e): 447,23 (M+H).

I-316: N2-[3-aminokarbonylo-4-(4-metylopiperazyno)]fenylo-5-metylo-N4-(2-okso-2,3dihydro-l,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0528] ¹H NMR (300 MHz, DMSO) δ 8,97 (s, 2H), 8,25 (s, 1H), 7,91 (s, 1H), 7,83 (t, J = 6,0, 2H), 7,45 (s, 1H), 7,36 (d, J= 8,4, 1H), 7,32 (s, 1H), 7,16 (d, J= 8,1, 1H), 7,03 (d, J= 8,4, 1H), 2,84 (t, 4H), 2,22 (s, 3H), 2,08 (s, 3H); LCMS: czystość: 92,35%; MS (m/e): 475,28 (M+H).

I-317: N2-[4-(izopropoksykarbonylometoksy)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0529] ¹H NMR (300 MHz, DMSO) δ 11,74 (s, 1H), 9,86 (br, 1H), 9,58 (br, 1H), 7,78 (s, 1H), 7,29-7,21 (m, 5H), 6,83 (d, J= 8,7, 2H), 4,97 (p, J = 6,9, 1H), 4,68 (s, 2H), 2,12 (s, 3H), 1,19 (d, J= 6,0, 6H); LCMS: czystość: 76,08%; MS (m/e): 450,24 (M+H).

I-318: N2-[4-(etyloaminokarbonyloamino)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0530] ¹H NMR (300 MHz, DMSO) δ 11,71 (s, 1H), 9,78 (br, 1H), 9,54 (br, 1H), 8,40 (s, 1H), 7,76 (s, 1H), 7,26 (s, 7H), 6,07 (s, 1H), 3,07 (q, J = 6,6, 2H), 2,12 (s, 3H), 1,02 (t, J = 6,9, 3H); LCMS: czystość: 94,25%; MS (m/e): 420,24 (M+H).

I-319: N2-[3-(aminokarbonylometoksy)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0531] 1H NMR (300 MHz, DMSO) δ 11,68 (s, 1H), 7,84 (s, 1H), 7,42 (s, 1H), 7,37 (s, 1H),

7,27 (s, 3H), 7,10 (m 3H), 6,61 (s, 1H), 4,29 (s, 2H), 2,13 (s, 3H); LCMS: czystość: 91,03%; MS (m/e): 407,19 (M+H).

I-320: 5-metylo-N2-[3-(morfolinokarbonylometoksy)]fenylo-N4-(2-okso-2,3-dihydro-1,3- 172 benzooksazol-5-ilo)-2,4-pirymidynodiamina [0532] ¹H NMR (300 MHz, DMSO) δ 11,68 (s, 1H), 9,95 (br, 1H), 9,58 (br, 1H), 7,85 (s, 1H), 7,30 (d, J= 8,7, 1H), 7,23 (d, J= 6,6, 2H), 7,11 (t, J = 7,8, 1H), 6,99 (d, J = 9,6, 2H), 6,61 (d, J = 7,2, 1H), 4,69 (s, 2H), 3,55 (s, 4H), 3,41 (s, 4H), 2,14 (s, 3H); LCMS: czystość: 96,33%; MS (m/e): 477,25 (M+H).

I-321: 5-metylo-N2-[3-(4-metylopiperazyn-1-ylo)karbonylo]fenylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0533] ¹H NMR (300 MHz, DMSO) δ 11,70 (s, 1H), 10,15 (br, 1H), 9,88 (br, 1H), 9,43 (br, 1H), 7,92 (s, 1H), 7,58 (d, J = 7,8, 1H), 7,52 (s, 1H), 7,30 - 7,22 (m, 4H), 7,06 (d, J = 7,2, 1H), 3,40 (br, 4H), 3,03 (br, 4H), 2,80 (s, 3H), 2,13 (s, 3H); LCMS: czystość: 95,46%; MS (m/e): 460,29 (M+H).

I-322: 5-metylo-N2-[4-(4-metylopiperazyn-1-ylo)karbonylo]fenylo-N4-(2-okso-2,3-dihydro1.3- benzooksazol-5-ilo)-2,4-pirymidynodiamina [0534] ¹H NMR (300 MHz, DMSO) δ 11,71 (s, 1H), 9,83 (br, 1H), 7,93 (s, 1H), 7,61 (d, J = 9,0, 2H), 7,30 (m, 5H), 3,39 (m, 2H), 3,23 (m, 2H), 3,06 (m, 2H), 2,81 (s, 3H), 2,13 (s, 3H); LCMS: czystość: 86,87%; MS (m/e): 460,30 (M+H).

I-323: 5-metylo-N2-[3-metyloaminokarbonylo-4-(4-metylopiperazyno)]fenylo-N4-(2-okso2.3- dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0535] ¹H NMR (300 MHz, DMSO) δ 11,73 (s, 1H), 10,02 (br, 1H), 9,64 (br, 2H), 8,45 (d, 1H), 7,87 (s, 1H), 7,58 (s, 1H), 7,48 (d, 1H), 7,21 (s, 3H), 7,03 (d, J = 8,4, 1H), 3,49 (d, J=

9,3, 2H), 3,17 (t, J= 6,6, 4H), 2,94 (d, 2H), 2,87 (s, 3H), 2,81 (d, J= 4,8, 3H), 2,13 (s, 3H); LCMS: czystość: 93,72%; MS (m/e): 489,30 (M+H).

I-324: N2-[4-(1-aminokarbonylo-1-metylo)etoksy]fenylo-5-metylo-N4-(2-okso-2,3-dihydro1.3- benzooksazol-5-ilo)-2,4-pirymidynodiamina [0536] ¹H NMR (300 MHz, DMSO) δ 8,83 (s, 1H), 8,28 (s, 1H), 7,82 (s, 1H), 7,49 (d, J = 9,0, 2H), 7,46 (s, 1H), 7,34 (d, J= 9,6, 1H), 7,29 (s, 1H), 7,18 (d, J= 8,7, 2H), 6,72 (d, J= 9,0, 2H), 2,06 (s, 3H), 1,32 (s, 6H); LCMS: czystość: 94,37%; MS (m/e): 435,21 (M+H).

I-325: 5-metylo-N2-(2-metylo-3-metyloaminokarbonylometoksy)fenylo-N4-(2-okso-2,3dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0537] ¹H NMR (300 MHz, DMSO) δ 8,15 (s, 1H), 8,06 (s, 1H), 7,83 (br, 1H), 7,76 (s, 1H), 7,39 (d, J= 9,3, 1H), 7,29 (s, 1H), 7,16 (d, J= 7,5, 1H), 7,04 (d, J= 8,1, 2H), 6,58 (d, J= 8,4, 1H), 4,42 (s, 2H), 2,65 (d, J = 4,5, 3H), 2,07 (s, 3H), 2,04 (s, 3H); LCMS: czystość: 94,87%; MS (m/e): 435,26 (M+H).

I-326: N2-(3-dimetyloaminokarbonylometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0538] ¹H NMR (300 MHz, DMSO) δ 11,30 (br, 1H), 8,94 (s, 1H), 8,31 (s, 1H), 7,87 (s, 1H),

7,34 (d, J= 6,6, 3H), 7,21 (d, J= 9,0, 2H), 6,99 (t, J= 8,1, 1H), 6,37 (d, J = 8,4, 1H), 4,60 (s,

- 173 2H), 2,94 (s, 3H), 2,82 (s, 3H), 2,08 (s, 3H); LCMS: czystość: 93,47%; MS (m/e): 435,22 (M+H).

I-327: N2-(3-cyjano-4-morfolino)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol5-ilo)-2,4-pirymidynodiamina [0539] ¹H NMR (300 MHz, DMSO) δ 11,44 (br, 1H), 9,20 (s, 1H), 8,41 (s, 1H), 8,12 (d, J =

2,4, 1H), 7,88 (s, 1H), 7,65 (d, J = 7,5, 1H), 7,24 (d, J = 8,1, 3H), 7,02 (d, J = 9,0, 1H), 3,71 (t, 4H), 2,97 (t, 4H), 2,08 (s, 3H); LCMS: czystość: 93,52%; MS (m/e): 444,22 (M+H).

I-328: N2-(3-metoksy-2-metylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol5-ilo)-2,4-pirymidynodiamina [0540] ¹H NMR (300 MHz, DMSO) δ 11,70 (s, 1H), 9,70 (s, 1H), 9,55 (s, 1H), 7,71 (s, 1H), 7,22 (m, 3H), 7,16 (d, J= 8,1, 1H), 6,92 (t, J = 6,9, 2H), 3,78 (s, 3H), 2,11 (s, 3H), 1,96 (s, 3H); LCMS: czystość: 94,95%; MS (m/e): 378,22 (M+H).

I-329: N2-[3-chloro-4-(pirydyn-4-ylo)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0541] ¹H NMR (300 MHz, DMSO) δ 11,72 (s, 1H), 9,55 (d, J = 7,8, 2H), 9,38 (s, 1H), 8,41 (s, 1H), 8,30 (d, J= 7,2, 2H), 7,51 (d, J= 8,7, 1H), 7,40 (s, 1H), 7,34 (s, 2H), 6,81 (s, 1H),

6,73 (d, 1H), 6,50 (br, 1H), 2,31 (s, 3H); LCMS: czystość: 68,83%; MS (m/e): 445,19 (M+H).

I-330: 5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-N2-[4-(pirydyn-4-ylo)-3trifluorometylo]fenylo-2,4-pirymidynodiamina [0542] ¹H NMR (300 MHz, DMSO) δ 11,74 (s, 1H), 9,65 (d, J = 7,2, 2H), 9,40 (s, 1H), 8,42 (s, 1H), 8,13 (d, J = 7,2, 2H), 7,39 (s, 1H), 7,34 (m, 3H), 7,11 (s, 1H), 6,93 (d, J = 8,1, 1H),

6,43 (br, 1H), 2,32 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 70,12; LCMS: czystość: 86,84%; MS (m/e): 479,21 (M+H).

I-331: N2-[3-hydroksymetylo-4-(4-metylopiperazyno)]fenylo-5-metylo-N4-(2-okso-2,3dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0543] ¹H NMR (300 MHz, DMSO) δ 11,70 (br, 1H), 9,52 (br, 1H), 7,82 (s, 1H), 7,37 (br, 2H), 7,25 (s, 3H), 6,94 (d, 1H), 4,45 (s, 2H), 3,49 (br, 4H), 3,14 (s, 3H), 2,86 (s, 4H), 2,12 (s, 3H); LCMS: czystość: 73,83%; MS (m/e): 462,30 (M+H).

I-332: 5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-N2-(4-piperazyno)fenylo2,4-pirymidynodiamina [0544] ¹H NMR (300 MHz, DMSO) δ 11,75 (s, 1H), 9,99 (br, 1H), 9,64 (br, 1H), 8,70 (br, 2H), 7,81 (s, 1H), 7,29 - 7,22 (m, 5H), 6,90 (d, J= 8,7, 2H), 3,24 (t, 8H), 2,12 (s, 3H); LCMS: czystość: 94,64%; MS (m/e): 418,24 (M+H).

I-333: N2-[4-(4-etyloaminokarbonylo)piperazyno]fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0545] ¹H NMR (300 MHz, DMSO) δ 11,75 (s, 1H), 9,88 (s, 1H), 9,69 (s, 1H), 7,74 (s, 1H),

7,30 - 7,16 (m, 5H), 6,89 (d, J = 7,8, 2H), 6,57 (s, 1H), 3,39 (t, 4H), 3,02 (t, 6H), 2,12 (s, 3H),

- 174 1,00 (t, J= 7,2, 3H); LCMS: czystość: 73,76%; MS (m/e): 489,28 (M+H).

I-334: N2-[4-(1-cyjano-1-metylo)etoksy]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0546] ¹H NMR (300 MHz, DMSO) δ 11,75 (s, 1H), 10,08 (s, 1H), 9,66 (s, 1H), 7,85 (s, 1H), 7,38 (d, J= 8,7, 2H), 7,28 (d, J= 8,7, 1H), 7,21 (s, 2H), 7,03 (d, J = 9,0, 2H), 2,13 (s, 3H), 1,63 (s, 6H); LCMS: czystość: 97,92%; MS (m/e): 417,24 (M+H).

I-335: N2-[3-(1-aminokarbonylo-1-metylo)etoksy]fenylo-5-metylo-N4-(2-okso-2,3-dihydro1.3- benzooksazol-5-ilo)-2,4-pirymidynodiamina [0547] ¹H NMR (300 MHz, DMSO) δ 11,72 (s, 1H), 9,97 (s, 1H), 9,54 (s, 1H), 7,86 (s, 1H), 7,38 (s, 1H), 7,30 (d, J= 9,6, 1H), 7,24 (d, J= 8,4, 3H), 7,09 (d, J= 4,5, 2H), 6,98 (s, 1H),

6,53 (s, 1H), 2,13 (s, 3H), 1,35 (s, 6H); LCMS: czystość: 97,33%; MS (m/e): 435,25 (M+H).

I-336: N2-(3-metoksy-4-metoksykarbonylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0548] ¹H NMR (300 MHz, DMSO) δ 9,36 (s, 1H), 8,42 (s, 1H), 7,93 (s, 1H), 7,51 (d, J = 8,4, 1H), 7,48 (s, 1H), 7,36 (d, J= 6,6, 1H), 7,30 (d, 2H), 7,21 (d, J= 9,3, 1H), 3,68 (s, 3H), 3,52 (s, 3H), 2,10 (s, 3H); LCMS: czystość: 85,55%; MS (m/e): 422,23 (M+H).

I-337: N2-(3-metoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4pirymidynodiamina [0549] ¹H NMR (300 MHz, DMSO) δ 11,55 (s, 1H), 8,94 (s, 1H), 8,33 (s, 1H), 7,86 (s, 1H), 7,31 (t, J= 6,9, 3H), 7,18 (t, J= 8,1, 2H), 7,00 (t, J= 8,1, 1H), 6,38 (d, J= 7,8, 1H), 3,57 (s, 3H), 2,08 (s, 3H); LCMS: czystość: 94,08%; MS (m/e): 364,22 (M+H).

I-338: 5-metylo-N2-(4-morfolino)fenylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)2.4- pirymidynodiamina [0550] ¹H NMR (300 MHz, DMSO) δ 11,74 (s, 1H), 9,68 (s, 1H), 7,74 (s, 1H), 7,27-7,16 (m, 5H), 6,88 (d, 2H), 3,71 (t, 4H), 3,04 (t, 4H), 2,12 (s, 3H); LCMS: czystość: 73,88%; MS (m/e): 419,18 (M+H).

I-339: N2-(3-cyjano-4-tiomorfolino)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0551] ¹H NMR (300 MHz, DMSO) δ 11,34 (br, 1H), 9,20 (s, 1H), 8,41 (s, 1H), 8,11 (s, 1H), 7,88 (s, 1H), 7,65 (d, J = 9,6, 1H), 7,23 (d, J = 6,3, 3H), 7,03 (d, J = 9,0, 1H), 3,20 (t, 4H),

2,74 (t, 4H), 2,08 (s, 3H); LCMS: czystość: 84,84%; MS (m/e): 460,24 (M+H).

I-340: N2-[3-metoksy-4-(4-metylopiperazyno)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0552] ¹H NMR (300 MHz, DMSO) δ 11,73 (s, 1H), 10,12 (s, 1H), 9,66 (s, 2H), 7,83 (s, 1H),

7,26 (d, J = 9,3, 1H), 7,22 (d, 2H), 6,94 (d, J = 9,6, 2H), 6,82 (d, J = 8,4, 1H), 3,50 (s, 3H),

3,45 (br, 4H), 3,18 (q, 2H), 2,85 (t, 5H), 2,13 (s, 3H); LCMS: czystość: 92,71%; MS (m/e):

462,25 (M+H).

- 175 I-341: N2-[3-cyjano-4-(4-metylopiperazyno)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0553] ¹H NMR (300 MHz, DMSO) δ 9,18 (s, 1H), 8,40 (s, 1H), 8,09 (s, 1H), 7,87 (s, 1H), 7,63 (d, J= 9,3, 1H), 7,23 (d, J = 8,7, 3H), 6,99 (d, J = 9,0, 1H), 2,98 (t, 4H), 2,21 (s, 3H), 2,07 (s, 3H); LCMS: czystość: 91,59%; MS (m/e): 457,27 (M+H).

I-342: N2-[3-(1-cyjano-1-metylo)etoksy]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0554] ¹H NMR (300 MHz, DMSO) δ 11,71 (s, 1H), 9,98 (s, 1H), 9,48 (s, 1H), 7,88 (s, 1H), 7,31-7,18 (m, 6H), 6,83 (d, J= 7,8, 1H), 2,13 (s, 3H), 1,57 (s, 6H); LCMS: czystość: 97,74%; MS (m/e): 417,27 (M+H).

I-343: N2-[4-(4-acetylo)piperazyno]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0555] ¹H NMR (300 MHz, DMSO) δ 8,73 (s, 1H), 8,25 (s, 1H), 7,81 (s, 1H), 7,48 (d, J = 8,4, 2H), 7,33 (d, J = 8,1, 1H), 7,30 (s, 1H), 7,20 (d, J = 8,1, 1H), 6,76 (d, J = 8,7, 2H), 3,54 (s, 4H), 2,99 (t, 2H), 2,92 (t, 2H), 2,05 (s, 3H), 2,01 (s, 3H); LCMS: czystość: 94,65%; MS (m/e): 460,28 (M+H).

I-344: N2-[4-(4-etoksykarbonylo)piperazyno]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0556] ¹H NMR (300 MHz, DMSO) δ 11,01 (br, 1H), 8,71 (s, 1H), 8,24 (s, 1H), 7,80 (s, 1H), 7,47 (d, J = 8,7, 2H), 7,32 (d, J = 11,1, 2H), 7,19 (d, J = 8,7, 1H), 6,75 (d, J = 8,7, 2H), 4,03 (q, J= 6,9, 2H), 3,46 (t, 4H), 2,94 (t, J = 4,5, 4H), 2,05 (s, 3H), 1,17 (t, J= 7,2, 3H); LCMS: czystość: 91,97%; MS (m/e): 490,26 (M+H).

I-345: N2-[3-(4-acetylo)piperazyno]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0557] ¹H NMR (300 MHz, DMSO) δ 11,74 (s, 1H), 10,04 (s, 1H), 9,71 (s, 1H), 7,82 (s, 1H),

7,27 (d, J= 9,3, 1H), 7,22 (d, J = 6,6, 2H), 7,11 (t, J= 8,1, 1H), 6,89 (s, 1H), 6,83 (d, J = 8,1, 1H), 6,74 (d, J= 8,1, 1H), 3,45 (t, 4H), 2,97 (t, 2H), 2,84 (t, 2H), 2,14 (s, 3H), 2,01 (s, 3H); LCMS: czystość: 100%; MS (m/e): 460,08 (M+H).

I-346: N2-[3-(4-etoksykarbonylo)piperazyno]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0558] ¹H NMR (300 MHz, DMSO) δ 11,69 (s, 1H), 9,85 (br, 1H), 9,52 (br, 1H), 7,81 (s, 1H), 7,24 (s, 3H), 7,09 (t, J= 8,1, 1H), 6,93 (s, 1H), 6,86 (d, J= 7,5, 1H), 6,69 (d, J= 6,9, 1H), 4,04 (d, J= 7,2, 2H), 3,38 (s, 4H), 2,90 (s, 4H), 2,12 (s, 3H), 1,18 (t, J= 6,9, 3H); LCMS: czystość: 93,55%; MS (m/e): 490,32 (M+H).

I-347: N2-(4-difluorometoksy-3-fluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0559] ¹H NMR (300 MHz, DMSO) δ 11,63 (s, 1H), 9,61 (s, 1H), 8,89 (br, 1H), 7,88 (s, 1H),

- 176 7,75 (d, J = 14,4, 1H), 7,29 - 7,10 (m, 5H), 7,05 (t, J= 74, 1H), 2,10 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 97,45 (d, J = 73); LCMS: czystość: 98,63%; MS (m/e): 418,21 (M+H).

I-348: N2-(3,5-dichloro-4-difluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0560] ¹H NMR (300 MHz, DMSO) δ 11,57 (s, 1H), 9,48 (s, 1H), 8,55 (s, 1H), 7,91 (s, 1H), 7,77 (s, 2H), 7,25 (d, J = 8,1, 1H), 7,20 (s, 1H), 7,16 (d, J= 8,1, 1H), 6,96 (t, J = 73, 1H), 2,08 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 95,79 (d, J= 73); LCMS: czystość: 93,57%; MS (m/e): 468,13 (M+H).

I-349: N2-(4-fluoro-3-metoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0561] ¹H NMR (300 MHz, DMSO) δ 11,34 (br, 1H), 8,96 (s, 1H), 8,33 (s, 1H), 7,87 (s, 1H), 7,46 (d, J = 8,1, 1H), 7,31 (d, J = 5,4, 2H), 7,23 (d, J = 8,7, 1H), 7,20 (d, J = 9,3, 1H), 6,93 (t, J = 9,9, 1H), 3,55 (s, 3H), 2,07 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 160,84; LCMS: czystość: 100%; MS (m/e): 382,03 (M+H).

I-350: N2-(3-fluoro-4-metoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0562] ¹H NMR (300 MHz, DMSO) δ 11,65 (s, 1H), 9,47 (br, 1H), 9,05 (br, 1H), 7,83 (s, 1H), 7,52 (d, J = 14,7, 1H), 7,24 (s, 3H), 7,10 (d, 1H), 6,99 (t, J= 9,3, 1H), 3,74 (s, 3H), 2,10 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 149,86; LCMS: czystość: 100%; MS (m/e): 382,02 (M+H).

I-351: N2-(3-metoksy-4-metylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol5-ilo)-2,4-pirymidynodiamina [0563] ¹H NMR (300 MHz, DMSO) δ 11,58 (s, 1H), 8,83 (s, 1H), 8,29 (s, 1H), 7,86 (s, 1H), 7,35 (d, J = 10,5, 2H), 7,25 (s, 1H), 7,20 (t, J = 6,9, 2H), 6,84 (d, J = 8,4, 1H), 3,50 (s, 3H), 2,07 (s, 3H), 2,01 (s, 3H); LCMS: czystość: 90,74%; MS (m/e): 378,26 (M+H).

I-352: N2-(3-fluoro-5-metoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0564] ¹H NMR (300 MHz, DMSO) δ 11,53 (s, 1H), 9,15 (s, 1H), 8,42 (s, 1H), 7,88 (s, 1H), 7,26 (s, 1H), 7,20 (d, J= 8,1, 3H), 6,99 (s, 1H), 6,22 (d, J= 10,8, 1H), 3,60 (s, 3H), 2,08 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 127,86; LCMS: czystość: 96,96%; MS (m/e): 382,20 (M+H).

I-353: N2-(3-difluorometoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0565] ¹H NMR (300 MHz, DMSO) δ 11,56 (s, 1H), 9,97 (br, 1H), 9,10 (br, 1H), 7,94 (s, 1H), 7,74 (s, 1H), 7,69 (s, 1H), 7,20 (m, 3H), 7,19 (t, J= 73, 1H), 7,01 (s, 1H), 2,13 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 77,31; LCMS: czystość: 95,73%; MS (m/e): 468,21 (M+H).

I-354: N2-(3-metoksy-4-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzo- 177 oksazol-5-ilo)-2,4-pirymidynodiamina [0566] ¹H NMR (300 MHz, DMSO) δ 11,67 (s, 1H), 9,88 (br, 1H), 9,06 (br, 1H), 7,92 (s, 1H), 7,35 (d, J = 9,0, 2H), 7,28 (d, 4H), 3,57 (s, 3H), 2,13 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 75,24; LCMS: czystość: 86,29%; MS (m/e): 432,23 (M+H).

I-355: N2-(3,5-di-tert-butylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0567] ¹H NMR (300 MHz, DMSO) δ 11,68 (s, 1H), 9,86 (s, 1H), 9,50 (s, 1H), 7,82 (s, 1H), 7,24 -7,17 (m, 5H), 7,09 (s, 1H), 2,13 (s, 3H), 1,10 (s, 18H); LCMS: czystość: 98,22%; MS (m/e): 446,35 (M+H).

I-356: N4-{3-[bis(1,1-dimetyloetoksy)]fosfinyloksymetylo-2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo}-N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-2,4-pirymidynodiamina [0568] ¹H NMR (300 MHz, DMSO) δ 9,37 (s, 1H), 8,50 (s, 1H), 8,28 (s, 1H), 7,96 (s, 1H), 7,78 (s, 1H), 7,60 (s, 1H), 7,32 (s, 2H), 6,68 (s, 1H), 5,62 (d, J = 10,8, 2H), 3,71 (s, 3H), 2,12 (s, 3H), 1,30 (s, 18H); ¹⁹F NMR (282 MHz, DMSO) δ - 76,83; ³¹P NMR (121 MHz, DMSO) δ - 10,51; LCMS: czystość: 95,06%; MS (m/e): 598,30.

I-357: N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-N4-[3-(fosfonooksy)metylo-2-okso2,3-dihydro-1,3-benzooksazol-5-ilo]-2,4-pirymidynodiamina [0569] ¹H NMR (300 MHz, DMSO) δ 7,95 (s, 1H), 7,67 (s, 1H), 7,29 (s, 2H), 6,66 (s, 1H), 5,56 (d, 2H), 3,74 (s, 3H), 2,12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 76,80; LCMS: czystość: 81,15%; MS (m/e): 542,16 (M+H).

I-358: sól dwusodowa N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-N4-[3(fosfonooksy)metylo-2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo]-2,4-pirymidynodiamina, [0570] ¹H NMR (300 MHz, DMSO) δ 7,92 (s, 1H), 7,53 (br, 3H), 7,18 (s, 2H), 6,59 (br, 2H),

5,44 (d, 2H), 3,79 (s, 3H), 2,12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 76,53; LCMS: czystość: 93,44%; MS (m/e): 542,20 (M+H).

I-359: N2-(3,5-difluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)2,4-pirymidynodiamina [0571] ¹H NMR (300 MHz, DMSO) δ 11,61 (s, 1H), 9,61 (s, 1H), 8,78 (s, 1H), 7,91 (s, 1H), 7,30 - 7,15 (m, 5H), 6,59 (t, J= 9,0, 1H), 2,10 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ 126,14; LCMS: czystość: 96,57%; MS (m/e): 370,20 (M+H).

I-360: N2-(3-fluoro-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0572] ¹H NMR (300 MHz, DMSO) δ 11,55 (s, 1H), 9,61 (s, 1H), 8,53 (s, 1H), 7,92 (d, J = 11,1, 2H), 7,69 (s, 1H), 7,22 (m, 3H), 6,96 (d, J = 8,7, 1H), 2,10 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 77,18, - 125,92; LCMS: czystość: 94,90%; MS (m/e): 420,22 (M+H).

I-361: N2-(4-fluoro-3-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina

- 178 [0573] ¹H NMR (300 MHz, DMSO) δ 11,54 (s, 1H), 9,35 (s, 1H), 8,42 (s, 1H), 8,08 (d, J = 5,7, 1H), 7,90 (s, 1H), 7,85 (d, 1H), 7,30 - 7,19 (m, 4H), 2,08 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 75,89, - 142,78; LCMS: czystość: 97,69%; MS (m/e): 420,21 (M+H).

I-362: N2-(4-fluoro-3-metylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0574] ¹H NMR (300 MHz, DMSO) δ 11,13 (br, 1H), 8,94 (s, 1H), 8,33 (s, 1H), 7,85 (s, 1H), 7,55 (d, J = 7,2, 1H), 7,35 (dd, J = 9,9, 5,4, 1H), 7,28 (m, 2H), 7,22 (d, J = 9,0, 1H), 6,88 (t, J = 9,3, 1H), 2,07 (s, 3H), 1,99 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 143,48; LCMS: czystość: 97,37%; MS (m/e): 366,22 (M+H).

I-363: N2-(3-fluoro-4-metylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0575] ¹H NMR (300 MHz, DMSO) δ 11,58 (s, 1H), 9,11 (s, 1H), 8,39 (s, 1H), 7,87 (s, 1H), 7,62 (d, J= 13,5, 1H), 7,28 - 7,15 (m, 4H), 6,98 (t, J= 8,4, 1H), 2,08 (s, 6H); ¹⁹F NMR (282 MHz, DMSO) δ - 132,82; LCMS: czystość: 98,10%; MS (m/e): 366,22 (M+H).

I-364: N2-(3-chloro-4-metylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0576] ¹H NMR (300 MHz, DMSO) δ 11,33 (br, 1H), 9,10 (s, 1H), 8,39(s, 1H), 7,86 (d, J = 5,7, 2H), 7,32 (d, J = 8,1, 1H), 7,23 (d, 3H), 7,05 (d, J = 8,4, 1H), 2,17 (s, 3H), 2,07 (s, 3H); LCMS: czystość: 96,65%; MS (m/e): 382,20 (M+H).

I-365: N2-(3,4,5-trimetylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-l,3-benzooksazol-5-ilo)2,4-pirymidynodiamina [0577] ¹H NMR (300 MHz, DMSO) δ 11,39 (br, 1H), 8,70 (s, 1H), 8,29 (s, 1H), 7,83 (s, 1H), 7,30 (d, J= 6,3, 2H), 7,21 (m, 3H), 2,06 (s, 3H), 1,99 (s, 6H), 1,98 (s, 3H); LCMS: czystość: 96,73%; MS (m/e): 376,27 (M+H).

I-366: N2-(3-chloro-4-trifluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0578] LCMS: czystość: 96,28%; MS (m/e): 452,19 (M+H).

I-367: N2-(4-trifluorometylotio)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol5-ilo)-2,4-pirymidynodiamina [0579] LCMS: czystość: 95,52%; MS (m/e): 434,16 (M+H).

I-368: N2-(3-fluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4pirymidynodiamina [0580] LCMS: czystość: 95,77%; MS (m/e): 352,20 (M+H).

[0581] LCMS: czystość: 97,05%; MS (m/e): 392,28 (M+H).

I-369: N2-(3,5-dimetylo-4-metoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina

- 179 I-370: N2-(3-karboksyamid-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0582] LCMS: czystość: 95,87%; MS (m/e): 445,24 (M+H).

I-371: N2-(3,5-diizopropylo-4-metoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0583] LCMS: czystość: 98,88%; MS (m/e): 448,33 (M+H).

I-372: N2-(3-izopropoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0584] LCMS: czystość: 100%; MS (m/e): 460,14 (M+H).

I-373: N2-(3-cyjano-4-metoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol5-ilo)-2,4-pirymidynodiamina [0585] LCMS: czystość: 94,66%; MS (m/e): 389,23 (M+H).

I-374: N2-(3,5-dimetylo-4-fluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0586] ¹H NMR (300 MHz, DMSO) δ 11,43 (br, 1H), 8,85 (s, 1H), 8,33 (s, 1H), 7,84 (s, 1H),

7,28 (d, J= 6,6, 4H), 7,21 (d, J = 9,0, 1H), 2,06 (s, 3H), 1,98 (s, 6H); ¹⁹F NMR (282 MHz, DMSO) δ - 147,89; LCMS: czystość: 97,65%; MS (m/e): 380,24 (M+H).

I-375: N2-(4-fluoro-3-trifluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0587] LCMS: czystość: 96,82%; MS (m/e): 436,21 (M+H).

I-376: N2-(3-fluoro-4-trifluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0588] LCMS: czystość: 97,88%; MS (m/e): 436,21 (M+H).

I-377: N2-(4-chloro-3-trifluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0589] LCMS: czystość: 95,28%; MS (m/e): 452,14 (M+H).

I-378: N2-(3-chloro-5-trifluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0590] LCMS: czystość: 95,29%; MS (m/e): 452,19 (M+H).

I-379: 5-metylo-N2-(3-metylo-5-trifluorometoksy)fenylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0591] LCMS: czystość: 97,81%; MS (m/e): 432,24 (M+H).

I-380: N2-(4-cyjano-3-metoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol5-ilo)-2,4-pirymidynodiamina

- 180 [0592] LCMS: czystość: 97,08%; MS (m/e): 389,07 (M+H).

I-381: N2-(3,5-difluoro-4-metoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0593] LCMS: czystość: 100%; MS (m/e): 400,04 (M+H).

I-382: 5-metylo-N2-(4-morfolinometylo)fenylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0594] LCMS: czystość: 85,62%; MS (m/e): 433,28 (M+H).

I-383: N2-(4-chloro-3-cyjano-5-etylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0595] LCMS: czystość: 90,90%; MS (m/e): 421,24 (M+H).

I-384: N2-[3-(2-metoksy)etoksy-5-trifluorometylo]fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0596] LCMS: czystość: 86,68%; MS (m/e): 476,27 (M+H).

I-385: N2-(4-difluorometoksy-3,5-dimetylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0597] LCMS: czystość: 96,79%; MS (m/e): 428,26 (M+H).

I-386: N2-[3-(1-aminokarbonylo-1-metylo)etoksy-4-fluoro]fenylo-5-metylo-N4-(2-okso-2,3dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0598] LCMS: czystość: 98,11%; MS (m/e): 453,04 (M+H).

I-387: N2-(4-difluorometoksy-3-metylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0599] LCMS: czystość: 100%; MS (m/e): 414,08 (M+H).

I-388: N2-(3,5-difluoro-4-difluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0600] LCMS: czystość: 93,98%; MS (m/e): 436,22 (M+H).

I-389: N2-[4-(1-aminokarbonylo-1-metylo)etoksy-3,5-dimetylo]fenylo-5-metylo-N4-(2-okso2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0601] LCMS: czystość: 91,03%; MS (m/e): 463,34 (M+H).

I-390: N2-(3-difluorometoksy-4-metylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0602] LCMS: czystość: 93,39%; MS (m/e): 414,25 (M+H).

I-391: N2-[4-(1-aminokarbonylo-1-metylo)etoksy-3-metylo]fenylo-5-metylo-N4-(2-okso-2,3dihydro-l,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0603] LCMS: czystość: 100%; MS (m/e): 449,14 (M+H).

- 181 I-392: N2-[3-(1-aminokarbonylo-1-metylo)etoksy-4-metylo]fenylo-5-metylo-N4-(2-okso-2,3dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0604] LCMS: czystość: 98,47%; MS (m/e): 449,11 (M+H).

I-393: bezylan N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiaminy, [0605] LCMS: czystość: 94,20%; MS (m/e): 432,23 (M+H).

I-394: N2-(4-chloro-3,5-dimetylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0606] LCMS: czystość: 96,66%; MS (m/e): 396,14 (M+H).

I-395: N2-[4-(1-aminokarbonylo-1-metylo)etoksy-3,5-difluoro]fenylo-5-metylo-N4-(2-okso2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0607] LCMS: czystość: 100%; MS (m/e): 471,08 (M+H).

I-396: N2-[3-(1-metoksy-2,2,2-trifluoroetylo)]fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0608] LCMS: czystość: 100%; MS (m/e): 446,10 (M+H).

I-397: N2-[3-(1-cyjano-1-metylo)etoksy-4-metylo]fenylo-5-metylo-N4-(2-okso-2,3-dihydrol,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0609] LCMS: czystość: 100%; MS (m/e): 431,15 (M+H).

I-398: N2-(3,4-difluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)2,4-pirymidynodiamina [0610] LCMS: czystość: 97,76%; MS (m/e): 370,08 (M+H).

I-399: N2-(3-chloro-4-fluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0611] LCMS: czystość: 100%; MS (m/e): 386,04 (M+H).

I-400: N2-(4-chloro-3-fluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5ilo)-2,4-pirymidynodiamina [0612] LCMS: czystość: 98,43%; MS (m/e): 386,07 (M+H).

I-401: N2-(3-difluorometoksy-5-fluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0613] LCMS: czystość: 92,54%; MS (m/e): 418,18 (M+H).

I-402: N2-[3-(1-aminokarbonylo-1-metylo)etoksy-5-fluoro]fenylo-5-metylo-N4-(2-okso-2,3dihydro-l,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0614] LCMS: czystość: 96,74%; MS (m/e): 453,23 (M+H).

I-403: 5-(5-metylo-2-m-toliloaminopirymidyn-4-yloamino)-3H-benzooksazol-2-on

- 182 [0615] ¹H NMR (DMSO, 300 MHz): δ 11,77 (s, 1H), 10,01 (s, 1H), 9,63 (s, 1H), 7,86 (s, 2H),

7,21 (m, 5H), 6,84 (d, J6,8, 1H), 2,13 (s, 3H), 2,05 (s, 3H) ppm; MS (ES) 348 (M+H);

I-404: 5-{2-[4-(3-dimetyloaminopropoksy)-3-trifluorometylofenyloamino]-5-metylopirymidyn-4-yloamino}-3H-benzooksazol-2-on [0616] ¹H NMR (DMSO, 300 MHz): δ 11,78 (s, 1H), 10,78 (s, 1H), 9,83 (s, 2H), 7,93 (s, 1H), 7,61 (s, 1H), 7,55 (d, J= 11,1, 1H), 7,19 (m, 3H), 4,11 (t, J = 5,8, 2H), 3,15 (m, 2H), 2,80 (s, 6H), 2,13 (m, 5H) ppm; MS (ES) 503 (M+H);

I-405: N4- {3-[bis(1,1-dimetyloetoksy)]fosfinyloksymetylo-2-okso-2,3-dihydro-1,3benzooksazol-5-ilo}-N2-(3,4,5-trimetylo)fenylo-5-metylo-2,4-pirymidynodiamina [0617] ¹H NMR (300 MHz, DMSO) δ 8,81 (s, 1H), 8,40 (s, 1H), 8,34 (s, 1H), 7,88 (s, 1H), 7,34 (m, 4H), 5,61 (d, J= 11,4, 2H), 2,09 (s, 9H), 2,01 (s, 3H), 1,32 (s, 18H); ³¹P NMR (121 MHz, DMSO) δ - 10,15; LCMS: czystość: 98,17%; MS (m/e): 598,43 (M+H).

I-406: 5-metylo-N4-[3-(fosfonooksy)metylo-2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo]-N2(3,4,5-trimetylo)fenylo-2,4-pirymidynodiamina [0618] LCMS: czystość: 78,10%; MS (m/e): 486,12 (M+H).

I-407: sól dwusodowa 5-metylo-N4-[3-(fosfonooksy)metylo-2-okso-2,3-dihydro-1,3benzooksazol-5-ilo]-N2-(3,4,5-trimetylo)fenylo-2,4-pirymidynodiaminy [0619] ¹H NMR (300 MHz, DMSO) δ 7,84 (s, 1H), 7,62 (s, 2H), 7,18 (br, 4H), 5,41 (d, 2H), 2,14 (s, 6H), 2,09 (s, 3H), 2,02 (s, 3H); LCMS: czystość: 93,88%; MS (m/e): 486,02 (M+H).

I-408: 5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-N2-(3,4,5-trifluoro)fenylo2,4-pirymidynodiamina [0620] ¹H NMR (300 MHz, DMSO) δ 11,68 (s, 1H), 9,96 (s, 1H), 9,32 (s, 1H), 7,92 (s, 1H), 7,40 (d, J= 6,6, 1H), 7,36 (d, J = 6,3, 1H), 7,30 (d, J= 8,4, 1H), 7,21 (s, 1H), 7,14 (d, J= 9,0, 1H), 2,12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 151,27; LCMS: czystość: 99,67%; MS (m/e): 388,15 (MH+).

I-409: tysolan N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiaminy [0621] ¹H NMR (300 MHz, DMSO) δ 11,64 (s, 1H), 10,04 (br, 1H), 9,62 (br, 1H), 7,90 (s, 1H), 7,45 (d, J = 7,8, 2H), 7,33 (s, 1H), 7,29 - 7,14 (m, 5H), 7,09 (d, J = 8,4, 2H), 6,83 (s, 1H), 3,67 (s, 3H), 2,26 (s, 3H), 2,14 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 77,21; LCMS: czystość: 100%; MS (m/e): 432,09 (MH+).

I-410: mesylan N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiaminy [0622] ¹H NMR (300 MHz, DMSO) δ 11,65 (s, 1H), 10,13 (s, 1H), 9,70 (br, 1H), 7,90 (s,

1H), 7,30 (s, 1H), 7,26 (d, J = 8,1, 2H), 7,17 (s, 1H), 7,12 (d, J = 8,4, 1H), 6,85 (s, 1H), 3,67 (s, 3H), 2,30 (s, 3H), 2,14 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 77,23; LCMS: czystość:

95,41%; MS (m/e): 432,17 (MH+).

- 183 I-411: siarczan N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiaminy [0623] ¹H NMR (300 MHz, DMSO) δ 11,65 (s, 1H), 10,13 (s, 1H), 9,74 (s, 1H), 7,90 (s, 1H), 7,30 - 7,24 (m, 3H), 7,16 (s, 1H), 7,12 (d, J= 8,1, 1H), 6,86 (s, 1H), 3,67 (s, 3H), 2,15 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 77,24; LCMS: czystość: 98,00%; MS (m/e): 432,15 (MH+).

I-412: chlorowodorek N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiaminy [0624] ¹H NMR (300 MHz, DMSO) δ 11,66 (s, 1H), 10,36 (br, 1H), 9,70 (br, 1H), 7,92 (s, 1H), 7,31 - 7,24 (m, 3H), 7,17 (s, 1H), 7,12 (d, J = 8,7, 1H), 6,84 (s, 1H), 3,67 (s, 3H), 2,14 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 77,24; LCMS: czystość: 98,03%; MS (m/e): 432,17 (MH+).

I-413: sól sodowa N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiaminy [0625] ¹H NMR (300 MHz, DMSO) δ 9,10 (s, 1H), 7,98 (s, 1H), 7,80 (s, 1H), 7,73 (s, 1H),

7,60 (s, 1H), 6,76 (s, 1H), 6,73 (d, J= 7,5, 1H), 6,64 (d, J= 7,8, 1H), 6,58 (s, 1H), 3,54 (s, 3H), 2,04 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 76,80; LCMS: czystość: 97,89%; MS (m/e): 432,18 (MH+).

I-414: sól cholinowa N2-(3-metoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiaminy [0626] ¹H NMR (300 MHz, DMSO) δ 9,10 (s, 1H), 7,98 (s, 1H), 7,80 (s, 1H), 7,72 (s, 1H),

7,60 (s, 1H), 6,76 (s, 1H), 6,73 (d, J = 7,8, 1H), 6,64 (d, J = 7,8, 1H), 6,58 (s, 1H), 3,81 (q, J = 4,5, 2H), 3,54 (s, 3H), 3,36 (t, J = 5,1, 2H), 3,07 (s, 9H), 2,04 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 76,80; LCMS: czystość: 100%; MS (m/e): 432,28 (MH+).

I-415: N2-(3,5-difluoro-4-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazol-5-ilo)-2,4-pirymidynodiamina [0627] ¹H NMR (300 MHz, DMSO) δ 11,64 (s, 1H), 10,03 (s, 1H), 8,86 (s, 1H), 7,96 (s, 1H), 7,50 (s, 1H), 7,46 (s, 1H), 7,28 (d, J= 8,4, 1H), 7,21 (s, 1H), 7,16 (d, J= 8,4, 1H), 2,12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 69,54, - 128,85; LCMS: czystość: 95,67%; MS (m/e): 438,15 (MH+).

I-416: N2-[3-(1-cyjano-1-metylo)etoksy-5-fluoro]fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0628] ¹H NMR (300 MHz, DMSO) δ 11,68 (s, 1H), 10,00 (br, 1H), 9,37 (br, 1H), 7,91 (s, 1H), 7,35 (s, 1H), 7,29 (d, J = 8,7, 1H), 7,21 (s, 1H), 7,18 (d, J = 8,4, 1H), 7,06 (s, 1H), 6,57 (d, J= 9,6, 1H), 2,13 (s, 3H), 1,63 (s, 6H); ¹⁹F NMR (282 MHz, DMSO) δ - 126,51; LCMS: czystość: 99,33%; MS (m/e): 435,21 (MH+).

I-417: N2-[3-(1-cyjano-1-metylo)etoksy-4-fluoro]fenylo-5-metylo-N4-(2-okso-2,3-dihydro1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina

- 184 [0629] ¹H NMR (300 MHz, DMSO) δ 11,67 (s, 1H), 7,86 (s, 1H), 7,56 (br, 1H), 7,32 (br, 1H), 7,23 (m, 4H), 2,12 (s, 3H), 1,58 (s, 6H); LCMS: czystość: 96,32%; MS (m/e): 435,23 (MH+).

I-418: N2-(4-chloro-3-difluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0630] ¹H NMR (300 MHz, DMSO) δ 11,58 (s, 1H), 9,33 (s, 1H), 8,41 (s, 1H), 7,90 (s, 1H), 7,78 (s, 1H), 7,59 (d, J = 9,0, 1H), 7,29 (m, 3H), 7,22 (d, J = 9,3, 1H), 6,93 (t, J= 73, 1H), 2,09 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 96,85 (d, J= 73); LCMS: czystość: 97,12%; MS (m/e): 434,09 (MH+).

I-419: 5-(2-(4-izopropylofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol2(3H)-on [0631] ¹H NMR (300 MHz, DMSO) δ 11,78 (s, 1H), 10,11 (s, 1H), 9,72 (s, 1H), 7,83 (s, 1H), 7,32 - 7,01 (m, 7H), 2,80 (dt, J = 13,6, 7,0, 1H), 2,13 (s, 3H), 1,13 (d, J = 6,9, 6H); LCMS (m/z): 376 (MH⁺).

I-420: 5-(2-(4-tert-butylofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol2(3H)-on [0632] ¹H NMR (300 MHz, DMSO) δ 11,81 (s, 1H), 10,21 (s, 1H), 9,82 (s, 1H), 7,84 (s, 1H), 7,29 (d, J= 8,6, 1H), 7,23 (br s, 5H), 7,12 (d, J= 8,6, 1H), 2,13 (s, 3H), 1,21 (s, 9H); LCMS (m/z): 390 (MH⁺).

I-421: 5-(2-(p-toluidyno)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0633] ¹H NMR (300 MHz, DMSO) δ 11,79 (s, 1H), 10,19 (s, 1H), 9,70 (s, 1H), 7,84 (s, 1H), 7,32 - 7,13 (m, 5H), 7,03 (d, J = 8,2, 2H), 2,22 (s, 3H), 2,12 (s, 3H); LCMS (m/z): 348 (MH⁺).

I-422: 5-(2-(3-(izopropoksymetylo)-4-metoksyfenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0634] ¹H NMR (300 MHz, DMSO) δ 11,74 (s, 1H), 10,03 (s, 1H), 9,60 (s, 1H), 7,79 (s, 1H), 7,39 - 7,11 (m, 5H), 6,88 (d, J = 9,0, 1H), 4,32 (s, 2H), 3,74 (s, 3H), 3,61 - 3,50 (m, 2H), 2,12 (s, 3H), 1,07 (d, J= 6,1, 6H); LCMS (m/z): 436 (MH⁺).

I-423: 5-(2-(3-(1-hydroksyetylo)-5-metoksyfenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0635] C21H21N5O4. MS (ESI) m/z 408,12 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 8,90 (s, 1H, NH), 8,31 (s, 1H, NH), 8,13 (s, 1H, NH), 7,86 (s, 1H, ArH), 7,30 (m, 2H, ArH), 7,25-7,14 (m, 2H, ArH), 7,07 (s, 1H, ArH), 6,40 (s, 1H, ArH), 4,44 (q, J = 6,4, 1H, CH), 2,07 (s, 3H, OCH3), 1,17 (d, J = 9,0, 3H, CH3).

I-424: 5-[2-(3-chloro-4-hydroksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzo oksazol-2-on [0636] MS (ES) 384 (M+H);

- 185 1-425: 5-[2-(4-hydroksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2on [0637] MS (ES) 350 (Μ+H);

I-426: 5-{2-[4-(2-dimetyloaminoetoksy)fenyloamino]-5-metylopirymidyn-4-yloamino}-3Hbenzooksazol-2-on [0638] ¹H W (DMSO, 300 ΜΗς): δ 12,03 - 11,73 (s, 1H), 10,42 - 10,23 (s, 1H), 9,64 9.42 (s, 1H), 7,88 (s, 1H), 7,36 (d, J = 9,0, 1H), 7,25 (d, J = 12,2, 2H), 6,86 (d, J = 9,0, 1H), 4,23 (m, 2H), 3,48 (m, 2H), 2,84 (s, 6H), 2,11 (s, 3H) ppm; MS (ES) 368 (Μ+H);

I-427: 5-(2-(3-metoksy-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4-yloamino)-7metylobenzo[d]oksazol-2(3H)-on [0639] ¹H WR (300 \lllz, DMSO) δ 11,62 (s, 1H), 10,15 (s, 1H), 9,46 (s, 1H), 7,97 (s, 1H), 7,40 (br s, 2H), 7,07 (s, 1H), 7,05 (s, 1H), 6,86 (s, 1H), 3,71 (s, 3H), 2,30 (s, 3H), 2,18 (s, 3H); LRMS (Μ+) m/z 446,10.

I-428: 5-(2-(3-metoksy-5-metylofenyloamino)-5-metylopirymidyn-4-yloamino)-7-metylobenzo[d]oksazol-2(3H)-on [0640] ¹H WR (300 ΜΙ Iz, DMSO) δ 11,70 (s, 1H), 9,95 (s, 1H), 9,67 (s, 1H), 7,89 (s, 1H),

7,10 (s, 1H), 7,09 (s, 1H), 6,84 (s, 1H), 6,81 (s, 1H), 6,51 (s, 1H), 3,63 (s, 3H), 2,31 (s, 3H), 2,18 (s, 3H), 2,12 (s, 3H); LRMS (Μ+) m/z 392,09.

I-429: 5-(2-(4-metoksy-3-metylofenyloamino)-5-metylopirymidyn-4-yloamino)-7-metylobenzo[d]oksazol-2(3H)-on [0641] ¹H WR (300 ΜΗ/, DMSO) δ 11,75 (s, 1H), 9,98 (s, 1H), 9,64 (s, 1H), 7,82 (s, 1H), 7,22 - 7,17 (m, 2H), 7,13 (s, 1H), 7,12 (s, 1H), 6,90 (d, J = 8,4, 1H), 3,79 (s, 3H), 2,30 (s, 3H), 2,17 (s, 3H), 2,02 (s, 3H); LRMS (Μ+) m/z 392,13.

I-430: 7-fluoro-5-(2-(3-metoksy-5-metylofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0642] ¹H WR (300 ΜΗ/, DMSO) δ 12,11 (s, 1H), 9,95 (s, 1H), 9,55 (s, 1H), 7,94 (s, 1H),

7.43 (d, J = 12,9, 1H), 7,16 (s, 1H), 6,88 (br s, 2H), 6,52 (s, 1H), 3,67 (s, 3H), 2,18 (br s, 6H); LRMS (Μ+) m/z 396,05.

I-431: 7-fluoro-5-(2-(4-metoksy-3-metylofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0643] ¹H WR (300 \lllz, DMSO) δ 12,14 (s, 1H), 10,02 (s, 1H), 9,59 (s, 1H), 7,87 (s, 1H), 7,48 (d, J= 12,1, 1H), 7,23 - 7,17 (m, 3H), 6,94 (d, J= 9,4, 1H), 3,81 (s, 3H), 2,18 (s, 3H), 2,08 (s, 3H); LRMS (Μ+) m/z 396,05.

I-432: 5-(2-(4-fluoro-3-metoksy-5-metylofenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0644] ¹H WR (300 \lllz, DMSO) δ 11,81 (s, 1H), 10,19 (s, 1H), 9,78 (s, 1H), 7,89 (s, 1H),

7,36 - 7,26 (m, 3H), 6,97 (d, J = 6,9, 1H), 6,92 (d, J = 5,3, 1H), 3,64 (s, 3H), 2,19 (s, 3H),

- 186 2,05 (s, 3H); LRMS (M+) m/z 396,14.

I-433: mrówczan 5-(2-(4-(difluorometoksy)-3-(fluorometylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-onu [0645] ¹H NMR (300 MHz, DMSO) δ 11,61 (br s, 1H), 9,18 (s, 1H), 8,37 (s, 1H), 7,88 (s, 1H), 7,79 (s, 1H), 7,67 (d, J = 9,0, 1H), 7,33 - 7,23 (m, 3H), 7,03 (d, J = 8,7, 1H), 7,00 (t, J= 63,9, 1H), 5,30 (s, 1H), 5,14 (s, 1H), 2,08 (s, 3H); LCMS (m/z): 432 (MH⁺).

I-434: N2-(4-cyjano-3-difluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazoksazol-5-ilo)-2,4-pirymidynodiamina [0646] 1H NMR (300 MHz, DMSO) δ 11,66 (s, 1H), 9,88 (br, 1H), 9,32 (br, 1H), 7,87 (s, 1H), 7,51 (d, 1H), 7,35 (br, 1H), 7,28 - 7,19 (m, 4H), 6,99 (t, J= 73, 1H), 2,12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 97,46 (d, J = 73); LCMS: czystość: 97,87%; MS (m/e): 425,19 (MH+).

I-435: N2-(3-difluorometoksy-4-fluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0647] ¹H NMR (300 MHz, DMSO) δ 11,62 (s, 1H), 9,94 (br, 1H), 8,75 (br, 1H), 7,96 (s, 1H), 7,75 (s, 1H), 7,65 (m, 2H), 7,27 (s, 3H), 7,07 (t, J= 73, 1H), 2,12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 97,82 (d, J= 73); LCMS: czystość: 99,34%; MS (m/e): 418,20 (MH+).

I-436: sól sodowa 5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-N2-(3,4,5trimetylo)fenylo-2,4-pirymidynodiaminy [0648] ¹H NMR (300 MHz, DMSO) δ 8,44 (s, 1H), 7,82 (s, 1H), 7,70 (s, 1H), 7,24 (s, 2H), 6,76 (s, 1H), 6,74 (d, J= 7,5, 1H), 6,66 (d, J= 7,5, 1H), 2,02 (s, 3H), 2,00 (s, 6H), 1,96 (s, 3H); LCMS: czystość: 98,47%; MS (m/e): 376,27 (MH+).

I-437: sól sodowa N2-(3,5-dimetylo-4-fluoro)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3benzooksazoksazol-5-ilo)-2,4-pirymidynodiaminy [0649] ¹H NMR (300 MHz, DMSO) δ 8,63 (s, 1H), 7,92 (s, 1H), 7,71 (s, 1H), 7,28 (d, J= 6,6, 2H), 6,74 (s, 1H), 6,66 (s, 2H), 2,02 (s, 3H), 1,96 (s, 6H); ¹⁹F NMR (282 MHz, DMSO) δ 148,58; LCMS: czystość: 100%; MS (m/e): 380,11 (MH+).

I-438: 5-(2-(3-(difluorometylo)-4-metylofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0650] C20H17F2N5O2. MS (ESI) m/z 398,13 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11,61 (s, 1H, NH), 9,43 (s, 1H, NH), 8,76 (s, 1H, NH), 7,87 (s, 1H, ArH), 7,73-7,53 (m, 3H, ArH), 7,08-7,05 (m, 2H, ArH, CH), 6,88 (s, 1H, ArH), 2,26 (s, 3H, CH3), 2,09 (s, 3H, CH3).

I-439: 5-(2-(3-(fluorometylo)-4-metylofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0651] C20H18FN5O2. MS (ESI) m/z 380,15 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11,58 (s,

1H, NH), 9,01 (s, 1H, NH), 8,37 (s, 1H, NH), 8,11 (s, 1H, ArH), 7,85 (s, 1H, ArH), 7,63 (s,

1H, ArH), 7,48 (m, 1H, ArH), 7,29-7,20 (m, 2H, ArH), 6,98 (d, J= 8,2, 1H, ArH), 5,19 (d, J=

- 187 53,3, 2H, CH2), 2,25 (s, 3H, CH3), 2,07 (s, 3H, CH3).

I-440: mrówczan 5-(2-(3-(difluorometylo)-5-metoksyfenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-onu [0652] ¹H NMR (300 MHz, DMSO) δ 11,55 (br s, 1H), 9,19 (s, 1H), 8,38 (s, 1H), 7,89 (s, 1H), 7,47 (s, 1H), 7,39 (s, 1H), 7,27 (dd, J = 6,8, 2,0, 2H), 7,19 (dd, J = 9,1, 1,8, 1H), 6,93 6,50 (m, 2H), 3,61 (s, 3H), 2,08 (s, 3H); LCMS (m/z): 414 (MH⁺).

I-441: 5-(2-(4-d3-metoksy-3-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0653] C20H13D3F3N5O3. MS (ESI) m/z 435,13 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11,61 (s, 1H, NH), 9,59 (s, 1H, NH), 9,00 (s, 1H, NH), 7,85 (s, 1H, ArH), 7,75-7,68 (m, 2H, ArH), 7,23-7,21 (m, 3H, ArH), 7,10 (d, J= 9,0, 1H, ArH), 2,10 (s, 3H, CH3).

I-442: mrówczan 5-(2-(4-(difluorometoksy)-3-(difluorometylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-onu [0654] ¹H NMR (300 MHz, DMSO) δ 11,54 (s, 1H), 9,26 (s, 1H), 8,38 (s, 1H), 7,92- 7,84 (m, 3H), 7,34 - 7,18 (m, 4H), 7,10 (d, J= 9,2, 1H), 6,93 (t, J = 26,9, 1H), 2,09 (s, 3H); LCMS (m/z): 450 (MH⁺).

I-443: 5-(5-metylo-2-(4-metylo-3-(pirydyn-4-ylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0655] ¹H NMR (300 MHz, DMSO) δ 11,61 (s, 1H), 9,99 (s, 1H), 9,41 (s, 1H), 8,58 (s, 2H), 7,86 (s, 1H), 7,43 - 7,36 (m, 2H), 7,30 (d, J= 4,9, 2H), 7,21 - 7,13 (m, 3H), 7,02 (d, J= 9,1, 1H), 2,16 (s, 3H), 2,11 (s, 3H); LCMS (m/z): 425 (MH⁺).

I-444: 5-(5-metylo-2-(4-metylo-3-(pirydyn-3-ylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0656] ¹H NMR (300 MHz, DMSO) δ 11,54 (s, 1H), 9,45 (br s, 1H), 8,51 (d, J= 4,8, 1H), 8,39 (s, 1H), 7,85 (s, 1H), 7,65 (d, J= 8,0, 1H), 7,50-7,45 (m, 2H), 7,40 - 7,35 (m, 1H), 7,22 (d, J = 8,7, 2H), 7,21 (s, 1H), 7,12 (d, J = 8,1, 1H), 6,99 (d, J = 8,0, 1H), 6,52 (br s, 1H), 2,12 (s, 3H), 2,09 (s, 3H); LCMS (m/z): 425 (MH⁺).

1-445: 5-(2-(3-acetylo-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0657] C21H16F3N5O3. MS (ESI) m/z 444,11 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 11,48 (s, 1H, NH), 9,57 (s, 1H, NH), 8,46 (s, 1H, NH), 8,37 (d, J= 5,9, 2H, ArH), 7,95 (s, 1H, ArH),

7,60 (s, H, ArH), 7,28-7,16 (m, 3H, ArH), 2,45 (s, 3H, CH3), 2,10 (s, 3H, CH3).

I-446: 5-(2-(3-(1-hydroksyetylo)-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0658] C21H18F3N5O3. MS (ESI) m/z 446,10 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,31 (s,

1H, NH), 8,39 (s, 1H, NH), 8,14 (s, 1H, NH), 7,97 (s, 1H, ArH), 7,91 (s, 1H, ArH), 7,75 (s,

1H, ArH), 7,30-7,27 (m, 2H, ArH), 7,20-7,17 (m, 1H, ArH), 7,09 (s, 1H, ArH), 4,54 (q, J =

- 188 6,4, 1H, CH), 2,01 (s, 3H, CH3), 1,19 (d, J = 6,4, 3H, CH3).

I-447: 5-[2-(4-d3-metoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2on [0659] ¹H NMR (DMSO, 300 MHz): δ 11,66 (s, 1H), 8,88 (s, 1H), 8,40 (s, 1H), 8,12 (s, 1H), 7,81 (s, 1H), 7,48 (d, J = 12,2, 1H), 7,33 (s, 2H), 7,23 (s, 2H), 6,72 (d, J = 9,1, 1H), 2,06 (s, 3H) ppm; MS (ES) 367 (M+H);

I-448: 5-[2-(3-chloro-4-d3-metoksyfenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0660] ¹H NMR (DMSO, 300 MHz): δ 11,76 - 11,48 (m, 1H), 9,11 (s, 1H), 8,46 (s, 1H), 8,15 (s, 1H), 7,84 (s, 2H), 7,39 (d, J = 11,3, 1H), 7,25 (m, 3H), 6,91 (d, J = 9,0, 1H), 2,07 (s, 3H) ppm; MS (ES) 401 (M+H);

I-449: 5-{2-[4-(2-dietyloaminoetoksy)fenyloamino]-5-metylopirymidyn-4-yloamino}-3Hbenzooksazol-2-on [0661] ¹H NMR (DMSO, 300 MHz): δ 11,99 (s, 1H), 10,76 (s, 1H), 9,87 (s, 1H), 9,84-9,67 (m, 1H), 7,91 (s, 1H), 7,42 - 7,24 (m, 4H), 7,18 (d, J= 8,6, 1H), 6,87 (d, J= 8,9, 2H), 4,25 (m, 2H), 3,50 (m, 2H), 3,20 (m, 4H), 2,13 (s, 3H), 1,22 (t, J= 7,2, 6H) ppm; MS (ES) 449 (M+H);

I-450: N4-{3-[bis(1,1-dimetyloetoksy)]fosfinyloksymetylo-2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo}-N2-(3,5-dimetylo-4-fluoro)fenylo-5-metylo-2,4-pirymidynodiamina [0662] ¹H NMR (300 MHz, DMSO) δ 8,92 (s, 1H), 8,38 (s, 2H), 7,89 (s, 1H), 7,40 (d, J = 6,6, 2H), 7,34 (s, 2H), 5,64 (d, J= 11,1, 2H), 2,09 (s, 3H), 2,08 (s, 6H), 1,32 (s, 18H); ¹⁹F NMR (282 MHz, DMSO) δ - 147,62; ³¹P NMR (121 MHz, DMSO) δ - 10,18; LCMS: czystość: 100%; MS (m/e): 602,26 (MH+).

I-451: sól dwusodowa N2-(3,5-dimetylo-4-fluoro)fenylo-5-metylo-N4-[3-(fosfonooksy)metylo-2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo]-2,4-pirymidynodiaminy [0663] ¹H NMR (300 MHz, DMSO) δ 7,85 (br, 1H), 7,73 (br, 2H), 7,20 (br, 4H), 5,42 (d, 2H), 2,13 (s, 6H), 2,09 (s, 3H); LCMS: czystość: 89,35%; MS (m/e): 490,03 (MH+).

I-452: 5-(2-(3,4-dimetoksy-5-metylofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0664] ¹H NMR (300 MHz, DMSO) δ 11,78 (s, 1H), 9,97 (s, 1H), 9,66 (s, 1H), 7,86 (s, 1H),

7,34 - 7,27 (m, 3H), 6,88 (br s, 2H), 3,67 (s, 3H), 3,62 (s, 3H), 2,19 (s, 3H), 2,03 (s, 3H); LRMS (M+) m/z 408,01.

I-453: 5-(2-(3,4-dimetoksy-5-metylofenyloamino)-5-metylopirymidyn-4-yloamino)-7-metylobenzo[d]oksazol-2(3H)-on [0665] ¹H NMR (300 MHz, DMSO) δ 11,71 (s, 1H), 9,97 (s, 1H), 9,60 (s, 1H), 7,85 (s, 1H), 7,16 (s, 1H), 7,10 (s, 1H), 6,89 (s, 1H), 6,86 (s, 1H), 3,67 (s, 3H), 3,60 (s, 3H), 2,29 (s, 3H), 2,18 (s, 3H), 2,03 (s, 3H); LRMS (M+) m/z 422,11.

I-454: 5-(2-(3,4-dimetoksy-5-metylofenyloamino)-5-metylopirymidyn-4-yloamino)-7-fluoro- 189 benzo[d]oksazol-2(3H)-on [0666] ¹H NMR (300 MHz, DMSO) δ 12,12 (s, 1H), 9,97 (s, 1H), 9,50 (s, 1H), 7,89 (s, 1H), 7,54 (d, J = 13,0, 1H), 7,18 (s, 1H), 6,93 (br s, 2H), 3,69 (s, 3H), 3,68 (s, 3H), 2,18 (s, 3H),

2,10 (s, 3H); LRMS (M+) m/z 426,08.

I-455: 5-{2-[3-chloro-4-(2-dietyloaminoetoksy)fenyloamino]-5-metylopirymidyn-4-yloamino} -3H-benzooksazol-2-on [0667] ¹H NMR (DMSO, 300 MHz): δ 11,59 (s, 1H), 9,51 (s, 1H), 8,93 (s, 1H), 8,44 (s, 1H), 7,82 (s, 1H), 7,68 (s, 1H), 7,19 (m, 2H), 6,73 (d, J= 8,8, 1H), 4,18 (m, 2H), 3,50 (m, 2H), 3,01 (m, 4H), 2,11 (s, 3H), 1,22 (t, J= 7,0, 6H) ppm; MS (ES) 484 (M+H);

I-456: 5-[2-(2,4-difluorofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2on [0668] ¹H NMR (DMSO, 300 MHz): δ 11,56 (s, 1H), 8,45 (s, 1H), 8,34 (s, 1H), 7,80 (s, 1H), 7,65 (dd, J = 9,1, 15,4, 1H), 7,40 - 7,20 (m, 3H), 7,13 (d, J= 8,6, 1H), 6,93 (t, J= 8,7, 1H), 2,06 (s, 3H) ppm; MS (ES) 370 (M+H);

I-457: 5-(5-metylo-2-(3-(1-(metyloamino)etylo)-5-(trifluorometylo)fenyloamino)pirymidyn4-yloamino)benzo[d]oksazol-2(3H)-on [0669] C22H21F3N6O2. MS (ESI) m/z 459,14 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,33 (s, 1H, NH), 8,39 (s, 1H, NH), 8,21 (s, 1H, NH), 7,95-7,91 (m, 2H, ArH), 7,75 (s, 1H, ArH), 7,32-7,11 (m, 4H, ArH), 3,57-3,44 (m, 4H, CH, CH3), 2,10 (s, 3H, CH3), 1,15 (d, J = 6,5, 3H, CH3).

I-458: 5-(2-(3-chloro-4,5-dimetoksyfenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0670] ¹H NMR (300 MHz, DMSO) δ 11,73 (s, 1H), 9,94 (s, 1H), 9,54 (s, 1H), 7,92 (s, 1H),

7,34 (d, J = 8,4, 1 H), 7,29 (s, 1H), 7,25 - 7,22 (m, 2H), 7,00 (s, 1H), 3,71 (s, 3H), 3,68 (s, 3H), 2,19 (s, 3H); LRMS (M+) m/z 428,19.

I-459: 5-(2-(3,5-dimetylo-4-(2-morfolinoetoksy)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0671] ¹H NMR (300 MHz, DMSO) δ 11,85 (s, 1H), 10,22 (s, 1H), 9,79 (s, 1H), 7,95 (s, 1H), 7,38 (d,J= 9,1, 1H), 7,27 - 7,23 (m, 2H), 7,11 (s, 2H), 4,07 - 4,03 (m, 4H), 3,84-3,79 (m, 2H), 3,63 - 3,60 (m, 4H), 3,32 - 3,21 (m, 2H), 2,19 (s, 3H), 2,09 (br s, 6H); LRMS (M+) m/z 491,14.

I-460: 5-(5-metylo-2-(3-(1-(metyloamino)butylo)-5-(trifluorometylo)fenyloamino)pirymidyn4-yloamino)benzo[d]oksazol-2(3H)-on [0672] C24H25F3N6O2. MS (ESI) m/z 487,15 (M+1)⁺.

I-461: 5-(2-(3-(1-(cyklopropyloamino)etylo)-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0673] C24H23F3N6O2. MS (ESI) m/z 485,14 (M+1)⁺. ¹H NMR (300 MHz, DMSO) δ 9,28 (s,

- 190 1H, NH), 8,40 (s, 1H, NH), 7,91 (s, 1H, ArH), 7,77 (s, 1H, ArH), 7,26-7,13 (m, 5H, ArH),

4,07 (m, 1H, CH), 2,08 (s, 3H, CH3), 1,77 (m, 1H, CH), 1,13 (d, J= 6,5, 3H, CH3), 0,22-016 (m, 4H, 2CH2).

I-462: 5-(2-(3-(1-(etyloamino)etylo)-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-on [0674] C23H23F3N6O2. MS (ESI) m/z 473,16 (M+1)⁺.

I-463: 5-(5-metylo-2-(3-(1-(pirolidyn-1-ylo)etylo)-5-(trifluoro-metylo)fenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0675] C25H25F3N6O2. MS (ESI) m/z 499,16 (M+1)⁺.

I-464: 5-(2-(3-(1-(azetydyn-1-ylo)etylo)-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0676] C24H23F3N6O2. MS (ESI) m/z 485,14 (M+1)⁺.

1-465: 5-(2-(3-(1-(cyklobutyloamino)etylo)-5-(trifluorometylo)fenyloamino)-5metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0677] C25H25F3N6O2. MS (ESI) m/z 499,18 (M+1)⁺.

I-466: 5-[2-(2,5-difluorofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2on [0678] ¹H NMR (DMSO, 300 MHz): δ 8,47 (s, 1H), 8,37 (s, 1H), 7,96 - 7,81 (m, 2H), 7,27 (d, J= 5,6, 2H), 7,18 (d, J= 9,2, 2H), 6,77 - 6,62 (m, 1H), 2,09 (s, 3H) ppm; MS (ES) 370 (M+H);

I-467: 5-[2-(2,3-difluorofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2on [0679] ¹H NMR (DMSO, 300 MHz): δ 8,60 (s, 1H), 8,34 (s, 1H), 7,85 (s, 1H), 7,60 (s, 1H),

7,35 (d, J= 10,7, 1H), 7,29 (s, 1H), 7,12 (d, J = 8,6, 1H), 6,99 (t, J= 6,5, 2H), 2,08 (s, 3H) ppm; MS (ES) 370 (M+H);

I-468: 5-[2-(2-fluorofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0680] ¹H NMR (DMSO, 300 MHz): δ 8,31 (s br, 2H), 8,16 (s, 1H), 7,90 - 7,76 (m, J= 8,8, 2H), 7,44 - 7,28 (m, J= 9,8, 2H), 7,24 - 7,08 (m, 2H), 7,07 - 6,92 (m, 2H), 2,07 (s, 5H) ppm; MS (ES) 352 (M+H);

I-469: N-cyklobutylo-3-[5-metylo-4-(2-okso-2,3-dihydrobenzooksazol-5-iloamino)pirymidyn-2-yloamino]-5-trifluorometylobenzamid [0681] ¹H NMR (DMSO, 300 MHz): δ 11,64 (s, 1H), 10,89 (s, 1H), 9,73 (s, 1H), 8,81 (d, J= 7,5, 1H), 8,10 - 7,90 (m, 3H), 7,82 (s, 1H), 7,15 (s, 3H), 4,38 (dd, J= 8,1, 16,1, 1H), 2,12 (s, 3H), 2,10 - 1,92 (m, 4H), 1,76 - 1,57 (m, 2H) ppm; MS (ES) 499 (M+H);

I-470: 5-[2-(4-fluorofenyloamino)-5-metylopirymidyn-4-yloamino]-3H-benzooksazol-2-on [0682] ¹H NMR (DMSO, 300 MHz): δ 11,62 (s, 1H), 9,06 (s, 1H), 8,40 (s, 1H), 8,11 (s, 1H),

- 191 7,85 (s, 1H), 7,71 - 7,53 (m, 2H), 7,31 (d, J= 5,3, 1H), 7,23 (d, J= 9,1, 1H), 6,96 (t, J= 8,9,

2H), 6,54 (s, 1H), 2,07 (s, 3H) ppm; MS (ES) 352 (M+H);

I-471: 5-(2-(4-fluoro-3-(pirydyn-4-ylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0683] ¹H NMR (300 MHz, DMSO) δ 11,53 (s, 1H), 9,90 (br s, 1H), 9,29 (br s, 1H), 8,58 (d, J= 6,1, 2H), 7,88 (s, 1H), 7,80 (d, J = 5,9, 1H), 7,55 - 7,46 (m, 1H), 7,38 (d, J= 4,7, 2H), 7,31 - 7,22 (m, 1H), 7,18(s, 1H), 7,17 (d, J = 9,7, 1H), 7,02 (d, J = 8,4, 1H), 2,12 (s, 3H); LCMS (m/z): 429 (MH⁺).

I-472: 5-(2-(4-fluoro-3-(pirydyn-3-ylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0684] ¹H NMR (300 MHz, DMSO) δ 11,56 (s, 1H), 9,97 (br s, 1H), 9,35 (br s, 1H), 8,55 (d, J = 4,8, 1H), 8,51 (s, 1H), 7,88 (s, 1H), 7,75 (t, J = 7,8, 2H), 7,43 (dd, J = 14,9, 9,8, 2H), 7,25 (t, J = 9,8, 1H), 7,17 (s, 1H), 7,16 (d, J= 7,5, 2H), 6,98 (d, J= 8,9, 1H), 2,12 (s, 3H); LCMS (m/z): 429 (MH⁺).

I-473: 5-(2-(3-(1-(izopropyloamino)etylo)-5-(trifluorometylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0685] C24H25F3N6O2. MS (ESI) m/z 486,49 (M+1)⁺.

I-474: 5-(2-(3,5-dimetylofenyloamino)-5-metylopirymidyn-4-yloamino)-7-metylobenzo[d]oksazol-2(3H)-on [0686] ¹H NMR (300 MHz, DMSO) δ 11,74 (s, 1H), 9,89 (s, 1H), 9,65 (s, 1H), 7,89 (s, 1H),

7,10 (s, 2H), 7,04 (s, 2H), 6,72 (s, 1H), 2,32 (s, 3H), 2,18 (s, 3H), 2,08 (s, 6H); LRMS (M+) m/z 376,24.

1-475: 7-metylo-5-(5-metylo-2-(3,4,5-trimetylofenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0687] ¹H NMR (300 MHz, DMSO) δ 11,75 (s, 1H), 9,98 (s, 1H), 9,67 (s, 1H), 7,87 (s, 1H),

7,11 (s, 2H), 7,05 (s, 2H), 2,30 (s, 3H), 2,17 (s, 3H), 2,07 (s, 3H), 2,06 (s, 6H); LRMS (M+) m/z 390,28.

I-476: 5-(2-(4-fluoro-3,5-dimetylofenyloamino)-5-metylopirymidyn-4-yloamino)-7-metylobenzo[d]oksazol-2(3H)-on [0688] ¹H NMR (300 MHz, DMSO) δ 11,74 (s, 1H), 9,94 (s, 1H), 9,59 (s, 1H), 7,88 (s, 1H), 7,14 (d, J= 6,4, 2H), 7,10 (br s, 2H), 2,31 (s, 3H), 2,17 (s, 3H), 2,05 (br s, 6H); LRMS (M+) m/z 394,25.

I-477: 5-[5-metylo-2-(2,3,4,5-tetrafluorofenyloamino)pirymidyn-4-yloamino]-3H-benzooksazol-2-on [0689] ¹H NMR (DMSO, 300 MHz): δ 9,02 - 8,81 (m, 1H), 8,49 (s, 1H), 8,27 (s, 1H), 7,98 7,77 (m, 2H), 7,31 (s, 1H), 7,28 - 7,13 (m, J= 9,6, 2H), 2,09 (s, 3H) ppm; MS (ES) 406 (M+H);

- 192 I-478: N2-(3-cyjano-5-difluorometoksy)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0690] ¹H NMR (300 MHz, DMSO) δ 11,50 (s, 1H), 9,60 (s, 1H), 8,52 (s, 1H), 8,03 (s, 1H), 7,94 (s, 1H), 7,68 (s, 1H), 7,22 (m, 3H), 7,15 (t, J= 73, 1H), 7,08 (s, 1H), 2,10 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 98,22 (d, J= 73); LCMS: czystość: 98,34%; MS (m/e): 425,09 (MH+).

I-479: 5-metylo-N2-(3-metylo-5-trifluorometylo)fenylo-N4-(2-okso-2,3-dihydro-1,3-benzooksazol-5-ilo)-2,4-pirymidynodiamina [0691] ¹H NMR (300 MHz, DMSO) δ 11,54 (s, 1H), 9,30 (s, 1H), 8,45 (s, 1H), 7,91 (s, 1H), 7,76 (s, 1H), 7,73 (s, 1H), 7,24 (m, 3H), 6,92 (s, 1H), 2,14 (s, 3H), 2,09 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 76,92; LCMS: czystość: 100%; MS (m/e): 416,02 (MH+).

I-480: 5-[5-metylo-2-(2,3,5-trifluorofenyloamino)pirymidyn-4-yloamino]-3H-benzooksazol2-on [0692] ¹H NMR (DMSO, 300 MHz): δ 8,87 - 8,65 (m, 1H), 8,48 (s, 1H), 7,88 (s, 1H), 7,82 7,67 (m, 1H), 7,25 (s, 1H), 7,20 (d, J = 8,5, 1H), 7,12 (d, J = 7,5, 1H), 7,01 - 6,84 (m, 1H), 2,09 (s, 3H) ppm; MS (ES) 388 (M+H);

I-481: 5-[5-metylo-2-(2,4,5-trifluorofenyloamino)pirymidyn-4-yloamino]-3H-benzooksazol2-on [0693] ¹H NMR (DMSO, 300 MHz): δ 8,45 (s, 1H), 8,37 (s, 1H), 8,09 - 7,91 (m, 1H), 7,84 (s, 1H), 7,48 (dd, J= 10,8, 18,5, 1H), 7,17 (m, 2H), 7,07 (d, J= 8,5, 1H), 2,07 (s, 3H) ppm; MS (ES) 388 (M+H);

I-482: mrówczan 5-(5-metylo-2-(3-metylo-4-(pirydyn-4-ylo)fenyloamino)pirymidyn-4yloamino)benzo[d]oksazol-2(3H)-onu [0694] ¹H NMR (300 MHz, DMSO) δ 9,45 (d, J = 7,2, 2H), 8,37 (d, J= 9,9, 2H), 8,12 (d, J= 7,2, 2H), 7,48 (s, 1H), 7,40 (d, J= 8,5, 1H), 7,26 (s, 2H), 6,61 - 6,53 (m, 2H), 6,19 (s, 2H), 2,38 (s, 3H), 2,29 (s, 3H); LCMS (m/z): 425 (MH⁺).

I-483: mrówczan 5-(5-metylo-2-(3-metylo-4-(pirydyn-3-ylo)fenyloamino)pirymidyn-4yloamino)benzo[d]oksazol-2(3H)-onu [0695] ¹H NMR (300 MHz, DMSO) δ 11,71 (s, 1H), 9,83 (s, 1H), 9,14 (s, 1H), 8,57-8,48 (m, 2H), 7,91 (s, 1H), 7,74 (d, J= 8,4, 1H), 7,51 (s, 1H), 7,48 - 7,37 (m, 2H), 7,31-7,24 (m, 3H), 7,07 (d, J= 8,4, 1H), 2,13 (s, 3H), 2,00 (s, 3H); LCMS (m/z): 424 (MH⁺).

I-484: 5-(2-(3-fluoro-4-(pirydyn-4-ylo)fenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0696] ¹H NMR (300 MHz, DMSO) δ 9,44 (s, 1H), 9,41 (s, 1H), 9,18 (s, 1H), 8,29 - 8,25 (m, 3H), 7,81 (t, J= 8,8, 1H), 7,09 (s, 1H), 6,97 - 6,84 (m, 4H), 6,58 (d, J= 8,7, 1H), 6,48 (d, J= 15,7, 1H), 2,27 (s, 3H); LCMS (m/z): 429 (MH⁺).

I-485: N2-(3,4-dimetoksy-5-trifluorometylo)fenylo-5-metylo-N4-(2-okso-2,3-dihydro-1,3- 193 benzooksazol-5-ilo)-2,4-pirymidynodiamina [0697] ¹H NMR (300 MHz, DMSO) δ 11,59 (s, 1H), 7,87 (s, 1H), 7,40 (br, 2H), 7,20 (s, 3H),

3,72 (s, 3H), 3,61 (s, 3H), 2,12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ - 75,83; LCMS: czystość: 100%; MS (m/e): 462,24 (MH+).

I-486: mrówczan 5-(2-(4-metoksy-3-(pirydyn-4-ylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-onu [0698] ¹H NMR (300 MHz, DMSO) δ 11,49 (s, 1H), 9,09 (s, 1H), 8,47 (d, J= 5,8, 3H), 7,84 (s, 1H), 7,68 (s, 1H), 7,59 (d, J= 9,0, 1H), 7,32 (s, 2H), 7,26 (d, J= 7,8, 2H), 7,02 (d, J= 9,0, 1H), 6,98 (d, J= 9,0, 1H), 3,72 (s, 3H), 2,07 (s, 3H); LCMS (m/z): 441 (MH⁺).

I-487: mrówczan 5-(2-(4-metoksy-3-(pirydyn-3-ylo)fenyloamino)-5-metylopirymidyn-4yloamino)benzo[d]oksazol-2(3H)-onu [0699] ¹H NMR (300 MHz, DMSO) δ 8,91 (s, 1H), 8,50 (s, 1H), 8,43 (d, J= 4,5, 1H), 8,27 (s, 1H), 8,14 (s, 1H), 7,84 (s, 1H), 7,71 (d, J = 7,9, 1H), 7,66 (s, 1H), 7,61 (d, J = 9,0, 1H), 7,35 7,25 (m, 3H), 6,96 (dd, J= 12,8, 9,1, 2H), 3,69 (s, 3H), 2,06 (s, 3H); LCMS (m/z): 441 (MH⁺).

I-488: 5-(2-(3,5-dimetylofenyloamino)-5-metylopirymidyn-4-yloamino)-7-fluorobenzo[d]oksazol-2(3H)-on [0700] ¹H NMR (300 MHz, DMSO) δ 12,13 (s, 1H), 9,87 (s, 1H), 9,51 (s, 1H), 7,93 (s, 1H),

7,48 (d, J = 12,2, 1H), 7,17 (s, 1H), 7,10 (s, 2H), 6,75 (s, 1H), 2,19 (s, 3H), 2,16 (br s, 6H); LRMS (M+) m/z 380,06.

I-489: 7-fluoro-5-(5-metylo-2-(3,4,5-trimetylofenyloamino)pirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0701] ¹H NMR (300 MHz, DMSO) δ 12,12 (s, 1H), 9,85 (s, 1H), 9,52 (s, 1H), 7,90 (s, 1H),

7,49 (d, J = 12,4, 1H), 7,17 (s, 1H), 7,10 (s, 2H), 2,18 (s, 3H), 2,14 (s, 6H), 2,11 (s, 3H); LRMS (M+) m/z 394,10.

I-490: 7-fluoro-5-(2-(4-fluoro-3,5-dimetylofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0702] ¹H NMR (300 MHz, DMSO) δ 12,13 (s, 1H), 9,93 (s, 1H), 9,50 (s, 1H), 7,92 (s, 1H), 7,48 (d, J= 12,4, 1H), 7,20 - 7,17 (m, 3H), 2,18 (s, 3H), 2,13 (br s, 6H); LRMS (M+) m/z 398,06.

I-491: 5-(2-(4-fluoro-3-metoksy-5-metylofenyloamino)-5-metylopirymidyn-4-yloamino)-7metylobenzo[d]oksazol-2(3H)-on [0703] ¹H NMR (300 MHz, DMSO) δ 11,71 (s, 1H), 9,91 (s, 1H), 9,48 (br s, 1H), 7,87 (s, 1H), 7,15 (s, 1H), 7,12 (br s, 1H), 7,04 (dd, J = 7,2, 1,4, 1H), 6,95 (d, J = 5,2, 1H), 3,63 (s, 3H), 2,29 (s, 3H), 2,18 (s, 3H), 2,06 (br s, 3H); LRMS (M+) m/z 410,02.

I-492: 7-fluoro-5-(2-(4-fluoro-3-metoksy-5-metylofenyloamino)-5-metylopirymidyn-4-yloamino)benzo[d]oksazol-2(3H)-on [0704] ¹H NMR (300 MHz, DMSO) δ 12.10 (s, 1H), 9.88 (s, 1H), 9.38 (s, 1H), 7.92 (s, 1H),

- 194 7.53 (d, J = 13, 0, 1H), 7.19 (s, 1H), 7.07 (br d, J = 6.7, 1H), 7.01 (br d, J = 5.1, 1H), 3.71 (s,

3H), 2.18 (s, 3H), 2.13 (s, 3H); LRMS (M +) m / z 414.05.

I-493: N2- (3,4-dimethyl-2-fluoro) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4 -pyrimidinediamine [0705] ¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.80 (s, 1H),

7.49 (t, J = 8.4, 1H), 7.38 (d, J = 8.4, 1H), 7.29 (s, 1H), 7.09 (d, J = 8.7 , 1H), 6.80 (d, J = 8.4, 1H), 2.18 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ-145.07; LCMS: purity: 100%; MS (m / e): 380.15 (MH +).

I-494: 5- (2- (3-methoxy-4- (pyridin-4-yl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one formate [0706] ¹H NMR (300 MHz, DMSO) δ 9.28 (d, J = 7.4, 2H), 8.46 (s, 1H), 8.32 (d, J = 7.4, 3H), 7, 68 (d, J = 8.8, 1H), 7.46 (s, 1H), 7.19 (s, 2H), 6.70 (s, 2H), 6.36 (d, J = 8, 8, 1H), 6.33 (s, 1H), 3.86 (s, 3H), 2.27 (s, 3H); LCMS (m / z): 441 (MH⁺).

I-495: N2- (3-chloro-5-difluoromethoxy) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine [0707] ¹H NMR (300 MHz, DMSO) δ 11.60 (s, 1H), 9.78 (br, 1H), 9.08 (br, 1H), 7.91 (s, 1H), 7.56 (s , 1H), 7.25 (d, 2H), 7.19 (d, 2H), 7.12 (t, J = 73, 1H), 6.78 (s, 1H), 2.12 (s, 3H); LCMS: purity: 97.32%; MS (m / e): 434.02 (MH +).

I-496: 5- [2- (3-chloro-4-methoxyphenylamino) -5-methylpyrimidin-4-ylamino] -3H-benzooxazol-2-one [0708] ¹H NMR (DMSO, 300 MHz): δ 11.59 (s, 1H), 9.06 (s, 1H), 8.46 (s, 1H), 7.94-7.77 (m, 2H), 7.38 (d, J = 9.0, 1H), 7.25 (d, J = 10.5, 3H), 6.93 (d, J = 9.1, 1H), 3.74 (s , 3H), 2.07 (s, 3H) ppm; MS (ES) 398 (M + H);

I-497: 5- [2- (3-chloro-5-trifluoromethyl-phenylamino) -5-methyl-pyrimidin-4-ylamino] -3-Hb-oxo-oxazol-2-one [0709] ¹H NMR (DMSO, 300 MHz): δ 11.55 (s br, 1H), 9.59 (s, 1H), 8.53 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.83 (s, 1H), 7.31-7.07 (m, 3H), 2.09 (s, 3H) ppm; MS (ES) 436/438 (M + H);

I-498: 5- [2- (2-methoxy-5-trifluoromethylphenylamino) -5-methylpyrimidin-4-ylamino] -3-Benzooxazol-2-one [0710] ¹H NMR (DMSO, 300 MHz): δ 11.52 (s, 1H), 8.50 (d, J = 10.0, 2H), 7.92 (s, 1H), 7.59 (s, 1H ), 7.29 (s, 1H), 7.26 - 7.04 (m, 3H), 3.91 (s, 3H), 2.09 (s, 3H) ppm; MS (ES) 432 (M + H);

I-499: 5- (2- (o-toluidino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0711] C19H17N5O2. MS (ESI) m / z 348.23 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.20 (s,

1H, NH), 8.11 (s, 1H, NH), 7.98 (s, 1H, ArH), 7.78 (s, 1H, ArH), 7.53 (d, J = 7.9, 1H, ArH),

7.36-7.28 (m, 1H, ArH), 7.14 (s, 1H, ArH), 7.11-7.04 (m, 3H, ArH), 6.96-6.91 (m , 1H, ArH),

- 195 2.16 (s, 3H, CH3), 2.05 (s, 3H, CH3).

I-500: 5- (2- (2,3-dimethylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol2 (3H) -one [0712] C20H19N5O2. MS (ESI) m / z 362.21 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.14 (s, 1H, NH), 8.12 (s, 1H, NH), 8.11 (s, 1H, NH, ArH), 7.74 (s, 1H, ArH), 7.39 (d, J = 8.8, 1H, ArH), 7.26-7.21 (m, 2H, ArH), 7.02-6.97 (m, 2H, ArH ), 6.90-6.88 (m, 1H, ArH), 2.18 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.00 (s, 3H, CH3).

I-501: 5- (2- (2,5-dimethylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol2 (3H) -one [0713] C20H19N5O2. MS (ESI) m / z 362.21 (M + 1)⁺.

I-502: 5- (2- (2-ethylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0714] C20H19N5O2. MS (ESI) m / z 362.21 (M + 1)⁺.

I-503: 5- (2- (3-ethylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0715] C20H19N5O2. MS (ESI) m / z 362.21 (M + 1)⁺.

I-504: 5- (2- (4-ethylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0716] C20H19N5O2. MS (ESI) m / z 362.21 (M + 1)⁺.

1-505: 5- (2- (3-fluoro-4- (pyridin-3-yl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one trifluoroacetic acid salt [0717] ¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 9.78 (s, 1H), 9.63 (d, J = 6.4, 1H), 9.49 (s, 1H) , 8.89 (d, J = 8.4, 1H), 8.43 (s, 1H), 8.27 - 8.17 (m, 1H), 7.50 - 7.25 (m, 5H) , 6.57 (dd, J = 8.5, 1.9, 1H), 6.48 (d, J = 14.6, 1H), 2.32 (s, 3H); LCMS (m / z): 429 (MH⁺).

I-506: 5- (2- (3-methoxy-4- (pyridin-3-yl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one formate [0718] ¹H NMR (300 MHz, DMSO) δ 11.76 (s, 1H), 10.41 (s, 1H), 9.64 (s, 1H), 8.77 (s, 1H), 8.61 (d , J = 5.1, 1H), 8.14 (d, J = 7.3, 1H), 7.93 (s, 1H), 7.67 (dd, J = 7.6, 5.4, 1H), 7.28 (d, J = 4.2, 2H), 7.26 (s, 2H), 7.22 (d, J = 5.7, 2H), 3.49 (s, 3H) , 2.15 (s, 3H); LCMS (m / z): 441 (MH⁺).

I-507: 5- (2- (2,4-difluoro-3-methoxyphenylamino) -5-methylpyrimidin-4-ylamino) -7-methylbenzo [d] oxazol-2 (3H) -one [0719] ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.91 (s, 1H), 9.62 (s, 1H), 7.90 (s, 1H), 7.32 (td , J = 8.8, 5.6, 1H), 7.19 - 7.12 (m, 1H), 7.09 (br s, 1H), 7.06 (d, J = 1.7, 1H ), 3.88 (s, 3H), 2.25 (s, 3H), 2.18 (br s, 3H); LRMS (M +) m / z 414.05.

I-508: 5- (2- (2,4-difluoro-3-methoxyphenylamino) -5-methylpyrimidin-4-ylamino) -7-fluorobenzo [d] oxazol-2 (3H) -one [0720] ¹H NMR (300 MHz, DMSO) δ 12.06 (s, 1H), 9.72 (s, 1H), 9.40 (s, 1H), 7.93 (s, 1H),

7.42 (d, J = 12.6, 1H), 7.36 - 7.28 (m, 1H), 7.19 (dd, J = 10.9, 1.7, 1H), 7.14 (d, J = 1.7, 1H),

- 196 3.91 (s, 3H), 2.18 (s, 3H); LRMS (Μ +) m / z 418.06.

I-509: 5- (2- (4- (6-chloropyridin-3-yl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one trifluoroacetate salt [0721] ¹H WR (300 \ IIIz, DMSO) δ 11.80 (s, 1H), 10.53 (s, 1H), 9.67 (s, 1H), 8.66 (s, 1H), 8.06 ( d, J = 8.5.1H), 7.94 (s, 1H), 7.57-7.55 (m, 5H), 7.36 (d, J = 8.5, 1H), 7, 29-7.21 (m, 2H), 2.15 (s, 3H); LCMS (m / z): 445 (ΜΗ +).

I-510: 5- (2- (4- (6- (3- (dimethylamino) propoxy) pyridin-3-yl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (trifluoroacetate salt) 3H) -one [0722] ¹H WR (300 \ IIIz, DMSO) δ 11.85 (s, 1H), 10.64 (s, 1H), 9.87 (s, 1H), 8.43 (s, 1H), 7.93 ( s, 1H), 7.88 - 7.79 (m, 1H), 7.51 - 7.43 (m, 4H), 7.36 (d, J = 8.5, 1H), 7.27 ( d, J = 1.6, 1H), 7.21 (d, J = 8.6, 1H), 7.04 (d, J = 8.7, 1H), 4.45 (d, J = 12 , 6, 2H), 3.51 (d, J = 9.2, 2H), 3.14 (dd, J = 24.6, 12.0, 4H), 2.84 (s, 3H), 2 , (S, 3H); LCMS (m / z): 509 (ΜΗ +).

I-511: 5- (2- (4- (6- (3- (dimethylamino) propoxy) pyridin-3-yl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (trifluoroacetate salt) 3H) -one [0723] ¹H WR (300 \ IIIz, DMSO) δ 11.85 (s, 1H), 10.67 (s, 1H), 9.84 (s, 1H), 8.40 (s, 1H), 7.97 - 7.92 (m, 2H), 7.50 (s, 4H), 7.36 (d, J = 8.5, 1H), 7.27 (s, 1H), 7.22 (d, J = 8.6, 1H), 6.88 (d, J = 8.6, 1H), 4.36 (t, J = 6.1, 2H), 3.27 - 3.17 (m, 2H), 2.81 (d, J = 4.1, 6H), 2.16 - 2.07 (m, 5H); LCMS (m / z): 512 (ΜΗ +).

I-512: 5- (5-methyl-2- (4- (6-morpholinopyridin-3-yl) phenylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one trifluoroacetate salt [0724] ¹H WR (300 \ IIIz, DMSO) δ 11.81 (s, 1H), 10.40 (s, 1H), 9.79 (s, 1H), 8.39 (s, 1H), 7.89 ( s, 1H), 7.87 (d, J = 9.0, 2H), 7.47 (q, J = 8.6, 4H), 7.35 (d, J = 8.4, 1H), 7.28-7.16 (m, 2H), 6.96 (d, J = 9.0, 1H), 3.73 - 3.68 (m, 4H), 3.52 - 3.47 (m , 4H), 2.15 (s, 3H), LCMS (m / z): 496 (ΜΗ +).

I-513: 5- (2- (2-Fluoro-3-methylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0725] C19H16FN5O2. MS (ESI) m / z 366.19 (Μ + 1) +.¹HW (300 µLz, DMSO) δ 8.37 (s, 1H, NH), 8.23 ​​(s, 1H, NH), 8.11 (s, 1H, NH), 7.83 (s, 1H, ArH), 7.68-7.64 (m, 1H, ArH), 7.37-7.29 (m, 2H, ArH), 7.12 (d, J = 8.6, 1H, ArH), 6.92-6.84 (m, 2H, ArH), 2.19 (s, 3H, CH3), 2.07 (s, 3H, CH3).

I-514: 5- (2- (2-fluoro-4-methylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0726] C19H16FN5O2. MS (ESI) m / z 366.20 (Μ + 1) +.

1-515: 5- (2- (2-fluoro-5-methylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0727] C19H16FN5O2. MS (ESI) m / z 366.16 (Μ + 1) +.

I-516:

N2- (3-difluoromethoxy-5-methyl) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-197 benzoxazol-5-yl) -2,4-pyrimidinediamine [0728] ¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H), 7.88 (s, 1H), 7.26 - 7.11 (m, 5H), 7.00 (t, J = 74, 1H), 6.59 (s, 1H), 2.12 (s, 3H), 2.08 (s, 3H); LCMS: purity: 94.88%; MS (m / e): 414.31 (MH +).

I-517: calcium salt 5-methyl-N4- [3- (phosphonooxy) methyl-2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl] -N2- (3,4,5-trimethyl) phenyl-2,4-pyrimidinediamine [0729] ¹H NMR (300 MHz, DMSO) δ 8.08 (br, 1H), 7.84 (br, 1H), 7.60 (br, 2H), 7.21 (br, 2H), 5.44 (d , 2H), 2.14 (s, 6H), 2.09 (s, 3H), 2.02 (s, 3H); LCMS: purity: 100%; MS (m / e):

486.39 (MH +).

I-518: 5- [5-methyl-2- (2-methyl-3-trifluoromethyl-phenylamino) -pyrimidin-4-ylamino] -3-Benzo-oxazol-2-one [0730] ¹H NMR (DMSO, 300 MHz): δ 8.40 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 7.79 (s, 1H),

7.73 (d, J = 7.8, 1H), 7.39 (d, J = 7.6, 1H), 7.37 - 7.20 (m, 3H), 7.02 (d, J = 8.7, 1H), 2.23 (s, 3H), 2.05 (s, 3H) ppm; MS (ES) 416 (M + H);

I-519: 5- (2- (5-acetyl-2-fluorophenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0731] C20H16FN5O3. MS (ESI) m / z 394.33 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.46 (s, 1H, NH), 8.58 (s, 1H, NH), 8.32-8.28 (m, 2H, NH, ArH), 7, 86 (s, 1H, ArH), 7.64-7.60 (m, 1H, ArH), 7.37-7.29 (m, 3H, ArH), 7.06 (d, J = 8.6 , 7H, ArH), 2.35 (s, 3H, CH3), 2.08 (s, 3H, CH3).

I-520: 5- (2- (2-chlorophenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) on [0732] ¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 9.62 (s, 2H), 7.93 (s, 1H), 7.72 (d, J = 7.7, 1H) , 7.60 (d, J = 7.7, 1H), 7.37 - 7.24 (m, 6H), 2.19 (s, 3H); LRMS (M +) m / z 367.98.

I-521: 5- (2- (2-chloro-5-methylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0733] ¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 9.63 (s, 1H), 9.44 (s, 1H), 7.94 (s, 1H), 7.54 (s , 1H), 7.47 (d, J = 8.2, 1H), 7.26 - 7.25 (m, 3H), 7.07 (d, J = 8.0, 1H), 2.19 (s, 3H), 2.13 (s, 3H); LRMS (M +) m / z 382.01.

I-522: N4- (7-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -5-methyl-N2- (3,4,5-trimethyl) phenyl-2 , 4-pyrimidinediamine [0734] ¹H NMR (300 MHz, DMSO) δ 11.92 (br, 1H), 8.79 (s, 1H), 8.36 (s, 1H), 7.87 (s, 1H), 7.44 (s , 1H), 7.31 (s, 1H), 7.24 (s, 2H), 2.06 (s, 3H), 2.01 (s, 6H), 1.98 (s, 3H); LCMS: purity: 93.26%; MS (m / e): 410.39 (MH +).

I-523: 5- (2- (2-fluoro-5- (1-hydroxyethyl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0735] C20H18FN5O3. MS (ESI) m / z 396.36 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.25-8.21

- 198 (m, 3H, 3NH), 7.82 (s, 1H, ArH), 7.63 (d, J = 8.0, 1H, ArH), 7.37-7.30 (m, 2H, ArH), 7.167.09 (m, 2H, ArH), 7.00-6.95 (m, 1H, ArH), 2.06 (s, 3H, CH3), 1.17 (d, J = 5, 3, 3H, CH3).

I-524: N4- {3- [bis (1,1-dimethylethoxy)] phosphinyloxymethyl-7-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl} -N2- (3,4 , 5-trimethyl) phenyl-5-methyl-2,4-pyrimidinediamine [0736] 1H NMR (300 MHz, DMSO) δ 8.88 (s, 1H), 8.45 (br, 1H), 8.42 ( s, 1H), 7.92 (s, 1H), 7.53 (s, 1H), 7.35 (s, 2H), 5.64 (d, J = 10.8, 2H), 2.12 (s, 6H), 2.09 (s, 3H), 2.02 (s, 3H), 1.33 (s, 18H); ³¹P NMR (121 MHz, DMSO) δ -10.08; LCMS: purity: 94.23%; MS (m / e): 632.57 (MH +).

I-525: N4- [7-chloro-3- (phosphonooxy) methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl] -5-methyl-N2- (3,4,5- trimethyl) phenyl-2,4-pyrimidinediamine [0737] 1H NMR (300 MHz, DMSO) δ 5.50 (d, 2H), 2.12 (s, 6H), 2.07 (s, 3H), 2, 03 (s, 3H); LCMS: purity: 100%; MS (m / e): 520.41 (MH +).

I-526: 5-Methyl-N4- [3- (phosphonooxy) methyl-2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl] -N2- (3,4,5-trimethyl) magnesium salt phenyl-2,4-pyrimidinediamine [0738] ¹H NMR (300 MHz, DMSO) δ 7.60 (br, 2H), 7.20 (br, 4H), 5.42 (d, 2H), 2.06 (s, 6H), 2.02 (s , 6H); LCMS: purity: 94.72%; MS (m / e): 486.41 (MH +).

I-527: 5- [2- (4-iodo-3,5-dimethylphenylamino) -5-methylpyrimidin-4-ylamino] -3H-benzooxazol-2-one [0739] ¹H NMR (DMSO, 300 MHz): δ 11.77 (s, 1H), 10.27 - 10.04 (m, 1H), 9.74 - 9.54 (m, 1H), 7.89 (s) , 1H), 7.31 (s, 1H), 7.20 (s, 3H), 2.14 (s, 6H), 2.12 (s, 3H) ppm; MS (ES) 488 (M + H);

I-528: disodium salt N4- [7-chloro-3- (phosphonooxy) methyl-2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl] -5-methyl-N2- (3,4, 5-trimethyl) phenyl-2,4-pyrimidinediamine [0740] LCMS: purity: 91.57%; MS (m / e): 520.38 (MH +).

I-529: 5- (2- (3,5-dimethoxy-4-methylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0741] ¹H NMR (300 MHz, DMSO) δ 11.77 (s, 1H), 10.04 (s, 1H), 9.54 (s, 1H), 7.86 (s, 1H), 7.35 - 7 , 27 (m, 3H), 6.74 (s, 2H), 3.57 (s, 6H), 2.19 (s, 3H), 1.97 (s, 3H); LRMS (M +) m / z 408.40.

I-530: 5- (2- (2-Fluoro-4,5-dimethylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0742] C20H18FN5O2. MS (ESI) m / z 380.21 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.27 (s, 1H, NH), 8.14 (s, 1H, NH), 8.06 (s, 1H, NH), 7.80 (s, 1H, ArH), 7.47 (d, J = 8.4, 1H, ArH), 7.36-7.28 (m, 2H, ArH), 7.11 (d, J = 8.6, 1H, ArH ), 6.97 (d, J = 12.2, 1H, ArH), 2.12 (s, 3H, CH3), 2.05 (s, 3H, CH3), 1.96 (s, 3H, CH3 ).

I-531: 5-methyl-N4- [4- (phosphonooxy) methyl-2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl] -N2- (3,4,5-trimethyl) dinolinium salt phenyl-2,4-pyrimidinediamine

- 199 [0743] ¹H NMR (300 MHz, DMSO) δ 9.28 (br, 1H), 7.82 (s, 1H), 7.66 (s, 2H), 7.18 (s, 2H),

5.39 (d, J = 7.2, 2H), 3.77 (s, 4H), 3.41 (t, J = 4.8, 4H), 3.04 (s, 18H), 2, 14 (s, 6H), 2.08 (s, 3H), 2.01 (s, 3H); LCMS: purity: 95.26%; MS (m / e): 486.39 (MH +).

I-532: 5- (2- (2-fluoro-4-methyl-3- (trifluoromethyl) phenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0744] C20H15F4N5O2 . MS (ESI) m / z 434.16 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H, NH), 8.53 (s, 1H, NH), 8.33 (s, 1H, NH), 7.99-7.92 ( m, 1H, ArH), 7.84 (s, 1H, ArH), 7.34-7.31 (m, 1H, ArH), 7.26 (s, 1H, ArH), 7.13-7, 10 (m, 1H, ArH), 7.05 (d, J = 8.6, 1H, ArH), 2.38 (s, 3H, CH3), 2.07 (s, 3H, CH3).

I-533: 5- (2- (2-fluoro-5-methoxyphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0745] ¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 8.45 (br s, 1H), 8.24 (br s, 1H), 7.85 (s, 1H), 7.45 (dd, J = 6.7, 3.2, 1H), 7.29 (d, J = 5.9, 1H), 7.28 (s, 1H), 7.10 (dd, J = 20, 6, 9.3, 2H), 6.51 - 6.45 (m, 1H), 3.54 (s, 3H), 2.08 (s, 3H); LCMS (m / z): 382 (MH⁺).

I-534: 5- (2- (2-Fluoro-3,4,5-trimethylphenylamino) -5-methylpyrimidin-4-ylamino) -benzo [d] oxazol-2 (3H) -one [0746] C21H18FN5O2. MS (ESI) m / z 394.38 (M + 1)⁺.

I-535: 5- (2- (3-methoxy-4,5-dimethylphenylamino) -5-methylpyrimidin-4-ylamino) -benzo [d] oxazol-2 (3H) -one [0747] ¹H NMR (300 MHz, DMSO) δ 11.83 (s, 1H), 10.22 (s, 1H), 9.74 (s, 1H), 7.89 (s, 1H), 7.35 - 7 , 26 (m, 3H), 6.91 (s, 1H), 6.80 (s, 1H), 3.57 (s, 3H), 2.18 (s, 3H), 2.02 (s, 6H); LRMS (M +) m / z 392.26.

I-536: (5- (2- (3-Methoxy-5-methylphenylamino) -5-methylpyrimidin-4-ylamino) -7-methyl-2-oxo-benzo [d] oxazol-3 (2H) -yl) -methyl phosphate [0748 ] ¹H NMR (300 MHz, D2O) δ 7.72 (s, 1H), 7.22 (s, 1H), 7.18 (s, 1H), 6.83 (s, 1H), 6.67 (s , 1H), 6.40 (s, 1H), 5.41 (d, J = 5.9, 2H), 3.60 (s, 3H), 2.19 (s, 3H), 2.12 ( s, 3H), 2.04 (s, 3H); LRMS (M-) m / z 500.17.

I-537: N2- (3,4-dimethyl-5-fluoro) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4 -pyrimidinediamine [0749] ¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 9.02 (s, 1H), 8.38 (s, 1H), 7.86 (s, 1H),

7.39 (d, J = 12.6, 1H), 7.26 - 7.20 (m, 3H), 7.14 (s, 1H), 2.07 (s, 3H), 2.04 ( s, 3H), 1.98 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ -133.44; LCMS: purity: 99.82%; MS (m / e): 380.40 (MH +).

I-538: (5- (2- (4-Fluoro-3-methoxy-5-methylphenylamino) -5-methylpyrimidin-4-ylamino) -2-oxo-benzo [d] oxazol-3 (2H) -yl) -methyl phosphate [0750 ] ¹H NMR (300 MHz, D2O) δ 7.67 (s, 1H), 7.40 (dd, J = 8.7, 2.1, 1H), 7.32 (d, J = 1.4,

1H), 7.14 (d, J = 8.7, 1H), 6.80 - 6.74 (m, 2H), 5.41 (d, J = 6.1, 2H), 3.64 ( s, 3H), 2.04 (s, 3H),

- 200 2.01 (s, 3H); LRMS (M-) m / z 504.10.

II-1: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6-dimethylaminopyridin-3-yl) -5-methylpyrimidine-2,4-diamine MS (ES) 378.06 (M + H), 376.10 (MH); ¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 9.88 (s, 1H), 9.59 (s, 1H), 8.20 - 8.06 (m, 1H), 8 , 08 - 7.93 (m, 1H), 7.92 - 7.77 (m, 2H), 7.24 (m, 2H), 6.98 - 6.83 (m, 1H), 3.06 (d, J = 4.2, 6H), 2.12 (s, 3H) ppm.

II-2: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6 - ((1R, 4R) -5-methyl-2,5-diazabicyclo [2.2.1 ] heptan-2-yl) pyridin-3-yl) -5-methylpyrimidine-2,4-diamine [0752] ¹H NMR (DMSO d6, 300 MHz): δ 8.54 (s, 1H), 8.21 (s, 1H), 8.14 (d, 1H, J = 1.8 Hz), 7.77 (s , 1H), 7.72 (dd, 1H, J = 2.2 and 8.8 Hz), 7.33 (d, 1H, J = 8.4 Hz), 7.29 (s, 1H), 7 , 15 (d, 1H, J = 8.4 Hz), 6.36 (d, 1H, J = 9.0 Hz), 4.48 (s, 1H), 3.52 (s, 1H), 3 , 38 (d, 1H, J = 9.9 Hz), 3.25 (d, 1H, J = 9.6 Hz), 2.82 (d, 1H, J = 9.6 Hz), 2.54 (s, 1H), 2.32 (s, 3H), 2.06 (s, 3H), 1.89 (d, 1H, J = 9.6 Hz), 1.76 (d, 1H, J = 9.3 Hz).

II-3: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6- (4-methyl-1,4-diazepan-1-yl) pyridin-3-yl) - 5-methylpyrimidine-2,4-diamine MS (ES) 447.11 (M + H), 445.23 (MH); ¹H NMR (300 MHz, DMSO) δ 8.61 (s, 1H), 8.25 (s, 1H), 8.16 (m, 2H), 7.78 (m, 3H), 7.33 (s , 3H), 7.24 - 7.10 (m, 1H), 6.58-6.43 (m, 1H), 3.75 (m, 2H), 3.50 (m, 2H), 2, 86 (m, 4H), 2.48 (m, 6H), 2.01 (m, 2H) ppm.

II-4: N4- (3-n-propylbenzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) - 5-methylpyrimidine-2,4-diamine [0754] ¹H NMR (300 MHz, DMSO) δ 9.82 (s, NH), 9.43 (s, NH), 8.24 (s, 1H), 7.88 (s, 1H), 7.61 (d , J = 8.0, 1H), 7.46 (s, 1H), 7.29 (t, J = 11.1, 1H), 6.81 (d, J = 9.3, 1H), 3 , 39-3.70 (m, 10H), 2.83 (s, 3H), 2.12 (s, 3H), 1.61 (tq, J = 12.9, 17.3, 2H), 0 , 81 (t, J = 7.4, 3H).

II-5: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6- (4-tert-butyloxycarbonylpiperazin-1-yl) pyridin-3-yl) -5-methylpyrimidine- 2,4-diamine [0755] ¹H NMR (300 MHz, DMSO) δ 11.56 (s, NH), 8.84 (s, NH), 8.39 (s, NH), 8.26 (s, H), 8.10 (s , H), 7.80 (s, 1H), 7.18 (d, J = 12.4, H), 7.02 (d, J = 9.0, H), 6.86 (d, J = 5.5, H), 6.70 (d, J = 12.8, H), 3.28-3.44 (m, 8H), 2.06 (s, 3H), 1.40 (s , 9H).

II-6: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6- (4-methylpiperidin-1-yl) pyridin-3-yl) 5-methylpyrimidine-2 , 4-diamine [0756] ¹H NMR (300 MHz, DMSO) δ 11.68 (s, NH), 9.50 (s, NH), 9.21 (s, NH), 8.07 (s, 1H), 7.81 (d , J = 23.2, 1H), 7.61 (d, J = 9.0, 1H), 7.28 (d, J = 38.7, 3H), 6.81 (d, J = 8, 9, 1H), 3.65 3.17 (m, 2H), 2.75 (t, J = 12.7, 2H), 2.09 (s, 3H), 1.73 - 1.45 (m , 3H), 1.06 (t, J = 14.0, 2H), 0.89 (d, J = 6.2, 3H).

II-7: N2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -N4- (3-isopropylbenzo [d] oxazol2 (3H) -on-5-yl) -5-methylpyrimidine- 2,4-diamine [0757] ¹H NMR (300 MHz, DMSO) δ 12.01 (s, NH), 9.73 (s, NH), 8.12 (s, 1H), 7.85 (s, 1H),

- 201 7.64 (d, J = 11.0, 1H), 7.45 (s, 1H), 7.31 (s, 2H), 6.84 (d, J = 6.1, 1H), 4.82 (s, 1H), 4.41 (s,

1H), 4.25 (d, J = 9.3, 2H), 3.96 (m, 1H), 3.02 (d, J = 15.6, 4H), 2.83 (s, 2H) , 2.13 (s, 3H), 1.37 (d, J = 6.7, 6H).

II-8: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6- (4-trifluoromethoxycarbonylpiperazin-1-yl) pyridin-3-yl) -5-methylpyrimidine-2, 4-diamine [0758] ¹H NMR (300 MHz, DMSO) δ 8.80 (s, NH), 8.40 - 8.21 (m, 2NH), 8.11 (s, 1H), 7.96 7.74 (m, 2H ), 7.30 (s, 2H), 7.19 (d, J = 8.5, 1H), 6.73 (d, J = 9.1, 1H), 3.73 - 3.25 (m , 8H), 2.06 (s, 3H).

II-9: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6- (4-methoxycarbonylpiperazin-1-yl) pyridin-3-yl) -5-methylpyrimidine- 2,4-diamine [0759] ¹H NMR (300 MHz, DMSO) δ 9.03 (s, NH), 8.72 (s, NH), 8.29 (s, NH), 8.15 (s, 1H),

7.83 (s, 1H), 7.57 (s, 1H), 7.44 - 7.09 (m, 3H), 7.02 (s, 1H), 3.64-3.40 (m, 11H), 2.08 (s, 3H).

II-10: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6- (piperazin-1-yl) pyridin-3-yl) -5-methylpyrimidine-2,4- diamine [0760] ¹H NMR (300 MHz, DMSO) δ 8.89 (s, NH), 8.79 (s, NH), 8.23 ​​(s, NH), 8.18 (s, 1H), 7.82 (d , J = 15.2, 2H), 7.38 (dd, J = 17.9, 48.5, 2H), 7.15 (d, J = 6.1, 1H), 6.64 (d, J = 9.2, 1H), 3.50-3.22 (m, 4H), 2.84-2.74 (m, 4H), 2.05 (s, 3H), 1.05 (s, NH).

II-11: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6- (3-methyl-4-tert-butoxycarbonylpiperazin-1-yl) pyridin-3-yl ) -5-methylpyrimidine-2,4-diamine [0761] ¹H NMR (300 MHz, DMSO) δ 12.01 (s, NH), 11.55 (s, NH), 8.76 (s, NH), 8.24 (s, 1H), 7.79 (s , 2H), 7.32 (d, J = 11.4, 2H), 7.17 (d, J = 8.4, 1H), 6.68 (d, J = 9.6, 1H), 3 , 95 (dd, J = 11.5, 21.3, 2H), 3.76 (d, J = 13.1, 1H), 3.67 - 3.41 (m, 1H), 3.09 ( t, J = 12.2, 1H), 2.89 (dd, J = 4.0, 13.0, 1H), 2.67 (dd, J = 6.8, 16.2, 1H), 2 , 06 (s, 3H), 1.40 (s, 9H), 1.09 (d, J = 6.6, 3H).

II-12: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6- (3-methylpiperazin-1-yl) pyridin-3-yl) 5-methylpyrimidine-2 , 4-diamine [0762] ¹H NMR (300 MHz, DMSO) δ 8.93 (s, NH), 8.79 (s, NH), 8.40 (s, NH), 8.21 (s, 1H), 7.92 - 7 , 75 (m, 2H), 7.39 - 7.24 (m, 2H), 7.18 (d, J = 8.6, 1H), 6.75 (d, J = 9.0, 1H) , 4.25 3.94 (m, 1H), 3.21 (d, J = 9.8, 1H), 3.10 (s, 1H), 2.88 (dd, J = 13.5, 22 , 1, 3H), 2.64 (dd, J = 13.3, 26.8, 1H), 2.06 (s, 3H), 1.19 (d, J = 6.2, 3H).

II-13: N4- (benzooxazolin-2-one-5-yl) -N2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine:

[0763] ¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30 - 8.28 (m, 2H), 7.87 7.84 (m, 2H ), 7.46 - 7.28 (m, 2H), 7.22 (d, J = 8.5, 1H), 6.71 (d, J = 9.1, 1H), 3.40 - 3 , 37 (m, 4H, with imposition on H2O), 2.44 - 2.41 (m, 4H), 2.25 (s, 3H), 2.11 (s, 3H); LCMS (M +) m / z 433.52.

II-14: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] 5-fluoropyrimidine-2 4-diamine

202 [0764] LCMS (M +) m / z 437.54; ¹H NMR (300 MHz, DMSO) δ 11.71 (br s, 1H), 9.31 (s, 1H),

8.95 (s, 1H), 8.28 - 8.27 (m, 1H), 8.05 (d, J = 3.7, 1H), 7.84 (br d, J = 8.9, 1H), 7.46 (d, J =

8.9, 1H), 7.36 (br s, 1H), 7.21 (d, J = 8.8, 1H), 6.77 (d, J = 8.8, 1H), 3.40 - 3.36 (m, 4H, with application on H2O), 2.44 - 2.41 (m, 4H), 2.25 (s, 3H).

II-15: N4- (benzimidazolin-2-one-5-yl) -N2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine [0765] LCMS (M +) m / z 432.55; ¹H NMR (300 MHz, DMSO) δ 10.55 (s, 1H), 10.50 (s, 1H), 8.63 (s, 1H), 8.28 (d, J = 2.3, 1H) , 8.17 (s, 1H), 7.86 (dd, J = 2.3, 9.1, 1H), 7.79 (s, 1H), 7.19 (d, J = 8.3, 1H), 7.12 (s, 1H), 6.87 (d, J = 8.3, 1H), 6.64 (d, J = 9.1, 1H), 3.37-3.34 ( m, 4H, with application on H2O), 2.44 - 2.41 (m, 4H), 2.24 (s, 3H), 2.09 (s, 3H).

II-16: N4- (benzimidazolin-2-one-5-yl) -N2- [2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-fluoropyrimidine-2,4-diamine:

[0766] ¹H NMR (300 MHz, DMSO) δ 10.56 (s, 1H), 10.52 (s, 1H), 9.16 (s, 1H), 8.85 (s, 1H), 8.27 (br d, J = 2.3, 1H), 8.00 (br d, J = 3.8, 1H), 7.84 (dd, J = 2.3, 9.1, 1H), 7.30 ( dd, J = 1.7,

8.2, 1H), 7.17 (d, J = 1.7, 1H), 6.86 (d, J = 8.2, 1H), 6.73 (d, J = 9.1, 1H ), 3.40-3.37 (m, 4H, with imposition on H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H); LCMS (M +) m / z 436.50.

II-17: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2 - ((2-morpholinyl) pyridin-5-yl) -5-methylpyrimidine-2,4-diamine [ 0767] LCMS (M +) m / z 420.01; ¹H NMR (300 MHz, DMSO) δ 11.74 (s, 1H), 9.99 (s, 1H), 9.72 (br s, 1H), 8.08 (s, 1H), 7.81 ( s, 1H), 7.61 (d, J = 8.8, 1H), 7.31 - 7.20 (m, 3H), 6.88 (d, J = 8.8, 1H), 3, 74 - 3.71 (m, 4H), 3.46 - 3.43 (m, 4H), 2.18 (s, 3H);

II-18: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2 - ((2-morpholinyl) pyridin-5-yl) -5-fluoropyrimidine-2,4-diamine [ 0768] LCMS (M +) m / z 423.98; ¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 9.82 (s, 1H), 9.61 (s, 1H), 8.35 (s, 1H), 8.19 (d , J = 4.1, 1H), 8.02 (br d, J = 9.0, 1H), 7.41 - 7.39 (m, 3H), 7.29 - 7.22 (m, 3H ), 3.79 - 3.76 (m, 4H), 3.54 - 3.51 (m, 4H).

II-19: N4- (benzimidazolin-2-one-5-yl) -N2 - ((2-morpholinyl) pyridin-5-yl) -5-fluoropyrimidine-2,4-diamine [0769] ¹H NMR (300 MHz, DMSO) δ 10.61 (s, 2H), 9.79 (br s, 1H), 9.55 (br s, 1H), 8.31 (s, 1H), 8.13 (d, J = 4.4, 1H), 7.92 (br d, J = 8.8, 1H), 7.22 (d, J = 8.1, 1H), 7.18 (s, 1H ), 7.10 (br d, J = 8.8, 1H), 6.89 (d, J = 8.1, 1H), 3.78 - 3.75 (m, 4H), 3.50 - 3.47 (m, 4H); LCMS (M +) m / z 423.00.

II-20: N4- (1,3-dimethylbenzimidazolin-2-one-5-yl) -N2- [2- (4-methylpiperazine) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine [0770] LCMS (M +) m / z 460.54; ¹H NMR (300 MHz, DMSO) δ 8.68 (s, 1H), 8.39 (br s, 1H),

8.27 (s, 1H), 7.82 (s, 1H), 7.71 (br d, J = 8.4, 1H), 7.53 (s, 1H), 7.23 (br d, J = 9.0, 1H), 7.09 (d, J = 8.4, 1H), 6.65 (d, J = 9.0, 1H), 3.37 - 3.34 (m, 7H , partly with overlay on H2O),

3.27 (s, 3H), 2.43 - 2.40 (m, 4H), 2.25 (s, 3H), 2.12 (s, 3H).

- 203 II-21: N4- (1,3-dimethylbenzimidazolin-2-one-5-yl) -N2- [2- (4-methylpiperazine) pyridin-5-yl] -5-fluoropyrimidine-2,4-diamine [0771 ] LCMS (M +) m / z 464.49; ¹H NMR (300 MHz, DMSO) δ 9.28 (s, 1H), 8.90 (s, 1H), 8.38 (d, J = 2.1, 1H), 8.03 (d, J = 3.8, 1H), 7.70 (d, J = 8.3, 1H), 7.61 (s, 1H), 7.27 (d, J = 8.8, 1H), 7.09 ( d, J = 8.3, 1H), 6.72 (d, J = 8.8, 1H), 3.37 (m, 7H, with application on H2O), 3.27 (s, 3H), 2 , 48 - 2.36 (m, 4H), 2.25 (s, 3H).

II-22: N2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-5-yl) -5-methylpyrimidine-2,4-diamine [0772] ¹H NMR (300 MHz, DMSO) δ 10.23 (s, 1H), 9.83 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.52 (d , J = 9.1, 1H), 7.43 (s, 1H), 7.31 (d, J = 8.7, 1H), 7.14 (d, J = 8.7, 1H), 6 , 84 (d, J = 9.1, 1H), 4.27-4.24 (m, 2H), 3.51-3.48 (m, 2H), 3.26 (s, 3H), 3 , 04-3.01 (m, 4H), 2.84 (s, 3H), 2.15 (s, 3H).

II-23: N2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) trifluoroacetate salt -5-methylpyrimidine-2,4-diamine [0773] ¹H NMR (300 MHz, DMSO) δ 10.21 (s, 1H), 9.90 (s, 1H), 9.74 (s, 1H), 8.11 (s, 1H),

7.84 (s, 1H), 7.61 (d, J = 6.0, 2H), 7.26 (dd, J = 8.8, 18.6, 2H), 6.90 (d, J = 9.0, 1H), 4.33 (d, J = 10.3, 2H), 3.50 (d, J = 8.6, 2H), 3.34 (s, 3H), 3.08 (d, J = 9.0, 4H), 2.85 (s, 3H), 2.14 (s, 3H).

II-24: N2- (6- (4-methylpiperazin-1-yl) pyridin-3-yl) -N4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-5-yl) -5-fluoropyrimidine-2,4-diamine [0774] ¹H NMR (300 MHz, DMSO) δ 9.38 (s, 1H), 8.93 (s, 1H), 8.33 (d, J = 2.5, 1H), 8.03 (d, J = 3.7, 1H), 7.68-7.66 (m, 2H), 7.30-7.22 (m, 2H), 6.74 (d, J = 8.9, 1H), 3, 37 (m, 4H), 3.24 (s, 3H), 2.55-2.49 (m, 7H).

II-25: Synthesis of 6- (5-methyl-2- (6- (4-methylpiperazin-1-yl) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0775 ] ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.97 (s, 1H), 9.49 (s, 1H), 8.15 (s, 1H), 7.82 (s , 1H), 7.65 (d, J = 11.7, 2H), 7.21 (d, J = 8.8, 1H), 7.05 (d, J = 8.4, 1H), 6 , 89 (d, J = 8.9, 1H), 4.34-4.31 (m, 4H), 3.09-3.07 (m, 4H), 2.85 (s, 3H), 2 , 13 (s, 3H).

II-26: N4- (benzooxazolin-2-one-5-yl) -N2- [3-methyl-2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine [0776] LCMS (m / z): 447 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 11.54 (s, 1H), 8.90 (s, 1H), 8.34 (s, 1H), 8.17 (d, 1H, J = 2, 4 Hz), 7.86 (d, 1H, J = 1.8 Hz), 7.83 (s, 1H), 7.26 (m, 3H), 2.92 (s, 4H), 2.48 (s, 4H), 2.26 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H).

II-27: N4- (benzimidazolin-2-one-5-yl) -N2- [3-methyl-2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine [0777] LCMS (m / z): 446 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 10.51 (s, 1H), 10.49 (s,

1H), 8.86 (s, 1H), 8.23 ​​(s, 1H), 8.14 (s, 1H), 7.91 (d, 1H, J = 7.5 Hz), 7.78 ( s, 1H), 7.06 (d,

- 204 2H, J = 9.9 Hz), 6.86 (d, 1H, J = 8.1 Hz), 4.10 (q, 1H, J = 5.1 Hz), 3.15 (d, 2H, J = 3.9 Hz),

3.02 (s, 3H), 2.88 (s, 3H), 2.51 (d, 2H, J = 12.0 Hz), 2.06 (s, 3H), 1.92 (s, 3H ).

II-28: N4- (benzooxazolin-2-one-5-yl) -N2- [3-methyl-2 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane- 2-yl) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine LCMS (m / z): 459 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 8.75 (s, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.26 (m, 2H), 7.18 (d, 1H, J = 8.4 Hz), 4.35 (s, 1H), 3.77 (br s, 2H), 3.50 (t, 2H, J = 3.6 Hz), 3.37 (m, 1H), 2.95 (m, 1H), 2.54 (s, 3H), 2.07 (s, 3H ), 1.99 (s, 3H), 1.82 (d, 1H, J = 9.6 Hz).

II-29: N4- (benzooxazolin-2-one-5-yl) -N2- [3-methyl-2 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane- 2-yl) pyridin-5-yl] -5-fluoropyrimidine-2,4-diamine LCMS (m / z): 463 (M + H).

II-30: N4- (benzooxazolin-2-one-5-yl) -N2- [3-methyl-2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5-fluoropyrimidine-2,4-diamine [0780] LCMS (m / z): 451 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 11.55 (s, 1H), 8.91 (s, 1H), 8.36 (s, 1H), 8.17 (d, 1H, J = 3, 8 Hz), 7.86 (d, 1H, J = 1.8 Hz), 7.83 (s, 1H), 7.26 (m, 3H), 2.92 (s, 4H), 2.48 (s, 4H), 2.26 (s, 3H), 2.01 (s, 3H).

II-31: N4- (benzooxazolin-2-one-5-yl) -N2- [2 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine LCMS (m / z): 445 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 8.54 (s, 1H), 8.21 (s, 1H), 8.14 (d, 1H, J = 1.8 Hz), 7.77 (s , 1H), 7.72 (dd, 1H, J = 2.2 and 8.8 Hz), 7.33 (d, 1H, J = 8.4 Hz), 7.29 (s, 1H), 7 , 15 (d, 1H, J = 8.4 Hz), 6.36 (d, 1H, J = 9.0 Hz), 4.48 (s, 1H), 3.52 (s, 1H), 3 , 38 (d, 1H, J = 9.9 Hz), 3.25 (d, 1H, J = 9.6 Hz), 2.82 (d, 1H, J = 9.6 Hz), 2.54 (s, 1H), 2.32 (s, 3H), 2.06 (s, 3H), 1.89 (d, 1H, J = 9.6 Hz), 1.76 (d, 1H, J = 9.3 Hz).

II-32: N4- (benzooxazolin-2-one-5-yl) -N2- [2 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridin-5- yl] -5-methylpyrimidine-2,4-diamine LCMS (m / z): 432 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 11.53 (s, 1H), 8.60 (s, 1H), 8.23 ​​(s, 1H), 8.17 (d, 1H, J = 2, 1 Hz), 7.78 (s, 1H), 7.75 (d, 1H, J = 2.4), 7.31 (m, 2H), 7.15 (d, 1H, J = 8.4 Hz), 6.39 (d, 1H, J = 8.7 Hz), 4.68 (s, 1H), 3.59 (s, 1H), 3.73 (d, 1H, J = 7.2 Hz), 3.60 (d, 1H, J = 7.2 Hz), 3.38 (m, 1H), 3.14 (d, 1H, J = 9.3 Hz), 2.05 (s, 3H), 1.88 (d, 1H, J = 9.9 Hz), 1.80 (d, 1H, J = 9.9 Hz).

II-33: N4- (benzooxazolin-2-one-5-yl) -N2- [2 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) pyridin-5-yl] -5-fluoropyrimidine-2,4-diamine LCMS (m / z): 448 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 9.28 (s, 1H), 8.84 (s,

1H), 8.16 (d, 1H, J = 1.8 Hz), 7.99 (d, 1H, J = 3.6 Hz), 7.75 (dd, 1H, J = 2.4 and 8 , 5 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.33 (s, 1H), 7.17 (d, 1H, J = 8.7 Hz), 6.48 ( d, 1H, J = 8.7 Hz), 4.60 (s,

1H), 3.86 (s, 1H), 3.48 (d, 1H, J = 9.9 Hz), 3.38 (d, 1H, J = 9.0 Hz), 2.96 (s, 2H), 2.52 (s, 3H),

2.04 (d, 1H, J = 9.6 Hz), 1.91 (d, 1H, J = 9.9 Hz).

- 205 II-34: N4- (benzooxazolin-2-one-5-yl) -N2- [2 - ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) pyridinium 5-yl] -5-fluoropyrimidine-2,4-diamine LCMS (m / z): 436 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 11.55 (s, 1H), 9.26 (s, 1H), 8.83 (s, 1H), 8.15 (d, 1H, J = 2, 1 Hz), 7.99 (d, 1H, J = 3.9 Hz), 7.75 (dd, 1H, J = 2.4 and 8.7 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.33 (s, 1H), 7.15 (d, 1H, J = 8.7 Hz), 6.45 (d, 1H, J = 9.0 Hz), 4.71 (s, 1H), 4.59 (s, 1H), 3.73 (d, 1H, J = 6.9 Hz), 3.60 (d, 1H, J = 7.2 Hz), 3.41 (d, 1H, J = 9.9 Hz), 3.16 (d, 1H, J = 10.2 Hz), 1.88 (d, 1H, J = 9.3 Hz), 1.81 (d , 1H, J = 10.8 Hz).

II-35: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- [2- (1-methylpiperidin-4-yl) aminopyridin-5-yl] -5-methylpyrimidine-2, 4-diamine [0785] LCMS: purity: 99.48%; MS (m / e): 447.31 (M + H);¹H NMR (300 MHz, DMSO) δ11.69 (s, 1H), 9.88 (br, 1H), 9.41 (br, 2H), 7.96 (s, 1H), 7.80 (s, 1H), 7.53 (br, 1H), 7.21 (m, 3H), 6.60 (br, 1H), 3.77 (br, 1H), 3.47 (d, J = 12.0 , 2H), 3.00 (q, 2H), 2.79 (d, J = 3.6, 3H), 2.12 (s, 3H), 2.08 (d, J = 12.3, 2H ), 1.60 (q, J = 13.5, 2H).

II-36: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- [2- (1H-piperidin-4-yl) aminopyridin-5-yl] -5-methylpyrimidine-2, 4-diamine LCMS: purity: 99.62%; MS (m / e): 433.25 (M + H);¹H NMR (300 MHz, DMSO) δ 11.73 (s, 1H), 10.00 (s, 1H), 9.68 (s, 1H), 8.01 (s, 1H), 7.82 (br , 3H), 7.55 (d, 1H), 7.21 (m, 2H), 7.15 (d, 1H), 6.88 (d, J = 8.7, 1H), 4.24 ( d, J = 12.9, 2H), 3.27 (br, 1H), 2.86 (t, J = 13.2, 2H), 2.12 (s, 3H), 1.90 (d, J = 10.8, 2H), 1.40 (q, J = 12.6, 2H).

II-37: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- [2- (8-methyl-8-azabicyclo [3.2.1] oct-3-yl) aminopyridine -5-yl] -5-methylpyrimidine-2,4-diamine LCMS: purity: 95.17%; MS (m / e): 473.37 (M + H);¹H NMR (300 MHz, DMSO) δ 11.67 (s, 1H), 9.81 (br, 1H), 9.37 (br, 2H), 7.98 (s, 1H), 7.78 (s , 1H), 7.50 (br, 1H), 7.20 (s, 3H), 6.65 (d, 1H), 3.82 (br, 2H), 2.67 (d, J = 4, 5, 3H), 2.26 (m, 4H), 2.12 (m, 4H), 2.12 (s, 3H).

II-38: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (4- (8-methyl-2,8-diazabicyclo [3.2.1] octan-2-yl) phenyl ) -5-methylpyrimidine-2,4-diamine MS (ES) 459.06 (M + H); ¹H NMR (CD3OD, 300 MHz) 8.33 (m, 2H), 8.17 (m, 1H), 7.69-6.61 (m, 7H), 4.52 (m, 1H), 4, 13 (m, 2H), 3.52 (m, 6H), 2.40-2.18 (m, 4H), 2.15 (s, 3H).

II-39: N4- (benzo [d] oxazolin-2 (3H) -on-5-yl) -N2- [3-trifluoromethyl-2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5- methylpyrimidine-2,4-diamine LCMS (m / z): 501 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 11.43 (s, 1H), 9.31 (s, 1H), 8.67 (s, 1H), 8.42 (s, 1H), 8.39 (d, 1H, J = 2.1 Hz), 7.89 (s, 1H), 7.22 (m, 3H), 2.96 (t, 4H, J = 4.8 Hz), 2.44 (br s, 4H), 2.22 (s, 3H), 2.09 (s, 3H).

II-40: N4- (benzooxazolin-2-one-5-yl) -N2- [3-fluoro-2 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptane- 2-yl) pyridin-5-yl] -5-methylpyrimidine-2,4-diamine LCMS (m / z): 463 (M + H); ¹H NMR (DMSO d6, 300 MHz): δ 9.03 (s, 1H), 8.40 (s,

- 206 1H), 8.04 (s, 1H), 7.91 (d, 1H, J = 15.9 Hz), 7.83 (s, 1H), 7.24 (m, 3H), 4, 56 (s, 1H), 4.00 (br

s), 3.57 (m, 2H), 3.06 (br s, 2H), 2.64 (s, 3H), 2.07 (s, 3H), 1.94 (d, 2H, J = 9.0 Hz).

II-41: (S) -2-methyl-4- {5- [5-methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) pyrimidin-2-ylamino] tert-butyl ester pyridin-2-yl} -piperazine-1-carboxylic acid [0791] ¹H NMR (DMSO, 300 MHz): δ 8.71 (s, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.85- 7.76 (m, 2H), 7.34-7.28 (m, 2H), 7.20-7.15 (m, 1H), 6.67 (d, J = 9.1, 1H), 3.89 (d, J =

12.2, 2H), 2.52-2.38 (m, 2H), 2.21 (s, 3H), 2.05 (s, 3H), 1.41 (s, 9H), 1.04 (d, J = 6.0, 3H) ppm; MS (ES) 533 (M + H).

II-42: 5- [5-methyl-2- (pyridin-3-ylamino) pyrimidin-4-ylamino] -3H-benzooxazol-2-one [0792] ¹H NMR (DMSO, 300 MHz): δ 9.01 (s, 1H), 8.82 (d, J = 5.5 Hz, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.70 - 7.89 (m, 2H), 7.43 (s, 1H), 7.10 - 7.28 (m, 2H), 6.97 (s, 2H), 2.28 (s, 3H) ppm; MS (ES) 335 (M + H).

II-43: 5- [2- (6-methanesulfonyl-pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino] -3H-benzooxazol-2-one [0793] ¹H NMR (DMSO, 300 MHz): δ 9.05 (s, 1H), 8.78 (d, J = 5.5 Hz, 1H), 8.49 (s, 1H), 8.31 (s, 1H), 7.61 - 7.83 (m, 2H), 7.47 (s, 1H), 7.11 - 7.23 (m, 2H), 6.91 (s, 1H), 3.15 (s, 3H), 2.22 (s, 3H) ppm; MS (ES) 413 (M + H).

II-44: 5- {5-methyl-2- [6 - ((S) -3-methylpiperazin-1-yl) pyridin-3-ylamino] pyrimidin-4-ylamino} -3H-benzooxazol-2-one [ 0794] MS (ES) 433 (M + H)

II-45: 5- {5-methyl-2- [6- (piperazine-1-carbonyl) pyridin-3-ylamino] pyrimidin-4-ylamino} -3H-benzooxazol-2-one [0795] MS (ES) 447 (M + H)

II-46: 5- {2- [6- (4-cyclopropylmethylpiperazine-1-carbonyl) pyridin-3-ylamino] -5-methylpyrimidin-4-ylamino} -3H-benzooxazol-2-one [0796] MS (ES ) 501 (M + H)

II-47: 5- {2- [6- (4-isobutylpiperazine-1-carbonyl) pyridin-3-ylamino] -5-methylpyrimidin-4-ylamino} -3H-benzooxazol-2-one [0797] MS (ES) 503 (M + H)

II-48: 5- {3-fluoro-5- [5-methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) pyrimidin-2-ylamino] pyridin-2- acid tert-butyl ester yl} -hexahydropyrrolo [3.4c] pyrrole-2-carboxyl [0798] ¹H NMR (DMSO, 300 MHz): δ 8.96 (s, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H),

7.89 - 7.94 (m, 1H), 7.83 (s, 1H), 7.14 - 7.33 (m, 3H), 3.14 (dd, J = 11.0, 3.0 Hz, 4H), 2.87 (br. P., 4H), 2.48 (br. P., 2H), 2.06 (s, 3H), 1.37 (s, 9H) ppm; MS (ES) 563 (M + H).

- 207 II-49: 5- {3-Fluoro-5- [5-methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) pyrimidin-2-ylamino] pyridinium acid tert-butyl ester 2-yl} -2,5-diazabicyclo [2.2.1] heptane-2-carboxyl [0799] ¹H NMR (DMSO, 300 MHz): δ 9.03 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.03 (br. S., 1H), 7 , 92 (d, J = 15.7 Hz, 1H), 7.83 (s, 1H), 7.14 - 7.36 (m, 3H), 4.59 (br. P. 1H), 4 , 36 (d, J = 17.9 Hz, 1H), 2.40 - 2.57 (m, 4H), 2.06 (s, 3H), 1.73 - 1.92 (m, 2H), 1.37 (s, 9H) ppm; MS (ES) 549 (M + H).

II-50: 5- {2- [5-fluoro-6- (hexahydropyrrolo [3.4-c] pyrrol-2-yl) pyridin-3-ylamino] -5-methylpyrimidin-4-ylamino} -3H-benzooxazol-2 -on [0800] ¹H NMR (DMSO, 300 MHz): δ 8.93 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 7.90 - 7.98 (m, 1H), 7.85 (s, 1H), 7.14 - 7.39 (m, 3H), 3.10 (dd, J = 11.0, 3.0 Hz, 4H) , 2.82 (br. P., 4H), 2.49 (br. P., 2H), 2.12 (s, 3H) ppm; MS (ES) 463 (M + H).

II-51: 5- {2- [6- (2,5-diazabicyclo [2.2.1] hept-2-yl) -5-fluoropyridin-3-ylamino] -5-methylpyrimidin-4-ylamino} -3H- benzooxazol-2-one MS (ES) 449 (M + H)

II-52: 5- {2- [6- (5-cyclopropylmethylhexahydropyrrolo [3.4-c] pyrrol-2-yl) -5-fluoropyridin-3-ylamino] -5-methylpyrimidin-4-ylamino} -3H-benzooxazol-2- he [0802] 1H NMR (DMSO, 300 MHz): δ 9.05 (s, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.99 - 7.87 (m, 1H), 7.84 (s, 1H), 7.20 (s, 2H), 3.33 (s, 4H), 3.16 - 2.98 (m, 2H), 2.94 - 2.74 (m, 2H), 2.70 - 2.54 (m, 2H), 2.50 (d, J = 6.9, 2H), 2.06 (s, 3H), 1.01-0.78 (m, 1H), 0.45 (s, 2H), 0.14 (s, 2H) ppm; MS (ES) 517 (M + H).

II-53: 5- {2- [6- (5-cyclopropanecarbonylhexahydropyrrolo [3.4-c] pyrrol-2-yl) -5-fluoropyridin-3-ylamino] -5-methylpyrimidin-4-ylamino} -3H-benzooxazol-2- he [0803] ¹H NMR (DMSO, 300 MHz): δ 1.54 (s, 1H), 9.01 (s, 1H), 8.45 (s, 1H), 8.11 (s, 1H), 8.00 ( s, 1H), 7.82 (s, 2H), 7.23 (d, J = 10.8, 2H), 3.99 - 3.73 (m, 2H), 3.56 (m, 5H) , 3.12 2.77 (m, 3H), 2.06 (s, 3H), 1.82-1.64 (m, 1H), 0.69 (s, 4H) ppm; MS (ES) 531 (M + H).

II-54: 5- {2- [6- (5-cyclopropylmethyl-2,5-diazabicyclo [2.2.1] hept-2-yl) -5-fluoropyridin-3-ylamino] -5-methylpyrimidin-4-ylamino} - 3H-benzooxazol-2-one [0804] ¹H NMR (DMSO, 300 MHz): δ 9.11-8.81 (m, 1H), 8.60 - 8.30 (m, 1H), 8.18 (s, 1H), 8.15 - 7 , 96 (m, 1H), 7.97 - 7.75 (m, 1H), 7.43 - 6.95 (m, 2H), 3.03 - 2.84 (m, 1H), 2.91 - 2.64 (m, 2H), 2.46 - 2.32 (m, 2H), 2.06 (s, 3H), 1.95 - 1.62 (m, 2H), 1.05 - 0 , 58 (m, 1H), 0.51 0.26 (m, 2H), 0.24 - 0.07 (m, 2H); ppm; MS (ES) 503 (M + H).

II-55: (R) -5- (2- (6- (3,4-dimethylpiperazin-1-yl) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -on [0805] C23H26N8O2. MS (ESI) m / z 447.57 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.71 (s,

1H, NH), 8.27 (s, 1H, NH), 8.25 (s, 1H, NH), 8.18 (s, 1H, ArH), 7.85-7.76 (m, 2H, Ar)

7.34-7.28 (m, 2H, ArH), 7.20-7.15 (m, 1H, ArH), 6.67 (d, J = 9.1, 1H, ArH), 3.89 (d, J = 12.2,

- 208 2H, CH2), 2.90-2.74 (m, 3H, CH, CH2), 2.52-2.38 (m, 2H, CH2), 2.21 (s, 3H, CH3), 2.05 (s,

3H, CH3), 1.04 (d, J = 6.0, 3H, CH3).

II-56: (R) -5- (2- (6- (4- (cyclopropylmethyl) -3-methylpiperazin-1-yl) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol 2 (3H) -one [0806] C26H30N8O2. MS (ESI) m / z 487.62 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.69 (s, 1H, NH), 8.26 (s, 1H, NH), 8.23 ​​(s, 1H, NH), 8.19 (s, 1H, ArH), 7.84-7.76 (m, 2H, ArH), 7.34-7.28 (m, 2H, ArH), 7.20-7.14 (m, 1H, ArH), 6, 67 (d, J = 9.5, 1H, ArH), 3.79 (d, J = 12.1, 2H, CH2), 3.52 (d, J = 13.3, 2H, CH2), 3 , 06-2.84 (m, 3H, CH, CH2), 2.62-2.42 (m, 2H, CH2), 2.21 (s, 3H, CH3), 2.08 (s, 3H, CH3), 1.02 (d, J = 5.5, 3H, CH3), 0.89-0.78 (m, 1H, CH), 0.500.37 (m, 2H, CH2), 0.12- 0.02 (m, 2H, CH2).

II-57: (R) -5- (5-methyl-2- (6- (3-methyl-4- (2,2,2-trifluoroacetyl) piperazin-1-yl) pyridin-3-ylamino) pyrimidin-4- ylamino) benzo [d] oxazol-2 (3H) -one [0807] C24H23F3N8O3. MS (ESI) m / z 529.53 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.74 (s, 1H, NH), 8.28 (s, 1H, ArH), 8.12 (s, 1H, NH), 7.85 (s, 1H, NH), 7.84-7.77 (m, 2H, ArH), 7.35-7.28 (m, 2H, ArH), 7.19-7.16 (m, 1H, ArH), 6, 74-6.68 (m, 1H, ArH), 4.21-3.54 (m, 7H, CH, 3CH2), 2.21 (s, 3H, CH3), 2.05 (s, 3H, CH3 ), 1.20 (d, J = 6.8, 3H, CH3).

II-58: (R) -2-methyl-4- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridine Diethyl -2-yl) piperazin-1-ylphosphonate [0808] C26H33N8O5P. MS (ESI) m / z 569.03 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 12.01 (s, 1H, NH), 11.67 (s, 1H, NH), 8.15 (s, 1H, ArH), 7.79 (s, 1H, ArH), 7.70-7.67 (m, 1H, ArH), 7.28-7.20 (m, 2H, ArH), 6.74-6.71 (m, 1H, ArH), 6, 61-6.54 (m, 1H, ArH), 3.96-3.54 (m, 11H, CH, 5CH2), 2.48 (s, 3H, CH3), 2.08 (s, 3H, CH3 ), 1.24-1.08 (m, 6H, 2CH3).

II-59: 5- (2- (6- (4,4-difluoropiperidin-1-yl) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0809] C22H21F2N7O2. MS (ESI) m / z 454.02 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.84 (s, 1H, NH), 8.40 (s, 1H, NH), 8.27 (s, 1H, ArH), 8.11 (s, 1H, ArH), 7.83-7.80 (m, 1H, ArH), 7.29-7.17 (m, 2H, ArH), 6.81 (d, J = 9.1, 1H, ArH), 6.54 (s, 1H, ArH), 3.68-3.48 (m, 4H, 2CH2), 2.06 (s, 3H, CH3), 1.98-1.87 (m, 4H, 2CH2 ).

II-60: 5- (2- (6- (4,4-dimethylpiperidin-1-yl) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0810 ] C24H27N7O2. MS (ESI) m / z 446.54 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H, NH), 8.94 (s, 1H, NH), 8.59 (s, 1H, NH), 8.16 (s, 1H, ArH), 8.11 (s, 1H, ArH), 7.78 (s, 1H, ArH), 7.27-7.17 (m, 2H, ArH), 6.71 (d, J = 8, 8, 1H, ArH), 6.53 (s, 1H, ArH), 3.68-3.08 (m, 4H, 2CH2), 2.06 (s, 3H, CH3), 1.47-1, 18 (m, 4H, 2CH2), 0.93 (s, 6H, 2CH3).

II-61: 5- (2- (6- (3,8-diazabicyclo [3.2.1] octane-3-yl) -5-methylpyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d ] oxazol-2 (3H) -one [0811] C24H26N8O2. MS (ESI) m / z 459.09 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 9.01 (s,

1H, NH), 8.36 (s, 1H, NH), 8.28 (s, 1H, ArH), 8.22 (s, 1H, NH), 7.90 (s, 1H, ArH), 7 , 84 (s,

- 209 1H, ArH), 7.42-7.14 (m, 3H, ArH), 3.08-2.95 (m, 6H, 2CH, 2CH2), 2.06 (s, 3H, CH3), 2.03 (s,

3H, CH3), 1.90-1.86 (m, 4H, 2CH2).

II-62: 5- (5-methyl-2- (5-methyl-6- (8-acetyl) -3,8-diazabicyclo [3.2.1] octan-3-yl) pyridin-3-ylamino) pyrimidin-4- ylamino) benzo [d] oxazol-2 (3H) -one [0812] C26H28N8O4. MS (ESI) m / z 516.82 (Μ + 1) +.

II-63: 5- (5-methyl-2- (5-methyl-6- (8- (2,2,2-trifluoroacetyl) -3,8-diazabicyclo [3.2.1] octane-3-yl) pyridin-3 -ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0813] C26H25F3N8O3. MS (ESI) m / z 555.25 (Μ + 1) +.¹H WR (300 \ IIIz, DMSO) δ 11.57 (s, 1H, NH), 9.06 (s, 1H, NH), 8.49 (s, 1H, NH), 8.17 (s, 1H , ArH), 7.88 (s, 1H, ArH), 7.84 (s, 1H, ArH), 7.31-7.16 (m, 3H, ArH), 3.65-3.38 (m , 6H, 2CH, 2CH2), 2.07 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.04-1.95 (m, 4H, 2CH2).

II-64: 5- (5-methyl-2- (5-methyl-6- (8-methyl-3,8-diazabicyclo [3.2.1] octan-3-yl) pyridin-3-ylamino) pyrimidin-4-ylamino ) benzo [d] oxazol-2 (3H) -one [0814] C25H28N8O2. MS (ESI) m / z 473.19 (Μ + 1) +.

II-65: 3- (3-methyl-5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridin-2-yl ) Tert-butyl octane-8-carboxylate -8-azabicyclo [3.2.1] C30H35N7O4. MS (ESI) m / z 558.13 (Μ + 1) +.¹HW (300 \ IIIz, DMSO) δ 11.57 (s, 1H, NH), 9.02 (s, 1H, NH), 8.37 (s, 1H, ArH), 8.35 (s, 1H, NH), 7.89 (s, 1H, ArH), 7.86 (s, 1H, ArH), 7.35-7.15 (m, 2H, ArH), 6.53 (s, 1H, ArH) , 3.66-3.44 (m, 3H, 3CH), 2.07 (s, 3H, CH3), 2.04 (s, 3H, CH3), 1.96-1.77 (m, 8H, 4CH2), 1.40 (s, 9H, 3CH3).

II-66: 5- (2- (6- (8-azabicyclo [3.2.1] octane-3-yl) -5-methylpyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazole -2 (3H) -one [0816] C25H27N7O2. MS (ESI) m / z 457.53 (Μ + 1) +.

II-67: 5- (2- (6- (8- (cyclopropylmethyl) -8-azabicyclo [3.2.1] octane-3-yl) -5-methylpyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0817] C29H33N7O2. MS (ESI) m / z 512.16 (Μ + 1) +.

II-68: 3- (3-methyl-5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridin-2-yl ) -8-azabicyclo [3.2.1] octane-8-carboxylate methyl [0818] C27H29N7O4. MS (ESI) m / z 516.16 (Μ + 1) +.¹H WR (300 \ IIIz, DMSO) δ 9.07 (s, 1H, NH), 8.45 (s, 1H, NH), 8.36 (s, 1H, NH), 8.26 (s, 1H , ArH), 7.91 (s, 1H, ArH), 7.81 (s, 1H, ArH), 7.31-7.18 (m, 3H, ArH), 3.63 (s, 3H, CH3 ), 3.45-3.20 (m, 3H, 3CH), 2.07 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.23-1.97 (m, 8H , 4CH2).

II-69: 5- (5-methyl-2- (5-methyl-6- (8- (2,2,2-trifluoroacetyl) -8-azabicyclo [3.2.1] octan-3-yl) pyridin-3 -ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0819] C27H26F3N7O3. MS (ESI) m / z 554.14 (Μ + 1) +.

II-70: (R) -5- (2- (6- (4-isopropyl-3-methylpiperazin-1-yl) pyridin-3-ylamino) -5-methyl-pyrimidin-4-ylamino) benzo [d ] oxazol-2 (3H) -one [0820] C25H30N8O2. MS (ESI) m / z 475.09 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 8.68 (s, 1H, NH), 8.26 (s, 1H, NH), 8.23 ​​(s, 1H, NH), 8.17 (s, 1H, ArH), 7.79 (s, br, 2H, ArH), 7.30 (s, br, 2H, ArH), 7.18-7.15 (m, 1H, ArH), 6.65 (d, J = 9.8, 1H, ArH), 3.91-3.80 (m, 1H, CH), 3.58-3.09 (m, 5H, CH, 2CH2), 2.81-2.70 (m, 2H, CH2), 2.05 (s, 3H, CH3), 1.04 (d, J = 6.5, 6H, 2CH3), 0.83 (d, J = 6.5, 3H, CH 3).

II-71: 5- (5-methyl-2- (6- (pyrrolidin-1-yl) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0821] ¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.97 (s, 1H), 9.51 (s, 1H), 8.05-7.91 (m, 3H), 7 , 32 - 7.19 (m, 3H), 6.96 (br s, 1H), 3.48 (br t, J = 6.1, 4H), 2.18 (s, 3H), 2.05 (br t, J = 6.1, 4H); LRMS (M +) m / z 403.99.

II-72: 7-methyl-5- (5-methyl-2- (6- (4-methylpiperazin-1-yl) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) - he [0822] ¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 7.84 - 7 , 81 (m, 2H), 7.27 (s, 1H), 7.13 (s, 1H), 6.77 (d, J = 9.3, 1H), 3.37 (m, 4H, z application on H2O), 2.93 (s, 3H), 2.58 - 2.47 (m, 4H, with application on DMSO), 2.32 (s, 3H), 2.11 (s, 3H); LRMS (M +) m / z 447.11.

II-73: 7-methyl-5- (5-methyl-2- (6-morpholinopyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0823] ¹H NMR (300 MHz, DMSO) δ 11.67 (s, 1H), 9.97 (s, 1H), 9.61 (s, 1H), 8.15 (d, J =

2.2, 1H), 7.82 (s, 1H), 7.59 (br d, J = 8.6, 1H), 7.13 (s, 1H), 7.07 (s, 1H), 6.86 (d, J = 8.6, 1H), 3.74 - 3.71 (m, 4H), 3.45 - 3.42 (m, 4H), 2.30 (s, 3H), 2.17 (s, 3H); LRMS (M +) m / z 434.07.

II-74: 5- (2- (6- (cyclopropylmethylamino) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0824] ¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.86 (s, 1H), 9.32 (s, 1H), 8.33 (br s, 1H), 8.08 ( s, 1H), 7.92 (s, 1H), 7.84 (d, J = 8.4, 1H), 7.32 - 7.29 (m, 3H), 6.94 (d, J = 8.4, 1H), 3.17 (br d, J = 7.0, 2H), 2.17 (s, 3H), 1.19 - 1.10 (m, 1H), 0.60 - 0 , 54 (m, 2H), 0.33-0.29 (m, 2H); LRMS (M +) m / z 404.04.

II-75: 7-fluoro-5- (5-methyl-2- (6- (4-methylpiperazin-1-yl) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) - he [0825] ¹H NMR (300 MHz, DMSO) δ 11.93 (br s, 1H), 8.93 (s, 1H), 8.42 - 8.37 (m, 2H), 7.94 - 7.91 (m , 2H), 7.65 (d, J = 13.6, 1H), 7.22 (s, 1H), 6.87 (d, J = 9.3, 1H), 3.20 - 2.94 (m, 8H), 2.72 (br s, 3H), 2.12 (s, 3H); LRMS (M +) m / z 451.00.

II-76: 7-fluoro-5- (5-methyl-2- (6-morpholinopyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0826] ¹H NMR (300 MHz, DMSO) δ 12.11 (s, 1H), 10.07 (s, 1H), 9.64 (s, 1H), 8.15 (br s,

1H), 7.88 (s, 1H), 7.66 (br d, J = 8.2, 1H), 7.43 - 7.40 (m, 1H), 7.16 (s, 1H), 6.94 (d, J = 9.4,

- 211 1H), 3.83 - 3.62 (m, 4H), 3.57 - 3.36 (m, 4H), 2.18 (s, 3H); LRMS (M +) m / z 438.07.

II-77: 5- (2- (5-bromopyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol2 (3H) -one [0827] ¹H NMR (300 MHz, DMSO) δ 11.86 (br s, 1H), 9.50 (s, 1H), 9.12 (s, 1H), 8.92 (s, 1H), 8.44 ( s, 1H), 8.01 (br s, 1H), 7.43 - 7.38 (m, 3H), 7.23 (br s, 1H), 2.37 (s, 3H); LRMS (M +) m / z 414.86.

II-79: N- (5- (5-methyl-4- (3-methyl-2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridin-2-yl ) methanesulfonamide [0828] ¹H NMR (300 MHz, DMSO) δ 9.08 (s, 1H), 8.52 (s, 1H), 8.45 (s, 1H), 7.91 (d, J = 8.9, 1H) , 7.87 (s, 1H), 7.58 (s, 1H), 7.25 (s, 2H), 6.79 (d, J = 8.9, 1H), 3.28 (s, 3H ), 3.17 (s, 3H), 2.10 (s, 3H).

II-80: 5- (2- (6- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [ 0829] ¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 9.79 (br s, 1H), 8.73 (br s, 1H), 8.37 (br s, 1H), 8, 19 (s, 1H), 7.78 (s, 1H), 7.77 (d, J = 8.2, 1H), 7.31 (d, J = 9.3, 2H), 7.29 ( s, 1H), 7.17 (d, J = 8.2, 1H), 6.42 (d, J = 9.3, 1H).

II-81: N- (1- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridin-2-yl) pyrrolidin- 3-yl) acetamide [0830] ¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H), 9.75 (br s, 1H), 8.14 (s, 1H), 8.02 (br s, 1H), 7.81 (br s, 2H), 7.26-7.22 (m, 4H), 6.84 - 6.62 (m, 1H), 4.35 (dd, J = 8.9, 4.5, 1H ), 2.20 2.12 (m, 2H), 2.12 (s, 3H), 1.98 - 1.88 (m, 2H), 1.82 - 1.77 (m, 2H), 1 , 81 (s, 3H).

II-82: 5- (2- (6- (3- (diethylamino) pyrrolidin-1-yl) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [ 0831] ¹H NMR (300 MHz, DMSO) δ 11.67 (s, 1H), 9.61 (s, 1H), 9.15 (s, 1H), 8.09 (s, 1H),

7.79 (s, 1H), 7.65 (d, J = 8.7, 1H), 7.23 (d, J = 12.1, 2H),), 7.21 (s, 1H), 6.50 (d, J = 8.7, 1H), 4.08 (dd, J = 14.8, 7.2, 1H), 3.84 (t, J = 9.1, 1H), 3 , 60 (t, J = 9.1, 1H), 3.47-3.16 (m, 4H), 2.53 - 2.37 (m, 2H), 2.22 - 2.04 (m, 2H), 2.10 (s, 3H), 1.24 (t, J = 7.0, 6H).

II-83: ​​2,2,2-trifluoro-N- (1- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2- ylamino) pyridin-2-yl) pyrrolidin-3-yl) acetamide [0832] ¹H NMR (300 MHz, DMSO) δ 9.68 (br s, 1H), 8.53 (s, 1H), 8.16 (s, 1H), 8.09 (s, 1H),

7.80 (d, J = 8.9, 1H), 7.75 (s, 1H), 7.21 (d, J = 8.5, 1H), 7.20 (s, 1H), 7, 03 (d, J = 8.5, 1H), 6.32 (d, J = 8.9, 1H), 4.43 (br s, 1H), 3.62 (dd, J = 10.8, 6.5, 1H), 3.45 (dd, J = 10.8, 6.5, 1H), 2.22 (dd, J = 12.9, 7.0, 2H), 2.05 (s , 3H), 2.06 - 1.93 (m, 2H).

II-84: 5- (5-methyl-2- (6- (3-morpholinopyrrolidin-1-yl) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one

II-85: 5- (2- (6- (4-methylpiperazin-1-yl) pyridin-3-ylamino) -5- (trifluoromethyl) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one

- 212 [0833] ¹H NMR (300 MHz, DMSO) δ 11.49 (s, 1H), 9.37 (s, 1H), 8.60 (s, 1H), 8.28 (s, 1H),

8.20 (s, 1H), 7.67 (d, J = 8.7, 1H), 7.22 (d, J = 8.5, 1H), 7.11 (s, 1H), 7, 09 (d, J = 8.5, 2H),

6.71 (d, J = 8.7, 1H), 4.20 (br s, 2H), 3.48 (br s, 2H), 3.05 (br s, 4H), 2.85 (s , 3H).

II-86: 1- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridin-2-yl) pyrrolidin-3 tert-butylylcarbamate [0834] ¹H NMR (300 MHz, DMSO) δ 8.51 (d, J = 9.2, 1H), 8.14 (s, 2H), 7.75 (s, 2H), 7.26 (s, 2H) , 7.09 - 7.03 (m, 1H), 6.27 (d, J = 8.7, 1H), 4.16 - 3.93 (m, -1H), 2.07 - 1.99 (m, 5H), 1.85 (dd, J = 12.1, 7.1, 2H), 1.38 (s, 9H).

II-87: methyl (1- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridin-2-yl) piperidin-3 (S) -tert-butyl-carbamate [0835] ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 9.95 (s, 1H), 9.65 (s, 1H), 8.00 (s, 1H), 7.77 (s , 1H), 7.57 (d, J = 7.8, 1H), 7.21 (d, J = 7.3, 2H), 7.20 (s, 1H), 6.88 (d, J = 7.8, 1H), 4.14 (t, J = 11.2, 2H), 2.88 (t, J = 12.2, 1H), 2.75 (s, 3H), 2.74 (d, J = 12.2, 1H), 2.63 (t, J =

5.6, 1H), 2.13 (s, 3H), 1.74 (br t, J = 10.5, 4H), 1.39 (s, 9H).

II-88: (R) -5- (5-methyl-2- (6- (3- (methylamino) piperidin-1-yl) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [J] oxazol 2 (3H) -on [0836] ¹H NMR (300 MHz, DMSO) δ 8.55 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.81 (d, J = 8.9, 1H) , 7.74 (s, 1H), 7.14 (s, 1H), 7.10 (d, J = 8.5, 1H), 6.96 (d, J = 8.5, 1H), 6 , 63 (d, J = 8.9, 1H), 4.09 (d, J = 11.6, 1H), 3.89 (d, J = 11.6, 1H), 2.79 - 2, 69 (m, 1H), 2.54 - 2.47 (m, 1H), 2.31 (s, 3H), 2.05 (s, 3H), 1.89 (d, J = 13.6, 1H), 1.67 (d, J = 13.6, 1H), 1.42 (d, J = 13.6, 1H), 1.25 - 1.13 (m, 2H).

II-89: (R) -5- (2- (6- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one

II-90: (S) -5- (2- (6- (3- (dimethylamino) pyrrolidin-1-yl) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one

II-91: methyl (1- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridin-2-yl) piperidin-3 (R) -tert-butyl-carbamate [0837] ¹H NMR (300 MHz, DMSO) δ 8.66 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.84 (d, J = 9.1, 1H) , 7.78 (s, 1H), 7.26 (d, J = 8.5, 1H), 7.23 (s, 1H), 7.09 (d, J = 8.5, 1H), 6 , 67 (d, J = 9.1, 1H), 4.09-3.99 (m, 2H), 2.73 (s, 3H), 2.61 - 2.39 (m, 3H), 2 , 04 (s, 3H), 1.71 (d, J = 12.4, 3H), 1.38 (app s, 10H).

II-92: (R) -5- (5-methyl-2- (6- (3- (methylamino) piperidin-1-yl) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol 2 (3H) -on [0838] ¹H NMR (300 MHz, DMSO) δ 8.73 (s, 1H), 8.28 (app s, 2H), 7.84 (d, J = 9.2, 1H),

7.80 (s, 1H), 7.34 (d, J = 8.6, 1H), 7.31 (s, 1H), 7.18 (d, J = 8.6, 1H), 6, 75 (d, J = 9.2, 1H), 4.02 (d, J = 10.4, 1H), 3.62 (d, J = 10.4, 1H), 3.16 - 3.02 (m, 3H), 2.58 (s, 3H), 2.05 (s, 3H), 1.97 (d, J = 11.0, 1H), 1.74 (d, J = 11.5 , 2H), 1.52 (dd, J = 17.1, 8.8, 2H).

- 213 II-94: 5- (2- (6- (3- (cyclopropylmethylamino) pyrrolidin-1-yl) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H )-he

II-95: (S) -5- (2- (6 - ((1-benzylpiperidin-3-yl) (methyl) amino) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one

II-96: 1-ethyl-3- (1- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridinium 2-yl) pyrrolidin-3-yl) urea

II-97: 1-tert-butyl-3- (1- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridin-2-yl) pyrrolidin-3-yl) urea

II-98: 1-benzyl-3- (1- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridinium 2-yl) pyrrolidin-3-yl) urea

II-99: (S) -5- (2- (6- (1-benzylpiperidin-3-ylamino) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one

II-100: (S) -5- (2- (6 - ((1-benzylpiperidin-3-yl) (methyl) amino) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol 2 (3H) -one

II-101: N- (1- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridin-2-yl) pyrrolidine 3-yl) cyclopropanecarboxamide

II-102: N- (1- (5- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) pyridin-2-yl) pyrrolidin- 3-yl) piwalamid

II-103: (S) -5- (5-methyl-2- (6- (methyl (piperidin-3-yl) amino) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H )-he

II-104: (S) -5- (5-methyl-2- (6- (piperidin-3-ylamino) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) - he

II-105: (S) -5- (2- (6- (1-benzylpiperidin-3-ylamino) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -he

II-106: (R) -5- (2- (6 - ((1-benzylpiperidin-3-yl) (methyl) amino) pyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol 2 (3H) -one

II-107: (R) -5- (5-methyl-2- (6- (piperidin-3-ylamino) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) - he

II-108: (R) -5- (5-methyl-2- (6- (methyl (piperidin-3-yl) amino) pyridin-3-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H )-he

II-109: N4- (benzo [d] oxazolin-2 (3H) -on-5-yl) -5-methyl-N2- [2 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) -3-trifluoromethylpyridin-5-yl] -2,4-pyrimidinediamine [0839] ¹H NMR (DMSO d6, 300 MHz): δ 8.99 (s, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H),

7.84 (s, 1H), 7.23 (m, 2H), 7.15 (d, 1H, J = 8.7 Hz), 4.46 (s, 1H), 3.48 (br, 1H ), 3.42 (d, 1H,

J = 9.6 Hz), 3.30 (d, 1H, J = 9.3 Hz), 2.79 (s, 2H), 2.32 (s, 3H), 2.08 (s, 3H) , 1.84 (d, 1H, J =

10.2 Hz), 1.68 (d, 1H, J = 8.7 Hz); LCMS (m / z): 513 (M + H).

- 214 II-110: N4- (benzo [d] oxazolin-2 (3H) -on-5-yl) -N2- [2- (4-ethylpiperazin-1-yl) -3-trifluoromethylpyridin-5-yl] -5-methyl-2,4-pyrimidinediamine [0840] ¹H NMR (DMSO d6, 300 MHz): δ 11.45 (s, 1H), 9.33 (s, 1H), 8.68 (s, 1H), 8.43 (s, 1H), 8.40 (d, 1H), 7.89 (s, 1H), 7.24 (s, 1H), 7.19 (m, 2H), 3.00 (t, 4H), 2.10 (s, 3H) , 1.05 (t, 3H, J = 6.6 Hz); LCMS (m / z): 515 (M + H).

II-111: N4- (benzo [d] oxazolin-2 (3H) -on-5-yl) -N2- [3-fluoro-2- (4-methylpiperazin-1-yl) pyridin-5-yl] -5- methyl-2,4-pyrimidinediamine [0841] ¹H NMR (DMSO d6, 300 MHz): δ 11.52 (br, 1H), 9.10 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 7.96 (d, 1H, J = 15.9 Hz), 7.85 (s, 1H), 7.21 (m, 3H), 3.19 (t, 4H), 2.49 (s, 4H), 2 , 24 (s, 3H), 2.08 (s, 3H); LCMS (m / z): 451 (M + H).

II-112: N4- (benzo [d] oxazolin-2 (3H) -on-5-yl) -N2- {2 - [(8S) -1,4-diazabicyclo [4.3.0] nonan-1-yl] - 3-fluoropyridin-5-yl} -5-methyl-2,4-pyrimidinediamine [0842] ¹H NMR (DMSO d6, 300 MHz): δ 11.51 (br, 1H), 9.09 (s, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 7.95 (dd, 1H, J = 15.9 Hz), 7.85 (s, 1H), 7.21 (m, 3H), 3.73 (d, 1H, J = 11.1 Hz), 3.61 (d, 1H, J = 12.6 Hz), 2.99 (d, 2H, J = 8.7 Hz), 2.84 (t, 1H, J = 11.4 Hz), 2.54 (br , 1H), 2.08 (m, 6H), 1.68 (m, 2H), 1.34 (m, 2H); LCMS (m / z): 477 (M + H).

II-113: N4- (benzo [d] oxazolin-2 (3H) -on-5-yl) -N2- {2 - [(8R) -1,4-diazabicyclo [4.3.0] nonan-1-yl] - 3-fluoropyridin-5-yl} -5-methyl-2,4-pyrimidinediamine LCMS (m / z): 477 (M + H).

II-114: N4- (benzo [d] oxazolin-2 (3H) -on-5-yl) -N2- [2- (4-ethylpiperazin-1-yl) -3-fluoropyridin-5-yl] -5 -methyl-2,4-pyrimidinediamine [0844] ¹H NMR (DMSO d6, 300 MHz): δ 11.67 (s, 1H), 10.18 (br, 1H), 9.50 (br, 2H), 8.04 (s, 1H), 7.89 (s, 1H), 7.76 (d, 1H, J = 13.2 Hz), 7.26 (d, 1H, J = 8.4 Hz), 7.18 (m, 2H), 3.87 (d, 2H, J = 9.6 Hz), 3.54 (d, 2H, J = 8.1 Hz), 3.20-3.09 (m, 6H), 2.13 (s, 3H) , 1.24 (t, 3H, J = 7.5 Hz); ¹⁹F NMR (DMSO d6, 282 MHz): δ -143.33; LCMS (m / z): 465 (M + H).

II-115: N4- (benzo [d] oxazolin-2 (3H) -on-5-yl) -N2- [3-cyano-2 - ((1S, 4S) -5-methyl-2,5-diazabicyclo [2.2 .1] heptan-2-yl) pyridin-5-yl] -5-methyl-2,4-pyrimidinediamine [0845] ¹H NMR (DMSO d6, 300 MHz): δ 11.60 (s, 1H), 9.86 (br, 1H), 9.45 (br, 2H), 8.34 (s, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.25 (d, 1H, J = 8.7 Hz), 7.15 (m, 2H), 4.90 (s, 1H), 4 , 36 (s, 1H), 3.92 (d, 1H, J = 12.9 Hz), 3.72 (d, 1H, J = 11.1 Hz), 3.70 (m, 1H), 3 , 15 (d, 1H), 2.87 (d, 3H, J = 4.8 Hz), 2.12 (s, 5H); LCMS (m / z): 470 (M + H).

II-116: N2- [3-chloro-2- (4-methylpiperazine) pyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5- il) -2,4-pyrimidinediamine [0846] ¹H NMR (300 MHz, DMSO) δ 9.17 (s, 1H), 8.43 (s, 1H), 8.25 (d, 1H), 8.21 (m, 2H),

7.86 (s, 1H), 7.20 (m, 3H), 3.05 (br, 4H), 2.42 (sbr, 4H), 2.20 (s, 3H), 2.08 (s , 3H); LCMS: purity: 94.13%; MS (m / e): 467.23 (M + H).

II-117: 5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N2- [2- (1,3,5-trimethyl-215 3,7 -diazabicyclo [3.3.1] nonan-7-yl) pyridin-5-yl] -2,4-pyrimidinediamine [0847] ¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 10.01 (br, 1H), 9.66 (br, 1H), 8.50 (br, 1H), 8.12 (s , 1H), 7.84 (s, 1H), 7.65 (d, 1H), 7.26 (d, J = 9.0, 2H), 7.09 (d, 1H), 6.97 ( d, J =

9.6, 1H), 3.96 (d, J = 12.0, 2H), 3.38 (d, J = 12.9, 2H), 2.83 (t, 2H), 2.66 ( d, J = 4.5, 3H), 2.13 (s, 3H), 1.48 (q, J = 14.0, 2H), 1.00 (s, 8H); LCMS: purity: 91.39%; MS (m / e): 501.38 (M + H).

II-118: N2- [3-chloro-2- (3-ethyl-3,7-diazabicyclo [3.3.0] octane-7-yl) pyridin-5-yl] -5-methylN4- (2-oxo- 2,3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0848] ¹H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 9.95 (br, 1H), 9.60 (br, 1H), 9.45 (br, 1H), 8.11 (s , 1H), 7.86 (m, 2H), 7.24 (d, 1H), 7.14 (m, 2H), 3.88 (br, 2H), 3.58 (d, J = 11, 1, 2H), 3.41 (m, 2H), 3.21 (t, 2H), 3.13 (t, 2H), 2.96 (m, 1H), 2.74 (m, 1H), 2.12 (s, 3H), 1.21 (t, J = 6.9, 3H); LCMS: purity: 94.05%; MS (m / e): 507.33 (M + H).

II-119: N2- [2- (3-ethyl-3,7-diazabicyclo [3.3.0] octane-7-yl) -3-trifluoromethylpyridin-5-yl] 5-methyl-N4- (2-oxo- 2,3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0849] ¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 9.98 (br, 1H), 9.72 (br, 1H), 9.53 (br, 1H), 8.48 (s , 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.18 (m, 3H), 3.89 (br, 2H), 3.38 - 3.15 (m, 6H), 2.98 (m, 2H), 2.69 (m, 2H), 2.12 (s, 3H), 1.21 (t, J = 7.2, 3H); LCMS: purity: 88.57%; MS (m / e): 541.37 (M + H).

II-120: 5-methyl-N2- [2- (3-methyl-3,7-diazabicyclo [3.3.0] octane-7-yl) pyridin-5-yl] -N4- (2-oxo-2,3- dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0850] ¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.84 (br, 2H), 8.02 (s, 1H), 7.80 (s, 1H), 7.60 (br , 1H), 7.21 (m, 3H), 6.61 (br, 1H), 3.85 (br, 2H), 3.58 - 3.44 (m, 4H), 3.30 (br, 2H), 3.08 (s, 2H), 2.82 (m, 3H), 2.12 (s, 3H); LCMS: purity: 95.06%; MS (m / e): 459.33 (M + H).

II-121: 5-methyl-N2- [2- (octahydroisoindol-1-yl) pyridin-5-yl] -N4- (2-oxo-2,3-dihydro1,3-benzooxazol-5-yl) -2 , 4-pyrimidinediamine [0851] ¹H NMR (300 MHz, DMSO) δ 11.59 (s, 1H), 9.71 (br, 1H), 8.05 (br, 1H), 7.83 (s, 2H), 7.26 (s , 1H), 7.22 (m, 2H), 6.84 (br, 1H), 3.44 (m, 2H), 3.31 (m, 2H), 2.36 (s, 2H), 2 , 12 (s, 3H), 1.59 (m, 2H), 1.39 (m, 6H); LCMS: purity: 92.74%; MS (m / e): 458.30 (M + H).

II-122: N2- [3-chloro-2- (octahydroisoindol-1-yl) pyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5- il) -2,4-pyrimidinediamine [0852] ¹H NMR (300 MHz, DMSO) δ 11.49 (br, 1H), 8.89 (s, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 8.00 (s , 1H), 7.82 (s, 1H), 7.21 (s, 2H), 7.17 (d, J = 9.3, 1H), 3.46 (m, 2H), 3.40 ( m, 2H), 2.17 (s, 2H), 2.07 (s, 3H), 1.52 (m, 4H), 1.35 (m, 4H); LCMS: purity: 84.77%; MS (m / e):

492.27 (M + H).

II-123: N2- (2-methoxypyridin-5-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0853] ¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.98 (s, 1H), 9.62 (s, 1H), 8.08 (d, J =

- 216 2.7, 1H), 7.81 (s, 1H), 7.71 (dd, J = 9.0, 2.7, 1H), 7.24 (d, J = 8.4, 1H ), 7.18 (s, 1H), 7.16 (d, J = 8.7, 1H), 6.75 (d, J = 9.0, 1H), 3.79 (s, 3H), 2.13 (s, 3H); LCMS: purity: 97.58%; MS (m / e): 365.23 (M + H).

II-124: N2- [2- (S-1,4-diazabicyclo [4.3.0] nonan-4-yl) -3-trifluoromethylpyridin-5-yl] -5-methyl-N4- (2-oxo-2,3 -dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0854] ¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 10.06 (br, 1H), 9.94 (br, 1H), 9.61 (br, 1H), 9.08 (br , 1H), 8.64 (s, 1H), 8.27 (s, 1H), 7.92 (s, 1H), 7.19 (m, 3H), 3.82 (m, 1H), 3 , 65 (m, 2H), 3.44 (m, 2H), 3.24 (m, 2H), 3.10 (m, 2H), 2.12 (s, 3H), 2.03 (m, 4H); ¹⁹F NMR (282 MHz, DMSO) δ - 76.17; LCMS: purity: 97.06%; MS (m / e): 527.32 (M + H).

II-125: N2- [2- (1,4-diazabicyclo [3.2.2] nonan-4-yl) -3-fluoropyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro -1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0855] ¹H NMR (300 MHz, DMSO) δ 11.66 (s, 1H), 10.14 (s, 2H), 9.61 (br, 1H), 7.97 (s, 1H), 7.87 (s , 1H), 7.65 (d, J = 14.1, 1H), 7.26 (d, J = 8.4, 1H), 7.17 (s, 1H), 7.13 (d, J = 8.7, 1H), 4.19 (s, 1H), 3.76 (t, J = 5.1, 2H), 3.46 (s, 2H), 3.38 (t, 4H), 2.13 (s, 3H), 2.06 (m, 4H); ¹⁹F NMR (282 MHz, DMSO) δ - 144.17; LCMS: purity: 97.39%; MS (m / e): 477.30 (M + H).

II-126: N2- [2- (4R-hydroxy-2-methylidene-pyrrolidin-1-yl) -pyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol- 5-yl) -2,4-pyrimidinediamine [0856] ¹H NMR (300 MHz, DMSO) δ 9.44 (s, 1H), 8.69 (s, 1H), 8.32 (s, 1H), 7.95 (d, J = 7.2, 1H) , 7.80 (s, 1H), 7.20 (d, J = 9.0, 1H), 6.83 (s, 1H), 5.24 (m, 1H), 4.40 (m, 3H ), 4.22 (m, 1H), 3.56 (m, 1H), 2.06 (s, 3H), 1.95 (m, 1H), 1.79 (m, 1H); LCMS: purity: 87.05%; MS (m / e): 432.35 (M + H).

II-127: 5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5 -yl) -N2- [2- (cis-3,4,5-trimethylpiperazine) pyridine 5-yl] -2,4-pyrimidinediamine [0857]¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 10.01 (br, 1H), 9.69 (br, 1H), 9.32 (br, 1H), 8.08 (s , 1H), 7.81 (s, 1H), 7.60 (d, J = 8.4, 1H), 7.24 (d, J = 8.7, 1H), 7.20 (s, 1H ), 7.14 (d, 1H), 6.95 (d, J = 9.6, 1H), 4.37 (d, J = 12.6, 2H), 3.29 (br, 2H), 2.85 (d, J = 4.8, 3H), 2.13 (s, 3H), 1.37 (d, J = 6.3, 6H); LCMS: purity: 93.68%; MS (m / e): 461.33 (M + H).

II-128: N2- [2- (1,4-diazabicyclo [4.4.0] decan-4-yl) pyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1, 3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0858] ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 10.07 (s, 1H), 9.71 (s, 1H), 9.56 (br, 1H), 8.08 (s , 1H), 7.82 (s, 1H), 7.61 (d, J = 9.0, 1H), 7.24 (d, J = 8.7, 1H), 7.20 (s, 1H) ), 7.14 (d, J = 8.1, 1H), 6.92 (d, J = 9.0, 1H), 4.35 (m, 2H), 3.45 (t, J = 11 , 7, 2H), 3.05 (m, 4H), 2.81 (t, J = 12.6, 1H), 2.13 (s, 3H), 1.82 (m, 4H), 1, 49 (t, 2H); LCMS: purity: 95.73%; MS (m / e): 473.33 (M + H).

II-129: 5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N2- [2- (trans-2,4,5-trimethylpiperazine) pyridine- 5-yl] -2,4-pyrimidinediamine [0859] ¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H), 9.93 (br, 1H), 9.74 (br, 2H), 8.03 (s,

- 217 1H), 7.80 (d, 1H), 7.58 (d, J = 7.5, 1H), 7.18 (m, 3H), 6.83 (d, J = 8.4, 1H), 4.66 (m, 1H), 4.19 (d, J = 14.7, 1H), 3.66 (m, 1H), 3.26 (m, 2H), 2.86 (d , 1H), 2.78 (d, 3H), 2.13 (s, 3H), 1.22 (d, J = 6.6, 3H), 1.16 (d, J = 6.6, 3H ); LCMS: purity: 91.43%; MS (m / e): 461.38 (M + H).

II-130: N2- [2- (trans-2,5-dimethylpiperazine) pyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5- il) -2,4-pyrimidinediamine [0860] ¹H NMR (300 MHz, DMSO) δ 11.73 (s, 1H), 10.07 (s, 1H), 9.71 (s, 1H), 8.82 (br, 2H), 8.04 (s , 1H), 7.81 (s, 1H), 7.58 (d, J = 9.9, 1H), 7.22 (d, J = 8.7, 1H), 7.18 (s, 1H ), 7.14 (d, J = 9.0, 1H), 6.82 (d, J = 9.3, 1H), 4.46 (s, 1H), 3.89 (d, J = 13 , 8, 1H), 3.66 (s, 1H), 3.30 (br, 1H), 3.28 (d, J = 14.1, 1H), 3.08 (d, J = 11.4 , 1H), 2.13 (s, 3H), 1.26 (d, J = 6.3, 3H), 1.13 (d, J = 6.6, 3H); LCMS: purity: 94.96%; MS (m / e): 447.31 (M + H).

II-131: N2- [2- (cis-3,5-dimethylpiperazine) pyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0861] ¹H NMR (300 MHz, DMSO) δ 11.68 (s, 1H), 9.85 (br, 1H), 9.44 (br, 1H), 9.00 (d, 1H), 8.46 (d , 1H), 8.12 (s, 1H), 7.82 (s, 1H), 7.64 (d, J = 8.1, 1H), 7.22 (m, 2H), 7.15 ( d, J = 8.4, 1H), 6.90 (d, J = 9.6, 1H), 4.33 (d, J = 11.7, 2H), 3.27 (m, 2H), 2.68 (t, J = 12.3, 2H), 2.12 (s, 3H), 1.27 (d, J = 6.6, 6H); LCMS: purity: 96.91%; MS (m / e): 447.18 (M + H).

II-132: N2- [2- (R-1,4-diazabicyclo [4.3.0] nonan-4-yl) pyridin-5-yl] -5-methyl-N4- (2-oxo2,3-dihydro- 1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0862] ¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 9.99 (s, 1H), 8.22 (s, 1H), 7.80 (s, 2H), 7.24 (m , 3H), 6.87 (m, 1H), 4.56 (m, 1H), 4.40 (m, 1H), 3.80 (m, 5H), 3.01 (m, 2H), 2 , 10 (s, 3H), 2.00 (m, 4H); LCMS: purity: 95.82%; MS (m / e): 459.25 (M + H).

II-133: 5-methyl-N2- [2- (7-methyl-2,7-diazaspiro [4.4] nonan-2-yl) pyridin-5-yl] -N4- (2-oxo-2,3-dihydro- 1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0863] ¹H NMR (300 MHz, DMSO) δ 11.64 (s, 1H), 9.90 (br, 1H), 8.02 (br, 1H), 7.77 (s, 1H), 7.21 (s , 3H), 6.47 (br, 1H), 3.56 (m, 4H), 3.15 (m, 4H), 2.87 (s, 3H), 2.11 (s, 3H), 1 , 99 (m, 4H); LCMS: purity: 95.44%; MS (m / e): 473.27 (M + H).

II-134: 5-methyl-N2- [2- (3S-methylmorpholino) pyridin-5-yl] -N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4 -pyrimidinediamine [0864] ¹H NMR (300 MHz, DMSO) δ 11.52 (s, 1H), 8.67 (s, 1H), 8.25 (d, J = 4.5, 2H), 7.80 (d, J = 9.6, 1H), 7.78 (s, 1H), 7.32 (d, J = 10.5, 1H), 7.28 (s, 1H), 7.16 (d, J = 8, 7, 1H), 6.60 (d, J = 9.0, 1H), 4.16 (d, 1H), 3.88 (d, J = 7.8, 1H), 3.63 (q, J = 10.2, 3H), 3.46 (t, J = 10.2, 1H), 2.94 (t, J = 12.3, 1H), 2.06 (s, 3H), 1, 03 (d, J = 6.6, 3H); LCMS: purity: 95.68%; MS (m / e): 434.10 (M + H).

II-135: 5-methyl-N2- [2- (2R-methylmorpholino) pyridin-5-yl] -N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4 -pyrimidinediamine [0865] ¹H NMR (300 MHz, DMSO) δ 11.53 (s, 1H), 8.76 (s, 1H), 8.33 (s, 1H), 8.25 (s, 1H),

7.80 (d, J = 9.6, 1H), 7.79 (s, 1H), 7.30 (d, J = 9.3, 1H), 7.29 (s, 1H), 7, 17 (d, J = 8.7, 1H),

6.67 (d, J = 8.4, 1H), 3.94 (d, J = 12.3, 1H), 3.85 (t, J = 11.4, 2H), 3.54 (t , J = 10.5, 2H), 2.67

- 218 (t, J = 12.3, 1H), 2.34 (t, J = 11.1, 1H), 2.06 (s, 3H), 1.14 (d, J = 5.7, 3H); LCMS: purity: 80.08%; MS (m / e): 434.10 (Μ + H).

II-136: N2- [2- (4-isopropylpiperazine) pyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4 -pyrimidinediamine [0866] ¹H WR (300 \ IIIz, DMSO) δ 8.66 (s, 1H), 8.23 ​​(s, 2H), 7.80 (d, J = 10.8, 1H), 7.78 (s, 1H ), 7.29 (d, J = 10.8, 1H), 7.27 (s, 1H), 7.14 (d, J = 8.4, 1H), 6.64 (d, J = 9 , 3, 1H), 4.08 (br, 4H), 2.64 (p, J = 6.0, 1H), 2.06 (s, 3H), 0.98 (d, J = 6.6 , 6H); LCMS: purity: 93.75%; MS (m / e): 461.32 (Μ + H).

II-137: N2- [2- (3-N, N-dimethylamino-8-azabicyclo [3.2.1] acetate-8-yl) pyridin-5-yl] -5-methyl-N4- (2-oxo-2, 3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0867] ¹H WR (300 Ylllz, DMSO) δ 11.72 (s, 1H), 10.00 (br, 1H), 9.70 (br, 1H), 9.12 (br, 1H), 8.02 (s , 1H), 7.81 (s, 1H), 7.64 (d, 1H), 7.26 (d, J = 8.4, 1H), 7.22 (s, 1H), 7.13 ( d, J = 9.3, 1H), 6.89 (d, 1H), 4.58 (s, 2H), 3.63 (s, 1H), 2.65 (d, J = 3.9, 6H), 2.13 (s, 3H), 1.94 (m, 4H), 1.78 (d, J = 7.8, 2H), 1.56 (t, 2H); LCMS: purity: 93.35%; MS (m / e): 487.36 (Μ + H).

II-138: 5-methyl-N2- [2- (2S-methylmorpholino) pyridin-5-yl] -N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4 -pyrimidinediamine [0868] ¹H WR (300 ΜΗ /, DMSO) δ 11.52 (s, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 7.79 ( m, 2H), 7.28 (m, 2H), 7.17 (d, J = 8.7, 1H), 6.67 (d, J = 9.0, 1H), 3.94 (d, J = 12.0, 1H),

3.86 (t, J = 11.4, 2H), 3.54 (t, J = 10.2, 2H), 2.67 (t, J = 12.0, 1H), 2.35 (t , J = 11.1, 1H), 2.07 (s, 3H), 1.14 (d, J = 6.0, 3H); LCMS: purity: 94.46%; MS (m / e): 434.20 (Μ + H).

II-139: 5-methyl-N2- {2 - [(1R, 4R) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl] pyridin-5-yl} N4- (2-oxo -2,3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0869] ¹H WR (300 Ylllz, DMSO) δ 11.56 (s, 1H), 8.96 (br, 1H), 8.65 (br, 1H), 8.12 (d, 1H), 7.76 (s , 1H), 7.70 (d, 1H), 7.27 (s, 2H), 7.17 (d, J = 9.0, 1H), 6.48 (d, 1H), 4.72 ( s, 1H), 4.61 (s, 1H), 3.74 (d, J = 7.5, 1H), 3.60 (d, J = 7.5, 1H), 3.41 (d, J = 9.6, 1H), 3.17 (d, J = 9.6, 1H), 2.07 (s, 3H), 1.86 (q, J = 9.3, 2H); LCMS: purity: 96.51%; MS (m / e): 432.22 (Μ + H).

II-140: N2- (2,3-dimethoxypyridin-5-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4- pyrimidinediamine [0870] ¹H WR (300 Ylllz, DMSO) δ 11.70 (s, 1H), 9.50 (br, 2H), 7.75 (s, 1H), 7.42 (s, 1H),

7.27 (d, 1H), 7.23 (s, 2H), 6.80 (s, 1H), 3.59 (s, 3H), 3.30 (s, 3H), 2.13 (s , 3H); LCMS: purity: 87.99%; MS (m / e): 395.21 (Μ + H).

II-141: N2- (2-methoxy-3-methylpyridin-5-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4- pyrimidinediamine [0871] ¹HW (300 \ IIIz, DMSO) δ 8.55 (s, 1H), 8.30 (s, 1H), 7.80 (s, 2H), 7.35 (s, 1H),

7.27 (d, J = 9.6, 1H), 7.26 (s, 1H), 7.18 (d, J = 8.7, 1H), 3.17 (s, 3H), 2, 06 (s, 3H), 1.92 (s, 3H); LCMS: purity: 90.12%; MS (m / e): 379.18 (Μ + H).

II-142:

N2- [2- (2-hydroxy) ethoxypyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3- 219 benzoxazol-5-yl) -2,4- pyrimidinediamine [0872] ¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.87 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 7.96 (d , J = 9.3, 1H), 7.82 (s, 1H), 7.29 (s, 2H), 7.18 (d, J = 8.4, 1H), 6.62 (d, J = 8.4, 1H), 4.78 (t, 1H), 4.15 (t, J = 5.1, 2H), 3.66 (q, J = 4.8, 2H), 2.07 (s, 3H); LCMS: purity: 95.34%; MS (m / e): 395.19 (M + H).

II-143: N2- [4-methyl-2- (4-methylpiperazine) pyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine [0873] ¹H NMR (300 MHz, DMSO) δ 11.68 (br, 1H), 9.63 (br, 2H), 8.00 (s, 1H), 7.73 (br, 1H), 7.16 (br , 2H), 6.89 (s, 1H), 4.36 (d, J = 9.0, 2H), 3.52 (d, 2H), 3.03 (d, 4H), 2.84 ( s, 3H), 2.11 (s, 3H), 2.09 (s, 3H); LCMS: purity: 90.64%; MS (m / e): 447.27 (M + H).

II-144: N2- (2-isopropoxypyridin-5-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0874] ¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 10.10 (s, 1H), 9.76 (s, 1H), 8.05 (d, J =

2.7, 1H), 7.82 (s, 1H), 7.66 (dd, J = 9.0, 2.7, 1H), 7.25 (d, J = 8.1, 1H), 7.15 (d, J = 12.0, 2H), 6.69 (d, J = 9.3, 1H), 5.13 (p, J = 6.0, 1H), 2.13 (s , 3H), 1.24 (d, J = 6.3, 6H); LCMS: purity: 100%; MS (m / e): 394.04 (M + H).

II-145: N2- [2- (2-methoxy) ethoxypyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4 -pyrimidinediamine [0875] ¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 8.87 (s, 1H), 8.30 (d, J = 6.9, 2H), 7.96 (d, J = 7.8, 1H), 7.83 (s, 1H), 7.30 (d, J = 7.5, 2H), 7.19 (d, J = 8.4, 1H), 6.63 ( d, J = 8.4, 1H), 4.26 (t, J = 4.2, 2H), 3.60 (t, J = 4.5, 2H), 3.26 (s, 3H), 2.06 (s, 3H); LCMS: purity: 85.13%; MS (m / e): 409.26 (M + H).

II-146: N2- [2- (1-aminocarbonyl-1-methyl) ethoxypyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine [0876] LCMS: purity: 98.61%; MS (m / e): 436.25 (M + H).

II-147: N2- (2-methoxy-3-trifluoromethylpyridin-5-yl) -5-methyl-N4- (2-oxo-2,3-dihydro1,3-benzooxazol-5-yl) -2,4- pyrimidinediamine [0877] LCMS: purity: 96.93%; MS (m / e): 433.22 (M + H).

II-148: N2- [2- (3-hydroxy) propoxypyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4 -pyrimidinediamine [0878] LCMS: purity: 85.08%; MS (m / e): 409.29 (M + H).

II-149: N2- [2- (3-methoxy) propoxypyridin-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4 -pyrimidinediamine [0879] LCMS: purity: 98.76%; MS (m / e): 423.22 (M + H).

II-150: 5- (2- (6- (1,4-diazabicyclo [3.2.2] nonan-4-yl) -5-chloropyridin-3-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d ] oxazol-2 (3H) -one

- 220 II-151: 5- [5-methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) pyrimidin-2-ylamino] pyridin-2-carboxylic acid cyclobutylamide [0880] ¹H NMR (DMSO, 300 MHz): δ 9.61 (s, 1H), 8.77 (s, 1H), 8.57 (d, J = 8.6, 1H), 8.49 (s, 1H ), 8.39 (d, J = 8.6, 1H), 8.33 (d, J = 11.1, 1H), 7.91 (d, J = 9.1, 1H), 7.76 (d, J = 8.7, 1H), 7.66 (d, J = 8.5, 1H), 7.41 (s, 1H), 7.25 (s, 1H), 6.95 (d , J = 8.5, 1H), 4.39 (dt, J = 8.5, 16.9, 2H), 2.08 (s, 3H), 1.60 (m, 5H) ppm; MS (ES) 432 (M + H);

II-152: N2- (5-methoxypyridin-3-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine [0881] ¹H NMR (300 MHz, DMSO) δ 9.38 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 8.38 (s, 1H), 7.32 (m , 4H), 6.85 (s, 2H), 3.91 (s, 3H), 2.29 (s, 3H); LCMS: purity: 100%; MS (m / e): 365.37 (MH +).

II-153: N2- (2,3-dimethylpyridin-5-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzooxazolbenzoxazol-5-yl) -2,4-pyrimidinediamine [ 0882] ¹H NMR (300 MHz, DMSO) δ 11.24 (br, 1H), 9.00 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.90 (s , 1H), 7.86 (s, 1H), 7.28 (d, J = 7.5, 1H), 7.27 (s, 1H), 7.21 (d, J = 9.3, 1H ), 2.26 (s, 3H), 2.07 (s, 3H), 1.96 (s, 3H); LCMS: purity: 97.66%; MS (m / e): 363.37 (MH +).

III-1: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (isoindolin-5-yl) -5-methylpyrimidine-2,4-diamine [0883] MS (ES) 375 , 23 (M + H); ¹H NMR (300 MHz, DMSO) δ 9.06 - 8.84 (m, 1H), 8.46 8.21 (m, 1H), 7.94 - 7.75 (m, 2H), 7.74 - 7.49 (m, 2H), 7.49 - 7.26 (m, 2H), 7.27 - 6.92 (m, 2H), 3.88 (m, 4H), 2.07 (s , 3H) ppm.

III-2: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (2-hydroxyisoindolin-5-yl) -5-methylpyrimidine-2,4-diamine [0884] MS (ES) 391.38 (M + H), 389.37 (MH);

III-3: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (2-tert-butoxoxycarbonylisoindolin-5-yl) -5-methylpyrimidine-2,4-diamine [0885] MS (ES) 475.06 (M + H), 473.20 (MH); ¹H NMR (300 MHz, DMSO) δ 9.01-8.81 (m, 1H), 8.37 - 8.21 (m, 1H), 7.75 (m, 2H), 7.54 (m, 2H), 7.29 (m, 2H), 7.18 - 6.98 (m, 2H), 3.78 (m, 4H), 2.11 (s, 3H), 1.51 (s, 9H ) ppm.

III-4: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (2-methylisoindolin-5-yl) -5-methylpyrimidine-2,4-diamine [0886] MS (ES) 389.08 (M + H), 3387.18 (MH).

III-5: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (2-ethylisoindolin-5-yl) -5-methylpyrimidine-2,4-diamine MS (ES) 403.15 (M + H), 401.77 (MH).

III-6: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (2-n-propylisoindolin-5-yl) -5-methyl-221 pyrimidine-2,4- diamine MS (ES) 417.50 (M + H), 415.45 (MH).

III-7: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (2-cyclopropylmethylisisoindolin-5-yl) -5-methylpyrimidine-2,4-diamine MS (ES ) 429.11 (M + H), 427.23 (MH).

III-8: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (2-isobutylisoindolin-5-yl) -5-methylpyrimidine-2,4-diamine [0890] MS (ES) 431.15 (M + H), 429.12 (MH).

III-9: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (2-isopentylisoindolin-5-yl) -5-methylpyrimidine-2,4-diamine [0891] MS (ES) 445.10 (M + H), 443.24 (MH).

III-10: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (2-cyclopentylmethylisoindolin-5-yl) -5-methylpyrimidine-2,4-diamine [0892] MS (ES ) 457.12 (M + H), 455.24 (MH).

III-11: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (2- (bicyclo [2.2.1] heptan-2-ylmethyl) isoindolin-5-yl) - 5-methylpyrimidine-2,4-diamine [0893] MS (ES) 481.10 (M + H), 479.26 (MH).

III-12: 5- [2- (2-acetyl-2,3-dihydro-1H-isoindol-5-ylamino) -5-methylpyrimidin-4-ylamino] -3H-benzooxazol-2-one [0894] ¹H NMR (DMSO, 300 MHz): δ 8.94 - 9.12 (m, 1H), 8.24 - 8.45 (m, 1H), 8.14 (s, 1H),

7.87 (br. P., 1H), 7.65 - 7.81 (m, 1H), 7.47 - 7.62 (m, 1H), 7.19 - 7.37 (m, 3H) , 7.09 (t, J = 6.7 Hz, 1H), 4.36 - 4.92 (m, 4H), 1.97 - 2.13 (m, 6H) ppm; MS (ES) 417 (M + H).

III-13: N- {2- [2- (2,2-dimethylpropionyl) -2,3-dihydro-1H-isoindol-5-ylamino] -5-methylpyrimidin-4-yl} -N- [3- ( 2,2-dimethylpropionyl) -2-oxo-2,3-dihydrobenzoxazol-5-yl] 2,2-dimethylpropionamide [0895] MS (ES) 627 (M + H)

III-14: 5- [2- (2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-ylamino) -5-methylpyrimidin-4-ylamino] -3H-benzooxazol-2-one [0896] MS (ES) 453 (M + H)

IV-1: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (7- (pyrrolidin-1-yl) -6,7,8,9-tetrahydro-5Hbenzo [ 7] annulen-2-yl) -5-methylpyrimidine-2,4-diamine. MS (ES) 471.16 (M + H), 469.26 (MH); ¹H NMR (300 MHz, DMSO) δ 11.87 (s, 1H),

10.58 (s, 1H), 9.87 - 9.62 (m, 1H), 7.92 (s, 2H), 7.29 (s, 2H), 7.22 (s, 2H), 7 , 01 (s, 1H), 3.52 3.26 (m, 1H), 3.21 - 2.93 (m, 4H), 2.81 - 2.53 (m, 2H), 2.44 - 2.17 (m, 2H), 2.12 (s, 3H), 2.05

- 1.65 (m, 4H), 1.41 - 1.11 (m, 4H) ppm.

- 222 IV-2: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6,7,8,9-tetrahydro-5H-benzo [7] annulen-5on- 3-yl) -5-methylpyrimidine-2,4-diamine MS (ES) 416.08 (M + H), 414.16 (MH); ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 10.57 (s, 1H), 9.81 (s, 1H), 7.89 (s, 1H), 7.69 (s , 1H), 7.56 (s, 1H), 7.45 (d, J = 8.2, 1H), 7.35 6.99 (m, 3H), 2.86 (m, 2H), 2 , 59 (m, 2H), 2.13 (s, 3H), 1.65 (m, 4H) ppm.

IV-3: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (6- (4-methylpiperazin-1-yl) pyridazin-3-yl) -5-methylpyrimidine-2, 4-diamine [0899] ¹H NMR (300 MHz, DMSO) δ 9.10 (s, NH), 8.39 (s, NH), 8.26 (d, NH), 8.21 (s, 1H), 7.95 (t , J = 13.8, 1H), 7.73 (s, 1H), 7.47 - 7.25 (m, 2H), 7.18 (d, J = 10.4, 1H), 3.20 -3.60 (m, 8H), 2.26 (s, 3H), 2.18 (s, 3H).

IV-4: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (1H-indazol-6-yl) -5-methylpyrimidine-2,4-diamine [0900] MS (m / e): 374.17 (M + H); ¹H NMR (300 MHz, DMSO) δ 9.08 (s, 1H), 8.29 (s, 1H),

8.24 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.47 (d, J = 9.0, 1H), 7.42 (s, 1H) , 7.19 (d, J = 8.4, 2H), 7.09 (d, J = 8.7, 1H), 2.11 (s, 3H); LCMS: purity: 94.20%.

IV-5: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (1,2-benzisoxazol-6-yl) -5-methylpyrimidine-2,4-diamine [0901 ] LCMS: purity: 88.71%; MS (m / e): 375.25 (M + H);¹H NMR (300 MHz, DMSO) δ 11.64 (s, 1H), 10.80 (s, 1H), 9.74 (br, 1H), 7.91 (s, 1H), 7.28 (m , 7H), 2.13 (s, 3H).

IV-6: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (1H-indazol-5-yl) -5-methylpyrimidine-2,4-diamine [0902] LCMS: purity : 99.84%; MS (m / e): 374.21 (M + H);¹H NMR (300 MHz, DMSO) δ

11.24 (br, 1H), 8.93 (s, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 7.65 (s , 1H), 7.43 (d, J = 9.0, 1H), 7.30 (m, 3H), 7.22 (d, J = 8.7, 1H), 2.09 (s, 3H ).

IV-7: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- [2- (piperazine) pyridin-4-yl] -5-methylpyrimidine-2,4-diamine [ 0903] LCMS: purity: 96.84%; MS (m / e): 419.34 (M + H);¹H NMR (300 MHz, DMSO) δ 11.98 (br, 1H), 11.70 (br, 1H), 7.83 (s, 1H), 7.60 (t, J = 5.7, 1H) , 7.43 (m, 2H), 7.27 (m, 2H),

6.28 (d, 1H), 5.97 (s, 1H), 3.74 (br, 4H), 2.11 (s, 3H).

IV-8: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- [2- (4-methylpiperazine) pyridin-4-yl] -5-methylpyrimidine-2,4-diamine [ 0904] LCMS: purity: 94.61%; MS (m / e): 433.34 (M + H);¹H NMR (300 MHz, DMSO) δ

12.25 (br, 1H), 11.74 (s, 1H), 9.42 (s, 1H), 8.32 (s, 1H), 7.68 (d, 1H), 7.55 (br , 1H), 7.31-7.25 (m, 3H), 6.31 (d, 1H), 6.00 (s, 1H), 4.32 (d, 2H), 3.90 (t, 4H), 3.39 (s, 3H), 2.26 (s, 3H).

IV-9: N4- (benzo [d] oxazol-2 (3H) -on-5-yl) -N2- (3-methyl-1,2-benzisoxazol-5-yl) -5-methylpyrimidine-2,4-diamine [0905] LCMS: purity: 100%; MS (m / e): 389.26 (M + H);¹H NMR (300 MHz, DMSO) δ

- 223 11.48 (br, 1H), 9.22 (s, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.70 (d, J = 8.7, 1H), 7.49 (d, J = 8.7, 1H), 7.34 (d, 2H), 7.21 (d, J = 9.0, 1H) , 2.21 (s, 3H), 2.10 (s, 3H).

IV-10: (Z) -2-methyl-9- [5-methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) pyrimidin-2-ylamino] -3,6-dihydro-2H-benzo [c] azocin-1-one [0906] ¹H NMR (DMSO-d6) δ: 11.55 (br. S., 1H), 9.08 (s, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7, 87 (s, 1H), 7.66 (s, 1H), 7.54 (d, J = 6.6 Hz, 1H), 7.23 - 7.33 (m, 1H), 7.17 (d , J = 8.5 Hz, 1H),

6.89 (d, J = 8.3 Hz, 1H), 5.92 (d, J = 5.2 Hz, 1H), 5.64 (br. P., 1H), 2.84 - 3, 02 (m, 4H), 2.08 (m, 6H) ppm; MS (ES) 443 (M + H);

IV-11: 5- [2- (2,2-difluoro-benzo [1,3] dioxol-4-ylamino) -5-methylpyrimidin-4-ylamino] 3H-benzooxazol-2-one [0907] ¹H NMR (DMSO, 300 MHz): δ 11.70 (s, 1H), 10.24 (br. P., 1H), 9.65 (br. P., 1H), 7.90 (s, 1H) ), 7.02 - 7.33 (m, 6H), 2.14 (s, 3H) ppm; MS (ES) 414 (M + H).

IV-12: 5- [2- (9-Isopropylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino) -5-methylpyrimidin-4-ylamino] -3H-benzooxazol-2-one [0908] ¹H NMR (DMSO, 300 MHz): δ 11.83 (s, 1H), 10.62 (br. P., 1H), 9.75 (br. P., 1H), 8.86 (br. S. ., 1H), 7.93 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.26 - 7.33 (m, 1H), 7.22 (s, 1H). ), 7.15 (br. P., 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.25 (br. P., 1H), 3.27 (br. P. , 1H), 2.83 (br. P., 2H), 2.43 2.53 (m, 2H), 2.13 (s, 3H), 1.95 (d, J = 9.4 Hz, 2H), 1.57 - 1.77 (m, 2H), 1.20 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.3 Hz, 3H) ppm; MS (ES) 459 (M + H).

IV-13: 5- {2- [9- (3-diethylaminopyrrolidin-1-yl) -6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino] -5-methylpyrimidin-4-ylamino} -3H- benzooxazol-2-one [0909] ¹H NMR (DMSO, 300 MHz): δ 10.70 (s, 1H), 10.16 (s, 1H), 9.82 (s, 1H), 7.93 (s, 1H), 7.67 ( d, 1H), 7.33 (s, 1H), 7.18 - 6.79 (m, 3H), 4.15 - 3.77 (m, 4H), 3.82 - 3.52 (m, 1H), 3.57 3.31 (m, 4H), 2.70 - 2.43 (m, 2H), 2.45 - 2.27 (m, 1H), 2.11 (s, 3H), 1.94-1.57 (m, 2H), 1.19 (s, 6H) ppm; MS (ES) 542 (M + H).

IV-14: 2-methyl-9- [5-methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) pyrimidin-2-ylamino] -3,4,5,6-tetrahydro-2H-benzo [c] azocin-1-on [0910] ¹H NMR (DMSO, 300 MHz): δ 11.75 - 11.32 (m, 1H), 9.03 (s, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 7.57 (d, J = 9.7, 2H), 7.30 (d, J = 3.9, 1H), 7.17 (d, J = 8.5 , 1H), 6.95 (d, J = 8.3, 1H), 3.25 - 2.99 (m, 2H), 2.95 (s, 3H), 2.77 - 2.55 (m , 2H), 2.42 - 2.21 (m, 2H), 2.07 (s, 3H), 1.85 - 1.47 (m, 2H), 1.49 - 1.12 (m, 2H ) ppm; MS (ES) 445 (M + H).

IV-15: 6- [5-methyl-4- (2-oxo-2,3-dihydrobenzoxazol-5-ylamino) pyrimidin-2-ylamino] 3,4-dihydro-2H-isoquinolin-1-one [0911] ¹H NMR (DMSO, 300 MHz): δ 11.71 (s, 1H), 10.49 (s, 1H), 9.79 (s, 1H), 7.93 (d, J = 21.2, 1H ), 7.72 (s, 1H), 7.54 (s, 1H), 7.23 (d, J = 6.2, 1H), 7.14 (s, 1H), 2.82 (s, 1H), 2.48 (s, 1H), 2.14 (s, 2H), 1.01 (d, J = 6.1, 1H) ppm; MS (ES) 403 (M + H).

IV-16: 5- [2- (2,2-dioxo-1H-benzo [e] [1.3.4] oxatiazin-7-ylamino) -5-methylpyrimidin-4- 224 ylamino] -3H-benzooxazol-2- he [0912] ¹H NMR (DMSO, 300 MHz): δ 11.96 - 11.53 (m, 1H), 10.61 - 10.24 (m, 1H), 9.99 9.56 (m, 1H), 7, 87 (s, 1H), 7.46 - 7.12 (m, 2H), 7.11 - 6.86 (m, 1H), 6.71 (s, 1H), 5.04 (s, 2H) , 2.12 (s, 3H) ppm; MS (ES) 441 (M + H).

IV-17: 5- [2- (2,2-dimethylbenzo [1,3] dioxol-5-ylamino) -5-methylpyrimidin-4-ylamino] 3H-benzooxazol-2-one [0913] ¹H NMR (DMSO, 300 MHz): δ 11.74 (s, 1H), 10.37 (s, 1H), 9.91 (s, 1H), 7.83 (s, 1H),

7.28 (d, J = 8.5, 1H), 7.19 (s, 1H), 7.11 (d, J = 10.2, 1H), 6.95 (s, 1H), 6, 70 (d, J = 8.5, 1H), 6.59 (d, J = 10.3, 1H), 2.12 (s, 3H), 1.57 (s, 6H) ppm; MS (ES) 406 (M + H).

IV-18: (Z) -5- (5-methyl-2- (1-oxo-2,3-dihydro-1H-benzo [c] azepin-7-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol 2 (3H) -one [0914] C22H18N6O3. MS (ESI) m / z 415.09 (M + 1)⁺.

IV-19: (Z) -5- (5-methyl-2- (2-methyl-1-oxo-2,3-dihydro-1H-benzo [c] azepin-7-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0915] C23H20N6O3. MS (ESI) m / z 429.11 (M + 1)⁺.

IV-20: (Z) -5- (5-methyl-2- (2-methyl-1-oxo-2,3-dihydro-1H-benzo [c] azepin-7-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0916] C23H20N6O3. MS (ESI) m / z 429.11 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.71 (s, 1H, NH), 10.28 (s, 1H, NH), 9.95 (s, 1H, NH), 7.93 (s, 1H, ArH), 7.67 (d, J = 13.0, 1H, ArH), 7.44 (s, 1H, ArH), 7.32 (m, 2H, ArH), 7.23-7.10 ( m, 2H, ArH), 6.27 (m, 2H, 2CH), 3.55 (d, J = 5.9, 2H, CH2), 3.02 (s, 3H, CH3), 2.14 ( s, 3H, CH 3).

IV-21: 5- (5-methyl-2- (2-methyl-1-oxo-2,3,4,5-tetrahydro-1H-benzo [c] azepin-7-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0917] C23H22N6O3. MS (ESI) m / z 431.12 (M + 1)⁺. ¹H NMR (300 MHz, DMSO) δ 11.65 (s, 1H, NH), 9.25 (s, 1H, NH), 8.12 (s, 1H, NH), 7.89 (s, 1H, ArH), 7.54 (m, 1H, ArH), 7.48-7.32 (m, 2H, ArH), 7.25-7.19 (m, 2H, ArH), 7.04 (d, J = 8.7, 1H, ArH), 3.09 (t, J = 5.8, 2H, CH2), 2.98 (s, 3H, CH3), 2.34 (t, J = 6.3 , 2H, CH2), 2.08 (s, 3H, CH3), 1.90 - 1.76 (m, 2H, CH2).

IV-22: 5.5 '- (5-methylpyrimidine-2,4-diyl) bis (azanediyl) dibenzo [d] oxazol-2 (3H) -one [0918] ¹H NMR (300 MHz, DMSO) δ 11.69 (s, 1H), 11.62 (s, 1H), 9.94 (s, 1H), 9.41 (s, 1H), 7.86 (s , 1H), 7.32 (br s, 3H), 7.25 - 7.15 (m, 3H), 2.19 (s, 3H); LRMS (M +) m / z 390.97.

IV-23: 5- (5-methyl-2- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-8-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol 2 (3H) -on [0919] ¹H NMR (300 MHz, DMSO) δ 11.70 (s, 1H), 10.02 (br s, 1H), 9.59 (br s, 1H), 9.49 (s, 1H), 7.88 (s, 1H), 7.29 - 7.24 (m, 4H), 7.11 (d, J = 8.0, 1H), 6.98 (s, 1H), 2.66 (br t, J = 6.2, 2H), 2.19 (s, 3H), 2.16 - 2.09 (m, 4H); LRMS (M +) m / z 417.06.

IV-24:

5- (5-methyl-2- (2-oxo-1,2,3,4-tetrahydroquinolin-7-ylamino) pyrimidin-4-yl-amino) benzo [d] oxazol-2 (3H) -one [ 0920] ¹H NMR (300 MHz, DMSO) δ 11.76 (s, 1H), 10.13 (s, 1H), 10.09 (s, 1H), 9.59 (s, 1H), 7.86 (s , 1H), 7.34 - 7.27 (m, 3H), 7.10 (d, J = 8.0, 1H), 7.04 (d, J = 8.0, 1H), 6.77 (s, 1H), 2.85 (t, J = 7.4, 2H), 2.46 (t, J = 7.4, 2H), 2.19 (s, 3H); LRMS (M +) m / z 403.00.

IV-25: 6- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) -2H-benzo [b] [1,4] oxazin-3 (4H) -one [0921] ¹H NMR (300 MHz, DMSO) δ 11.76 (s, 1H), 10.76 (s, 1H), 10.05 (s, 1H), 9.59 (s, 1H), 7.84 (s , 1H), 7.30 - 7.28 (m, 3H), 7.07 (dd, J = 8.6, 2.2, 1H), 6.87 (d, J = 8.6, 1H) , 6.83 (br s, 1H), 4.58 (s, 2H), 2.18 (s, 3H); LRMS (M +) m / z 405.00.

IV-26: 5- (2- (3,3-dimethyl-2-oxoindolin-6-ylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0922] ¹H NMR (300 MHz, DMSO) δ 11.83 (s, 1H), 10.37 (s, 1H), 10.11 (s, 1H), 9.70 (s, 1H), 7.84 (s , 1H), 7.32 (d, J = 8.4, 1H), 7.27 - 7.25 (m, 3H), 7.21 (dd, J = 8.2, 2.0, 1H) , 6.79 (d, J = 8.2, 1H), 2.18 (s, 3H), 1.12 (s, 6H); LRMS (M +) m / z 417.05.

IV-27: 5- (5-methyl-2- (1-methyl-2-oxoindolin-5-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0923] ¹H NMR (300 MHz, DMSO) δ 11.80 (s, 1H), 10.29 (s, 1H), 9.78 (s, 1H), 7.87 (s, 1H), 7.40 - 7 , 37 (m, 2H), 7.27 - 7.24 (m, 3H), 6.93 (d, J = 8.2, 1H), 3.43 (s, 2H), 3.13 (s , 3H), 2.19 (s, 3H); LRMS (M +) m / z 403.98.

IV-28: 5- (5-methyl-2- (1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-5-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol 2 (3H) -on [0924] ¹H NMR (300 MHz, DMSO) δ 11.73 (s, 1H), 10.92 (s, 1H), 10.13 (s, 1H), 9.63 (s, 1H), 7.80 (s , 1H), 7.32 - 7.28 (m, 3H), 7.06 - 7.01 (m, 3H), 3.31 (s, 3H), 2.18 (s, 3H); LRMS (M +) m / z 404.00.

IV-29: 5- (5-methyl-2- (2-oxo-2,3-dihydro-1H-benzo [d] imidazol-5-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -on [0925] ¹H NMR (300 MHz, DMSO) δ 11.78 (s, 1H), 10.68 (s, 2H), 10.14 (s, 1H), 9.66 (s, 1H), 7.79 (s , 1H), 7.31 - 7.29 (m, 3H), 6.99 (d, J = 8.1, 1H), 6.94 (s, 1H), 6.87 (d, J = 8 , 1, 1H), 2.18 (s, 3H); LRMS (M +) m / z 389.96.

IV-30: 5- (5-methyl-2- (1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-8-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0926] ¹H NMR (300 MHz, DMSO) δ 11.69 (s, 1H), 10.16 (s, 1H), 9.73 (s, 1H), 7.92 (s, 1H), 7.49 (s , 1H), 7.30 - 7.23 (m, 3H), 7.17 (br s, 2H), 2.96 (s, 3H), 2.60 (t, J = 6.5, 2H) , 2.19 (s, 3H), 2.17-2.12 (m, 2H), 2.09-2.02 (m, 2H); LRMS (M +) m / z 431.08.

IV-31: 5- (5-methyl-2- (2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol 2 (3H) -on [0927] ¹H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 9.20 (s, 1H), 8.93 (s, 1H), 8.32 (s, 1H),

- 226 7.84 (s, 1H), 7.52 (s, 1H), 7.38 (d, J = 8.6, 1H), 7.29 (d, J = 8.6, 2H), 7.21 (d, J = 8.6, 1H),

6.71 (d, J = 8.6, 1H), 2.40 (t, J = 7.1, 2H), 2.11 - 1.90 (m, 7H).

IV-32: 7- (5-methyl-4- (2-oxo-2,3-dihydrobenzo [d] oxazol-5-ylamino) pyrimidin-2-ylamino) -2H-benzo [b] [1,4] oxazin-3 (4H) -one [0928] ¹H NMR (300 MHz, DMSO) δ 11.72 (s, 1H), 10.63 (s, 1H), 10.25 (s, 1H), 9.75 (s, 1H), 7.85 (s , 1H), 7.29 (d, J = 8.5, 1H), 7.21 (s, 1H), 7.14 (d, J = 8.5, 1H), 7.11 (s, 1H ), 6.85 (d, J = 8.5, 1H), 6.73 (d, J = 8.5, 1H), 4.42 (s, 2H), 2.12 (s, 3H).

IV-33: 5- (5-methyl-2- (2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0929] ¹H NMR (300 MHz, DMSO) δ 11.75 (s, 1H), 10.08 (s, 1H), 10.09 (s, 1H), 9.66 (s, 1H), 7.82 (s , 1H), 7.29 (d, J = 9.0, 1H), 7.22 (app s, 2H), 7.21 (d, J = 8.5, 1H), 7.10 (d, J = 8.5, 1H), 6.72 (d, J = 8.5, 1H), 2.60 (t, J = 7.4, 2H), 2.35 (t, J = 7.4 , 2H), 2.12 (s, 3H).

IV-34: 5- (5-methyl-2- (1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepin-7-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0930] ¹H NMR (300 MHz, DMSO) δ 11.79 (s, 1H), 10.39 (s, 1H), 9.78 (s, 1H), 7.90 (s, 1H), 7.34-7 , 15 (m, 6H), 3.14 (s, 3H), 2.31 (t, J = 6.6, 2H), 2.13 (s, 3H), 2.04 (t, J = 6 , 6, 2H), 1.86 (t, J = 6.6, 2H).

IV-35: 5-methyl-N2- (3,4-methylenedioxy) phenyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine [0931] ¹H NMR (300 MHz, DMSO) δ 10.58 (br, 1H), 8.84 (s, 1H), 8.30 (s, 1H), 7.81 (s, 1H), 7.36 (s , 1H), 7.25 (s, 2H), 7.17 (d, J = 9.6, 1H), 6.95 (d, J = 8.7, 1H), 6.67 (d, J = 8.4, 1H), 5.86 (s, 2H), 2.07 (s, 3H); LCMS: purity: 87.13%; MS (m / e): 378.23 (M + H).

IV-36: N2- (2,2-difluoro-2H-1,3-benzodioxol-5-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl ) -2,4-pyrimidinediamine [0932] ¹H NMR (300 MHz, DMSO) δ 9.21 (s, 1H), 8.40 (s, 1H), 7.85 (s, 2H), 7.20 (s, 2H), 7.17 (s , 2H), 7.14 (m, 1H), 2.08 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ -65.40; LCMS: purity: 95.27%; MS (m / e): 414.22 (M + H).

IV-37: N2- (3,4-ethylenedioxy) phenyl-5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine [0933] ¹H NMR (300 MHz, DMSO) δ 8.75 (s, 1H), 8.29 (s, 1H), 7.80 (s, 1H), 7.28 (t, J = 2.4, 2H) , 7.24 (d, J = 8.1, 1H), 7.18 (d, J = 8.4, 1H), 6.92 (d, J = 8.7, 1H), 6.59 ( d, J = 9.0, 1H), 4.11 (s, 4H), 2.07 (s, 3H); LCMS: purity: 89.62%; MS (m / e): 392.25 (M + H).

IV-38: N2- (2,2-dimethyl-2H-1,3-benzodioxol-5-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl ) -2,4-pyrimidinediamine [0934] ¹H NMR (300 MHz, DMSO) δ 11.50 (s, 1H), 8.83 (s, 1H), 8.38 (s, 1H), 7.79 (s, 1H),

7.27 (m, 2H), 7.20 (s, 2H), 6.80 (dd, J = 2.1, 8.4, 1H), 6.56 (d, J = 8.4, 1H ), 2.07 (s, 3H), 1.56 (s, 6H); LCMS: purity: 96.72%; MS (m / e): 406.26 (M + H).

- 227 IV-39: N2- [spiro (2,1'-cyclohexane) -1,3-benzodioxol-5-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazole -5-yl) -2,4-pyrimidinediamine [0935] ¹H NMR (300 MHz, DMSO) δ 11.51 (s, 1H), 8.78 (s, 1H), 8.30 (s, 1H), 7.80 (s, 1H), 7.31 (s , 1H), 7.26 (s, 1H), 7.25 (d, J = 8.1, 1H), 7.18 (d, J = 7.5, 1H), 6.82 (d, J = 9.0, 1H), 6.57 (d, J = 9.0, 1H), 2.06 (s, 3H), 1.80 (t, 4H), 1.62 (t, 4H), 1.43 (t, 2H); LCMS: purity: 90.25%; MS (m / e): 446.22 (M + H).

IV-40: N2- (1,3-dimethyl-1H-pyrazolo [3,4-b] pyridin-5-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazole -5-yl) -2,4-pyrimidinediamine [0936] ¹H NMR (300 MHz, DMSO) δ 9.16 (s, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H),

7.89 (s, 1H), 7.30 (s, 1H), 7.29 (d, J = 7.5, 1H), 7.17 (d, J = 7.8, 1H), 3, 89 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H); LCMS: purity: 94.01%; MS (m / e): 403.23 (M + H).

IV-41: 5-methyl-N2- (1-methylindazol-6-yl) -N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0937] ¹H NMR (300 MHz, DMSO) δ 10.87 (br, 1H), 9.20 (s, 1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.93 (s , 1H), 7.79 (s, 1H), 7.47 (d, J = 8.7, 1H), 7.36 (s, 1H), 7.34 (d, J = 10.8, 1H ), 7.21 (d, J = 8.4, 2H), 3.57 (s, 3H), 2.12 (s, 3H); LCMS: purity: 96.12%; MS (m / e): 388.24 (M + H).

IV-42: 5-methyl-N2- (1-methylindazol-5-yl) -N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0938] ¹H NMR (300 MHz, DMSO) δ 11.56 (s, 1H), 8.98 (s, 1H), 8.37 (s, 1H), 8.08 (s, 1H), 7.85 (s , 1H), 7.62 (s, 1H), 7.43 (d, J = 3.3, 2H), 7.33 (d, J = 8.4, 1H), 7.29 (s, 1H) ), 7.23 (d, J = 8.4, 1H), 3.96 (s, 3H), 2.10 (s, 3H); LCMS: purity: 93.96%; MS (m / e): 388.25 (M + H).

IV-43: 5-methyl-N2- (3-methylisoxazolo [5,4-b] pyridin-5-yl) -N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) - 2,4-pyrimidinediamine [0939] ¹H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 10.06 (br, 1H), 9.27 (br, 1H), 8.59 (s, 1H), 8.40 (s , 1H), 7.90 (s, 1H), 7.21 (s, 3H), 2.28 (s, 3H), 2.14 (s, 3H); LCMS: purity: 93.10%; MS (m / e): 390.17 (M + H).

IV-44: N2- [4- (2-methoxyethyl) -2H-1,4-benzooxazin-3 (4H) -on-7-yl] -5-methyl-N4- (2-oxo2,3-dihydro- 1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0940] ¹H NMR (300 MHz, DMSO) δ 11.69 (s, 1H), 9.91 (br, 1H), 7.84 (s, 1H), 7.30 (d, J = 8.7, 1H) , 7.22 (s, 1H), 7.17 (s, 2H), 7.12 (d, J = 9.3, 1H), 6.98 (d, J = 9.0, 1H), 4 , 50 (s, 2H), 4.01 (t, 2H), 3.47 (t, J = 5.4, 2H), 3.20 (s, 3H), 2.13 (s, 3H); LCMS: purity: 93.04%; MS (m / e): 463.24 (M + H).

IV-45: N2- [2,2-dimethyl-4- (2-methoxyethyl) -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -on-7-yl] 5 -methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine [0941] ¹H NMR (300 MHz, DMSO) δ 11.67 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.64 (s, 1H),

7.28 (d, J = 8.7, 1H), 7.19 (s, 2H), 4.13 (t, 2H), 3.48 (t, 2H), 3.20 (s, 3H) , 2.13 (s, 3H), 1.34 (s,

6H); LCMS: purity: 86.59%; MS (m / e): 492.25 (M + H).

- 228 IV-46: 5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N2- (2H-pyrido [3,2-b] [1, 4] oxazin-3 (4H) -on-7-yl) -2,4-pyrimidinediamine [0942] ¹H NMR (300 MHz, DMSO) δ 11.64 (s, 1H), 11.15 (s, 1H), 9.81 (br, 1H), 9.38 (br, 1H), 7.85 (s , 2H), 7.55 (s, 1H), 7.27 (d, J = 8.7, 1H), 7.21 (s, 1H), 7.18 (d, 1H), 4.51 ( s, 2H), 2.12 (s, 3H); LCMS: purity: 92.36%; MS (m / e): 406.18 (M + H).

IV-47: 5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -N2- (2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -on-6-yl) -2,4-pyrimidinediamine [0943] ¹H NMR (300 MHz, DMSO) δ 10.97 (s, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 7.89 (s, 1H), 7.64 (d , J = 9.3, 1H), 7.41 (d, 2H), 7.21 (d, J = 8.7, 1H), 7.18 (d, J = 10.5, 1H), 6 , 54 (s, 1H), 4.53 (s, 2H), 2.09 (s, 3H); LCMS: purity: 85.46%; MS (m / e): 406.19 (M + H).

IV-48: 5-methyl-N2- (3-methylindazol-6-yl) -N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine [0944] ¹H NMR (300 MHz, DMSO) δ 12.18 (s, 1H), 11.54 (s, 1H), 9.08 (s, 1H), 8.30 (s, 1H), 8.04 (s , 1H), 7.91 (s, 1H), 7.42 (d, J = 8.7, 3H), 7.21 (d, J = 9.0, 2H), 2.38 (s, 3H ), 2.10 (s, 3H); LCMS: purity: 95.21%; MS (m / e): 388.19 (M + H).

IV-49: 5-methyl-N2- (3-methylindazol-5-yl) -N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0945] ¹H NMR (300 MHz, DMSO) δ 12.38 (s, 1H), 11.56 (s, 1H), 9.02 (s, 1H), 8.45 (s, 1H), 7.95 (s , 1H), 7.86 (s, 1H), 7.41 (d, 1H), 7.35 (d, 2H), 7.28 (d, 1H), 7.18 (d, 1H), 2 , (S, 3H), 2.08 (s, 3H); LCMS: purity: 98.29%; MS (m / e): 388.20 (M + H).

IV-50: N2- [2,2-dimethyl-2H-1,4-benzooxazin-3 (4H) -on-7-yl] -5-methyl-N4- (2-oxo-2,3-dihydro-1, 3-benzooxazol-5-yl) -2,4-pyrimidinediamine LCMS: purity: 90.73%; MS (m / e): 433.12 (M + H).

IV-51: 5- (5-methyl-2- (6-methylpyridin-2-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol2 (3H) -one

IV-52: 5- (5-methyl-2- (5-methylpyridin-2-ylamino) pyrimidin-4-ylamino) benzo [d] oxazol2 (3H) -one

IV-53: 5- [2- (isoquinolin-6-ylamino) -5-methylpyrimidin-4-ylamino] -3H-benzooxazol-2-one [0947] ¹H NMR (DMSO, 300 MHz): δ 12.01 (s, 1H), 9.70 (s, 2H), 9.37 - 9.04 (m, 1H), 8.71 (s, 2H), 8.42 - 7.85 (m, 2H), 7.69 (s, 1H), 7.53 (s, 1H), 7.44 - 7.05 (m, 1H), 6.84 (s, 1H), 2.22 (s, 3H) ppm; MS (ES) 385 (M + H);

IV-54: 5- [5-methyl-2- (naphthalen-2-ylamino) pyrimidin-4-ylamino] -3H-benzooxazol-2-one [0948] ¹H NMR (DMSO, 300 MHz): δ 11.85 (s, 1H), 10.94 (s, 1H), 10.06 (s, 1H), 7.94 (d, J =

14.9, 2H), 7.80 (d, J = 8.7, 1H), 7.39 (dd, J = 8.5, 17.9, 3H), 7.30 - 7.03 (m , 2H), 2.16 (s, 3H) ppm; MS (ES) 384 (M + H);

- 229 IV-55: 5- [2- (4-methoxynaphthalen-2-ylamino) -5-methylpyrimidin-4-ylamino] -3H-benzooxazol-2-one [0949] ¹H WR (1 ^^ (), 300 ΜΗς): δ 9.15 (s, 1H), 8.42 (s, 1H), 7.93 (t, J = 9.5, 2H), 7.42 7.25 (m, 3H), 7.25 - 7.10 (m, 2H), 3.81 (s, 3H), 2.11 (s, 3H) ppm; MS (ES) 414 (Μ + H);

IV-56: 5- [2- (4-hydroxynaphthalen-2-ylamino) -5-methylpyrimidin-4-ylamino] -3H-benzooxazol-2-one [0950] ¹H WR (DMSO, 300 ΜΗς): δ 8.48 (s, 1H), 8.18 - 8.08 (m, 1H), 8.09 - 8.01 (m, 1H),

7.90 - 7.79 (m, 1H), 7.71 (s, 1H), 7.46 - 7.35 (m, 2H), 7.24 (m, 3H), 6.82 (d, J = 8.0, 1H), 6.72 (d, J = 8.4, 1H), 2.01 (s, 3H) ppm; MS (ES) 400 (Μ + H);

IV-57: 5- [2- (isoquinolin-7-ylamino) -5-methylpyrimidin-4-ylamino] -3H-benzooxazol-2-one [0951] ¹H WR ^ SO, 300 ΜΗς): δ 12.08 (s, 1H), 9.64 (s, 2H), 9.12 (m, 1H), 8.78 (s, 2H), 8.40 - 7.79 (m, 2H), 7.61 (s, 1H), 7.48 (s, 1H), 7.34 (m, 1H), 6.79 (s, 1H), 2.13 (s , 3H) ppm; MS (ES) 385 (Μ + H);

IV-58: N2- (4-methoxypyridin-2-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [0952] ¹H WR (300 Ylllz, DMSO) δ 11.70 (s, 1H), 9.27 (s, 1H), 8.93 (s, 1H), 8.38 (d, J = 8.1, 1H) , 8.29 (s, 1H), 7.31 (s, 1H), 7.27 (m, 2H), 6.67 (d, 1H), 6.41 (s, 1H), 3.92 ( s, 3H), 2.27 (s, 3H); LCMS: purity: 83.21%; MS (m / e): 365.36 (ΜΗ +).

IV-59: 5- [5-methyl-2- (2,4,6-trifluorophenylamino) pyrimidin-4-ylamino] -3H-benzooxazol2-one [0953] ¹H WR (DMSO, 300 ΜΗς): δ 11.54 (s, 1H), 8.69 - 8.49 (m, 1H), 8.40 (s, 1H), 7.76 (s, 1H), 7.36 - 7.14 (m, 4H), 7.05 (d, J = 8.5, 1H), 2.04 (s, 3H) ppm; MS (ES) 388 (Μ + H);

IV-60: 5- (2- (2,6-dimethylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol2 (3H) -one [0954] C20H19N5O2. MS (ESI) m / z 362.21 (Μ + 1) +.

IV-61: 5- [5-methyl-2- (2,4,6-trimethylphenylamino) pyrimidin-4-ylamino] -3H-benzooxazol2-one [0955] ¹HW (DMSO, 300 ΜΙ ^: δ 11.63 - 11.41 (m, 1H), 9.46 - 9.27 (m, 1H), 8.48-8.34 (m, 1H), 8, 20 (s, 1H), 8.13 (s, 1H), 7.75 - 7.53 (m, 1H), 6.87 (d, J = 9.7, 1H), 6.58 (s, 2H), 2.21 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H) ppm; MS (ES) 376 (Μ + H) ;

IV-62: 5- (2- (2-fluoro-6-methylphenylamino) -5-methylpyrimidin-4-ylamino) benzo [d] oxazol-2 (3H) -one [0956] C19H16FN5O2. MS (ESI) m / z 366.23 (Μ + 1) +.¹HW (300 \ IIIz, DMSO) δ 8.19 (s,

1H, NH), 8.15 (s, 1H, NH), 8.10 (s, 1H, NH), 7.72 (s, 1H, ArH), 7.36-7.33 (m, 1H, ArH), 7.23 (s, 1H, ArH), 7.10-7.03 (m, 3H, ArH), 6.96-6.93 (m, 1H, ArH), 2.15 (s, 3H, CH3), 2.02 (s, 3H,

CH 3).

- 230 IV-63: N2- (3-fluoropyridin-4-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzooxazol-5-yl) -2,4-pyrimidinediamine [ 0957] ¹H NMR (300 MHz, DMSO) δ 9.06 (d, 2H), 8.87 (d, J = 8.1, 1H), 8.19 (s, 1H), 7.10 (s, 1H) , 7.01 (m, 3H), 2.22 (s, 3H); LCMS: purity: 96.38%; MS (m / e): 353.36 (MH +).

IV-64: N2- (3-fluoropyridin-4-yl) -5-methyl-N4- (2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl) -2,4-pyrimidinediamine trifluoroacetic acid salt [0958] ¹H NMR (300 MHz, DMSO) δ 11.72 (s, 1H), 9.24 - 9.16 (m, 3H), 8.99 (s, 1H), 8.94 (d, J = 7, 5, 1H), 8.28 (s, 1H), 7.37 (s, 1H), 7.32 (s, 2H), 7.13 (t, J = 7.5, 1H), 2.25 (s, 3H); ¹⁹F NMR (282 MHz, DMSO) δ -161.09; LCMS: purity: 87.83%; MS (m / e): 353.35 (MH +).

Example 2: Determination of CD23 expression on Ramos B cells stimulated by IL-4 [0959] B cells stimulated with interleukin-4 (IL-4) cytokine activate the JAK / Stat pathway through phosphorylation of kinases of the JAK, JAK-1 and JAK- family of kinases 3, which in turn phosphorylate and activate the Stat-6 transcription factor. One of the genes amplified by activated Stat-6 is a low affinity IgE receptor, CD23. To study the effect of inhibitors on JAK kinase families, human Ramos B cells were stimulated with human IL-4 and surface expression of CD23 was measured.

[0960] The Ramos B cell line was purchased from ATCC (ATCC Catalog No. CRL-1596). Cells were grown in RPMI 1640 (Cellgro, MediaTech, Inc., Herndon, VA, catalog number 10-040CM) with 10% FBS, heat inactivated (JRH Biosciences, Inc., Lenexa, Kansas, catalog number 12106 - 500 M) , in accordance with the ATCC propagation protocol. Cells were cultured at a density of 3.5 x 10⁵. The day before the experiment, Ramos B cells were diluted to 3.5 x 10⁵cells / ml to ensure that they are in the logarithmic growth phase.

[0961] Cells were centrifuged and resuspended in RPMI with 5% serum. 5 x 10 was used⁴cells per point in a 96-well tissue culture plate. Cells were pre-incubated with compound or DMSO (Sigma-Aldrich, St. Louis, MO, Cat. No. D2650) medium control for 1 hour at 37 ° C in an incubator. Cells were then stimulated with IL-4 (Peprotech, Rocky Hill Inc., New Jersey, Cat. No. 200-04) to a final concentration of 50 units / ml over 20-24 hours. The cells were then centrifuged and stained with anti-CD23PE (BD Pharmingen, San Diego, CA, catalog number 555711) and analyzed by FACS. Detection was carried out using a BD LSRI System Flow Cytometer, purchased from Becton Dickinson Biosciences, San Jose, California. IC 50 calculated from the results of this determination is provided in Table IX.

Example 3: IL-2 stimulated primary human T cell proliferation assay [0962] Primary human T cells derived from peripheral blood and pre-activated by stimulation of the T cell receptor and CD28, proliferate in vitro in response to the interleukin-2 (IL-2) cytokine 2). This proliferative response is dependent on the activation of kinases

- 231 JAK 1 and JAK-3 tyrosine that phosphorylate and activate the Stat-5 transcription factor.

[0963] Human primary T cells were obtained as follows. All blood was obtained from a healthy volunteer, mixed in a 1: 1 ratio with PBS, layered on Ficoll Hypaque (Amersham Pharmacia Biotech, Piscataway, NJ, catalog number # 17-1440-03) in a 2: 1 blood / PBS: Ficoll ratio and centrifuged for 30 minutes at 4 ° C at 1750 rpm. Serum: ficoll lymphocytes at the interface are recovered and washed twice with 5 volumes of PBS. Cells were resuspended in Yssel medium (Gemini Bio-products, Woodland,

CA, catalog number 400-103) containing 40 U / ml recombinant IL2 (R and D Systems,

Minneapolis, MN, catalog number 202-IL (20 μg)) and inoculated into a flask pre-coated with a 1 μg / ml anti-CD3 (BD ​​Pharmingen, San Diego, CA, catalog number 555336) and 5 μg / ml anti-CD28 antibody ( Immunotech, Beckman Coulter of Brea California, catalog number IM1376). Primary T cells were stimulated for 3-4 days, then transferred to a fresh flask and maintained in RPMI with 10% FBS and 40 U / ml IL-2.

[0964] The day before the assay setting, the primary T cells were centrifuged and resuspended in fresh RPMI with 10% FBS but without IL-2 and fasted overnight. In the assay, primary T cells were centrifuged and resuspended in 2 x 10 Yssel medium⁶cells / ml. A 50 gi cell suspension containing 80 U / ml IL-2 was added to each well of a flat bottom 96 well black plate. For unstimulated control, IL-2 was omitted in the last column of the plate. Compounds were serially diluted in dimethyl sulfoxide (DMSO, 99.7% purity, tested for cell culture, SigmaAldrich, St. Louis, MO, catalog number D2650) from 5 mM to 3-fold dilutions, then diluted 1: 250 in Yssel medium. 50 Pl of 2X was added to the well in duplicate and the cells allowed to proliferate for 72 hours at 37 ° C.

[0965] Proliferation was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega), which determines the number of viable cells in culture, based on quantitative analysis of the current ATP, as an indicator of metabolically active cells. The substrate was thawed and brought to room temperature. After mixing Cell Titer-Glo reagent and diluent together, 100 μl was added to each well. The plates were mixed on an orbital shaker for two minutes to induce lysis and incubated at ambient temperature for another ten minutes, allowing signal equilibration. Detection was carried out using a Wallac Victor2 1420 Multilabel Counter, purchased from Perkin Elmer, Shelton, CT.

Example 4: Determination of ICAM1 expression on A549 epithelial cells stimulated by IFN [0966] Lung epithelial cells, A549, enhance ICAM-1 (CD54) surface expression in response to a variety of different stimuli. Therefore, using ICAM1 expression as a reading, the effect of a compound on different signaling pathways can be assessed in the same cell type. IFNy enhances ICAM-1 by activating the JAK / Stat pathway. In this case, enhancement of ICAM-1 expression by IFNy was evaluated.

[0967] The A549 lung cancer epithelial cell line was from American Type Culture

- 232 Collection. Routine culture was carried out with F12K media (Mediatech, Inc., Lenexa, KS, catalog number 10-025-CV) with 10% fetal bovine serum, 100 IU penicillin and 100 ng / ml streptomycin (complete F12K medium). Cells were incubated in a humidified atmosphere containing 5% CO2 at 37 ° C. Prior to use in the assay, A549 cells were washed with PBS and treated with trypsin (Mediatech Inc., Catalog No. 25-052-CI) for cell detachment. The trypsin cell suspension was neutralized with all F12K medium and centrifuged to pellet the cells. The cell pellet was resuspended in complete F12K medium at a concentration of 2.0x10⁵/ Ml. Cells were seeded at 20,000 per well,

100 μΐ of the total volume on a flat-bottom tissue culture plate and allowed to adhere overnight.

[0968] On the second day, A549 cells were pre-incubated with test compound or DMSO (control) (Sigma-Aldrich, St. Louis, MO, catalog number D2650) for 1 hour. The cells were then stimulated with IFNγ (75 ng / ml) (Peprotech Inc, Rocky Hill, NJ, catalog number 300-02) and allowed to incubate for 24 hours. The final dose range of the test compound was 30 μΜ to 14 Nm in 200 μl F12K medium containing 5% FBS, 0.3% DMSO.

[0969] On the third day, the cell medium was removed and the cells were washed with 200 μl PBS (phosphate buffered saline). Trypsin for cell dissociation was added to each well followed by neutralization by the addition of 200 μl complete F12K medium. Cells were plated and stained with anti-human ICAM-1 (CD54) APC conjugated mouse antibody (BD Pharmingen, San Diego, CA, catalog number # 559771) for 20 minutes at 4 ° C. Cells were washed with ice-cold FACS buffer (PBS + 2% FBS) and surface expression of ICAM-1 was analyzed by flow cytometry. Detection was carried out using a BD LSRI System Flow Cytometer, purchased from BD Biosciences, San Jose, California. Events were gated for light scattering and the geometric mean was calculated (BectonDickinson CellQuest software version 3.3, Franklin Lakes, NJ). Geometric means were plotted as a function of compound concentration to form a dose response curve.

Example 5: ICAM1 Expression Assay on U937 IFNy Stimulated Myeloid Leukemia Cells [0970] U937 human monocytic cells enhance ICAM-1 (CD54) surface expression in response to a variety of different stimuli. Therefore, using ICAM-1 expression as a reading, the effect of a compound on different signaling pathways can be assessed in the same cell type. IFNy enhances ICAM-1 by activating the JAK / Stat pathway. In this example, the enhancement of ICAM-1 expression by IFNy was evaluated.

[0971] The U937 human monocyte cell line was obtained from Rockville ATCC

Maryland, catalog number CRL-1593,2 and grown in RPM1-1640 containing 10% (v / v) FCS. U937 cells were cultured in 10% RPMI. Cells were then seeded at a concentration of 100,000 cells per 160 μl in 96-well flat bottom plates. Test compounds were further diluted as follows: 10 mM test compound was diluted 1: 5 in

- 233 DMSO (3 μΐ 10 mM test compound in 12 μΐ DMSO), then in serial 1: 3 dilutions of the test compound in DMSO (6 μL test compound was serially diluted in 12 μΐ DMSO, obtaining 3-fold dilutions). Then 4 μΐ of test compound was transferred to 76 μΐ 10% RPMI to give a 10X solution (100 μM test compound, 5% DMSO). For control wells, 4 μΐ DMSO was diluted in 76 μΐ 10% RPMI. The assay was performed in duplicate with 8 points (8 concentrations of 3-fold dilutions of 10 μM) and with 4 wells of TVIKO DMSO (control wells) under stimulated conditions and 4 wells DMSO under unstimulated conditions.

[0972] The diluted compound plate was mixed 2X with Mukimek (Beckman Couker from Brea, Kakfornia), and then 20 μΐ of diluted compounds were transferred to a 96 well plate containing 160 μΐ of cells, which were then mixed again twice at low speeds. Cells and compounds were then pre-incubated for 30 minutes at 37 ° C with 5% CO2.

[0973] A 10X stimulation mix was made by preparing a solution of 100 χιηΐ of Adzki IFNy solution in 10% RPMI. Cells and compound were then stimulated with 20 μl of IFN? Stimulation mix, resulting in a final concentration of 10 ng IFNy, 10 μM test compound and 0.5% DMSO. Cells were maintained under conditions suitable for stimulation for 18-24 hours at 37 ° C with 5% CO2.

[0974] Cells were transferred to a 96-well round bottom staining plate and then kept in Ada throughout the staining procedure. Cells were centrifuged at 1000 rpm for 5 minutes at 4 ° C after which the supernatant was removed. After removal of the supernatant, 1 μΐ of APC conjugated with mouse anti-Judean ICAM-1 antibody was added per 100 μΐ of FACS buffer. Cells were then incubated on Ada in the dark for 30 minutes. After incubation, 150 μΐ FACS buffer was added and the cells were centrifuged at 1000 rpm for 5 minutes at 4 ° C, after which the supernatant was removed. After removing the supernatant, 200 μΐ FACS buffer was added and the cells were resuspended. After suspension, the cells were centrifuged at 1000 rpm for 5 minutes at 4 ° C. The supernatant was removed before resuspending the cells in 150 μΐ FACS buffer.

[0975] Detection was carried out using a BD LSRI System FIow Cytometer flow cytometer, purchased from BD Biosciences, San Jose, Cakfornia. Viable cells were gated for light scattering and the geometric mean ICAM-APC (Becton-Dickinson CekQuest version 3.3 software, Frankkn Lakes, NJ) was measured. Both% viable cells and ICAM-1 expression were inactivated. Assays for the compounds tested were carried out in parallel with a control compound of known activity. EC₅₀ 40-100 nM is usually used for the control relationship.

Example 6: Fluorescence polarization assay for JAK1, JAK2 and JAK3 kinases [0976] This assay can be used to determine the potency of a compound described herein against certain JAK kinases and the activity of a compound described herein in inhibiting the activity of certain JAK kinases in vitro.

Reagents and buffers

- 234 Tyrosine Kinase Kit green (Invitrogen, catalog number P2837) (tyrosine kinase test kit)

Acetylated Bovine gamma globulin (BGG) (Invitrogen, catalog number P2255) (acetylated bovine gamma globulin)

Active JAK1 (Carna Biosciences) Active JAK2 (Carna Biosciences) Active JAK3 (Carna Biosciences) (Active JAK1) (Active JAK2) (Active JAK3)

TK2 Peptide (Biotin-EGPWLEEEEEAYGWMDF-CONH₂) (SynPep Custom Synthesis). Methods [0977] Test compounds were serially diluted in DMSO starting from 500x the desired final concentration, and then diluted to 1% DMSO in kinase buffer (20 mM HEPES, pH 7.4, 5 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.1 mg / ml acetylated BGG). Test compound in 1% DMSO (0.2% DMSO final) was mixed in a 1: 5 ratio with ATP and substrate in kinase buffer at ambient temperature.

[0978] Kinase reactions were performed in a final volume of 20 pi, containing the peptide substrate and ATP, and were initiated by the addition of kinase in kinase buffer. Reactions were carried out at ambient temperature. The final substrate, ATP and enzyme concentrations and reaction times for various kinase assays are given in Table VIII.

<td colspan="6">Table VIII</td>

<td colspan="6">Final substrate, ATP, enzyme and reaction times</td>

<td>Enzyme</td><td>Amount of Enzyme to the Reaction</td><td>substratum</td><td>Concentration substrate</td><td>Concentration ATP</td><td>Marking Time</td>

<td>JAK1</td><td>20 ng</td><td>TK2</td><td>10 μΜ</td><td>5 μΜ</td><td>20 min</td>

<td>JAK2</td><td>0.3 ng</td><td>TK2</td><td>10 μΜ</td><td>5 μΜ</td><td>20 min</td>

<td>JAK3</td><td>2 ng</td><td>TK2</td><td>10 μΜ</td><td>5 μΜ</td><td>20 min</td>

[0979] Reactions were stopped by adding 20 μl PTK quenching mix containing EDTA / anti-phosphotyrosine antibody (1X final) / phosphopeptide fluorescent label (0.5X final) diluted in FP dilution buffer according to manufacturer's instructions (Invitrogen). Plates were incubated for 30 minutes in the dark at ambient temperature and then read using a Polarion fluorescence polarization plate reader (Tecan).

[0980] Data was converted to the amount of phosphopeptide present using a calibration curve generated by competition with the competition phosphopeptide provided in Tyrosine

- 235 Kinase Kit green (tyrosine kinase test kit, Green (Invitrogen)). For determination

IC50, compounds were tested at eleven concentrations in duplicate and curve fitting was performed by non-linear regression analysis using Matlab version 6.5 (Mathworks, Inc, Natick, MA, USA).

Example 7: JAK2-dependent constitutively active cell proliferation assays [0981] A mutation in the JH2 pseudokinase JAK2 domain (JAK2 V617F) was described in chronic myeloproliferative disorder as well as a subset of acute myeloid leukemia (AML) cell lines. The mutation of the negative regulatory JH2 domain deregutes the kinase, allowing for constitutive binding to the EPO receptor and activation. UKE-1 cells, derived from an AML patient, express JAK2 V617F, which drives their proliferation. The IL-3-dependent BaF3 myeloid leukemia cell line was designed to express JAK2 V617F allowing IL-3 independent proliferation. The effect of JAK inhibitors on the proliferation of these cell lines can be used to assess the cellular activity of these compounds against JAK2.

Reagents and buffers [0982] Dimethyl sulfoxide (DMSO) (Sigma-Aldrich, Catalog Number D2650) (Control)

Iscove's DMEM, ATCC, Catalog number 30-2005

M HEPES, Cellgro, catalog number 25-060-CI (100 ml)

100 mM Sodium pyruvate, Cellgro, catalog number 25-000-CI (100 ml)

Penicillin / Streptomycin, 10000 U / ml each, Cellgro, Catalog number 30-002-CI (100 ml)

RPMI1640 (Cellgro, catalog number 10-040-CM)

Bovine fetal serum (JRH, Catalog number 12106-500M)

Horse serum, donor, Hyclone, Catalog number SH30074.02 (100 ml) μM hydrocortisone solution, Sigma Catalog number H6909-10ml (10 ml)

Culture conditions [0983] BaF3 V617F cells were maintained and seeded in RPMI medium with 10% FBS. Seeding density for these cells 1 X 10⁵ cells / ml.

[0984] UKE-1 was maintained and plated in DMEM Iscove medium containing 10% FBS, 10% horse plasma, 1% penicillin / streptomycin and 1 µM hydrocortisone. The seeding density for these cells was 0.4 x 10⁶ cells / ml

Methods [0985] Cells were resuspended in appropriate medium at the required cell density (see above). 100 μl cell suspension was added to each well of a flat bottom 96- 236 well white plate. The compound was serially diluted in DMSO in the range of 5 mM to 3-fold dilutions, and then diluted 1: 250 in RPMI 1640 medium containing 5% FBS and penicillin / streptomycin. 100 Pl of the resulting 2X compound solution was added to each well in duplicate, and the cells were allowed to proliferate for 72 hours at 37 ° C.

[0986] Proliferation was measured using the CellTiter-Glo assay. The substrate was thawed and brought to room temperature. After removing the upper 100 μl medium from each well, 100 μl Cell Titer-Glo mixed reagent was added to each well. The plates were mixed on an orbital shaker for three minutes to induce lysis and incubated at ambient temperature for an additional five minutes allowing signal equilibration. Luminescence was read on a Wallaca Reader.

[0987] The results of the ability of the compounds described herein to inhibit JAK3 activity, when tested under the conditions described in Example 3 above, are shown in Table V below. The designations of the compounds in Table V are in accordance with those in Tables I-IV above. In Table V, activity is indicated by the following ranges: "A" means compounds having IC₅₀ &lt;0.5 μΜ; "B" means compounds exhibiting IC₅₀ &gt; 0.5 μΜ and &lt;5 μΜ; "C" means compounds having IC₅₀ &gt; 5 μΜ and &lt;10 μΜ; and "D" means compounds with activity&gt; 10 μΜ.

[0988] The results of the ability of the compounds described herein to inhibit JAK3 activity, when tested under the conditions described in Example 3 above, are shown in Table V below. The designations of the compounds in Table V are in accordance with those in Table I-IV above. In Table V, activity is indicated by the following ranges: "A" means compounds having IC 50 &lt;0.5 μΜ; "B" means compounds having IC50&gt; 0.5 μΜ and &lt;5 μΜ; "C" means compounds having IC50&gt; 5 μΜ and &lt;10 μΜ; and "D" means compounds with activity&gt; 10 μΜ.

- 237 -

<td colspan="2">Table V</td>

<td> 1-1</td><td>B</td>

<td>I-2</td><td>AND</td>

<td>I-3</td><td>AND</td>

<td> 1-4</td><td>AND</td>

<td> 1-5</td><td>B</td>

<td> 1-6</td><td>AND</td>

<td> 1-7</td><td>AND</td>

<td> 1-9</td><td>AND</td>

<td> 1-16</td><td>AND</td>

<td> 1-17</td><td>AND</td>

<td>I-20</td><td>AND</td>

<td> 1-21</td><td>AND</td>

<td> 1-22</td><td>AND</td>

<td> 1-23</td><td>D</td>

<td> 1-26</td><td>AND</td>

<td> 1-27</td><td>AND</td>

<td> 1-28</td><td>AND</td>

<td>I-2S</td><td>D</td>

<td> 1-33</td><td>AND</td>

<td> 1-36</td><td>AND</td>

<td colspan="2">Table V</td>

<td> 1-41</td><td>B</td>

<td>I-44</td><td>AND</td>

<td>I-45</td><td>AND</td>

<td>I-46</td><td>AND</td>

<td>I-47</td><td>AND</td>

<td>I-40</td><td>AND</td>

<td>I-49</td><td>AND</td>

<td>I-50</td><td>AND</td>

<td>I-60</td><td>D</td>

<td> 1-65</td><td>AND</td>

<td>I-66</td><td>AND</td>

<td>I-60</td><td>AND</td>

<td>I-7D</td><td>AND</td>

<img file="PL2389372T3_D0041.tif" />

<td colspan="2">Table V</td>

<td> 1-115</td><td>AND</td>

<td> 1-116</td><td>AND</td>

<td> 1-117</td><td>AND</td>

<td> 1-113</td><td>AND</td>

<td> 1-119</td><td>AND</td>

<td> 1-120</td><td>AND</td>

<td> 1-121</td><td>B</td>

<td> 1-122</td><td>AND</td>

<td> 1-123</td><td>AND</td>

<td> 1-124</td><td>AND</td>

<td> 1-125</td><td>AND</td>

<td> 1-126</td><td>AND</td>

<td> 1-127</td><td>AND</td>

<td> 1-123</td><td>AND</td>

<td> 1-129</td><td>AND</td>

<td> 1-130</td><td>AND</td>

<td> 1-131</td><td>AND</td>

<td> 1-132</td><td>AND</td>

<td> 1-133</td><td>AND</td>

<td> 1-134</td><td>AND</td>

<td> 1-135</td><td>AND</td>

<td> 1-136</td><td>AND</td>

<td> 1-137</td><td>AND</td>

<td> 1-136</td><td>AND</td>

<td> 1-139</td><td>AND</td>

<td> 1-140</td><td>AND</td>

<td> 1-141</td><td>AND</td>

<td> 1-142</td><td>AND</td>

<td colspan="2"> 1-143</td>

<td> 1-144</td><td>AND</td>

<td> 1-145</td><td>AND</td>

<td> 1-146</td><td>B</td>

<td> 1-147</td><td>AND</td>

<td> 1-146</td><td>AND</td>

- 238 -

<td colspan="2">Table V</td>

<td> 1-149</td><td>AND</td>

<td> 1-150</td><td>AND</td>

<td> 1-151</td><td>AND</td>

<td>Μ 52</td><td>B</td>

<td> 1-153</td><td>AND</td>

<td> 1-154</td><td>AND</td>

<td> 1-155</td><td>AND</td>

<td> 1-150</td><td>AND</td>

<td> 1-157</td><td>AND</td>

<td> 1-150</td><td>AND</td>

<td> 1-150</td><td>AND</td>

<td> 1-100</td><td>AND</td>

<td> 1-101</td><td>AND</td>

<td> 1-102</td><td>D</td>

<td> 1-103</td><td>AND</td>

<td> 1-104</td><td>AND</td>

<td> 1-105</td><td>AND</td>

<td> 1-100</td><td>AND</td>

<td> 1-107</td><td>AND</td>

<td> 1-100</td><td>B</td>

<td> 1-100</td><td>AND</td>

<td> 1-170</td><td>D</td>

<td> 1-171</td><td>AND</td>

<td> 1-172</td><td>AND</td>

<td> 1-173</td><td>AND</td>

<td> 1-174</td><td>AND</td>

<td> 1-175</td><td>AND</td>

<td> 1-170</td><td> 0</td>

<td> 1-177</td><td>AND</td>

<td> 1-170</td><td>AND</td>

<td> 1-170</td><td>D</td>

<td>1-1SO</td><td>AND</td>

<td> 1-101</td><td>AND</td>

<td> 1-102</td><td>AND</td>

<td> 1-103</td><td>AND</td>

<td> 1-104</td><td>AND</td>

<td> 1-105</td><td>D</td>

<td colspan="2">Table V</td>

<td> 1-100</td><td>AND</td>

<td> 1-107</td><td>AND</td>

<td> 1-100</td><td>AND</td>

<td>And 100</td><td>AND</td>

<td> 1-100</td><td>AND</td>

<td> 1-101</td><td>AND</td>

<td> 1-102</td><td>AND</td>

<td> 1-103</td><td>B</td>

<td> 1-104</td><td>AND</td>

<td> 1-105</td><td>AND</td>

<td> 1-106</td><td>AND</td>

<td> 1-107</td><td>D</td>

<td> 1-100</td><td>AND</td>

<td> 1-100</td><td>AND</td>

<td>I-200</td><td>AND</td>

<td> 1-201</td><td>AND</td>

<td> (-202</td><td>AND</td>

<td> 1-203</td><td>AND</td>

<td> 1-204</td><td>AND</td>

<td> 1-205</td><td>AND</td>