# Patent

## Title
2,4-pyrimidinediamine compounds and their uses

## Abstract

The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.

## Background
1. CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of application Ser. No. 10/355,543 filed Jan. 31, 2003, now pending, which claims benefit under 35 U.S.C. § 119(e) to application Ser. No. 60/353,333 filed Feb. 1, 2002; application Ser. No. 60/353,267 filed Feb. 1, 2002; application Ser. No. 60/399,673 filed Jul. 29, 2002; and application Ser. No. 60/434,277 filed Dec. 17, 2002. The contents of application Ser. No. 10/355,543 are incorporated herein by reference.


2. FIELD OF THE INVENTION
The present invention relates generally to 2,4-pyrimidinediamine compounds, pharmaceutical compositions comprising the compounds, intermediates and synthetic methods of making the compounds and methods of using the compounds and compositions in a variety of contexts.
3. BACKGROUND OF THE INVENTION
Crosslinking of Fc receptors, such as the high affinity receptor for IgE (FcεRI) and/or the high affinity receptor for IgG (FcγRI) activates a signaling cascade in mast, basophil and other immune cells that results in the release of chemical mediators responsible for numerous adverse events. For example, such crosslinking leads to the release of preformed mediators of Type I (immediate) anaphylactic hypersensitivity reactions, such as histamine, from storage sites in granules via degranulation. It also leads to the synthesis and release of other mediators, including leukotrienes, prostaglandins and platelet-activating factors (PAFs), that play important roles in inflammatory reactions. Additional mediators that are synthesized and released upon crosslinking Fc receptors include cytokines and nitric oxide.
The signaling cascade(s) activated by crosslinking Fc receptors such as FcεRI and/or FcγRI comprises an array of cellular proteins. Among the most important intracellular signal propagators are the tyrosine kinases. And, an important tyrosine kinase involved in the signal transduction pathways associated with crosslinking the FcεRI and/or FcγRI receptors, as well as other signal transduction cascades, is Syk kinase (see Valent et al., 2002, Intl. J. Hematol. 75(4):257–362 for review).
As the mediators released as a result of FcεRI and FcγRI receptor cross-linking are responsible for, or play important roles in, the manifestation of numerous adverse events, the availability of compounds capable of inhibiting the signaling cascade(s) responsible for their release would be highly desireable. Moreover, owing to the critical role that Syk kinase plays these and other receptor signaling cascade(s), the availability of compounds capable of inhibiting Syk kinase would also be highly desirable.
4. SUMMARY OF THE INVENTION
In one aspect, the present invention provides novel 2,4-pyrimidinediamine compounds that, as will be discussed in more detail below, have myriad biological activities. The compounds generally comprise a 2,4-pyrimidinediamine “core” having the following structure and numbering convention:




The compounds of the invention are substituted at the C2 nitrogen (N2) to form a secondary amine and are optionally further substituted at one or more of the following positions: the C4 nitrogen (N4), the C5 position and/or the C6 position. When substituted at N4, the substituent forms a secondary amine. The substituent at N2, as well as the optional substituents at the other positions, may range broadly in character and physico-chemical properties. For example, the substituent(s) may be a branched, straight-chained or cyclic alkyl, a branched, straight-chained or cyclic heteroalkyl, a mono- or polycyclic aryl a mono- or polycyclic heteroaryl or combinations of these groups. These substituent groups may be further substituted, as will be described in more detail below.
The N2 and/or N4 substituents may be attached directly to their respective nitrogen atoms, or they may be spaced away from their respective nitrogen atoms via linkers, which may be the same or different. The nature of the linkers can vary widely, and can include virtually any combination of atoms or groups useful for spacing one molecular moiety from another. For example, the linker may be an acyclic hydrocarbon bridge (e.g, a saturated or unsaturated alkyleno such as methano, ethano, etheno, propano, prop[1]eno, butano, but[1]eno, but[2]eno, buta[1,3]dieno, and the like), a monocyclic or polycyclic hydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, and the like), a simple acyclic heteroatomic or heteroalkyldiyl bridge (e.g., —O—, —S—, —S—O—, —NH—, —PH—, —C(O)—, —C(O)NH—, —S(O)—, —S(O)2—, —S(O)NH—, —S(O)2NH—, —O—CH2—, —CH2—O—CH2—, —O—CH═CH—CH2—, and the like), a monocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano, pyridino, thiopheno, piperidino, piperazino, pyrazidino, pyrrolidino, and the like) or combinations of such bridges.
The substituents at the N2, N4, C5 and/or C6 positions, as well as the optional linkers, may be further substituted with one or more of the same or different substituent groups. The nature of these substituent groups may vary broadly. Non-limiting examples of suitable substituent groups include branched, straight-chain or cyclic alkyls, mono- or polycyclic aryls, branched, straight-chain or cyclic heteroalkyls, mono- or polycyclic heteroaryls, halos, branched, straight-chain or cyclic haloalkyls, hydroxyls, oxos, thioxos, branched, straight-chain or cyclic alkoxys, branched, straight-chain or cyclic haloalkoxys, trifluoromethoxys, mono- or polycyclic aryloxys, mono- or polycyclic heteroaryloxys, ethers, alcohols, sulfides, thioethers, sulfanyls (thiols), imines, azos, azides, amines (primary, secondary and tertiary), nitriles (any isomer), cyanates (any isomer), thiocyanates (any isomer), nitrosos, nitros, diazos, sulfoxides, sulfonyls, sulfonic acids, sulfamides, sulfonamides, sulfamic esters, aldehydes, ketones, carboxylic acids, esters, amides, amidines, formadines, amino acids, acetylenes, carbamates, lactones, lactams, glucosides, gluconurides, sulfones, ketals, acetals, thioketals, oximes, oxamic acids, oxamic esters, etc., and combinations of these groups. Substituent groups bearing reactive functionalities may be protected or unprotected, as is well-known in the art.
In one illustrative embodiment, the 2,4-pyrimidinediamine compounds of the invention are compounds according to structural formula (I):




including salts, hydrates, solvates and N-oxides thereof, wherein:
L1 and L2 are each, independently of one another, selected from the group consisting of a direct bond and a linker;
R2 is selected from the group consisting of (C1–C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C3–C8) cycloalkyl optionally substituted with one or more of the same or different R8 groups, cyclohexyl optionally substituted with one or more of the same or different R8 groups, 3–8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R8 groups, (C5–C15) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups and 5–15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R4 is selected from the group consisting of hydrogen, (C1–C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C3–C8) cycloalkyl optionally substituted with one or more of the same or different R8 groups, cyclohexyl optionally substituted with one or more of the same or different R8 groups, 3–8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R8 groups, (C5–C15) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups and 5–15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R5 is selected from the group consisting of R6, (C1–C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C1–C4) alkanyl optionally substituted with one or more of the same or different R8 groups, (C2–C4) alkenyl optionally substituted with one or more of the same or different R8 groups and (C2–C4) alkynyl optionally substituted with one or more of the same or different R8 groups;
each R6 is independently selected from the group consisting of hydrogen, an electronegative group, —ORd, —SRd, (C1–C3) haloalkyloxy, (C1–C3) perhaloalkyloxy, —NRcRc, halogen, (C1–C3) haloalkyl, (C1–C3) perhaloalkyl, —CF3, —CH2CF3, —CF2CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, —N3, —S(O)Rd, —S(O)2Rd, —S(O)2ORd, —S(O)NRcRc; —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd, —OS(O)2ORd, —OS(O)NRcRc, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc, —OC(O)Rd, —SC(O)Rd, —OC(O)ORd, —SC(O)ORd, —OC(O)NRcRc, —SC(O)NRcRc, —OC(NH)NRcRc, —SC(NH)NRcRc, —[NHC(O)]nRd, —[NHC(O)]nORd, —[NHC(O)]nNRcRc and —[NHC(NH)]nNRcRc, (C5–C10) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups, (C6–C16) arylalkyl optionally substituted with one or more of the same or different R8 groups, 5–10 membered heteroaryl optionally substituted with one or more of the same or different R8 groups and 6–16 membered heteroarylalkyl optionally substituted with one or more of the same or different R8 groups;
R8 is selected from the group consisting of Ra, Rb, Ra substituted with one or more of the same or different Ra or Rb, —ORa substituted with one or more of the same or different Ra or Rb, —B(ORa)2, —B(NRcRc)2, —(CH2)m—Rb, —(CHRa)m—Rb, —O—(CH2)m—Rb, —S—(CH2)m—Rb, —O—CHRaRb, —O—CRa(Rb)2, —O—(CHRa)m—Rb, —O—(CH2)m—CH[(CH2)mRb]Rb, —S—(CHRa)m—Rb, —C(O)NH—(CH2)m—Rb, —C(O)NH—(CHRa)m—Rb, —O—(CH2)m—C(O)NH—(CH2)m—Rb, —S—(CH2)m—C(O)NH—(CH2)m—Rb, —O—(CHRa)m—C(O)NH—(CHRa)m—Rb, —S—(CHRa)m—C(O)NH—(CHRa)m—Rb, —NH—(CH2)m—Rb, —NH—(CHRa)m—Rb, —NH[(CH2)mRb], —N[(CH2)mRb]2, —NH—C(O)—NH—(CH2)m—Rb, —NH—C(O)—(CH2)m—CHRbRb and —NH—(CH2)m—C(O)—NH—(CH2)m—Rb;
each Ra is independently selected from the group consisting of hydrogen, (C1–C6) alkyl, (C3–C8) cycloalkyl, cyclohexyl, (C4–C11) cycloalkylalkyl, (C5–C10) aryl, phenyl, (C6–C16) arylalkyl, benzyl, 2–6 membered heteroalkyl, 3–8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4–11 membered cycloheteroalkylalkyl, 5–10 membered heteroaryl and 6–16 membered heteroarylalkyl;
each Rb is a suitable group independently selected from the group consisting of ═O, —ORd, (C1–C3) haloalkyloxy, —OCF3, ═S, —SRd, ═NRd, ═NORd, —NRcRc, halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Rd, —S(O)2Rd, —S(O)2ORd, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd, —OS(O)2ORd, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc, —C(NRa)NRcRc, —C(NOH)Ra, —C(NOH)NRcRc, —OC(O)Rd, —OC(O)ORd, —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)NRcRc, —[NHC(O)]nRd, —[NRaC(O)]nRd, —[NHC(O)]nORd, —[NRaC(O)]nORd, —[NHC(O)]nNRcRc, —[NRaC(O)]nNRcRc, —[NHC(NH)]nNRcRc and —[NRaC(NRa)]nNRcRc;
each Rc is independently a protecting group or Ra, or, alternatively, each Rc is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is independently a protecting group or Ra;
each m is independently an integer from 1 to 3; and
each n is independently an integer from 0 to 3.
In another aspect, the present invention provides prodrugs of the 2,4-pyrimidinediamine compounds. Such prodrugs may be active in their prodrug form, or may be inactive until converted under physiological or other conditions of use to an active drug form. In the prodrugs of the invention, one or more functional groups of the 2,4-pyrimidinediamine compounds are included in promoieties that cleave from the molecule under the conditions of use, typically by way of hydrolysis, enzymatic cleavage or some other cleavage mechanism, to yield the functional groups. For example, primary or secondary amino groups may be included in an amide promoiety that cleaves under conditions of use to generate the primary or secondary amino group. Thus, the prodrugs of the invention include special types of protecting groups, termed “progroups,” masking one or more functional groups of the 2,4-pyrimidinediamine compounds that cleave under the conditions of use to yield an active 2,4-pyrimidinediamine drug compound. Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, carbonyls, phenols, catechols, diols, alkynes, phosphates, etc. Myriad progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs of the invention. Specific examples of promoieties that yield primary or secondary amine groups that can be included in the prodrugs of the invention include, but are not limited to amides, carbamates, imines, ureas, phosphenyls, phosphoryls and sulfenyls. Specific examples of promoieties that yield sulfanyl groups that can be included in the prodrugs of the invention include, but are not limited to, thioethers, for example S-methyl derivatives (monothio, dithio, oxythio, aminothio acetals), silyl thioethers, thioesters, thiocarbonates, thiocarbamates, asymmetrical disulfides, etc. Specific examples of promoieties that cleave to yield hydroxyl groups that can be included in the prodrugs of the invention include, but are not limited to, sulfonates, esters and carbonates. Specific examples of promoieties that yield carboxyl groups that can be included in the prodrugs of the invention included, but are not limited to, esters (including silyl esters, oxamic acid esters and thioesters), amides and hydrazides.
In one illustrative embodiment, the prodrugs of the invention are compounds according to structural formula (I) in which the protecting group of Rc and Rd is a progroup.
Replacing the hydrogens attached to N2 and N4 in the 2,4-pyrimidinediamines of structural formula (I) with substituents adversely affects the activity of the compounds. However, as will be appreciated by skilled artisans, these nitrogens may be included in promoieties that, under conditions of use, cleave to yield 2,4-pyrimidinediamines according to structural formula (I). Thus, in another illustrative embodiment, the prodrugs of the invention are compounds according to structural formula (II):




including salts, hydrates, solvates and N-oxides thereof, wherein:
R2, R4, R5, R6, L1 and L2 are as previously defined for structural formula (I); and
R2b and R4b are each, independently of one another, a progroup.
In another aspect, the present invention provides compositions comprising one or more compounds and/or prodrugs of the invention and an appropriate carrier, excipient or diluent. The exact nature of the carrier, excipient or diluent will depend upon the desired use for the composition, and may range from being suitable or acceptable for veterinary uses to being suitable or acceptable for human use.
In still another aspect, the present invention provides intermediates useful for synthesizing the 2,4-pyrimidinediamine compounds and prodrugs of the invention. In one embodiment, the intermediates are 4-pyrimidineamines according to structural formula (III):




including salts, hydrates, solvates and N-oxides thereof, wherein R4, R5, R6 and L2 are as previously defined for structural formula (I); LG is a leaving group such as, for example, —S(O)2Me, —SMe or halo (e.g., F, Cl, Br, I); and R4c is hydrogen or a progroup.
In another embodiment, the intermediates are 2-pyrimidineamines according to structural formula (IV):




including salts, hydrates, solvates and N-oxides thereof, wherein R2, R5, R6 and L1 are as previously defined for structural formula (I); LG is a leaving group, such as, for example, —S(O)2Me, —SMe or halo (e.g., F, Cl, Br, I) and R2c is hydrogen or a progroup.
In yet another embodiment, the intermediates are 4-amino- or 4-hydroxy-2-pyrimidineamines according to structural formula (V):




including salts, hydrates, solvates and N-oxides thereof, wherein R2, R5, R6 and L1 are as previously defined for structural formula (I), R7 is an amino or hydroxyl group and R2c is hydrogen or a progroup.
In another embodiment, the intermediates are N4-substituted cytosines according to structural formula (VI):




including salts, hydrates, solvates and N-oxides thereof, wherein R4, R5, R6 and L2 are as previously defined for structural formula (I) and R4c is hydrogen or a progroup.
In yet another aspect, the present invention provides methods of synthesizing the 2,4-pyrimidinediamine compounds and prodrugs of the invention. In one embodiment, the method involves reacting a 4-pyrimidineamine according to structural formula (III) with an amine of the formula HR2cN—L1—R2, where L1, R2 and R2c are as previously defined for structural formula (IV) to yield a 2,4-pyrimidinediamine according to structural formula (I) or a prodrug according to structural formula (II).
In another embodiment, the method involves reacting a 2-pyrimidineamine according to structural formula (IV) with an amine of the formula R4—L2—NHR4c where L4, R4 and R4c are as previously defined for structural formula (III) to yield a 2,4-pyrimidinediamine according to structural formula (I) or a prodrug according to structural formula (II).
In yet another embodiment, the method involves reacting a 4-amino-2-pyrimidineamine according to structural formula (V) (in which R7 is an amino group) with an amine of the formula R4—L2—NHR4c, where L2, R4 and R4c are as defined for structural formula (III), to yield a 2,4-pyrimidinediamine according to structural formula (I) or a prodrug according to structural formula (II). Alternatively, the 4-amino-2-pyrimidineamine may be reacted with a compound of the formula R4—L2—LG, where R4 and L2 are as previously defined for structural formula (I) and LG is a leaving group.
In still another embodiment, the method involves halogenating a 4-hydroxy-2-pyrimidineamine according to structural formula (V) (R7 is a hydroxyl group) to yield a 2-pyrimidineamine according to structural formula (IV) and reacting this pyrimidineamine with an appropriate amine, as described above.
In yet another embodiment, the method involves halogenating an N4-substituted cytosine according to structural formula (VI) to yield a 4-pyrimidineamine according to structural formula (III) and reacting this pyrimidineamine with an appropriate amine, as described above.
The 2,4-pyrimidinediamine compounds of the invention are potent inhibitors of degranulation of immune cells, such as mast, basophil, neutrophil and/or eosinophil cells. Thus, in still another aspect, the present invention provides methods of regulating, and in particular inhibiting, degranulation of such cells. The method generally involves contacting a cell that degranulates with an amount of a 2,4-pyrimidinediamine compound or prodrug of the invention, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to regulate or inhibit degranulation of the cell. The method may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with cellular degranulation.
While not intending to be bound by any theory of operation, biochemical data confirm that the 2,4-pyrimidinediamine compounds exert their degranulation inhibitory effect, at least in part, by blocking or inhibiting the signal transduction cascade(s) initiated by crosslinking of the high affinity Fc receptors for IgE (“FcεRI”) and/or IgG (“FcγRI”). Indeed, the 2,4-pyrimidinediamine compounds are potent inhibitors of both FcεRI-mediated and FcγRI-mediated degranulation. As a consequence, the 2,4-pyrimidine compounds may be used to inhibit these Fc receptor signalling cascades in any cell type expressing such FcεRI and/or FcγRI receptors including but not limited to macrophages, mast, basophil, neutrophil and/or eosinophil cells.
The methods also permit the regulation of, and in particular the inhibition of, downstream processes that result as a consequence of activating such Fc receptor signaling cascade(s). Such downstream processes include, but are not limited to, FcεRI-mediated and/or FcγRI-mediated degranulation, cytokine production and/or the production and/or release of lipid mediators such as leukotrienes and prostaglandins. The method generally involves contacting a cell expressing an Fc receptor, such as one of the cell types discussed above, with an amount of a 2,4-pyrimidinediamine compound or prodrug of the invention, or an acceptable salt, hydrate, solvent, N-oxide and/or composition thereof, effective to regulate or inhibit the Fc receptor signaling cascade and/or a downstream process effected by the activation of this signaling cascade. The method may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with the Fc receptor signaling cascade, such as diseases effected by the release of granule specific chemical mediators upon degranulation, the release and/or synthesis of cytokines and/or the release and/or synthesis of lipid mediators such as leukotrienes and prostaglandins.
In yet another aspect, the present invention provides methods of treating and/or preventing diseases characterized by, caused by or associated with the release of chemical mediators as a consequence of activating Fc receptor signaling cascades, such as FcεRI and/or FcγRI-signaling cascades. The methods may be practiced in animals in veterinary contexts or in humans. The methods generally involve administering to an animal subject or human an amount of a 2,4-pyrimidinediamine compound or prodrug of the invention, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to treat or prevent the disease. As discussed previously, activation of the FcεRI or FcγRI receptor signaling cascade in certain immune cells leads to the release and/or synthesis of a variety of chemical substances that are pharmacological mediators of a wide variety of diseases. Any of these diseases may be treated or prevented according to the methods of the invention.
For example, in mast cells and basophil cells, activation of the FcεRI or FcγRI signaling cascade leads to the immediate (i.e., within 1–3 min. of receptor activation) release of preformed mediators of atopic and/or Type I hypersensitivity reactions (e.g., histamine, proteases such as tryptase, etc.) via the degranulation process. Such atopic or Type I hypersensitivity reactions include, but are not limited to, anaphylactic reactions to environmental and other allergens (e.g., pollens, insect and/or animal venoms, foods, drugs, contrast dyes, etc.), anaphylactoid reactions, hay fever, allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic dermatitis, eczema, urticaria, mucosal disorders, tissue disorders and certain gastrointestinal disorders.
The immediate release of the preformed mediators via degranulation is followed by the release and/or synthesis of a variety of other chemical mediators, including, among other things, platelet activating factor (PAF), prostaglandins and leukotrienes (e.g., LTC4) and the de novo synthesis and release of cytokines such as TNFα, IL4, IL-5, IL-6, IL-13, etc. The first of these two processes occurs approximately 3–30 min. following receptor activation; the latter approximately 30 min.–7 hrs. following receptor activation. These “late stage” mediators are thought to be in part responsible for the chronic symptoms of the above-listed atopic and Type I hypersensitivity reactions, and in addition are chemical mediators of inflammation and inflammatory diseases (e.g., osteoarthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel disease, irritable bowel syndrome, spastic colon, etc.), low grade scarring (e.g., scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction), and sicca complex or syndrome. All of these diseases may be treated or prevented according to the methods of the invention.
Additional diseases which can be treated or prevented according to the methods of the invention include diseases associated with basophil cell and/or mast cell pathology. Examples of such diseases include, but are not limited to, diseases of the skin such as scleroderma, cardiac diseases such as post myocardial infarction, pulmonary diseases such as pulmonary muscle changes or remodeling and chronic obstructive pulmonary disease (COPD) and diseases of the gut such as inflammatory bowel syndrome (spastic colon).
The 2,4-pyrimidinediamine compounds of the invention are also potent inhibitors of the tyrosine kinase Syk kinase. Thus, in still another aspect, the present invention provides methods of regulating, and in particular inhibiting, Syk kinase activity. The method generally involves contacting a Syk kinase or a cell comprising a Syk kinase with an amount of a 2,4-pyrimidinediamine compound or prodrug of the invention, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to regulate or inhibit Syk kinase activity. In one embodiment, the Syk kinase is an isolated or recombinant Syk kinase. In another embodiment, the Syk kinase is an endogenous or recombinant Syk kinase expressed by a cell, for example a mast cell or a basophil cell. The method may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with Syk kinase activity.
While not intending to be bound by any particular theory of operation, it is believed that the 2,4-pyrimdinediamine compounds of the invention inhibit cellular degranulation and/or the release of other chemical mediators primarily by inhibiting Syk kinase that gets activated through the gamma chain homodimer of FcεRI (see, e.g., FIG. 2). This gamma chain homodimer is shared by other Fc receptors, including FcγRI, FcγRIII and FcαRI. For all of these receptors, intracellular signal transduction is mediated by the common gamma chain homodimer. Binding and aggregation of those receptors results in the recruitment and activation of tyrosine kinases such as Syk kinase. As a consequence of these common signaling activities, the 2,4-pyrimidinediamine compounds described herein may be used to regulate, and in particular inhibit, the signaling cascades of Fc receptors having this gamma chain homodimer, such as FcεRI, FcγRI, FcγRIII and FcαRI, as well as the cellular responses elicited through these receptors.
Syk kinase is known to play a critical role in other signaling cascades. For example, Syk kinase is an effector of B-cell receptor (BCR) signaling (Turner et al., 2000, Immunology Today 21:148–154) and is an essential component of integrin beta(1), beta(2) and beta(3) signaling in neutrophils (Mocsai et al., 2002, Immunity 16:547–558). As the 2,4-pyrimidinediamine compounds described herein are potent inhibitors of Syk kinase, they can be used to regulate, and in particular inhibit, any signaling cascade where Syk plays a role, such as, fore example, the Fc receptor, BCR and integrin signaling cascades, as well as the cellular responses elicited through these signaling cascades. The particular cellular response regulated or inhibited will depend, in part, on the specific cell type and receptor signaling cascade, as is well known in the art. Non-limiting examples of cellular responses that may be regulated or inhibited with the 2,4-pyrimidinediamine compounds include a respiratory burst, cellular adhesion, cellular degranulation, cell spreading, cell migration, phagocytosis (e.g., in macrophages), calcium ion flux (e.g., in mast, basophil, neutrophil, eosinophil and B-cells), platelet aggregation, and cell maturation (e.g., in B-cells).
Thus, in another aspect, the present invention provides methods of regulating, and in particular inhibiting, signal transduction cascades in which Syk plays a role. The method generally involves contacting a Syk-dependent receptor or a cell expressing a Syk-dependent receptor with an amount of a 2,4-pyrimidinediamine compound or prodrug of the invention, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to regulate or inhibit the signal transduction cascade. The methods may also be used to regulate, and in particular inhibit, downstream processes or cellular responses elicited by activation of the particular Syk-dependent signal transduction cascade. The methods may be practiced to regulate any signal trasduction cascade where Syk is not known or later discovered to play a role. The methods may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with activation of the Syk-dependent signal transduction cascade. Non-limited examples of such diseases include those previously discussed.



5. BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 provides a cartoon illustrating allergen-induced production of IgE and consequent release of preformed and other chemical mediators from mast cells;
FIG. 2 provides a cartoon illustrating the FcεR1 signal transduction cascade leading to degranulation of mast and/or basophil cells;
FIG. 3 provides a cartoon illustrating the putative points of action of compounds that selectively inhibit upstream FcεRI-mediated degranulation and compounds that inhibit both FcεRI-mediated and ionomycin-induced degranulation;
FIG. 4 provides graphs illustrating the effects of certain 2,4-pyrimidinediamine compounds, DMSO (control) and ionomycin on Ca2+ flux in CHMC cells;
FIG. 5 provides graphs illustrating the immediacy of the inhibitory activity of compounds R921218 and R926495;
FIG. 6 provides a graph illustrating the effect of washout on the inhibitory activity of compounds R921218 and R921302;
FIG. 7 provides data showing that varying concentrations of compounds R921218 (A) and R921219 (B) inhibit phosporylation of various proteins downstream of Syk kinase in the IgE receptor signal transduction cascade in activated BMMC cells;
FIG. 8 provides data showing dose responsive inhibition of Syk kinase phosphorylation of an endogenous substrate (LAT) and a peptide substrate in the presence of increasing concentrations of compounds R921218 (X), R921219 (Y) and R921304 (Z);
FIG. 9 provides data showing that the inhibition of Syk kinase by compound R921219 is ATP competitive;
FIG. 10 provides data showing that varying concentrations of compounds R921219 (A) and R218218 (B) inhibit phosphorylation of proteins downstream of Syk kinase, but not LYN kinase, in the FcεRI signal transduction cascade in activated CHMC cells; also shown is inhibition of phosphorylation of proteins downstream of LYN kinase but not Syk kinase, in the presence of a known LYN kinase inhibitor (PP2); and
FIGS. 11A–D provide data showing inhibition of phosphorylation of proteins downstream of Syk kinase in the FcεRI signal transduction cascade in BMMC cells.



6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
6.1 Definitions
As used herein, the following terms are intended to have the following meanings:
“Alkyl” by itself or as part of another substituent refers to a saturated or unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having the stated number of carbon atoms (i.e., C1–C6 means one to six carbon atoms) that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl , prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature “alkanyl,” “alkenyl” and/or “alkynyl” is used, as defined below. In preferred embodiments, the alkyl groups are (C1–C6) alkyl.
“Alkanyl” by itself or as part of another substituent refers to a saturated branched, straight-chain or cyclic alkyl derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like. In preferred embodiments, the alkanyl groups are (C1–C6) alkanyl.
“Alkenyl” by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl ; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like. In preferred embodiments, the alkenyl group is (C2–C6) alkenyl.
“Alkynyl” by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl , etc.; and the like. In preferred embodiments, the alkynyl group is (C2–C6) alkynyl.
“Alkyldiyl” by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group having the stated number of carbon atoms (i.e., C1–C6 means from one to six carbon atoms) derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms. Typical alkyldiyl groups include, but are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as, butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl, but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl, but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl, 2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl, buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl, but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Where it is specifically intended that the two valencies are on the same carbon atom, the nomenclature “alkylidene” is used. In preferred embodiments, the alkyldiyl group is (C1–C6) alkyldiyl. Also preferred are saturated acyclic alkanyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and the like (also referred to as alkylenos, defined infra).
“Alkyleno” by itself or as part of another substituent refers to a straight-chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne. The locant of a double bond or triple bond, if present, in a particular alkyleno is indicated in square brackets. Typical alkyleno groups include, but are not limited to, methano; ethylenos such as ethano, etheno, ethyno; propylenos such as propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenos such as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used. In preferred embodiments, the alkyleno group is (C1–C6) or (C1–C3) alkyleno. Also preferred are straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.
“Heteroalkyl,” Heteroalkanyl,” Heteroalkenyl,” Heteroalkynyl,” Heteroalkyldiyl” and “Heteroalkyleno” by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl and alkyleno groups, respectively, in which one or more of the carbon atoms are each independently replaced with the same or different heteratoms or heteroatomic groups. Typical heteroatoms and/or heteroatomic groups which can replace the carbon atoms include, but are not limited to, —O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)2—, —S(O)NR′—, —S(O)2NR′—, and the like, including combinations thereof, where each R′ is independently hydrogen or (C1–C6) alkyl.
“Cycloalkyl” and “Heterocycloalkyl” by themselves or as part of another substituent refer to cyclic versions of “alkyl” and “heteroalkyl” groups, respectively. For heteroalkyl groups, a heteroatom can occupy the position that is attached to the remainder of the molecule. Typical cycloalkyl groups include, but are not limited to, cyclopropyl; cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such as cyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl and cyclohexenyl; and the like. Typical heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, etc.), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, etc.), morpholinyl (e.g., morpholin-3-yl, morpholin-4-yl, etc.), piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, etc.), and the like.
“Acyclic Heteroatomic Bridge” refers to a divalent bridge in which the backbone atoms are exclusively heteroatoms and/or heteroatomic groups. Typical acyclic heteroatomic bridges include, but are not limited to, —O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)2—, —S(O) NR′—, —S(O)2NR′—, and the like, including combinations thereof, where each R′ is independently hydrogen or (C1–C6) alkyl.
“Parent Aromatic Ring System” refers to an unsaturated cyclic or polycyclic ring system having a conjugated π electron system. Specifically included within the definition of “parent aromatic ring system” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, tetrahydronaphthalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers thereof.
“Aryl” by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon group having the stated number of carbon atoms (i.e., C5–C15 means from 5 to 15 carbon atoms) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers thereof. In preferred embodiments, the aryl group is (C5–C15) aryl, with (C5–C10) being even more preferred. Particularly preferred aryls are cyclopentadienyl, phenyl and naphthyl.
“Arylaryl” by itself or as part of another substituent refers to a monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non-identical parent aromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of parent aromatic ring systems involved. Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-naphthyl, binaphthyl, biphenyl-naphthyl, and the like. Where the number of carbon atoms in an arylaryl group are specified, the numbers refer to the carbon atoms comprising each parent aromatic ring. For example, (C5–C15) arylaryl is an arylaryl group in which each aromatic ring comprises from 5 to 15 carbons, e.g., biphenyl, triphenyl, binaphthyl, phenylnaphthyl, etc. Preferably, each parent aromatic ring system of an arylaryl group is independently a (C5–C15) aromatic, more preferably a (C5–C10) aromatic. Also preferred are arylaryl groups in which all of the parent aromatic ring systems are identical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.
“Biaryl” by itself or as part of another substituent refers to an arylaryl group having two identical parent aromatic systems joined directly together by a single bond. Typical biaryl groups include, but are not limited to, biphenyl, binaphthyl, bianthracyl, and the like. Preferably, the aromatic ring systems are (C5–C15) aromatic rings, more preferably (C5–C10) aromatic rings. A particularly preferred biaryl group is biphenyl.
“Arylalkyl” by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylakenyl and/or arylalkynyl is used. In preferred embodiments, the arylalkyl group is (C6–C21) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1–C6) and the aryl moiety is (C5–C15). In particularly preferred embodiments the arylalkyl group is (C6–C13), e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C1–C3) and the aryl moiety is (C5–C10).
“Parent Heteroaromatic Ring System” refers to a parent aromatic ring system in which one or more carbon atoms are each independently replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups to replace the carbon atoms include, but are not limited to, N, NH, P, O, S, S(O), S(O)2, Si, etc. Specifically included within the definition of “parent heteroaromatic ring systems” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Also included in the definition of “parent heteroaromatic ring system” are those recognized rings that include common substituents, such as, for example, benzopyrone and 1-methyl-1,2,3,4-tetrazole. Specifically excluded from the definition of “parent heteroaromatic ring system” are benzene rings fused to cyclic polyalkylene glycols such as cyclic polyethylene glycols. Typical parent heteroaromatic ring systems include, but are not limited to, acridine, benzimidazole, benzisoxazole, benzodioxan, benzodioxole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotriazole, benzoxaxine, benzoxazole, benzoxazoline, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.
“Heteroaryl” by itself or as part of another substituent refers to a monovalent heteroaromatic group having the stated number of ring atoms (e.g., “5–14 membered” means from 5 to 14 ring atoms) derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, benzimidazole, benzisoxazole, benzodioxan, benzodiaxole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotriazole, benzoxazine, benzoxazole, benzoxazoline, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like, as well as the various hydro isomers thereof. In preferred embodiments, the heteroaryl group is a 5–14 membered heteroaryl, with 5–10 membered heteroaryl being particularly preferred.
“Heteroaryl-Heteroaryl” by itself or as part of another substituent refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a ring system in which two or more identical or non-identical parent heteroaromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of parent heteroaromatic ring systems involved. Typical heteroaryl-heteroaryl groups include, but are not limited to, bipyridyl, tripyridyl, pyridylpurinyl, bipurinyl, etc. Where the number of atoms are specified, the numbers refer to the number of atoms comprising each parent heteroaromatic ring systems. For example, 5–15 membered heteroaryl-heteroaryl is a heteroaryl-heteroaryl group in which each parent heteroaromatic ring system comprises from 5 to 15 atoms, e.g., bipyridyl, tripuridyl, etc. Preferably, each parent heteroaromatic ring system is independently a 5–15 membered heteroaromatic, more preferably a 5–10 membered heteroaromatic. Also preferred are heteroaryl-heteroaryl groups in which all of the parent heteroaromatic ring systems are identical.
“Biheteroaryl” by itself or as part of another substituent refers to a heteroaryl-heteroaryl group having two identical parent heteroaromatic ring systems joined directly together by a single bond. Typical biheteroaryl groups include, but are not limited to, bipyridyl, bipurinyl, biquinolinyl, and the like. Preferably, the heteroaromatic ring systems are 5–15 membered heteroaromatic rings, more preferably 5–10 membered heteroaromatic rings.
“Heteroarylalkyl” by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylakenyl and/or heteroarylalkynyl is used. In preferred embodiments, the heteroarylalkyl group is a 6–21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is (C1–C6) alkyl and the heteroaryl moiety is a 5–15-membered heteroaryl. In particularly preferred embodiments, the heteroarylalkyl is a 6–13 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C1–C3) alkyl and the heteroaryl moiety is a 5–10 membered heteroaryl.
“Halogen” or “Halo” by themselves or as part of another substituent, unless otherwise stated, refer to fluoro, chloro, bromo and iodo.
“Haloalkyl” by itself or as part of another substituent refers to an alkyl group in which one or more of the hydrogen atoms is replaced with a halogen. Thus, the term “haloalkyl” is meant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls. For example, the expression “(C1–C2) haloalkyl” includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.
The above-defined groups may include prefixes and/or suffixes that are commonly used in the art to create additional well-recognized substituent groups. As examples, “alkyloxy” or “alkoxy” refers to a group of the formula —OR′′, “alkylamine” refers to a group of the formula —NHR′′ and “dialkylamine” refers to a group of the formula —NR′′R′′, where each R′′ is independently an alkyl. As another example, “haloalkoxy” or “haloalkyloxy” refers to a group of the formula —OR′′′, where R′′′ is a haloalkyl.
“Protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1–8, 1971–1996, John Wiley & Sons, NY. 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 where the hydroxyl group is either acylated or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.
“Prodrug” refers to a derivative of an active 2,4-pyrimidinediamine compound (drug) that requires a transformation under the conditions of use, such as within the body, to release the active 2,4-pyrimidinediamine drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Prodrugs are typically obtained by masking a functional group in the 2,4-pyrimidinediamine drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active 2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid or base, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature. The agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.
A wide variety of progroups, as well as the resultant promoieties, suitable for masking functional groups in the active 2,4-pyrimidinediamines compounds to yield prodrugs are well-known in the art. For example, a hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivo to provide the hydroxyl group. An amino functional group may be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in vivo to provide the amino group. A carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group. Other specific examples of suitable progroups and their respective promoieties will be apparent to those of skill in the art.
“Progroup” refers to a type of protecting group that, when used to mask a functional group within an active 2,4-pyrimidinediamine drug to form a promoiety, converts the drug into a prodrug. Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use. Thus, a progroup is that portion of a promoiety that cleaves to release the functional group under the specified conditions of use. As a specific example, an amide promoiety of the formula —NH—C(O)CH3 comprises the progroup —C(O)CH3.
“Fc Receptor” refers to a member of the family of cell surface molecules that binds the Fc portion (containing the specific constant region) of an immunoglobulin. Each Fc receptor binds immunoglobulins of a specific type. For example the Fcα receptor (“FcαR”) binds IgA, the FcεR binds IgE and the FcγR binds IgG.
The FcαR family includes the polymeric Ig receptor involved in epithelial transport of IgA/IgM, the mycloid specific receptor RcαRI (also called CD89), the Fcα/μR and at least two alternative IgA receptors (for a recent review see Monteiro & van de Winkel, 2003, Annu. Rev. Immunol, advanced e-publication. The FcαRI is expressed on neutrophils, eosinophils, moncytes/macrophages, dendritic cells and kupfer cells. The FcαRI inclues one alpha chain and the FcR gamma homodimer that bears an activation motif (ITAM) in the cytoplasmic domain and phosphorylates Syk kinase.
The FcεR family includes two types, designated FcεRI and FcεRII (also known as CD23). FcεRI is a high affinity receptor (binds IgE with an affinity of about 1010M−1) found on mast, basophil and eosinophil cells that anchors monomeric IgE to the cell surface. The FcεRI possesses one alpha chain, one beta chain and the gamma chain homodimer discussed above. The FcεRII is a low affinity receptor expressed on mononuclear phagocytes, B lymphocytes, eosinophils and platelets. The FcεRII comprises a single polypeptide chain and does not include the gamma chain homodimer.
The FcγR family includes three types, designated FcγRI (also known as CD64), FcγRII (also known as CD32) and FcγRIII (also known as CD16). FcγRI is a high affinity receptor (binds IgG1 with an affinity of 108M−1) found on mast, basophil, mononuclear, neutrophil, eosinophil, deudritic and phagocyte cells that anchors nomomeric IgG to the cell surface. The FcγRI includes one alpha chain and the gamma chain dimer shared by FcαRI and FcεRI.
The FcγRII is a low affinity receptor expressed on neutrophils, monocytes, eosinophils, platelets and B lymphocytes. The FcγRII includes one alpha chain, and does not include the gamma chain homodimer discussed above.
The FcγRIII is a low affinity (bindes IgG1 with an affinity of 5×105M−1) expressed on NK, eosinophil, macrophage, neutrophil and mast cells. It comprises one alpha chain and the gamma homodimer shared by FcαRI, FcεRI and FcγRI.
Skilled artisans will recognize that the subunit structure and binding properties of these various Fc receptors, cell types expressing them, are not completely characterized. The above discussion merely reflects the current state-of-the-art regarding these receptors (see, e.g., Immunobiology: The Immune System in Health & Disease, 5th Edition, Janeway et al., Eds, 2001, ISBN 0-8153-3642-x, FIG. 9.30 at pp. 371), and is not intended to be limiting with respect to the myriad receptor signaling cascades that can be regulated with the compounds described herein.
“Fc Receptor-Mediated Degranulation” or “Fc Receptor-Induced Degranulation” refers to degranulation that proceeds via an Fc receptor signal transduction cascade initiated by crosslinking of an Fc receptor.
“IgE-Induced Degranulation” or “FcεRI-Mediated Degranulation” refers to degranulation that proceeds via the IgE receptor signal transduction cascade initiated by crosslinking of FcεR1-bound IgE. The crosslinking may be induced by an IgE-specific allergen or other multivalent binding agent, such as an anti-IgE antibody. Referring to FIG. 2, in mast and/or basophil cells, the FcεRI signaling cascade leading to degranulation may be broken into two stages: upstream and downstream. The upstream stage includes all of the processes that occur prior to calcium ion mobilization (illustrated as “Ca2+” in FIG. 2; see also FIG. 3). The downstream stage includes calcium ion mobilization and all processes downstream thereof. Compounds that inhibit FcεRI-mediated degranulation may act at any point along the FcεRI-mediated signal transduction cascade. Compounds that selectively inhibit upstream FcεRI-mediated degranulation act to inhibit that portion of the FcεRI signaling cascade upstream of the point at which calcium ion mobilization is induced. In cell-based assays, compounds that selectively inhibit upstream FcεRI-mediated degranulation inhibit degranulation of cells such as mast or basophil cells that are activated or stimulated with an IgE-specific allergen or binding agent (such as an anti-IgE antibody) but do not appreciably inhibit degranulation of cells that are activated or stimulated with degranulating agents that bypass the FcεRI signaling pathway, such as, for example the calcium ionophores ionomycin and A23187.
“IgG-Induced Degranulation” or “FcγRI-Mediated Degranulation” refers to degranulation that proceeds via the FcγRI signal transduction cascade initiated by crosslinking of FcγRI-bound IgG. The crosslinking may be induced by an IgG-specific allergen or another multivalent binding agent, such as an anti-IgG or fragment antibody. Like the FcεRI signaling cascade, in mast and basophil cells the FcγRI signaling cascade also leads to degranulation which may be broken into the same two stages: upstream and downstream. Similar to FcεRI-mediated degranulation, compounds that selectively inhibit upstream FcγRI-mediated degranulation act upstream of the point at which calcium ion mobilization is induced. In cell-based assays, compounds that selectively inhibit upstream FcγRI-mediated degranulation inhibit degranulation of cells such as mast or basophil cells that are activated or stimulated with an IgG-specific allergen or binding agent (such as an anti-IgG antibody or fragment) but do not appreciably inhibit degranulation of cells that are activated or stimulated with degranulating agents that bypass the FcγRI signaling pathway, such as, for example the calcium ionophores ionomycin and A23187.
“Ionophore-Induced Degranulation” or “Ionophore-Mediated Degranulation” refers to degranulation of a cell, such as a mast or basophil cell, that occurs upon exposure to a calcium ionophore such as, for example, ionomycin or A23187.
“Syk Kinsase” refers to the well-known 72 kDa non-receptor (cytoplasmic) spleen protein tyrosine kinase expressed in B-cells and other hematopoetic cells. Syk kinase includes two consensus Src-homology 2 (SH2) domains in tandem that bind to phosphorylated immunoreceptor tyrosine-based activation motifs (“ITAMs”), a “linker” domain and a catalytic domain (for a review of the structure and function of Syk kinase see Sada et al., 2001, J. Biochem. (Tokyo) 130:177–186); see also Turner et al., 2000, Immunology Today 21:148–154). Syk kinase has been extensively studied as an effector of B-cell receptor (BCR) signaling (Turner et al., 2000, supra). Syk kinase is also critical for tyrosine phosphorylation of multiple proteins which regulate important pathways leading from immunoreceptors, such as Ca2+ mobilization and mitogen-activated protein kinase (MAPK) cascades (see, e.g., FIG. 2) and degranulation. Syk kinase also plays a critical role in integrin signaling in neutrophils (see, e.g., Mocsai et al. 2002, Immunity 16:547–558).
As used herein, Syk kinase includes kinases from any species of animal, including but not limited to, homosapiens, simian, bovine, porcine, rodent, etc., recognized as belonging to the Syk family. Specifically included are isoforms, splice variants, allelic variants, mutants, both naturally occuring and man-made. The amino acid sequences of such Syk kinases are well known and available from GENBANK. Specific examples of mRNAs encoding different isoforms of human Syk kinase can be found at GENBANK accession no. gi|21361552|ref|NM—003177.2|, gi|496899|emb|Z29630.1|HSSYKPTK[496899] and gi|15030258|gb|BC011399.1|BC011399[15030258], which are incorporated herein by reference.
Skilled artisans will appreciate that tyrosine kinases belonging to other families may have active sites or binding pockets that are similar in three-dimensional structure to that of Syk. As a consequence of this structural similarity, such kinases, referred to herein as “Syk mimics,” are expected to catalyze phosphorylation of substrates phosphorylated by Syk. Thus, it will be appreciated that such Syk mimics, signal transduction cascades in which such Syk mimics play a role and biological responses effected by such Syk mimics and Syk mimic-dependent signaling cascades may be regulated, and in particular inhibited, with the 2,4-pyrimidinediamine compounds described herein.
“Syk-Dependent Signaling Cascade” refers to a signal transduction cascade in which Syk kinase plays a role. Non-limiting examples of such Syk-dependent signaling cascades include the FcαRI, FcεRI, FcγRI, FcγRIII, BCR and integrin signaling cascades.
6.2 The 2,4-Pyrimidinediamine Compounds
The compounds of the invention are generally 2,4-pyrimidinediamine compounds according to structural formula (I):




including salts, hydrates, solvates and N-oxides thereof, wherein:
L1 and L2 are each, independently of one another, selected from the group consisting of a direct bond and a linker;
R2 is selected from the group consisting of (C1–C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C3–C8) cycloalkyl optionally substituted with one or more of the same or different R8 groups, cyclohexyl optionally substituted with one or more of the same or different R8 groups, 3–8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R8 groups, (C5–C15) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups and 5–15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R4 is selected from the group consisting of hydrogen, (C1–C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C3–C8) cycloalkyl optionally substituted with one or more of the same or different R8 groups, cyclohexyl optionally substituted with one or more of the same or different R8 groups, 3–8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R8 groups, (C5–C15) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups and 5–15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R5 is selected from the group consisting of R6, (C1–C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C1–C4) alkanyl optionally substituted with one or more of the same or different R8 groups, (C2–C4) alkenyl optionally substituted with one or more of the same or different R8 groups and (C2–C4) alkynyl optionally substituted with one or more of the same or different R8 groups;
each R6 is independently selected from the group consisting of hydrogen, an electronegative group, —ORd, —SRd, (C1–C3) haloalkyloxy, (C1–C3) perhaloalkyloxy, —NRcRc, halogen, (C1–C3) haloalkyl, (C1–C3) perhaloalkyl, —CF3, —CH2CF3, —CF2CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, —N3, —S(O)Rd, —S(O)2Rd, —S(O)2ORd, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd, —OS(O)2ORd, —OS(O)NRcRc, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc, —OC(O)Rd, —SC(O)Rd, —OC(O)ORd, —SC(O)ORd, —OC(O)NRcRc, —SC(O)NRcRc, —OC(NH)NRcRc, —SC(NH)NRcRc, —[NHC(O)]nRd, —[NHC(O)]nORd, —[NHC(O)]nNRcRc and —[NHC(NH)]nNRcRc, (C5-C10) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups, (C6–C16) arylalkyl optionally substituted with one or more of the same or different R8 groups, 5–10 membered heteroaryl optionally substituted with one or more of the same or different R8 groups and 6–16 membered heteroarylalkyl optionally substituted with one or more of the same or different R8 groups;
R8 is selected from the group consisting of Ra, Rb, Ra substituted with one or more of the same or different Ra or Rb, —ORa substituted with one or more of the same or different Ra or Rb, —B(ORa)2, —B(NRcRc)2, —(CH2)m—Rb, —(CHRa)m—Rb, —O—(CH2)m—Rb, —S—(CH2)m—Rb, —O—CHRaRb, —O—CRa(R)2, —O—(CHRa)m—Rb, —O—(CH2)m—CH[(CH2)mRb]Rb, —S—(CHRa)m—Rb, —C(O)NH—(CH2)m—Rb, —C(O)NH—(CHRa)m—Rb, —O—(CH2)m—C(O)NH—(CH2)m—Rb, —S—(CH2)m—C(O)NH—(CH2)m—Rb, —O—(CHRa)m—C(O)NH—(CHRa)m—Rb—S—(CHRa)m—C(O)NH—(CHRa)m—Rb, —NH—(CH2)m—Rb, —NH—(CHRa)m—Rb, —NH[(CH2)mRb], —N[(CH2)mRb]2, —NH—C(O)—NH—(CH2)m—Rb, —NH—C(O)—(CH2)m—CHRbRb and —NH—(CH2)m—C(O)—NH—(CH2)m—Rb;
each Ra is independently selected from the group consisting of hydrogen, (C1–C6) alkyl, (C3–C8) cycloalkyl, cyclohexyl, (C4–C11) cycloalkylalkyl, (C5–C10) aryl, phenyl, (C6–C16) arylalkyl, benzyl, 2–6 membered heteroalkyl, 3–8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4–11 membered cycloheteroalkylalkyl, 5–10 membered heteroaryl and 6–16 membered heteroarylalkyl;
each Rb is a suitable group independently selected from the group consisting of ═O, —ORd, (C1–C3) haloalkyloxy, —OCF3, ═S, —SRd, ═NRd, ═NORd, —NRcRc, halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Rd, —S(O)2Rd, —S(O)2ORd, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd, —OS(O)2ORd, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc, —C(NRa)NRcRc, —C(NOH)Ra, —C(NOH)NRcRc, —OC(O)Rd, —OC(O)ORd, —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)NRcRc, —[NHC(O)]nRd, —[NRaC(O)]nRd, —[NHC(O)]nORd, —[NRaC(O)]nORd, —[NHC(O)]nNRcRc, —[NRaC(O)]nNRcRc, —[NHC(NH)]nNRcRc and —[NRaC(NRa)]nNRcRc;
each Rc is independently Ra, or, alternatively, each Rc is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is independently Ra;
each m is independently an integer from 1 to 3; and
each n is independently an integer from 0 to 3.
In the compounds of structural formula (I), L1 and L2 represent, independently of one another, a direct bond or a linker. Thus, as will be appreciated by skilled artisans, the substituents R2 and/or R4 may be bonded either directly to their respective nitrogen atoms or, alternatively, spaced away from their respective nitrogen atoms by way of a linker. The identity of the linker is not critical and typical suitable linkers include, but are not limited to, (C1–C6) alkyldiyls, (C1–C6) alkanos and (C1–C6) heteroalkyldiyls, each of which may be optionally substituted with one or more of the same or different R8 groups, where R8 is as previously defined for structural formula (I). In a specific embodiment, L1 and L2 are each, independently of one another, selected from the group consisting of a direct bond, (C1–C3) alkyldiyl optionally substituted with one or more of the same or different Ra, suitable Rb or R9 groups and 1–3 membered heteroalkyldiyl optionally substituted with one or more of the same or different Ra, suitable Rb or R9 groups, wherein R9 is selected from the group consisting of (C1–C3) alkyl, —ORa, —C(O)ORa, (C5–C10) aryl optionally substituted with one or more of the same or different halogens, phenyl optionally substituted with one or more of the same or different halogens, 5–10 membered heteroaryl optionally substituted with one or more of the same or different halogens and 6 membered heteroaryl optionally substituted with one or more of the same or different halogens; and Ra and Rb are as previously defined for structural formula (I). Specific R9 groups that may be used to substitute L1 and L2 include —ORa, —C(O)ORa, phenyl, halophenyl and 4-halophenyl, wherein Ra is as previously defined for structural formula (I).
In another specific embodiment, L1 and L2 are each, independently of one another, selected from the group consisting of methano, ethano and propano, each of which may be optionally monosubstituted with an R9 group, where R9is as previously defined above.
In all of the above embodiments, specific Ra groups that may be included in R9 groups are selected from the group consisting of hydrogen, (C1–C6) alkyl, phenyl and benzyl.
In still another specific embodiment, L1 and L2 are each a direct bond such that the 2,4-pyrimidinediamine compounds of the invention are compounds according to structural formula (Ia):




including salts, hydrates, solvates and N-oxides thereof, wherein R2, R4, R5 and R6 are as previously defined for structural formula (I). Additional specific embodiments of the 2,4-pyrimidinediamine compounds of the invention are described below.
In a first embodiment of the compounds of structural formulae (I) and (Ia), R2, R4, R5, R6, L1 and L2 are as previously defined for their respective structures (I) and (Ia), with the proviso that R2 is not 3,4,5-trimethoxyphenyl, 3,4,5-tri (C1–C6) alkoxyphenyl or




where R21, R22 and R23 are as defined for R1, R2 and R3, respectively of U.S. Pat. No. 6,235,746, the disclosure of which is incorporated by reference. In a specific embodiment of this first embodiment, R21 is hydrogen, halo, straight-chain or branched (C1–C6) alkyl optionally substituted with one or more of the same or different R25 groups, hydroxyl, (C1–C6) alkoxy optionally substituted with one or more of the same or different phenyl or R25 groups, thiol (—SH), (C1–C6) alkylthio optionally substituted with one or more of the same or different phenyl or R25 groups, amino (—NH2), —NHR26 or —NR26R26; R22 and R23 are each, independently of one another, a (C1–C6) straight-chain or branched alkyl optionally substituted with one or more of the same or different R25 groups; R25 is selected from the group consisting of halo, hydroxyl, (C1–C6) alkoxy, thiol, (C1–C6) alkylthio, (C1–C6) alkylamino and (C1–C6) dialkylamino; and each R26 is independently a (C1–C6) alkyl optionally substituted with one or more of the same or different phenyl or R25 groups or a —C(O)R27, where R27 is a (C1–C6) alkyl optionally substituted with one or more of the same or different phenyl or R25 groups.
In another specific embodiment of this first embodiment, R21 is methoxy optionally substituted with one or more of the same or different halo groups and/or R22 and R23 are each, independently of one another, a methyl or ethyl optionally substituted with one or more of the same or different halo groups.
In a second embodiment of the compounds of structural formulae (I) and (Ia), R2, R4, R5 and L2 are as previously described for their respective structures (I) and (Ia), L1 is a direct bond and R6 is hydrogen, with the proviso that R2 is not 3,4,5-trimethoxyphenyl, 3,4,5-tri (C1–C6) alkoxyphenyl or




where R21, R22 and R23 are as defined above, in connection with the first embodiment.
In a third embodiment, the 2,4-pyrimidinediamine compounds of structural formulae (I) and (Ia) exclude one or more of the following compounds:
N2,N4-bis(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R070790);
N2,N4-bis(2-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R081166);
N2,N4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R088814);
N2,N4-bis(2-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R088815);
N2,N4-bisphenyl-5-fluoro-2,4-pyrimidinediamine (R091880);
N2,N4-bis(3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (R092788);
N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R067962);
N2,N4-bis(2,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067963);
N2,N4-bis(3,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067964);
N2,N4-bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R0707153);
N2,N4-bis(2,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R070791);
N2,N4-bis(3-bromophenyl)-5-fluoro-2,4-pyrimidinediamine (R008958);
N2,N4-bis(phenyl)-5-fluoro-2,4-pyrimidinediamine;
N2,N4-bis(morpholino)-5-fluoro-2,4-pyrimidinediamine; and
N2,N4-bis[(3-chloro-4-methoxyphenyl)]-5-fluoro-2,4-pyrimidinediamine.
In a fourth embodiment, the compounds of structural formulae (I) and (Ia) exclude compounds according to the following structural formula (Ib):




wherein R24 is (C1–C6) alkyl; and R21, R22 and R23 are as previously defined in connection with the first embodiment.
In a fifth embodiment, the compounds of structural formulae (I) and (Ia) exclude the compounds described in Examples 1–141 of U.S. Pat. No. 6,235,746, the disclosure of which is incorporated herein by reference.
In a sixth embodiment, the compounds of structural formulae (I) and (Ia) exclude compounds defined by formula (1) or formula 1(a) of this U.S. Pat. No. 6,235,746 (see, e.g., the disclosure at Col. 1, line 48 through Col. 7, line 49 and Col. 8, lines 9–36, which is incorporated by reference).
In a seventh embodiment, the compounds of structural formulae (I) and (Ia) exclude compounds in which R5 is cyano or —C(O)NHR, where R is hydrogen or (C1–C6) alkyl, when R2 is a substituted phenyl; R4 is a substituted or unsubstituted (C1–C6) alkyl, (C3–C8) cycloalkyl, 3–8 membered cycloheteralkyl or 5–15 membered heteroaryl; and R6 is hydrogen.
In an eighth embodiment, the compounds of structural formulae (I) and (Ia) exclude the compounds defined by formulae (I) and (X) of WO 02/04429 or any compound disclosed in WO 02/04429, the disclosure of which is incorporated herein by reference.
In a ninth embodiment of the compounds of structural formulae (I) and (Ia), when R5 is cyano or —C(O)NHR, where R is hydrogen or (C1–C6) alkyl; and R6 is hydrogen, then R2 is other than a substituted phenyl group.
In a tenth embodiment, the compounds of structural formulae (I) and (Ia) exclude compounds in which R2 and R4 are each independently a substituted or unsubstituted pyrrole or indole ring which is attached to the remainder of the molecule via its ring nitrogen atom.
In an eleventh embodiment, the compounds of structural formulae (I) and (Ia) exclude compounds defined by formulae (I) and (IV) of U.S. Pat. No. 4,983,608 or any compound disclosed in U.S. Pat. No. 4,983,608, the disclosure of which is incorporated herein by reference.
Those of skill in the art will appreciate that in the compounds of formulae (I) and (Ia), R2 and R4 may be the same or different, and may vary broadly. When R2 and/or R4 are optionally substituted rings, such as optionally substituted cycloalkyls, cycloheteroalkyls, aryls and heteroaryls, the ring may be attached to the remainder of the molecule through any available carbon or heteroatom. The optional substituents may be attached to any available carbon atoms and/or heteroatoms.
In a twelfth embodiment of the compounds of structural formulae (I) and (Ia), R2 and/or R4 is an optionally substituted phenyl or an optionally substituted (C5–C15) aryl, subject to the provisos that (1) when R6 is hydrogen, then R2 is not 3,4,5-trimethoxyphenyl or 3,4,5-tri (C1–C6) alkoxyphenyl; (2) when R2 is a 3,4,5-trisubstituted phenyl, then the substituents at the 3- and 4-positions are not simultaneously methoxy or (C1–C6) alkoxy; or (3) when R6 is hydrogen and R4 is (C1–C6) alkyl, (C3-C8) cycloalkyl, 3–8 membered cycloheteroalkyl or 5–15 membered heteroaryl, then R5 is other than cyano. Alternatively, R2 is subject to the provisos described in connection with the first or second embodiments. The optionally substituted aryl or phenyl group may be attached to the remainder of the molecule through any available carbon atom. Specific examples of optionally substituted phenyls include phenyls that are optionally mono-, di- or tri-substituted with the same or different R8 groups, where R8 is as previously defined for structural formula (I) and subject to the above provisos. When the phenyl is mono-substituted, the R8 substituent may be positioned at either the ortho, meta or para position. When positioned at the ortho, meta or para position, R8 is preferably selected from the group consisting of (C1-C10) alkyl, (C1–C10) branched alkyl, —ORa optionally substituted with one or more of the same or different Rb groups, —O—C(O)ORa, —O—(CH2)m—C(O)ORa, —C(O)ORa, —O—(CH2)m—NRcRc, —O—C(O)NRcRc, —O—(CH2)m—C(O)NRcRc, —O—C(NH)NRcRc, —O—(CH2)m—C(NH)NRcRc and —NH—(CH2)m—NRcRc, where m, Ra and Rc are as previously defined for structural formula (I). In one embodiment of these compounds, —NRcRc is a 5–6 membered heteroaryl which optionally includes one or more of the same or different additional heteroatoms. Specific examples of such 5–6 membered heteroaryls include, but are not limited to, oxadiazolyl, triazolyl, thiazolyl, oxazolyl, tetrazolyl and isoxazolyl.
In another embodiment of these compounds, —NRcRc is a 5–6 membered saturated cycloheteroalkyl ring which optionally includes one or more of the same or different heteroatoms. Specific examples of such cycloheteroalkyls include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl.
In still another embodiment of these compounds, each Ra is independently a (C1–C6) alkyl and/or each —NRcRc is —NHRa, where Ra is a (C1–C6) alkyl. In one specific embodiment, R8 is —O—CH2—C(O)NHCH3. In another specific embodiment R8 is —OH.
When the phenyl is di-substituted or tri-substituted, the R8 substituents may be positioned at any combination of positions. For example, the R8 substituents may be positioned at the 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6-, 2,5,6- or 3,4,5-positions. In one embodiment of compounds including a disubstituted phenyl, the substituents are positioned other than 3,4. In another embodiment they are positioned 3,4. In one embodiment of compounds including a trisubstituted phenyl, the substituents are positioned other than 3,4,5 or, alternatively, no two of the substituents are positioned 3,4. In another embodiment, the substituents are positioned 3,4,5.
Specific examples of R8 substituents in such di- and trisubstituted phenyls include the various R8 substituents described above in connection with the ortho, meta and para substituted phenyls.
In another specific embodiment, R8 substituents useful for substitituting such di- and trisubstituted phenyls include (C1–C6) alkyl, (C1–C6) alkoxy, methoxy, halo, chloro, (C1–C6) perhaloalkyl, —CF3, (C1–C6) perhaloalkoxy and —OCF3. In a preferred embodiment, such R8 substituents are positioned 3,4 or 3,5. Specific examples of preferred di-substituted phenyl rings include 3-chloro4-methoxy-phenyl, 3-methoxy4-chlorophenyl, 3-chloro4-trifluoromethoxy-phenyl, 3-trifluoromethoxy4-chloro-phenyl, 3,4-dichloro-phenyl, 3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl, with the provisos that: (1) when R4 is one of the above-identified phenyls, and R5 and R6 are each hydrogen, then R2 is not 3,4,5-tri(C1–C6)alkoxyphenyl or 3,4,5-trimethoxyphenyl; (2) when R2 is 3,4-dimethoxyphenyl and R5 and R6 are each hydrogen, then R4 is not 3-(C1–C6)alkoxyphenyl, 3-methoxyphenyl, 3,4-di-(C1–C6) alkoxyphenyl or 3,4-dimethoxyphenyl; (3) when R4 is 3-chloro4-methoxyphenyl and R5 is halo or fluoro, and optionally R6 is hydrogen, then R2 is not 3-chloro-4-(C1–C6)alkoxyphenyl or 3-chloro4-methoxyphenyl; (4) when R4 is 3,4-dichlorophenyl, R5 is hydrogen, (C1–C6) alkyl, methyl, halo or chloro and optionally R6 is hydrogen, then R2 is not a phenyl mono substituted at the para position with a (C1–C6) alkoxy group which is optionally substituted with one or more of the same or different Rb, —OH or —NRcRc groups, where Rb and Rc are as previously described for structural formula (I); and/or (5) R2 and/or R4 is not 3,4,5-tri(C1–C6)alkoxyphenyl or 3,4,5-trimethoxyphenyl, especially when R5 and R6 are each hydrogen.
In another embodiment of compounds including a trisubstituted phenyl, the trisubstituted phenyl has the formula:




wherein: R31 is methyl or (C1–C6) alkyl; R32 is hydrogen, methyl or (C1–C6) alkyl; and R33 is a halo group.
In a thirteenth embodiment of the compounds of structural formulae (I) and (Ia), R2 and/or R4 is an optionally substituted heteroaryl. Typical heteroaryl groups according to this thirteenth embodiment comprise from 5 to 15, and more typically from 5 to 11 ring atoms, and include one, two, three or four of the same or different heteratoms or heteroatomic groups selected from the group consisting of N, NH, O, S, S(O) and S(O)2. The optionally substituted heteroaryl may be attached to its respective C2 or C4 nitrogen atom or linker L1 or L2 through any available carbon atom or heteroatom, but is typically attached via a carbon atom. The optional substituents may be the same or different, and may be attached to any available carbon atom or heteroatom. In one embodiment of these compounds, R5 is other than bromo, nitro, trifluoromethyl, cyano or —C(O)NHR, where R is hydrogen or (C1–C6) alkyl. In another embodiment of these compounds, when R2 and R4 are each a substituted or unsubstituted pyrrole or indole, then the ring is attached to the remainder of the molecule via a ring carbon atom. In still another embodiment of compounds including an optionally substituted heteroaryl group, the heteroaryl is unsubstituted or substituted with from one to four of the same or different R8 groups, where R8 is as previously defined for structural formula (I). Specific examples of such optionally substituted heteroaryls include, but are not limited to, the following heteroaryl groups:













    
    
        wherein:
        
            p is an integer from one to three;
            each
        
        
    
    






independently represents a single bond or a double bond;

    
    
        
        
            R35 is hydrogen or R8, where R8 is as previously defined for structural formula (I);
            X is selected from the group consisting of CH, N and N—O;
            each Y is independently selected from the group consisting of O, S and NH;
            each Y1 is independently selected from the group consisting of O, S, SO, SO2, SONR36, NH and NR37;
            each Y2 is independently selected from the group consisting of CH, CH2, O, S, N, NH and NR37;
            R36 is hydrogen or alkyl;
            R37 is selected from the group consisting of hydrogen and a progroup, preferably hydrogen or a progroup selected from the group consisting of aryl, arylalkyl, heteroaryl, Ra, Rb—CRaRb—O—C(O)R8, —CRaRb—O—PO(OR8)2, —CH2—O—PO(OR8)2, —CH2—PO(OR8)2, —C(O)—CRaRb—N(CH3)2, —CRaRb—O—C(O)—CRaRb—N(CH3)2, —C(O)R8, —C(O)CF3 and —C(O)—NR8—C(O)R8;
            A is selected from the group consisting of O, NH and NR38;
            R38 is selected from the group consisting of alkyl and aryl;
            R9, R10, R11 and R12 are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R9and R10 and/or R11 and R12 are taken together form a ketal;
            each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester, carbamate and sulfonyl;
            Q is selected from the group consisting of —OH, OR8, —NRcRc, —NHR39—C(O)R8, —NHR39—C(O)OR8, —NR39—CHR40—Rb, —NR39—(CH2)m—Rb and —NR39—C(O)—CHR40—NRcRc;
            R39 and R40 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl; arylalkyl and NHR8; and
            Ra, Rb and Rc are as previously defined for structural formula (I). Preferred Rb substitutents for Q are selected from —C(O)OR8, —O—C(O)R8, —O—P(O)(OR8)2 and —P(O)(OR8)2.
        
        
    
    


In one embodiment of the above-depicted heteroaryls, as well as other 5–15 membered heteroaryls according to this embodiment of the invention, each R8 is independently selected from the group consisting of Rd, —NRcRc, —(CH2)m—NRcRc, —C(O)NRcRc, —(CH2)m—C(O)NRcRc, —C(O)ORd, —(CH2)m—C(O)ORd and —(CH2)m—ORd, where m, Rc and Rd are as previously defined for structural formula (I).
In a specific embodiment, Rd and/or Rc is selected from the group consisting of Ra and (C3–C8) cycloalkyl optionally substituted with one or more of the same or different hydroxyl, amino or carboxyl groups.
In another embodiment of the above-depicted heteroaryls, each R35 is hydrogen or (C1–C6) ethyl or methyl.
In still another embodiment of the above-depicted heteroaryls, the aromatic ring connectivity is either at the 5 or 6 position. It should be understood that either R2 or R4 can utilize the heteroaryl groups discussed throughout this specification.
In a fourteenth embodiment of the compounds of structural formulae (I) and (Ia), R2 and R4 are each, independently of one another, an optionally substituted phenyl, aryl or heteroaryl, with the provisos that: (1) when L1 is a direct bond and R6 and optionally R5 is hydrogen, then R2 is other than 3,4,5-trimethoxyphenyl or 3,4,5-tri(C1–C6) alkoxyphenyl; (2) when L1 and L2 are each a direct bond, R6 is hydrogen and R5 is halo, then R2 and R4 are not each simultaneously 3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-C6) alkoxyphenyl; (3) when R4 is 3-methoxyphenyl or 3-(C1–C6) alkoxyphenyl and R2 is a 3,4,5-trisubstituted phenyl, the substituents positioned at the 3 and 4 positions are not both simultaneously methoxy or (C1–C6) alkoxy; (4) when R2 is a substituted phenyl and R6 is hydrogen, then R5 is other than cyano or —C(O)NHR, where R is hydrogen or (C1–C6) alkyl; and/or (5) when R2 and R4 are each independently a substituted or unsubstituted pyrrole or indole, then the pyrrole or indole is attached to the remainder of the molecule via a ring carbon atom. Alternatively, R2 is subject to the provisos described in connection with the first or second embodiment.
In this fourteenth embodiment of the invention, the R2 and R4 substituents may be the same or different. Specific optionally substituted phenyl, aryl and/or heteroaryls include those illustrated above in connection with the twelfth and thirteenth embodiments.
In a fifteenth embodiment of the compounds of structural formulae (I) and (Ia), including the above-described first through fourteenth embodiments thereof, R6 is hydrogen and R5 is an electronegative group. As will be recognized by skilled artisans, electronegative groups are atoms or groups of atoms that have a relatively great tendency to attract electrons to themselves. Specific examples of electronegative groups according to this fourteenth embodiment include, but are not limited to, —CN, —NC, —NO2, halo, bromo, chloro, fluoro, (C1–C3) haloalkyl, (C1–C3) perhaloalkyl, (C1–C3) fluoroalkyl, (C1–C3) perfluoroalkyl, —CF3, (C1–C3) haloalkoxy, (C1–C3) perhaloalkoxy, (C1–C3) fluoroalkoxy, (C1–C3) perfluoroalkoxy, —OCF3, —C(O)Ra, —C(O)ORa, —C(O)CF3 and —C(O)OCF3. In a specific embodiment, the electronegative group is a halogen-containing electronegative group, such as —OCF3, —CF3, bromo, chloro or fluoro. In another specific embodiment, R5 is fluoro, subject to the proviso that the the compound is not any compound according to the third embodiment.
In a sixteenth embodiment, the compounds of structural formulae (I) and (Ia) are compounds according to structural formula (Ib):




and salts, hydrates, solvates and N-oxides thereof, wherein R11, R12, R13 and R14 are each, independently of one another, selected from the group consisting of hydrogen, hydroxy, (C1–C6) alkoxy and —NRcRc; and R5, R6 and Rc are as previously defined for structural formula (I), with the proviso that when R13, R5 and R6 are each hydrogen, then R11 and R12 are not simultaneously methoxy, (C1–C6) alkoxy or (C1–C6) haloalkoxy
In a seventeenth embodiment, the compounds of structural formulae (I) and (Ia) are compounds according to structural formula (Ic):




and salts, hydrates, solvates and N-oxides thereof, wherein:
R4 is selected from the group consisting of 5–10 membered heteroaryl and 3-hydroxyphenyl;
R5 is F or —CF3; and
R8 is —O(CH2)m—Rb, where m and Rb are as previously defined for structural formula (I). In a specific embodiment, R8 is —O—CH2—C(O)NH-CH3 and/or R4 is a heteroaryl according to the thirteenth embodiment.
In an eighteenth embodiment, the compounds of structural formulae (I) and (Ia) include any compound selected from TABLE 1 that inhibits an Fc receptor signal transduction cascade, a Syk kinase activity, a Syk-kinase dependent receptor signal transduction cascade or cell degranulation as measured in an in vitro assay, optionally subject to the proviso that the compound is not a compound excluded by the above-described third embodiment and/or other embodiments. In a specific embodiment, such compounds have an IC50 of about 20 μM or less as measured in an in vitro degranulation assay, such as one of the degranulation assays described in the Examples section.
In a nineteenth embodiment, the compounds of structural formulae (I) and (Ia) include any compound selected from TABLE 1 that inhibits the FcγR1 or FcεR1 receptor cascade with an IC50 of about 20 μM or less as measured in an in vitro assay, such as one of the in vitro assays provided in the Examples section, optionally subject to the proviso that the compound is not a compound excluded by the above-described third embodiment and/or other embodiments.
Also specifically described are combinations of the above first through nineteenth specific embodiments.
Those of skill in the art will appreciate that the 2,4-pyrimidinediamine compounds described herein may include functional groups that can be masked with progroups to create prodrugs. Such prodrugs are usually, but need not be, pharmacologically inactive until converted into their active drug form. Indeed, many of the active 2,4-pyrimidinediamine compounds described in TABLE 1, infra, include promoieties that are hydrolyzable or otherwise cleavable under conditions of use. For example, ester groups commonly undergo acid-catalyzed hydrolysis to yield the parent carboxylic acid when exposed to the acidic conditions of the stomach, or base-catalyzed hydrolysis when exposed to the basic conditions of the intestine or blood. Thus, when administered to a subject orally, 2,4-pyrimidinediamines that include ester moieties may be considered prodrugs of their corresponding carboxylic acid, regardless of whether the ester form is pharmacologically active. Referring to TABLE 1, numerous ester-containing 2,4-pyrimidinediamines of the invention are active in their ester, “prodrug” form.
In the prodrugs of the invention, any available functional moiety may be masked with a progroup to yield a prodrug. Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc. Myriad progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs of the invention.
In one illustrative embodiment, the prodrugs of the invention are compounds according to structural formula (1) in which Rc and Rd may be, in addition to their previously-defined alternatives, a progroup.
Replacing the hydrogens attached to N2 and N4 in the 2,4-pyrimidinediamines of structural formula (I) with substituents adversely effects the activity of the compounds. However, as will be appreciated by skilled artisans, these nitrogens may be included in promoieties that, under conditions of use, cleave to yield 2,4-pyrimidinediamines according to structural formula (I). Thus, in another embodiment, the prodrugs of the invention are compounds according to structural formula (II):




including salts, hydrates, solvates and N-oxides thereof, wherein:
R2, R4, R5, R6, L1 and L2 are as previously defined for structural formula (I); and
R2b and R4b are each, independently of one another, a progroup. Specific examples of progroups according to this embodiment of the invention include, but are not limited to, (C1–C6) alkyl, —C(O)CH3, —C(O)NHR36 and —S(O)2R36, where R36 is (C1–C6) alkyl, (C5–C15) aryl and (C3–C8) cycloalkyl.
In the prodrugs of structural formula (II), the various substituents may be as described for the various first through twentieth embodiments previously described for the compounds of structural formulae (I) and (Ia), or combinations of such embodiments.
Those of skill in the art will appreciate that many of the compounds and prodrugs of the invention, as well as the various compound species specifically described and/or illustrated herein, may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. For example, the compounds and prodrugs of the invention may include one or more chiral centers and/or double bonds and as a consequence may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers and diasteromers and mixtures thereof, such as racemic mixtures. As another example, the compounds and prodrugs of the invention may exist in several tautomeric forms, including the enol form, the keto form and mixtures thereof. As the various compound names, formulae and compound drawings within the specification and claims can represent only one of the possible tautomeric, conformational isomeric, optical isomeric or geometric isomeric forms, it should be understood that the invention encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the compounds or prodrugs having one or more of the utilities described herein, as well as mixtures of these various different isomeric forms. In cases of limited rotation around the 2,4-pryimidinediamine core structure, atrop isomers are also possible and are also specifically included in the compounds of the invention.
Moreover, skilled artisans will appreciate that when lists of alternative substituents include members which, owing to valency requirements or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group. For example, skilled artisans will appreciate that while all of the listed alternatives for Rb can be used to substitute an alkyl group, certain of the alternatives, such as ═O, cannot be used to substitute a phenyl group. It is to be understood that only possible combinations of substituent-group pairs are intended.
The compounds and/or prodrugs of the invention may be identified by either their chemical structure or their chemical name. When the chemical structure and the chemical name conflict, the chemical structure is determinative of the identity of the specific compound.
Depending upon the nature of the various substituents, the 2,4-pyrimidinediamine compounds and prodrugs of the invention may be in the form of salts. Such salts include salts suitable for pharmaceutical uses (“pharmaceutically-acceptable salts”), salts suitable for veterinary uses, etc. Such salts may be derived from acids or bases, as is well-known in the art.
In one embodiment, the salt is a pharmaceutically acceptable salt. Generally, pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion or an aluminum ion) or coordinates with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.).
The 2,4-pyrimidinediamine compounds and of the invention, as well as the salts thereof, may also be in the form of hydrates, solvates and N-oxides, as are well-known in the art.
6.3 Methods of Synthesis
The compounds and prodrugs of the invention may be synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods. Suitable exemplary methods that may be routinely adapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugs of the invention are found in U.S. Pat. No. 5,958,935, the disclosure of which is incorporated herein by reference. Specific examples describing the synthesis of numerous compounds and prodrugs of the invention, as well as intermediates therefor, are provided in the Examples section. All of the compounds of structural formulae (I), (Ia) and (II) may be prepared by routine adaptation of these methods.
A variety of exemplary synthetic routes that can be used to synthesize the 2,4-pyrimidinediamine compounds of the invention are described in Schemes (I)–(XI), below. In Schemes (I)–(XI), like-numbered compounds have similar structures. These methods may be routinely adapted to synthesize the prodrugs according to structural formula (II).
In one exemplary embodiment, the compounds can be synthesized from substituted or unsubstituted uracils or thiouracils as illustrated in Scheme (I), below:




In Scheme (I), R2, R4, R5, R6, L1 and L2 are as previously defined for structural formula (I), X is a halogen (e.g., F, Cl, Br or I) and Y and Y′ are each, independently of one another, selected from the group consisting of O and S. Referring to Scheme (I), uracil or thiouracil 2 is dihalogenated at the 2- and 4-positions using standard halogenating agent POX3 (or other standard halogenating agent) under standard conditions to yield 2,4-bishalo pyrimidine 4. Depending upon the R5 substituent, in pyrimidine 4, the halide at the C4 position is more reactive towards nucleophiles than the halide at the C2 position. This differential reactivity can be exploited to synthesize 2,4-pyrimidinediamines according structural formula (I) by first reacting 2,4-bishalopyrimidine 4 with one equivalent of amine 10, yielding 4N-substituted-2-halo4-pyrimidineamine 8, followed by amine 6 to yield a 2,4-pyrimidinediamine according structural formula (I). 2N,4N-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be obtained by reacting 2,4-bishalopyrimidine 4 with excess 6 or 10, respectively.
In most situations, the C4 halide is more reactive towards nucleophiles, as illustrated in the Scheme. However, as will be recognized by skilled artisans, the identity of the R5 substituent may alter this reactivity. For example, when R5 is trifluoromethyl, a 50:50 mixture of 4N-substituted-4-pyrimidineamine 8 and the corresponding 2N-substituted-2-pyrimidineamine is obtained. Regardless of the identity of the R5 substituent, the regioselectivity of the reaction can be controlled by adjusting the solvent and other synthetic conditions (such as temperature), as is well-known in the art.
The reactions depicted in Scheme (I) may proceed more quickly when the reaction mixtures are heated via microwave. When heating in this fashion, the following conditions may be used: heat to 175° C. in ethanol for 5–20 min. in a Smith Reactor (Personal Chemistry) in a sealed tube (at 20 bar pressure).
The uracil or thiouracil 2 starting materials may be purchased from commercial sources or prepared using standard techniques of organic chemistry. Commercially available uracils and thiouracils that can be used as starting materials in Scheme (I) include, by way of example and not limitation, uracil (Aldrich #13,078-8; CAS Registry 66-22-8); 2-thio-uracil (Aldrich #11,558-4; CAS Registry 141-90-2); 2,4-dithiouracil (Aldrich #15,846-1; CAS Registry 2001-93-6); 5-acetouracil (Chem. Sources Int'l 2000; CAS Registry 6214-65-9); 5-azidouracil; 5-aminouracil (Aldrich #85,528-6; CAS Registry 932-52-5); 5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7); 5-(trans-2-bromovinyl)-uracil (Aldrich #45,744-2; CAS Registry 69304-49-0); 5-(trans-2-chlorovinyl)-uracil (CAS Registry 81751-48-2); 5-(trans-2-carboxyvinyl)-uracil; uracil-5-carboxylic acid (2,4-dihydroxypyrimidine-5-carboxylic acid hydrate; Aldrich #27,770-3; CAS Registry 23945-44-0); 5-chlorouracil (Aldrich #22,458-8; CAS Registry 1820-81-1); 5-cyanouracil (Chem. Sources Int'l 2000; CAS Registry 4425-56-3); 5-ethyluracil (Aldrich #23,044-8; CAS Registry 4212-49-1); 5-ethenyluracil (CAS Registry 37107-81-6); 5-fluorouracil (Aldrich #85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS Registry 696-07-1); 5-methyluracil (thymine; Aldrich #13,199-7; CAS Registry 65-714); 5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5); uracil-5-sulfamic acid (Chem. Sources Int'l 2000; CAS Registry 5435-16-5); 5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CAS Registry 54-20-6); 5-(2,2,2-trifluoroethyl)-uracil (CAS Registry 155143-31-6); 5-(pentafluoroethyl)-uracil (CAS Registry 60007-38-3); 6-aminouracil (Aldrich #A5060-6; CAS Registry 873-83-6) uracil-6-carboxylic acid (orotic acid; Aldrich #0-840-2; CAS Registry 50887-69-9); 6-methyluracil (Aldrich #D11,520-7; CAS Registry 62648-2); uracil-5-amino-6-carboxylic acid (5-aminoorotic acid; Aldrich #19,121-3; CAS Registry #7164-43-4); 6-amino-5-nitrosouracil (6-amino-2,4-dihydroxy-5-nitrosopyrimidine; Aldrich #27,689-8; CAS Registry 5442-24-0); uracil-5-fluoro-6-carboxylic acid (5-fluoroorotic acid; Aldrich #42,513-3; CAS Registry 00000-00-0); and uracil-5-nitro-6-carboxylic acid (5-nitroorotic acid; Aldrich #18,528-0; CAS Registry 600779-49-9). Additional 5-, 6- and 5,6-substituted uracils and/or thiouracils are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
Amines 6 and 10 may be purchased from commercial sources or, alternatively, may be synthesized utilizing standard techniques. For example, suitable amines may be synthesized from nitro precursors using standard chemistry. Specific exemplary reactions are provided in the Examples section. See also Vogel, 1989, Practical Organic Chemistry, Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.
Skilled artisans will recognize that in some instances, amines 6 and 10 and/or substituents R5 and/or R6 on uracil or thiouracil 2 may include functional groups that require protection during synthesis. The exact identity of any protecting group(s) used will depend upon the identity of the functional group being protected, and will be apparent to these of skill in the art. Guidance for selecting appropriate protecting groups, as well as synthetic strategies for their attachment and removal, may be found, for example, in Greene & Wuts, Protective Groups in Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New York (1999) and the references cited therein (hereinafter “Greene & Wuts”).
A specific embodiment of Scheme (I) utilizing 5-fluorouracil (Aldrich #32,937-1) as a starting material is illustrated in Scheme (Ia), below:




In Scheme (Ia), R2, R4, L1 and L2 are as previously defined for Scheme (I). According to Scheme (Ia), 5-fluorouracil 3 is halogenated with POCl3 to yield 2,4-dichloro-5-fluoropyrimidine 5, which is then reacted with excess amine 6 or 10 to yield N2,N4-bis substituted 5-fluoro-2,4-pyrimidinediamine 11 or 13, respectively. Alternatively, asymmetric 2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may be obtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with one equivalent of amine 10 (to yield 2-chloro-N4-substituted-5-fluoro-4-pyrimidineamine 7) followed by one or more equivalents of amine 6.
In another exemplary embodiment, the 2,4-pyrimidinediamine compounds of the invention may be synthesized from substituted or unsubstituted cytosines as illustrated in Schemes (IIa) and (IIb), below:








In Schemes (IIa) and (IIb), R2, R4, R5, R6, L1, L2 and X are as previously defined for Scheme (I) and PG represents a protecting group. Referring to Scheme (IIa), the C4 exocyclic amine of cytosine 20 is first protected with a suitable protecting group PG to yield N4-protected cytosine 22. For specific guidance regarding protecting groups useful in this context, see Vorbrüggen and Ruh-Pohlenz, 2001, Handbook of Nucleoside Synthesis, John Wiley & Sons, NY, pp. 1–631 (“Vorbrüggen”). Protected cytosine 22 is halogenated at the C2 position using a standard halogenation reagent under standard conditions to yield 2-chloro4N-protected4-pyrimidineamine 24. Reaction with amine 6 followed by deprotection of the C4 exocyclic amine and reaction with amine 10 yields a 2,4-pyrimidinediamine according to structural formula (I).
Alternatively, referring to Scheme (IIb), cytosine 20 may be reacted with amine 10 or protected amine 21 to yield N4-substituted cytosine 23 or 27, respectively. These substituted cytosines may then be halogenated as previously described, deprotected (in the case of N4-substituted cytosine 27) and reacted with amine 6 to yield a 2,4-pyrimidinediamine according to structural formula (I).
Commercially-available cytosines that may be used as starting materials in Schemes (IIa) and (IIb) include, but are not limited to, cytosine (Aldrich #14,201-8; CAS Registry 71-30-7); N4-acetylcytosine (Aldrich #37,791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich #27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine. Other suitable cytosines useful as starting materials in Schemes (IIa) are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
In still another exemplary embodiment, the 2,4-pyrimidinediamine compounds of the invention may be synthesized from substituted or unsubstituted 2-amino4-pyrimidinols as illustrated in Scheme (III), below:




In Scheme (III), R2, R4, R5, R6, L1, L2 and X are as previously defined for Scheme (I) and Z is a leaving group as discussed in more detail in connection with Scheme IV, infra. Referring to Scheme (III), 2-amino-4-pyrimidinol 30 is reacted with amine 6 (or optionally protected amine 21) to yield N2-substituted4-pyrimidinol 32, which is then halogenated as previously described to yield N2-substituted4-halo-2-pyrimidineamine 34. Optional deprotection (for example if protected amine 21 was used in the first step) followed by reaction with amine 10 affords a 2,4-pyrimidinediamine according to structural formula (I). Alternatively, pyrimidinol 30 can be reacted with acylating agent 31.
Suitable commercially-available 2-amino4-pyrimidinols 30 that can be used as starting materials in Scheme (III) include, but are not limited to, 2-amino-6-chloro-4-pyrimidinol hydrate (Aldrich #A4702-8; CAS Registry 00000-00-0) and 2-amino-6-hydroxy4-pyrimidinol (Aldrich #A5040-1; CAS Registry 56-09-7). Other 2-amino-4-pyrimidinols 30 useful as starting materials in Scheme (III) are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
Alternatively, the 2,4-pyrimidinediamine compounds of the invention may be prepared from substituted or unsubstituted 4-amino-2-pyrimidinols as illustrated in Scheme (IV), below:




In Scheme (IV), R2, R4, R5, R6, L1 and L2 are as previously defined for Scheme (I) and Z represents a leaving group. Referring to Scheme (IV), the C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towards nucleophiles than the C4-amino such that reaction with amine 6 yields N2-substituted-2,4-pyrimidinediamine 42. Subsequent reaction with compound 44, which includes a good leaving group Z, or amine 10 yields a 2,4-pyrimidinediamine according to structural formula (I). Compound 44 may include virtually any leaving group that can be displaced by the C4-amino of N2-substituted-2,4-pyrimidinediamine 42. Suitable leaving groups Z include, but are not limited to, halogens, methanesulfonyloxy (mesyloxy; “OMs”), trifluoromethanesulfonyloxy (“OTf”) and p-toluenesulfonyloxy (tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”) and metanitro benzene sulfonyloxy (“nosylate”). Other suitable leaving groups will be apparent to those of skill in the art.
Substituted 4-amino-2-pyrimidinol starting materials may be obtained commercially or synthesized using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
In still another exemplary embodiment, the 2,4-pyrimidinediamine compounds of the invention can be prepared from 2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines as illustrated in Scheme (V), below:




In Scheme (V), R2, R4, R5, R6, L1, L2 and X are as defined for Scheme (I) and Z is as defined for Scheme (IV). Referring to Scheme (V), 2-amino4-chloropyrimidine 50 is reacted with amino 10 to yield 4N-substituted-2-pyrimidineamine 52 which, following reaction with compound 31 or amine 6, yields a 2,4-pyrimidinediamine according to structural formula (I). Alternatively, 2-chloro-4-amino-pyrimidine 54 may be reacted with compound 44 followed by amine 6 to yield a compound according to structural formula (I).
A variety of pyrimidines 50 and 54 suitable for use as starting materials in Scheme (V) are commercially available, including by way of example and not limitation, 2-amino-4,6-dichloropyrimidine (Aldrich #A4860-1; CAS Registry 56-05-3); 2-amino-4-chloro-6-methoxy-pyrimidine (Aldrich #51,864-6; CAS Registry 5734-64-5); 2-amino-4-chloro-6-methylpyrimidine (Aldrich #12,288-2; CAS Registry 5600-21-5); and 2-amino4-chloro-6-methylthiopyrimidine (Aldrich #A4600-5; CAS Registry 1005-38-5). Additional pyrimidine starting materials are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
Alternatively, 4-chloro-2-pyrimidineamines 50 may be prepared as illustrated in Scheme (Va):




In Scheme (Va), R5 and R6 are as previously defined for structural formula (I). In Scheme (Va), dicarbonyl 53 is reacted with guanidine to yield 2-pyrimidineamine 51. Reaction with peracids like m-chloroperbenzoic acid, trifluoroperacetic acid or urea hydrogen peroxide complex yields N-oxide 55, which is then halogenated to give 4-chloro-2-pyrimidineamine 50. The corresponding 4-halo-2-pyrimidineamines may be obtained by using suitable halogenation reagents.
In yet another exemplary embodiment, the 2,4-pyrimidinediamine compounds of the invention can be prepared from substituted or unsubstituted uridines as illustrated in Scheme (VI), below:




In Scheme (VI), R2, R4, R5, R6, L1, L2 and X are as previously defined for Scheme (I) and the superscript PG represents a protecting group, as discussed in connection with Scheme (IIb). According to Scheme (VI), uridine 60 has a C4 reactive center such that reaction with amine 10 or protected amine 21 yields N4-substituted cytidine 62 or 64, respectively. Acid-catalyzed deprotection of N4-substituted 62 or 64 (when “PG” represents an acid-labile protecting group) yields N4-substituted cytosine 28, which may be subsequently halogenated at the C2-position and reacted with amine 6 to yield a 2,4-pyrimidinediamine according to structural formula (I).
Cytidines may also be used as starting materials in an analogous manner, as illustrated in Scheme (VII), below:




In Scheme (VII), R2, R4, R5, R6, L1, L2 and X are as previously defined in Scheme (I) and the superscript PG represents a protecting group as discussed above. Referring to Scheme (VII), like uridine 60, cytidine 70 has a C4 reactive center such that reaction with amine 10 or protected amine 21 yields N4-substituted cytidine 62 or 64, respectively. These cytidines 62 and 64 are then treated as previously described for Scheme (VI) to yield a 2,4-pyrimidinediamine according to structural formula (I).
Although Schemes (VI) and (VII) are exemplified with ribosylnucleosides, skilled artisans will appreciate that the corresponding 2′-deoxyribo and 2′,3′-dideoxyribo nucleosides, as well as nucleosides including sugars or sugar analogs other than ribose, would also work.
Numerous uridines and cytidines useful as starting materials in Schemes (VI) and (VII) are known in the art, and include, by way of example and not limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem. Sources #ABCR F07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem. Sources Int'l 2000; CAS Registry 957-75-5); 5-iodo-2′-deoxyuridine (Aldrich #1-775-6; CAS Registry 5442-2); 5-fluorouridine (Aldrich #32,937-1; CAS Registry 316-46-1); 5-iodouridine (Aldrich #85,259-7; CAS Registry 1024-99-3); 5-(trifluoromethyl)uridine (Chem. Sources Int'l 2000; CAS Registry 70-00-8); 5-trifluoromethyl-2′-deoxyuridine (Chem. Sources Int'l 2000; CAS Registry 70-00-8). Additional uridines and cytidines that can be used as starting materials in Schemes (VI) and (VII) are available from General Intermediates of Canada, Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France (www.interchim.com), or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
The 2,4-pyrimidinediamine compounds of the invention can also be synthesized from substituted pyrimidines, such as chloro-substituted pyrimidines, as illustrated in Schemes (VII) and (IX), below:








In Schemes (VIII) and (IX), R2, R4, L1, L2 and Ra are as previously defined for structural formula (I) and “Ar” represents an aryl group. Referring to Scheme (VIII), reaction of 2,4,6-trichloropyrimidine 80 (Aldrich #T5,620-0; CAS#3764-01-0) with amine 6 yields a mixture of three compounds: substituted pyrimidine mono-, di- and triamines 81, 82 and 83, which can be separated and isolated using HPLC or other conventional techniques. Mono- and diamines 81 and 82 may be further reacted with amines 6 and/or 10 to yield N2,N4,N6-trisubstituted-2,4,6-pyrimidinetriamines 84 and 85, respectively.
N2,N4-bis-substituted-2,4-pyrimidinediamines can be prepared in a manner analogous to Scheme (VIII) by employing 2,4-dichloro-5-methylpyrimidine or 2,4-dichloro-pyrimidine as starting materials. In this instance, the mono-substituted pyrimidineamine corresponding to compound 81 is not obtained. Instead, the reaction proceeds to yield the N2,N4-bis-substituted-2,4-pyrimidinediamine directly.
Referring to Scheme (IX), 2,4,5,6-tetrachloropyrimidine 90 (Aldrich #24,671-9; CAS#1780-40-1) is reacted with excess amine 6 to yield a mixture of three compounds: 91, 92, and 93, which can be separated and isolated using HPLC or other conventional techniques. As illustrated, N2,N4-bis-substituted-5,6,-dichloro-2,4-pyrimidinediamine 92 may be further reacted at the C6 halide with, for example a nucleophilic agent 94 to yield compound 95. Alternatively, compound 92 can be converted into N2,N4-bis-substituted-5-chloro-6-aryl-2,4-pyrimidinediamine 97 via a Suzuki reaction. 2,4-Pyrimidinediamine 95 may be converted to 2,4-pyrimidinediamine 99 by reaction with Bn3SnH.
As will be recognized by skilled artisans, 2,4-pyrimidinediamines according to the invention, synthesized via the exemplary methods described above or by other well-known means, may also be utilized as starting materials and/or intermediates to synthesize additional 2,4-pyrimidinediamine compounds of the invention. A specific example is illustrated in Scheme (X), below:




In Scheme (X), R4, R5, R6, L2 and Ra are as previously defined for structural formula (I). Each Ra′ is independently an Ra, and may be the same or different from the illustrated Ra. Referring to Scheme (X), carboxylic acid or ester 100 may be converted to amide 104 by reaction with amine 102. In amine 102, Ra′ may be the same or different than Ra of acid or ester 100. Similarly, carbonate ester 106 may be converted to carbamate 108.
A second specific example is illustrated in Scheme (XI), below:




In Scheme (XI), R4, R5, R6, L2 and Rc are as previously defined for structural formula (I). Referring to Scheme (XI), amide 110 or 116 may be converted to amine 114 or 118, respectively, by borane reduction with borane methylsulfide complex 112. Other suitable reactions for synthesizing 2,4-pyrimidinediamine compounds from 2,4-pyrimidinediamine starting materials will be apparent to those of skill in the art.
Although many of the synthetic schemes discussed above do not illustrate the use of protecting groups, skilled artisans will recognize that in some instances substituents R2, R4, R5, R6, L1 and/or L2 may include functional groups requiring protection. The exact identity of the protecting group used will depend upon, among other things, the identity of the functional group being protected and the reaction conditions used in the particular synthetic scheme, and will be apparent to those of skill in the art. Guidance for selecting protecting groups and chemistries for their attachment and removal suitable for a particular application can be found, for example, in Greene & Wuts, supra.
Prodrugs according to structural formula (II) may be prepared by routine modification of the above-described methods. Alternatively, such prodrugs may be prepared by reacting a suitably protected 2,4-pyrimidinediamine of structural formula (I) with a suitable progroup. Conditions for carrying out such reactions and for deprotecting the product to yield a prodrug of formula (II) are well-known.
Myriad references teaching methods useful for synthesizing pyrimidines generally, as well as starting materials described in Schemes (I)–(IX), are known in the art. For specific guidance, the reader is referred to Brown, D. J., “The Pyrimidines”, in The Chemistry of Heterocyclic Compounds, Volume 16 (Weissberger, A., Ed.), 1962, Interscience Publishers, (A Division of John Wiley & Sons), New York (“Brown I”); Brown, D. J., “The Pyrimidines”, in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C., Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), New York (Brown II”); Brown, D. J., “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 & 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 & Sons, Inc., New York, pp. 1–1509 (Brown IV”); Kenner, G. W. and Todd, A., in Heterocyclic Compounds, Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter 7 (pyrimidines); Paquette, L. A., Principles of Modern Heterocyclic Chemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1–401 (uracil synthesis pp. 313, 315; pyrimidine synthesis pp. 313–316; amino pyrimidine synthesis pp. 315); Joule, J. A., Mills, K. and Smith, G. F., Heterocyclic Chemistry, 3rd Edition, 1995, Chapman and Hall, London, UK, pp. 1–516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook of Nucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1–631 (protection of pyrimidines by acylation pp. 90–91; silylation of pyrimidines pp. 91–93); Joule, J. A., Mills, K. and Smith, G. F., Heterocyclic Chemistry, 4th Edition, 2000, Blackwell Science, Ltd, Oxford, UK, pp. 1–589; and Comprehensive Organic Synthesis, Volumes 1–9 (Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.
6.4 Inhibition of Fc Receptor Signal Cascades
Active 2,4-pyrimidinediamine compounds of the invention inhibit Fc receptor signalling cascades that lead to, among other things, degranulation of cells. As a specific example, the compounds inhibit the FcεRI and/or FcγRI signal cascades that lead to degranulation of immune cells such as neutrophil, eosinophil, mast and/or basophil cells. Both mast and basophil cells play a central role in allergen-induced disorders, including, for example, allergic rhinitis and asthma. Referring to FIG. 1, upon exposure allergens, which may be, among other things, pollen or parasites, allergen-specific IgE antibodies are synthesized by B-cells activated by IL-4 (or IL-13) and other messengers to switch to IgE class specific antibody synthesis. These allergen-specific IgEs bind to the high affinity FcεRI. Upon binding of antigen, the FcεR1-bound IgEs are cross-linked and the IgE receptor signal transduction pathway is activated, which leads to degranulation of the cells and consequent release and/or synthesis of a host of chemical mediators, including histamine, proteases (e.g., tryptase and chymase), lipid mediators such as leukotrienes (e.g., LTC4), platelet-activating factor (PAF) and prostaglandins (e.g., PGD2) and a series of cytokines, including TNF-α, IL-4, IL-13, IL-5, IL-6, IL-8, GMCSF, VEGF and TGF-β. The release and/or synthesis of these mediators from mast and/or basophil cells accounts for the early and late stage responses induced by allergens, and is directly linked to downstream events that lead to a sustained inflammatory state.
The molecular events in the FcεRI signal transduction pathway that lead to release of preformed mediators via degranulation and release and/or synthesis of other chemical mediators are well-known and are illustrated in FIG. 2. Referring to FIG. 2, the FcεRI is a heterotetrameric receptor composed of an IgE-binding alpha-subunit, a beta subunit, and two gamma subunits (gamma homodimer). Cross-linking of FcεRI-bound IgE by multivalent binding agents (including, for example IgE-specific allergens or anti-IgE antibodies or fragments) induces the rapid association and activation of the Src-related kinase Lyn. Lyn phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMS) on the intracellular beta and gamma subunits, which leads to the recruitment of additional Lyn to the beta subunit and Syk kinase to the gamma homodimer. These receptor-associated kinases, which are activated by intra- and intermolecular phosphorylation, phosphorylate other components of the pathway, such as the Btk kinase, LAT, and phospholipase C-gamma PLC-gamma). Activated PLC-gamma initiates pathways that lead to protein kinase C activation and Ca2+ mobilization, both of which are required for degranulation. FcεR1 cross-linking also activates the three major classes of mitogen activated protein (MAP) kinases, i.e. ERK1/2, JNK1/2, and p38. Activation of these pathways is important in the transcriptional regulation of proinflammatory mediators, such as TNF-α and IL-6, as well as the lipid mediator leukotriene CA (LTC4).
Although not illustrated, the FcγRI signaling cascade is believed to share some common elements with the FcεRI signaling cascade. Importantly, like FcεRI, the FcγRI includes a gamma homodimer that is phosphorylated and recruits Syk, and like FcεRI, activation of the FcγRI signaling cascade leads to, among other things, degranulation. Other Fc receptors that share the gamma homodimer, and which can be regulated by the active 2,4-pyrimidinediamine compounds include, but are not limited to, FcαRI and FcγRIII.
The ability of the 2,4-pyrimidinediamine compounds of the invention to inhibit Fc receptor signaling cascades may be simply determined or confirmed in in vitro assays. Suitable assays for confirming inhition of FcεRI-mediated degranulation are provided in the Examples section. In one typical assay, cells capable of undergoing FcεRI-mediated degranulation, such as mast or basophil cells, are first grown in the presence of IL-4, Stem Cell Factor (SCF), IL-6 and IgE to increase expression of the FcεRI, exposed to a 2,4-pyrimidinediamine test compound of the invention and stimulated with anti-IgE antibodies (or, alternatively, an IgE-specific allergen). Following incubation, the amount of a chemical mediator or other chemical agent released and/or synthesized as a consequence of activating the FcεRI signaling cascade may be quantified using standard techniques and compared to the amount of the mediator or agent released from control cells (i.e., cells that are stimulated but that are not exposed to test compound). The concentration of test compound that yields a 50% reduction in the quantity of the mediator or agent measured as compared to control cells is the IC50 of the test compound. The origin of the mast or basophil cells used in the assay will depend, in part, on the desired use for the compounds and will be apparent to those of skill in the art. For example, if the compounds will be used to treat or prevent a particular disease in humans, a convenient source of mast or basophil cells is a human or other animal which constitutes an accepted or known clinical model for the particular disease. Thus, depending upon the particular application, the mast or basophil cells may be derived from a wide variety of animal sources, ranging from, for example, lower mammals such as mice and rats, to dogs, sheep and other mammals commonly employed in clinical testing, to higher mammals such as monkeys, chimpanzees and apes, to humans. Specific examples of cells suitable for carrying out the in vitro assays include, but are not limited to, rodent or human basophil cells, rat basophil leukemia cell lines, primary mouse mast cells (such as bone marrow-derived mouse mast cells “BMMC”) and primary human mast cells isolated from cord blood (“CHMC”) or other tissues such as lung. Methods for isolating and culturing these cell types are well-known or are provided in the Examples section (see, e.g., Demo et al., 1999, Cytometry 36(4):340–348 and copending application Ser. No. 10/053,355, filed Nov. 8, 2001, the disclosures of which are incorporated herein by reference). Of course, other types of immune cells that degranulate upon activation of the FcεRI signaling cascade may also be used, including, for example, eosinophils.
As will be recognized by skilled artisans, the mediator or agent quantified is not critical. The only requirement is that it be a mediator or agent released and/or synthesized as a consequence of initiating or activating the Fc receptor signaling cascade. For example, referring to FIG. 1, activation of the FcεRI signaling cascade in mast and/or basophil cells leads to numerous downstream events. For example, activation of the FcεRI signal cascade leads to the immediate release (i.e., within 1–3 min. following receptor activation) of a variety of preformed chemical mediators and agents via degranulation. Thus, in one embodiment, the mediator or agent quantified may be specific to granules (i.e., present in granules but not in the cell cytoplasm generally). Examples of granule-specific mediators or agents that can be quantified to determine and/or confirm the activity of a 2,4-pyrimidinediamine compound of the invention include, but are not limited to, granule-specific enzymes such as hexosaminidase and tryptase and granule-specific components such as histamine and serotonin. Assays for quantifying such factors are well-known, and in many instances are commercially available. For example, tryptase and/or hexosaminidase release may be quantified by incubating the cells with cleavable substrates that fluoresce upon cleavage and quantifying the amount of fluorescence produced using conventional techniques. Such cleavable fluorogenic substrates are commercially available. For example, the fluorogenic substrates Z-Gly-Pro-Arg-AMC (Z=benzyloxycarbonyl; AMC=7-amino-4-methylcoumarin; BIOMOL Research Laboratories, Inc., Plymouth Meeting, Pa. 19462, Catalog No. P-142) and Z-Ala-Lys-Arg-AMC (Enzyme Systems Products, a division of ICN Biomedicals, Inc., Livermore, Calif. 94550, Catalog No. AMC-246) can be used to quantify the amount of tryptase released. The fluorogenic substrate 4-methylumbelliferyl-N-acetyl-β-D-glucosaminide (Sigma, St. Louis, Mo., Catalog #69585) can be used to quantify the amount of hexosaminidase released. Histamine release may be quantified using a commercially available enzyme-linked immunosorbent assay (ELISA) such as Immunotech histamine ELISA assay #IM2015 (Beckman-Coulter, Inc.). Specific methods of quantifying the release of tryptase, hexosaminidase and histamine are provided in the Examples section. Any of these assays may be used to determine or confirm the activity of the 2,4-pyrimidinediamine compounds of the invention.
Referring again to FIG. 1, degranulation is only one of several responses initiated by the FcεRI signaling cascade. In addition, activation of this signaling pathway leads to the de novo synthesis and release of cytokines and chemokines such as IL-4, IL-5, IL-6, TNF-α, IL-13 and MIP1-α), and release of lipid mediators such as leukotrienes (e.g., LTC4), platelet activating factor (PAF) and prostaglandins. Accordingly, the 2,4-pyrimidinediamine compounds of the invention may also be assessed for activity by quantifying the amount of one or more of these mediators released and/or synthesized by activated cells.
Unlike the granule-specific components discussed above, these “late stage” mediators are not released immediately following activation of the FcεRI signaling cascade. Accordingly, when quantifying these late stage mediators, care should be taken to insure that the activated cell culture is incubated for a time sufficient to result in the synthesis (if necessary) and release of the mediator being quantified. Generally, PAF and lipid mediators such as leukotriene C4 are released 3–30 min. following FcεRI activation. The cytokines and other late stage mediators are released approx. 4–8 hrs. following FcεRI activation. Incubation times suitable for a specific mediator will be apparent to those of skill in the art. Specific guidance and assays are provided in the Examples section.
The amount of a particular late stage mediator released may be quantified using any standard technique. In one embodiment, the amount(s) may be quantified using ELISA assays. ELISA assay kits suitable for quantifying the amount of TNFα, IL-4, IL-5, IL-6 and/or IL-13 released are available from, for example, Biosource International, Inc., Camarillo, Calif. 93012 (see, e.g., Catalog Nos. KHC3011, KHC0042, KHC0052, KHC0061 and KHC0132). ELISA assay kits suitable for quantifying the amount of leukotriene C4 (LTC4) released from cells are available from Cayman Chemical Co., Ann Arbor, Mich. 48108 (see, e.g., Catalog No. 520211).
Typically, active 2,4-pyrimidinediamine compounds of the invention will exhibit IC50s with respect to FcεRI-mediated degranulation and/or mediator release or synthesis of about 20 μM or lower, as measured in an in vitro assay, such as one of the in vitro assays described above or in the Examples section. Of course, skilled artisans will appreciate that compounds which exhibit lower IC50s, for example on the order of 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, or even lower, are particularly useful.
Skilled artisans will also appreciate that the various mediators discussed above may induce different adverse effects or exhibit different potencies with respect to the same adverse effect. For example, the lipid mediator LTC4 is a potent vasoconstrictor—it is approximately 1000-fold more potent at inducing vasoconstriction than histamine. As another example, in addition to mediating atopic or Type I hypersensitivity reactions, cytokines can also cause tissue remodeling and cell proliferation. Thus, although compounds that inhibit release and/or synthesis of any one of the previously discussed chemical mediators are useful, skilled artisans will appreciate that compounds which inhibit the release and/or synthesis of a plurality, or even all, of the previously described mediators find particular use, as such compounds are useful for ameliorating or avoiding altogether a plurality, or even all, of the adverse effects induced by the particular mediators. For example, compounds which inhibit the release of all three types of mediators—granule-specific, lipid and cytokine—are useful for treating or preventing immediate Type I hypersensitivity reactions as well as the chronic symptoms associated therewith.
Compounds of the invention capable of inhibiting the release of more than one type of mediator (e.g., granule-specific or late stage) may be identified by determining the IC50 with respect to a mediator representative of each class using the various in vitro assays described above (or other equivalent in vitro assays). Compounds of the invention which are capable of inhibiting the release of more than one mediator type will typically exhibit an IC50 for each mediator type tested of less than about 20 μM. For example, a compound which exhibits an IC50 of 1 μM with respect to histamine release (IC50histamine) and an IC50 of 1 nM with respect to leukotriene LTC4 synthesis and/or release (IC50LTC4) inhibits both immediate (granule-specific) and late stage mediator release. As another specific example, a compound that exhibits an IC50tryptase of 10 μM, an IC50LTC4 of 1 μM and an IC50IL-4 of 1 μM inhibits immediate (granule-specific), lipid and cytokine mediator release. Although the above specific examples utilize the IC50s of one representative mediator of each class, skilled artisans will appreciate that the IC50s of a plurality, or even all, mediators comprising one or more of the classes may be obtained. The quantity(ies) and identity(ies) of mediators for which IC50 data should be ascertained for a particular compound and application will be apparent to those of skill in the art.
Similar assays may be utilized to confirm inhibition of signal transduction cascades initiated by other Fc receptors, such as FcαRI, FcγRI and/or FcγRIII signaling, with routine modification. For example, the ability of the compounds to inhibit FcγRI signal transduction may be confirmed in assays similar to those described above, with the exception that the FcγRI signaling cascade is activated, for example by incubating the cells with IgG and an IgG-specific allergen or antibody, instead of IgE and an IgE-specific allergen or antibody. Suitable cell types, activating agents and agents to quantify to confirm inhibition of other Fc receptors, such as Fc receptors that comprise a gamma homodimer, will be apparent to those of skill in the art.
One particularly useful class of compounds includes those 2,4-pyrimidinediamine compounds that inhibit the release of immediate granule-specific mediators and late stage mediators with approximately equivalent IC50s. By approximately equivalent is meant that the IC50s for each mediator type are within about a 10-fold range of one another. Another particularly useful class of compounds includes those 2,4-pyrimidinediamine compounds that inhibit the release of immediate granule-specific mediators, lipid mediators and cytokine mediators with approximately equivalent IC50s. In a specific embodiment, such compounds inhibit the release of the following mediators with approximately equivalent IC50s: histamine, tryptase, hexosaminidase, IL-4, IL-5, IL-6, IL-13, TNFα and LTC4. Such compounds are particularly useful for, among other things, ameliorating or avoiding altogether both the early and late stage responses associated with atopic or immediate Type I hypersensitivity reactions.
Ideally, the ability to inhibit the release of all desired types of mediators will reside in a single compound. However, mixtures of compounds can also be identified that achieve the same result. For example, a first compound which inhibits the release of granule specific mediators may be used in combination with a second compound which inhibits the release and/or synthesis of cytokine mediators.
In addition to the FcεRI or FcγRI degranulation pathways discussed above, degranulation of mast and/or basophil cells can be induced by other agents. For example, ionomycin, a calcium ionophore that bypasses the early FcεRI or FcγRI signal transduction machinery of the cell, directly induces a calcium flux that triggers degranulation. Referring again to FIG. 2, activated PLCγ initiates pathways that lead to, among other things, calcium ion mobilization and subsequent degranulation. As illustrated, this Ca2+ mobilization is triggered late in the FcεRI signal transduction pathway. As mentioned above, and as illustrated in FIG. 3, ionomycin directly induces Ca2+ mobilization and a Ca2+ flux that leads to degranulation. Other ionophores that induce degranulation in this manner include A23187. The ability of granulation-inducing ionophores such as ionomycin to bypass the early stages of the FcεRI and/or FcγRI signaling cascades may be used as a counter screen to identify active compounds of the invention that specifically exert their degranulation-inhibitory activity by blocking or inhibiting the early FcεRI or FcγRI signaling cascades, as discussed above. Compounds which specifically inhibit such early FcεRI or FcγRI-mediated degranulation inhibit not only degranulation and subsequent rapid release of histamine, tryptase and other granule contents, but also inhibit the pro-inflammatory activation pathways causing the release of TNFα, IL-4, IL-13 and the lipid mediators such as LTC4. Thus, compounds which specifically inhibit such early FcεRI and/or FcγRI-mediated degranulation block or inhibit not only acute atopic or Type I hypersensitivity reactions, but also late responses involving multiple inflammatory mediators.
Compounds of the invention that specifically inhibit early FcεRI and/or FcγRI-mediated degranulation are those compounds that inhibit FcεRI and/or FcγRI-mediated degranulation (for example, have an IC50 of less than about 20 μM with respect to the release of a granule-specific mediator or component as measured in an in vitro assay with cells stimulated with an IgE or IgG binding agent) but that do not appreciably inhibit ionophore-induced degranulation. In one embodiment, compounds are considered to not appreciably inhibit ionophore-induced degranulation if they exhibit an IC50 of ionophore-induced degranulation of greater than about 20 μM, as measured in an in vitro assay. Of course, active compounds that exhibit even higher IC50s of ionophore-induced degranulation, or that do not inhibit ionophore-induced degranulation at all, are particularly useful. In another embodiment, compounds are considered to not appreciably inhibit ionophore-induced degranulation if they exhibit a greater than 10-fold difference in their IC50s of FcεRI and/or FcγRI-mediated degranulation and ionophore-induced degranulation, as measured in an in vitro assay. Assays suitable for determining the IC50 of ionophore-induced degranulation include any of the previously-described degranulation assays, with the modification that the cells are stimulated or activated with a degranulation-inducing calcium ionophore such as ionomycin or A23187 (A.G. Scientific, San Diego, Calif.) instead of anti-IgE antibodies or an IgE-specific allergen. Specific assays for assessing the ability of a particular 2,4-pyrimidinediamine compound of the invention to inhibit ionophore-induced degranulation are provided in the Examples section.
As will be recognized by skilled artisans, compounds which exhibit a high degree of selectivity of FcεRI-mediated degranulation find particular use, as such compounds selectively target the FcεRI cascade and do not interfere with other degranulation mechanisms. Similarly, compounds which exhibit a high degree of selectivity of FcγRI-mediated degranulation find particular use, as such compounds selectively target the FcγRI cascade and do not interfere with other degranulation mechanisms. Compounds which exhibit a high degree of selectivity are generally 10-fold or more selective for FcεRI- or FcγRI -mediated degranulation over ionophore-induced degranulation, such as ionomycin-induced degranulation.
Biochemical and other data confirm that the 2,4-pyrimidinediamine compounds described herein are potent inhibitors of Syk kinase activity. For example, in experiments with an isolated Syk kinase, of twenty four 2,4-pyrimidinediamine compounds tested, all but two inhibited the Syk kinase catalyzed phosphorylation of a peptide substrate with IC50s in the submicromolar range. The remaining compounds inhibited phosphorylation in the micromolar range. In addition, of sixteen compounds tested in an in vitro assay with mast cells, all inhibited phosphorylation of Syk kinase substrates (e.g., PLC-gamma1, LAT) and proteins downstream of Syk kinase (e.g., JNK, p38, Erk1/2 and PKB, when tested), but not proteins upstream of Syk kinase in the cascade (e.g., Lyn). Phosphorylation of Lyn substrates was not inhibited by the 2,4-pyrimidinediamine compounds tested. Moreover, for the following compounds, a high correlation was observed between their inhibition of Syk kinase activity in biochemical assays (IC50s in the range of 3 to 1850 nM) and their inhibition of FcεR1-mediated degranulation in mast cells (IC50s in the range of 30 to 1650 nM): R950373, R950368, R921302, R945371, R945370, R945369, R945365, R921304, R945144, R945140, R945071, R940358, R940353, R940352, R940351, R940350, R940347, R921303, R940338, R940323, R940290, R940277, R940276, R940275, R940269, R940255, R935393, R935372, R935366, R935310, R935309, R935307, R935304, R935302, R935293, R935237, R935198, R935196, R935194, R935193, R935191, R935190, R935138, R927050, R926968, R926956, R926931, R926891, R926839, R926834, R926816, R926813, R926791, R926782, R926780, R926757, R926753, R926745, R926715, R926508, R926505, R926502, R926501, R926500, R921218, R921147, R920410, R909268, R921219, R908712, R908702.
Accordingly, the activity of the 2,4-pyrimidinediamine compounds of the invention may also be confirmed in biochemical or cellular assays of Syk kinase activity. Referring again to FIG. 2, in the FcεRI signaling cascade in mast and/or basophil cells, Syk kinase phosphorylates LAT and PLC-gamma1, which leads to, among other things, degranulation. Any of these activities may be used to confirm the activity of the 2,4-pyrimidinediamine compounds of the invention. In one embodiment, the activity is confirmed by contacting an isolated Syk kinase, or an active fragment thereof with a 2,4-pyrimidinediamine compound in the presence of a Syk kinase substrate (e.g., a synthetic peptide or a protein that is known to be phophorylated by Syk in a signaling cascade) and assessing whether the Syk kinase phosphorylated the substrate. Alternatively, the assay may be carried out with cells that express a Syk kinase. The cells may express the Syk kinase endogenously or they may be engineered to express a recombinant Syk kinase. The cells may optionally also express the Syk kinase substrate. Cells suitable for performing such confirmation assays, as well as methods of engineering suitable cells will be apparent to those of skill in the art. Specific examples of biochemical and cellular assays suitable for confirming the activity of the 2,4-pyrimidinediamine compounds are provided in the Examples section.
Generally, compounds that are Syk kinase inhibitors will exhibit an IC50 with respect to a Syk kinase activity, such as the ability of Syk kinase to phosphorylate a synthetic or endogenous substrate, in an in vitro or cellular assay in the range of about 20 μM or less. Skilled artisans will appreciate that compounds that exhibit lower IC50s, such as in the range of 10 μM, 100 nM, 10 nM, 1 nM, or even lower, are particularly useful.
6.5 Uses and Compositions
As previously discussed, the active compounds of the invention inhibit Fc receptor signaling cascades, especially those Fc receptors including a gamma homodimer, such as the FcεRI and/or FcγRI signaling cascades, that lead to, among other things, the release and/or synthesis of chemical mediators from cells, either via degranulation or other processes. As also discussed, the active compounds are also potent inhibitors of Syk kinase. As a consequence of these activities, the active compounds of the invention may be used in a variety of in vitro, in vivo and ex vivo contexts to regulate or inhibit Syk kinase, signaling cascades in which Syk kinase plays a role, Fc receptor signaling cascades, and the biological responses effected by such signaling cascades. For example, in one embodiment, the compounds may be used to inhibit Syk kinase, either in vitro or in vivo, in virtually any cell type expressing Syk kinase. They may also be used to regulate signal transduction cascades in which Syk kinase plays a role. Such Syk-dependent signal transduction cascades include, but are not limited to, the FcεRI, FcγRI, FcγRIII, BCR and integrin signal transduction cascades. The compounds may also be used in vitro or in vivo to regulate, and in particular inhibit, cellular or biological responses effected by such Syk-dependent signal transduction cascades. Such cellular or biological responses include, but are not limited to, respiratory burst, cellular adhesion, cellular degranulation, cell spreading, cell migration, cell aggregation, phagcytosis, cytokine synthesis and release, cell maturation and Ca2+ flux. Importantly, the compounds may be used to inhibit Syk kinase in vivo as a therapeutic approach towards the treatment or prevention of diseases mediated, either wholly or in part, by a Syk kinase activity. Non-limiting examples of Syk kinase mediated diseases that may be treated or prevented with the compounds are those discussed in more detail, below.
In another embodiment, the active compounds may be used to regulate or inhibit the Fc receptor signaling cascades and/or FcεRI- and/or FcγRI-mediated degranulation as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by and/or associated with the release or synthesis of chemical mediators of such Fc receptor signaling cascades or degranulation. Such treatments may be administered to animals in veterinary contexts or to humans. Diseases that are characterized by, caused by or associated with such mediator release, synthesis or degranulation, and that can therefore be treated or prevented with the active compounds include, by way of example and not limitation, atopy or anaphylactic hypersensitivity or allergic reactions, allergies (e.g., allergic conjunctivitis, allergic rhinitis, atopic asthma, atopic dermatitis and food allergies), low grade scarring (e.g., of scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction), diseases associated with tissue destruction (e.g., of COPD, cardiobronchitis and post myocardial infarction), diseases associated with tissue inflammation (e.g., irritable bowel syndrome, spastic colon and inflammatory bowel disease), inflammation and scarring.
When used to treat or prevent such diseases, the active compounds may be administered singly, as mixtures of one or more active compounds or in mixture or combination with other agents useful for treating such diseases and/or the symptoms associated with such diseases. The active compounds may also be administered in mixture or in combination with agents useful to treat other disorders or maladies, such as steroids, membrane stablizers, 5LO inhibitors, leukotriene synthesis and receptor inhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgG isotype switching or IgG synthesis, β-agonists, tryptase inhibitors, aspirin, COX inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines, to name a few. The active compounds may be administered per se in the form of prodrugs or as pharmaceutical compositions, comprising an active compound or prodrug.
Pharmaceutical compositions comprising the active compounds of the invention (or prodrugs thereof) may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping or lyophilization processes. The compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
The active compound or prodrug may be formulated in the pharmaceutical compositions per se, or in the form of a hydrate, solvate, N-oxide or pharmaceutically acceptable salt, as previously described. 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 may also be formed.
Pharmaceutical compositions of the invention may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.
For topical administration, the active compound(s) or prodrug(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.
Useful injectable preparations 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 agent. The formulations for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.
Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc., before use. To this end, the active compound(s) may be dried. by any art-known technique, such as lyophilization, and reconstituted prior to use.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.
For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art with, for example, sugars, films or enteric coatings. Compounds which are particularly suitable for oral administration include Compounds R940350, R935372, R935193, R927050 and R935391.
Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophoreTM or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound or prodrug, as is well known.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.
For nasal administration or administration by inhalation or insufflation, the active compound(s) or prodrug(s) can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit 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 comprised of gelatin) may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
A specific example of an aqueous suspension formulation suitable for nasal administration using commercially-available nasal spray devices includes the following ingredients: active compound or prodrug (0.5–20 mg/ml); benzalkonium chloride (0.1–0.2 mg/mL); polysorbate 80 (TWEEN® 80; 0.5–5 mg/ml); carboxymethylcellulose sodium or microcrystalline cellulose (1–15 mg/ml); phenylethanol (14 mg/ml); and dextrose (20–50 mg/ml). The pH of the final suspension can be adjusted to range from about pH5 to pH7, with a pH of about pH 5.5 being typical.
Another specific example of an aqueous suspension suitable for administration of the compounds via inhalation, and in particular for such administration of Compound R921218, contains 1–20 mg/mL Compound or prodrug, 0.1–1% (v/v) Polysorbate 80 (TWEEN®80), 50 mM citrate and/or 0.9% sodium chloride.
For ocular administration, the active compound(s) or prodrug(s) may be formulated as a solution, emulsion, suspension, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Pat. Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851.
For prolonged delivery, the active compound(s) or prodrug(s) can be formulated as a depot preparation 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 a sparingly soluble salt. Alternatively, transdermal delivery systems manufactured as an adhesive disc or patch which slowly releases the active compound(s) for percutaneous absorption may be used. To this end, permeation enhancers may be used to facilitate transdermal penetration of the active compound(s). Suitable transdermal patches are described in for example, U.S. Pat. Nos. 5,407,713.; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475.
Alternatively, other pharmaceutical delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver active compound(s) or prodrug(s). Certain organic solvents such as dimethylsulfoxide (DMSO) may also be employed, although usually at the cost of greater toxicity.
The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s). The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.
6.6 Effective Dosages
The active compound(s) or prodrug(s) of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated. The compound(s) may be administered therapeutically to achieve therapeutic benefit or prophylactically to achieve prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder. For example, administration of a compound to a patient suffering from an allergy provides therapeutic benefit not only when the underlying allergic response is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the allergy following exposure to the allergen. As another example, therapeutic benefit in the context of asthma includes an improvement in respiration following the onset of an asthmatic attack, or a reduction in the frequency or severity of asthmatic episodes. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.
For prophylactic administration, the compound may be administered to a patient at risk of developing one of the previously described diseases. For example, if it is unknown whether a patient is allergic to a particular drug, the compound may be administered prior to administration of the drug to avoid or ameliorate an allergic response to the drug. Alternatively, prophylactic administration may be applied to avoid the onset of symptoms in a patient diagnosed with the underlying disorder. For example, a compound may be administered to an allergy sufferer prior to expected exposure to the allergen. Compounds may also be administered prophylactically to healthy individuals who are repeatedly exposed to agents known to one of the above-described maladies to prevent the onset of the disorder. For example, a compound may be administered to a healthy individual who is repeatedly exposed to an allergen known to induce allergies, such as latex, in an effort to prevent the individual from developing an allergy. Alternatively, a compound may be administered to a patient suffering from asthma prior to partaking in activities which trigger asthma attacks to lessen the severity of, or avoid altogether, an asthmatic episode.
The amount of compound administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art.
Effective dosages may be estimated initially from in vitro assays. For example, an initial dosage for use in animals may be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC50 of the particular compound as measured in as in vitro assay, such as the in vitro CHMC or BMMC and other in vitro assays described in the Examples section. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans. For guidance, the reader is referred to Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 146, latest edition, Pagamonon Press, and the references cited therein.
Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described above are well-known in the art. Suitable animal models of 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 et al., 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 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. Ordinarily skilled artisans can routinely adapt such information to determine dosages suitable for human administration. Additional suitable animal models are described in the Examples section.
Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration and various factors discussed above. Dosage amount and interval may be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect. For example, the compounds may be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of active compound(s) may not be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.
Preferably, the compound(s) will provide therapeutic or prophylactic benefit without causing substantial toxicity. Toxicity of the compound(s) may be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effect is the therapeutic index. Compounds(s) that exhibit high therapeutic indices are preferred.
The invention having been described, the following examples are offered by way of illustration and not limitation.
7. EXAMPLES
7.1 Synthesis of Starting Materials and Intermediates Useful for Synthesizing The 2,4-Pyrimidinediamine Compounds According to Schemes (I)–(V)
Sections 7.1.1–7.1.141 of copending application Ser. No. 10/355,543 filed Jan. 31, 2003 describe the synthesis of various 2-chloro-4N-substituted-pyrimidinediamine useful for synthesizing 2,4-pyrimidinediamine compounds described herein. The content of these Sections 7.1.1–7.1.141 are incorporated by reference.
7.2 Synthesis of Amines and Amine Precursors
Sections 7.2.1–7.2.47 of copending application Ser. No. 10/355,543 filed Jan. 31, 2003 describe the synthesis of various amines useful for synthesizing 2,4-pyrimidinediamine compounds described herein. The content of these Sections 7.2.1–7.2.47 are incorporated herein by reference.
7.3 Synthesis of 2,4-Pyrimidinediamines
Sections 7.3.1–7.3.1165 of copending application Ser. No. 10/355,543 filed Jan. 31, 2003 describe the synthesis of the 2,4-pyrimidinediamine compounds listed below. The content of these Sections 7.3.1–7.3.1165 are incorporated herein by reference. Compounds R008951, R008952, R008953, R008955, R008956, R008958, R070153 and R070790 as described in Example 7.3.1099 below (Section 7.3.1099 of copending Ser. No. 10/355,543 filed Jan. 31, 2003) were purchased from Contact Services.












Example
Compound
Chemical Name







7.3.1
R926069
N2,N4-Bis(4-ethoxyphenyl)-2,4-pyrimidinediamine


7.3.2
R921218
N2,N4-Bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.3
R926017
N2,N4-Bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.4
R926018
N2,N4-Bis(3-fluoro-4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.5
R926037
N2,N4-Bis(3,4-tetrafluoroethylendioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.6
R926038
N2,N4-Bis(3-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.7
R926039
N2,N4-Bis(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.8
R926064
N2,N4-Bis(3-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.9
R926339
N2,N4-Bis(3-hydroxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.10
R926340
N2,N4-Bis(4-ethoxycarbonylamino-3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.11
R926341
N2,N4-Bis(-3-hydroxy-4-methylphenyl)-5-fluoro-2,4-pyrimidinediaminediamine


7.3.12
R926342
N2,N4-Bis[4-(2-methoxyethyleneoxy)phenyl]-5-fluoro--2,4-pyrimidinediamine


7.3.13
R909237
N2,N4-Bis(dihydrobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminediamine


7.3.14
R926065
N2,N4-Bis(3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.15
R926086
N2,N4-Bis[4-(N,N-dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.16
R926109
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.17
R926110
N2,N4-Bis(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.18
R926114
N2,N4-Bis[4-(N-morpholino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.19
R926206
N2,N4-Bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.20
R926209
N2,N4-Bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.21
R926222
N2,N4-Bis(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.22
R926223
N2,N4-Bis(3-chloro-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.23
R926224
N2,N4-Bis(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.24
R926225
N2,N4-Bis(4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.25
R926240
N2,N4-Bis[(4-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.26
R926254
(±)-N2,N4-Bis[4-methoxycarbonyl(α-methyl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.27
R926255
N2,N4-Bis[(3-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.28
R926387
N2,N4-Bis(3-acetyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.29
R926394
N2,N4-Bis(3-benzyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.30
R926398
N2,N4-Bis(2-phenylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.31
R926404
N2,N4-Bis(2-phenylphenyl)-5-methyl-2,4-pyrimidinediamine


7.3.32
R926399
N2,N4-Bis[(4-methoxy-3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.33
R926400
N2,N4-Bis[(2-methoxy-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.34
R926401
N2,N4-Bis[(2-methoxy-5-methyl-4-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.35
R926402
N2,N4-Bis[(2-methyl-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.36
R926403
N2,N4-Bis[(3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.37
R926405
N2,N4-Bis(4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.38
R926469
N2,N4′-Bis(4-hydroxy-3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.39
R926574
N2,N4-Bis[4-(tert-butoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.40
R926582
N2,N4-Bis(indol-5-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.41
R926319
N2,N4-Bis(4-cyanomethylphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine


7.3.42
R926320
N2,N4-Bis(3-indazol-6-yl)-5-ethoxycarbonyl-2,4-pyrimidinediamine


7.3.43
R926321
N2,N4-Bis(3-indazol-7-yl)-5-ethoxycarbonyl-2,4-pyrimidinediamine


7.3.44
R926325
N2,N4-Bis[6-(1,4-benzoxazine-3-onyl)]-5-ethoxycarbonyl-2,4-pyrimidinediamine


7.3.45
R926331
N2,N4-Bis(4-ethoxycarbonylmethyleneaminophenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine


7.3.46
R926058
N2,N4-Bis(4-ethoxyphenyl)-6-methoxycarbonyl-2,4-pyrimidinediamine


7.3.47
R926068
N2,N4-Bis(4-ethoxyphenyl)-5-methyl-2,4-pyrimidinediamine


7.3.48
R926072
N2,N4-Bis(4-ethoxyphenyl)-6-chloro-2,4-pyrimidinediamine


7.3.49
R926242
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-methyl-2,4-pyrimidinediamine


7.3.50
R926243
N2,N4-Bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine


7.3.51
R926248
N2,N4-Bis(3-hydroxyphenyl)-5-methyl-2,4-pyrimidinediamine


7.3.52
R926249
N2,N4-Bis(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.53
R926256
N2,N4-Bis[(4-methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.54
R926257
(±)-N2,N4-Bis[4-methoxycarbonyl(alpha-methyl)methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.55
R926258
N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-5-methyl-2,4-pyrimidinediamine


7.3.56
R926259
(±)-N2,N4-Bis[4-ethoxycarbonyl(alpha-methyl)methyleneoxyphenyl]-5-methyl-2,4-




pyrimidinediamine


7.3.57
R926397
N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-methyl-2,4-pyrimidinediamine


7.3.58
R940089
N2,N4-Bis-(3,4-dimethoxypenyl)-5-nitro-2,4-pyrimidinediamine


7.3.59
R940090
N2,N4-Bis-(4-ethoxypenyl)-5-nitro-2,4-pyrimidinediamine


7.3.60
R940095
N2,N4-Bis-(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine


7.3.61
R940096
N2,N4-Bis-[(4-ethoxycarbonylmethyleneoxy)phenyl]-5-nitro-2,4-pyrimidinediamine


7.3.62
R940100
N2,N4-Bis-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-nitro-2,4-pyrimidinediamine


7.3.63
R940215
N2,N4-Bis-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.64
R940216
N2,N4-Bis-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.65
R940217
N2,N4-Bis-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.66
R940222
N2,N4-Bis-(4-Acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.67
R940297
N2,N4-Bis(3-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.68
R926688
N2,N4-Bis(3,4,5-trimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.69
R925800
N2,N4-Bis(2-methyl-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine


7.3.70
R925801
N2,N4-Bis(2-methoxy-5-methyl-4-phenylphenyl)-5-bromo-2,4-pyrimidinediamine


7.3.71
R926594
N2,N4-Bis(indol-6-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.72
R926604
N2,N4-Bis(2-methoxycarbonyl benzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.73
R926605
N2,N4-Bis[4-(methoxycarbonylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.74
R926616
N2,N4-Bis(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.75
R926617
N2,N4-Bis(coumarin-6-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.76
R926620
N2,N4-Bis(4-methoxymethyl)coumarin-7-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.77
R925757
N2,N4-Bis(3-(hydroxymethyl)phenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.78
R925767
N2,N4-Bis[(2R)-hydroxy-(1S)-methyl-2-phenylethyl]-5-fluoro-2,4-pyrimidinediamine


7.3.79
R925768
N2,N4-Bis(2-hydroxy-2-phenylethyl)-5-fluoro-2,4-pyrimidinediamine


7.3.80
R925769
N2,N4-Bis(furfuryl)-5-fluoro-2,4-pyrimidinediamine


7.3.81
R925770
N2,N4-Bis(piperonyl)-5-fluoro-2,4-pyrimidineamine


7.3.82
R925772
N2,N4-Dibenzyl-5-fluoro-2,4-pyrimidinediamine


7.3.83
R925776
N2,N4-Bis(3,4-methylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.84
R925791
N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-fluoro-2,4-pyrimidinediamine


7.3.85
R945057
N2,N4-Bis(4-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.86
R926234
N2,N4-Bis(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.87
R926675
N2,N4-Bis(3-chloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.88
R926676
N2,N4-Bis[3-chloro-4-(ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.89
R926681
N2,N4-Bis(3-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.90
R926682
N2,N4-Bis(3-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.91
R926683
N2,N4-Bis(2-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.92
R926701
N2,N4-Bis(4-isopropoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.93
R925771
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine


7.3.94
R925778
N2,N4-Bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine


7.3.95
R925779
N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-bromo-2,4-pyrimidinediamine


7.3.96
R925792
N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-bromo-2,4-pyrimidinediamine


7.3.97
R925798
N2,N4-Bis(2-phenylphenyl)-5-bromo-2,4-pyrimidinediamine


7.3.98
R925799
N2,N4-Bis(2-methoxy-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine


7.3.99
R925802
N2,N4-Bis(4-methoxy-3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine


7.3.100
R925803
N2,N4-Bis(3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine


7.3.101
R925773
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-cyano-2,4-pyrimidinediamine


7.3.102
R925774
N2,N4-Bis(3-hydroxyphenyl)-5-cyano-2,4-pyrimidinediamine


7.3.103
R925775
N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-cyano-2,4-pyrimidinediamine


7.3.104
R935192
N2,N4-Bis(1-methyl-indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.105
R935205
N2,N4-Bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.106
R935211
N2,N4-Bis[1-(methoxycarbonyl)methyl-indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.107
R935188
N2,N4-Bis(indazolin-6-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.108
R935189
N2,N4-Bis(indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.109
R925814
N2,N4-Bis(1-ethoxycarbonyl-2-methylpropyl)-5-cyano-2,4-pyrimidinediamine


7.3.110
R925815
N2,N4-Bis(1-methoxycarbonyl-3-methylbutyl)-5-cyano-2,4-pyrimidinediamine


7.3.111
R925819
N2,N4-Bis(methoxycarbonylbenzyl)-5-cyano-2,4-pyrimidinediamine


7.3.112
R926662
N2,N4-Bis[4-(ethoxycarbonylmethyl)phenyl]-5-cyano-2,4-pyrimidinediamine


7.3.113
R935000
N2,N4-Bis(2-methoxy-5-phenylphenyl)-5-methyl-2,4-pyrimidinediamine


7.3.114
R935001
N2,N4-Bis[(2-methyl-5-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine


7.3.115
R935002
N2,N4-Bis[(4-methoxy-3-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine


7.3.116
R935003
N2,N4-Bis[(4-phenyl-2-methoxy-5-methyl)phenyl]-5-methyl-2,4-pyrimidinediamine


7.3.117
R935004
N2,N4-Bis[[di-(4-methoxyphenyl)]methyl]-5-fluoro-2,4-pyrimidinediamine


7.3.118
R935005
N2,N4-Bis(diphenylmethyl)-5-fluoro-2,4-pyrimidinediamine


7.3.119
R935006
N2,N4-Bis[di-(4-chlorophenyl)methyl]-5-fluoro-2,4-pyrimidinediamine


7.3.120
R935016
N2,N4-Bis[1(R)-4-methoxyphenylethyl]-5-bromo-2,4-pyrimidineamine


7.3.121
R935075
N2,N4-Bis[3-(2-hydroxyethoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.122
R935076
N2,N4-Bis[3-(2-methoxyethyl)oxyphenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.123
R935077
N2,N4-Bis(5-hydroxy-2-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.124
R935114
N2,N4-Bis(3-methoxycarbonylmethylenephenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.125
R935162
N2,N4-Bis(3,4-propylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.126
R935163
N2,N4-Bis(3-chloro-4-fluoropheny)-2,4-pyrimidinediamine


7.3.127
R925849
N2,N4-Bis(3-hydroxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine


7.3.128
R925852
N2,N4-Bis(3,4-ethylendioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine


7.3.129
R925864
N2,N4-Bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine


7.3.130
R925790
N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-2,4-pyrimidinediamine


7.3.131
R925804
N2,N4-Bis(2-phenylphenyl)-2,4-pyrimidinediamine


7.3.132
R925805
N2,N4-Bis(2-methoxy-5-phenylphenyl)-2,4-pyrimidinediamine


7.3.133
R945041
N2,N4-Bis(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.134
R925806
N2,N4-Bis(4-methoxy-3-phenylphenyl)-2,4-pyrimidinediamine


7.3.135
R925807
N2,N4-Bis(2-methyl-5-phenylphenyl)-2,4-pyrimidinediamine


7.3.136
R925808
N2,N4-Bis(2-methoxy-5-methyl-4-phenylphenyl)-2,4-pyrimidinediamine


7.3.137
R925862
N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine


7.3.138
R925863
N2,N4-Bis(3-hydroxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine


7.3.139
R926663
N2,N4-Bis[4-(ethoxycarbonylmethyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine


7.3.140
R926623
N2,N4-Bis(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.141
R926461
N2,N4-Bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine


7.3.142
R945051
N2,N4-Bis(3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.143
R945145
N2,N4-Bis(benzothiophen-3-ylmethyl)-5-fluoro-2,4-pyrimidinediamine


7.3.144
R945152
N2,N4-Bis[4-(N-benzylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.145
R945038
N2,N4-Bis(3-hydroxy-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.146
R950160
N2,N4-Bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.147
R950091
N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.148
R950122
N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.149
R950182
N2,N4-Bis[3-(dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.150
R950130
N2,N4-Bis(3-amino-4-methylphenyl)-2,4-pyrimidinediamine


7.3.151
R950129
N2,N4-Bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.152
R950083
N2,N4-Bis[(4-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.153
R950090
N2,N4-Bis(4-benzyloxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.154
R950092
N2,N4-Bis(3-cyano-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.155
R950100
N2,N4-Bis[3-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.156
R950108
N2,N4-Bis[3-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.157
R950120
N2,N4-Bis[4-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.158
R950170
N2,N4-Bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-




pyrimidinediamine


7.3.159
R950167
N2,N4-Bis[2-(2-hydroxyethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.160
R950168
N2,N4-Bis[2-(2-aminoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.161
R950169
N2,N4-Bis[2-(2-(N-benzylamino)ethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-




pyrimidinediamine


7.3.162
R950172
N2,N4-Bis[2-(N-morpholinocarbonyl)benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.163
R950173
N2,N4-Bis[2-(2-N-morpholinoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-




pyrimidinediamine


7.3.164
R950135
N2,N4-Bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.165
R950138
N2,N4-Bis(3-amino-2,4-difluorophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.166
R950139
N2,N4-Bis(3-amino-4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.167
R950134
N2,N4-Bis(3-amino-5-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.168
R950140
N2,N4-Bis(3-amino-5-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.169
R950141
N2,N4-Bis(3-amino-5-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.170
R950093
N2,N4-Bis(4-hydroxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.171
R950107
N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine Hydrogen Chloride salt


7.3.172
R950121
N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine Hydrogen Chloride Salt


7.3.173
R950109
N2,N4-Bis(3-aminophenyl)-2,4-pyrimidinediamine


7.3.174
R950131
N2,N4-Bis(3-amino-2,4-difluorophenyl)-2,4-pyrimidinediamine


7.3.175
R950142
N2,N4-Bis(3-amino-4-ethoxyphenyl)-2,4-pyrimidinediamine


7.3.176
R950132
N2,N4-Bis(3-amino-5-methoxycarbonylphenyl)-2,4-pyrimidinediamine


7.3.177
R950143
N2,N4-Bis(3-amino-5-trifluoromethylphenyl)-2,4-pyrimidinediamine


7.3.178
R950133
N2,N4-Bis(3-amino-5-chlorophenyl)-2,4-pyrimidinediamine


7.3.179
R950125
N2,N4-Bis[3-amino-4-(N-phenylamino)-phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.180
R950123
N2,N4-Bis[3-amino-4-(N-phenylamino)-phenyl]-2,4-pyrimidinediamine


7.3.181
R950157
N2,N4-Bis(5-amino-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.182
R950158
N2,N4-Bis(5-amino-2-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.183
R950159
N2,N4-Bis(3-amino-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.184
R950146
N2,N4-Bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.185
R950147
N2,N4-Bis(2-fluoro-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.186
R950148
N2,N4-Bis(4-fluoro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.187
R950144
N2,N4-Bis(4-methyl-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine (R950144)


7.3.188
R950149
N2,N4-Bis(4-chloro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.189
R950150
N2,N4-Bis(2-hydroxyethyleneamino-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.190
R950151
N2,N4-Bis(2-methoxy-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.191
R950152
N2,N4-Bis(4-fluoro-3-nitrophenyl)-2,4-pyrimidinediamine


7.3.192
R950153
N2,N4-Bis(4-methyl-3-nitrophenyl)-2,4-pyrimidinediamine


7.3.193
R950154
N2,N4-Bis(4-chloro-3-nitrophenyl)-2,4-pyrimidinediamine


7.3.194
R950155
N2,N4-Bis(2-hydroxy-5-nitrophenyl)-2,4-pyrimidinediamine


7.3.195
R950156
N2,N4-Bis(2-hydroxyethyleneamino-5-nitrophenyl)-2,4-pyrimidinediamine


7.3.196
R950166
N2,N4-Bis[3-(N-isopropyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.197
R950171
N2,N4-Bis[3-N-(2-hydroxy-1-methylethyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.198
R950177
N2,N4-Bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.199
R950178
N4-(3-Aminophenyl)-N2-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.200
R950179
N2-(3-Aminophenyl)-N4-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.201
R950184
N2,N4-Bis(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.202
R950183
N2,N4-Bis(3-ethoxycarbonylmethyleneaminophenyl)-N2-(ethoxycarbonylmethyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.203
R950180
N2-(3-Aminophenyl)-N4-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine and N4-




(3-Aminophenyl)-N2-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.204
R950181
N2,N4-Bis(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.205
R950174
N2,N4-Bis[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.206
R950175
N2-(3-Aminophenyl)-N4-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.207
R950176
N4-(3-Aminophenyl)-N2-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.208
R926210
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.209
R925758
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine


7.3.210
R925760
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine


7.3.211
R925765
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxy-2-phenylethyl)-2,4-pyrimidinediamine


7.3.212
R925766
N2-(3,4-Ethylendioxyphenyl)-5-fluoro-N4-[(2R)-hydroxy-(1S)-methyl-2-phenylethyl)-2,4-




pyrimidinediamine


7.3.213
R925794
N4-Cyclohexyl-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.214
R925795
N4-(4-Carboxycyclohexyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.215
R925796
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.216
R925823
N2-Allyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.217
R926237
N4-(3,4-Ethylenedioxyphenyl)-N2-(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.218
R926690
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.219
R926704
5-Fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.220
R926376
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine


7.3.221
R909236
N2-[4-(2-N,N-Dimethylamino)ethoxyphenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.222
R909238
N2-(1,4-Benzoxazin-3-on-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.223
R909241
N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.224
R909242
N4-(1,4-Benzoxazin-6-yl)-N2-[3-ethoxyocarbonylmethyleneoxyphenyl]-5-fluoro-2,4-




pyrimidinediamine


7.3.225
R909243
N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineN4-(1,4-




Benzoxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.226
R909245
N4-(1,4-Benzoxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.227
R909246
N4-(1,4-Benzoxazin-6-yl)-N2-(3-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.228
R909248
N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine


7.3.229
R909250
N2-(2,3-Dihydrobenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.230
R909255
N4-(1,4-Benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.231
R926706
5-Fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-




pyrimidinediamine


7.3.232
R926699
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.233
R926709
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.234
R926710
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.235
R926711
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.236
R926716
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)phenyl]-2,4-




pyrimidinediamine


7.3.237
R926717
N2-[3-[4-(2-Chloro-6-fluorobenzyl)piperazino]propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.238
R926719
N2-(4-tert-Butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.239
R926721
N4-[(5-Chloro-1-benzothiophen-3-yl)methyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.240
R926722
N4-[(5-Chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.241
R926723
N4-[2-[(2-Chloro-6-fluorobenzyl)thio]ethyl]-N2-(3,4-ethylenedioxy)-5-fluoro-2,4-pyrimidinediamine


7.3.242
R945168
N2-(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.243
R926724
N4-[2-[(2-Chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.244
R926743
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-phenyl-5-methylisoxazol-4-yl)-2,4-pyrimidinediamine


7.3.245
R926744
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dimethylisoxazol-4-yl)-2,4-pyrimidinediamine


7.3.246
R926727
N2-[2-(Ethoxycarbonylmethylenethio)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.247
R926740
N2-[2-(Ethoxycarbonylmethyleneoxy)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.248
R925797
5-Bromo-N2-(3,4-ethylenedioxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.249
R925822
N2-Allyl-5-bromo-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.250
R925820
5-Cyano-N2-(3,4-ethylenedioxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine


7.3.251
R935172
N4-[4-[Ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.252
R935173
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-




pyrimidinediamine


7.3.253
R935182
5-Fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-




pyrimidinediamine


7.3.254
R935185
5-Fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-




pyrimidinediamine


7.3.255
R935187
N4-[3-(1-Bis(ethoxycarbonyl)ethoxy)phenyl]-5-fluoro-N2-[4-isopropoxyphenyl)-2,4-




pyrimidinediamine


7.3.256
R935190
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.


7.3.257
R935191
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(indazolin-6-yl)-2,4-pyrimidinediamine


7.3.258
R935193
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine


7.3.259
R935194
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(1-methy-indazoline-5-yl)-2,4-pyrimidinediamine


7.3.260
R935197
5-Fluoro-N2-(indazoline-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.261
R935198
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine


7.3.262
R935199
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(indazoline-5-yl)-2,4-pyrimidinediamine


7.3.263
R935203
5-Fluoro-N2-(4-isopropoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine


7.3.264
R935204
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine


7.3.265
R935207
N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.266
R935208
N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.267
R935209
5-Fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-




pyrimidinediamine


7.3.268
R935214
5-Fluoro-N2-(3,5-dimethoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine


7.3.269
R935215
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.270
R935218
5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.271
R935219
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.272
R935220
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.273
R950203
N4-(3,4-Ethylenedioxyphenyl)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine


7.3.274
R950204
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(4-methoxyphenyloxy)ethyl]-2,4-pyrimidinediamine


7.3.275
R950205
N2-[2,3-Dihydrobenzo[b]furan-5-ylmethyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.276
R950206
N2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.277
R950201
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(methylthio)-1,3-benzothiaz-6-yl]-2,4-




pyrimidinediamine


7.3.278
R950213
N2-[2,3-Dihydrobenzo[b]furan-5-ylmethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.279
R950214
N2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.280
R950212
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methylthio)-1,3-benzothiaz-6-yl)-2,4-pyrimidinediamine


7.3.281
R950227
N2-(3-Aminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.282
R950253
N2-(1,4-Benzoxazin-6-yl)]-5-fluoro-N4-(3-nitrophenyl)-2,4-pyrimidinediamine


7.3.283
R950215
N2-(Ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.284
R950229
N2-(Ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-




pyrimidinediamine


7.3.285
R925821
5-Cyano-N2-(3-hydroxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine


7.3.286
R926680
5-Fluoro-N4-[2-fluoro-4-(methoxymethyleneoxy)phenyl]-N2-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.287
R926748
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine


7.3.288
R926749
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine


7.3.289
R926750
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine


7.3.290
R926751
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine


7.3.291
R945063
N4-[4-(Aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.292
R945071
N4-[4-(Cyanomethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.293
R945109
N4-(3-Cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.294
R945110
N4-(3-Cyanophenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine


7.3.295
R945117
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(indol-3-yl)ethyl]-2,4-pyrimidinediamine


7.3.296
R945118
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.297
R945124
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.298
R945125
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.299
R945064
N2-[4-(Aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.300
R945132
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.301
R945133
N2-[4-(Aminocarbonylmethoxy)phenyl]-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-




yl)methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.302
R945128
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.303
R945129
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.304
R945137
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.305
R945138
5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.306
R945139
N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.307
R945146
N4-(Benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.308
R945147
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine


7.3.309
R945148
N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-




2,4-pyrimidinediamine


7.3.310
R945151
N4-[(2,5-Dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.311
R945153
N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.312
R945155
N4-[4-(N-Benzylpiperazino)phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.313
R945162
N2-[(2,5-Dimethyl-3-furyl)methyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.314
R945163
N2-[4-(N-Benzylpiperazino)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.315
R945164
N2-(Benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.316
R945165
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-pyridylmethyl)-2,4-pyrimidinediamine


7.3.317
R945166
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-pyridylmethyl)-2,4-pyrimidinediamine


7.3.318
R926802
N4-(3,5-Dimethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.319
R926803
N4-(3,5-Dimethoxyphenyl)-N2-(2-ethoxycarbonylindol-7-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.320
R926108
N2-(3,4-Dimethoxyphenyl)-N4-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.321
R926146
N4-(4-Ethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.322
R926213
N4-(4-Ethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.323
R926145
N4-(3,4-Dimethoxyphenyl)-N2-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.324
R926147
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.325
R926113
N2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.326
R926395
N2-(4-Ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.327
R926396
5-Bromo-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.328
R926211
N2-(4-Ethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.329
R926212
N2-(3,4-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.330
R926218
N2-(3-Chloro-4-fluorophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.331
R926219
N2-(4-tert-Butylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.332
R926220
N4-(3,4-Ethylenedioxyphenyl)-N2-(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.333
R926221
N4-(3,4-Ethylenedioxyphenyl)-N2-(3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.334
R926229
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxyethyl)-2,4-pyrimidinediamine


7.3.335
R926230
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxybenzyl)-2,4-pyrimidinediamine


7.3.336
R926386
N2-(2,2-Difluorobenzodioxol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.337
R926476
N2-(2-Ethoxycarbonylindol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.338
R926480
N2-(4-Cyanomethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.339
R926482
N2-(3-Ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.340
R925745
N2-(3-Ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.341
R925746
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxyethyl)-2,4-pyrimidinediamine


7.3.342
R925747
N2-(4-Ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.343
R940233
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.344
R940235
N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.345
R940250
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-




2,4-pyrimidinediamineN2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-[4-[3-(N-




morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine


7.3.346
R940251
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-




2,4-pyrimidinediamine


7.3.347
R940253
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-




2,4-pyrimidinediamine


7.3.348
R940266
N2-(3-tert-Butylphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidinediamine


7.3.349
R940284
Mixture of 5-Fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-




pyrimidinediamine and 5-fluoro-N2-(2-ethoxoxycarbonylbenzofur-5-yl)-N4-(3-isopropylphenyl)-2,4-




pyrimidinediamine


7.3.350
R940281
N4-(3-tert-Butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine


7.3.351
R940283
5-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine


7.3.352
R926786
N2-(1,1-Dihydroisobenzofuran-1-one-6-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.353
R926787
N2-[3-(3-Acetamidophenoxy)propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.354
R926788
N2-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.355
R926789
N2-(2,4-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.356
R926790
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine


7.3.357
R926791
N2-(3,5-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.358
R926792
N2-(2,5-Dimethyl-4-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.359
R926793
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(5-methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine


7.3.360
R926795
N4-(3,5-Dimethoxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.361
R926797
N4-(3,4-Ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-




pyrimidinediamine


7.3.362
R926798
N4-(3-Hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-




pyrimidinediamine


7.3.363
R926614
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine


7.3.364
R926615
N2-(2-Ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.365
R926777
N2-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.366
R926778
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine


7.3.367
R926779
5-Fluoro N4-(3-hydroxyphenyl)-N2-(5-methyl-4-oxazolyl-2-phenyl)-2,4-pyrimidinediamine


7.3.368
R926780
N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (R926780)


7.3.369
R926572
N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-




methoxycarbonylmethyleneoxyphenyl-2,4-pyrimidinediamine


7.3.370
R926487
5-Fluoro-N4-(3-isopropoxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine


7.3.371
R926474
N4-(4-tert-Butylphenyl)-N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.372
R926477
N4-(4-tert-Butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine


7.3.373
R926485
N2-(3,4-Ethylenedioxyphenyl)-N4-(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-




pyrimidinediamine


7.3.374
R926774
N4-(3-Ethoxycarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.375
R926775
N4-(3-Ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.376
R945177
N4-(4-Aminocarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.377
R935019
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[di-(4-chlorophenyl)methyl]-2,4-pyrimidinediamine


7.3.378
R935020
N4-(Fluoren-9-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.379
R935021
(±)-5-Fluoro-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.380
R935023
(±)-5-Bromo-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.381
R935025
5-Bromo-N2-(3-hydroxyphenyl)-N4-(N-methyl-2-carbomethoxypyrrol-4-yl)-2,4-pyrimidinediamine


7.3.382
R935029
4-Amino-5-bromo-N2-(3-hydroxyphenyl)-2-pyrimidineamine


7.3.383
R935134
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.384
R935135
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.385
R935136
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.386
R935137
5-Fluoro-N4-(2-methoxycarbonylbenzofura-5-yl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-




yl)methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.387
R935138
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.388
R935139
5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.389
R935140
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.390
R935141
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.391
R935142
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.392
R935143
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.393
R935144
5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.394
R935145
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.395
R935146
5-Fluoro-N2-(2-methoxycarbonylbenzofura-5-yl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-




yl)methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.396
R935147
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.397
R935148
N2-(3,4-Ethylenedioxyphenyl)-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-2,4-




pyrimidinediamine


7.3.398
R935150
N2-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-




pyrimidinediamine


7.3.399
R935179
N2-[4-(2,3-Dihydroxypropoxy)phenyl]-N4-(3,4-ethylenedioxypheny)-5-fluoro-2,4-




pyrimidinediamine


7.3.400
R935180
N2-[4-(2,3-Dihydroxypropoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.401
R935175
N2-[4-(2,3-Dihydroxypropoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.402
R935169
N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.403
R935164
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[(N-methyl-2-methoxycarbonyl)pyrrol-4-yl]-2,4-




pyrimidinediamine


7.3.404
R935165
5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[(N-methyl-2-carbomethoxy)pyrrole-4-yl]-2,4-




pyrimidinediamine


7.3.405
R935166
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[(N-methyl-2-methoxycarbonyl)pyrrol-4-yl]-2,4-




pyrimidinediamine


7.3.406
R935167
N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-




pyrimidinediamine


7.3.407
R935159
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.408
R935157
N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-




methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine


7.3.409
R935152
N2-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.410
R940257
N2-(3-tert-Butylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.411
R940258
Mixture of N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-




methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and N4-(3-chloro-4-hydroxy-5-




methylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.412
R940260
N2-(3-tert-Butylphenyl)-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R940260)


7.3.413
R940261
N2-[2-(N-Benzylpiperazino)ethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.414
R940262
N2-[2-(N-Benzylpiperazino)ethyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.415
R940263
N2-[4-(N-Benzylpiperidino)]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.416
R940264
N2-[4-(N-Benzylpiperidino)]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.417
R940270
N4-(3-tert-Butylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.418
R940271
N4-(3-tert-Butylphenyl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.419
R940275
N2-(3-tert-Butylcarbonylaminophenyl)-N4-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.420
R940294
N4-(3,3-Dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-




pyrimidinediamine


7.3.421
R940285
N2-[3-Ethoxycarbonylmethyleneoxyphenyl]-N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-




2,4-pyrimidinediamine


7.3.422
R926804
N2-(3,5-Dimethoxyphenyl)-N4-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.423
R926805
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-trifluoromethylphenyl)]-2,4-pyrimidinediamine


7.3.424
R926808
N2-(2-Ethoxycarbonylindol-7-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine


7.3.425
R926809
N4-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-5-fluoro-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-




2,4-pyrimidinediamine


7.3.426
R926813
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine


7.3.427
R926814
N2-(2-Ethoxycarbonylindol-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyridinediamine


7.3.428
R950207
N2-(3-Aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.429
R950186
N4-(3,4-Ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.430
R950185
N4-(3,5-Dichloro-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.431
R950162
N4-(3-Aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-2,4-pyrimidinediamine


7.3.432
R950163
N4-(3-Aminophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.433
R950164
N4-(3-Aminophenyl)-5-fluoro-N2-(3-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.434
R950165
N4-(3-Aminophenyl)-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.435
R950210
N2-(3-Furylmethylene)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.436
R950211
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(4-methoxyphenyloxyethyleneamino)-2,4-pyrimidinediamine


7.3.437
R950137
N4-(3-Aminophenyl)-N2-[[N3-[N4-(3-aminophenyl)]-5-fluoro-2,4-pyrimidinediamine]aminophenyl]-




5-fluoro-2,4-pyrimidinediamine


7.3.438
R950208
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(hydroxyethyleneamino)phenyl]-2,4-




pyrimidinediamine


7.3.439
R950209
N2-[3-Bis(hydroxyethyl)aminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.440
R925858
6-Ethoxycarbonyl-N4-(ethoxycarbonylmethyl)-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-5-nitro-




2,4-pyrimidinediamine


7.3.441
R925837
N4-Benzyloxy-5-ethoxycarbonyl-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine


7.3.442
R925824
N4-Benzyloxy-5-ethoxycarbonyl-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.443
R945025
N2,N4-Bis[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.444
R945032
N2,N4-Bis[4-(cyanomethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.445
R945033
N2,N4-Bis[4-(1H-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.446
R945034
N2,N4-Bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.447
R945035
N2,N4-Bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.448
R945036
N2,N4-Bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.449
R945037
N2,N4-Bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.450
R926412
N2,N4-Bis(3-isopropylaminocarbonyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.451
R945040
N2,N4-Bis[4-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.452
R945045
N2,N4-Bis[3-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.453
R945043
N2,N4-Bis(4-hydroxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.454
R945046
N2,N4-Bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.454
R945047
5-Fluoro-N2,N4-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl],[4-(2-methyl-1,2,3,4-




tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.454
R945048
N2,N4-Bis[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.455
R945052
N4-(4-Aminocarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-




2,4-pyrimidinediamine


7.3.456
R945053
N4-(4-Cyanomethyleneoxyphenyl])5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.457
R945056
N2,N4-Bis[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.458
R945060
N2-(4-Aminocarbonylmethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-




2,4-pyrimidinediamine


7.3.459
R945061
N2,N4-Bis(3-hydroxy-4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.460
R945062
N2-(4-Cyanomethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.461
R945065
N2,N4-Bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.462
R945066
N2,N4-Bis(4-methoxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.463
R945067
N2,N4-Bis(3-carboxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.464
R945068
N2,N4-Bis(4-carboxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.465
R945070
N2-(4-Cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.466
R945172
N4-(4-Cyanomethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.467
R945096
N2,N4-Bis[4-[2-methoxyimino(amino)ethyleneoxy]phenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.468
R945097
N2-(4-Carboxymethyleneoxyphenyl)-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.469
R945127
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.470
R945130
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.471
R945131
5-Fluoro-N4-(2-methoxycarbonylbenzofuran-5-yl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-




yl)methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.472
R945134
N4-(2-Carboxybenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-




yl)methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.473
R945135
N4-(2-Aminocarbonylbenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-




yl)methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.474
R945167
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-methoxyimino(amino)ethyleneoxy)phenyl]-2,4-




pyrimidinediamine


7.3.475
R945175
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-methoxyimino(amino)ethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.476
R926495
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.477
R921219
N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.478
R909239
N4-(3,4-Ethylendioxyphenyl)-5-fluoro-N2-[4-(N-2-




hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.479
R909240
N4-(3,4-Ethylendioxyphenyl)-5-fluoro-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.480
R909251
N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-2-hydroxypropylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.481
R909252
N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-3-hydroxypropylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.482
R909254
N4-(1,4-Benzoxazin-6-yl)-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-




pyrimidinediamine


7.3.483
R926703
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(N-pyrrolidino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.484
R926708
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.485
R926494
N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.486
R926712
N4-(4-tert-Butylphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.487
R940295
N4-(3-tert-Buthylpheny)-5-fluoro-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.488
R926562
N2,N4-Bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-2,4-pyrimidinediamine


7.3.489
R926563
N2,N4-Bis(4-N-pyrrolidinocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.490
R940296
N4-(3-tert-Butylpheny)-N2-[3-(N-1,3-dihydroxypropyl-2-amino)carbonylmethyleneoxyphenyl]-5-




fluoro-2,4-pyrimidinediamine


7.3.491
R940290
N2-[3-(N-2,3-Dihydroxypropylamino)




carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine


7.3.492
R940288
5-Fluoro-N4-(3-isopropylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.493
R926718
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-dimethylamino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.494
R945149
N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-




piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.495
R926713
N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.496
R926796
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.497
R926800
5-Ethoxycarbonyl-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.498
R926801
N4-(3,5-Dimethoxyphenyl)-5-ethoxycarbonyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.499
R926714
N4-(4-tert-Butylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.500
R926742
N4-(3-Hydroxyphenyl)-5-trifluoromethyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.501
R926745
5-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.502
R945156
N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.503
R940291
N4-(3-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofur-5-yl]-2,4-




pyrimidinediamine


7.3.504
R926505
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.505
R926746
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.506
R926715
5-Fluoro-N2-[2-(2-hydroxy-1,1-dimethylethylamino)carbonylbenzofuran-5-yl]-N4-(3-




hydroxyphenyl)-2,4-pyrimidinediamine


7.3.507
R926730
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.508
R945170
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.509
R926489
5-Fluoro-N4-(3-isopropoxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.510
R926772
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.511
R926506
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.512
R926508
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.513
R926732
5-Fluoro-N4-[3,4-(1,1,2,2-tetrafluoroethylendioxy)phenyl]-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.514
R940254
N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.515
R940276
N4-(3-tert-Butylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-




pyrimidinediamine


7.3.516
R940277
N4-(3-tert-Butylphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-




fluoro-2,4-pyrimidinediamine


7.3.517
R940293
N4-(3,3-Dihydroisobenzofuran-1-one-6-yl)-N2-[3-(N-2,3-




dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.518
R926733
N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.519
R926734
N2-[3-(N-2,3-Dihydroxypropylamino)




carbonylmethyleneoxyphenyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.520
R926738
5-Fluoro-N4-(3-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.521
R926739
N2-[3-(N-2,3-Dihydroxypropylamino)




carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3-methoxyphenyl)-2,4-pyrimidinediamine


7.3.522
R945140
N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.523
R926488
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.524
R926493
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.525
R926497
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.526
R926500
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.527
R925844
5-Cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.528
R925845
5-Cyano-N4-[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-




2,4-pyrimidinediamine


7.3.529
R925846
5-Cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.530
No Rigel
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-trifluoromethylphenyl)-2,4-



Number
pyrimidinediamine


7.3.531
R926812
N4-[4-(4,5-Dichloro-1H-imidazol-1-ylphenyl)]-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.532
R926815
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylaminocarbonyllindol-7-yl)-2,4-




pyridinediamine


7.3.533
R926484
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.534
R926492
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.535
R926496
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.536
R926498
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-




2,4-pyrimidinediamine


7.3.537
R926503
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.538
R926764
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxy-1,1-




dimethylethylamino)carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.539
R926765
N2-[3-(N-Cyclohexylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-




2,4-pyrimidinediamine


7.3.540
R926766
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-methyl-N-(2-




hydroxyethyl)amino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.541
R926767
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.542
R925755
N4-(3,4-Ethylenedioxyphenyl)-N2-[3-(N,N-dimethylamino)carbonylmethyleneoxyphenyl]-5-fluoro-




2,4-pyrimidinediamine


7.3.543
R926781
N2-[3-[N,N-Bis-(2-hydroxyethylamino)]




carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.544
R926782
N2-[3-(N-2,3-Dihydroxypropylamino)




carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.545
R926783
N2-[2-(N-2,3-Dihydroxypropylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-




fluoro-2,4-pyrimidinediamine


7.3.546
R926784
N2-[3-(N-1,3-Dihydroxy-2-propylamino)




carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.547
R926785
N2-[2-(N-1,3-Dihydroxy-2-propylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-




fluoro-2,4-pyrimidinediamine


7.3.548
R940265
N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-




morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.549
R950187
N4-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.550
R950188
N4-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.551
R926776
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyeleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.552
R945173
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.553
R909253
N2-[4-(2-N,N-Dimethylaminoethyl)oxyphenyl]-5-fluoro-N4-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.554
R909247
N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.555
R909249
N2-(4-Dihydrobenzofuranyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.556
R940267
N2-(3-tert-Butylphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-




pyrimidinediamine


7.3.557
R926491
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.558
R926491
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.559
R926810
N2-(3,5-Dimethoxyphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.560
R925851
5-Bromo-N2-(3,4-ethylenedioxyphenyl)-N4-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.561
R926741
N2-(3-Hydroxyphenyl)-5-trifluoromethyl-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.562
R925860
N2,N4-Bis[4-(N-n-butylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine


7.3.563
R925861
N2,N4-Bis[4-(N-isopropylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine


7.3.564
R925853
N2,N4-Bis[4-(N-n-propylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine


7.3.565
R925854
N2,N4-Bis[4-(N-morphonlino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine


7.3.566
R925855
N2,N4-Bis[4-(N-piperidino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine


7.3.567
R925859
N2,N4-Bis[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-




pyrimidinediamine


7.3.568
R950254
N4-(3-Aminophenyl)-N2-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.569
R950200
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-




morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine


7.3.570
R950191
N4-(3,4-Ethylenedioxyphenyl)-N2-[3-N-methylamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-




pyrimidinediamine


7.3.571
R950192
N2-[3-(N-Amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.572
R950193
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-




pyrimidinediamine


7.3.573
R950194
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-(N-methyl)-




piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine


7.3.574
R950195
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-




hydroxyethyleneamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.575
R950196
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)ethyleneaminocarbonylmethyleneaminophenyl]-2,4-pyrimidinediamine


7.3.576
R950197
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-5-




fluoro-2,4-pyrimidinediamine


7.3.577
R950198
N2-[3-(N-Benzylamino)ethyleneaminocarbonylmethyleneaminophenyl]-N4-(3,4-




ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.578
R950199
N2-[3-(N,N′-Bis(2-N-hydroxyethyl)amino)carbonylmethyleneaminophenyl]-N4-(3,4-




ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.579
R950217
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-




pyrimidinediamine


7.3.580
R950219
N2-(3-Aminocarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.581
R950220
N2-[3-(N,N-Dimethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.582
R950221
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-




pyrimidinediamine


7.3.583
R950222
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-2,4-




pyrimidinediamine


7.3.584
R950223
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[N-(N-methyl)piperazino]carbonylmethyleneaminophenyl]-




2,4-pyrimidinediamine


7.3.585
R950224
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneaminophenyl]-




2,4-pyrimidinediamine


7.3.586
R950225
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-




methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine


7.3.587
R950226
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-2-




morpholinoethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine


7.3.588
R935184
5-Fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-




pyrimidinediamine


7.3.589
R935196
N2-[3-(1-Bis(N-methylaminocarbonyl)ethoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-




pyrimidineamine


7.3.590
R935202
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-




pyrimidinediamine


7.3.591
R935206
N2,N4-Bis[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.592
R935212
N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.593
R935213
N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-(N-methylamino)carbonyl-fur-4-




yl)methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.594
R935216
5-Fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-




pyrimidinediamine


7.3.595
R935217
N2,N4-Bis[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.596
R926486
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.597
R926490
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholinomethylene)benzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.598
R926510
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-methylamino)ethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.599
R926770
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.600
R940255
N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.601
R945142
N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-




pyrimidinediamine bis Hydrogen Chloride Salt


7.3.602
R945144
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(2-hydroxyethyloxy)phenyl]-2,4-pyrimidinediamine


7.3.603
R945150
N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-




pyrimidinediamine Dihydrochloride Salt


7.3.604
R945157
N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-




pyrimidinediamine Dihydrochloride Salt


7.3.605
R926501
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.606
R926504
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.607
R926509
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-N-methylaminoethyl)phenyl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.608
R926511
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.609
R926768
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.610
R926502
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.611
R926769
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-




pyrimidinediamine Dihydrochloride Salt


7.3.612
R926773
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.613
R926771
N2-[3-[2-(N,N-Dimethylamino)ethyloxy]phenyl]-N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.614
R940256
N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.615
R940269
N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.616
R926816
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.617
R926696
N4-(3,4-Ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine


7.3.618
R926700
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(hydroxymethyl)-(1H)-indol-5-yl]-2,4-pyrimidinediamine


7.3.619
R926705
5-Fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-[4-(isopropoxy)phenyl]-2,4-pyrimidinediamine


7.3.620
R926707
5-Fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.621
R926728
N4-(4-tert-Butyl)phenyl)-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.622
R926735
5-(Hydroxymethyl)-N2-[3-(2-hydroxyethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.623
R940287
N4-(3-tert-Butylphenyl)-5-fluoro-N2-[(2-hydroxymethylene)benzofur-5-yl]-2,4-pyrimidinediamine


7.3.624
R940287
5-Fluoro-N4-(3-isopropylphenyl)-N2-[(2-hydroxymethylene]benzofur-5-yl]-2,4-pyrimidinediamine


7.3.625
R940286
5-Fluoro-N4-(3-isopropylphenyl)-N2-[(2-hydroxymethylene]benzofur-5-yl]-2,4-pyrimidinediamine


7.3.626
R940282
N4-(3-tert-Butylphenyl)-5-fluoro-N2-[3-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.627
R940292
N4-[3,4-Bis(hydroxymethyl)phenyl]-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-




pyrimidinediamine


7.3.628
R935149
N2-(3,4-Ethylenedioxyphenyl)-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-5-fluoro-2,4-




pyrimidinediamine


7.3.629
R935151
5-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(4-isopropoxyphenyl)-2,4-




pyrimidinediamine


7.3.630
R935153
5-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.631
R935154
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine


7.3.632
R935155
5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.633
R935156
5-Fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.634
R935158
5-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[4-(2-hydroxyethoxy)phenyl]-2,4-




pyrimidinediamine


7.3.635
R935160
5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.636
R935161
5-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-




pyrimidinediamine


7.3.637
R935168
5-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-(4-isopropoxyphenyl)-2,4-




pyrimidinediamine


7.3.638
R935170
5-Fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.639
R935171
5-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)--2,4-




pyrimidinediamine


7.3.640
R935174
5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-




pyrimidinediamine


7.3.641
R935176
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine


7.3.642
R935177
5-Fluoro-N2-[4-(2-hydroxy-1,1,dimethylethyl)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-




pyrimidinediamine


7.3.643
R935178
5-Fluoro-N2-[3-(2-hydroxyethyloxy)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-




pyrimidinediamine


7.3.644
R935181
N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine


7.3.645
R935183
5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine


7.3.646
R935186
5-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine


7.3.647
R926720
N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.648
R926726
N4-(4-tert-Butylphenyl)-N2-(3-carboxymethyleneoxyphenyl)-5-fluor-2,4-pyrimidinediamine


7.3.649
R926731
5-Fluoro-N2-[3-(carboxymethyleneoxy)phenyl]-N4-[4-(isopropoxy)phenyl]-2,4-pyrimidinediamine


7.3.650
R926560
N2,N4-Bis(4-carboxymethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine


7.3.651
R926483
N2-(3-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.652
R945126
N2-(3-Carboxymethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.653
R926238
N2-(4-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.654
R926564
N2-(4-Carboxymethyleneoxyphenyl)-5-Fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.655
R926478
N2-(2-Carboxybenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.656
R926479
N2-(2-Carboxyindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.657
R926481
N4-(4-tert-Butylphenyl)-N2-(2-carboxybenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.658
R940280
N4-(3-tert-Butylphenyl)-N2-[3-carboxymethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.659
R950190
N2-(3-Carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.660
R950230
N2-(Carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethyloxy)phenyl]-2,4-




pyrimidinediamine


7.3.661
R950231
5-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-




hydroxyethylamino)]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine


7.3.662
R950232
N2-[3-(N-2-Aminoethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-




hydroxyethylenoxy)phenyl]-2,4-pyrimidinediamine


7.3.663
R950233
5-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-




methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine


7.3.664
R950234
5-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-




methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine


7.3.665
R950235
N2-[3-[N-(2-N-Benzylamino)ethylamino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-




hydroxyethylamino)phenyl]-2,4-pyrimidinediamine


7.3.666
R950236
5-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-




morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine


7.3.667
R950237
N2-[3-(3-N,N-Dimethylaminopropyl)




aminocarbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-




pyrimidinediamine


7.3.668
R950238
N2-[3-[N-(2,3-Dihydroxypropyl)amino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-




hydroxyethylamino)phenyl]-2,4-pyrimidinediamine


7.3.669
R950239
5-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-




morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine


7.3.670
R926514
2,4-Bis[N-(L)-tyrosine methyl ester]-5-ethoxycarbonylpyrimidine


7.3.670
R926513
5-Ethoxycarbonyl-2-methoxy-4-[N-(L)-tyrosine methyl ester]pyrimidine


7.3.671
R926252
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine


7.3.672
R926253
N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine


7.3.673
R926526
2,4-Bis[N-(L)-phenylalaninyl ethyl ester]-5-ethoxycarbonylpyrimidine


7.3.674
R926527
2,4-Bis[N-(L)-valinyl ethyl ester]-5-ethoxycarbonylpyrimidine


7.3.675
R926528
5-Ethoxycarbonyl-N2-(3-hydroxyphenyl)-4-[N-(L)-phenylalanine ethyl ester]-2-pyrimidineamine


7.3.676
R926536
N2-(3,4-Ethylenedioxyphenyl)-5-ethoxycarbonyl-4-[N-(L)-phenyl glycinyl ethyl ester)-2-




pyrimidineamine


7.3.677
R926579
N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-




methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine


7.3.678
R926580
N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-5-




methoxycarbonyl-2,4-pyrimidinediamine


7.3.679
R926583
N4-(4-Carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-




methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine


7.3.680
R926584
N2-(4-Carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(4-




methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine


7.3.681
R926535
5-Carboxy-N2-(3-hydroxyphenyl)-N4-[N-(L)-phenylglycine)-2-pyrimidineamine


7.3.682
R925856
5-Amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.683
R925857
5-Amino-6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine


7.3.684
R925865
5-Amino-N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine


7.3.685
R926567
5-Amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-




pyrimidinediamine


7.3.686
R926571
N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-




(phenylaminocarbonylamino)-2,4-pyrimidinediamine


7.3.687
R926585
5-Allylaminocarbonylamino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl)-




2,4-pyrimidinediamine


7.3.688
R926586
N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylformyl)-2,4-




5-pyrimidinetriamine


7.3.689
R926587
N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylmethylene




aminocarbonylamino)-2,4-pyrimidinediamine


7.3.690
R926588
N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-




(cyclopentylaminocarbonylamino)-2,4-pyrimidinediamine


7.3.691
R926589
N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-




(chloroacetylaminocarbonylamino)-2,4-pyrimidinediamine


7.3.692
R920669
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-trifluoro-2,4-pyridinediamine


7.3.693
R920668
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-pyridyl)-2,4-pyrimidinediamine


7.3.694
R920664
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-n-hexyloxyphenyl)-2,4-pyrimidindiamine


7.3.695
R920666
N2-(4-n-Butyloxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine


7.3.696
R920670
N4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.697
R920671
N4-(4-n-Butyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine


7.3.698
R920672
N4-(4-n-Hexyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine


7.3.699
R920818
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.700
R920819
N4-(3-Hydroxyphenyl)-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.701
R920820
N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.702
[NEED R
N4-(3-Benzyloxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-



NO.]
pyrimidineamine


7.3.703
R920917
N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidineamine


7.3.704
[NEED R
N4-(3-Benzyloxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-



NO.]
pyrimidineamine


7.3.705
R920910
N4-(3-Hydroxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidineamine


7.3.706
R920861
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidineamine


7.3.707
R920860
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidineamine


7.3.708
R920894
N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidineamine


7.3.709
R920893
N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-




pyrimidineamine


7.3.710
R925810
N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-(1,2,3,4-tetrazol-5-yl)-2,4-pyrimidinediamine


7.3.711
R925838
N2-[4-(N-Cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-




hydroxyphenyl)-2,4-pyrimidinediamine


7.3.712
R925839
5-Ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.713
R925840
N2-[4-(N-2,3-Dihydroxypropylamino)




carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-




(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.714
R925841
N2,N4-Bis[4-[N-(3-methoxybenzylamino)




carbonylmethyleneoxy]phenyl]-5-bromo-2,4-pyrimidinediamine


7.3.715
R925842
5-Bromo-N4-[4-[(N-cyclopropylmethylamino)




carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.716
R925843
5-Bromo-N2-(3-hydroxyphenyl)-N4-[4-(N-3-methoxybenzylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.717
R926698
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine


7.3.718
R926016
N2,N4-Bis(4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.719
R926406
N2-(3,4-Ethylenedioxyphenyl)-N4-(3,4-methylenedioxyphenylhydrazinyl)-5-fluoro-2-




pyrimidineamine


7.3.720
R926566
N2,N4-Bis(4-ethoxycarbonylmethylenedioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-




pyrimidinediamine


7.3.721
R950202
N2,N4-Bis[2-(methylthio)-1,3-benzothiaz-6-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.722
R950240
N4-[3-(2-Hydroxyethyleamino)phenyl]-N2-[3-(N-(N-methyl)-




piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine


7.3.723
R950241
N4-[3-(2-Hydroxyethyleamino)phenyl]-N2-[3-(N-piperazino)-carbonylmethyleneaminophenyl]-5-




fluoro-2,4-pyrimidinediamine


7.3.724
R950251
(±)-N4-(3-Aminophenyl)-5-fluoro-N2-(3-(3-carboxy-3-D,L-N-




phtaloylamino)propylenecarbonylaminophenyl)-2,4-pyrimidinediamine


7.3.725
R950255
(±)-N4-(3-Aminophenyl)-5-fluoro-N2-[3-(3-carboxy-3-amino)propylenecarbonylaminophenyl]-2,4-




pyrimidinediamine


7.3.726
R926559
5-Methoxycarbonyl-N2,N4-bis[4-(N-pyrrolidino)




carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine


7.3.727
R925565
N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyridinediamine


7.3.728
R926799
N2-(3-Ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(3,4-




tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine


7.3.729
R926811
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-2-(D)-(+)-




biotinylethylamino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.730
R926725
5-Fluoro-N4-(3-hydroxyphenyl)-N2[2-(N-methyl-N-2-hydroxyethyl)carbonylbenzofuran-5-yl)-2,4-




pyrimidinediamine


7.3.731
R926228
N2,N4-Bis(3-ethoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.732
R908696
N2-(3-chloro-4-methylbenzyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.733
R908697
(±)-N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-phenylethyl)-2,4-pyrimidinediamine


7.3.734
R925745
N2-(3-Ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.735
R920394
N4-(3,4-Difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.736
R920396
N4-(4-Chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.736.1
R920397
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.737
R920398
5-Fluoro-N4-(5-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.738
R920399
5-Fluoro-N4-(6-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.739
R920405
N4-(5-Chloropyridin-2-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.740
R920406
N4-(6-Chloropyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.741
R927016
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(4-methylpyridin-2-yl)-2,4-




pyrimidinediamine


7.3.742
R920407
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-trifluoromethoxyphenyl)-2,4-




pyrimidinediamine


7.3.743
R920408
N4-(3,4-Difluoromethylenedioxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.744
R920410
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.745
R926827
N4-(4-Ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.746
R926828
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-methoxy-3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.747
R926829
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.748
R926832
N4-(3-Chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.749
R926833
5-Fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.750
R926834
5-Fluoro-N4-(3-hydroxy-4-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.751
R926835
5-Fluoro-N4-(4-methoxy-3-trifluoromethylphenyl)-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.752
R926838
5-Fluoro-N4-(4-fluoro-3-trifluoromethylphenyl)-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.753
R926839
N4-(3-Chloro-4-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.754
R926840
N4-(2-Chloro-5-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.755
R926830
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.756
R926848
N2-[3-(N-Cyclopropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-




2,4-pyrimidinediamine


7.3.757
R926851
N4-(4-Cyano-3-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.758
R926855
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(tetrazol-5-yl)phenyl]-2,4-




pyrimidinediamine


7.3.759
R926856
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(N-methylphthalimido-4-yl)-2,4-




pyrimidinediamine


7.3.760
R926859
N4-(2,5-Dimethoxy-4-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.761
R926862
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-methoxycarbonyl-5-




trifluoromethylphenyl)-2,4-pyrimidinediamine


7.3.762
R926870
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-




yl)phenyl]-2,4-pyrimidinediamine


7.3.763
R926871
N4-[3-(2-(3-Chlorophenyl)-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.764
R926879
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethoxyphenyl]-2,4-




pyrimidinediamine


7.3.765
R926880
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethylphenyl]-2,4-




pyrimidinediamine


7.3.766
R926881
N4-(4-Chloro-3-trifluoromethylphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine


7.3.767
R926883
5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-N4-(quinolin-6-yl)-2,4-




pyrimidinediamine


7.3.768
R926886
5-Fluoro-N4-(2-methoxypyridin-5-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.769
R927023
5-Fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.770
R920404
N4-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-




pyrimidinediamine


7.3.771
R927042
N4-(4-Chloro-3-methoxyphenyl))-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-




2,4-pyrimidinediamine


7.3.772
R920411
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.773
R926866
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(3-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-




pyrimidinediamine


7.3.774
R926794
N4-(3,4-Difluoromethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.775
R926885
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine


7.3.776
R926887
N4-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.777
R927017
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(5-methylpyridin-2-yl)-2,4-pyrimidinediamine


7.3.778
R927018
N4-(6-Chloropyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.779
R927019
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine


7.3.780
R927020
N4-(5-Chloropyridin-2-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.781
R926860
N4-(4-Chloro-2,5-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-primidinediamine


7.3.782
R927026
N4-(4-Chlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine


7.3.783
R927027
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine


7.3.784
R926863
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-




pyrimidinediamine


7.3.785
R926857
N2-(4-Chloro-2,5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.786
R926846
N2-(3-Bromo-5-trifluorophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.787
R926841
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1H-pyrazol-3-yl)phenyl]-2,4-pyrimidinediamine


7.3.788
R926842
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine


7.3.789
R926831
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine


7.3.790
R926844
N2-(3-Chloro-4-trifluoromethylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinedimine


7.3.791
R926843
5-Fluoro-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine


7.3.792
R926845
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxy-2-methylphenyl)-2,4-pyrimidinediamine


7.3.793
R926847
N2-[5-(N-Aminocarbonylmethylene-2-oxo-1,3-oxazol-3(2H)-yl)phenyl]-N4-(3,4-




ethylenedioxyphenyl)-5-fluoro-2,4-pyrmidinediamine


7.3.794
R926874
N2-[3-(2-Ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.795
R926836
N2,N4-Bis(3-boronylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.796
R926837
N2-(3-Boronylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.797
R927030
(±)-N4-(3,4-Difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-




pyrimidinediamine


7.3.798
R927024
(±)-N4-(4-Chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-




pyrimidinediamine


7.3.799
R927031
(±)-N4-(3,4-Dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-




pyrimidinediamine


7.3.800
R927032
(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-




2,4-pyrimidinediamine


7.3.801
R927025
(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-[2-(2-




hydroxyethyleneoxy)pyridin-5-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.802
R927028
(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluorophenyl)-2,4-




pyrimidinediamine


7.3.803
R927029
(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(3,4-difluoromethylenedioxyphenyl)-5-




fluoro-2,4-pyrimidinediamine


7.3.804
R927035
(±)-N4-(3,4-Difluorophenyl)-5-fluoro-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-




2,4-pyrimidinediamine


7.3.805
R927036
(±)-N4-(4-Chlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-




pyrimidinediamine


7.3.806
R927037
(±)-N4-(3,4-Dichlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-




2,4-pyrimidinediamine


7.3.807
R927038
(±)-N4-(2,6-Dimethoxypyridin-3-yl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-




5-fluoro-2,4-pyrimidinediamine


7.3.808
R927039
(±)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-[2-(2-




hydroxyethyleneoxy)pyridin-5-yl]-2,4-pyrimidinediamine


7.3.809
R927040
(±)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-(3-




trifluoromethoxyphenyl)-2,4-pyrimidinediamine


7.3.810
R927041
(±)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-N4-(3,4-




difluoromethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.811
R926238
N2-(4-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.812
R920395
N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine Hydrogen Chloride Salt


7.3.813
R926826
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine Trifluoro Acetic Acid Salt


7.3.814
R926752
5-Fluoro-N4-[(1H)-indol-6-yl]-N2-[4-methoxy-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-




2,4-pyrimidinediamine


7.3.815
R926753
5-Fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-




2,4-pyrimidinediamine


7.3.816
R926754
5-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.817
R926755
5-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.818
R926756
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxyborylphenyl)-2,4-pyrimidinediamine


7.3.819
R926757
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-




2,4-pyrimidinediamine


7.3.820
R926758
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-methyl-3-[(N-




methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.821
R926759
5-Fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[4-methyl-3-[(N-




methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.822
R926760
5-Fluoro-N2,N4-bis[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.823
R926761
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine


7.3.824
R926762
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine


7.3.825
R926763
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.826
R926890
5-Fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.827
R926891
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-




2,4-pyrimidinediamine


7.3.828
R926892
5-Fluoro-N4-(3-fluoro-4-methoxyphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-




2,4-pyrimidinediamine


7.3.829
R926893
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxy-5-methylphenyl)-2,4-pyrimidinediamine


7.3.830
R926894
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-fluoro-5-trifluoromethylphenyl)-2,4-




pyrimidinediamine


7.3.831
R926895
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-methyl-5-trifluoromethylphenyl)-2,4-




pyrimidinediamine


7.3.832
R926896
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(5-methoxy-2-methylphenyl)-2,4-pyrimidinediamine


7.3.833
R926897
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-fluoro-5-methylphenyl)-2,4-pyrimidinediamine


7.3.834
R926898
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-difluorophenyl)-2,4-pyrimidinediamine


7.3.835
R926899
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidinediamine


7.3.836
R926900
N4-[3-(Benzothiazol-2-yl)-4-chlorophenyl]-5-fluoro-N2-[3-[(N-




methylamino)carbonylmethyleneoxy]phenyl)-2,4-pyrimidinediamine


7.3.837
R926902
5-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-methoxy-4-methylphenyl)-




2,4-pyrimidinediamine


7.3.838
R926903
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)-(1H)-indol-6-yl])-2,4-pyrimidinediamine


7.3.839
R926904
5-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[2-(methoxycarbonyl)-(1H)-




indol-6-yl]-2,4-pyrimidinediamine


7.3.840
R926905
N4-[3-[[4-(Ethoxycarbonyl)pipiridino]methyl]phenyl]-5-fluoro-N2-[3-[(N-




methylamino)carbonylmethyleneoxy]phenyl-2,4-pyrimidinediamine


7.3.841
R926906
N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.842
R926907
N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-




2,4-pyrimidinediamine


7.3.843
R926908
N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxy-4-




methylphenyl)-2,4-pyrimidinediamine


7.3.844
R926909
N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-




pyrimidinediamine


7.3.845
R926913
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl-1,1-




dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.846
R926914
5-Fluoro-N4-(1,2,3,4-tetrahydroisoquin-7-yl)-N2-[3-[(N-




methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.847
R926915
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonyl-1,1-




dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.848
R926917
5-Fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-




methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.849
R926916
5-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[3-[[(N-




isopropylamino)carbonyl]-N-isopropylamino)carbonyloxy]phenyl]-2,4-pyrimidinediamine


7.3.850
R926918
N4-[3-[[N-(Ethoxycarbonylmethyl)amino]carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-




methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.851
R926919
N4-[3-[(N-(Ethylamino)carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-




methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.852
R926922
5-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(4-methyl-3-




trifluoromethylphenyl)-2,4-pyrimidinediamine


7.3.853
R926923
5-Fluoro-N4-(4-fluoro-3-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.854
R926925
5-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-trifluoromethylthiophenyl)-




2,4-pyrimidinediamine


7.3.855
R926926
N2-[3,5-Bis(methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.856
R926927
5-Fluoro-N2-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.857
R926928
N2-[3-[(N-Ethylamino)carbonyloxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.858
R926929
5-Fluoro-N2-[3-hydroxy-5-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-hydroxyphenyl)-




2,4-pyrimidinediamine


7.3.859
R926930
N2-[3,5-Bis[(N-methylamino)carbonylmethyleneoxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.860
R926931
5-Fluoro-N4-[(1H)-indol-5-yl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.861
R926932
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[(1H)-indol-5-yl]-2,4-pyrimidinediamine


7.3.862
R926933
5-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine


7.3.863
R926934
5-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-morpholinocarbonyl)phenyl]-2,4-pyrimidinediamine


7.3.864
R926935
N2-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-




pyrimidinediamine


7.3.865
R926936
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine


7.3.866
R926937
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-propylamino)carbonyl]phenyl]-2,4-pyrimidinediamine


7.3.867
R926938
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morphonlinocarbonyl)phenyl]-2,4-pyrimidinediamine


7.3.868
R926939
N2-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.869
R926940
N4-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.870
R926941
N4-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-[3-[(N-




methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.871


7.3.872
R926942
N4-(1-Ethoxy-1,2,3,4-tetrahydronaphthalen-7-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.873
R926943
5-Fluoro-N4-(3,4-dihydronaphthalen-7-yl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.874
R926944
5-Fluoro-N4-(3,4-dihydronaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-




2,4-pyrimidinediamine


7.3.875
R926945
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.876
R926946
N2,N4-Bis(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.877
R926947
5-Fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-N2-[3-[(N-




methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.878
R926948
5-Fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxyiminonaphthalen-7-yl)-N2-[3-[(N-




methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.879
R926949
5-Fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-N2-[3-[(N-




methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine


7.3.880
R926950
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-




pyrimidinediamine


7.3.881
R926951
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-




2,4-pyrimidinediamine


7.3.882
R926953
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-




5-yl]-2,4-pyrimidinediamine


7.3.883
R926954
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-




methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine


7.3.884
R926955
N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-




5-yl]-2,4-pyrimidinediamine


7.3.885
R926956
5-Fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-N4-(4-isopropoxyphenyl)-




2,4-pyrimidinediamine


7.3.886
R925809
N2,N4-Bis(3-phenylphenyl)-2,4-pyrimidinediamine


7.3.887
R940110
2-Dimethylamine-5-fluoro-N4-(thyrosinyl methyl ester) pyrimidine


7.3.888
R940299
5-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-




pyrimidinediamine


7.3.889
R940300
5-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methyloxycarbonyl-4-




methoxyphenyl)-2,4-pyrimidinediamine


7.3.890
R940301
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine


7.3.891
R940304
5-Fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine


7.3.892
R940306
5-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methylaminocarbonyl-4-




methoxyphenyl)-2,4-pyrimidinediamine


7.3.893
R940307
(R)-N2-[3-(dihydroxypropylaminocarbonylmethyleneoxy)-phenyl]-5-fluoro-N4-(3-isopropylphenyl)-




2,4-pyrimidinediamine


7.3.894
R940308
N4-(3-tert-Butylpheny)-5-fluoro-N2-[3-(1,1-dimethyl-2-hydroxyethylaminocarbonylmethyleneoxy)-




phenyl]-2,4-pyrimidinediamine


7.3.895
R940309
N4-(3-Aminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-




pyrimidinediamine


7.3.896
R940311
N4-[3-(2-(N4-(3-aminomethylenephenyl)-5-fluoro-4-pyrimidineamine)-N-methylaminomethylene)-




phenyl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidineamine


7.3.897
R940312
5-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-iso-propylaminocarbonyl-4-




methoxyphenyl)-2,4-pyrimidinediamine


7.3.898
R940314
5-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-[3-(N-morpholinomethylene)-4-




methoxyphenyl]-2,4-pyrimidinediamine


7.3.899
R940316
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-morpholinomethylene)-4-




methoxyphenyl]-2,4-pyrimidinediamine


7.3.900
R940317
N4-(3-N-methylaminomethylenephenyl)-5-fluoro-N2-[3-




(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.901
R940318
N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-piperazinomethylene)-4-




methoxyphenyl]-2,4-pyrimidinediamine


7.3.902
R940319
N4-(3-(N-tert-Butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-5-fluoro-N2-[3-




(methylaminocarbonyl methyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.903
R940321
N4-(3-N,N-Dimethylaminomethylene-4-methoxyphenyl)-5-fluoro-N2-[3-




(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.904
R940323
N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-




(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.905
R940337
N4-[3-Dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-[3-




(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.906
R940338
N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-




pyrimidinediamine


7.3.907
R940343
N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-




(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.908
R940345
N4-[(2,2-Dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-N2-[3-




(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.909
R940346
N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.910
R940347
N4-[(2,2-Dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-




(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.911
R940348
N4-[3-Dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-




2,4-pyrimidinediamine


7.3.912
R940349
N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.913
R940350
N2,N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.914
R940351
N2-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-




one)-6-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.915
R940352
N2,N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.916
R940353
N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-




yl)-2,4-pyrimidinediamine


7.3.917
R940354
N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-




yl)-2,4-pyrimidinediamine


7.3.918
R950244
N2,N4-Bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine


7.3.919
R950245
N4-(3-N,N-Diacetylaminophenyl)-N2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-




pyrimidinediacetylamine


7.3.920
R950246
N4-(3-N-Acetylaminophenyl)-N2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-




pyrimidinediacetylamine


7.3.921
R950247
N2,N4-Bis(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine


7.3.922
R950261
N4-(3-Nitrophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.923
R950262
N4-(3-Aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine HCl salt


7.3.924
R950264
N4-(3-Aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamineN4-(3-Bis-N-methylaminophenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.925
R950264
N4-(3-Bis-N-methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.926
R950265
N4-(3-N-Hydroxyethylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.927
R950266
N4-(3-Bis(N-hydroxyethyl)aminophenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.928
R950267
N4-(3-N-Methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.929
R950290
N4-(3-Hydroxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.930
R950291
N4-(3-Hydroxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-hydroxycarbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.931
R950293
N4-(3-Methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.932
R950294
N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-




ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.933
R950295
N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-




methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.934
R950296
N4-(4-Ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.935
R950344
N4-(4-Hydroxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.936
R950345
N4-(2,3-Dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.937
R950346
N4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.938
R950347
N4-(4-Hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.939
R950348
N4-(2,3-Dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.940
R950349
N4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.941
R950356
N4-(2,3-Dihydro-4-O-methyloxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.942
R950368
N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.943
R950371
N4-(3-Methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.944
R950372
N4-(3-Phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.945
R950373
N4-(3-Methyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.946
R950374
N4-(3-Phenyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.947
R950376
N2,N4-Bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.948
R950377
N2,N4-Bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.949
R950378
N2,N4-Bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.950
R950379
N2,N4-Bis(3-methyloximephenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.951
R950380
N2,N4-Bis(3-phenyloximephenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.952
R950381
N2,N4-Bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.953
R950382
N4-(4-Acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.954
R950383
N4-(4-Azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.955
R950385
N4-(4-Benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.956
R950386
N4-(3-Hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.957
R950388
N4-(3-Amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.958
R950389
N4-(4-Ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.959
R950391
N2,N4-Bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.960
R950392
N4-(3-Methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.961
R950393
N4-(4-Acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.962
R945236
N4-[2,4-Dihydro-1-oxo-4H-imidazo[2,1-c][1,4]benzoxazin-8-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.963
R945237
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-oxo-1,2,3,6-tetrahydropyrimido[2,1-c][1,4]benzoxazin-9-yl]-




2,4-pyrimidinediamine


7.3.964
R945242
5-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-




one-7-yl]-2,4-pyrimidinediamine


7.3.965
R945263
5-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-7-yl]-




2,4-pyrimidinediamine


7.3.966
R945280
5-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-




one-6-yl]-2,4-pyrimidinediamine


7.3.967
R945299
5-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-6-yl]-




2,4-pyrimidinediamine


R908698
R908698
N4-(1,4-Benzoxazin-3-on-7-yl))-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.969
R908699
N2-(1,4-Benzoxazin-3-on-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.970
R908701
N4-(1,4-Benzoxazine-3-on-7-yl)-5-fluoro-N2-((N-methyl acetamido-2)-3-phenoxy)-2,4-




pyrimidinediamine N4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-[(N-methyl acetamido-2)-3-




phenoxy)]-2,4-pyrimidinediamine


7.3.971
R908701
R908701)N4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-[(N-methyl acetamido-2)-3-phenoxy)]-2,4-




pyrimidinediamine


7.3.972
R908702
N4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.973
R908703
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(N-methyl-1,4-benzoxazine-3-on-6-yl)-2,4-pyrimidinediamine


7.3.974
R908704
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine


7.3.975
R908706
5-Fluoro-N2-[(N-methyl acetamido-2)-3-phenoxy]-N4-(N-methyl-1,4-benzoxazin-7-yl)-2,4-




pyrimidinediamine N2-(1,4-Benzoxazin-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.976
R908706
N2-(1,4-Benzoxazin-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.977
R908707
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine


7.3.978
R908709
5-Fluoro-N4-(3-hydroxyphenyl)N2-(N-Methyl-1,4-benzoxazine-3-on-7-yl)-2,4-pyrimidinediamine5-




Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-2,4-pyrimidinediamine


7.3.979
R908709
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-2,4-pyrimidinediamine


7.3.980
R908734
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-6-yl)-2,4-pyrimidinediamine N2-(N-




Ethylcarbonylmethyleneoxy-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-




hydroxyphenyl)phenyl]pyrimidinediamine


7.3.981
R908734
N2-(N-Ethylcarbonylmethyleneoxy-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-




hydroxyphenyl)phenyl]pyrimidinediamine


7.3.982
R908712
(+/−)-5-Fluoro-N2-[(N-methyl acetamido-2)-3-phenoxy]-N4-(2-methyl-1,4-benzoxazin-6-yl)-2,4-




pyrimidinediamine


7.3.983
R908734
N2-(N-Ethylcarbonylmethyleneoxy-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-




hydroxyphenyl)phenyl]pyrimidinediamine


7.3.984
R909255
N4-(1,4-Benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoropyrimidinediamine


7.3.985
R909259
5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-6-




yl)pyrimidinediamine


7.3.986
R909260
5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-[6-(N-methyl-1,4-benzoxazin-3-




onyl)]pyrimidinediamine


7.3.987
R909261
5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-3-on-




7-yl)]-2,4-pyrimidinediamine


7.3.988
R909263
(+/−)-5-Fluoro-N4-(3-hydroxyphenyl]-N2-(2-methyl-1,4-benzothiazin-3-on-6-yl)pyrimidinediamine


7.3.989
R909264
5-Fluoro-N2-[3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)-2,4-pyrimidinediamine


7.3.990
R909265
N4-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-




methylaminocarbonylmethyleneoxy)phenyl]pyrimidinediamine


7.3.991
R909266
N4-(1,4-Benzoxazin-7-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-




pyrimidinediamine


7.3.992
R909267
N2-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N4-(3-




hydroxyphenyl)pyrimidinediamine


7.3.993
R909268
N2-(1,4-Benzoxazin-3-on-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.994
R909290
N2-[3-(N,N-Dimethylaminocarbonylmethyleneoxy)phenyl]-N4-(1,4-benzoxazin-6-yl)-5-fluoro--2,4-




pyrimidinediamine


7.3.995
R909292
N4-(4N-Carboxamidino-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.996
R909308
N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-




pyrimidinediamine


7.3.997
R909309
N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-




methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.998
R909309
N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-




methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.999
R935221
N4-(2,4-Diiodo-3-hydroxypheny)-5-fluoro-N2-(3-iodo-1-methyl-indazoline-5-yl)-2,4-




pyrimidinediamine


7.3.1000
R935222
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1001
R935223
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1002
R935224
5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.1003
R935225
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-




2,4-pyrimidinediamine


7.3.1004
R935237
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1005
R935238
N2,N4-Bis[1-(2-hydroxyethyl)indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.1006
R935239
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1007
R935240
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-




2,4-pyrimidinediamine


7.3.1008
R935242
5-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1009
R935248
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-hydroxyethyl)indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.1010
R935249
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1011
R935250
5-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1012
R935251
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine


7.3.1013
R935252
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine


7.3.1014
R935253
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine


7.3.1015
R935255
5-Fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.1016
R935256
5-Fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.1017
R935258
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1018
R935259
5-Fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.1019
R935261
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine


7.3.1020
R935262
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-6-yl)-2,4-pyrimidinediamine


7.3.1021
R935263
N2-(3-Chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-




2,4-pyrimidinediamine


7.3.1022
R935264
N2-(3-Chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine


7.3.1023
R935266
5-Fluoro-N4-(indazoline-5-yl)-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.1024
R935267
N2-(3,4-Ethyelenedioxyphenyl)-5-fluoro-N4-(indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1025
R935268
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1026
R935269
5-Fluoro-N4-(indazoline-5-yl)-N2-[3-(methoxycarbonyl methyleneoxy)phenyl]-2,4-




pyrimidinediamine


7.3.1027
R935270
5-Fluoro-N4-(indazoline-5-yl)-N2-(indazoline-6-yl)-2,4-pyrimidinediamine


7.3.1028
R935271
5-Fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-N2-[3-(N-




methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine


7.3.1029
R935276
5-Fluoro-N2-(4-isopropoxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine


7.3.1030
R935277
N2-(3,4-Ethylenedioxyphenyl)-5-Fluoro-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine


7.3.1031
R935278
5-Fluoro-N2-(3-hydroxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine


7.3.1032
R935279
5-Fluoro-N4-(indazoline-5-yl)-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-




pyrimidinediamine


7.3.1033
R935280
5-Fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-




pyrimidinediamine


7.3.1034
R935281
5-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-




pyrimidinediamine


7.3.1035
R935286
N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.1036
R935287
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.1037
R935288
N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-




2,4-pyrimidinediamine


7.3.1038
R935289
N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(isopropoxyphenyl)-2,4-




pyrimidinediamine


7.3.1039
R935290
5-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.1040
R935291
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylamino)carbonyl]ethyl-indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.1041
R935292
N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.1042
R935293
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine


7.3.1043
R935294
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.1044
R935295
N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-




pyrimidinediamine


7.3.1045
R935297
5-Fluoro-N4-[2-(N-methylaminocarbonyl)benzofuran-5-yl]-N2-[1-[2(N-methylaminocarbonyl)ethyl]-




indazoline-6-yl]-2,4-pyrimidinediamine


7.3.1046
R935298
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-(2-methyl-indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1047
R935299
5-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1048
R935300
N4-(3,4-Ethyelenedioxyphenyl)-5-fluoro-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1049
R935301
N2-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.1050
R935302
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1051
R935303
N4-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-




pyrimidinediamine


7.3.1052
R935304
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine


7.3.1053
R935305
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1054
R935306
N4-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-




pyrimidinediamine


7.3.1055
R935307
5-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine


7.3.1056
R935308
5-Fluoro-N4-(2-hydroxymethylbenzofur-5-yl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.1057
R935309
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-




2,4-pyrimidinediamine


7.3.1058
R935310
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1059
R935320
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-




2,4-pyrimidinediamine


7.3.1060
R935321
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.1061
R935322
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2-methoxy-4-(o-




toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine


7.3.1062
R935323
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-[2-methoxy-4-(o-




toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine


7.3.1063
R935324
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-




toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine


7.3.1064
R935336
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-




2,4-pyrimidinediamine


7.3.1065
R935337
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.1066
R935338
5-Fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-




pyrimidinediamine


7.3.1067
R935339
N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2-methoxy-4-(o-




toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine


7.3.1068
R935340
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-




toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine


7.3.1069
R935351
N4-(4-Chlorophenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1070
R935352
N4-(4-Chlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine


7.3.1071
R935353
N4-(4-Chlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine


7.3.1072
R935354
N4-(3-Chloro-4-trifluoromethoxy-phenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-




2,4-pyrimidinediamine


7.3.1073
R935355
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine


7.3.1074
R935356
5-Fluoro-N2-(1-methylindazoline-5-yl)-N4-(3-trifluoromethoxypheny)-2,4-pyrimidinediamine


7.3.1075
R935357
N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-




pyrimidinediamine


7.3.1076
R935358
N4-(3,4-Difluorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine


7.3.1077
R935359
N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-




pyrimidinediamine


7.3.1078
R935360
N2-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-




pyrimidinediamine


7.3.1079
R935361
5-Fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-




2,4-pyrimidinediamine


7.3.1080
R935362
5-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-




pyrimidinediamine


7.3.1081
R935363
5-Fluoro-N2-(indazoline-6-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine


7.3.1082
R935364
5-Fluoro-N2-(indazoline-5-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine


7.3.1083
R935365
N4-(4-Chlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1084
R935366
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1085
R935367
5-Fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-N2-(3,4,5-trimethoxyphenyl)-




2,4-pyrimidinediamine


7.3.1086
R935368
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine


7.3.1087
R935369
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-[2(N-




methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine


7.3.1088
R935370
N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1089
R935371
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1090
R935372
N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine


7.3.1091
R935373
N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1092
R935374
N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine


7.3.1093
R935375
N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine


7.3.1094
R935376
N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine


7.3.1095
R935377
N4-(6-Chloro-3-pyridyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-




pyrimidinediamine


7.3.1096
R935378
N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-




pyrimidinediamine


7.3.1097
R935379
N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine


7.3.1098
R935380
N4-6-Dimethoxy-3-pyridyl)-5-fluoro-N2-[1-methylindazoline-5-yl]-2,4-pyrimidinediamine


7.3.1099
R008951
N2,N4-Bis (3-chlorophenyl)-5-Fluoro-2,4-pyrimidinediamine



R067962



R026209


7.3.1099
R008952
N2,N4-Bis (2,5-dimethylphenyl)-5-Fluoro-2,4-pyrimidinediamine



R067963


7.3.1099
R008953
N2,N4-Bis (3,4-dimethylphenyl)-5-Fluoro-2,4-pyrimidinediamine



R067964


7.3.1099
R008955
N2,N4-Bis (2-methoxyphenyl)-5-Fluoro-2,4-pyrimidinediamine



R081166


7.3.1099
R008956
N2,N4-Bis (2,4-dimethylphenyl)-5-Fluoro-2,4-pyrimidinediamine



R070791


7.3.1099
R008958
N2,N4-Bis (3-bromophenyl)-5-Fluoro-2,4-pyrimidinediamine


7.3.1099
R088814
N2,N4-Bis (4-methoxyphenyl)-5-Fluoro-2,4-pyrimidinediamine



R926017


7.3.1099
R088815
N2,N4-Bis (2-chlorophenyl)-5-Fluoro-2,4-pyrimidinediamine


7.3.1099
R091880
N2,N4-Bisphenyl-5-Fluoro-2,4-pyrimidinediamine


7.3.1099
R092788
N2,N4-Bis (3-methylphenyl)-5-Fluoro-2,4-pyrimidinediamine


7.3.1099
R920846
N2-(3-hydroxyplhenyl)-N4-[4-(tetrazol-5-yl)methoxyphenyl)]-5-trifluoromethyl-2,4-




pyrimidinediamine


7.3.1099
R070153
N2,N4-Bis (4-chlorophenyl)-5-Fluoro-2,4-pyrimidinediamine


7.3.1099
R070790
N2,N4-Bis (4-ethoxyphenyl)-5-Fluoro-2,4-pyrimidinediamine



R926036


7.3.1099
R926736
N2-(3,4-ethylenedioxyphenyl)-N4-[3-(N-methylaminomethyleneoxyphenyl)]-5-trifluoromethyl-2,4-




pyrimidinediamine and




N2-[3-(N-methylaminomethyleneoxyphenyl)]-N4-(3,4-ethylenedioxyphenyl)-5-trifluoromethyl-2,4-




pyrimidinediamine


7.3.1099
R935117
N2,N4-Bis (3-carboxymethylphenyl)-5-Fluoro-2,4-pyrimidinediamine


7.3.1099
R926593
N2,N4-Bis (2-methoxycarbonylindol-6-yl)-5-Fluoro-2,4-pyrimidinediamine


7.3.1099
R950189
N2-(3,4-ethylenedioxyphenyl)-N4-methyl-5-Fluoro-2,4-pyrimidinediamine


7.3.1099
R950216
N2-(3-hydroxyphenyl)-N4-(3-ethoxymethyleneoxyphenyl)-5-Fluoro-2,4-pyrimidinediamine


7.3.1099
R950218
N2-(3-hydroxyphenyl)-N4-[3-(N-methylamino)carbonylmethyleneaminophenyl]-5-Fluoro-2,4-




pyrimidinediamine


7.3.1100


7.3.1101
R926408
N2,N4,N6-Tris(3-hydroxyphenyl)-2,4,6-pyrimidinetriamine


7.3.1101
R926409
N2,N4,N6-Tris(3-hydroxyphenyl)-2,4,6-pyrimidinetriamine


7.3.1102
R926411
N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-6-chloro-2,4-pyrimidinediamine


7.3.1103
R926245
N2,N4-Bis(3,4-ethylenedioxyphenyl)-6-chloro-2,4-pyrimidinediamine


7.3.1103
R926516
N2,N4,N6-Tris(3,4-ethylenedioxyphenyl)-2,4,6-pyrimidinetriamine


7.3.1104


7.3.1105
R926555
6-Chloro-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(methoxycarbonylmethyl)-2,4-




pyrimidinediamine


7.3.1106
R926467
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine


7.3.1107
R926569
N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine


7.3.1108
R926576
N2,N4-Bis(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine


7.3.1109

Reaction of 2,4,5,6-tetrachloropyrimidine with 3-hydroxyaniline


7.3.1109
R926590
N4-(3-Hydroxyphenyl)-2,5,6-trichloro-4-pyrimidineamine


7.3.1109
R926591
N2,N4-Bis(3-hydroxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine


7.3.1109
R926592
N4,N6-Bis(3-hydroxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine


7.3.1110
R926595
N2,N4-Bis(3-hydroxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine


7.3.1111
R926475
N2,N4-Bis(3,4-ethyelenedioxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine


7.3.1112
R926530
6-Chloro N4-(3-hydroxyphenyl)-4-pyrimidineamine


7.3.1113
R925784
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine


7.3.1114
R925785
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(2-furanyl)-2,4-pyrimidinediamine


7.3.1115
R925786
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-chlorophenyl)-2,4-pyrimidinediamine


7.3.1116
R925787
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(3-chlorophenyl)-2,4-pyrimidinediamine


7.3.1117
R925813
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine


7.3.1118
R925816
N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-hydroxyphenyl)-2,4-pyrimidinediamine


7.3.1119
R925783
N2,N4-Bis(3-hydroxyphenyl)-5-phenyl-2,4-pyrimidinediamine


7.3.1120
R925788
N2,N4-Bis(3-hydroxyphenyl)-5-(3,4-methylenedioxyphenyl)-2,4-pyrimidinediamine


7.3.1121
R925811
N2,N4-Bis(3,4-ethylenedioxyphenyl)-6-phenyl-2,4-pyrimidinediamine


7.3.1122
R925812
N2,N4-Bis(3-hydroxyphenyl)-6-phenyl-2,4-pyrimidinediamine


7.3.1123
R926747
N2-(3-Aminocarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-




pyrimidinediamine


7.3.1124
R926461
N2,N4-Bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine


7.3.1125
R945169
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,4,5,6-tetrahydro-2-pyrimidyl)methyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.1126
R926702
5-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-[(4,4-dimethyl-3-oxazolin-2-yl)methyleneoxy]phenyl]-2,4-




pyrimidinediamine


7.3.1127
R950290
N4-(3-Hydroxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.1128
R950291
N4-(3-Hydroxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-hydroxycarbonylmethyleneoxyphenyl]-




2,4-pyrimidinediamine


7.3.1129
R950293
N4-(3-Methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.1130
R950294
N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-




ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1131
R950295
N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-




methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1132
R950296
N4-(4-Ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1133
R950344
N4-(4-Hydroxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1134
R950345
N4-(2,3-Dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonyl




methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1135
R950346
N4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1136
R950347
N4-(4-Hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.1137
R950348
N4-(2,3-Dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1138
R950349
N4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1139
R950356
N4-(2,3-Dihydro-4-O-methyloxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1140
R950368
N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1141
R950371
N4-(3-Methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.1142
R950372
N4-(3-Phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.1143
R950373
N4-(3-Methyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.1144
R950374
N4-(3-Phenyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.1145
R950376
N2,N4-Bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.1146
R950377
N2,N4-Bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.1147
R950378
N2,N4-Bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.1148
R950379
N2,N4-Bis(3-methyloximephenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.1149
R950380
N2,N4-Bis(3-phenyloximephenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.1150
R950381
N2,N4-Bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamine


7.3.1151
R950382
N4-(4-Acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonyl




methyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1152
R950383
N4-(4-Azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1153
R950385
N4-(4-Benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.1154
R950386
N4-(3-Hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1155
R950388
N4-(3-Amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-




pyrimidinediamine


7.3.1156
R950389
N4-(4-Ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1157
R950391
N2,N4-Bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine


7.3.1158
R950392
N4-(3-Methoxycarbonyl-4-trifluoro methoxyphenyl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1159
R950393
N4-(4-Acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine


7.3.1160
R950399
N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine HCl salt


7.3.1161
R950400
N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine succinic acid salt


7.3.1162
R950401
N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine maleic acid salt


7.3.1163
R950402
N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine fumaric acid salt


7.3.1164
R950403
N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine citric acid salt


7.3.1165
R950404
N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-




methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine HNO3 salt









7.4 Synthesis of Prodrugs
Exemplary prodrugs according to structural formula (II) were synthesized as described below.
7.4.1 N-2(4)-Acetyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R926233)
A mixture of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine, acetyl chloride (4 equivalents), pyridine (4 equivalents) in CH2Cl2 was stirred at room temperature for 48 h. After an aqueous work up the residue was chromatographed on silica gel to give N-2(4)-acetyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.23 (d, 1H, J=5.4 Hz), 7.03 (d, 1H, J=2.4 Hz), 7.90–7.80 (m, 3H), 6.76 (m, 2H), 4.28 (bs, 4H), 2.10 (s, 3H); 19F NMR (CDCl3); −42125; LCMS: ret. time: 27.94 min.; purity: 99%; MS (m/e): 439 (MH+).
7.4.2 N2,N4-Bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine (R950244)
N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine, dimethylaminopyridine (DMAP) and acetic anhydride were refluxed in pyridine for 1 hour. The mixture was cooled to room temperature, concentrated, and the residue was subjected to column chromatography on silica gel (CHCl3:Acetone, 2:1) to give N2,N4-bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine. LCMS: ret. time: 17.03 min.; purity: 87.0%; MS (m/e): 478.89 (MH+).
7.4.3 N4-(3-N,N-Diacetylaminophenyl)-N2-(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine (R950245)
N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine, dimethylaminopyridine (DMAP) and acetic anhydride were refluxed in pyridine for 1 hour. The mixture was cooled to room temperature, concentrated, and the residue was subjected to column chromatography on silica gel (CHCl3:Acetone, 2:1) to give N4-(3-N,N-diacetylaminophenyl)-N2-(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine. LCMS: ret. time: 19.27 min.; purity: 92.6%; MS (m/e): 521.01 (MH+).
7.4.4 N4-(3-N-Acetylaminophenyl)-N2-(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine (R950246)
N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine, dimethylaminopyridine (DMAP) and acetic anhydride were refluxed in pyridine for 1 hour. The mixture was cooled to room temperature, concentrated, and the residue was subjected to column chromatography on silica gel (CHCl3:Acetone, 2:1) to give N4-[3-N-acetylaminophenyl]-N2-(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine. LCMS: ret. time: 18.89 min.; purity: 83.0%; MS (m/e): 520.97 (MH+).
7.5 The 2,4-Pyrimidinediamine Compounds of the Invention Inhibit FcεRI Receptor-Mediated Degranulation
The ability of the 2,4-pyrimidinediamine compounds of the invention to inhibit IgE-induced degranulation was demonstrated in a variety of cellular assays with cultured human mast cells (CHMC) and/or mouse bone marrow derived cells (BMMC). Inhibition of degranulation was measured at both low and high cell density by quantifying the release of the granule specific factors tryptase, histamine and hexosaminidase. Inhibition of release and/or synthesis of lipid mediators was assessed by measuring the release of leukotriene LTC4 and inhibition of release and/or synthesis of cytokines was monitored by quantifying TNF-α, IL-6 and IL-13. Tryptase and hexosaminidase were quantified using fluorogenic substrates as described in their respective examples. Histamine, TNFα, IL-6, IL-13 and LTC4 were quantified using the following commercial ELISA kits: histamine (Immunotech #2015, Beckman Coulter), TNFα (Biosource #KHC3011), IL-6 (Biosource #KMC0061), IL-13 (Biosource #KHC0132) and LTC4 (Cayman Chemical #520211). The protocols of the various assays are provided below.
7.5.1 Culturing of Human Mast and Basophil Cells
Human mast and basophil cells were cultured from CD34-negative progenitor cells as described below (see also the methods described in copending U.S. application Ser. No. 10/053,355, filed Nov. 8, 2001, the disclosure of which is incorporated herein by reference).
7.5.1.1 Preparation of STEMPRO-34 Complete Medium
To prepare STEMPRO-34 complete medium (“CM”), 250 mL STEMPRO-34TM serum free medium (“SFM”; GibcoBRL, Catalog No. 10640) was added to a filter flask. To this was added 13 mL STEMPRO-34 Nutrient Supplement (“NS”; GibcoBRL, Catalog No. 10641) (prepared as described in more detail, below). The NS container was rinsed with approximately 10 mL SFM and the rinse added to the filter flask. Following addition of 5 mL L-glutamine (200 mM; Mediatech, Catalog No. MT 25–005-CI and 5 mL 100× penicillin/streptomycin (“pen-strep”; HyClone, Catalog No. SV30010), the volume was brought to 500 mL with SFM and the solution was filtered.
The most variable aspect of preparing the CM is the method by which the NS is thawed and mixed prior to addition to the SFM. The NS should be thawed in a 37° C. water bath and swirled, not vortexed or shaken, until it is completely in solution. While swirling, take note whether there are any lipids that are not yet in solution. If lipids are present and the NS is not uniform in appearance, return it to the water bath and repeat the swirling process until it is uniform in appearance. Sometimes this component goes into solution immediately, sometimes after a couple of swirling cycles, and sometimes not at all. If, after a couple of hours, the NS is still not in solution, discard it and thaw a fresh unit. NS that appears non-uniform after thaw should not be used.
7.5.1.2 Expansion of CD34+ Cells
A starting population of CD34-positive (CD34+) cells of relatively small number (1–5×106 cells) was expanded to a relatively large number of CD34-negative progenitor cells (about 24×109 cells) using the culture media and methods described below. The CD34+ cells (from a single donor) were obtained from Allcells (Berkeley, Calif.). Because there is a degree of variation in the quality and number of CD34+ cells that Allcells typically provides, the newly delivered cells were transferred to a 15 mL conical tube and brought up to 10 mL in CM prior to use.
On day 0, a cell count was performed on the viable (phase-bright) cells and the cells were spun at 1200 rpm to pellet. The cells were resuspended to a density of 275,000 cells/mL with CM containing 200 ng/mL recombinant human Stem Cell Factor (“SCF”; Peprotech, Catalog No. 300-07) and 20 ng/mL human flt-3 ligand (Peprotech, Catalog No. 300-19) (“CM/SCF/flt-3 medium”). On about day 4 or 5, the density of the culture was checked by performing a cell count and the culture was diluted to a density of 275,000 cells/mL with fresh CM/SCF/flt-3 medium. On about day 7, the culture was transferred to a sterile tube and a cell count was performed. The cells were spun at 1200 rpm and resuspended to a density of 275,000 cells/mL with fresh CM/SCF/flt-3 medium.
This cycle was repeated, starting from day 0, a total of 3–5 times over the expansion period.
When the culture is large and being maintained in multiple flasks and is to be resuspended, the contents of all of the flasks are combined into a single container prior to performing a cell count. This ensures that an accurate cell count is achieved and provides for a degree of uniformity of treatment for the entire population. Each flask is checked separately for contamination under the microscope prior to combining to prevent contamination of the entire population.
Between days 17–24, the culture can begin to go into decline (i.e., approximately 5–10% of the total number of cells die) and fail to expand as rapidly as before. The cells are then monitored on a daily basis during this time, as complete failure of the culture can take place in as little as 24 hours. Once the decline has begun, the cells are counted, spun down at 850 rpm for 15 minutes, and resuspended at a density of 350,000 cells/mL in CM/SCF/flt-3 medium to induce one or two more divisions out of the culture. The cells are monitored daily to avoid failure of the culture.
When greater than 15% cell death is evident in the progenitor cell culture and some debris is present in the culture, the CD34-negative progenitor cells are ready to be differentiated.
7.5.1.3 Differentiation of CD34-Negative Progenitor Cells into Mucosal Mast Cells
A second phase is performed to convert the expanded CD34-negative progenitor cells into differentiated mucosal mast cells. These mucosal cultured human mast cells (“CHMC”) are derived from CD34+ cells isolated from umbilical cord blood and treated to form a proliferated population of CD34-negative progenitor cells, as described above. To produce the CD43-negative progenitor cells, the resuspension cycle for the culture was the same as that described above, except that the culture was seeded at a density of 425,000 cells/mL and 15% additional media was added on about day four or five without performing a cell count. Also, the cytokine composition of the medium was modified such that it contained SCF (200 ng/mL) and recombinant human IL-6 (200 ng/mL; Peprotech, Catalog No. 200-06 reconstituted to 100 ug/mL in sterile 10 mM acetic acid) (“CM/SCF/IL-6 medium”).
Phases I and II together span approximately 5 weeks. Some death and debris in the culture is evident during weeks 1–3 and there is a period during weeks 2–5 during which a small percentage of the culture is no longer in suspension, but is instead attached to the surface of the culture vessel.
As during Phase I, when the culture is to be resuspended on day seven of each cycle, the contents of all flasks are combined into a single container prior to performing a cell count to ensure uniformity of the entire population. Each flask is checked separately for contamination under the microscope prior to combining to prevent contamination of the entire population.
When the flasks are combined, approximately 75% of the volume is transferred to the communal container, leaving behind about 10 mL or so in the flask. The flask containing the remaining volume was rapped sharply and laterally to dislodge the attached cells. The rapping was repeated at a right angle to the first rap to completely dislodge the cells.
The flask was leaned at a 45 degree angle for a couple of minutes before the remaining volume was transferred to the counting vessel. The cells were spun at 950 rpm for 15 min prior to seeding at 35–50 mL per flask (at a density of 425,000 cells/mL).
7.5.1.4 Differentiation of CD34-Negative Progenitor Cells into Connective Tissue-Type Mast Cells
A proliferated population of CD34-negative progenitor cells is prepared as above and treated to form a tryptase/chymase positive (connective tissue) phenotype. The methods are performed as described above for mucosal mast cells, but with the substitution of IL-4 for IL-6 in the culture medium. The cells obtained are typical of connective tissue mast cells.
7.5.1.5 Differentiation of CD34-Negative Progenitor Cells into Basophil Cells
A proliferated population of CD34-negative progenitor cells is prepared as described in Section 6.4.1.2, above, and used to form a proliferated population of basophil cells. The CD34-negative cells are treated as described for mucosal mast cells, but with the substitution of IL-3 (at 20–50 ng/mL) for IL-6 in the culture medium.
7.5.2 CHMC Low Cell Density IgE Activation: Tryptase and LTC4 Assays
To duplicate 96-well U-bottom plates (Costar 3799) add 65 ul of compound dilutions or control samples that have been prepared in MT [137 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl2, 1.0 mM MgCl2, 5.6 mM Glucose, 20 mM Hepes (pH 7.4), 0.1% Bovine Serum Albumin, (Sigma A4503)] containing 2% MeOH and 1% DMSO. Pellet CHMC cells (980 rpm, 10 min) and resuspend in pre-warmed MT. Add 65 ul of cells to each 96-well plate. Depending on the degranulation activity for each particular CHMC donor, load 1000–1500 cells/well. Mix four times followed by a 1 hr incubation at 37° C. During the 1 hr incubation, prepare 6× anti-IgE solution [rabbit anti-human IgE (1 mg/ml, Bethyl Laboratories A80–109A) diluted 1:167 in MT buffer]. Stimulate cells by adding 25 ul of 6× anti-IgE solution to the appropriate plates. Add 25 ul MT to un-stimulated control wells. Mix twice following addition of the anti-IgE. Incubate at 37° C. for 30 minutes. During the 30 minute incubation, dilute the 20 mM tryptase substrate stock solution [(Z-Ala-Lys-Arg-AMC2TFA; Enzyme Systems Products, #AMC-246)] 1:2000 in tryptase assay buffer [0.1 M Hepes (pH 7.5), 10% w/v Glycerol, 10 uM Heparin (Sigma H4898) 0.01% NaN3]. Spin plates at 1000 rpm for 10 min to pellet cells. Transfer 25 ul of supernatant to a 96-well black bottom plate and add 100 ul of freshly diluted tryptase substrate solution to each well. Incubate plates at room temperature for 30 min. Read the optical density of the plates at 355 nm/460 nm on a spectrophotometric plate reader.
Leukotriene C4 (LTC4) is also quantified using an ELISA kit on appropriately diluted supernatant samples (determined empirically for each donor cell population so that the sample measurement falls within the standard curve) following the supplier's instructions.
7.5.3 CHMC High Cell Density IgE Activation: Degranulation (Tryptase, Histamine), Leukotriene (LTC4), and Cytokine (TNFalpha, IL-13) Assays
Cultured human mast cells (CHMC) are sensitized for 5 days with IL-4 (20 ng/ml), SCF (200 ng/ml), IL-6 (200 ng/ml), and Human IgE (CP 1035K from Cortx Biochem, 100–500 ng/ml depending on generation) in CM medium. After sensitizing, cells are counted, pelleted (1000 rpm, 5–10 minutes), and resuspended at 1–2×106 cells/ml in MT buffer. Add 100 ul of cell suspension to each well and 100 ul of compound dilutions. The final vehicle concentration is 0.5% DMSO. Incubate at 37° C. (5% CO2) for 1 hour. After 1 hour of compound treatment, stimulate cells with 6× anti-IgE. Mix wells with the cells and allow plates to incubate at 37° C. (5% CO2) for one hour. After 1 hour incubation, pellet cells (10 minutes, 1000 RPM) and collect 200 ul per well of the supernatant, being careful not to disturb pellet. Place the supernatant plate on ice. During the 7-hour step (see next) perform tryptase assay on supernatant that had been diluted 1:500. Resuspend cell pellet in 240 ul of CM media containing 0.5% DMSO and corresponding concentration of compound. Incubate CHMC cells for 7 hours at 37° C. (5% CO2). After incubation, pellet cells (1000 RPM, 10 minutes) and collect 225 ul per well and place in −80° C. until ready to perform ELISAS. ELISAS are performed on appropriately diluted samples (determined empirically for each donor cell population so that the sample measurement falls within the standard curve) following the supplier's instructions.
7.5.4 BMMC High Cell Density IgE Activation: Degranulation (Hexosiminidase, Histamine), Leukotriene (LTC4), and Cytokine (TNFalpha, IL-6) Assays
7.5.4.1 Preparation of WEHI-Conditioned Medium
WEHI-conditioned medium was obtained by growing murine myelomonocytic WEHI-3B cells (American Type Culture Collection, Rockville, Md.) in Iscove's Modified Eagles Media (Mediatech, Hernandon, Va.) supplemented with 10% heat-inactivated fetal bovine serum (FBS; JRH Biosciences, Kansas City, Mo.), 50 μM 2-mercaptoethanol (Sigma, St. Louis, Mo.) and 100 IU/mL penicillin-steptomycin (Mediatech) in a humidified 37° C., 5% CO2/95% air incubator. An initial cell suspension was seeded at 200,000 cells/mL and then split 1:4 every 3–4 days over a period of two weeks. Cell-free supernatants were harvested, aliquoted and stored at −80° C. until needed.
7.5.4.2 Preparation of BMMC Medium
BMMC media consists of 20% WEHI-conditioned media, 10% heat-inactivated FBS (JHR Biosciences), 25 mM HEPES, pH7.4 (Sigma), 2 mM L-glutamine (Mediatech), 0.1 mM non-essential amino acids (Mediatech), 1 mM sodium pyruvate (Mediatech), 50 μM 2-mercaptoethanol (Sigma) and 100 IU/mL penicillin-streptomycin (Mediatech) in RPMI 1640 media (Mediatech). To prepare the BMMC Media, all components are added to a sterile IL filter unit and filtered through a 0.2 μm filter prior to use.
7.5.4.3 Protocol
Bone marrow derived mast cells (BMMC) are sensitized overnight with murine SCF (20 ng/ml) and monoclonal anti-DNP (10 ng/ml, Clone SPE-7, Sigma # D-8406) in BMMC media at a cell density of 666×103 cells/ml. After sensitizing, cells are counted, pelleted (1000 rpm, 5–10 minutes), and resuspended at 1–3×106 cells/ml in MT buffer. Add 100 ul of cell suspension to each well and 100 ul of compound dilutions. The final vehicle concentration is 0.5% DMSO. Incubate at 37° C. (5% CO2) for 1 hour. After 1 hour of compound treatment, stimulate cells with 6× stimulus (60 ng/ml DNP-BSA). Mix wells with the cells and allow plates to incubate at 37° C. (5% CO2) for one hour. After 1 hour incubation, pellet cells (10 minutes, 1000 RPM) and collect 200 ul per well of the supernatant, being careful not to disturb pellet, and transfer to a clean tube or 96-well plate. Place the supernatant plate on ice. During the 4–5 hour step (see next) perform the hexosiminidase assay. Resuspend cell pellet in 240 ul WEI-conditioned media containing 0.5% DMSO and corresponding concentration of compound. Incubate BMMC cells for 4–5 hours at 37° C. (5% CO2). After incubation, pellet cells (1000 RPM, 10 minutes) and collect 225 ul per well and place in −80° C. until ready to perform ELISAS. ELISAS are performed on appropriately diluted samples (determined empirically for each donor cell population so that the sample measurement falls within the standard curve) following the supplier's instructions.
Hexosaminidase assay: In a solid black 96-well assay plate, add 50 uL hexosaminidase substrate (4-methylumbelliferyl-N-acetyl-β-D-glucosaminide; 2 mM) to each well. Add 50 uL of BMMC cell supernatant (see above) to the hexoseaminidase substrate, place at 37° C. for 30 minutes and read the plate at 5, 10, 15, and 30 minutes on a spectrophotometer.
7.5.5 Basophil IgE or Dustmite Activation: Histamine Release Assay
The basophil activation assay was carried out using whole human peripheral blood from donors allergic to dust mites with the majority of the red blood cells removed by dextran sedimentation. Human peripheral blood was mixed 1:1 with 3% dextran T500 and RBCs were allowed to settle for 20–25 min. The upper fraction was diluted with 3 volumes of D-PBS and cells were spun down for 10 min at 1500 rpm, RT. Supernatant was aspirated and cells were washed in an equal volume MT-buffer. Finally, cells were resuspended in MT-buffer containing 0.5% DMSO in the original blood volume. 80 uL cells were mixed with 20 uL compound in the presence of 0.5% DMSO, in triplicate, in a V-bottom 96-well tissue culture plate. A dose range of 8 compound concentrations was tested resulting in a 10-point dose response curve including maximum (stimulated) and minimum (unstimulated) response. Cells were incubated with compound for 1 hour at 37° C., 5% CO2 after which 20 uL of 6× stimulus [1 ug/mL anti-IgE (Bethyl Laboratories) 667 au/mL house dustmite (Antigen Laboratories)] was added. The cells were stimulated for 30 minutes at 37° C., 5% CO2. The plate was spun for 10 min at 1500 rpm at room temperature and 80 uL the supernatant was harvested for histamine content analysis using the histamine ELISA kit supplied by Immunotech. The ELISA was performed according to supplier's instructions.
7.5.6 Results
The results of low density CHMC assays (Section 6.4.3), the high density BMMC assays (Section 6.4.5) and the basophil assays (Section 6.4.6) are provided in TABLE 1. The results of the high density CHMC assays (Section 6.4.4) are provided in TABLE 2. In TABLES I and 2, all reported values are IC50s (in μM). A value of “9999” indicates an IC50>10 μM, with no measurable activity at a 10 μM concentration. Most compounds tested had IC50s of less than 10 μM with many exhibiting IC50s in the sub-micromolar range.
7.6 The 2,4-Pyrimidinediamine Compounds Inhibit FcγRI Receptor-Mediated  Degranulation
The ability of the 2,4-pyrimidinediamine compounds of the invention to inhibit FcγRI-mediated degranulation was demonstrated with Compounds R921218, R921302, R921303, R940347, R920410, R927050, R940350, R935372, R920323, R926971 and R940352 in assays similar to those described in Section 6.4, with the exception that the cells were not primed with IgE and were activated with rabbit anti-human IgG Fab fragment (Bethyl Laboratories, Catalog No. A80-105).
All of the compounds tested exhibited IC50s in the sub micromolar range.










TABLE 1









Low Density
















CHMC
CHMC
CHMC
CHMC
CHMC
Basophils
Basophils


Test
anti-IgE
Ionomycin
anti-IgE
anti-IgE
Ionomycin
anti-IgE
Ionomycin


Compound
Tryptase
Tryptase
LTC4
Hexos.
Hexos.
Histamine
Histamine





R008951


R008952


R008953


R008955


R008956


R008958


R067934


R067963


R070153


R070790
1.665
9999


R070791


R081166


R088814


R088815


R091880


R092788


R908696
3.553


R908697
9999
9999


R909236
0.996
9999


R909237
9999
9999


R909238
0.174
9999


R909239
0.264
9999


R909240
0.262
9999


R909241
0.181
9999


R909242
0.567
9999


R909243
0.263
>10


R909245
0.255
6.242


R909246
0.169
9999


R909247
2.393
9999


R909248
3.582
9999


R909249
9999
9999


R909250
8.025
9999


R909251
0.138
9999


R909252
0.248
9999


R909253
7.955
9999


R909254
0.136
9999


R920664
9999
9999


R920665
1.1
9999


R920666
2.53
9999


R920668
3.2
9999


R920669
0.42
9999


R920670
2.18
9999


R920671
9999
9999


R920672
9999
9999


R920818
9999
9999


R920819
10
9999


R920820
9999
9999


R920846
9999
9999


R920860
1.009
9999


R920861
0.598
>10


R920893
1.239
9999


R920894
0.888
5.566


R920910
0.751
7.922


R920917
1.579
9.729


R921218
0.499
9999
0.55
0.6
9999
0.24
9999


R921219
0.059
9999



0.025
9999


R925734



9.2
>10


R925747
1.021
3.1


R925755
0.898
9999


R925757
2.8
9999


R925758
1.175
9999


R925760
4.85
9999


R925765
6.8
9999


R925766
8.9
9999


R925767
10


R925768
9999


R925769
9999


R925770
9999


R925771
0.5
2.8
0.22


R925772
9999
9999


R925773
0.673
9999


R925774
0.435
9999


R925775
0.225
9999
0.2


R925776
2.1
9999


R925778
0.225
9999
0.18


R925779
0.265
9999
0.19


R925783
2.9
9999


R925784
3.2
9999


R925785
2.5
9999


R925786
1.85
9999


R925787
9
9999


R925788
2.4
9999


R925790
9999
9999


R925791
9999
9999


R925792
6.25
9999


R925794
9999
9999


R925795
9999
9999


R925796
2
9999


R925797
0.85
9999
0.28


R925798
9999
9999


R925799
9999
9999


R925800
9999
9999


R925801
9999
9999


R925802
9999
9999


R925803
9999
9999


R925804
9999
9999


R925805
9999
9999


R925806
9999
9999


R925807
9999
9999


R925808
9999
9999


R925810
9999
9999


R925811
3.3
9999


R925812
5.8
9999


R925813
9999
9999


R925814
9999
9999


R925815
9999
9999


R925816
6
9999


R925819
9999
9999


R925820
9999
9999


R925821
9999
9999


R925822
9999
9999


R925823
9999
9999


R925824
9999
9999


R925837
9999
9999


R925838
9999
9999


R925839
9999
9999


R925840
9999
9999


R925841
9999
9999


R925842
7.3
9999


R925843
9999
9999


R925844
5.1
9999


R925845
2.3
9999


R925846
9999
9999


R925849
8.2
9999


R925851
0.925
9999


R925852
3
9999


R925853
9999
9999


R925854
9999
9999


R925855
4.2
9999


R925856
9.85
9999


R925857
5.95
9999


R925858
8.05
7.3


R925859
9999
9999


R925860
9999
9999


R925861
9999
9999


R925862
0.7
9999


R925863
0.274
9999


R925864
9999
9999


R925865
9999
9999


R926016





9999
9999


R926017



1.43
9999
0.53
9999


R926018





9999
10


R926037





9999
9999


R926038





9999
9999


R926039





9999
9999


R926058





9999
9999


R926064



6.2


R926065



3.5


R926068



>10


R926069



9.1


R926072



>10


R926086





2.5
9999


R926108


0.76
0.787
6.4
0.95
9999


R926109
0.538
5.5
0.73
0.55
>10
0.15
9999


R926110
1.071
9999
1.42
1.2
>10
0.3
9999


R926113
0.413

0.49
0.413
9999
0.27
9999


R926114



3.427
8.1
1.7
10


R926145



4.764
>10


R926146


1.59
0.761
6.7


R926147



1.899
>10


R926206





>10
>10


R926209





>10
9999


R926210
0.926
9999
0.8
700
9999
0.37
>10


R926211
1.299
9.8

2.7
9999
1.55
>10


R926212
0.654
9999
0.45


0.5
>10


R926213
1.639
5.5



1.75
>10


R926218



>10


R926219



1.102
6.7


R926220



>10


R926221



8.5


R926222



>10


R926223



>10


R926224



>10


R926225



>10


R926228



>10


R926229



>10


R926230



>10


R926234



>10


R926237
1.207
6.2


R926240
0.381
1.7
0.145


R926241
7
9999


R926242
4.2
9999


R926243
3.1
9999


R926245
3.1
9.4


R926248
0.9
9999
0.76


R926249
0.5
9999
0.25


R926252
2.8


R926253
0.8

0.675


R926254
1.3
4


R926255
1.4
4.5


R926256
0.275
5.1
0.23


R926257
1.5
7.5


R926258
0.9
9999
0.59


R926259
2.5
6.2


R926319
9999
9999


R926320
9999
9999


R926321
9999
9999


R926325
9999
9999


R926331
9999
9999


R926339
0.66
9999


R926340
3.23
9999


R926341
0.875
9999


R926342
10
9999


R926376
9999


R926386
9999
9999


R926387
0.65
9999
0.7


R926394
9999
9999


R926395
0.875
6.4
0.29


R926396
0.7
2.6
0.16


R926397
9999
9999


R926398
9999
9999


R926399
9999
9999


R926400
9999
9999


R926401
9999
9999


R926402
9999
9999


R926403
9999
9999


R926404
9999
9999


R926405
3.4
9999


R926406
9999
9999


R926408
9.6
9999


R926409
3.15
9999


R926411
0.69
2.5


R926412
0.62
9999


R926461
0.725
9999


R926467
1.175
8.8


R926469
9999


R926474
2.5
9999


R926475
2.15
>10


R926476
0.6
7.7


R926477
0.27
9999


R926478
9999


R926479
9999


R926480
1.9
9999


R926481
1.445
9999


R926482
1.037
>10


R926483
9999


R926484
1.523
9999


R926485
4.012
9999


R926486
0.647
7.403


R926487
0.554
8.867
1.25


R926488
0.331
>10
0.752


R926489
1.414
>10


R926490
1.571
9999


R926491
1.158
>10


R926492
0.645
9999


R926493
0.25
9.181
0.078


R926494
0.313
9999
0.078


R926495
0.121
>10
0.078


0.04
9999


R926496
0.571
>10


R926497
0.138
9999



0.27
9999


R926498
0.209
>10


R926499
0.29
>10


R926500
0.418
>10


R926501
0.298
>10



0.609
9999


R926502
0.483
>10



0.405
9999


R926503
0.452
>10


R926504
0.569
>10


R926505
0.145
9999


R926506
0.343
9999


R926508
0.127
9999



0.065
9999


R926509
1.16
9999


R926510
0.44
>10


R926511
0.786
>10


R926514
9999
9999


R926516
1
9999


R926526
9999
9999


R926527
9999
9999


R926528
8.75
9999


R926535
9999
9999


R926536
9999
9999


R926555
9999
9999


R926559
7.7
9999


R926560
9999
9999


R926562
9999
9999


R926563
9999
9999


R926564
3.75
9999


R926565
0.625
3.3


R926566
2.73
9999


R926567
9.3
9999


R926569
0.61
3.07


R926571
9999
9999


R926572
1.8
6.08


R926574
1.96
2.63


R926576
9999
9999


R926579
9999
9999


R926580
10
9999


R926582
1.3
9999


R926583
9999
9999


R926584
9999
9999


R926585
9999
9999


R926586
2.75
9999


R926587
9999
9999


R926588
7.85
9999


R926589
0.325
10


R926591
2.62
9999


R926593
0.68
8.3
0.495


R926594
9999
9999


R926595
4.85
9999


R926604
2.85
9999


R926605
2.45
9999


R926614
0.228
9999


R926615
0.445
9999


R926616
0.625
3.25


R926617
9.45
9999


R926620
8.35
9999


R926623
9999
9999


R926662
9999
9999


R926663
9999
9999


R926675
0.63
9999


R926676
0.76
9999


R926680
1.71
9999


R926681
0.775
9999


R926682
8.41
9999


R926683
10
9999


R926688
2.25
>10


R926690
0.146
>10


R926696
0.309
>10


R926698
9999


R926699
0.76
9999


R926700
0.157
>10


R926701
2.2
9999


R926702
0.886
9999


R926703
0.525
9999


R926704
0.564
9999


R926705
0.263
9999
0.533


R926706
0.07
2.406
0.078


R926707
0.214
9999


R926708
0.472
9999


R926709
0.858
9999


R926710
1.763
9999


R926711
1.245
9999


R926712
1.084
9999


R926713
0.446
8.741


R926714
0.428
>10


R926715
0.588
>10


R926716
1.06
9999


R926717
7.874
9999


R926718
1.826
9999


R926719
0.1335
4.024


R926720
1.555
9999


R926721
4.441
9999


R926722
5.96
9999


R926723
2.591
9999


R926724
2.059
9999


R926725
0.431
9999


R926726
9999
9999


R926727
0.387
9999


R926728
0.482
>10


R926730
0.251
9999


R926731
9999
9999


R926732
0.444
9999


R926733
1.496
9999


R926734
4.493
9999


R926735
3.712
9999


R926736
0.288
9999


R926737
0.059
9999


R926738
0.342
9999


R926739
0.508
9999


R926740
4.422
9999


R926741
2.908
9999


R926742
0.127




0.043
9999


R926743
9999


R926744
9999


R926745
0.083
9999


R926746
0.989
9999


R926747
0.213
>10


R926748
0.345
>10


R926749
0.472
9999


R926750
0.361
>10


R926751
0.598
9999


R926764
0.252
5.64


R926765
0.324
4.39


R926766
0.756
9999


R926767
0.387
>10


R926768
0.443
>10


R926769
1.067
9999


R926770
0.583
9999


R926771
2.049
9999


R926772
0.337
7.501


R926773
0.548
7.849


R926774
1.934
7.935


R926775
3.47
>10


R926776
0.81
9999


R926777
0.378
9999


R926778
0.414
9999


R926779
9999
9999


R926780
0.152
>10


R926781
0.573
9999


R926782
0.173
>10


R926783
0.304
>10


R926784
0.252
9999


R926785
0.222
>10


R926786
0.504
9999


R926787
5.422
9999


R926788
0.336
6.341


R926789
2.315
9999


R926790
0.462
7.412


R926791
0.233
>10


R926792
3.197
9999


R926793
3.073
9999


R926795
2.041
>10


R926796
0.914
9999


R926797
2.235
9999


R926798
2.347
5.87


R926799
9999
9999


R926800
4.581
9999


R926801
10
9999


R926802
1.251
>10


R926803
1.541
>10


R926804
1.578
7.109


R926805
0.764
9999


R926806
0.374
9999


R926807
0.291
9999


R926808
0.368
9999


R926809
0.78
3.052


R926810
1.221
9999


R926811
3.662
9999


R926812
0.185
>10


R926813
0.152
9999


R926814
1.101
9999


R926815
1.181
9999


R926816
0.084
9999


R935000
9999
9999


R935001
9999
9999


R935002
9999
9999


R935003
9999
9999


R935004
9999
9999


R935005
9999
9999


R935006
10
9.8


R935016
9999
9999


R935019
8.8
9999


R935020
9999
9999


R935021
9999
9999


R935023
9999
9999


R935025
1.04
9999


R935029
2.83
9999


R935075
0.93
9999


R935076
4.15
9999


R935077
9999
9999


R935114
1.725
9999


R935117
9999


R935134
0.909
1.799


R935135
10
9999


R935136
0.952
2.129


R935137
10
9999


R935138
0.096
0.552


R935139
0.846
9999


R935140
0.275
0.959


R935141
0.727
>10


R935142
0.873
>10


R935143
0.573
>10


R935144
0.63
9999


R935145
0.548
>10


R935146
3.802
9999


R935147
1.404
9999


R935148
2.218
9.423


R935149
0.708
>10


R935150
1.926
9.738


R935151
0.479
>10


R935152
0.505
9.316


R935153
0.238
>10


R935154
0.127
>10


R935155
0.401
9999


R935156
0.149
>10


R935157
0.256
4.656


R935158
0.551
>10


R935159
0.232
4.135


R935160
0.202
>10


R935161
0.277
9999


R935162
0.269
>10


R935163
9999
9999


R935164
0.204
9999


R935165
4.988
9999


R935166
0.568
9999


R935167
2.132
>10


R935168
0.488
9.484


R935169
0.999
8.007


R935170
0.673
9999


R935171
0.536
9999


R935172
1.385
6.808


R935173
0.454
>10


R935174
1.384
9999


R935175
0.885
9999


R935176
1.169
9999


R935177
0.889
>10


R935178
0.515
9999


R935179
0.557
9999


R935180
1.22
9999


R935181
1.76
9999


R935182
0.124
2.469


R935183
0.729
9999


R935184
0.605
9999


R935185
0.351
6.642


R935186
0.211
9999


R935187
9.059
>10


R935188
0.239
9999


R935189
0.619
9999


R935190
0.156
9999


R935191
0.151
9999


R935192
0.337
9999


R935193
0.136
9999


R935194
0.11
9999


R935196
0.117
9999


R935197
0.174
>10


R935198
0.126
>10


R935199
0.45
>10


R935202
0.181
9.765


R935203
0.562
>10


R935204
0.554
9999


R935205
2.959
9999


R935206
4.711
9999


R935207
9999
9999


R935208
1.274
9999


R935209
0.526
1.035


R935211
1.238
9999


R935212
1.427
9999


R935213
0.619
10


R935214
0.453
5.499


R935218
4.712
9999


R935219
5.409
9999


R935220
3.789
9999


R940089
9999
9999


R940090
9999
9999


R940095
9999
9999


R940100
9999
9999


R940215
0.845
9999


R940216
0.2675
7.3


R940217
9999
9999


R940222
9999
9999


R940233
0.132
>10


R940235
0.8
>10


R940250


R940251


R940253
1.006
>10


R940254
0.986
9999


R940255
1.033
9999


R940256
1.104
9999


R940257
0.667
9999


R940258
0.473
5.72


R940260
1.126
9999


R940261
9999
9999


R940262
9999
9999


R940263
9999
9999


R940264
10
9999


R940265
0.239
>10


R940266
9999
9999


R940267
3.151
9999


R940269
1.654
9999


R940270
2.144
8.739


R940271
0.401
6.821


R940275
0.862
9999


R940276
0.211
9999


R940277
0.141
9999


R940280
6.999
9999


R940281
0.525
5.529


R940282
0.401
3.015


R940283
0.553
4.982


R940284
0.465
3.744


R940285
3.499
9999


R940286
0.337
7.082


R940287
0.288
7.684


R940288
0.208
9999


R940289
0.272
9999


R940290
0.116
9999


R940291
0.396
9999


R940292
0.683
9999


R940293
9999
9999


R940294
1.366
9999


R940295
0.126
8.812


R940296
0.41
>10


R940297
3.465
10


R945025
9999
9999


R945032
0.37
9999


R945033
9999
9999


R945034
1.85
9999


R945035
9999
9999


R945036
9999
9999


R945037
9999
9999


R945038
9999
9999


R945040
9999
9999


R945041
9999
9999


R945042
9999
9999


R945043
9999
9999


R945045
9999
9999


R945046
0.82
>10


R945047
0.845
9999


R945048
0.76
9999


R945051
0.95
>10


R945052
0.425
2.48


R945053
0.1185
1.48


R945056
10
9999


R945057
10
9999


R945060
0.9375
>10


R945061
10
9999


R945062
0.625
>10


R945063
1.55
>10


R945064
0.53
>10


R945065
1.425
>10


R945066
5.2
nd


R945067
9999
nd


R945068
9999
nd


R945070
0.45
>10


R945071
0.205
>10


R945096
1.75
>10


R945097
10
9999


R945109
1.025
>10


R945110
0.602
9999


R945117
4.077
9999


R945118
0.668
9999


R945124
0.69
7.852


R945125
0.896
>10


R945126
9999
9999


R945127
0.704
8.955


R945128
0.685
8.8


R945129
1.003
>10


R945130
1.874
9999


R945131
0.77
9999


R945132
0.571
8.77


R945133
1.064
>10


R945134
9999
9999


R945135
0.986
8.245


R945137
1.649
>10


R945138
1.058
6.733


R945139
1.016
>10


R945140
0.573
>10


R945142
1.049
>10


R945144
0.244
9999


R945145
9999
>10


R945146
3.756
9999


R945147
3.546
9999


R945148
0.307
9999


R945149
0.391
>10


R945150
0.467
>10


R945151
4.07
9999


R945152
6.94
9999


R945153
0.688
6.561


R945155
1.878
>10


R945156
0.787
9999


R945157
1.477
9999


R945162
9999
9999


R945163
0.922
4.251


R945164
10
9999


R945165
9999
9999


R945166
9999
9999


R945167
0.761
9999


R945168
10
9999


R945169
10
9999


R945170
0.661
>10


R945171
1.327
9999


R945172
1.179
9999


R945173
1.419
9999


R945175
1.648
9999


R950082
9999
9999


R950083
9999
9999


R950090
9999
9999


R921302
0.37
9999



0.19
9999


R950092
9999
9999


R950093
0.64
5.55


R950100
0.71
>10


R950107
0.46
>10


R950108
2.075
>10


R950109
7.95


R950120
3
9999


R950121
4.25
>10


R950122
3.025
9999


R950123
3.25
8.45


R950125
1.375
6.3


R950129
0.665
>10


R950130
4.9


R950131
9999


R950132
9


R950133
2.2
>10


R950134
1.875
9999


R950135
0.85
>10


R950137
2.23
9999


R950138
9.5


R950139
1.375
9999


R950140
2.825
9999


R950141
0.31
>10


R950142
10


R950143
8.23


R950144
10


R950145
9999


R950146
9999


R950147
9999


R950148
2.275
9999


R950149
10
9999


R950150
9999
9999


R950151
9999


R950152
10


R950153
9999


R950154
2.075
9999


R950155
9999


R950156
9999


R950157
9999


R950158
9.98


R950159
0.61
9999


R950160
1
9999


R950162
0.434
>10


R950163
0.874
9999


R950164
1.893
9999


R950165
1.288
9999


R950166
1.889
9999


R950167
9999
9999


R950168
6.496
8.653


R950169
1.273
9.518


R950170
9999
9999


R950171
0.585
>10


R950172
0.983
9999


R950173
2.368
>10


R950174
4.618
9999


R950175
1.688
9999


R950176
1.342
9999


R950177
2.361
8.434


R950178
0.688
>10


R950179
0.955
>10


R950180
0.278
9999


R950181
0.254
9999


R950182
0.627
9999


R950183
4.797
9999


R950184
2.222
9999


R950185
1.03
8.81


R950186
0.558
>10


R950187
0.724
>10


R950188
2.327
9999


R950189
10
9999


R950190
1.573
9999


R950191
0.178
9999


R950192
0.244
9999


R950193
0.61
9999


R950194
2.04
9999


R950195
0.473
9999


R950196
2.2
9999


R950197
0.531
9999


R950198
0.406
>10


R950199
0.408
9999


R950200
0.245
9999


R950201
0.261
9999


R950202
3.218
9999


R950203
9.035
9999


R950204
6.285
9999


R950205
8.997
9999


R950206
3.66
>10


R950207
0.164
9999


R950208
0.267
9999


R950209
0.748
9999


R950210
10
9999


R950211
10
9999


R950212
0.253
9999


R950213
9999
9999


R950214
10
9999


R950215
0.409
9999


R950216
0.327
9999


R950217
0.34
9999


R950218
0.292
9999


R950219
0.439
9999


R950220
0.489
9999


R950221
0.636
9999


R950222
0.865
9999


R950223
0.763
9999


R950224
0.687
9999


R950225
5.283
9999


R950226
1.374
9999


R950227
1.029
9999


R950229
0.98
9999


R950230
7.91
9999


R950231
1.968
9999


R950232
10
9999


R950233
0.98
9999


R950234
10
9999


R950235
4.095
9999


R950236
0.955
9999


R950237
9999
9999


R950238
10
9999


R950239
2.063
9999


R950240
1.766
9999


R950241
3.275
9999


R950251
9999
9999


R950253
0.697
9999


R950254
0.496
9999


R950255
10
9999


R908698
1.67
9999


R908699
0.217
9999


R908700
1.273
9999


R908701
0.099
7.643


R908702
0.104
7.395


R908703
0.63
9999


R908704
0.511
9999


R908705
0.801
9999


R908706
0.445
9999


R908707
1.834
9999


R908709
2.414


R908710
1.838
99


R908711
1.761


R908712
0.075
99


R908734
1.379


R909255
0.244
9999


R909259
0.43
9999


R909260
1.041
9999


R909261
0.93
9999


R909263
0.289
9999


R909264


R909265
99


R909266
99


R909267
0.589
9999


R909268
0.071
9999


R909290
0.226


R909292
1.172


R909308
0.671
9999


R909309
0.083
9999


R920394


R920395
0.092
9999


R920396


R920397


R920398


R920399


R920404


R920405


R920406


R920407


R920408


R920410
0.125
9999


R920411
0.564
9999


R925745
1.766
9999


R926238
9999


R926752
0.338
9999


R926753
0.108
9999


R926754
0.388
9999


R926755
1.693
9999


R926756
1.365
9999


R926757
0.158
9999


R926759
0.688
9999


R926760
2.893
9999


R926761
0.245
9999


R926762
0.386
9999


R926763
0.195
9999


R926794
1.382
9999


R926826
0.613
9999


R926827
1.098
9999


R926828
0.306
9999


R926829
0.688
9999


R926830
0.569
10


R926831
0.133
10


R926832
0.365
9999


R926833
1.129
9999


R926834
0.145
9999


R926835
0.296
9999


R926836
10
9999


R926837
2.994
9999


R926838
0.583
9999


R926839
0.161
9999


R926840
1.1
9999


R926841
0.551
9999


R926842
7.733
9999


R926843
7.371
9999


R926844
1.1
9999


R926845
2.558
7.812


R926846
0.86
6.264


R926847
1.479
6.264


R926848
0.254
10


R926851
0.446


R926855
9999
9999


R926856
0.734
9999


R926857
1.209
9999


R926859


R926860
1.949
99


R926862
0.774
9999


R926863


R926866


R926870
3.294


R926871
2.146


R926874
0.638
9999


R926879
0.397
9999


R926880


R926881


R926883


R926885


R926886


R926887
1.747


R926890
0.361
9999


R926891
0.152
9999


R926892
0.685
9999


R926893
10
9999


R926894
9999
9999


R926895
0.339
9999


R926896
1.622
9999


R926897
1.727
9999


R926898
1.1
9999


R926899
1.1
9999


R926900
9999
9999


R926902
1.37
4.586


R926903
0.243
9999


R926904
0.538


R926905
99


R926906
0.794


R926907
0.764


R926908
0.585


R926909
0.379


R926913
0.548
9999


R926914
1.86
9999


R926915
1.713
9999


R926916
1.958
9999


R926917
1.169
9999


R926918
2.521
9999


R926919
1.413
9999


R926922
0.305
9999


R926923
0.346
9999


R926925
0.307
99


R926926
0.401
9999


R926927
0.348
9999


R926928
0.575
9999


R926929
1.916
9999


R926930
99
9999


R926931


R926932
0.31
9999


R926933


R926934


R926935
4.44


R926936


R926937


R926938


R926939
3.615


R926940
7.754


R926941
4.195


R926942
4.81


R926943


R926944
0.225
99


R926945
0.457
9999


R926946


R926947
0.354
9999


R926948
0.246
9999


R926949
0.089
9999


R926950
99
9999


R926951
0.183
9999


R926953
0.049
9999


R926954
0.284
9999


R926955
0.36
9999


R926956
0.211
9999


R927016
1.408


R927017
2.449


R927018
1.446


R927019
1.179


R927020
1.316
9999


R927023
0.918
9999


R935221
9999
9999


R935222
0.52
9999


R935223
0.469
9999


R935224
4.578
9999


R935225
6.495
9999


R935237
0.24
9999


R935238
1.854
9999


R935239
0.609
9999


R935240
0.606
9999


R935242
2.855
9999


R935248
1.1
9999


R935249
1.1
9999


R935250
1.1
9999


R935251


R935252


R935253


R935255
0.374
9999


R935256
0.324
9999


R935258
1.191
9999


R935259
1.777
9999


R935261
0.391
9999


R935262
0.516
9999


R935263
0.106
10


R935264
0.135
9999


R935266
2.97


R935267
2.463


R935268
1.059


R935269
1.715


R935271


R935276
2.33


R935277
22.883
8.9


R935278
4.753
9999


R935279
0.889
9999


R935280
99


R935281
1.399
9999


R935286
1.158
9999


R935287
0.403
9999


R935288
1.58
9999


R935289
1.688
9999


R935290
0.34
9999


R935291
1.364
9999


R935292
0.483
9999


R935293
0.141
9999


R935294
0.388
9999


R935295
1.943
9999


R935296
99
9999


R935297
7.328
9999


R935298
0.252
99


R935299
0.21
9999


R935300
0.243
9999


R935301
4.05
99


R935302
0.189
9999


R935303
0.244
99


R935304
0.188
9999


R935305
0.495
9999


R935306
0.345
99


R935307
0.139
99


R935308
0.275
9999


R935309


R935310


R935320
2.769


R935321
2.986


R935322
3.416


R935323
9999


R935324
9999


R935336
0.341
9999


R935337
9999


R935338
0.411
9999


R935339
9999


R935340
3.606


R935351
9999
9999


R935352


R935353
9999
9999


R935354
99
9999


R935355
9999
9999


R935356
99


R935357
99
9999


R935358
9999
9999


R935359
1.027
9999


R935360
0.903
9999


R935361
1.438
9999


R935362
0.409
9999


R935363
0.405
9999


R935364
0.563
9999


R935365
0.373
9999


R935366
0.216
9999


R935367
0.053
9999


R940079
9999


R940110
9999
9999


R940299
2.497
9999


R940300
10
9999


R940301
1.975
9999


R940304
9999
9999


R940306
1.1
9999


R940307
0.291
9999


R940308
0.612
4.168


R940309
1.132
9999


R940311
1.95


R940312
2.557


R940314
4.197


R940316
1.858


R940317
0.913
9999


R940318
3.792


R940319
9999


R940321
9999


R940323
0.048
9999


R940337
1.098


R940338
0.073
9999


R921303
0.033
99


R940345
1.712


R940346
0.142
99


R940347
0.063
99


R940348
2.189


R940349
0.044
7.4


R940350
0.092
4


R940351
0.12
2.7


R940352
0.101
9999


R940353
0.091
9999


R940354
0.115
99


R945236
0.562
9999


R945237
0.461
9999


R945242
0.247
9999


R945263
1.642


R921304
0.085
9999


R945299


R950244
9999


R950245
9999


R950246
9999


R950247
9999


R950261
0.611
9999


R950262
0.285
9999


R950263
0.284
3.299


R950264
0.198
9999


R950265
0.312
9999


R950266
0.645
9999


R950267
0.18
9999


R950290
9999
9999


R950291
9999
9999


R950293
3.689
8.155


R950294
2.005
8.005


R950295
2.041
8.795


R950296
0.495
9999


R950344
99


R950345
1.962
99


R950346
0.345
9999


R950347
0.548


R950348
0.066


R950349
0.078
9999


R950356


R950368
0.038
9999


R950371


R950372
1.348
9999


R950373


R950374
0.599
9999


R950376
2.539


R950377
99


R950378


R950379
0.545
9999


R950380
3
9999


R950381
0.11
99


R950382


R950383
0.114
9999


R950385


R950386
0.973


R950388
2.518


R950389
0.612
9999


R950391
999
9999


R950392
0.956
9999


R950393
0.404
9999


R945028


R935241


R940298


R940302


R940303


R940305


R935260
9999


R909258


R940313
9999


R940315
9999


R935275
9999


R940320
9999


R940322
9999
9999


R926910
9999
9999


R926911
9999
9999


R926912
9999
9999


R926853
9999
9999


R926852
9999
9999


R926854
9999
9999


R926920
9999
9999


R926921
99
9999


R926924
99
9999


R926858


R926861
9999
9999


R945298
9999
9999


R940328
9999


R926869


R926873
9999


R926875
9999


R926876
9999


R926877
9999


R940336
9999


R926878
9999


R926882
9999


R926884
9999


R926889
9999


R920400
9999


R920401
9999


R920402
9999


R920403
9999


R940342
99


R920409
9999


R940344
9999


R926888
9999


R926758


R927024
0.326
99


R927025
0.326


R927026
9999
9999


R927027
9999
9999


R927028
0.208
9999


R927029


R927030
0.26
9999


R927031
0.215
99


R927032
0.899


R927035
0.583
9999


R927036


R927037
0.233
9999


R927038
1.05
9999


R927039
1.23
9999


R927040
1.05
9999


R927041
0.788
9999


R927042


R935270


R935368
0.082
9999


R935369
0.255
9999


R935370


R935371
0.794
9999


R935372
0.06
9999


R935373
0.274
9999


R935374
0.356
9999


R935375
10
9999


R935376


R935377


R935378
0.566
9999


R935379


R935380
1.61
99












High Density















Basophils
BMMC
BMMC
BMMC
BMMC
BMMC
BMMC


Test
Dust mite
anti-IgE
Ionomycin
anti-IgE
anti-IgE
anti-IgE
anti-IgE


Compound
Histamine
hexos
Hexos.
histamine
LTC4
TNF-alpha
IL-6





R008951


R008952


R008953


R008955


R008956


R008958


R067934


R067963


R070153


R070790


R070791


R081166


R088814


R088815


R091880


R092788


R908696


R908697


R909236


R909237


R909238

<0.22

<0.22
0.521
0.432
<0.22


R909239


R909240


R909241

<0.22

<0.22
1.021
0.253
<0.22


R909242


R909243


R909245


R909246


R909247


R909248


R909249


R909250


R909251


R909252


R909253


R909254


R920664


R920665


R920666


R920668


R920669


R920670


R920671


R920672


R920818


R920819


R920820


R920846


R920860


R920861


R920893


R920894


R920910


R920917


R921218
0.302
0.133
9999
0.203
0.766
0.274
0.100


R921219
0.020
0.069

0.058
0.040
0.039
0.009


R925734

9999
9999


R925747

3.1


R925755


R925757


R925758


R925760


R925765


R925766


R925767


R925768


R925769


R925770


R925771


R925772


R925773


R925774


R925775


R925776


R925778


R925779


R925783


R925784


R925785


R925786


R925787


R925788


R925790


R925791


R925792


R925794


R925795


R925796


R925797


R925798


R925799


R925800


R925801


R925802


R925803


R925804


R925805


R925806


R925807


R925808


R925810


R925811


R925812


R925813


R925814


R925815


R925816


R925819


R925820


R925821


R925822


R925823


R925824


R925837


R925838


R925839


R925840


R925841


R925842


R925843


R925844


R925845


R925846


R925849


R925851


R925852


R925853


R925854


R925855


R925856


R925857


R925858


R925859


R925860


R925861


R925862


R925863


R925864


R925865


R926016

9999
9999


R926017

1.4
9.6


R926018

8.5
9999


R926037

9999
9999


R926038

9999
9999


R926039

9999
9999


R926058

9999
9999


R926064

5.9
7.3


R926065

9999
9999


R926068

7.4
8.2


R926069

4.5
4.4


R926072

9999
9999


R926086

2.8
7.3


R926108

0.9
9999


R926109

0.6
3.2


R926110

1
4.5


R926113

0.65
9999


R926114

9999
9999


R926145

2.4
8.8


R926146

1.35
5


R926147

2
7.1


R926206

6.6
8.6


R926209

10
9.1


R926210

0.6
>10


R926211

3.9
>10


R926212

0.5
5


R926213


R926218

9999
9999


R926219

2.5
3.2


R926220

9999
9999


R926221

9.9
9999


R926222

9999
9999


R926223

9999
9999


R926224

9999
9999


R926225

9999
9999


R926228

9999


R926229


R926230


R926234

9999


R926237

1.9


R926240


R926241


R926242


R926243


R926245


R926248


R926249


R926252


R926253


R926254


R926255


R926256


R926257


R926258


R926259


R926319


R926320


R926321


R926325


R926331


R926339


R926340


R926341


R926342


R926376


R926386


R926387


R926394


R926395


R926396


R926397


R926398


R926399


R926400


R926401


R926402


R926403


R926404


R926405


R926406


R926408


R926409


R926411


R926412


R926461


R926467


R926469


R926474


R926475


R926476


R926477


R926478


R926479


R926480


R926481


R926482


R926483


R926484


R926485


R926486


R926487


R926488


R926489


R926490


R926491


R926492


R926493


R926494


R926495
0.038
0.056

0.089
0.24
0.077
0.028


R926496


R926497
0.205


R926498

<0.22

0.515
0.995
0.614
<0.22


R926499


R926500


R926501
0.645


R926502
0.491


R926503


R926504


R926505

<0.22

<0.22
<0.22
<0.22
<0.22


R926506


R926508
0.054
0.086

0.107
0.162
0.054
0.026


R926509


R926510


R926511


R926514


R926516


R926526


R926527


R926528


R926535


R926536


R926555


R926559


R926560


R926562


R926563


R926564


R926565


R926566


R926567


R926569


R926571


R926572


R926574


R926576


R926579


R926580


R926582


R926583


R926584


R926585


R926586


R926587


R926588


R926589


R926591


R926593


R926594


R926595


R926604


R926605


R926614


R926615


R926616


R926617


R926620


R926623


R926662


R926663


R926675


R926676


R926680


R926681


R926682


R926683


R926688


R926690


R926696


R926698


R926699


R926700


R926701


R926702


R926703


R926704


R926705


R926706


R926707

<0.056

<0.056
0.39
0.088
<0.056


R926708


R926709


R926710


R926711


R926712


R926713


R926714


R926715


R926716


R926717


R926718


R926719


R926720


R926721


R926722


R926723


R926724


R926725


R926726


R926727


R926728


R926730


R926731


R926732


R926733


R926734


R926735


R926736


R926737

0.075

0.073
0.046
0.068
0.017


R926738


R926739


R926740


R926741

0.961

1.025
9999
0.772
0.537


R926742
0.055
0.041

0.055
0.105
0.053
0.022


R926743


R926744


R926745


R926746


R926747


R926748


R926749


R926750


R926751


R926764


R926765


R926766


R926767


R926768


R926769


R926770


R926771


R926772


R926773


R926774


R926775


R926776


R926777


R926778


R926779


R926780

<0.22

<0.22
0.461
<0.22
<0.22


R926781


R926782

<0.22

<0.22
1.461
0.276
<0.22


R926783


R926784


R926785

0.989

0.561
1.411
1.312
0.513


R926786


R926787


R926788


R926789


R926790


R926791

0.064

<0.056
0.896
0.205
<0.056


R926792


R926793


R926795


R926796


R926797


R926798


R926799


R926800


R926801


R926802


R926803


R926804


R926805


R926806


R926807


R926808


R926809


R926810


R926811


R926812


R926813


R926814


R926815


R926816


R935000


R935001


R935002


R935003


R935004


R935005


R935006


R935016


R935019


R935020


R935021


R935023


R935025


R935029


R935075


R935076


R935077


R935114


R935117


R935134


R935135


R935136


R935137


R935138

<0.22

<0.22
0.373
0.409
<0.22


R935139


R935140


R935141


R935142


R935143


R935144


R935145


R935146


R935147


R935148


R935149


R935150


R935151


R935152


R935153


R935154

0.104

0.085
0.547
0.131
0.041


R935155


R935156

<0.22

<0.22
0.433
0.22
<0.22


R935157


R935158


R935159


R935160

<0.22

0.317
0.876
0.484
<0.22


R935161


R935162


R935163


R935164


R935165


R935166


R935167


R935168


R935169


R935170


R935171


R935172


R935173


R935174


R935175


R935176


R935177


R935178


R935179


R935180


R935181


R935182


R935183


R935184


R935185


R935186


R935187


R935188


R935189


R935190


R935191

0.068

0.043
0.213
0.071
0.027


R935192


R935193

0.08

0.048
0.312
0.092
0.037


R935194

0.125

0.054
0.493
0.118
0.034


R935196


R935197


R935198


R935199


R935202


R935203


R935204


R935205


R935206


R935207


R935208


R935209


R935211


R935212


R935213


R935214


R935218


R935219


R935220


R940089


R940090


R940095


R940100


R940215


R940216


R940217


R940222


R940233


R940235


R940250


R940251


R940253


R940254


R940255


R940256


R940257


R940258


R940260


R940261


R940262


R940263


R940264


R940265

0.981

0.306
1.211
1.131
0.486


R940266


R940267


R940269


R940270


R940271


R940275


R940276

0.136

0.073
0.332
0.251
<0.056


R940277

0.279

0.315
0.625
0.262
0.181


R940280


R940281


R940282


R940283


R940284


R940285


R940286


R940287


R940288


R940289


R940290

0.255

0.545
0.59
0.246
0.1


R940291


R940292


R940293


R940294


R940295


R940296


R940297


R945025


R945032


R945033


R945034


R945035


R945036


R945037


R945038


R945040


R945041


R945042


R945043


R945045


R945046


R945047


R945048


R945051


R945052


R945053


R945056


R945057


R945060


R945061


R945062


R945063


R945064


R945065


R945066


R945067


R945068


R945070


R945071


R945096


R945097


R945109


R945110


R945117


R945118


R945124


R945125


R945126


R945127


R945128


R945129


R945130


R945131


R945132


R945133


R945134


R945135


R945137


R945138


R945139


R945140


R945142


R945144


R945145


R945146


R945147


R945148


R945149


R945150

>2

>2
9999
0.709
0.634


R945151


R945152


R945153


R945155


R945156


R945157


R945162


R945163


R945164


R945165


R945166


R945167


R945168


R945169


R945170


R945171


R945172


R945173


R945175


R950082


R950083


R950090


R921302
0.282


R950092


R950093


R950100


R950107


R950108


R950109


R950120


R950121


R950122


R950123


R950125


R950129


R950130


R950131


R950132


R950133


R950134


R950135


R950137


R950138


R950139


R950140


R950141


R950142


R950143


R950144


R950145


R950146


R950147


R950148


R950149


R950150


R950151


R950152


R950153


R950154


R950155


R950156


R950157


R950158


R950159


R950160


R950162


R950163


R950164


R950165


R950166


R950167


R950168


R950169


R950170


R950171


R950172


R950173


R950174


R950175


R950176


R950177


R950178


R950179


R950180


R950181


R950182


R950183


R950184


R950185


R950186


R950187


R950188


R950189


R950190


R950191

<0.22

>2
0.401
<0.22
<0.22


R950192


R950193


R950194


R950195


R950196


R950197


R950198


R950199


R950200


R950201


R950202


R950203


R950204


R950205


R950206


R950207

<0.22

<0.22
0.288
<0.22
<0.22


R950208


R950209


R950210


R950211


R950212


R950213


R950214


R950215


R950216


R950217


R950218


R950219


R950220


R950221


R950222


R950223


R950224


R950225


R950226


R950227


R950229


R950230


R950231


R950232


R950233


R950234


R950235


R950236


R950237


R950238


R950239


R950240


R950241


R950251


R950253


R950254


R950255


R908698


R908699


R908700


R908701


R908702


R908703


R908704


R908705


R908706


R908707


R908709


R908710


R908711


R908712


R908734


R909255


R909259


R909260


R909261


R909263


R909264


R909265


R909266


R909267


R909268


R909290


R909292


R909308


R909309


R920394


R920395


R920396


R920397


R920398


R920399


R920404


R920405


R920406


R920407


R920408


R920410


R920411


R925745


R926238


R926752


R926753


R926754


R926755


R926756


R926757


R926759


R926760


R926761


R926762


R926763


R926794


R926826


R926827


R926828


R926829


R926830


R926831


R926832


R926833


R926834


R926835


R926836


R926837


R926838


R926839


R926840


R926841


R926842


R926843


R926844


R926845


R926846


R926847


R926848


R926851


R926855


R926856


R926857


R926859


R926860


R926862


R926863


R926866


R926870


R926871


R926874


R926879


R926880


R926881


R926883


R926885


R926886


R926887


R926890


R926891


R926892


R926893


R926894


R926895


R926896


R926897


R926898


R926899


R926900


R926902


R926903


R926904


R926905


R926906


R926907


R926908


R926909


R926913


R926914


R926915


R926916


R926917


R926918


R926919


R926922


R926923


R926925


R926926


R926927


R926928


R926929


R926930


R926931


R926932


R926933


R926934


R926935


R926936


R926937


R926938


R926939


R926940


R926941


R926942


R926943


R926944


R926945


R926946


R926947


R926948


R926949


R926950


R926951


R926953


R926954


R926955


R926956


R927016


R927017


R927018


R927019


R927020


R927023


R935221


R935222


R935223


R935224


R935225


R935237


R935238


R935239


R935240


R935242


R935248


R935249


R935250


R935251


R935252


R935253


R935255


R935256


R935258


R935259


R935261


R935262


R935263


R935264


R935266


R935267


R935268


R935269


R935271


R935276


R935277


R935278


R935279


R935280


R935281


R935286


R935287


R935288


R935289


R935290


R935291


R935292


R935293


R935294


R935295


R935296


R935297


R935298


R935299


R935300


R935301


R935302


R935303


R935304


R935305


R935306


R935307


R935308


R935309


R935310


R935320


R935321


R935322


R935323


R935324


R935336


R935337


R935338


R935339


R935340


R935351


R935352


R935353


R935354


R935355


R935356


R935357


R935358


R935359


R935360


R935361


R935362


R935363


R935364


R935365


R935366


R935367


R940079


R940110


R940299


R940300


R940301


R940304


R940306


R940307


R940308


R940309


R940311


R940312


R940314


R940316


R940317


R940318


R940319


R940321


R940323


R940337


R940338


R921303


R940345


R940346


R940347


R940348


R940349


R940350


R940351


R940352


R940353


R940354


R945236


R945237


R945242


R945263


R921304


R945299


R950244


R950245


R950246


R950247


R950261


R950262


R950263


R950264


R950265


R950266


R950267


R950290


R950291


R950293


R950294


R950295


R950296


R950344


R950345


R950346


R950347


R950348


R950349


R950356


R950368


R950371


R950372


R950373


R950374


R950376


R950377


R950378


R950379


R950380


R950381


R950382


R950383


R950385


R950386


R950388


R950389


R950391


R950392


R950393


R945028


R935241


R940298


R940302


R940303


R940305


R935260


R909258


R940313


R940315


R935275


R940320


R940322


R926910


R926911


R926912


R926853


R926852


R926854


R926920


R926921


R926924


R926858


R926861


R945298


R940328


R926869


R926873


R926875


R926876


R926877


R940336


R926878


R926882


R926884


R926889


R920400


R920401


R920402


R920403


R940342


R920409


R940344


R926888


R926758


R927024


R927025


R927026


R927027


R927028


R927029


R927030


R927031


R927032


R927035


R927036


R927037


R927038


R927039


R927040


R927041


R927042


R935270


R935368


R935369


R935370


R935371


R935372


R935373


R935374


R935375


R935376


R935377


R935378


R935379


R935380



















TABLE 2









High Density



















CHMC








Toxicity



high
CHMC
CHMC
CHMC
CHMC
CHMC
Toxicity
Toxicity
Toxicity
BJAB



density
high density
high density
high density
high density
high density
Jurkat
Jurkat
BJAB
Cell



hexos
tryptase
histamine
LTC4
TNF-alpha
IL-13
Light Scat.
Cell Titer Glo
Light Scat.
Titer Glo





















R008951












R008952


R008953


R008955


R008956


R008958


R067934


R067963


R070153


R070791


R081166


R088814


R088815


R091880


R092788






9999

9999


R909241







3.736


R921219
0.124
0.121
0.162
0.034
0.190
0.175

>10

>10


R925775






9999

9999


R925778






9999

9999


R925779






>10

9999


R925797






>10

9999


R926108






>10

>10


R926109
0.783
0.906
1.827
0.808
1.504
1.664
>10

9999


R926110






>10

>10


R921218
0.464
0.647
0.463
0.695
1.752
2.0776
>10

>10


R926113
1.448
1.649
1.848
0.468
5.678
3.569
>10

>10


R926146






9999

9999


R926210






>10

9999


R926240






10

9999


R926248






>10

9999


R926249






>10

9999


R926253






9999

9999


R926256






>10

9999


R926258






9999

9999


R926387






>10

9999


R926395






>10

9999


R926396






>10

9999


R926411






8.5

>10


R926486
1.088
1.313
1.928
0.834
0.455


R926488
0.521
0.623
0.792
0.201
2.443
1.012


R926493
0.889
1.093
1.324
0.474
>2


>4.33


R926494
0.640
>2
9999
0.326
9999


R926495
0.100
0.235
0.066
0.241
0.362
0.449

>10

>10


R926496
0.429
0.533
0.809
0.414
0.622


R926497
1.106
1.234
1.333

1.876
9999


R926501
>2
>2
9999

9999
9999

>4.33

>4.33


R926502
>2
>2
>2

1.807
>2

1.513


R926505







4.199


R926508
0.170
0.434
0.105

0.505
0.763

>10

>10


R926510
0.921
1.115
1.667

0.417
0.686

2.77


R926511
1.183
1.474
1.73

1.307
>2

>4.33

>4.33


R926614
>10
>10


>10
6.442


R926696
<1.1
<1.1
<1.1
<1.1
<1.1
1.773

>5.0


R926699
<1.1
<1.1
1.44
<1.1
<1.1
1.294


R926700
<1.1
<1.1
<1.1
<1.1
<1.1
2.053


R926703
1.512
1.947
>2
0.724
>2


R926704
>2
9999
9999
9999
9999


R926705
1.007
1.256
0.641
0.494
9999


R926706
>2
9999
9999
1.491
9999


R926742
0.104
0.217
0.080

0.385
0.667

9

>10


R926745







>10

>10


R926780







>5.0


R926782







>4.33

>4.33


R935075
0.647
1.212
0.443
<0.22
>2


>4.33

>4.33


R935154







>4.33


R935156







4.054


R940216
<1.1
<1.1
1.176
<1.1
3.188
3.006


R940233
0.577
0.642
0.586
0.118
2.247
1.781

>4.33

>4.33


R945032
0.357
0.458
0.439
0.0929
1.082
0.291


R945033
8.151
8.868


>10
5.983


R945071
<1.1
<1.1
<1.1
<1.1
<1.1
<1.1


R945128
1.279
1.749
0.547
0.729
>2
ND


R945140
0.994
1.112
1.551

1.714
9999


R945142
>2
>2
9999

>2
9999


R945150







>4.33

>4.33


R921302
0.682
0.795
1.588
0.514
1.173
1.672


R950141
0.567
0.618
0.627
0.201
1.059
0.798


R950207







>4.33









7.7 The 2,4-Pyrimidinediamine Compounds of the Invention Selectively Inhibit the Upstream IgE Receptor Cascade
To confirm that many of the 2,4-pyrimidinediamine compounds of the invention exert their inhibitory activity by blocking or inhibiting the early IgE receptor signal transduction cascade, several of the compounds were tested in cellular assays for ionomycin-induced degranulation, as described below.
7.7.1 CHMC Low Cell Density Ionomycin Activation: Tryptase Assay
Assays for ionomycin-induced mast cell degranulation were carried out as described for the CHMC Low Density IgE Activation assays (Section 6.4.3, supra), with the exception that during the 1 hour incubation, 6× ionomycin solution [5 mM ionomycin (Sigma I-0634) in MeOH (stock) diluted 1:416.7 in MT buffer (2 μM final)] was prepared and cells were stimulated by adding 25 μl of the 6× ionomycin solution to the appropriate plates.
7.7.2 Basophil Ionomycin Activation: Histamine Release Assay
Assays for ionomycin-induced basophil cell degranulation were carried out as described for the Basophil IgE or Dustmite Activation Assay (Section 6.4.6, supra), with the exception that following incubation with compound, cells were stimulated with 20 μl of 2 μM ionomycin.
7.7.3 Results
The results of the ionomycin-induced degranulation assays, reported as IC50 values (in μM) are provided in TABLE 1, supra. Of the active compounds tested (i.e., those that inhibit IgE-induced degranulation), the vast majority do not inhibit ionomycin-induced degranulation, confirming that these active compounds selectively inhibit the early (or upstream) IgE receptor signal transduction cascade.
These results were confirmed for certain compounds by measuring anti-IgE-induced and ionomycin-induced calcium ion flux in CHMC cells. In these Ca2+ flux tests, 10 μM R921218 and 10 μM R902420 inhibited anti-IgE-induced Ca2+ flux, but had no effect on ionomycin-induced Ca2+ flux (See FIG. 4).
7.8 The Inhibitory Effect of the 2,4-Pyrimidinediamine Compounds of the Invention is Immediate
To test the immediacy of their inhibitory effect, certain 2,4-pyrimidinediamines of the invention were added simultaneously with anti-IgE antibody activator in the cellular assays described above. All compounds tested blocked IgE-induced degranulation of CHMC cells to the same extent as observed when the compounds were pre-incubated with CHMC cells for 10 or 30 min. prior to receptor cross-linking.
7.9 Kinetics of Pharmacological Activity In Vitro
Compounds R921218, R921302, R921219, R926240, R940277, R926742, R926495, R909243 and R926782 were tested in washout experiments. In the experiments, CHMC cells were either activated immediately with anti-IgE antibody in the presence of 1.25 μM compound (time zero), or the compound was washed out followed by activation with anti-IgE antibody at 30, 60 or 120 min. The inhibitory activity of these compounds was greatly diminished 30 min. after compound removal, indicating that constant exposure of mast cells to these compounds is required for maximal inhibition of degranulation The other compounds tested yielded similar results.
7.10 Toxicity: T- and B-Cells
The ability of the compounds of the invention to exert their inhibitory activity without being toxic to cells of the immune system was demonstrated in cellular assays with B- and T-cells. The protocols for the assays are provided below.
7.10.1 Jurkat (T-Cell) Toxicity
Dilute Jurkat cells to 2×105 cells/ml in complete RPMI (10% heat-inactivated fetal bovine serum) media and incubate at 37° C., 5% CO2 for 18 hours. Add 65 ul cells at 7.7×105 cells/ml to a 96-well V-bottom plate (TC-treated, Costar) containing 65 ul 2× compound (final vehicle concentration is 0.5% DMSO, 1.5% MeOH). Mix, incubate plates for 18–24 hr at 37° C., 5% CO2. Toxicity was assessed by flow cytometric analysis of cellular light scatter
7.10.2 BJAB (B-Cell) Toxicity
The B-cell line BJAB was cultured in log phase in RPMI1640+10% heat-inactivated fetal bovine serum, 1× L-glutamine, 1× penicillin, 1× streptavidin and 1× beta-mercaptoethanol at 37° C., 5% CO2. First, BJABs were harvested, spun and resuspended in culture medium to a concentration of 7.7×105 cells/mL. 65 uL cells were mixed with 65 uL compound, in duplicate and in the presence of 0.1% DMSO in a V-bottomed 96-well tissue culture plate. Cells were incubated with compound at various dilutions at 37° C., 5% CO2. Toxicity was assessed by flow cytometric analysis of cellular light scatter.
7.10.3 Toxicity: Cell Titer Glo Assay
Seed 50 μl cells (1×106/ml) into each well containing 50 μl compound. The final vehicle concentration is 0.5% DMSO, 1.5% MeOH. Shake plates for 1 minute to mix cells and compound. Incubate plates at 37° C. (5% CO2) for 18 hours. Next day, harvest 50 μl cells from each well, add to 50 μl Cell Titer Glo reagent (Invitrogen). Shake plates for 1 minute. Read on luminometer.
7.10.4 Results
The results of the T- and B-cell toxicity assays, reported as IC50 values (in μM), are presented in TABLE 2, supra. With a few exceptions (see TABLE 1), all compounds tested were non-toxic to both B- and T-cells at effective inhibitory concentrations. Assays performed with primary B-cells yielded similar results.
7.11 The 2,4-Pyrimidine Compounds are Tolerated in Animals
The ability of the compounds of the invention to exert their inhibitory activity at doeses below those exhibiting toxicity in animals was demonstrated with compounds R921218, R921219 and R921302.
7.11.1 R921218
R921218 was studied in an extensive program of non-clinical safety studies that concluded this agent to be well tolerated in both rodents and non-rodents. To summarize the outcome of toxicology/non-clinical safety testing with R921218; this agent produced no dose limiting toxicity by the intranasal route of administration in non-rodents (rabbits and primates) or by the oral route of administration in rodents (mice and rats) during 14-day repeat-dose toxicity studies at doses many fold above the anticipated dose expected to produce efficacy in man. There were no adverse findings in a core safety pharmacology battery of cardiovascular, respiratory and/or central nervous system function. There was no evidence for mutagenic or clastogenic potential in genetic toxicology testing nor were there untoward effects after exposure to skin and eyes. A short discussion of key toxicology studies is provided.
A 14-day repeat-dose intranasal toxicity study in Cynomolgus monkeys was performed at doses of 2.1, 4.5 or 6.3 mg/kg/day. In life parameters included: clinical observations, body weights, food consumption, ophthalmology, blood pressure, electrocardiography, hematology, clinical chemistry, urinalysis, immunotoxicological assessment, gross necropsy, organ weights, toxicokinetic assessments and histopathology (including the nasal cavity). There were no adverse findings attributed to R921218 in any study parameter and the NOAEL (no observed adverse effect level) was considered 6.3 mg/kg/day.
A 14-day repeat-dose intranasal toxicity study in New Zealand White rabbits was performed at doses of 1.7, 3.4 or 5.0 mg/kg/day. In life parameters included: clinical observations, body weights, food consumption, ophthalmology, hematology, clinical chemistry, gross necropsy, organ weights, toxicokinetic assessments and histopathology (including the nasal cavity). There were no adverse findings attributed to R921218 in any study parameter and the NOAEL (no observed adverse effect level) was considered 5.0 mg/kg/day.
7.11.2 R921219
In pilot dose finding studies a single dose oral dose of 600 mg/kg was considered a NOEL (no observed effect level) while multiple (7-day) doses of 200 mg/kg/day and above were not tolerated.
In the in vitro Salmonella-Escherichia coli/Mammalian-Microsome Reverse Mutation Assay (Ames test), R921219 was found to test positive in tester strain TA1537, with and without metabolic activation, confirming the results of an earlier study. R921219 was not found to adversely affect any of the other 4 tester strains. R921219 was not found to possess clastogenic potential when studied in an in vitro chromosomal aberration assay.
7.11.3 R921302
Several non-GLP pilot toxicity studies have been conducted in rodents. In the mouse an oral dose of 1000 mg/kg was tolerated for up to 7-days. In a 14-day oral toxicity study in the mouse was conducted with doses of 100, 300 and 1000 mg/kg. A dose of 1000 mg/kg was not tolerated, while a dose of 300 mg/kg promoted evidence for histopathological changes in the vulva. A dose of 100 mg/kg was considered the NOAEL (no observed adverse effect level) in the study. A 28-day oral toxicity study in the mouse was conducted at doses of 100 mg/kg q.d., 100 mg/kg b.i.d., 300 mg/kg q.d. and 300 mg/kg b.i.d. R921302 was not tolerated at 300 mg/kg q.d. or b.i.d. The lower doses (100 mg/kg q.d. or b.i.d.) appeared to be well tolerated (results of clinical and histopathology are not yet known). In the rat oral doses of 50, 150 and 300 mg/kg given for 32 days appeared to be well tolerated (results of clinical and histopathology are not yet known).
In the in vitro Salmonella-Escherichia coli/Mammalian-Microsome Reverse Mutation Assay (Ames test), R921302 was found to test positive in tester strain TA98 with S9 and TA1537, with and without metabolic activation. R921302 was not found to adversely affect any of the other 3 tester strains. R921302 was not clastogenic when assessed in an in vitro chromosomal aberration assay.
7.12 The 2,4-Pyrimidinediamine Compounds are Orally Bioavailable
Over 50 2,4-pyrimidinediamine compounds of the invention were tested for oral bioavailability. For the study, compounds were dissolved in various vehicles (e.g. PEG 400 solution and CMC suspension) for intravenous and oral dosing in the rats. Following administration of the drug, plasma samples were obtained and extracted. The plasma concentrations of the compounds were determined by high performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Pharmacokinetic analyses were performed based on the plasma concentration data. The pharmacokinetic parameters of interest include Clearance (CL), Volume of distribution at steady-state (Vss), terminal half-life (t1/2), and oral bioavailability (%F).
These pharmacokinetic studies indicate that many of the 2,4-pyrimidinediamine compounds are orally available, with %F up to approximately 50% (in the range of 0–50%). The half-lives ranged from 0.5 to 3 hr. In particular, Compounds R940350, R935372, R935193, R927050 and R935391 exhibited good oral bioavailabilities and half-lives in rats. Thus, these studies confirm that these 2,4-pyrimidinediamine compounds are suitable for oral administration.
7.13 The Compounds Are Effective for the Treatment of Allergies
The in vivo efficacy of compounds R926109, R921218, R921219, R921302, R926495, R926508, R926742, R926745 and R945150 towards allergies was evaluated in the mouse model of passive cutaneous anaphylaxis (PCA). This model provides a direct measure of IgE-induced degranulation of tissue mast cells. In this model, IgE primed animals are exposed to an allergen challenge, and the change in permeability of dermal vasculature that results from histamine release from mast cells is measured by change in the amount of dye leakage into surrounding tissue. Inhibition of mediator release by compounds that modulate mast cell degranulation is easily measured by extracting the dye from the tissue.
7.13.1 Study Protocol and Results
In the PCA assay mice are passively sensitized by intradermal injection with anti-dinitrophenol (DNP) IgE antibodies (Day-1). At predetermined times animals are treated with the test agent (Day 0). The modulatory effect of the agent on cutaneous mast cell degranulation is measured following intravenous injection of DNP conjugated to human serum albumin (HSA-DNP), together with Evans blue dye. The resulting cross-linking of the IgE receptor and subsequent mast cell degranulation-induced increase in vascular permeability is determined by measuring the amount of dye extravasation into the tissue. Dye is extracted from the tissue by formamide, and the absorbance of this extract is read at 620 nm. The inhibitory effect of drug treatment is reported as the percent inhibition compared to vehicle treatment, that is, the percent reduction in A620.
Two compounds have been tested as positive controls: the histamine antagonist diphenhydramine and the serotonin antagonist cyproheptadine. Both mediators (histamine and serotonin) are released upon IgE-mediated degranulation from the mouse mast cell. Both reference compounds inhibit the PCA response; cyproheptadine was used routinely in subsequent experiements. Cyproheptadine reproducibly inhibited the PCA response by 61% +/−4% (8 mg/kg, i.p., 30 minutes pretreatment time, n=23 experiments).
7.13.1.1 Results
A dose-dependent inhibition of the FcεR—mediated vascular leakage was observed with increasing doses of R921218, R926109, R921219 and RR921302. These compounds were administered either in a solution formulation (67%PEG/33% citrate buffer) or an aqueous suspension (1.5% Avicel). These results demonstrate the strong correlation between compound plasma levels, in vivo efficacy, and in vitro potency. The most potent compound, R921219, was active with circulating exposure levels of approximately 10 μg/ml (68% inhibition at a dose level of 100 mg/kg) compared with R921302, a relatively less potent molecule, which reduced plasma extravasation by 42% at a dose level of 100 mg/kg. Further, the length of exposure to circulating compound was reflected in the duration of inhibitory activity. R921302, determined to be the most metabolically stable compound in pharmacokinetics studie, inhibited the vascular permeability for 1–2 hours prior to antigen-induced receptor signaling, where after the efficacy began to decrease. These data are summarized in TABLE 3 and TABLE 4.







TABLE 3







Efficacy of R921218, R926109, R921219 and R921302


in the PCA Assay
















Pretreat-


Plasma


Com-


ment
Dose
% Inhi-
level


pound
Route
Vehicle
time (min)
(mg/kg)
bition
(μg/ml)
















R921218
PO
67% PEG/
10
50
7
3




33%

100
11
4




citrate buffer

200
50
18


R926109
PO
67% PEG/
15
50
22
N.D.




33%

100
32




citrate buffer

200
48


R921219
PO
1.5%
15
30
25
0.4




Avicel/water

100
68
4






300
92
11


R921302
PO
1.5%
60
50
35
25




Avicel/water

100
42
38






150
56
64






200
93
105
















TABLE 4







Duration of action of R921219 and R921302 in the PCA Assay



















Plasma


Com-


Dose
Pretreatment
%
level


pound
Route
Vehicle
(mg/kg)
time (min)
Inhibition
(μg/ml)
















RR921302
PO
1.5%
200
30
89
88




Avicel/

60
83
53




water

120
82
61






240
37
8









Similar in vivo activity was observed with compounds R926495, R926508, R926742, R926745 and R926150, which were able to inhibit the PCA response after administration by the oral route in a PEG-based formulation (data not shown).
7.14 The Compounds are Effective in the Treatment of Asthma
The efficacy of compounds R921218, R921302, R926495, R926508, R926742 and R921219 in the treatment of asthma was demonstrated in the sheep model of allergic asthma. Sheep develop bronchoconstriction within minutes of exposure to inhaled antigen (Ascaris suum), with maximal airflow obstruction during the early allergic response (EAR). Release of preformed mast cell mediators is likely responsible for this early phase of airflow obstruction. In addition to the EAR, the sheep model allows us to evaluate the effect of our compounds on the late asthmatic reaction (LAR) and non-specific airway hyperresponsiveness (AHR), which occur as a result of topical or local administration of allergen to the airway. In the sheep, AHR develops a few hours following antigen challenge, and can persist for up to 2 weeks. The results described below demonstrate the potential of the tested compounds to inhibit a cascade of events that may be a result of release of cytokines from the mast cell.
7.14.1 Study Protocol
In the sheep model of allergic asthma, sheep are administered aerosols of test article via an endotracheal tube, followed by an aerosol challenge with antigen extracted from the roundworm, Ascaris suum, to which the sheep are naturally allergic. Allergen challenge leads to direct bronchoconstriction (both EAR and LAR) and a persistent non-specific AHR. These three characteristics are similar to those seen in human allergic asthmatics. The activity of the test agent is determined by changes in the lung resistance (RL), which is calculated from measurements of transpulmonary pressure, flow, and respiratory volume. The historical control data obtained from the same sheep following saline treatment compared with an allergen challenge show that a sharp increase of RL occurs during the EAR and persists for approximately 2–3 hours following allergen challenge. The LAR is a less pronounced increase in RL, which starts approximately 5–6 hours following allergen challenge and is resolved by 8 hours post-challenge. Twenty-four hours after the challenge, a dose response to carbachol is measured to determine the AHR, which is expressed as the dose of carbachol required to increase RL by 400% over baseline. (This measurement is referred to as the provocative concentration of carbachol that elicits a 400% increase in RL over baseline (PC400). The data are compared to historical control data for the same individual when administered a saline control aerosol and challenged with Ascaris suum.
7.14.2 Result
All the compounds tested showed inhibitory effects in the LAR and the AHR, and several of these agents inhibited the EAR as well. The optimal response for each compound in a series of studies to evaluate activity at several pretreatment times and using several different solution and suspension formulations are shown in TABLE 5. The efficacy of R921218 on the EAR appeared to be dependent on the formulation, with the greatest effect seen at 30 mg/sheep administered as a solution aerosol in 10% ethanol. R926495, R926742, R926508 and R921219, administered in four different sheep at 45 mg/sheep in an aqueous suspension 60 minutes prior to allergen challenge, demonstrate that the LAR and AHR is blocked. In addition to these late parameters, the EAR was greatly reduced by treatment with R921219, R926508 or R926495. The efficacy of RR921302 was investigated using a 45%PEG400/55% citrate buffer vehicle. Under these conditions, R921302, administered at 30 mg/sheep 60 minutes prior to challenge, blocked the LAR and AHR, and EAR was unaffected.
These data clearly demonstrate that these compounds are able to block the asthmatic responses in allergic sheep. All compounds inhibited the AHR and LAR significantly when compared to the historical control. The EAR was significantly inhibited by R921219, R926508 and R926495 (54%, 21% and 33% respectively). In contrast, R921218, R921302 and R926742 failed to inhibit the EAR when administered in an aqueous suspension.







TABLE 5







Efficacy Of Exemplary Compounds In A Sheep Model Of Allergic Asthma














Dose
Pretreatment

EAR (%
LAR (%
AHR (%


Compound
(mg/sheep)
time (min)
Vehicle
inhibition)
inhibition)
inhibition)
















R921218
30
15
10% ethanol
66
78
101


R926742
45
60
Aqueous
−19
87
94


R926495
45
60
suspension
33
85
41


R926508
45
60

21
90
88


R921219
45
60

56
75
90


RR921302
30
60
45% PEG400/55%
−28
86
82





citrate buffer









7.15 The Compounds are Effective in the Treatment of Asthma
The efficacy of compounds R921304 and R921219 in the treatment of asthma was also demonstrated in a mouse model of allergic asthma.
7.15.1 Study Protocol
Mice are sensitized to ovalbumin (chicken protein) in the presence of an adjuvant (Alum) by the intraperitoneal route on day 0 and day 7. One week later, mice are challenged intranasally with ovalbumin on Days 14, 15 and 16 (more stringent model) or on Day 14 (less stringent model). This sensitization and challenge regimen leads to airway hyperresponsiveness and inflammation in the lungs, which are two dominant characteristics of human allergic asthma. In the mouse model, the in vivo airway responses are measured using a whole body plethysmograph which determines the PENH (enhanced Pause, Buxco Electronics). The PENH is a dimensionless value comprised of the peak inspiratory flow (PIF), peak expiratory flow (PEF), time of inspiration, time of expiration and relaxation time, and is considered a validated parameter of airway responsiveness. Responses to allergen challenge (OVA) are compared with animals challenged with saline only. Twenty-four hours after challenge, mice are exposed to increasing doses of methacholine (muscarinic receptor agonist) which results in smooth muscle contraction. The ovalbumin-challenged mice demonstrate a significant airway hyperresponsiveness to methacholine when compared to the saline challenged mice. In addition, a cellular infiltrate in the airway is observed in ovalbumin challenged mice when compared with the saline challenged mice. This cellular infiltrate is mainly characterized by eosinophils, but a smaller influx of neutrophils and mononuclear cells is also present.
The use of this model for the evaluation of small molecule inhibitors of mast cell degranulation has been validated is several ways. First, using mast cell deficient mice (W/Wv) it has been shown that the ovalbumin-induced responses are dependent upon the presence of mast cells. In the mast cell deficient mice, ovalbumin sensitization and challenge did not result in airway hyperresponsiveness and eosinophil influx. Second, the mast cell stabilizer, Cromolyn, was able to block the ovalbumin-induced airway hyperresponsiveness and inflammation (data not shown). The use of this model to evaluate compounds for the treatment of asthmatic responses that may be mediated by mechanisms other than mast cell stablization, is further supported by the inhibitory effect of the steroids, dexamethasone and budesonide, on methacoline-induced bronchocontriction.
7.15.2 Results
The efficacy of R921304 was evaluated by intranasal administration on 10 consecutive days, from Day 7 through Day 16, at a dose level of 20 mg/kg, with the last 3 doses administered 30 minutes prior to either saline or ovalbumin challenge. R921304 was able to inhibit the ovalbumin-induced airway hyperresponsiveness to methacholine when compared to the vehicle treated mice.
In a less stringent protocol, in which the mice were challenged with ovalbumin only once on Day 14, R921219 administered subcutaneously at 70 mg/kg in 67%PEG400/33% citrate buffer 30 minutes prior to saline or ovalbumin challenge, demonstrates that R921219 completely blocked the ovalbumin-induced airway hyperresponsiveness and cellular influx.
These results clearly demonstrate that R921219 and R921304 are efficacious in inhibiting the airway responses in a mouse model of allergic asthma.
7.16 2,4-Pyrimidinediamine Compounds Inhibit Phosphorylation of Proteins Downstream of Syk kinase in Activated Mast Cells
The inhibitory effect of the 2,4-pyrimidinediamine compounds on the phosphorylation of proteins downstream of Syk kinase was tested with compounds R921218, R218219 and R921304 in IgE receptor-activiated BMMC cells.
For the assay, BMMC cells were incubated in the presence of varying concentrations of test compound (0.08 μM, 0.4 μM, 2 μM and 10 μM) for 1 hr at 37° C. The cells were then stimulated with anti-IgE antibody as previously described. After 10 min, the cells were lysed and the cellular proteins separated by electrophoresis (SDS PAGE).
Following electrophoresis, the phosphorylation of the proteins indicated in FIGS. 7, 10 and 11A–D were assessed by immunoblot. Antibodies were purchased from Cell Signaling Technology, Beverley, Mass.
Referring to FIGS. 7, 10 and 11A–D, the indicated compounds tested inhibited phosphorylation of proteins downstream of Syk, but not upstream of Syk, in the IgE receptor signaling cascade, confirming both that the compounds inhibit upstream IgE induced degranulation, and that the compounds exhert their inhibitory activity by inhibiting Syk kinase.
7.17 2,4-Pyrimidinediamine Compounds Inhibit Syk Kinase in Biochemical Assays
Several 2,4-pyrimidinediamine compounds were tested for the ability to inhibit Syk kinase catalyzed phosphorylation of a peptide substrate in a biochemical fluorescenced polarization assay with isolated Syk kinase. In this experiment, Compounds were 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 Bovine Gamma Globulin). Compound in 1% DMSO (0.2% DMSO final) was mixed with ATP/substrate solution at room temperature. Syk kinase (Upstate, Lake Placid N.Y.) was added to a final reaction volume of 20 uL, and the reaction was incubated for 30 minutes at room temperature. Final enzyme reaction conditions were 20 mM HEPES, pH 7.4, 5 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.1 mg/mL acetylated Bovine Gamma Globulin, 0.125 ng Syk, 4 uM ATP, 2.5 uM peptide substrate (biotin-EQEDEPEGDYEEVLE-CONH2, SynPep Corporation). EDTA (10 mM final)/anti-phosphotyrosine antibody (1× final)/fluorescent phosphopeptide tracer (0.5× final) was added in FP Dilution Buffer to stop the reaction for a total volume of 40 uL according to manufacturer's instructions (PanVera Corporation) The plate was incubated for 30 minutes in the dark at room temperature. Plates were read on a Polarion fluorescence polarization plate reader (Tecan). Data were converted to amount of phosphopeptide present using a calibration curve generated by competition with the phosphopeptide competitor provided in the Tyrosine Kinase Assay Kit, Green (PanVera Corporation).
The results of the assay are shown in TABLE 6, below:










TABLE 6







Compound No.
IC50 (in μM)



















R926505
0.0703



R926508
0.1315



R926594
0.7705



R926715
0.534



R926745
0.0925



R926782
0.1165



R926791
0.207



R926813
0.4047



R926816
0.0615



R935138
0.2288



R935190
0.0465



R935191
0.045



R935193
0.075



R935194
0.1687



R935196
0.2655



R940255
0.7705



R940256
2.787



R940269
0.685



R940275
0.7335



R940276
0.1265



R940277
0.2143



R940290
0.187



R945071
0.4295



R945140
0.611



R945142
2.007



R945144
0.383



R921302
0.2678



R908702
0.0378



R908712
0.024



R909268
0.1253



R920410
0.157



R926753
0.108



R926757
0.5103



R926834
0.292



R926839
0.055



R926891
0.1695



R926931
0.2553



R935237
0.0455



R935293
0.0465



R935302
0.0265



R935304
0.042



R935307
0.057



R935309
0.098



R935310
0.2003



R940323
0.062



R940338
0.028



R921303
0.00045



R940347
0.0345



R921304
0.01275



R950368
0.0107



R950373
0.0665










These data demonstrate that all of the compounds tested, except for R945142 and R909236 inhibit Syk kinase phosphorylation with IC50s in the submicromolar range. All compounds tested inhibit Syk kinase phosphorylation with IC50s in the micromolar range.
Although the foregoing invention has been described in some detail to facilitate understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.
All literature and patent references cited throughout the application are incorporated by reference into the application for all purposes.

## Claims

1. N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine or a salt, hydrate, solvate and/or N-oxide thereof.

2. A pharmaceutical composition comprising N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine or a salt, hydrate, solvate and/or N-oxide thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.

3. The composition of claim 2 which comprises a pharmaceutically acceptable salt of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine or a hydrate, solvate and/or N-oxide thereof.

4. The composition of claim 2 in which the salt is a hydrochloride salt, a hydrogen sulfate salt, a sulfate salt, a phosphate salt, an alkane sulfonate salt, a methane sulfonate salt, an ethane sulfonate salt or a p-toluene sulfonate salt.

5. A method of inhibiting IgG-induced or IgE-induced degranulation of a cell, comprising contacting a cell capable of undergoing IgG-induced or IgE-induced degranulation with an amount of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine or a salt, hydrate, solvate and/or N-oxide thereof, effective to inhibit IgG-induced or IgE-induced degranulation of the cell.

6. The method of claim 5 in which the cell is a human mast, basophil cell, neutrophil or eosinophil cell.

7. A method of inhibiting IgG-induced or IgE-induced mast or basophil cell degranulation in an animal, comprising administering to the animal an amount of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine and/or a salt, hydrate, solvate and/or N-oxide thereof, effective to inhibit IgG-induced or IgE-induced mast or basophil cell degranulation.

8. The method of claim 7 in which the animal is a human.

9. The method of claim 8 in which human is suffering from a disease selected from allergic diseases, low grade scarring, diseases associated with tissue destruction, diseases associated with tissue inflammation, and inflammation.

10. The method of claim 9 in which the allergic disease is selected from conjunctivitis, rhinitis, asthma, atopic dermatitis and food allergies.

11. The method of claim 9 in which the low grade scarring is selected from scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction.

12. The method of claim 9 in which the disease associated with tissue destruction is selected from COPD, cardiobronchitis and post myocardial infarction.

13. The method of claim 9 in which the disease associated with tissue inflammation is selected from irritable bowel, spastic colon and inflammatory colon disease.

14. A method of inhibiting a Syk kinase, comprising the step of contacting a Syk kinase or an active fragment thereof with an effective amount of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine or a salt, hydrate, solvate and/or N-oxide thereof.

15. The method of claim 14 which is practiced in vitro with an isolated or recombinant Syk kinase.

16. The method of claim 14 which is practiced in vitro with a cell or cell population that expresses an endogenous or recombinant Syk kinase.

17. The method of claim 14 which is practiced in vivo.

18. A method of inhibiting a Syk kinase in an animal, comprising the step of administering to the animal an amount of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine or a salt, hydrate, solvate and/or N-oxide thereof, effective to inhibit a Syk kinase.

19. The method of claim 18 in which the animal is a human.