Title of Invention

PYRIMIDINYL SULFONAMIDE COMPOUNDS WHICH INHIBIT LEUKOCYTE ADHESION MEDIATED BY VLA-4

Abstract

Disclosed are compounds, which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and in particular, leukocyte adhesion mediated by VLA-4 Such compounds are useful in the treatment of inflammatory diseases in a human or animal subject such as asthma, Alzheimer's disease, atherosclerosis. AIDS dementia, diabetes inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be, administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Full Text

PYRIMIDINYL SULFONAMIDE COMPOUNDS WHICH INHIBIT LEUKOCYTE ADHESION MEDIATED BY VLA-4 BACKGROUND OF THE INVENTION [0001] This application claims priority from U.S. Provisional Patent Application No. 60/777,595, filed on February 27, 2006, the disclosure of which is incorporated by reference in its entirety. Field of the Invention [0002] This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by α4 integrins, where the α4 integrin is preferably VLA-4. This invention also relates to pharmaceutical compositions comprising such compounds as well as methods for treating, e.g., inflammation, using either the compounds or the pharmaceutical compositions of this invention. References [0003] The following publications are cited in this application as superscript numbers: 1 Hemler and Takada, European Patent Application Publication No. 330.506. publishec August 30. 1989 2 Elices. et al., Cell, 60:577 584 (1990) 3 Springer, Nature, 346:425 434 (1990) 4 Osbom, Cell, 62:3 6 (1990) 5 Veddcr, et al., Surgery, 106:509 (1989) 6 Protolani, et al., J. Exp. Mod., 180:795 (! 994) 7 Abraham, el al., J. din. Invest., 93:776 (1994) 8 Mulligan, et al., J. Immunology, 150:2407 (1993) 9 Cybulsky, et al.. Science, 251:788 (1991) 10 Li. et al., Arterioscler. Thromb., 13:197 (1993) 11 Sassevillc. et al.. Am. J. Path., 144:27 (1994) 12 Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494 (1993) 13 Burkly, et al., Diabetes, 43:529 (1994) 14 Baron, et al.. J. Clin. Invest., 93:1700 (1994) 15 Hamann, et al., J. Immunology, 152:3238 (1994) 16 Ycdnock, ct al., Nature, 356:63 (1992) 17 Baron, et al., J. Hxp. Med., 177:57 (1993) 18 van Dinther-Janssen, et al., J. Immunology, 147:4207 (1991) 19 van Dinther-Janssen, ct al., Annals. Rheumatic Dis., 52:672 (1993) 20 lilices, ct al., J. Clin. Invest., 93:405 (1994) 21 Postigo, et al., J. Clin. Invest., 89:1445 (1991) 22 Paul, et al., Transpl. Proceed., 25:813 (1993) 23 Okarhara, ct al., Can. Res., 54:3233 (1994) 24 Paavonen, ct al., Int. J. Can., 58:298 (1994) 25 Schadcndorf, ct al., J. Path., 170:429 (1993) 26 Bao, ct al.. Dirt".. 52:239 (1993) 2? Lauri, ct al., British J. Cancer, 68:862 (1993) 28 Kawaguchi, et al., Japanese J. Cancer Res., 83:1304 (1992) 29 Konradi, et al., PCT/US00/01686, filed, January 21. 2000 [0004] All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety. State of the Art [0005] VLA-4 (also referred to as α4β1 intcgrin and CD49d/CD29), first identified by Hcmlcr and Takada,1 is a member of the β1 intcgrin family of cell surface receptors, each of which comprises two subunits, an a chain and a β chain. VLA-4 contains an aA chain and a β1 chain. There arc at least nine pi integrities, all sharing the same β1 chain and each having a distinct a chain. These nine receptors all bind a different complement of the various cell matrix molecules, such as fibroncctin, laminin, and collagen. VLA-4, for example, binds to fibroncctin. VLA-4 also binds non-matrix molecules that arc expressed by cndothclial and other cells. These non-matrix molecules include VCAM-1. which is expressed on cytokine-activated human umbilical vein cndothclial cells in culture. Distinct epitopes of VLA-4 arc responsible for the fibroncctin and VCAM-1 binding activities and each activity has been shown to be inhibited independently.2 [0006] Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive for leukocytes. The mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothclial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection. For reviews of adhesion receptors of the immune system, sec, for example, Springer' and Osborn.4 [0007] Inflammatory brain disorders, such as experimental autoimmune encephalomyeitis tEAE), multiple sclerosis (MS) and meningitis, arc examples of central nervous system disorders in which the endothelium leukocyte adhesion mecanism results in destruction to otherwise healthy brain tissue. Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis. [0008] In other organ systems, tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes. For example, it has been shown that the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult (Vedder. et al.).5 Other inflammatory or medical conditions mediated by an adhesion mechanism include, by way of example, asthma.68 Alzheimer's disease, atherosclerosis,9,10AIDS dementia," diabetes12 11 (including acute juvenile onset diabetes), inflammatory bowel disease15 (including ulccrativc colitis and Crohn's: disease), multiple sclerosis,16-17 rheumatoid arthritis,18-21 tissue transplantation,22 tumor metastasis,23-28 meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, rclinitis. atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome. [0009] Substituted aminopyrimidines, as a class, have been disclosed as inhibiting binding of VLA-4 to VCAM-1 and, accordingly, exhibit anti-infiammatory properties.29 While these compounds possess antagonist properties to such binding, enhanced bioavailability of these compounds would augment their efficacy. SUMMARY OF THE INVENTION [0010] This invention provides compounds, pharmaceutically acceptable salts and esters thereof, compositions thereof, syntheses thereof, and methods for treating VLA-4 mediated diseases. Based on in vivo data for those compounds of this invention, which were so evaluated, these compounds are contemplated to exhibit enhanced bioavailability when orally delivered as measured by conventional area under the curve (AUC) analysis. [0011] In one embodiment, the present invention provides compounds of formula 1: wherein: R1 is selected from the group consisting of C1 to C4alkyl and C1 to C4 haloalkyl; and R2 is selected from the group consisting of C1 to C4 alkyl, C2 to C4 alkenyl, C2 to C4 alkynyl, and C3-C6 cycloalkyl: or pharmaceutically acceptable salts, or esters thereof. [0012] In some embodiments, R1 is C1 to C2 alkyl. In other embodiments. R1 is methyl or trifluoromcthyl. In still other embodiments. R1 is methyl. [0013] In some embodiments, R2 is C1 to C4 alkyl. In other embodiments, R2 is C1 to C2 alkyl. In still other embodiments, R2 is methyl, ethyl, isopropyl or n-propyl. In another embodiment R2 is methyl or ethyl, and in yet another embodiment, R2 is isopropyl. [0014] In some embodiments, R2 is C3 to C6 cycloalkyl. In other embodiments, R2 is cyclopcntyl. [0015] In some embodiments, R2 is C2 to C4 alkcnyl. In other embodiments, R2 is allyl. [0016] In some embodiments, R2 is C2 to C4 alkynyl. In other embodiments, R2 is propargyl. [0017] Examples of compounds of this invention include those having the R1 and R2 groups recited in Table 1 (including pharrraccutically acceptable salts, or esters thereof). [0018] In another embodiment, the present invention provides a compound of formula II: wherein: R1 is selected from the group consisting of C1 to C4 alkyl and C1 to C4 haloalkyl; and R2 is selected from the group consisting of C1 to C4 alkyl, C2 to C4 alkenyl, C2 to C4 alkynyl, and C4-C6 cycloalkyl; or pharmaceutically acceptable salts, or esters thereof. [00l9] In some embodiments, R1 is C1 to C2 alkyl. In other embodiments, R1 is methyl or trifluoromcthyl. In still other embodiments, R1 is methyl. [0020] In some embodiments. R2 is C1 to C1 allkyl. In other embodiments, R2 is C1 to C2. alkyl. In still other embodiments, R2 is methyl, ethyl, isopropl or n-propyl. In another embodiment R2 is methyl or ethyl, and in yet another embodiment. R2 is isopropyl. [0021] In some embodiments, R2 is C3 to C6 cycloalkyl. In other embodiments, R2 is cyclopcntyl. [0022] In some embodiments, R2 is C2 to C4 alkenyl. In other embodiments, R2 is allyl. [0023] In some embodiments, R2 is C2 to C4 alkynyl. In other embodiments. R2 is propargyl. [0024] Examples of compounds of this invention include those having the R1 and R2 groups recited in Table 2 (including pharmaceutically acceptable salts, or esters thereof). [0025] Oitho and meta substitution of the pyrrolidinyicarbonyloxy group on the phenyl ring are also within the scope of this invention. [0026] This invention also provides for the compounds in Table 3 as well as their pharmaccutically acceptable salts, or esters thereof. [0027] In another aspect, this invention provides pharmaceutical compositions comprising a pharmaccutically acceptable carrier and a therapcutically effective amount of one or more of the compounds defined herein. [0028] In one of its method aspects, this invention is directed to a method for treating a disea.se mediated al least in pan by α4 integrin. preferably Vl.A-4, in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaccutically acceptable carrier and a thcmpcutically effective amount of one or more of the compounds of this invention. [0029] The compounds and pharmaceutical compositions of this invention are useful for treating disease conditions mediated at least in part by α4 integrins, where the α4 integrin is preferably VLA-4 or leucocyte adhesion. Such disease conditions include, by way of example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, rctinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome. [0030] Other disease conditions include, but are not limited to, inflammatory conditions such as erythema nodosum, allergic conjunctivitis, optic neuritis, uvcitis, allergic rhinitis. Ankylosing spondylitis, psoriatic arthritis, vasculitis, Reiter's syndrome, systemic lupus crythematosus, progressive systemic sclerosis, polymyositis, dcrmatomyositis, Wegncr's granulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporal arteritis, pericarditis, myocarditis, congestive heart failure, polyarteritis nodosa, hypcrsensitivity syndromes, allergy, hypcrcosinophilic syndromes, Churg-Strauss syndrome, chronic obstructive pulmonary disease, hypcrsensitivity pneumonitis, chronic active hepatitis, interstitial cystitis, autoimmune endocrine failure, primarv biliary cirrhosis, autoimmune aplastic anemia, chronic persistent hepatitis and thvruiditis. [0031] In one embodiment, the disease condition mediated by α4 integrin is an inflammatory disease. [0032] In another embodiment, the disease condition is an autoimmune disease. [0033] In some embodiments, the disease is selected from asthma, multiple sclerosis and inflammatory bowel disease. In other embodiments the disease is Crohn's disease. In yet other embodiments the disease is rheumatoid arthritis. [0034] In another aspect, this invention provides a method for preparing a compound of formula 1: wherein: R1 is selected from the group consisting of C1 to C4 alkyl and C1 to C4 haloalkyl; and R2 is selected from the group consisting of C1 to C4 alkyl, C2 to C4 alkenyl, C2 to C1 alkynyl. and C3-C6 cycloalkyl; or pharmaceutically acceptable salts., or esters thereof, which method comprises: a) contacting a compound of formula III where Pg is a carboxyl protecting group; with a C1 to C4 aldehyde or ketone, a C2 to C4 alkenyl aldehyde or ketonc, C2 to C4 alkynyl aldehyde or kctonc, C3-C6 cycloalkyl ketone and bcnzaldchyde under reductive amination conditions to provide for a compound of formula IV: b) contacting compound IV with a sulfonyl halidc of the formula R1SO2Z where Z is halo under conditions to form a compound of formula V: and c) removing the carboxyl protecting group to provide for a compound of formula I. [0035] In another aspect, this invention provides a method for preparing a compound of formula 1 n wherein: R1 is selected from the group consisting of C1 to C4 alkyl and C1 to C4 haloalkyl; and R2 is selected from the group consisting of C1 to C4 alkyl, C2 to C4 alkenyl, C2 to C4 aikynyl, and C3-C6 cycloalkyl; or pharmaceutically acceptable salts, or esters, thereof, which method comprises: a) contacting a compound of formula VI where Pg is a carboxyl protecting group; with an excess of R1SO2X to provide for a compound of formula VII: b) selectively rermoving a single -SO2R1 group from the compound of formula VII to provide a compound of formula VIII. v) contacting compound VIII with an alkylating agent with a formula R2-X, wherein X is halo, or with dimethylsulfatc when R2 is methyl, lo form a compound of formula IX: and d) removing the carboxyl protecting group to provide for a compound of formula I. DETAILED DESCRIPTION OF THE INVENTION [0036] As stated above, this invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated at least in part by α4 intcgrins, preferably VLA.4. However, prior to describing this invention in further detail, the following terms will first be defined. Definitions [0037] Unless otherwise stated, the following terms used in the •specification and claims have the meanings given below: [0038] As used herein and unless otherwise defined, "alkyl" refers to monovalent straight and branched hydrocarbyl groups having from 1 to 4 carbon atoms and preferably 1 to 3 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. [0039] "Alkenyl" refers to straight or branched monovalent hydrocarbyl groups from 2 to 4 carbon atoms and preferably 2 to 3 carbon atoms and having at least 4 and preferably 1 site of vinyl (>C=C (-CH=CH2) allyl (-CH2CH=CH2). n-propen-1-yl (-CH=CHCH4), n-buten-2-yl (-CH2CH=CHCH2), and the like. Included within this term arc the ris and trans isomcrs or mixtures of these isomers. [0040] "Alkynyl" refers to straight or branchec monovalent hydrocarbyl groups having from 2 to 4 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably 1 site of acctylcnic -C=C- unsaturation. Examples of such alkynyl groups include acctylenyl (-OCH), propargyl (-CH2C=CH), n-propyn-]-yl (-CH=CHCH3), and the like. [0041] "Halo" or "halogen" refers to fluo-o, chloro, bromo and iodo and preferably is either fluoro or chloro. [0042] "Haloalkyl" refers to alkyl groups having from 1 to 5 halo groups. Preferably, such groups have from 1 to 3 halo groups and 1 to 2 carbon atoms. Exemplary haloalkyl groups include halomethyl (e.g., fluoromethyl), dihalomcthyl (e.g., difluoromcthyl), trihalomcthyl (e.g., trifluoromethyl), halocthyl (e.g. 2-chlorocth-l-yl), trihalocthyl (e.g., 2,2.2-trinuorocth-1 -y 1), halopropyl (e.g., 3-chloroprop-I-yl and trihalopropyl (e.g., 3,3,3- trifluoroprop-1 -yl). [0043] "Pharmaccutically acceptable carrier" means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier" as used in the specification and claims includes both one and more than one such carrier. [0044] "Pharmaceutically acceptable .sah" refers ro salts which retain the biological etfectives and properties of the compounds of this invention and which are not biologically or otherwise undesirable. In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. [0045| Pharmaccutically-acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but arc not limited to, salts of primary, secondary, and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substiluted alkyl) amines. tri(substitutcd alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl am ires, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubso'luted cycloalkyl aminc, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkcnyl) amines, tri(cycloalkenyl) amines, substituted cyeloalkcnyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, hctcroaryl amines, diheteroaryl amines, triheteroaryl amines, hetcrocyclic amines, dihcterocyclic amines, triheterocydic amines, mixed di- and tri-amincs where at least two of the substituents on the aminc are different and arc .selected from the group consisting of alkyl, substituted alky], alkcnyl. substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, hetcroaryl, hetcrocyclic, and the like. Also included arc amines where the two or three substituents. together with the amino nitrogen, form a hetcrocyclic or hcteroaryl group. [0046] Examples of suitable amines include, by way of example only, isopropylamine, trimcthyl aminc. diethyl aminc, tri(iso-propyl) amine, tri(n-propyl) amine, cthanolamine, 2-dimcthylaminoethanol, tromethamine, lysine, arginine, histidinc, caffeine, procaine, hydrabaminc, cholinc, betaine, ethylenediamine, glucosaminc, N-alkylglucamincs, thcobrominc, purincs, pipcra/ine, piperidinc, morpholine, N-ethylpiperidinc, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the like. [0047] Plurmaceutically acceptable acid addition salts mav be prepared from inorganic and organic acids. Salts deri\ed from inorgaric acids include hydrochloric acid. hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propicnic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, mcthancsulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. [0048] The term "pharmaceutically-acccptable cation" refers to the cation of a pharmaccutically-acccptablc salt. [0049] It is understood that in all substitulec' groups defined herein, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substitucnt which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein, fn such cases, the maximum number of such substituents is three. That is to say that each of the above definitions is constrained by a limitation that, for example, substituted aryl groups are limited to -substituted ary!-(substituted aryl ^(substituted aryl). [0050] "Treating"1 or '-treatment" of a disease includes: (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but docs not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. [0051] A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. [0052] Intcgrins arc a large family of homologous transmembranc linker proteins that are the principal receptors on animal cells for binding most extracellular matrix proteins, such as collayen. fibronectin. and laminin. the integrins are heterodimers comprised of an a chain and a β chain. To date, twenty different integrin heterodimers, made from 9 different a subunits and 14 different β subunits, have been identified. The term " 4 intcgrins"' refers to the class of heterodimcr, enzyme-linked cell-surface receptors that contain the a 4 subunit paired with any of the β subunits. VLA-4 is an example of an a 4 integrin, and is a heterodimcr of the  4 and β1 subunits, and is also referred to as  4 β1 integrin. Compound Preparation [0053] The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e.. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) arc given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0054] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups arc described in T. W. Greene and G. VI. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. [0055] Furthermore, the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stercoisomcrs, i.e., as individual cnan:iomers or diastcreomers, or as stercoisomer- enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stercosclective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents arid the like. [0056] Most compounds of this invention were named using C'hemDraw \. !0.(), (available from Cambridgesoft at 100 Cambridge Park Drive, Cambridge, VIA 02140). [0057] In one embodiment, the compounds of this invention can be prepared as described below in Scheme 1 where for illustrative purposes only, R1 is methyl and R2 is isopropyl. Scheme 1 where Pg is a carboxyl protecting group such as benzyl, /-butyl, and the like. [0058] Scheme 1 is particularly useful in the preparation of compounds where R2 is alkyl or cycloalkyl. [0059] In Scheme 1. the starting 5-aminopyrimidine intermediates, compound 1.1, are described in detail in US Patent No. US 7,026,328 Bl and, lor the sake of illustration only, arc shown in this scheme as 4-substitutcd phcnylalanine derivatives. It is understood, of course, that 2- and 3-substituted phcnylalanine derivatives would follow a similar reaction pathway. [0060] Specifically, in Scheme 1, 5-amino-2-diethylamino-4-substituted pyrimidine, compound 1.1 (prepared from by corresponding 5-nitro-pyrimidinc by reduction with 5% Pd/C or 5% PtO? by weight) is reacted under convcntioanl reductive animation conditions with a slight excess of a C1-C4 aldehyde or ketone which is Scheme 1 is illustrated by acetone. In Scheme I, the 5-amino group of compound 1.1 forms an intermediate imine (not shown) which is in situ reduced to the corresponding aminc, compound 1.2, by conventional reducing agents such as sodium cyanoborohydrido, sodium borohydride, hydrogen over a suitable catalyst such as PtO2, and the like. The reaction i.s conducted in a suitable inert diluent such as tetrahydrof jran, mcthylcnc chloride, and the like. The reaction is maintained at from about 0cC to about 30°C until the reaction is substantially complete which typically occurs within a bout 0.5 to 16 hours. Upon completion of the reaction, the compound 1.2 is recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography, filtration, and the like or, alternatively, is employed in the next step without purification and/or isolation. [0061] Conversion of the amine group in compound 1.2 to the corresponding alkylsulfonylamido group, compound 1.3, proceeds via conventional methods. Tor example, in one method, compound 1.2 is contacted with a slight excess of an alkaneMilfonyl halide, such as methancsulfonyl chloride, in the presence of a suitable base such as triethylaminc, diisopropylcthylam.ne and the like in order to scavenge the acid generated. The reaction is preferably conducted in a suitable inert solvent such as tetrahydrofuran, dioxanc, chloroform and the like. The reaction is preferably conducted at from about -5o to -30oC and is continued until the reaction is substantially complete which typically occurs in 0.5 to 16 hours. Upon completion of the reaction, compound 1.3 can be recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography, filtration, and the like or, alternatively, is employed in the next step without purification and/or isolation. [0062] Alkvlsulfonyl halidcs are either krown compounds or compounds that can be prepared by con\enton svnthctie procedures. Such compounds are typically prepared from the corresponding sulfonic acid, i.e., from the compounds of the formula R1-SO4H where R1 is as defined above, using phosphorus trichloride and phosphorus pcntachloridc. The reaction is generally conducted by contacting the sulfonic acid with about 2 to 5 molar equivalents of phosphorus trichloride or phosphorus pcntachloridc, either neat or in an inert solvent, such as dichloromethane, at a temperature in the range of 0°C to about 80°C for about 1 to about 48 hours to afford the sulfonyl chloride. Alternatively, the sulfonyl chloride can be prepared from the corresponding thiol compound, i.e., from compounds of the formula R1-SH where R1 is as defined above, by treating the thiol with chlorine (Cl2) and water under conventional reaction conditions. [0063] Examples of sulfonyl chlorides for use in this invention include, but are not limited to. methanesulfonyl chloride, ethanesalfonyl chloride, 2-propanesulfonyl chloride. l-butancsu!fonyl chloride, trifluoromcthanc.su!fonyl chloride, 2,2,2-trifluoroethancsulfonyl chloride, and the like. [0064] The carboxyl protecting group of compound 1.3 is then removed by conventional conditions to provide for compound 1.4. a compound of Formula 1. In one embodiment, a t-butyl protecting group can be removed by contact with formic acid. In another embodiment, a benzyl protecting group can be removed by contact with hydrogen in the presence of a palladium/carbon catalyst typically in a protic solvent such as methanol under elevated hydrogen pressures. Upor completion of the reaction, compound 1.4 can be recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography, filtration, and the like. [0065] In another embodiment, the compounds of this invention can be prepared as described below in Scheme 2: Scheme 2 where R1 and R" is as defined herein; Pg is a carboxyl protecting group and X is halo. [0066] In Scheme 2, the starting 5-amhopyrimidine intermediates, compound 1.1, are described in detail in US Patent No. US 7,026,328 Bl and, for the sake of illustration only, are shown in this scheme as 4-substitutcd phenylalaninc derivatives. It is understood, of course, that 2- and 3-substituted phenylalaninc derivatives would follow a similar reaction pathway. [0067] Specifically, in Scheme 2, 5-amino-2-diethylamino-4-substituted pyrirnidine, compound 1.1 (prepared from by corresponding 5-nitro-pyrimidine by reduction with 5% Pd/C or 5% PtO2 by weight) is reacted with a slight excess of an R1-sulfonyl halidc. such as methancsulfonyl chloride, in the presence of a suitable base such as triethylamine, diisopropylethylamine and the like in order to scavenge the acid generated. The reaction is preferably conducted in a suitable inert solvent such as tctrahydrofuran, dioxane, dichloromethane, chloroform and the like. The reaction is preferably conducted at from about -5° to 30°C and is continued until the reaction is substantially complete which typically occurs in 0.5 to 16 hours. Upon completion of the reaction, compound 1.5 can be recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography, filtration, and the like or, alternatively, is employed in the next step without purification and or isolation. [0068] Selective removal of a single R SO:- group from compound 1.5 proceeds under conventional conditions. For example, reaction of compound 1.5 with base in a protic solvent such as methanol, cthanol, or water, optionally in (he presence of THF and the like, e.g. a 1:1 mixture of mcthanol/tetrahydrofuran or 1:1 mixture of water tetrahydrofuran provides for compound 1.6. The reaction mixture comprises an excess of a suitable base such as potassium carbonate, sodium carbonate and the like and the reaction is preferably maintained at elevated temperatures such 20° to 60°C. The reaction is continued until substantially complete which typically occurs in 24-144 hours. Upon completion of the reaction, compound 1.6 can be recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography, filtration, and the like or, alternatively, is employed in ihc next step without purification and/or isolation. [0069] Reaction of compound 1.6 with an excess of an alkyl halide, a dialkyl sulfate, an alkenyl halide, an alkynyl halide, or a cycloalkyl halide (i.e.. X-R2 - the "halide compound") proceeds under conventional conditions to provide for compound 1.7. The reaction is typically conducted by contacting compound 1.6 with from about 1.1 to 20 equivalent so of the halide compound in an inert diluent such as acetone, chloroform, methylenc chloride and the like in ihc presence of a base such as potassium carbonate, tricthylaminc and the like to scavenge the acid generated during reaction. The reaction is preferably conducted at from about 20" to 60°C and is continued until the reaction is substantially complete which typically occurs in 0.1 to 16 hours. Upon completion of the reaction, compound 1.6 can be recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography. filtration, and the like or, alternatively, is employed in the next step without purification and/or isolation. [0070] The carboxyl protecting group of compound 1.7 is then removed by conventional conditions to provide for compound 1.8, a compound of Formula 1. In one embodiment, a t-butyl protecting group can be removed by contact with formic acid. In another embodiment, a benzyl protecting group can be removed by contact with hydrogen in the presence of a palladium/carbon catalyst typically in a protic solvent such as methanol under elevated hydrogen pressures. Upon completion of the reaction, compound 1.8 can be recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography. nitration, and the like. [0071] In still another embodiment, the compounds of this invention can be prepared as described below in Scheme 3: Scheme 3 whore R1 is as defined above, Pg is a carboxy! protecting group such as benzyl. t-butyl, and the like and R2 is an alkyl. alkenyl, alkynyl, or phenvlalkylonc group ha\ing a CH2 moiety attached to the iodo group. [0072] In Scheme 1. the starting 5-aminopyrimidinc intermediates, compound I.I, are described in detail in US Patent No 7,026,328 Bl and, for the sake of illustration only, are shown in this .scheme as 4-substitutcd phcnylalanine derivatives. It is understood, of course, that 2- and 3-substitutcd phcnylalanine derivatives would follow a similar reaction pathway. [0073] Specifically, in Scheme 1, 5-atnino-2-diethylamino-4-substitutcd pyrimidinc, compound 1.1 (prepared from by corresponding 5-nitro-pyrimidinc by reduction with 5% Pd. C or 5% PtO2 by weight) is converted to the corresponding trifluoroacctamide, compound 1.8, by conventional methods. For example, a slight excess of trifluoroacetic anhydride is combined with compound 1.1 in a suitable inert diluent such as tctrahydrofuran, methylcnc chloride, pyridinc, and the like. The reaction is maintained at from about 0°C to about 30°C until the reaction is substantially complete which typically occurs within about 0.5 to 24 hours. Upon completion of the reaction, the compound 1.8 is recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography, filtration, and the like or, alternatively, is employed in the next step without purification and/or isolation. [0074] Conversion of compound 1.8 to the corresponding N(R2).N-trifluoroacctamido- pyrimidinc, compound 1.9, again proceeds via conventional techniques. For example, an excess of the halide, R2-I, is combined with compound 1.8 in a suitable inert diluent such as DMF in the presence of an excess of a suitable base such as potassium carbonate. In one embodiment, approximately two equivalents of R2-l and potassium carbonate arc employed. The reaction is maintained under ambient conditions in a scaled container and is continued until the reaction is substantially complete which typically occurs in 20-72 hours. Upon completion of the reaction, the compound 1.9 is recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography, filtration, and the like or, alternatively, is employed in the next step without purification and/or isolation. [0075] The trifluoroacetyl group is then removed to provide for the corresponding am inc. compound 1.10. In this embodiment, the trifluoroaceptyl group acts as an amino protecting group. As above, this reactior conventionally proceeds, for example. bv contacting compound 1.9 with a large excess of a suitable base such a.s potassium carbonate in a mixture of water and a protic solvent such as methanol. The reaction is conducted at elevated temperatures such t.s 40° to 60°C and is continued until the reaction is substantially complete. Upon completion of the reaction, the compound 1.10 is recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography, filtration, and the like or, alternatively, is employed in the next step without purification and/or isolation. [0076] Next, conversion of the amine group in compound 1.10 to the corresponding alkylsulfonylamido group, compound 1.11, proceeds via conventional methods. For example, in one method, compound 1.10 is contacted with a slight excess of an alkylsulfonyl halidc in the presence of a suitable base such as triethylamine, diisopropylcthylaminc and the like in order to scavenge the acid generated. The reaction is preferably conducted in a suitable inert solvent such as tetrahydrofuran, dioxanc. chloroform and the like. The reaction is preferably conducted at from about 0° to 30°C and is continued until the reaction is substantially complete which typically occurs in 2-48 hours. Upon completion of the reaction, compound 1.11 can be recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography, filtration, and the like or, alternatively, is employed in the next step without purification and or isolation. [0077] The carboxyl protecting group of compound 1.11 can be removed by conventional conditions to provide for compound 1.12, a compound of Formula I. In one embodiment, a A-butyl protecting group can be removed by contact with formic acid. In another embodiment, a benzyl protecting group can be removed by contact with hydrogen in the presence of a palladium/carbon catalyst typically in a protic solvent such as methanol under elevated hydrogen pressures. Upon completion of the reaction, compound 1.12 can be recovered by conventional methods including neutralization, evaporation, extraction, precipitation, chromatography, filtration, and the like. [0078] The invention also also includes esters of the compounds of this invention. The preparation of esters is illustrated in the various schemes described above, such as in scheme !. (compound ! .3), in scheme 2 'compound 1.7). and in scheme 3 (compound 1.1 1). Furthermore. F.xamplc 1 describes the preparation of (S)-4-(3-tcrt-butoxy-2-(2- (dicthylamino)-5-(N-isopropylmethylsulfonamido)-pyrimidin-4-ylamino)-3- oxopropyl)phenyl pyrrolidinc-l-carboxylatc, and Hxamplc 4 describes the preparation of (S)-4-(3-tert-butoxy-2-(2-(dicthylamino)-5-(N-(prop-2-ynyl)mcthyl- sulfonamido)pyrimidin-4-ylamino)-3-oxopropyl)phcnyI pyrrolidinc-1-carboxylate. Esters of the acids of this invention can also be prepared from the acids by ways well known in the art. For example, amino acid methyl esters can be prepared using the method of Brenner and Hubcr, llclv. Chim. Acta 1953, 36, 1109. Pharmaceutical Formulations [0079] When employed as Pharmaceuticals, the compounds of rhis invention arc usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intrana.»,al. These compounds arc effective as both injcctable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. [0080] This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of Formula I-II above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipicnt. diluted by an excipicnt or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. The excipicnt employed is typically an excipicnt suitable for administration to human subjects or other mammals. When the excipicnt serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injcctable solutions, and sterile packaged powders. [0081] In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is subMantially insoluble. it ordinarils is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. [0082] Some examples of suitable excipicnts include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginatcs, tragacanth, gelatin, calcium silicate, rnicrocrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil. wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoaies sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. [0083] Administration of therapeutic agents by intravenous formulation is well known in the pharmaceutical industry. An intravenous formulation should possess certain qualities aside from being just a composition in which the therapeutic agent is soluble. For example, the formulation should promote the overall stability of the active ingrcdient(s), also, the manufacture of the formulation should be cost effective. All of these factors ultimately determine the overall success and usefulness of an intravenous formulation. [0084] Other accessory additives that may be included in pharmaceutical formulations of compounds of the present invention as follow: solvents: clhanol. glycerol, propylene glycol; stabilizers: ethylcne diaminc tetraacetic acid (EDTA), citric acid; antimicrobial preservatives: benzyl alcohol, methyl paraben, propyl paraben; buffering agents: citric acid/sodium citrate, potassium hydrogen tartratc, sodium hydrogen tartrate, acetic acid/sodium acetate, maleic acid/sodium malcate, sodium hydrogen phthalate, phosphoric acid/potassium dihydrogen phosphate, phosphoric acid/disodium hydrogen phosphate; and tonicity modifiers: sodium chloride, mannitol, dextrose. [0085] The presence of a buffer may be necessary to maintain the aqueous pH in the range of from about 4 to about 8 and more preferably in a range of from about 4 to about 6. The buffer system is generally a mixture of a weak acid and a soluble salt thereof, e.g., sodium citrate citric acid; or the monocation or dication salt of a dibasic acid, e.g., potassium hydrogen tartrate; sodium huirogen tartnue, phosphoric acid, potassium dihydrogen phosphate, and phosphoric acid, disodium hydrogen phosphate. [0086] The amount of buffer system used is dependent on (1) the desired pH; and (2) the amount of drug. Generally, the amount of buffer used is in a 0.5:1 to 50:1 mole ratio of buffcrdrug (where the moles of buffer are taken as the combined moles of the buffer ingredients, e.g., sodium citrate and citric acid) of formulation to maintain a pH in the range of 4 to 8 and generally, a 1:1 to 10:1 mole ratio of buffer (combined) to drug present is used. [0087] One useful buffer in the invention is sodium citrate/citric acid in the range of 5 to 50 mg per mL of sodium citrate to 1 to 1:5 mg per ml., of citric acid, sufficient to maintain an aqueous pH of 4-6 of the composition. [0088] The buffer agent may also be present to prevent the precipitation of the drug through soluble metal complex formation with dissolved metal ions, e.g., Ca, Mg, Fe. Al, Ba, which may leach out of glass containers or rubber stoppers or be present in ordinary tap water. The agent may act as a competitive complcxing agent with the drug and produce a soluble metal complex leading to the presence of undesirable particulatcs. [0089] In addition, the presence of an agent, e.g., sodium chloride in an amount of about of 1-8 mg/mL, to adjust the tonicity to the same value of human blood may be required to avoid the swelling or shrinkage of crythrocytes upon administration of the intravenous formulation leading to undesirable side effects such as nausea or diarrhea and possibly to associated blood disorders. In general, the tonicity of the formulation matches that of human blood which is in the range of 282 to 288 mOsm/kg, and in general is 285 mOsm/kg , which is equivalent to the osmotic pressure corresponding to a 0.9% solution of sodium chloride. [0090] The intravenous formulation can be administered by direct intravenous injection, i.v. bolus, or can be administered by infusion by addition to an appropriate infusion solution such as 0.9% sodium chloride injection or other compatible infusion solution. [0091] The compositions arc preferably formulated in an oral unit dosage form, each dosage containing from about I to about 250 mg, more usually from about 5 to about 100 mg, for example about 10 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association witha suitable pharmaceutical excipient. [0092] The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, (he actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. [0093] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present itnention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughou: the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid prcformulation is then subdivided into unit dosage forms of the type described above containing from, for cxample, 0.1 to about 500 mg of the active ingredient of the present invention. [0094] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cctyl alcohol, and cellulose acetate. [0095] The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. [0096] Compositions for inhalation or insjfrlation include solutions and suspensions in pharmaccutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaccutically acceptable excipicnts as described supra. P-cferably the compositions arc administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaccutically acceptable solvents may bo nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. [0097] The following formulation examples illustrate the pharmaceutical compositions of the present invention. (as 10% solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0mg [0105] The active ingredient, starch, and cellulose arc passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidonc is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced arc dried at 50°C to 60°C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg. Formulation Example 5 [0106] Capsules, each containing 40 mg of medicament are made as follows: Ingredient Quantity (mg/capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1 0 mg Total 150.0 mg [0107] The active ingredient, starch and magnesium stearate are blended, passed through i So. 20 mesh U.S. sieve and filled into hard gelatin capsules in 150 mg quantities. Formulation Example 6 [0108] Suppositories, each containing 25 mg of active ingredient are made as follows: Ingredient Amount Active Ingredient 25 mg .Saturated fatty acid glycerides to 2,000 mg [0109] The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Formulation Example 7 [0110] Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows: [0111] The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymcthyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. [0112] The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425.0 mg quantities. Formulation Example 10 [0114] An intravenous formulation may be prepared as follows: Ingredient Quantity Active Ingredient 250 mg Isotonic saline 1000 ml. [0115]| Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdemnal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Sec, e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. [0116] Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such impiantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,011,472, which is herein incorporated by reference. [0117] Indirect techniques, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs. Latcntiation is generally achieved through blocking of the hydroxyi, earbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-artcrial infusion of hypcrtonic solutions, which can transiently open the blood-brain barrier. [0118] Other suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA. 17th ed. (1985). [0l19] As noted above, the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half-life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et a)., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837.028 each of which is incorporated herein by reference. [0l20] Compounds having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications. Stability can be assayed in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or human plasma or serum. A number of such protein stability assays have been described (see, e.g., Vcrhocf ct al., Eur. J. Drug Metab. Pharmacokinet., 1990, 15(2V.83-93). [0121] The conjugates of this invention arc VLA-4 antagonists and arc contemplated to provide enhanced in vivo retention as compared to the non-conjugated compounds. Such improved retention of the conjugate within the body would result in lower required dosages of the drug, which, in turn, would result in fewer side effects and reduced likelihood of toxicity. In addition, the drug formulation may be administered less frequently to the patient while achieving a similar or improved therapeutic effect. [0122] The conjugates of this invention are anticipated to exhibit inhibition. in vivo, of adhesion of leukocytes to endothelial cells mediated by VLA-4 by competitive binding to VLA-4. Preferably, the compounds of this invention can be used in intravenous formulations for the treatment of diseases mediated by VLA-4 or leukocyte adhesion. Such diseases include inflammatory diseases in mammalian patients such as asthma, Alzheimer's disease, atherosclerosis, AIDS dencntia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome. The formulations of the present invention are especially useful in the treatment of inflammatory bowel disease, such as Crohn' multiple sclerosis and rheumatoid arthritis. [0123] Appropriate in vivo models for demonstrating efficacy in treating inflammatory conditions include EAE (experimental autoimmune enccphalomyclitis) in mice, nits, guinea pigs or primates, as well as other inflammatory models dependent upon  integrins. [0124] Inflammatory bowel disease or "JBD" refers to the group of disorders that cause the intestines to become inflamed, generally manifested with symptoms including abdominal cramps and pain, diarrhea, weight loss and intestinal bleeding. 1BD is a collective term for two similar diseases ulceative colitis ("UC") and Crohn's disease ("CD") [0125] Crohn's disease ('"CD") is a chronic autoimmune disorder that results in inflammation of the gastrointestinal (GI) tract. Although any area of the GI tract may be involved, CD most commonly affects the small intestine and/or colon. In Crohn's disease, all layers of the intestine may be involved, and there can be normal healthy bowel in between patches of diseased bowel. CD is associated with fibrosis, stenosis and fissuring, fustulac between disease tracts and adjacent structures (i.e., bladder, other bowel segments, skin) and abecss. CD patients are typically p-esent with diarrhea, abdominal pain and weight loss. The abdominal pain usually is insidious and may be associated with a tender, inflammatory mass. Fever, weight loss, stomatitis, perianal llstulae and/or fissure, arthritis, and erythema nodosum are all commonly seen. There is considerable morbidity associated with CD, particularly in patients with disease not controlled by currently available drugs. Up to 75% of patients with moderate to severe disease require surgery and up to 75% ot these patients will experience pest surgical disease recurrence within 10 years and up to 50% will undergo a repeat surgery within 20 years. This high rate of recurrence indicates a need for new effective treatments for foth active disease and maintenance of disease remission.. [0126] Elcerative colitis or "UC" is a chronic, episodic, inflammatory disease of the large intestine and rectum characterized by bloody diarrhea. Ulcerative colitis is an inflammatory response limited largely to the colonic mucosa and submucosa. Ulccrative colitis can be categorized according to location: "proctitis" imolves only the rectum, "proctosigmoiditis" affects the rectum and sigmoid colon, "left-sided colitis" encompasses the entire left side of the large intestine, "pancolitis" inflames the entire colon. Lymphocytes and macrophages arc numerous in lesions of inflammatory bowel disease and may contribute to inflammatory injury. An exemplary animal model of inflammatory bowel disease (1BD) is carried out with HL A-B27 transgenic rats. These rats ovcrexpress the human HLA-B27 molecule (heavy chain and beta globulin gene) that is associated with spondyloarthropathics, a group of inflammatory conditions affecting the skeleton. Prior to onset of skeletal inflammatory changes these animals develop non-granulomaious inflammation in the small intestine and diffuse crypt abscesses on the colon, a pathology that is similar to that of Crohn's Disease in .lumans. Efficacy studies were performed in the HLA-B27 transgenic rat IBD model with compounds of this invention as described in Example J below. [0127] Asthma is a disease characterized by increased responsiveness of the tracheobronchial tree to various stimuli potentiating paroxysmal constriction of the bronchial airways. The stimuli cause release of various mediators of inflammation from IgiZ-coatcd mast ceils including histammc, eosinophilic and ncutrophilic chemotacJic factors, leukotrincs, prostaglandin and platelet activating factor. Release of these factors recruits basophils, cosinophils and neutrophiis, which cause inflammatory injury. [0128] Some appropriate animal models fo,: the in vivo study of asthma may include the rat asthma model, the mouse asthma model and the shcepmodel as described in Example Li. [0129] Achcroselerosis is a disease of arteries {e.g., coronary, carotid, aorra and iliac). The basic lesion, the athcroma, consists of a raised focal plaque within the intima. having a core of lipid and a covering fibrous cap. Atheromas compromise arterial blood flow and weaken affected arteries. Myocardial and cerebral infarcts are a major consequence of this disease. Macrophages and leukocytes arc recruited to atheromas and contribute to inflammatory injury. [0130] Rheumatoid arthritis is a chronic, relipsing inflammatory disease that primarily causes impairment and destruction of joints. Rheumatoid arthritis usually first affects the small joints of the hands and feet but then may involve the wrists, elbows, ankles and knees. The arthritis results from interaction of synovial cells with leukocytes that infiltrate from the circulation into the synovial lining of the joints. See e.g.. Paul, Immunology (3d ed., Raven Press, 1993). Overtime, bone erosion, destruction of cartilage, and complete loss of joint integrity can occur. Eventually, multiple organ systems may be affected. [0131] Joint damage in rheumatoid arthritis begins with the proliferation of synovia) macrophages and fibroblasts after a triggering incident, possibly autoimmune or infectious. Lymphocytes infiltrate perivascular regions, and endothelial cells proliferate. Neovascularization then occurs. Blood vessels in the affected joint become occluded with small clots of inflammatory cells. Over time, inflamed synovial tissue begins to grow- irregularly, forming invasive pannus tissue. Pannus invades and destroys cartilage and bone. Multiple cytokincs, intcrleukins. proteinascs. and growth factors are released, causing further joint destruction and the development of systemic complications. See, Fircstcin G.S. Etiology and pathogencsis of rheumatoid arthritis, Ruddy S, Harris ED, Sledge CB, Kcltey WN, eds. Kcilcy's Textbook of Rheumatology, 7th ed. Philadelphia: W.B. Saundcrs, 2005:996-1042. [0132] Appropriate animal models for the study of rheumatoid arthritis may include Adjuvant Induced Arthritis ("AIA") and Collagen Induced Arthritis ("CIA") as described in Examples G and H herein. [0133] Another indication for the compounds of this invention is in the treatment of organ or graft rejection mediated by VLA-4. Over recent years there has been a considerable improvement in the efficiency of surgical techniques for transplanting tissues .md organs such as skin, kidney, liver, heart, lung, pancreas and bone marrow. Perhaps the principal outstanding problem is the lack of satisfactory agents for inducing immunotolerancc in the recipient to the transplanted allograft or organ. When allogcneic cells or organs are transplanted into a host (V.c., the donor and donee arc different individuals from the same species), the host immune system is likely to mount an immune response to foreign antigens in the transplant (host-versus-graft disease) leading to destruction of the transplanted tissue. CD8" cells, CD4 cells and monocytes are all involved in the rejection of transplant tissues. Compounds of this invention which bind to alpha-4 integrin arc useful, inter alia, to block alloantigcn-induced immune responses in the donee thereby preventing such cells from participating in ihe destruction of the transplanted tissue or organ. Sec, e.g.. Paul ei al., Transplant Internationa/ 9. 420-425 (1996); Georc7.ynski et al.. Immunology 87, 573-580 (1996); Georcyznski et al.. Transplant. Immunol. 3, 55-61 (1995); Yang et al., Transplantation 60, 71-76 (1995); Anderson et al., APMIS 102, 23-27 (1994). [0134] A related use for compounds of this invention, which bind to VLA-4 is in modulating the immune response involved in "graft versus host" disease ("GVHD'"). See e.g., Schlegel et al., J. Immunol. 155, 3856-3865 (1995). GVHD is a potentially fatal disease that occurs when immunologically competent cells arc transferred to an allogcncic recipient. In this situation, the donor's immunocompctent cells may attack tissues in the recipient. Tissues of the skin, gut epithelia and liver arc frequent targets and may be destroyed during the course of GVHD. The disease presents an especially severe problem when immune tissue is being transplanted, such as in bone marrow transplantation; but less severe GVHD has also been reported in other cases as well, including heart and liver transplants. The therapeutic agents of the present invention are used, inter alia, to block activation of the donor T-cells thereby interfering with their ability to lysc target cells in the host. [0135] A further use of the compounds of this invention is inhibiting tumor metastasis. Several tumor cells have been reported to express VLA-4 and compounds, which bind VLA-4 block adhesion of such cells to cndothelial cells. Stcinback ct al., Ural. Res. 23, 175-83 (1995); Orosz et al., Int. J. Cancer 60, 867-71 (1995); Frccdman ct al., Leuk. Lymphoma 13, 47-52 (1994); Okaharact al.. Cancer Res. 54, 3233-6 (1994). [0136] A further use of the compounds of this invention is in treating multiple sclorosiv Multiple sclerosis is a progressive neurological autoimmune discus that affects an estimated 250,000 to 350,000 people in the United States. Multiple sclerosis is thought to be the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myclin, the insulating sheath covering nerve fibers. In an animal model for multiple sclerosis, murine monoclonal antibodies directed against VLA-4 have been shown to block the adhesion of leukocytes to the endothdium, and thus prevent inflammation of the central nervous system and subsequent paralysis in the animals. [0137] Pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia. PA. 17th ed.(1985). [0138] The amount administered to the patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions arc administered to a patient already suffering, from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "therapeuticaliy efiectivc dose." Amounts effective for this use will depend on the rtisea.se condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the inflammation, the age. weight and general condition of the patient, and the like, with reference to the appropriate animal model data, such as that provided herein. Methods for estimating appropriate human dosages, based on such data, are known in the art. (sec, for example. Wagner, J.G. Pharmacokinetics for the Pharmaceutical Scientist. Tcchnomic, Inc., Lancaster, PA 1993). [0139] The conditions administered tg a patient arc in the form of pharmaceutical composites described above. These compositions may be sterilized by conventional .sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophulized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration [0140] Compounds having the desired biological activity may be modified is necessary to provide desired properties such as improved pharnucological progenies(e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications. Stability can be assayed in a variety of ways such us by meaning the half-life of the proteins during incubation with peptidascs or human plasma or .scrum. A number of such protein stability assays have been described (see, e.g., Verhoef et al., Eur. J. Drug Metab. Pharmacokinct., 1990 15(2):83-93). [014l] The therapeutic dosage of the compounds of the present invention will vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. For example, for intravenous administration, the dose will typically be in the range of about 20 μg to about 2000 μg per kilogram body weight, preferably about 20 ug to about 500 μg, more preferably about 100 μg to about 300 μg per kilogram body weight. Suitab c dosage ranges for intranasal administration arc generally about 0.1 pg to 1 mg per kilogram body weight. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. [0142] Compounds of this invention arc also capable of binding or antagonizing the actions of α4β1, and α4β7 integrins. Accordingly, compounds of this invention are also useful for preventing or reversing the symptoms, disorders or diseases induced by the binding of these integrins to their respective ligands. [0143] In another aspect of the inventior, the compounds and compositions described herein can be used to inhibit immune cell migration from the bloodstream to the central nervous system in the instance of, for example, multiple sclerosis, or to areas which result in inflammatory-induced destruction of the myclin. Preferably, these reagents inhibit immune cell migration in a manner that inhibits demyelination and that further may promote rcmyelination. The reagents may also prevent demyelination and promote rcmyelinalion of the central nervous system for congenital metabolic disorders in which infiltrating immune cells affect the development myclin sheath, mainly in the CNS. The reagents preferably also reduce paralysis when administered to a subject with paralysis induced by a demyelinating disease or condition. [0144] Inflammatory disease that are included for treatment by the compositions, compounds and methods disclosed herein include generally conditions relating to demyelination. Histologically, myclin abnormalities arc either demyelinating or dysmyclinating. Demyelination implies the destruction of myclin. Dysmyelination refers to defective formation or maintenance of myclin resulting from dysfunction of the oligodendrocytes. Preferably, the compositions and methods disclosed herein are contemplated to treat diseases and conditions relating to demyelination and aid with rcmyelination. Additional diseases or conditions contemplated for treatment include meningitis, encephalitis, and spinal cord injuries and conditions generally which induce demyelination as a result of an inflammatory response. |0145| The compositions, compounds and cocktails disclosed herein are contemplated for use in treating conditions and diseases associated with demyelination. Diseases and conditions involving demyelination include, but are not limited to. multiple sclerosis. congenital metabolic disorders (e.g., phenylketonuria (PKU), Tay-Sachs disease, Nicmann-Pick disease, Gauchcr's disease, Hurlcr's syndrome, Krabbe's disease and other leukodystrophies that impact the developing sheath), neuropathies with abnormal myclination (e.g., Guillain Barre. chronic immune demyclinating polyneuropathy (CIDP), multifocal CIDP, Multifocal Motor Neuropathy (MMN), anti-MAG (Myclin-Associatcd Glycoprotein) syndrome, GALOP (Gait disorder, Autoantibody, Late-age, Onset, Polyneuropathy) syndrome, anti-sulfatide antibody syndrome, anti-GM2 antibody syndrome, POFMS (Polyneuropathy, Organomegaly, Fndocrinopathy, M-Protcin and Skin changes) syndrome also known as Crow-Fukasc Syndrome and Takatsuki disease, pcrineuritis, IgM anti-GDIb antibody syndrome), drug related demyclination (e.g., caused by the administration of chloroquine, FK506, pcrhexilinc, procainamidc, and zimeldine), other hereditary demyclinating conditions (e.g., carbohydrate-deficient glycoprotein, Cockayne's syndrome, congenital hypomyelinating, congenital muscular dystrophy. Harbor's disease, Marincsco-Sjögren syndrome, metachromatic leukodystrophy, Pelizaeus- Merzbacher disease, Refsum disease, prion related conditions, and Salla disease) and other demyclinating conditions (e.g., meningitis, encephalitis (also known as acute disseminated cnccphalomyclitis, ADEM), or spinal cord injury) or diseases. [0146] There arc various disease models that can be used to study these diseases in vivo. For example, animal models include but are not limited to: [0147] The most common demyclinating disease is multiple sclerosis ('"MS"), but many other metabolic and inflammatory disorders result in deficient or abnormal myelination. MS is a chronic neurologic disease, which appears in early adulthood and progresses to a significant disability in most cases. There arc approximately 350,000 cases of MS in the United States alone. Outside of trauma, MS is the most frequent cause of neurologic disability in early to middle adulthood. [0148] The cause of MS is yet to be determined. MS is characterized by chronic inflammation, demyclination and gliosis (scarring). Demyelination may result in either negative or positive effects on axonal conduction. Positive conduction abnormalities include slowed axonal conduction, variable conduction block that occurs in the presence of high-but not low-frequency trains of impulses or complete conduction block. Positive conduction abnormalities include ectopic impulse generation, spontaneously or following mechanical stress and abnormal "cross-talk" between dcmyclinated exons. [0149] T cells reactive against myclin proteins, either myclin basic protein (MBP) or myclin proteolipid protein (PLP) have been observed to mediate CNS inflammation in experimental allergic cncephalomyclitis. Patients have also been observed as having elevated levels of CNS immunoglobulin (lg). It is further possible that some of the tissue damage observed in MS is mediated by cytokine products of activated T cells, macrophages or astrocytes. [0150] Today, 80% patients diagnosed with MS live 20 years after onset of illness. Therapies for managing MS include: (1) treatment aimed at modification of the disease course, including treatment of acute exacerbation and directed to long-term suppression of the disease; (2) treatment of the symptoms of MS; (3) prevention and treatment of medical complications; and (4) management of secondary personal and social problem^ [0151] The onset of MS may be dramat.c or so mild as to not cause a patient to seek medical attention. The most common symptoms include weakness in one or more limbs, visual blurring due to optic neuritis, sensory disturbances, diplopia and ataxia. The course of disease may be stratified into three general categories: (1) relapsing MS, (2) chronic progressive MS, and (3) inactive MS. Relapsing MS is characterized by recurrent attacks of neurologic dysfunction. MS attacks generally evolve over days to weeks and may be followed by complete, partial or no recovery. Recovery from attacks generally occurs within weeks to several months from the peak of symptoms, although rarely some recovery may continue for 2 or more years. [0152] Chronic progressive MS results in gradually progressive worsening without periods of stabilization or remission. This form develops in patients with a prior history of relapsing MS, although in 20% of patients, no relapses can be recalled. Acute relapses also may occur during the progressive course. [0153] A third form is inactive MS. Inactive MS is characterized by fixed neurologic deficits of variable magnitude. Most patients with inactive MS have an earlier history of relapsing MS. [0154] Disease course is also dependent on the age of the patient. For example, favourable prognostic factors include early onset (excluding childhood), a relapsing course and little residual disability 5 years after onset. By contrast, poor prognosis is associated with a late age of onset (i.e., age 40 or older) and a progressive course. These variables arc interdependent, since chronic progressive MS tends to begin at a later age that relapsing MS. Disability from chronic progressive MS is usually due to progressive paraplegia or quadriplegia (paralysis) in patients. In one aspect of the invention, patients will preferably be treated when the patient is in remission rather then in a relapsing stage of the disease. [0155] Short-term use of either adrenocorticotropic hormone or oral corticosteroids (e.g., oral prednisone or intravenous methylprednisolone) is the only specific therapeutic measure for treating patients with acute exacerbation of MS. [0156] Newer therapies for MS include treating the patient w ith interforon beta-lb. intcrferon beta-la. and Copaxonc" (formerly known as copolymer I). These three drugs have been shown to significantly reduce the relapse rate of the discase. These drugs are self-administercd intramuscularly or subcutaneously. [0157] However, none of the current treatment modalities inhibit demyelination, let alone promotes or allows spontaneous rcmyclination or reduces paralysis. One aspect of the invention contemplates treating MS with agents disclosed herein either alone or in combination with other standard treatrrent modalities. [0158] Radiation also can induce dcmyelination. Central nervous system (CNS) toxicily due to radiation is believed to be cause by (I) damage lo vessel structures, (2) deletion of oligodendrocyte-2 astrocyte progenitors and mature oligodendrocytes. (3) deletion of neural Mem cell populations in the hippocampus, cerebellum and cortex, and generalised alterations of cytokinc expression. Most radiation damage results from radiotherapies administered during the treatment of certain cancers. See for review Belka era!., 2001 Br. ./. Cancer 85: 1233-9. However, radiation exposure may also be an issue for astronauts (Hopcwcll, 1994 Adv. Space Res. 14: 433-42) as well as in the event of exposure to radioactive substances. [0159] These conditions and diseases are also contemplated for palliative or ameliorating treatments. EXAMPLES [0160] The following synthetic and biological examples arc offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. Unless otherwise stated, all temperatures are in degrees Celsius. In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. Scheme 4 [0162] In Scheme 4, compound 4 was prepared in a three pot sequence from the 5- nitropyrmidine compound 1. The synthetic protocol of Scheme 4 significantly simplifies the preparation of this compound by one or more of the following: 1) a substantially accelerated nitro group reduction step; 2) a streamlined reduction/reductive amination sequence that is performed in the same flask with the same solvent and the same catalyst, so manipulations arc reduced and exposure of the oxygen sensitive products to air is minimized; 3) the conditions for the reductive amination step minimizes generation of a bis- isopropylamino pyrimidine side product thereby eliminating the need for a chromatographic purification of compound 3; 4) conditions arc described whereby it is possible to purify the mono- isopropylaminopyrimidine intermediate, compound 2, by trituration of the corresponding L-tartaric acid salt (though the need for this discrete purification of compound 2 also has been rendered unnecessary by the improvements in the reductive amination step), and 5) conditions for the discrete purification of compound 3 by crystallization from MTBE.-hexane or MTBE-cyclohcxane have been identified. [0163] In the reaction steps of Scheme 4, flash chromatography was performed using a Biotage Flash 751., using 800 g KP-Sil silica cartridges (32-63 μM, 60 angstrom, 500-550 m2/g). R1s are reported for analytical thin layer chromatography, using EM Sciences Silica Gel 60 F(254), 250 μM thick plates for normal phase. NMR spectra were obtained on a Varian Gemini 300 MHz spectrometer (300 MHz for 'H spectra and 75 MHz for 13C spectra). Analytical HPLC was performed on an Agilent 1100 Series HPLC with a Phcnomcnex Luna, 3 μm, (2-18, 30 x 4.6 mm column. The detector was UV at 210nm. Solvents were 0.1% 'ITA in water and 0.1% TFA in acctonitrilc. The standard flow rate was 1.5 mL/min. and the standard method was named Ml with the solvent gradient changing from 20% CH?CN to 70% CHXN over 2.33 minutes. An alternate method was named M2 with a flow rate of 2 mL/min and a gradient changing from 20% CH3CN to 70% CH3CN over 1.75 minutes. Method M15 had a flow rate of 1.5 ml/min. with the solvent composition changing from 20% CH2CN to 70% CH3.CN over 10 min.. holding at 70% for 2 min.. then ramping to 95% over 1 min. and holding at 95% for 2 minutes. LC/MS was performed on an Agilent 1100 Scries HPLC with a Series 1100 MSD with electrospray ionization (unless otherwise indicated as chemical ionization). The column and conditions were matched to the free standing HPLC. [0164] Nitropyrimidinc-carbamate (100 g, 189 mmol) and PtO2 (6.33 g, 27.85 mmol) were suspended in 360 mL of wet THF (5% H2O). The mixture was stirred at room temperature under hydrogen (60 psi). After 3 hours, TLC (50% EtOAc/hexancs on silica gel) indicated complete reduction of the nitro group (TLC analysis on silica with EtOAc showed Rf— 0.2 (streaky) for the amino-pyrimidinc and Rt= 0.86 for the starting nitropyrimidino-carbamatc.) In this regard, the use of PtO2 for both steps in this two-step process permitted a one-pot reaction with that added feature that the rate of reduction of the nitro group was dramatically accelerated, In any event, care be taken to minimize exposure to air/oxygen as the aminopyrimidine product is prone to oxidation. [0165] Ethanol (200 mL), acetone (21 mL, 1.5 cq.), and glacial acetic acid (3.0 mL, 0.28 eq.) were added to the aminopyrimidine solution in the hydrogenation flask. After evacuaring and purging, the flask was pressurized with H2 (60 psi). The reductive animation was allowed to proceed overnight. I'LC on .silica using EtOAc a.s the eluant gave an Rr = 0.41 (streaky) for the isopropylamino-pyrimidine and an Rr= 0.11 for the starting aminopyrimidine carbamate. Both TLC and LC7MS confirmed complete reaction with virtually no bis-isopropylaminopyrimidine produced. If necessary, HPLC can be used as an alternative means to monitor progress of the reaction. The crude reaction solution was diluted with EtOAc (1 L) and filtered through a pad of basic alumina (400 mL). The alumina was rinsed with KtOAc (200 mL) and EtOH (200 mL) and the combined organic solutions were concentrated in vacua. The flask was vented under N2 The viscous oil was redissolved in anhydrous toluene (700 mL) and concentrated. After venting the flask under nitrogen, the product was dried again by azcotropic removal of another 400 mL of toluene. A viscous reddish-brown oil was obtained. [0166] As evidenced by the LC MS, very little bis-isopropylaminopyrimidine carbamatc impurity was produced with this procedure as compared to prior methods wherein the bis- isopropylamino pyrimidinc carbamatc mpurity required removal by chromatography. [0167] If a formal purification of the mono-isopropylamino pyrimidine 2 step is required, it can be precipitated from THF'ether as the (L)-tartaric acid salt and triturated. A small-scale example follows: (5.09 g, 99.6% yield) L-Tartaric acid (1.42 g) was dissolved in hot THF (45 mL). The ho: tartaric acid solution was added to the gum of the isopropylamino-pyrimidine 2 (5.1 g). 'rhe mixture was swirled and warmed until homogeneous. The solution changed from pink-purple in color to tan. The solution was concentrated in vacua to give a tan gum. Ethcr (~ 150 mL) was added whereupon oiling was observed. The ether mixture was concentrated in vacua. Acetone (~20 mL) and then ether (-200 mL) was added, and the formation of a gummy oil was again observed. The mixture was concentrated for a third time. Mcthylenc chloride (5-10 mL) was added followed by ether (-80 mL). A tan precipitate was observed to form underneath a bright orange-pink supernatant. The mixture was filtered. The precipitate was rinsed with ether (50 mL) and then again with a mixture (-60 mL) of acetone and ether (1:1). The precipitate was dried under vacuum overnight to give a cream colored solid (4.9 g, 76% yield). A small aliquot of the solid tartaric acid salt was dissolved in i-PrOH and EtOH and passed through a small plug of basic alumina to give the free base. The aliquot of free base was analyzed by TLC and LC MS. The remaining salt was suspended in a mixture of CH:C1: (250 ml.) and IN NaHCO, (150 mL). With mixing and some bubbling, the solid dissolved and the free base aminc was extracted into the organic layer. The aqueous layer was extracted once more with EtOAc (150 mL) and the organic extracts were combined and dried over MgSO4 (~150g). The dried organic solution was passed through a plug of basic alumina (-100 g) to give a light pink solution that was concentrated in vacua to give a tan-pink gum (3.28 g, 64% yield from starting nitrocarbamate). [0168] Several other acids were investigated in an attempt to form salts with the mono- isopropylaminopyrimidine carbamate 2. p-Tolucnesulfonic acid and mcthanesulfonic acid gave oils. Solid salts could be formed with HCI and H3PO4, but tartaric acid appeared to give the most favorable solubility characteristics. The HCI and phosphoric acid salts seemed to dissolve readily in a CH2Cl2, i-PrOH, and acetone, whereas the tartaric acid salt seemed to be mostly insoluble in CH2Cl2 and only partially soluble in the other solvents. [0169] lsopropylaminopyrimidinc carbamate 2 from Step ] (assume 189 mmol) was dissolved in pyridine (680 mL) and the solution was cooled to 0°C under N2. Mcthancsulfonyl chloride (44 mL, 3.0 cq.) was added via syringe pump over 20 min. to the cold pyridine solution of the isopropylaminopyrimidine carbamate. The ice bath was removed and the solution was allowed to warm to RT. The solution was allowed to stir for six hours. A small aliquot was removed and a mini-workup was performed (diluted with EtOAc, washed with 5% KH2PO4, brine, and then dried over MgSO4). Analysis by TLC showed the reaction to be complete and generally clean (only one spot besides a baseline spot from residual pyridine. The bulk reaction solution was concentrated. When 650 mL of distillate had been collected, the blood red oil was diluted with EtOAc (2 L). The organic solution was washed with 5% KH2PO4 (1 L and 750 mL). 0.2 N citric acid (1 L). and brine (1.L). T'he organic solution was dried over MgSO4 (150 g). The dried organic solution was filtered through a pad of silica gel (1 L.) to give a green-black solution. The flask and silica gel were rinsed with EtOAc (1.5 L) to bring the total volume of organic solution to 3.5 L. The solution was filtered through a pad of basic alumina (300 mL) to give a deep green solution. The solution was concentrated in vacuo. A reddish gum (150 g) was obtained. [0170] The flask was flushed with nitrogen, capped and placed in the refrigerator whereupon a red-brown solid formed. LC/MS indicated acceptable purity, but TLC analysis indicated a bright red baseline spot as well as two to three very faint impurities. The odor of pyridine was still present. The red-brown solid was dissolved in a mixture of CH2Cl2 (100 mL), THF (200 mL), and ether (800 mL). The solution was filtcred/cluted through a pad of silica gel (1 L) and the silica was rinsed with ether (3 L). Most of the colored baseline impurity was retained on the silica gel. The solution was concentrated to give a red oil that dried to a pink foamy solid (100 g) that analyzed to be 94.7% pure by LC 'MS. The material was then chromatographed on silica gel (2 L) clutcd with CH2Cl2 (3 L), CH2Cl2 and ether (1:1; 4 L), ether (4 L), cther: THF (1:1; 4 L), and EtOAc with 5% EhN and 2% EtOH (4 L). The CH2Cl2:ethcr eluent gave a red oil of mixed fractions (12.4 g; Fraction A) and the ether eluent gave a tan oil (13 g; Fraction B) that was generally pure. The bulk of the material remained on the column and it was realized that the desired product had crystallized on the column. Elution with ethenTHF and EtOAc (with 5% Et3N and 2% EtOH) allowed the product to redissolve and clutc in concentrated plug (Fraction C) Fraction A and Fraction B were combined and concentrated together. Fraction C was concentrated separately. Upon concentrating and drying, crystals formed in both fractions. Further investigations found that the solid could be rccrystallised from methyl tert-butyl ether (MTBE), cyclohexane, cther-hexanc( 1:1), MTBE-hcxancs, or cyclohexanc-hcxancs. Combined Fractions A and B and Fraction C were each rccrystallizcd from MTBE-hcxancs to give the tert-butyl ester 3 as a white solid (57.75g total with a purity >99%) and red filtratc/mothcr liquors. The mother liquors were concentrated to give a red oil (24 g). The mother liquor oil was chromatographed on a Biotagc 75 and clutcd with 4% THF in CH2Cl2 (12 L) to give enriched fractions that were then concentrated and re-crystallized to give an additional 14 g of purified tert-butyl ester. [0171] LC/MS by method M2 gaw tR =97 min. with M Z = 619 for [M+l ]" for the desired product. [0172] LC/MS by method M15 gave tR 6.09 min. with M/Z = 619 for [M+l ] for the desired product. [0173] 1H NMR (CDCl2 300 MHz) δ, ppm: 0.88 (d, j - 6 Hz. 1.4H), 1.04 (d, j = 6 Hz, 2H), 1.20 (m, 10H), 1.37 (s, 4.8H), 1.39 (s, 4.811), 1.93 (AA'BB', 411), 2.80 (s, 1.7H), 2.9 (s, 1.6H), 3.18 (m, 2.411), 3.4-3.7 (m overlapping two apparent triplets. 8.3H), 4.40 (sextet, j 6 Hz, I.1H), 4.8 (sextet, 1H), 5.64 (d, j = 6.5 Hz, 0.5H), 5.70 (d, j - 6.5 H/., 0.5H), 7.03 (m, 2H), 7.18 (apparent dd, 2H), 7.80 (d, j - 4 Hz, IH). The 'll NMR shows returners. [0174] It is contemplated that treatment with the methancsulfonyl chloride be done in THF with little or no additional ba.se. If base is used, a base such as triethylamine or diisopropylethylaminc should be employed. [0175] A formic acid (1.5 L) solution of the t-butyl ester from Step 2 (57.75 g, 0.093 mol) was heated to 50 °C overnight and then concentrated in vacua. Alternatively, the reaction can also be performed at 70o or 80° for 60-90 minutes. [0176] Water (~100 mL) was added to the crude product and the mixture was concentrated to dryness. The residue was dried under high vacuum. The crude product was dissolved and concentrated twice from 1.0N HC1 (250 mL and 200 mL). The product was twice dissolved in hot THF and concentrated to dryness to yield a foamy solid. The foamy solid was dried under high vacuum at 65° for two hours. This solid was scraped from the flask and dried in the vacuum oven overnight (60°C, 28 in. Hg) to give the hydrochloride salt of (S)-2-(2-(diethylamino)-5-(N- isopropylmcthylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidinc-l- earbonyloxy)phenyr)propanoic acid -5 (50.9 gm 98.3% pure). [0177]] LC/MS by method M15 gave tR=l.96 min. with M/Z 563. [0178] LC/MS by method M2 gave tR = 1.43 min. with M Z = 563. [0179] 1H NMR (CD,OD, 300 MHz) δ, ppm: 0.80 (d,,j = 6 Hz, 1.4H), 1.02 (d,,j 6 Hz, 1.611), 1.23(m, 9.2H), 1.80-2.0 (AA'BB' - m, 5.2H), 2.99 (d, 3.211), 3.2-3.45 (m, 4.5H), 3.45-3.8 (m, 7.611), 4.40 (sextet, 1H), 4.90 (m, 3H), 7.00 (d. 2H), 7.23 (d. 2H), 7.60 (d, 0.25H), 7.75 (d, 1H), 7.83 (d. 0.25H). [0180] 11CNMR(CD3OD,75MIIz)δ, ppm: 6.5, 14.7, 14.8,15.4, 15.5, 19.4,20.0,20.2, 29.91, 30.44, 33.95, 34.15, 41.03, 41.08, (41.71, 41.99, 42.28, 42.6, 42.8, 43.1 - solvent peaks), 47.21, 47.36, 50.01,50.42. 62.43, 102.11, 102.23, 116.78, 124.9, 125.19, 128.54, 129.01, 138.49. 139.02, 145.53, 145.60. 145.78, 148.68. 156.77. 156.86, 166.91, 167.07. [0181] Nitro-carbamatc (compound 5, 10.8 g, 20 mmol) was slurricd in THF(35 mL;) and water (1 ml.. 3 ol%) was added. The solution was stirred, Adams cataksi ('0.360 g. 6 mole of)) was added and the solution was de-oxygenated by three cycles of evacuation (50 mm Hg) and refilling with dry nitrogen (10 psi). Finally, the reaction vessel was pressurized with hydrogen (60 psi) and reaction mixture was vigorously stirred for 90 min. If necessary or desired, progress of the hydrogenation reaction can be monitored by TLC (silica gel, cluting with dichloromethar.c:mcthanol (95:5)). Rr of nitrocarbamatc is 0.95, primary aminc - 0.16. [0182] The hydrogen was replaced by dry nitrogen (three cycles of evacuation and refilling with nitrogen). The ethanol (25 mL), acetic acid (0.3 mL) and acetaldchyde (1.2 ml., 21 mmol, 1.05 eq) were added, vessel was partially evacuated at low prcsssures (ca. 150 mm Hg) in order to minimize loss of the volatile acetaldchyde, refilled with nitrogen (10 psi) and reaction mixture was stirred vigorously for 50 min. At the end of this time, nitrogen was replaced by hydrogen (60 psi) by partial evacuation and re-prcssurizing with hydrogen two times. The mixture was stirred for another 45 min. Progress of reductive amination may be monitored by TLC (slica gel, eluting with dichloromethane:mcthanol (95:5). Rt of primary aminc ~ 0.16, secondary aminc - 0.32 and tertiary aminc - 0.43. At the end of process, hydrogen was flushed out by three cycles of evacuation and refilling with nitrogen, the catalyst was filtered off on a bed of Celite using meihanol to rinse, the filtrates were stripped to dryness to give amber oil (11.9 g). The product is sensitive to oxygen, resulting in considerable darkening and appearance of low Rr material in TLC. All handling should be done with appropriate precautions. [0183] The reaction product was purified by flash chromatography using dichloro- methane:methanol mixture (97:3), containing 0.3% of ammonium hydroxide. Fractions containing N-cthyl product were combned to give 7.9 g of compound 6 as an amber oil (98.5% pure; 73% yield). The purity of the crude product appears to be adequate for many purposes, especially if product of the subsequent anticipated reactions is known to be crystalline. [0184] 1H-NMR, CDC13, (δ): 7.60 (s, 1H), 7.17 (d, J-8.4Hz, 2H), 7.05 (d, J-8.4Hz, 211), 5.75 (d, J=7.5Hz, ]H), 4.84 (q, J=6.6Hz, 1H), 3.64-3.46 (m, 8H), 3.19 (d, J-6.3Hz, 2H), 2.86(q,J=7.2Hz, 2H), 1.94 (m,4H), 1.39 (s,9H), 1.20-1.11 (m, 9H). [0185] 13C-NMR, CDC13, (δ): 171.7, 157.7, 157.5, 153.1. 150.3, 145.8, 133.7, 130.2. 121.5. 1 P.4. 81.8. 54.7, 46.4. 46.3. 42.4, 41.7. 37.4. 28.0. 25.8. 24.9. 15.5. 13.5. [0186] MS(m z): 527.3 [M-I]. Steps 2 and 3: (S)-2-(2-(diethylamino)-5-(N-ethylmcthylsulfonamido)-pyrimidin-4- vlamino)-3-(4-(pyrrolidine-l-carbonyloxy)phenyl)propanoic acid 7 [0187] Following the procedures of Steps 2 and 3 of Example 1, compound 6 was converted to the corresponding (S)-2-(2-(diethylamino)-5-(N- ethyImcthylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-l- carbonyloxy)phenyl)propanoic acid 7 which was characterized as follows: [0188] 1H-NMR, CDC1;, (δ): 8.17 (s, 111), 7.77 (s, 1H), 7.26-7.23 (m, 211), 7.00-6.98 (d. 2H), 4.85-4.82 (m. 1H), 3.58-3.51 (m, 6H), 3.43-3.39 (m, 3H). 2.96-2.84 (m, 311), 2.01- 1.91 (m,4H), 1.29-0.97 (m,9H); [0189] 13C-NMR. CDCh, (δ):175.6, 65.7, 157.2, 155.2, 152.0, 151.8. 151.7, 151.3. 136.0. 135.9, 131.5. 123.0. 110.5,56.7,43.8,39.4,39.2,37.4,26.7,25.8. 14.4. 13.3; and [0191] Follow ing the procedures of Example 1 and employing cyclopentanone in place of acetone (Example 1) or acctaldchyde (Example 2), (S)-2-(5-(N- cyclopentylmcthylsulfonamido)-2-(dicthylamino)pyrimidin-4-ylamino)-3-(4-(pyrrolidinc- l-carbonyloxy)phenyl)propanoic acid 8 was prepared and characterized as follows: [0192] 1H-NMR, CDCh, (δ): 7.74-7.71 (d, 1H), 7.28-7.24 (m, 2H), 7.04-7.00 (m, 2H), 5.00-4.95 (m, 1H), 4.37-4.27 (m, 1H), 3.60-3.37 (m, 9H), 3.00-2.97 (d, 3H), 2.03-1.78 (m, 6H), 1.67-1.40 (m. 6H). 1.31-1.23 (m. 6H): [0193] 13C-NMR, CDCh, (δ): 73.6 173.4. 163.1, 155.1, 152.4, 152.0. 145.3, !44.7, 135.5, 135.1, 131.6, 131.4, 123.2, 109.6, 109.4,62.5,62.3,56.7,56.5,48.1.40.3,40.1, 36.8, 36.4, 31.2. 30.5, 26.7, 25.8, 23.2, 23.1, 12.7; and [0194] MS: M(-H)589. Example 4 Preparation of (S)-2-(2-(diethyIamino)-5-(N-(prop-2- ynvl)methylsulfonamido)pyrimidin-4-vlamino)-3-(4-(pyrrolidine-l- carbon\loxy)|)hcnvl)propanoic acid (13) [0195] The synthetic protocol employed in Example 4 is summarized in Scheme 6 illustrated below: Step 1: (S)-4-(3-tert-butoxy-2-(2-(diethylamino)-5-(-N-(methylsulfonyl)- methylsulfonamido)pyrimidin-4-\lamino)-3-oxopropyl)phenyl pyrrolidine-l- carboxylate (10) [0196] Aminopyrimidinf (2.0 g, 4.0 mmol - compound 9) (prepared by reduction of compound 1) was dissolved in dichloromcthane (10 ml.). THF (10 ml.) and tricthylamine (2.8 ml, 20 mmol) were added and the reaction cooled in an ice bath. Mcthancsulfonyl chloride (1.1 mL, 14 mmol) was added and the reaction warmed to room temperature over 18 hours. The reaction mixture was concentrated in vacua and the residue taken up in ethyl acetate. The solution was washed with 0.2 N citric acid, water, sat. NallCO3, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacua to yield crude product as a brown foam. The residue was purified by flash chromatography (2:3 ethyl acetate hcxancs) to yield 2.2 g (73%) of the di-sulfonylatcd material as a yellow foam (compound 10). Step 2: (S)-4-(3-tert-butoxy-2-(2-(diethylamino)-5-(methylsuIfonamido)-pyrinidin-4- ylamino)-3-oxopropyl)phenyl pyrrolidine-l-carboxylate (11) [0197] Compound 10 (2.2 g, 3.4 mmol) was dissolved in mcthanol (5 mL) and THF (5 mL). 1.0 M K2CO3 (10 mL) was addeo and the reaction mixture was heated at 40oC for 96 hours. The reaction mixture was acidified to pi 1 3 with 2N HC1 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacua to yield 1.68 g (86%) product as a beige foam, compound 11. The crude material was used without purification. Step3:(S)-4-(3-tert-butoxy-2-(2-(diethylamino)-5-(N-(prop-2-ynyl)melhyI- sulfonarnido)pyrimidin-4-ylamino)-3-oxopropyl)phenvl pyrrolidine-l-carboxylate (ID [0198] Compound 11 (0.20 g, 0.35 mmol), K2CO3 (0.073 g, 0.53 mmol), and acetone (3 ml.) were placed in a sealed tube and stirred at room temperature for one hour. Propargyl chloride (0.26 ml., 3.5 mmol) was added and the reaction was sealed and heated at reflux for 48 hours. The reaction mixture was concentrated in vacua and the residue taken up in ethyl acetate. The solution was washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacua to yield crude product as an orange film. The residue was purified by flash chronatography (1:1 ethyl acetatc.hexanes) to yield 0.11 u (51%) of compound 12 as a transparent film. [0199] MS(mz)615,(M-H). Step4:(S)-2-(2-(diethylamino)-5-(N-(prop-2-ynyI)methylsulfonamido)-pyrimidin-4- yIamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)propanoicacid (13) [0200] Formic acid (2 mL) was added to t-butyl ester (100 mg) and stirred at 40nC over night. The formic acid was removed under reduced pressure to yield compound 13 in quantitive yield and characterized as follows: [0201] 1H-NMR, CDCl2, (δ): 8.13 (s, 1H), 7.97 (s, III), 7.26-7.24 (d, 2H), 7.02-6.99 (d, 211), 4.59-4.44 (m, 1 H), 4.04-3.79 (m, H), 3.64-3.53 (m, 611), 3.45-3.39 (t. 311), 3.08-2.84 (m,4H), 2.84-1.89 (m, 4H)1.22-1.17 (t. 6H); [0202] 13C-NMR. CDCl2 (δ): 165.3, 155.3, 151.8, 136.1. 131.5, 123.0,76.1,76.0.56.8, 49.9, 48.1, 43.8, 41.2, 40.2, 37.4, 26.7, 25.9, 13.3; and [0204] Following the procedures of lixamplc 4 and employing dimethylsulfatc in place of propargyl chloride, the title compound was prepared and was characterized as follows: [0205] 1H-NMR, CDCl3, (δ): 8.14 (s, 1H), 7.83 (s, 1H), 7.26-7.23 (d, 211), 7.01-6.98 (d, 2H), 4.84-4.81 (m, 1H), 3.60-3.53 (m, 6H), 3.43-3.38 (m, 3H), 3.09 (s, 3H), 2.94 (s, 3H), 2.00-1.91 (m, 4H), 1.22-1.18 (t, 6H); [0206] 13C-NMR, CDCl3, (δ):175.5, 165.4, 160.7, 156.3, 155.3, 151.8, 149.1, 136.0, 131.6, 123.0, 113.4, 56.9,43.9,38.8, 38.1, 37.4, 26.7, 25.8, 13.2; and [0207] MS-M(-H)535. Example A 4 Integrin Adhesion Assay: .lurkatTM Cell Adhesion to Human Plasma Fibronectin Procedure [0208] 96 well plates (Costar 3590 LIA plates) were coated with human fibronectin (Gibco/BRL. cat #33016-023) at a concentration of 10 μg/ml. overnight at 4°C. The plates were then blocked with a solution of bovine serum albumin (RSA; 0.3%) in .saline. JurkatTM cells (maintained in log phase growth) were labeled with calccin AM according to the manufacturer's instructions, and suspended at a concentration of 2 x 106 cells ml, in Hepes. Saline/BSA. The cells were then exposed to test and control compounds for 30 minutes at room temperature before transfer to individual wells of the fibronectin coated plate. Adhesion was allowed to occur for 35 minutes at 37°C. The wells were then washed by gentle aspiration and pipetting with fresh saline. Fluorescence associated with the remaining adherent cells was quantified using a fluorescence plate reader at EX 485/EM 530. [0209] Cell cultures were prepared by first splitting the stationary phase JurkatTM cells at 1:10 on day one and 1:2 on day two to perform assay on day 3. The cells split 1:10 on day one were split 1:4 on day 3 for a day 4 assay. [0210] The assay plates were prepared by first making a working solution of Gibco'BRL Human Fibroncctin (cat # 33016-023) in PBS+4, at 10 μg/mL. [0211] A Costar 3590 EIA plate was then coated with 50 μL well for 2 hours at room temperature (though it can also be left overnight at 4°C). Finally the plate was aspirated and blocked with Hepcs/Salinc Buffer, 100 μLwcll, for 1 hour at rt followed by washing three times with 150 μL of PBS + +. [0212] Compound dilutions were accomplished by preparing 1:3 serial dilutions of compounds as follows. For each plate '4 compounds/plate) 600 μL were added to 4 Bio- Rad Titcrtubcs in a Titertube rack. Enough compound was added to each appropriate tube to give a 2X concentration using methods well known in the art. Using Falcon Flexiplates, 100 ΜL of Hepes Saline buffer or human serum were added to rows B through G. A multi- channel pipetter set to 180 μL was used to with four tips spaced evenly on the pipetter. Each set of tour tubes was mixed 5 times and 180 μL of 2X compound was transferred to the first column of each compound dilution in Row B, leaving Row A empty. 180 μL were added to the other wells in Row A. Serial dilutions were performed down the plate by transferring 50 μL to the next dilution and mixing 5 times, changing tips each time after mixing. Dilutions were stopped at Row E Row G had no compound present. [0213] A 20 μg/ml solution in HEPES'salinc buffer or human scrum, of 21/6 antibody was the positive control and was set aside in a reagent trough to add to cell suspension plate. [0214] The cell staining was accomplished by first harvesting the log-phase JurkatTM cells by centrifugation in 50 ml, tubes 11 100 rpm for 5 minutes). The cells were resuspended in 50 ml. PBS+ , spun, and resuspended in 20 mL PBS+. The cells were stained by adding 20 μL of Calccin AM for 30 minutes at RT. The volume was brought to 50 mL with HEPES/salinc buffer and the cells were counted, spun, and resuspended to 2 x 106 cells, ml. in HEPES saline buffer or human serum. [0215] The compounds were incubated using the following procedure. In a new flcxiplate, 65 μL of stained cells were added to Rows B through H. Then 65 μL of 2X compounds were added to the appropriate rows following the plate setup and mixed 3X. 65 μL of 2X-21/6 antibody were added to Row H and mixed 3 times. Finally the plate was incubated at room temperature for 30 minutes. [0216] Fibronectin adhesion was measured using a fluorescent plate reader at EX 485/EM 530 after the following work up procedure. After incubation, the cells were mixed 3X and 100 μL were transferred to the fibronectin coated plates and incubated at 37°C for about 35 minutes. Each plate was washed, row by row, by gently pipetting 100 μL of RT PBS down the sides of the wells and turning the plate 90 degrees to aspirate. This procedure was repeated for a total of 3 washes. Each well was filled with 100 μL after washing by pipetting down the side of the well. [0220] Cells were then incubated for 30 minutes at room temperature, washed twice with phosphate-buffered saline ("PBS") containing 2% fetal bovine scrum and 1 mM each of calcium chloride and magnesium chlordc (assay medium) to remove unbound 15 7 antibody. [0221] The cells were then exposed to phycocrythrin-conjugatcd goat F(ab')2 anti-mouse IgG Fc (Immunotech, Westbrook, ME), which had been adsorbed for any non-specific cross-rcactivity by co-incubaiion with 5% scrum from the animal species being studied, at 1:200 and incubated in the dark at 4°C for 30 minutes. [0222] Cells were washed twice with assay medium and resuspended in the same. They were then analyzed with a standard fluorescence activated cell sorter ("FACS") analysis as described in Yednock et al., J. Biol. Chem., 1995, 270:28740. [0223] The data was then graphed as fluorescence versus dose, e.g., in a normal dose- response fashion. The dose levels that result in the upper plateau of the curve represent the levels needed to obtain efficacy in an in vivo model. [0224] The results of the a4-depcndent in vitro potency assay indicate that certain compounds of this invention when tested in this assay showed inhibition of 4 intcgrin at an EC50 of less than 20 μg'mL. Example C In vitro Assay For Determining Binding of Compounds to VLA-4 [0225] An in vitro assay was used to assess binding of candidate compounds to  intcgrin. Compounds which bind in this assay can be used to assess VCAM-1 levels in biological samples by conventional assays (e.g., competitive assays). This assay is sensitive to IC50 values as low as about I ΜM. [0226] The activity of  integrin was measured by the interaction of soluble VCAM-1 with JurkatTM cells (e.g., American Tyoc Culture Collection Nos. TIB 152, TIB 153, and CKL 8163), a human T-cell line which expresses high levels of  integrin. VCAM-I interacts with the cell surface in an  integrin-dependent fashion (Yednock, et al. J. Biol. Chem., 1995. 270:28740). [0227] Recombinant soluble VCAM-1 was expressed as a chimcric fusion protein containing the seven extracellular domains of VCAM-1 on the N-tcrminus and the human igG1 heavy chain constant region on the C-tcrminus. The VCAM-1 fusion protein was made and purified by the manner described by Yednock, supra. [0228] JurkatIM cells were grown in RPMI 1640 supplemented with 10% fetal bovine serum, penicillin, streptomycin and glutaminc as described by Yednock, supra. [0229] JurkatTM cells were incubated with 1.5 mM MnCl and 5 μg/mL 15/7 antibody for 30 minutes on ice. Mn-2 activates the receptor to enhance ligand binding, and 15/7 is a monoclonal antibody that recognizes an activated/ligand occupied conformation of  intcgrin and locks the molecule into this conformation thereby stabilizing the VCAM-1 a4 integrin interaction. Yednock, et al., supra. Antibodies similar to the 15/7 antibody have been prepared by other investigators (Luque, et al, 1996, J. Biol. Chcm. 271:11067) and may be used in this assay. [0230] Cells were then incubated for 30 minutes at room temperature with candidate compounds, in various concentrations ranging from 66 μM to 0.01 μM using a standard 5- point serial dilution. 15 μL soluble recombinant VCAM-1 fusion protein was then added to JurkatTM cells and incubated for 30 minutes on ice. Yednock et al., supra. [0231] Cells were then washed two times and resuspended in PE-conjugated goat P(ab'): anti-mouse igG Fc (Immunotech, Westbrook, Me.) at 1 :200 and incubated on ice. in the dark, for 30 minutc.v Cells were washed twice and analyzed with a standard fluorescence activated cell sorter ("["ACS") analysis as described in Yednock, et al., supra. [0232] Compounds having an IC50 of less than about 15 μM possess binding affinity to  [0233] When tested in this assay, the compounds prepared in the above examples has or is expected to have an IC50 of 15 μM or less (or is expected to be active in vivo). A certain compound of this assay had an IC50 of less than 5 μM. Example D Cassette Dosing and Serum Analysis for determination of Bioavailability [0234] The oral bioavailability was screened by dosing rats with a cassette, i.e. mixture of 6 compounds per dosing solution. The cassette includes 5 test articles and a standard compound, for a total dose of 10 mg/kg. Each compound/test article was converted to the sodium salt with equimolar 1 N NaOH and dissolved in water at 2 mg/mL. The cassette was prepared by mixing equal volumes of each of the six solutions. The cassette dosing solution was mixed well and then the pH was adjusted to 7.5-9. The dosing solution was prepared the day before the study and is stirred overnight at room temperature. [0235] Male Sprague Dawley (SD) rats from Charles River Laboratories. 6-8 weeks old, were used in this screen. Rats were quarantined for at least one day and had continuous access to food and water. On the night before the administration of the cassette, the rats were fasted for approximately 16 h. [0236] Four SD rats were assigned in each cassette. A single dose of the dosing solution was administered orally to each rat. The dosing volume (5 mL kg) and time were recorded and rats were fed 2 h after dosing. [0237] Blood samples were collected via cardiac puncture at the following time points: 4 h, 8 h and 12 h. Immediately prior to blood collection, rats were anesthetized with CO2 gas within 10-20 seconds. After the 12-hour samples were collected, the rats were euthanized via CO2 asphyxiation followed by cervical dislocation. [0238] Blood samples were kept in heparinized microtainer tubes under subambicnt temperature (4oC) before they are processed. Blood samples uere eentrifuged ( 10.000 rpm for 5 minutes) and pla»ma samples were remo\ed and stored in 4-20oC freezer until analyzed for drug levels. Drug levels in the plasma were analyzed using the following protocol for direct plasma precipitation. [0239] The in vivo plasma samples were prepared in a 1.5 ml. 96-well plate, by adding, in order, 100 μL of the test plasma, 150 ul of methanol. followed by vortcxing for 10-20 seconds. 150 ΜL of 0.05 ng/μL of an Internal Standard in acetonitrile were added and vortexed for 30 seconds. [0240] The standard curve samples were prepared in a 1.5 ml. 96-well plate, by adding, in order, 100 μL of control mouse plasma, followed by 150 μL of methanol and sortexing for 10-20 seconds. 150 μl. of 0.05 ng/μl.. of an Internal Standard in acetonitrile were added and vortexed for 30 .seconds. The samples were spiked with 0-200 ng (10 concentrations) of the compound of interest in 50% methanol to obtain a standard curve range of 0.5 ngmL to 2,000 ng/mL. Again, the sample is vortexed for 30 seconds. [0241] The samples were then spun for 20-30 minutes at 3,000 rpm in an Eppcndorf microfuge before 80-90% of supernatant is transferred into a clean 96-well plate. The organic solvent was then evaporated until the samples arc dry (under NS at 40oC 30-60 min. (ZymarkTurbovap)). [0242] The residue was then dissolved in 200-600 L mobile phase (50% CH3OH/0.1% TFA). LC/MS/MS was then run using a PE-Scicx AP1-3000 triple quadurpolc mass spectrometer (SN0749707), Pcrkin-Elmer, Scrics200auto-sampler, and Shimadzu 10A pump. Acquisition was done with PE-Scicx Analyst (v 1.1) and data analysis and quantification were accomplished using PE-Scicx Analyst (v 1.1). A 5-50 μl sample volume was injected onto a reverse phase ThermoHypcrsil DASH-18 column (Keystone 2.0 x 20 mm, 5 urn, PN: 8823025-701) using a mobile phase of 25% CH3OH. 0.1% TFA-100% CH3OH, 0.1% TFA. The run time was about 8 minutes at a flow rate of about 300 μL/minutcs. [0243] The Area Under the Curve (AUC) was calculated using the linear trapezoidal rule from r-0 to the last plasma concentration sampling time tx (see Handbook of Basic Pharmacokinetics, Wolfgang A. Ritschel and Gregory L. Kcarns, 5th ed, 1999). AUC1 u - r'V(Cn - CY,) 2)) • (tn ; - tn) tin (uu mL)h] [0244] In the case of the cassette dosing paradigm, samples at 4.8 and 12 h post extravascular dosing, the AUC was calculated from t = 0 to t = 12 h. [0245] Each of the compounds in Examples 1-5 above when tested in this assay provided for an AUC of at least 5 ugh/mL when normalized for administration at a 10 mg/kg dose. Example E Asthma Models (El) [0246] Inflammatory conditions mod ated by  integrin include, for example, cosinophil influx, airway hyper-responsiveness and occlusion that occurs with chronic asthma. The following describes animal models of asthma that are used to study the in vivo effects of the compounds of this invention for use in treating asthma. Rat Asthma Model (E2) [0247] Following the procedures described by Chapman, et al., Am J. Rcsp. Crit. Care Med., 153-4, A219 (1996) and Chapman, et al., Am. J. Resp. Crit. Care Med. 155:4, A881 (1997), both of which arc incorporated by reference in their entirety. [0248] Ovalbumin (OA; 10 ug/mL) is mixed with aluminum hydroxide (10 mg/ml.) and injected (i.p.) in Brown Norway rats on day 0. Injections of OA, together with adjuvant, arc repeated on days 7 and 14. On day 21, sensitized animals arc restrained in plastic tubes and exposed (60 minutes) to an aerosol of OA (10 mg/kg) in a nose-only exposure system. Animals are sacrificed 72 hours later with pentobarbital (250 mg/kg, i.p.). The lungs are lavaged via a tracheal cannula using 3 aliquots (4 ml..) of Hank's solution (HBSS x 10, 100 ml; EDTA 100 mM. 100 mL, HEPES 1 M, 25 ml: made up to 1 L with H2O); recovered cells arc pooled and the total volume of recovered fluid adjusted to 12 mL by- addition of Hank's solution. Total cells arc counted (Sysmex microccll counter 1-500, TOA Medical Electronics Otd., Japan) and smears are made by diluting recovered fluid (to approximately 106 cclls/mL) and pipetting an aliquot (100 ul) into a centrifuge (Cytospin, Shandon, U.K.). Smears arc air dried, fixed using a solution of fast green in methanol (2 mg/mL) for 5 seconds and stained with cosin G (5 seconds) and thiazine (5 seconds) (Diff- Quick, Browne Ltd. U.K.) in order to differentiate cosinophils, neutrophils, macrophages and lymphoevtes. A total of 500 cells per simer are counted by light microsopy under oil immersion 1x 100). Compounds of this invention can be formulated into a 0 5% carboxymcthylcellulo.se and 2% Tween 80 suspension and administered orally to rats which had been sensitized to the allergen, ovalbumin. Compounds which inhibited allergen-induced leucocyte accumulation in the airways of actively sensitized Brown Norway rats are considered to be active in this model. Mouse Asthma Model (E3) [0249] Compounds arc also evaluated in a mouse model of acute pulmonary inflammation following the procedures described by, Kung, et al., Am .J. Respir. Cell Mol. Biol., 13:360-365, (1995) and Schneider, et al., (1999). Am J. Respir. Cell Mol. Biol. 20:448-457, (1999), which are each incorporated by reference in their entirety. Female Black/6 mice (8-12 weeks of age) are sensitized on day 1 by an intraperitoneal injection of 0.2 ml. ova/alum mixture containing 23 μg of ova (Grade 4, Sigma) and 2 mg inject Alum (Pierce). A booster injection is administered on day 14. Mice are challenged on days 28 and 29 with aerosolized 1% ova (in 0.9% saline) for 20 minutes. Mice are euthanized and bronchavcolar lavagc samples (3 ml.) are collected on day 30, 48 hours post first challenge, liosinophils are quantified by a FACS/K1TC staining method. Compounds of this invention are formulated into a 0.5% carboxymethylccllulosc and 2% Twcen 80 suspension and administered orally to mice which had been sensitized to the allergen, ovalbumin. Compounds which inhibited allergen-induced leucocyte accumulation in the airways of actively sensitized C57BL/6 mice arc considered to be active in this model. Sheep Asthma Model (E4) [0250] This model employs the procedures described by Abraham, et al., J.Clin, Invest, 93:776-787 (1994) and Abraham, et al., Am J. Respir. Crit. Care Med., 156:696-703 (1997), both of which are incorporated by reference in their entirety. Compounds of this invention are evaluated by intravenous (saline aqueous solution), oral (2% Twccn 80, 0.5% carboxymcthylccllulose), and aerosol administration to sheep which arc hypersensitive to Ascaris suum antigen. Compounds which decrease the early antigen- induced bronchial response and/or block the late-phase airway response, e.g. have a protective effect against antigen-induced late responses and airway hypcr-rcsponsiveness ("AHR"). are considered to be active in this model. [0251] Allergic sheep which are shown to develop both early and kite bronchial responses to inhaled Ascaris suum antigen are used to study the airway effects of the candidate compounds. Following topical anesthesia of the nasal passages with 2% lidocainc, a balloon catheter is advanced through one nostril into the lower esophagus. The animals are then incubated with a suffed endotrachcal tube through the other nostril with a flexible fiberoptic bronchoscope as a guide. [0252] Pleural pressure is estimated according to Abraham (1994). Aerosols (see formulation below) are generated using a disposable medical nebulizer that provided an aerosol with a mass median aerodynamic diameter of 3.2 μm as determined with an Andersen cascade impactor. The nebulizer is connected to a dosimeter system consisting of a solenoid valve and a source of compressed air (20 psi). The output of the nebulizer is directed into a plastic T-picec, one end of which is connected to the inspiratory port of a piston respirator. The .solenoid valve is activated for 1 .second at the beginning of the inspiratory cycle of the respirator. Aerosols arc delivered at VT of 500 mL and a rate of 20 breaths/minute. A 0.5% sodium bicarbonate solution only is used as a control. [0253] To assess bronchial responsiveness, cumulative concentration-response curves to carbachol is generated according to Abraham (1994). Bronchial biopsies are taken prior to and following the initiation of treatment and 24 hours after antigen challenge. Bronchial biopsies are preformed according to Abraham (1994). [0254| An in vitro adhesion study of alveolar maerophages can also be performed according to Abraham (1994), and a percentage of adherent cells can be calculated. Aerosol formulation [0255] A solution of compound n 0.5% sodium bicarbonate/saline (w/v) at a concentration of 30.0 mg/mL is prepared using the following procedure: Procedure: 1. Add 0.5g sodium bicarbonate into a 100 mL volumetric flask. 2. Add approximately 90.0 ml. saline and sonicate until dissolved. 3. Q.S. to 100.0 mL with saline and mix thoroughly. B. Preparation of 30.0 mu/mL Compound: 10.0 mL Procedure: 1. Add 0.300 g of the compound into a 10.0 ml. volumetric flask. 2. Add approximately 9.7 ml. of 0.5% sodium bicarbonate saline stock solution. 3. Sonicate until the compound is completely dissolved. 4. Q.S. to 10.0 mL with 0.5% sodium bicarbonate / saline stock solution and mix thoroughly. Example F Adjuvant-Induced Arthritis in Rats [0256] Adjuvant induced arthritis ("A1A") is an animal model useful in the study of rheumatoid arthritis ("RA"), which is induced by injecting M. tuberculosis in the base of the tail of Lewis rats. Between 10 and !5 days following injection, animals develop a severe, progressive arthritis. [0257] Generally, compounds arc tested for their ability to alter hind paw swelling and bone damage resulting from adjuvant induced edema in rats. To quantitate the inhibition of hind paw swelling resulting from AIA, two phases of inflammation have been defined: (1) the primary and secondary injected hind paw, and (2) the secondary uninjected hind paw, which generally begins developing about eleven days from the induction of inflammation in the injected paw. Reduction of the latter type of inflammation is an indication of immunosupprcssivc activity. Cf. Chang, Arth. Rheum., 20, 1135-1141 (1977). [0258] Using an animal model of RA, such as AIA, enables one to study the cellular events invoked in the early stages of the disease. CD44 expression on macrophages and lymphocytes is up regulated during the early development of adjuvant arthritis, whereas LFA 1 expression is up regulated later in the development of the disease. Understanding the interactions between adhesion molecules and cndothelium at the earliest stages of adjuvant arthritis could lead to significant advances in the methods used in the treatment of RA. Example G Collagen Induced Arthritis in Rats [0259] Purpose: To determine the efficacy of a representative compound of the invention ('"Compound A") administered by po bid dosing (Days (-1) -20) for inhibition of the inflammation, cartilage destruction and bone rcsorption that occurs in developing type II collagen arthritis in rats. [0260] Animals: 54 Female Lewis rats (Harlan), weighing 125-150 g on arrival, (inject 50 with collagen to get 50 responders on days 10,11,12 for 6 groups of 10). The animals (10/group for arthritis. 4/group for normal control), housed 4-5/cagc, were acclimated for 4-8 days. The animals were dosed at po3mg, kg bid, pol0mg'kg bid, and po30mg/kg bid. [0261] Materials: Agents or drugs in vehicle, Type II collagen, Frcund's incomplete adjuvant, mcthotrcxatc (Sigma), Compound A General Study Design [0262] Dosing was initiated on day m nus 1. [0263] The acclimated animals were anesthetized with isofluranc and given collagen injections (DO). On day 6 they were anesthetized again for the second collagen injection. Collagen was prepared by making a 4 mg/mL solution in 0.01 N acetic acid, l-qual volumes of collagen and Freund's incomplete adjuvant, were emulsified by hand mixing until a bead of this material held its form when placed in water. Hach animal received 300 u.L of the mixture each time spread over 3 sites on back. [0264] Calipering of normal (pre-disease) right and left ankle joints were done on day 9. On days 10-12, onset of arthritis occured. [0265] Rats were weighed on days (-) 1. 6. 9.10.11.12.13.14.15,16.17,18.19. and 20 of the study and caliper measurement* of ..inkles taken every day beginning on day 9. Final body weights were taken on day 20. Atier final body weight measurement, animals, were anesthetized for terminal plasma collection and then euthanized. [0266] Both hind paws and knees were removed. Hind paws were weighed, placed (with knees) in formalin and then processed for microscopy. Processing of Joints [0267] Following 1-2 days in fixative and then 4-5 days in decalcifier, the ankle joints were cut in half longitudinally, knees were cut in half in the frontal plane, processed, embedded, sectioned and stained with toluidine blue. [0268] Compound A demonstrated significant inhibition compared to controls receiving no treatmentof ankle inflammation and ankle histopathology at doses tested (3.0mg kg, 10.0 mgkg and 30.0 mg/kg). Example H Induction of Colitis in HLA-B27 Rats [0269] The efficacy of the compounds of the present invention in reversing colitis was determined in HLA-B27 transgenic rats. HLA-B27 transgenic rats have been utilized as an animal model of Inflammatory Bowel Disease which mimics Crohn's Disease in humans. The rats ovcrcxprcss the human MHC class I HLA-B27 heavy chain and beta-2 microglobulin proteins, which induces i variety of autoimmune diseases that include inflammation of the colon. [0270] The therapeutic effect of Compound A of this invention in resolving colitis was evaluated in HLA-B27 transgenic rats. Diseased rats were dosed subcutancously with l00mg'kg of Compound A of this invention twice a day for 16 days. Animal samples dosed with l00mg/kg of Compound A of this invention showed clinical and histological resolution of colitis and mimicked similar efficacy with the positive control group treated with anti-alpha4 antibody GG5/3. [0271] Disease Activity Index (DAI) scores indicated overall improved scores for rats dosed with l00mg/kg of Compound A of this invention and 10mg'/kg of GG5/3 (positive control) than rats dosed with vehicle. Fecal consistency and FOB scores for rats dosed with Compound A and GG5 .3 were satisfically different from the vehicle group. Induction of Colitis [0272] 20 HLA-B27 (6-9 weeks old) transgenic rats were ordered from Taconic. Rats acclimated in animal facility for 10 weeks. Animal bedding was mixed from different cages once a week to control for a "dirty" environmental flora. Treatments [0273] Rats were enrolled and randomized into four groups (n 5) based on weight and DAI scores (F'C >3, FOB >2). The experimental groups were dosed subcutancously with Compound A 100mg/kg (pH 2.8) twice a day for 16 days and terminated at trough. The control groups included a vehicle-treated (pH 3.2) group and a GG5/3 (mouse anti-rat aIpha-4 integrin antibody) positive control group dosed subcutancously at l0mg/kg (5 ml., kg) on dO. d3, and d6 and terminated at trough on d8 (Table H1). Compound A and Endpoint Read-outs [0274] Disease Activity Index scores, Fecal Consistency test and Fecal Occult Blood test, were taken 4 times a week to generate in-life clinical scores. The primary read-out for the study was a histopathological analysis of cccum, proximal colon, mid-colon, and distal colon.. An IBD scoring system was applied (Table H2). [0275] Disease Activity Index (DAI) scores were lower for rats dosed with Compound A nnd GG5/3 (positive control) than the vehicle group. Fecal Consistency and Fecal Occult Blood Test AUC scores for Compound A and GG5/3 (positive control) dose groups wore also statistically different from the sueh elc. [0276] While some embodiments of the invention have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention. WHAT IS CLAIMED IS: 1. A compound of formula 1: wherein: R1 is selected from the group consisting of C: to C4 alkyl and C1 to C4 haloalkyl; and R2 is selected from the group consisting of C1 to C4 alkyl, C2 to C4 alkenyl, C2 to C4 alkynyl, and C3-C6 cycloalkyly or pharmaccutically acceptable salts, or esters thereof. 2. The compound according to Claim 1, wherein R1 is C1 to C2 alkyl. 3. The compound according to Claim 1, wherein R1 is methyl or trifluoromethyl. 4. The compound according to Claim 1, wherein R1 is methyl. 5. The compound according to Claim 1, wherein R2 is C1 to C1 alkyl. 6. The compound according to Claim 1, wherein R2 is C1 to C4 alkyl. 7. The compound according to Claim 6, wherein R2 is methyl or ethyl. S. The compound according to Claim 6, wherein R2 is isopropyl. 9. The compound according to Claim 1, wherein R2 is C1 to C6, cycloalkyl. 10. The compound according to Claim 9, wherein R2 is cyclopcntvl. I1. The compound according to Claim 1, wherein R2 is C2 to C4 alkenyl. 12. The compound according to Claim 11, wherein R2 is allyl. 13. The compound according to Claim 1, wherein R2 is C2 to C4 alkynyl. 14. The compound according to Claim 13, wherein R2 is propargyl. 15. A compound of formula 11: wherein: R1 is selected from the group consisting of C1 to C4 alkyl and C1 to C4 haloalkyl; and R2 is selected from the group consisting of C1 to C4 alkyl, C2 to C4 alkenyl, C2 to C4 alkynyl, and C3-C6 cycloalkyl; or pharmaceutically acceptable salts, or esters, thereof. 16. The compound according to Claim 15, wherein R1 is C1 to C2 alkyl. 17. The compound according to Claim 15, wherein R1 is methyl or irifluoromcthyl. 18. The compound according to Claim 15, wherein R1 is methyl. 19. The compound according to Claim 15, wherein R2 is C1 to C4 alkyl. 20. The compound according to Claim 15, wherein R2 is C1 to C3 alkyl. 21. The compound according to Claim 20, wherein R2 is methyl or ethyl. 22. The compound according to Claim 20, wherein R2 is isopropyl. 23. The compound according to Claim 16, wherein R2 is C3 to C6 cycloalkyl. 24. The compound according to Claim 23, wherein R2 is cyclopcntyl. 25. The compound according to Claim 15, wherein R2 is C2 to C4 alkenyl. 26. The compound according to Claim 25, wherein R2 is allyl. 27. The compound according to Claim 15, wherein R2 is C2 to C4 alkynyl. 28. The compound according to Claim 27, wherein R2 is propargyl. 29. A compound selected from the group consisting of: (S)-2-(2-(dicthylamino)-5-(N-ethyl-1,1,1- trinuoromethylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-l- carbonyloxy)phcnyl)propanoic acid; (S)-2-(2-(diethylamino)-5-(N-isopropylmethylsulfonamido)pyrimidin-4- ylamino)-3-(4-(pyrrolidine-1 -carbonyloxy)phcnyl)propanoic acid; (S)-2-(5-(N-cyclopentylmethylsulfonamido)-2-(dicthylamino)pyrimidin-4- yaminu)-3-(4-{pyrrolidinc-1-earbonyloxy)phenyl)propanolc acid: (S)-2-(2-(dicthylaniino)-5-(N-methylmethylsulfonamido)pyrimidin-4- ylamino)-3-(4-(pyrrolidinc-1-carbonyloxy)phcnyl)propanoic acid; (S)-2-(2-(dicthylumino)-5-(N-(prop-2-ynyl)mcthylsulfonamido)pyrimidin- 4-ylamino)-3-(4-(pyrrolidine-1-carbonyioxy)phenyl)propanoic acid; (S)-2-(2-(diehylamino)-5-(N-cthylmethylsulfonarnido)pyrimidin-4- ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phcnyl)propanoic acid; (S)-2-(5-(N-allylmethylsulfonamido)-2-(diethylamino)pyrimidin-4- ylamino)-3-(4-(pyrrolidinc-1-carbonyloxy)phenxy)propanoic acid; (S)-2-(2- (diethylamino)-5-(N-cthylbutylsulfonamido)pyrimidin-4-ylamino)-3-(4-(pyrrolidine-]- carbonyloxy)phcnyl)-propangic acid; (S)-2-(S-(3-chIoro-N-ethylpropylsulfonamido)-2-(diethylamino)-pyrimidin- 4-ylamino)-3-(4-(pyrrolidinc-1-carbonyloxy)phcnyi)propanoic acid; (S)-2-(5-(3-chloro-N-methylpropyl-Nulfonamidg)-2- (diethylamino)pyrimidin-4-ylamino)-3-(4-(pyrrolidinc-l-carbonyloxy)phenyl)propanoic acid; (S)-2-(2-(diethylamino)-5-(N-ethyl-3,5,3-trifluoropropylsufonamid\o- pyrimidin-4-ylamino)-3-(4-(pyrrolidine-l-carbonyloxy)phenyl)propanoic acid: (S)-2-(2-(diethlamino)-5-(N-ethylprgpylsulfonamido)pyrimidin-4- ylamino)-3-(4-(pyrrolidine-1-carbonyloxy)phenyl)-prupatioic acid, and (S)-2-(2-(diethylamino)-5-(N-ethyl-2-methylpropylsulfonamido)pyrimidin- 4-ylamino)-3-(4-(pyrrolidinc-1 -carbonyk)xy)-phenyl)propanoic acid; as well as pharmaceutically acceptable salts or esters, thereof. 30. A pharmaceutical composition comprising a pharmacemically acceptable carrier and a therapeutical! y effective amount of one or more of the compounds us set forth in Claim l. 31. A method for treating a disease mediated at least in part by 4 intcgrin in a patient, which method comprises administering a pharmaceutical composition according to Claim 30. 32. A method for reducing and or preventing an inflammatory component of a disease in a mammalian patient which method comprises administering to said mammal the pharmaceutical composition of Claim 30. 33. A method for reducing and/or preventing an autoimmune response in a mammalian patient which method comprises administering to said mammal the pharmaceutical composition of Claim 30. 34. The method of Claim 31, wherein the disease is selected from asthma, multiple sclerosis and inflammatory bowel disease. 35. The method of Claim 31 wherein the disease is Crohn's disease. 36. The method of Claim 31, wherein the disease is rheumatoid arthritis. 37. A method for preparing a compound of formula I: wherein: R1 is selected from the group consisting of C1 to C4 alkyl and C1 to C4 haloalkyl: and R2 is selected from the group consisting of C1 to C4 alkyl, C2 to C4 alkenyl, C2 to C4 alkynyl, and C3-C6 cycloalkyl; or pharmaccutically acceptable salts, or esters thereof, which method comprises: a) contacting a compound of formula III where Pg is a carboxyl protecting group; with a C1 to C4 aldehyde or ketone, a C2 to C4 alkenyl aldehyde or kctonc, C2 to C4 alkynyl aldehyde or ketone, C3-C6 cycloalkyl kctonc and benzaldchydc under reductive amination conditions to provide for a compound of formula IV: > b) contacting compound IV with a sulfonyl halidc of the formula R1SO2Z where Z is halo under conditions to form a compound of formula V: n and c) removing the carboxyl protecting group to provide for a compound of formula 1. 38. A method for preparing a compound of formula I: wherein: Rl is selected from the group consisting of C1 to C4 alkyl and C1 to C4 haloalkyl; and R2 is selected from the group consisting of C1 to C4 alkyl. C3 to C4 alkenyl, C2 to C4 alkynyl, and C3-C6 cycloalkyl; or pharmaceutically acceptable salts, or esters thereof. which method comprises: a) contacting a compound of formula VI where Pg is a carboxyl protecting group; with an excess of R1SO2X to provide for a compound of formula VII: b) selectively removing a single -SO2R group from the compound of formula VII to provide a compound of formula VIII: c) contacting compound VIH with an alkylating agent with a formula R2-X, wherein X is halo, or with dimethylsulfate when R2 is methyl, to form a compound of formula IX: and d) removing the carboxyl protecting group to provide for a compound of formula I. Disclosed are compounds, which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and in particular, leukocyte adhesion mediated by VLA-4 Such compounds are useful in the treatment of inflammatory diseases in a human or animal subject such as asthma, Alzheimer's disease, atherosclerosis. AIDS dementia, diabetes inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be, administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Documents:

3409-KOLNP-2008-(10-06-2014)-ABSTRACT.pdf

3409-KOLNP-2008-(10-06-2014)-ANNEXURE TO FORM 3.pdf

3409-KOLNP-2008-(10-06-2014)-CLAIMS.pdf

3409-KOLNP-2008-(10-06-2014)-CORRESPONDENCE.pdf

3409-KOLNP-2008-(10-06-2014)-FORM-18.pdf

3409-KOLNP-2008-(10-06-2014)-FORM-2.pdf

3409-KOLNP-2008-(10-06-2014)-OTHERS.pdf

3409-KOLNP-2008-(10-06-2014)-PETITION UNDER RULE 137.pdf

3409-kolnp-2008-abstract.pdf

3409-KOLNP-2008-ASSIGNMENT.pdf

3409-kolnp-2008-claims.pdf

3409-KOLNP-2008-CORRESPONDENCE-1.1.pdf

3409-KOLNP-2008-CORRESPONDENCE-1.2.pdf

3409-kolnp-2008-correspondence.pdf

3409-kolnp-2008-description (complete).pdf

3409-kolnp-2008-form 1.pdf

3409-KOLNP-2008-FORM 13.pdf

3409-KOLNP-2008-FORM 18.pdf

3409-KOLNP-2008-FORM 3-1.1.pdf

3409-kolnp-2008-form 3.pdf

3409-kolnp-2008-form 5.pdf

3409-kolnp-2008-gpa.pdf

3409-kolnp-2008-international publication.pdf

3409-kolnp-2008-international search report.pdf

3409-kolnp-2008-pct priority document notification.pdf

3409-kolnp-2008-pct request form.pdf

3409-kolnp-2008-specification.pdf

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