\.
`
`66/G2/10WANNA)Old
`
`snsetor
`
`:
`January 25, 1999
`_Date of Deposit
`Thereby certify that this paper or fee is being deposited with the United States Postal Service “Express Mail
`Post Office to Addressee” service under 37 C.F.R. 1.10 on the date indicated above and is addressed to the Assistant
`, Comunissioner for Patents, Washington, D.C. 20231.
`
`\-
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`
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`
`ac Sa
`—_ ——™
`5o =n
`“4 =—q
`
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`mm =
`wo =
`
`“Express Mail”mailing label No. |ae
`
`©
`
`om
`
`a
`
`(Typed or printed namé
`
` (Signature of persop
`
`
`
`
`Patent
`Attorney's Docket No. 002010-041
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UTILITY PATENT
`APPLICATION TRANSMITTAL LETTER
`
`Box PATENT APPLICATION
`Assistant Commissioner for Patents
`Washington, D.C. 20231
`
`Sir:
`
`
`
`
`Enclosedfor filing is the utility patent application of Susan Ashwell. Reinhardt Bernhard
`Baudy. Michael A. Pleiss, Dimitrios Sarantakis and Eugene D. Thorsett for COMPOUNDS
`WHICH INHIBIT LEUKOCYTE ADHESION MEDIATED BY VLA-4.SELAIININIAIYDYVILARKS
`
`Also enclosed are:
`
`[J
`
`[
`
`]
`
`[
`
`[
`
`[
`
`[
`
`[
`
`]
`
`]
`
`]
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`]
`
`]
`
`~
`
`
`
`sheet(s) of [
`
`] formal
`
`[
`
`] informal drawing(s);
`
`] hereby made to
`aclaim for foreign priority under 35 U.S.C. §§ 119 and/or 365is [
`?
`filed in
`on
`
`[
`
`] in the declaration;
`
`acertified copy of the priority document;
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`a Constructive Petition for Extensions of Time;
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`statement(s) claiming small entity status;
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`an Assignment document;
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`an Information Disclosure Statement; and
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`[x] Other:
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`_postcard, application cover sheet
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`.
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`The unexecuted declaration of the inventor(s) [ x ] also is enclosed.
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`[
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`] Please amendthe specification by inserting beforethefirst line the sentence --This
`application claims priority under 35 U.S.C. $$119 and/or 365 to
`
`filed in
`onee
`; the entire content of which
`is hereby incorporated by reference.--
`
`(11/98)
`
`

`

`
`
`
`®
`
`Utility Patent eo. Transmittal Letter
`
`Attorney's Docket No. 002010-041
`Page 2
`
`The filing fee has been calculated as follows [
`preliminary amendment:
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`] and in accordance with the enclosed
`
`EXTRA
`CLAIMS
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`RATE
`
`FEE
`
`$760.00
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`Application Fee
`
`.
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`5
`
`Independent
`Claims
`
`MINUS 20 =
`
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`
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`If verified Statement claiming small entity status is enclosed, subtract 50% of Total
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`Please address all correspondence concerning the present application to:
`
`Gerald F. Swiss, Esq.
`Burns, Doane, Swecker & Mathis, L.L.P.
`P.O. Box 1404
`Alexandria, Virginia 22313-1404
`
`Respectfully submitted,
`
`BURNS, DOANE, SWECKER & MATHIS, L.L.P.
`
`
`
`(11/98)
`
`

`

`EL184215743US
`“Express Mail” mailing label No.
`
`_Date of Deposit,
`January
`25. 1999
`Thereby certify that this paper or fee is being deposited with the United States Postal Service
`“Express Mail
`Post Office to Addressee” service under 37 C.F.R. 1.10 on the date indicated above and is addressed to the
`Assistant Commissioner for Patents, Washington, D.C. 20231.
`Bepnardo Cayceslo
`
`
`
`PATENT
`Attorney Docket No. 002010-041
`
`BE IT KNOWN, that we, Susan Aswell, Reinhardt Bernhard Baudy,
`
`Dimitrios Sarantakis, Michael A. Pleiss and Eugene D. Thorsett, have invented
`
`new and useful improvementsin:
`
`COMPOUNDS WHICH INHIBIT
`LEUKOCYTE ADHESION MEDIATED BY VLA-4
`
`
`
`

`

`"
`
`®
`
`g
`
`PATENT
`Attorney Docket No. 002010-041
`
`
`
`COMPOUNDS WHICH INHIBIT LEUKOCYTE ADHESION
`MEDIATED BY VLA-4
`
`BACKGROUND OF THE INVENTION
`
`Field of the Invention
`
`This invention relates to compounds which inhibit leukocyte adhesion
`
`and, in particular, leukocyte adhesion mediated by VLA-4.
`
`5
`
`References
`
`The following publications, patents and patent applications are cited
`
`in this application as superscript numbers:
`
`10
`
`15
`
`20
`
`25
`
`Hemler and Takada, European Patent Application Publication
`No. 330,506, published August 30, 1989
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`?
`
`‘Elices, et al., Cell, 60:577-584 (1990)
`
`Springer, Nature, 346:425-434 (1990)
`
`Osborn, Cell, 62:3-6 (1990)
`
`Vedder, et al., Surgery, 106:509 (1989)
`
`Pretolani, et al., J. Exp. Med., 180:795 (1994)
`
`Abraham,et al., J. Clin. Invest., 93:776 (1994)
`
`Mulligan, et al., J. Immunology, 150:2407 (1993)
`
`
`Cybulsky, et al., Science, 251:788 (1991)
`
`10
`
`Li, et al., Arterioscler. Thromb. , 13:197 (1993)
`
`

`

`--2--
`
`Sasseville, et al., Am. J. Path., 144:27 (1994)
`
`Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494
`(1993)
`
`
`Burkly, et al., Diabetes, 43:529 (1994)
`
`Baron,et al., J. Clin. Invest., 93:1700 (1994)
`
`Hamann,et al., J. Immunology, 152:3238 (1994)
`
`Yednock, et al., Nature, 356:63 (1992)
`
`Baron,et al., J. Exp. Med. , 177:57 (1993)
`
`van Dinther-Janssen, et al., J. Immunology, 147:4207 (1991)
`
`van Dinther-Janssen, et al., Annals. Rheumatic Dis. , 52:672
`(1993)
`
`Elices, et al., J. Clin. Invest. , 93:405 (1994)
`
`
`Postigo, et al., J. Clin. Invest., 89:1445 (1991)
`
`Paul, et al., Transpl. Proceed. , 25:813 (1993)
`
`Okarhara, et al., Can. Res. , 54:3233 (1994)
`
`
`Paavonen,et al., Int. J. Can., 58:298 (1994)
`
`Schadendorf, et al., J. Path., 170:429 (1993)
`
`Bao, et al., Diff., 52:239 (1993)
`
`
`Lauri, et al., British J. Cancer, 68:862 (1993)
`
`Kawaguchi, et al., Japanese J. Cancer Res. , 83:1304 (1992)
`
`Kogan,et al., U.S. Patent No. 5,510,332, issued April 23,
`1996
`
`International Patent Appl. Publication No. WO 96/01644
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`29
`
`30
`
`
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`

`

`
`
`
`3
`
`All of the above publications, patents and patent applications are
`
`herein incorporated by reference in their entirety to the same extent as if
`
`each individual publication, patent or patent application was specifically and
`
`individually indicated to be incorporated by referencein its entirety.
`
`State of the Art
`
`VLA-4 (also referred to as a6, integrin and CD49d/CD29), first
`
`identified by Hemler and Takada! is a memberof the B1 integrin family of
`
`cell surface receptors, each of which comprises two subunits, an a chain and
`
`10
`
`a chain. VLA-4 contains an «4 chain and a B1 chain. There areat least
`
`nine B1 integrins, all sharing the same 61 chain and each having a distinct «
`
`chain. These nine receptors all bind a different complement of the various -
`
`cell matrix molecules, such as fibronectin, laminin, and collagen. VLA-4,
`
`for example, binds to fibronectin. VLA-4 also binds non-matrix molecules
`
`15
`
`that are expressed by endothelial and other cells. These non-matrix
`
`molecules include VCAM-1, which is expressed on cytokine-activated
`
`human umbilical vein endothelial cells in culture. Distinct epitopes of VLA-
`
`4 are responsible for the fibronectin and VCAM-1 bindingactivities and each
`
`activity has been shownto be inhibited independently.”
`
`20
`
`Intercellular adhesion mediated by VLA-4 and other cell surface
`
`receptors is associated with a numberof inflammatory responses. Atthe site
`
`of an injury or other inflammatory stimulus, activated vascular endothelial
`
`cells express molecules that are adhesive for leukocytes. The mechanics of
`
`25
`
`leukocyte adhesion to endothelial cells involves, in part, the recognition and
`
`binding of cell surface receptors on leukocytes to the correspondingcell
`
`surface molecules on endothelial 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
`
`30
`
`immune system, see, for example, Springer’ and Osborn‘.
`
`

`

`
`
`
`
`-4-
`
`Inflammatory brain disorders, such as experimental autoimmune
`
`encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are
`
`examples of central nervous system disorders in which the
`
`endothelium/leukocyte adhesion mechanism 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.
`
`10
`
`In other organ systems, tissue damage also occurs via an adhesion
`
`mechanism resulting in migration or activation of leukocytes. For example,
`
`it has been shownthat 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°). Other inflammatory
`
`15
`
`conditions mediated by an adhesion mechanism 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
`
`20
`
`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 occursin adult
`
`respiratory distress syndrome.
`
`25
`
`In view of the above, assays for determining the VLA-4 level in a
`
`biological sample containing VLA-4 would be useful, for example, to
`
`diagnosis VLA-4 mediated conditions. Additionally, despite these advances
`
`in the understanding of leukocyte adhesion, the art has only recently
`
`addressed the use of inhibitors of adhesion in the treatment of inflammatory
`
`

`

`
`
`-- 5 -
`
`brain diseases and other inflammatory conditions**°. The present invention
`
`addresses these and other needs.
`
`SUMMARYOF THE INVENTION
`
`This invention provides compounds which bind to VLA-4. Such
`
`compoundscan be used, for example, to assay for the presence of VLA-4 in
`
`a sample and in pharmaceutical compositions to inhibit cellular adhesion
`
`mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The
`
`compoundsof this invention have a binding affinity to VLA-4 as expressed
`
`10
`
`by an IC.) of about 15 4M or less (measured as described in Example A
`
`below) which compoundsare defined by formula I below:
`
`e P 8i
`
`R'—S—N—C—Q—C(H)—C.
`I
`|
`|
`O R2 Ré
`
`OH
`
`I
`
`15
`
`wherein
`
`R! is selected from the group consisting of alkyl, substituted alkyl,
`
`20
`
`cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
`
`aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
`
`substituted heterocylic, ;
`
`R’ is selected from the group consisting of hydrogen,alkyl,
`
`substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
`
`25
`
`cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
`
`heterocyclic, substituted heterocyclic, and R! and R? together with the
`
`nitrogen atom bound to R’ and the SO, group can form a heterocyclic or a
`
`substituted heterocyclic group;
`
`R? is selected from the group consisting of hydrogen,alkyl,
`substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
`
`30
`
`

`

`--6--
`
`cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
`
`heterocyclic, substituted heterocyclic, and, when R’ does not form a
`
`heterocyclic group with R', R? and R’ together with the nitrogen atom bound
`
`to R? and the carbon atom bound to R? can form a heterocyclic group or a
`
`substituted heterocyclic group;
`
`R* is selected from the group consisting of hydrogen,alkyl,
`
`substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
`
`cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
`heterocyclic, substituted heterocyclic, and, when R? does not form a
`
`10
`
`heterocyclic or a substituted heterocyclic group with R’, then R? and R*
`
`together with the carbon atom to which they are attached can form a
`
`cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic
`
`group;
`
`R° is selected from the group consisting of isopropyl, -CH,-W and
`
`substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted
`
`alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl,
`
`substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic,
`
`substituted heterocyclic, acylamino, carboxyl, carboxylalkyl, carboxyl-
`
`20
`
`substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl,
`
`carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-
`
`substituted heteroaryl, carboxyheterocyclic, carboxy-substituted heterocyclic,
`
`and hydroxyl with the proviso that when R° is =CH-W then (H)is removed
`
`from the formula and W is not hydroxyl;
`
`25
`
`Q is selected from the group consisting of:
`
`(i)
`
`
`
`15
`=CH-W, whereWis selected from the group consisting of hydrogen, alkyl,
`
`

`

`
`
`co
`
`-- 7 --
`
`wherein X is selected from the group consisting of oxygen, sulfur and
`
`NH;
`
`(ii)
`
`R8
`
`—CH-N—
`
`R/
`
`wherein R’ is selected from the group consisting of hydrogen, alkyl
`
`and substituted alkyl;
`
`R? is selected from the group consisting of hydrogen, alkyl and
`
`substituted alkyl; or R’ and R® together with the nitrogen atom boundto R’
`
`and the carbon boundto R® can form a heterocyclic or substituted
`
`10
`
`heterocyclic ring;
`
`(iti)
`
`wherein R° is selected from the group consisting of hydrogen, alkyl
`
`and substituted alkyl;
`
`15
`
`R"is selected from the group consisting of hydrogen, alkyl and
`
`substituted alkyl; or R’ and R’ together with the nitrogen atom boundto R’,
`
`the carbon atom bound to R'° and the -C(X)- group can form a heterocyclic
`
`or substituted heterocyclic group;
`
`X is selected from the group consisting of oxygen, sulfur and NH;
`
`20
`
`

`

`(iv)
`
`
`
`wherein R" and R” together with the nitrogen atom bound to R"™ and
`
`the >C=N- group bound to R” form a heterocyclic, substituted
`
`heterocyclic, heteroaryl, or substituted heteroaryl ring; and
`
`5
`
`(v)
`
`wherein R®is selected from the group consisting of hydrogen, alkyl,
`
`and substituted alkyl;
`
`R*is selected from the group consisting of hydrogen,alkyl, and
`
`substituted alkyl;
`
`10
`
`X is selected from the group consisting of oxygen, sulfur and NH;
`
`and pharmaceutically acceptable salts thereof.
`
`In another embodiment, the compoundsof this invention can also be
`
`provided as prodrugs which convert (e.g., hydrolyze, metabolize, etc.) in
`
`15
`
`vivo to a compound of formula I above.
`
`In a preferred example of such an
`
`embodiment, the carboxylic acid in the compound of formula I is modified
`
`into a group which,in vivo, will convert to the carboxylic acid (including
`
`salts thereof).
`
`In a particularly preferred embodiment, such prodrugs are
`
`represented by compounds of formula IA:
`
`20
`
`

`

`-9--
`
`“Ngee
`
`|
`
`IA
`
`
`
`wherein
`
`R!'is selected from the group consisting of alkyl, substituted alkyl,
`cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
`
`10
`
`aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and
`
`substituted heterocylic,;
`
`R? is selected from the group consisting of hydrogen,alkyl,
`
`substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
`
`cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
`
`15
`
`heterocyclic, substituted heterocyclic, and R' and R’ together with the
`
`nitrogen atom boundto R? and the SO, group can form a heterocyclic or a
`
`substituted heterocyclic group;
`
`R? is selected from the group consisting of hydrogen, alkyl,
`
`substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
`
`20
`
`cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
`
`heterocyclic, substituted heterocyclic, and, when R? does not form a
`
`heterocyclic group with R', R’ and R? together with the nitrogen atom bound
`to R? and the carbon atom bound to R? can form a heterocyclic group or a
`
`substituted heterocyclic group;
`
`25
`
`R‘ is selected from the group consisting of hydrogen,alkyl,
`substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
`
`cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
`
`heterocyclic, substituted heterocyclic, and, when R? does not form a
`
`heterocyclic or a substituted heterocyclic group with R’, then R° and R*
`
`30
`
`together with the carbon atom to which they are attached can forma
`
`

`

`-- 10 --
`
`cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic
`
`group;
`
`R° is selected from the group consisting of isopropyl, -CH,-W and
`
`=CH-W, whereWis selected from the group consisting of hydrogen, alkyl,
`
`substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted
`
`alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl,
`
`substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic,
`
`substituted heterocyclic, acylamino, carboxyl, carboxylalkyl, carboxyl-
`
`substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl,
`
`10
`
`carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-
`
`substituted heteroaryl, carboxyheterocyclic, carboxy-substituted heterocyclic,
`
`and hydroxyl with the proviso that when R° is =CH-W then (H)is removed
`
`
`
`from the formula andWis not hydroxyl;
`
`R°is selected from the group consisting of amino, alkoxy, substituted
`
`15
`
`alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy,
`
`heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted
`
`heterocyclyloxy, -NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl,
`
`or substituted aryl, and -NH(CH,),COOY’ where Y’ is hydrogen,alkyl,
`
`substituted alkyl, aryl, or substituted aryl, and p is an integer of from 1 to 8;
`
`20
`
`Q is selected from the group consisting of:
`
`(i)
`
`wherein X is selected from the group consisting of oxygen, sulfur and
`
`NH;
`
`25
`
`

`

`(ii)
`
`--11--
`
`R8&
`
`—CH-N—
`
`R?’
`
`
`
`wherein R’ is selected from the group consisting of hydrogen,alkyl
`
`and substituted alkyl;
`
`R®is selected from the group consisting of hydrogen, alkyl and
`
`substituted alkyl; or R’ and R® together with the nitrogen atom boundto R’
`
`and the carbon bound to R® can form a heterocyclic or substituted
`
`heterocyclic ring;
`
`(iii)
`
`x
`
`—_CH-C—N—
`
`R10
`
`R9
`
`10
`
`wherein R? is selected from the group consisting of hydrogen, alkyl
`
`and substituted alkyl;
`
`R”is selected from the group consisting of hydrogen, alkyl and
`
`substituted alkyl; or R? and Rtogether with the nitrogen atom boundto R’,
`
`15
`
`the carbon atom bound to R" and the -C(X)- group can form a heterocyclic
`
`or substituted heterocyclic group;
`
`X is selected from the group consisting of oxygen, sulfur and NH;
`
`and
`
`20
`
`

`

`-12--
`
`(iv)
`
`
`
`wherein R" and R” together with the nitrogen atom bound to R" and
`
`the >C=N- group bound to R” form a heterocyclic, substituted
`
`heterocyclic, heteroaryl, or substituted heteroaryl ring; and
`
`(v)
`
`x
`
`pyBN
`bs i
`
`wherein R®is selected from the group consisting of hydrogen,alkyl,
`
`and substituted alkyl;
`
`R"is selected from the group consisting of hydrogen, alkyl, and
`
`substituted alkyl;
`
`10
`
`X is selected from the group consisting of oxygen, sulfur and NH;
`
`and pharmaceutically acceptable salts thereof.
`
`Preferably, in the compounds of formula I and IA above, R' is
`
`selected from the group consisting of alkyl, substituted alkyl, aryl,
`
`15
`
`substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and
`
`substituted heteroaryl. Even more preferably R' is selected from the group
`
`consisting of methyl, isopropyl, 7-butyl, benzyl, phenethyl, phenyl, 4-
`
`methylphenyl, 4-t-butylphenyl, 2,4,6-trimethylpheny1, 2-fluorophenyl, 3-
`
`fluorophenyl, 4-fluorophenyl, 2,4-difluoropheny], 3,4-difluorophenyl, 3,5-
`
`20
`
`difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-
`
`dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-flucrophenyl, 4-
`
`

`

`
`
`
`
`-- 13 --
`
`bromophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-
`
`dimethoxyphenyl, 4-t-butoxyphenyl, 4-(3’-dimethylamino-n-propoxy)-
`
`phenyl, 2-carboxyphenyl, 2-(methoxycarbonyl)phenyl, 4-GH1,NC(O)-)phenyl,
`
`4-(H,NC(S)-)phenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-
`
`trifluoromethoxyphenyl, 3 ,5-di-(trifluoromethyl)phenyl, 4-nitrophenyl, 4-
`
`aminophenyl, 4-(CH;C(O)NH-)phenyl, 4-(PhNHC(O)NH-)phenyl, 4-
`
`amidinophenyl, 4-methylamidinophenyl, 4-(CH,SC(=NH)-)phenyl, 4-
`
`chloro-3-(H,NS(O),-)phenyl, 1-naphthyl, 2-naphthyl, pyridin-2-yl, pyridin-3-
`
`yl, pyrimidin-2-yl, quinolin-8-yl, 2-(trifluoroacetyl)-1,2,3,4-
`
`10
`
`tetrahydroisoquinolin-7-yl, morpholin-4-yl, 2-thienyl, 5-chloro-2-thienyl,
`
`2,5-dichloro-4-thienyl, 1-N-methylimidazol-4-yl, 1-N-methylpyrazol-3-yl, 1-
`
`N-methylpyrazol-4-yl, 1-N-butylpyrazol-4-yl, 1-N-methyl-3-methy]-5-
`
`chloropyrazol-4-yl, 1-N-methyl-5-methyl-3-chloropyrazol-4-yl, 2-thiazoly]
`
`and 5-methyl-1,3 ,4-thiadiazol-2-y1.
`
`15
`
`Preferably, in the compounds of formula I and IA above,R’ is
`
`hydrogen, methyl, phenyl, benzyl, -(CH,),-2-thienyl, and -(CH)),-6.
`
`In one embodiment, R' and R’ together with the nitrogen atom bound
`
`20
`
`to R? and the SO, group bound to R! are joined to form a heterocyclic group
`
`or substituted heterocyclic group. Preferred heterocyclic and substituted
`
`heterocyclic groups include those having from 5 to 7 ring atoms having 2 to
`
`3 heteroatoms in the ring selected from the group consisting of nitrogen,
`
`oxygen and sulfur which ring is optionally fused to another ring such as a
`
`25
`
`phenyl or cyclohexyl ring to provide for a fused ring heterocycle of from 10
`
`to 14 ring atoms having 2 to 4 heteroatoms in the ring selected from the
`
`group consisting of nitrogen, oxygen and sulfur. Specifically preferred
`
`R!/R? joined groups include, by way of example, benzisothiazolony!
`
`(saccharin-2-yl), N-2,10-camphorsultamyl and 1,1-dioxo-2,3-dihydro-3 ,3-
`
`30
`
`dimethyl-1 ,2-benzisothiazol-2-yl.
`
`

`

`
`
`-- 14 --
`
`In one preferred embodiment, R’ and R* together with the nitrogen
`
`atom bound to R? substituent and the carbon boundto the R® substituent form
`
`a heterocyclic group or a substituted heterocyclic group of 4 to 6 ring atoms
`
`having 1 to 2 heteroatoms in the ring selected from the group consisting of
`
`nitrogen, oxygen and sulfur which ring is optionally substituted with 1 to 2
`
`substituents selected from the group consisting of fluoro, methyl, hydroxy,
`
`oxo (=O), amino, phenyl, thiophenyl, thiobenzyl, (thiomorpholin-4-
`
`yl)C(O)O- , CH;S(O),- and CH,S(O),O-, or can be fused to another ring
`
`such as a phenyl or cycloalkyl ring to provide for a fused ring heterocycle of
`
`10
`
`from 10 to 14 ring atoms having | to 2 heteroatoms in the ring selected from
`
`the group consisting of nitrogen, oxygen and sulfur. Such heterocyclic rings
`
`include azetidinyl (e.g., L-azetidinyl), thiazolidinyl (e.g., L-thiazolidinyl),
`
`piperidinyl (e.g., L-piperidinyl), piperazinyl (e.g., L-piperazinyl),
`
`dihydroindolyl (e.g., L-2,3-dihydroindol-2-yl), tetrahydroquinoliny! (e.g.,
`
`15
`
`L-1,2,3,4-tetrahydroquinolin-2-yl), thiomorpholinyl (e.g., L-thiomorpholin-
`
`3-yl), pyrrolidinyl (e.g., L-pyrrolidinyl), substituted pyrrolidinyl such as
`4-hydroxypyrrolidinyl (e.g., 4-c-(or 6-)hydroxy-L-pyrrolidinyl), 4-
`oxopyrrolidinyl (e.g., 4-oxo-L-pyrolidinyl), 4-fluoropyrrolidiny! (e.g., 4-«-
`
`(or B-)fluoro-L-pyrrolidinyl), 4,4-difluoropyrrolidinyl (e.g., 4,4-difluoro-L-
`
`20
`
`pyrrolidinyl), 4-(thiomorpholin-4-y1C(O)O-)pyrrolidinyl (e.g., 4-«-(or B-)-
`
`(thiomorpholin-4-ylC(O)O-)-L-pyrrolidiny1, 4-(CH,S(O),O0-)pyrrolidinyl
`
`(e.g., 4-a-(or B-)(CH,S(O),O0-)-L-pyrrolidinyl, 3-phenylpyrrolidinyl (e.g., 3-
`
`a-(or B-)phenyl-L-pyrrolidinyl), 3-thiophenylpyrrolidinyl (e.g., 3-a-(or B-)-
`
`thiophenyl-L-pyrrolidinyl), 4-aminopyrrolidinyl (e.g., 4-a-(or B-)amino-L-
`
`25
`
`pyrrolidinyl), 3-methoxypyrrolidinyl (e.g., 3-«-(or B-)methoxy-L-
`
`pytrolidinyl), 4,4-dimethylpyrrolidinyl, substituted piperazinyl such as 4-N-
`
`Cbz-piperazinyl and 4-(CH,S(O),-)piperazinyl, substituted thiazolidinyl such
`
`as 5,5-dimethylthiazolindin-4-yl, 1,1-dioxo-thiazolidinyl (e.g., L-1,1-dioxo-
`
`thiazolidin-2-yl), substituted 1,1-dioxo-thiazolidinyl such as L-1,1-dioxo-5,5-
`
`

`

`-- 15 --
`
`dimethylthiazolidin-2-yl, 1,1-dioxothiomorpholinyl (e.g., L-1,1-dioxo-
`
`thiomorpholin-3-yl) and the like.
`
`Preferably, in the compounds of formula I and IA above, R’ includes
`
`5
`
`all of the isomers arising by substitution with methyl, phenyl, benzyl,
`
`diphenylmethyl, -CH,CH,-COOH, -CH,-COOH, 2-amidoethyl, iso-butyl, f-
`
`butyl, -CH,O-benzyl and hydroxymethyl. Additionally, in another preferred
`
`embodiment, R? and R? together with the nitrogen atom boundto R’ can
`
`form a heterocyclic group or substituted heterocyclic group.
`
`10
`
`Preferably, in the compounds of formula I and IA above, R’ is
`selected from the group consisting of methyl, ethyl, phenyl and where R’ and
`
`R‘ are joined together with the carbon atom to which they are attached to
`
`form a cycloalkyl group of from 3 to 6 carbon atomsor a heterocyclic group
`
`15
`
`of from 3 to 8 ring atoms. Preferred cycloalky! alkyl groups include
`
`cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
`
`Q is preferably -C(O)N(O)-, -CH,NH-, -CH(OH)C(O)NH-,
`
`-NHC(O)NHE-, or tetrazol-1,5-diyl.
`
`20
`
`R> is preferably selected from all possible isomers arising by
`
`substitution with the following groups:
`
`4-methylbenzyl,
`
`4-hydroxybenzyl,
`
`25
`
`4-methoxybenzyl,
`
`4-t-butoxybenzyl,
`
`4-benzyloxybenzyl,
`
`4-[b-CH(CH,)O-]benzyl,
`
`4-[-CH(COOH)O-]benzyl,
`
`30
`
`4-[BocNHCH,C(O)NH-]benzyl,
`
`
`
`
` a
`
`

`

`-- 16 --
`
`4-chlorobenzyl,
`
`4-[NH,CH,C(O)NH-]benzyl,
`
`4-carboxybenzyl,
`
`4-[CbzNHCH,CH,NH-]benzyl,
`
`3-hydroxy-4-(@-OC(O)NH-)benzyl,
`
`4-[HOOCCH,CH,C(O)NH-]benzyl,
`
`benzyl,
`
`4-[2'-carboxylphenoxy-]benzyl,
`
`4-[@-C(O)NH-Jbenzyl,
`
`
`
`
`
`10
`
`3-carboxybenzyl,
`
`15
`
`4-iodobenzyl,
`
`4-hydroxy-3,5-diiodobenzy1,
`
`4-hydroxy-3-iodobenzyl,
`
`4-[2’-carboxyphenyl-]benzyl,
`
`-CH,CH,-,
`
`4-nitrobenzyl,
`
`2-carboxybenzyl,
`
`4-[dibenzylamino]-benzyl,
`
`4-[(1’-cyclopropylpiperidin-4'-yl)C(O)NH-]benzyl,
`
`20
`
`4-[-NHC(O)CH,NHBoc]benzyl,
`
`4-carboxybenzyl,
`
`4-hydroxy-3-nitrobenzyl,
`
`4-[-NHC(O)CH(CH,)NHBoc]benzyl,
`
`4-[-NHC(0O)CH(CH,6)NHBoc]benzy1,
`
`25
`
`isobutyl,
`
`methyl,
`
`4-[CH,C(O)NH-]benzyl,
`
`-CH,-(-indolyl),
`
`n-butyl,
`
`30
`
`t-butyl-OC(O)CH,-,
`
`

`

`
`
`
`--17--
`
`t-butyl-OC(O)CH,CH,-,
`
`H,NC(O)CH,-,
`
`H,NC(O)CH,CH,-,
`
`BocNH-(CH),),-,
`
`t-butyl-OC(O)-(CH)),-,
`
`HOOCCH,-,
`
`HOOC(CH,).-,
`
`H,N(CH,).-,
`
`isopropyl,
`
`(1-naphthyl)-CH,-,
`
`(2-naphthyl)-CH,-,
`
`(2-thiophenyl)-CH.-,
`
`(-CH,-OC(O)NH-(CH,),-,
`
`cyclohexyl-CH,-,
`
`10
`
`15
`
`benzyloxy-CH,-,
`
`HOCH,-,
`
`5-(3-N-benzyl)imidazoly1-CH,-,
`
`2-pyridyl-CH,-,
`
`3-pyridyl-CH,-,
`
`4-pyridyl-CH,-,
`
`20
`
`5-(3-N-methyl)imidazolyl-CH,-,
`
`N-benzylpiperid-4-yl-CH,-,
`
`N-Boc-piperidin-4-yl-CH,-,
`
`N-(pheny]-carbony])piperidin-4-yl-CH,-,
`
`25
`
`H;,;CSCH,CH,-,
`
`1-N-benzylimidazol-4-yl-CH,-,
`
`iso-propyl-C(O)NH-(CH,),-,
`
`iso-butyl-C(O)NH-(CH,).-,
`
`phenyl-C(O)NH-(CH,),-,
`
`30
`
`benzyl-C(O)NH-(CH,),-,
`
`

`

`-- 18 --
`
`allyl-C(O)NH-(CH)).-,
`
`4-(3-N-methylimidazolyl)-CH,-,
`
`4-imidazolyl,
`
`4-[(CH,),NCH,CH,CH,-O-]benzyl,
`
`4-[(benzyl),N-]-benzyl,
`
`4-aminobenzyl,
`
`allyloxy-C(O)NH(CH,),-,
`
`allyloxy-C(O)NH(CH,);-,
`
`allyloxy-C(O)NH(CH,),-,
`
`
`
`
`
`
`10
`
`NH,C(O)CH,-,
`
`o-CH=,
`
`2-pyridyl-C(O)NH-(CH)),-,
`
`4-methylpyrid-3-yl-C(O)NH-(CH,).-,
`
`3-methylthien-2-yl-C(O)NH-(CH,),-,
`
`15
`
`2-pyrrolyl-C(O)NH-(CH,),-,
`
`2-furanyl-C(O)NH-(CH,),-,
`
`4-methylphenyl-SO,-N(CH;)CH,C(O)NH(CH)),-,
`
`4-[cyclopentylacetylenyl]-benzyl,
`
`4-[-NHC(O)-(N-Boc)-pyrrolidin-2-yl)]-benzyl-,
`
`20
`
`1-N-methylimidazol-4-yl-CH,-,
`
`1-N-methylimidazol-5-yl-CH,-,
`
`imidazol-5-yl-CH,-,
`
`6-methylpyrid-3-yl-C(O)NH-(CH),),-,
`
`4-[2’-carboxymethylphenyl]-benzyl,
`
`25
`
`4-[-NHC(O)NHCH,CH,CH,-$]-benzyl,
`
`4-[-NHC(O)NHCH,CH,-96]-benzyl,
`
`-CH,C(O)NH(CH,),0,
`
`4-[(CH,),O0-]-benzyl,
`
`4-[-C=C-o-4'$]-benzyl,
`
`30
`
`4-[-C=C-CH,-O-S(O),-4’-CH;-]-benzyl,
`
`

`

`-- 19 --
`
`4-[-C=C-CH,NHC(O)NH,]-benzyl,
`
`4-[-C=C-CH,-0-4’-COOCH,CH;-]-benzyl,
`
`4-[-C=C-CH(NH.,)-cyclohexyl]-benzyl,
`
`-(CH,),NHC(O)CH,-3-indolyl1,
`
`-(CH,),NHC(O)CH,CH,-3-indolyl,
`
`-(CH,),NHC(O)-3-(-methoxyindoly]),
`-(CH,),NHC(0)-3-(1-methylindolyl),
`_
`-(CH,),NHC(0)-4-(-SO,(CH;,)-),
`
`-(CH,),NHC(Q)-4-(C(O)CH,)-phenyl,
`
`
`
`
`10
`
`-(CH,),NHC(O)-4-fluorophenyl,
`
`-(CH,),NHC(O)CH,O-4-fluorophenyl,
`
`4-[-C=C-(2-pyridyl)]benzyl,
`
`4-[-C=C-CH,-O-phenyl]benzyl,
`
`4-[-C=C-CH,OCH,]benzyl,
`
`15
`
`4-[-C=C-(3-hydroxypheny])]benzyl,
`
`4-[-C=C-CH,-0-4'-(-C(O)OC,H,)phenyl]benzy1,
`
`4-[-C=C-CH,CH(C(O)OCH,),]benzyl,
`
`4-[-C=C-CH,NH-(4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl),
`
`3-aminobenzyl,
`
`20
`
`4-[-C=C-CH,CH( NHC(O)CH,)C(O)OH]-benzyl,
`
`-CH,C(O)NHCH(CH,)o,
`
`-CH,C(O)NHCH,-(4-dimethylamino)-,
`
`-CH,C(O)NHCH,-4-nitrophenyl,
`
`-CH,CH,C(O)N(CH,)CH,-,
`
`25
`
`-CH,CH,C(O)NHCH,CH,-(N-methy])-2-pyrrolyl,
`
`-CH,CH,C(O)NHCH,CH,CH,CH3,
`
`-CH,CH,C(O)NHCH,CH.,-3-indolyl,
`
`-CH,C(O)N(CH;)CH,phenyl,
`
`-CH,C(O)NH(CH,),-(N-methy)-2-pyrrolyl,
`
`30
`
`-CH,C(O)NHCH,CH,CH,CH,,
`
`

`

`-- 20 --
`
`-CH,C(O)NHCH,CH,-3-indolyl,
`
`-(CH,),C(O)NHCH(CH;),
`
`-(CH,),C(O)NHCH,-4-dimethylaminophenyl,
`
`-(CH,),C(O)NHCH,-4-nitrophenyl,
`
`-CH,C(O)NH-4-[-NHC(O)CH;-phenyl],
`
`-CH,C(O)NH-4-pyridyl,
`
`-CH,C(O)NH-4-[dimethylaminopheny]],
`
`-CH,C(O)NH-3-methoxyphenyl,
`
`-CH,CH,C(O)NH-4-chlorophenyl,
`
`
`
`
`
`
`10
`
`-CH,CH,C(O)NH-2-pyridyl,
`
`-CH,,CH,C(O)NH-4-methoxyphenyl,
`
`-CH,CH,C(O)NH-3-pyridyl,
`
`4-[(CH,),NCH,CH,O-]benzy1,
`
`-(CH,);NHC(NH)NH-SO,-4-methylphenyl,
`
`15
`
`4-[(CH,),NCH,CH,O-]benzyl,
`
`-(CH,),NHC(O)NHCH,CH;,
`
`-(CH,),NHC(O)NH-phenyl,
`
`-(CH,),NHC(O)NH-4-methoxyphenyl,
`
`4-[4’-pyridyl-C(O)NH-Jbenzyl,
`
`20
`
`4-[3’-pyridyl-C(O)NH-]benzyl,
`
`4-[-NHC(O)NH-3'-methylpheny]]benzyl,
`
`4-[-NHC(O)CH,NHC(O)NH-3’-methylphenyl]benzy1,
`
`4-[-NHC(O)-(2’ ,3’-dihydroindol-2-y)]Jbenzyl,
`
`4-[-NHC(O)-(2’ ,3’-dihydro-N-Boc-indol-2-yl)]benzyl,
`
`25
`
`p-[-OCH,CH,-1’-(4’-pyrimidiny])-piperazinyl]benzyl,
`
`4-[-OCH.CH.,-(1’-piperidinyl)benzyl,
`
`4-[-OCH,CH,-(1’-pyrrolidinyl)]benzyl,
`
`4-[-OCH,CH,CH,-(1'-piperidiny])]benzyl-,
`
`-CH,-3-(1,2,4-triazolyl),
`
`30
`
`4-[-OCH,CH,CH,-4-G’-chloropheny])-piperazin-1-yl]benzyl,
`
`

`

`2] --
`
`4-[-OCH,CH,N()CH,CH;]benzyl,
`
`4-[-OCH,-3’-(N-Boc)-piperidinyl]benzyl,
`
`4-[di-n-pentylamino]benzyl,
`
`4-[n-pentylamino]benzyl,
`
`4-[di-iso-propylamino-CH,CH,O-]benzyl,
`
`4-[-OCH,CH,-(N-morpholiny])]benzy1,
`
`4-[-O-(3'-(N-Boc)-piperidinyl]benzyl,
`
`4-[-OCH,CH(NHBoc)CH,cyclohexyl]benzyl,
`
`p-[OCH,CH,-(N-piperidinyl]benzyl,
`
`
`
`
`
`
`10
`
`4-[-OCH,CH,CH,-(4-m-chloropheny1)-piperazin-1-yl]benzyl,
`
`4-[-OCH,CH,-(N-homopiperidinyl)benzyl,
`
`4-[-NHC(O)-3'-(N-Boc)-piperidinyl]benzyl,
`
`4-[-OCH,CH,N(benzyl),]benzyl,
`
`-CH,-2-thiazolyl,
`
`15
`
`3-hydroxybenzyl,
`
`4-[-OCH,CH,CH,N(CH;),]benzyl,
`
`4-[-NHC(S)NHCH.CH.-(N-morpholino)]benzy1,
`
`4-[-OCH,CH,N(C,Hs)]benzyl,
`4-[-OCH,CH,CH,N(C,H;),]benzyl,
`
`20
`
`4-[CH,(CH,),NH-]benzyl,
`
`4-[N-n-butyl, N-z-pentylamino-]benzyl,
`
`4-[-NHC(O)-4’-piperidinyl]benzyl,
`
`4-[-NHC(O)CH(NHBoc)(CH,),NHCbz]benzyl,
`
`4-[-NHC(O)-(1',2’,3’,4’-tetrahydro-N-Boc-isoquinolin-1’-yl]benzyl,
`
`25
`
`p-[-OCH,CH,CH,-1’-(4’-methy])-piperazinyl]benzy1,
`
`-(CH,),NH-Boc,
`
`3-[-OCH,CH,CH,N(CH;),]benzyl,
`
`4-[-OCH,CH,CH,N(CH:;),|benzyl,
`
`3-[-OCH,CH,-(1'-pyrrolidinyl)]benzyl,
`
`30
`
`4-[-OCH,CH,CH,N(CH;)benzyl]benzyl,
`
`

`

`-- 22 --
`
`4-[-NHC(S)NHCH,CH,CH,-(N-morpholino)]|benzyl,
`
`4-[-OCH,CH,-(N-morpholino)]|benzyl,
`
`4-[-NHCH,-(4’-chlorophenyl)]benzyl,
`
`4-[-NHC(O)NH-(4’-cyanopheny])]benzyl,
`
`4-[-OCH,COOH]benzyl,
`
`4-[-OCH,COO-?-butyl]benzyl,
`
`4-[-NHC(O)-5’-fluoroindol-2-yl]benzyl,
`
`4-[-NHC(S)NH(CH,),-1-piperidinyl]benzyl,
`
`4-[-N(SO,CH;)(CH,);-N(CH3),]benzy1,
`
`
`
`10
`
`4-[-NHC(O)CH,CH(C(O)OCH,$)-NHCbz]benzyl,
`
`4-[-NHS(O),CF;]benzyl,
`
`3-[-O-(N-methylpiperidin-4’-yl]benzyl1,
`
`4-[-C(=NH)NH,]benzyl,
`
`4-[-NHSO,-CH,Cl]benzyl,
`
`15
`
`4-[-NHC(O)-(1’ ,2',3’,4’-tetrahydroisoquinolin-2'-yl]benzy1,
`
`4-[-NHC(S)NH(CH,)3-N-morpholino]benzyl,
`
`4-[-NHC(O)CH(CH,CH,CH,CH,NH,)NHBoc]benzyl,
`
`4-[-C(O)NH,]benzyl,
`
`4-[-NHC(O)NH-3’-methoxyphenyl]benzyl,
`
`20
`
`4-[-OCH,CH,-indol-3’-yl]benzyl,
`
`4-[-OCH,C(O)NH-benzyl]benzyl,
`
`4-[-OCH,C(O)O-benzyl]benzyl,
`
`4-[-OCH,C(O)OHIbenzyl,
`
`4-[-OCH,-2'-(4' ,5'-dihydro)imidazolyl]benzyl,
`
`25
`
`-CH,C(O)NHCH,-(4-dimethylamino)phenyl,
`
`-CH,C(O)NHCH,-(4-dimethylamino)phenyl,
`
`4-[-NHC(O)-L-2'-pyrrolidinyl-N-SO,-4'-methylphenyl]benzyl],
`
`4-[-NHC(O)NHCH,CH,CH,]benzyl,
`
`4-aminobenzyl]benzyl,
`
`

`

`
`
`
`
`-- 23 --
`
`4-[-OCH,CH,-1-(4-hydroxy-4-(3-methoxypyrrol-2-yl)-
`
`piperazinyl]benzyl,
`
`4-[-O-(N-methylpiperidin-4’-yl]benzyl,
`
`3-methoxybenzyl,
`
`4-[-NHC(O)-piperidin-3'-yl]benzyl,
`
`4-[-NHC(O)-pyridin-2'-yl]benzyl,
`
`4-[-NHCH,-(4'-chlorophenyl)]benzyl,
`
`4-[-NHC(0)-(N-(4'-CH3-6-SO,)-L-pyrrolidin-2’-y]l)]benzyl,
`
`4-[-NHC(O)NHCH,CH,-$]benzyl,
`
`10
`
`4-[-OCH,C(O)NH,Jbenzyl,
`
`4-[-OCH,C(O)NH-+t-butyl]benzyl,
`
`4-[-OCH,CH,-1-(4-hydroxy-4-pheny])-piperidinyl]benzyl,
`
`4-[-NHSO,-CH =CH,]benzyl,
`
`4-[-NHSO,-CH,CH,Ci]benzyl,
`
`15
`
`-CH,C(O)NHCH,CH,N(CHs3),,
`
`4-[(1'-Cbz-piperidin-4’-y])C(O)NH-]benzyl,
`
`4-[(1'-Boc-piperidin-4’-yl)C(O)NH-]benzyl,
`
`4-[(2’-bromophenyl)C(O)NH-]benzyl,
`
`4-[-NHC(O)-pyridin-4’-yl]benzyl,
`
`20
`
`4-[(4'-(CH,),NC(O)O-)pheny!)-C(O)NH-]benzyl,
`
`25
`
`4-[-NHC(O)-1’-methylpiperidin-4'-yl-]benzyl,
`
`4-(dimethylamino)benzyl,
`
`4-[-NHC(O)-(1’-N-Boc)-piperidin-2’-yl]benzyl,
`
`3-[-NHC(O)-pyridin-4’-yl]benzyl,
`
`4-[(tert-butyl-O(O)CCH,-O-benzy1)-NH-]benzyl,
`[BocNHCH,C(O)NH-]butyl,
`4-benzylbenzyl,
`
`2-hydroxyethyl,
`
`4-[(Et),NCH,CH,CH,NHC(S)NH-]benzyl,
`
`30
`
`4-[(1'-Boc-4’-hydroxypyrrolidin-2’-y])C(O)NH-]benzyl,
`
`

`

`Sl
`
`
`
`4-[0CH,CH,CH,NHC(S)NH-]benzyl,
`
`4-[(perhydroindolin-2’-yl)C(O)NH-]benzy],
`
`2-[4-hydroxy-4-(3-methoxythien-2-yl)piper