ZA200105314B - Acyl derivatives which treat VLA-4 related disorders. - Google Patents

Acyl derivatives which treat VLA-4 related disorders. Download PDF

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ZA200105314B
ZA200105314B ZA200105314A ZA200105314A ZA200105314B ZA 200105314 B ZA200105314 B ZA 200105314B ZA 200105314 A ZA200105314 A ZA 200105314A ZA 200105314 A ZA200105314 A ZA 200105314A ZA 200105314 B ZA200105314 B ZA 200105314B
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South Africa
Prior art keywords
substituted
alkyl
heteroaryl
aryl
heterocyclic
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ZA200105314A
Inventor
Andrei Konradi
Eugene D Thorsett
Gregory S Welmaker
Dimitrios Sarantakis
Francine S Grant
Ying-Zi Xu
Michael A Pleiss
Susan Ashwell
Anthony Kreft
Darren B Dressen
Christopher Semko
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Elan Pharm Inc
Wyeth Corp
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Publication of ZA200105314B publication Critical patent/ZA200105314B/en

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
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Description

ACYL DERIVATIVES WHICH TREAT VLA-4 RELATED DISORDERS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Serial No. 60/116,923, filed January 22, 1999, and U.S. Serial No. 60/160,999, filed October 21, 1999; the disclosures of which are incorporated herein by reference in their entirety.
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.
References
The following publications, patents and patent applications are cited in this application as superscript numbers: ! Hemler and Takada, European Patent Application Publication
No. 330,506, published August 30, 1989 2 Elices, et al., Cell, 60:577-584 (1990) 3 Springer, Nature, 346:425-434 (1990) 4 Osborn, Cell, 62:3-6 (1990) 3 Vedder, et al., Surgery, 106:509 (1989) 6 Pretolani, et al., J. Exp. Med., 180:795 (1994) 7 Abraham, et al., J. Clin. Invest., 93:776 (1994)
8 Mulligan, et al., J. Immunology, 150:2407 (1993) ’ Cybulsky, et al., Science, 251:788 (1991)
Li, et al., Arterioscler. Thromb., 13:197 (1993) n Sasseville, et al., Am. J. Path., 144:27 (1994) 2 Yang, et al., Proc, Nat. Acad. Science (USA), 90:10494 10 (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 Yednock, et al., Nature, 356:63 (1992) 7 Baron, et al., J. Exp. Med., 177:57 (1993) 18 van Dinther-Janssen, et al., J. Immunology, 147:4207 (1991) 19 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52:672 (1993) 2 Elices, et al., J. Clin. Invest., 93:405 (1994) a Postigo, et al., J. Clin. Invest. 89:1445 (1991) » zn Paul, et al., Transpl. Proceed. 25:813 (1993)
Bn Okarhara, et al., Can. Res., 54:3233 (1994) u Paavonen, et al., Int. J. Can., 58:298 (1994) 5 Schadendorf, et al., J. Path., 170:429 (1993) 26 Bao, et al., Diff., 32:239 (1993) 0 a Lauri, et al., British J. Cancer, 68:862 (1993) 2 Kawaguchi, et al., Japanese J. Cancer Res., 83:1304 (1992)
bd Kogan, et al., U.S. Patent No. 5,510,332, issued April 23, 30 International Patent Appl. Publication No. WO 96/01644 ’ 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 reference in its entirety.
State of the Ant
VLA-4 (also referred to as «,B, integrin and CD49d/CD29), first identified by Hemler and Takada' is a member of the B1 integrin family of cell surface receptors, each of which comprises two subunits, an « chain and ) 15 a B chain. VLA-4 contains an a4 chain and a B1 chain. There are at least . nine B1 integrins, all sharing the same B1 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 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 binding activities and each activity has been shown to be inhibited independently?
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 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 immune system, see, for example, Springer® and Osborn.
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.
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 3). Other inflammatory or medical 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'®2!, 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.
In view of the above, assays for determining the VLA 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 brain diseases and other inflammatory conditions®*°. The present invention addresses these and other needs.
SUMMARY OF THE INVENTION
This invention provides compounds which bind to VLA-4. Such compounds can 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 compounds of this invention have a binding affinity to VLA-4 as expressed by an ICs, of about 15 uM or less (as measured using the procedures } described in Example A below).
Accordingly, in one of its method aspects, this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which ) method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula Ia and/or Ib:
R2__ WR? RY R3__ WwW RE RY
Ps A and PY A X
R? Q R1 Q 0 lo}
Ia Ib wherein, in formula Ia, R! and R?, together with the carbon atom and
W to which they are bound respectively, are joined to form an aryl,
cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula Ib, R' and R?, together with the carbon atom and W" to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic; and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula Ia or Ib is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl,
thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -08(0),-alkyl, -OS(0),-
substituted alkyl, -OS(0),-aryl, -OS(O),-substituted aryl, -OS(O),-heteroaryl,
I
-0OS(0),-substituted heteroaryl, -OS(O),-heterocyclic, -08(0),-substituted heterocyclic, -OSO,-NRR where each R is independently hydrogen or alkyl, -NRS(0),-alkyl, -NRS(O),-substituted alkyl, -NRS(0O),-aryl, -NRS(O),- substituted aryl, -NRS(O),-heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(0),-heterocyclic, -NRS(0),-substituted heterocyclic, -NRS(O),-NR- alkyl, -NRS(0O),-NR-substituted alkyl, -NRS(0),-NR-aryl, -NRS(O),-NR- substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl, -NRS(0),-NR-heterocyclic, -NRS(0),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N [S(O)-R’], and -N[S(O),-
NR’], where each R’ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R® and R* are independently selected from the group consisting of hydrogen, isopropyl, -CH,Z where Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, , carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, . carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, ) . carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxy!-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and where R’ and R* are joined to form a substituent selected from the group consisting of =CHZ where Z is defined above provided that Z is not hydroxyl or thiol, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic and substituted heterocyclic;
Q is selected from the group consisting of -O-, -S-, -S(0)-, -S(0),, and -NR*-;
R® is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted
—~8-- cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R* and R! or R* and R?, together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group;
W is selected from the group consisting of nitrogen and carbon; and
W’ is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O),;
X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and -NR”R"” where each R” is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula Ia and/or Ib has a binding affinity to VLA-4 as expressed by an IC, of about 15uM or less.
Preferably, in the above method, R® is -(CH,),-Ar-R°, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl; R® is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxythiocarbonylamino, thioamidino, thiocarbonyiamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; and x is an integer from 0 to 4. R® is preferably alkyl or hydrogen; more preferably, R* is hydrogen.
More preferably, R® is a group of the formula:
Ro en wherein R® and x are as defined herein. Preferably, R® is in the para position of the phenyl ring; and x is an integer of from 1 to 4, more preferably, x is 1.
In a preferred embodiment, R° is selected from -O-Z-NR!'R!" and . -0-Z-R'? wherein R' and R'"’ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and where R"* and R'" are joined to form a heterocycle or a -substituted heterocycle, R'? is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group } _ consisting of -C(O)- and -SO,-. More preferably, R® is -OC(O)NR''R!", wherein R"! and R!" are as defined herein.
In the above method. Z is preferably -C(O)-. Preferably, Q is -NR-.
In a preferred embodiment, the above method employs a compound of formula Ila or IIb;
R3 R¥
ON Q A Ila
N Oo
RsSO,” “Re
R Re (2) mb
RR © wherein R’, R* and X are as defined herein; ring A and ring B independently form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring;
R® is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
RS is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R'® where R' is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; or optionally, one of, R* and ring A, R* and R®, R* and R®, or R® and
R®, together with the atoms to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic ring; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and provided that ring B does not form a 6-amino or substituted amino pyrimidin-4-yl group.
Preferably, ring A forms a pyridazine, pyrimidine or pyrazine ring; more preferably, a pyrimidine or pyrazine ring; wherein the pyridazine,
pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
Preferably, ring B forms a pyridazine, pyrimidine, pyrazine, 1-oxo- 1,2,5-thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or a 1,1-dioxo-1,2,5- thiadiazole ring; wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group oo consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, oo substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
In another preferred embodiment, the method employs a compound aE of formula Illa, llc, IIId, Ile or IIIf:
R7 p. R3 R®
X
Nn Illa
N Le ©
R5SO4” \Rs 1
R Nan R3 R3 x
R17 NF pe - Ic
R18 R¢
R16
A R3 R? = X IIId
R20 N
R18 R¢ o
R16
A
NN R3R® x Ille = on
R21 R¥ 0) i py x mf
RS—N N
CL wherein R?, R* and X are as defined herein;
R¥ is selected from the group consisting of hydrogen and alkyl or, optionally, one of, R* and R’, R*' and R®, RS and R%, RS and R®, or R® and
R®, together with the atoms to which they are bound, are joined to form a heterocyclic, a substituted heterocyclic, a heteroaryl or substituted heteroaryl group optionally containing from 1 to 3 additional hetero ring atoms selected from the group consisting of oxygen, nitrogen and sulfur:
R*" is selected from the group consisting of hydrogen and alkyl;
RS is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
RS is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R'® where R'® is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R? and R® are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R'® and RY are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R' is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R¥ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R* is selected from the group consisting of alkyl, substituted alkyl, atkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bislor2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
Preferably, the method employs a compound of formula IIId, ITle or
IIIf.
In another of its method aspects, this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula IVa and/or IVb:
R! " X' and R? N xX
R13 Le
IVa IVb wherein, in formula IVa, R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula IVb, R' and R?, together with the carbon atom and W’ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl! or heterocyclic group and optionally containing or additionally containing in the case the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic; and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula IVa or IVb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, . aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl,
guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalky!, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy,
substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -05(0),-alkyl, -0S8(0),- substituted alkyl, -OS(0);-aryl, -OS(O)-substituted aryl, -OS(O)-heteroaryl, -0S(0),-substituted heteroaryl, -0S(0),-heterocyclic, -0S(0),-substituted heterocyclic, -OSO,-NRR where each R is independently hydrogen or alkyl,

Claims (106)

PCT/US00/01686 ® 256 - CLAIMS:
1. Use of a compound of formula Ia and/or Ib: R2 R ~w RI RY ~w RI RY PS X and PY X R? Q R! Q 0 0 Ia Ib wherein, in formula Ia, R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula Ib, R! and RZ, together with the carbon atom and W’ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl, heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl, or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic; AMENDED SHEET
® PCT/US00/01686 — 257 ~ oo and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula Ia or Ib is optionally substituted, on any ring a atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino,
guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,
heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(0),-alkyl, -OS(0),-substituted alkyl, -0S8(0),-
: aryl, -OS(0),-substituted aryl, -OS(O).-heteroaryl, -OS(O),-substituted heteroaryl, -OS(O),-heterocyclic, -OS(0),-substituted heterocyclic, -OSO,- NRR where each R is independently hydrogen or alkyl, -NRS(O)-alkyl, -
NRS(O),-substituted alkyl, -NRS(O),-aryl, -NRS(O),-substituted aryl, - NRS(O),-heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(O),-heterocyclic, -NRS(Q),-substituted heterocyclic, -NRS(O),-NR- alkyl, -NRS(O),-NR-substituted alkyl, -NRS(O),-NR-aryl, -NRS(0O),-NR- substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl, -NRS(O),-NR-heterocyclic, -NRS(0),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N[S(O),-R']; and -N[S(O),-NR'], where each R’ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; AMENDED SHEET -
( PCT/US00/01686
R? and R” are independently selected from the group consisting of hydrogen, isopropyl, -CH,Z where Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalky!, carboxyl-substituted alkyl, carboxyl-cycloalkyl,
carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl,
substituted cycloalkyl, heteroaryl, ‘substituted heteroaryl, heterocyclic and : | 10 substituted heterocyclic, and where R’ and R* are joined to form a substituent selected from the group consisting of =CHZ where Z is defined above provided that Z is not hydroxyl or thiol, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic and substituted heterocyclic;
Q is selected from the group consisting of -O-, -S-, -S5(0)-, -S(0), and -NR*-;
R* is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted ary],
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R* and R’ or R* and R?, together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group; W is selected from the group consisting of nitrogen and carbon; and W’ is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O); X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substinuted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, AMENDED SHEET
PCT/US00/01686 ® 259 - substituted heterocyclyloxy and -NR"R" where each R" is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula Ia and/or Ib has a binding affinity to VLA-4 as expressed by an IC, of amount 15M or less, in the manufacture of a medicament for treating a disease mediated by VLA-4 in a patient.
2. Use according to Claim 1, wherein R? is -(CH,),-A1-R®, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl; R? is selected from the group consisting acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; and x is an integer from O to 4; and R* is hydrogen.
3. Use according to Claim 2, wherein R? is a group of the formula: Ro wherein R® and x are defined in Claim 2. 4, Use according to Claim 3, wherein R’ is in the para position of the phenyl ring and x is an integer from 1 to 4. AMENDED SHEET
PCT/US00/01686
5. Use according to Claim 4, wherein R’ is selected from the group consisting of -O-Z-NR'R'" and -O-Z-R™ wherein R' and RY are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, where R'' and R'!" are joined to form a heterocycle or a substituted heterocycle, R'" is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C(O)- and -SO,-.
6. Use according to Claim 5, wherein Z is -C(O)-.
7. Use according to Claim 6, wherein R® is -OC(O)NR''R'".
8. Use according to Claim 1, wherein Q is -NR*-.
9. Use according to Claim 1, wherein the compound has formula IIa or IIb: R3 RY x o Q N Oo RsSO; \ Re i Re Re Ib HA 8 N- oO = AMENDED SHEET
PCT/US00/01686 ® 261 - wherein ring A and B independently form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring; RS is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; R® is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substitute heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R'® where RY is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substitute heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; or optionally, one of, R* and ring A, R* and R’, R* and RS, R® and RS, together with the atoms to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic ring; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and provided that ring B does not form a 6-amino or substituted amino pyrimidin-4-y1 group.
10. Use according to Claim 9, wherein ring A forms a pyridazine, pyrimidine or pyrazine ring, wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocylic, substituted heterocyclic and halogen; and ring B forms a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5- thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring, wherein the pyridazine, AMENDED SHEET
PCT/US00/01686 ® -- 262 -- pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocylic, substituted heterocyclic and halogen.
11. Use according to Claim 1, wherein the compound has formula Illa, IIIc, II1d, Ille or IIIf: R7 X N he O rssOy’ Nps R! Nay RI RY . X : R17 Z Nr Me Ri R¥ © R18 = X md Ro” \ R18 R4” Q AMENDED SHEET
® © PCT/US00/01686
RS R17 NN RIRY N= X R21 R¥ O a N oN R3 RY.
MA x ms RS—N N s | Le 6 wherein R* is selected from the group consisting of hydrogen and alkyl or, optionally, one of, R* and R®, R*' and R®, R® and R®, R® and R®, or R® and R®, together with the atoms to which they are bound, are joined to form a heterocyclic, a substituted heterocyclic, a heteroaryl or substituted heteroaryl group optionally containing from I to 3 additional hetero ring atoms selected from the group consisting of oxygen, nitrogen and sulfur; R* is selected from the group consisting of hydrogen and alkyl; R® is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; AMENDED SHEET o | PCT/US00/01686
~~ Réis selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO.R' where R'® is selected from the - group consisting of alkyl, substiruted alkyl, cycloalkyl, substirted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl; heteroaryl, substituted heteroaryl; R’ and R® are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; ~ R'and R” are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and R" is selected from the group consisting of alkyl, substituted alkyl, : alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R* is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
: 25 R? is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
bis1or2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
AMENDED SHEET
PCT/US00/01686 ® 265 -
12. Use according to Claim 11, wherein the compound is selected from formula IIId, [IIe or IIIf.
13. Use of a compound of formula IVa and/or IVb: R? R Pid R14 R1S Sw R14 R1S R1 oe and A . L IVa IVb wherein, in formula IVa, R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula IVb, R! and R?, together with the carbon atom and W’ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl, heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic; AMENDED SHEET
® PCT/US00/01686 and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula IVa or IVb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thicamidino, aminoacy!, aminocarbonylamino,
. aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substinuted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substinted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S(0),-alkyl, -OS(O),-substituted alkyl, -OS(0),- - aryl, -OS(0),-substituted aryl, -0S(0),-heteroaryl, -OS(0),-substituted heteroaryl, -OS(O),-heterocyclic, -0S(0),-substituted heterocyclic, -0S0,- NRR where each R is independently hydrogen or alkyl, -NRS(O),-alkyl, -NRS(O),-substituted alkyl, -NRS(O),-aryl, -NRS(O),- substituted aryl, -NRS(O),-heteroary!, -NRS(O),-substituted heteroaryl, -NRS(O),-heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O),-NR- alkyl, -NRS(O),-NR-substituted alkyl, -NRS(O),-NR-aryl, -NRS(0),-NR- substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl, -NRS(O),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N[S(O)-R’], and -N[S(0),-NR’}, where each R’ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; AMENDED SHEET
@ : PCT/US00/01686 RB is selected from the group consisting of hydrogen, C, ,, alkyl, Cy, and Cy-C, jg alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from R*; and Cy is optionally substituted with one to four substituents independently selected from R®; R" is selected from the group consisting of hydrogen, Coro alkyl,
Cy. alkenyl, C, 4 alkynyl, Cy, Cy-C, alkyl, Cy-C, , alkenyl and Cy-C, ,, alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from phenyl and RX, and Cy is optionally substituted with one to four substituents independently selected from R’; or RP, R" and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N , Oand S; : RY is selected from the group consisting of C,.,, alkyl, C;.10 alkenyl,
C,.10 alkynyl, aryl, aryl-C,..a alkyl, heteroaryl, heteroaryl-C, , alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R*, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R’; or R', R' and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, Oand S; R* is selected from the group consisting of Cy and a group selected from R*, wherein Cy is optionally substituted with one to four substituents independently selected from R® R® is selected from the group consisting of R*, C, alkyl, Cy alkenyl, C, ,, alkynyl, aryl C, alkyl, heteroaryl C...0 alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from RS; R¢ is selected from the group consisting of halogen, NO,, C(O)OR!, : C, salkyl, C alkoxy, aryl, aryl C,, alkyl, aryloxy, heteroaryl, NR'RS, R'C(O)Rt, NR'C(O)NR'R#, and CN; AMENDED SHEET
® | PCT/US00/01636 - R? and Re are independently selected from hydrogen, C, ,, alkyl, C, alkenyl, C,., alkynyl, Cy and Cy C,,j0alkyl, wherein alkyl, alkenyl, ~ alkynyl and Cy are optionally substituted with one to four substituents independently selected from R°; or R? and R° together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; R'and R¢ are independently selected from hydrogen, C, ,, alkyl, Cy and Cy-C,,, alkyl wherein Cy is optionally substituted with Ci.10 alkyl; or R" and R* together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R" is selected from the group consisting of hydrogen, C, ,, alkyl, C,, alkenyl, C,.,, alkynyl, cyano, aryl, aryl C, galkyl, heteroaryl, heteroaryl C,_,, “alkyl, and -SO,R/; wherein alkyl, alkenyl, and alkynl are optionally substituted with one to four substitutents independently selected from R®; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R®; R'is selected from the group consisting of C,.10 alkyl, C, ,, alkenyl,
C..i0 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R*; : R* is selected from the group consisting of -OR?, -NO,, halogen, -5(0).R*, -SR¢, -5(0),0R?, -5(0),NR‘R*, -NRR*, -O(CR'R),NR?R®, -C(O)R, -CO,R?, -CO,(CR'R®),CONRR®, -OC(O)RY, -CN, -C(O)NRIRS, -NR!C(O)R?, -OC(O)NRR®, -NR’C(O)OR, -NRC(O)NR?R*, -CR¥N-OR®), CF;, oxo, NR'C(O)NR?SO,R!, NR!S(0),,R*, -OS(0),0R", and -OP(O)(OR?%),; RY is selected from the group consisting of R*, C,,, alkyl, C, alkenyl, C,.,, alkynyl, aryl C, jpalkyl, heteroaryl C, ,, alkyl, cycloalkyl, AMENDED SHEET
PCT/US00/01686 J -- 269 heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from RX; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10; W is selected from the group consisting of carbon and nitrogen; W’ is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O),; X’ is selected from the group consisting of -C(O)OR’, -P(O)(ORY)(OR9), -P(0)(RY)(OR"), -S(0),, OR", -C(O)NR'R", and -5-tetrazolyl; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula IVa and/or IVb has a binding affinity to VLA-4 as expressed by an ICs, of about 15uM or less, in the manufacture of a medicament for treating a disease mediated by VLA-4 in a patient.
14. Use according to Claim 13, wherein R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring.
15. Use according to Claim 14, wherein R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, 1-0xo-1 ,2,5-thiadiazole or 1,1-dioxo- 1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, 1-oxo- 1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen. AMENDED SHEET
PCT/US00/01686 ® --270 --
16. Use according to Claim 13, wherein X’ is -C(O)OR".
17. Use according to Claim 13, wherein the compound has formula Va, Vc, Vd, Ve or Vf: R7 J urs NZ N RR MX NO ) x Va Nhe RISO, “ee RY ASN R14 R18 R17 Z A Co Ve R18 R13 i R16 Pe N RRS AX ow a X' R18 R13 . AMENDED SHEET
® PCT/US00/01686 : R16 "A oo XN RMR? PS N NS : Ve
> .R21 bos ie N~ SsN R14 RIS SLA RS—N N X' I he wherein R? is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; RS is selected from the group consisting of hydrogen, alkyl, : substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted : cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R!® where R' is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and R’ and R? are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, AMENDED SHEET
PCT/US00/01686 € 272 substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R' and RY are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and R!® is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitute heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substitute heterocyclic and halogen; R2 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bis 1 or 2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
18. Use according to Claim 17, wherein the compound is selected from formula Vd, Ve or Vf.
19. Use of a compound of formula Va and/or VIb: AMENDED SHEET
® PCT/US00/01686
R2 R2 : : ~w R*R2> Sw R#R2» J and A k " Ly Via VIb wherein, in formula VIa, R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula VIb, R! and R?, together with the carbon atom and W' to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic; and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula VIa or VIb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thicamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, AMENDED SHEET
® | PCT/US00/01686 substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosuifone, thiol, thicalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, : oxythiocarbonylamino, -OS(0),-alkyl, -OS(0),-substituted alkyl, -O8(0),- aryl, -OS(0O),-substituted aryl, -OS(O),-heteroaryl, -0S(0),-substituted 3 : heteroaryl, -OS(O),-heterocyclic, -OS(O),-substituted heterocyclic, -0S0,- NRR where each R is independently hydrogen or alkyl, -NRS(O),-alkyl, - . NRS(O),-substituted alkyl, -NRS(O),-aryl, -NRS(O),-substituted aryl, - NRS(O),-heteroaryl, -NRS(O),-substituted heteroaryl, : -NRS(0),-heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O),-NR- alkyl, -NRS(O),-NR-substituted alkyl, -NRS(0),-NR-aryl, -NRS(O),-NR- substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(O),-NR-substituted : heteroaryl, -NRS(O),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N[S(O%-R’]), and -N[S(O)-NR'], where each R’ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; RZ is selected from the group consisting of hydrogen, Ci. alkyl optionally substituted with one to four substituents independently selected from R* and Cy optionally substituted with one to four substituents independently selected from R®’; R* is selected from the group consisting of Ar'-Ar®-C,_,, alkyl, Ar-ARC,, alkenyl, Ar'-Ar’-C,,, alkynyl, wherein Ar! and Ar? are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from R®; alkyl, alkenyl and : AMENDED SHEET
@® PCT/US00/01686 : -~ 275 —- alkynyl are optionally substituted with one to four substituents independently selected from R*; R% is selected from the group consisting of hydrogen, C...0 alkyl,
C,.i0 alkenyl, C, alkynyl, aryl, aryl C, ,,alkyl, heteroaryl, and heteroaryl C,. alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R*, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R®;
a. R* is selected from the group consisting of Cy, -OR?, -NO,, halogen 10 -S(O)mR*, -SR?, -§(0),0R?, -S(0) NR?R®, -NR*R*, -O(CR"R¥),NRYR*, -C(O)R?, -CO;R”, -CO,(CRR*"),CONR?R*’, -OC(O)R?, -CN, -C(O)NR*R®, -NR¥C(O)R®, -OC(O)NR*R*, -NR¥C(O)OR*, : -NR“C(O)NR?R*, -CR*(N-OR*), CF;, and -OCF;; wherein Cy is optionally substituted with one to four substituents independently selected from R*; R* is selected from the group consisting of R*, C,.,, alkyl, Cito alkenyl, C,,o alkynyl, aryl C,., alkyl, heteroaryl C, alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from R°'; Ris selected from the group consisting of halogen, amino, carboxy, C4 alkyl, C, alkoxy, aryl, aryl C, alkyl, hydroxy, CF,, and aryloxy; R? and R* are independently selected from hydrogen, C,_,, alkyl, C, 0 alkenyl, C,.,o alkynyl, Cy and Cy C, alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R¥'; or R* and R¥ together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; R" and R® are independently selected from hydrogen, C,.,, alkyl, Cy and Cy-C,.i0 alkyl; or R” and R¥' together with the carbon to which they are AMENDED SHEET
PCT/US00/01686 ® 276 attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; RY is selected from the group consisting of hydrogen, Cj alkyl, Cy.10 alkenyl, C, , alkynyl, cyano, aryl, aryl C,.,, alkyl, heteroaryl, heteroaryl C, jo alkyl, or -SO,R"; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R*; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R®; R" is selected from the group consisting of Co alkyl, Cy. alkenyl, C,. alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from RY; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X" is selected from the group consisting of -C(O)OR?, -P(0)(OR¥)(OR?), -P(O)(R*)(OR®), -S(0),OR?, -C(O)NRYR", and -3- tetrazolyl; m is an integer from 1 to 2; n is an integer from 1 to 10; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula IVa and/or IVb has a binding affinity to VLA-4 as expressed by an IC,, of about 15uM or less, ) in the manufacture of a medicament for treating a disease mediated by VLA-4 in a patient.
20. Use according to Claim 19, wherein R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring. AMENDED SHEET
PCT/US00/01686 ® 277
21. Use according to Claim 20, wherein R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, 1-oxo0-1,2,5-thiadiazole or 1, 1-dioxo- 1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, 1-oxo- 1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
22. Use according to Claim 19, wherein X" is -C(O)ORY.
23. Use according to Claim 19, wherein R* is -CH,-Ar*-Ar' and R® is hydrogen.
24. Use according to Claim 19, wherein the compound has formula VIIa, VIlc, VIId, VIle or VIIf: R7 A Va Ny xX" Via Nhe RSSO} Rs R! Nan R24 R25 MO vm R17 Z I xX" . Rie RZ AMENDED SHEET
_ PCT/US00/01686
R16 oo py R24 R25 Ne Vid = : R17 ! X" R20 R23 R16 R17 XN R24R2S N = MC Be x VIle R21 R23 i S : ZN N N R24 R25 \ / BYE Vif R5—N N x" Las R6 wherein R? is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; R¢ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, AMENDED SHEET
PCT/US00/01686 ® -- 279 -- heteroaryl, substituted heteroaryl, and -SO,R'® where R'® is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and R7 and R® are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R'¢ and R'7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitute heterocyclic and halogen; and R' is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R? is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bis 1 or 2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
25. Use according to Claim 24, wherein the compound is selected from formula VIId, VIle or VIIf. AMENDED SHEET
PCT/US00/01686 ® 280
26. Use according to Claims 1, 13 or 19, wherein the disease mediated by VLA-4 is an inflammatory disease.
27. A compound of formula Ia and/or Ib: R2 Sw RORY Sw Re RY ML X and PY X RY A R! AN 0 o) Ia Ib wherein, in formula Ia, R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula Ib, R! and R?, together with the carbon atom and W’ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl, heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic; and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula Ia or Ib is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group AMENDED SHEET consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy,
substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl,
substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(0),-alkyl, -OS(0),-substituted alkyl, -OS(0),- aryl, -OS(0),-substituted aryl, -OS(O),-heteroaryl, -0S(0),-substituted heteroaryl, -OS(0),-heterocyclic, -OS(O),-substituted heterocyclic, -OSO,- NRR where each R is independently hydrogen or alkyl, -NRS(O)-alkyl, - NRS(O),-substituted alkyl, -NRS(O),-aryl, ~-NRS(O),-substituted aryl, - NRS(O),-heteroaryl, -NRS(O),-substituted heteroaryl,
-NRS(0),-heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O),-NR-
alkyl, -NRS(0),-NR-substituted alkyl, -NRS(0),-NR-aryl, -NRS(0),-NR- substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(0O),-NR-substituted heteroaryl, -NRS(0O),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N[S(0),-R’), and -N[S(0),-NR’}, where each R’ is independently selected from the group consisting of alkyl,
substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
R? is -(CH,),-Ar-R°, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl; R’ is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino,
oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; and x is an integer from O to 4; R* is selected from the group consisting of hydrogen, isopropyl,
-CH,Z where Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl- substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic,
carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
Q is selected from the group consisting of -O-, -S-, -S(O)-, -S(0),,
and -NR*-;
R* is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R* and R' or R* and R?, together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group;
W is selected from the group consisting of nitrogen and carbon; and
W’ is selected from the group consisting of nitrogen, carbon, oxygen,
sulfur, S(O). and S(O);
X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,
substituted heterocyclyloxy and -NR“R” where each R” is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; and enantiomers, diasteromers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula Ia and/or Ib has a binding affinity to VLA-4 as expressed by an IC, of about 15uM or less.
28. The compound of Claim 27, wherein R® is a group of the formula: R9 : - wherein R’ and x are as defined in Claim 27; and R* is hydrogen.
29. The compound of Claim 28, wherein R’ is in the para position of the phenyl ring, and x is an integer from 1 to 4.
30. The compound of Claim 29, wherein R’ is selected from the group consisting of -O-Z-NR"'R'"" and -O-Z-R'? wherein R!' and R"" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and where R!! and R'" are joined to form a heterocycle or a substituted heterocycle, R' is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C(O)- and -SO;-.
31. The compound of Claim 30, wherein Z is -C(O)-.
32. The compound of Claim 31, wherein R’ is -OC(O)NR''R!"",
33. The compound of Claim 27, wherein Q is -NR*-.
34. The compound of Claim 27, wherein the compound has formula Ila or IIb: R3 R3 X Ia ( : _ pe N 0) RsSO,” “Re io Re Re X N-< 0) rR FR wherein ring A and ring B independently form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring; R? is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R® is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R' where R" is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; or optionally, one of, R* and ring A, R* and R®, R* and RS, or R® and R®, together with the atoms to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic ring; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and provided that ring B does not form a 6-amino or substituted amino pyrimidin-4-yl group.
35. The compound of Claim 34, wherein ring A forms a pyridazine, pyrimidine or pyrazine ring, wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen, and ring B forms a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5- thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring, wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
36. The compound of Claim 27, wherein the compound has formula Illa, Tlic, IIid, IIle or IIIf: rR? JY 3 3 X PN Ila N he > R5SOs” \Re
R18 Nan R3 RY X R17 Zz oy Ic
R18 R¢¥ oO R16 : 1 N“ SN RR? PZ X Id R20 R18 R4" 0
R16 R17 AS R3 R? x Mle N 8 Rt Re ©
(De NN RS Re MA ~( x ms RS—N N : Le : Le 0) wherein R* is selected from the group consisting of hydrogen and alkyl or, optionally, one of, R* and R®, R*' and R®, R® and R®, RS and R®, or R® and R®, together with the atoms to which they are bound, are joined to form a heterocyclic, a substituted heterocyclic, a heteroaryl or substituted heteroaryl group optionally containing from 1 to 3 additional hetero ring atoms selected : from the group consisting of oxygen, nitrogen and sulfur;
R* is selected from the group consisting of hydrogen and alkyl;
R® is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R® is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, and -SO,R!® where R'® is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R’ and R® are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R'® and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and R'® is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R® js selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R? is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bis 1or2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
37. The compound of Claim 36, wherein the compound is selected from formula IIId, Ile or IIIf.
38. A compound of formula IVa: Rw RY Ris R! JA Va L wherein R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl group having two nitrogen atoms in the heteroaryl ring;
and further wherein said heteroaryl group is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacy!, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl,
“substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,
: : heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(0),-alkyl, -OS(O),-substituted alkyl, -08(0),-
aryl, -OS(0O),-substituted aryl, -OS(O),-heteroaryl, -OS(O),-substituted heteroaryl, -OS(0),-heterocyclic, -OS(O),-substituted heterocyclic, -OSO0,- NRR where each R is independently hydrogen or alkyl, -NRS(0),-alkyl, -NRS(O),-substituted alkyl, -NRS(O),-aryl, -NRS(O),-substituted aryl, -NRS(O),-heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(O),-
heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O),-NR-alkyl, -NRS(O),-NR-substituted alkyl, -NRS(0),-NR-aryl, -NRS(O),-NR-substituted aryl, -NRS(0O),-NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl, -NRS(0),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N[S(0),-R’], and -N[S(O),-NR’], where each R’ is independently selected from the group consisting of alkyl, substituted alkyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; RB is selected from the group consisting of hydrogen, C, alkyl, Cy, and Cy-C, alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from R?; and Cy is optionally substituted with one to four substituents independently selected from RY; R' is selected from the group consisting of hydrogen, C,_,, alkyl, Coro alkenyl, C, , alkynyl, Cy, Cy-C, , alkyl, Cy-C, ,, alkenyl and Cy-C, ,, alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from phenyl and RX, and Cy is optionally substituted with one to four substituents independently selected from R': or RP, R" and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, Oand S; RY is selected from the group consisting of C, ,, alkyl,
Cy. alkenyl, C, alkynyl, aryl, aryl-C, ,, alkyl, heteroaryl, heteroaryl-C, ,, alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R*, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R’; or R*, RY and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N,Oand S; R? is selected from the group consisting of Cy and a group selected from R*, wherein Cy is optionally substituted with one to four substituents independently selected from R® R® is selected from the group consisting of R®, Ci.oalkyl, C, 4p alkenyl, C, ,, alkynyl, aryl C, alkyl, heteroaryl C, ,, alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R°; R® is selected from the group consisting of halogen, NO,, C(O)OR',
-- 291 ~ Ciaalkyl, C,, alkoxy, aryl, aryl C,, alkyl, aryloxy, heteroaryl, NR'RE, R'C(O)Rt, NR'C(O)NR'RE, and CN; R? and R° are independently selected from hydrogen, C, , alkyl, C, , alkenyl, C, ,, alkynyl, Cy and Cy C, alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from RS; or R? and R° together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; R"and Re are independently selected from hydrogen, C, ,, alkyl, Cy and Cy-C, ,, alkyl wherein Cy is optionally substituted with Ci.10 alkyl; or R" and RE together with the carbon to which they are attached form a i : ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R" is selected from the group consisting of hydrogen, C,., alkyl, C,,, alkenyl, C,. alkynyl, cyano, aryl, aryl C,,, alkyl, heteroaryl, heteroaryl C,,, ; alkyl, and -SO,R’; wherein alkyl, alkenyl, and alkynl are optionally obi substituted with one to four substitutents independently selected from R*: and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R®; Ri is selected from the group consisting of C, ,, alkyl, C,,, alkenyl, C10 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R*; R* is selected from the group consisting of -OR¢, -NO,, halogen, -S(0).R?, -SR, -S(0),0RY, -S(0) NRR*, -NR°R¢, -O(CRR#),NR°R¢, -C(O)R¢, -CO,R?, -CO,(CR'RE),CONR‘R*, -OC(O)R?, -CN, -C(O)NR‘R, -NR‘C(O)R®, -OC(O)NR°R¢, -NR’C(O)OR?, -NRC(O)NR‘R*, -CR¥(N-OR), CF;, oxo, NR‘C(O)NRSO,R', NRS(0)_R", -0S(0),0R¢, and -OP(O)(ORY),;
RY is selected from the group consisting of R*, C,,, alkyl, Co alkenyl, GC, alkynyl, aryl C, alkyl, heteroaryl C,_, alkyl, cycloalkyl, heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substitutents independently selected from R*: Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10; W is selected from the group consisting of carbon and nitrogen; W’ is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(0),; X’ is selected from the group consisting of -C(O)OR¢, -P(O)(OR*)(OR*), -P(O)(RY)(OR"), -8(0),,OR¢, -C(O)NRR", and -5- tetrazolyl; and enatiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formuta IV has a binding affinity to VLA-4 as expressed by an ICy, of about 154M or less: and provided that when R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a 2- arylpyrimidin-4-y! group and R" is hydrogen, then R* is not alkyl of from 1 to 6 carbon atoms optionally substituted with hydroxyl; and when R' and RZ, together with the carbon atom and W to which they are bound respectively, are joined to form a 5-arylpyrazin-2-yl group and R" is hydrogen, then RY is not 4-hydroxybenzyl.
39. The compound of Claim 38, wherein R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1- dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, I-ox0-1,2,5-thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
40. The compound of Claim 38, wherein X' is -C(O)OR?.
41. The compound of Claim 38, wherein the compound has formula Va, Vc, Vd, Ve or Vf:
- . BR 14 R15 N= RR s HN . R N Va i. N Les ris; Os Re Nan R14 R15 Ve PSY R17 | X' R18 Rm R16 N A N RMR? P'S == vd Pn X' R18 R13
R16 R17 A 14R1S DY R21 R13 le S N” ON RM RIS a WG R&—N N X ke RS wherein
R’ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R® is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R'® where R' is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and
--295 —~ R’ and R?® are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R'® and RY are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and R'is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R? is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R? is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bis 1or2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
42. The compound of Claim 41, wherein the compound is selected from formula Vd, Ve or Vf.
43. A compound of formula VIa and/or VIb; “Sw R24 R25 “Sw Reps A pe and A - Ls Via Vib wherein, in formula VIa, R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic;
in formula VIb, R' and R?, together with the carbon atom and W’ to which they are bound respectively, are joined to form a cycloalkyl,
cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula Vla or VIb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino,
alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalky!, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino,
oxythiocarbonylamino, -08(0),-alkyl, -OS(O),-substituted alkyl, -0S(0),- aryl, -OS(0),-substituted aryl, -OS(O),-heteroaryl, -OS(O),-substituted heteroaryl, -OS(0),-heterocyclic, -OS(O),-substituted heterocyclic, -080,-
NRR where each R is independently hydrogen or alkyl, -NRS(0),-alkyl, -NRS(0O),-substituted alkyl, -NRS(O),-aryl, -NRS(O),-
substituted aryl, -NRS(0O),-heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(O),-heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O),-NR- alkyl, -NRS(O),-NR-substituted alkyl, -NRS(O),-NR-aryl, -NRS(0),-NR-
; substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl, -NRS(O),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N[S(O)-R’], and -N[S(0),-NR’], where each R’ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
RZ is selected from the group consisting of hydrogen, Ci.10 alkyl optionally substituted with one to four substituents independently selected from R* and Cy optionally substituted with one to four substituents independently selected from R”; R* is selected from the group consisting of Ar'-Ar?-C, , alkyl, Ar'-Ar>-C, j, alkenyl, Ar'-Ar’-C, , alkynyl, wherein Ar' and Ar? are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from R*; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from R*; R* is selected from the group consisting of hydrogen, C,_,, alkyl,
C,.10 alkenyl, C,.), alkynyl, aryl, aryl C, alkyl, heteroaryl, and heteroaryl C,. alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R*, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R*; 10 R* is selected from the group consisting of Cy, -OR*, -NO,, halogen S(0).R?, -SRY, -§(0),0R¢, -S(0),,NR*R*, -NR*R®’, -O(CR"R#),NR¢R*, -C(O)R¥, -CO,R¥, -CO,(CRfR#),CONR‘R, -OC(O)R?, -CN, -C(O)NRR®, -NR¥C(O)R®, -OC(O)NRYR®’, -NR¥C(O)OR*’, -Nr¥C(O)NR?*R¢, -CR*(N-OR*), CF,, and -OCF;; wherein Cy is optionally substituted with one to four substituents independently selected from R; R” is selected from the group consisting of R¥', C, ,, alkyl, C, ,, alkenyl, C, j, alkynyl, aryl C,_, alkyl, heteroaryl C, ,,alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from R*; R is selected from the group consisting of halogen, amino, carboxy,
C,. alkyl, C,, alkoxy, aryl, aryl C,, alkyl, hydroxy, CF, and aryloxy; R* and R* are independently selected from hydrogen, C, ,, alkyl, C, 0 alkenyl, C,,, alkynyl, Cy and Cy C,_j,alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R; or R* and R* together with the atoms to which they are attached form a heterocyclic ring of S to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; Rf and R¥ are independently selected from hydrogen, C, ,, alkyl, Cy and Cy-C, , alkyl; or R" and R#' together with the carbon to which they are
-~ 299 -- attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R" is selected from the group consisting of hydrogen, C,.,, alkyl,
C,.10 alkenyl, C, ,, alkynyl, cyano, aryl, aryl C,_, alkyl, heteroaryl, heteroaryl C, , alkyl, or -SO,R¥; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently ‘selected from R*’; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R*; R" is selected from the group consisting of C, ,, alkyl, C,.,, alkenyl,
C,.10 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from RE; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X" is selected from the group consisting of -C(O)OR?, -P(O)(OR?)(OR*), -P(O)(R*)}(OR®), -S(0),,OR?, -C(O)NRYR", and -5- - tetrazolyl; m is an integer from 1 to 2; n is an integer from 1 to 10; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof’, and further wherein the compounds of formula VIa and/or VIb have a binding affinity to VLA-4 as expressed by an IC, of about 15uM or less.
44. The compound of Claim 43, wherein R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring.
45. The compound of Claim 44, wherein R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1- dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, 1-oxo0-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
46. The compound of Claim 43, wherein X" is -C(O)OR?.
47. The compound of Claim 43, wherein R* is -CH,-Ar?-Ar' and RZ is hydrogen.
48. The compound of Claim 43, wherein the compound has formula VIIa, Vlic, VIId, Vile or VIIf: R7 : I NZ SN R24 R25 IN R AN xX" Vila N es R5S0% “Rs
25 . Rie j Nan R24R25 Pe R17 N xX" VIIc R18 R23
R16 BY 24 R25 NTN RR Ne Vid = LU R1 X R20 R23 R16 R17 XN R2R2 : N_ = NE Vile A 23 1s R21 R : 0 S N° °N R24 RZ \ 4 YE VIIf R5— N N x" ke R6 wherein R? is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; R¢ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, and -SO,R!® where R! is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and R’ and R® are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R'® and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and R' is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R? is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R?! is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bislor2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
49. The compound of Claim 48, wherein the compound is selected from formula VIId, VIIe or VIIf.
50. A compound selected from the group consisting of: N-(2-chloro-5-nitropyrimidin-4-y1)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine,
N-[5-(N-4-toluenesulfonylamino)pyrimidin-4-y1]-L-4-(N,N- dimethylcarbamyloxy)phenylalanine zerr-butyl ester, N-[5-(N-4-toluenesulfonylamino)pyrimidin-4-yl]-L-4-(N,N- dimethylcarbamyloxy)phenylalanine,
N-[5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-y1]-L-4-(N,N- dimethylcarbamyloxy)phenylalanine tert-butyl ester, N-[5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-y1}-L-4-(N,N- dimethylcarbamyloxy)phenylalanine, N-{5-(N, N-di-4-toluenesuifonylamino)pyrimidin-4-yl}-L-4-(N,N- dimethylcarbamyloxy)phenylalanine,
N-[5-[N-(1-N -methylpyrazol-4-ylsulfonyl)-N-methylamino]pyrimidin- 4~yl]-L-4-(N,N-dimethylcarbamyloxy)phenylalanine, N-[5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-y1}-L-4-(N,N- dimethylcarbamyloxy)phenylalanine isopropyl ester,
N-[5-(N-methyl-N-3-pyridylsulfonylamino)pyrimidin-4-y1}-L-4-(N.N- dimethylcarbamyloxy)phenylalanine ferr-buty! ester, N-(5-(N-methyl-N-(1-butylpyrazol-4-yl)sul fonylamino)pyrimidin-4-yl)-
L-4-(N, N-dimethylcarbamyloxy)phenylalanine, N-(5-(2,4-dimethoxypyrimidin-5-yl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine,
N-(5-(2,6-difluorophenyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(5-(2-hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine,
40 N-(2-(N-cyclohexylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine,
N-(2-(N-methyl-N-(1-methylpiperidin-4-yl)amino)-5-(2- tolyl)pyrimidin-4-yl)-L-4-(N, N-dimethylcarbamyloxy)phenylalanine, N-(2-(N-ethyl-N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L -4-(N,N-
dimethylcarbamyloxy)phenylalanine, N-(5-(2,4-6-trimethylphenyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine,
N-(5-isopropylpyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine, N-(2-(N-methyl-N-butylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine,
N-(2-(N-ethyl-N-propylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N.
N- dimethylcarbamyloxy)phenylalanine,
N-(2-(N,N-diethylamino)-5 -(2-tolyh)pyrimidin-4-yl)-L-4-(N, N-
dimethylcarbamyloxy)phenylalanine, N-(2-(N-methy!-N-ethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N.
N- dimethylcarbamyloxy)phenylalanine,
N-(5-benzyloxypyrimidin-4-yl)-L-phenylalanine, N-(5-benzyloxypyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine,
N-(5-(N-methyl-N-4-toluenesulfonylamino)pyrimidin-4-yl)-L- phenylalanine,
N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine,
N-(5-phenylpyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(3-(N-methyl-N-4-toluenesulfonylamino)pyrazin-2-yl)-L-4-(N, N-
40 dimethylcarbamyloxy)phenylalanine, N-(5-(2,2,2-trifluoroethyl)pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine,
~ N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4- methylpiperazin-1-ylcarbonyloxy)phenylalanine isopropyl ester, N-(5-benzylpyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-yl)-L-4-(4- methylpiperazin-1-ylcarbonyloxy)phenylalanine tert-butyl ester, N-(5-(2-trifluoromethylpheny!)pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine, N-(5-(2-N, N-dimethylcarbamylethyl)pyrimidin-4-y1)-L-4-(N, V- dimethylcarbamyloxy)phenylalanine, N-(5«(N-methyl-N-3-(1-methylpyrazole)sulfonylamino)pyrimidin-4-yl)- L-4-(N, N-dimethylcarbamyloxy)phenylalanine isopropyl ester,
. N-(6-phenylpyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(6-(2-trifluoromethylphenyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, : 25 = N-(6-(2-hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(5-cyclohexylpyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine, N-(2-(N-methyl-N-2-furanmethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L- 4-(N,N-dimethylcarbamyloxy)phenylalanine, N-(2-(N-methyl-N-4-chlorophenylamino)-5-(2-tolyl)pyrimidin-4-yl)-L- 4-(N, N-dimethylcarbamyloxy)phenylalanine, N-(5-(3-thienyl)pyrimidin-4-y1)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, 40 N-(5-(2-thienyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(2-(N-methyl-N-2-hydroxyethylamino)-5-(2-fluorophenyl)pyrimidin- 4-yl)-L-4-(N, N-dimethylcarbamyloxy)phenylalanine,
N-(5-(piperidin-1-yl)pyrimidin-4-y!)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(5-(1-propylbutyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(2-(N-methyl-N-cyclobutylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4- (N,N-dimethylcarbamyloxy)phenylalanine, N-(2-(N-mcthyl-N-cyclobutylamino)-5-ethylpyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(2-(N,N-bis-(2-hydroxyethyl)amino)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-
(N.N-dimethylcarbamyloxy)phenylalanine, N-(2-(N-methyl-N-phenylamino)-5-(2-tolyl)pyrimidin-4-y1)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(2-(isopropoxy)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(2-(N-methyl-N-3-methylbutylamino)-5-(2-tolyl)pyrimidin-4-yl)-L- 4-(N,N-dimethylcarbamyloxy)phenylalanine, N-(2-(N-methylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(2-(2-tolyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(2<(N-methyl-N-2-hydroxyethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L- 4-(N, N-dimethylcarbamyloxy)phenylalanine, N-(2-(N-methyl-N-2-methylpropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L- 4-(N,N-dimethylcarbamyloxy)phenylalanine, 40 N-(2-(N-methyl-N-propylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(2-(N,N-dimethylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine,
N-(2-(N-methyl-N-cyclohexylamino)-5-(3-pyridyl)pyrimidin-4-yl)-L-4- (N, N-dimethylcarbamyloxy)phenylalanine, N-(5-(2-phenyl-2,2-difluoroethyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(5-(2-phenyl-2,2-difluoroethyl)-6-chloropyrimidin-4~y1)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine, N~(2-(N-methyl-N-cyclohexylamino)pyrimidin-4-y!)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(5-propylpyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine, o p . N-(5-(2-methoxyphenypyrimidin-4-yl)-L-4-(N, N- y 20 dimethylcarbamyloxy)phenylalanine, N-(5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine,
. 25 -. N-(2-(N-Methyl-N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-
. (N, N-dimethylcarbamyloxy)phenylalanine, N-(2-(N-isopropylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine isopropyl ester, N-(3-(N-methyl-N-4-toluenesulfonylamino)pyrazin-2-yl)-L- phenylalanine isopropyl ester, N-(5«(2-phenylethyl)pyrimidin-4-y1)-L-phenylalanine isopropyl ester, N-(5-(N-methyl-N-3-pyridinesulfonylamino)pyrimidin-4-y1)-L-4-(4- 40 methylpiperazin-1-ylcarbonyloxy)phenylalanine, N+(2-(N-methy-N-cyclohexylamino)-5-(2-tolyl)pyrimidin-4-yl)-L-4- (N, N-dimethylcarbamyloxy)phenylalanine,
N-(5-(2-tolyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine isopropyl ester, N-(5-(3-nitrophenyl)pyrimidin-4-yl)-L-4-(N, N-
dimethylcarbamyloxy)phenylalanine, N-(5-(3-pyridyl)pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine,
N-(5-(2-phenylethyl)pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine, N-(2-N,N-dimethylamino-5-(N-methyl-N-4- toluenesulfonylamino)pyrimidin-4-yl)-L-phenylalanine,
N-(5-(2-tolyl)pyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(2-(N-methyl-N-cyclohexylamino)-5-(2-methoxyphenyl)pyrimidin-4-
y1)-L-4-(2,6-dimethoxypheny!l)phenylalanine, N-(2-(N-methy!-N-isopropylamino)-5-(2-fluorophenyl)pyrimidin-4-y1)- L-4-(2,6-dimethoxyphenyl)phenylalanine,
N-(2-(N-methyl-N-isopropylamino)-5-(2-fluorophenyl)pyrimidin-4-yl)- L-4-(2-methoxyphenyl)phenylalanine, N-(2-(N-methyl-N-cyclohexylamino)-5-(2,6-difluorophenyl)pyrimidin- 4-yD-L-4-(2,6-difluorophenyl)phenylalanine,
N-(2-(N-methyl-N-cyclohexylamino)-5-(2- hydroxymethylphenyl)pyrimidin-4-yl)-L-4-(2,6- dimethoxypheny!)phenylalanine,
N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2,4,6- trimethylpheny!)pyrimidin-4-yl)-L-4-(2,6- dimethoxyphenyl)phenylalanine, N-(2-(N-methyl-N-cyclohexylamino)-5-(2-
40 trifluoromethylphenyl)pyrimidin-4-y1)-L-4-(2- cyanophenyl)phenylalanine, N-(2-(N-methyl-N-cyclohexylamino)-5-(3-thienyl)pyrimidin-4-yl)-L-4- (2,6-dimethoxyphenyl)phenylalanine,
N-(2-(N-methyl-N-cyclohexylamino)-5-(2-thieny!l)pyrimidin-4-yl)-L-4- (4-trifluoromethylphenyl)phenylalanine, N-(2-(N-methyl-N-cyclohexylamino)-5-(3-pyridyl)pyrimidin-4-yl)-L-4- (2,6-dimethoxyphenyl)phenylalanine, N-(2-(N-methyl-N-cyclohexylamino)-5-(3-nitrophenyl)pyrimidin-4-yl)- L-4-(2,6-dimethoxyphenyl)phenylalanine, N~(2-(N-methyl-N-cyclohexylamino)-5-(2,6-dichlorophenyl)pyrimidin- 4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine, N-(2-(N-methyl-N-cyclohexylamino)-5-(4-pyridyl)pyrimidin-4-y1)-L-4- (3-hydroxymethylphenyl)phenylalanine, N-(2-(N-ethyl-N-isopropylamino)-5-(2,6-dimethoxypheny!)pyrimidin- 4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine, « - : N-(2-(N-methyl-N-cyclohexylamino)-5-(2,3-dichlorophenyl)pyrimidin- . 20 © 4-yl)-L-4-(2,6-dimethoxyphenyl)phenylalanine, N-(2-(N-methyl-N-ethylamino)-5-(2,4,6-trimethylphenyl)pyrimidin-4- yD)-L-4-(2-cyanophenyl)phenylalanine,
~~. N-(2-(N-methyl-N-isopropylamino)-5-(2,4,6- : trimethylphenyl)pyrimidin-4-y!)-L-4-(3-pyridyl)phenylalanine, ‘ N-(2-(N,N-bis-(2-hydroxyethyl)amino)-5-(2.4,6- trimethylphenyl)pyrimidin-4-yl)-L-4-(2-cyanophenyl)phenylalanine. N-(2-(N-methyl-N-(1-methylpiperidin-4-yl)amino)-5-(2- cyanophenyl)pyrimidin-4-yl)-L-4-(2,6-difluorophenyl)phenylalanine, N-(2-(N-ethyl-N-isopropylamino)-5-(2,4,6-trimethylphenyl)pyrimidin- 4-yl)-L-4-(o-tolyl)phenylalanine, N-(2-(N-methyl-N-4-chlorophenylamino)-5-(2,4,6- trimethylphenyl)pyrimidin-4-yl)-L-4-(2,6- dimethoxyphenyl)phenylalanine, 40 N-(5-(N-methyl-N-2-(phenyl)ethylamino)pyrimidin-4-y1)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine, N-(5-(N-methyl-N-hexylamino)pyrimidin-4-yl)-L-4-(V,N- 45 dimethylcarbamyloxy)phenylalanine,
N-(5-(N-methyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine, N-(5-(N-methyl-N-tert-butylamino)pyrimidin-4-y!)-L-4-(N, N-
dimethylcarbamyloxy)phenylalanine, N-(5-(N-ethyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine,
N-(5-(N-methyl-N-2-(4-pyridyl)ethyl-pyrimidin-4-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine, N-(5-(N-methyl-N-2-(phenyl)ethylamino)pyrimidin-4-y1)-L-4-(4-(2,6- dimethoxyphenyl)phenylalanine,
N-(5-(N-methyl-N-hexylamino)pyrimidin-4-yl)-L-4-(2,6- dimethoxyphenyl)phenylalanine, N-(5-(N-methyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(2,6-
dimethoxyphenyl)phenylalanine, N-(5-(N-methyl-N-zert-butylamino)pyrimidin-4-y1)-L-4-(2,6- dimethoxyphenyl)phenylalanine,
N-(5-(N-ethyl-N-isopropylamino)pyrimidin-4-yl)-L-4-(2,6- dimethoxyphenyl)phenylalanine, N-(5-(N-methyl-N-2-(4-pyridyl)ethyl-pyrimidin-4-yl)-L-4-(2,6- : dimethoxyphenyl)phenylalanine,
N-(2-(N-methyl-N-cyclohexylamino)-5-ethylpyrimidin-4-yl)-L-4-(N, N- dimethylcarbamyloxy)phenylalanine, N-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-
tyrosine, N-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4- (N,N-dimethylcarbamyloxy)phenylalanine,
40 N-(4-(N,N-dimethylamino)-1-oxo-1,2,5-thiadiazol-3-yl)-L-4-(N,N- dimethylcarbamyloxy)phenylalanine tert-butyl ester, N-[4-(2-(3-methylphenylaminocarbonylamino)eth-1-ylamino)-1,1- dioxo-1,2,5-thiadiazol-3-yl]-L-4-(N,N-
45 dimethylcarbamyloxy)phenylalanine
N-(4-(N,N-di-n-hexylamino)-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-4-(4- methylpiperazin-1-ylcarbonyloxy)phenylalanine, N~(5-(2,2,2-trifluoroethy!)pyrimidin-d-yl)-L-4-(2,6- dimethoxyphenyl)phenylalanine, N-(2-(N-cyclohexyl-N-methyl)-5-(2-toly!)pyrimidin-4-yl)-L-4-(2,6- dimethoxyphenyl)phenylalanine, N-(5-(2-fluorophenyl)pyrimidin-4-yl)-L-4-(2,6- dimethoxyphenyl)phenylalanine, N-(2-(N-methyl-N-propyl)-5-(2-tolyl)pyrimidin-4-yl)-L-4-(2,6- dimethoxyphenyl)phenylalanine, N-(3-chloropyrazin-2-yl)-L-4-[1 -(tert-butoxycarbonyl)piperidin-4- ylcarbonylamino]phenylalanine ethyl ester,
. _ and pharmaceutically acceptable salts thereof.
51. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of i formula Ia and/or Ib: R2 ~w R3 R3 Rw R? RY MN X and PY X R1 Q R? Q o 0 Ia Ib wherein, in formula Ia, R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and
-~ 312 —- heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula Ib, R' and R?, together with the carbon atom and W’ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula Ia or Ib is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,
acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino,
guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy,
heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(0),-alkyl, -OS(O),-substituted alkyl, -OS(O),- aryl, -OS(0),-substituted aryl, -OS(0),-heteroaryl, -OS(O),-substituted heteroaryl, -OS(0),-heterocyclic, -OS(O),-substituted heterocyclic, -OSO,- NRR where each R is independently hydrogen or alkyl, -NRS(O),-alkyl, -
~ 313 -- NRS(O),-substituted alkyl, -NRS(O),-aryl, -NRS(O),-substituted aryl, - NRS(O),-heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(0),-heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O),-NR- alkyl, -NRS(0),-NR-substituted alkyl, -NRS(0),-NR-aryl, -NRS(O),-NR-
substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl, -NRS(0O),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N[S(0),-R’], and -N[S(O),-NR’}], where each R’ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic; R} is -(CH,),-Ar-R°, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl; R® is selected from the group consisting of acyl, . 3 acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl, and x is an integer from 0 to 4; RY is selected from the group consisting of hydrogen, isopropyl, -CH,Z where Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl- substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Q is selected from the group consisting of -O-, -S-, -S(0)-, -S(O),, and -NR*-;
R* is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R* and R' or R* and R?, together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group; W is selected from the group consisting of nitrogen and carbon: and W’ is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(0),; X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and -NR”R” where each R” is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; and enantiomers, diasteromers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula Ia and/or Ib has a binding affinity to VLA-4 as expressed by an IC; of about 15 uM or less.
52. The pharmaceutical composition of Claim 51, wherein R® is a group of the formula: RY om wherein R® and x are as defined in Claim 47; and R* is hydrogen.
53. The pharmaceutical composition of Claim 52, wherein R’® is in the para position of the phenyl ring; and x is an integer from 1 to 4.
54. The pharmaceutical composition of Claim 53, wherein R’ is selected from the group consisting of -O-Z-NRMR!!" and -O-Z-R" wherein R' and R'" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and where R'! and R'"" are joined to form a heterocycle or a substituted heterocycle, R'? is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C(O)- and -SO,-. ;
55. The pharmaceutical composition of Claim 54, wherein Z is -C(0)-.
56. The pharmaceutical composition of Claim 55, wherein R’ is -OC(O)NR'R',
57. The pharmaceutical composition of Claim 51, wherein Q is -NR*-.
58. The pharmaceutical composition of Claim 51, wherein the compound has formula IIa or IIb:
R3 R®¥ X Ila ( : )_, A N 0) RsSO; “RS RRs X IIb N-< lo) RR FR wherein ring A and ring B form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring;
R? is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
RS is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, and -SO,R!® where R'® is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
or optionally, one of, R* and ring A, R* and R%, R* and RS, or R® and RS, together with the atoms to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic ring; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and provided that ring B does not form a 6-amino or substituted amino pyrimidin-4-y! group.
59. The pharmaceutical composition of Claim 58, wherein ring A forms a pyridazine, pyrimidine or pyrazine ring, wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen, and ring B forms a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5- thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring, wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents
: . selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
60. The pharmaceutical composition of Claim SI, wherein the compound has formula lla, IIc, IIId, Ile or IIIf: R7 N L 4 (o) Illa RsSOg5” AN R6
R1 Nan R3 RY 3 R17 = Pr X ic : R18 R¥ 0 R16 : 1 A Mx 11d R20 Re Rv ©
R16 R17 Ile NN RI RY N X Fry R21 R¥ 0
Ne pq X mf Ri—N N Le he 0 wherein
R* is selected from the group consisting of hydrogen and alkyl or, optionally, one of, R* and R®, R*' and R®, R® and R%, R® and Ré, or R® and
R®, together with the atoms to which they are bound, are joined to form a heterocyclic, a substituted heterocyclic, a heteroaryl or substituted heteroaryl group optionally containing from 1 to 3 additional hetero ring atoms selected from the group consisting of oxygen, nitrogen and sulfur;
R¥ is selected from the group consisting of hydrogen and alkyl;
RS is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
RS is selected from the group consisting of hydrogen, alkyl,
substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R'® where R¥ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
R” and R? are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
R' and RY are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R!8 is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R* is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R? is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bis 1or2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
61. The pharmaceutical composition of Claim 60, wherein the compound is selected from formula IIId, Ile or IIIf.
62. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula IVa: RZ__ Ww RM R15 R p's IVa kes wherein R’ and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl group having two nitrogen atoms;
and further wherein said heteroaryl group is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy,
substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl,
substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(0),-alkyl, -OS(O),-substituted alkyl, -OS(0),- aryl, -OS(0),-substituted aryl, -OS(O),-heteroaryl, -OS(O),-substituted heteroaryl, -OS(0),-heterocyclic, -OS(0),-substituted heterocyclic, -0S0,- NRR where each R is independently hydrogen or alkyl, -NRS(O),-alkyl, -NRS(O),-substituted alkyl, -NRS(O),-aryl, -NRS§(0),-substituted aryl, -NRS(0),-heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(O),- heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O),-NR-alkyl,
-NRS(O),-NR-substituted alkyl, -NRS(O),-NR-aryl, -NRS(O),-NR-substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl, -NRS(O),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N{S(0),-R'], and -N[S(O),-NR’], where each R’ is independently selected from the group consisting of alkyl, substituted alkyl,
aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R" is selected from the group consisting of hydrogen, C, ,,alkyl, Cy, and Cy-C, ,, alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from R*; and Cy is optionally substituted with one to four substituents independently selected from R®; R' is selected from the group consisting of hydrogen, C, ,, alkyl, C, ,, alkenyl, C, , alkynyl, Cy, Cy-C, , alkyl, Cy-C, ,, alkenyl and Cy-C, alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from phenyl and RX, and Cy is optionally substituted with one to four substituents independently selected from R’; or RY, R'" and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, O and S; RY is selected from the group consisting of C, ,, alkyl,
C,.10 alkenyl, C, , alkynyl, aryl, aryl-C, ,, alkyl, heteroaryl, heteroaryl-C, ,, alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R*, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R’; or R", RY and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N,Oand S; R? is selected from the group consisting of Cy and a group selected from R*, wherein Cy is optionally substituted with one to four substituents independently selected from R* R® is selected from the group consisting of R*, C, ,, alkyl, Co alkenyl, C, jo alkynyl, aryl C, ,alkyl, heteroaryl C, ,, alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R°; Re is selected from the group consisting of halogen, NO,, C(O)OR',
Cialkyl, C, alkoxy, aryl, aryl C,, alkyl, aryloxy, heteroaryl, NR'R, R'C(O)R#, NR'C(O)NRR?, and CN; R? and Re are independently selected from hydrogen, C,.,, alkyl, C, 0 alkenyl, C, , alkynyl, Cy and Cy C, j,alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R<; or R? and R¢ together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; Rf and R® are independently selected from hydrogen, C, ,, alkyl, Cy and Cy-C, ,, alkyl wherein Cy is optionally substituted with Ci.10 alkyl; or R" and R® together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R" is selected from the group consisting of hydrogen, C,_, alkyl, C, ,, alkenyl, C, ,, alkynyl, cyano, aryl, aryl C, ,, alkyl, heteroaryl, heteroaryl C, ,, alkyl, and -SO,R’; wherein alkyl, alkenyl, and alkynl are optionally substituted with one to four substitutents independently selected from R®; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R®; R'is selected from the group consisting of C, 4 alkyl, C,.1 alkenyl,
C,.0 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl! and aryl are each optionally substituted with one to four substituents independently selected from RS; R* is selected from the group consisting of -OR?, -NO,, halogen, -S(0)R?, -SR, -§(0),0R¢, -S(0),,NRR*, -NR'R*, -O(CR'R#) NR'R¢, -C(O)R?, -CO,R?, -CO,(CR'R!),CONR'R®, -OC(O)RY, -CN, -C(O)NR°R®, -NRIC(O)R, -OC(O)NRIR*, -NR!C(O)OR?, -NR!C(O)NRR¢, -CRYN-0OR?), CF,, oxo, NR'‘C(O)NRSO,R!, NR?S(0),.R°, -OS(0),0R¢, and -OP(O)(ORY),;
RY is selected from the group consisting of R*, C, ,, alkyl, C, alkenyl, C,.,, alkynyl, aryl C, alkyl, heteroaryl C,., alkyl, cycloalkyl, heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substitutents independently selected from R*; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10: W is selected from the group consisting of carbon and nitrogen; W’ is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O),; X’ is selected from the group consisting of -C(O)ORY, -P(O)(OR")(OR"), -P(O)(RY)(OR?), -S(0),,OR?, -C(O)NR?R", and -5- tetrazolyl; and enatiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula IV has a binding - affinity to VLA-4 as expressed by an ICs, of about 15M or less; and provided that when R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a 2- arylpyrimidin-4-yl group and R' is hydrogen, then R' is not alkyl of from 1 to 6 carbon atoms optionally substituted with hydroxyl; and when R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a 5-arylpyrazin-2-yl group and R™ is hydrogen, then R® is not 4-hydroxybenzyl.
63. The pharmaceutical composition of Claim 62, wherein R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, 1-oxo- 1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or a 1,1-dioxo-1,2,5-
\ thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
64. The pharmaceutical composition of Claim 62, wherein X' is -C(O)OR¢,
65. The pharmaceutical composition of Claim 62, wherein the compound has formula Va, Vc, Vd, Ve or Vf: R7 PY 14 15 NZ N R'4 R ) NS X ' SN X Va Nk ReSQL Neo R16 Nan R14 R15 A R17 N X! | Ve R18 Rt
R16 A R14 R15 = MC vd R20 N > & : R18 R13 R16 R17 XN RMR! EE Ve R21 R13 .
Nk NN Rw RS MN R&—N N X he RS wherein RS is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; RS is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R" where R" is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and R” and R® are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R' and RY are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and R'is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R? is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R? is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bis 1 or2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
66. The pharmaceutical composition of Claim 6S, wherein the compound is selected from formula Vd, Ve or Vf.
67. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula Via and/or VIb: R? R? ~w R#R2z Sw R2#R2> Al , and A kes Les Via Vib wherein, in formula VIa, R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroary! or heterocyclic group is mono-cyclic; in formula VIb, R! and R?, together with the carbon atom and W’ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic;
and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula VIa or VIb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,
acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalky!, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thicheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -O8(0),-alkyl, -OS(O),-substituted alkyl, -OS(0),- aryl, -OS(0O),-substituted aryl, -OS(O),-heteroaryl, -OS(O),-substituted heteroaryl, -OS(0),-heterocyclic, -OS(O),-substituted heterocyclic, -OSO,- NRR where each R is independently hydrogen or alkyl,
-NRS(0O),-alkyl, -NRS(O),-substituted alkyl, -NRS(O),-aryl, -NRS(O),- substituted aryl, -NRS(O),-heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(O),-heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O),-NR- alkyl, -NRS(O),-NR-substituted alkyl, -NRS(O),-NR-aryl, -NRS(O),-NR- substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl, -NRS(O),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N[S(O),-R’], and -N[S(0),-NR’}, where each R’ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
RP is selected from the group consisting of hydrogen, C, ,, alkyl optionally substituted with one to four substituents independently selected from R* and Cy optionally substituted with one to four substituents independently selected from R®; R* is selected from the group consisting of Ar'-Ar?-C,,, alkyl, Ar!-Ar’-C, ,, alkenyl, Ar'-Ar>-C,,, alkynyl, wherein Ar' and Ar? are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from R”; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from R*; R? is selected from the group consisting of hydrogen, C, ,, alkyl,
C,.10 alkenyl, C, ,, alkynyl, aryl, aryl C, qalkyl, heteroaryl, and heteroaryl C,. 10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R*, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R*’; R* is selected from the group consisting of Cy, -ORY, -NO,, halogen -S(0)..R?, -SR?, -S(0),0R", -S(0),NR*R*, -NR*R*, -O(CR"R¢),NR!R*, -C(O)R?, -CO,R?¥, -CO,(CR"R®),CONR?R*, -OC(O)R?, -CN, -C(O)NR?R®, -NR¥C(O)R", -OC(O)NR?R®, -NR*C(O)OR*, -Nr*C(O)NR?YR®, -CR¥(N-OR*), CF;, and -OCF,;; wherein Cy is optionally substituted with one to four substituents independently selected from R; RY is selected from the group consisting of R*, C, ,, alkyl, C, io alkenyl, C,.,, alkynyl, aryl C,.,, alkyl, heteroaryl C, alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from R%; R® is selected from the group consisting of halogen, amino, carboxy,
C,. alkyl, C,, alkoxy, aryl, aryl C,, alkyl, hydroxy, CF;, and aryloxy;
R? and R* are independently selected from hydrogen, C, ,, alkyl, C,.,, alkenyl, GC, ,, alkynyl, Cy and Cy C, salkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R*; or R* and R* together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; R’ and R# are independently selected from hydrogen, C, ,, alkyl, Cy and Cy-C, ,, alkyl; or R" and R¥ together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R" is selected from the group consisting of hydrogen, C, ,, alkyl,
C..i0 alkenyl, C, o alkynyl, cyano, aryl, aryl C,_,, alkyl, heteroaryl, heteroaryl C, , alkyl, or -SO,R’; wherein alkyl, alkenyl, and alkynyl! are optionally substituted with one to four substitutents independently selected from R*; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R®’; R¥ is selected from the group consisting of C, alkyl, C,,, alkenyl,
C,.,0 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R<’; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X" is selected from the group consisting of -C(O)OR?, -P(O)(OR?)(OR®), -P(O)(R*)(OR®), -5(0),OR?, -C(O)NR*R", and -5- tetrazolyl; m is an integer from 1 to 2; n is an integer from 1 to 10; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof;
and further wherein the compounds of formula VIa and/or VIb have a binding affinity to VLA-4 as expressed by an IC, of about 15 uM or less.
68. The pharmaceutical composition of Claim 67, wherein R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl! ring.
69. The pharmaceutical composition of Claim 68, wherein R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, 1-oxo- 1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
70. The pharmaceutical composition of Claim 67, wherein X" is -C(O)OR®.
71. The pharmaceutical composition of Claim 67, wherein R* is -CH,-Ar?-Ar! and R? is hydrogen.
72. The pharmaceutical composition of Claim 67, wherein the compound has formula VIIa, Vile, VIId, VIle or VIIf:
R7 A R24 R25 LAK NS Nn x" Vila N zs RsSO; “Re 16 R Nan R24 R25 P MM Vic R17 " xX" R18 R23 R16 Pe N R24 R25
MC . R! X VIld R20 R23’ R16 R17 N R24 R25 A Vile R21 hes tk Nid Ss N R24 R25 py B'S VIIf R5—N N xX" lhe wherein R? is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; R® is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R'® where R!° is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and R’ and R® are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R' and R"? are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and R" is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R* is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R? is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bis1lor2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
73. The pharmaceutical composition of Claim 72, wherein the compound is selected from formula VIId, Vile or VIIf.
74. A method for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of Claims 27, 38, 43 or 50 under conditions wherein said compound binds to VLA4.
PCT/US00/01686 ® 336 —
75. A substance or composition for use in a method of treating a disease mediated by VLA-4 in a patient, said substance or composition comprising a compound of formula Ia and/or Ib: R2 ~w RR? Rw Rs RY PS X and PY X R? Q R! Q O 0 Ia Ib wherein, in formula Ia, R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula Ib, R' and R?, together with the carbon atom and W’ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl, heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl, or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic; AMENDED SHEET
PCT/US00/01686 ® -- 337 -- and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or . heterocyclic group of formula Ia or Ib is optionally substituted, on any ring atom capable of substitution, with [-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy. acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl. substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl. cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalky!. thioaryl. substituted thioaryl, thiocycloalkyl, substituted thiocycloalky!, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S(0),-alkyl, -05(0),-substituted alkyl, -0S(0),- aryl, -OS(0),-substituted aryl, -0S(0),-heteroaryl, -0S(0),-substituted heteroaryl, -OS(0),-heterocyclic, -0S(0),-substituted heterocyclic, -OSO,- NRR where each R is independently hydrogen or alkyl, -NRS(O),-alkyl, - NRS(O),-substituted alkyl, -NRS(O);-ary!, -NRS(O);-substiruted aryl, - NRS(O),-heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(O),-heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O)-NR- alkyl, -NRS(O),-NR-substituted alkyl, -NRS(O),-NR-aryl, -NRS(O),-NR- substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(0),-NR-substituted heteroaryl, -NRS(O),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N[S(O)-R’]; and -N[S(0)%-NR']; where each R’ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; AMENDED SHEET
PCT/US00/01686 ® -- 338 --
R® and R¥ are independently selected from the group consisting of hydrogen, isopropyl, -CH,Z where Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl,
: carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and where R® and R* are joined to form a substituent selected from the group consisting of =CHZ where Z is defined above provided that Z is aot hydroxyl or thiol, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic and substituted heterocyclic;
Q is selected from the group consisting of -O-, -S-, -S(0)-, -S(O), and -NR*-;
RY is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R* and R! or R* and R?, together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group;
W is selected from the group consisting of nitrogen and carbon; and
WW’ is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O);
X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted -aryloxy, heteroaryloxy. substituted heteroaryloxy, heterocyclyloxy,
AMENDED SHEET
PCT/US00/01686 ® 339 - substituted heterocyclyloxy and -NR"R" where each R" is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula Ia and/or Ib has a binding affinity to VLA-4 as expressed by an ICs, of amount 15uM or less, and said method comprising administering an effective amount of said substance or composition.
76. A substance or composition for use in a method of treatment according to Claim 75, wherein R® is -(CH,),-Ar-R°, where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl; R’ is selected from the group consisting acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thicamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; and x is an integer from O to 4; and R*" is hydrogen.
77. A substance or composition for use in a method of treatment according to Claim 76, wherein R® is a group of the formula: R9 wherein R® and x are defined in Claim 2. AMENDED SHEET
PCT/US00/01686 ® 340
78. A substance or composition for use in a method of treatment according to Claim 77, wherein R® is in the para position of the phenyl ring and x is an integer from 1 to 4.
79. A substance or composition for use in a method of treatment according to Claim 78, wherein R® is selected from the group consisting of -O- Z-NR''R"" and -O-Z-R" wherein R!! and R'" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, where R'' and R'" are joined to form a heterocycle or a substituted heterocycle, R!? is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C(O)- and -SO,-.
80. A substance or composition for use in a method of treatment according to Claim 79, wherein Z is -C(O)-.
81. A substance or composition for use in a method of treatment according to Claim 80, wherein R® is -OC(O)NR'R'".
82. A substance or composition for use in a method of treatment according to Claim 75, wherein Q is -NR*-.
83. A substance or composition for use in a method of treatment according to Claim 75, wherein the compound has formula Ila or IIb: R3 RY X a a N Riso; “RS RR mh (8) N< oO Rg Fe AMENDED SHEET
. PCT/US00/01686 wherein ring A and B independently form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring; R’ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; RS is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substitute heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R!® where R' is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substitute heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; or optionally, one of, R* and ring A, R* and R®, R* and R®, R’ and R®, together with the atoms to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic ring; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and provided that ring B does not form a 6-amino or substituted amino pyrimidin-4-yl group.
84. A substance or composition for use in a method of treatment according to Claim 83, wherein ring A forms a pyridazine, pyrimidine or pyrazine ring, wherein the pyridazine, pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocylic, substituted heterocyclic and halogen; and ring B forms a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5- thiadiazole or a 1,1-dioxo-1,2,5-thiadiazole ring, wherein the pyridazine, AMENDED SHEET
PCT/US00/01686 ® 342 pyrimidine or pyrazine ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocylic, substituted heterocyclic and halogen.
85. A substance or composition for use in a method of treatment according to Claim 75, wherein the compound has formula Illa, IIc, IIId, [Ile or IIIf: R7 X R AS Ia A ke © RssO¢” Re R? N~ 3 Ty RIRE X mic RY oe rie R¥ Oo R18 pu R3 RY _ Po md R2 R18 R#¥ Q AMENDED SHEET
® PCT/US00/01686 R16 R17 XN RI RY
No. _~ X R21 R#" O N 10 Nk S N Pa R3 RY. pg x mf REN N iy Le 0 wherein R* is selected from the group consisting of hydrogen and alkyl or, optionally, one of, R* and R*, R* and R®, R® and R®, R® and R®, or R¢ and R®, together with the atoms to which they are bound, are joined to form a heterocyclic, a substituted heterocyclic, a heteroaryl or substituted heteroaryl group optionally containing from 1 to 3 additional hetero ring atoms selected from the group consisting of oxygen, nitrogen and sulfur; R* is selected from the group consisting of hydrogen and alkyl; R? is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; AMENDED SHEET
® PCT/US00/01686
RCs selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R'® where R" is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl. cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl; heteroaryl, substituted heteroaryl;
R” and R?® are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted k heterocyclic and halogen: © Rand RY are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substimted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and
R'® is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic and substituted heterocyclic;
R* is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen;
: 25 R?! is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
bislor2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof. : AMENDED SHEET
PCT/US00/01686 ® -- 345 --
86. A substance or composition for use in a method of treatment according to Claim 85, wherein the compound is selected from formula I1ld, IIe or IIIf.
87. A substance or composition for use in a method for treating a disease mediated by VLA-4 in a patient, said substance or composition comprising a compound of formula IVa and/or IVb: 2 R Rw R14 RS Sw Y ox and R! | xX R13 R13 IVa IVb wherein, in formula IVa, R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula IVb, R' and R?, together with the carbon atom and W’ to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl, heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic; AMENDED SHEET
® 346 PCT/US00/01686 and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula IVa or IVD is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, : aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substiruted cycloalkyl, guanidino,
. - 10 guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, subsututed heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S(0),-alkyl, -0S(0),-substituted alkyl, -OS(0),-- aryl, -OS(O),-substituted aryl, -0S(0),-heteroaryl, -OS(0),-substituted ’ heteroaryl, -OS(O),-heterocyclic, -OS(0),-substituted heterocyclic, -OSO,- NRR where each R is independently hydrogen or alkyl, -NRS(O),-alkyl, -NRS(O),-substituted alkyl, -NRS(O),-aryl, -NRS(O),- substituted aryl, -NRS(O),-heteroaryl, -NRS(O).-substituted heteroaryl, -NRS(O),-heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O),-NR- alkyl, -NRS(Q),-NR-substituted alkyl, -NRS(O),-NR-aryl, -NRS(0),-NR- substituted aryl, -NRS(O),-NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl, -NRS(O),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R 1s hydrogen or alkyl, -N[S(O),-R’], and -N[S(0),-NR‘], where each R’ is independently selected from the group consisting of alkyl, substinuted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; AMENDED SHEET
® = 347 -- - PCT/US00/01686 RY is selected from the group consisting of hydrogen, C,., alkyl, Cy, and Cy-C, alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from R*; and Cy is optionally substituted with one to four substituents independently selected from R®: R'* is selected from the group consisting of hydrogen, C..0 alkyl, Cho alkenyl, Co alkynyl, Cy, Cy-C, , alkyl, Cy-C,_o alkenyl and Cy-C, ,, alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from phenyl and RX, and Cy is optionally substituted with one to four substituents independently selected from R’; © 10 or RY, R" and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, O and S; : R' is selected from the group consisting of Co alkyl, C4 alkenyl,
C,.j0 alkynyl, aryl, aryl-C, alkyl, heteroaryl, heteroaryl-C, ,, alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R*, and ary) and heteroaryl are optionally substituted with one to four substituents independently selected from R’; or R", RY and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and §; R* is selected from the group consisting of Cy and a group selected from R*, wherein Cy is optionally substituted with one to four substituents independently selected from R% R® is selected from the group consisting of R?, C, 0 alkyl, C,., alkenyl, C,.,, alkynyl, aryl C, alkyl, heteroaryl Ci.10 alkyl, witereln alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R%; Rc“ is selected from the group consisting of halogen, NG,, C(O)OR', Ca alkyl, C4 alkoxy, aryl, aryl C,, alkyl, aryloxy, heteroaryl, NR'R?, R'C(O)R, NR'C(O)NR'R?, and CN; AMENDED SHEET.
® -- 348 -- PCT/US00/01686 R? and R® are independently selected from hydrogen, C, , alkyl, C,., alkenyl, C,., alkynyl, Cy and Cy C,_j,alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from RS: b) or R¢ and R® together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; R"and R* are independently selected from hydrogen, C,_, alkyl, Cy and Cy-C,., alkyl wherein Cy is optionally substituted with C,.10 alkyl; or *- 10 R" and Re together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R" is selected from the group consisting of hydrogen, C,,, alkyl, C,, alkenyl, C, ,, alkynyl, cyano, aryl, aryl C, 5 alkyl, heteroaryl, heteroaryl C, , alkyl, and -SO,R’; wherein alkyl, alkenyl, and alkynl are optionally substituted with one to four substitutents independently selected from R*: and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R?; R'is selected from the group consisting of C4 alkyl, C, ,o alkenyl,
C...0 alkynyl, and aryl; wherein alkyl, alkenyl, alkyny! and ary! are each optionally substituted with one to four substituents independently selected from RS; R* is selected from the group consisting of -OR?, -NO,, halogen, -S(0)R?, -SRY, -S(0),0RY, -5(0), NRR*, -NRUR", -O(CR'R#),NR‘RS, -C(O)R?, -CO,R¢, -CO,(CR'R¥),CONRR®, -OC(O)R¢, -CN , -C(O)NRUR¢, -NRIC(O)R®, -OC(O)NRR®, -NRC(O)OR*, -NR*C(O)NRR", -CRYN-OR"), CF;, oxo, NR‘C(O)NRSO,R}, NR!S(0),R¢, -OS(0),0R?, and -OP(O)(OR%,; Ris selected from the group consisting of R*, C,,, alkyl, Cio alkenyl, Cy, alkynyl, aryl C, alkyl, heteroaryl C,, alkyl, cycloalkyl, AMENDED SHEET
PCT/US00/01686 o 349 heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R¥; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10; W is selected from the group consisting of carbon and nitrogen; W’ is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O),; X’ is selected from the group consisting of -C(O)OR", -P(O)(OR%)(OR9, -P(O)(RH(OR?), -S(0),,OR?, -C(O)NR'R", and -5-tetrazolyl; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula IVa and/or IVb has a binding affinity to VLA-4 as expressed by an ICs, of about 15uM or less, and said method comprising administering an effective amount of said substance or composition.
88. A substance or composition for use in a method of treatment according to Claim 87, wherein R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring.
89. A substance or composition for use in a method of treatment according to Claim 88, wherein R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen. AMENDED SHEET
PCT/US00/01686 ® -- 350 --
90. A substance or composition for use in a method of treatment according to Claim 87, wherein X’ is -C(O)OR".
91. A substance or composition for use in a method of treatment according to Claim 87, wherein the compound has formula Va, Vc, Vd, Ve or Vf: R7 BY 14 15 N= h RR GPS SP x Va N kes reso, ke R? Nay R14 R15 R17 = 2 Ve Ri R113 R16 PY N RMR A we R20 | X' R18 R13 AMENDED SHEET
® -- 351 -- PCT/US00/01686 R16 “A XN RMR? N a N Se Ve LY (Me ‘10 NTN R14 RIS MLN RS—N x I ks = wherein
R? is selected from the group consisting of alkyl, substituted alkyl, alkenyl. substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted
~ cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
R® is selected from the group consisting of hydrogen, alkyl, substtuted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO,R' where R' is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substiruted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and
R7 and R? are independently selected from the group consisting of hydrogen, alkyl. substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, AMENDED SHEET
PCT/US00/01686 ® substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R!S and R!7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; and R™ is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitute heterocyclic; R¥ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substitute heterocyclic and halogen; R? is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bis 1lor?2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
92. A substance or composition for use in a method of treatment according to Claim 91, wherein the compound is selected from formula Vd, Ve or Vf.
93. A substance or composition for use in a method for treating a disease mediated by VLA-4 in a patient, said substance or composition comprising a compound of formula VIa and/or VIb: AMENDED SHEET
® -- 353 -- PCT/US00/01686 AN R24 R25 Ri W R% Res NE N , and R A N My Jes Les Via VIb wherein, in formula Va, R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group 1s mono-cyclic; in formula VIb, R' and R?, together with the carbon atom and W' to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 10 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heterocyclic group is mono-cyclic; and further wherein said aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclic group of formula VIa or VIb is optionally substituted, on any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, .acylarnino, thiccarbonylamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thicamidino, aminoacyl, aminocarbonylamino, aminothjocarbonylaminoe, aminocarbonyloxy, aryl, substituted aryl, aryloxy, AMENDED SHEET
® 354 -- PCT/US00/01686 substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(0),-alkyl, -OS(O),-substituted alkyl, -OS(0),- ~- 10 aryl, -OS5(0),-substituted aryl, -OS(O),-heteroaryl, -0S(0),-substiruted : heteroaryl, -OS(0),-heterocyclic, -OS(0),-substituted heterocyclic, -0SO,- NRR where each R is independently hydrogen or alkyl, -NRS(O),-alkyl, - NRS(O),-substituted alkyl, -NRS(0),-aryl, -NRS(O),-substituted aryl, - NRS(O),-heteroaryl, -NRS(O),-substituted heteroaryl,
~NRS(0),-heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O),-NR- alkyl, -NRS(O),-NR-substituted alkyl, -NRS(O),-NR-aryl, -NRS(O),-NR- substituted aryl, -NRS(O),-NR-heteroaryl, -INRS(O),-NR-substituted : heteroaryl, -NRS(O),-NR-heterocyclic, -NRS(O),-NR-substituted heterocyclic where R is hydrogen or alkyl, -N[S(O}-R'], and -N{S(O}%-NR'], where each R’ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; RZ is selected from the group consisting of hydrogen, C,_, alkyl optionally substituted with one to four substituents independently selected from R* and Cy optionally substituted with one to four substituents independently selected from R; R* is selected from the group consisting of Ar'-Ar?-C,, alkyl, : Ar'-Ac-C, , alkenyl, Ar'-Ar*-C, , alkynyl, wherein Ar' and Ar? are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from R®; alkyl, alkeny! and : AMENDED SHEET
® -- 355 -- PCT/US00/01686 alkynyl are optionally substituted with one to four substituents independently selected from R*; R® is selected from the group consisting of hydrogen, C, ,, alkyl,
C,.i0 alkenyl, CG, 0 alkynyl, aryl, aryl C, alkyl, heteroaryl, and heteroaryl C,. wo alkyl, wherein alkyl, alkenyl and alkynyl! are optionally substituted with one to four substituents selected from R*’, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from RY; R* is selected from the group consisting of Cy, -OR*, -NO,, halogen == 10 -S(O)mR¥, -SR¥, -8(0),0R?, -S(0)_ NR*R*, -NRYR*, -O(CR"Rf),NRYR*, -C(O)R®, -CO,R”, -CO4(CR"R*),CONRYR®, -OC(O)R?, -CN, -C(O)NR?R®, -NRYC(O)R®, -OC(O)NR!R®, -NRYC(O)OR*, -NR“C(O)NR*R*, -CR*(N-OR*®), CF,. and -OCF;; wherein Cy is optionally substituted with one to four substituents independently selected from R; R® is selected from the group consisting of RY, C, ,, alkyl, C, alkenyl, Cy. alkynyl, aryl C,., alkyl, heteroaryl C, alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from R°’; Re is selected from the group consisting of halogen, amino, carboxy, C4 alkyl, C, alkoxy, aryl, aryl C,_ alkyl, hydroxy, CF,, and aryloxy; R? and R* are independently selected from hydrogen, C,.,, alkyl, C0 alkenyl, C,.j0 alkynyl, Cy and Cy C, ,alkyl, wherein alkyl, alkenyl, alkyny! and Cy are optionally substituted with one to four substituents independently selected from RY; or RY and R* together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; R and R¥ are independently selected from hydrogen, C,.,, alkyl, Cy and Cy-Cy.j0 alkyl; or R” and R¥ together with the carbon to which they are AMENDED SHEET
PCT/US00/01686 ® -- 356 -- attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R" is selected from the group consisting of hydrogen, Cy, alkyl, C,. alkenyl, C,.,, alkynyl, cyano, aryl, aryl C, , alkyl, heteroaryl, heteroaryl Cio alkyl, or -SO,R"; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R?¥; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R”; Ris selected from the group consisting of C,_;, alkyl, C,.o alkenyl, C,. alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R%; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X" is selected from the group consisting of ~-C(O)OR, -P(O)(ORY)(OR®), -P(O)(R*)(OR*), -5(0),OR?, -C(O)NRYR", and -5- tetrazolyl; m is an integer from 1 to 2; n is an integer from 1 to 10; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula IVa and/or IVb has a binding affinity to VLA-4 as expressed by an ICs, of about 15uM or less, and said method comprising administering an effective amount of said substance or composition.
94. A substance or composition for use in a method of treatment according to Claim 93, wherein R' and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl or substituted heteroaryl group having two nitrogen atoms in the heteroaryl ring. AMENDED SHEET
PCT/US00/01686 ® -- 357 --
95. A substance or composition for use in a method of treatment according to Claim 94, wherein R! and R?, together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, 1-oxo-1,2,5-thiadiazole or 1,1-dioxo-1,2,5-thiadiazole ring is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen.
96. A substance or composition for use in a method of treatment according to Claim 93, wherein X" is -C(O)OR".
97. A substance or composition for use in a method of treatment according to Claim 93, wherein R* is -CH,-Ar?-Ar' and R® is hydrogen.
98. A substance or composition for use in a method of treatment according to Claim 93, wherein the compound has formula VIIa, Vic, VIId, VlIle or VIIf: R7 PY 24 R25 x XY Ny xX" Via A ke RSSO; “RS R? Nan R24 R25 z Ne Vie R17 Nx ris R23 AMENDED SHEET
® -- 358 -- PCT/US00/01686 R16 pe R24 R25 Ne vid = R17 ! xX" R20 R23 R16 = 10 R17 XN R24R2S No _= Ne Fo xX Vile R21 R23
Ns S : STN N N R24 R2s \ 4 vg VIIf R—N ) xX" Lk wherein R® is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; R® is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, AMENDED SHEET
PCT/US00/01686 ® -- 359 -- heteroaryl, substituted heteroaryl, and -SO,R!® where R' is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and R’ and R® are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R' and R!” are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitute heterocyclic and halogen; and R® is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R% is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and halogen; R? is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; bis 1lor?2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
99. A substance or composition for use in a method of treatment according to Claim 98, wherein the compound is selected from formula VIId, Vlle or VIIf. AMENDED SHEET
PCT/US00/01686
100. A substance or composition for use in a method of treatment according to Claims 75, 87, or 93, wherein the disease mediated by VLA-4 is an inflammatory disease.
101. Use according to Claim 1 or Claim 13 or Claim 19, substantially as herein described and illustrated.
102. A compound according to any one of Claims 27 to 50, substantially as herein described and illustrated.
103. A composition according to any one of Claims 51 to 73, substantially as herein described and illustrated.
104. A method according to Claim 74, substantially as herein described and illustrated.
105. A substance or composition for use in a method of treatment according to any one of Claims 75 to 100, substantially as herein described and illustrated.
106. A new use of a compound of any one of Claims 27 to 50 or of a composition of any one of Claims 51 to 73, a new method for binding VLA- 4, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
ZA200105314A 1999-01-22 2001-06-27 Acyl derivatives which treat VLA-4 related disorders. ZA200105314B (en)

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