Beta-amino acid derivatives--inhibitors of leukocyte adhesion mediated by VLA-4

A compound of Formula (I):

• 13
• wherein:
• R1 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;
• R3 and R3a are independently selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, or —(Alkb)mRb in which Alkb is a C1-3alkylene chain, m is 0 or 1 and Rb is hydroxy, thiol, nitro, cyano, carboxy, —CO2Rc (wherein Rc is alkyl), —SO3H, —SORc, —SO2Rc, —SO3Rc, —OCO2Rc, —C(O)H, —CORc, —OCORc, —CSRc, —NRdRe (wherein Rd and Re are independently hydrogen, alkyl, or substituted alkyl), —CONRdRe, —OCONRdRe, —NRdCORe, —CSNRdRe, —NRdCSRe, —SO2NRdRe, —NRdSO2Re, —NRdCONReRf (where Rf is hydrogen alkyl, or substituted alkyl) or —NrdSO2NReRf;
• 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;
• A is an aryl, heteroaryl, cycloalkyl, or heterocyclic group wherein said aryl, heteroaryl, cycloalkyl, or heterocyclic 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(O)2-alkyl, —OS(O)2-substituted alkyl, —OS(O)2-aryl, —OS(O)2-substituted aryl, —OS(O)2-heteroaryl, —OS(O)2-substituted heteroaryl, —OS(O)2-heterocyclic, —OS(O)2-substituted heterocyclic, —OSO2—NRR where each R is independently hydrogen or alkyl, —NRS(O)2-alkyl, —NRS(O)2-substituted alkyl, —NRS(O)2-aryl, —NRS(O)2-substituted aryl, —NRS(O)2-heteroaryl, —NRS(O)2-substituted heteroaryl, —NRS(O)2-heterocyclic, —NRS(O)2-substituted heterocyclic, —NRS(O)2—NR-alkyl, —NRS(O)2—NR-substituted alkyl, —NRS(O)2—NR-aryl, —NRS(O)2—NR-substituted aryl, —NRS(O)2—NR-heteroaryl, —NRS(O)2—NR-substituted heteroaryl, —NRS(O)2—NR-heterocyclic, —NRS(O)2—NR-substituted heterocyclic where R is hydrogen or alkyl, —N[S(O)2-R′]2 and —N[S(O)2—NR′]2 where each R′ is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
• R2a is either:
• (i) an —Ar1—R9 group where Ar1 is aryl or heteroaryl optionally substituted with one or two substituents selected from the group consisting of hydroxy, acyl, acylamino, aminoacyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, aminoacyl, aminocarbonyloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, halo, nitro provided that said acyl, acylamino, acyloxy, substituted alkyl, substituted alkoxy and substituted thioalkyl do not carry an aryl, substituted aryl, heteroaryl or substituted heteroaryl group;
• and R9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl provided that when R9 is acylamino or acyloxy then the acylamino or acyloxy group does not carry an aryl, substituted aryl, heteroaryl or substituted heteroaryl group;
• or
• (ii) a group of formula (a) or (b):
• 14
• wherein:
• Ar2 is an aryl or heteroaryl group optionally substituted, in addition to ring B or C, with one or two substituent(s) selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, substituted alkoxy, acyloxy, substituted acyloxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, acylamino, substituted acylamino, N-acyl-N-alkylamino, substituted N-acyl-N-alkylamino, (alkylsulfonyl)amino, substituted (alkylsulfonyl)amino, N-(alkylsulfonyl)-N-alkylamino, substituted N-(alkylsulfonyl)-N-alkylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, cyano, acyl, substituted acyl, carboxy, substituted carboxy, thiol, alkylthio, substituted alkylthio, alkylsulfoxy, substituted alkylsulfoxy, alkylsulfonyl, and substituted alkylsulfonyl;
• Z is —O— or —S—;
• B is a group wherein W, together with —C(═Z)NR2—, forms a saturated or unsaturated heterocyclic group containing 2 to 5 carbon atoms and 0 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and —SOn— (where n is 0 to 2) wherein said saturated or unsaturated heterocyclic group is optionally fused with one or two ring(s) structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group to form a bi- or tri-fused ring system and further wherein said heterocyclic group and each of such ring structures are optionally substituted with 1 to 3 substituents selected from the group consisting of with one or two substituent(s) selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, substituted alkoxy, acyloxy, substituted acyloxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, acylamino, substituted acylamino, N-acyl-N-alkylamino, substituted N-acyl-N-alkylamino, alkylene dioxy, (alkylsulfonyl)amino, substituted (alkylsulfonyl)amino, N-(alkylsulfonyl)-N-alkylamino, substituted N-(alkylsulfonyl)-N-alkylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, cyano, acyl, substituted acyl, carboxy, substituted carboxy, nitro, thiol, alkylthio, substituted alkylthio, alkylsulfoxy, substituted alkylsulfoxy, alkylsulfonyl, substituted alkylsulfonyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• R2 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
• C is a group wherein W′, together with —C(═Z)N—, forms a saturated or unsaturated heterocyclic group containing 2 to 5 carbon atoms and 0 to 4 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and —SOn— (where n is 0 to 2) wherein said saturated or unsaturated heterocyclic group is optionally fused with one or two ring(s) structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group to form a bi- or tri-fused ring system and further wherein said heterocyclic group and each of such ring structures are optionally substituted with 1 to 3 substituents selected from the group consisting of with one or two substituent(s) selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, substituted alkoxy, alkylenedioxy, acyloxy, substituted acyloxy, amino, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, acylamino, substituted acylamino, N-acyl-N-alkylamino, substituted N-acyl-N-alkylamino, (alkylsulfonyl)amino, substituted (alkylsulfonyl)amino, N-(alkylsulfonyl)-N-alkylamino, substituted N-(alkylsulfonyl)-N-alkylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, cyano, nitro, acyl, substituted acyl, carboxy, substituted carboxy, thiol, alkylthio, substituted alkylthio, alkylsulfoxy, substituted alkylsulfoxy, alkylsulfonyl, substituted alkylsulfonyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• or
• (iii) HetAr where HetAr is a nitrogen containing heteroaryl that is optionally substituted with an aryl or substituted aryl group;
• and enantiomers, diasteromers and pharmaceutically acceptable salts thereof;
• and further wherein the compound of Formula I has a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less.