Integrin antagonists

A compound of Formula (IG):

• or stereoisomeric forms thereof, tautomeric forms thereof, pharmaceutically acceptable salt forms thereof or prodrug forms thereof, wherein:
• G is selected from:
• D1 is selected from:
• NR2R4, OR3, SR3, F, Cl, Br, CF3, and C1-C4 alkyl;
• R2 at each occurrence is independently selected from:
• H, OR3, C1-C6 alkyl, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, (C0-C6 alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, C3-C7 cycloalkyl(C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl(C0-C6alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, C1-C6 alkylsulfonyl, aryl(C0-C6 alkyl)sulfonyl, heteroaryl(C0-C6 alkyl)sulfonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• R3 at each occurrence is independently selected from:
• H, C1-C6 alkyl, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, (C0-C6 alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl (C0-C4 alkyl) carbonyl, cycloalkyl (C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl (C0-C6 alkyl) carbonyl, heteroaryl (C0-C6 alkyl)carbonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• R4 is selected from:
• H, C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C4 alkyl), C3-C7 cycloalkyl(C0-C4 alkyl)carbonyl, cycloalkyl(C0-C4 alkoxy)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), aryl(C0-C6 alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, aryl(C1-C6 alkoxy)carbonyl, and heteroaryl(C1-C6 alkoxy)carbonyl, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• alternatively, R2 and R4 when both substituents on the same nitrogen atom as in (—NR2R4) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
• said heterocycle being optionally substituted with 0-3 groups selected from oxo, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), C1-C6 alkylcarbonyl, C3-C7 cycloalkyl(C0-C5 alkyl)carbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C5 alkoxy)carbonyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), aryl(C1-C5 alkoxy)carbonyl, heteroaryl(C1-C5 alkoxy)carbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl;
• R5 is selected from:
• H, NR2R4, OR3, NO2, NO, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), aryl(C0-C6 alkyl), or heteroaryl(C0-C6 alkyl), wherein said aryl and heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• R6 is selected from:
• H, NR2R4, OR3, C1-C6 alkyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), CF3, F, Cl, and Br, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• alternatively, R5 and R6, when substituents on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms or a 5-7 membered carbocyclic ring, said carbocyclic or heterocyclic ring being aromatic or nonaromatic, said carbocyclic or heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2 and aryl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• R7 is selected from:
• H, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• alternatively, —NHR2 and R7, when substituents on adjacent atoms, are taken together with the atoms to which they are attached to form a 5-7 membered heterocyclic ring containing 2 or 3 nitrogen atoms, said heterocyclic ring being aromatic or nonaromatic, said heterocyclic ring being substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, NO2, and aryl, wherein said aryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• U1 is selected from:
• —(CH2)n-,
• —Q1-(CH2)m-,
• —(CH2)m-Q2—,
• —(CH2)t-Q2-CH2—,
• —CH2-Q2-(CH2)t-,
• —(CH2)t-N(R3)—C(═O)—,
• —(CH2)t-N(R3)—S(═O)2—,
• —(CH2)t-C(═O)—N(R3)—,
• —(CH2)t-S(═O)2—N(R3)—,
• —C(═O)—N(R4)—(CH2)t-,
• —N(R4)—,
• —N(R4)—(CH2)q-Q2-,
• —N(R4)—C(═O)—(CH2)r-, and
• —N(R4)—(CH2)t-C(═O)—;
• U2 is selected from:
• —(CH2)h-,
• —Q1-(CH2)r-,
• —(CH2)r-Q2-,
• —(CH2)i-N(R3)—C(═O)—,
• —(CH2)i-N(R3)—S(═O)2—,
• —(CH2)i-C(═O)—N(R3)—,
• —(CH2)i-S(═O)2—N(R3)—,
• —(CH2)i-Q2—CH2—,
• —CH2-Q2-(CH2)i-,
• —C(═O)—N(R4)—(CH2)i-,
• —N(R4)—,
• —N(R4)—(CH2)2-Q2-,
• —N(R4)—C(═O)—(CH2)i-, and
• —N(R4)—(CH2)t-C(═O)—;
• U4 is selected from:
• —(CH2)h-,
• —(CH2)2-Q2,
• —(CH2) 2—O—CH2—,
• —(CH2)r-C(═O)—,
• —C(═O)—(CH2)r-, and
• —C(═O)—N(R4)—(CH2)r;
• Q1 is —O—, —S—, or N(R4);
• Q2 is —O—, —S—, —S(═O)—, —S(═O)2—, or N(R3);
• R8 and R9 are independently selected from:
• H, C1-C10 alkyl, NO2, CF3, F, Cl, Br, C1-C10 alkylcarbonyl, —NR2R4, OC(═O)OR10, OR10, OC(═O)NR10R11, OCH2CO2R10, CO2CH2CO2R10, CO2R10, C(═O)R10, NR10C(═O)R11. NR7C(═O)OR10, NR7C(═O)NR10R11, NR7SO2NR10R11, NR7SO2R10, SR10, SR10, S(═O)R10, SO2R10, SO2NR10R11, SiMe3, R10OOC(C1-C6 alkyl). R2R4N(C2-C6 alkyl), R10OOC(C1-C6 alkoxy), R2R4N(C2-C6 alkoxy), C2-C6 alkenyl, C3-C10 cycloalkyl, C3-C10 cycloalkylmethyl, aryl, and aryl(C1-C5 alkyl)-, wherein said aryl groups are substituted with 0-2 substituents independentyl selected from a group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• R10 and R11 are independently selected from:
• H, C1-C8 alkyl, C3-C6 alkenyl, C3-C10 cycloalkyl(C0-C4 alkyl), aryl(C0-C4 alkyl), and heteroaryl(C0-C4 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substitutents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
• alternatively, R10 and R11 when both substituents on the same nitrogen atom an in (—NR10R11) can be taken together with the nitrogen atom to which are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperridinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
• said heterocycle being optionally substituted with 0-3 groups selected from oxo, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C4 alkyl), C1-C6 alkylcarbonyl, C3-C7 cycloalkyl(C0-C5 alkyl) carbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkyl(C0-C5 alkoxy)carbonyl, aryl(C0-C5 alkyl), heteroaryl(C0-C5 alkyl), aryl(C1-C5 alkoxy)carbonyl, heteroaryl(C1-C5 alkoxy) carbonyl, C1-C6 alkylsulfonyl arysulfonyl and heteroarysulfonyl;
• W is selected form :
• —(C(R12)2)pC(═O)N(R13)-, and
• —C(═O)—N(R13)-(C(R12)2)p-;
• X is —(C(R12)2)pC(R12)(R14)-C(R12)2- or —(C(R12)2)p-C(R12)(R15)-;
• alternatively, W and X can be taken together to be
• R12 at each occurence is independently selected from:
• H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl(C0-C4 alkyl)-, (C1-C4 alkyl)carbonyl, aryl(C0-C6 alkyl), and heteroaryl(C0-C6 alkyl), wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• R13 is selected from:
• H, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C6 alkyl), aryl(C0-C6 alkyl), or heteroaryl(C0-C6 alkyl), wherein said aryl and heteroaryl groups substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• R14 is selected from:
• H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy(C1-C6 alkyl), aryl(C0-C6 alkoxy C1-C6 alkyl), C1-C6 alkylthio(C1-C6 alkyl), C1-C6 alkylsulfonyl(C1-C6 alkyl), aryl(C0-C6 alkylthio C1-C6 alkyl), aryl(C0-C6 alkylsulfonyl C1-C6 alkyl), C3-C10 cycloalkyl(C0-C6 alkyl), aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), R17R20NC(═O)(C1-C4 alkyl), R10OC(═O)(C1-C4 alkyl), and R17R20N(C1-C4 alkyl), provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may optionally by substituted independently with 0-1 R16 or 0-2 R8;
• R15 is selected from:
• H, R16, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl (C0-C6 alkyl), C1-C6 alkoxy(C1-C6 alkyl), C1-C6 alkylamino(C1-C6 alkyl), C2-C10 dialkylamino (C1-C6 alkyl), (C1-C10 alkyl)carbonyl, aryl(C0-C6 alkyl)carbonyl, heteroaryl(C0-C6 alkyl)carbonyl, aryl(C0-C6 alkyl), heteroaryl(C0-C6 alkyl), CO2R17, C(═O)R17, CONR17R20, SO2NR17R20, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• Y is selected from —C(═O)R19, —SO3H, and —PO3H;
• R16 is selected from:
• —N(R20)-C(═O)-O-R17,
• —N(R20)-C(═O)-R17,
• —N(R20)-C(═O)-NH-R17,
• —N(R20)SO2-R17, and
• —N(R20)SO2-NR20R17;
• R17 is selected from:
• C1-C10 alkyl, C3-C10 cycloalkyl, aryl(C0-C6 ), heteroaryl(C0-C6 alkyl), arylaryl(C0-C6 alkyl), heteroarylaryl(C0-C6 alkyl), arylheteroaryl(C0-C6 alkyl), and heteroarylheteroaryl (C0-C6 ), wherein said aryl or heteroaryl groups are optionally subtituted with 0-3 substituents independently selected from the group consisting of:
• C1-C4 alkyl, C1-C4 alkoxy, aryl, F, Cl, Br, CN, NH2, CF3, and NO2;
• R18 is selected from:
• H,
• —C(═O)OR17,
• —C(═O)R17,
• —C(═O)NHR17,
• —SO2R17.
• —SO2NR20R17,
• C1-C10 alkyl,
• C3-C10 cycloalkyl (C0-C6 alkyl),
• aryl (C0-C6 alkyl), and
• heteroaryl(C0-C6 alkyl),
• wherein said aryl group is optionally substituted with 0-3 substituents independently selected from the group consisting of:
• C1-C4 alkyl, C1-C4 alkoxy, aryl, F, Cl, Br, —CN, —NH2, —CF3, and —NO2;
• R19 is selected from:
• hydroxy,
• C1-C10 alkoxy,
• C3-C10 cycloalkyloxy,
• aryloxy,
• aryl(C1-C6 alkoxy),
• C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy,
• C2-C10 alkoxycarbonylloxy(C1-C2 alkyl)oxy,
• C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy,
• C3-C10 cycloalkylcarbonyloxy(C1-C2 )oxy,
• C3-C10 cycloalkoxycarbonylox(C1-C2 alkyl)oxy,
• C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy,
• aryloxycarbonyl(C1-C2 alkyl)oxy,
• aryloxycarbonyloxy(C1-C2 alkyl)oxy,
• arylcarbonylloxy(C1-C2 alkyl)oxy,
• C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C1-C2 alkyl)oxy,
• (5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methoxyloxy,
• (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
• (R10)(R11)N-(C1-C10 alkoxy) and
• —(CH2)kN+(R21)(R22)(R23)z-;
• R20 is selected from:
• H, C1-C6 alkyl, C3-C7 cycloalkyl(C0-C6 alkyl)-, aryl, aryl(C0-C6 alkyl)-, and heteroaryl(C0-C6 alkyl), wherein said aryl or hetroaryl groups are optionally substituted with 0-3 substituents independently selected from the group consisting of:
• C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2;
• z- is a pharmaceutically acceptable anion selected from halide, bisulfate, sulfae, hydrogenphosphate, phosphate, toluenesulfonate, methanesulfonate, ethanesulfonate, acetate, trifluoroacetate, citrate, oxalate, succinate, and molonate;
• R22, R22 and R23 are independently selected from:
• H, C1-C9 alkyl, C-C7 cycloalkyl(C0-C4 alkyl), aryl (C0-C6 alkyl), heteroaryl, and heteroaryl(C0-C6 alkyl), wherein said alkyl or aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, OH, F, Cl, Br, CF3, and NO2;
• alternatively R21 and R22 can be taken together to form a 5-7 membered heterocyclic aromatic or non-aromatic ring system containing 1-3 heteroatoms selected from N, O and S and R23 is defined as above or R21, R22, and R23can be taken together to form a heterobicyclic ring system containing 1-3 heteroatoms selected from N, O and S, wherein said heterocyclic or heterobicyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, —CN, —NH2, —CF3, and —NO2;
• h is 0-4;
• i is 0-2;
• k is 2-6;
• m is 1-4;
• n is 0-5;
• q is 2-3;
• r is 0-3;
• t is 1-3;
• and
• p is 0-2;
• provided that h, i, m, n, q, r, t, and p at each occurrence, are chosen such that the number of in-chain atoms between Y and the pyrimidine, pyrimidone, triazine or triazinone of G is in the range of 8-12.