Vitronectin receptor antagonist pharmaceuticals

A kit for treating cancer, comprising a compound comprising a targeting moiety and a chelator, wherein the targeting moiety is bound to the chelator, is a quinolone nonpeptide, and binds to a receptor that is upregulated during angiogenesis and the compound has 0–1 linking groups between the targeting moiety and chelator, wherein the receptor is the integrin αvβ3 or αvβ3 and the compound is of the formula:

• (Q)d—Ln—Ch or (Q)d—Ln—(Ch)d′
• wherein, Q is a compound of Formula (II):
• including stereoisomeric forms thereof or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
• R1e is selected from:
• Ae is —CH2— or —N(R10e)—;
• A1e and Be are independently —CH2— or —N(R10e)—;
• De is —N(R10e)— or —S—;
• Ee—Fe is —C(R2e)═C(R3e)— or —C(R2e)2C(R3e)2—;
• Je is —C(R2e)— or —N—;
• Ke, Le and Me are independently —C(R2e)— or —C(R3e)—;
• R2e and R3e are independently selected from:
• H, C1–C4 alkoxy, NR11eR12e, halogen, NO2, CN, CF3, C1–C6 alkyl, C3–C6 alkenyl, C3–C7 cycloalkyl, C3–C7 cycloalkyl(C1–C4 alkyl), aryl(C1–C6 alkyl)-, (C1–C6 alkyl)carbonyl, (C1–C6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0–4 R7e,
• alternatively, when R2e and R3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5–7 membered carbocyclic or 5–7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0–2 groups selected from C1–C4 alkyl, C1–C4 alkoxy, halo, cyano, amino, CF3 and NO2;
• R2ae is selected from:
• H, C1–C10 alkyl, C2–C6 alkenyl, C3–C11 cycloalkyl, C3–C7 cycloalkyl(C1–C4 alkyl), aryl, aryl(C1–C4 alkyl)-, (C2–C7 alkyl)carbonyl, arylcarbonyl,
• (C2–C10 alkoxy)carbonyl, C3–C7 cycloalkoxycarbonyl,
• C7–C11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C1–C10 alkoxy)carbonyl,
• C1–C6 alkylcarbonyloxy(C1–C4 alkoxy)carbonyl, arylcarbonyloxy(C1–C4 alkoxy)carbonyl, and
• C3–C7 cycloalkylcarbonyloxy(C1–C4 alkoxy)carbonyl;
• R7e is selected from:
• H, hydroxy, C1–C4 alkyl, C1–C4 alkoxy, aryl, aryl(C1–C4 alkyl)-, (C1–C4 alkyl)carbonyl, CO2R18ae, SO2R11e, SO2NR10eR11e, OR10e, and N(R11e)R12e;
• Ue is selected from:
• —(CH2)ne—, —(CH2)neO(CH2)me—, —(CH2)neN(R12)(CH2)me—, —NH(CH2)ne—, —(CH2)neC(═O)(CH2)me—,
• —(CH2)neS(O)pe(CH2)me—, —(CH2)neNHNH(CH2)me—,
• —N(R10e)C(═O)—, —NHC(═O)(CH2)ne—, —C(═O)N(R10e)—, and —N(R10e)S(O)pe—;
• Ge is N or CR19e;
• We is —C(═O)—N(R10e)—(C1–C3 alkylene)-, in which the alkylene group is substituted by R8e and by R9e:
• R8e and R9e are independently selected from:
• H, CO2R18be, C(═O)R18be, CONR17R18be,
• C1–C10 alkyl substituted with 0–1 R6e,
• C2–C10 alkenyl substituted with 0–1 R6e,
• C2–C10 alkynyl substituted with 0–1 R6e,
• C3–C8 cycloalkyl substituted with 0–1 R6e,
• C5–C6 cycloalkenyl substituted with 0–1 R6e,
• (C1–C10 alkyl)carbonyl,
• C3–C10 cycloalkyl(C1–C4 alkyl)-,
• phenyl substituted with 0–3 R6e,
• naphthyl substituted with 0–3 R6e,
• a 5–10 membered heterocyclic ring containing 1–3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0–2 R7e,
• C1–C10 alkoxy substituted with 0–2 R7e,
• hydroxy, nitro, —N(R10e)R11e, —N(R16e)R17e, aryl(C0–C6 alkyl)carbonyl, aryl(C3–C6 alkyl), heteroaryl(C1–C6 alkyl), CONR18aeR20e, SO2R18ae, and SO2NR18aeR20e,
• providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1–2 R7e;
• R6e is selected from:
• H, C1–C10 alkyl, hydroxy, C1–C10 alkoxy, nitro, C1–C10 alkylcarbonyl, —N(R11e)R12e, cyano, halo, CF3, CHO, CO2R18be, C(═O)R18be, CONR17eR18be, OC(═O)R10e, OR10e, OC(═O)NR10eR11e, NR10eC(═O)R10e, NR10eC(═O)OR21e, NR10eC(═O)NR10eR11e, NR10eSO2NR10eR11e, NR10eSO2R21e, S(O)pR11e, SO2NR10eR11e,
• aryl substituted with 0–3 groups selected from halogen, C1–C6 alkoxy, C1–C6 alkyl, CF3, S(O)meMe, and —NMe2,
• aryl(C1–C4 alkyl)-, said aryl being substituted with 0–3 groups selected from halogen, C1–C6 alkoxy, C1–C6 alkyl, CF3, S(O)peMe, and —NMe2, and
• a 5–10 membered heterocyclic ring containing 1–3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0–2 R7e;
• R10e is selected from:
• H, CF3, C3–C6 alkenyl, C3–C11 cycloalkyl, aryl, (C3–C11 cycloalkyl)methyl, aryl(C1–C4 alkyl), and C1–C10 alkyl substituted with 0–2 R6e;
• R11e is selected from:
• H, hydroxy, C1–C8 alkyl, C3–C6 alkenyl, C3–C11 cycloalkyl, (C3–C11 cycloalkyl)methyl, C1–C6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C1–C4 alkyl)-, aryl(C1–C4 alkyl), adamantylmethyl, and
• C1–C10 alkyl substituted with 0–2 R4e;
• R4e is selected from:
• H, C1–C6 alkyl, C3–C7 cycloalkyl, C3–C7 cycloalkyl(C1–C4 alkyl)-, (C1–C10 alkyl)carbonyl, aryl, heteroaryl, aryl(C1–C6 alkyl)-, and heteroaryl(C1–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,
• alternatively, when R10e and R11e are both substituents on the same nitrogen atom (as in —NR10eR11e) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
• 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
• said heterocycle being substituted with 0–3 groups selected from:
• C1–C6 alkyl, aryl, heteroaryl, aryl(C1–C4 alkyl)-, (C1–C6 alkyl)carbonyl, (C3–C7 cycloalkyl)carbonyl, (C1–C6 alkoxy)carbonyl, aryl(C1–C4 alkoxy)carbonyl, C1–C6 alkylsulfonyl, and arylsulfonyl;
• R12e is selected from:
• H, C1–C6 alkyl, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C1–C6 alkyl)carbonyl, (C1–C6 alkoxy)carbonyl, (C1–C6 alkyl)aminocarbonyl, C3–C6 alkenyl, C3–C7 cycloalkyl, C3 –C7 cycloalkyl(C1–C4 alkyl)-, aryl, heteroaryl(C1–C6 alkyl)carbonyl, heteroarylcarbonyl, aryl(C1–C6 alkyl)-, (C1–C6 alkyl)carbonyl, arylcarbonyl, C1–C6 alkylsulfonyl, arylsulfonyl, aryl(C1–C6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C1–C6 alkyl)sulfonyl, aryloxycarbonyl, and aryl(C1–C6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0–2 substituents selected from the group consisting of C1–C4 alkyl, C1–C4 alkoxy, halo, CF3, and nitro;
• R16e is selected from:
• —C(═O)OR18ae, —C(═O)R18be, —C(═O)N(R18be)2,
• —C(═O)NHSO2R18ae, —C(═O)NHC(═O)R18be,
• —C(═O)NHC(═O)OR18ae, —C(═O)NHSO2NHR18be, —SO2R18ae,
• —SO2N(R18be)2, and —SO2NHC(═O)OR18be;
• R17e is selected from:
• H, C1–C6 alkyl, C3–C7 cycloalkyl, C3–C7 cycloalkyl(C1–C4 alkyl)-, aryl, aryl(C1–C6 alkyl)-, and heteroaryl(C1–C6 alkyl);
• R18ae is selected from:
• C1–C8 alkyl optionally substituted with a bond to Ln, C3–C11 cycloalkyl optionally substituted with a bond to Ln, aryl(C1–C6 alkyl)- optionally substituted with a bond to Ln, heteroaryl(C1–C6 alkyl)- optionally substituted with a bond to Ln, (C1–C6 alkyl)heteroaryl optionally substituted with a bond to Ln, biaryl(C1–C6 alkyl) optionally substituted with a bond to Ln, heteroaryl optionally substituted with a bond to Ln, phenyl substituted with 3–4 R19e and optionally substituted with a bond to Ln, naphthyl substituted with 0–4 R19e and optionally substituted with a bond to Ln, and a bond to Ln, wherein said aryl or heteroaryl groups are optionally substituted with 0–4 R19e;
• R18be is H or R18ae;
• R19e is selected from:
• H, halogen, CF3, CO2H, CN, NO2, —NR11eR12e, OCF3, C1–C8 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C3–C11 cycloalkyl, C3–C7 cycloalkyl(C1–C4 alkyl)-, aryl(C1–C6 alkyl)-, C1–C6 alkoxy, C1–C4 alkoxycarbonyl, aryl, aryl-O—, aryl-SO2—, heteroaryl, and heteroaryl-SO2—, wherein said aryl and heteroaryl groups are substituted with 0–4 groups selected from hydrogen, halogen, CF3, C1–C3 alkyl, and C1–C3 alkoxy;
• R20e is selected from:
• hydroxy, C1–C10 alkyloxy, C3–C11 cycloalkyloxy, aryloxy, aryl(C1–C4 alkyl)oxy,
• C2–C10 alkylcarbonyloxy(C1–C2 alkyl)oxy-,
• C2–C10 alkoxycarbonyloxy(C1–C2 alkyl)oxy-,
• C2–C10 alkoxycarbonyl(C1–C2 alkyl)oxy-,
• C3–C10 cycloalkylcarbonyloxy(C1–C2 alkyl)oxy-,
• C3–C10 cycloalkoxycarbonyloxy(C1–C2 alkyl)oxy-,
• C3–C10 cycloalkoxycarbonyl(C1–C2 alkyl)oxy-,
• aryloxycarbonyl(C1–C2 alkyl)oxy-,
• aryloxycarbonyloxy(C1–C2 alkyl)oxy-,
• arylcarbonyloxy(C1–C2 alkyl)oxy-,
• C1–C5 alkoxy(C1–C5 alkyl)carbonyloxy(C1–C2 alkyl)oxy,
• (5-(C1–C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
• (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
• (R10e)(R11e)N—(C1–C10 alkoxy)-;
• R21e is selected from:
• C1–C8 alkyl, C2–C6 alkenyl, C3–C11 cycloalkyl, (C3–C11 cycloalkyl)methyl, aryl, aryl(C1–C4 alkyl)-, and C1–C10 alkyl substituted with 0–2 R7e;
• R22e is selected from:
• —C(═O)—R18be, —C(═O)N(R18be)2, —C(═O)NHSO2R18ae, —C(═O)NHC(═O)R18be, —C(═O)NHC(═O)OR18ae, and —C(═O)NHSO2NHR18be;
• Ye is selected from:
• —COR20e, —SO3H, —PO3H, —CONHNHSO2CF3, —CONHSO2R18ae, —CONHSO2NHR18be, —NHCOCF3, —NHCONHSO2R18ae, —NHSO2R18ae, —OPO3H2, —OSO3H, —PO3H2, —SO2NHCOR18ae,
• —SO2NHCO2R18ae,
• me is 0–2;
• ne is 0–4;
• pe is 0–2;
• re is 0–2;
• with the following proviso:
• ne and me are chosen such that the number of atoms connecting R1e and Ye is in the range of 8–14;
• d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• d′ is 1–100;
• Ln is a linking group having the formula:
• ((W)h—(CR6R7)g)x—(Z)k—((CR6aR7a)g′—(W)h′)x′;
• W is independently selected at each occurrence from the group:
• O, S, NH, NHC(═O), C(═O)NH, NR8C(═O), C(═O)NR8, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO2, SO2NH, (OCH2CH2)s, (CH2CH2O)s′, (OCH2CH2CH2)s″, (CH2CH2CH2O)t, and (aa)t′;
• aa is independently at each occurrence an amino acid;
• Z is selected from the group:
• aryl substituted with 0–3 R10, C3-10 cycloalkyl substituted with 0–3 R10, and a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O and substituted with 0–3 R10;
• R6, R6a, R7, R7a, and R8 are independently selected at each occurrence from the group:
• H, ═O, COOH, SO3H, PO3H, C1–C5 alkyl substituted with 0–3 R10, aryl substituted with 0–3 R10, benzyl substituted with 0–3 R10, and C1–C5 alkoxy substituted with 0–3 R10, NHC(═O)R11, C(═O)NHR11, NHC(═O)NHR11, NHR11, R11, and a bond to Ch;
• R10 is independently selected at each occurrence from the group:
• a bond to Ch, COOR11, C(═O)NHR11, NHC(═O)R11, OH, NHR11, SO3H, PO3H, —OPO3H2, —OSO3H, aryl substituted with 0–3 R11, C1-5 alkyl substituted with 0–1 R12, C1-5 alkoxy substituted with 0–1 R12, and a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O and substituted with 0–3 R11;
• R11 is independently selected at each occurrence from the group:
• H, alkyl substituted with 0–1 R12, aryl substituted with 0–1 R12, a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O and substituted with 0–1 R12, C3-10 cycloalkyl substituted with 0–1 R12, polyalkylene glycol substituted with 0–1 R12, carbohydrate substituted with 0–1 R12, cyclodextrin substituted with 0–1 R12, amino acid substituted with 0–1 R12, polycarboxyalkyl substituted with 0–1 R12, polyazaalkyl substituted with 0–1 R12, peptide substituted with 0–1 R12, wherein the peptide is comprised of 2–10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to Ch;
• R12 is a bond to Ch;
• k is selected from 0, 1, and 2;
• h is selected from 0, 1, and 2;
• h′ is selected from 0, 1, and 2;
• g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• g′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• s is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• s′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• s″ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• x is selected from 0, 1, 2, 3, 4, and 5;
• x′ is selected from 0, 1, 2, 3, 4, and 5;
• Ch is a metal bonding unit having a formula selected from the group:
• A1, A2, A3, A4, A5, A6, A7, and A8 are independently selected at each occurrence from the group:
• NR13, NR13R14, S, SH, S(Pg), O, OH, PR13, PR13R14, P(O)R15R16, and a bond to Ln;
• E is a bond, CH, or a spacer group independently selected at each occurrence from the group:
• C1–C10 alkyl substituted with 0–3 R17, aryl substituted with 0–3 R17, C3-10 cycloalkyl substituted with 0–3 R17, heterocyclo-C1-10 alkyl substituted with 0–3 R17, wherein the heterocyclo group is a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O, C6-10 aryl-C1-10 alkyl substituted with 0–3 R17, C1-10 alkyl-C6-10 aryl-substituted with 0–3 R17, and a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O and substituted with 0–3 R17;
• R13 and R14 are each independently selected from the group:
• a bond to Ln, hydrogen, C1–C10 alkyl substituted with 0–3 R17, aryl substituted with 0–3 R17, C1-10 cycloalkyl substituted with 0–3 R17, heterocyclo-C1-10 alkyl substituted with 0–3 R17, wherein the heterocyclo group is a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O, C6-10 aryl-C1-10 alkyl substituted with 0–3 R17, C1-10 alkyl-C6-10 aryl-substituted with 0–3 R17, a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O and substituted with 0–3 R17, and an electron, provided that when one of R13 or R14 is an electron, then the other is also an electron;
• alternatively, R13 and R14 combine to form ═C(R20)(R21);
• R15 and R16 are each independently selected from the group:
• a bond to Ln, —OH, C1–C10 alkyl substituted with 0–3 R17, C1–C10 alkyl substituted with 0–3 R17, aryl substituted with 0–3 R17, C3-10 cycloalkyl substituted with 0–3 R17, heterocyclo-C1-10 alkyl substituted with 0–3 R17, wherein the heterocyclo group is a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O , C6-10 aryl-C1-10 alkyl substituted with 0–3 R17, C1-10 alkyl-C6-10 aryl-substituted with 0–3 R17, and a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O and substituted with 0–3 R17;
• R17 is independently selected at each occurrence from the group:
• a bond to Ln, ═O, F, Cl, Br, I, —CF3, —CN, —CO2R18, —C(═O)R18, —C(═O)N(R18)2, —CHO, —CH2OR18, —OC(═O)R18, —OC(═O)OR18a, —OR18, —OC(═O)N(R18)2, —NR19C(═O)R18, —NR19C(═O)OR18a, —NR19C(═O)N(R18)2, —NR19SO2N(R18)2, —NR19SO2R18a, —SO3H, —SO2R18a, —SR18, —S(═O)R18a, —SO2N(R18)2, —N(R18)2, —NHC(═S)NHR18, ═NOR18, NO2, —C(═O)NHOR18, —C(O)NHNR18R18a, —OCH2CO2H, 2-(1-morpholino)ethoxy, C1–C5 alkyl, C2–C4 alkenyl, C3–C6 cycloalkyl, C3–C6 cycloalkylmethyl, C2–C6 alkoxyalkyl, aryl substituted with 0–2 R18, and a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O;
• R18, R18a, and R19 are independently selected at each occurrence from the group:
• a bond to Ln, H, C1–C6 alkyl, phenyl, benzyl, C1–C6 alkoxy, halide, nitro, cyano, and trifluoromethyl;
• Pg is a thiol protecting group;
• R20 and R21 are independently selected from the group:
• H, C1–C10 alkyl, —CN, —CO2R25, —C(═O)R25, —C(═O)N(R25)2, C2–C10 1-alkene substituted with 0–3 R23, C2–C10 1-alkyne substituted with 0–3 R23, aryl substituted with 0–3 R23, unsaturated 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O and substituted with 0–3 R23, and unsaturated C3-10 carbocycle substituted with 0–3 R23;
• alternatively, R20 and R21, taken together with the divalent carbon radical to which they are attached form:
• R22 and R23 are independently selected from the group:
• H, R24, C1–C10 alkyl substituted with 0–3 R24, C2–C10 alkenyl substituted with 0–3 R24, C2–C10 alkynyl substituted with 0–3 R24, aryl substituted with 0–3 R24, a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O and substituted with 0–3 R24, and C3-10 carbocycle substituted with 0–3 R24;
• alternatively, R22, R23 taken together form a fused aromatic or a 5–10 membered heterocyclic ring system containing 1–4 heteroatoms independently selected from N, S, and O;
• a and b indicate the positions of optional double bonds and n is 0 or 1;
• R24 is independently selected at each occurrence from the group:
• ═O, F, Cl, Br, I, —CF3, —CN, —CO2R25, —C(═O)R25, —C(═O)N(R25)2, —N(R25)3+, —CH2OR25, —OC(═O)R25, —OC(═O)OR25a, —OR25, —OC(═O)N(R25)2, —NR26C(═O)R25, —NR26C(═O)OR25a, —NR26C(═O)N(R25)2, —NR26SO2N(R25)2, —NR26SO2R25a, —SO3H, —SO2R25a, —SR25, —S(═O)R25a, —SO2N(R25)2, —N(R25)2, ═NOR25, —C(═O)NHOR25, —OCH2CO2H, and 2-(1-morpholino)ethoxy;
• and,
• R25, R25a, and R26 are each independently selected at each occurrence from the group:
• hydrogen and C1–C6 alkyl, or a pharmaceutically acceptable salt thereof, and at least one agent selected from the group consisting of a chemotherapeutic agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.