US2003124120A1PendingUtilityA1
Quinolone vitronectin receptor antagonist pharmaceuticals
Priority: Mar 31, 1998Filed: Oct 11, 2002Published: Jul 3, 2003
Est. expiryMar 31, 2018(expired)· nominal 20-yr term from priority
Inventors:Thomas D. Harris
C07K 5/06191A61K 49/0002A61K 49/04A61K 49/085A61K 49/10A61K 49/223A61K 51/0455A61K 51/0459A61K 51/0497C07D 401/12C07D 401/14C07D 403/12C07D 403/14C07K 5/0205C07K 5/0207C07K 5/0215C07K 5/06139C07K 5/0806C07K 5/0821C07K 5/1008C07K 5/1024C07K 7/02C07K 7/06C07K 7/64C07K 9/003
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Claims
Abstract
The present invention describes novel compounds of the formula: (Q) d —L n —C h , useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient. The present invention also provides novel compounds useful for monitoring therapeutic angiogenesis treatment and destruction of new angiogenic vasculature. The pharmaceuticals are comprised of a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.
Claims
exact text as granted — not AI-modifiedWhat is claimed is described below:
1 . 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.
2 . A compound according to claim 1 , wherein the targeting moiety comprises a quinolone and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Ax1, α v β 3 , α v β 5 , α 5 β 1 , α 4 β 1 , α 1 β 1 , and α 2 β 2 and the linking group is present between the targeting moiety and chelator.
3 . A compound according to claim 2 , wherein the receptor is the integrin α v β 3 and the compound is of the formula:
(Q) d -L n -C h or (Q) d -L n -(C h ) d′
wherein, Q is a compound of Formula (I):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R 1e is selected from:
D e is selected from:
—N(R 12e )—, or —S—;
J e is selected from:
—C(R 2e )— or —N—;
K e , L e and M e are independently selected from:
—C(R 2e )— or —C (R 3e )—;
R 2 e and R 3 e are independently selected from:
H, C 1 -C 4 alkoxy, NR 11e R 12e , ═NR 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 6 -C 10 aryl substituted with 0-4 R 7e , C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, or C 7 -C 11 arylcarbonyl;
alternatively, when R 2e and R 3e 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 optionally substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 or NO 2 ;
U e is selected from:
—(CH 2 ) n e —,
—(CH 2 ) n e O(CH 2 ) m e —,
—(CH 2 ) n e N(R 12e )(CH 2 ) m e —,
—(CH 2 ) n e C(═O)(CH 2 ) m e —,
—(CH 2 ) n e S(O) p e (CH 2 ) m e —,
—(CH 2 ) n e NHNH(CH 2 ) m e —,
—N(R 10e )C(═O)—,
—C(═O)N(R 10e )—, or
—N (R 10e )S(O) p e —;
W e is —C(═O)—N(R 10e )—(C 1 -C 3 alkylene)-, in which the alkylene group may be substituted by:
CO 2 R 18ae ,
C(═O)R 18ae ,
CONR 17e R 18ae ,
C 1 -C 10 alkyl, substituted with 0-1 R 6e ,
C 5 -C 10 alkenyl, substituted with 0-1 R 6e
C 5 -C 10 alkynyl, substituted with 0-1 R 6e ,
C 3 -C 8 cycloalkyl, substituted with 0-1 R 6e ,
C 5 -C 6 cycloalkenyl, substituted with 0-1 R 6e ,
C 1 -C 10 alkylcarbonyl,
C 3 -C 10 cycloalkylalkyl,
phenyl substituted with 1-3 R 6e ,
naphthyl substituted with 0-3 R 6e ,
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 R 7e ,
hydroxy,
C 5 -C 10 alkoxy,
nitro,
N (R 10e ) R 11e ,
—N(R 16e )R 17e ,
C 5 -C 10 alkyl substituted with 0-3 R 7e ,
aryl (C 0 -C 6 alkyl)carbonyl,
aryl(C 3 -C 6 alkyl),
heteroaryl(C 1 -C 6 alkyl),
CONR 18ae R 20e ,
SO 2 R 18ae , or
SO 2 NR 18ae R 20e and providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p e R 11e , SO 2 NR 10e R 11e ,
C 6 -C 10 aryl optionally substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, or —NMe 2 ;
C 7 -C 11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, Cl-C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, or —NMe 2 , or
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 R 7e ;
R 7e is selected from:
H, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, (C 1 -C 4 alkyl)carbonyl, Co 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , or N(R 11e )R 12e ;
Y e is selected from:
—COR 20e , —SO 3 H, —PO 3 H, —CONHNHSO 2 CF 3 , —CONHSO 2 R 18ae , —CONHSO 2 NHR 18be , ‘NHCOCF 3 , —NHCONHSO 2 R 18ae ,
—NHSO 2 R 18ae , —OPO 3 H 2 , —OSO 3 H, —PO 3 H 2 , —SO 3 H, —SO 2 NHCOR 18ae , —SO 2 NHCO 2 R 18ae , or
R 10e is selected from:
H, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, aryl, aryl(C 1 -C 4 alkyl), or C 1 -C 10 alkyl substituted with 0-2 R 4e ;
R 11e is selected from:
H, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 -C 10 aryl, heteroaryl, heteroarylalkyl, aryl(C 1 -C 4 alkyl), adamantylmethyl, or C 1 -C 10 alkyl substituted with 0-2 R 4e ;
alternatively, when R 10e and R 11e are both substituents on the same nitrogen atom (as in —NR 10e R 11e ) 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 or 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from: C 1 -C 6 alkyl, C 6 -C 10 aryl, heteroaryl, C 7 -C 11 arylalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
R 4e is selected from:
H, C 1 -C 10 alkyl, C 1 -C 10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
R 12e is selected from:
H, C 1 -C 6 alkyl, triphenylmethyl, methoxymethyl (MOM), methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl (SEM), (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl; (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl C 1 -C 6 alkyl, (C 1 -C 6 alkyl)carbonyl, or arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, or aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 13e is selected from:
C 7 -C 8 alkyl, C 3 -C 11 cycloalkyl, aryl(C 1 -C 6 alkyl)-, heteroaryl(C 1 -C 6 alkyl)-, biaryl(C 1 -C 6 alkyl), biaryl optionally substituted with 1-4 R 19e ; heteroaryl optionally substituted with 1-4 R 19e , phenyl substituted with 3-4 R 19e or naphthyl substituted with 1-4 R 19e ;
R 14e is selected from:
H, C 1 -C 4 alkyl, phenyl(C 1 -C 4 alkyl), or a bond to L n ;
R 16e is selected from:
—C(═O)OR 18ae ,
—C(═O)R 18be ,
—C(═O)N(R 18be ) 2 ,
—C(═O)NHSO 2 R 18ae ,
—C(═O)NHC(═O)R 18be ,
—C(═O)NHC(═O)OR 18ae ,
—C(═O)NHSO 2 NHR 18be ,
—SO 2 R 18ae ,
—SO 2 N(R 18be ) 2 or,
—SO 2 NHC(═O)OR 18be ;
R 17e is selected from:
H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from:
C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is selected from:
R 18ae or H;
R 19e is selected from:
H, halogen, CF 3 , CO 2 H, CN, NO 2 , NR 11e R 12e , C l -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, OCF 3 , or C 1 -C 4 alkoxycarbonyl, aryl, —O-aryl, —SO 2 -aryl, heteroaryl, or —SO 2 -heteroaryl, wherein said aryl and heteroaryl groups may be substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
R 20e is selected from:
hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, C 6 -C 10 aryloxy, C 7 -C 11 aralkyloxy, C 3 -C 10 alkylcarbonyloxyalkyloxy, C 3 -C 10 alkoxycarbonyloxyalkyloxy, C 2 -C 10 alkoxycarbonylalkyloxy, C 5 -C 10 cycloalkylcarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonylalkyloxy, C 7 -C 11 aryloxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonyloxyalkyloxy, C 8 -C 12 arylcarbonyloxyalkyloxy, C 5 -C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 -C 10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C 10 -C 14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R 11e )(R 12e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from:
C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 7e ;
m e is 0-2;
n e is 0-4;
p e is 0-2;
with the following provisos:
(1) n e and m e are chosen such that the number of atoms connecting R 1e and Y e is in the range of 8-14;
(2) in the definition of W e , the substituent on the alkylene group may not be an unsubstituted pyridyl radical
d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
L n is a linking group having the formula:
(CR 6 R 7 ) g —(W) h —(CR 6a R 7a ) g′ -(Z) k -(W) h′ —(CR 8 R 9 ) g″ —(W) h″ —(CR 8a R 9a ) g″′ —(W) h′″ —(CR 8b R 9b ) g″″
W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , SO 2 NH, (OCH 2 CH 2 ) s , (CH 2 CH 2 O) s′ , (OCH 2 CH 2 CH 2 ) s″ , (CH 2 CH 2 CH 2 O) t , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-3 R 10 , C 3-10 cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;
R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 8b , R 9 , R 9a , and R 9b are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, PO 3 H, C 1 -C 5 alkyl substituted with 0-3 R 10 , aryl substituted with 0-3 R 10 , benzyl substituted with 0-3 R 10 , and C 1 -C 5 alkoxy substituted with 0-3 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to C h ;
R 10 is independently selected at each occurrence from the group: a bond to C h , COOR 11 , C(═O)NHR 11 , NHC(═O)R 11 , NHOH, NHR 11 , SO 3 H, PO 3 H, —OPO 3 H 2 , —OSO 3 H, aryl substituted with 0-3 R 11 , C 1-5 alkyl substituted with 0-1 R 12 , C 1-5 alkoxy substituted with 0-1 R 12 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 11 ;
R 11 is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R 12 , aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 12 , C 3-10 cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 12 , carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 12 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C h ;
R 12 is a bond to C h ;
k is selected from 0, 1, and 2;
h is selected from 0, 1, and 2;
h′ is selected from 0, 1, 2, 3, 4, and 5;
h″ is selected from 0, 1, 2, 3, 4, and 5;
h″′ is selected from 0, 1, 2, 3, 4, and 5;
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;
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;
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;
C h is a metal bonding unit having a formula selected from the group:
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), O, OH, PR 13 , PR 13 R 14 , P(O)R 15 R 16 , and a bond to L n ;
E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl-substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 13 and R 14 are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 1-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl-substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
alternatively, R 13 and R 14 combine to form ═C(R 20 )(R 21 );
R 15 and R 16 are each independently selected from the group: a bond to L n , —OH, C 1-10 alkyl substituted with 0-3 R 17 , C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C 1-10 alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O, C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 17 , C 1-10 alkyl-C 6-10 aryl-substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 17 is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CHO, —CH 2 OR 18 , —OC(═O)R 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , —NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —SR 18 , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , NO 2 , —C(═O)NHOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, 2-(1-morpholino)ethoxy, C 1 -C 5 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 2 -C 6 alkoxyalkyl, aryl substituted with 0-2 R 18 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O;
R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, C 1 -C 6 alkyl, phenyl, benzyl, C 1 -C 6 alkoxy, halide, nitro, cyano, and trifluoromethyl;
Pg is a thiol protecting group;
R 20 and R 21 are independently selected from the group: H, C 1 -C 10 alkyl, —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , C 2 -C 10 1-alkene substituted with 0-3 R 23 , C 2 -C 10 1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 , and unsaturated C 3-10 carbocycle substituted with 0-3 R 23 ;
alternatively, R 20 and R 21 , taken together with the divalent carbon radical to which they are attached form:
R 22 and R 23 are independently selected from the group: H, R 24 , C 1 -C 10 alkyl substituted with 0-3 R 24 , C 2 -C 10 alkenyl substituted with 0-3 R 24 , C 2 -C 10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 24 , and C 3-10 carbocycle substituted with 0-3 R 24 ;
alternatively, R 22 , R 23 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;
R 24 is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 25 , —C(═O)R 25 , —C(═O)N(R 25 ) 2 , —N(R 25 ) 3 + , —CH 2 OR 25 , —OC(═O)R 25 , —OC(═O)OR 25a , —OR 25 , —OC(═O)N(R 25 ) 2 , —NR 26 C(═O)R 25 , —NR 26 C(═O)OR 25a , —NR 26 C(═O)N(R 25 ) 2 , —NR 26 SO 2 N(R 25 ) 2 , —NR 26 SO 2 R 25a , —SO 3 H, —SO 2 R 25a , —SR 25 , —S(═O)R 25a , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , ═NOR 25 , —C(═O)NHOR 25 , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy; and,
R 25 , R 25a , and R 26 are each independently selected at each occurrence from the group: hydrogen and C 1 -C 6 alkyl;
and a pharmaceutically acceptable salt thereof.
4 . A compound according to claim 3 , wherein Q is a compound of Formula (III):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R 1e is selected from:
U e is selected from:
—(CH 2 ) n e —,
—(CH 2 ) n e O(CH 2 ) m e —,
—(CH 2 ) n e C(═O)(CH 2 ) m e —, or
—N(R 10e )C(═O)—;
R 8e is selected from:
CO 2 R 18ae ,
C(═O)R 18ae ,
CONR 17e R 18ae ,
C 1 -C 10 alkyl, substituted with 0-1 R 6e ,
C 5 -C 10 alkenyl, substituted with 0-1 R 6e ,
C 5 -C 10 alkynyl, substituted with 0-1 R 6e ,
C 3 -C 8 cycloalkyl, substituted with 0-1 R 6e ,
C 5 -C 6 cycloalkenyl, substituted with 0-1 R 6e ,
C 1 -C 10 alkylcarbonyl,
C 3 -C 10 cycloalkylalkyl,
phenyl substituted with 1-3 R 6e ,
naphthyl substituted with 0-3 R 6e ,
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 R 7e ,
R 9e is selected from:
C 1 -C 10 alkyl, substituted with 0-1 R 6e ,
C 5 -C 10 alkenyl, substituted with 0-1 R 6e ,
C 5 -C 10 alkynyl, substituted with 0-1 R 6e ,
C 3 -C 8 cycloalkyl, substituted with 0-1 R 6e ,
C 5 -C 6 cycloalkenyl, substituted with 0-1 R 6e ,
C 1 -C 10 alkylcarbonyl,
C 3 -C 10 cycloalkylalkyl,
phenyl substituted with 1-3 R 6e ,
naphthyl substituted with 0-3 R 6e ,
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 R 7e ,
hydroxy,
C 5 -C 10 alkoxy,
nitro,
N(R 10e )R 11e ,
N(R 16e )R 17e ,
aryl(C 0 -C 6 alkyl)carbonyl,
aryl(C 3 -C 6 alkyl),
heteroaryl(C 1 -C 6 alkyl),
CONR 18ae R 20e ,
SO 2 R 18ae , or
SO 2 NR 18ae R 20e , and providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p e R 11e , SO 2 NR 10e R 11e ,
C 6 -C 10 aryl optionally substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, or —NMe 2 ;
C 7 -C 11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, or —NMe 2 , or
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 R 7e ;
R 7e is selected from:
H, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10 , or N(R 11e )R 12e ;
Y e is selected from:
—COR 20e , —CONHNHSO 2 CF 3 , —CONHSO 2 R 18ae , or —CONHSO 2 NHR 18be ;
R 10e is selected from:
H, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, aryl, aryl(C 1 -C 4 alkyl), or C 1 -C 10 alkyl substituted with 0-2 R 4e ;
R 11e is selected from:
H, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 -C 10 aryl, heteroaryl, heteroarylalkyl, aryl(C 1 -C 4 alkyl), adamantylmethyl, or C 1 -C 10 alkyl substituted with 0-2 R 4e ;
alternatively, when R 10e and R 11e are both substituents on the same nitrogen atom (as in —NR 10e R 11e ) 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 or 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from: C 1 -C 6 alkyl, C 6 -C 10 aryl, heteroaryl, C 7 -C 11 arylalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
R 4e is selected from:
H, C 1 -C 10 alkyl, C 1 -C 10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
R 12e is selected from:
H, C 1 -C 6 alkyl, triphenylmethyl, methoxymethyl (MOM), methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl (SEM), (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl; (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl C 1 -C 6 alkyl, (C 1 -C 6 alkyl)carbonyl, or arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, or aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 13e is selected from:
C 7 -C 8 alkyl, C 3 -C 11 cycloalkyl, aryl(C 1 -C 6 alkyl)-, heteroaryl(C 1 -C 6 alkyl)-, biaryl(C 1 -C 6 alkyl), biaryl optionally substituted with 1-4 R 19e ; heteroaryl optionally substituted with 1-4 R 19e , phenyl substituted with 3-4 R 19e or naphthyl substituted with 1-4 R 19e ;
R 14e is selected from:
H, C 1 -C 4 alkyl, phenyl(C 1 -C 4 alkyl), or a bond to L n ;
R 16e is selected from:
—C(═O)OR 18ae ,
—C(═O)R 18be ,
—C(═O)N(R 18be ) 2 ,
SO 2 R 18ae , or
—SO 2 N(R 18be ) 2 ;
R 17e is selected from:
H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from:
C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is selected from:
R 18ae or H;
R 19e is selected from:
H, halogen, CF 3 , CO 2 H, CN, NO 2 , NR 11e R 12e , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, OCF 3 , or C 1 -C 4 alkoxycarbonyl, aryl, —O-aryl, —SO 2 -aryl, heteroaryl, or —SO 2 -heteroaryl, wherein said aryl and heteroaryl groups may be substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
R 20e is selected from:
hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, C 6 -C 10 aryloxy, C 7 -C 11 aralkyloxy, C 3 -C 10 alkylcarbonyloxyalkyloxy, C 3 -C 10 alkoxycarbonyloxyalkyloxy, C 2 -C 10 alkoxycarbonylalkyloxy, C 5 -C 10 cycloalkylcarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonylalkyloxy, C 7 -C 11 aryloxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonyloxyalkyloxy, C 8 -C 12 arylcarbonyloxyalkyloxy, C 5 -C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 -C 10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C 10 -C 14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R 11e )(R 12e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from:
C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 7e ;
m e is 0-2;
n e is 0-3;
p e is 0-2;
with the following provisos:
(1) n e and m e are chosen such that the number of atoms connecting R 1e and Y e is in the range of 8-14;
(2) if R 8e is H, then R 9e may not be an unsubstituted pyridyl radical;
(3) if R 9e is H, then R 8e may not be an unsubstituted pyridyl radical.
d is selected from 1, 2, 3, 4, and 5;
W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , SO 2 NH, (OCH 2 CH 2 ) s , (CH 2 CH 2 O) s′ , (OCH 2 CH 2 CH 2 ) s″ , (CH 2 CH 2 CH 2 O) t , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-1 R 10 , C 3 - 10 cycloalkyl substituted with 0-1 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 10 ;
R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 8b , R 9 , R 9a , and R 9b are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, PO 3 H, C 1 -C 5 alkyl substituted with 0-3 R 10 , aryl substituted with 0-3 R 10 , benzyl substituted with 0-3 R 10 , and C 1 -C 5 alkoxy substituted with 0-3 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to C h ;
R 10 is independently selected at each occurrence from the group: a bond to C h , COOR 11 , C(═O)NHR 11 , NHC(═O)R 11 , NHOH, NHR 11 , SO 3 H, PO 3 H, —OPO 3 H 2 , —OSO 3 H, aryl substituted with 0-3 R 11 , C 1-5 alkyl substituted with 0-1 R 12 , C 1-5 alkoxy substituted with 0-1 R 12 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 11 ; R 11 is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R 12 , aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 12 , C 3-10 cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 12 , carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 12 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, 3,6-O-disulfo-B-D-galactopyranosyl, bis(phosphonomethyl)glycine, and a bond to C h ;
k is 0 or 1;
s is selected from 0, 1, 2, 3, 4, and 5;
s′ is selected from 0, 1, 2, 3, 4, and 5;
s″ is selected from 0, 1, 2, 3, 4, and 5;
t is selected from 0, 1, 2, 3, 4, and 5;
A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), OH, and a bond to L n ;
E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3-10 cycloalkyl substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 ;
R 13 , and R 14 are each independently selected from the group: a bond to L n , hydrogen, C 1 -C 10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 14 is an electron, then the other is also an electron;
alternatively, R 13 and R 14 combine to form ═C(R 20 )(R 21 );
R 17 is independently selected at each occurrence from the group: a bond to L n , ═O, F, Cl, Br, I, —CF 3 , —CN, —CO 2 R 18 , —C(═O)R 18 , —C(═O)N(R 18 ) 2 , —CH 2 OR 18 , —OC(═O)R 18 , —OC(═O)OR 18a , —OR 18 , —OC(═O)N(R 18 ) 2 , —NR 19 C(═O)R 18 , —NR 19 C(═O)OR 18a , —NR 19 C(═O)N(R 18 ) 2 , —NR 19 SO 2 N(R 18 ) 2 , —NR 19 SO 2 R 18a , —SO 3 H, —SO 2 R 18a , —S(═O)R 18a , —SO 2 N(R 18 ) 2 , —N(R 18 ) 2 , —NHC(═S)NHR 18 , ═NOR 18 , —C(═O)NHNR 18 R 18a , —OCH 2 CO 2 H, and 2-(1-morpholino)ethoxy;
R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, and C 1 -C 6 alkyl;
R 20 and R 21 are independently selected from the group: H, C 1 -C 5 alkyl, —CO 2 R 25 , C 2 -C 5 1-alkene substituted with 0-3 R 23 , C 2 -C 5 1-alkyne substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 23 ;
alternatively, R 20 and R 21 , taken together with the divalent carbon radical to which they are attached form:
R 22 and R 23 are independently selected from the group: H, and R 24 ;
alternatively, R 22 , R 23 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;
R 24 is independently selected at each occurrence from the group: —CO 2 R 25 , —C(═O)N(R 25 ) 2 , —CH 2 OR 25 , —OC(═O)R 25 , —OR 25 , —SO 3 H, —N(R 25 ) 2 , and —OCH 2 CO 2 H; and,
R 25 is independently selected at each occurrence from the group: H and C 1 -C 3 alkyl.
5 . A compound according to claim 4 , 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:
R 1e is selected from:
A e is selected from:
—CH 2 —, or —N(R 12e )—;
A 1e and B e are independently:
—CH 2 — or —N(R 10e )—;
D e is selected from:
—N(R 12e )—, or —S—;
E e -F e is selected from:
—C(R 2e )═C(R 3e )—, or —C(R 2e ) 2 C(R 3e ) 2 —;
J e is selected from:
—C(R 2e )— or —N—,
K e , L e and M e are independently selected from:
—C(R 2e )— or —C(R 3e )—;
R 2e and R 3e are independently selected from:
H, C 1 -C 4 alkoxy, NR 11e R 12e , ═NR 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 6 -C 10 aryl substituted with 0-4 R 7e , C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, or C 7 -C 11 arylcarbonyl;
alternatively, when R 2e and R 3e 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 optionally substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 or NO 2 ;
R 2ae is absent or R 12e ;
U e is selected from:
—(CH 2 ) n e —,
—(CH 2 ) n e O(CH 2 ) m e —,
—(CH 2 ) n e N(R 12e )(CH 2 ) m e —,
—(CH 2 ) n e C(═O)(CH 2 ) m e —,
—(CH 2 ) n e S(O) p (CH 2 ) m e —,
—(CH 2 ) n e NHNH(CH 2 ) m e —,
—N(R 10e )C(═O)—,
—C(═O)N(R 10e )—, or
—N(R 10e )S(O) p e —;
G e is selected from:
N or CR 19e ;
W e is —C(═O)—N(R 10e )—(C 1 -C 3 alkylene)-, in which the alkylene group may be substituted by:
CO 2 R 18ae ,
C(═O) R 8ae ,
CONR 17e R 18ae ,
C 1 -C 10 alkyl, substituted with 0-1 R 6e ,
C 2 -C 10 alkenyl, substituted with 0-1 R 6e ,
C 2 -C 10 alkynyl, substituted with 0-1 R 6e ,
C 3 -C 8 cycloalkyl, substituted with 0-1 R 6e ,
C 5 -C 6 cycloalkenyl, substituted with 0-1 R 6e ,
C 1 -C 10 alkylcarbonyl,
C 3 -C 10 cycloalkylalkyl,
aryl substituted with 0-3 R 6e ,
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 R 7e ,
hydroxy,
C 1 -C 10 alkoxy,
nitro,
OR 22e
N(R 10e )R 11e ,
—N(R 16e ) R 17e ,
aryl(C 0 -C 6 alkyl)carbonyl,
aryl(C 1 -C 6 alkyl),
heteroaryl(C 1 -C 6 alkyl),
CONR 18ae R 20e ,
SO 2 R 18ae , or
SO 2 NR 18ae R 20e , and providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
Y e is selected from:
—COR 20e , —SO 3 H, —PO 3 H, —CONHNHSO 2 CF 3 , —CONHSO 2 R 18ae , —CONHSO 2 NHR 18be , —NHCOCF 3 , —NHCONHSO 2 R 18ae , —NHSO 2 R 18ae , —OPO 3 H 2 , —OSO 3 H, —PO 3 H 2 , —SO 3 H, —SO 2 NHCOR 18ae , —SO 2 NHCO 2 R 18ae , or
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e O 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p e R 11e , SO 2 NR 10e R 11e ,
C 6 -C 10 aryl optionally substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, or —NMe 2 ;
C 7 -C 11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, or —NMe 2 ,
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 R 7e ;
R 7e is selected from:
H, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, (C 1 -C 4 alkyl)carbonyl,
CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , or N(R 11e )R 12e ;
R 10e is selected from:
H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, aryl(C 1 -C 4 alkyl), C 1 -C 10 alkyl substituted with 0-2 R 6e , or a bond to L n ;
R 11e is selected from:
H, hydroxy, C 1 to C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 -C 10 aryl, heteroaryl, heteroarylalkyl, C 7 -C 11 arylalkyl, adamantylmethyl, or C 1 -C 10 alkyl substituted with 0-2 R 4e ;
alternatively, when R 10e and R 11e are both substituents on the same nitrogen atom (as in —NR 10e R 11e ) they can 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 or 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from: C 1 -C 6 alkyl, C 6 -C 10 aryl, heteroaryl, C 7 -C 11 arylalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
R 4e is selected from:
H, C 1 -C 10 alkyl, C 1 -C 10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
R 12e is selected from:
H, C 1 -C 6 alkyl, triphenylmethyl, methoxyphenyldiphenylmethyl, methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl; (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl C 1 -C 6 alkyl, (C 1 -C 6 alkyl)carbonyl, or arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, or aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from:
—C(═O)OR 18ae ,
—C(═O)R 18be ,
—C(═O)N(R 18be ) 2 ,
—C(═O)NHSO 2 R 18ae ,
—C(═O)NHC(═O)R 18be ,
—C(═O)NHC(═O)OR 18ae ,
—C(═O)NHSO 2 NHR 18be ,
—SO 2 R 18ae ,
—SO 2 N(R 18be ) 2 or,
—SO 2 NHC(═O)OR 18be ;
R 17e is selected from:
H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from:
C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is selected from:
R 18ae or H;
R 19e is selected from:
H, halogen, CF 3 , CO 2 H, CN, NO 2 , NR 11e R 12e , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, OCF 3 , or C 1 -C 4 alkoxycarbonyl, aryl, —O-aryl, —SO 2 -aryl, heteroaryl, or —SO 2 -heteroaryl, wherein said aryl and heteroaryl groups may be substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
R 20e is selected from:
hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, C 6 -C 10 aryloxy, C 7 -C 11 aralkyloxy, C 3 -C 10 alkylcarbonyloxyalkyloxy, C 3 -C 10 alkoxycarbonyloxyalkyloxy, C 2 -C 10 alkoxycarbonylalkyloxy, C 5 -C 10 cycloalkylcarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonylalkyloxy, C 7 -C 11 aryloxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonyloxyalkyloxy, C 8 -C 12 arylcarbonyloxyalkyloxy, C 5 -C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 -C 10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C 10 -C 14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R 11e )(R 12e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from:
—C(═O)—R 18be ,
—C(═O)N(R 18be ) 2 ,
—C(═O)NHSO 2 R 18ae ,
—C(═O)NHC(═O) R 18be ,
—C(═O)NHC(═O)OR 18ae or,
—C(═O)NHSO 2 NHR 18be ,
m e is 0-2;
n e is 0-4;
p e is 0-2;
r e is 0-2;
with the following provisos:
(1) n e , m e and q e are chosen such that the number of atoms connecting R 1e and Y e is in the range of 8-14;
(2) when all R 19e groups are H, G e must be N;
(3) when G e is CR 19e , at least one R 19e group cannot be H.
or Q is a peptide selected from the group:
R 1 is L-valine, D-valine or L-lysine optionally substituted on the E amino group with a bond to L n ;
R 2 is L-phenylalanine, D-phenylalanine, D-1-naphthylalanine, 2-aminothiazole-4-acetic acid or tyrosine, the tyrosine optionally substituted on the hydroxy group with a bond to L n ;
R 3 is D-valine;
R 4 is D-tyrosine substituted on the hydroxy group with a bond to L n ;
provided that one of R 1 and R 2 in each Q is substituted with a bond to L n , and further provided that when R 2 is 2-aminothiazole-4-acetic acid, K is N-methylarginine;
provided that at least one Q is a compound of Formula IIa or IIb;
C h is
A 1 is selected from the group: OH, and a bond to L n ;
A 2 , A 4 , and A 6 are each N;
A 3 , A 5 , and A 8 are each OH;
A 7 is a bond to L n or NH-bond to L n ;
E is a C 2 alkyl substituted with 0-1 R 17 ;
R 17 is ═O;
alternatively, C h is
A 1 is selected from the group: OH, and a bond to L n ;
A 2 , A 3 and A 4 are each N;
A 5 , A 6 and A 8 are each OH;
A 7 is a bond to L n ;
E is a C 2 alkyl substituted with 0-1 R 17 ;
R 17 is ═O;
alternatively, C h is
A 1 is NH 2 or N═C(R 20 )(R 21 );
E is a bond;
A 2 is NHR 13 ;
R 13 is a heterocycle substituted with R 17 , the heterocycle being selected from pyridine and pyrimidine;
R 17 is selected from a bond to L n , C(═O)NHR 18 and C(═O)R 18 ;
R 18 is a bond to L n ;
R 24 is selected from the group: —CO 2 R 25 , —OR 25 , —SO 3 H, and —N(R 25 ) 2 ; and,
R 25 is independently selected at each occurrence from the group: hydrogen and methyl.
6 . A compound according to claim 5 , wherein Q is a compound of Formula (IV):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R 1e is selected from:
R 2e and R 3e are independently selected from:
H, C 1 -C 4 alkoxy, NR 11e R 2e , ═NR 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 6 -C 10 aryl substituted with 0-4 R 7e , C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, or C 7 -C 11 arylcarbonyl;
alternatively, when R 2e and R 3e 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 optionally substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 or NO 2 ;
U e is selected from:
—(CH 2 ) n e —,
—(CH 2 ) n e O(CH 2 )m e —,
—N(R 10e )C(═O)—, or
—C(═O)N(R 10e )—;
G e is selected from:
N or CR 9e ;
R 8e is selected from:
CO 2 R 18ae ,
C(═O)R 18ae ,
CONR 17 e R 18ae ,
C 1 -C 10 alkyl, substituted with 0-1 R 6e ,
C 2 -C 10 alkenyl, substituted with 0-1 R 6e ,
C 2 -C 10 alkynyl, substituted with 0-1 R 6e ,
C 3 -C 8 cycloalkyl, substituted with 0-1 R 6e ,
C 5 -C 6 cycloalkenyl, substituted with 0-1 R 6e ,
C 1 -C 10 alkylcarbonyl,
C 3 -C 10 cycloalkylalkyl,
aryl substituted with 0-3 R 6e ,
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 R 7e ,
R 9e is selected from:
hydroxy,
C 1 -C 10 alkoxy,
nitro,
OR 22e
N(R 10e ) R 11e ,
—N(R 16e )R 17e ,
aryl(C 0 -C 6 alkyl)carbonyl,
aryl(C 1 -C 6 alkyl),
heteroaryl(C 1 -C 6 alkyl),
CONR 18ae R 20e ,
SO 2 R 18ae , or
SO 2 NR 18ae R 20e , and providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
Y e is selected from:
—COR 20e , —CONHNHSO 2 CF 3 , —CONHSO 2 R 18ae , or —CONHSO 2 NHR 18be ;
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p e R 11e , SO 2 NR 10e R 11e ,
C 6 -C 10 aryl optionally substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, or —NMe 2 ;
C 7 -C 11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, or —NMe 2 ,
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 R 7e ;
R 7e is selected from:
H, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , or N(R 11e )R 12e ;
R 10e is selected from:
H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, aryl(C 1 -C 4 alkyl), C 1 -C 10 alkyl substituted with 0-2 R 6e , OR A BOND TO L N ;
R 11e is selected from:
H, hydroxy, C 1 to C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 -C 10 aryl, heteroaryl, heteroarylalkyl, C 7 -C 11 arylalkyl, adamantylmethyl, or C 1 -C 10 alkyl substituted with 0-2 R 4e ;
alternatively, when R 10e and R 11e are both substituents on the same nitrogen atom (as in —NR 10e R 11e ) they can 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 or 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from: C 1 -C 6 alkyl, C 6 -C 10 aryl, heteroaryl, C 7 -C 11 arylalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
R 4e is selected from:
H, C 1 -C 10 alkyl, C 1 -C 10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
R 12e is selected from:
H, C 1 -C 6 alkyl, triphenylmethyl, methoxyphenyldiphenylmethyl, methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl; (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl C 1 -C 6 alkyl, (C 1 -C 6 alkyl)carbonyl, or arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, or aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from:
—C(═O) OR 18ae ,
—C(═O)R 18be ,
—C(═O)N(R 18be ) 2 ,
—SO 2 R 18ae , or
—SO 2 N(R 18be ) 2 ;
R 17e is selected from:
H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl(C 1 - 6 alkyl);
R 18ae is selected from:
C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is selected from:
R 18ae or H;
R 19e is selected from:
H, halogen, CF 3 , CO 2 H, CN, NO 2 , NR 11e R 12e , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, OCF 3 , or C 1 -C 4 alkoxycarbonyl, aryl, —O-aryl, —SO 2 -aryl, heteroaryl, or —SO 2 -heteroaryl, wherein said aryl and heteroaryl groups may be substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
R 20e is selected from:
hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, C 6 -C 10 aryloxy, C 7 -C 11 aralkyloxy, C 3 -C 10 alkylcarbonyloxyalkyloxy, C 3 -C 10 alkoxycarbonyloxyalkyloxy, C 2 -C 10 alkoxycarbonylalkyloxy, C 5 -C 10 cycloalkylcarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonylalkyloxy, C 7 -C 11 aryloxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonyloxyalkyloxy, C 8 -C 12 arylcarbonyloxyalkyloxy, C 5 -C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 -C 10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C 10 -C 14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R 11e )(R 12e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 11 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from:
—C(═O)—R 18be ,
—C(═O)N(R 18be ) 2 ,
—C(═O)NHSO 2 R 18ae ,
—C(═O)NHC(═O)R 18be ,
—C(═O)NHC(═O)OR 18ae or,
—C(═O)NHSO 2 NHR 18be ,
m e is 0-2;
n e is 0-4;
p e is 0-2;
with the following provisos:
(1) n e and m e are chosen such that the number of atoms connecting R 1e and Y e is in the range of 8-14;
(2) when all R 19e groups are H, G e must be N;
(3) when G e is CR 19e , at least one R 19e group cannot be H.
7 . A compound according to claim 3 , wherein the compound is selected from the group:
2-(((4-(4-(((3-(2-(2-(3((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)-propoxy)ethoxy)-ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)-sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoic acid; 3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)-propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)-phenyl)phenyl)sulfonyl)amino)propanoic acid; 2-(((4-(3-(N-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)-propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic; 3-((1-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid; 3-((1-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-(((1-hydroxyimidazole-2-yl)amino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid; 3-((1-(3-(3-(N-(3-(2-(2-(3-((6-((1-aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propoxy)ethoxy)-ethoxy)propyl)carbamoyl)propanoylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid; 2-(2-aza-2-(5-(N-(1,3-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)-ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)(2-pyridyl))amino)vinyl)benzenesulfonic acid; DOTA conjugate of 3-((1-(3-(3-(N-(3-(2-(2-(N-(L-Asp-L-asp)3-aminopropoxy)ethoxy)ethoxy)propyl)carbamoyl)-propanoylamino)propyl-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid; DOTA/2-amino-N,N′-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)-sulfonyl)amino)ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)-propyl)carbamoyl)propanoylamino)propoxy)-ethoxy)ethoxy)propyl)pentane-1,5-diamide conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-sulfopropyl)-propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-3-(4-(phosphonooxy)-phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-Amino-3-(4-(sulfooxy)-phenyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(ethyl-3,6-O-disulfo-b-D-galactopyranosyl)carbamoyl)butanoylamino)-propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(6-deoxy-b-cyclodextryl)carbamoyl)butanoylamino)-propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic acid conjugate; DOTA/2-(((4-(3-(N-(3-(2-(2-(3-(2-amino-4-(N-(w-methoxypolyethylene(5,000) glycoxyethyl)carbamoyl)-butanoylamino)propoxy)ethoxy)ethoxy)-propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic acid conjugate; 2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-aminohexanoylamino)propoxy)ethoxy)ethoxy)-propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic acid; 2-(((4-(3-(N-(3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)cyclododecylacetylamino)-6-(2-(bis(phosphonomethyl)amino)acetylamino)hexanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic acid conjugate; and 2-(((4-(3-(N-(3-(2-(2-(3-(2-(2-((2-((2-(bis(carboxymethyl)-amino)ethyl)(carboxymethyl)amino)ethyl)(carboxymethyl)amino)acetylamino)-3-sulfopropyl)propoxy)ethoxy)-ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic acid. or a pharmaceutically acceptable salt form thereof.
8 . A kit comprising a compound of claim 3 , or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier.
9 . A kit according to claim 8 , wherein the kit further comprises one or more ancillary ligands and a reducing agent.
10 . A kit according to claim 9 , wherein the ancillary ligands are tricine and TPPTS.
11 . A kit according to claim 9 , wherein the reducing agent is tin(II).
12 . A diagnostic or therapeutic metallopharmaceutical composition, comprising: a metal, a chelator capable of chelating the metal and a targeting moiety, wherein the targeting moiety is bound to the chelator, is a peptide or peptidomimetic and binds to a receptor that is upregulated during angiogenesis and the compound has 0-1 linking groups between the targeting moiety and chelator.
13 . A composition according to claim 12 , wherein the metallopharmaceutical is a diagnostic radiopharmaceutical, the metal is a radioisotope selected from the group: 99m Tc, 95 Tc, 111 In, 62 Cu, 64 Cu, 67 Ga, and 68 Ga, the targeting moiety comprises an indazole and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Ax1, α v β 3 , α v β 5 , α 5 β 1 , α 4 β 1 , α 1 β 1 , and α 2 β 2 and the linking group is present between the targeting moiety and chelator.
14 . A composition according to claim 13 , wherein the targeting moiety is an indazole and the receptor is α v β 3 .
15 . A composition according to claim 13 , wherein the radioisotope is 99m Tc or 95 Tc, the radiopharmaceutical further comprises a first ancillary ligand and a second ancillary ligand capable of stabilizing the radiopharmaceutical.
16 . A composition according to claim 15 , wherein the radioisotope is 99m Tc.
17 . A composition according to claim 16 , wherein the radiopharmaceutical is selected from the group:
99m Tc(2-(((4-(4-(((3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)-ethoxy)propyl)amino)sulfonyl)phenyl)phenyl)-sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoic acid)(tricine)(TPPTS); 99m Tc(2-(((4-(3-(N-(3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)-ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))-carbonylamino)propanoic acid)(tricine)(TPPDS); 99m Tc(3-((1-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid)(tricine)(TPPTS); 99m Tc(HYNIC-3-((1-(3-((6-((-Aza-2-(2-sulfophenyl)vinyl)amino)(3-pyridyl))carbonylamino)propyl)-7-(((1-hydroxyimidazole-2-yl)amino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid trifluoroacetate salt)(tricine)(TPPTS); 99m Tc(3-((-(3-(3-(N-(3-(2-(2-(3-((6-(diazenido)(3-pyridyl))carbonylamino)propoxy)ethoxy)-ethoxy)propyl)carbamoyl)propanoylamino)propyl)-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid)(tricine)(TPPTS); 99m Tc(2-(2-(5-(N-(1,3-bis(3-(2-(2-(3-(3-(N-(3-(3-(N-(3-carboxy-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)-ethyl)carbamoyl)-7-((imidazole-2-ylamino)methyl)4-oxohydroquinolyl)propyl)carbamoyl)propanoylamino)propoxy)ethoxy)ethoxy)propyl)carbamoyl)(2-pyridyl)diazenido))(tricine)(TPPTS);
18 . A composition according to claim 14 , wherein the radioisotope is 111 In.
19 . A composition according to claim 18 , wherein the radiopharmaceutical is a In-111 complex of 3-((7-((-Imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)-propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)-phenyl)phenyl)sulfonyl)amino)propanoic acid.
20 . A composition according to claim 12 , wherein the metallopharmaceutical is a therapeutic radiopharmaceutical, the metal is a radioisotope selected from the group: 186 Re, 188 Re, 153 Sm, 166 Ho, 177 Lu, 149 Pm, 90 Y, 212 Bi, 103 Pd, 109 Pd, 159 Gd, 140 La, 198 Au, 199 Au, 169 Yb, 175 Yb, 165 Dy, 166 Dy, 67 Cu, 105 Rh, 111 Ag, and 192 Ir, the targeting moiety is a nonpeptide and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α v β 3 , α v β 5 , α 5 β 1 , α 4 β 1 , α 1 β 1 , and α 2 β 2 and the linking group is present between the targeting moiety and chelator.
21 . A composition according to claim 20 , wherein the targeting moiety is an indazole and the receptor is α v β 3 .
22 . A composition according to claim 21 , wherein the radioisotope is 153 Sm.
23 . A composition according to claim 21 , wherein the radioisotope is 177 Lu.
24 . A composition according to claim 23 , wherein the radiopharmaceutical is selected from the group:
177 Lu complex of 3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)-propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)-phenyl)phenyl)sulfonyl)amino)propanoic acid and 177 Lu complex of the DOTA conjugate of 3-((1-(3-(3-(N-(3-(2-(2-(N-(L-Asp-L-Asp)3-aminopropoxy)-ethoxy)ethoxy)propyl)carbamoyl)propanoylamino)propyl-7-((imidazole-2-ylamino)methyl)-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((2,4,6-trimethylphenyl)sulfonyl)amino)propanoic acid.
25 . A composition according to claim 21 , wherein the radioisotope is 90 Y.
26 . A composition according to claim 25 , wherein the radiopharmaceutical is 90 Y complex of 3-((7-((Imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)-2-(((4-(4-(((3-(2-(2-(3-(2-(1,4,7,10-tetraaza-4,7,10-tris(carboxylmethyl)cyclododecyl)acetylamino)-propoxy)ethoxy)ethoxy)propyl)amino)sulfonyl)-phenyl)phenyl)sulfonyl)amino)propanoic acid.
27 . A composition according to claim 12 , wherein the metallopharmaceutical is a MRI contrast agent, the metal is a paramagnetic metal ion selected from the group: Gd(III), Dy(III), Fe(III), and Mn(II), the targeting moiety is a nonpeptide and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α v β 3 , α v β 5 , α 5 β 1 , α 4 β 1 , and α 1 β 1 , and α 2 β 2 the linking group is present between the targeting moiety and chelator.
28 . A composition according to claim 27 , wherein the targeting moiety is an indazole and the receptor is α v β 3 .
29 . A composition according to claim 28 , wherein the metal ion is Gd(III).
30 . A composition according to claim 29 , wherein the contrast agent is a Gadolinium complex of 2-(((4-(3-(N-(3-(2-(2-(3-(2-(2-((2-((2-(bis(carboxymethyl)-amino)ethyl)(carboxymethyl)amino)ethyl)(carboxymethyl)amino)acetylamino)-3-sulfopropyl)propoxy)ethoxy)-ethoxy)propyl)carbamoyl)propoxy)-2,6-dimethylphenyl)-sulfonyl)amino)-3-((7-((imidazol-2-ylamino)methyl)-1-methyl-4-oxo(3-hydroquinolyl))carbonylamino)propanoic acid.
31 . A composition according to claim 12 , wherein the metallopharmaceutical is a X-ray contrast agent, the metal is selected from the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir, the targeting moiety is a cyclic pentapeptide, the receptor is α v β 3 , and the linking group is present between the targeting moiety and chelator.
32 . A method of treating rheumatoid arthritis in a patient comprising: administering a therapeutic radiopharmaceutical of claim 12 capable of localizing in new angiogenic vasculature to a patient by injection or infusion.
33 . A method of treating cancer in a patient comprising: administering to a patient in need thereof a therapeutic radiopharmaceutical of claim 12 by injection or infusion.
34 . A method of imaging formation of new blood vessels in a patient comprising: (1) administering a diagnostic radiopharmaceutical, a MRI contrast agent, or a X-ray contrast agent of of claim 12 to a patient by injection or infusion; (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.
35 . A method of imaging cancer in a patient comprising: (1) administering a diagnostic radiopharmaceutical of claim 12 to a patient by injection or infusion; (2) imaging the patient using planar or SPECT gamma scintigraphy, or positron emission tomography.
36 . A method of imaging cancer in a patient comprising:
(1) administering a MRI contrast agent of claim 27; and (2) imaging the patient using magnetic resonance imaging.
37 . A method of imaging cancer in a patient comprising:
(1) administering a X-ray contrast agent of claim 31; and (2) imaging the patient using X-ray computed tomography.
38 . A compound, comprising: a targeting moiety and a surfactant, wherein the targeting moiety is bound to the surfactant, is a nonpeptide, and binds to a receptor that is upregulated during angiogenesis and the compound has 0-1 linking groups between the targeting moiety and surfactant.
39 . A compound according to claim 38 , wherein the targeting moiety comprises an indazole and the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, α v β 3 , α v β 5 , α 5 β 1 , α 4 β 1 , α 1 β 1 , and α 2 β 2 and the linking group is present between the targeting moiety and surfactant.
40 . A compound according to claim 39 , wherein the receptor is the integrin α v β 3 and the compound is of the formula:
(Q) d -L n -S f
wherein, Q is a compound of Formula (I):
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R 1e is selected from:
D e is selected from:
—N(R 12e )—, or —S—;
J e is selected from:
—C(R 2e )— or —N—;
K e, L e and M e are independently selected from:
—C(R 2e )— or —C(R 3e )—;
R 2e and R 3e are independently selected from:
H, C 1 -C 4 alkoxy, NR 11e R 12 e, ═NR 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 6 -C 10 aryl substituted with 0-4 R 7e , C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, or C 7 -C 11 arylcarbonyl;
alternatively, when R 2e and R 3e 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 optionally substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 or NO 2 ;
U e is selected from:
—(CH 2 ) n e —,
—(CH 2 ) n e O(CH 2 ) m e —,
—(CH 2 ) n e N(R 12e )(CH 2 ) m e —,
—(CH 2 ) n e C(═O)(CH 2 ) m e —,
—(CH 2 ) n e S(O) p e (CH 2 ) m e —,
—(CH 2 ) n e NHNH(CH 2 ) m e —,
—N(R 10e )C(═O)—,
—C(═O)N(R 10e )—, or
—N(R 10e )S(O) p e —;
W e is —C(═O)—N(R 10e )—(C 1 -C 3 alkylene)-, in which the alkylene group may be substituted by:
CO 2 R 18ae ,
C(═O)R 18ae ,
CONR 17e R 18ae ,
C 1 -C 10 alkyl, substituted with 0-1 R 6e ,
C 5 -C 10 alkenyl, substituted with 0-1 R 6e
C 5 -C 10 alkynyl, substituted with 0-1 R 6e ,
C 3 -C 8 cycloalkyl, substituted with 0-1 R 6e ,
C 5 -C 6 cycloalkenyl, substituted with 0-1 R 6e ,
C 1 -C 10 alkylcarbonyl,
C 3 -C 10 cycloalkylalkyl,
phenyl substituted with 1-3 R 6e ,
naphthyl substituted with 0-3 R 6e ,
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 R 7e ,
hydroxy,
C 5 -C 10 alkoxy,
nitro,
N(R 10e )R 11e ,
—N(R 16e )R 17e ,
C 5 -C 10 alkyl substituted with 0-3 R 7e ,
aryl(C 0 -C 6 alkyl) carbonyl,
aryl(C 3 -C 6 alkyl),
heteroaryl(C 1 -C 6 alkyl),
CONR 18ae R 20e ,
SO 2 R 18ae , or
SO 2 NR 18ae R 20e and providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e SO 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p e R 11e , SO 2 NR 10e R 11e ,
C 6 -C 10 aryl optionally substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, or —NMe 2 ;
C 7 -C 11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, or —NMe 2 , or
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 R 7e ;
R 7e is selected from:
H, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , or N(R 11e )R 12e ;
Y e is selected from:
—COR 20e , —SO 3 H, —PO 3 H, —CONHNHSO 2 CF 3 , —CONHSO 2 R 18ae , —CONHSO 2 NHR 18be , —NHCOCF 3 , —NHCONHSO 2 R 18ae , —NHSO 2 R 18ae , —OPO 3 H 2 , —OSO 3 H, —PO 3 H 2 , —SO 3 H, —SO 2 NHCOR 18ae , —SO 2 NHCO 2 R 18ae , or
R 10e is selected from:
H, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, aryl, aryl(C 1 -C 4 alkyl), or C 1 -C 10 alkyl substituted with 0-2 R 4e ;
R 11e is selected from:
H, hydroxy, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 -C 10 aryl, heteroaryl, heteroarylalkyl, aryl(C 1 -C 4 alkyl), adamantylmethyl, or C 1 -C 10 alkyl substituted with 0-2 R 4e ;
alternatively, when R 10e and R 11e are both substituents on the same nitrogen atom (as in —NR 10e R 11e ) 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 or 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from: C 1 -C 6 alkyl, C 6 -C 10 aryl, heteroaryl, C 7 -C 11 arylalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
R 4e is selected from:
H, C 1 -C 10 alkyl, C 1 -C 10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
R 12e is selected from:
H, C 1 -C 6 alkyl, triphenylmethyl, methoxymethyl (MOM), methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl (SEM), (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl; (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl C 1 -C 6 alkyl, (C 1 -C 6 alkyl)carbonyl, or arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, or aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 13e is selected from:
C 7 -C 8 alkyl, C 3 -C 11 cycloalkyl, aryl(C 1 -C 6 alkyl)-, heteroaryl(C 1 -C 6 alkyl)-, biaryl(C 1 -C 6 alkyl), biaryl optionally substituted with 1-4 R 19e ; heteroaryl optionally substituted with 1-4 R 19e , phenyl substituted with 3-4 R 19e or naphthyl substituted with 1-4 R 19e ;
R 14e is selected from:
H, C 1 -C 4 alkyl, phenyl(C 1 -C 4 alkyl), or a bond to L n ;
R 16e is selected from:
—C(═O)OR 18ae ,
—C(═O)R 18be ,
—C(═O)N(R 18be ) 2 ,
—C(═O)NHSO 2 R 18ae ,
—C(═O)NHC(═O)R 18be ,
—C(═O)NHC(═O)OR 18ae ,
—C(═O)NHSO 2 NHR 18be ,
—SO 2 R 18ae ,
—SO 2 N(R 18be ) 2 or,
—SO 2 NHC(═O)OR 18be ;
R 17e is selected from:
H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from:
C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is selected from:
R 18ae or H;
R 19e is selected from:
H, halogen, CF 3 , CO 2 H, CN, NO 2 , NR 11e R 12e , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, OCF 3 , or C 1 -C 4 alkoxycarbonyl, aryl, —O-aryl, —SO 2 -aryl, heteroaryl, or —SO 2 -heteroaryl, wherein said aryl and heteroaryl groups may be substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
R 20e is selected from:
hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, C 6 -C 10 aryloxy, C 7 -C 11 aralkyloxy, C 3 -C 10 alkylcarbonyloxyalkyloxy, C 3 -C 10 alkoxycarbonyloxyalkyloxy, C 2 -C 10 alkoxycarbonylalkyloxy, C 5 -C 10 cycloalkylcarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonylalkyloxy, C 7 -C 11 aryloxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonyloxyalkyloxy, C 8 -C 12 arylcarbonyloxyalkyloxy, C 5 -C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 -C 10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C 10 -C 14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R 11e )(R 12e )N-(C 1 -C 10 alkoxy)-;
R 21e is selected from:
C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 7e ;
m e is 0-2;
n e is 0-4;
p e is 0-2;
with the following provisos:
(1) n e and m e are chosen such that the number of atoms connecting R 1e and Y e is in the range of 8-14;
(2) in the definition of W e , the substituent on the alkylene group may not be an unsubstituted pyridyl radical
d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
S f is a surfactant which is a lipid or a compound of the formula:
A 9 is selected from the group: OH and OR 27 ;
A 10 is OR 27 ;
R 27 is C(═O)C 1-20 alkyl;
E 1 is C 1-10 alkylene substituted with 1-3 R 28 ;
R 28 is independently selected at each occurrence from the group: R 30 , —PO3H—R 30 , ═O, —CO 2 R 29 , —C(═O)R 29 , —C(═O)N(R 29 ) 2 , —CH 2 OR 29 , —OR 29 , —N(R 29 ) 2 , C 1 -C 5 alkyl, and C 2 -C 4 alkenyl;
R 29 is independently selected at each occurrence from the group: R 30 , H, C 1 -C 6 alkyl, phenyl, benzyl, and trifluoromethyl;
R 30 is a bond to L n ;
L n is a linking group having the formula:
(CR 6 R 7 ) g —(W) h —(CR 6a R 7a ) g′ -(Z) k —(W) h′ —(CR 8 R 9 ) g″ —(W) h″ —(CR 8a R 9a ) g″′
W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , (OCH 2 CH 2 ) 20-200 , (CH 2 CH 2 O) 20-200 , (OCH 2 CH 2 CH 2 ) 20-200 , (CH 2 CH 2 CH 2 O) 20-200 , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-3 R 10 , C 3-10 cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;
R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are independently selected at each occurrence from the group: H, ═O, COOH, SO 3 H, PO 3 H, C 1 -C 5 alkyl substituted with 0-3 R 10 , aryl substituted with 0-3 R 10 , benzyl substituted with 0-3 R 10 , and C 1 -C 5 alkoxy substituted with 0-3 R 10 , NHC(═O)R 11 , C(═O)NHR 11 , NHC(═O)NHR 11 , NHR 11 , R 11 , and a bond to S f ;
R 10 is independently selected at each occurrence from the group: a bond to S f , COOR 11 , OH, NHR 11 , SO 3 H, PO 3 H, aryl substituted with 0-3 R 11 , C 1 - 5 alkyl substituted with 0-1 R 12 , C 1 - 5 alkoxy substituted with 0-1 R 12 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 11 ;
R 11 is independently selected at each occurrence from the group: H, aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R 12 , C 3 - 10 cycloalkyl substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , and a bond to S f ;
R 12 is a bond to S f ;
k is selected from 0, 1, and 2;
h is selected from 0, 1, and 2;
h′ is selected from 0, 1, 2, 3, 4, and 5;
h″ is selected from 0, 1, 2, 3, 4, and 5;
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;
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;
t′ is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
and a pharmaceutically acceptable salt thereof.
42 . 41 . A compound according to claim 40 , wherein the compound is of the formula:
Q-L n -S f
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:
R 1e is selected from:
A e is selected from:
—CH 2 —, or —N(R 12e )—;
A 1e and B e are independently:
—CH 2 — or —N(R 10e )—;
D e is selected from:
—N(R 12e )—, or —S—;
E e -F e is selected from:
—C(R 2e )═C(R 3e )—, or —C(R 2e ) 2 C(R 3e ) 2 —;
J e is selected from:
—C(R 2e )— or —N—,
K e , L e and M e are independently selected from:
—C(R 2e )— or —C(R 3e )—;
R 2e and R 3e are independently selected from:
H, C 1 -C 4 alkoxy, NR 11e R 12e , ═NR 12e , halogen, NO 2 , CN, CF 3 , C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 6 -C 10 aryl substituted with 0-4 R 7e , C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 1 -C 4 alkoxycarbonyl, or C 7 -C 11 arylcarbonyl;
alternatively, when R 2e and R 3e 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 optionally substituted with 0-2 groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 or NO 2 ;
R 2ae is absent or R 12e ;
U e is selected from:
—(CH 2 ) n e —,
—(CH 2 ) n e O(CH 2 ) m e —,
—(CH 2 ) n e N(R 12e )(CH 2 ) m e —,
—(CH 2 ) n e C(═O)(CH 2 ) m e —,
—(CH 2 ) n e S(O) p (CH 2 0 m e —,
—(CH 2 ) n e NHNH(CH 2 ) m e —,
—N(R 10e )C(═O)—,
—C(═O)N(R 10e )—, or
—N(R 10e )S(O) p e —;
G e is selected from:
N or CR 19e ;
W e is —C(═O)—N(R 10e )—(C 1 -C 3 alkylene)-, in which the alkylene group may be substituted by:
CO 2 R 18ae ,
C(═O) R 18ae ,
CONR 17e R 18ae ,
C 1 -C 10 alkyl, substituted with 0-1 R 6e ,
C 2 -C 10 alkenyl, substituted with 0-1 R 6e ,
C 2 -C 10 alkynyl, substituted with 0-1 R 6e ,
C 3 -C 8 cycloalkyl, substituted with 0-1 R 6e ,
C 5 -C 6 cycloalkenyl, substituted with 0-1 R 6e ,
C 1 -C 10 alkylcarbonyl,
C 3 -C 10 cycloalkylalkyl,
aryl substituted with 0-3 R 6e ,
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 R 7e ,
hydroxy,
C 1 -C 10 alkoxy,
nitro,
OR 22e
N(R 10e ) R 11e ,
—N(R 16e )R 17e ,
aryl(C 0 -C 6 alkyl) carbonyl,
aryl(C 1 -C 6 alkyl),
heteroaryl(C 1 -C 6 alkyl),
CONR 18ae R 20e ,
SO 2 R 18ae , or
SO 2 NR 18ae R 20e , and providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R 7e ;
Y e is selected from:
—COR 20e , —SO 3 H, —PO 3 H, —CONHNHSO 2 CF 3 , —CONHSO 2 R 18ae , —CONHSO 2 NHR 18be , —NHCOCF 3 , —NHCONHSO 2 R 18ae , —NHSO 2 R 18ae , —OPO 3 H 2 , —OSO 3 H, —PO 3 H 2 , —SO 3 H, —SO 2 NHCOR 18ae , —SO 2 NHCO 2 R 18ae , or
R 6e is selected from:
H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, —N(R 11e )R 12e , cyano, halo, CF 3 , CHO, CO 2 R 18be , C(═O)R 18be , CONR 17e R 18be , OC(═O)R 10e , OR 10e , OC(═O)NR 10e R 11e , NR 10e C(═O)R 10e , NR 10e C(═O)OR 21e , NR 10e C(═O)NR 10e R 11e , NR 10e O 2 NR 10e R 11e , NR 10e SO 2 R 21e , S(O) p e R 11e , SO 2 NR 10e R 11e ,
C 6 -C 10 aryl optionally substituted with 0-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m e Me, or —NMe 2 ;
C 7 -C 11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) p e Me, or —NMe 2 ,
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 R 7e ;
R 7e is selected from:
H, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, (C 1 -C 4 alkyl)carbonyl, CO 2 R 18ae , SO 2 R 11e , SO 2 NR 10e R 11e , OR 10e , or N(R 11e ) R 12e ;
R 10e is selected from:
H, CF 3 , C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, aryl(C 1 -C 4 alkyl), C 1 -C 10 alkyl substituted with 0-2 R 6e , or a bond to L n ;
R 11e is selected from:
H, hydroxy, C 1 to C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 -C 10 aryl, heteroaryl, heteroarylalkyl, C 7 -C 11 arylalkyl, adamantylmethyl, or C 1 -C 10 alkyl substituted with 0-2 R 4e ;
alternatively, when R 10e and R 11e are both substituents on the same nitrogen atom (as in —NR 10e R 11e ) they can 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 or 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from: C 1 -C 6 alkyl, C 6 -C 10 aryl, heteroaryl, C 7 -C 11 arylalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 6 -c 10 arylsulfonyl;
R 4e is selected from:
H, C 1 -C 10 alkyl, C 1 -C 10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
R 12e is selected from:
H, C 1 -C 6 alkyl, triphenylmethyl, methoxyphenyldiphenylmethyl, methoxymethyl (MOM), trimethylsilylethoxymethyl (SEM), (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl; (C 1 -C 6 alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl C 1 -C 6 alkyl, (C 1 -C 6 alkyl)carbonyl, or arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C 1 -C 6 alkyl)sulfonyl, aryloxycarbonyl, or aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
R 16e is selected from:
—C(═O)OR 18ae ,
—C(═O)R 18be ,
—C(═O)N(R 18be ) 2 ,
—C(═O)NHSO 2 R 18ae ,
—C(═O)NHC(═O)R 18be ,
—C(═O)NHC(═O)OR 18ae ,
—C(═O)NHSO 2 NHR 18be ,
—SO 2 R 18ae ,
—SO 2 N(R 18be ) 2 or,
—SO 2 NHC(═O)OR 18be ;
R 17e is selected from:
H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl(C 1 -C 6 alkyl);
R 18ae is selected from:
C 1 -C 8 alkyl optionally substituted with a bond to L n , C 3 -C 11 cycloalkyl optionally substituted with a bond to L n , aryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , heteroaryl(C 1 -C 6 alkyl)-optionally substituted with a bond to L n , (C 1 -C 6 alkyl)heteroaryl optionally substituted with a bond to L n , biaryl(C 1 -C 6 alkyl) optionally substituted with a bond to L n , heteroaryl optionally substituted with a bond to L n , phenyl substituted with 3-4 R 19e and optionally substituted with a bond to L n , naphthyl substituted with 0-4 R 19e and optionally substituted with a bond to L n , and a bond to L n , wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R 19e ;
R 18be is selected from:
R 18ae or H;
R 19e is selected from:
H, halogen, CF 3 , CO 2 H, CN, NO 2 , NR 11e R 12e , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, OCF 3 , or C 1 -C 4 alkoxycarbonyl, aryl, —O-aryl, -SO 2 -aryl, heteroaryl, or —SO 2 -heteroaryl, wherein said aryl and heteroaryl groups may be substituted with 0-4 groups selected from hydrogen, halogen, CF 3 , C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
R 20e is selected from:
hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, C 6 -C 10 aryloxy, C 7 -C 11 aralkyloxy, C 3 -C 10 alkylcarbonyloxyalkyloxy, C 3 -C 10 alkoxycarbonyloxyalkyloxy, C 2 -C 10 alkoxycarbonylalkyloxy, C 5 -C 10 cycloalkylcarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonylalkyloxy, C 7 -C 11 aryloxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonyloxyalkyloxy, C 8 -C 12 arylcarbonyloxyalkyloxy, C 5 -C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 -C 10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C 10 -C 14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R 11e )(R 12e )N—(C 1 -C 10 alkoxy)-;
R 21e is selected from: C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 7e ;
R 22e is selected from:
—C(═O)—R 18be ,
—C(═O)N(R 18be ) 2 ,
—C(═O)NHSO 2 R 18ae ,
—C(═O)NHC(═O)R 18be ,
—C(═O)NHC(═O)OR 18ae or,
—C(═O)NHSO 2 NHR 18be ,
m e is 0-2;
n e is 0-4;
p e is 0-2;
r e is 0-2;
with the following provisos:
(1) n e , m e and q e are chosen such that the number of atoms connecting R 1e and Y e is in the range of 8-14;
(2) when all R 19e groups are H, G e must be N;
(3) when G e is CR 19e , at least one R 19e group cannot be H.
S f is a surfactant which is a lipid or a compound of the formula:
A 9 is OR 27 ;
A 10 is OR 27 ;
R 27 is C(═O)C 1-15 alkyl;
E 1 is C 14 alkylene substituted with 1-3 R 28 ;
R 28 is independently selected at each occurrence from the group: R 30 , —PO 3 H—R 30 , ═O, —CO 2 R 29 , —C(═O)R 29 , —CH 2 OR 29 , —OR 29 , and C 1 -C 5 alkyl;
R 29 is independently selected at each occurrence from the group: R 30 , H, C 1 -C 6 alkyl, phenyl, and benzyl;
R 30 is a bond to L n ;
L n is a linking group having the formula:
(CR 6 R 7 ) g —(W) h —(CR 6a R 7a ) g′ -(Z) k -(W) h′ —(CR 8 R 9 ) g″ —(W) h″ —(CR 8a R 9a ) g″′
W is independently selected at each occurrence from the group: O, S, NH, NHC(═O), C(═O)NH, C(═O), C(═O)O, OC(═O), NHC(═S)NH, NHC(═O)NH, SO 2 , (OCH 2 CH 2 ) 20-200 , (CH 2 CH 2 O) 20-200 , (OCH 2 CH 2 CH 2 ) 20-200 , (CH 2 CH 2 CH 2 O) 20-200 , and (aa) t′ ;
aa is independently at each occurrence an amino acid;
Z is selected from the group: aryl substituted with 0-3 R 10 , C 3 - 10 cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;
R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are independently selected at each occurrence from the group: H, ═O, C 1 -C 5 alkyl substituted with 0-3 R 10 , and C 1 -C 5 alkoxy substituted with 0-3 R 10 , and a bond to S f ;
R 10 is independently selected at each occurrence from the group: a bond to S f , COOR 11 , OH, NHR 11 , C 1-5 alkyl substituted with 0-1 R 12 , and C 1-5 alkoxy substituted with 0-1 R 12 ;
R 11 is independently selected at each occurrence from the group: H, aryl substituted with 0-1 R 12 , C 3-10 cycloalkyl substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , and a bond to S f ;
R 12 is a bond to S f ;
k is selected from 0, 1, and 2;
h is selected from 0, 1, and 2;
h′ is selected from 0, 1, 2, 3, 4, and 5;
h″ is selected from 0, 1, 2, 3, 4, and 5;
g is selected from 0, 1, 2, 3, 4, and 5;
g′ is selected from 0, 1, 2, 3, 4, and 5;
g″ is selected from 0, 1, 2, 3, 4, and 5;
g″′ is selected from 0, 1, 2, 3, 4, and 5;
s is selected from 0, 1, 2, 3, 4, and 5;
s′ is selected from 0, 1, 2, 3, 4, and 5;
s″ is selected from 0, 1, 2, 3, 4, and 5;
t is selected from 0, 1, 2, 3, 4, and 5;
t′ is selected from 0, 1, 2, 3, 4, and 5;
and a pharmaceutically acceptable salt thereof.
42 . An ultrasound contrast agent composition, comprising:
(a) a compound of claim 40 , comprising: an quinolone that binds to the integrin α v β 3 , a surfactant and a linking group between the quinolone and the surfactant; (b) a parenterally acceptable carrier; and, (c) an echogenic gas.
43 . An ultrasound contrast agent composition of claim 42 , further comprising: 1,2-dipalmitoyl-sn-glycero-3-phosphotidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, and N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine.
44 . An ultrasound contrast agent composition of claim 43 , wherein the echogenic gas is a C 2-5 perfluorocarbon.
45 . A method of imaging cancer in a patient comprising:
(1) administering, by injection or infusion, a ultrasound contrast agent composition of claim 41 to a patient; and (2) imaging the patient using sonography.
46 . A method of imaging formation of new blood vessels in a patient comprising: (1) administering, by injection or infusion, a ultrasound contrast agent composition of of claim 40 to a patient; (2) imaging the area of the patient wherein the desired formation of new blood vessels is located.
47 . A therapeutic radiopharmaceutical composition, comprising:
(a) a therapeutic radiopharmaceutical of claim 12; and, (b) a parenterally acceptable carrier.
48 . A diagnostic radiopharmaceutical composition, comprising:
(a) a diagnostic radiopharmaceutical, a MRI contrast agent, or a X-ray contrast agent of claim 12; and, (b) a parenterally acceptable carrier.Join the waitlist — get patent alerts
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