US2014315801A1PendingUtilityA1
Methods of treatment of cell proliferative and/or ophthalmic diseases, disorders and conditions using inhibitors of protein tyrosine kinase activity
Est. expiryApr 16, 2030(~3.8 yrs left)· nominal 20-yr term from priority
Inventors:Stephane RaeppelFranck RaeppelStephen William ClaridgeLijie ZhanFrederic GaudetteMichael MannionNorifumi SatoYohei YukiMasashi KishidaArkadii Vaisburg
A61P 35/00A61P 43/00A61P 9/10A61P 27/02C07K 5/06C07D 495/04C07F 9/6561A61K 38/005C07D 519/00A61K 31/4365
56
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Claims
Abstract
This invention relates to methods for treating cell proliferative diseases and conditions and ophthalmic diseases, disorders and conditions using compounds that inhibit protein tyrosine kinase activity. In particular the invention relates to the methods of treatment which utilize compounds that inhibit the protein tyrosine kinase activity of growth factor receptors, resulting in the inhibition of receptor signaling, for example, the inhibition of VEGF receptor signaling.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of inhibiting angiogenesis and/or treating a disease responsive to inhibition of kinase activity and/or treating a cell proliferative disease and/or treating an ophthalmic disease, condition or disorder in patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I):
including N-oxides, tautomers, pharmaceutically acceptable salts, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein,
D is
M is
Z is O;
Ar is phenyl substituted with a halogen; and
G is
wherein
R 38 is selected from the group consisting of
C 2 -C 6 alkynyl-heterocyclyl,
R 37 O—C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C(O)—C 0 -C 6 alkyl-heterocyclyl-CH 2 —,
R 37 —O—C(O)—C 1 -C 6 alkyl-heterocyclyl-C(O)—,
(R 9 )(R 10 )N—C 1 -C 6 alkyl-C(O)-heterocyclyl-CH 2 —,
(R 9 )(R 10 )N—C(O)—C 1 -C 6 alkyl-heterocyclyl-CH 2 —,
(R 9 )(R 10 )N—C 1 -C 6 alkyl-C(O)—O—C 1 -C 6 alkyl-heterocyclyl-CH 2 —,
NC—C 1 -C 6 alkyl-heterocyclyl-CH 2 —,
F 3 C—C 1 -C 6 alkyl-heterocyclyl-CH 2 —,
C 1 -C 6 alkyl-C(O)—O—C 1 -C 6 alkyl-C(O)-(5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-,
(optionally substituted 8- to 10-membered fused heterocyclyl)-C 1 -C 6 alkyl-,
F-heterocyclyl-C 1 -C 6 alkyl-,
heteroaryl-C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl-,
R 37 —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C(O)—C 1 -C 6 alkyl-O-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C(O)—C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl-,
(R 6 ) 2 N-heterocyclyl-C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-C(O)—N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
C 1 -C 6 alkylC(O)—O—C 1 -C 6 alkyl-C(O)—N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-C(O)—N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
heteroaryl-C 1 -C 6 alkyl-C(O)—N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-S(O) 2 —N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-O—C(O)—N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-N(R 6 )—C(O)—N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-heterocyclyl-C(O)—N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-N(R 6 )—C(O)—N(R 6 )-heterocyclyl)-C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-heterocyclyl-C(O)—C 1 -C 6 alkyl-,
heterocyclyl-C(O)—C 1 -C 6 alkyl-,
(C 1 -C 6 alkyl) 2 N-heterocyclyl-C(O)—C 1 -C 6 alkyl-,
(Boc)(H)N-heterocyclyl-C(O)—C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-O—C(O)-heterocyclyl-C(O)—C 1 -C 6 alkyl-,
Boc-heterocyclyl-C(O)—C 1 -C 6 alkyl-,
Ac—O—C 1 -C 6 alkyl-C(O)-heterocyclyl-C(O)—C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-C(O)-heterocyclyl-C(O)—C 1 -C 6 alkyl-,
(Boc)(H)N—C 1 -C 6 alkyl-C(O)-heterocyclyl-C(O)—C 1 -C 6 alkyl-,
NH 2 —C 1 -C 6 alkyl-C(O)-heterocyclyl-C(O)—C 1 -C 6 alkyl-,
(C 1 -C 6 alkyl)(H)N—C(O)-heterocyclyl-C(O)—C 1 -C 6 alkyl-,
NH 2 -heterocyclyl-C(O)—C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-O—C 1 -C 6 alkyl-heterocyclyl-C(O)—,
C 1 -C 6 alkyl-O—C(O)—N(R 6 )-heterocyclyl-C(O)—,
(R 6 )(R 6 )N-heterocyclyl-C(O)—,
(R 6 )(R 6 )N-heterocyclyl-C 1 -C 6 alkyl-,
heterocyclyl-O—C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-N(R 6 )—C(O)—N(R 6 )-heterocyclyl-C(O)—,
(R 6 )(R 6 )N—C(O)-heterocyclyl-O—C 1 -C 6 alkyl-,
C 2 -C 6 alkenyl-C(O)—N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-C(O)-heterocyclyl-O—C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—(CH 2 ) j —[(CH 2 ) i O] x —C 1 -C 6 alkyl-N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
halo-C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl-,
halo-C 1 -C 6 alkyl-N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C(O)—C 1 -C 6 alkyl-N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
R 37 —O—C(O)—C 1 -C 6 alkyl-N(R 6 )—C(O)—N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-,
(C 1 -C 6 alkyl)(H)N—C(O)-heterocyclyl-N[C 1 -C 6 alkyl-C(O)—OH]—C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-O—C(O)-heterocyclyl-C 1 -C 6 alkyl-,
HO—C(O)-heterocyclyl-C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-heterocyclyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-,
(R 6 )(R 6 )N—C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-,
(C 1 -C 6 alkyl)(C 1 -C 6 alkyl)N-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-C(O)-[(C 1 -C 6 alkyl)(C 1 -C 6 alkyl)heterocyclyl]-C 1 -C 6 alkyl-,
C 2 -C 6 alkenyl-C(O)-[(C 1 -C 6 alkyl)(C 1 -C 6 alkyl)heterocyclyl]-C 1 -C 6 alkyl-,
R 37 —O—C 1 -C 6 alkyl-[(C 1 -C 6 alkyl)(C 1 -C 6 alkyl)heterocyclyl]-C 1 -C 6 alkyl-,
R 37 O—C(O)—C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C(O)—C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl-,
spiro-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-C(O)-spiro-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl-,
C 1 -C 6 alkyl-C(O)—O—C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
heterocyclyl-C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
(R 6 )(R 6 )N—C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
heterocyclyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
(R 6 )(R 6 )N—C 2 -C 6 alkenyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
heterocyclyl-C 2 -C 8 alkenyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
(R 6 )(R 6 )N—C 1 -C 6 alkyl-N(R 6 )—C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-,
heterocyclyl-C(O)—,
(R 6 )(R 6 )N—C(O)-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C(O)—C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-,
C 2 -C 6 alkenyl-C(O)—O—C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-,
(R 6 )(R 6 )N—C(O)-heterocyclyl-C(O)—,
R 37 O—C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O—C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl-(heterocyclyl)-,
R 37 O—C(O)—C 1 -C 6 alkyl-heterocyclyl-C(O)—,
R 37 O—C 1 -C 6 alkyl-heterocyclyl-C(O)—,
R 37 O—C 1 -C 6 alkyl-C(O)-heterocyclyl-C(O)—,
C 1 -C 6 alkyl-O—C(O)—N(R 6 )—C 1 -C 6 alkyl-C(O)—O—C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-
R 37 O—(CH 2 ) n [(CH 2 ) i O] x —C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-,
HO-heterocyclyl-C 1 -C 6 alkyl-,
R 37 O-cycloalkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-
and
R 37 O—(CH 2 ) n [(CH 2 ) i O] x —C 1 -C 6 alkyl-C(O)—N(R 6 )-heterocyclyl-C 1 -C 6 alkyl-;
each R 6 is independently H or C 1 -C 6 alkyl;
R 37 is selected from the group consisting of H, C 1 -C 6 alkyl and C 3 -C 10 cycloalkyl;
j is an integer ranging from 0 to 4;
i is 2 or 3;
x is an integer ranging from 0 to 6;
n is an integer ranging from 0 to 4;
R 9 is selected from the group consisting of H, —OH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, —(CH 2 ) n3 (C 6 -C 10 aryl), —(CH 2 ) n3 (C 5 -C 10 heteroaryl), —(CH 2 ) n3 (5-10 membered heterocyclyl), —(CH 2 ) n3 O(CH 2 ) i3 OR 37 and —(CH 2 ) n3 OR 37 , wherein the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing R 9 groups are optionally substituted;
R 10 is selected from the group consisting of H, —OH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, —(CH 2 ) n4 (C 6 -C 10 aryl), —(CH 2 ) n4 (C 5 -C 10 heteroaryl), —(CH 2 ) n4 (5-10 membered heterocyclyl), —(CH 2 ) n4 O(CH 2 ) i4 OR 37 and —(CH 2 ) n4 OR 37 , wherein the alkyl, aryl, heteroaryl and heterocyclyl moieties of the foregoing R 10 groups are optionally substituted;
n3 is an integer ranging from 0 to 6;
i3 is an integer ranging from 2 to 6
n4 is an integer ranging from 0 to 6; and
i4 is an integer ranging from 2 to 6.
2 . The method according to claim 1 , wherein said compound is as defined in claim 1 , except that
R 38 is selected from the group consisting of (R 23 )(R 24 )(O)P—C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl-, (optionally substituted 7- or 8-membered heterocyclyl)-C 1 -C 6 alkyl-, (optionally substituted 8- to 10-membered fused heterocyclyl)-C 1 -C 6 alkyl-, (optionally substituted spiro-heterocyclyl)-C 1 -C 6 alkyl-, (optionally substituted bridged bicyclic ring system)-C 1 -C 6 alkyl-, (substituted piperazine)-C 1 -C 6 alkyl-, (R 9 )(R 10 )N—C 1 -C 6 alkyl-C(O)—O—C 1 -C 6 alkyl-C(O)-(5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, C 1 -C 6 alkyl-S(O) 0-2 —C 1 -C 6 alkyl-(5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, (R 23 )(R 24 )P(O)O—C 1 -C 6 alkyl-C(O)-(5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, R 37 S(O) 0-2 -aryl-C(O)—O—C 1 -C 6 alkyl-C(O)-(5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, R 37 O—C 1 -C 6 alkyl-piperazine-C 1 -C 6 alkyl-, R 37 O—C(O)—C 1 -C 6 alkyl-(5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, (R 9 )(R 10 )N—C 1 -C 6 alkyl-piperazine-C 1 -C 6 alkyl-, R 37a O—C(O)—C 1 -C 6 alkyl-N(R 37 )—C(O)—C 1 -C 6 alkyl-(5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, R 11 —C 1 -C 6 alkyl-C(O)-piperazine-C 1 -C 6 alkyl-, C 0 -C 6 alkyl-(5 or 6-membered heterocyclyl)-C 1 -C 6 alkyl-piperazine-C 1 -C 6 alkyl-, (5-10-membered optionally substituted heterocyclyl)-C 1 -C 6 alkyl-O-(oxo substituted 5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, (5-10-membered optionally substituted heterocyclyl)-C 1 -C 6 alkyl-N(R 1 )-(oxo substituted 5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, (5-10-membered optionally substituted heterocyclyl)-C 1 -C 6 alkyl-S(O) 0-2 -(oxo substituted 5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, R 29 O—C(O)—C(H)(C(O)—OR 29a )—O—C 1 -C 6 alkyl-(5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, R 29 O—C(O)—C(H)(C(O)—OR 29a )—O—C 1 -C 6 alkyl-C(O)-(5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl- and (substituted piperidine)-C 1 -C 6 alkyl-; wherein R 1 is H or C 1 -C 6 alkyl; R 11 is —OH, —O—C 1 -C 6 alkyl, optionally substituted 5 to 10-membered heterocyclyl, or —O-(amino acid); R 23 is selected from the group consisting of H, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, —O-aryl, cycloalkyl, —O-cycloalkyl, heteroaryl, —O-heteroaryl, 5 to 10-membered heterocyclyl, —O-(5 to 10-membered heterocyclyl), —C 1 -C 6 alkyl-aryl, —O—C 1 -C 6 alkyl-aryl, —C 1 -C 6 alkyl-heteroaryl, —O—C 1 -C 6 alkyl-heteroaryl, —C 1 -C 6 alkyl-cycloalkyl, —O—C 1 -C 6 alkyl-cycloalkyl, —C 1 -C 6 alkyl-(5 to 10-membered heterocyclyl) and —O—C 1 -C 6 alkyl-(5 to 10-membered heterocyclyl); R 24 is selected from the group consisting of H, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, —O-aryl, cycloalkyl, —O-cycloalkyl, heteroaryl, —O-heteroaryl, 5 to 10-membered heterocyclyl, —O-(5 to 10-membered heterocyclyl), —C 1 -C 6 alkyl-aryl, —O—C 1 -C 6 alkyl-aryl, —C 1 -C 6 alkyl-heteroaryl, —O—C 1 -C 6 alkyl-heteroaryl, —C 1 -C 6 alkyl-cycloalkyl, —O—C 1 -C 6 alkyl-cycloalkyl, —C 1 -C 6 alkyl-(5 to 10-membered heterocyclyl) and —O—C 1 -C 6 alkyl-(5 to 10-membered heterocyclyl); R 29 is selected from the group consisting of H, C 1 -C 6 alkyl and a cation; R 29a is selected from the group consisting of H, C 1 -C 6 alkyl and a cation; and R 37a is H or C 1 -C 6 alkyl;
3 . A method of inhibiting angiogenesis and/or treating a disease responsive to inhibition of kinase activity and/or treating a cell proliferative disease and/or treating an ophthalmic disease, condition or disorder in patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound of Formula (II)
including N-oxides, tautomers, pharmaceutically acceptable salts, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein,
D is
R 38 is selected from the group consisting of (oxo substituted heterocyclyl)-C 1 -C 2 alkyl- (wherein the oxo substituted heterocyclyl is further optionally substituted with a substituent selected from the group consisting of —N(R 9 )(R 10 ), C 1 -C 6 alkyl, —N(R 37 )(Ac), and —OH), C 1 -C 6 alkyl-heterocyclyl-(CH 2 ) 1-2 —, (heterocyclyl)-C(O)— (wherein the heterocyclyl is optionally substituted with C 1 -C 6 alkyl), C 0 -C 6 alkyl-heterocyclyl-(CH 2 ) 1-3 —, HO-heterocyclyl-CH 2 —, (R 9 )(R 10 )N-heterocyclyl-CH 2 —, (R 9 )(R 10 )N—C 0 -C 6 alkyl-heterocyclyl-C(O)—, (C 1 -C 6 alkyl)-C(O)-heterocyclyl-CH 2 —, R 37 O—C 1 -C 6 alkyl-heterocyclyl-CH 2 —, R 37 O—C 1 -C 6 alkyl-C(O)-heterocyclyl-(CH 2 ) 1-6 —, R 37 O—C(O)—C 0 -C 6 alkyl-heterocyclyl-CH 2 —, R 37 —O—C(O)—C 1 -C 6 alkyl-heterocyclyl-C(O)—, R 37 —O—C(O)-heterocyclyl-C(O)—, C 0 -C 6 alkyl-heterocyclyl-C 0 -C 6 alkyl-heterocyclyl-C(O)— (R 9 )(R 10 )N—C 1 -C 6 alkyl-C(O)-heterocyclyl-CH 2 —, (R 9 )(R 10 )N—C(O)—C 1 -C 6 alkyl-heterocyclyl-CH 2 —, (R 9 )(R 10 )N—C 1 -C 6 alkyl-C(O)—O—C 1 -C 6 alkyl-heterocyclyl-CH 2 —, R 37 O—C 1 -C 6 alkyl-heterocyclyl-CH 2 —, NC—C 1 -C 6 alkyl-heterocyclyl-CH 2 —, heterocyclyl-C 1 -C 6 alkyl-heterocyclyl-CH 2 —, F 3 C—C 1 -C 6 alkyl-heterocyclyl-CH 2 —, C 1 -C 6 alkyl-S(O) 2 -heterocyclyl-CH 2 —, heteroaryl-C 1 -C 6 alkyl-heterocyclyl-CH 2 —, (R 9 )(R 10 )N—C 1 -C 6 alkyl-C(O)—O—C 1 -C 6 alkyl-C(O)-heterocyclyl-CH 2 —, C 1 -C 6 alkyl-C(O)—O—C 1 -C 6 alkyl-C(O)-(5 to 10-membered heterocyclyl)-C 1 -C 6 alkyl-, (optionally substituted 8- to 10-membered fused heterocyclyl)-C 1 -C 6 alkyl-, (di-fluoro substituted heterocyclyl)-C 1 -C 6 alkyl-, C 0 -C 6 alkyl-(5 or 6-membered heterocyclyl)-C 1 -C 6 alkyl-piperazine-C 1 -C 6 alkyl-, R 37 O—C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-;
R 37 is H, C 1 -C 6 alkyl;
R 9 is H, C 1 -C 6 alkyl;
R 10 is H, C 1 -C 6 alkyl
R 2 is H or F;
R 2a is H, F or Cl.
4 . The method according to claim 3 , wherein said compound has the Formula (XVIII):
including N-oxides, tautomers, pharmaceutically acceptable salts, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein,
R 38 is R 37 O—C 1 -C 6 alkyl-C(O)-heterocyclyl-CH 2 —; and
R 37 is H or C 1 -C 6 alkyl.
5 . The method according to claim 1 , wherein said compound is selected from the group consisting of
including N-oxides, tautomers, pharmaceutically acceptable salts, and racemic and scalemic mixtures, diastereomers and enantiomers thereof.
6 . The method according to claim 1 , wherein R 38 is selected from the group consisting of R 37 O—C(O)—C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl-, C 1 -C 6 alkyl-heterocyclyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-, R 37 O—C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-, (R 6 )(R 6 )N—C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-, R 37 O—C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-, R 37 O—C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl- and R 37 O—(CH 2 ) j —[(CH 2 ) i O] x —C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-, wherein each of said alkyl and heterocyclyl is optionally substituted.
7 . The method according to claim 1 , wherein when R 38 is attached to D by a C 1 -C 6 alkyl, the C 1 -C 6 alkyl is —CH 2 —.
8 . The method according to claim 2 , wherein R 38 is selected from the group consisting of R 37 O—C(O)—C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl-, C 1 -C 6 alkyl-heterocyclyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-, R 37 O—C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-, (R 6 )(R 6 )N—C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-, R 37 O—C 1 -C 6 alkyl-C(O)-heterocyclyl-C 1 -C 6 alkyl-, R 37 O—C 1 -C 6 alkyl-heterocyclyl-C 1 -C 6 alkyl- and R 37 O—(CH 2 ) j —[(CH 2 ) i O] x —C 1 -C 6 alkyl-N(R 6 )—C(O)-heterocyclyl-C 1 -C 6 alkyl-, wherein each of said alkyl and heterocyclyl is optionally substituted.
9 . The method according to claim 2 , wherein when R 38 is attached to D by a C 1 -C 6 alkyl, the C 1 -C 6 alkyl is —CH 2 —.
10 . The method according to claim 1 , wherein R 38 is selected from (heterocyclyl optionally substituted with one or more C 1 -C 6 alkyl)-C 1 -C 6 alkyl- and (substituted piperazine)-C 1 -C 6 alkyl-.
11 . The method according to claim 1 , wherein said compound has the following formula:
12 . The method according to claim 1 , wherein said compound has the following formula:
13 . The method according to claim 1 , wherein said compound has the following formula:
14 . The method according to claim 1 , wherein said compound has the following formula:Cited by (0)
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