IP Library › Granted Patent US 8,906,852

Granted Patent B2

US 8,906,852 · App. 13/082,923 · Granted Dec 9, 2014

Inhibitors of protein tyrosine kinase activity

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Quick Facts

Patent No.: US 8,906,852
App. No.: 13/082,923
Granted: Dec 9, 2014
Kind: B2

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Abstract

This invention relates to compounds that inhibit protein tyrosine kinase activity. In particular the invention relates to 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. The invention also provides compounds, compositions and methods for treating cell proliferative diseases and conditions and ophthalmic diseases, disorders and conditions.

Claims (152)

1. A compound having the 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 )-heterocycyl-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)-heterocycyl-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;

i4 is an integer ranging from 2 to 6.

2. A compound having the Formula (Ia),

including N-oxides, tautomers, pharmaceutically acceptable salts, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein all substituents are as defined in Formula (I) according to 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 compound having the 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 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), 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; and

G is

4. The compound according to claim 3 , having 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. A compound selected from the group consisting of

including N-oxides, tautomers, pharmaceutically acceptable salts, and racemic and scalemic mixtures, diastereomers and enantiomers thereof.

6. The compound 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 compound 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. A composition comprising a compound according to claim 1 .

9. The compound 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.

10. The compound 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 —.

11. A composition comprising a compound according to claim 2 .

12. A composition comprising a compound according to claim 3 .

13. A composition comprising a compound according to claim 5 .

14. A compound having the formula:

15. A compound having the formula:

16. A compound having the formula:

17. A compound having the formula:

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 15, 2011

From: RAEPPEL, STEPHANE; RAEPPEL, FRANCK; CLARIDGE, STEPHEN WILLIAM; ZHAN, LIJIE; GAUDETTE, FREDERIC; MANNION, MICHAEL; VAISBURG, ARKADII

To: METHYLGENE INC.

Reel/Frame 026446/0855 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 15, 2011

From: SATO, NORIFUMI; YUKI, YOHEI; KISHIDA, MASASHI

To: OTSUKA PHARMACEUTICAL CO. LTD.

Reel/Frame 026446/0915 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 15, 2011

From: OTSUKA PHARMACEUTICAL CO. LTD.

To: METHYLGENE INC.

Reel/Frame 026446/0956 →