Proteasome inhibitors

• US 20090099132A1
• Filed: 10/16/2007
• Published: 04/16/2009
• Est. Priority Date: 10/16/2007
• Status: Active Grant

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Olhava, Edward J., Danca, Mihaela Diana
• Granted Patent: US 7,838,673 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein P is R^dC(O)—

, R^d—

O—

C(O)—

, R^d—

N(R^4x)—

C(O)—

, R^d—

S(O)₂—

, or R^d—

N(R^4x)—

S(O)₂—

;

R^d is selected from the group consisting of C_1-6 aliphatic, C_1-6 fluoroaliphatic, —

R^D, T¹-R^D, and -T¹-R^2d;

T¹ is a C_1-6 alkylene chain substituted with 0-2 independently selected R^3a or R^3b, wherein the alkylene chain optionally is interrupted by —

C(R⁵)═

C(R⁵)—

, —

C≡

C—

, or —

O—

;

R^D is a substituted or unsubstituted aromatic, heterocyclyl, or cycloaliphatic ring, any of which is optionally fused to a substituted or unsubstituted aromatic, heterocyclyl, or cycloaliphatic ring;

R^2d is halo, —

OR⁵, —

SR⁶, —

S(O)R⁶, —

SO₂R⁶, —

SO₂N(R⁴)₂, —

N(R⁴)₂, —

NR⁴C(O)R⁵, —

NR⁴C(O)—

N(R⁴)₂, —

NR⁴CO₂R⁶, —

N(R⁴)SO₂R⁶, —

N(R⁴)SO₂N(R⁴)₂, —

O—

C(O)R⁵, —

OC(O)N(R⁴)₂, —

C(O)R⁵, —

CO₂R⁵, or —

C(O)N(R⁴)₂;

each R^3a independently is selected from the group consisting of —

F, —

OH, —

O(C_1-4 alkyl), —

CN, —

N(R⁴)₂, —

C(O)(C_1-4 alkyl), —

CO₂H, —

CO₂(C_1-4 alkyl), —

C(O)NH₂, and —

C(O)NH(C_1-4 alkyl);

each R^3b independently is a C_1-3 aliphatic optionally substituted with R^3a or R⁷;

each R⁴ independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;

or two R⁴ on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;

each R⁵ independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;

each R⁶ independently is an optionally substituted aliphatic, aryl, or heteroaryl group;

each R⁷ is a substituted or unsubstituted aromatic group; and

R^4x is hydrogen, C_1-4 alkyl, C_1-4 fluoroalkyl, or C_6-10 ar(C_1-4)alkyl, the aryl portion of which is substituted or unsubstituted.

3. The compound of claim 2, wherein P is R^d—

C(O)—

.

4. The compound of claim 1, wherein R^A is substituted or unsubstituted phenyl.

5. The compound of claim 1, wherein R^a and R^b, taken together with the carbon atom to which they are attached, form a cyclopropyl or cyclobutyl ring, either of which is substituted with 0-2 substituents —

R^B;

each R^B independently is a C_1-4 aliphatic, C_1-4 fluoroaliphatic, —

R^1b, -T²-R^1b;

T² is C_1-4 alkylene; and

R^1b is a substituted or unsubstituted aromatic or cycloaliphatic group.

6. The compound of claim 4, wherein R^1b is substituted or unsubstituted phenyl.

7. The compound of claim 1, wherein R^a and R^b are each —

CH₃.

8. The compound of claim 1, wherein R^c has the formula —

(CH₂)_m—

R^C, m is 1 or 2, and R^C is substituted or unsubstituted phenyl.

9. The compound of claim 1, wherein R^c is C_1-4 aliphatic.

10. The compound of claim 9, wherein R^c is isobutyl.

11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

12. A method for treating cancer, comprising administering to a patient in need of such treatment a pharmaceutical composition according to claim 11.