Derivatives of 1-amino-2-cyclobutylethylboronic acid

• US 20100081633A1
• Filed: 09/25/2009
• Published: 04/01/2010
• Est. Priority Date: 09/29/2008
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Li, Jing, Fleming, Paul E.
• Granted Patent: US 8,664,200 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07K 5/06 Dipeptides
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/08 : Tripeptides

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):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof, wherein;

A is 0, 1, or 2;

P is hydrogen or an amino-group-blocking moiety;

R^a1 is C_1-6 aliphatic, C_1-6 fluoroaliphatic, —

(CH₂)_m—

CH₂—

R^B, —

(CH₂)_m—

CH₂—

NHC(═

NR⁴)NH—

Y, —

(CH₂)_m—

CH₂—

CON(R⁴)₂, —

(CH₂)_m—

CH₂—

N(R⁴)CON(R⁴)₂, —

(CH₂)_m—

CH(R⁶)N(R⁴)₂, —

(CH₂)_m—

CH(R⁵)—

OR⁵, or —

(CH₂)_m—

CH(R⁵)—

SR⁵;

each R^a2 independently is hydrogen, C_1-6 aliphatic, C_1-6 fluoroaliphatic, —

(CH₂)_m—

CH₂—

R^B, —

(CH₂)_m—

CH₂—

NHC(═

NR⁴)NH—

Y, —

(CH₂)_m—

CH₂—

CON(R⁴)₂, —

(CH₂)_m—

CH₂—

N(R⁴)CON(R⁴)₂, —

(CH₂)_m—

CH(R⁶)N(R⁴)₂, —

(CH₂)_m—

CH(R⁵)—

OR⁵, or —

(CH₂)_m—

CH(R⁵)—

SR⁵;

each Y independently is hydrogen, —

CN, —

NO₂, or —

S(O)₂—

R¹⁰

each R^B independently is a substituted or unsubstituted mono- or bicyclic ring system;

each R⁴ independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;

or two R⁴ on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 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 a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;

each R⁶ independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group;

each R¹⁰ independently is C_1-6 aliphatic, C_6-10 aryl, or —

N(R⁴)₂;

m is 0, 1, or 2;

Z¹ and Z² are each independently hydroxy, alkoxy, aryloxy, or aralkoxy;

or Z¹ and Z² together form a moiety derived from a boronic acid complexing agent.

2. The compound of claim 1, wherein P is R^c—

C(O)—

, R^c—

O—

C(O)—

, R^c—

N(R^4c)—

C(O)—

, R^c—

S(O)₂—

, or R^c—

N(R^4c)—

S(O)₂—

;

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

R^D, -T¹-R^D, and -T¹-R^2c;

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 mono- or bicyclic ring system;

R^2c 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 substituted or unsubstituted with R^3a or R⁷;

each R⁷ is a substituted or unsubstituted aromatic group; and

R^4c 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, characterized by formula (I-B):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof.

4. The compound of claim 3, wherein A is 0.

5. The compound of claim 3, wherein R^a1 and R^a2 are each independently C_1-6 aliphatic, C_1-6 fluoroaliphatic, or —

(CH₂)_m—

CH₂—

R^B, and in is 0 or 1.

6. The compound of claim 5, wherein R^B is a substituted or unsubstituted phenyl.

7. The compound of claim 6, wherein R^a1 is —

CH₂—

R^B, and R^B is phenyl.

8. The compound of claim 3, wherein R^a1 is —

(CH₂)_m—

CH(C_1-4 alkyl)-OH.

9. The compound of claim 3, wherein R^D is substituted on substitutable ring carbon atoms with 0-2 R^d and 0-2 R^8d;

each R^d independently is selected from the group consisting of C_1-6 aliphatic,

C_1-6 fluoroaliphatic, halo, —

R^1d, —

R^2d, -T²-R^1d, -T²-R^2d,

T² 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—

;

each R^1d independently is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;

each R^2d independently is —

NO₂, —

CN, —

C(R⁵)═

C(R⁵)₂, —

C≡

C—

R⁵, —

OR⁵, —

SR⁶, —

S(O)R⁶, —

SO₂R⁶, —

SO₂N(R⁴)₂, —

N(R⁴)₂, —

NR⁴C(O)R⁵, —

NR⁴C(O)N(R⁴)₂, —

N(R⁴)C(═

NR⁴)—

N(R⁴)₂, —

N(R⁴)C(═

NR⁴)—

R⁶, —

NR⁴CO₂R⁶, —

N(R⁴)SO₂R⁶, —

N(R⁴)SO₂N(R⁴)₂, —

O—

C(O)R⁵, —

OC(O)N(R⁴)₂, —

C(O)R⁵, —

CO₂R⁵, —

C(O)N(R⁴)₂, —

C(O)N(R⁴)—

OR⁵, —

C(O)N(R⁴)C(═

NR⁴)—

N(R⁴)₂, —

N(R⁴)C(═

NR⁴)—

N(R⁴)—

C(O)R⁵, or —

C(═

NR⁴)—

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 substituted or unsubstituted with R^3a or R⁷, or two substituents R^3b on the same carbon atom, taken together with the carbon atom to which they are attached, form a 3- to 6-membered cycloaliphatic ring;

each R⁷ independently is a substituted or unsubstituted aryl or heteroaryl ring;

each R^8d independently is selected from the group consisting of C_1-4 aliphatic, C_1-4 fluoroaliphatic, halo, —

OH, —

O(C_1-4 aliphatic), —

NH₂, —

NH(C_1-4 aliphatic), and —

N(C_1-4 aliphatic)₂; and

each substitutable ring nitrogen atom in R^D is unsubstituted or is substituted with —

C(O)R⁵, —

C(O)N(R⁴)₂, —

CO₂R⁶, —

SO₂R⁶, —

SO₂N(R⁴)₂, C_1-4 aliphatic, a substituted or unsubstituted C_6-10 aryl, or a C_6-10 ar(C_1-4alkyl, the aryl portion of which is substituted or unsubstituted.

10. The compound of claim 3, wherein:

each saturated ring carbon atom in R^D is unsubstituted or is substituted with ═

O, R^d or R^8d;

each unsaturated ring carbon atom in R^D is unsubstituted or is substituted with R^d or R^8d;

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

R^1d, —

R^2d, -T²-R^1d, -T²-R^2d,

T² 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—

;

each R^1d independently is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;

each R^2d independently is —

NO₂, —

CN, —

C(R⁵)═

C(R⁵)₂, —

C≡

C—

R⁵, —

OR⁵, —

SR⁶, —

S(O)R⁶, —

SO₂R⁶, —

SO₂N(R⁴)₂, —

N(R⁴)₂, —

NR⁴C(O)R⁵, —

NR⁴C(O)N(R⁴)₂, —

N(R⁴)C(═

NR⁴)—

N(R⁴)₂, —

N(R⁴)C(═

NR⁴)—

R⁶, —

NR⁴CO₂R⁶, —

N(R⁴)SO₂R⁶, —

N(R⁴)SO₂N(R⁴)₂, —

O—

C(O)R⁵, —

OC(O)_N(R⁴)₂, —

C(O)R⁵, —

CO₂R⁵, —

C(O)N(R⁴)₂, —

C(O)N(R⁴)—

OR⁵, —

C(O)_N(R⁴)C(═

NR⁴)—

N(R⁴)₂, —

N(R⁴)C(═

NR⁴)—

N(R⁴)—

C(O)R⁵, or —

C(═

NR⁴)—

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 substituted or unsubstituted with R^3a or R⁷, or two substituents R^3b on the same carbon atom, taken together with the carbon atom to which they are attached, form a 3- to 6-membered cycloaliphatic ring;

each R⁷ independently is a substituted or unsubstituted aryl or heteroaryl ring;

each R^8d independently is selected from the group consisting of C_1-4 aliphatic, C_1-4 fluoroaliphatic, halo, —

OH, —

O(C_1-4 aliphatic), —

NH₂, —

NH(C_1-4 aliphatic), and —

N(C_1-4 aliphatic)₂; and

each substitutable ring nitrogen atom in R^D is unsubstituted or is substituted with —

C(O)R⁵, —

C(O)N(R⁴)₂, —

CO₂R⁶, —

SO₂R⁶, —

SO₂N(R⁴)₂, C_1-4 aliphatic, a substituted or unsubstituted C_6-10 aryl, or a C_6-10 ar(C_1-4)alkyl, the aryl portion of which is substituted or unsubstituted.

11. The compound of claim 7, wherein R^D is a substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl.

12. The compound d of claim 7, characterized by formula (II):

or a pharmaceutically acceptable salt or boronic acid anhydride thereof, wherein;

P has the formula R^D—

SO₂—

or R^D—

C(O)—

;

R^D is a substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl;

each saturated ring carbon atom in R^D is unsubstituted or is substituted with ═

O, R^d, or R^8d;

each unsaturated ring carbon atom in R^D is unsubstituted or is substituted with R^d or R^8d;

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

R^1d, —

R^2d, -T²-R^1d, and -T²-R^2d;

T² is a C_1-3 alkylene chain that is unsubstituted or is substituted with R^3a or R^3b;

each R^1d independently is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;

each R^2d independently is —

OR⁵, —

SR⁶, —

S(O)R⁶, —

SO₂R⁶, —

SO₂N(R⁴)₂, —

N(R⁴)₂, NR⁴C(O)R⁵, —

NR⁴C(O)N(R⁴)₂, —

O—

C(O)R⁵, —

OC(O)N(R⁴)₂, —

C(O)R⁵, —

CO₂R⁵, or —

C(O)N(R⁴)₂; and

each R^8d independently is selected from the group consisting of C_1-4 aliphatic, C_1-4 fluoroaliphatic, halo, —

OH, —

O(C_1-4 aliphatic), —

NH₂, —

NH(C_1-4 aliphatic), and —

N(C_1-4 aliphatic)₂.

13. The compound of claim 12, wherein R^d has the formula -Q-R^E;

Q is —

O—

, —

NH—

, or —

CH₂—

; and

R^E is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl or cycloaliphatic ring.

14. The compound of claim 12, wherein where R^D is a phenyl, pyridinyl, pyrazinyl, or pyrimidinyl, which is substituted with a substituent of formula —

O—

R^E, and R^E is a substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, or pyrimidinyl.

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

16. A method for treating cancer, comprising administering to a patient in need of such treatment a pharmaceutical composition according to claim 15.