Derivatives of 1-amino-2-cyclopropylethylboronic acid

• US 8,513,218 B2
• Filed: 03/30/2011
• Issued: 08/20/2013
• Est. Priority Date: 03/31/2010
• Status: Expired due to Fees

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Fleming, Paul E., Li, Jing
• Primary Examiner(s): VAJDA, KRISTIN ANN
• Application Number:
  US13/075,306
• Publication Number:
  US 20110245203A1
• Time in Patent Office: 874 Days
• Field of Search: 514/64, 546/13, 544/69, 544/229, 548/110, 548/405, 564/8
• US Class Current: 514/64
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids

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^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 monocyclic, bicyclic or tricyclic 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^3a 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):

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

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

(CH₂)_m—

CH₂—

R^B, and m is 0 or 1.

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

7. 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(N⁴)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.

8. 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.

9. The compound of claim 3, wherein R^D is a substituted or unsubstituted monocyclic, bicyclic, or tricyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, oxodihydroindolyl, oxodihydrobenzoxazinyl, dihydrobenzoxazinyl, benzofuropyridyl, pyridoindolyl, and benzofuropyrazinyl.

10. The compound of claim 3, characterized by formula (II):

11. The compound of claim 10, wherein R^d has the formula -Q-R^E;

Q is —

O—

, —

NH—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, or —

CH₂—

; and

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

12. The compound of claim 10, wherein 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, pyrimidinyl, quinolinyl, benzothiazolyl, benzimidazolyl, or indolyl.

13. The compound of claim 10, wherein:

R^D is phenyl substituted with 0-1 R^d; and

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

14. The compound of claim 13, wherein:

P is R^D—

SO₂—

;

R^D is phenyl substituted with 1 R^d;

R^d is substituted or unsubstitued oxazolyl, thiazolyl, or imidazolyl;

wherein if substituted, R^d is substituted with 1 R^dd; and

R^dd is methyl, ethyl, trifluoromethyl, chloro, or fluoro.

15. The compound of claim 10, wherein:

P is R^D—

SO₂—

;

R^D is phenyl substituted with —

O—

R^E,

R^E is a substituted or unsubstituted pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, benzothiazolyl, benzimidazolyl, or indolyl;

wherein if substituted, R^E is substituted with 1-2 occurrences of R^dd; and

each R^dd is independently C_1-4 aliphatic, C_1-4 fluoroaliphatic, or halo.

16. The compound of claim 15, wherein:

R^E is a substituted or unsubstituted pyridinyl;

wherein if substituted, R^E is substituted with 1 occurrence of R^dd; and

R^dd is methyl, ethyl, trifluoromethyl, chloro, or fluoro.

17. The compound of claim 10, wherein:

P is R^D—

SO₂—

;

R^D is phenyl substituted with —

O—

R^E,

R^E is a substituted or unsubstituted pyridinyl, pyrazinyl, or pyrimidinyl;

wherein if substituted, R^E is substituted with 1-2 occurrences of R^dd; and

each R^dd is independently C_1-4 aliphatic, C_1-4 fluoroaliphatic, or halo.

18. The compound of claim 17, wherein:

R^E is a substituted or unsubstituted pyridinyl;

wherein if substituted, R^E is substituted with 1 occurrence of R^dd; and

R^dd is methyl, ethyl, trifluoromethyl, chloro, or fluoro.

19. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

20. The compound of claim 10, wherein:

P is R^D—

C(O)—

; and

R^D is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, naphthyl, quinolinyl, quinoxalinyl, benzimidazolyl, or dihydrobenzoxazinyl substituted with 0-1 R^d and 0-2 R^8d.

21. The compound of claim 10, wherein:

P is R^D—

C(O)—

; and

R^D is phenyl or pyrazinyl, substituted with 0-1 R^d and 0-2 R^8d.

22. A compound of formula (I), or a pharmaceutically acceptable salt or boronic acid anhydride or boronic acid ester thereof wherein the compound is: