KINASE KNOCKDOWN VIA ELECTROPHILICALLY ENHANCED INHIBITORS

• US 20100113520A1
• Filed: 11/05/2008
• Published: 05/06/2010
• Est. Priority Date: 11/05/2008
• Status: Abandoned Application

• Current Assignee: Principia Biopharma Inc. (Sanofi )
• Original Assignee: Principia Biopharma Inc. (Sanofi )
• Inventors: Miller, Richard
• Application Number:
  US12/265,594
• Publication Number:
  US 20100113520A1
• Time in Patent Office: Days
• US Class Current: 514/326
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 233/88 Nitrogen atoms, e.g. allantoin
• CPC Class Codes: C07D 263/48 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 277/28 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

Provided herein are electrophilically enhanced kinase inhibitors. Also provided herein are methods of making and utilizing the same.

Claims

1. A compound of Formula I:

wherein;

each R¹ is independently H, alkyl, halo, hydroxy, alkoxy, cyano, nitro, C(═

X)YR², or YC(═

X)R²;

each X is independently S or O;

each Y is independently S or O;

each R² is independently H or alkyl;

L is A_n, wherein

each A is independently NR¹, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

wherein each m is independently 0-2;

n is 0-5;

Q¹ is N or CR²;

Q² is NR²,S or O;

E —

(CR¹¹R¹²)_r—

(CR⁵═

CR⁵)_q—

(C R¹¹R¹²)^r, —

(CR⁶R⁷)—

X², —

NR⁸(C═

O)O—

;

—

O(C═

O)NR⁸—

;

—

(CR⁸R¹³(C═

O)—

;

or CR⁸R¹³(C═

O)—

,

R¹¹ and R¹² are independently H, CN, NO₂, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or taken together are ═

S, ═

N—

OR⁸, or ═

O;

wherein each R⁸ is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl;

each R⁵ is independently H, halo, hydroxy, alkoxy, cyano, nitro, S(O)_1-2R⁸, —

C(═

X)YR⁸, —

YC(═

X)R⁸, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroalkyl, or two R⁵ are taken together to form a bond;

each r is independently 0-2;

q is 0-2;

R⁶ and R⁷ are independently H, halo, hydroxy, alkoxy, cyano, nitro, —

C(═

X)YR⁸, —

YC(═

X)R⁸, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroalkyl, or is a bond to Z;

or R⁶ and R⁷ taken together are ═

O or ═

S;

X² is halo, OR⁹, NR⁹_v, N₃, SR⁹, or SCN;

wherein R⁹ is —

(S(0)^t)_u—

R¹⁰;

wherein each R¹⁰ is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl;

or X² and R⁷ when taken together with the carbon to which they are bound form an oxirane or oxetane;

wherein t is 1-2, wherein u is 0-1, wherein v is 2-3;

R¹³ is halo;

Z is —

(Z¹)_p—

Z² or is absent,

Z¹ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl

Z² is H, NR³₂, S(O)_mR³, OR³, C(═

X)YR³, —

Y(C═

X)R³, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

each R³ is independently H, halo, hydroxy, alkoxy, cyano, nitro, —

C(═

X)YR⁴, —

YC(X) R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl, wherein R⁴ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl;

p is 0-4;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein each R¹ is independently H, halo or alkyl.

5. The compound of claim 1, wherein Q¹ is N.

6. The compound of claim 1, wherein n is 1-2.

7. The compound of claim 1, wherein E is —

(C═

O)—

(CH═

CH)—

, —

(CH═

CH)—

(C═

O)—

, —

C(CN)═

CH—

, —

CH═

C(CN)—

, —

C(NO₂)═

CH—

, or —

CH═

C(NO₂)—

.

8. The compound of claim 1, wherein n is 2, and wherein one A is tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, pyridinyl, piperazinyl, or morpholino.

9. The compound of claim 1, wherein Z² is a substituted or unsubstituted piperazinyl, or a substituted or unsubstituted morpholino.

10. The compound of claim 1 having the Formula II:

wherein

R^1a is H, or lower alkyl;

R^2a is H, halo, or lower alkyl;

R¹¹ is H;

R¹² is H;

or R¹¹ and R¹² taken together are ═

O;

R^5a is H, CN, NO₂, or SO₂R⁸; and

R^5b is H, CN, NO₂, or SO₂R⁸.

11. The compound of claim 10, wherein R^1a is CH₃ and R^1b is Cl.

12. The compound of claim 10, wherein R¹¹ and R¹² taken together are ═

O, and wherein R^5a and R^5b are H.

2. (canceled)

3. (canceled)

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I

wherein:

each R¹ is independently H, alkyl, halo, hydroxy, alkoxy, cyano, nitro, C(═

X)YR², or YC(═

X)R²;

each X is independently S or O;

each Y is independently S or O;

each R² is independently H or alkyl;

L is A_n, wherein

each A is independently NR¹, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

wherein each m is independently 0-2;

n is 0-5;

Q¹ is N or CR²;

Q² is NR², S, or O;

E is an electrophile;

Z is —

(Z¹)_p—

Z² or is absent,

Z¹ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl

Z² H, NR³₂, S(O)_mR³, OR³, C(═

X)YR³, —

Y(C═

X)R³, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

each R³ is independently H, halo, hydroxy, alkoxy, cyano, nitro, —

C(═

X)YR⁴, —

YC(═

X) R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl, wherein R⁴ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl;

p is 0-4;

or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

14. A method of treating a disorder mediated by a cysteine containing kinase comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula I:

wherein;

each R¹ is independently H, alkyl, halo, hydroxy, alkoxy, cyano, nitro, C(═

X)YR², or YC(═

X)R²;

each X is independently S or O;

each Y is independently S or O;

each R² is independently H or alkyl;

L is A_n, wherein

each A is independently NR¹, S(O)_m, O, C(═

X)Y, Y(C═

X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

wherein each m is independently 0-2;

n is 0-5;

Q¹ is N or CR² ;

Q² is NR² , S, or O;

E is an electrophile;

Z is —

(Z¹)_p—

Z² or is absent,

Z¹ is NR³, O, C(═

X)Y, Y(C═

X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl

Z² is H, S(O)_mR³, OR³, —

C(═

X)YR<sup>3, —

Y(C═

X)R3</sup>, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

each R³ is independently H, halo, hydroxy, alkoxy, cyano, nitro, —

C(═

X)YR⁴, —

YC(═

X) R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl, wherein R⁴ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl;

p is 0-4;

or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the cysteine containing kinase comprises a cysteine in proximity to the ATP binding site of the kinase.

16. The method of claim 14, wherein the cysteine containing kinase is BTK, BMX, TEC, TXK, ITK, EGFR, ErbB2, ErbB4, JAK3, or BLK.

17. The method of claim 14, wherein the disorder is cancer, an inflammatory disorder, or an autoimmune disorder mediated by the cysteine containing kinase.

18. A method of binding a cysteine containing kinase to a compound of Formula I comprising contacting the kinase with the compound of Formula I, wherein the compound of Formula I has the structure:

wherein;

each R¹ is independently H, alkyl, halo, hydroxy, alkoxy, cyano, nitro, C(═

X)YR², or YC(═

X)R²;

each X is independently S or O;

each Y is independently S or O;

each R² is independently H or alkyl;

L is A_n, wherein

each A is independently NR¹, S(O)_m, O, C(═

X)Y, Y(C═

X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

wherein each m is independently 0-2;

n is 0-5;

Q¹ is N or CR²;

Q² is NR², S, or O;

E is an electrophile;

Z is —

(Z¹)_p—

Z² or is absent,

Z¹ is NR³, O, C(═

X)Y, Y(C═

X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl

Z² is H, NR³₂, S(O)_mR³, OR³, —

C(═

X)YR³, —

Y(C═

X)R³, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;

each R³ is independently H, halo, hydroxy, alkoxy, cyano, nitro, —

(C═

X)YR⁴, —

YC(═

X) R⁴, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl, wherein R⁴ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl;

p is 0-4;

or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the cysteine containing kinase is BTK, BMX, TEC, TXK, ITK, EGFR, ErbB2, ErbB4, JAK3, or BLK.

20. The method of claim 18, wherein the kinase is contacted with the compound of Formula I in vivo.