IP Library › Granted Patent US 9,102,678

Granted Patent B2

US 9,102,678 · App. 13/644,216 · Granted Aug 11, 2015

Compounds and methods for inhibiting mitotic progression

Inventors: Christopher F. Claiborne (Cambridge, MA); Lloyd J. Payne (Cambridge, GB); Richard J. Boyce (Boxworth, GB); Todd B. Sells (Bellingham, MA); Stephen G. Stroud (Medford, MA); Stuart Travers (Meppershall, GB); Tricia J. Vos (Medford, MA); Gabriel S. Weatherhead (Cambridge, MA)

Assignee: Millennium Pharmaceuticals, Inc.

C07D487/04 C07D487/14 C07D491/14 C07D495/14 C07D513/14

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Quick Facts

Patent No.: US 9,102,678
App. No.: 13/644,216
Granted: Aug 11, 2015
Kind: B2

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Abstract

This invention relates to compounds and methods for the treatment of cancer. In particular, the invention provides compounds that inhibit Aurora kinase, pharmaceutical compositions comprising the compounds, and methods of using the compounds for the treatment of cancer.

Claims (2521)

1. A process for preparing a compound of formula (IIa):

wherein:

Ring A is substituted with 0-2 independently selected R b ;

Ring B is substituted with 0-2 independently selected R c ;

each R b independently is selected from the group consisting of C 1-6 aliphatic, R 2b , R 7b , -T 1 -R 2b , and -T 1 -R 7b ;

each R 2b independently is

halo, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 , N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —NR 4 CO 2 R 6 , —O—CO 2 R 5 , —OC(O)N(R 4 ) 2 , —O—C(O)R 5 , —CO 2 R 5 , —C(O)—C(O)R 5 , —C(O)R 5 , —C(O)N(R 4 ) 2 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —N(R 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —P(O)(R 5 ) 2 , or —P(O)(OR 5 ) 2 ;

each R 7b independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group;

each R c independently is selected from the group consisting of C 1-6 aliphatic, R 2c , R 7c , -T 1 -R 2c , and -T 1 -R 7c ;

each R 2c independently is

halo, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —NR 4 CO 2 R 6 , —O—CO 2 R 5 , —OC(O)N(R 4 ) 2 , —O—C(O)R 5 , —CO 2 R 5 , —C(O)—C(O)R 5 , —C(O)R 5 , —C(O)N(R 4 ) 2 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —N(R 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —P(O)(R 5 ) 2 , or —P(O)(OR 5 ) 2 ;

each R 7c independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group;

T 1 is a C 1-6 alkylene chain optionally substituted with R 3 or R 3b , wherein T 1 or a portion thereof optionally forms part of a 3- to 7-membered ring;

Ring C is aryl or heteroaryl ring substituted with 0-2 independently selected R d and 0-3 independently selected R 2d or C 1-6 aliphatic groups;

each R d independently is selected from the group consisting of C 1-6 aliphatic, R 2d , R 7d , -T 2 -R 2d , -T 2 -R 7d , —V-T 3 -R 2d , and —V-T 3 -R 7d ;

T 2 is a C 1-6 alkylene chain optionally substituted with R 3 or R 3b , wherein the alkylene chain optionally is interrupted

by —C(R 5 )═C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )CO 2 —, —C(O)N(R 4 )—, —C(O)—, —C(O)—C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, —OC(O)N(R 4 )—, —N(R 4 )—N(R 4 )—, —N(R 4 )SO 2 —, or —SO 2 N(R 4 )—, and wherein T 2 or a portion thereof optionally forms part of a 3-7 membered ring;

T 3 is a C 1-6 alkylene chain optionally substituted with R 3 or R 3b , wherein the alkylene chain optionally is interrupted

by —C(R 5 )═C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )CO 2 —, —C(O)N(R 4 )—, —C(O)—, —C(O)—C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, —OC(O)N(R 4 )—, —N(R 4 )—N(R 4 )—, —N(R 4 )SO 2 —, or —SO 2 N(R 4 )—, and wherein T 3 or a portion thereof optionally forms part of a 3-7 membered ring;

V is —C(R 5 )═C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )CO 2 —, —C(O)N(R 4 )—, —C(O)—, —C(O)—C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, —OC(O)N(R 4 )—, —C(NR 4 )═N—, —C(OR 5 )═N—, —N(R 4 )—N(R 4 )—, —N(R 4 )SO 2 —, —N(R 4 )SO 2 N(R 4 )—, —P(O)(R 5 )—, —P(O)(OR 5 )—O—, —P(O)—O—, or —P(O)(NR 5 )—N(R 5 )—;

R 2d is halo, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —NR 4 CO 2 R 6 , —O—CO 2 R 5 , —OC(O)N(R 4 ) 2 , —O—C(O)R 5 , —CO 2 R 5 , —C(O)—C(O)R 5 , —C(O)R 5 , —C(O)N(R 4 ) 2 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —N(R 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —P(O)(R 5 ) 2 , or —P(O)(OR 5 ) 2 ; and

each R 7d independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group;

each R 3 independently is selected from the group consisting of

halo, —OH, —O(C 1-3 alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-3 alkyl), —CO 2 H, —CO 2 (C 1-3 alkyl), —C(O)NH 2 , and —C(O)NH(C 1-3 alkyl);

each R 3b independently is a C 1-3 aliphatic optionally substituted with R 3 or R 7 , 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 carbocyclic ring;

each R 4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 5- to 8-membered heteroaryl or heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S;

each R 5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;

each R 6 independently is an optionally substituted aliphatic or aryl group; and

each R 7 independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group,

said process comprising step (e) of:

treating a compound of formula (v) with an aryl or heteroaryl guanidine of formula (vi):

wherein Rings A, B and C are as defined above, to afford the compound of formula (IIa).

2. The process of claim 1 , further comprising step (d), prior to step (e), of providing a compound of formula (iv)

and treating the compound of formula (iv) with Me 2 NCH(OMe) 2 to prepare the compound of formula (v) for use in step (e).

3. The process of claim 2 , further comprising the step (c), prior to step (d), of providing a compound of formula (iii)

and treating the compound of formula (iii) with a strong acid, followed by treatment under basic conditions to prepare the compound of formula (iv) for use in step (d).

4. The process of claim 3 , further comprising the step (b), prior to step (c), of providing a compound of formula (ii)

and coupling the compound of formula (ii) with the compound HC≡CCH 2 NHBoc to prepare the compound of formula (iii) for use in step (c).

5. The process of claim 4 , further comprising step (a), prior to step (b), of providing a compound of formula (i)

and subjecting the compound of formula (i) to diazotization of the amine and iodide displacement to prepare the compound of formula (ii) for use in step (b).

6. The process of claim 1 , wherein Ring A has the structure:

Ring B has the structure:

and

R b1 , R b2 , R b3 , R c1 , R c2 , R c3 , R c4 and R c5 are as defined in row a, b, c, d, e, g, h, i, j, k, l, m, n, p, q, r, s, t, u, v, w, x, y, z, aa, ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al or am as set out below:

Substituent

R b1

R b2

R b3

R c1

R c2

R c3

R c4

R c5

CF 3

OMe

CO 2 Me

OMe

CF 3

CO 2 Me

CH 2 N(Me) 2

OMe

iPr

OMe

CO 2 Me

CH 3

CO 2 Me

—

(pyridyl)

—

(pyridyl)

7. The process of claim 2 , wherein Ring A has the structure:

Ring B has the structure:

and

Substituent

R b1

R b2

R b3

R c1

R c2

R c3

R c4

R c5

CF 3

OMe

CO 2 Me

OMe

CF 3

CO 2 Me

CH 2 N(Me) 2

OMe

iPr

OMe

CO 2 Me

CH 3

CO 2 Me

—

(pyridyl)

—

(pyridyl)

8. The process of claim 3 , wherein Ring A has the structure:

Ring B has the structure:

and

Substituent

R b1

R b2

R b3

R c1

R c2

R c3

R c4

R c5

CF 3

OMe

CO 2 Me

OMe

CF 3

CO 2 Me

CH 2 N(Me) 2

OMe

iPr

OMe

CO 2 Me

CH 3

CO 2 Me

—

(pyridyl)

—

(pyridyl)

9. The process of claim 4 , wherein Ring A has the structure:

Ring B has the structure:

and

R b1 , R b2 , R b3 , R c1 , R c2 , R c3 , R c4 , R c5 are as defined in row a, b, c, d, e, g, h, i, j, k, l, m, n, p, q, r, s, t, u, v, w, x, y, z, aa, ab, ac, ad, ae, af, ag, ah, ai, aj, ak, al or am as set out below:

Substituent

R b1

R b2

R b3

R c1

R c2

R c3

R c4

R c5

CF 3

OMe

CO 2 Me

OMe

CF 3

CO 2 Me

CH 2 N(Me) 2

OMe

iPr

OMe

CO 2 Me

CH 3

CO 2 Me

—

(pyridyl)

—

(pyridyl)

10. The process of claim 5 , wherein Ring A has the structure:

Ring B has the structure:

and

Substituent

R b1

R b2

R b3

R c1

R c2

R c3

R c4

R c5

CF 3

OMe

CO 2 Me

OMe

CF 3

CO 2 Me

CH 2 N(Me) 2

OMe

iPr

OMe

CO 2 Me

CH 3

CO 2 Me

—

(pyridyl)

—

(pyridyl)

11. A process for preparing a compound of formula (IIIa):

wherein:

R b2 is hydrogen or R b ;

R b3 is hydrogen or R b ;

each R b independently is selected from the group consisting of C 1-3 aliphatic, C 1-3 fluoroaliphatic, and R 2b ;

each R 2b independently is halo, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , and —N(R 4 ) 2 ;

R c1 is hydrogen or R c ;

R c5 is hydrogen or R c ;

each R c independently is selected from the group consisting of C 1-3 aliphatic, C 1-3 fluoroaliphatic, and R 2c ;

each R 2c independently is halo, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , and —N(R 4 ) 2 ;

Ring C is aryl or heteroaryl ring substituted with 0-2 independently selected R d and 0-3 independently selected R 2d or C 1-6 aliphatic groups;

each R d independently is selected from the group consisting of C 1-6 aliphatic, R 2d , R 7d , -T 2 -R 2d , -T 2 -R 7d , —V-T 3 -R 2d , and —V-T 3 -R 7d ;

T 2 is a C 1-6 alkylene chain optionally substituted with R 3 or R 3b , wherein the alkylene chain optionally is interrupted

T 3 is a C 1-6 alkylene chain optionally substituted with R 3 or R 3b , wherein the alkylene chain optionally is interrupted

by —C(R 5 )═C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )CO 2 —, —C(O)N(R 4 )—, —C(O)—, —C(O)—C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, —OC(O)N(R 4 )—, —N(R 4 )—N(R 4 )—, —N(R 4 )SO 2 —, or —SO 2 N(R 4 )—, and wherein T 3 or a portion thereof optionally forms part of a 3-7 membered ring;

V is —C(R 5 )=C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )CO 2 —, —C(O)N(R 4 )—, —C(O)—, —C(O)—C(O)—, —CO 2 —, —OC(O)—, —OC(O)O—, —OC(O)N(R 4 )—, —C(NR 4 )═N—, —C(OR 5 )═N—, —N(R 4 )—N(R 4 )—, —N(R 4 )SO 2 —, —N(R 4 )SO 2 N(R 4 )—, —P(O)(OR 5 )—O—, —P(O)—O—, or —P(O)(NR 5 )—N(R 5 )—;

R 2d is halo, —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR R 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 2 ) 2 , —NR 4 CO 2 R 5 , —O—CO 2 R 5 , —OC(O)N(R 4 ) 2 , —O—C(O)R 5 , —CO 2 R 5 , —C(O)—C(O)R 5 , —C(O)R 5 , —C(O)N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —N(R 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —P(O)(R 5 ) 2 , or —P(O)(OR 5 ) 2 ; and

each R 7d independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group;

each R 3 independently is selected from the group consisting of

halo, —OH, —O(C 1-3 alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-3 alkyl), —CO 2 H, —CO 2 (C 1-3 alkyl), —C(O)NH 2 , and —C(O)NH(C 1-3 alkyl);

each R 5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; and

each R 6 independently is an optionally substituted aliphatic or aryl group; and

each R 7 independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group,

said process comprising step (e) of:

treating a compound of formula (v) with an aryl or heteroaryl guanidine of formula (vi):

wherein

Ring A is

Ring B is

and Ring C is as defined above,

to afford the compound of formula (IIIa).

12. The process of claim 11 , further comprising step (d), prior to step (e), of providing a compound of formula (iv)

and treating the compound of formula (iv) with Me 2 NCH(OMe) 2 to prepare the compound of formula (v) for use in step (e).

13. The process of claim 12 , further comprising the step (c), prior to step (d), of providing a compound of formula (iii)

and treating the compound of formula (iii) with a strong acid, followed by treatment under basic conditions to prepare the compound of formula (iv) for use in step (d).

14. The process of claim 13 , further comprising the step (b), prior to step (c), of providing a compound of formula (ii)

and coupling the compound of formula (ii) with the compound HC≡CCH 2 NHBoc to prepare the compound of formula (iii) for use in step (c).

15. The process of claim 14 , further comprising step (a), prior to step (b), of providing a compound of formula (i)

and subjecting the compound of formula (i) to diazotization of the amine and iodide displacement to prepare the compound of formula (ii) for use in step (b).

16. The process of claim 11 , wherein:

R b2 , R b3 , R c1 and R c5 are as defined in row a, b, c, d, e, f, g, h, i, k, l, m, n, o, r, aa, ab, ac, ad, af, ag, ah or aj as set out below:

Substituent

R b2

R b3

R c1

R c5

CF 3

OMe

CF 3

OMe

iPr

OMe

CH 3

17. The process of claim 12 , wherein:

R b2 , R b3 , R c1 and R c5 are as defined in row a, b, c, d, e, f, g, h, i, k, l, m, n, o, r, aa, ab, ac, ad, af, ag, ah or aj as set out below:

Substituent

R b2

R b3

R c1

R c5

CF 3

OMe

CF 3

OMe

iPr

OMe

CH 3

18. The process of claim 13 , wherein:

R b2 , R b3 , R c1 and R c5 are as defined in row a, b, c, d, e, f, g, h, i, k, l, m, n, o, r, aa, ab, ac, ad, af, ag, ah or aj as set out below:

Substituent

R b2

R b3

R c1

R c5

CF 3

OMe

CF 3

OMe

iPr

OMe

CH 3

19. The process of claim 14 , wherein:

R b2 , R b3 , R c1 and R c5 are as defined in row a, b, c, d, e, f, g, h, i, k, l, m, n, o, r, aa, ab, ac, ad, af, ag, ah or aj as set out below:

Substituent

R b2

R b3

R c1

R c5

CF 3

OMe

CF 3

OMe

iPr

OMe

CH 3

20. The process of claim 15 , wherein:

R b2 , R b3 , R c1 and R c5 are as defined in row a, b, c, d, e, f, g, h, i, k, l, m, n, o, r, aa, ab, ac, ad, af, ag, ah or aj as set out below:

Substituent

R b2

R b3

R c1

R c5

CF 3

OMe

CF 3

OMe

iPr

OMe

CH 3

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 3, 2012

From: CLAIBORNE, CHRISTOPHER F.; PAYNE, LLOYD J.; BOYCE, RICHARD J.; SELLS, TODD B.; STROUD, STEPHEN G.; TRAVERS, STUART; VOS, TRICIA J.; WEATHERHEAD, GABRIEL S.

To: MILLENNIUM PHARMACEUTICALS, INC.

Reel/Frame 029072/0175 →

Continuity (5)

Continuation 12472583 · May 27, 2009

Continuation 11127855 · May 12, 2005

Provisional Application 60571653 · May 14, 2004

Provisional Application 60617221 · Oct 8, 2004

Related Publication 20140046055A1 · Feb 13, 2014