JP2008518015A5

JP2008518015A5 -

Info

Publication number: JP2008518015A5
Application number: JP2007539037A
Authority: JP
Filing date: 2005-10-25
Publication date: 2008-11-13

Claims

A compound comprising at least one phosphonate group and a substructure of any one of formulas 100 to 106, or a pharmaceutically acceptable salt thereof:

here:

The bond represented by is a single bond or a double bond;
R ²⁹ is hydrogen, alkyl, or —C (═O) R ³⁶ ;
R ³⁰ is hydrogen or substituted alkyl; and R ³¹ and R ³² are independently hydrogen, alkyl, or substituted aryl; or R ³¹ and R ³² are taken together with the nitrogen atom to which they are attached. Form a substituted or unsubstituted heterocycle;
R ³³ is —O—, —NR ³⁵ — or absent;
R ³⁴ is —O— or absent;
R ³⁵ is hydrogen or alkyl;
R ³⁶ is hydrogen, alkyl, alkenyl, or alkynyl;
R ⁵⁶ is —N— or —CR ⁶⁸ ; and R ⁶⁸ is hydrogen or alkyl.
A compound, or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 comprising a substructure of any one of formula II to formula XVII, or a pharmaceutically acceptable salt thereof:

here:
Each R ³⁹ and R ⁴⁰ is independently hydrogen, fluorine, chlorine, bromine or iodine;
na and ma are each independently 1, 2, 3 or 4;
R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ are independently hydrogen, fluorine, chlorine, bromine or iodine;
R ⁴⁵ is hydrogen, —NH— (C ₆ -C ₂₀ ) aryl or —NH-substituted (C ₆ -C ₂₀ ) aryl;
A _a is a carbocyclic or heterocyclic ring;
R ⁴⁶ is a substituted heterocycle;
R ⁴⁹ is hydrogen, — (C ₆ -C ₂₀ ) aryl or — (C ₆ -C ₂₀ ) -substituted aryl;
R ⁵⁰ is hydrogen, substituted alkyl, or —C (═O) NR ⁵¹ R ⁵² ;
R ⁵¹ and R ⁵² are independently hydrogen, alkyl, or substituted alkyl;
R ⁵⁵ is a bond or alkylene;
R ⁵⁶ is —N— or —CR ⁵⁷ —;
R ⁵⁷ is hydrogen or alkyl;
R ⁵⁸ is hydrogen, halo, alkyl, fused carbocycle or fused heterocycle;
And R ^59, = ^{CR 64} - or = ^{N-NR 64} - is;
R ⁶⁰ is phenyl or pyrrolyl;
Each R ⁶¹ is independently an alkyl or polar group;
Each R ⁶⁴ is independently hydrogen or alkyl;
R ⁶⁷ is substituted aryl; and nb is 0, 1, 2, or 3.
A compound, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, comprising a substructure of formulas 1-24, or a pharmaceutically acceptable salt thereof:

here:
A ⁰ is A ¹ ;
A ¹ is:

A ³ are the following:

Y ¹ is independently O, S, N (R ^x ), N (OR ^x ), or N (N (R ^x ) (R ^x ));
Y ² is independently a bond, O, N (R ^x ), N (OR ^x ), N (N (R ^x ) (R ^x )), or —S (O) _{M 2} —; and Y ² Is bound to two phosphorus atoms, Y ² can also be C (R ² ) (R ² );
R ^x is independently H, R ² , W ³ , a protecting group, or the following formula:

R ^y is independently H, W ³ , R ² or a protecting group;
R ² is independently H, R ³ or R ⁴ , wherein each R ⁴ is independently substituted with 0 to 3 R ³ groups;
R ³ ^is R ^3a, R ^3b, is a ^{R 3c} or ^{R 3d,} provided that ^{when R 3} is bound to a heteroatom, ^{R 3} ^is a ^{R 3c} or ^{R 3d;}
R ^3a is F, Cl, Br, I, —CN, N ₃ or —NO ₂ ;
R ^3b is Y ¹ ;
R ^3c is —R ^x , —N (R ^x ) (R ^x ), —SR ^x , —S (O) R ^x , —S (O) ₂ R ^x , —S (O) (OR ^x ), _{^{^{^{-S (O) 2 (OR x}}}} ), - OC (Y 1) R x, -OC (Y 1) OR x, -OC (Y 1) (N (R x) (R x)), - SC ( ^{^{^{^{Y 1) R x, -SC (}}}} Y 1) OR x, -SC (Y 1) (N (R x) (R x)), - N (R x) C (Y 1) R x, -N ( R ^x ) C (Y ¹ ) OR ^x , or —N (R ^x ) C (Y ¹ ) (N (R ^x ) (R ^x ));
R ^3d is —C (Y ¹ ) R ^x , —C (Y ¹ ) OR ^x or —C (Y ¹ ) (N (R ^x ) (R ^x ));
R ⁴ is alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R ⁵ is R ⁴ , wherein each R ⁴ is substituted with 0 to 3 R ³ groups;
W ³ is W ⁴ or W ⁵ ;
W ⁴ is R ⁵ , —C (Y ¹ ) R ⁵ , —C (Y ¹ ) W ⁵ , —SO ₂ R ⁵ , or —SO ₂ W ⁵ ;
W ⁵ is a carbocyclic or heterocyclic ring, where W ⁵ is independently substituted with 0 to 3 R ² groups;
W ⁶ is W ³ and is independently substituted with 1, 2 or 3 A ³ groups;
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M1a, M1c and M1d are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
R ²¹ is substituted alkyl or substituted aryl;
R ²⁹ is hydrogen, alkyl, or —C (═O) R ³⁶ ;
R ³⁰ is hydrogen or substituted alkyl;
R ³¹ and R ³² are independently hydrogen, alkyl, or substituted aryl; or R ³¹ and R ³² together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle;
R ³³ is —O—, —NR ³⁵ — or absent;
R ³⁴ is —O— or absent;
R ³⁵ is hydrogen or alkyl;
R ³⁶ is hydrogen, alkyl, alkenyl, or alkynyl;
R ⁵⁸ is hydrogen or halo;
R ⁶⁵ is hydrogen, alkyl or halo; and R ⁶⁶ is a carbocycle, heterocycle, substituted carbocycle, or substituted heterocycle, and is substituted with one or more A ⁰ ;
A compound, or a pharmaceutically acceptable salt thereof.

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

And W ^5a is a carbocyclic or heterocyclic ring, where W ^5a is independently substituted with 0 or 1 R ² groups,
Compound.

The compound according to claim 3, wherein M12a is 1.

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

And W ^5a is a carbocycle, which is independently substituted with 0 or 1 R ² groups,
Compound.

A ¹ is a formula: A compound according to claim 3:

Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound.

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

A ¹ is a formula: A compound according to claim 3:

Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound.

The compound according to any one of claims 3 to 16, wherein A ³ is represented by the following formula:

Y ^1a is O or S; and Y ^2a is O, N (R ^x ) or S.
Compound.

Y ^2b is O or N (R ^x ),
Compound.

R ¹ is independently H or alkyl of 1 to 18 carbon atoms;
Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound.

Y ^2b is O or N (R ^x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound.

23. The compound of claim 22, wherein M12d is 1.

W ⁵ is a carbocycle, a compound according to claim 25.

W ⁵ is phenyl, A compound according to claim 27.

29. The compound of claim 28, wherein M12b is 1.

Y ^1a is O or S; and Y ^2a is O, N (R ^x ) or S.
Compound.

Y ^2b is O or N (R ^x ),
Compound.

33. The compound of claim 32, wherein R < ¹ > is H.

35. The compound of claim 32, wherein M12d is 1.

Wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R ² groups,
Compound.

Where R ¹ is independently H or alkyl of 1 to 18 carbon atoms,
Compound.

Y ^1a is O or S; and Y ^2a is O, N (R ² ) or S.
Compound.

Y ^1a is O or S;
Y ^2b is O or N (R ² ); and Y ^2c is O, N (R ^y ) or S.
Compound.

R ¹ is independently H or alkyl of 1 to 18 carbon atoms;
Y ^1a is O or S;
Y ^2b is O or N (R ² );
Y ^2d is O or N (R ^y ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound.

Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound.

Y ^2b is O or N (R ² ),
Compound.

Y ^1a is O or S; and Y ^2a is O, N (R ² ) or S.
Compound.

Y ^2b is O or N (R ² ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
Compound.

Y ^2b is O or N (R ² ),
Compound.

A ⁰ is a the formula A compound according to claim 3:

Where each R is independently (C ₁ -C ₆ ) alkyl.
Compound.

53. A compound according to any one of claims 1 to 52, isolated and purified.

Serine / threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase and / or EGF 54. The compound of any one of claims 1 to 53, which inhibits receptor tyrosine kinase.

55. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound according to any one of claims 1 to 54.

55. A unit dosage form containing a compound according to any one of claims 1 to 54 and a pharmaceutically acceptable excipient.

A composition for inhibiting the kinase in vitro or in vivo, contains a compound according to any one of 請 Motomeko 1-54, the composition that is suitable for contact with the sample, Composition .

58. The composition of claim 57, wherein the contacting is made in vivo.

A composition for inhibiting kinases in a mammal, comprising a compound according to any one of 請 Motomeko 1-54, composition.

60. The composition of claim 59, wherein the compound is formulated with a pharmaceutically acceptable carrier.

61. The composition of claim 60, wherein the formulation contains a second active ingredient.

The kinase is serine / threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase 62. The composition of any one of claims 57 to 61, wherein the composition is and / or EGF receptor tyrosine kinase.

And have you to a patient in need of treatment for cancer a composition for treating cancer, comprising a compound according to any one of 請 Motomeko 1-54, composition.

55. A compound according to any one of claims 1 to 54 for use in medical therapy.

66. Use of a compound according to claim 65 for the preparation of a medicament that inhibits a kinase in an animal.

The kinase is serine / threonine kinase, tyrosine kinase, Bcr-Abl kinase, cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3 kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase, protein kinase C, insulin receptor tyrosine kinase. 66. Use according to claim 65, which is and / or an EGF receptor tyrosine kinase.

55. Use of a compound according to any one of claims 1 to 54 for the preparation of a medicament for treating cancer in an animal.

Methods for preparing the compounds described in the schemes and examples herein.