Trifluoromethyl substituted benzamides as kinase inhibitors

• US 20060035897A1
• Filed: 08/10/2005
• Published: 02/16/2006
• Est. Priority Date: 08/11/2004
• Status: Abandoned Application

• Current Assignee: Georg Martiny-Baron, Giorgio Caravatti, Pascal Furet, Patricia Imbach
• Original Assignee: Georg Martiny-Baron, Giorgio Caravatti, Lawrence Blas Perez, Pascal Furet, Patricia Imbach, Tao Sheng
• Inventors: Furet, Pascal, Sheng, Tao, Caravatti, Giorgio, Imbach, Patricia, Martiny-Baron, Georg, Perez, Lawrence Blas
• Application Number:
  US11/201,348
• Publication Number:
  US 20060035897A1
• Time in Patent Office: Days
• US Class Current: 514/248
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 217/02 with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• CPC Class Codes: C07D 237/30 Phthalazines
• CPC Class Codes: C07D 239/74 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
• CPC Class Codes: C07D 239/84 Nitrogen atoms
• CPC Class Codes: C07D 277/62 Benzothiazoles

Abstract

The invention relates to trifluoromethyl substituted benzamide compounds of the formula I, pharmaceuticals comprising these compounds, their use as or for the manufacture of pharmaceuticals, particularly as inhibitors of protein kinases, especially of ephrin receptor kinases, and/or the treatment of a condition, disorder or disease state mediated by a protein kinase activity and/or a proliferative disease, methods of treatment comprising administering the compounds, especially of therapeutic and prophylactic treatment, methods for the manufacture of the compounds and novel intermediates and partial steps for their synthesis.

Claims

1. A compound of the formula I,

wherein

R₁ is hydrogen or —

N(R₆R₇) wherein each of R₆ and R₇ is alkyl or R₆ and R₇, together with the nitrogen to which they are bound, form a 5- to 7-membered heterocyclic ring, where the additional ring atoms are selected from carbon and 0, 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur and which ring is unsubstituted or, if a further nitrogen ring atom is present, unsubstituted or substituted by alkyl at that nitrogen;

R₂ is hydrogen or —

CH₂—

N(R₆R₇) wherein each of R₆ and R₇ is alkyl or R₆ and R₇, together with the nitrogen to which they are bound, form a 5- to 7-membered heterocyclic ring, where the additional ring atoms are selected from carbon and 0, 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur and which ring is unsubstituted or, if a further nitrogen ring atom is present, unsubstituted or substituted by alkyl at that nitrogen;

with the proviso that at least one of R₁ and R₂ is hydrogen;

R₃ is halo or C₁-C₇-alkyl;

R₄ is bicyclic heterocyclyl selected from the group consisting of

wherein

X is CH, N or C—

NH₂;

Y is CH or N;

with the proviso that not both of X and Y are N simultaneously; and

R₅ is hydrogen, C₁-C₇-alkyl or unsubstituted or substituted phenyl;

A is —

C(═

O)—

NH—

with the —

NH—

bound to the ring comprising Q and Z in formula I or —

NH—

C(═

O)—

with the —

C(═

O)—

bound to the ring comprising Q and Z in formula I;

Z is CH or N; and

Q is —

S—

or —

CH═

CH—

;

or a salt thereof where one or more salt-forming groups are present.

2. A compound or formula I according to claim 1, wherein Q is —

CH═

CH— and

R₁, R₂, R₃, R₄, R₅, A and Z are as defined in claim 1, or a—

preferably pharmaceutically acceptable—

salt thereof.

3. A compound of the formula I according to claim 1, wherein A is —

C(═

O)—

NH—

with the —

NH—

bound to the ring comprising Q and Z in formula I and R₁, R₂, R₃, R₄, R₅, Q and Z are as defined in claim 1, or a—

preferably pharmaceutically acceptable—

salt thereof.

4. A compound of the formula I according to claim 1, wherein one of R₁ and R₂ is hydrogen and the other is hydrogen or a moiety selected from the group consisting of

wherein “

Alk”

is alkyl, preferably lower alkyl, more preferably methyl or ethyl; and

R₃, R₄, R₅, A, Q and Z are as defined in claim 1, or a—

preferably pharmaceutically acceptable—

salt thereof.

5. A compound of the formula I according to claim 1, wherein

each of R₁ and R₂ is hydrogen;

R₃ is C₁-C₇-alkyl, especially methyl;

R₄ is bicyclic heterocyclyl selected from the group consisting of

wherein

X is CH, N or C—

NH₂;

Y is CH or N;

with the proviso that not both of X and Y are N simultaneously;

and R₅ is hydrogen, C₁-C₇-alkyl or phenyl;

(wherein R₄ is preferably

A is —

C(═

O)—

NH—

(with the —

NH—

bound to the ring comprising Q and Z in formula I) or —

NH—

C(═

O)—

(with the —

C(═

O)—

bound to the ring comprising Q and Z in formula I);

Z is CH; and

Q is —

CH═

CH—

;

or a—

preferably pharmaceutically acceptable—

salt thereof where one or more salt-forming groups are present.

6. A compound of the formula I according to claim 1, wherein R₄ is

7. A compound of the formula I according to claim 1, selected from the group consisting of

N-(3-isoquinolin-7-yl-4-methyl-phenyl)-3-trifluoromethyl-benzamide,

N-(4-methyl-3-quinazolin-6-yl-phenyl)-3-trifluoromethyl-benzamide,

3-isoquinolin-7-yl-4-methyl-N-(3-trifluoromethyl-phenyl)-benzamide,

4-methyl-3-quinazolin-6-yl-N-(3-trifluoromethyl-phenyl)-benzamide,

N-(3-benzothiazol-6-yl-4-methyl-phenyl)-3-trifluoromethyl-benzamide,

3-benzothiazol-6-yl-4-methyl-N-(3-trifluoromethyl-phenyl)-benzamide,

N-(4-methyl-3-phthalazin-6-yl-phenyl)-3-trifluoromethyl-benzamide,

4-methyl-3-phthalazin-6-yl-N-(3-trifluoromethyl-phenyl)-benzamide,

N-(3-benzothiazol-5-yl-4-methyl-phenyl)-3-trifluoromethyl-benzamide,

3-benzothiazol-5-yl-4-methyl-N-(3-trifluoromethylphenyl)benzamide,

N-(3-Isoquinolin-7-yl-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,

3-Isoquinolin-7-yl-4-methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide,

4-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide,

4-(4-Methyl-piperazin-1-ylmethyl)-N-(4-methyl-3-quinazolin-6-yl-phenyl)-3-trifluoromethyl-benzamide,

4-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-quinazolin-6-yl-benzamide,

N-(4-Methyl-3-phthalazin-6-yl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide,

4-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-phthalazin-6-yl-benzamide,

N-(4-Methyl-3-phthalazin-6-yl-phenyl)-4-piperidin-1-ylmethyl-3-trifluoromethyl-benzamide,

4-Dimethylaminomethyl-N-(3-isoquinolin-7-yl-4-methyl-phenyl)-3-trifluoromethyl-benzamide,

4-Dimethylaminomethyl-N-(4-methyl-3-phthalazin-6-yl-phenyl)-3-trifluoromethyl-benzamide,

N-(4-Methyl-3-phthalazin-6-yl-phenyl)-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,

N-(3-Isoquinolin-7-yl-4-methyl-phenyl)-4-morpholin-4-ylmethyl-3-trifluoromethyl-benzamide,

4-Methyl-3-phthalazin-6-yl-N-(4-piperidin-1-ylmethyl-3-trifluoromethyl-phenyl)-benzamide,

4-Methyl-N-(4-morpholin-4-ylmethyl-3-trifluoromethyl-phenyl)-3-phthalazin-6-yl-benzamide,

N-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-4-methyl-3-phthalazin-6-yl-benzamide,

4-Methyl-3-phthalazin-6-yl-N-(4-pyrrolidin-1-ylmethyl-3-trifluoromethyl-phenyl)-benzamide,

and N-(3-(2-Aminoquinazolin-6-yl)-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

or a pharmaceutically acceptable salt thereof where a salt-forming group is present.

8. A process for the manufacture of a compound of the formula I, or a salt thereof, according to claim 1, comprising reacting a boronic acid derivative of the formula II,

wherein D₁ and D₂ are hydroxy or substituted hydroxy, or together with the binding boron atom and two binding oxygen atoms form a ring of the formula IIA,

wherein E is alkylene, substituted alkylene, unsubstituted or substituted cycloalkylene, unsubstituted or substituted bicycloalkylene or unsubstituted or substituted tricycloalkylene,

with a coupling partner of the formula III,

R₄-L 

 

(III)

wherein R₄ is as defined according to claim 1 and L is a leaving group;

and, if desired, transforming a compound of formula I into a different compound of formula I, transforming a salt of an obtainable compound of formula I into the free compound or a different salt, and/or transforming an obtainable free compound of formula I into a salt thereof.

9. A pharmaceutical composition comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 and a pharmaceutically acceptable carrier.

10. A compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 for use in the diagnostic and/or therapeutic treatment of the animal, especially mammalian, or human body.

11. The use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 in the treatment, or for the preparation of a pharmaceutical preparation for the treatment of, one or more diseases or disorders that depend on one or more protein kinases, especially on one or more protein tyrosine kinases, especially selected from the group consisting of ephrin receptor kinases, preferably EphB4 kinase, c-abl, KDR, c-Src, c-raf, b-raf, Tie/Tek and KDR kinase;

or a mutated variant thereof.

12. The use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 in the treatment, or for the manufacture of a pharmaceutical composition for the treatment, of a proliferative disease.

13. A method of treatment for a disease that responds to inhibition of a kinase and/or is a proliferative disease;

which comprises administering a prophylactically or especially therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1, especially to a warm-blooded animal, for example a human, that, on account of one of the mentioned diseases, requires such treatment.

14. A combination comprising a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 and a second drug substance, or a pharmaceutically acceptable salt thereof.