Chemical compounds   

Abstract: Pyrimidine derivatives, which are useful as VEGFR2 inhibitors are described herein. The described invention also includes methods of making such pyrimidine derivatives as well as methods of using the same in the treatment of hyperproliferative diseases.

BACKGROUND OF THE INVENTION

The present invention relates to pyrimidine derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such pyrimidine derivatives are useful in the treatment of diseases associated with inappropriate or pathological angiogenesis.

The process of angiogenesis is the development of new blood vessels from the pre-existing vasculature. Angiogenesis is defined herein as involving: (i) activation of endothelial cells; (ii) increased vascular permeability; (iii) subsequent dissolution of the basement membrane and extravasation of plasma components leading to formation of a provisional fibrin gel extracellular matrix; (iv) proliferation and mobilization of endothelial cells; (v) reorganization of mobilized endothelial cells to form functional capillaries; (vi) capillary loop formation; and (vi) deposition of basement membrane and recruitment of perivascular cells to newly formed vessels. Normal angiogenesis is active during tissue growth from embryonic development through maturity and then enters a period of relative quiescence during adulthood. Normal angiogenesis is also activated during wound healing, and at certain stages of the female reproductive cycle. Inappropriate or pathological angiogenesis has been associated with several disease states including various retinopathies, ischemic disease, atherosclerosis, chronic inflammatory disorders, and cancer. The role of angiogenesis in disease states is discussed, for instance, in Fan et al, Trends in Pharmacol Sci. 16:54-66; Shawver et al, DDT Vol. 2, No. 2 Feb. 1997; Folkmann, 1995, Nature Medicine 1:27-31.

In cancer the growth of solid tumors has been shown to be dependent on angiogenesis. The progression of leukemias as well as the accumulation of fluid associated with malignant ascites and pleural effusions also involve pro-angiogenic factors. (See Folkmann, J., J. Nat\'l. Cancer Inst., 1990, 82, 4-6.) Consequently, the targeting of pro-angiogenic pathways is a strategy being widely pursued in order to provide new therapeutics in these areas of great, unmet medical need.

Central to the process of angiogenesis are vascular endothelial growth factor (VEGF) and its receptors, termed vascular endothelial growth factor receptor(s) (VEGFRs), The roles VEGF and VEGFRs play in the vascularization of solid tumors, progression of hematopoietic cancers and modulation of vascular permeability have drawn great interest in the scientific community. VEGF is a polypeptide, which has been linked to inappropriate or pathological angiogenesis (Pinedo, H. M. et al The Oncologist, Vol. 5, No. 90001, 1-2, April 2000). VEGFR(s) are protein tyrosine kinases (PTKs) that catalyze the phosphorylation of specific tyrosine residues in proteins that are involved in the regulation of cell growth, differentiation, and survival. (A. F. Wilks, Progress in Growth Factor Research, 1990, 2, 97-111; S. A. Courtneidge, Dev. Supp. I, 1993, 57-64; J. A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R. F. Paulson, Semin. Immunol., 1995, 7(4), 267-277; A. C. Chan, Curr. Opin. Immunol., 1996, 8(3), 394-401).

Three PTK receptors for VEGF have been identified: VEGFR1 (Flt-1); VEGFR2 (Flk-1 and KDR) and VEGFR3 (Flt-4). These receptors are involved in angiogenesis and participate in signal transduction. (Mustonen, T. et al J. Cell Biol. 1995:129:895-898; Ferrara and Davis-Smyth, Endocrine Reviews, 18(1):4-25, 1997; McMahon, G., The Oncologist, Vol. 5, No 90001, 3-10, April 2000).

Of particular interest is VEGFR2, which is a transmembrane receptor PTK expressed primarily in endothelial cells. Activation of VEGFR-2 by VEGF is a critical step in the signal transduction pathway that initiates tumor angiogenesis. VEGF expression may be constitutive to tumor cells and can also be upregulated in response to certain stimuli. One such stimulus is hypoxia, where VEGF expression is upregulated in both tumor and associated host tissues. The VEGF ligand activates VEGFR2 by binding to its extracellular VEGF binding site. This leads to receptor dimerization of VEGFRs and autophosphorylation of tyrosine residues at the intracellular kinase domain of VEGFR2. The kinase domain operates to transfer a phosphate from ATP to the tyrosine residues, thus providing binding sites for signaling proteins downstream of VEGFR-2 leading ultimately to angiogenesis. (Ferrara and Davis-Smyth, Endocrine Reviews, 18(1):4-25, 1997; McMahon, G., The Oncologist, Vol. 5, No. 90001, 3-10, April 2000.)

Consequently, antagonism of the VEGFR2 kinase domain would block phosphorylation of tyrosine residues and serve to disrupt initiation of angiogenesis. Specifically, inhibition at the ATP binding site of the VEGFR2 kinase domain would prevent binding of ATP and prevent phosphorylation of tyrosine residues. Such disruption of the pro-angiogenesis signal transduction pathway associated with VEGFR2 should therefore inhibit tumor angiogenesis and thereby provide a potent treatment for cancer or other disorders associated with inappropriate angiogenesis.

The present inventors have discovered novel pyrimidine derivative compounds, which are inhibitors of VEGFR-2 kinase activity. Such pyrimidine derivatives are useful in the treatment of disorders, including cancer, associated with inappropriate angiogenesis.

SUMMARY

In one aspect of the present invention, there is provided a compound of Formula (I):

or a salt, solvate, or physiologically functional derivative thereof: wherein:

X1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl; X2 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C(O)R1, or aralkyl; X3 is hydrogen or halogen; X4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, heteroaralkyl, cyanoalkyl, —(CH2)pC═CH(CH2)tH, —(CH2)pC≡C(CH2)tH, or C3-C7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is N or C—R, wherein R is hydrogen, halogen, or cyano; Q1 is hydrogen, halogen, C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 alkoxy, or C1-C2 haloalkoxy;

Q3 is A1 when Q2 is A2 and Q3 is A2 when Q2 is A1; wherein

A1 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OR1, and

A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl, NR3R4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R1 is C1-C4 alkyl; R2, R3, and R4 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, —S(O)2R5, and —C(O)R5; R5 is C1-C4 alkyl, or C3-C7 cycloalkyl; and when Z is oxygen then Z1 is S(O)2 and when D is

then X2 is C1-C4 alkyl, C1-C4 haloalkyl, C(O)R1, or aralkyl.

In a second aspect of the present invention, there is provided a compound of Formula (II):

or a salt, solvate, or physiologically functional derivative thereof: wherein: X1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl; X2 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C(O)R1, or aralkyl; X3 is hydrogen or halogen; X4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, heteroaralkyl, cyanoalkyl, —(CH2)pC═CH(CH2)tH, —(CH2)pC≡C(CH2)tH, or C3-C7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is N or C—R, wherein R is hydrogen, halogen, or cyano; Q1 is hydrogen, halogen, C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 alkoxy, or C1-C2 haloalkoxy;

Q3 is A1 when Q2 is A2 and Q3 is A2 when Q2 is A1; wherein

A1 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OR1, and

A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl, NR3R4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R1 is C1-C4 alkyl; R2, R3, and R4 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, —S(O)2R5, and —C(O)R5; R5 is C1-C4 alkyl, or C3-C7 cycloalkyl; and when Z is oxygen then Z1 is S(O)2.

In a third aspect of the present invention, there is provided a compound of Formula (III):

or a salt, solvate, or physiologically functional derivative thereof: wherein: X1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl; X2 is C1-C4 alkyl, C1-C4 haloalkyl, or C(O)R1; X3 is hydrogen or halogen; X4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, heteroaralkyl, cyanoalkyl, —(CH2)pC═CH(CH2)tH, —(CH2)pC≡C(CH2)tH, or C3-C7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is N or C—R, wherein R is hydrogen, halogen, or cyano; Q1 is hydrogen, halogen, C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 alkoxy, or C1-C2 haloalkoxy;

Q3 is A1 when Q2 is A2 and Q3 is A2 when Q2 is A1; wherein

A1 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OR1, and

A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl, NR3R4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R1 is C1-C4 alkyl; R2, R3, and R4 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, —S(O)2R5, and —C(O)R5; R5 is C1-C4 alkyl, or C3-C7 cycloalkyl; and when Z is oxygen then Z′ is S(O)2.

In a fourth aspect of the present invention, there is provided a compound of Formula (IV):

or a salt, solvate, or physiologically functional derivative thereof: wherein: X1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 hydroxyalkyl; X2 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C(O)R1, or aralkyl; X3 is hydrogen or halogen; X4 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, heteroaralkyl, cyanoalkyl, —(CH2)pC═CH(CH2)tH, —(CH2)pC≡C(CH2)tH, or C3-C7 cycloalkyl; p is 1, 2, or 3; t is 0 or 1; W is N or C—R, wherein R is hydrogen, halogen, or cyano; Q1 is hydrogen, halogen, C1-C2 haloalkyl, C1-C2 alkyl, C1-C2 alkoxy, or C1-C2 haloalkoxy;

Q3 is A1 when Q2 is A2 and Q3 is A2 when Q2 is A1; wherein

A1 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, —OR1, and

A2 is the group defined by -(Z)m-(Z1)-(Z2), wherein Z is CH2 and m is 0, 1, 2, or 3, or Z is NR2 and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH2NR2 and m is 0 or 1; Z1 is S(O)2, S(O), or C(O); and Z2 is C1-C4 alkyl, NR3R4, aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R1 is C1-C4 alkyl; R2, R3, and R4 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, —S(O)2R5, and —C(O)R5; R5 is C1-C4 alkyl, or C3-C7 cycloalkyl; and when Z is oxygen then Z1 is S(O)2.

In a fifth aspect of the present invention, there is provided a pharmaceutical composition including a therapeutically effective amount of a compound of formula (I) or a salt, solvate, or a physiologically functional derivative thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.

In a sixth aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by inappropriate VEGFR2 activity, including: administering to said mammal a therapeutically effective amount of a compound of formula (I) or a salt, solvate or a physiologically functional derivative thereof.

In a seventh aspect of the present invention, there is provided a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof for use in therapy.

In an eighth aspect of the present invention, there is provided the use of a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate VEGFR2 activity.

In a ninth aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by inappropriate VEGFR2 activity, including: administering to said mammal therapeutically effective amounts of (i) a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof and (ii) an agent to inhibit growth factor receptor function.

In an tenth aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being characterized by inappropriate angiogenisis, including: administering to said mammal a therapeutically effective amount of a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof.

In an eleventh aspect of the present invention, there is provided a method of treating cancer in a mammal, including administering to said mammal a therapeutically effective amount of a compound of formula (I), or salt, solvate or physiologically functional derivative thereof.

In a twelfth aspect of the present invention, there is provided a method of treating cancer in a mammal, including administering to said mammal therapeutically effective amounts of (i) a compound of formula (I), or salt, solvate or physiologically functional derivative thereof and (ii) at least one additional anti-cancer therapy.

DETAILED DESCRIPTION

As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.