JP2003523390A - Tyrosine kinase inhibitor - Google Patents

Abstract

  (57) [Summary] The present invention relates to compounds that inhibit, modulate and / or modulate tyrosine kinase signaling; compositions containing the compounds; and the use thereof for angiogenesis, cancer, tumor growth, atherosclerosis, aging in mammals. The present invention relates to a method for treating tyrosine kinase-dependent diseases and conditions such as macular degeneration, diabetic retinopathy, and inflammatory diseases.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to compounds that inhibit, regulate and / or modulate tyrosine kinase signaling; compositions containing the compounds; and angiogenesis, cancer, tumor growth, atherosclerosis in mammals, It relates to their use in the treatment of tyrosine kinase dependent diseases and conditions such as age-related macular degeneration, diabetic retinopathy, inflammatory diseases.

BACKGROUND OF THE INVENTION Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate group of adenosine triphosphate to tyrosine residues in protein substrates. Tyrosine kinases play a crucial role in signal transduction in many cellular functions by substrate phosphorylation. Although the detailed mechanism of signal transduction is still unknown, tyrosine kinases have been revealed to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation.

Tyrosine kinases can be classified as receptor-type or non-receptor-type. Receptor tyrosine kinases have extracellular, transmembrane and intracellular moieties, and non-receptor tyrosine kinases are intracellular entirely.

Receptor tyrosine kinases are composed of numerous transmembrane receptors with diverse physiological activities. In fact, approximately 20 different receptor tyrosine kinase subfamilies have been identified. Certain tyrosine kinase subfamilies, referred to as the HER subfamily, include EGFR, HER2, HER3 and HER4.
Consists of. Ligands of this receptor subfamily include epidermal growth factor, TGF-
α, amphiregulin, HB-EGF, β-cellulin (betace
llulin) and heregulin (heregulin). Another subfamily of these receptor tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR and IR-R. The PDGF subfamily includes PDGF-α and β receptors, CSFIR, c-kit and FLK-.
II, etc. Next, the FLK family consisting of kinase insertion region receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and fms-like tyrosine kinase-1 (flt-1) is there. The PDGF and FLK families are usually considered together because the two groups are similar. For a detailed discussion of receptor tyrosine kinases, see
See the report by Plowman et al. (Plowman et al., DN & P 7 (6): 334-339, 1994).
(Incorporated herein by reference).

Non-receptor tyrosine kinases also consist of many subfamilies, including Sr.
c, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak,
Examples include Jak, Ack, and LIMK. Each of these subfamilies is further subdivided into various receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, F.
gr and Yrk. The Src subfamily of enzymes has been associated with tumorigenesis. For a detailed discussion of non-receptor tyrosine kinases, see Boren's report (Bolen, Oncogene, 8: 2025-2031 (1993)), incorporated herein by reference.

Both receptor and non-receptor tyrosine kinases have been suggested in cell signaling pathways leading to many pathological conditions such as cancer, psoriasis and hyperimmune responses.

It has been suggested that several receptor tyrosine kinases and their associated growth factors play some role in angiogenesis. However, some may indirectly promote angiogenesis (Mustonen and Alitalo, J. Cell Biol. 129:
895-898, 1995). One such receptor tyrosine kinase is fetal liver kinase 1 or FLK-1. The human analogue of FLK-1 is the kinase insert domain containing receptor KDR, which binds VEGF with high affinity,
It is also referred to as vascular endothelial growth factor receptor 2 or VEGFR-2. Finally,
The mouse form of this receptor has also been designated NYK (Oelrichs et al., Oncogene).
8 (1): 11-15, 1993). VEGF and KDR are ligand-receptor pairs that play an important role in the proliferation of vascular endothelial cells and the formation and development of blood vessels called angiogenesis and angiogenesis, respectively.

Angiogenesis is characterized by hyperactivity of vascular endothelial growth factor (VEGF). VEG
F actually consists of a family of ligands (Klagsburn and D'Amore, Cyto
kine & Growth Factor Reviews 7: 259-270, 1996). VEGF binds to the widespread high affinity membrane tyrosine kinase receptor KDR and a related fms-like tyrosine kinase-1, also called Flt-1 or vascular endothelial growth factor receptor 1 (VEGFR-1). To do. Cell culture and gene knockout experiments have revealed that each receptor contributes to various aspects of angiogenesis. KDR is VE
Mediating the mitotic function of GF, Flt-1 appears to regulate non-mitotic functions such as those associated with cell adhesion. Therefore, inhibiting KDR regulates the level of mitotic VEGF activity. Indeed, tumor growth has been shown to be sensitive to the anti-angiogenic effects of VEGF receptor antagonists (Kim et al.
al., Nature 362, pp. 841-844, 1993).

Therefore, solid tumors depend on angiogenesis for the angiogenesis necessary to support their growth, so that they can be treated with tyrosine kinase inhibitors. The solid tumors include histiocytic lymphoma, cancer of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung cancer such as lung adenocarcinoma and small cell lung cancer. Another example is a cancer in which overexpression or activation of a Raf-activating oncogene (eg, K-ras, erb-B) is observed. Such cancers include pancreatic cancer and breast cancer. Therefore, inhibitors of these tyrosine kinases are useful in the prevention and treatment of proliferative disorders that depend on that enzyme.

The angiogenic activity of VEGF is not limited to tumors. VEGF is responsible for most of the angiogenic activity that occurs in or near the retina in diabetic retinopathy. This vascular growth in the retina results in loss of vision, which leads to blindness. Ocular VEGF mRNA and protein are increased by retinal vein occlusion in primates and reduced pO ₂ levels in mice resulting in neovascularization. Intraocular injection of anti-VEGF monoclonal antibody or VEGF receptor immunofusion inhibits ocular neovascularization in both primate and rodent models. Ocular VE regardless of the cause of VEGF induction in human diabetic retinopathy
Inhibition of GF is useful in treating this disease.

VEGF expression is also greatly increased in hypoxic regions of animal and human tumors adjacent to necrotic regions. VEGF is also elevated by the expression of the oncogenes ras, raf, src and mutant p53, all associated with the targeted cancer. Monoclonal anti-VEGF antibody inhibits human tumor growth in nude mice. The same tumor cells continue to express VEGF in culture, but the antibody does not reduce its mitotic rate. Therefore, tumor-derived VEGF does not function as an autocrine mitotic factor. Thus, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitotic activities. The monoclonal antibodies further inhibit the growth of typically poorly vascularized human colon cancer in athymic mice and reduce the number of tumors arising from inoculated cells.

[0012] Viral expression of the VEGF-binding construct Flt-1 of Flk-1, a mouse KDR receptor homologue that removes the cytoplasmic tyrosine kinase domain by cleavage but retains the membrane anchor, probably due to viral expression of endothelial cells VEGF present throughout the membrane. The dominant negative mechanism of heterodimer formation with the receptor substantially arrests the growth of transplantable glioblastoma in mice. Embryonic stem cells, which normally grow as solid tumors in nude mice, do not produce detectable tumors when both VEGF alleles are knocked out. Taken together, these data indicate a role for VEGF in solid tumor growth. Inhibition of KDR and Flt-1 has been suggested in pathological angiogenesis, and it is known that tumor growth is dependent on angiogenesis, so these receptors implicate angiogenesis in the overall pathology. Useful in the treatment of certain diseases such as inflammation, diabetic retinal angiogenesis, and various forms of cancer (Weidner et al., N. Engl. J. Med., 324, pp. 1-8, 1991). .

Therefore, it is desirable to identify small compounds that specifically inhibit, regulate and / or modulate tyrosine kinase signaling, which is the object of the present invention.

DISCLOSURE OF THE INVENTION The present invention relates to compounds capable of inhibiting, modulating and / or modulating the signal transduction of both receptor and non-receptor tyrosine kinases. One embodiment of the invention is illustrated by the compounds of formula I below and pharmaceutically acceptable salts and stereoisomers of the compounds.

[0015]

[Chemical 4]

BEST MODE FOR CARRYING OUT THE INVENTION The compounds of the present invention are useful in the inhibition of kinases and are represented by the compounds of formula I below or a pharmaceutically acceptable salt or stereoisomer of the compound. .

[0017]

[Chemical 5] Wherein Q is S, O or -E = D-;

[0018]

[Chemical 6] Is

[0019]

[Chemical 7]   Selected from;   a is 0 or 1;   b is 0 or 1;   s is 1 or 2;   m is 0, 1 or 2;   E = D is C = N, N = C or C = C;   R¹, R^1a, R^FourAnd R⁵Independently,   1) H,   2) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC₁~ C₁₀Alkyl,   3) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bAryl,   4) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC_Two~ C₁₀Alkenyl,   5) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC_Two~ C₁₀Alkynyl,   6) R⁶SO optionally substituted with 1 to 3 substituents selected from_mC₁ ~ C₁₀Alkyl,   7) R⁶SO optionally substituted with 1 to 3 substituents selected from_mAnts
The   8) CO_TwoH,   9) halogen,   10) CN,   11) OH,   12) O_bC₁~ C₆Perfluoroalkyl and   13) (C = O)_aNR⁷R⁸   Selected from;   R^TwoAnd R^ThreeIndependently,   1) H,   2) (C = O) O_aC₁~ C₁₀Alkyl,   3) (C = O) O_aAryl,   4) C₁~ C₁₀Alkyl,   5) SO_mC₁~ C₁₀Alkyl,   6) SO_mAryl,   7) (C = O)_aO_bC_Two~ C₁₀Alkenyl,   8) (C = O)_aO_bC_Two~ C₁₀Alkynyl and   9) selected from the group consisting of aryl; the alkyl, aryl, alkenyl
And alkynyl is R⁶Even if substituted with 1 to 3 substituents selected from
well;   R^4aIs   1) (C = O) O_aC₁~ C₁₀Alkyl,   2) (C = O) O_aAryl,   3) C₁~ C₁₀Alkyl,   4) SO_mC₁~ C₁₀Alkyl,   5) SO_mAryl,   6) (C = O)_aO_bC_Two~ C₁₀Alkenyl,   7) (C = O)_aO_bC_Two~ C₁₀Alkynyl and   8) selected from the group consisting of aryl; the alkyl, aryl, alkenyl
And alkynyl is R⁶Even if substituted with 1 to 3 substituents selected from
well;   R⁶Is   1) H,   2) (C = O)_aO_bC₁~ C₆Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
)_aO_bAryl,   4) C_Two~ C₁₀Alkenyl,   5) C_Two~ C₁₀Alkynyl,   6) R^6aA heterocycle optionally substituted with 1 to 3 substituents selected from   7) CO_TwoH,   8) halogen,   9) CN,   10) OH,   11) Oxo,   12) O_bC₁~ C₆Perfluoroalkyl or   13) NR⁷R⁸And   R^6aIs   1) H,   2) SO_mAryl,   3) SO_mC₁~ C₆Alkyl,   4) (C = O)_aO_bC₁~ C₆Alkyl,   5) (C = O)_aO_bAryl,   6) C_Two~ C₁₀Alkenyl,   7) C_Two~ C₁₀Alkynyl,   8) heterocycles,   9) CO_TwoH,   10) halogen,   11) CN,   12) OH,   13) Oxo,   14) O_bC₁~ C₆Perfluoroalkyl or   15) N (C₁~ C₆Alkyl)_TwoAnd   R⁷And R⁸Independently,   1) H,   2) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bC₁~ C₁₀Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bAryl,   4) R^6aC optionally substituted with 1 to 3 substituents selected from₁~ C ₁₀ Alkyl,   5) R^6aAryl optionally substituted with 1 to 3 substituents selected from
,   6) R^6aC optionally substituted with 1 to 3 substituents selected from_Two~ C ₁₀ Alkenyl,   7) R^6aC optionally substituted with 1 to 3 substituents selected from_Two~ C ₁₀ Alkynyl and   8) Heterocycle   Selected from; or   R⁷And R⁸But, together with the nitrogen to which they are bound, besides that nitrogen,
5 having one or two additional heteroatoms selected from N, O and S
Forming a 7-membered heterocycle; the heterocycle is R^6a1-3 selected from
It may be substituted with a substituent.

A second embodiment is represented by compounds of formula I above wherein Q is E = D.
In the third embodiment, E = D is further defined as C = C.

[0021]   A fourth embodiment of the invention is that Q is E = D: E = D is C = C;   R¹, R^1a, R^FourAnd R⁵Independently,   1) H,   2) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC₁~ C₆Alkyl,   3) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bAryl,   4) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC_Two~ C₆Alkenyl,   5) CO_TwoH,   6) halogen,   7) CN,   8) OH,   9) O_bC₁~ C_ThreePerfluoroalkyl and   10) (C = O)_aNR⁷R⁸   Selected from;   R^TwoAnd R^ThreeIndependently,   1) H,   2) (C = O) O_aC₁~ C₆Alkyl and   3) C₁~ C₆Selected from the group consisting of alkyl;   R^4aBut (C = O) O_aC₁~ C₆Alkyl or C₁~ C₆In alkyl
R;   R⁶But,   1) H,   2) (C = O)_aO_bC₁~ C₆Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
)_aO_bAryl,   4) C_Two~ C₆Alkenyl,   5) R^6aA heterocycle optionally substituted with 1 to 3 substituents selected from   6) CO_TwoH,   7) halogen,   8) CN,   9) OH,   10) Oxo   11) O_bC₁~ C_ThreePerfluoroalkyl or   12) NR⁷R⁸And   R^6aBut,   1) H,   2) SO_mAryl,   3) SO_mC₁~ C₆Alkyl,   4) (C = O)_aO_bC₁~ C₆Alkyl,   5) (C = O)_aO_bAryl,   6) C_Two~ C₆Alkenyl,   7) heterocycles,   8) CO_TwoH,   9) halogen,   10) CN,   11) OH,   12) Oxo,   13) O_bC₁~ C_ThreePerfluoroalkyl or   14) N (C₁~ C₆Alkyl)_TwoAnd   R⁷And R⁸Independently,   1) H,   2) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bC₁~ C₆Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bAryl,   4) R^6aC optionally substituted with 1 to 3 substituents selected from₁~ C ₆ Alkyl,   5) R^6aAryl optionally substituted with 1 to 3 substituents selected from
,   6) R^6aC optionally substituted with 1 to 3 substituents selected from_Two~ C ₆ Alkenyl and   7) Heterocycle   Selected from; or   R⁷And R⁸But, together with the nitrogen to which they are bound, besides that nitrogen,
5 having one or two additional heteroatoms selected from N, O and S
Forming a 7-membered heterocycle; the heterocycle is R^6a1-3 selected from
Compounds of formula I above, optionally substituted with substituents.

[0022]   In a fifth embodiment of the invention, the compound of formula I is   Q is E = D: E = D is C = C;   a is 0 or 1;   b is 0 or 1;   s is 1;   R¹And R^FourIndependently,   1) H,   2) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC₁~ C₆Alkyl,   3) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bAryl,   4) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC_Two~ C₆Alkenyl,   5) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC_Two~ C₆Alkynyl,   6) CO_TwoH,   7) halogen,   8) CN,   9) OH,   10) O_bC₁~ C_ThreePerfluoroalkyl and   11) (C = O)_aNR⁷R⁸   Selected from;   R^TwoAnd R^ThreeAre independently selected from H and methyl;   R^4aIs methyl;   R⁵And R^1aIs H;   R⁶But,   1) H,   2) (C = O)_aO_bC₁~ C₆Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
)_aO_bAryl,   4) C_Two~ C₁₀Alkenyl,   5) C_Two~ C₁₀Alkynyl,   6) R^6aA heterocycle optionally substituted with 1 to 3 substituents selected from   7) CO_TwoH,   8) halogen,   9) CN,   10) OH,   11) Oxo   12) O_bC₁~ C_ThreePerfluoroalkyl or   13) NR⁷R⁸And   R^6aBut,   1) H,   2) SO_mAryl,   3) SO_mC₁~ C₆Alkyl,   4) (C = O)_aO_bC₁~ C₆Alkyl,   5) (C = O)_aO_bAryl,   6) C_Two~ C₁₀Alkenyl,   7) C_Two~ C₁₀Alkynyl,   8) heterocycles,   9) CO_TwoH,   10) halogen,   11) CN,   12) OH,   13) Oxo,   14) O_bC₁~ C_ThreePerfluoroalkyl or   15) N (C₁~ C₆Alkyl)_TwoAnd   R⁷And R⁸Independently,   1) H,   2) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bC₁~ C₆Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bAryl,   4) R^6aC optionally substituted with 1 to 3 substituents selected from₁~ C ₁₀ Alkyl,   5) R^6aAryl optionally substituted with 1 to 3 substituents selected from
,   6) R^6aC optionally substituted with 1 to 3 substituents selected from_Two~ C ₆ Alkenyl,   7) R^6aC optionally substituted with 1 to 3 substituents selected from_Two~ C ₆ Alkynyl and   8) Heterocycle   Selected from; or   R⁷And R⁸But together with the nitrogen to which they are bound, R^6aSelected from
A piperidinyl group which may be substituted with one or two substituents
It is determined so that a dinyl group, a morpholinyl group or a pyrrolidinyl group may be formed.
Is meant

Yet another embodiment of the present invention is 3- (4-methyl-5-oxo-4,5-dihydro-1H-pyrrolo [3,2-b] pyridin-2-yl) -1H-quinoline. −
It is a compound which is 2-one or a pharmaceutically acceptable salt or stereoisomer of the compound.

Also included within the scope of the invention is a pharmaceutical composition comprising a compound of formula I as described above and a pharmaceutically acceptable carrier. The present invention also includes a method of treating or preventing cancer in a mammal in need thereof, the method comprising administering to said mammal a therapeutically effective amount of a compound of formula I. Preferred cancers for treatment are selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lungs. Another group of preferred forms of cancer are histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, glioblastoma.
lastomas) and breast cancer.

Further, a method of treating or preventing a disease in which angiogenesis is suggested, comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I. Methods are also included. Such diseases in which angiogenesis is suggested are ocular diseases such as retinal angiogenesis, diabetic retinopathy, age-related macular degeneration.

Within the scope of the present invention is a method of treating or preventing an inflammatory disease comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I. Methods are also included. Examples of such inflammatory diseases include rheumatoid arthritis,
These include psoriasis, contact dermatitis, and delayed hypersensitivity reaction.

A method of treating or preventing a tyrosine kinase dependent disease or condition in a mammal, wherein a therapeutically effective amount of a compound of formula I is administered to a mammalian patient in need of such treatment. Also included are methods that have steps. The therapeutic dose will vary with the particular disease and will be apparent to those of skill in the art without undue experimentation.

A method of treating or preventing retinal angiogenesis, which method comprises administering to a mammal in need of such treatment a compound of formula I in a therapeutically effective amount. included. Methods of treating or preventing eye diseases such as diabetic retinopathy and age-related macular degeneration are also part of this invention. Within the scope of the present invention is the treatment or prevention of inflammatory diseases such as rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reaction,
And methods of treating or preventing bone-related illnesses selected from osteosarcoma, osteoarthritis and rickets.

The present invention further includes 1) an estrogen receptor modulator; 2) an androgen receptor modulator; 3) a retinoid receptor modulator; 4) a cytotoxic agent; 5) an antiproliferative agent; 6) a prenyl protein transferase inhibitor. 7) HMG-CoA reductase inhibitor; 8) HIV protease inhibitor; 9) reverse transcriptase inhibitor; and 10) another angiogenesis inhibitor in combination with a second compound It is also envisaged to use the compounds claimed in the description. Preferred angiogenesis inhibitors are tyrosine kinase inhibitors, epidermal-derived growth factor inhibitors, fibroblast-derived growth factor inhibitors, platelet-derived growth factor inhibitors, MMP (substrate metalloprotease) inhibitors, integrin blockers, interferon- α, interleukin-12, pentosan polysulfate,
From the group consisting of antibodies against cyclooxygenase inhibitors, carboxamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetylcarbonyl) -fumagillol, thalidomide, angiostatin, troponin-1 and VEGF. To be selected. Preferred estrogen receptor modulators are tamoxifen and raloxifene.
).

Claims include a method of treating cancer, which is combined with radiation therapy and / or 1) an estrogen receptor modulator; 2) an androgen receptor modulator; 3) a retinoid receptor modulator; 4) Cytotoxic agent; 5) Anti-proliferative agent; 6) Prenyl protein transferase inhibitor; 7) HMG-CoA reductase inhibitor; 8) HIV protease inhibitor; 9) Reverse transcriptase inhibitor; and 10) Another blood vessel. Also included is a method which comprises the step of administering a therapeutically effective amount of a compound of formula I in combination with a compound selected from an anti-neoplastic agent.

Another embodiment of the present invention is a method of treating cancer comprising administering a therapeutically effective amount of a compound of formula I in combination with paclitaxel or trastuzumab.

Within the scope of the present invention is a method of reducing or preventing tissue damage following a cerebral ischemic event, the method comprising administering a therapeutically effective amount of a compound of formula I.

Another embodiment of the invention is a therapeutically effective amount of Formula I in combination with a COX-2 inhibitor.
A method for treating or preventing cancer, which comprises the step of administering the compound.

[0034]   The above and other aspects of the invention will be apparent from the description provided herein.

“Tyrosine kinase-dependent disease or condition” refers to a pathological condition that depends on the activity of one or more tyrosine kinases. Tyrosine kinases are directly or indirectly involved in signal transduction pathways of various cellular activities such as proliferation, adhesion and migration and differentiation. Diseases associated with tyrosine kinase activity include tumor cell proliferation, pathological neovascularization that supports solid tumor growth, ocular neovascularization (such as diabetic retinopathy, age-related macular degeneration) and inflammation (psoriasis, Such as rheumatoid arthritis).

The compounds of the present invention may have asymmetric centers, chiral axes and planes (
EL Eliel and SH Wilen, Stereochemistry of Carbon Compounds, John W
iley & Sons, New York, 1994, pp. 1119-1190), racemates, racemic mixtures and individual diastereomers, all possible isomers and mixtures of which are included in the present invention. Be done. Further compounds disclosed herein are
It may exist as a tautomer, and both tautomers are included in the scope of the present invention even when only one tautomeric structure is drawn. For example, the following claims to compound A are understood to include tautomeric structure B and vice versa, and also include mixtures thereof.

[0037]

[Chemical 8]

When any variable (eg, aryl, heterocycle, R ¹ , R ^2, etc.) occurs more than ^once in any constituent, its definition in each case is as in any other case. Is also independent of. Furthermore, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn from substituents into the ring system (eg, from R ¹ , R ² , R ³ , R ^4, etc.) indicate that the indicated bond can be attached to any ring carbon atom that is substitutable. Shows. If the ring system is polycyclic, the bond shall be attached to a suitable carbon atom of the proximal ring only.
For example, especially

[0039]

[Chemical 9] X and Z are C, Y is N, R ⁵ is CH ₃ , R ³ is H, and (R ⁴ ) _t is as defined in the claims, It can be one of the following:

[0040]

[Chemical 10]

Those skilled in the art can select substituents and substitution patterns of the compounds of the present invention and can be easily synthesized from chemically stable and readily available raw materials by methods known in the art and the methods described below. It will be clear that a compound can be provided which is

The term “alkyl” as used herein is intended to include branched, straight chain and cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example _{C 1-10,} such as in _{"C 1 -10} alkyl" includes straight-chain, 6, 7, 8, 9 or 10 carbons in branched or cyclic arrangement Is defined to include groups having For example, “C _1-10 alkyl” specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, as well as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthalene, methylene. There are cycloalkyls such as cyclohexyl. "Alkoxy" represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge.

[0043]   If no number of carbon atoms is specified, the term "alkenyl" refers to 2 to 1 carbon atoms.
A straight-chain, branched or cyclic non-cyclic group having 0 and at least a carbon-carbon double bond.
Refers to an aromatic hydrocarbon group. Preferably one carbon-carbon double bond is present and four
The following non-aromatic carbon-carbon double bonds may be present. So "C_Two~ C ₆ "Alkenyl" means an alkenyl group having 2 to 6 carbon atoms. Al
Kenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
is there. A straight chain, branched or cyclic alkenyl group as described above for alkyl.
The moiety can have a double bond, and when a substituted alkenyl group is specified
It may be replaced.

The term “alkynyl” has 2 to 10 carbon atoms and contains at least carbon-
It refers to a linear, branched or cyclic hydrocarbon group having a carbon triple bond. There may be 3 or less carbon-carbon triple bonds. Thus, _"C 2 -C ₆ alkynyl" means an alkynyl group having 2 to 6 carbon atoms. Alkynyl groups include ethynyl, propynyl and butynyl. As mentioned above for alkyl, the straight, branched or cyclic portion of the alkynyl group may have triple bonds and may be substituted if a substituted alkynyl group is specified.

As used herein, the term “aryl” means a stable monocyclic or bicyclic carbocyclic ring having 7 or fewer members in each ring, wherein one or more rings are aromatic rings. To do.
Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. When the aryl substituent is bicyclic and one ring is non-aromatic, the bond is understood to be through the aromatic ring.

The term heteroaryl, as used herein, refers to a 7-membered member in which at least one ring is an aromatic ring and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. The following stable monocyclic or bicyclic rings are represented. Heteroaryl groups included within the scope of this definition include acridinyl, carbazoyl, cinolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, Pyrazinyl, pyridazinyl, pyridinyl,
Examples include, but are not limited to, pyrimidinyl, pyrrolyl, tetrahydroquinoline and the like. If the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, then the respective bonds are either via an aromatic ring or via a heteroatom-containing ring. Understood to exist.

As will be appreciated by those in the art, “halo” or “halogen” as used herein is meant to include chlorine, fluorine, bromine and iodine. The term “heterocycle” as used herein refers to a 5-10 membered aromatic or non-aromatic heterocycle having 1 to 4 heteroatoms selected from the group consisting of O, N and S. It is meant to include a bicyclic group. Thus, "heterocycle" is meant to include the above heteroaryls and their dihydro and tetrahydro analogs. Further examples of “heterocycle” include benzimidazolyl, benzofuranyl, benzoflazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carborinyl, cinolinyl, furanyl, imidazolyl, indolinyl, indolyl, indorazinyl. , Indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthopyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrimidyl, pyrimidyl, pyrimidyl, pyrimidyl, pyrimidyl, pyrimidyl , Quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopi Dil, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzooxa. Zolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl , Dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, di Dorotoriazoriru, dihydro azetidinyloxyimino, methylenedioxy benzoyl, there are tetrahydrofuranyl and tetrahydrothienyl and their N- oxides, but is not limited thereto.

Pharmaceutically acceptable salts of the compounds of this invention include, for example, conventional non-toxic salts of the compounds of this invention formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; as well as acetic acid, propionic acid, succinic acid, glycolic acid, Stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid,
Benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, salts produced from organic acids such as oxalic acid, isethionic acid, trifluoroacetic acid, etc. is there.

In one example, R ⁷ and R ⁸ are taken together with the nitrogen to which they are attached, in addition to the nitrogen, one or two other heteroatoms selected from N, O and S. Is defined as being optionally substituted with 1 to 3 substituents selected from R ^6a . Examples of 5- to 7-membered ring systems that may be formed in this way include, but are not limited to:

[0050]

[Chemical 11]

[0051]   Preferably Q is E = D and E = D is C = C.

Preferably R ¹ is H, C ₁ -C ₆ alkyl or aryl. Most preferably R ¹ is H or C ₁ -C ₆ alkyl.

A preferred definition of R ^1a is H.

Preferably R ² and R ³ are independently H, C ₁ -C ₆ alkyl or (C═O
) Is a _C 1 -C ₆ alkyl. Most preferably R ² and R ³ are independently H or C ₁ -C ₆ alkyl.

Preferably R ⁴ is OH, OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl.

Preferably R ^4a is C ₁ -C ₆ alkyl.

Preferably R ⁵ is H or C ₁ -C ₆ alkyl. Most preferably R ⁵ is H.

The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which possess a basic or acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography, or in a suitable solvent or solvent of various combinations, in stoichiometric or excess amounts with the inorganic or organic acid and the free base to form the desired salt. It is manufactured by reacting. Similarly,
Salts of acidic compounds are formed by reaction with the appropriate inorganic or organic base.

The compounds of the present invention can be prepared by using the reactions shown in the schemes below, in addition to other standard procedures known in the literature or illustrated in the experimental procedures.
Therefore, these schemes are not limited to the compounds listed and the particular substituents used for purposes of illustration. The numbering of substituents shown in the schemes is not necessarily related to those used in the claims.

[0060]   Schematic description   As shown in Scheme 1, quinoline reagent 1-2 was reported by Marcice et al.
s, F; Godard, A.; Queguiner, G. J. Heterocyclic Chem. 1989, 26, 1589-1
594). Derivative with altered substitution
Modify its procedure and use standard synthetic protocols known in the art.
Can be manufactured in. Next, the intermediate 1-2 was converted into a suitable N-protected pyrrolo compound (
Coupling with structure 1-4) produces a chlorinated intermediate of structure 1-5. R ^Four At least one of the substituents is OH or OR on the carbon adjacent to the ring nitrogen.
it is conceivable that. By heating 1-5 in an acetic acid aqueous solution, the desired dechlorinated product 1
We get -6. Scheme 2 uses this route to finally produce [3,2] -pyridino-py
An example of obtaining the roll 2-3 is shown.

As shown in Scheme 3, α-alkyloxypyridino-pyrrole 3-1 is replaced with H
It can be converted to the corresponding pyrimidinone analog 3-2 by heating with the Br aqueous solution. Alternatively, as shown in Scheme 4, the pyrimidinone analog can be synthesized via the N-oxide intermediate 4-2. Scheme 5 shows a procedure for N-alkylation of pyrimidinone-pyrrole 3-2 to give compounds of formula I. As will be apparent to those skilled in the art, other electrophiles can be used to alkylate or acylate the nitrogen.

[0062]

[Chemical 12]

[0063]

[Chemical 13]

[0064]

[Chemical 14]

[0065]

[Chemical 15]

[0066]

[Chemical 16]

[0067]   Use   The present invention is directed to the treatment of tyrosine kinase dependent diseases in mammals, especially humans.
It is useful as a medicine. Such diseases include tumor cell proliferation, solid tumor growth.
Pathological neovascularization (or angiogenesis) that supports length, ocular neovascularization (diabetic reticulum)
Membranosis, age-related macular degeneration, etc.) and inflammation (psoriasis, rheumatoid arthritis, etc.)
is there.

The compounds of the present invention can be administered to patients for the treatment of cancer. The compounds of the present invention influence tumor growth by inhibiting tumor angiogenesis (J.
Rak et al., Cancer Research, 55: 4575-4580, 1995). The anti-angiogenic properties of the compounds of this invention are also useful in the treatment of certain forms of blindness associated with retinal angiogenesis.

The disclosed compounds are also useful in the treatment of certain bone-related conditions such as osteosarcoma, osteoarthritis and rickets also referred to as tumorigenic osteomalacia (Hasegawa et al.,
Skeletal Radiol., 28, pp. 41-45, 1999; Gerber et al., Nature Medicine,
Vol.5, No.6, pp. 623-628, June 1999). Furthermore, VEGF promotes osteoclastic bone resorption by KDR / Flk-1 expressed in mature osteoclasts (FE
BS Let. 473: 161-164 (2000); Endocrinology, 141: 1667 (2000)), the compounds of the present invention are also useful in the treatment and prevention of conditions associated with bone resorption such as osteoporosis and Paget's disease. .

The claimed compounds may also be used to reduce or prevent tissue damage following a cerebral ischemic event such as stroke by reducing post-ischemic cerebral edema, tissue damage and reperfusion damage ( Drug News Perspect 11: 265-270 (1998); J. Clin. Inve
st. 104: 1613-1620 (1999)).

The compounds of the invention may be administered to mammals, preferably humans, according to standard pharmaceutical practice, either alone or preferably in combination with a pharmaceutically acceptable carrier or diluent, optionally such as alum. Known adjuvants can be added and administered in a pharmaceutical composition. The compounds can be administered orally or parenterally, such as intravenously, intramuscularly, intraperitoneally, subcutaneously, rectally and topically.

For oral use of the chemotherapeutic compounds according to the invention, the selected compounds may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and a lubricant such as magnesium stearate is generally added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents can be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, it is usual to prepare sterile solutions of the active ingredient,
H must be adjusted and buffered appropriately. For intravenous administration, the total solute concentration should be controlled to render the formulation isotonic.

The compounds of this invention may also be co-administered with other known therapeutic agents that are selected for their particular utility for the condition being treated. For example, in the case of bone-related disorders,
Combinations that are considered useful are alendronate and risedronate (rise
anti-resorptive bisphosphonates such as dronate; integrin blockers such as α _v β ₃ antagonists (defined below); PREMPRO®, PREMAR
Conjugated estrogens used in hormone replacement therapy such as IN (R) and ENDOMETRION (R); raloxifene, droloxifene, CP-336156 (Pfizer) and lasofoxifene (l).
Asofoxifene) and other selective estrogen receptor modulators (SERMs); cathepsin K inhibitors; combined use with ATP proton pump inhibitors.

The compounds of the present invention are also useful in combination with known anti-cancer agents. Such known anticancer agents include estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV proteases. These include inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors. The compounds of the invention are particularly useful in combination with radiation therapy. The synergistic effect of VEGF inhibition in combination with radiation therapy has been reported in the art (see WO 00/61186).

“Estrogen receptor modulators” refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include tamoxifen, raloxifene, and idoxifene (
idoxifene), LY353381, LY117081, toremifene (toremifen)
e), fulvestrant, 4- [7- (2,2-dimethyl-1-
Oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] -phenyl-2,2-dimethylpropanoic acid, 4,4 '. -Dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, etc., but are not limited thereto.

“Androgen receptor modulators” refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide (
nilutamide), flutamide (flutamide), bicalutamide (bicalutamide), lyazolol (liarozole) and abiraterone acetate (abiraterone).

“Retinoid receptor modulators” refers to compounds that interfere with or inhibit the binding of retinoids to their receptors, regardless of mechanism. Examples of retinoid receptor modulators include bexaritene, tretinoin, 13-cis-retinoic acid,
9-cis-retinoic acid, α-difluoromethylornithine, ILX23-75
53, trans-N- (4'-hydroxyphenyl) retinamide, N-4-carboxyphenylretinamide and the like.

“Cytotoxic agent” refers to a compound that causes cell death primarily by directly interfering with the function of cells or by inhibiting or interfering with meiosis of cells, including alkylating agents, tumor necrosis factors, Examples include intercalating agents, microtubulin inhibitors and topoisomerase inhibitors.

Examples of cytotoxic agents are tirapazimine, sertenef
, Cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimastine, dibromodulcitol, ranimustine, fotemustin (fotemusti)
ne), nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide,
Nimustine, dibrospidium chloride, pumitepa (pu
mitepa), lobaplatin, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven
), Dexifosfamide, cis-aminedichloro (2-methylpyridine) platinum, benzylguanine, glufosfamide
, GPX100, (trans, trans, trans) -bis-μ- (hexane-
1,6-diamine) -μ- [diamine-platinum (II)] bis [diamine (chloro) platinum (II)] tetrachloride, diaridinyl spermine, arsenic trioxide, 1
-(11-dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisanthrene, mitoxantrone, pirarubicin, pinafide (p).
inafide), valrubicin, amrubicin, antineoplastic drug 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin, galarubicin
, Elinafide, MEN10755 and 4-demethoxy-3-.
Examples include, but are not limited to, deamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO00 / 50032).

Examples of the microtubulin inhibitor include paclitaxel, vindesine sulfate, 3 ′, 4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol. , Rhizoxin, dolastatin, mibobulin isethionate
, Auristatin, cemadotin, RPR1098
81, BMS184476, vinflunine, cryptophycin (
cryptophycin), 2,3,4,5,6-pentafluoro-N- (3-fluoro-
4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine,
N, N-Dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258 and BMS1887.
There are 97 etc.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitec.
an), 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4,5-kl] acridine -2- (6H) propanamine, 1
-Amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4
-Methyl-1H, 12H-benzo [de] pyrano [3 ', 4': b, 7] indolizino [1,2b] quinoline-10,13 (9H, 15H) dione, lurtotecan, 7- [2 -(N-isopropylamino) ethyl]-(20S
) Camptothecin, BNP1350, BNPI1100, BN80915, BN
80942, etoposide phosphate, teniposide, sobuzoxane, 2
′ -Dimethylamino-2′-deoxy-etoposide, GL331, N- [2- (
Dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl-6H-pyrido [4,3-b] carbazole-1-carboxamide, aslacrine
), (5a, 5aB, 8aa, 9b) -9- [2- [N- [2- (dimethylamino) ethyl] -N-methylamino] ethyl] -5- [4-hydroxy-3,5-.
Dimethoxyphenyl] -5,5a, 6,8,8a, 9-hexohydrofuro (3 '
, 4 ′: 6,7) naphtho (2,3-d) -1,3-dioxole-6-one, 2
, 3- (Methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c] -phenanthridinium, 6,9-bis [(2-aminoethyl) amino] benzo [g] isoginoline ( isoguinoline) -5,10-dione, 5- (3-
Aminopropylamino) -7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de] acridin-6-one, N- [1- [2 (diethylamino) Ethylamino] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6-[[2- (dimethylamino) Ethyl] amino] -3-hydroxy-7H-indeno [2,1-c]
There are quinolin-7-ones and dimesna.

“Antiproliferative agents” include G3139, ODN698, RVASKRAS, GEM2
31 and antisense RNA and DNA oligonucleotides such as INX3001 and enocitabine, carmofur, tegafur, pentostatin, doxyfluridine, trimetrexate, fludarabine, capecitabine, galacitabine, cytarabine ocphosfate ocfoate. , Fosteabine sodium hydrate, raltitrexed, paltitrexid, paltitrexid, emitefur, thiazofurin, decitabine, nolatrexed, nolatrexed, pemetrexed, nemetrexed, pemetrexed, pemetrexed
ine), 2'-deoxy-2'-methylidene cytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2,3-dihydro-benzofuryl) sulfonyl] -N '-(3. 4-dichlorophenyl) urea, N6- [4-deoxy-4- [N2- [2 (E), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero-BL-mano-heptopyranosyl] adenine , Aplidine (
aplidine), ecteinascidin (ecteinascidin), troxacitabine (troxaci
tabine), 4- [2-amino-4-oxo-4,6,7,8-tetrahydro-3
H-pyrimidino [5,4-b] [1,4] thiazin-6-yl- (S) -ethyl] -2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl -8- (carbamoyloxymethyl) -4
-Formyl-6-methoxy-14-oxa-1,11-diazatetracyclo (7
． 4.1.0.0) -tetradeca-2,4,6-trien-9-yl acetate, swainsonine, lometrexol, dexrazoxane (de
xrazoxane), methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-BD-arabinofuranosylcytosine and 3-
There are antimetabolites such as aminopyridine-2-carboxaldehyde and thiosemicarbazone. "Antiproliferative agents" include monoclonal antibodies against growth factors other than those listed under "Angiogenesis inhibitors," such as trastuzumab,
And tumor suppressor genes such as p53, which can be transmitted via recombinant virus-mediated gene transfer (see, eg, US Pat. No. 6,069,134).

“HMG-CoA reductase inhibitor” refers to an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase. A compound having an inhibitory activity against HMG-CoA reductase can be easily confirmed by using an assay known in the art. For example, US Pat. No. 4,231,938, column 6, and WO
See the assays described or cited on pages 30-33 of 84/02131. The terms "HMG-CoA reductase inhibitor" and "inhibitor of HMG-CoA reductase" have the same meaning as used herein.

Examples of HMG-CoA reductase inhibitors that can be used include lovastatin (
MEVACOR (registered trademark); US Pat. No. 4,231,938, 4294926,
4319039), simvastatin (simvastatin; ZOCOR (registered trademark); see U.S. Pat. Nos. 4,444,784, 4,820,850, and 4,916,239).
, Pravastatin (PRAVACHOL (R); U.S. Pat.
(Registered trademark); U.S. Pat. 5342952
No.) and cerivastatin (also referred to as rivastatin and BAYCHOL®; see US Pat. No. 5,177,080) and the like. The structural formulas of the above and other HMG-CoA reductase inhibitors that can be used in the method of the present invention are reported by Yarupani (M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Indust.
ry, pp.85-89 (February 5, 1996), page 87 and U.S. Pat. No. 478208.
4 and 4885314. As used herein, HMG-
The term CoA reductase inhibitor refers to all pharmaceutically acceptable lactone and ring-opened acid forms (ie, of the compounds having HMG-CoA reductase inhibitory activity).
The lactone ring has opened to form the free acid) and salts and ester forms thereof, and the use of such salts, esters, ring-opening acids and lactone forms is within the scope of this invention. Be done. A diagram of the lactone moiety and its corresponding ring-opened acid form is shown below as Structural Formulas I and II.

[0085]

[Chemical 17]

For HMG-CoA reductase inhibitors where a ring-opened acid form may exist, the salt and ester forms may preferably be formed from the ring-opened acid, all such forms being used herein. Included in the term "HMG-CoA reductase inhibitor". Preferably the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, most preferably simvastatin. As used herein, the term "pharmaceutically acceptable salt" with respect to HMG-CoA reductase inhibitors refers to compounds used in the present invention prepared by reacting a suitable organic or inorganic base with the free acid. Means non-toxic salts of, especially sodium, potassium, aluminum, calcium, lithium, magnesium,
Formed from cations such as zinc and tetramethylammonium, as well as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N -Benzylphenethylamine, 1
There are salts formed from amines such as -p-chlorobenzyl-2-pyrrolidin-1'-yl-methylbenzimidazole, diethylamine, piperazine and tris (hydroxymethyl) aminomethane. Further examples of HMG-CoA reductase inhibitors in salt form include acetates, benzenesulfonates, benzoates,
Bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate Salt, estrate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamin, hydrobromide, hydrochloride, hydroxynaphthoic acid Salt, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucus, napsylate, nitrate, olein Acid salt, oxalate, pamoate, palmitate, pantothenate, phosphate / diphosphate, polygalacturonic acid Salts, salicylates, stearates, basic acetates, succinates, tannates, tartrates, teoclates, tosylates, triethiodides and valerates, but not limited to It is not something that will be done.

The ester derivatives of the HMG-CoA reductase inhibitor compounds described above, when absorbed into the bloodstream of warm-blooded animals, release the drug form so that the drug may provide improved therapeutic efficacy. It may act as a prodrug that can be cleaved in various ways.

“Prenyl protein transferase inhibitor” means farnesyl protein transferase (FPTase), geranyl geranyl protein transferase type I (
GGPTase-I) and geranylgeranyl protein transferase type II (
GGPTase-II, also referred to as RabGGPTase) or any combination of prenyl protein transferase enzymes. Examples of the prenyl protein transferase inhibitory compound include (±) -6
-[Amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methyl-2 (1H) -quinolinone, (-)-6- [ Amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl) -1-methyl-2
(1H) -quinolinone, (+)-6- [amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl] -4- (3-chlorophenyl)
-1-Methyl-2 (1H) -quinolinone, 5 (S) -n-butyl-1- (2,3
-Dimethylphenyl) -4- [1- (4-cyanobenzyl) -5-imidazolylmethyl] -2-piperazinone, (S) -1- (3-chlorophenyl) -4- [1
-(4-Cyanobenzyl) -5-imidazolylmethyl] -5- [2- (ethanesulfonyl) methyl) -2-piperazinone, 5 (S) -n-butyl-1- (2-methylphenyl) -4- [1- (4-Cyanobenzyl) -5-imidazolylmethyl] -2-piperazinone, 1- (3-chlorophenyl) -4- [1- (4-cyanobenzyl) -2-methyl-5-imidazolylmethyl]- 2-piperazinone, 1-
(2,2-Diphenylethyl) -3- [N- (1- (4-cyanobenzyl) -1
H-imidazol-5-ylethyl) carbamoyl] piperidine, 4- {5- [
4-hydroxymethyl-4- (4-chloropyridin-2-ylmethyl) -piperidin-1-ylmethyl] -2-methylimidazol-1-ylmethyl} benzonitrile, 4- {5- [4-hydroxymethyl-4- (3-chlorobenzyl) -piperidin-1-ylmethyl] -2-methylimidazol-1-ylmethyl} benzonitrile, 4- {3- [4- (2-oxo-2H-pyridin-1-yl) benzyl]- 3H-imidazol-4-ylmethyl} benzonitrile, 4- {3- [
4- (5-chloro-2-oxo-2H- [1,2 '] bipyridin-5'-ylmethyl] -3H-imidazol-4-ylmethyl} benzonitrile, 4- {3- [
4- (2-oxo-2H- [1,2 '] bipyridin-5'-ylmethyl] -3H
-Imidazol-4-ylmethyl} benzonitrile, 4- [3- (2-oxo-
1-Phenyl-1,2-dihydropyridin-4-ylmethyl) -3H-imidazol-4-ylmethyl} benzonitrile, 18,19-dihydro-19-oxo-5H, 17H-6,10: 12,16-dimetheno- 1H-imidazo [4,3-
c] [1,11,4] dioxaazacyclo-nonadecine-9-carbonitrile,
(±) -19,20-Dihydro-19-oxo-5H-18,21-ethano-1
2,14-Etheno-6,10-metheno-22H-benzo [d] imidazo [4,3
-K] [1,6,9,12] oxatriaza-cyclooctadecine-9-carbonitrile, 19,20-dihydro-19-oxo-5H, 17H-18,21-.
Ethano-6,10: 12,16-dimetheno-22H-imidazo [3,4-h] [
1,8,11,14] oxatriazacycloeicosine-9-carbonitrile and (±) -19,20-dihydro-3-methyl-19-oxo-5H-18,
21-Ethano-12,14-etheno-6,10-metheno-22H-benzo [d]
Examples include imidazo [4,3-k] [1,6,9,12] oxa-triazacyclooctadecine-9-carbonitrile.

Other examples of prenyl protein transferase inhibitors are described in WO 96/30343,
WO97 / 18813, WO97 / 21701, WO97 / 23478, WO9
7/38665, WO98 / 28980, WO98 / 29119, WO95 / 3
2987, US Pat. No. 5,420,245, US Pat. No. 5,523,430, US Pat.
532359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S. Pat. No. 5,602,098, European Patent Publication 0618221, European Patent Publication 06751.
12, European Patent Publication 0604181, European Patent Publication 0696593, WO94 /
19357, WO95 / 08542, WO95 / 11917, WO95 / 126
12, WO95 / 12572, WO95 / 10514, US Pat.
No., WO95 / 10515, WO95 / 10516, WO95 / 24612, W
O95 / 34535, WO95 / 25086, WO96 / 05529, WO96
/ 06138, WO96 / 06193, WO96 / 16443, WO96 / 21
701, WO96 / 21456, WO96 / 22278, WO96 / 24611
, WO96 / 24612, WO96 / 05168, WO96 / 05169, WO
96/00736, US Pat. No. 5,571,792, WO96 / 17861, WO9
6/33159, WO96 / 34850, WO96 / 34851, WO96 / 3
0017, WO96 / 30018, WO96 / 30362, WO96 / 3036
3, WO96 / 31111, WO96 / 31477, WO96 / 31478, W
O96 / 31501, WO97 / 00252, WO97 / 03047, WO97
/ 03050, WO97 / 04785, WO97 / 02920, WO97 / 17
070, WO97 / 23478, WO97 / 26246, WO97 / 30053
, WO97 / 44350, WO98 / 02436 and US Pat. No. 5,532,359.
Publications and patents. There are also examples of prenyl protein transferase inhibitors for angiogenesis in the literature (European J. of Can
cer, Vol. 35, No. 9, pp. 1394-1401 (1999)).

Examples of HIV protease inhibitors include amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450.
, Indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, A
BT-378, AG1776 and BMS-232632. Examples of reverse transcriptase inhibitors are delaviridine and efavirens.
z), GS-840, HBY097, lamivudine, nevirapine (n
evirapine), AZT, 3TC, ddC and ddI.

“Angiogenesis inhibitors” refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include tyrosine kinase receptor Flt-
1 (VEGFR1) and Flk-1 / KDR (VEGFR20) inhibitors, tyrosine kinase inhibitors, epidermal-derived, fibroblast-derived or platelet-derived growth factor inhibitors, MMP (substrate metalloprotease) inhibitors, integrins Blockers, cyclooxygenase inhibitors such as interferon-alpha, interleukin-12, pentosan polysulfate, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, and selections such as celecoxib and rofecoxib. Cyclooxygenase-2 inhibitor (P
NAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Opthalm
ol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994); FEBS Let
ters, Vol. 372, p.83 (1995); Clin, Orthop. Vol. 313, p.76 (1995); J. Mol.
Endocrinol., Vol. 16, p. 1O7 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105
(1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998
); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p.
.9116 (1999)), carboxamidotriazole, combretastatin A-4,
Squalamine, 6-O-chloroacetyl-carbonyl) -fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonist (Fe
rnandez et al., J. Lab. Clin. Med. 105: 141-145 (1985)) and antibodies against VEGF, but are not limited thereto (Nature Biotechno).
logy, Vol. 17, pp.963-968 (October 1999); Kim et al., Nature, 362, 841-8.
44 (1993); WO00 / 44777 and WO00 / 61186).

As mentioned above, the combination with NSAIDs is a potent COX-2 inhibitor, NSA.
It concerns the use of IDs. NSAIDs for the purposes of this specification are potent if they have a COX-2 inhibitory IC ₅₀ of 1 μM or less, as measured by the cellular or microsomal assays disclosed herein.

The present invention further includes the combination with a selective COX-2 inhibitor, NSAID. For the purposes of this specification, NSAI, a selective inhibitor of COX-2
D A, discloses cellular assays or specificity of COX-2 inhibition over COX-1 inhibition as measured by the ratio of _{IC 50} for COX-2 relative to _{IC 50} for COX-1 evaluated by the microsomal assay below Is defined to be at least 100 times. Such compounds include U.S. Pat. No. 5,474,995 issued Dec. 12, 1995, U.S. Pat. No. 5,861,419 issued Jan. 19, 1999, U.S. Pat. No. 600184 issued Dec. 14, 1999.
3, US Pat. No. 6,020,343 issued February 1, 2000, US Pat. No. 5,409,944 issued April 25, 1995, US Pat. No. 5,436,265 issued July 25, 1995, July 16, 1996. US Pat. No. 5,536,752 issued
No. 5,550,142 issued Aug. 27, 1996, U.S. Pat. No. 5,604,260 issued Feb. 18, 1997, U.S. Pat. No. 5,698,584 issued Dec. 16, 1997, Jan. 20, 1998. Issued US Pat. No. 5,710,014
No. 0, WO94 / 15932 published on July 21, 1994, US Pat. No. 5,344,991 issued June 6, 1994, and US Patent No. 5 issued July 28, 1992.
134142, U.S. Pat. No. 5,380,738, issued Jan. 10, 1995, 1.
U.S. Pat. No. 5,393,790 issued Feb. 20, 996, Nov. 14, 1995.
U.S. Pat. No. 5,466,823, issued May 27, 1997, U.S. Pat. No. 5,633,272 and U.S. Pat. No. 5,932,598, Aug. 3, 1999, both of which are incorporated herein by reference. However, the present invention is not limited to these.

Examples of other specific COX-2 inhibitors include 3- (3-fluorophenyl) -4- (4- (methylsulfonyl) phenyl)
2- (5H) -furanone; 3- (3,4-difluorophenyl) -4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanone; 3- (3,4-dichlorophenyl)- 4- (4- (Methylsulfonyl) phenyl) -2- (5H) -furanone; 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2- (5H)-
Furanone; 5,5-dimethyl-3- (3-fluorophenyl) -4- (methylsulfonyl) phenyl) -2- (5H) -furanone; 3- (4-methylsulfonyl) phenyl-2-phenyl-5 Trifluoromethylpyridine; 2- (3-chlorophenyl) -3- (4-methylsulfonyl) phenyl-5-
Trifluoromethyl-pyridine; 2- (4-chlorophenyl) -3- (4-methylsulfonyl) phenyl-5
Trifluoromethyl-pyridine; 2- (4-Fluorophenyl) -3- (4-methylsulfonyl) phenyl-5
-Trifluoromethyl-pyridine; 3- (4-methylsulfonyl) phenyl-2- (3-pyridinyl) -5-trifluoromethylpyridine; 5-methyl-3- (4-methylsulfonyl) phenyl-2-phenylpyridine 2- (4-chlorophenyl) -5-methyl-3- (4-methylsulfonyl) phenylpyridine; 5-methyl-3- (4-methylsulfonyl) phenyl-2- (3-pyridinyl) pyridine; 5-chloro 2- (4-chlorophenyl) -3- (4-methylsulfonyl) phenylpyridine; 5-chloro-3- (4-methylsulfonyl) phenyl-2- (2-pyridinyl) pyridine; 5-chloro-3- ( 4-Methylsulfonyl) phenyl-2- (3-pyridinyl) pyridine; 5-chloro-3- (4-methylsulfonyl) phene Le-2- (4-pyridinyl) pyridine; 5-chloro-3- (4-methylsulfonyl) phenyl-2- (2-methyl-5
2- (4-chlorophenyl) -3- (4-methylsulfonyl) phenylpyridinyl-5-carboxylic acid methyl ester; 2- (4-chlorophenyl) -3- (4-methylsulfonyl) phenyl Pyridinyl-5-carboxylic acid; 5-cyano-2- (4-chlorophenyl) -3- (4-methylsulfonyl) phenylpyridine; 5-chloro-3- (4-methylsulfonyl) phenyl-2- (3 -Pyridyl)
Pyridinehydromethanesulfonate; 5-chloro-3- (4-methylsulfonyl) phenyl-2- (3-pyridyl)
Pyridine hydrochloride; 5-chloro-3- (4-methylsulfonyl) phenyl-2- (2-methyl-5)
-Pyridinyl) pyridine hydrochloride; 5-chloro-3- (4-methylsulfonyl) phenyl-2- (2-ethyl-5)
-Pyridinyl) pyridine; 5-chloro-3- (4-methylsulfonyl) phenyl-2- (2-ethyl-5)
-Pyridinyl) pyridinehydromethanesulfonate; 3- (3,4-difluorophenoxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- ( 3-Fluorophenoxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (3,5-difluorophenoxy) -5,5-dimethyl-4 -(Methylsulfonyl) phenyl) -5H-furan-2-one; 3-phenoxy-5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (2 , 4-Difluorophenoxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (4-chlorophenoxy) -5,5- Methyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (3,4-dichlorophenoxy) -5,5-dimethyl-4- (methylsulfonyl) phenyl) -5H- Furan-2-one; 3- (4-Fluorophenoxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (4-Fluorophenylthio) -5,5-Dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (3,5-difluorophenylthio) -5,5-dimethyl-4- (4- (
Methylsulfonyl) phenyl) -5H-furan-2-one; 3-phenylthio-5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (N-phenyl Amino) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (N-methyl-N-phenylamino) -5,5-dimethyl-4- (4- (
Methylsulfonyl) phenyl) -5H-furan-2-one; 3-Cyclohexyloxy-5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3-phenylthio-4 -(4- (Methylsulfonyl) phenyl) -5H-furan-2-one; 3-benzyl-5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3 -(3,4-Difluorophenylhydroxymethyl) -5,5-dimethyl-
4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (3,4-difluorobenzoyl) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H 3-furan-2-one; 3-benzoyl-5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 4- (4- (methylsulfonyl) phenyl) -3 -Phenoxy-1-oxaspiro [4,4] non-3-en-2-one; 4- (4- (methylsulfonyl) phenyl) -3-phenylthio-1-oxaspiro [4,4] non-3-ene -2-one; 4- (2-oxo-3-phenylthio-1-oxaspiro [4,4] non-3
-En-4-yl) benzenesulfonamide; 3- (4-fluorobenzyl) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (3 , 4-Difluorophenoxy) -5-methoxy-5-methyl-4- (
4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (5-chloro-2-pyridyloxy) -5,5-dimethyl-4- (4- (
Methylsulfonyl) phenyl) -5H-furan-2-one; 3- (2-Pyridyloxy) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl) -5H-furan-2-one; 3- (6-methyl-2-pyridyloxy) -5,5-dimethyl-4- (4- (
Methylsulfonyl) phenyl) -5H-furan-2-one; 3- (3-isoquinolinoxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (4- (Methylsulfonyl) phenyl) -2-phenoxycyclopent-
2-enone; 3- (4- (methylsulfonyl) phenyl) -2- (3,4-difluorophenoxy) cyclopent-2-enone; 5,5-dimethyl-4- (4-methylsulfonylphenyl) -3- (5-Bromopyridin-2-yloxy) -5H-furan-2-one; 5,5-Dimethyl-4- (4-methylsulfonylphenyl) -3- (2-propoxy) -5H-furan-2-one; 2- (3,4-Difluorophenoxy) -3- (4-methylsulfonylphenyl) -cyclopent-2-enone; 3- (5-benzothiophenyloxy) -5,5-dimethyl-4- (4-methyl Sulfonyl) phenyl) -5H-furan-2-one; 5,5-dimethyl-4- (4-methylsulfonyl-phenyl) -3- (pyridyl-4-oxy) -5H Furan-2-one; 5,5-dimethyl-4- (4-methylsulfonyl-phenyl) -3- (pyridyl-3-oxy) -5H-furan-2-one; 3- (2-methyl-5- Pyridyloxy) -5,5-dimethyl-4- (4- (
Methylsulfonyl) phenyl) -5H-furan-2-one; 3- (2-Fluoro-4-trifluoromethyl) phenoxy-4- (4-methylsulfonyl) phenyl) -5,5-dimethyl-5H-furan- 2-one; 3- (5-chloro-2-pyridylthio) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 2- (3,5-difluorophenoxy) -3- (4-Methylsulfonylphenyl) -cyclopent-2-enone; 3- (2-pyrimidineoxy) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 3- (3-Methyl-2-pyridyloxy) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 3- (3-chloro- - pyridyloxy) -5,5-dimethyl-4- (4- (
Methylsulfonyl) phenyl) -5H-furan-2-one; 3- (3- (1,2,5-thiadiazolyl) oxy) -4- (4- (methylsulfonyl) phenyl) -5,5-dimethyl-5H. -Furan-2-one; 3- (5-isoquinolinoxy) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 3- (6-amino-2-pyridyloxy ) -5,5-Dimethyl-4- (4- (
Methylsulfonyl) phenyl) -5H-furan-2-one; 3- (3-chloro-4-fluoro) phenoxy-4- (methylsulfonyl) phenyl) -5,5-dimethyl-5H-furan-2-one; 3- (6-quinolinoxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (5-nitro-2-pyridyloxy) -5,5 -Dimethyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 3- (2-thiazolylthio) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan. -2-one; 3- (3-chloro-5-pyridyloxy) -5,5-dimethyl-4- (4- (
Methylsulfonyl) phenyl) -5H-furan-2-one; 5,5-Dimethyl-4- (4-methylsulfonylphenyl) -3- (2-propoxy) -5H-furan-2-one; 3- (3 -Trifluoromethyl) phenoxy-4- (4-methylsulfonyl)
Phenyl) -5,5-dimethyl-5H-furan-2-one; 5,5-dimethyl- (4- (4-methylsulfonyl) phenyl) -3- (piperidine-1-carbonyl) -5H-furan-2 5,5-dimethyl-3- (2-butoxy) -4- (4-methylsulfonylphenyl) -5H-furan-2-one; 5,5-dimethyl-4- (4-methylsulfonylphenyl) -3- (3-Pentoxy) -5H-furan-2-one; 2- (5-chloro-2-pyridyloxy) -3- (4-methylsulfonyl) phenylcyclopent-2-enone; 3- (4 -Methyl-2-pyridyloxy) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (3,4-difluorophenoxy) -5- ethyl 5-methyl-4- (4-methylsulfonyl) phenyl -5H- furan-2-one; (5R)-3-(4-chlorophenoxy) -5-ethyl-5-methyl-4- (
4-Methylsulfonyl) phenyl-5H-furan-2-one; 3- (2-methyl-3-pyridyloxy) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one 3- (4-methyl-5-nitro-2-pyridyloxy) -5,5-dimethyl-
4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 3- (5-chloro-4-methyl-2-pyridyloxy) -5,5-dimethyl-
4- (4-Methylsulfonyl) phenyl-5H-furan-2-one; 3- (5-Fluoro-4-methyl-2-pyridyloxy) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl -5H-furan-2-one; 3- (3-chloro-2-pyridyloxy) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 3- (4 -Fluorophenoxy) -5-methyl-4- (4-methylsulfonyl) phenyl-5-propyl-5H-furan-2-one; 3- (N, N-diethylamino) -5,5-dimethyl-4- ( 4- (Methylsulfonyl) phenyl) -5H-furan-2-one; 5,5-dimethyl-4- (4-methylsulfonyl-phenyl) -3- (3,5
-Dichloro-2-pyridyloxy) -5H-furan-2-one; (5R) -3- (4-bromophenoxy) -5-ethyl-5-methyl-4- (
4-Methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (4-methoxyphenoxy) -5-ethyl-5-methyl-4-
(4-Methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (5-chloro-2-pyridyloxy) -5-methyl-4- (4
-Methylsulfonyl) phenyl-5- (2,2,2-trifluoroethyl) -5
H-furan-2-one; 3- (5-chloro-2-pyridyloxy) -5-methyl-4- (4-methylsulfonyl) phenyl-5-propyl-5H-furan-2-one; 3- ( 1-Cyclopropyl-ethoxy) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl) -5H-furan-2-one; 5-methyl-4- (4- (methylsulfonyl) phenyl) -3 -(2- (propoxy) -5- (2-trifluoroethyl) -5H-furan-2-one; 5 (R) -5-ethyl-5-methyl-4- (4- (methylsulfonyl) phenyl) -3- (2-propoxy) -5H-furan-2-one; 5,5-dimethyl-3- (2,2-dimethylpropyloxy) -4 (4- (methylsulfonyl) phenyl) -5H-furan- 2-on; 5 (R)- -(1-Cyclopropyl-ethoxy) -5-ethyl-5-methyl-4- (4- (methylsulfonyl) phenyl-5H-furan-2-one; 5 (S) -5-ethyl-5-methyl- 4- (4- (methylsulfonyl) phenyl-3- (2-propoxy) -5H-furan-2-one; 3- (1-cyclopropylethoxy) -5,5-dimethyl-4- (4- (methyl Sulfonyl) phenyl) -5H-furan-2-one; 3- (1-Cyclopropylethoxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 5 , 5-Dimethyl-3- (isobutoxy) -4- (4- (methylsulfonyl)
Phenyl) -5H-furan-2-one; 3- (4-Bromophenoxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (2 -Quinolinoxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (2-chloro-5-pyridyloxy) -5,5-dimethyl-4 -(4- (
Methylsulfonyl) phenyl) -5H-furan-2-one; 3- (6-benzothiazolyloxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2- ON; 3- (6-chloro-2-pyridyloxy) -5,5-dimethyl-4- (4- (
(5R-methylsulfonyl) phenyl) -5H-furan-2-one; 3- (4-quinazolyloxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; ) -3- (5-Fluoro-2-pyridyloxy) -5-ethyl-5-methyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (4- Fluorophenoxy) -5-ethyl-5-methyl-4-
(4-Methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (5-fluoro-2-pyridyloxy) -5-methyl-4- (
4-Methylsulfonyl) phenyl-5- (2,2,2-trifluoroethyl)-
5H-furan-2-one; 3- (1-isoquinolinyloxy) -5,5-dimethyl-4- (methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (4 -Fluorophenoxy) -5-methyl-4- (4-methylsulfonyl) phenyl-5- (2,2,2-trifluoroethyl) -5H-furan-2-one; 3- (3-fluoro-2- Pyridyloxy) -5,5-dimethyl-4- (4-
(Methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (3,4-difluorophenoxy) -5-methyl-4- (4-
Methylsulfonyl) phenyl-5- (2,2,2-trifluoroethyl) -5H
-Furan-2-one; (5R) -3- (5-chloro-2-pyridyloxy) -5-ethyl-5-methyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 3- (3,4-Difluorophenoxy) -5-methyl-5-trifluoromethyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 3- (3,4-difluorophenoxy)- 5-Methyl-4- (4- (methylsulfonyl) phenyl) -5-propyl-5H-furan-2-one; 3-Cyclobutyloxy-5,5-dimethyl-4- (4-methylsulfonylphenyl-5H 3-furan-2-one; 3- (1-indanyloxy) -5,5-dimethyl-4- (4- (methylsulfonyl) phenyl) -5H-furan-2-one; 3- (2-indanyloxy) ) -5,5-Dimethyl-4- (4-methylsulfonyl) phenyl) -5H-furan-2-one; 3-Cyclopentyloxy-5,5-dimethyl-4- (4-methylsulfonylphenyl) -5H- Furan-2-one; 3- (3,3-dimethylcyclopentyloxy) -5,5-dimethyl-4- (
4-Methylsulfonyl) -phenyl) -5H-furan-2-one; 3-isopropoxy-5-methyl-4- (4-methylsulfonylphenyl)-
5-propyl-5H-furan-2-one; 3- (2-methoxy-5-pyridyloxy) -5,5-dimethyl-4- (4-
Methylsulfonyl) phenyl-5H-furan-2-one; 3- (5-methyl-2-pyridyloxy) -5,5-dimethyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; (5RS) -3- (3,4-difluorophenoxy) -5-methyl-4- (4
-Methylsulfonyl) phenyl-5- (2,2,2-trifluoroethyl) -5
H-furan-2-one; 3- (3-chloro-4-methoxyphenoxy) -5,5-dimethyl-4- (4
-Methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (3-chloro-4-methoxyphenoxy) -5-ethyl-5-
Methyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (4-chlorophenoxy) -5-trifluoroethyl-5-methyl-4- (4-methylsulfonyl) ) Phenyl-5H-furan-2-one; (5R) -3- (4-bromophenoxy) -5-trifluoroethyl-5-methyl-4- (4-methylsulfonyl) phenyl-5H-furan-2- 5-cyclopropylmethyl-3- (3,4-difluorophenoxy) -5-methyl- (4-methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (3-fluorophenoxy) ) -5-Ethyl-5-methyl-4-
(4-Methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3- (4-chloro-3-fluorophenoxy) -5-ethyl-5.
Methyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; (5R) -3-phenoxy-5-ethyl-5-methyl-4- (4-methylsulfonyl) phenyl-5H-furan- 2-one; (5R) -3- (4-chloro-3-methylphenoxy) -5-ethyl-5-methyl-4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 3- ( 4-chloro-3-methylphenoxy) -5,5-dimethyl-4- (4-
(5R) -3- (5-Bromo-2-pyridyloxy) -4- (4-methylsulfonylphenyl) -5-methyl-5- (2,2) methylsulfonyl) phenyl-5H-furan-2-one; , 2-Trifluoroethyl) -5
H-furan-2-one; (5R) -3- (5-bromo-2-pyridyloxy) -4- (4-methylsulfonylphenyl) -5-ethyl-5-methyl-5H-furan-2-one 3- (5-chloro-6-methyl-2-pyridyloxy) -5,5-dimethyl-
4- (4-methylsulfonyl) phenyl-5H-furan-2-one; 3- (5-cyclopropyl-2-pyridyloxy) -5,5-dimethyl-4-
(4-methylsulfonyl) phenyl-5H-furan-2-one; 3- (1-cyclopropylethoxy) -4- (4-methylsulfonyl) phenyl-5H-furan-2-one; and 3- (cyclopropyl) Methoxy) -4- (4-methylsulfonyl) phenyl-
5H-furan-2-one or a pharmaceutically acceptable salt or stereoisomer thereof.

COX-2 inhibitors which are particularly useful in the therapeutic methods of the present invention include: 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2- (5H)-
Franon:

[0096]

[Chemical 18] And 5-chloro-3- (4-methylsulfonyl) phenyl-2- (2-methyl-5)
-Pyridinyl) pyridine:

[0097]

[Chemical 19]

[0098]   Alternatively, these are pharmaceutically acceptable salts.

General and specific synthetic procedures for making the above COX-2 inhibitor compounds are described in US Pat. No. 5,474,995 issued Dec. 12, 1995, 1999 1
U.S. Pat. No. 5,861,419, issued Jan. 19, and U.S. Pat. No. 6,0018,43, issued Dec. 14, 1999, both of which are incorporated herein by reference.

Compounds useful in the present invention, since described as being specific inhibitors of COX-2, include, but are not limited to, the following or pharmaceutically acceptable salts thereof: It is not something that will be done.

[0101]

[Chemical 20]

The compound useful in the present invention as well as the method for synthesizing the compound, which is described as being a specific inhibitor of COX-2, is described in WO94 /
15932, US Pat. No. 5,344,991, issued June 6, 1994, 1992.
U.S. Pat. No. 5,134,142 issued July 28, 1995, U.S. Pat. No. 5,380,738 issued Jan. 10, 1995, U.S. Pat. No. 5,393 issued Feb. 20, 1995.
790, US Pat. No. 5,466,823, issued Nov. 14, 1995, 199.
Described in US Pat. No. 5,633,272 issued May 27, 1995 and US Pat. No. 5,932,598 issued August 3, 1999, pending applications and publications, which are incorporated herein by reference. Has been done.

A compound useful in the present invention as a specific inhibitor of COX-2 and a method for synthesizing the compound is described in US Pat. No. 5,474,995 issued Dec. 12, 1995.
No. 5,861,419 issued January 19, 1999, December 12, 1999
U.S. Pat. No. 6,0018,43 issued on May 14, U.S. Pat. No. 6,020,343 issued on Feb. 1, 2000, U.S. Pat. No. 5,409,944 issued on Apr. 25, 1995.
No. 5,436,265 issued July 25, 1995, US Pat. No. 5,536,752 issued July 16, 1996, US Pat. No. 5,550,142 issued August 27, 1996, February 18, 1997. Issued US Pat. No. 5,604,260
No. 5,698,584 issued Dec. 16, 1997 and 1998
US Pat. No. 5,710,140, issued Jan. 20, 2004, pending applications and publications, which are incorporated herein by reference.

Other examples of angiogenesis inhibitors include endostathione (endostation), ukrain, rampinase, IM862, 5-methoxy-4-.
[2-Methyl-3- (3-methyl-2-butenyl) oxiranyl] -1-oxaspiro [2,5] oct-6-yl (chloroacetyl) carbamate, acetyldinanaline, 5-amino-1 -[[3,5-Dichloro-4
-(4-chlorobenzoyl) phenyl] methyl] -1H-1,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin,
RPI4610, NX31838, sulfated manopentaose phosphate (manopentao
se), 7,7- (carbonyl-bis [imino-N-methyl-4,2-pyrrolocarbonylimino [N-methyl-4,2-pyrrole] -carbonylimino] -bis-
(1,3-naphthalene disulfonate) and 3-[(2,4-dimethylpyrrol-5-yl) methylene] -2-indolinone (SU5416), but not limited thereto.

The “integrin blocker” used above refers to a compound that selectively antagonizes, inhibits or prevents the binding of a physiological ligand to α _v β ₃ integrin; a physiological ligand to α _v β ₅ integrin A compound that antagonizes, inhibits, or prevents the binding of phospholipids; a compound that antagonizes, inhibits, or prevents the binding of physiological ligands to both α _v β ₃ and α _v β ₅ integrins; and certain compounds expressed on capillary endothelial cells. Refers to compounds that antagonize, inhibit or interfere with the activity of integrins. The term also refers to antagonists of α _v β ₆ , α _v β ₈ , α ₁ β ₁ , α ₂ β ₁ , α ₅ β ₁ , α ₆ β ₁ and α ₆ β ₄ integrins. The term also refers to α _v β ₃ , α _v β ₅ , α _v β ₆ , α _v β ₈ , α ₁ β ₁ , α ₂ β ₁ , α ₅ β ₁ , α ₆ β ₁ and α ₆ β ₄ integrins. It also refers to any combination of antagonists.

Some specific examples of tyrosine kinase inhibitors include N- (trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide, 3-[(
2,4-dimethylpyrrol-5-yl) methylidenyl) indoline-2-one,
17- (allylamino) -17-demethoxygeldanamycin, 4- (3-chloro-4-fluorophenylamino) -7-methoxy-6- [3- (4-morphonyl) propoxyl] quinazoline, N- ( 3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) -4-quinazoline amine, BBX1382, 2,3
9,10,11,12-Hexahydro-10- (hydroxymethyl) -10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo [1,2,3-
fg: 3 ′, 2 ′, 1′-kl] pyrrolo [3,4-i] [1,6] benzodiazocin-1-one, SH268, genistein, STI571, CEP2563,
4- (3-chlorophenylamino) -5,6-dimethyl-7H-pyrrolo [2,3
-D] pyrimidine methanesulfonate, 4- (3-bromo-4-hydroxyphenyl) amino-6,7-dimethoxyquinazoline, 4- (4'-hydroxyphenyl) amino-6,7-dimethoxyquinazoline, SU6668, STI571A,
N-4-chlorophenyl-4- (4-pyridylmethyl) -1-phthalazineamine and EMD121974.

The compounds of the invention are further useful, alone or in combination with a platelet fibrinogen receptor (GPIIb / IIIa) antagonist such as tirofiban, to inhibit metastasis of cancer cells. Tumor cells can activate platelets to a large extent via thrombin generation. This activation is associated with the release of VEGF. VEGF release promotes metastasis by increasing blood exudation at sites of adhesion to vascular endothelium (Amirkhosravi, Platelets 10, 285-292, 1999).
Therefore, the compound of the present invention may have an effect of inhibiting metastasis, either alone or in combination with a GPIIb / IIIa antagonist. Examples of other fibrinogen receptor antagonists include abciximab, eptifibatide
), Sibrafiban, lamifiban, lotrafiban, cromofiban and CT50352.

When formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent (s) within its approved dosage range.
Alternatively, if the combination formulation is inappropriate, the compounds of the invention can be used sequentially with known pharmaceutically acceptable agents.

“Administration” and its derivatives (eg, “administration” of a compound) with respect to a compound of the present invention refer to the introduction of said compound or a prodrug of said compound into the system of an animal in need of treatment. means. When the compound of the present invention or a prodrug of the compound is provided in combination with one or more other drugs (eg, cytotoxic agents, etc.), “administration” and its derivative forms refer to the compound or its prodrug, respectively. It is understood to include simultaneous and sequential introduction of drugs and other drugs.

As used herein, the term “composition” includes those that contain the given ingredients in the given amounts, as well as those that are obtained, directly or indirectly, by a combination of the given ingredients in the given amounts. To do.

The term “therapeutically effective amount” as used herein refers to the physiological or medical response in a tissue, system, animal or human that is pursued by a researcher, veterinarian, doctor or other clinical party. By the amount of active compound or drug that induces.

The term “treatment of cancer” refers to administration to a mammal suffering from a cancerous condition, which has the effect of ameliorating the cancerous condition by killing the cancerous cells and further inhibiting the growth and / or metastasis of the cancer. It also refers to the effect that occurs.

The present invention further provides a pharmaceutical composition useful in the treatment of cancer, with or without a pharmaceutically acceptable carrier or diluent, in a therapeutically effective amount of a compound of the invention. Is administered. Suitable compositions of the present invention include a compound of the present invention and a pharmaceutically acceptable carrier (eg, a pH level of eg 7.
4 saline solution) and the like. The solution can be introduced into the patient's bloodstream by local bolus injection.

When administering a compound according to the present invention to a human patient, the daily dose will usually vary depending on the age, weight and response of the individual patient and the severity of the patient's symptoms,
Determined by the prescribing physician.

In one example of use, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration is from about 0.1 mg / kg / day to about 60 mg / mg / day, preferably about 0.
． It is performed in an amount of 5 mg / kg / day to about 40 mg / mg / day.

[0116]   Assay   The compounds of the invention described in the examples were tested according to the following assay,
It was found that they have kinase inhibitory activity. Other assays are publicly available
Knowledge and would be readily implemented by one of ordinary skill in the art (eg, Dhanab
al et al., Cancer Res. 59: 189-197; Xin et al., J. Biol. Chem. 274: 9116.
-9121; Sheu et al., Anticancer Res. 18: 4435-4441; Ausprunk et al., Dev.  Biol. 38: 237-248; Gimbrone et al., J. Natl. Cancer Inst. 52: 413-427;
Nicosia et al., In Vitro 18: 538-549).

[0117]   VEGF Receptor Kinase Assay   Polyglutamic acid, tyrosine, 4: 1 (pEY) substrate combined with radiolabeled phosphate
VEGF receptor kinase activity is measured by incorporation. Phosphorylated pEY product
It is captured on a filter membrane and the incorporation of radiolabeled phosphate is monitored by scintillation counting.
Quantification.

[0118]   material   VEGF receptor kinase   Human KDR (Terman, B.I., et al, Oncogene (1991) vol.6, pp.1677-1683)
And Flt-1 (Shibuya, M. et al., Oncogene (1990) vol.5, pp.519-524.
Intracellular glutathione S-transferase (G
ST) Cloned as a gene fusion protein. It is a cell of KDR kinase
The cytoplasmic region as an in-frame fusion at the C-terminus of the GST gene
I went there. Baculovirus expression of soluble recombinant GST kinase domain fusion protein
Using the vector (pAcG2T, Pharmingen), Spodoptera frugiperda (S
f21) Expressed in insect cells (Invitrogen).

[0119]   Cell lysis buffer   50 mM Tris (pH 7.4), 0.5 M NaCl, 5 mM DTT, 1
mM EDTA, 0.5% Triton X-100, 10% glycerin, 10 m
g / mL of each leupeptin, pepstatin and aprotinin, 1 mM phenyl
Lumethylsulfonyl fluoride (both Sigma).

[0120]   Wash buffer   50 mM Tris (pH 7.4), 0.5 M NaCl, 5 mM DTT, 1
mM EDTA, 0.05% Triton X-100, 10% glycerin, 10
mg / mL of each leupeptin, pepstatin and aprotinin, 1 mM fe
Nylmethylsulfonyl fluoride.

[0121]   Dialysis buffer   50 mM Tris (pH 7.4), 0.5 M NaCl, 5 mM DTT, 1
mM EDTA, 0.05% Triton X-100, 50% glycerin, 10
mg / mL of each leupeptin, pepstatin and aprotinin, 1 mM fe
Nylmethylsulfonyl fluoride.

[0122]   10x reaction buffer   200 mM Tris (pH 7.4), 1.0 M NaCl, 5 mM MnCl _Two 10 mM DTT, 5 mg / mL bovine serum albumin (Sigma).

[0123]   Enzyme dilution buffer   50 mM Tris (pH 7.4), 0.1 M NaCl, 1 mM DTT, 1
0% glycerin, 100 mg / mL BSA.

[0124]   10 times substrate   750 μg / mL poly (glutamic acid, tyrosine 4: 1) (Sigma).

[0125]   Stop solution   30% trichloroacetic acid, 0.2M sodium pyrophosphate (all Fisher
).

[0126]   Cleaning liquid   15% trichloroacetic acid, 0.2M sodium pyrophosphate.

[0127]   Filter plate   Millipore #MAFC NOB, GF / C glass fiber 96 well
plate.

[0128]   Method   A. Protein purification   1. Recombinant virus of Sf21 cells with multiplicity of infection of 5 virus particles / cell
And was grown at 27 ° C. for 48 hours.

2. Both steps were performed at 4 ° C. Infected cells were harvested by centrifugation at 1000 × g, lysed with 1/10 volume of cell lysis buffer for 30 minutes at 4 ° C., then centrifuged at 100,000 × g for 1 hour. The supernatant was passed through a glutathione Sepharose column (Pharmacia) equilibrated with cell lysis buffer and washed with 5 volumes of the same buffer followed by 5 volumes of wash buffer. Wash buffer /
Elute the recombinant GST-KDR protein with 10 mM reduced glutathione (Sigma),
It was dialyzed against dialysis buffer.

[0130]   B. VEGF Receptor Kinase Assay   1. 5 μL of inhibitor or control is added to a 50% DMSO solution of assay.

2. 10-fold reaction buffer 5 μL, 25 mM ATP / 10 μCi [ ³³ P] AT
Add 35 μL of reaction mixture containing 5 μL of P (Amersham) and 5 μL of 10 × substrate.

3. The reaction is initiated by the addition of 10 μL of KDR (25 nM) enzyme dilution buffer solution.

[0133]   4. Stir and incubate at room temperature for 15 minutes.

[0134]   5. Stop by adding 50 μL of stop solution.

[0135]   Incubate at 6.4 ° C for 15 minutes.

[0136]   7. Transfer 90 μL of each to the filter plate.

[0137]   8. Suction and washing with washing solution are performed 3 times.

9. Add 30 μL of scintillation cocktail, seal the plate and count on a scintillation counter (Wallac Microbeta).

[0139]   Human umbilical vein endothelial cell mitogenic assay   Expression of the VEGF receptor, which mediates the cell division response to growth factors, is associated with vascular endothelium.
Very limited to cells. Human umbilical vein endothelial cells (HUVEC) in culture
Proliferating in response to VEGF treatment, a KDR kinase inhibitor for VEGF stimulation
It can be used as an assay system to quantify the effect. In this assay,
Incubation of suspension HUVEC monolayers with vehicle or test compound for 2 hours prior to VEGF
Alternatively, basic fibroblast growth factor (bFGF) is added. [^ThreeH] Thymidine fine
Of VEGF or bFGF by measuring the uptake into vesicle DNA
Seeking a split response.

[0140]   material   HUVEC   Obtain Frozen HUVEC as Primary Culture Isolate (from Clonetics Corp)
. Cells are maintained in Endothelial Growth Medium (EGM; Clonetics) and mitotic at passage 3-7.
Used for sei.

[0141]   Culture plate   NUNCLON 96-well polystyrene tissue culture plate (NUNC # 167008)
.

[0142]   Assay medium   Dulbecco's Modified Medium (Low Glucose) containing Eagle's medium containing 1 g / mL glucose.
DMEM; Mediatech) and 10% by volume of fetal calf serum (Clonetics).

[0143]   Test compound   The working drug substance of the test compound was continuously added with 100% dimethyl sulfoxide (DMSO).
Serially dilute to 400 times the desired final concentration. Final dilution to 1x concentration
Are prepared directly in assay medium and added immediately to cells.

[0144]   10 times growth factor   Human VEGF₁₆₅(500 ng / mL; R & D Systems) and bFGF (1
0 ng / mL; R & D Systems) assay media solution is prepared.

[0145]   10 times [ ³ H] thymidine   [Methyl-^Three[H] Thymidine (20 Ci / mmol; Dupont-NEN) low glucose
Dilute with DMEM to 80 μCi / mL.

[0146]   Cell wash medium   Hanks containing 1 mg / mL bovine serum albumin (Boehringer-Mannheim)
Liquid (Mediatech).

[0147]   Cell lysate   1N NaOH, 2% (weight / volume) Na_TwoCO_Three.

[0148]   Method   1. The HUVEC monolayer maintained in EGM was recovered by trypsinization,
Density of 4000 cells / 100 μL / well of assay medium in a 6-well plate
Plate on. 5% CO over 24 hours at 37 ° C_TwoIn a humidified atmosphere containing
Place the cells to stop growing.

2. Growth arrest medium is replaced with 100 μL of assay medium containing either vehicle (0.25 vol% DMSO) or the desired final concentration of test compound. All measurements are performed in triplicate. The cells are then incubated at 37 ° C./5% CO ₂ for 2 hours to allow the test compound to be taken up by the cells.

After a pretreatment period of 3.2 hours, cells are stimulated by adding 10 μL of either assay medium, 10x VEGF solution or 10x bFGF solution to each well.
The cells are then incubated at 37 ° C / 5% CO ₂ .

4. After 24 hours in the presence of growth factors, 10-fold [ ³ H] thymidine (10
μL / well).

5. Three days after adding [ ³ H] thymidine, the medium is removed by aspiration and the cells are washed twice with cell wash medium (400 μL / well and then 200 μL / well).
Well). Next, the washed adherent cells are lysed by adding a cell lysing solution (100 μL / well), and the temperature is raised to 37 ° C. for 30 minutes. Transfer the cell lysate to a 7 mL glass scintillation vial containing 150 μL of water. Scintillation cocktail (5 mL / vial) is added and cell-associated radioactivity is determined by liquid scintillation spectroscopy.

According to the above assay, the compound of formula I is an inhibitor of VEGF and therefore
It is useful for inhibiting angiogenesis in the treatment of eye diseases such as diabetic retinopathy and the treatment of cancer such as solid tumors. The compounds of the present invention inhibit VEGF-stimulated mitogenesis of human vascular endothelial cells in culture with an IC ₅₀ of 0.01-5.0 μM. These compounds are further related tyrosine kinases (eg FGFR1 and Src families; Eliceiri et al., Molecular Cell, Vol. 4, pp. 915-924,
December 1999) is also shown.

[0154]   Example   The examples provided below are intended to provide a better understanding of the present invention.
It was done. The particular materials, species and conditions used will further affect the invention.
It is intended to be illustrative and not limiting of the reasonable scope of the invention.

[0155]   Example 1   3- (5-methoxy-1H-pyrrolo [3,2-b] pyridin-2-yl) -1 H-quinolin-2-one

[0156]

[Chemical 21]

Step 1: Synthesis of 2-chloro-3-iodo-quinoline (Intermediate A)

[0158]

[Chemical formula 22]

3- (2-chloro) -quinolineboronic acid (5.05 g, 24.3 mmol, 1
Equivalent; Report by Marsais et al. (Marsais, F; Godard, A .; Queguiner, GJ Het
erocyclic Chem. 1989, 26, 1589-1594)) and N-iodosuccinimide (5.48 g, 24.4 mmol, 1.00 eq) in acetonitrile (300 mL) in the dark at 23 ° C. Stir for 20 hours. The reaction mixture was concentrated to dryness and the resulting yellow solid was partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The organic layer was washed with water, dried over magnesium sulfate and concentrated to give 2-chloro-3-iodo-quinoline (Intermediate A) as a pale yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.67 (s, 1H), 7.9
9 (brd, 1H, J = 8.4 Hz), 7.75 (brt, 1H, J = 7.7H)
z), 7.72 (brd, 1H, J = 7.8 Hz), 7.57 (brt, 1H,
J = 7.6 Hz).

Step 2: Synthesis of Intermediate B

[0162]

[Chemical formula 23]

5-Methoxy-1H-pyrrolo [3,2-b] pyridine (0.930 g, 6.2
8 mmol, 1 equivalent; Report by Mazeas et al. (Mazeas, D.; Guillaumet, G.; Viau
d, MC Heterocycles 1999, 50, 1065-1080)),
rt-Butyl dicarbonate (1.64 g, 4.05 mmol, 1.20 eq)
And 4-dimethylaminopyridine (10 mg, 0.082 mmol, 0.01
A solution of 3 eq) in methylene chloride (30 mL) was stirred at 23 ° C. for 1 hour. The reaction mixture was concentrated and the residue was flash column chromatographed (first 10
Purification with 0% hexanes then 30% ethyl acetate / hexanes gradient) afforded intermediate B as a colorless oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ8.24 (brd, 1H, J =
9.0 Hz), 7.72 (brd, 1H, J = 3.4 Hz), 6.69 (d, 1
H, J = 9.0 Hz), 6.63 (d, 1H, J = 3.9 Hz), 3.99 (s
3H), 1.67 (s, 9H).

Step 3: Synthesis of Intermediate C

[0166]

[Chemical formula 24]

Step 1: Pentane solution of tert-butyllithium (1.7 M, 3.95 mL)
, 6.72 mmol, 1.20 eq) to Intermediate B (1.39 g, 5.60 mm)
ol, 1 eq) in THF (70 mL) at -78 ° C. The resulting orange-red solution was stirred for 15 minutes and trimethyltin chloride (2.23 g, 11.2 mmol,
A solution of 2.00 eq) in THF (4.0 mL) was added. The reaction mixture was warmed to 23 ° C. and partitioned between pH 7 aqueous phosphate buffer and a 1: 1 mixture of ethyl acetate and hexane (100 mL). The organic layer was dried over sodium sulfate and concentrated.

Step 2: The residue, Intermediate A (0.800 g, 2.76 mmol, 0.50
0 equivalent), tetrakis (triphenylphosphine) palladium (0.160 g,
0.140 mmol, 0.025 eq) and cuprous iodide (0.053 g, 0
． A solution of 28 mmol, 0.05 eq) in dioxane (40 mL) was deoxygenated and it was heated at 90 ° C. for 20 hours. Cool the reaction mixture, brine (150 mL)
And ethyl acetate (150 mL). The organic layer was dried over sodium sulfate and concentrated. Flash column chromatography of the residue (first 100%
Hexane, then 30% ethyl acetate / hexane gradient)
Intermediate C was obtained as a light yellow foam.

¹ H NMR (300 MHz, CDCl ₃ ) δ8.44 (d, 1H, J = 9.
2 Hz), 8.18 (s, 1H), 8.08 (d, 1H, J = 8.5 Hz), 7
． 88 (d, 1H, J = 8.2 Hz), 7.79 (ddd, 1H, J = 8.5)
7.0, 1.5 Hz), 7.63 (ddd, 1H, J = 8.5, 7.0, 1.5
Hz), 6.78 (d, 1H, J = 8.8Hz), 6.72 (s, 1H), 4.
02 (s, 3H), 1.27 (s, 9H).

[0170]   Step 4: 3- (5-Methoxy-1H-pyrrolo [3,2-b] pyridin-2-i Le) -1H-quinolin-2-one   A solution of intermediate C (900 mg, 2.20 mmol) was added to acetic acid and water 1: 1.
The mixture was heated under reflux for 16 hours in the mixed solution (50 mL). The reaction mixture is concentrated and the residue is
Saturated aqueous sodium bicarbonate solution (150 mL) and hot ethyl acetate (200 mL three times)
) With. The combined organic layers were dried over sodium sulfate and concentrated. The rest
The distillate was suspended in ethyl ether (200 mL), filtered, air dried, and combined with the title compound.
The product was obtained as a yellow solid.

¹ H NMR (300 MHz, (CD ₃ ) ₂ SO) δ 12.23 (s, 1H)
, 11.75 (s, 1H), 8.58 (s, 1H), 7.86 (brd, 1H,
J = 9.2 Hz), 7.75 (brd, 1H, J = 7.6 Hz), 7.54 (b
rt, 1H, J = 7.8 Hz), 7.39 (d, 1H, J = 8.2 Hz), 7.
26 (brt, 1H, J = 7.6 Hz), 7.18 (brs, 1H), 6.57
(D, 1H, J = 8.5 Hz), 3.88 (s, 3H).

[0172] HRMS (electrospray _{FT / ICR) C 17 H 14} N 3 O 2 [M + H] + Calculated 292.1081; found 292.1059.

Hands, D .; Bishop, B .; Cameron, M .; Edwards, JS
Cottrell, IF; Wright, SH B Synthesis 1996, 887-882) and using the corresponding azaindoles as raw materials, Example 2 was repeated.
~ 4 compounds were synthesized.

[0174]   Example 2   3- (5-methoxy-1H-pyrrolo [2,3-c] pyridin-2-yl) -1 H-quinolin-2-one

[0175]

[Chemical 25]

Step 1: Synthesis of intermediate D

[0177]

[Chemical formula 26]

5-Methoxy-1H-pyrrolo [2,3-c] pyridine (190 mg, 1.28
mmol, 1 equivalent; Report by Mazeas et al. (Mazeas, D .; Guillaumet, G.; Viaud,
MC Heterocycles 1999, 50, 1065-1080),)
t-Butyldicarbonate (336 mg, 1.54 mmol, 1.20 eq) and 4-dimethylaminopyridine (10 mg, 0.082 mmol, 0.064).
A solution of (eq.) In methylene chloride (20 mL) was stirred at 23 ° C. for 2 hours. The reaction mixture was concentrated and the residue was flash column chromatographed (first 100
% Hexanes, then 20% ethyl acetate / hexanes gradient) to afford Intermediate E as a colorless oil. It solidified if left stationary (180
mg, 56%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.89 (brs, 1H), 7
． 70 (brd, 1H, J = 4.0 Hz), 6.86 (s, 1H), 6.48 (
d, 1H, J = 3.9 Hz), 3.98 (s, 3H), 1.68 (s, 9H).

[0180]   Step 2: 3- (5-Methoxy-1H-pyrrolo [2,3-c] pyridin-2-i Le) -1H-quinolin-2-one   Step 1: Pentane solution of tert-butyllithium (1.7 M, 0.45 mL
, 0.77 mmol, 1.20 eq) to intermediate D (160 mg, 0.644 m)
mol (1 eq) to a solution of THF (15 mL) at -78 ° C. Obtained bright yellow
The color solution was stirred for 10 minutes and trimethyl borate (0.144 mL, 1.29 mmo
1, 2.00 eq) was added. The reaction mixture was warmed to 0 ° C. and half saturated
Partitioned between aqueous ammonium and ethyl acetate (2 x 75 mL). Organic layer
It was dried over sodium sulfate and concentrated to give a white solid (160 mg).

Step 2: The solid, Intermediate A (150 mg, 0.51 mmol, 1.0 eq)
, Tetrakis (triphenylphosphine) palladium (30mg, 0.026m
mol, 0.05 eq) and potassium phosphate (327 mg, 1.54 mmol)
, 3.00 equiv.) In dioxane (15 mL) was deoxygenated and it was heated to reflux for 20 hours. The reaction mixture was cooled, water (75 mL) and ethyl acetate (2 mL at 75 mL).
Times). The organic layer was dried over sodium sulfate and concentrated. The residue was flashed on a silica gel column (first 40% EtOAc / hexane, 100%.
(Gradient to EtOAc). Fractions containing mainly the desired coupling product were concentrated.

Step 3: A 1: 1 mixed solution of this residue in acetic acid and water was heated to reflux for 20 hours. The reaction mixture was concentrated and the residue was subjected to reverse phase column chromatography (first 5%
Acetonitrile / water, then 100% acetonitrile gradient). The desired fractions were concentrated and the residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the title compound as a yellow solid.

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 12.22 (s, 1H)
12.00 (s, 1H), 8.62 (s, 1H), 8.49 (s, 1H), 7
． 74 (brd, 1H, J = 7.7 Hz), 7.53 (brt, 1H, J = 7.7.
7 Hz), 7.37 (brd, 1H, J = 8.2 Hz), 7.23 (brt, 1
H, J = 7.5 Hz), 7.12 (s, 1H), 6.84 (s, 1H), 3.8
4 (s, 3H).

[0184] HRMS (electrospray _{FT / ICR) C 17 H 14} N 3 O 2 [M + H] + Calculated 292.1081; found 292.1068.

[0185]   Example 3   3- (5-oxo-4,5-dihydro-1H-pyrrolo [3,2-b] pyridine -2-yl) -1H-quinolin-2-one

[0186]

[Chemical 27]

A solution of the product from Example 1 (100 mg, 0.343 mmol) in 48% HBr in water was heated to reflux for 20 hours. The reaction mixture was cooled, the precipitated yellow solid was filtered and washed with 1N aqueous hydrochloric acid solution. The filtered solid was dried under vacuum to give the title product as a yellow solid.

¹ H NMR (300 MHz, (CD ₃ ) ₂ SO) δ 14.20 (brs, 1
H), 12.51 (s, 1H), 12.40 (s, 1H), 8.81 (s, 1H
), 8.29 (brd, 1H, J = 9.2 Hz), 7.81 (brd, 1H, J)
= 7.9 Hz), 7.60 (brt, 1H, J = 7.0 Hz), 7.41 (d,
1H, J = 8.2 Hz), 7.30 (brt, 1H, J = 7.6 Hz), 7.1
4 (brs, 1H), 6.70 (d, 1H, J = 8.8 Hz).

[0189]   Example 4   3- (5-oxo-5,6-dihydro-1H-pyrrolo [2,3-c] pyridine -2-yl) -1H-quinolin-2-one

[0190]

[Chemical 28]

The title compound was prepared by reaction of HBr with the corresponding methyl ether according to the procedure in Example 3 above.

[0192]   Example 5   3- (4-oxo-4,5-dihydro-1H-pyrrolo [3,2-c] pyridine -2-yl) -1H-quinolin-2-one

[0193]

[Chemical 29]

The title compound was prepared by oxidation of the product from Example 3 followed by rearrangement (see Scheme 4).

[0195]   Example 6   3- (4-methyl-5-oxo-4,5-dihydro-1H-pyrrolo [3,2- b] pyridin-2-yl) -1H-quinolin-2-one

[0196]

[Chemical 30]

Sodium tert-butoxide (10 mg, 0.11 mmol, 1.0 eq) and methyl iodide (13 μL, 0.22 mmol, 2.0 eq) were added in that order to the product from Example 3 (30 mg, 0.11 mmol, 1 eq) of THF (
10 mL) suspension at 23 ° C. The reaction mixture was stirred for 20 hours. Additional sodium tert-butoxide (20 mg, 0.22 mmol, 2.0 eq) and methyl iodide (26 μL, 0.44 mmol, 4.0 eq) were added in two equal portions over 1 hour and the reaction mixture was added. Was stirred for an additional hour. Water (5 mL) was added and the resulting mixture was concentrated to a volume of 2 mL. The mixture was purified by reverse phase HPLC to give the title compound as a yellow solid.

¹ H NMR (300 MHz, (CD ₃ ) ₂ SO) δ 12.28 (s, 1H)
, 11.94 (s, 1H), 8.56 (s, 1H), 7.78 (d, 1H, J =
9.5 Hz), 7.73 (brd, 1H, J = 7.9 Hz), 7.53 (brt
, 1H, J = 7.0 Hz), 7.38 (brd, 1H, J = 8.2 Hz), 7.
26 (brt, 1H, J = 7.3 Hz), 7.03 (brd, J = 1.5 Hz)
, 6.18 (d, 1H, J = 9.2 Hz).

Hands, D .; Bishop, B .; Cameron, M .; Edwards, JS
Cottrell, IF; Wright, SH B Synthesis 1996, 887-882) and using the corresponding azaindoles as raw materials, Example 7 was repeated.
~ 9 compounds were synthesized. The product can be converted to the N-alkylated compound of Formula I by the procedure of Scheme 4 followed by the alkylation of Scheme 5 or by other procedures readily available in the chemical literature.

[0200]   Example 7   3- (1H-pyrrolo [2,3-c] pyridin-2-yl) -1H-quinoline- 2-on

[0201]

[Chemical 31]

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 12.26 (s, 1H)
, 12.03 (s, 1H), 8.89 (brs, 1H), 8.70 (brs, 1
H), 8.09 (brd, 1H, J = 5.0 Hz), 7.78 (brd, 1H,
J = 7.7 Hz), 7.57 (brt, 1H, J = 8.0 Hz), 7.53 (b
rd, 1H, J = 5.3 Hz), 7.40 (brd, 1H, J = 8.3 Hz),
7.31 (brs, 1H), 7.28 (brt, 1H, J = 7.6 Hz).

[0203]   Example 8   3- (1H-pyrrolo [3,2-c] pyridin-2-yl) -1H-quinoline- 2-on

[0204]

[Chemical 32]

¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 12.23 (s, 1H)
, 11.97 (s, 1H), 8.87 (brs, 1H), 8.61 (s, 1H)
, 8.18 (brs, 1H), 7.75 (brd, 1H, J = 7.7 Hz), 7
． 55 (brt, 1H, J = 8.0 Hz), 7.50 (brs, 1H), 7.4
5 (brs, 1H), 7.39 (brd, 1H, J = 8.2 Hz), 7.27 (
brt, 1H, J = 7.6 Hz).

[0206]   Example 9   3- (1H-pyrrolo [3,2-b] pyridin-2-yl) -1H-quinoline- 2-on

[0207]

[Chemical 33]

¹ H NMR (400 MHz, (CD ₃ OD) δ8.62 (s, 1H), 8.
31 (dd, 1H, J = 4.7, 1.3 Hz), 7.92 (brd, 1H, J =
8.2 Hz), 7.81 (brd, 1H, J = 7.8 Hz), 7.58 (brt
1H, J = 7.6 Hz), 7.40 (brd, 1H, J = 8.0 Hz), 7.
34 (brs, 1H), 7.31 (brt, 1H, J = 8.0 Hz), 7.18
(Dd, 1H, J = 8.2, 4.7 Hz).

HRMS (Electrospray FT / ICR): Calcd for C ₁₆ H ₁₁ N ₃ O [M + H] ⁺ 262.0975; found 262.0975.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 17/06 A61P 17/06 19/00 19/00 19/02 19/02 27/02 27/02 29 / 00 29/00 101 101 35/00 35/00 43/00 105 43/00 105 111 111 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AE, AG, AL AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD , GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US , UZ, VN, YU, ZA, ZW (72) Inventor Hartman, Jioji Day, USA, New Jersey 07065-0907, Lowway, East Lincarn Avenyu 126 (72) Inventor Hangate, Randall Davryu United States , New Jersey 07065-0907, Lowway, East Lincoln Avenyu 126F Term (reference) 4C065 AA04 AA05 BB04 CC01 DD02 EE02 HH01 HH09 JJ01 JJ03 JJ04 KK05 LL01 PP12 4C084 AA19 AA23 AZA23 AA23 AA23 AA23 AA23 AA23 AA23 AA23 ZB212 ZB262 ZC022 ZC202 ZC352 4C086 AA01 AA02 AA03 CB05 MA01 MA02 MA03 MA04 NA14 ZA33 ZA89 ZA96 ZB11 ZB15 ZB21 ZB26 ZC02 ZC20 ZC35

Claims (32)

[Claims] 1. A compound of the following formula I or a pharmaceutically acceptable salt of said compound:
Or stereoisomer.     [Chemical 1]   [In the formula,   Q is S, O or -E = D-;     [Chemical 2] Is     [Chemical 3]   Selected from;   a is 0 or 1;   b is 0 or 1;   s is 1 or 2;   m is 0, 1 or 2;   E = D is C = N, N = C or C = C;   R¹, R^1a, R^FourAnd R⁵Independently,   1) H,   2) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC₁~ C₁₀Alkyl,   3) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bAryl,   4) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC_Two~ C₁₀Alkenyl,   5) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC_Two~ C₁₀Alkynyl,   6) R⁶SO optionally substituted with 1 to 3 substituents selected from_mC₁ ~ C₁₀Alkyl,   7) R⁶SO optionally substituted with 1 to 3 substituents selected from_mAnts
The   8) CO_TwoH,   9) halogen,   10) CN,   11) OH,   12) O_bC₁~ C₆Perfluoroalkyl and   13) (C = O)_aNR⁷R⁸   Selected from;   R^TwoAnd R^ThreeIndependently,   1) H,   2) (C = O) O_aC₁~ C₁₀Alkyl,   3) (C = O) O_aAryl,   4) C₁~ C₁₀Alkyl,   5) SO_mC₁~ C₁₀Alkyl,   6) SO_mAryl,   7) (C = O)_aO_bC_Two~ C₁₀Alkenyl,   8) (C = O)_aO_bC_Two~ C₁₀Alkynyl and   9) selected from the group consisting of aryl; the alkyl, aryl, alkenyl
And alkynyl is R⁶Even if substituted with 1 to 3 substituents selected from
well;   R^4aIs   1) (C = O) O_aC₁~ C₁₀Alkyl,   2) (C = O) O_aAryl,   3) C₁~ C₁₀Alkyl,   4) SO_mC₁~ C₁₀Alkyl,   5) SO_mAryl,   6) (C = O)_aO_bC_Two~ C₁₀Alkenyl,   7) (C = O)_aO_bC_Two~ C₁₀Alkynyl and   8) selected from the group consisting of aryl; the alkyl, aryl, alkenyl
And alkynyl is R⁶Even if substituted with 1 to 3 substituents selected from
well;   R⁶Is   1) H,   2) (C = O)_aO_bC₁~ C₆Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
)_aO_bAryl,   4) C_Two~ C₁₀Alkenyl,   5) C_Two~ C₁₀Alkynyl,   6) R^6aA heterocycle optionally substituted with 1 to 3 substituents selected from   7) CO_TwoH,   8) halogen,   9) CN,   10) OH,   11) Oxo,   12) O_bC₁~ C₆Perfluoroalkyl or   13) NR⁷R⁸And   R^6aIs   1) H,   2) SO_mAryl,   3) SO_mC₁~ C₆Alkyl,   4) (C = O)_aO_bC₁~ C₆Alkyl,   5) (C = O)_aO_bAryl,   6) C_Two~ C₁₀Alkenyl,   7) C_Two~ C₁₀Alkynyl,   8) heterocycles,   9) CO_TwoH,   10) halogen,   11) CN,   12) OH,   13) Oxo,   14) O_bC₁~ C₆Perfluoroalkyl or   15) N (C₁~ C₆Alkyl)_TwoAnd   R⁷And R⁸Independently,   1) H,   2) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bC₁~ C₁₀Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bAryl,   4) R^6aC optionally substituted with 1 to 3 substituents selected from₁~ C ₁₀ Alkyl,   5) R^6aAryl optionally substituted with 1 to 3 substituents selected from
,   6) R^6aC optionally substituted with 1 to 3 substituents selected from_Two~ C ₁₀ Alkenyl,   7) R^6aC optionally substituted with 1 to 3 substituents selected from_Two~ C ₁₀ Alkynyl and   8) Heterocycle   Selected from; or   R⁷And R⁸But, together with the nitrogen to which they are bound, besides that nitrogen,
5 having one or two additional heteroatoms selected from N, O and S
Forming a 7-membered heterocycle; the heterocycle is R^6a1-3 selected from
It may be substituted with a substituent. ] 2. The compound according to claim 1, wherein Q is E = D. 3. The compound according to claim 2, wherein E = D is C = C. 4.   R¹, R^1a, R^FourAnd R⁵Independently,   1) H,   2) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC₁~ C₆Alkyl,   3) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bAryl,   4) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC_Two~ C₆Alkenyl,   5) CO_TwoH,   6) halogen,   7) CN,   8) OH,   9) O_bC₁~ C_ThreePerfluoroalkyl and   10) (C = O)_aNR⁷R⁸   Selected from;   R^TwoAnd R^ThreeIndependently,   1) H,   2) (C = O) O_aC₁~ C₆Alkyl and   3) C₁~ C₆Selected from the group consisting of alkyl;   R^4aBut (C = O) O_aC₁~ C₆Alkyl or C₁~ C₆In alkyl
R;   R⁶But,   1) H,   2) (C = O)_aO_bC₁~ C₆Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
)_aO_bAryl,   4) C_Two~ C₆Alkenyl,   5) R^6aA heterocycle optionally substituted with 1 to 3 substituents selected from   6) CO_TwoH,   7) halogen,   8) CN,   9) OH,   10) Oxo   11) O_bC₁~ C_ThreePerfluoroalkyl or   12) NR⁷R⁸And   R^6aBut,   1) H,   2) SO_mAryl,   3) SO_mC₁~ C₆Alkyl,   4) (C = O)_aO_bC₁~ C₆Alkyl,   5) (C = O)_aO_bAryl,   6) C_Two~ C₆Alkenyl,   7) heterocycles,   8) CO_TwoH,   9) halogen,   10) CN,   11) OH,   12) Oxo,   13) O_bC₁~ C_ThreePerfluoroalkyl or   14) N (C₁~ C₆Alkyl)_TwoAnd   R⁷And R⁸Independently,   1) H,   2) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bC₁~ C₆Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bAryl,   4) R^6aC optionally substituted with 1 to 3 substituents selected from₁~ C ₆ Alkyl,   5) R^6aAryl optionally substituted with 1 to 3 substituents selected from
,   6) R^6aC optionally substituted with 1 to 3 substituents selected from_Two~ C ₆ Alkenyl and   7) Heterocycle   Selected from; or   R⁷And R⁸But, together with the nitrogen to which they are bound, besides that nitrogen,
5 having one or two additional heteroatoms selected from N, O and S
Forming a 7-membered heterocycle; the heterocycle is R^6a1-3 selected from
The compound according to claim 3, which may be substituted with a substituent. 5.   a is 0 or 1;   b is 0 or 1;   s is 1;   R¹And R^FourIndependently,   1) H,   2) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC₁~ C₆Alkyl,   3) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bAryl,   4) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC_Two~ C₆Alkenyl,   5) R⁶May be substituted with 1 to 3 substituents selected from (C = O) _a O_bC_Two~ C₆Alkynyl,   6) CO_TwoH,   7) halogen,   8) CN,   9) OH,   10) O_bC₁~ C_ThreePerfluoroalkyl and   11) (C = O)_aNR⁷R⁸   Selected from;   R^TwoAnd R^ThreeAre independently selected from H and methyl;   R^4aIs methyl;   R⁵And R^1aIs H;   R⁶But,   1) H,   2) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
)_aO_bC₁~ C₆Alkyl, = O)_aO_bAryl, C_Two~ C₁₀Alkenyl
,   3) C_Two~ C₁₀Alkynyl,   4) R^6aA heterocycle optionally substituted with 1 to 3 substituents selected from   5) CO_TwoH,   6) halogen,   7) CN,   8) OH,   9) Oxo   10) O_bC₁~ C_ThreePerfluoroalkyl or   11) NR⁷R⁸And   R^6aBut,   1) H,   2) SO_mAryl,   3) SO_mC₁~ C₆Alkyl,   4) (C = O)_aO_bC₁~ C₆Alkyl,   5) (C = O)_aO_bAryl,   6) C_Two~ C₁₀Alkenyl,   7) C_Two~ C₁₀Alkynyl,   8) heterocycles,   9) CO_TwoH,   10) halogen,   11) CN,   12) OH,   13) Oxo,   14) O_bC₁~ C_ThreePerfluoroalkyl or   15) N (C₁~ C₆Alkyl)_TwoAnd   R⁷And R⁸Independently,   1) H,   2) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bC₁~ C₆Alkyl,   3) R^6aIt may be substituted with 1 to 3 substituents selected from (C═O
) O_bAryl,   4) R^6aC optionally substituted with 1 to 3 substituents selected from₁~ C ₁₀ Alkyl,   5) R^6aAryl optionally substituted with 1 to 3 substituents selected from
,   6) R^6aC optionally substituted with 1 to 3 substituents selected from_Two~ C ₆ Alkenyl,   7) R^6aC optionally substituted with 1 to 3 substituents selected from_Two~ C ₆ Alkynyl and   8) Heterocycle   Selected from; or   R⁷And R⁸But together with the nitrogen to which they are bound, R^6aSelected from
A piperidinyl group which may be substituted with one or two substituents
A benzyl group, a morpholinyl group or a pyrrolidinyl group may be formed.
The compound according to. 6. 3- (4-Methyl-5-oxo-4,5-dihydro-1H-
A compound which is pyrrolo [3,2-b] pyridin-2-yl) -1H-quinolin-2-one, or a pharmaceutically acceptable salt or stereoisomer of the compound. 7. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 8. A method of treating or preventing cancer in a mammal in need thereof, the method comprising administering to said mammal a therapeutically effective amount of a compound of claim 1. 9. The method for treating or preventing cancer according to claim 8, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. 10. The method for treating or preventing cancer according to claim 8, wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, glioblastoma and breast cancer. 11. A method for treating or preventing a disease in which angiogenesis is suggested, wherein a therapeutically effective amount of the compound of claim 1 is administered to a mammal in need of such treatment. A method having stages. 12. The method of claim 11, wherein the disease is an eye disease. 13. A method of treating or preventing retinal angiogenesis, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. . 14. A method of treating or preventing diabetic retinopathy, comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of the compound of claim 1. Method. 15. A method of treating or preventing age-related macular degeneration, comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of the compound of claim 1. How to have. 16. A method of treating or preventing an inflammatory disease, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1. 17. The method according to claim 16, wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reaction. 18. A method of treating or preventing a tyrosine kinase-dependent disease or condition, the method comprising administering a therapeutically effective amount of a compound of claim 1. 19. A pharmaceutical composition produced by combining the compound according to claim 1 and a pharmaceutically acceptable carrier. 20. A method for producing a pharmaceutical composition, which comprises the step of combining the compound according to claim 1 and a pharmaceutically acceptable carrier. 21. A method of treatment or prophylaxis of a bone-related condition selected from osteosarcoma, osteoarthritis and rickets, which method comprises the step of administering a therapeutically effective amount of a compound according to claim 1. . 22.   1) Estrogen receptor modulator;   2) Androgen receptor modulators;   3) Retinoid receptor modulators;   4) cytotoxic agents;   5) antiproliferative agents;   6) prenyl protein transferase inhibitors;   7) HMG-CoA reductase inhibitors;   8) HIV protease inhibitors;   9) a reverse transcriptase inhibitor; and   10) Another angiogenesis inhibitor   The composition of claim 7, further comprising a second compound selected from 23. The second compound is a tyrosine kinase inhibitor, an epidermal-derived growth factor inhibitor, a fibroblast-derived growth factor inhibitor, a platelet-derived growth factor inhibitor,
MMP inhibitor, integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitor, carboxamide triazole, combretastatin A-4, squalamine, 6-O-chloroacetylcarbonyl) -fumagillol, thalidomide 23. The composition of claim 22, which is another angiogenesis inhibitor selected from the group consisting of antibodies to angiostatin, troponin-1 and VEGF. 24. The composition of claim 22, wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene. 25. A method of treating cancer comprising administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy. 26. A method for treating or preventing cancer, which comprises 1) an estrogen receptor modulator; 2) an androgen receptor modulator; 3) a retinoid receptor modulator; 4) a cytotoxic agent; 5) an antiproliferative agent. 6) prenyl protein transferase inhibitor; 7) HMG-CoA reductase inhibitor; 8) HIV protease inhibitor; 9) reverse transcriptase inhibitor; and 10) combination with a compound selected from another angiogenesis inhibitor A method comprising administering a therapeutically effective amount of a compound of claim 1 at. 27. A method for treating cancer, comprising radiotherapy and 1) estrogen receptor modulator; 2) androgen receptor modulator; 3) retinoid receptor modulator; 4) cytotoxic agent; 5) antiproliferative agent. Agent) 6) prenyl protein transferase inhibitor; 7) HMG-CoA reductase inhibitor; 8) HIV protease inhibitor; 9) reverse transcriptase inhibitor; and 10) a compound selected from another angiogenesis inhibitor A method comprising the step of administering a therapeutically effective amount of the compound of claim 1 in combination. 28. A method of treating or preventing cancer comprising administering a therapeutically effective amount of the compound of claim 1 and paclitaxel or trastuzumab. 29. A method of treating or preventing cancer, the method comprising administering a therapeutically effective amount of a compound of claim 1 and a GPIIb / IIIa antagonist. 30. The method of claim 34, wherein the GPIIb / IIIa antagonist is tirofiban. 31. A method of reducing or preventing tissue damage following a cerebral ischemic event, the method comprising administering a therapeutically effective amount of a compound of claim 1. 32. A method of treating or preventing cancer, the method comprising administering a therapeutically effective amount of a compound of claim 1 in combination with a COX-2 inhibitor.