JP2002523459A - New angiogenesis inhibitor - Google Patents

Abstract

  (57) [Summary] The present invention relates to compounds that inhibit tyrosine kinase enzymes, compositions containing tyrosine kinase inhibitory compounds, and tyrosine kinase inhibitors, which are useful in treating tyrosine kinase-dependent diseases / conditions in mammals, such as neovascularization, cancer, atherosclerosis The present invention relates to a method for treating sclerosis, diabetic retinopathy or an autoimmune disease.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]Background of the Invention  Tyrosine kinase is the terminal phosphate of adenosine triphosphate on protein substrates.
It is a class of enzymes that catalyze the transfer of acids to tyrosine residues. Tyrosine kinase
Is important in signal transduction for many cell functions by phosphorylation of substrates
Is believed to play an important role. The exact mechanism of signaling remains
Although unclear, tyrosine kinases are involved in cell growth, carcinogenesis and cell differentiation.
It has been shown to be an important contributing factor. Therefore, these tyrosinki
Inhibitors of the enzyme are useful for the prevention and treatment of proliferative diseases dependent on these enzymes.
Useful for

[0002] For example, the treatment methods described herein relate to neovascularization. Neovascularization occurs in connection with tumor growth and in certain diseases of the eye. It is characterized by excessive activity of vascular endothelial growth factor.

[0003] Vascular endothelial growth factor (VEGF) is a high affinity transmembrane tyrosine kinase receptor KD
Binds to R and Flt-1. Cell culture and gene knockout experiments indicate that each receptor contributes to a different aspect of angiogenesis. KDR is VEG
It mediates the mitogenic function of F, whereas Flt-1 appears to regulate non-mitogenic functions, such as those associated with cell adhesion. Thus, inhibition of KDR modulates mitogenic VEGF activity.

[0004] The growth of blood vessels in the retina eventually leads to blinded visual degeneration. V
EGF is responsible for most angiogenic activities that occur in or near the retina in diabetic retinopathy. VEGF mRNA and protein in the eye, retinal vein occlusion in primates, in mice increased by conditions such as pO ₂ levels decreased leading to neovascularization. Intraocular injection of anti-VEGF monoclonal antibodies or VEGF receptor immunofusion inhibits ocular neovascularization in both primate and rodent models. VEG in human diabetic retinopathy
Regardless of the cause of F induction, inhibition of ocular VEGF is useful in treating the disease.

[0005] VEGF expression is also significantly increased in hypoxic areas of animal and human tumors adjacent to necrotic areas. Monoclonal anti-VEGF antibody inhibits human tumor growth in nude mice. These same tumor cells continue to express VEGF in culture, but these antibodies do not slow down their mitosis. Thus, tumor-derived VEGF does not function as an autocrine mitogen. Thus, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotaxis and mitogenic activity. These monoclonal antibodies also typically inhibit the growth of poorly vascularized colon cancer in athymic mice and reduce the number of tumors arising from inoculated cells. The mouse KDR receptor homolog, Flk-, has been cleaved to remove the cytoplasmic tyrosine kinase domain but leave the membrane anchor.
Expression of one VEGF-binding construct visually abolishes the growth of transplantable glioblastoma in mice, presumably due to the predominant negative mechanism of heterodimer formation with the transmembrane endothelial cell VEGF receptor. 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 or Flt-1 has been implicated in pathogenic neovascularization, which is a disease in which neovascularization is part of its overall pathology, such as diabetic retinal neovascularization as well as various forms of cancer. Useful in therapy.

[0006] Cancers that can be treated according to the present invention exhibit high levels of gene and protein expression. Examples of such cancers include brain, urogenital, lymphatic, stomach, laryngeal and lung cancers. These include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancer. Further examples include Raf-activated oncogenes (eg, K-ras, er
Cancers in which overexpression or activation of b-B) is observed are included. In particular, such cancers include pancreatic and breast cancer.

[0007] The present invention provides compounds that inhibit tyrosine kinase enzymes, compositions comprising tyrosine kinase inhibitory compounds, and tyrosine kinase inhibitors, which are useful in treating tyrosine kinase dependent diseases / conditions in mammals, such as neovascularization, cancer, Atherosclerosis,
The present invention relates to a method for treating diabetic retinopathy or inflammatory disease.

[0008]Summary of the Invention  The compound has the formula Ia:

[0009]

Embedded image Or according to their pharmaceutically acceptable salts, hydrates or prodrugs, wherein X is N or C; R ₁ and R ₃ are independently H, C _1-10 alkyl, C _{3-6 cycloalkyl, C 5-10} aryl, halo, _{OH, C 3-10} heterocyclyl, or _{C 5-1} is ₀ heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl ^{R a} Optionally substituted with one to three members selected from: R ₂ is independently H, C _1-6 alkyl, C _5-10 aryl, C _3-6 cycloalkyl, OH, NO ₂ , —. NH _2, or a halogen; _{R 4} and _{R 5, independently, H, C 1-10 alkyl, C 3-6 cycloalkyl, C 1-6} alkoxy C _2-10 alkenyl, C _{2-10 alkynyl, C 5-10 aryl, C 3-10 heterocyclyl, C 1-6} alkoxy _NR 7 _{R 8, halo,} NO 2, OH, a -NH ₂ or _{C 5-10} heteroaryl, said alkyl , Alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one to three members selected from ^Ra ;
Or R ₄ and R ₅ are one to three further heteroatoms selected from the group consisting of N, O and S, optionally substituted with one to three members selected from R ^a may together form a heterocyclic 5-9 membered saturated or unsaturated ring containing, ^{R a} _{is, H, C 1-10} alkyl, _halogen, NO 2, _{R, NHC 1-6} alkyl _R 9, _{oR, -NR, RNR 7 R 8} , NR 7 R 8, R 7 R 8, CN, C 5- 10 _{aryl, C 5-10} heteroaryl or _{C 3-10} heterocyclyl; R is, H, _{C 1 -6} alkyl or C _1-6 alkyl R ₉ ; R ₉ is C _5-10 aryl, C _3-10 heterocyclyl, or C _5-10 heteroaryl, wherein the aryl, heteroaryl and heterocyclyl are optionally substituted with 1 connected to three members selected from ^a; and R ₇ and _{R 8} are _{independently, H, C 1-10 alkyl, C 3-6} cycloalkyl, _{COR, C 5-10} aryl , a C _3-10 heterocyclyl, or C _{5-1 0} heteroaryl, said alkyl, aryl, heteroaryl and or heterocyclyl is optionally substituted with 1 connected to three members selected from R ^a, or NR ⁷ R ⁸ together form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one or two further heteroatoms selected from the group consisting of N, O and S be able to.

[0010] Further compounds are of the formula I:

[0011]

Embedded imageOr disclosed according to their pharmaceutically acceptable salts, hydrates or prodrugs
Wherein X is N or C;₁Is H, C_1-10Alkyl, C_3-6Cycloalkyl, C_5-10Ants
, Halo, OH, C_3-10Heterocyclyl or C_5-10Heteroaryl
The alkyl, alkenyl, alkynyl, aryl, heteroaryl and
Heterocyclyl is R^aOptionally substituted with one to three members selected from
R; R₂And R₃Is independently H, C_1-6Alkyl, C_5-10Aryl, C_{3 -6} Cycloalkyl, OH, NO₂, -NH₂Or halogen; R₄Is H, C_1-10Alkyl, C_3-6Cycloalkyl, C_1-6Arco
Kishi C_2-10Alkenyl, C_2-10Alkynyl, C_5-10Aryl, C _3-10 Heterocyclyl, C_1-6Alkoxy NR₇R₈, NO₂, OH, -N
H₂Or C_5-10Heteroaryl, said alkyl, alkenyl, alkynyl
, Aryl, heteroaryl and heterocyclyl are represented by R^aOne selected from
Optionally substituted with three members; R₅Is H or C_1-6Alkyl, OR, halo, NH₂Or NO₂In
R; R^aIs H, C_1-10Alkyl, halogen, NO₂, OR, -NR, NR₇ R₈, R₇R₈, C_5-10Aryl, C_5-10Heteroaryl or C_{3-1 0} R is H, or C_1-6Alkyl, C_1-6Alkyl R₉R₉Is C_5-10Aryl, C_3-10Heterocyclyl or C_5-10F
Teroaryl; and R₇And R₈Is independently H, C_1-10Alkyl, C_3-6Cycloalkyl
, COR, C_5-10Aryl, C_3-10Heterocyclyl or C_{5-1 0} Is heteroaryl or NR₇R₈Means N, O and S in addition to the nitrogen atom
A heterocyclic ring containing one or two further heteroatoms selected from the group consisting of
5-10 membered saturated or unsaturated rings can be formed together.

Formula I:

[0013]

Embedded image Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are described as above, or a pharmaceutically acceptable salt or hydrate or prodrug thereof. Also disclosed are pharmaceutical compositions comprising a in combination with a carrier.

A method for treating or preventing a tyrosine kinase-dependent disease or condition in a mammal, comprising treating a mammal patient in need of such treatment with a tyrosine kinase-dependent disease or condition in a therapeutic amount of a compound of Formula I. Or a method comprising administering a pharmaceutically acceptable salt, hydrate or prodrug thereof.

A method of treating or preventing cancer in a mammalian patient in need of such treatment, comprising administering to said patient an anticancer effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Also included are methods that involve administering an acceptable salt, hydrate or prodrug.

A method for treating or preventing a disease involving neovascularization, comprising administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydration thereof. Also encompassed by the invention are methods that involve administering an agent or prodrug in an amount effective to reduce neovascularization.

In particular, a method of treating or preventing an ocular disease in which neovascularization occurs, wherein the compound of formula I or a pharmaceutically acceptable compound thereof is administered to a mammalian patient in need of such treatment. Included herein are methods that include administering a salt, hydrate or prodrug in an amount effective to treat the ocular condition.

In particular, a method of treating or preventing retinal neovascularization, comprising administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt thereof;
Included herein are methods that include administering a hydrate or prodrug in an amount effective to treat retinal neovascularization. Diabetic retinopathy is an example of a disease in which neovascularization or retinal neovascularization is part of the overall etiology. Also included are methods of treating or preventing age-related macular degeneration.

[0019] These and other aspects of the invention will be apparent from the teachings contained herein.

[0020]DETAILED DESCRIPTION OF THE INVENTION  The present invention is described herein in detail using the terms defined below unless otherwise specified.
Describe in detail.

The term “alkyl,” unless otherwise defined, refers to a monovalent alkane (hydrocarbon) -derived group containing 1 to 10 carbon atoms. It may be linear, branched or cyclic. Preferred straight or branched chain alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cycloheptyl, cyclopentyl and cyclohexyl.

Alkyl also includes straight or branched chain alkyl groups that contain or are interrupted by a cycloalkylene moiety. Examples include:

[0023]

Embedded image (Where: x + y = 0-10; and w + z = 0-9). The alkylene and monovalent alkyl moiety (s) of the alkyl group should be attached to the cycloalkylene moiety at any available point of attachment. Is possible.

When substituted alkyl is present, this refers to straight, branched or cyclic alkyl as defined herein, which is substituted with 1-3 groups of ^Ra as described herein.

The term “alkenyl” refers to a straight, branched or cyclic hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon double bond.
Preferably there is one carbon-carbon double bond and up to 4 non-aromatic (non-resonant)
A carbon-carbon double bond may be present. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above for alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and is substituted with one to three Ra when ^a substituted alkenyl group is provided. It may be.

The term “alkynyl” refers to a straight, branched or cyclic hydrocarbon group containing 2 to 10 carbon atoms and at least one carbon-carbon triple bond.
There may be up to three carbon-carbon triple bonds. Preferred alkynyl groups include ethynyl, propynyl and butynyl, as described above for alkyl, the straight, branched or cyclic portion of the alkynyl group can contain triple bonds;
And may be substituted by 1-3 groups R ^a if a substituted alkynyl group is provided.

Aryl refers to a 5-10 membered aromatic ring such as phenyl, substituted phenyl and the like, as well as a fused ring such as naphthyl and the like. Thus, an aryl comprises at least one ring having at least 5 atoms, there are up to two such rings containing up to 10 atoms, and alternating (resonating) between adjacent carbon atoms ) Has a double bond. Preferred aryl groups are phenyl and naphthyl. The aryl group may be further substituted with 1-3 groups of ^Ra as defined herein. Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.

The term heterocyclic, heteroaryl, heterocyclyl or heterocyclic, as used herein without note, refers to a stable 5-7 membered monocyclic or bicyclic, or 7
To a 10-membered bicyclic heterocyclic ring system, wherein any of these rings may be saturated or unsaturated, and may be a carbon atom and 1 to 1 selected from the group consisting of N, O and S. Consisting of three heteroatoms, the nitrogen and sulfur heteroatoms may be optionally oxidized, the nitrogen heteroatoms may optionally be quaternized, and any of the heterocycles defined above may be Includes any bicyclic group fused to the benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom that results in a stable structure. Heterocyclic, heteroaryl or heterocyclic may be substituted by 1-3 groups R ^a. Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperazinyl, including all possible isomers
Oxopiperidinyl, 2-oxopyrrolidine, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl
Oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, hydrol Includes tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.

The term “alkoxy” refers to a group having a specified length in either a straight or branched configuration, including double or triple bonds when the length is two or more carbon atoms. You may go out. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxyallyloxy, propargyloxy and the like.

The term “halogen” is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.

The term “prodrug” refers to a compound that is a drug precursor that, after administration and absorption, releases the drug in vivo by some metabolic process. Exemplary prodrugs, acylamido amino compounds of the present invention, for example, amides of alkanol (C _1-6) acid, aryl acid (e.g., benzoic acid) and alkane (C 1 _-6) amide diacid included.

A tyrosine kinase-dependent disease or condition refers to a hyperproliferative disorder initiated / maintained by abnormal tyrosine kinase enzyme activity. Examples include psoriasis, cancer, immunomodulation (
(Graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis (eg, tumor growth, diabetic retinopathy) and the like.

One aspect of the present invention is a compound of formula Ia:

[0034]

Embedded image Or according to their pharmaceutically acceptable salts, hydrates or prodrugs, wherein X is N or C; R ₁ and R ₃ are independently H, C _1-10 alkyl, C _{3 -6 cycloalkyl, C 5-10} aryl, halo, _{OH, C 3-10} heterocyclyl, or _{C 5-1} is ₀ heteroaryl; said alkyl selected, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl of ^{R a} Optionally substituted with one to three members: R ₂ is independently H, C _1-6 alkyl, C _5-10 aryl, C _3-6 cycloalkyl, OH, NO ₂ , —NH ₂ , or there halogen; _{R 4} and _{R 5, independently, H, C 1-10 alkyl, C 3-6 cycloalkyl, C 1-6} alkoxy C _{2-10 alkenyl, C 2- 0 alkynyl, C 5-10 aryl, C 3-10 heterocyclyl, C 1-6} alkoxy _NR 7 _{R 8, halo,} a NO 2, OH, -NH ₂ or _{C 5-10} heteroaryl, said alkyl, alkenyl , Alkynyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one to three members selected from ^Ra .
Or R ₄ and R ₅ are one to three further heteroatoms selected from the group consisting of N, O and S, optionally substituted with one to three members selected from R ^a may together form a heterocyclic 5-9 membered saturated or unsaturated ring containing, ^{R a} _{is, H, C 1-10} alkyl, _halogen, NO 2, _{R, NHC 1-6} alkyl _R 9, _{oR, -NR, RNR 7 R 8} , NR 7 R 8, R 7 R 8, CN, C 5- 10 _{aryl, C 5-10} heteroaryl or _{C 3-10} heterocyclyl; R is, H, _{C 1 -6} alkyl or C _1-6 alkyl R ₉ ; R ₉ is C _5-10 aryl, C _3-10 heterocyclyl, or C _5-10 heteroaryl, wherein the aryl, heteroaryl and heterocyclyl are optionally substituted with 1 connected to three members selected from ^a; and R ₇ and _{R 8} are _{independently, H, C 1-10 alkyl, C 3-6} cycloalkyl, _{COR, C 5-10} aryl , a C _3-10 heterocyclyl, or C _{5-1 0} heteroaryl, said alkyl, aryl, heteroaryl and or heterocyclyl is optionally substituted with 1 connected to three members selected from R ^a, or NR ⁷ R ⁸ together form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one or two further heteroatoms selected from the group consisting of N, O and S be able to.

One aspect of the invention is described wherein X is C and all other variables are as described above.

Another aspect of the present invention is described wherein X is N and all other variables are as described above.

R ₄ is C _1-10 alkyl, C _3-6 cycloalkyl, C _5-10 aryl,
C _5-10 heteroaryl, or C _3-10 heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one to three members selected from ^Ra , and Yet another aspect of the invention is described, wherein all variables are as described above.

In yet another aspect, R ₁ is C _1-10 alkyl, C _5-10 aryl, C _3-10 heterocyclyl, or C _5-10 heteroaryl, wherein said alkyl, aryl, heteroaryl and The invention is described wherein the heterocyclyl is optionally substituted with one to three members selected from ^Ra , and all other variables are as described above.

^Ra is H, C _1-10 alkyl, halogen, C _1-6 alkyl R ₉ , CN, R
, OR, NR, RNR ₇ R ₈ , NR ₇ R ₈ , R ₇ R ₈ , and all other variables are as described above.

A preferred subset of the compounds of the invention is: R₁And R₃Are independently H, C_1-10Alkyl, C_5-10Aryl, C _3-10 Heterocyclyl or C_5-10Heteroalkyl; said alkyl,
Aryl, heteroaryl and heterocyclyl are represented by R^aOne or more selected from
Optionally substituted with three members: R₂Are independently H, C_1-6Alkyl, C_3-6Cycloalkyl, OH, or
Is halogen; R₄And R₅Are independently H, C_1-10Alkyl, C_3-6Cycloalkyl
, C_5-10Aryl, C_5-10Heteroaryl, C_3-10Heterocyclyl
, C_1-6Alkoxy NR₇R₈, NO₂, OH, -NH₂Or the said
Alkyl, aryl, heteroaryl and heterocyclyl are represented by R^a1 selected from
Optionally replaced with one to three members; all other variables are as described above.
It is realized in the case.

Other preferred subsets of the compounds of the invention are: wherein R ₁ and R ₃ are independently C _5-10 aryl, C _3-10 heterocyclyl,
Or be a _{C 5-10} heteroaryl; said aryl, heteroaryl and heterocyclyl is optionally substituted with 1 connected to three members selected from ^{R a:} _{R 2} is H or _{C 1-6} alkyl; R ₄ is, to connect one to three substituents selected from R ^a optionally substituted with three members, piperidinyl, piperazinyl, 2-oxopiperazinyl, oxopiperidinyl, oxopyrrolodinyl, 2 -Oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidinyl, pyridinonyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolinyl, isoxazolinyl, isoxazolinyl , Thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl , Tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl; and all other variables are as described above.

Another aspect of the present invention is a compound of formula I:

[0043]

Embedded image X is N or C; R ₁ is H, C _1-10 alkyl, C _5-10 aryl, C _3-10 heterocyclyl, or C _5-10 heteroaryl; said alkyl , Aryl, heteroaryl and heterocyclyl are optionally substituted with one to three members selected from R ^a ; R ₂ and R ₃ are independently H, C _1-6 alkyl, OH, NO ₂ ,- NH ₂ ,
R ₄ is C _5-10 aryl, C _3-10 heterocyclyl, C _1-6 alkoxyNR ₇ R ₈ , or C _5-10 heteroaryl, and the alkyl, alkenyl, alkynyl, aryl, optionally substituted with 1 connected to three members heteroaryl and heterocyclyl is selected from ^{_R a; R} ₅ is, _{H, C 1-6} alkyl, oR, halo, NH ₂ or NO _2; ^{R a} is , _{H, C 1-10} alkyl, _{halogen, NO 2, R, OR,} -NR, N
_{R 7 R 8, R 7 R} 8, C 5-10 _{aryl, C 5-10} heteroaryl or _{C 3 -10} heterocyclyl; R is, H, or _{C 1-6 alkyl, C 1-6} alkyl _{R 9} R ₉ is C _5-10 aryl, C _3-10 heterocyclyl, or C _5-10 heteroaryl; and R ₇ and R ₈ are independently H, C _1-10 alkyl, C _{3 -6} cycloalkyl, _{COR, C 5-10 aryl,} a _{C 3-10} heterocyclyl, or _{C 5-1 0} heteroaryl, or _NR 7 _{R 8,} in addition to the nitrogen atom N, O and S
Heterocyclic 5-10 membered saturated or unsaturated rings containing one or two additional heteroatoms selected from the group consisting of can be formed together.

One aspect of the invention is described wherein X is C and all other variables are as described above.

Another aspect of the present invention is described wherein X is N and all other variables are as described above.

R ₄ is C _1-10 alkyl, C _3-6 cycloalkyl, C _5-10 aryl,
C _5-10 heteroaryl, or C _3-10 heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one to three members selected from ^Ra , and Yet another aspect of the invention is described, wherein all variables are as described above.

In yet another aspect, R ₁ is C _1-10 alkyl, C _5-10 aryl, C _3-10 heterocyclyl, or C _5-10 heteroaryl, wherein said alkyl, aryl, heteroaryl and The invention is described wherein the heterocyclyl is optionally substituted with one to three members selected from ^Ra , and all other variables are as described above.

Preferred embodiments of the present invention are: R ₁ is H, C _1-10 alkyl, C _5-10 aryl, C _3-10 heterocyclyl, or C _5-10 heteroaryl; said alkyl, aryl, hetero Aryl and heterocyclyl are optionally substituted with one to three members selected from R ^a ; R ₂ and R ₃ are independently H, C _1-6 alkyl, C _3-6 cycloalkyl,
R ₄ is H, C _1-10 alkyl, C _3-6 cycloalkyl, C _5-10 aryl, C _5-10 heteroaryl, C _3-10 heterocyclyl, C _1-6 alkoxy; NR ₇ R ₈ , NO ₂ , OH, —NH _z , or the alkyl, aryl,
Heteroaryl and heterocyclyl are optionally substituted with one to three members selected from ^Ra ; and all other variables are as described above.

Another preferred embodiment of the present invention is: R ₁ is C _5-10 aryl, C _3-10 heterocyclyl or C _5-10 heteroaryl; said aryl, heteroaryl and heterocyclyl are selected from R ^a R ₂ and R ₃ are independently H or C _1-6 alkyl; R ₄ is C _1-10 alkyl, C _5-10 Aryl, C _5-10 heteroaryl, C _3-10 heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one to three members selected from R ^a ; Realized when all variables are as described above.

Yet another embodiment of the present invention provides a compound of formula IIa:

[0051]

Embedded imageOr a pharmaceutically acceptable salt, hydrate or prodrug thereof.
Wherein X and W are independently N or C;₁And R₃Is independently H, C_1-10Alkyl, C_3-6Cycloalkyl
, C_5-10Aryl, halo, OH, C_3-10Heterocyclyl or C_{5-1 0} Heteroaryl; said alkyl, alkenyl, alkynyl, aryl, f
Teroaryl and heterocyclyl are represented by R^aOne to three members selected from
Optionally substituted with₂Is independently H, C_1-6Alkyl, C_5-10Aryl, C_3-6Shiku
Low alkyl, OH, NO₂, -NH₂Or halogen; R₅Is independently H, C_1-10Alkyl, C_3-6Cycloalkyl, C_{1- 6} Alkoxy C_2-10Alkenyl, C_2-10Alkynyl, C_5-10Ants
, C_3-10Heterocyclyl, C_1-6Alkoxy NR₇R₈, Halo, NO ₂ , OH, -NH₂Or C_5-10Heteroaryl, said alkyl, alk
Nyl, alkynyl, aryl, heteroaryl and heterocyclyl are represented by R^aChoose from
Optionally substituted with one to three members selected; R₁₀Is H or C_1-6Alkyl, C_1-6Alkyl R₉, C_5-10A
Reel, C_3-10Heterocyclyl, NHC_1-6Alkyl R₉And the al
Kill (R is C_1-6Alkyl)), aryl, heteroaryl and hete
Rocyclyl is R^aOptionally substituted with one to three members selected from: R^aIs H, C_1-10Alkyl, halogen, NO₂, OR, -NR, RNR ₇ R₈, NR₇R₈, R₇R₈, CN, C_5-10Aryl, C_5-10Hetero
Aryl or C_3-10R is H, C_1-6Alkyl or C_1-6Alkyl R₉R₉Is C_5-10Aryl, C_3-10Heterocyclyl or C_5-10F
A teloaryl, wherein the aryl, heteroaryl and heterocyclyl are R^aOr
Optionally substituted with one to three members selected from₇And R₈Is independently H, C_1-10Alkyl, C_3-6Cycloalkyl
, COR, C_5-10Aryl, C_3-10Heterocyclyl or C_5-10F
A teloaryl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are
Lil is R^aOptionally substituted with one to three members selected from
Or NR⁷R⁸Is selected from the group consisting of N, O and S in addition to the nitrogen atom
Heterocyclic 5-10 membered saturated or unsaturated containing one or two additional heteroatoms
Saturated rings can be formed together.

One aspect of the present invention is described wherein X or W is independently C, and all other variables are as described above.

One aspect of the invention is described wherein X or W is independently N, and all other variables are as described above.

R ₁₀ is H, C _1-10 alkyl, C _1-6 alkyl R ₉ , C _5-10 aryl, C _5-10 heteroaryl, or C _3-10 heterocyclyl, wherein said alkyl, aryl , Heteroaryl and heterocyclyl are optionally substituted with one to three members selected from R ^a , and further aspects of the invention are described wherein all other variables are as described above.

Examples of compounds of the present invention are: 1) 1-phenyl-5- (4-methoxyphenyl) benzimidazole, 2) 1-phenyl-5- (4- (2- (1- Piperidinyl) ethoxy) phenyl) benzimidazole, 3) 3-phenyl-6- (4-methoxylphenyl) imidazo [4,5-b] pyridine, 4) 3-phenyl-6- (4- (2- (1- (1- Piperidinyl) ethoxy) phenyl) imidazo [4,5-b] pyridine, 5) 3-phenyl-6- (4- (2- (1-piperidinyl) ethoxyphenyl)
Imidazo [4,5-b] pyridine, 6) 3- (2-thiazoyl) -6- (4- (3- (1-piperidinyl) propylphenyl) imidazo [4,5-b] pyridine, 7) 1- (2-thiazoyl) -5- (4- (3- (1-piperidinyl) propyl) phenyl) benzimidazole, 8) 1- (3-thiophenyl) -5- (4- (3- (1-piperidinyl) propyl ) Phenyl) imidazo [4,5-b] pyridine, 9) 1- (3-thiophenyl) -5- (4- (3- (1-piperidinyl) propyl) phenyl) benzimidazole, 10) 3- (3- Thiophenyl) -6- (4- (3- (1-piperidinyl) propylphenyl) imidazo [4,5-b] pyridine, 11) 1-phenyl-5- [5- (2-piperidin-1-yl-ethoxy) )- Lysine-2-yl]-1H-benzimidazole, 12) 1- (4-cyanophenyl) -5- [6- (2-piperidin-1-yl -
Ethoxy) -pyridin-3-yl] -1H-benzimidazole, 13) 1-phenyl-5- [6- (2-piperidin-1-yl-ethoxy) -pyridin-3-yl] -1H-benzimidazole, 14) 1- (3-cyanophenyl) -5- [6- (2-piperidin-1-yl-
Ethoxy) -pyridin-3-yl] -1H-benzimidazole, 15) 1- (3-thiophene) -5- [6- (2-piperidin-1-yl-ethoxy) -pyridin-3-yl] -1H -Benzimidazole, 16) [5- (1-phenyl-1H-benzimidazol-5-yl) -pyridin-2-yl]-(2-piperidin-1-yl-ethyl) -amine, 17) [5 -(1-phenyl-1H-benzimidazol-5-yl) -pyridin-2-yl]-(2-morpholin-1-yl-ethyl) -amine, 18) 1- (3-pyridyl) -5- (4- (2- (1-piperidinyl) ethoxy) phenyl) benzimidazole, 19) 4- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-
Piperidin-1-yl-propyl) -1H-pyridin-2-one, 20) 4- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-
Piperidin-1-yl-ethyl) -1H-pyridin-2-one 21) 1- (2-morpholin-4-yl-ethyl) -4- (1-phenyl-1H
-Benzimidazol-5-yl) -1H-pyridin-2-one, 22) 1- (3-dimethylamino-propyl) -4- (1-phenyl-1H-benzimidazol-5-yl) -1H -Pyridin-2-one, 23) 1- (1-methyl-piperidin-3-ylmethyl) -4- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 24 ) 1- [3- (4-Methylpiperazin-1-yl) -propyl)]-4- (
1-phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 25) 1- (2-dimethylamino-propyl) -4- (1-phenyl-1H-benzimidazol-5) -Yl) -1H-pyridin-2-one, 26) 1- (3-dimethylamino-2-methyl-propyl) -4- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyridine -2-one, 27) 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -4- (1
-Phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 28) 1- (3-piperidin-1-yl-propyl) -4- (1-thiophene-
3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one,
29) 1- (3-Piperidin-1-yl-ethyl) -4- (1-thiophene-3
-Yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 30) 1- (2-morpholin-4-yl-ethyl) -4- (1-thiophen-3
-Yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 31) 1- (3-dimethylamino-propyl) -4- (1-thiophen-3-yl-1H-benzimidazo. Ru-5-yl) -1H-pyridin-2-one, 32) 1- (1-methyl-piperidin-3-ylmethyl) -4- (1-thiophen-3-yl-1H-benzimidazole-5- Yl) -1H-pyridin-2-one, 33) 1- [3- (4-methylpiperazin-1-yl) -propyl)]-4- (
1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 34) 1- (2-dimethylamino-propyl) -4- (1-thiophen-3-yl -1H-benzimidazol-5-yl) -1H-pyridin-2-one, 35) 1- (3-dimethylamino-2-methyl-propyl) -4- (1-thiophen-3-yl-1H- Benzimidazol-5-yl) -1H-pyridin-2-
On, 36) 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -4- (1
-Thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 37) 5- (1-phenyl-1H-benzimidazol-5-yl) -1- (3 −
Piperidin-1-yl-propyl) -1H-pyridin-2-one, 38) 5- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-
Piperidin-1-yl-ethyl) -1H-pyridin-2-one, 39) 1- (2-morpholin-4-yl-ethyl) -5- (1-phenyl-1H
-Benzimidazol-5-yl) -1H-pyridin-2-one, 40) 1- (3-dimethylamino-propyl) -5- (1-phenyl-1H-benzimidazol-5-yl) -1H -Pyridin-2-one, 41) 1- (1-methyl-piperidin-3-ylmethyl) -5- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 42 ) 1- [3- (4-Methylpiperazin-1-yl) -propyl)]-5- (
1-phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one 43) 1- (2-dimethylamino-propyl) -5- (1-phenyl-1H-benzimidazol-5) -Yl) -1H-pyridin-2-one, 44) 1- (3-dimethylamino-2-methyl-propyl) -5- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyridine -2-one, 45) 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -5- (
1-phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 46) 1- (3-piperidin-1-yl-propyl) -5- (1-thiophene-
3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one,
47) 1- (3-Piperidin-1-yl-ethyl) -5- (1-thiophene-3
-Yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 48) 1- (2-morpholin-4-yl-ethyl) -5- (1-thiophen-3
-Yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 49) 1- (3-dimethylamino-propyl) -5- (1-thiophen-3-yl-1H-benzimidazo. Ru-5-yl) -1H-pyridin-2-one, 50) 1- (1-methyl-piperidin-3-ylmethyl) -5- (1-thiophen-3-yl-1H-benzimidazol-5) Yl) -1H-pyridin-2-one, 51) 1- [3- (4-methylpiperazin-1-yl) -propyl)]-5- (
1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one 52) 1- (2-dimethylamino-propyl) -5- (1-thiophen-3-yl -1H-benzimidazol-5-yl) -1H-pyridin-2-one, 53) 1- (3-dimethylamino-2-methyl-propyl) -5- (1-thiophen-3-yl-1H- Benzimidazol-5-yl) -1H-pyridin-2-
On, 54) 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -5- (1
-Thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 55) 5- (1-phenyl-1H-benzimidazol-5-yl) -1- (3 −
Piperidin-1-yl-propyl) -1H-pyrimidin-2-one, 56) 5- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-
Piperidin-1-yl-ethyl) -1H-pyrimidin-2-one, 57) 1- (2-morpholin-4-yl-ethyl) -5- (1-phenyl-1H
-Benzimidazol-5-yl) -1H-pyrimidin-2-one, 58) 1- (3-dimethylamino-propyl) -5- (1-phenyl-1H-benzimidazol-5-yl) -1H. -Pyrimidin-2-one, 59) 1- (1-Methyl-piperidin-3-ylmethyl) -5- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 60 ) 1- [3- (4-Methylpiperazin-1-yl) -propyl)]-5- (
1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidine-2-
On) 61) 1- (2-dimethylamino-propyl) -5- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 62) 1- (3-dimethylamino -2-methyl-propyl) -5- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 63) 1- [2- (4-cyano-piperidin-1- Yl) -ethyl] -5- (1
-Phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 64) 1- (3-piperidin-1-yl-propyl) -5- (1-thiophene-
3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 65) 1- (3-piperidin-1-yl-ethyl) -5- (1-thiophen-3
-Yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one,
66) 1- (2-morpholin-4-yl-ethyl) -5- (1-thiophene-3
-Yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one,
67) 1- (3-dimethylamino-propyl) -5- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 68) 1- (1- Methyl-piperidin-3-ylmethyl) -5- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-
On, 69) 1- [3- (4-Methylpiperazin-1-yl) -propyl)]-5- (
1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 70) 1- (2-dimethylamino-propyl) -5- (1-thiophen-3-yl -1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 71) 1- (3-dimethylamino-2-methyl-propyl) -5- (1-thiophen-3-yl-1H- Benzimidazol-5-yl) -1H-pyrimidine-2
-One, 72) 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -5- (1
-Thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one; 73) 4- (1-phenyl-1H-benzimidazol-5-yl) -1- (3 −
Piperidin-1-yl-propyl) -1H-pyrimidin-2-one, 74) 4- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-
Piperidin-1-yl-ethyl) -1H-pyrimidin-2-one, 75) 1- (2-morpholin-4-yl-ethyl) -4- (1-phenyl-1H
-Benzimidazol-5-yl) -1H-pyrimidin-2-one, 76) 1- (3-dimethylamino-propyl) -4- (1-phenyl-1H-benzimidazol-5-yl) -1H. -Pyrimidin-2-one, 77) 1- (1-Methyl-piperidin-3-ylmethyl) -4- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 78 ) 1- [3- (4-Methylpiperazin-1-yl) -propyl)]-4- (
1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidine-2-
79) 1- (2-Dimethylamino-propyl) -4- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 80) 1- (3-dimethylamino -2-methyl-propyl) -4- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 81) 1- [2- (4-cyano-piperidin-1- Yl) -ethyl] -4- (1
-Phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 82) 1- (3-piperidin-1-yl-propyl) -4- (1-thiophene-
3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 83) 1- (3-piperidin-1-yl-ethyl) -4- (1-thiophen-3
-Yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one,
84) 1- (2-morpholin-4-yl-ethyl) -4- (1-thiophene-3
-Yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one,
85) 1- (3-dimethylamino-propyl) -4- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 86) 1- (1- Methyl-piperidin-3-ylmethyl) -4- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-
On, 87) 1- [3- (4-Methylpiperazin-1-yl) -propyl)]-4- (
1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 88) 1- (2-dimethylamino-propyl) -4- (1-thiophen-3-yl -1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 89) 1- (3-dimethylamino-2-methyl-propyl) -4- (1-thiophen-3-yl-1H- Benzimidazol-5-yl) -1H-pyrimidine-2
-One, 90) 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -4- (1
-Thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 91) 1- (4-pyridyl) -5- (4- (2- (1-piperidinyl) ethoxy). 92) 1- (3-pyridyl) -5- [6- (2-piperidin-1-yl-ethoxy) -pyridin-3-yl] -1H-benzimidazole, and 93) 1- (4-pyridyl) -5- [6- (2-piperidin-1-yl-ethoxy) -pyridin-3-yl] -1H-benzimidazole or a pharmaceutically acceptable salt, hydrate or pro-form thereof drag.

The invention described herein includes a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof, in combination with a carrier. As used herein, the terms “pharmaceutically acceptable salts” and “hydrates” refer to salts and hydrated forms of the compounds that are obvious to medicinal chemists, ie, the physical or pharmacokinetic properties of the compound. Refers to those that have a favorable effect on the biological properties, for example, solubility, palatability, absorption, distribution, metabolism and excretion. Equally important in choice,
Other factors that are more practical in practice are raw material cost, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.

When a compound of Formula I exists as a non-pharmaceutically acceptable salt or hydrate, it can be converted to a pharmaceutically acceptable salt or hydrate according to the present invention.

When the compound is negatively charged, it is balanced by a counter ion, for example, an alkali metal cation such as sodium or potassium. Other suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium, for example, tetramethylammonium, tetrabutylammonium, choline,
Triethylhydroammonium, meglumine, triethanolhydroammonium and the like. An appropriate number of counterions associate with the molecule to keep the overall charge neutral. Similarly, if the compound is positively charged, eg, protonated, there will be an appropriate number of negatively charged counterions to keep the overall charge neutral.

[0059] Pharmaceutically acceptable salts also include acid addition salts. Thus, the compounds can be used in the form of salts derived from inorganic or organic acids or bases. Examples include:
Acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglucone Acid salt, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptanate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodic acid Salt, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectate, persulfate, 3 -Phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoic acid It is included. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salt, N-methyl-D- Glucamine, as well as salts with amino acids, such as arginine,
Lysine and the like are included. Further, the basic nitrogen-containing group is a lower alkyl halide,
For example, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; and diamyl sulfates, long-chain halides, for example, chloride, bromide and decyl iodide, lauryl , Myristyl and stearyl, benzyl iodides and aralkyl halides such as phenethyl can also be quaternized. Other pharmaceutically acceptable salts include sulfate ethanolates and sulfates.

The compounds of the present invention may have asymmetric centers and may occur as racemates, racemic mixtures and individual diastereomers or enantiomers, and all isomeric forms are included in the present invention. When any variable (eg, aryl, heterocycle, R1, etc.) occurs more than one time in any constituent or in Formula I, the definition at each occurrence, unless otherwise stated, is defined at all other occurrences. Has nothing to do with its definition in the occurrence of.

The compounds of the present invention can be formulated into pharmaceutical compositions by combining the compounds with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below.

These compounds can be used in the form of a powder or a crystal, a solution or a suspension. These can be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.

Thus, the carrier used can be, for example, either a solid or liquid. Examples of solid carriers include lactose, gypsum, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water and the like.
Similarly, oral carriers can include slow release materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

Topical applications are formulated in hydrophobic or hydrophilic bases to form ointments, creams, lotions, formulated in aqueous, oily or alcoholic liquids to form paints, or dry diluents. It can be formulated therein to form a powder. Such topical formulations can be used to treat inflammatory diseases in addition to ocular diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis, delayed hypersensitivity reactions, and the like.

Examples of oral solid dosage forms include tablets, capsules, troches, lozenges, and the like. The dosage form will vary widely, but will preferably be from about 25 mg to about 500 mg. Examples of oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules, and the like. Examples of injectable dosage forms include sterile injectable solutions, for example, solutions, emulsions and suspensions. Examples of injectable solids include powders that reconstitute, dissolve or suspend before injection.

In injectable compositions, the carrier typically comprises sterile water, saline or other injectable liquid, for example, peanut oil for intramuscular injection. Similarly, various buffers, preservatives and the like can be included.

For the methods of treatment disclosed herein, the dosage may vary depending on the general condition of the patient, the nature of the disease being treated and other factors. An example of a suitable oral dosage range is about 0.1 to about 80 mg / kg daily, in single or divided doses.
Examples of suitable parenteral dosage ranges are from about 0.1 to about 80 mg / kg daily, in single or divided doses, administered by intravenous or intramuscular injection. An example of a topical dosage range is from about 0.1 mg to about 150 mg applied externally about 1 to 4 times a day. An example of an inhaled dosage range is from about 0.01 mg / kg to about 1 mg / kg daily.

The following examples illustrate compounds that can be synthesized, but they are not limited by the compounds in the table or by any substituents used in the schemes for illustration.

The compounds can be administered as a single agent or in combination with other therapeutically active compounds in the usual formulation. The following non-limiting examples are illustrative of the compounds of the present invention and are not intended to limit the invention in any way.

Embodiment 1

[0071]

Embedded image 1-bromo-4-fluoro-3-nitrobenzene (3) (1.14 mL, 9.
(0.6 mmol) was dissolved in 5 mL of anhydrous 1-methyl-2-pyrrolidinone under argon. After adding aniline (0.870 mL, 9.55 mmol), N,
N-Diisopropylethylamine (1.90 mL, 10.9 mmol) was added and the resulting solution was heated to 120C. After 14 hours, additional aniline (0.0
(82 mL, 0.90 mmol) and heating was continued for 8 hours. The reaction solution was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (3x). The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to 4
I got

¹ H NMR (CDCl ₃ ) δ 9.46 (bs, 1H), 8.35 (d, 1
H,. J = 2.4 Hz), 7.45-7.40 (m, 3H), 7.29-7.2
5 (m, 3H), 7.10 (d, 1H, J = 9.2 Hz).

[0073]

Embedded image Bromoaromatic 4 (0.218 g, 0.744 mmol) and 4-methoxy-boronic acid (0.125 g, 0.823 mmol) were added to dioxane (4 mL) and water (
3 mL). Sodium carbonate (0.60 g, 5.7 mmol)
Was added and the resulting mixture was degassed and placed under argon. Tetrakis (triphenylphosphine) palladium (0) (0.043 g, 0.037 mmol)
Was added and the reaction was heated to 80 ° C. After 14 hours, the reaction was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (3x). The combined extracts were washed with Na ₂ S
Dried over O ₄ , filtered and concentrated to dryness. Purification by flash column chromatography (2 × 16 cm silica gel, 6: 1 hexane / ethyl acetate) afforded 5.

¹ H NMR (CDCl ₃ ) d 9.48 (bs, 1H), 8.40 (d, 1
H, J = 2.4 Hz), 7.58 (dd, 1H, J = 2.4, 9.2 Hz), 7
. 50 (d, 2H, 9.0 Hz), 7.43 (t, 2H, J = 9.0 Hz), 7
. 32-7.22 (m, 4H), 6.98 (d, 2H, J = 9.0 Hz), 3.
83 (s, 3H).

[0075]

Embedded image 1-phenyl-5- (4-methoxyphenyl) benzimidazole (imid
aole) Nitroaniline 5 (0.213 g, 0.665 mmol) and palladium on carbon (10%, 100 mg) were stirred in 8 mL of 3: 1 EtOH / AcOH. The reaction was placed under a balloon of H _2. After 2 hours, the reaction was filtered through a plug of celite and the filtrate was concentrated to dryness. The obtained residue was dissolved in 1.5 mL of trimethyl orthoformate and heated at 120 ° C. for 30 minutes. The solution was cooled and concentrated to dryness, flash column chromatography (2 × 15 c
m silica gel, 1: 1 hexane / ethyl acetate) to give 6.

¹ H NMR (CDCl ₃ ) δ 8.14 (s, 1H), 8.04 (d, 1H)
, J = 0.9 Hz), 7.62-7.50 (m, 8H), 7.48 (t, 1H,
J = 7.1 Hz), 7.01 (d, 2H, J = 8.8 Hz), 3.87 (s, 3
H); FAB mass spectrometry _{^{[M + H] + 301.1;}} C 20 H 16 N 2 O analysis calculated for: C, 79.98; H, 5.37 ; N, 9.33. Observed value: C,
79.71; H, 5.48; N, 9.21.

[0077]

Embedded image Place benzimidazole 6 (0.039 g) in an oven-dried flask under argon.
, 0.13 mmol), aluminum chloride (0.175 g, 1.31 mmol)
, And sodium iodide (0.200 g, 1.33 mmol). Anhydrous acetonitrile (1 mL) and dichloromethane (0.5 mL) were added and the reaction was heated to reflux. After 44 hours, the reaction was cooled to ambient temperature, quenched with water and extracted 3 × with ethyl acetate. The combined extracts were dried over Na ₂ SO _4, filtered and concentrated to dryness. The residue obtained was triturated with ether, filtered and dried to give phenol 7.

¹ H NMR (CDCl ₃ ) δ 9.48 (s, 1H), 8.58 (s, 1H)
), 7.93 (s, 1H), 7.73-7.71 (m, 2H), 7.67-7.
63 (m, 3H), 7.57-7.49 (m, 4H), 6.86 (d, 2H, J
= 8.6 Hz).

[0079]

Embedded image 1-phenyl-5- (4- (2- (1-piperidinyl) ethoxy) phenyl)
Benzimidazole Benzimidazole 7 (0.025 g, 0.087 mmol) and N- (2-
Chloroethyl) piperidine hydrochloride (11 mg, 0.059 mmol) was treated with anhydrous N,
Dissolved in N-dimethylformamide (0.5 mL). Cesium carbonate (0.08
(5 g, 0.26 mmol) was added and the resulting mixture was heated to 50 ° C. 2 o'clock
After a while, additional N- (2-chloroethyl) piperidine hydrochloride (11 mg, 0.0
59 mmol) was added. After 1 hour, cool the reaction and quench the reaction with water
Extracted with ethyl acetate (3x). The combined extracts were washed with brine, Na₂SO ₄ , Filtered and concentrated to dryness. Flash column chromatography
Fee (2 × 16 cm silica gel, 9: 1 CH)₂Cl₂/ MeOH)
To give 8 as a colorless oil.

¹ H NMR (CDCl ₃ ) δ 8.14 (s, 1H), 8.03 (d, 1H
, J = 0.9 Hz), 7.62-7.50 (m, 8H), 7.48 (t, 1H,
J = 7.2 Hz), 7.01 (d, 2H, J = 8.8 Hz), 4.21 (bt,
2H, J = 5.3 Hz), 2.87 (bs, 2H), 2.59 (bs, 4H),
1.66 (bs, 4H), 1.48 (bs, 2H); mass spectrometry [M + H] ⁺ 398.3.

Embodiment 2

[0082]

Embedded image 5-Bromo-2-hydroxy-3-nitropyridine (9) (5.736 g, 0
. 0262 mol) and 15 mL of thionyl chloride were added under argon. Thereafter, N, N dimethylformamide (1 mL) was added, and the solution was brought to reflux temperature for 1 hour.
Heated for hours. At the end of the reaction, the bromohydroxynitropyridine was completely dissolved in the solution. After cooling to ambient temperature, 5 mL of toluene was added and the solution was concentrated under vacuum. The product, 5-bromo-2-chloro-3-nitropyridine, was a yellow crystalline solid.

The bromochloronitropyridine was dissolved in 15 mL of anhydrous 1-methyl-2-pyrrolidinone. After adding aniline (3.580 mL, 0.0393 mol), N
, N-diisopropylethylamine (13.69 mL, 0.0786 mol) was added and the solution was heated to 120 ° C. After 1.5 hours, the solution was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate and washed with brine.
Thereafter, the organic layer was dried over sodium sulfate, filtered, concentrated, and dried in vacuo. The crude product was purified by flash column chromatography (7.5 × 16c
m silica gel, 10: 1 hexane: ethyl acetate) to give 10.

¹ H NMR (CDCl ₃ ) δ 10.04 (bs, 1H), 8.65 (dd
, 1H, J = 2.2 Hz), 8.50 (dd, 1H, J = 2.4 Hz), 7.6
0 (d, 2H, J = 8.6 Hz), 7.40 (t, 2H, J = 7.5 Hz), 7
. 21 (t, 1H, J = 7.3 Hz).

[0085]

Embedded image After dissolving bromoaromatic 10 (30 mg, 0.102 mmol) and 4-methoxyphenylboronic acid (17 mg, 0.112 mmol) in 0.75 mL of dioxane, 204 μL of 2M sodium carbonate was added. After flushing the vessel with argon, tetrakis (triphenylphosphine) palladium (0) (6 mg
, 0.005 mmol) and 0.56 mL of water. The vessel was flushed again with argon and heated to 80 ° C. for 2.5 hours. The solution was cooled to room temperature and diluted with water. The product was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The organic layer was concentrated and the product was dried in vacuum. The crude mixture was purified by flash column chromatography (2.5 × 8 cm silica gel, 8:
(2 hexane: ethyl acetate) to give 11.

¹ H NMR (CDCl ₃ ) δ 10.09 (bs, 1H), 8.71 (dd
, 1H, J = 2.4 Hz), 8.66 (dd, 1H, J = 2.4), 7.67 (
d, 2H, J = 7.9), 7.49 (d, 2H, J = 8.8 Hz), 7.41 (
t, 2H, J = 7.7 Hz, 7.18 (t, 1H, J = 7.3 Hz), 7.0
0 (d, 2H, J = 8.6 Hz), 3.86 (s, 3H).

[0087]

Embedded image 3-phenyl-6- (4-methoxylphenyl) imidazo [4,5-b] pyridine nitroaniline 11 (1.333 g, 4.15 mmol), Zn dust (6.
(239 g, 95.40 mmol), and 10 mL of acetic acid were mixed under argon. The solution was heated to 60 ° C. for 1 hour until the solution became light green. The zinc dust was removed by vacuum filtration using celite and washed with acetic acid. The filtrate was concentrated to 20
mL of trimethyl orthoformate was added. The solution was heated to 100 ° C. for 2 hours and then cooled to ambient temperature. The solution was concentrated and the crude mixture was purified by flash column chromatography (5 × 16 cm silica gel, 6: 4 ethyl acetate: hexane) to give 12.

¹ H NMR (CDCl ₃ ) δ 8.61 (dd, 1 H, J = 2.0 Hz),
8.32 (s, 1H), 8.22 (dd, 1H, J = 2.0), 7.74 (d,
2H, J = 7.9 Hz), 7.55-7.50 (m, 4H), 7.39 (t, 1
H, J = 7.3), 6.99 (d, 2H, J = 8.8 Hz), 3.80 (s, 3
H). Mass spectrometry [M + H] ⁺ 302.3.

Embodiment 3

[0090]

Embedded image Imidazopyridine 12 (202 mg, 0.670 mmol) was added to hydrobromic acid 10
mL and 10 mL of acetic acid were added. The solution was stirred at room temperature for 5 minutes and then 100
Heated at ° C for 17 hours. The solution was cooled to ambient temperature and concentrated. Toluene (1
5 mL) was added and the solution was concentrated again. The concentrate was placed in vacuum for 40 minutes while heating at 40 ° C. and then further dried in vacuum at ambient temperature. Purification was performed by reverse phase column chromatography to give 13.

¹ H NMR (CD ₃ OD) δ 9.45 (s, 1H), 8.82 (dd, 1
H, J = 1.8 Hz), 8.37 (dd, 1H, J = 1.8 Hz), 7.91 (
d, 2H, J = 7.7 Hz), 7.68 (t, 2H, J = 8.1 Hz), 7.6
3-7.57 (m, 3H), 6.95 (d, 2H, J = 8.6 Hz).

[0092]

Embedded image 3-phenyl-6- (4- (2- (1-piperidinyl) ethoxy) phenyl)
Imidazo [4,5-b] pyridine Cesium carbonate (296 mg, .908 mmol) and 1- (2-chloroethyl) piperidine monohydrochloride (84 mg, .454 mmol) were flame-dried under argon in a round bottom flask. Added. Imidazopyridine 13 (87 mg, .303 mmol) was dissolved in 1.5 mL of anhydrous N, N dimethylformamide under argon. The vessel was heated at 50 ° C. for 16 hours and cooled to ambient temperature. The solution was diluted to 100 mL with saturated sodium bicarbonate and the product was extracted with ethyl acetate. The aqueous layer was extracted again with dichloromethane w / 3% 1-butanol. The organic layer was washed with saturated sodium bicarbonate and dried over sodium sulfate. The organic layers were concentrated under suction to remove ethyl acetate and methylene chloride; 1-butanol and residual DMF were removed under high pressure. The product is purified by flash column chromatography (silica gel 2.5 × 32.5 cm, 10: 1 methylene chloride: methanol)
Purified using An excess of trifluoroacetic acid was added to the product to form a salt, and the mixture was triturated with ether. The TFA salt was dried in vacuo with phosphorus pentoxide to give 14 (1.10 TFA salt).

¹ H NMR (CD ₃ OD) δ 8.66 (s, 1H), 8.55 (dd, 1
H, J = 2.0 Hz), 8.17 (dd, 1H, J = 2.0 Hz), 7.82 (
d, 2H, J = 8.6 Hz), 7.59-7.52 (m, 4H), 7.46 (t
, 1H, J = 7.5 Hz), 7.01 (d, 2H, J = 8.8 Hz), 4.85
(S, 2H), 4.15 (t, 2H, J = 5.5 Hz), 2.84 (t, 2H,
J = 5.5 Hz), 2.62 (bs, 4H), 1.65 (m, 4H), 1.50
(M, 2H). Analytical values calculated for C ₂₅ H ₂₆ N ₄ O · 1.10 TFA:
C, 62.35; H, 5.21; N, 10.69. Found: C, 62.32; H
, 4.93; N, 10.53.

Embodiment 4

[0095]

Embedded image Bromoaromatic 4 (7.10 g, 24.1 mmol) and powdered zinc (36.2)
g, 554 mmol, 23 eq.) in 80 mL of glacial acetic acid. The mixture was heated at 60 ° C. After 1 hour, the reaction was cooled and filtered through a plug of celite,
Concentrated to dryness. The obtained residue was dissolved in 60 mL of formic acid and heated at 100 ° C. overnight. The reaction was cooled and concentrated to dryness. Purification by flash column chromatography (6 × 25 cm silica, 55:45 hexane / EtOAc) provided 5.88 g of benzimidazole 15 (89% yield). ¹ H NM
R (CDCl ₃ ) δ 8.18 (s, 1H), 8.05 (d, 1H, J = 1.7)
Hz), 7.60 (t, 2H, J = 7.1 Hz), 7.54-7.48 (m, 3
H), 7.46 (dd, 1H, J = 1.8, 8.8 Hz), 7.40 (d, 1H)
, J = 8.8 Hz).

[0096]

Embedded image 1-Piperidineethanol (1.13 mL, 8.51 mmol) was dissolved in 10 mL of anhydrous DMF under Ar. The solution was cooled to 0 ° C and NaH (225m
g, 9.38 mmol). After 10 minutes, the mixture was warmed to room temperature and
Bromo-2-fluoropyridine (1.50 g, 8.52 mmol) was added.
After 1 hour, the reaction was quenched with water and extracted 3 × with EtOAc. The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give 2.20 g (91% yield) of alkoxypyridine 16. ¹ H NMR (CDCl ₃ ) δ 8.17 (d, 1H
, J = 2.6 Hz), 7.62 (dd, 1H, J = 2.6, 8.8 Hz), 6.
67 (d, 1H, J = 8.8 Hz), 4.40 (t, 2H, J = 6.0 Hz),
2.74 (t, 2H, J = 5.9 Hz), 2.49 (m, 4H), 1.60 (m
, 4H), 1.44 (m, 2H).

[0097]

Embedded image 1-phenyl-5- [6- (2-piperidin-1-yl-ethoxy) -pyridin-3-yl] -1H-benzimidazole benzimidazole 15 (2.91 g, 10.7 mmol), diboron pinacol ester (2.97 g, 11.7 mmol) and potassium acetate (3.14 g)
, 32.0 mmol) was stirred in 20 mL of anhydrous DMF under Ar. PdC
l ₂ (dppf) (0.26 g, 0.32 mmol) was added and the solution was degassed and heated to 80 ° C. After 20 hours, the reaction was quenched with 125 mL of water and 50 mL of saturated Na
Quenched with aqueous Cl and extracted 3 × with EtOAc. The combined extracts were washed with Na ₂ S
Dried over O ₄ , filtered and concentrated to give 2.77 g of crude borate. The crude borate (650 mg, 2.03 mmol), alkoxypyridine 16 (5
26 mg, 1.85 mmol) _was added 2M _Na 2 CO 3 (861mg, 8.12 mmol), and 4mL of dioxane in a round bottom flask. After flushing three times with argon, Pd (PPh ₃ ) ₄ (117 mg, 10 mmol) was added,
Again the vessel was flushed with argon three times. The vessel was heated to 80 ° C. under argon. After 22 hours, the reaction was cooled to room temperature and then quenched with 25 mL of water. The mixture was extracted with 4 × 20 mL of ethyl acetate and the combined organic layers were 1 ×
Washed with 20 mL of brine. The organic layer was dried over sodium sulfate, filtered and concentrated. Reversed phase column chromatography (Waters 2 × 40 mm C
Purification was performed using a −18 column, H ₂ O: acetonitrile mobile phase gradient). The resulting oil was triturated with ether, filtered and washed with ether to give 16, a white TFA salt (150 mg, 16% yield). Mp: 160.5-162 [deg.] C.

¹ H NMR (CDCl ₃ ) δ 8.41 (d, 1 H, J = 2.4 Hz), 8
. 19 (s, 1H), 8.01 (d, 1H, J = 1.3 Hz), 7.90 (dd
, 1H, J = 11.0 Hz), 7.61 (m, 3H, J = 13.6), 7.52
(M, 4H, J = 31.0 Hz), 6.86 (d, 1H, J = 8.4 Hz), 4
. 79 (t, 2H, J = 9.9 Hz), 3.76 (bd, 2H, J = 11.9H)
z), 3.51 (t, 2H, J = 9.7 Hz), 2.80 (bt, 2H, J = 2
3.1 Hz), 2.06 (m, 2H, J = 26.2 Hz), 1.89 (s, 2H
), 1.65 (s, 2H).

Embodiment 5

[0100]

Embedded image Process

[0101]

Embedded image 5-bromo-1-phenyl-1H-benzimidazole (11) (13.4 g)
, 49.1 mmol), 4-pyridylboronic acid (6.63 g, 54.0 mmol), palladium (II) acetate (551 mg, 2.45 mmol) and triphenylphosphine (1.93 g, 7.36 mmol) Was stirred under Ar in 80 mL of n-PrOH in a flask equipped with a reflux concentrator. Sodium carbonate (6
. 24 g, 58.9 mmol) was dissolved in 30 mL of water, and the resulting solution was treated with nPr
Added to the OH mixture. The resulting mixture was degassed three times by alternating vacuum and argon atmosphere. Thereafter, the reaction was heated to reflux. After 18 hours, the cooled reaction was diluted with water and extracted three times with EtOAc. The combined extracts were washed with saturated NaCl (aq), dried over sodium sulfate, filtered and concentrated. Flash column chromatography (95: 5 CH ₂ Cl ₂ / MeOH)
Yielded 8.82 g of 1-phenyl-5-pyridin-4-yl-1H-benzimidazole (yield 66%).

¹ H NMR (CDCl ₃ ) δ 8.68 (d, J = 6.0 Hz, 2H), 8
. 18 (s, 1H), 8.17 (s, 1H), 7.63-7.59 (m, 6H)
, 7.56-7.51 (m, 3H). Mass spectrometry _{(for ^{C 18 H 13 N 3):}} [M + H] + 272.1182, theory 272.1182.

[0103]

Embedded image 1-phenyl-5-pyridin-4-yl-1H-benzimidazole (12)
(8.82 g, 32.5 mmol) was dissolved in 120 mL of CH ₂ Cl ₂ . The resulting solution was cooled to 0 ° C. and added to mCPBA (11.2 g, 65.0 mmol). After stirring for 2.5 days, additional mCPBA (3.0 g, 17 mmol) was added. After an additional 24 hours, the reaction solution was applied directly to a column (8 × 20 cm) pre-wetted with CH ₂ Cl ₂ . 9: by flash column chromatography eluting with ₁ CH ₂ Cl ₂ / MeOH, the 7.40 g 5-(1-oxy -
(Pyridin-4-yl) -1-phenyl-1H-benzimidazole (13) (yield 79%) was obtained.

¹ H NMR (CDCl ₃ ) δ 8.40 (d, J = 6.0 Hz, 2H), 8
. 18 (s, 1H), 8.11 (d, J = 1.5 Hz, 1H), 7.66-7.
47 (m, 9H). Mass spectrometry _{(for ^{C 18 H 13 N 3):}} [M + H] + 288.1131, theory 288.1131.

5- (1-oxy-pyridin-4-yl) -1-phenyl-1H-benzimidazole (13)

[0106]

Embedded image (7.40 g, 25.8 mmol) in 48.6 mL of acetic anhydride (52.6 g,
515 mmol) and the resulting mixture was heated to reflux. After 8 hours, the reaction was concentrated to dryness and the resulting residue was dissolved in 50 mL of MeOH. Concentrated ammonium hydroxide (10 mL) was added and the solution was stirred for 16 hours.
Then concentrated to dryness the solution, the residue was purified by flash column chromatography _{(95: 5-90: 10 CH 2} Cl 2 / MeOH elution) 4.57 g of purified by 4- (1-phenyl -1H -Benzimidazol-5-yl)-
1H-pyridin-2-one (14) (yield 62%) was obtained. ¹ H NMR (CD
Cl ₃ ) δ 11.59 (bs, 1H), 8.18 (s, 1H), 8.13 (d
, J = 0.9 Hz, 1H), 7.64-7.60 (m, 4H), 7.55-7.
51 (m, 3H), 7.42 (d, J = 7.0 Hz, 1H), 6.88 (d, J
= 1.3 Hz, 1H), 6.65 (dd, J = 1.8, 7.0 Hz, 1H). Elemental analysis (for 0.40 hydrate): Calculated C, 73.40, H, 4.72, N
, 14.27; found C, 73.33, H, 5.00, N, 13.91.

4- (1-Phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one (14)

[0108]

Embedded image (4.57 g, 15.9 mmol) was dissolved in 30 mL of anhydrous DMF under Ar. Sodium iodide (2.86 g, 19.1 mmol), cesium carbonate (1
1.9 g, 36.6 mmol) and N-chloropropylpiperidine HCl salt (3
. (78 g, 19.1 mmol) was added and the reaction was warmed to 40 ° C. After 3 days, additional N-chloropropylpiperidine HCl salt (1.9 g, 9.6 mmol) and cesium carbonate (6.0 g, 18 mmol) were added. After an additional 16 hours, the bulk of DMF was removed in vacuo. The residue was diluted with water and extracted 3 × with 5% n-BuOH in _CH 2 Cl _2. The combined organic phases were dried over _Na 2 SO _4, filtered and concentrated. By preparative reverse-phase HPLC the residue in several batches, a sample was dissolved in MeOH, 5: 95 acetonitrile / water _(0.1% H 3 _PO 4)
And purified at 50:50. The fractions containing pure product were concentrated to remove the bulk of acetonitrile, basified to pH 8 with Na ₂ CO ₃ (s) and extracted 3 × with 5% BuOH in CH ₂ Cl ₂ . The combined organic phase was filtered by dried over _Na 2 SO _4, pure 4 (1-phenyl -1H- benzoimidazol-5-yl) concentrated to 3.70 g-1-(3- piperidin - 1-yl-propyl) -1H
-Pyridin-2-one (15) was obtained. ¹ H NMR (CDCl ₃ ) δ 8.1
7 (s, 1H), 8.10 (s, 1H), 7.63-7.50 (m, 7H), 7
. 45 (d, J = 7.1 Hz, 1H), 6.85 (d, J = 1.6 Hz, 1H)
, 6.52 (dd, J = 1.8, 7.1 Hz, 1H), 4.05 (t, J = 6.5.
8Hz, 2H), 2.38-2.34 (m, 4H), 2.00 (t, J = 6.8)
Hz, 2H), 1.65-1.58 (m, 6H), 1.45 (M, 2H). Elemental analysis: calculated value C, 75.70, H, 6.84, N, 13.58; actual value C, 75
. 32, H, 6.87, N, 13.37.

[0109]

Embedded image 5-bromo-1-phenyl-1H-benzimidazole (11) (9.71 g)
, 35.6 mmol), diboron pinacol ester (9.93 g, 39.1 mmol), potassium acetate (10.5 g, 107 mmol) and dichloro [1,1
'-Bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (0.78 g, 1.1 mmol) in 40 mL of anhydrous DM under Ar
Stirred in F. The solution was replaced by a vacuum and argon atmosphere
Degassed times. The reaction was heated to 80 ° C. for 18 hours. After cooling, the reaction was diluted with water and extracted 3 × with EtOAc. The combined organic phases are dried over Na ₂ SO ₄ , filtered and concentrated to 11.8 g of 1-phenyl-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane- 2-yl) -1H-benzimidazole (16) was obtained, which was used without purification.

[0110]

Embedded image Sodium hydride (0.073 g, 3.0 mmol) was stirred in 4 mL of anhydrous DMF under Ar. The solution was cooled to 0 C and 3-iodo-5-hydroxypyridine (0.305 g, 1.38 mmol) was added slowly. After the bubbling subsided, N-chloropropylpiperidine hydrochloride (0.330 g, 1.67 mmol) was added slowly. Thereafter, the reaction was warmed to ambient temperature. After 40 hours, the reaction was diluted with water and extracted 3 × with EtOAc. The combined organic phases are washed with saturated NaCl (
and washed with aq) dried over _Na 2 SO _4, filtered and concentrated. Flash column chromatography (2 × 16 cm silica, 9: 1 CH ₂ Cl ₂ / MeOH
), 192 mg of 5-iodo-1- (3-piperidin-1-yl-propyl) -1H-pyridin-2-one (18) (40% yield) was obtained. ¹ H N
MR (CDCl ₃ ) δ 7.72 (d, J = 2.6 Hz, 1H), 7.40 (d
d, J = 2.6, 9.5 Hz, 1H), 6.37 (d, J = 9.5 Hz, 1H)
3.96 (t, J = 6.6 Hz, 2H), 2.35 (bs, 4H), 2.26
(T, J = 6.6 Hz, 2H), 1.92 (t, 6.6 Hz, 2H), 1.60
(M, 4H), 1.46 (m, 2H).

[0111]

Embedded image 5-Iodo-1- (3-piperidin-1-yl-propyl) -1H-pyridin-2-one (18) (0.096 g, 0.28 mmol), 1-phenyl-5-
(4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-benzimidazole (0.081 g, 0.25 mmol), palladium (II) acetate (0.003 g , 0.013 mmol), triphenylphosphine (0.010 g, 0.038 mmol) and sodium carbonate (0.080 g,
(0.75 mmol) was stirred in 1.6 mL of a 3: 1 mixture of dioxane / water.
The mixture was degassed 3 × by alternating vacuum and argon atmosphere. The reaction was heated at 80 ° C. for 18 hours, cooled and diluted with water. The aqueous phase is EtO
Extracted 3 × with Ac and the resulting organic phase was dried over Na ₂ SO ₄ , filtered and concentrated. Flash column chromatography (85:15 CH ₂ Cl ₂ / MeO
Purification by elution with H) yielded 0.073 g of 5- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-piperidin-1-yl-propyl) -1H-.
Pyridin-2-one (19) (yield 71%) was obtained. ¹ H NMR (CDCl ₃ ) δ 9.60 (s, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.7
4-7.67 (m, 2H), 7.64-7.48 (m, 6H), 7.39 (dd
, J = 2.5, 9.5 Hz, 1H), 6.68 (d, J = 9.5 Hz, 1H),
4.13 (t, J = 6.5 Hz, 2H), 2.42 (bs, 6H), 2.10 (
t, J = 6.5 Hz, 2H), 1.64 (m, 4H), 1.46 (m, 2H).
Mass spectrometry _{(for ^{C 26 H 28 N 4 O)}} : [M + H] + 413.233
4, theoretical value 413.2336.

[0112]

Embedded image In a flame dried round bottom flask equipped with a stir bar, 1-phenyl-5- (4,4
4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1
H-benzimidazole (16) (2.00 g, 6.25 mmol), triphe
Nylphosphine (147 mg, .562 mmol) palladium (II) acetate (4
2 mg,. 187 mmol), 2M Na ₂ CO ₃ Aqueous solution (9.37 mL, 18
. 7 mmol), 4-chloro-2-methylthiopyrimidine (1.00 g, 6.2)
(4 mmol), 3 mL of water, and 14 mL of 1-propanol were added. Container
Flushed with argon three times and placed in an 80 ° C. oil bath with stirring. By HPLC
The reaction was complete after 1.7 hours, cooled to -RT and the solvent was removed under vacuum.
For work-up, dissolution in 150 mL of ethyl acetate, 50 mL of 1/2 saturated NaHC
O ₃ Add aqueous solution, extract, then re-extract the aqueous layer with 2 × 40 mL EtOAc.
Out was included. Wash the combined organics with 1.times.50 mL of 1/2 saturated saline
Na ₂ SO ₄ , Filtered and concentrated in vacuo. Flash column chromatography
Matography (60 mm x 200 mm silica gel, 20: 1 CH ₂ Cl ₂ :
(MeOH mobile phase) to give 1.54 g of compound (21) (yield
77%). 1H NMR (CDCl ₃ 7.) δ 8.64 (d, 1H);
56 (d, 1H), 8.20 (s, 1H), 8.18 (dd, 1H), 7.63
(M, 3H), 7.53 (m, 3H), 7.47 (d, 1H), 2.68 (s,
3H).

[0113]

Embedded image Oxone in water at 0 ° C. (potassium peroxymonosulfate, 11.87 g, 19.3)
(1 mmol) of the starting methylbenzimidazole sulfide (MeOH) in MeOH.
21) (1.54 g, 4.83 mmol) was added. The reaction mixture was warmed to RT and monitored by HPLC. Starting methyl sulfide changed from methyl sulfoxide to methyl sulfone over 12 hours. After the reaction was completed, the MeOH was removed under vacuum. The reaction mixture was extracted with 3 × 40 mL of CH ₂ Cl ₂ . The combined organic layers were washed with brine 40 mL, filtered and dried over _Na 2 SO _4, to give 1.5g of the solvent was removed under vacuum (22) (crude yield 90%).

¹ H NMR: (CDCl ₃ ) δ 8.92 (d, 1 H, J = 5.3 Hz),
8.66 (d, 1H, J = 1.6 Hz), 8.27 (dd, 1H, J = 1.6,
7.1 Hz), 8.23 (s, 1H), 8.00 (d, 1H, J = 5.4 Hz)
, 7.65 (m, 3H), 7.54 (m, 3H), 3.47 (s, 3H).

[0115]

Embedded image To a flask containing the starting methyl sulfone (500 mg, 1.427 mmol) was added 56% LiOH hydrate (244 mg, 5.708 mmol). To this vessel was added 5 mL of tetrahydrofuran and 5 mL of water. The reaction mixture was cooled to 0 ° C. for 2 hours and then gradually warmed to RT. The reaction was stirred at RT overnight. The reaction is complete after 20 hours, THF by low vacuum rotary evaporation and water by high vacuum rotary evaporation. The crude material was diluted with 15 mL of MeOH, sonicated, and filtered through a cotton and 0.7 μM syringe filter into a round bottom flask. The filtrate was concentrated to give 480 mg of crude product (23). The solvent was removed again by rotary evaporation.

¹ H NMR: (CD ₃ OD) δ 8.47 (s, 1H), 8.40 (s, 1
H), 8.20 (d, 1H, J = 5.2 Hz), 8.07 (dd, 1H, J = 1)
. 4, 7.3 Hz), 7.65 (m, 5H), 7.55 (m, 1H), 6.92
(D, 1H, J = 5.3Hz). High resolution mass spectrometry: measured mass = 289.1
068 (theoretical mass 289.1084).

[0117]

Embedded image Accommodates the starting benzimidazole (23) (66 mg, .229 mmol)
The flask was charged with N-3-chloropiperidine HCl (54 mg, .275 mmol),
Cesium carbonate (164 mg, .504 mmol) and 4 mL of anhydrous N, N-dimethyl
Tilformamide was added. The vessel is stirred under argon at 60 ° C. oil
Put in the bath. After 1 day the reaction was heated to 80 ° C. and after 4 days there was no further progress
After that, the reaction was stopped. The solvent is removed by high vacuum rotary evaporation and the residue is Me
Diluted with OH and filtered through a 0.7 μM syringe filter. Reverse phase column
Chromatography (Waters 2 × 40 mm C-18 stationary phase, 1% TF
ACN containing A: H ₂ O mobile phase gradient). By concentrating the appropriate HPLC fractions 2
Separate products were obtained-mass spectrometry (low res. M + 1 = 414.3)
as well as ¹ N-alkylated and O-alkylated isomers by 1 H NMR
confirmed. The yield of the TFA salt was: N-alkylated (24) (38.6 mg, yield
32%) and O-alkylation (not shown) (6.2 mg, 5% yield). 4
-(1-Phenyl-1H-benzimidazol-5-yl) -1- (3-piperidi
1-yl-propyl) -1H-pyrimidin-2-one ¹ H NMR is below
Is as follows: (CDCl ₃ ) Δ 8.63 (d, 1H, J = 7.9 Hz), 8
. 34 (d, 1H, J = 10.1 Hz), 7.92 (d, 1H, J = 6.9 Hz)
), 7.62 (m, 6H), 7.01 (d, 1H, J = 7.0 Hz), 4.11
(T, 2H, J = 7.0 Hz), 3.64 (m, 2H), 3.17 (m, 2H)
, 2.68 (m, 2H), 2.39 (m, 2H), 1.92 (m, 6H).

The following compounds can be made by literature methods and / or in combination with the methods disclosed herein.

[0119]

Embedded image Kinase inhibition is indicated according to the following protocol.

[0120]VEGF receptor kinase assay  VEGF receptor kinase activity is determined by converting radiolabeled phosphate to polyglutamic acid,
Syn is measured by incorporation into a 4: 1 (pEY) substrate. Phosphorylated pEY
The product is captured on a filter membrane and emitted by scintillation counting.
Quantify the uptake of labeled phosphate.

[0121]material  VEGF receptor kinase  Human KDR (Terman, BI, et al. Oncogene (1991) v
ol. 6, pp. 1677-1683) and Flt-1 (Shibuya, M .;
Oncogene (1990) vol. 5, pp. 519-524)
Glutathione S-transferase (GST)
) Cloned as a gene fusion protein. This is a cell of KDR kinase
Cloned at the carboxy terminus of the GST gene as an in-frame fusion
And achieved by. Soluble recombinant GST-kinase domain fusion protein
, Spodoptera frugiperda (Spodoptera frugiperda)
) (Sf21) Baculovirus in insect cells (Invitrogen)
Expression was performed using an expression vector (pAcG2T, Pharmingen).

[0122]Lysis buffer  50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM
EDTA, 0.5% triton X-100, 10% glycerol, leupe
Putin, pepstatin and aprotinin at 10 mg / ml and 1 mM respectively.
Phenylmethylsulfonyl iodide (all Sigma).

[0123]Wash buffer  50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM
EDTA, 0.05% triton X-100, 10% glycerol, Roy
Peptin, pepstatin and aprotinin at 10 mg / ml each and 1 mM
Phenylmethylsulfonyl fluoride.

[0124]Dialysis buffer  50 mM Tris pH 7.4, 0.5 M NaCl, 5 mM DTT, 1 mM
EDTA, 0.05% triton X-100, 50% glycerol, Roy
Peptin, pepstatin and aprotinin at 10 mg / ml each and 1 mM
Phenylmethylsulfonyl fluoride.

[0125]10x reaction buffer  200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl₂ , 10 mM DTT and 5 mg / ml bovine serum albumin (Sigma).

[0126]Enzyme dilution buffer  50 mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT, 10%
Glycerol, 100 mg / ml BSA.

[0127]10x substrate  750 μg / ml poly (glutamic acid, tyrosine; 4: 1) (Sigma).

[0128]Stop solution  30% trichloroacetic acid, 0.2 M sodium pyrophosphate (both Fishe
r).

[0129]Cleaning solution  15% trichloroacetic acid, 0.2 M sodium pyrophosphate.

[0130]Filter plate  Millipore #MAFC NOB, GF / C glass fiber 96 well.

[0131]Method  A.Protein purification  1. Infect Sf21 cells with recombinant virus at an infection efficiency of 5 virus particles / cell
And grown at 27 ° C. for 48 hours.

[0132] 2. All steps were performed at 4 ° C. The infected cells were collected by centrifugation at 1000 × g, lysed in 1/10 volume of lysis buffer at 4 ° C. for 30 minutes,
Centrifuged at 00,000 × g for 1 hour. Next, the supernatant was transferred to a glutathione Sepharose column (Pharmacia) equilibrated with lysis buffer and washed with 5 volumes of the same buffer, followed by 5 volumes of wash buffer. Recombinant GST-K
DR protein was eluted with wash buffer / 10 mM reduced glutathione (Sigma) and dialyzed against dialysis buffer.

B.VEGF receptor kinase assay  Add 1.5 μl of inhibitor or control to the assay in 50% DMSO.

2.5 μl of 10 × reaction buffer, 5 μl of 25 mM ATP / 10 μCi [ ³³ P] 35 μl containing ATP (Amersham) and 5 μl of 10 × substrate
Of the reaction mixture is added.

[0135] 3. The reaction is started by adding 10 μl of KDR (25 nM) in enzyme dilution buffer.

[0136] 4. Mix and incubate at room temperature for 15 minutes.

5. Stop by adding 50 μl stop solution.

6. Incubate at 4 ° C. for 15 minutes.

7. Transfer a 90 μl aliquot to the filter plate.

[0140] 8. Aspirate and wash three times with wash solution.

9. Add 30 μl of scintillation cocktail, seal the plate and add W
Count in an allac Microbeta scintillation counter.

[0142]Human umbilical vein endothelial cell mitogenesis assay  VEGF receptor expression mediates the mitogenic response to growth factors
Limited to ductal endothelial cells. Human umbilical vein endothelial cells (HUVECs) in culture
Effect of KDR kinase inhibitor on VEGF stimulation, proliferating in response to F treatment
Can be used as an assay system for quantifying In the assay described
Can be used to convert quiescent HUVEC monolayers to VEGF or basic fibroblast growth factor (bFG).
Treat with vehicle or test compound 2 hours before addition of F). VEGF or b
The mitogenic response to FGF is a response to cellular DNA [³H] Incorporation of thymidine
Determined by measuring.

[0143]material  HUVEC  HUVECs frozen as primary culture isolates were obtained from Clonetics Corp.
Obtained from. The cells were transferred to Endothelial Growth Medium (
EGM; Clonetics) and used for mitogenic assays at passages 3-7
I have.

[0144]Culture plate  NUNCLON 96-well polystyrene tissue culture plate (NUNC # 1
67008).

[0145]Assay medium  Dulbecco's modification of Eagle's medium containing 1 g / ml glucose (low glucose D
MEM; Mediatech) with 10% (v / v) fetal calf serum (Clonet)
ics).

[0146]Test compound  The inventory of test compounds is continuously made with 100% dimethyl sulfoxide (DMSO),
Dilute to 400 times higher than their desired final concentration. 1x from final dilution
The concentration is made directly in the assay medium just before adding the cells.

[0147]10x growth factor  Human VEGF₁₆₅(500 ng / ml; R & D Systems) and bF
A solution of GF (10 ng / ml; R & D Systems) was prepared in the assay medium.
To make.

[0148]10 × ^[3 H] thymidine  [Methyl-³H] thymidine (20 Ci / mmol; Dupont-NEN)
Dilute to 80 μCi / ml with low glucose DMEM.

[0149]Cell washing medium  1 mg / ml bovine serum albumin (Boehringer-Mannhei
m) Hank's Balanced Salt Solution (Mediatech).

[0150]Cell lysis solution  1N NaOH, 2% (w / v) Na₂CO₃.

[0151]Method  1. The HUVEC monolayer maintained in EGM was recovered by trypsinization and 96
4000 cells / 100 μl assay medium per well of well plate
Apply at a density. Cells are grown in 5% CO₂24 hours at 37 ° C in a humidified atmosphere containing
Growth-stop.

[0152] 2. The growth-stop medium is replaced with 100 μl assay medium containing either vehicle (0.25% [v / v] DMSO) or the desired final concentration of test compound. All decisions are made three times. The cells are then incubated for 2 hours at 37 ° C./5% CO ₂ to allow the test compound to enter the cells.

3. After a pre-treatment period of 2 hours, 10 μl / well of assay medium, 10 × V
Stimulate cells by adding either EGF solution or 10 × bFGF solution. Thereafter, the cells are incubated at 37 ° C./5% CO ₂ .

[0154] 4. After 24 hours in the presence of growth factors, 10 × [ ³ H] thymidine (10 μl / well) is added.

[0155] 5. Three days after the addition of [ ³ H] thymidine, the medium is removed by aspiration and the cells are washed twice with cell wash medium (400 μl / well, then 200 μl / well).
Next, the washed adherent cells were added to a cell lysis solution (100 μl / well) for 3 hours.
Solubilize by warming at 7 ° C. for 30 minutes. Transfer cell lysate to a 7 ml glass scintillation vial containing 150 μl water. Scintillation cocktail (5 ml / vial) is added and cell-related radioactivity is determined by liquid scintillation spectroscopy.

Based on the foregoing assays, the compounds of formula I are inhibitors of VEGF, and therefore are useful for inhibiting neovascularization, for example, in the treatment of ocular diseases, eg, diabetic retinopathy, and in cancer, eg, It is useful in the treatment of solid cancer. The compounds of the present invention inhibit VEGF-stimulated mitogenesis of human vascular endothelial cells in culture by 150-650 nM.
Inhibits with an IC ₅₀ value of In addition, these compounds are related tyrosine kinases (
It also shows selectivity for FGFR1 and Src family, for example.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/5377 A61K 31/5377 A61P 17/00 A61P 17/00 17/06 17/06 27/02 27 / 02 29/00 29/00 101 101 35/00 35/00 43/00 111 43/00 111 C07D 401/04 C07D 401/04 401/14 401/14 403/04 403/04 403/12 403/12 409 / 14 409/14 417/04 417/04 471/04 107 471/04 107Z (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH) , GM, KE, LS, MW, SD, SL, SZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GD, GE, HR, HU, ID, IL, IN, IS, JP, KG, KR, KZ, LC, LK, LR, LT, LV, MD, MG, MK, MN, MX , NO, NZ, PL, RO, RU, SG, SI, SK, SL, TJ, TM, TR, TT, UA, US, UZ, VN, YU. Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Cunningham, April M. United States of America, New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) ) Inventor Kester, Timothy J. United States, New Jersey 07065, Lowway, East Lincoln Avenue, 126 F-term (reference) 4C063 AA01 AA03 AA05 BB01 BB03 BB05 BB08 CC26 CC31 CC34 DD10 DD12 DD29 4C065 AA04 AA07 BB06 DD03 EE02 HH04 JJ01 KK08 PP08 4C086 AA01 AA02 AA03 BC21 BC39 BC42 CB05 GA07 GA08 MA02 MA05 MA17 MA22 MA23 MA28 MA35 MA37 MA52 MA55 MA63 MA66 ZA89 ZB11 ZB15 ZB26

Claims (33)

[Claims] 1. Formula Ia: ## STR1 ## (Where X is N or C; R ₁ and R ₃ are independently H, C _1-10 alkyl, C _3-6 cycloalkyl, C _5-10 aryl, halo, OH, C _{3- 10} heterocyclyl, or _{C 5-1 0} heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl is optionally substituted with 1 connected to three members selected from ^{R a:} _{R 2} is Independently, H, C _1-6 alkyl, C _5-10 aryl, C _3-6 cycloalkyl, OH, NO ₂ , —NH ₂ , or halogen; R ₄ and R ₅ are independently H, C _{1-10 alkyl, C 3-6 cycloalkyl, C 1-6} alkoxy C _{2-10 alkenyl, C 2-10 alkynyl, C 5-10 aryl, C 3-10} heterocyclyl, C _-6 alkoxy _NR 7 _{R 8, halo,} NO 2, OH, a -NH ₂ or _{C 5-10} heteroaryl, 1 said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl selected from ^{R a} Optionally substituted with one to three members,
Or R ₄ and R ₅ are one to three further heteroatoms selected from the group consisting of N, O and S, optionally substituted with one to three members selected from R ^a may together form a heterocyclic 5-9 membered saturated or unsaturated ring containing, ^{R a} _{is, H, C 1-10} alkyl, _halogen, NO 2, _{R, NHC 1-6} alkyl _R 9, _{oR, -NR, RNR 7 R 8} , NR 7 R 8, R 7 R 8, CN, C 5- 10 _{aryl, C 5-10} heteroaryl or _{C 3-10} heterocyclyl; R is, H, _{C 1 -6} alkyl or C _1-6 alkyl R ₉ ; R ₉ is C _5-10 aryl, C _3-10 heterocyclyl, or C _5-10 heteroaryl, wherein the aryl, heteroaryl and heterocyclyl are optionally substituted with 1 connected to three members selected from ^a; and R ₇ and _{R 8} are _{independently, H, C 1-10 alkyl, C 3-6} cycloalkyl, _{COR, C 5-10} aryl , a C _3-10 heterocyclyl, or C _{5-1 0} heteroaryl, said alkyl, aryl, heteroaryl and or heterocyclyl is optionally substituted with 1 connected to three members selected from R ^a, or NR ₇ R ₈ together form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one or two further heteroatoms selected from the group consisting of N, O and S be able to. Or a pharmaceutically acceptable salt, hydrate or prodrug thereof. 2. A compound according to claim 1, wherein X is C and all other variables are as described above. 3. A compound according to claim 1, wherein X is N and all other variables are as described above. Wherein R ₄ is _{C 1-10 alkyl, C 3-6 cycloalkyl,} a _{C 5 -10 aryl, C 5-10} heteroaryl, or _{C 3-10} heterocyclyl, said alkyl, aryl, heteroaryl The compound according to claim 1, wherein the aryl and heterocyclyl are optionally substituted with one to three members selected from ^Ra , and all other variables are as described above. Wherein R ₁ is _{C 1-10 alkyl, C 5-10 aryl,} a _{C 3-1 0} heterocyclyl, or _{C 5-10} heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl ^{R a} A compound according to claim 1, optionally substituted with one to three members selected from and wherein all other variables are as described above. 6. ^Ra is H, C _1-10 alkyl, halogen, C _1-6 alkyl R ₉ , CN, R, OR, NR, RNR ₇ R ₈ , NR ₇ R ₈ , R ₇ R ₈ . ,
2. A compound according to claim 1, wherein all other variables are as described above. Is 7. R ₁ and _{R 3, independently, H, C 1-10 alkyl, C 5-10 aryl, C 3-10} heterocyclyl, or _{C 5-10} heteroaryl; said alkyl, aryl, Heteroaryl and heterocyclyl are optionally substituted with one to three members selected from R ^a ; R ₂ is independently H, C _1-6 alkyl, C _3-6 cycloalkyl, OH, or halogen; R ₄ and R ₅ are independently H, C _1-10 alkyl, C _3-6 cycloalkyl, C _5-10 aryl, C _5-10 heteroaryl, C _3-10 heterocyclyl, C _1-6 An alkoxyNR ₇ R ₈ , NO ₂ , OH, —NH ₂ or wherein the alkyl, aryl, heteroaryl and heterocyclyl are 1 selected from ^Ra.
2. A compound according to claim 1, optionally substituted with one to three members; and all other variables are as described above. 8. R ₁ and R ₃ are independently C _5-10 aryl, C _3-10 heterocyclyl, or C _5-10 heteroaryl; said aryl, heteroaryl and heterocyclyl are selected from R ^a. Optionally substituted with one to three members: R ₂ is H or C _1-6 alkyl; R ₄ is optionally substituted with one to three members selected from R ^a , Piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidine, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl Pyridyl, pyrazinyl, pyrimidinyl, pyrimidinyl, pyridinonyl, pyrida Dinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzothiazolyl , Tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl; and all other variables are as described above. The compound according to claim 7, wherein 9. Structural formula: embedded image(Where X is N or C; R₁Is H, C_1-10Alkyl, C_3-6Cycloalkyl, C_5-10Ants
, Halo, OH, C_3-10Heterocyclyl or C_5-10Heteroaryl
The alkyl, alkenyl, alkynyl, aryl, heteroaryl and
Heterocyclyl is R^aOptionally substituted with one to three members selected from
R; R₂And R₃Is independently H, C_1-6Alkyl, C_5-10Aryl, C_{3 -6} Cycloalkyl, OH, NO₂, -NH₂Or halogen; R₄Is H, C_1-10Alkyl, C_3-6Cycloalkyl, C_1-6Arco
Kishi C_2-10Alkenyl, C_2-10Alkynyl, C_5-10Aryl, C _3-10 Heterocyclyl, C_1-6Alkoxy NR₇R₈, NO₂, OH, -N
H₂Or C_5-10Heteroaryl, said alkyl, alkenyl, alkynyl
, Aryl, heteroaryl and heterocyclyl are represented by R^aOne selected from
Optionally substituted with three members; R₅Is H or C_1-6Alkyl, OR, halo, NH₂Or NO₂In
R; R^aIs H, C_1-10Alkyl, halogen, NO₂, OR, -NR, NR₇ R₈, R₇R₈, C_5-10Aryl, C_5-10Heteroaryl or C_{3-1 0} R is H, or C_1-6Alkyl, C_1-6Alkyl R₉R₉Is C_5-10Aryl, C_3-10Heterocyclyl or C_5-10F
Teroaryl; and R₇And R₈Is independently H, C_1-10Alkyl, C_3-6Cycloalkyl
, COR, C_5-10Aryl, C_3-10Heterocyclyl or C_{5-1 0} Is heteroaryl or NR₇R₈Means N, O and S in addition to the nitrogen atom
A heterocyclic ring containing one or two further heteroatoms selected from the group consisting of
5-10 membered saturated or unsaturated rings can be formed together. Or a pharmaceutically acceptable salt, hydrate or prodrug thereof. 10. A compound according to claim 9, wherein X is C and all other variables are as described above. 11. A compound according to claim 9, wherein X is N and all other variables are as described above. 12. R₄Is C_1-10Alkyl, C_3-6Cycloalkyl, C _5-10 Aryl, C_5-10Heteroaryl, or C_3-10Heterocyclyl
Wherein the alkyl, aryl, heteroaryl and heterocyclyl are R^aOr
Optionally substituted with one to three members selected from:
10. The compound according to claim 9, wherein the variables are as described above. 13. R ₁ is a _{C 1-10 alkyl, C 5-10 aryl, C 3- 10} heterocyclyl, or _{C 5-10} heteroaryl, said alkyl, aryl, heteroaryl, and heterocyclyl of ^{R a} 1 to 3 to be selected
10. A compound according to claim 9 optionally substituted with one member and all other variables are as described above. 14. R ₁ is H, C _1-10 alkyl, C _5-10 aryl,
C _3-10 heterocyclyl, or C _5-10 heteroaryl; wherein the alkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one to three members selected from ^Ra ; R ₂ and R ₃ is independently H, C _1-6 alkyl, C _3-6 cycloalkyl,
R ₄ is H, C _1-10 alkyl, C _3-6 cycloalkyl, C _5-10 aryl, C _5-10 heteroaryl, C _3-10 heterocyclyl, C _1-6 alkoxy; NR ₇ R ₈ , NO ₂ , OH, —NH _z , or the alkyl, aryl,
The compound according to claim 9, wherein heteroaryl and heterocyclyl are optionally substituted with one to three members selected from ^Ra ; and all other variables are as described above. 15. R ₁ is C _5-10 aryl, C _3-10 heterocyclyl, or C _5-10 heteroaryl; said aryl, heteroaryl and heterocyclyl are one to three selected from ^Ra . members are optionally substituted with; _{R 2} and _{R 3} are, independently, H or _{C 1-6} alkyl; _{R 4 is C 1-10 alkyl, C 5-10 aryl, C 5-10} heteroaryl Aryl, C _3-10 heterocyclyl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one to three members selected from ^Ra ; and all other variables are as described above. The compound according to claim 9, which is 16. Structural formula IIa:(Where X and W are independently N or C; R₁And R₃Is independently H, C_1-10Alkyl, C_3-6Cycloalkyl
, C_5-10Aryl, halo, OH, C_3-10Heterocyclyl or C_{5-1 0} Heteroaryl; said alkyl, alkenyl, alkynyl, aryl, f
Teroaryl and heterocyclyl are represented by R^aOne to three members selected from
Optionally substituted with₂Is independently H, C_1-6Alkyl, C_5-10Aryl, C_3-6Shiku
Low alkyl, OH, NO₂, -NH₂Or halogen; R₅Is independently H, C_1-10Alkyl, C_3-6Cycloalkyl, C_{1- 6} Alkoxy C_2-10Alkenyl, C_2-10Alkynyl, C_5-10Ants
, C_3-10Heterocyclyl, C_1-6Alkoxy NR₇R₈, Halo, NO ₂ , OH, -NH₂Or C_5-10Heteroaryl, said alkyl, alk
Nyl, alkynyl, aryl, heteroaryl and heterocyclyl are represented by R^aChoose from
Optionally substituted with one to three members selected; R₁₀Is H or C_1-6Alkyl, C_1-6Alkyl R₉, C_5-10A
Reel, C_3-10Heterocyclyl, NHC_1-6Alkyl R₉And the al
Kill (R is C_1-6Alkyl)), aryl, heteroaryl and hete
Rocyclyl is R^aOptionally substituted with one to three members selected from: R^aIs H, C_1-10Alkyl, halogen, NO₂, OR, -NR, RNR ₇ R₈, NR₇R₈, R₇R₈, CN, C_5-10Aryl, C_5-10Hetero
Aryl or C_3-10R is H, C_1-6Alkyl or C_1-6Alkyl R₉R₉Is C_5-10Aryl, C_3-10Heterocyclyl or C_5-10F
A teloaryl, wherein the aryl, heteroaryl and heterocyclyl are R^aOr
Optionally substituted with one to three members selected from₇And R₈Is independently H, C_1-10Alkyl, C_3-6Cycloalkyl
, COR, C_5-10Aryl, C_3-10Heterocyclyl or C_5-10F
A teloaryl, wherein said alkyl, aryl, heteroaryl and heterocyclyl are
Lil is R^aOptionally substituted with one to three members selected from
Or NR₇R₈Is selected from the group consisting of N, O and S in addition to the nitrogen atom
Heterocyclic 5-10 membered saturated or unsaturated containing one or two additional heteroatoms
Saturated rings can be formed together. Or a pharmaceutically acceptable salt, hydrate or prodrug thereof. 17. The compound according to claim 16, wherein X or W is independently CH, and all other variables are as described above. 18. A compound according to claim 16, wherein X or W is independently N, and all other variables are as described above. 19. R₁₀But H, C_1-10Alkyl, C_1-6Alkyl R ₉ , C_5-10Aryl, C_5-10Heteroaryl, or C_3-10Heteroshi
A krill, wherein the alkyl, aryl, heteroaryl and heterocyclyl are
R^aOptionally substituted with one to three members selected from the group consisting of
17. The compound according to claim 16, wherein all variables are as described above. 20. 1-phenyl-5- (4-methoxyphenyl) benzimidazole, 1-phenyl-5- (4- (2- (1-piperidinyl) ethoxy) phenyl) benzimidazole, 3-phenyl-6 (4-methoxylphenyl) imidazo [4,5-b] pyridine, 3-phenyl-6- (4- (2- (1-piperidinyl) ethoxy) phenyl) imidazo [4,5-b] pyridine, 3-phenyl -6- (4- (2- (1-piperidinyl) ethoxyphenyl) imidazo [4,5-b] pyridine, 3- (2-thiazoyl) -6- (4- (3- (1-piperidinyl) propylphenyl ) Imidazo [4,5-b] pyridine, 1- (2-thiazoyl) -5- (4- (3- (1-piperidinyl) propyl) phenyl) benzimidazole, 1- ( - thiophenyl) -5- (4- (3- (1-piperidinyl) propyl)
Phenyl) imidazo [4,5-b] pyridine, 1- (3-thiophenyl) -5- (4- (3- (1-piperidinyl) propyl)
Phenyl) benzimidazole, 3- (3-thiophenyl) -6- (4- (3- (1-piperidinyl) propylphenyl) imidazo [4,5-b] pyridine, 1-phenyl-5- [5- (2 -Piperidin-1-yl-ethoxy) -pyridin-2-yl] -1H-benzimidazole, 1- (4-cyanophenyl) -5- [6- (2-piperidin-1-yl-ethoxy) -pyridine- 3-yl] -1H-benzimidazole, 1-phenyl-5- [6- (2-piperidin-1-yl-ethoxy) -pyridin-3-yl] -1H-benzimidazole, 1- (3-cyanophenyl ) -5- [6- (2-Piperidin-1-yl-ethoxy) -pyridin-3-yl] -1H-benzimidazole, 1- (3-thiophene) -5- [6- (2-pipe 1-yl - ethoxy)
-Pyridin-3-yl] -1H-benzimidazole, [5- (1-phenyl-1H-benzimidazol-5-yl) -pyridin-2-
Yl]-(2-piperidin-1-yl-ethyl) -amine, [5- (1-phenyl-1H-benzimidazol-5-yl) -pyridin-2-
Yl]-(2-morpholin-1-yl-ethyl) -amine, 4- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-piperidin-1-yl-propyl) -1H -Pyridin-2-one, 4- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-piperidin-1-yl-ethyl) -1H-pyridin-2-one, 1- ( 3-pyridyl) -5- (4- (2- (1-piperidinyl) ethoxy) phenyl) benzimidazole, 1- (4-pyridyl) -5- (4- (2- (1-piperidinyl) ethoxy) phenyl) Benzimidazole, 1- (3-pyridyl) -5- [6- (2-piperidin-1-yl-ethoxy)-
Pyridin-3-yl] -1H-benzimidazole and 1- (4-pyridyl) -5- [6- (2-piperidin-1-yl-ethoxy)-
Pyridin-3-yl] -1H-benzimidazole or a pharmaceutically acceptable salt, hydrate or prodrug thereof. 21. 1- (2-morpholin-4-yl-ethyl) -4- (1-
Phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one,
1- (3-dimethylamino-propyl) -4- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- (1-methyl-piperidin-3-ylmethyl) -4- (1-phenyl-1H
-Benzimidazol-5-yl) -1H-pyridin-2-one, 1- [3- (4-methylpiperazin-1-yl) -propyl)]-4- (1-phenyl-1H-benzimidazol -5-yl) -1H-pyridin-2-one, 1- (2-dimethylamino-propyl) -4- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one 1- (3-dimethylamino-2-methyl-propyl) -4- (1-phenyl-1
H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -4- (1-phenyl-1H-benzimidazo. Ru-5-yl) -1H-pyridin-2-one, 1- (3-piperidin-1-yl-propyl) -4- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- (3-piperidin-1-yl-ethyl) -4- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2 -One, 1- (2-morpholin-4-yl-ethyl) -4- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- ( 3-dimethylamino-propyl) -4- (1-thio E down-yl -1
H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- (1-methyl-piperidin-3-ylmethyl) -4- (1-thiophen-3
-Yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- [3- (4-methylpiperazin-1-yl) -propyl)]-4- (1-thiophen-3 -Yl-1H-benzimidazol-5-yl) -1H-pyridine-
2-one, 1- (2-dimethylamino-propyl) -4- (1-thiophen-3-yl-1
H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- (3-dimethylamino-2-methyl-propyl) -4- (1-thiophene-
3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one,
1- [2- (4-cyano-piperidin-1-yl) -ethyl] -4- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2
-One, 5- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-piperidin-1-yl-propyl) -1H-pyridin-2-one, 5- (1-phenyl- 1H-benzimidazol-5-yl) -1- (3-piperidin-1-yl-ethyl) -1H-pyridin-2-one, 1- (2-morpholin-4-yl-ethyl) -5- ( 1-phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- (3-dimethylamino-propyl) -5- (1-phenyl-1H-benzimidazol-5-yl ) -1H-pyridin-2-one, 1- (1-methyl-piperidin-3-ylmethyl) -5- (1-phenyl-1H
-Benzimidazol-5-yl) -1H-pyridin-2-one, 1- [3- (4-methylpiperazin-1-yl) -propyl)]-5- (1-phenyl-1H-benzimidazol -5-yl) -1H-pyridin-2-one, 1- (2-dimethylamino-propyl) -5- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyridin-2-one 1- (3-dimethylamino-2-methyl-propyl) -5- (1-phenyl-1
H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -5- (1-phenyl-1H-benzimidazo. Ru-5-yl) -1H-pyridin-2-one, 1- (3-piperidin-1-yl-propyl) -5- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- (3-piperidin-1-yl-ethyl) -5- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2 -One, 1- (2-morpholin-4-yl-ethyl) -5- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- ( 3-dimethylamino-propyl) -5- (1-thio E down-yl -1
H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- (1-methyl-piperidin-3-ylmethyl) -5- (1-thiophen-3
-Yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- [3- (4-methylpiperazin-1-yl) -propyl)]-5- (1-thiophen-3 -Yl-1H-benzimidazol-5-yl) -1H-pyridine-
2-one, 1- (2-dimethylamino-propyl) -5- (1-thiophen-3-yl-1
H-benzimidazol-5-yl) -1H-pyridin-2-one, 1- (3-dimethylamino-2-methyl-propyl) -5- (1-thiophene-
3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2-one,
1- [2- (4-cyano-piperidin-1-yl) -ethyl] -5- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyridin-2
-One, 5- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-piperidin-1-yl-propyl) -1H-pyrimidin-2-one, 5- (1-phenyl- 1H-benzimidazol-5-yl) -1- (3-piperidin-1-yl-ethyl) -1H-pyrimidin-2-one, 1- (2-morpholin-4-yl-ethyl) -5- ( 1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- (3-dimethylamino-propyl) -5- (1-phenyl-1H-benzimidazol-5-yl ) -1H-Pyrimidin-2-one, 1- (1-methyl-piperidin-3-ylmethyl) -5- (1-phenyl-1H
-Benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- [3- (4-methylpiperazin-1-yl) -propyl)]-5- (1-phenyl-1H-benzimidazol -5-yl) -1H-pyrimidin-2-one,
1- (2-dimethylamino-propyl) -5- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- (3-dimethylamino-2-methyl-propyl) ) -5- (1-Phenyl-1)
H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -5- (1-phenyl-1H-benzimidazo. Ru-5-yl) -1H-pyrimidin-2-one, 1- (3-piperidin-1-yl-propyl) -5- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- (3-piperidin-1-yl-ethyl) -5- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2 -One, 1- (2-morpholin-4-yl-ethyl) -5- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- ( 3-dimethylamino-propyl) -5- 1- thiophen-3-yl -1
H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- (1-methyl-piperidin-3-ylmethyl) -5- (1-thiophen-3
-Yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one,
1- [3- (4-methylpiperazin-1-yl) -propyl)]-5- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one; 1- (2-dimethylamino-propyl) -5- (1-thiophen-3-yl-1
H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- (3-dimethylamino-2-methyl-propyl) -5- (1-thiophene-
3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -5- (1-thiophene- 3-yl-1H-benzimidazol-5-yl) -1H-pyrimidine-
2-one, 4- (1-phenyl-1H-benzimidazol-5-yl) -1- (3-piperidin-1-yl-propyl) -1H-pyrimidin-2-one, 4- (1-phenyl -1H-benzimidazol-5-yl) -1- (3-piperidin-1-yl-ethyl) -1H-pyrimidin-2-one, 1- (2-morpholin-4-yl-ethyl) -4- (1-Phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- (3-dimethylamino-propyl) -4- (1-phenyl-1H-benzimidazol-5- Yl) -1H-pyrimidin-2-one, 1- (1-methyl-piperidin-3-ylmethyl) -4- (1-phenyl-1H
-Benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- [3- (4-methylpiperazin-1-yl) -propyl)]-4- (1-phenyl-1H-benzimidazol -5-yl) -1H-pyrimidin-2-one,
1- (2-dimethylamino-propyl) -4- (1-phenyl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- (3-dimethylamino-2-methyl-propyl ) -4- (1-Phenyl-1)
H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -4- (1-phenyl-1H-benzimidazo. Ru-5-yl) -1H-pyrimidin-2-one, 1- (3-piperidin-1-yl-propyl) -4- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- (3-piperidin-1-yl-ethyl) -4- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2 -One, 1- (2-morpholin-4-yl-ethyl) -4- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- ( 3-dimethylamino-propyl) -4- 1- thiophen-3-yl -1
H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- (1-methyl-piperidin-3-ylmethyl) -4- (1-thiophen-3
-Yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one,
1- [3- (4-methylpiperazin-1-yl) -propyl)]-4- (1-thiophen-3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one; 1- (2-dimethylamino-propyl) -4- (1-thiophen-3-yl-1
H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- (3-dimethylamino-2-methyl-propyl) -4- (1-thiophene-
3-yl-1H-benzimidazol-5-yl) -1H-pyrimidin-2-one, 1- [2- (4-cyano-piperidin-1-yl) -ethyl] -4- (1-thiophene- 3-yl-1H-benzimidazol-5-yl) -1H-pyrimidine-
A compound according to claim 1 which is 2-one, or a pharmaceutically acceptable salt, hydrate or prodrug thereof. 22. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, in combination with a carrier. 23. A method for treating or preventing cancer in a mammalian patient in need of such treatment, comprising administering to said patient an anticancer effective amount of a compound of claim 1. A method comprising: 24. The method for treating or preventing cancer according to claim 23, wherein the cancer includes brain, urogenital, lymphatic, stomach, laryngeal and lung cancer. 25. The method according to claim 23, wherein the cancer comprises histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, geoblastoma, and breast cancer. 26. A method for treating or preventing a disease involving neovascularization, wherein the compound or a pharmaceutically acceptable salt thereof is used in a mammalian patient in need of such treatment. Administering a prodrug or hydrate in an amount effective to reduce neovascularization. 27. The method according to claim 26, wherein the disease is a disease of the eye. 28. A method of treating or preventing retinal neovascularization, wherein the compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof is administered to a mammalian patient in need of such treatment. Alternatively, a method comprising administering a hydrate in an amount effective to treat retinal neovascularization. 29. A method for treating or preventing diabetic retinopathy, wherein the compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof is administered to a mammalian patient in need of such treatment. Alternatively, a method comprising administering an amount of a hydrate effective to treat diabetic retinopathy. 30. A method for treating or preventing age-related macular degeneration, comprising administering to a mammalian patient in need of such treatment a compound of claim 1 or a pharmaceutically acceptable salt thereof. A method comprising administering a drug or hydrate in an amount effective for inflammation. 31. A method for treating or preventing an inflammatory disease, comprising administering to a mammalian patient in need of such treatment a compound of claim 1 or a pharmaceutically acceptable salt, prodrug or a pharmaceutically acceptable salt thereof. A method comprising administering the hydrate in an amount effective for inflammation. 32. The method according to claim 31, wherein the inflammatory disease comprises rheumatoid arthritis, psoriasis, contact dermatitis and a delayed hypersensitivity reaction. 33. A method of inhibiting tyrosine kinase comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of the composition of claim 1.