KR20050072824A - Indolyl pyrazinone derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis - Google Patents

Abstract

This invention relates to a compound of Formula I (I)and its use in treating hyper-proliferative disorders and diseases associated with angiogenesis.

Description

Indolyl Pyrazinone Derivatives Useful for Treating Hyper-Proliferative Disorders and Diseases Associated with Angiogenesis}

The present invention relates to novel indolyl pyrazinone compounds, pharmaceutical compositions comprising the compounds and the use of the compounds and compositions for the prevention and / or treatment of hyperproliferative diseases and diseases associated with angiogenesis.

Compound of the Invention

One embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.

here,

Represents a 6-membered aromatic ring containing 0, 1 or 2 N atoms;

R ¹ and R ² are H; Halo; CF ₃ ; C (O) R ⁹ ; ;

(C ₁ -C ₆ ) alkyl optionally substituted with up to 2 substituents selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl;

And N [(C ₁ -C ₃₎ alkyl] ₂ a (wherein alkyl is twice or less each independently (C ₁ -C ₃₎ are optionally substituted with alkoxy) each independently optionally substituted with substituents selected from 1 or 2, (C ₁ -C ₆ ) alkoxy;

OH, F, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , NH (C ₁ -C ₃ ) alkyl, phenyl, pyrrolidinyl, and NH (C ₁ -C ₃ ) alkyl having alkyl optionally substituted with up to 2 substituents each independently selected from;

OH, F, phenyl, and (C ₁ -C ₃ ) alkoxy, where alkoxy N [(C ₁ -C ₃ ) alkyl] ₂ having alkyl independently optionally substituted with up to 2 substituents independently selected from each other;

N [(C ₁ -C ₃₎ alkyl] ₂ less than twice an optionally substituted pyrrolidinyl;

Phenyl optionally substituted with up to 2 substituents each independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN

Are each independently selected from If it contains 1 or 2 N atoms, R ¹ and R ² must each be H,

R ¹ and R ² together with the adjacent C atoms to which they are attached, Conditionally that the ring is formed only when it does not contain this N atom, a ring selected from benzo, dioxo and imidazo, wherein the imidazo is optionally substituted no more than twice with (C ₁ -C ₃ ) alkyl. Forming;

R ³ is H, (C ₁ -C ₄ ) alkyl, OH, NO ₂ , NH ₂ , NH (C ₁ -C ₄ ) alkyl, NHC (O) (C ₁ -C ₄ ) alkyl and NHC (O) phenyl Wherein said phenyl is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN);

R ⁴ is H; OH; Halo; CN; C (O) R ⁶ ; S (O) ₂ R ⁷ ; OSi [(C ₁ -C ₄₎ alkyl] _3; Tetrazolyl; Thienyl; Pyrrolyl; Pyrimidinyl; Oxazolyl; Furanyl;

Each optionally OH, F, OC (O) NHphenyl, NHC (O) (C ₁ -C ₃ ) alkyl, C (O) NH ₂ , C (O) NH (C ₁ -C ₃ ) alkyl, C (O _{) N [(C 1 -C 3} ) alkyl] _2, ,

(C ₁ -C ₃ ) alkoxy optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy,

NHC (O) NH (C ₁ -C ₃ ) alkyl (the alkyl is optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F and phenyl),

NHC (O) NHphenyl (The phenyl is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , CN, and Optionally substituted with up to 2 substituents independently selected from

NHC (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is optionally substituted independently up to two times with (C ₁ -C ₃ ) alkoxy,

NH-phenyl (the phenyl is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CN, and Optionally substituted with up to 2 substituents independently selected from

N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy,

(C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CN, CF ₃ , and Phenyl optionally substituted with up to 2 substituents independently selected from

N [(C ₁ -C ₃₎ alkyl] ₂ less than twice an optionally substituted pyrrolidinyl

(C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₂ -C ₆ ) alkynyl substituted with;

(C ₁ -C ₃ ) alkoxy, pyrrolidinyl, , And N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted with up to 2 substituents independently selected from OH, F, (C ₁ -C ₃ ) alkoxy and phenyl) (C ₁ -C ₆ ) alkoxy optionally substituted with up to 2 substituents independently selected from;

N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each of said alkyl groups is 2 or less independently selected from OH, (C ₁ -C ₃ ) alkyl, F, (C ₁ -C ₃ ) alkoxy, and phenyl Is optionally substituted independently with a substituent of;

Oxadiazolyl optionally substituted up to twice with (C ₁ -C ₃ ) alkyl;

(C ₁ -C ₃ ) alkoxy, CN, (C ₁ -C ₃ ) alkyl, halo, , ,

C (O) (C ₁ -C ₃ ) alkyl (optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkoxy, OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl) , And

C (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each said alkyl group is independently optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy

Phenyl optionally substituted with up to 2 substituents independently selected from;

Pyridyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl;

C (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each said alkyl group is optionally substituted independently up to two times with (C ₁ -C ₃ ) alkoxy; And

O-pyridyl optionally substituted with up to 2 substituents independently selected from CF ₃ , halo, and (C ₁ -C ₃ ) alkyl

Is selected from;

R ⁵ is selected from H, halo, CN, (C ₁ -C ₆ ) alkoxy, and (C ₁ -C ₆ ) alkyl;

R ⁶ is OH; NHR ¹⁰ ; O- (C ₃ -C ₆ ) cycloalkyl; (C ₁ -C ₃ ) alkoxy; O- (C ₂ -C ₆ ) alkenyl; O- (C ₃ -C ₆ ) alkynyl;

(C ₁ -C ₆ ) alkyl optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl;

N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each said alkyl group is OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₃ ) alkoxy, S (O) Independently with up to 2 substituents independently selected from ₂ -phenyl, S (O) ₂ (C ₁ -C ₃ ) alkyl, phenyl, furyl, tetrahydrofuryl, (C ₃ -C ₆ ) cycloalkyl, and pyridyl Optionally substituted);

N [(C ₁ -C ₃ ) alkyl] R ⁸ , wherein [(C ₁ -C ₃ ) alkyl] is optionally substituted no more than twice with (C ₁ -C ₃ ) alkoxy;

N [(C ₃ -C ₆ ) cycloalkyl] (C ₁ -C ₃ ) alkyl, wherein said alkyl is (C ₁ -C ₃ ) alkoxy, OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ Up to ₂ independently selected from S (O) ₂ -phenyl, S (O) ₂ (C ₁ -C ₃ ) alkyl, phenyl, furyl, tetrahydrofuryl, (C ₅ -C ₆ ) cycloalkyl, and pyridyl Is substituted with a substituent of;

NH ₂ , NH (C ₁ -C ₃ ) alkyl, N [(C ₁ -C ₄ ) alkyl] ₂ , C (O) NH ₂ , NHC (O) (C ₁ -C ₃ ) alkyl, NHS (O) ₂ (C ₁ -C ₃ ) alkyl, pyridyl, N [(C ₁ -C ₃ ) alkyl] C (O) NH (C ₁ -C ₃ ) alkyl, N [(C ₁ -C ₃ ) alkyl] C Independent from (O) (C ₁ -C ₃ ) alkyl, and (C ₁ -C ₃ ) alkyl (N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₃ ) alkoxy, and pyrrolidinyl Optionally substituted with up to 2 substituents selected from: pyrrolidinyl optionally substituted with up to 2 substituents independently selected;

(C ₁ -C ₃₎ optionally less than two times substituted with alkyl know morpholinyl;

(C ₁ -C ₃₎ the double or less of alkyl optionally substituted thiomorpholinyl;

Pyrazinyl, C (O) NH ₂ , C (O) NH-phenyl, C (O) -furanyl, C (O) (C ₁ -C ₃ ) alkyl, C (O) NH (C ₁ -C ₃ ) Alkyl, C (O) N [(C ₁ -C ₃ ) alkyl] R ⁸ , S (O) ₂ (C ₁ -C ₃ ) alkyl, S (O) ₂ -phenyl, ,

Pyridyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN and CF ₃ ,

Phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN, halo, CF ₃ , and (C ₁ -C ₃ ) alkoxy,

OH, F, phenyl, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , pyrrolidinyl, C (O) -pyrrolidinyl, , And (C ₁ -C ₃ ) alkyl optionally substituted with up to 2 substituents independently selected from pyridyl (optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy)

Piperazinyl optionally substituted with up to 2 substituents independently selected from; And

Piperidinyl optionally substituted with up to 2 substituents independently selected from phenyl, pyridyl, pyrrolidinyl and oxo-dihydrobenzimidazolyl

Is selected from;

R ⁷ is NH ₂ ; Pyrrolidinyl; ;

NH (C ₁ -C ₃ ) alkyl, wherein said alkyl is optionally substituted up to two times with (C ₁ -C ₃ ) alkoxy;

NH-phenyl (the phenyl is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN, (C ₁ -C ₄ ) alkoxy, halo and CF ₃ );

N [(C ₁ -C ₃₎ alkyl] _2, (wherein each alkyl is optionally substituted with twice or less independently alkoxy (C ₁ -C _4)); And

Phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ and CN

Is selected from;

R ⁸ is (C ₁ -C ₃ ) alkoxy; Pyridyl; Piperidinyl; Selected from pyranyl and phenyl, each ring moiety optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkoxy, and (C ₁ -C ₃ ) alkyl;

R ⁹ is (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy; OH; ;

Phenyl optionally substituted with (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN;

N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each said alkyl group is OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₄ ) alkoxy, S (O) _{2-phenyl, S (O) 2 (C} 1 -C 3) alkyl, it is optionally independently substituted with phenyl, furyl, tetrahydrofuryl, (C ₃ -C ₆₎ cycloalkyl, and pyridyl); And

N [(C ₁ -C _{3) alkyl],} optionally substituted pyrrolidinyl as

Is selected from, Only when is not containing N atoms, R ⁹ is also selected from pyridyl, thienyl, and NHR ¹⁰ ;

R ¹⁰ is H; Indolyl;

OH, F, phenyl, (C ₁ -C ₄ ) alkoxy, NHC (O) (C ₁ -C ₃ ) alkyl, S- (C ₁ -C ₃ ) alkyl, benzimidazolyl, indolyl, thienyl, Pyrazolyl, ,

N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl),

(C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, CN, halo, CF ₃ , S (O) ₂ (C ₁ -C ₃ ) alkyl, S (O) ₂ phenyl, and phenyl optionally substituted with up to 2 substituents independently selected from S (O) ₂ NH ₂ ,

Pyridyl optionally substituted up to twice with CF ₃ ,

Imidazolyl optionally substituted up to twice with (C ₁ -C ₃ ) alkyl,

Furyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl, and

Optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkoxy, (O), and (C ₁ -C ₄ ) alkyl (OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl Pyrrolidinyl optionally substituted with up to 2 substituents independently selected from

(C ₁ -C ₄ ) alkyl optionally substituted with up to 2 substituents independently selected from;

S (O) ₂ -phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₃ ) alkyl, halo, and CN;

(C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, and phenyl (the phenyl is (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, halo, CF ₃ , and CN Optionally substituted with up to 2 substituents independently selected from pyrazolyl optionally substituted with up to 2 substituents independently selected from;

Benzothiazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl;

Thiazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl;

Thiadiazolyl optionally substituted with up to 2 substituents independently selected from CF ₃ , (C ₃ -C ₆ ) cycloalkyl, and (C ₁ -C ₆ ) alkyl;

CN, _{halo, CF 3, N [(C} 1 -C 4) alkyl] _2, indolyl, ,

O-pyridyl optionally substituted with C (O) NH (C ₁ -C ₄ ) alkyl,

Pyridyl, Optionally, OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl, and (C ₁ -C ₄ ) alkoxy (N [(C ₁ -C ₄ ) alkyl] ₂ where one alkyl group is optionally substituted with phenyl Substituted), or With an optionally substituted (C ₁ -C ₄₎ alkoxy optionally in the substituents selected independently 2 or less substituted (C ₁ -C ₄₎ alkyl

Phenyl optionally substituted with up to 2 substituents independently selected from;

Pyridyl optionally substituted with phenoxy, wherein the phenoxy is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkyl and (C ₁ -C ₄ ) alkoxy; And

Indazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl

Is selected from;

R ¹¹ And R ¹² are independently selected from H, F and Cl, provided that one of R ¹¹ and R ¹² is F or Cl, the other must be H;

X is selected from O, S, CH ₂ , and NH,

When X is NH, H on NH is pyridyl, pyrazinyl, phenyl,

Or OH, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , C (O) -pyrrolidinyl, N [(C ₁ -C ₄ ) alkyl] ₂ , and phenyl ( Said phenyl is optionally substituted with up to 2 substituents independently selected from CN and (C ₁ -C ₃ ) alkoxy) (C ₁ -C ₄ ) alkyl optionally substituted with up to 2 substituents independently selected from

Is replaced by

When X is O, S, or CH ₂ , Part Optionally substituted by replacing any H atoms on the moiety with (C ₁ -C ₄ ) alkyl.

The terms used above have the following meanings:

Terms Represents a 6-membered aromatic ring having 0, 1 or 2 N atoms. That is, one embodiment of Ar is an aromatic ring having 6 C atoms. The 6 C atom contains a 2 C atom whose Ar ring shares with an adjacent pyrazinone ring. This definition also includes the replacement of one or two C atoms of the aromatic ring with an N atom. The N atom may be located at any position of the aromatic ring except that it cannot be located adjacent to the C atom shared by the pyrazinone ring adjacent to the Ar ring. Examples of six-membered aromatic N-containing rings include pyrido, pyrimido, pyrazino, and pyridazo.

When R ¹ and R ² together form a ring, each of R ¹ and R ² is attached to an adjacent C atom which is shared with the Ar ring, thereby R ¹ / R ² Ring is R ¹ / R ² R ¹ and R ² are each independently attached to any available C atom on the Ar ring, except that the ring and the Ar ring are fused to the Ar ring through two adjacent C atoms shared.

R ⁴ is attached to 5 or 6 atoms of the indolyl portion of the central molecule.

R ⁵ is attached to the central molecule at a portion not occupied by the R ⁴ groups of 5 or 6 atoms of the indole portion. In other words, when R ⁴ is attached to 5 atoms of the indolyl moiety, R ⁵ is attached to 6 atoms of the indolyl moiety and vice versa.

The term "optionally substituted" means that unless otherwise indicated, the modified moiety may have from 1 to at least 2 indicated substituents. Each substituent can replace any H atom on the modified moiety as long as the replacement is chemically possible and chemically stable. For example, chemically labile compounds are those in which each two substituents are bonded to a single C atom through the heteroatom of each substituent. Another example of a chemically labile compound is an alkoxy group bonded to the unsaturated carbon of the alkene to form an enol ether. When there are two substituents in any part, each substituent is selected independently of the other substituents, and thus the substituents may be the same or different.

The terms “(C ₁ -C ₃ ) alkyl” and “(C ₁ -C ₄ ) alkyl” and “(C ₁ -C ₆ ) alkyl” each represent about 1 to about 3, about 4, or about 6 C atoms. It refers to a linear or branched saturated carbon group containing. Such groups include, but are not limited to, methyl, ethyl, n -propyl, isopropyl, and the like.

The term "(C ₃ -C ₆ ) cycloalkyl" means a saturated monocyclic alkyl group having 3 to about 6 C atoms and includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "(C ₂ -C ₆ ) alkenyl" has from about 2 to about 6 C atoms, and when a C atom is bonded by a double bond to one adjacent C atom, it must be a single bond to any other adjacent C atom On the condition that two or more adjacent C atoms in the alkenyl group are bonded to a linear or branched carbon group bonded by a double bond. Alkenyl groups are attached to the rest of the molecule through a single bond.

The term (C ₂ -C ₆ ) alkynyl has about 2 to about 6 C atoms, and when a C atom is bonded by a triple bond to one adjacent C atom, it must be a single bond to any other adjacent C atom Under the conditions, it is meant a linear or branched carbon group wherein at least two adjacent C atoms in the alkynyl group are bonded by triple bonds. Alkynyl groups are attached to the rest of the molecule by a single bond.

The terms "(C ₁ -C ₃ ) alkoxy", "(C ₁ -C ₄ ) alkoxy" and "(C ₁ -C ₆ ) alkoxy" each represent about 1 to about 3, about 4, or about 6 C atoms And a linear or branched saturated carbon group attached to an O atom. The O atom is the attachment portion of the alkoxy substituent to the rest of the molecule. Such groups include, but are not limited to, methoxy, ethoxy, n -propoxy, isopropoxy and the like.

The term "halo" means an atom selected from Cl, Br, F and I.

The term "phenoxy" refers to a phenyl ring attached to an O atom attached to the rest of the molecule.

When "(O)" is used in the formula, it means = O. That is, = O means that the O atom is double bonded to the C or S atom to which it is attached.

The formula “N [C ₁ -C ₃ ) alkyl] ₂ ” means that each of the two possible alkyl groups attached to the N atom is selected independently of the rest and thus they may be the same or different.

When a phenyl ring or heterocycle is attached to the rest of the molecule, it is attached by replacing any H atom on the phenyl ring or heterocycle, respectively, with a bond to the rest of the molecule, so long as the replacement is chemically possible and chemically stable.

Means morpholinyl, thiomorpholinyl, piperidinyl or piperazinyl. Each is optionally substituted as described above.

Representative compounds of the invention are shown by way of example in Table 1.

Asymmetry, that is, the mirror image of the compound cannot overlap with the compound, may exist in the compound of formula (I) due to the inherent structure of the molecule. Examples of such asymmetric molecules include certain allenyl compounds. The compounds of the present invention may also contain one or more asymmetric centers depending on the position and nature of the various substituents selected. A molecule having a single asymmetric center can be a mixture of enantiomers (R, S), or a single (R) or (S) enantiomer. A molecule having one or more asymmetric centers may be a mixture of diastereomers, or a single diastereomer. In addition, compounds may exhibit asymmetry due to limited rotation of a given bond, eg, a central bond that bonds two substituted aromatic rings of a particular compound. All such configurations and forms (including enantiomers, diastereomers, and other optical isomers) are intended to be included within the scope of this invention. Separate, pure or partially purified stereoisomers of compounds of formula (I) are each within the scope of the present invention. Preferred compounds are those that have an absolute configuration or form that give them more desirable biological activity.

The use of pharmaceutically acceptable salts of the compounds of the invention is also within the scope of the invention. The term "pharmaceutically acceptable salts" means one of the inorganic or organic salts of the compounds of the present invention having acceptable properties for the intended therapeutic use. See, eg, SM Berge, et al. "Pharmaceutical Salts", J. Pharm . Sci . 1977 , 66, 1-19.

Representative salts of the compounds of the present invention include conventional non-toxic salts and quaternary ammonium salts prepared from organic or inorganic acids or bases, for example, by methods known in the art. For example, the acid addition salt may be acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, Cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydrogen iodide Acid salts, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulphate Pate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thio Oh sulfonate, tosylate, and undecanoate is. The term acid addition salt also includes hydrates and solvent addition forms in which the compounds of the present invention can form. Examples of such forms are, for example, hydrates, alcoholates and the like.

Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. In addition, basic nitrogen containing groups include methyl, ethyl, propyl, and lower alkyl halides such as butyl chloride, bromide and iodide; Dialkyl sulfates including dimethyl, diethyl, and dibutyl sulfate; Quaternized with agents such as diamyl sulfate, decyl, lauryl, myristyl and stearyl chloride, long chain halides such as bromide and iodide, aralkyl halides such as benzyl and phenethyl bromide, and others Can be.

Esters of suitable compounds of the invention are pharmaceutically acceptable esters such as alkyl esters including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters and the like. Although methyl esters are preferred, additional esters such as phenyl- (C ₁ -C ₅ ) alkyl can be used.

Unless otherwise expressly indicated in the context, whenever the terms “compound of the invention”, “compound of the invention” and the like are used herein, they are chemically possible pharmaceutically acceptable salts and / or esters and referenced compounds All stereoisomeric forms of are included.

Process for the preparation of compounds of the present invention

In general, the compounds used in the present invention are commercially available, routine, customary chemical methods, or by standard techniques known in the art, known methods similar thereto, and / or methods described herein, or It can be prepared using starting materials preparable according to the synthesis described herein.

Typically, R ³ is H, (C ₁ -C ₄₎ alkyl, or of the formula (I), formula (Ia) OH [wherein R ³ is H], (Ib) [wherein R ³ is NO _2], and Compounds of (Ic) wherein R ³ is NH ₂ can be synthesized as shown in Scheme 1. Compounds of formula (I) wherein R ³ is OH require protection of the OH group prior to the first step; Deprotection may occur during the third step. Compounds of formula (I) wherein R ³ is (C ₁ -C ₄ ) alkyl are described in Zeitschrift fuer, incorporated herein by reference from (Ia), where R ³ is H. Naturforschung, Teil B: Anorganische Chemie, Organische Chemie, 30B (11-12), 954-8; 1975 by a three step procedure similar to the procedure of [1975]. Protecting groups are used, except for compounds wherein R ¹ or R ² are optionally substituted amines or pyrrolidinyl (see Scheme 4) or R ³ is H and R ⁴ is S (O) ₂ R ⁷ (see Scheme 11) Treatment of the substituted indole of formula (II) yields an N -protected indole of formula (III). The compound of formula (III) can then be deprotonated and quenched using an electrophile to provide a dicarbonyl indole compound of formula (IV). The compound of formula (IV) may be condensed with the aryl 1,2-diamine of formula (V) to produce a compound of formula (Ia). Nitrification of the compound of formula (Ia, wherein R ³ is H) can provide 3-nitroindole compounds of formula (Ib), wherein R ³ is NO ₂ . Reduction of the nitro functional group of the compound of compound (Ib) can provide a compound of formula (Ic) wherein R ³ is NH ₂ .

Scheme 1

Formula (II) compound is easily available, or Scheme 15 to obtain the (R ⁴ is an optionally substituted phenyl or optionally for the synthesis of compounds of the pyridyl formula (II) substituted), and scheme 16 (R ⁴ Boc protected for the synthesis of compounds of formula (II) [ie, formula (III)], which is (C ₁ -C ₄ ) alkoxy optionally substituted by Scheme 19 (R ⁴ is N [(C ₁ -C ₃₎ ) Alkyl] ₂ for the synthesis of compounds of formula (II), Scheme 21 (for the synthesis of compounds of formula (II), wherein R ³ is H).

Compounds of formula (V) are readily available or substituted Scheme 14 readily available as this di-nitro compound, or substituted See Scheme 20, which is readily available as this nitroaniline compound.

Compounds wherein R ³ is NH (C ₁ -C ₄ ) alkyl, NHC (O) (C ₁ -C ₄ ) alkyl, or NHC (O) phenyl are synthesized starting with the compound of formula (Ic) according to Scheme 5. do.

Schemes 2, 3, 5 to 10, 12 and 13 each represent a starting material of formula (Ia) [applicable when R ³ is H, or as R ³ is alkyl, as in Scheme 8, formula (Ia)] R ⁴ -sub-group compounds of (Ib) (applicable when Schemes 2, 3, 6, 7, 9, 10, 12 and 13, R ³ is NO ₂ , or H, or alkyl) It describes a method for preparing a compound having a specific R ⁴ subgroup. As described above, the compound of formula (Ic) from Scheme 1, wherein R ³ is NH ₂ and R ⁴ is as defined, without limitation, is a compound wherein R ³ is NH (C ₁ -C ₄ ) according to Scheme 5. Can be converted to a compound that is alkyl, NHC (O) (C ₁ -C ₄ ) alkyl, or NHC (O) phenyl.

Scheme 2 shows how compounds of formula (I) where R ³ is NO ₂ and R ⁴ is CN can be converted to compounds of formula (I) wherein R ⁴ is C (O) R ⁶ by standard functional group manipulations. . For example, cyanoindole (Id) can be hydrolyzed to indole carboxylic acid (Ie) under basic conditions. Coupling of an acid (Ie) with an amine provides amides of various formulas (If).

Scheme 2

Another compound of formula (I), wherein R ³ is NO ₂ and R ¹¹ and R ¹² are both H, is characterized by a two-step procedure using an imidazolyl carbonyl intermediate as shown in Scheme 3 followed by an acid by a reduction reaction ( Can be prepared by the conversion of Ie) to an alcohol of formula (Ig). Treatment of alcohol (Ig) with a halogenating agent such as SOBr ₂ gives the compound of formula (Ih). Reaction of halide (Ih) with either alcohol or amine produces ether (Ii) or amine (Ij), respectively.

Scheme 3

Compounds of formula (Ik) in which the Ar ring is benzo, R ¹ or R ² are amino substituents and R ³ is H can be prepared as shown in Scheme 4. The conversion of difluoronitrobenzene of formula (VI) to aniline of formula (VII) is carried out by ammonia replacement of fluoronitrobenzene. Substitution of the second fluoro group from the compound of formula (VII) by the amine of formula (VIII) provides a phenylenediamine intermediate of formula (IX). Following reduction of the nitro group in (IX), intramolecular condensation with ketoester (IV) gives a compound of formula (Ik).

Scheme 4

Compounds of formula (Ic) wherein R ³ is NH ₂ may be alkylated or acylated to yield compounds of formula (Im) as shown in Scheme 5.

Scheme 5

The preparation of compounds of formula (In) wherein R ³ is NO ₂ and R ⁴ is an amido substituted pyrrolidine amide, prepared using the method described in Scheme 2, is shown in Scheme 6. Pyrrolidine amide (In) can be converted to a primary amine derivative (Io), which can be acylated to provide the amide (Ip).

Scheme 6

Compounds of formula (Iq) wherein R ³ is NO ₂ and R ⁴ is acylsulfonamide are prepared as shown in Scheme 7. Indole carboxylic acid (Ie) reacts with sulfonamide to produce sulfonyl carboxamide (Iq).

Scheme 7

The preparation of compounds of formula (It) wherein R ³ is H and R ⁴ is a pyridyloxy group is shown in Scheme 8. The methoxyindole of formula (Ir) can be converted to hydroxyindole (Is) as shown and then coupled with halopyridine to provide a biaryl ether (It).

Scheme 8

Other compounds of formula (Iw) wherein R ³ is NO ₂ and R ⁴ is urea substituted pyrrolidine amide can be prepared as shown in Scheme 9. The protected amine (Iu, prepared using the method described in Scheme 2) and TFA can react to produce N -methylamine of formula (Iv). Secondary amines (Iv) can be converted to urea (Iw).

Scheme 9

Other compounds of formula (I) wherein R ³ is NO ₂ and R ⁴ is oxadiazole can be prepared by the conversion of amides of formula (If) to dehydrated heterocycles of formula (Ix) as shown in Scheme 10 .

Scheme 10

Compounds of formula (Iy) can be prepared as shown in Scheme 11. For example, boronic acid indole of formula (X) combines with aryl chloride to provide indole of formula (XI). Acidic hydrolysis of aryl chlorides of formula (XI) may produce quinoxalinone of formula (Iy).

Scheme 11

Hydroxymethyl indole of formula (Ig), wherein R ³ is NO ₂ and R ⁴ is hydroxymethyl, can be reacted with isocyanates to provide carbamate of formula (Iz) as shown in Scheme 12.

Scheme 12

The compound of formula (Ie) can be converted to an acid chloride of formula (XII) and reacted with an alcohol to produce an ester derivative of formula (Iaa) as shown in Scheme 13.

Scheme 13

Preparation of Intermediate

The compound of formula (V) used in Scheme 1 above is commercially available or can be prepared by reducing a suitable 1,2-dinitroaryl precursor (XIII) as shown in Scheme 14.

Scheme 14

Biaryl indole compounds of formula (IIIb) wherein R ⁴ is phenyl or pyridyl can be prepared as shown in Scheme 15. Palladium catalyzed cross coupling between indole boronic acid of formula (IIb) and optionally substituted phenyl or pyridyl bromide is performed to obtain indole of formula (IIc). Protection (IIc) in indole nitrogen provides the biaryl intermediate of formula (IIIb).

Scheme 15

Intermediate indole, wherein R ⁴ is a morpholinyl-substituted alkoxy group, used to prepare the compound of formula (I), can be prepared from hydroxyindole (IIIc) as shown in Scheme 16. The conversion of (IIIc) to amine of formula (IIIe) is carried out in two steps via intermediate haloether (IIId). The indole of formula (IIIe) proceeds to the final product of formula (I) by the schemes described above.

Scheme 16

When substituted piperazine is used to prepare a compound of formula (I) wherein R ⁴ is an alkyl or acyl group substituted by piperazine, the substituted piperazine is of formula (XIV) by treating with methylsulfonyl chloride. It can be prepared by the conversion of the compound to sulfonamide (XV). The product, N- Boc protected piperazine (XV), can be converted to monosubstituted piperazine of formula (XVI) by exposing (XV) to an acid such as TFA as shown in Scheme 17. The resulting compound of formula (XVI) can be used, for example, in the last step of Scheme 2.

Scheme 17

Amine derivatives of formula (XVIII) can be prepared by conversion via reductive amination of ketones of formula (XVII) as shown in Scheme 18. This scheme is converted to N [(C ₃ -C ₆ ) cycloalkyl] [(C ₁ -C ₃ ) alkyl] and substituted N [(C ₁ -C ₄ ) alkyl] ₂ , and for example The last step of 2, which may be inserted in the last step of preparing the compound of formula (Ij) of Scheme 3, and the synthesis of an amine compound as compound (VIII) of Scheme 4.

Scheme 18

Compounds of formula (IIIf) can be prepared as shown in Scheme 19. The conversion of fluoronitrobenzene of formula (XIX) to aniline of formula (XX) can be carried out by replacement of fluorine of (XIX). Nitroaniline (XX) can be converted to aminoindole (IIIf).

Scheme 19

Compounds of formula (Vb) can be prepared as shown in Scheme 20. Palladium auxiliary coupling of bromonitroaniline of formula (XXI) with aryl boronic acid may provide arylnitroaniline of formula (XII). Reduction of the nitro group can provide a diamine of formula (Vb).

Scheme 20

Compounds of formula (IIIg) can be synthesized from anilines of formula (XXIII) as shown in Scheme 21. Aniline can be converted to the diazonium salt of formula (XXIV) and then reduced to substituted phenyl hydrazine of formula (XXV). Hydrazine may be converted to a phenyl hydrazone of formula (XXVI) which may undergo an acid assisted cyclization to yield a substituted indole of formula (IIIg).

Scheme 21

It is understood that sensitive or reactive substituents attached to intermediates or compounds of formula (I) need to be protected and deprotected during the preparation. In general, protecting groups can be added and removed by conventional methods known in the art (see, eg, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999)). .

Additionally, reactions to N- or O -acylation, alkylation, or sulfonylation of intermediates and compounds of formula (I) with acyl halides, alkyl halides and sulfonyl halides, and suitable bases, respectively It is understood that the conditions are generally compatible as known in the art. For example, the conditions for carrying out the N -acylation reaction as described in any of the specific examples below may also be used to carry out the N -sulfonylation reaction by substituting an acyl halide with a suitable sulfonyl halide.

The following specific examples are presented to illustrate the invention described herein, but should not be construed as limiting the scope of the invention in any way.

Abbreviations and acronym (acronym)

When the following abbreviations are used throughout the disclosure, they have the following meanings:

AcCl acetyl chloride

AcOH acetic acid

Boc t -butoxycarbonyl

CDI Carbonyl Diimidazole

Celite (registered trademark) A registered trademark of diatomaceous earth products of Celite.

DMAP 4- ( N, N -dimethyl) amino pyridine

DME Dimethoxyethane

DMF N, N -dimethyl formamide

DMSO- d ₆ Dimethyl sulfoxide- d ₆

ESI Electrospray Ionization

EtOAc ethyl acetate

EtOH Ethanol

¹ H NMR proton nuclear magnetic resonance

Hex Hexane

HPLC high performance liquid chromatography

LCMS Liquid Chromatography / Mass Spectroscopy

MeOH Methanol

MS mass spectrometry

Palladium on Pd / C Carbon

R _f TLC retention factor

rt room temperature

RT holding time (HPLC)

TBDMS tert -butyldimethylsilyl

TBDMSCl tert -butyldimethylsilyl chloride

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMS Tetramethylsilane

General Experiment Procedure

Electron impact mass spectra (EI-MS) were equipped with Hewlett Packard 5890 Gas Chromatography (GC) using a J & W DB-5 column (0.25 μM coating; 30 m x 0.25 mm). Obtained using one Hurek Packard 5989A mass spectrometer. The ion source was kept at 250 ° C. and the spectra were scanned between 50-800 atomic mass units (amu) at 2 seconds per scan.

High pressure liquid chromatography-electrospray mass spectroscopy (LC-MS) was obtained using one of the following;

(A) Hewlett-Packard with a quaternary pump, variable wavelength meter set to 254 nm, YMC Pro C-18 column (2 × 23 mm, 120 A) and Finnigan LCQ ion trap mass spectrometer using electrospray ionizer 1100 HPLC. The spectra were scanned between 120-1200 amu using variable ion times depending on the number of ions in the source. Eluents were A: 0.02% TFA and 2% acetonitrile in water and B: 0.018% TFA and 2% water in acetonitrile. Gradient elution of B from 10% to 95% at a flow rate of 1.0 ml / min over 3.5 minutes was used by maintaining the initial value for 0.5 minutes and finally maintaining 95% B for 0.5 minutes. The total run time was 6.5 minutes.

(B) Micromass using two Gilson 306 pumps, Gilson 215 autosampler, Gilson diode array detector, YMC Pro C-18 column (2 × 23 mm, 120 A) and Z-spray electrospray ionizer ) Gilson HPLC system with LCZ single quadrupole mass spectrometer. The spectra were scanned between 120-800 amu over 1.5 seconds. ELSD (Evaporative Light Scattering Detector) data were measured as analogue pathways. Eluents were A: 0.02% TFA and 2% acetonitrile in water and B: 0.018% TFA and 2% water in acetonitrile. Gradient elution of B from 10% to 95% at a flow rate of 1.5 ml / min over 3.5 minutes was used as the initial value for 0.5 minutes and 90% B for 0.5 minutes. The total run time was 4.8 minutes. Extra switching valves were used for column switching and regeneration.

A series of one-dimensional NMR spectra were measured with a 300 MHz Varian Mercury-plus spectrometer. Samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs and transferred to 5 mm ID Wilmad NMR tubes. Spectroscopy was measured at 293K. Chemical shifts are reported in ppm, for ¹ H spectroscopy, 2.49 ppm for DMSO-d ₆ , 1.93 ppm for CD ₃ CN, 3.30 ppm for CD ₃ OD, 5.32 ppm for CD ₂ Cl ₂ and 7.26 ppm for CDCl ₃ . For ¹³ C spectroscopy, appropriate solvent signals such as 39.5 ppm for DMSO-d ₆ , 1.3 ppm for CD ₃ CN, 49.0 ppm for CD ₃ OD, 53.8 ppm for CD ₂ Cl ₂ and 77.0 ppm for CDCl ₃ were used.

Example 1

Preparation of 3- (1H-indol-2-yl) -2 (1H) -quinoxalinone

Step 1. Preparation of tert-butyl 2- [methoxy (oxo) acetyl] -1H-indole-1-carboxylate

In a 250 ml round bottom flask, 2.0 g (9.21 mmol, 1 equivalent) of N-Boc indole dissolved in 40 ml of THF was injected. The mixture was cooled to -78 ° C and 1.1 equivalent (6.33 mL, 1.6 M pentane solution) was added dropwise. The mixture was stirred for 30 minutes and 2.17 g (18.4 mmol, 2 equivalents) of dimethyl oxalate solution dissolved in 20 ml of THF was added quickly at once. The reaction temperature was then brought to room temperature. After 30 minutes, the reaction appeared to be complete by TLC. The mixture was diluted in 50 ml water and transferred to a separatory funnel and extracted with EtOAc (3 × 200 ml). The combined organics were dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by flash chromatography (15% EtOAc / Hex) to give 2.02 g (72%) of the desired product in the form of a yellow oil. ¹ H-NMR (CD ₃ CN) δ 8.06 (d, 1H), 7.75 (d, 1H), 7.55 (d, 1H), 7.37 (d, 1H), 7.32 (s, 1H), 3.87 (s, 3H), 1.67 (s, 9H).

Step 2. 3- (1H-Indol-2-yl) -2 (1H)- Quinoxalinone  Produce

300 mg (0.99 mmol, 1 equivalent) of tert-butyl 2- [methoxy (oxo) acetyl] -1H-indole-1-carboxylate and 118 mg (1.09 mmol, 1.1 equivalents) in 10 ml acetic acid in a 25 ml round bottom flask 1,2-phenylenediamine was injected. The flask was equipped with a reflux condenser and heated at 130 ° C. for 2 hours. At this point, 1 ml of TFA was added to completely remove the Boc group. The mixture was cooled to room temperature and diluted with 10 ml of water. The resulting precipitate was filtered off and washed with more 20 ml water to give 199 mg (77%) of the desired product as an orange solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 12.62 (s, 1H), 11.61 (s, 1H), 7.86 (s, 1H), 7.83 (d, 1H), 7.65 (d, 1H), 7.54 (d, 1H), 7.50 (d, 1H), 7.36 (t, 1H), 7.35 (t, 1H), 7.20 (t, 1H), 7.02 (t, 1H); LCMS RT = 2.96 min; [M + H] ⁺ = 262.23.

Example 2

Preparation of 3- (3-nitro-1H-indol-2-yl) -2 (1H) -quinoxalinone

A reflux condenser was installed in a 100 ml round bottom flask and injected with 3- (1H-indol-2-yl) -2 (1H) -quinoxalinone (Example 1, 400 mg, 1.53 mmol) dissolved in 30 ml benzene and 6 ml DMF. It was. The mixture was heated to 100 ° C. and 538 mg (4.59 mmol, 3 equiv) of isoamyl nitrite were added. After 2 hours the reaction appeared to be complete and left to cool to room temperature. The solvent was removed in vacuo and the residue suspended in CH ₃ CN and sonicated. The remaining solid was filtered to yield 404 mg (86%) of the desired product as a yellow solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 13.15 (s, 1H), 12.84 (s, 1H), 8.12-8.08 (m, 1H), 7.89 (d, 1H), 7.69-7.59 (m, 2H), 7.45-7.37 (m, 4H); LCMS RT = 2.86 min; [M + H] ⁺ = 307.22.

Example 3

Preparation of 3- (3-amino-1 H-indol-2-yl) -2 (1H) -quinoxalinone

In an argon atmosphere, 10 mg of 10% Pd / C was injected into a 25 ml round bottom flask. 5 ml of THF was added thereto. To this mixture was added 100 mg (0.33 mmol) of 3- (3-nitro-1H-indol-2-yl) -2 (1H) -quinoxalinone (Example 2) in the form of a solution dissolved in 3 ml DMF and 5 ml THF. It was. The atmosphere was switched to H ₂ using a balloon and stirred at room temperature for 1 hour. H ₂ was removed and the mixture was filtered through Celite® under an argon blanket. Solvent was removed to yield 71 mg (78%) of the desired product in the form of a red solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 12.39 (s, 1H), 10.57 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.28 (d, 1H), 7.23 (t, 2H), 7.16 (t, 1H), 7.02 (br s, 2H), 6.88 (t, 1H); LCMS RT = 2.33 min; [M + H] ⁺ = 277.28.

Example 12

Preparation of 6,7-dimethoxy-3- (5-cyano-1H-indol-2-yl) -2 (1H) -quinoxalinone

Step 1. Preparation of tert-Butyl 5-cyano-1H-indole-1-carboxylate

Into a 100 ml round bottom flask was injected 1H-indole-5-carbonitrile (2.0 g, 14.07 mmol) dissolved in 20 ml of dry THF. DMAP (0.86 g, 7.03 mmol) was added to this solution and the mixture was stirred at rt for 0.5 h. At this point, Boc ₂ O (3.07 g, 14.07 mmol) was added and the reaction stirred for 2 hours more. The reaction was quenched with water and extracted twice with ethyl ether. The combined organic layers were washed with 1N HCl, water, brine, dried over MgSO ₄ and concentrated to give 3.26 g (96%) of the desired product in the form of a white solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 8.20-8.14 (m, 2H), 7.83 (d, 1H), 7.70 (d, 1H), 6.80 (d, 1H), 1.63 (s, 9H).

Step 2. Preparation of Methyl (5-cyano-1H-indol-2-yl) (oxo) acetate

Into a 100 ml round bottom flask was injected 2.0 g (8.26 mmol, 1 equivalent) of tert-butyl-5-cyano-1H-indole-1-carboxylate (step 1) dissolved in 25 ml THF. The mixture was cooled to -78 ° C and 1.1 eq (5.34 ml, 1.7 M pentane solution) was added dropwise. The mixture was stirred for 1 hour and 2.14 g (18.16 mmol, 2.2 equiv) of dimethyl oxalate dissolved in 5 ml THF was added quickly at once. The reaction temperature was raised to 0 ° C. and observed by TLC, followed by stirring until completion (about 2 hours). The mixture was diluted with 30 ml water and transferred to a separatory funnel and extracted with EtOAc (3 × 100 ml). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated to give a brown residue. MeOH (10 ml) was added to the residue to give an insoluble yellow solid, which was filtered, washed with MeOH, dried and purified to give 444.3 mg (23.6%) of the desired product as a yellow solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 12.63 (s, 1H), 8.40 (s, 1H), 7.77 (s, 1H), 7.65 (d, 1H), 7.60 (d, 1H), 3.93 (s, 3H).

Step 3. Preparation of 6,7-Dimethoxy-3- (5-cyano-1H-indol-2-yl) -2 (1H) -quinoxalinone

114.1 mg (0.50 mmol, 1 equivalent) of 5-cyano-2- [methoxy (oxo) acetyl] -1H-indole (step 2) and 132.6 mg 1,2- dissolved in 5 ml acetic acid in a 25 ml round bottom flask. Diamino-4,5-dimethoxybenzene hydrochloride (0.55 mmol, 1.1 equiv) was injected. The flask was equipped with a reflux condenser and heated at 130 ° C. for 3 hours. The mixture was cooled to room temperature and diluted with 5 ml water. The resulting precipitate was filtered, washed with more 10 ml water and 5 ml MeCN, and then dried in an oven to give 127.1 mg (73.4%) of the desired product as a yellow solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 12.67 (s, 1H), 12.08 (s, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.49 (d, 1H), 7.27 (s, 1 H), 6.85 (s, 1 H), 3.87 (s, 6 H); LCMS RT = 2.68 min; [M + H] ⁺ = 347.2.

Example 13

Preparation of 6-[(3S) -3- (dimethylamino) -1-pyrrolidinyl] -3- (1H-indol-2-yl) -2 (1H) -quinoxalinone

Step 1. Preparation of 5-fluoro-2-nitroaniline

The compound was prepared as described in WO 02/22598. To a round bottom flask equipped with a dry ice condenser (acetone / dry ice) was added 2,4-difluoronitrobenzene (15 g, 94 mmol) and THF (20 ml). Ammonia was bubbled into the solution at −78 ° C. for 10 minutes. The reaction temperature was brought to room temperature and the reaction was refluxed for 7 hours. Stirring was continued overnight allowing ammonia to evaporate after removing the condenser. The reaction was diluted with dichloromethane and washed with water (3 x 100 ml). The organic layer was dried over MgSO ₄ and concentrated under reduced pressure to give a solid. This solid was purified by chromatography to give 10.5 g (72%) of 5-fluoro-2-nitroaniline. _{^{1 H NMR (DMSO- d 6)}} : δ 6.38-6.52 (m, 1H), 6.66-6.72 (d, 1H), 7.79 (s, 2H), 7.98-8.09 (dd, 1H). LRMS RT = 2.48; [M + H] = 157.

Step 2. (3S) -1- (3-Amino-4-nitrophenyl)- N, N Preparation of -dimethyl-3-pyrrolidinamine

The compound was prepared as described in WO 02/22598. To a round bottom flask equipped with a reflux condenser was added 5-fluoro-2-nitroaniline (4 g, 26.0 mmol) dissolved in 1-methyl-2-pyrrolidine (40 ml). (3S) -N, N-dimethyl-3-pyrrolidinamine (5.85 g, 51.2 mmol) was added to the stirring solution and the reaction was heated to 80 ° C. for 3 hours. The reaction was cooled to room temperature and then poured into ice water. The product was diluted in dichloromethane and washed with saturated sodium bicarbonate solution (3x100 ml). The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give a solid. The product was purified by chromatography to give 4.7 g (74%) of (3S) -1- (3-amino-4-nitrophenyl) -N, N-dimethyl-3-pyrrolidinamine. _{^{1 H NMR (DMSO- d 6)}} : δ 1.81-1.92 (m, 1H), 2.02-2.13 (m, 7H), 2.87-2.91 (m, 1H), 3.06-3.16 (t, 1H), 3.22-3.33 (m, 1H), 3.41-3.8 (dt, 2H), 5.80 (s, 1H), 6.00-6.14 (dd, 1H), 7.25 (s, 2H), 7.75-7.83 (dd, 1H). LRMS RT = 0.25; [M + H] = 251.

Step 3. 6-[(3S) -3- (Dimethylamino) -1- Pyrrolidinyl ] -3- (1H-indol-2-yl) -2 (1H) -quinoxalinone

This compound was prepared using the method described in Examples 49-50 and 2, via reaction of the product prepared in Example 13, step 2 with the product of example 1, step 1. ¹ H-NMR (DMSO- d ₆ ) δ 12.25 (s, 1H), 11.41 (s, 1H), 7.65-7.51 (m, 3H), 7.58-7.49 (d, 1H), 7.22-7.18 (m, 1H ), 7.16-7.01 (m, 1H), 6.80-6.72 (d, 1H), 6.38 (s, 1H), 3.67-3.52 (m, 2H), 3.24-3.14 (t, 1H), 2.97-2.81 (m , 1H), 2.35 (s, 6H), 1.99-1.83 (m, 1H). LCMS RT = 2.06 min; [M + H] = 374.

Example 18

Preparation of 3- {5- [3- (1-piperazinyl) propoxy] -1H-indol-2-yl} -2 (1H) -quinoxalinone

Step 1. Preparation of tert-Butyl 5-hydroxy-1H-indole-1-carboxylate

Tert-butyl 5- (benzyloxy) -1H-indole-1-carboxylate (5.75 g, 17.8 mmol) prepared according to the procedure described in Example 12, step 1 was added to an ethanol mixture of 10% Pd / C. Added. Ammonium formate was added and the reaction stirred for 6 hours. The mixture was filtered through Celite (R) under an argon blanket and then the solvent was removed. The residue was purified by flash chromatography to give 3.5 g tert-butyl 5-hydroxy-1H-indole-1-carboxylate (74%). _{^{1 H-NMR (DMSO- d 6}} ) δ 9.19 (s, 1H), 7.84-7.78 (d, 1H), 7.58-7.52 (d, 1H), 6.91 (s, 1H), 7.78-7.69 (m, 1H ), 6.65-6.42 (m, 1 H), 1.68-1.59 (s, 9 H).

Step 2. Preparation of tert-Butyl 5- (3-bromopropoxy) -1H-indole-1-carboxylate

In a 250 ml flask, tert-butyl 5- (benzyloxy) -1H-indole-1-carboxylate (3.3 g, 14 mmol) dissolved in 100 ml acetone was injected. 1,3-dibromopropane (5.74 ml, 56.6 mmol) was added and cesium carbonate (5.5 g, 17 mmol) was added. The reaction was heated to reflux for 5 hours. The reaction was cooled to rt and diluted with water (200 ml). The mixture was transferred to a separatory funnel and extracted with ethyl acetate (2 x 150 ml). The combined organics were dried (MgSO ₄ ), filtered and evaporated. The residue was then purified by flash chromatography to give 4.7 g of tert-butyl 5- (3-bromopropoxy) -1H-indole-1-carboxylate (94%). ¹ H-NMR (DMSO- d ₆ ) δ 7.99-7.89 (d, 1H), 7.61 (s, 1H), 7.17 (s, 1H), 6.98-6.91 (d, 1H), 6.62 (s, 1H), 4.16-4.05 (t, 2H), 3.64 (t, 2H), 2.37-2.20 (m, 2H). LCMS RT = 3.55 min; [M] ⁺ = 254.1.

Step 3. Preparation of tert-Butyl 5- [3- (4-morpholinyl) propoxy] -1 H-indole-1-carboxylate

In a 250 ml flask, tert-butyl 5- (3-bromopropoxy) -1H-indole-1-carboxylate (1.5 g, 4.2 mmol) dissolved in 50 ml tetrahydrofuran was injected. Morpholine (0.41 ml, 4.66 mmol) and pyridine (0.38 ml, 4.66 mmol) were added. The reaction was heated to reflux for 5 hours. The reaction temperature was cooled to room temperature and the reaction diluted with water (200 ml). The mixture was transferred to a separatory funnel and extracted with ethyl acetate (2 × 100 ml). The combined organics were dried (MgSO ₄ ), filtered and evaporated. The residue was then purified by flash chromatography to give 1.1 g tert-butyl 5- [3- (morpholinyl) propoxy] -1H-indole-1-carboxylate (72%). ¹ H-NMR (DMSO- d ₆ ) δ 7.93-7.85 (d, 1H), 7.59 (s, 1H), 7.09 (s, 1H), 6.93-6.85 (m, 1H), 6.59 (s, 1H), 4.06-3.97 (t, 2H), 3.57 (s, 4H), 2.46-2.23 (m, 6H), 1.92-1.83 (m, 2H), 1.62 (s, 9H). LCMS RT = 0.61 min; [M + H] ⁺ = 361.3.

Step 4. Preparation of tert-butyl 2- [methoxy (oxo) acetyl] -5- [3- (4-morpholinyl) propoxy] -1 H-indole-1-carboxylate

This compound was prepared by the method described in Example 1, Step 1, using the product of Example 18, Step 3 and dimethyl oxalate as starting materials. ¹ H-NMR (DMSO- d ₆ ) δ 7.86-7.80 (d, 1H), 7.38 (s, 1H), 7.20-7.29 (m, 1H), 7.18-7.10 (d, 1H), 4.06-3.99 (t , 2H), 3.80 (s, 3H), 3.57 (s, 4H), 2.47-2.24 (m, 6H), 1.96-1.83 (m, 2H), 1.59 (s, 9H).

Step 5. Preparation of 3- {5- [3- (1-piperazinyl) propoxy] -1 H-indol-2-yl} -2 (1 H) -quinoxalinone.

This compound was prepared by the method described in Example 1, Step 2, using the product of Example 18, Step 4 and 1,2-phenylenediamine as starting materials. _{^{1 H-NMR (DMSO- d 6}} ) δ 12.59 (s, 1H), 11.43 (s, 1H), 7.82-7.78 (d, 1H), 7.72 (s, 1H), 7.55-7.47 (m, 1H), 7.42-7.39 (m, 1H), 7.37-7.29 (m, 2H), 7.13 (s, 1H), 6.87-6.81 (m, 1H), 4.08-3.98 (t, 2H), 3.57 (s, 4H), 2.46-2.23 (m, 6 H), 1.97-1.81 (m, 2 H). LCMS RT = 2.45 min; [M + H] = 405.

Example 21

Preparation of N- [3- (4-morpholinyl) propyl] -2- (3-oxo-3,4-dihydro-2-quinoxalinyl) -1 H-indole-5-carboxamide

2- (3-oxo-3,4-dihydro-2-quinoxalinyl) -1H-indole-5-carboxylic acid dissolved in 3 ml THF and 3 ml DMF in a 20 ml tan vial (Example 17, 75.0 mg, 0.25 mmol) and 0.10 ml (0.74 mmol) of TEA were injected. To it PyBOP (39.0 mg, 0.27 mmol) and 3- (4-morpholinyl) propylamine (0.04 ml, 0.27 mmol) were added and the reaction stirred at room temperature. After 45 minutes, the volatiles were removed and the residue was purified using preparative HPLC (CH ₃ CN / H ₂ O 0.1% TFA). Fractions of interest were combined to remove CH ₃ CN in vacuo. The remaining aqueous solution was basified with saturated NaHCO ₃ solution and extracted with EtOAc (3 × 150 ml). The combined organics were dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was suspended in CH ₃ CN, sonicated and the solid was filtered to give 23 mg (21%) of the desired product as a yellow solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 12.64 (s, 1H), 11.84 (s, 1H), 8.38 (t, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 7.83 (d, 1H), 7.70 (d, 1H), 7.52 (dd, 2H), 7.37-7.32 (m, 2H), 3.57 (t, 4H), 3.30 (m, 2H), 2.40-2.31 (m, 6H), 1.70 (quint, 2H); LCMS RT = 2.30 min; [M + H] ⁺ = 432.29.

Example 22

Preparation of 3-nitro-2- (3-oxo-3,4-dihydro-2-quinoxalinyl) -1 H-indole-5-carboxylic acid

3-nitro-2- (3-oxo-3,4-dihydro-2-quinoxalinyl) -1H-indole-5-carbonitrile dissolved in 6 ml of 4M KOH solution in a 15 ml round bottom flask equipped with a condenser Example 19, 52.0 mg, 0.16 mmol) was injected. The mixture was heated at 120 ° C. for 3 hours. At this point, the reaction was cooled to room temperature and acidified with concentrated hydrochloric acid. The solid was filtered and vacuum dried at 60 ° C. to give 52 mg (95%) of the desired product as a yellow solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 13.43 (s, 1H), 12.99 (br s, 1H), 12.90 (s, 1H), 8.73 (s, 1H), 7.98 (d, 1H), 7.90 (d , 1H), 7.70 (d, 1H), 7.66 (d, 1H), 7.40 (dd, 2H); LCMS RT = 2.58 min; [M + H] ⁺ = 351.26.

Example 49-50

3- (1H-indol-2-yl) -6- [3- (4-morpholinyl) propoxy] -2 (1H) -quinoxalinone and 3- (1H-indol-2-yl) -7 Preparation of-[3- (4-morpholinyl) propoxy] -2 (1H) -quinoxalinone

Step 1. Preparation of 5- [3- (4-morpholinyl) propoxy] -2-nitroaniline

5- [3- (4-morpholinyl) propoxy] -2-nitroaniline (706 mg, 69%) contains 3-amino-4-nitrophenol (1.0 g, 3.6 mmol) and 1,3-dibro Morpropane was obtained through two steps, O-alkylation under Cs ₂ CO ₃ catalyst and N-alkylation of morpholine under pyridine catalyst. _{^{1 H-NMR (DMSO- d 6}} ) δ 7.36 (s, 1H), 7.25 (s, 2H), 7.17-7.09 (m, 1H), 6.97-6.88 (d, 1H), 3.98-3.84 (t, 2H ), 3.56 (s, 4H), 2.50-2.22 (m, 6H), 1.85-1.78 (m, 2H). LCMS RT = 0.25 min; [M + H] ⁺ = 282.3.

Step 2. 3- (1H-Indol-2-yl) -6- [3- (4-morpholinyl) propoxy] -2 (1H) -quinoxalinone and 3- (1H-indol-2-yl Preparation of) -7- [3- (4-morpholinyl) propoxy] -2 (1H) -quinoxalinone

Methyl (5-cyano-1H-indol-2-yl) (oxo) acetate (255 mg, 0.79 mmol, Example 12, step 2) and 219 mg (0.79 mmol) in 5-ml round bottom flask were dissolved in 10 ml acetic acid. [3- (4-morpholinyl) propoxy] -2-nitroaniline (from step 1) was injected and iron powder (219 mg) was injected. The flask was equipped with a reflux condenser and heated at 130 ° C. for 2 hours. The mixture was cooled to rt and diluted with 80 ml of diethyl ether. The resulting precipitate was filtered and dissolved in water (100 ml) and EtOAc / MeOH (100 ml, 10 ml). The organic layer was separated and the aqueous layer was extracted twice with EtOAc / MeOH (100 ml, 10 ml). The organic extracts were combined and dried over MgSO ₄ . Filtration and concentration under reduced pressure gave a residue. Two positional isomers were separated by flash chromatography (30% EtOAc / 5% MeOH / Hex) to give 45 mg of 3- (1H-indol-2-yl) -7- [3- (4-morpholinyl) propoxy ] -2 (1H) -quinoxalinone (Example 49, 17%) and 15 mg of 3- (1H-indol-2-yl) -6- [3- (4-morpholinyl) propoxy] -2 (1H) -quinoxalinone (Example 50, 5%) was obtained.

Example 49, 3- (1H-indol-2-yl) -7- [3- (4-morpholinyl) propoxy] -2 (1H) -quinoxalinone: ¹ H-NMR (DMSO- d ₆ ) δ 12.61 (s, 1H), 12.09 (s, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 7.65-7.60 (d, 1H), 7.57-7.47 (d, 1H), 7.37- 7.22 (m, 2H), 7.20-7.16 (m, 1H), 4.14-4.01 (t, 2H), 3.55 (s, 1H), 2.58-2.20 (m, 6H), 1.97-1.81 (t, 2H); LCMS RT = 2.11 min; [M + H] ⁺ = 430.2.

Example 50, 3- (1H-indol-2-yl) -6- [3- (4-morpholinyl) propoxy] -2 (1H) -quinoxalinone: ¹ H-NMR (DMSO- d ₆ ) δ 12.61 (s, 1H), 12.09 (s, 1H), 8.21 (s, 1H), 7.82 (s, 1H), 7.78-7.73 (d, 1H), 7.64-7.58 (d, 1H), 7.52- 7.43 (d, 1H), 6.98-6.91 (d, 1H), 6.79 (s, 1H), 4.14-4.01 (t, 2H), 3.55 (s, 1H), 2.58-2.20 (m, 6H), 1.97- 1.81 (m, 2 H); LCMS RT = 2.21 min; [M + H] ⁺ = 430.2.

Example 56

3-Amino-2- (3-oxo-3,4-dihydro-quinoxalin-2-yl) -1 H-indole-5-carboxylic acid (2-methoxy-ethyl) -methyl-amide

3-amino-2- (3-oxo-3,4-dihydro-2-quinoxalinyl) -1H-indole-5-carboxylic acid (3.77 g, 10.8 mmol, dissolved in 250 ml DMF in a 500 ml round bottom flask) 1 equivalent, Example 22) was injected. To this was added 1.65 ml of triethylamine (11.8 mmol, 1.1 equiv). After all solids were dissolved, 6.16 g (11.8 mmol, 1.1 equiv) of PyBOP® was added. After 5 min stirring at room temperature, (2-methoxy-ethyl) -methyl-amine (1.06 g, 11.8 mmol, 1.1 equiv) was added and the mixture was stirred overnight (17 h). At this point, the mixture was placed in low vacuum (˜10 minutes) and then filled with dry argon. To this was added 377 mg of 10% Pd / C (dry), the atmosphere was removed in vacuo and the atmosphere was converted to hydrogen. Reduction was observed by HPLC and Pd was removed by filtration under an argon blanket after the starting material was consumed. The filtrate was evaporated to dryness and the residue was purified by HPLC (5-85% 0.1% TFA CH ₃ CN / 0.1% TFA water). The desired fractions were collected and the CH ₃ CN was removed in vacuo. The remaining aqueous solution was basified with saturated NaHCO ₃ solution and extracted with EtOAc (1 × 350 ml). The organics were separated, washed with water (100 ml), washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and evaporated. 75 ml of hot water was added to the red solid and the solid was sonicated and filtered to give 2.77 g (66%) of the desired product in the form of a red solid. ¹ H-NMR (DMSO-d ₆ ) δ 12.43 (br s, 1H), 10.79 (br s, 1H), 7.94 (s, 1H), 7.73 (d, 1H), 7.46 (d, 1H), 7.33- 7.28 (m, 1 H), 7.26-7.18 (m, 3 H), 7.10 (br s, 1 H); LCMS RT = 2.11 min; [M + H] = 392.2; EA calcd C 64.44; H 5.41; N 17.89, found C 64.18, H 5.19, N 17.70.

Example 104

3-acetylamino-2- (3-oxo-3,4-dihydro-quinoxalin-2-yl) -1 H-indole-5-carboxyl

Preparation of Acid (2-methoxy-ethyl) -methyl-amide

52.0 mg (0.13 mmol, 1 equivalent) of 3-amino-2- (3-oxo-3,4-dihydro-quinoxalin-2-yl) -1H-indole- dissolved in 5 ml THF in a 50 ml round bottom flask. 5-carboxylic acid (2-methoxy-ethyl) methylamide (Example 56) was injected. To this was added 12.6 mg (0.16 mmol, 0.013 ml, 1.2 equiv) of pyridine and 11.5 mg (0.15 mmol, 0.010 ml, 1.1 equiv) of acetyl chloride. These were stirred for 72 hours at room temperature. The mixture was then diluted with 40 ml water and 50 ml brine and transferred to a separatory funnel. This mixture was extracted with EtOAc (3 × x75 ml). The combined organics were dried (Na ₂ SO ₄ ), filtered and evaporated to give 45 mg (78%) of the pure desired product as an orange solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 12.82 (s, 1H), 11.72 (s, 1H), 10.73 (s, 1H), 7.93 (s, 1H), 7.87 (d, 1H), 7.62 (d, 1H), 7.53 (dt, 1H), 7.37 (dt, 2H), 7.23 (d, 1H), 3.70-3.11 (br m, 7H), 3.01 (s, 3H), 2.22 (s, 3H); LCMS RT = 2.63 min; [M + H] = 434.14.

Example 134

3-amino-2- (6,7-dichloro-3-oxo-3,4-dihydro-2-quinoxalinyl) -N- [2- (diethylamino) ethyl] -N-methyl-1H- Preparation of Indole-5-Carboxamide

2- (6,7-dichloro-3-oxo-3,4-dihydro-2-quinoxalinyl) -3-nitro-1H-indole-5-carboxylic acid (0.100 g, 0.239 mmol) in a 25 ml flask , DMF (5 ml) and Et ₃ N (0.037 ml, 0.262 mmol) were injected. PyBOP (0.137 g, 0.262 mmol) and N- [2- (diethylamino) ethyl] -N-methylamine (0.034 g, 0.262 mmol) were added to this solution. The mixture was stirred at rt overnight. SnCl ₂ (0.226 g, 1.913 mmol) was added and the mixture was stirred at 80 ° C. for 4 h. The mixture was filtered and concentrated. The residue was taken up in 30 ml water and extracted with EtOAc (3 × 20 ml). The organics were concentrated and the residue was purified by preparative HPLC (CH ₃ CN / H ₂ O 0.1% TFA). ¹ H NMR (400 MHz, DMSO) δ 12.49 (s, 1H), 10.71 (s, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.34 (s, 1H), 7.30 (s, 1H), 7.21 (d, J = 9.6 Hz, 2H), 3.44 (bs, 2H), 2.99 (s, 3H), 2.33 (bs, 2H), 0.93 (br d, 6H); LCMS RT = 2.47 min; [M + H] = 501.1.

Example 151

N-((3R) -1-{[3-amino-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indol-5-yl] carbonyl} pyrrolidine Preparation of -3-yl) acetamide

Step 1. 3- (5-{[(3R) -3-Aminopyrrolidin-1-yl] carbonyl} -3-nitro-1H-indol-2-yl) quinoxalin-2 (1H) -one Manufacture

tert-butyl ((3R) -1-{[3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indol-5-yl] carbonyl} pyrroli TFA (1 ml) was added to a CH ₂ Cl ₂ (5 ml) solution of din-3-yl) carbamate (prepared using the experimental method described to make Example 56, 0.40 g, 0.77 mmol). The resulting red solution was stirred for 3 hours to remove volatiles at room temperature and Et ₂ O was added. Removal of volatiles yields a crude crude residue. Et ₂ O was added to this residue and the mixture was sonicated. The precipitated yellow solid was filtered, washed with Et ₂ O and dried in an oven to give 360 mg of a yellow solid (88%). This material was used for the next step reaction without further purification.

Step 2. N-((3R) -1-{[3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indol-5-yl] carbonyl} Preparation of Pyrrolidin-3-yl) acetamide

3- (5-{[(3R) -3-aminopyrrolidin-1-yl] carbonyl} -3-nitro-1H-indol-2-yl) quinol dissolved in DMF (5 ml) in a 50 ml round bottom flask Saline-2 (1H) -one (0.10 g, 0.19 mmol) was injected. AcCl (0.015 g, 0.19 mmol) was added to this solution, and the mixture was stirred at room temperature for 3 hours. Pd / C was added, the atmosphere was switched to H ₂ and the reaction stirred for 3 hours. The resulting red solution was filtered and concentrated, and the resulting residue was purified by HPLC (CH ₃ CN / water = 15-80%) to give 14.6 mg of a red solid (18%). ¹ H-NMR (DMSO- d ₆ ) δ 12.44 (s, 1H), 10.82 (s, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.75-7.71 (d, 1H), 7.47- 7.43 (d, 1H), 7.39-7.35 (d, 1H), 7.32-7.28 (m, 1H), 7.25-7.21 (m, 2H), 7.13 (s, 2H), 4.13 (s, 1H), 3.80 ( s, 1H), 3.70-3.49 (m, 3H), 2.11-2.01 (m, 1H), 1.85-1.74 (m, 4H). LCMS RT = 1.97 min; [M + H] ⁺ = 431.0.

Example 152

Preparation of tert-butyl 5- (4-cyanophenyl) -1H-indole-1-carboxylate

Step 1. Preparation of 4- (1H-indol-5-yl) benzonitrile

N ₂ was bubbled into a DME (55 ml) solution of 5-indolylboronic acid (1.50 g, 9.32 mmol) for 10 minutes. To this solution was a CH ₂ Cl ₂ solution (1: 1) (0.382 g, 0.440 mmol) of 1,1′-bis- (diphenylphosphineferrocene) dichloropalladium (II) complex, 1.0 M Na ₂ CO ₃ solution. (22 ml, 22 mmol) and 4-bromobenzonitrile (1.60 g, 8.87 mmol) were added. N ₂ was then bubbled into the reaction mixture for 10 minutes and the mixture was heated at 60 ° C. for 1 hour. The reaction was quenched with H ₂ O and extracted with EtOAc (3 ×). The combined organic layers were washed with H ₂ O and brine, dried (MgSO ₄ ) and concentrated to give 2.24 g of a brownish solid crude residue which was used for the next step reaction without purification. _{^{1 H-NMR (DMSO- d 6}} ) δ 11.24 (s 1H), 7.91 (s, 1H), 7.85 (s, 4H), 7.47-7.45 (m, 2H), 7.39 (d, 1H), 6.49 (d , 1H).

Step 2. Preparation of tert-Butyl 5- (4-cyanophenyl) -1H-indole-1-carboxylate

Into a 100 ml round bottom flask was injected 4- (1H-indol-5-yl) benzonitrile (2.24 g, 10.3 mmol) dissolved in 100 ml dry THF. DMAP (0.630 g, 5.13 mmol) was added to this solution and the mixture was stirred at rt for 0.5 h. Boc ₂ O (2.24 g, 10.3 mmol) was added and the reaction stirred for 2 hours. The reaction was then quenched with H ₂ O and extracted with Et ₂ O (2 ×). The combined organic layers were washed with 1N HCl, H ₂ O, brine, dried (MgSO ₄ ) and concentrated to give 2.20 g (67%) of an off-white solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 8.13-8.11 (d, 1H), 8.00 (s, 1H), 7.90 (s, 4H), 7.72-7.68 (m, 2H), 6.77 (d, 1H), 1.63 (s, 9 H).

Example 155

Preparation of 3- {3-amino-5-[{4-phenylpiperidin-1-yl) carbonyl] -1 H-indol-2-yl} quinoxalin-2 (1H) -one

3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indole-5-carboxylic acid (Example 22, 250 mg) in SOCl ₂ (20.0 ml, 272 mmol) solution , 0.710 mmol) was added at room temperature and the resulting brown suspension was heated at 85 ° C. for 4 hours. The suspension was concentrated under reduced pressure and the residue was dried in vacuo for 24 hours to give 262 mg of a light yellow solid. Crude acid chloride was used without further purification. The solid was suspended in anhydrous CH ₂ Cl ₂ (30 ml) and 4-phenylpiperidine (128 mg, 0.780 mmol) was added at room temperature followed by Et ₃ N (0.110 ml, 0,780 mmol). After a few minutes the reaction became a clear solution, which was stirred for 24 hours at room temperature. 10% Pd / C (50 mg) was added to this solution and the reaction was hydrogenated at 1 atm and room temperature for 2 hours. The reaction was diluted with DMF (100 ml) to dissolve the yellow precipitate (product) and then quenched with saturated NH ₄ Cl (200 ml). The mixture was extracted with EtOAc (2 × 200 ml) and the organics were dried (Na ₂ SO ₄ ). The solution was filtered and concentrated in vacuo to give a red residue. The crude product was dissolved in DMF and purified by reverse phase preparative HPLC. The desired fragment was diluted with EtOAc (150 ml) and washed with saturated NaHCO ₃ (100 ml). The organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a red solid. This was suspended in CH ₂ Cl ₂ and hexane, sonicated, filtered, washed with hexane and dried to give a red brick solid product in 9% yield (30 mg, 0.065 mmol). _{TLC: R f = 0.40 (66} % EtOAc / hexane; LC-MS (ESI): [M + H] + = 464.2 @ RT = 2.87 _{^{bun; 1 H NMR (DMSO- d 6}} ) δ 12.43 (1H, s) , 10.81 (1H, s), 7.98 (1H, s), 7.73 (1H, d, J = 9.2 Hz), 7.48 (1H, d, J = 8.8 Hz), 7.15-7.35 (9H, m), 4.25 ( 2H, v bs), 3.00 (2H, bs), 2.83 (1H, m), 1.80 (2H, m), 1.64 (2H, m).

Example 156

Preparation of 3- [3-amino-5- (morpholin-4-ylmethyl) -1H-indol-2-yl] quinoxalin-2 (1H) -one

Step 1. Preparation of 3- [3-amino-5- (hydroxymethyl) -1 H-indol-2-yl] quinoxalin-2 (1H) -one

Anhydrous DMF (500 ml) solution of 3-nitro- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indole-5-carboxylic acid (Example 22, 4.36 g, 12.3 mmol) To CDI (3.03 g, 18.5 mmol) was added at room temperature and this dark yellow solution was stirred at room temperature for 48 hours. The reaction was concentrated to 200 ml volume at 30 ° C. and reduced pressure and diluted with anhydrous THF (100 ml). The reaction was cooled to 0 ° C. in an ice bath and stirred vigorously with the addition of a solution of H ₂ O (100 ml) of NaBH ₄ (980 mg, 24.64 mmol) at room temperature. Gas was generated in the reaction for the first 1 minute, which was stirred for 40 minutes at 0 ° C. and quenched with addition of concentrated hydrochloric acid (50 ml) over 2 minutes. The mixture was stirred for 5 minutes in an ice bath and the stirred saturated NaHCO ₃ (1 L) solution was added in portions at room temperature over 10 minutes. It was extracted with EtOAc (3 × 1 L). The yellow precipitate was filtered from two layers, washed with water and with EtOAc. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to approximately 50 ml (DMF). It was diluted with 1: 1 MeOH / EtOAc (300 ml), sonicated for 30 minutes, and left for 24 hours. The yellow precipitate was filtered off with washing with EtOAc and hexanes. The two precipitates were combined and dried under vacuum and P ₂ O _{5 to} give a yellow solid product in 64% yield (2.74 g, 8.16 mmol). TLC: R _f = 0.69 (EtOAc); LC-MS (ESI): [M + H] ⁺ = 337.0 @ RT = 2.13 min; _{^{1 H NMR (DMSO- d 6)}} δ 12.80 (2H, v bs), 8.04 (1H, s), 7.85 (1H, d, J = 8.0 Hz), 7.63 (1H, m), 7.52 (1H, d, J = 8.4 Hz), 7.38 (2H, m), 7.29 (1H, d, J = 7.2 Hz), 5.29 (1H, t, J = 5.6 Hz), 4.64 (2H, d, J = 5.2 Hz).

Step 2. Preparation of 3- [3-nitro-5- (bromomethyl) -1H-indol-2-yl] quinoxalin-2 (1H) -one

To anhydrous DMF (15.0 ml, 195 mmol) solution of 3- [3-nitro-5- (hydroxymethyl) -1H-indol-2-yl] quinoxalin-2 (1H) -one (3.04 g, 8.94 mmol) , Anhydrous CH ₂ Cl ₂ (30 ml), followed by SOBr ₂ (17.5 ml, 223 mmol) was added at ambient temperature over 1 minute. The reaction heats up and bubbles are produced violently for several minutes. The mixture is stirred at ambient temperature for 1 hour during which time the reaction becomes a dark gray solution. The reaction was poured into CH ₂ Cl ₂ (1.5 L) and quenched carefully with saturated NaHCO ₃ (1.7 L). The reaction temperature was kept below 25 ° C. and the final pH was 7.5. The yellow precipitate that forms in both layers during quenching was filtered off and washed with H ₂ O (3 × 50 ml). The aqueous layer was extracted with CH ₂ Cl ₂ (1 L) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford a yellow semi-suspension of remaining DMF (5 ml). It was diluted with CH ₂ Cl ₂ (10 ml) and a large amount of hexane was added (200 ml) to give a yellow precipitate. This solid was filtered off, washed with hexane and added to the precipitate obtained above and the collected solids were dried under vacuum conditions and P ₂ O ₅ to give the product as a yellow solid (2.81 g, 75%). This crude bromide was used without further purification. TLC: R _f = 0.35 (66% EtOAc / hexanes); LC-MS (ESI): [M + H] ⁺ = 398.9 / 400.8 @ RT = 2.85 min.

Step 3. Preparation of 3- [5- (morpholin-4-ylmethyl) -3-nitro-1H-indol-2-yl] quinoxalin-2 (1H) -one

Morpholine in anhydrous DMF (1.5 ml) solution of crude 3- [3-amino-5- (bromomethyl) -1H-indol-2-yl] quinoxaline-2 (1H) -one (100 mg, 0.250 mmol) (1.00 ml, 11.5 mmol) was added at room temperature and the tan solution was stirred at room temperature for 5 hours. The reaction was quenched with saturated NH ₄ Cl (200 mL) and extracted with EtOAc (3 × 250 mL). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to yield a yellow oil. This was purified by silica gel chromatography (10% MeOH / EtOAc) to give a yellow solid in 99% yield (105 mg, 0.250 mmol). TLC: R _f = 0.33 (5% MeOH / EtOAc); LC-MS (ESI): [M + H] ⁺ = 406.0 @ RT = 1.73 min .; _{^{1 H NMR (DMSO- d 6)}} δ 13.11 (1H, bs), 12.82 (1H, bs), 8.02 (1H, s), 7.87 (1H, d, J = 8.0 Hz), 7.65 (1H, t, J = 7.2 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.38 (3H, m), 3.62 (2H, s), 3.57 (4H, m), 2.34 (4H, m).

Step 4. Preparation of 3- [3-amino-5- (morpholin-4-ylmethyl) -1H-indol-2-yl] quinoxalin-2 (1H) -one

To anhydrous DMF (5 ml) solution of 3- [5- (morpholin-4-ylmethyl) -3-nitro-1H-indol-2-yl] quinoxalin-2 (1H) -one (100 mg, 0.240 mmol) 10% Pd / C (10 mg) was added at room temperature. The reaction was hydrogenated at 1 atmosphere for 1 hour. The mixture was purified directly by silica gel chromatography (10% MeOH / EtOAc) to give a red brick solid product in 28% yield (78 mg, 0.21 mmol). TLC: R _f = 0.55 (EtOAc); LC-MS (ESI): [M + H] ⁺ = 375.8 @ RT = 1.51 min; _{^{1 H NMR (DMSO- d 6)}} δ 12.38 (1H, s), 10.53 (1H, s), 7.70 (2H, m), 7.37 (1H, d, J = 8.4 Hz), 7.28 (1H, m), 7.22 (2H, m), 7.11 (1H, d, J = 8.4 Hz), 7.01 (2H, s), 3.56 (4H, m), 3.47 (2H, s), 2.35 (4H, bs).

Example 158

Preparation of 1- (methylsulfonyl) piperazine

Step 1. Preparation of tert-butyl 4- (methylsulfonyl) piperazine-1-carboxylate

Et ₃ N (0.65 g, 6.4 mmol) was added to a solution of CH ₂ Cl ₂ (10 ml) of tert-butyl piperazine-1-carboxylate (0.60 g, 3.2 mmol). The mixture was stirred for 10 minutes, methanesulfonyl chloride (0.40 g, 3.5 mmol) was added and the mixture was stirred overnight at room temperature. The reaction was quenched with H ₂ O and extracted with CH ₂ Cl ₂ ( ₂ ×). The combined organic layers were washed with H ₂ O and brine, dried (MgSO ₄ ), filtered and concentrated to yield 0.80 g of an off-white solid (93%). _{^{1 H-NMR (DMSO- d 6}} ) δ 3.41-3.38 (t, 4H), 3.08-3.04 (t, 4H), 2.85 (s, 3H), 1.40 (s, 9H).

Step 2. Preparation of 1- (methylsulfonyl) piperazine

To a solution of CH ₂ Cl ₂ (10 ml) of tert-butyl 4- (methylsulfonyl) piperazine-1-carboxylate (0.80 g, 3.0 mmol) was added TFA (1 ml). The mixture was stirred at room temperature for 3 hours to remove volatiles. Et ₂ O was added to the residue and removed in vacuo to yield a yellow residue. The mixture was sonicated after addition of Et ₂ O. The white solid precipitate was filtered off, washed with Et ₂ O and dried in an oven to give 530 mg of an off white solid (64%). _{^{1 H-NMR (DMSO- d 6}} ) δ 9.06 (s, 2H), 3.34-3.31 (m, 4H), 3.21-3.18 (m, 4H), 2.98 (s, 3H). LCMS [M + H] ⁺ = 165.1.

Example 160

Preparation of 3- {3-amino-5-[(2-methoxyethoxy) methyl] -1 H-indol-2-yl} quinoxalin-2 (1H) -one

Crude 3- [3-amino-5- (bromomethyl) -1H-indol-2-yl] quinoxalin-2 (1H) -one (Example 156, steps 1-2,; 1.50 g, 3.76 mmol ) A minimum amount of anhydrous DMF was added to a 2-methoxyethanol (29.4 ml, 372 mmol) suspension at room temperature to give a clear solution (35 ml). To this was added K ₂ CO ₃ powder (1.56 g, 11.3 mmol) and further DMF (10 ml). The mixture was stirred at rt for 18 h. The reaction was filtered to remove K ₂ CO ₃ and concentrated to give an oily residue. It was again dissolved in DMF (5 ml) and refiltered to further remove K ₂ CO ₃ solids. The solvent was again removed in vacuo and the gum product was dried in vacuo for 3 hours to remove all solvents. The ether linked intermediate was dissolved in anhydrous DMF (60 ml) and 10% Pd / C (3.0 g) was added. This was hydrogenated at 1 atmosphere for 45 minutes. The red reaction solution was filtered to remove Pd / C, washed with MeOH (200 ml) and concentrated to 50 ml (DMF) volume. This was refiltered to remove traces of Pd / C and more precipitated K ₂ CO ₃ . The filtrate was concentrated to 30 ml volume of DMF and purified by reverse phase preparative HPLC. The desired fractions were diluted with EtOAc (1 L) and washed with saturated NaHCO ₃ (500 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and vacuum dried to give a red solid. It was suspended in CH ₂ Cl ₂ (150 ml) and diluted with hexanes (200 ml). The red brick solid was filtered, washed with hexane and dried in vacuo under P ₂ O ₅ to obtain the product in 29% yield (400 mg, 1.10 mmol). TLC: R _f = 0.70 (EtOAc); LC-MS (ESI): [M + H] ⁺ = 365.1 @ RT = 2.14 min; _{^{1 H NMR (DMSO- d 6)}} δ 12.40 (1H, s), 10.60 (1H, s), 7.73 (2H, m), 7.41 (1H, d, J = 8.4 Hz), 7.29 (1H, m), 7.24 (2H, m), 7.13 (1H, dd, J = 1.2, 8.4 Hz), 7.04 (2H, s), 4.49 (2H, s), 3.55 (2H, m), 3.49 (2H, m), 3.25 (3H, s).

Example 196

Preparation of 3-amino-N-[(4-methoxyphenyl) sulfonyl] -2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1 H-indole-5-carboxamide

3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indole-5-carboxylic acid (Example 22, 0.100 g, 0.285 mol) in a 25 ml round bottom flask ), DMF (5 ml), 4-methoxybenzenesulfonamide (0.059 g, 0.314 mmol) and DMAP (0.038 g, 0.314 mmol) were added followed by EDCI (0.060 g, 0.314 mmol). The reaction mixture was stirred at ambient temperature for 4 hours and the flask was purged with argon. Pd / C (0.250 g) was added to the flask and equipped with a hydrogen balloon, then the flask was purged (3 ×). The hydrogenation reaction was carried out with stirring at room temperature for 12 hours. The reaction mixture was filtered and purified by HPLC. The desired fractions were combined and saturated NaHCO ₃ (5 ml) was added and the mixture was extracted with EtOAc (3 × 50 ml). The combined organics were dried over Na ₂ SO ₄ and concentrated to give a red solid. ¹ H NMR (400 MHz, DMSO) δ 12.43 (s, 1H), 10.90 (s, 1H) 8.5 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz ), 7.45 (d, J = 9.2), 7.35 (m, 3H), 7.29 (m, 3H), 7.25 (bs, 2H), 7.09 (d, J = 8.4), 3.85 (s, 3H). LCMS RT = 2.77 min; [M + H] ⁺ = 490.1.

Example 214

N- (1-{[3-amino-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indol-5-yl] carbonyl} pyrrolidin-3-yl Preparation of) -N'-isopropyl-N-methylurea

Step 1. 3- (5-{[3- (methylamino) pyrrolidin-1-yl] carbonyl} -3-nitro-1H-indol-2-yl) quinoxalin-2 (1H) -one Produce

tert-butyl methyl (1-{[3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indol-5-yl] carbonyl} pyrrolidine-3 -FA) TFA (10 ml) was added to a solution of CH ₂ Cl ₂ (10 ml) of 0.70 g, 0.77 mmol, prepared by the experimental method described to produce Example 56, and the resulting red solution was Stir overnight at room temperature. Volatile materials were evaporated and ethyl ether was added. Evaporation of the volatiles again gives a yellow crude residue. This residue was basified to pH 9 with saturated NaHCO ₃ . The yellow solid precipitated was filtered, washed with water and dried in an oven to give 471 mg of a yellow solid (83%). This material was used without further purification.

Step 2. N- (1-{[3-amino-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1 H-indol-5-yl] carbonyl} pyrrolidine- Preparation of 3-yl) -N'-isopropyl-N-methylurea

In a 25 ml round bottom flask, 3- (5-{[3- (methylamino) pyrrolidin-1-yl] carbonyl} -3-nitro-1H-indol-2-yl) quinoxaline-2 (1H)- On (0.10 g, 0.23 mmol) toluene (10 ml) solution was injected. Isopropyl isocyanate (0.020 g, 0.23 mmol) was added to this suspension and the mixture was stirred at reflux overnight. The solvent was evaporated, ether was added to the residue and sonicated. The precipitated solid was filtered off, washed with ether and dried in an oven to give the desired yellow solid. The crude yellow solid was taken up in DMF (5 ml) and Pd / C was added to this solution. The atmosphere was switched to hydrogen and the reaction stirred for 3 hours. The resulting red solution was filtered and the Pd residue was washed with DMF. The red solution was concentrated and the residue was purified by HPLC (MeCN / water = 15-80%). Fractions were combined and evaporated to remove acetonitrile. The red solution was basified with saturated NaHCO ₃ , the red precipitate was filtered, washed with water (5 ×) and dried in an oven to give 66 mg of a red solid (59%). _{^{1 H-NMR (DMSO- d 6}} ) δ 12.43 (s, 1H), 10.81 (s, 1H), 8.12 (s, 1H), 7.76-7.73 (d, 1H), 7.49-7.43 (d, 1H), 7.40-7.35 (m, 1H), 7.33-7.29 (m, 1H), 7.28-7.21 (m, 2H), 7.15 (s, 2H), 6.02 (s, 1H), 3.81-3.39 (m, 5H), 2.73 (s, 3 H), 1.99-1.87 (m, 2 H), 1.09-0.95 (m, 6 H). LCMS RT = 2.17 min; [M + H] ⁺ = 488.1.

Example 217

Preparation of 3- [3-amino-5- (3,5-dichloro-pyridin-4-yloxy) -1 H-indol-2-yl] -1 H-quinoxalin-2-one

Step 1. Preparation of 3- (5-hydroxy-1H-indol-2-yl) -1H-quinoxalin-2-one

Cool a solution of CH ₂ Cl ₂ (150 ml) of 3- (5-methoxy-1H-indol-2-yl) -1H-quinoxalin-2-one (Example 6, 1.80 g, 6.18 mmol) to 0 ° C. It was. BBr ₃ (5.84 ml, 61.8 mmol) was added dropwise to the solution. The mixture was stirred at rt for 24 h. The reaction was poured into ice (200 g). The resulting mixture was extracted with EtOAc (3 × 300 ml). The organic layer was washed with brine (500 ml), dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was crystallized in MeOH and water (1: 6) to give 1.70 g (99%) of product. 1 H NMR (400 MHz, DMSO) δ 12.56 (s, 1H), 11.31 (s, 1H), 8.79 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.30-7.32 (m, 3H), 6.90 (s, 1H), 6.73 (d J = 8.4 Hz, 1H); LCMS (ESI-MS) RT = 2.27; 276.2 (M + H) ⁺ .

Step 2. Preparation of 3- [5- (3,5-Dichloro-pyridin-4-yloxy) -1 H-indol-2-yl] -1 H-quinoxalin-2-one

DMF (2 ml) solution of 3- (5-hydroxy-1H-indol-2-yl) -1H-quinoxalin-2-one (100 mg, 0.36 mmol) and potassium tert-butoxide (44.5 mg, 0.40 mmol) Was stirred at room temperature for 2 hours. To this solution, 3,4,5-trichloropyridine (65.8 mg, 0.36 mmol) and K ₂ CO ₃ (29.9 mg, 0.22 mmol) were added. The mixture was heated to 100 ° C overnight. The reaction was cooled to room temperature and poured into water (20 ml). The crude product precipitated out as a yellow solid. The solid was filtered off, washed with water and dried to give 120 mg (79%) of the product. 1 H NMR (400 MHz, DMSO) δ 12.60 (b, 1H), 11.69 (s, 1H), 8.75 (s, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.73 (s, 1H), 7.51 (m, 2H), 7.34-7.32 (m, 2H), 7.05 (s, 1H), 6.95 (d J = 8.8 Hz, 1H); LCMS (ESI-MS) RT = 3.77; 423.2 (M + H) ⁺ .

Step 3. Preparation of 3- [5- (3,5-Dichloro-pyridin-4-yloxy) -3-nitro-1H-indol-2-yl] -1 H-quinoxalin-2-one

To a solution of DMF (3 ml) of 3- [5- (3,5-dichloro-pyridin-4-yloxy) -1H-indol-2-yl] -1H-quinoxalin-2-one (110 mg, 0.26 mmol) Isoamyl nitrate (80 uL, 0.57 mmol) was added. The reaction was heated to 90 ° C. for 2 hours and then cooled to room temperature. The mixture was poured into water (25 ml). The product precipitated out as a yellow solid. The solid was filtered off, washed with water and dried to give 95 mg (62%) of crude product which was used without further purification.

Step 4. Preparation of 3- [3-amino-5- (3,5-dichloro-pyridin-4-yloxy) -1 H-indol-2-yl] -1 H-quinoxalin-2-one

AcOH of 3- [5- (3,5-dichloro-pyridin-4-yloxy) -3-nitro-1H-indol-2-yl] -1H-quinoxalin-2-one (95 mg, 0.16 mmol) 2 ml) and water (20 uL) solution were degassed with nitrogen for 5 minutes. Activated iron powder (325 mesh, 95 mg, 1.70 mmol) was added and the mixture was stirred at rt overnight. The reaction was neutralized with saturated NaHCO ₃ solution (50 ml) and extracted with EtOAc (3 × 30 ml). The organic layer was washed with brine (50 ml), dried and concentrated. The residue was purified by silica gel column chromatography (EtOAc: hexane = 1: 1) to afford 35 mg (49%) of the desired material. 1 H NMR (400 MHz, DMSO) δ 12.45 (s, 1H), 10.66 (s, 1H), 8.78 (s, 2H), 7.73 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz , 1H), 7.24-7.00 (m, 5H), 6.85 (s, 2H); LCMS (ESI-MS) RT = 2.99; 438.2 (M + H) ⁺ .

Example 228

Preparation of 3- (5-{[tert-butyl (dimethyl) silyl] oxy} -1 H-indol-2-yl) quinoxalin-2 (1H) -one

Step 1. Preparation of 5-{[tert-butyl (dimethyl) silyl] oxy} -1 H-indole

Into a 250 ml round bottom flask was injected 5-hydroxyindole (5.00 g, 37.6 mmol, 1 equiv) dissolved in 75 ml DMF. To this imidazole (2.7 g, 1.05 equiv) and TBDMSCl (5.90 g, 1.05 equiv) were added and the reaction stirred at room temperature for 2 hours. DMF was removed in vacuo and the residue was partitioned between water (150 ml) and EtOAc (150 ml). EtOAc was removed and the aqueous layer was extracted with EtOAc (2 × 100 ml). The combined organics were dried (Na ₂ SO ₄ ), filtered and evaporated to yield 9.2 g of a white solid which was used without further purification.

Step 2. Preparation of tert-Butyl 5-{[tert-butyl (dimethyl) silyl] oxy} -1 H-indole-1-carboxylate

Into a 250 ml round bottom flask was injected 9.3 g (37.6 mmol, 1 equivalent) of 5-t-butyldimethylsiloxyindole dissolved in 75 ml THF. To this was added 4-DMAP (4.8 g, 1.05 equiv) and di-t-butyl dicarbonate (8.6 g, 1.05 equiv) to give rise to gas evolution. After gas evolution ceased (after 5 minutes), the reaction appeared to be complete via TLC. THF was then removed and the residue was partitioned between water (150 ml) and EtOAc (150 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was filtered through a silica plug to remove the remaining 4-DMAP. The desired fractions were combined and evaporated to yield 12.2 g of a white solid, which was used without further purification.

Step 3. Preparation of tert-Butyl 5-{[tert-butyl (dimethyl) silyl] oxy} -2- [methoxy (oxo) acetyl ] -1H-indole-1-carboxylate

Into a 500 ml round bottom flask was injected N-Boc-5-t-butyldimethylsiloxyindole (12.2 g, 35.1 mmol, 1 equiv) dissolved in 100 ml of THF. It was cooled to -78 deg. C and 24.1 ml of t-BuLi (1.7 M pentane solution, 38.6 mmol, 1.1 equiv) was added dropwise. It was stirred for 1 hour and dimethyl oxalate (9.1 g, 2.2 equiv) was quickly added in the form of a 40 ml THF solution. The reaction was then allowed to come to room temperature and stirred for a further 2 hours. At this point, the reaction was diluted with water (200 ml) and extracted with EtOAc (3 × 150 ml). The collected organics were dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was then purified by silica gel chromatography (10% EtOAc / Hex) to give 8.9 g (58%) of the product as a white solid. ¹ H NMR (CD ₂ Cl ₂ ) δ 7.72 (d, 1H), 7.34 (d, 1H), 6.77 (s, 1H), 6.61 (d, 1H), 6.25 (d, 1H), 1.44 (s, 9H ), 0.80 (s, 9H), 0.00 (s, 6H); TLC R _f = 0.60 (25% EtOAc / Hex).

Step 4. Preparation of 3- (5-{[tert-butyl (dimethyl) silyl] oxy} -1 H-indol-2-yl) quinoxalin-2 (1H) -one

In a 500 ml round bottom flask, N-Boc-5-t-butyldimethylsiloxy-2-methyloxalylindole (8.70 g, 20.0 mmol, 1 equivalent) dissolved in 250 ml AcOH was injected. 1,2-phenylenediamine (2.4 g, 1.1 equiv) was added thereto and the reaction mixture was heated to 130 ° C. After 1 hour, the reaction was cooled to room temperature and poured into 60 ml of water to give a yellow solid. This solid was filtered and dried in vacuo at 60 ° C. to yield 7.8 g (99%) of the desired product as a yellow solid. _{^{1 H NMR (DMSO- d 6)}} δ 12.39 (s, 1H), 11.26 (s, 1H), 7.61 (d, 1H), 7.52 (s, 1H), 7.30 (dt, 1H), 7.20 (d, 1H ), 7.14 (m, 2H), 6.85 (d, 1H), 6.57 (dd, 1H), 0.78 (s, 9H), 0.00 (s, 6H); LCMS RT = 3.98 min; [M + H] = 392.3.

Example 236

Preparation of 3- [3-amino-5- (2,3-dihydroxy-1H-tetrazol-5-yl) -1H-indol-2-yl] quinoxalin-2 (1H) -one

Step 1. Preparation of 3- [5- (2,3-dihydro-1H-tetrazol-5-yl) -3-nitro-1H-indol-2-yl] quinoxalin-2 (1H) -one

Into a 25 ml round bottom flask was injected 3- [3-nitro-5-cyano-1H-indol-2-yl] -1H-quinoxalin-2-one (Example 19, 150 mg, 0.45 mmol) dissolved in 5 ml DMF. It was. NaN ₃ (58.9 mg, 0.90 mmol) and NH ₄ Cl (48.4 mg, 0.90 mmol) were injected therein, and the reaction was heated to 120 ° C. After 1 hour, only byproducts were visible and 1 ml water was added. A further 1 hour of stirring only caused a small change. Further NaN ₃ (176 mg) and NH ₄ Cl (145 mg) were added and the reaction stirred over the weekend. At this point, no starting material remained. The solid was filtered off and most of the volatiles (~ 2 ml) were removed. The mixture was then diluted with water and filtered to give 117 mg (69%) of a yellow solid which was used without further purification. LCMS Rt = 2.22 min; [M + H] = 375.0.

Step 2. Preparation of 3- [3-amino-5- (2,3-dihydroxy-1 H-tetrazol-5-yl) -1 H-indol-2-yl] quinoxalin-2 (1H) -one

3- [3-nitro-5- (1H-tetrazol-5-yl) -1H-indol-2-yl] -1H-quinoxalin-2-one (117 mg, 0.31) in 6 ml DMF in a 25 ml round bottom flask mmol) was injected. A catalytic amount of 10% Pd / C was added thereto and the dissolved gases were removed under vacuum. The atmosphere was switched to H ₂ and the reaction stirred at rt until completion of the reaction. The Pd / C was then filtered off and the volatiles were removed in vacuo. The solid was suspended in CH ₃ CN, sonicated for 2 minutes and then refiltered to remove remaining DMF. The desired product was isolated in the form of a red solid (84 mg, 82%). ¹ H-NMR (DMSO- d ₆ ; N- H unsubstituted in tetrazole) δ 12.47 (s, 1H), 10.93 (s, 1H), 8.59 (s, 1H), 7.76 (d, 2H), 7.60 (s , 1H), 7.32 (t, 1H), 7.25 (t, 2H), 7.19 (br s, 2H). LCMS RT = 2.09 min; [M + H] = 345.0.

Example 266

Preparation of 3- (3-hydroxy-1H-indol-2-yl) quinoxalin-2 (1H) -one

Step 1. Preparation of 3-{[tert-butyl (dimethyl) silyl] oxy} -1 H-indole

Into a 100 ml round bottom flask was injected 3-hydroxyindole (1.00 g, 7.51 mmol) and TBDMSCl (11.3 ml, 1.0 M THF solution). Imidazole (0.767 g, 11.3 mmol) was added followed by DBU (0.057 g, 0.38 mmol). The mixture was stirred at rt for 18 h, concentrated and used without further purification.

Step 2. Preparation of tert-butyl 3-{[tert-butyl (dimethyl) silyl] oxy} -1 H-indole-1-carboxylate

To a 100 ml round bottom flask was added 3-{[tert-butyl (dimethyl) silyl] oxy} -1 H-indole (0.600 g, 2.42 mmol) and 100 ml THF, DMAP (0.311 g, 2.55 mmol) and di-tert-butyl Di-carbonate (0.556 g, 2.55 mmol) was added. The reaction was stirred at rt for 3 h, concentrated and used without further purification.

Step 3. Preparation of tert-butyl 3-{[tert-butyl (dimethyl) silyl] oxy} -2- [methoxy (oxo) acetyl] -1 H-indole-1-carboxylate

To a 100 ml round bottom flask was added tert-butyl 3-{[tert-butyl (dimethyl) silyl] oxy} -1 H-indole-1-carboxylate (0.500 g, 1.44 mol) and 100 ml THF. The reaction was cooled to -78 ° C and t-BuLi (1.7 M pentane solution, 0.93 ml, 1.6 mmol) was added slowly over 30 minutes. The solution was stirred at −78 ° C. for 2 hours and then dimethyl oxalate (0.425 g, 3.60 mmol) was added all at once. The mixture was stirred at −78 ° C. for 10 minutes and brought to 0 ° C. for 1.5 hours. The mixture was quenched with water (100 ml) and concentrated. The residue was purified by column chromatography and Hex / EtOAc (1: 1) to afford 80% pure material. This material was used in the next reaction without further purification.

Step 4. Preparation of 3- (3-hydroxy-1H-indol-2-yl) quinoxalin-2 (1H) -one

Tert-butyl 3-{[tert-butyl (dimethyl) silyl] oxy} -2- [methoxy (oxo) acetyl] -1H-indole-1-carboxylate (0.030 g, 0.090 mmol) in a 100 ml round bottom flask Was added, 1,2-phenylenediamine (0.010 g, 0.094 mmol) and AcOH (3 ml) were added. The mixture was then heated to 100 ° C. for 18 hours. The mixture was concentrated and purified by HPLC. LCMS: RT = 2.94 min, [M + H] < + > = 278.7.

Example 304

Preparation of 3- [3-amino-5- (5-methyl-1,3,4-oxadiazol-2-yl) -1H-indol-2-yl] quinoxalin-2 (1H) -one

N-acetyl-3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indole-5-carbohydrazide carbamate in a 30 ml round bottom flask (Example Prepared using the experimental method described to make 56, 0.200 g, 0.492 mmol) was added and 5 ml of DMF / Benzene (1/1) was added. P ₂ O ₅ (0.284 g, 2.46 mmol) was added and the reaction heated at 100 ° C. for 18 h. After the mixture was cooled to room temperature, 10% Pd / C (100 mg) was added and the atmosphere was switched to H ₂ . The mixture was stirred overnight, diluted with water (30 ml) and extracted with EtOAc (3 × 30 ml). The residue was purified by HPLC to give 0.009 g of a red solid (5%). _{^{1 H NMR (DMSO- d 6)}} δ 12.49 (s, 1H), 11.06 (s, 1H), 8.55 (s, 1H), 7.70 (m, 1H), 7.62 (d, 1H), 7.33 (s, 1H ), 7.25 (m, 1 H), 2.58 (s, 3 H); LCMS RT = 2.32 min; [M + H] = 359.3.

Example 307

3-amino-N-cyclopentyl-N- (2-methoxyethyl) -2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1 H-indole-5-carboxamide Produce

Step 1. Preparation of N- (2-methoxyethyl) cyclopentylamine

Sodium triacetoxyborohydride (7.05 g, 33.3 mmol) and AcOH in a solution of CH ₂ Cl ₂ (10 ml) of cyclopentanone (2.00 g, 23.8 mmol) and 2-methoxyethylamine (1.78 g, 23.8 mmol) (1.36 ml, 23.8 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction was quenched with saturated NaHCO ₃ solution and extracted with CH ₂ Cl ₂ (2 ×). The combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated to yield 0.70 g (20.5%) of crude free base in the form of a yellow oil, which was used for the next step reaction without further purification. ¹ H-NMR (DMSO- d ₆ ) δ 3.37-3.33 (m, 2H), 3.21 (s, 3H), 2.98-2.95 (m, 1H), 2.63-2.58 (t, 2H), 1.71-1.62 (m , 2H), 1.59-1.52 (m, 2H), 1.43-1.38 (m, 2H), 1.27-1.17 (m, 2H). LCMS RT = 0.76 min; [M + H] ⁺ = 144.2.

Step 2. 3-Amino-N-cyclopentyl-N- (2-methoxyethyl) -2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1 H-indole-5-car Preparation of Voxamide

Using Example 56, 3-amino-N-cyclopentyl-N- (2-methoxyethyl) -2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1 H-indole -5-Carboxamide was added to the product of Step 1 of Example 307 with 3-nitro-2- (3-oxo-3,4-dihydro-2-quinoxalinyl) -1H-indole-5-carboxylic acid Obtained in the form of a red solid (50 mg, 39%) from Example 22. _{^{1 H-NMR (DMSO- d 6}} ) δ 12.45 (s, 1H), 10.81 (s, 1H), 7.94 (s, 1H), 7.79-7.74 (d, 1H), 7.46-7.41 (d, 1H), 7.38-6.98 (m, 6H), 4.24-4.12 (m, 1H), 3.58-3.20 (m, 7H), 1.82-1.58 (m, 6H), 1.45-1.36 (m, 2H). LCMS RT = 2.74 min; [M + H] ⁺ = 446.2.

Example 319

Preparation of tert-butyl 5-[(2-methoxyethyl) (methyl) amino] -2- [methoxy (oxo) acetyl] -1H-indole-1-carboxylate

Step 1. Preparation of N- (2-methoxyethyl) -N-3-dimethyl-4-nitroaniline

To a round bottom flask equipped with a reflux condenser was added 5-fluoro-2-nitrotoluene (10 g, 65.0 mmol) dissolved in 1-methyl-2-pyrrolidine (150 ml). N- (2-methoxyethyl) methylamine (21 ml, 200 mmol) was added to the stirring solution and the reaction was heated at 80 ° C. for 3 hours. After cooling to room temperature, the product was purified by chromatography to give 10.5 g (72%) of a yellow solid. _{^{1 H NMR (DMSO- d 6)}} : δ 2.62 (s, 3H), 3.01 (s, 3H), 3.24 (s, 3H), 3.40-3.45 (m, 2H), 3.57-3.61 (m, 2H), 6.58-6.62 (m, 2H) ..

Step 2. N- (2-methoxyethyl) -N-methyl-1H-indol-5-amine

A round bottom flask equipped with a reflux condenser was charged with N- (2-methoxyethyl) -N-3-dimethyl-4-nitroaniline (9.5 g, 42 mmol) and DMF (200 ml). N, N-dimethylformamide dimethylacetal (6.0 g, 50 mmol) and pyrrolidine (3.6 g, 50 mmol) were added and the reaction was heated to reflux for 3 hours. After cooling to room temperature, the volatile components were removed in vacuo and the oily residue was taken up in DMF (100 ml). This solution was added to 10% Pd / C (950 mg) under argon atmosphere. The balloon was used to switch the atmosphere to H ₂ and the reaction was stirred at rt for 17 h. H _{2 was} then removed and the mixture was filtered through Celite® under an argon blanket. Then the solvent was removed and the product was purified by chromatography. The desired product was a red oil (7.9 g, 92%). ¹ H-NMR (DMSO- d ₆ ) δ 2.80-2.83 (m, 4H), 3.22 (s, 3H), 2.39-2.43 (m, 2H), 2.46-2.52 (m, 2H), 6.22-6.24 (m , 1H), 6.72-6.76 (d, 1H), 6.81 (s, 1H), 7.18-7.23 (m, 2H), 10.61 (br s, 1H); LCMS RT = 0.27 min; [M + H] ⁺ = 205.09.

Step 3. Preparation of tert-Butyl 5-[(2-methoxyethyl) (methyl) amino] -1H-indole-1-carboxylate

Tert-butyl 5-[(2) from N- (2-methoxyethyl) -N-methyl-1H-indol-5-amine (7.8 g, 38 mmol) using the method described in Example 12, step 1 -Methoxyethyl) (methyl) amino] -1H-indole-1-carboxylate was obtained as a colorless solid (7.2 g, 61%). _{^{1 H-NMR (DMSO- d 6}} ) δ 1.63 (s, 9H), 2.90 (s, 3H), 3.21 (s, 3H), 3.40-3.45 (m, 4H), 6.43-6.46 (m, 1H), 6.75-6.84 (m, 2H), 7.46-7.50 (d, 1H), 7.78-7.83 (d, 1H).

Step 4. Preparation of tert-Butyl 5-[(2-methoxyethyl) (methyl) amino] -2- [methoxy (oxo) acetyl] -1H-indole-1-carboxylate

Tert from tert-butyl 5-[(2-methoxyethyl) (methyl) amino] -1H-indole-1-carboxylate (3.5 g, 12 mmol) using the method described in Example 18, step 2 -Butyl 5-[(2-methoxyethyl) (methyl) amino] -2- [methoxy (oxo) acetyl] -1H-indole-1-carboxylate in the form of an oil (3.6 g, 80%) . _{^{1 H-NMR (DMSO- d 6}} ) δ 1.59 (s, 9H), 3.93 (s, 3H), 3.21 (s, 3H), 3.41-3.58 (m, 4H), 6.85 (m, 1H), 7.05- 7.13 (d, 1 H), 7.25 (s, 1 H), 7.75-7.79 (d, 1 H).

Step 5. Preparation of 3- {5-[(2-methoxyethyl) (methyl) amino] -1 H-indol-2-yl} -6,7-dimethylquinoxalin-2 (1H) -one

Tert-butyl 5-[(2-methoxyethyl) (methyl) amino] -2- [methoxy (oxo) acetyl] -1H-indole-1- using the method described in Example 12, step 3 3- {5-[(2-methoxyethyl (methyl) amino] -1H- from carboxylate (240 mg, 0.62 mmol) and 1,2-diamino-4,5-dimethylbenzene (69 mg, 0.64 mmol) Indol-2-yl} -6,7-dimethylquinoxaline-2 (1H) -one was obtained in the form of a red powder (204 mg, 88%) ¹ H-NMR (DMSO- d ₆ ) δ 2.35 (s, 6H ), 2.83 (s, 3H), 3.20 (s, 3H), 3.38-3.51 (m, 4H), 6.80-6.85 (m, 1H), 7.09 (s, 1H), 7.36-7.40 (d, 1H), 7.55-7.61 (1 H), 11.19 (s, 1 H), 12.41 (s, 1 H); LCMS RT = 1.86 min; [M + H] ⁺ = 377.46.

Example 336-337

2- [7- (4-fluorophenyl) -3-oxo-3,4-dihydroquinoxalin-2-yl] -1H-indole-5-carbonitrile and 2- [6- (4-fluoro Phenyl) -3-oxo-3,4-dihydroquinoxalin-2-yl] -1 H-indole-5-carbonitrile

Step 1. Preparation of (4'-fluoro-3-nitrobiphenyl-4-yl) amine

N ₂ was bubbled into a solution of 4-bromo-6-nitroaniline (3.0 g, 14 mmol) in DME (25 ml) for 10 minutes, followed by 1,1′-bis (diphenylphosphino-ferrocene) dichloropalladium (II ) Complex, CH ₂ Cl ₂ (1: 1) (0.60 g, 0.69 mmol), Na ₂ SO ₄ 1.0M solution (35 ml, 35 mmol) and 4-fluorophenylboronic acid (2.0 g, 15 mmol) were added. The reaction mixture was further bubbled with nitrogen for 10 minutes and heated to 60 ° C. for 1 hour. The reaction was quenched with water and extracted with EtOAc (3 ×). The combined organic layers were washed with water and brine, dried (MgSO ₄ ) and concentrated to give a crude residue, which was chromatographed with hexane / EtOAc = 3/1 to give 2.8 g (88%) of the product as an orange solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 8.16 (s 1H), 7.75-7.73 (d, 1H), 7.68-7.54 (m, 2H), 7.53 (s, 2H), 7.27-7.11 (m, 2H) , 7.09-7.08 (d, 1 H).

Step 2. Preparation of 4'-fluorobiphenyl-3,4-diamine

To the dry flask was added 10% Pd / C (0.013 g) under argon atmosphere. MeOH (100 ml) and (4'-fluoro-3-nitrobiphenyl-4-yl) amine (2.71 g, 11.7 mmol) were added, the atmosphere was switched to hydrogen and the mixture was stirred at rt overnight. The reaction mixture was filtered through celite, washed with MeOH and concentrated to give 2.26 g (96%) of a purple solid. _{^{1 H-NMR (DMSO- d 6}} ) δ 7.47-7.44 (m, 2H), 7.17-7.13 (m, 2H), 6.78 (s, 1H), 6.67-6.64 (d, 1H), 6.55-6.53 (d , 1H), 4.59-4.54 (d, 4H). LCMS RT = 1.74 min; [M + H] ⁺ = 203.2.

Step 3. 2- [7- (4-fluorophenyl) -3-oxo-3,4-dihydroquinoxalin-2-yl] -1 H-indole-5-carbonitrile and 2- [6- (4 Preparation of -fluorophenyl) -3-oxo-3,4-dihydroquinoxalin-2-yl] -1H-indole-5-carbonitrile

AcOH (10 ml) solution of 4'-fluorobiphenyl-3,4-diamine (2.28 g, 11.3 mmol) and 2- [methoxy (oxo) acetyl] -1 H-indole (5) (2.33 g, 10.3 mmol) Heated to 100 ° C. overnight. The reaction mixture was cooled to room temperature and diluted with water. The yellow solid precipitated was filtered, washed with water (5x) and dried in an oven to yield 3.11 g (80%) of a yellow solid. ¹ H-NMR (DMSO- d ₆ ) δ 12.83-12.79 (d, 1H), 12.21-12.19 (d, 1H), 8.24 (d, 1H), 8.05-7.64 (m, 6H), 7.55-7.32 (m , 4H). LCMS RT = 3.49 min; [M + H] ⁺ = 381.3.

Example 354

Preparation of 3-amino-N- (2-methoxyethyl) -N-methyl-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1 H-indole-5-sulfonamide

Step 1. Preparation of 2- (3-chloroquinoxalin-2-yl) -N- (2-methoxyethyl) -N-methyl-1H-indole-5-sulfonamide

A vial filled with bis (diphenylphosphino) ferrocenepalladium (II) chloride (0.164 g, 0.220 mmol) 2,3-dichloroquinoxaline (0.669 g, 3.36 mmol), (5-{[(2-methoxyethyl ) (Methyl) amino] sulfonyl} -1H-indol-2-yl) boronic acid (0.700 g, 2.24 mmol) and NaHCO ₃ (0.951 g, 8.97 mmol) were added followed by DME (5 ml). Water (0.5 ml, nitrogen bubbling for 10 minutes) was added to the reaction and the mixture was heated at 75 ° C. for 1 hour. A further 10 mol% Pd was added and the mixture was stirred for 1.5 hours. When boronic acid was used up, the reaction was concentrated in vacuo and the residue was purified by HPLC to give 0.300 g of a brown solid (31%). _{^{1 H NMR (DMSO- d 6)}} δ 12.39 (s, 1H), 8.22 (d, 1H), 8.20 (dd, δ 1H), 8.08 (dd, 1H), 7.98-7.89 (m, 2H), 7.74 ( dd, 1H), 7.61 (dd, 1H), 3.46 (t, 2H), 3.23 (s, 3H), 3.13 (t, 2H), 2.72 (s, 3H); LCMS RT = 3.34 min; [M + H] = 431.1.

Step 2. Preparation of N- (2-methoxyethyl) -N-methyl-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indole-5-sulfonamide

Dissolve 2- (3-chloroquinoxalin-2-yl) -N- (2-methoxyethyl) -N-methyl-1H-indole-5-sulfonamide (0.280 g, 0.650 mmol) in AcOH (20 ml) Heated to reflux (130 ° C.) for 18 hours. The solvent was removed under vacuum and the residue was taken up in EtOAc. The organic layer was washed with saturated NaHCO ₃ solution and concentrated to give the product as a red solid (0.250 g, 93%). _{^{1 H NMR (DMSO- d 6)}} δ 8.15 (s, 1H), 7.98 (s, 1H), 7.83 (dd, 1H), 7.71 (s, 1H), 7.69 (d, 1H), 7.56-7.52 (m , 2H), 7.34 (d, 1H), 3.44 (t, 2H), 3.21 (s, 3H), 3.10 (t, 2H), 2.68 (s, 3H); LCMS RT = 2.71 min; [M + H] = 413.6.

Step 3. N- (2- Methoxyethyl ) -N- methyl -3-nitro-2- (3-oxo-3,4- Dihydroquinoxaline -2-yl) -1H-indole-5-sulfonamide

Using the method described in Example 2, N- (2-methoxyethyl) -N-methyl-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indole- N- (2-methoxyethyl) -N-methyl-3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) from 5-sulfonamide (0.100 g, 0.240 mmol) -1H-indole-5-sulfonamide was obtained as a dark yellow solid (0.085 g, 76%). This material was used without purification or characterization.

Step 4. 3-Amino-N- (2-methoxyethyl) -N-methyl-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1 H-indole-5-sulfonamide Manufacture

Using the method described in Example 3, N- (2-methoxyethyl) -N-methyl-3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl)- N- (2-methoxyethyl) -N-methyl-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) from 1H-indole-5-sulfonamide (0.085 g, 0.160 mmol) -1H-indole-5-sulfonamide (0.012 g, 17%) was obtained. _{^{1 H NMR (DMSO- d 6)}} δ 12.50 (s, 1H), 11.16 (s, 1H), 8.40 (s, 1H), 7.79 (dd, 1H), 7.63 (d, 1H), 7.47 (dd, 1H ), 7.35-7.31 (m, 1H), 7.26-7.23 (m, 2H), 3.44 (t, 2H), 3.12 (s, 3H), 3.09 (t, 2H), 2.71 (s, 3H); LCMS RT = 2.59 min; [M + H] = 428.5.

Example 375

Preparation of [3-amino-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indol-5-yl] methyl phenylcarbamate

Step 1. [3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1 H-indol-5-yl] methyl Phenylcarbamate  Produce

Anhydrous DMF (5 ml) solution of 3- [5- (hydroxymethyl) -3-nitro-1H-indol-2-yl] quinoxalin-2 (1H) -one (Example 156, 0.100 g, 0.290 mmol) To phenyl isocyanate (0.193 g, 1.62 mmol) was added at room temperature and the tan solution was stirred at 80 ° C. for 24 h. The reaction was diluted with CH ₂ Cl ₂ (20 ml) and purified by silica gel chromatography (hexane / EtOAc) to afford 0.099 g of a yellow solid (72%). TLC: R _f = 0.80 (50% hexanes / EtOAc); LC-MS (ESI): [M + H] ⁺ = 456.2 and [M + Na] + = 478.1 @ RT = 3.48 min.

Step 2. [3-Amino-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1 H-indol-5-yl] methyl Phenylcarbamate  Produce

Glacial acetic acid of [3-nitro-2- (3-oxo-3,4-dihydroxyquinoxalin-2-yl) -1H-indol-5-yl] methyl phenylcarbamate (0.040 g, 0.09 mmol) 12 ml) The suspension was sonicated for 1 hour and iron powder (325 mesh, 0.100 g, 1.79 mmol) was added to this very fine yellow suspension. The mixture was stirred at room temperature and under nitrogen atmosphere for 2 hours. To the red suspension was quenched by the slow addition of saturated NaHCO ₃ (300 ml). The mixture was extracted with EtOAc (2 × 300 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to yield 0.026 g of a red solid (70%). TLC: R _f = 0.61 (50% hexanes / EtOAc); LC-MS (ESI): [M + H] ⁺ = 426.2 @ RT = 2.87 min.

Example 418

Preparation of cyclohexyl 3-amino-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1 H-indole-5-carboxylate

3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indole-5-carboxylic acid (Example 22, 250 mg) in SOCl ₂ (20.0 ml, 272 mmol) solution , 0.710 mmol) was added at room temperature and the resulting brown suspension was heated at 85 ° C. for 4 hours. The suspension is concentrated under reduced pressure and the residue is dried in vacuo for 24 hours to give 262 mg of 3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indole-5- Carbonyl chloride was obtained in the form of a light yellow solid. 3-nitro-2- (3-oxo-3,4-dihydroquinoxalin-2-yl) -1H-indole-5-carbonyl chloride (0.07 g, 0.19 mmol) and CH ₂ Cl in a 250 ml round bottom flask ₂ (3 ml) was injected. To this was added cyclohexanol (0.03 ml, 0.38 mmol) and Et ₃ N (0.03 ml, 0.21 mmol) and the reaction was stirred at 60 ° C. for 18 hours. SnCl ₂ (0.43 g, 1.9 mmol) was added and the reaction stirred at 60 ° C. for 12 h. The reaction was diluted with water (30 ml) and DMF (100 ml). The mixture was extracted with EtOAc (3 × 100 ml) and the combined organics were dried (Na ₂ SO ₄ ) and purified by HPLC. The collected fractions were concentrated to give 0.026 g of red solid (33%). _{^{1 H NMR (DMSO- d 6)}} δ 12.55 (s, 1H), 11.19 (s, 1H), 8.56 (s, 1H), 7.78 (m, 1H), 7.54 (d, 1H), 7.36 (m, 1H ), 7.27 (m, 1 H), 4.93 (m, 1 H), 1.98-1.55 (m, 10 H); LCMS RT = 3.38 min; [M + H] = 403.3.

Various compounds of the present invention can be readily obtained using the methods described above or other recognized chemical processes known in the art or can be readily prepared using suitable starting materials already described herein.

In general, the desired salt of a compound of the invention may be prepared by methods well known in the art in situ at the final isolation or purification of the compound. For example, the desired salt can be prepared by individually reacting the purified compound in free base or free acid form with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, and isolating the salt formed. For example, for basic compounds, the free base is treated with anhydrous HCl in a suitable solvent such as THF and the salt is isolated with hydrochloride. In the case of acidic compounds, the salts can be obtained, for example, by treating the free acid with anhydrous ammonia in a suitable solvent such as ether and then isolating the ammonium salt. These methods are clear to the person skilled in the art as prior art.

The esters of the compounds identified herein are subjected to conventional methods such as, for example, by reactions catalyzed by acid catalysts of carboxylic acid compounds and alcohols, or by reaction under Mitsunobu conditions of carboxylic acid compounds and alcohols. Can be obtained by These methods are clear to the person skilled in the art as prior art.

Purification of the isomers for the compounds of the invention and separation of the isomer mixtures can be accomplished by known techniques known in the art.

Compositions of Compounds of the Invention

The compounds of the present invention can be administered and used in a pharmaceutical composition suitably formulated to a patient in need thereof to achieve the desired pharmacological effect. Patients aimed at the present invention are mammals, including humans, in need of treating (including prophylactic treatment) a particular condition or disease. Therefore, the present invention includes a pharmaceutical composition consisting of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the present invention, or a salt or ester thereof. Pharmaceutically acceptable carriers are any carriers that are relatively non-toxic and harmless to patients at concentrations consistent with the effective activity of the active ingredient, such that any side effects due to the carrier will not contaminate the beneficial effect of the active ingredient. A pharmaceutical effective amount of a compound is an amount that can produce or affect the particular condition being treated. The compounds of the present invention can be used orally, parenterally, topically, in combination with pharmaceutically acceptable carriers well known in the art, using any effective conventional dosage unit form, including immediate, slow and regular release formulations. Nasal, ophthalmic, ear, sublingual, rectal, vaginal, and the like can be administered.

For oral administration, the compounds may be formulated in solid or liquid formulations, such as capsules, pills, tablets, troches, lozenges, solubilizers, powders, solutions, suspensions or emulsions, and for the preparation of pharmaceutical compositions It may be prepared according to methods known in the art. The solid unit dosage form may be a capsule, which may be in the form of a normal hard or soft shell gelatin, including, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, calcium phosphate, corn starch and the like.

In another embodiment, the compounds of the present invention may be prepared using conventional tablet materials such as lactose, sucrose and corn starch, binders such as acacia, corn starch or gelatin, potato starch, arginine acid, corn starch and guar gum, gum tram. Disintegration agents, for example, talc, stearic acid or magnesium, calcium or zinc stearate, which improve the fluidity of the granulation of tablets Lubricants, dyes, colorants and flavoring agents aimed at improving tablet aesthetic quality and preventing tablets from adhering to the surface of tablets and others; In combination. Excipients suitable for use in oral liquid dosage forms include dicalcium phosphate and water and, for example, ethanol, benzyl alcohol and polyethylene alcohol, with or without the addition of pharmaceutically acceptable surfactants, suspending agents or emulsions. Diluents such as alcohols. Various other materials may be present as coatings or to modify the physical form of the dosage unit into other forms. For example, tablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of aqueous suspensions. They provide the active ingredient as a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as, for example, the sweetening, flavoring or coloring agents mentioned above may also be present.

The pharmaceutical composition of the present invention may be in the form of an oil emulsion in water. The oil phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable latexing agents include (1) gums occurring in nature, such as gum acacia and gum tragacanth, (2) phosphatides occurring in nature, such as soy and lecithin, (3) fatty acids and sorbitan monooleate Esters or partial esters derived from hexitol anhydride, (4) condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Latex may also include sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredient in, for example, vegetable oils such as arachis oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. Oily suspensions may include thickening agents, for example beeswax, hardened paraffin or cetyl alcohol. The suspension may also comprise one or more preservatives such as, for example, ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents and one or more sweeteners such as, for example, sucrose or saccharin.

Syrups and elixirs may be combined with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also include preservatives such as protecting agents, methyl and propyl parabens, and flavoring and coloring agents.

The compounds of the present invention may also contain pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, carbomer, methicellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsions and other pharmacological aids. Sterile liquids or liquid mixtures, with or without water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, 2,2- Pharmacological carriers, which may be glycerol ketals such as dimethyl-1,1-dioxolane-4-methanol, ethers such as poly (ethylene glycol) 400, oils, fatty acids, fatty acid esters or fatty acid glycerides, or acetylated fatty acid glycerides; Parenteral as an injectable dosage form of the compound together in a physiologically acceptable dilution Alternatively, ie, subcutaneously, intravenously, intraocularly, into the synovial bag, intramuscularly, or between the peritoneum.

Examples of oils that can be used in the parenteral formulations of the invention include, for example, petroleum, animal, vegetable or synthetic origin oils such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oils. admit. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters include, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium and triethanolamine salts, and suitable detergents include, for example, cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkylamine acetates such as alkyl, aryl and Anionic detergents such as olefin sulfonates, alkyls, olefins, ethers and monoglyceride sulfates, and sulfosuccinates, for example fatty amine oxides, fatty acid alkanolamides and poly (oxyethylene-oxypropylene) or ethylene oxides or Nonionic detergents such as propylene oxide copolymers and amphoteric detergents such as, for example, alkyl-beta-aminopropionate and 2-alkylimidazoline quaternary ammonium salts and mixtures thereof.

Parenteral compositions of the present invention generally comprise from about 0.5% to about 25% of the active ingredient by weight in solution. Preservatives and buffers may also be beneficial. In order to minimize or eliminate the irritation of the injection site, such compositions may include nonionic surfactants having a hydrophile-lipophile balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations ranges from about 5% to about 15% by weight. The surfactant may be a single component having the above HLB, or may be a mixture of two or more components having the preferred HLB.

Examples of surfactants used in parenteral formulations include, for example, high ethylene oxide with a hydrophobic base formed by the condensation reaction of polyethylene sorbitan fatty acid esters such as sorbitan monooleate with propylene oxide and propylene glycol. There is a collection of molecular weight additives.

The pharmaceutical composition may be in the form of a sterile injectable aqueous suspension. Such suspensions are suitable dispersing or wetting agents and suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, lecithin, Condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadeca-ethyleneoxycetanol, ethylene oxide and fatty acids and polyoxyethylene sorbitol monoole Forces that occur in nature, such as condensation products of partial esters derived from hexitol, such as ate, or of partial esters derived from hexitol anhydrides such as ethylene oxide and fatty acids and polyoxyethylene sorbitan monooleate, for example. Can be party Using a powder or wetting agents may be formulated according to known methods.

Sterile injectable preparations may be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents. Diluents and solvents that can be used are, for example, water, Ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile fatty oils are commonly used as a solvent or suspending medium. For this purpose any bland fatty oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

The compositions of the present invention may also be administered in the form of suppositories for rectal administration of the drug. Such compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperature but liquid at rectal temperature and which melts to release the drug in the rectum. Such materials include, for example, cocoa butter and polyethylene glycols.

Another formulation used in the method of the invention uses a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or discontinuous infusion of controlled amounts of a compound of the invention. The construction and use of transdermal patches for the delivery of pharmacological agents are well known in the art (see, eg, US Pat. No. 5,023,252, issued June 11, 1991, incorporated herein by reference). . Such patches may be configured for continuous, pulsatile, or on-demand delivery of the pharmacological agent.

Controlled release formulations for parenteral administration include polymer microspheres and polymer gel formulations of liposomes known in the art.

It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmacological agents is well known in the art. For example, direct techniques, such as administering drugs directly to the brain, usually involve drug delivery conduits into the patient's ventricular system to bypass the blood-brain barrier. Such implantable delivery systems for use in delivery of agents to specific anatomical locations in the body are described in US Pat. No. 5,011,472, issued April 30, 1991.

Compositions of the present invention may also include other conventional pharmaceutically acceptable formulation ingredients, which are generally, as necessary or preferably, treated as carriers or diluents. Conventional procedures for preparing such compositions in suitable dosage forms can be used. These components and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, MF et al, "Compendium of Excipients for Parenteral Formulations " PDA Journal of Pharmaceutical Science & Technology 1998 , 52 (5), 238-311; Strickley, RG "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999) -Part-1" PDA Journal of Pharmaceutical Science & Technology 1999 , 53 (6), 324-349; And Nema, S. et al , "Excipients and Their Use in Injectable Products " PDA Journal of Pharmaceutical Science & Technology 1997 , 51 (4), 166-171.

Commonly used pharmacological ingredients, which may be suitably used to formulate the composition in accordance with the intended route of administration, are:

Acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);

Alkalizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine);

Adsorbents (examples include but are not limited to powdered cellulose and activated carbon);

Aerosol propellants (examples include but are not limited to carbon dioxide, CCl ₂ F ₂ , F ₂ ClC-CClF ₂ and CClF ₃ );

Air substituents (examples include but are not limited to nitrogen and argon);

Antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);

Antimicrobial preservatives (examples include but are not limited to benzoalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal);

Antioxidants (e.g. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulphate) Foxylates, including but not limited to sodium metabisulfite);

Adhesives (examples include but are not limited to block copolymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);

Buffers (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydride and sodium citrate dihydrate);

Carriers (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and injectable bacterium) Is not);

Chelating agents (examples include but are not limited to edetate disodium and edetic acid);

Colorants (examples include but are not limited to FD & C Red 3, FD & C Red 20, FD & C Yellow 6, FD & C Blue 2, D & C Green 5, D & C Orange 5, D & C Red 8, Caramel and Ferric Oxide Red Is not);

Clarifying agents (examples include but are not limited to bentonite);

Emulsions (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);

Encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate);

Flavoring agents (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin);

Humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol);

Emollients (examples include but are not limited to mineral oil and glycerin);

Oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil);

Ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, mineral oil, hydrophilic mineral oil, white ointment, yellow ointment and rosewater ointment);

Penetration enhancers (transdermal delivery) (e.g. monohydroxy and polyhydroxy alcohols, mono or polyhydric alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, three Paline, terpins, amides, ethers, ketones, and urea);

Plasticizers (examples include but are not limited to diethyl phthalate and glycerol);

Solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation);

Curing agents (examples include but are not limited to cetyl alcohol, cetyl ester wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax);

Suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures));

Surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate);

Suspending agents (examples include but are not limited to: radish, bentonite, carbomer, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum) Not limited);

Sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose);

Tablet antitack agents (examples include but are not limited to magnesium stearate and talc);

Tablet binders (examples include but are not limited to acacia, arginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, uncrosslinked polyvinyl pyrrolidone and pregelatinized starch);

Tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch);

Tablet coatings (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac);

Tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate);

Tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polyacrylic potassium, crosslinked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate and starch);

Tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc);

Tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate);

Tablet / capsule opaque agents (examples include but are not limited to titanium dioxide);

Tablet polishes (examples include but are not limited to carnuba wax and white wax);

Thickeners (examples include but are not limited to beeswax, cetyl alcohol and paraffin);

Osmotic agents (examples include but are not limited to dextrose and sodium chloride);

Viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomer, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); And

Wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate and polyoxyethylene stearate)

It includes.

It is believed that one skilled in the art can, using the preceding information, make the best use of the present invention. However, the following are examples of pharmaceutical formulations that can be used in the methods of the invention. These are for illustrative purposes only and are not to be construed as limiting the invention in any way.

According to the present invention pharmaceutical compositions can be exemplified as follows.

Sterile IV Solution : A 5 mg / ml solution of the desired compound of the invention is made using sterile water for injection and pH is adjusted if necessary. The solution is diluted to 1-2 mg / ml using sterile 5% dextrose for administration and administered by IV infusion over 60 minutes.

Lyophilized powder for IV administration : The sterile preparation includes (i) 10-1000 mg of lyophilized powder form of the target compound of the invention (ii) 32-327 mg / ml sodium citrate and (iii) 300-3000 mg dex It can be made using Tran 40. The formulation is reconstituted with a sterile injectable saline or dextrose 5% to a concentration of 10-20 mg / ml, which is further diluted to 0.2-0.4 mg / ml with saline or dextrose 5% and in 15-60 minutes. Administered via IV rapid injection or IV infusion.

Intramuscular Suspension : The following solutions or suspensions can be prepared for intramuscular injection:

50 mg / ml of the water-insoluble compound of the present invention

5mg / ml Sodium Carboxymethylcellulose

TWEEN 80 at 4 mg / ml

9 mg / ml sodium chloride

9mg / ml benzyl alcohol

Hard Shell Capsules : A large number of unit capsules are made by filling each of the standard two-piece hard galantin capsules with 100 mg powdered active ingredient, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate.

Soft gelatin capsules : A mixture of active ingredients dissolved in digestible oils, such as soybean oil, cottonseed oil or olive oil, is prepared and infused with molten gelatin using a positive displacement pump to form a soft gelatin capsule containing 100 mg of active ingredient. do. This capsule is washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a drug mixture that can be mixed with water.

Tablets : A large number of tablets are prepared by conventional procedures such that the dosage unit is 100 mg active ingredient, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg lactose. Are manufactured. Appropriate water-soluble and non-water-soluble coatings can be applied to enhance taste, improve elegance and stability, or slow absorption.

Immediate release tablets / capsules : These are solid oral dosage forms made by conventional and novel methods. These units are administered orally without water for immediate dissolution and drug delivery. The active ingredients are mixed in a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets via cold drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoplastic sugars and polymers or boiling components to produce a porous matrix for the immediate release without the need for water.

Methods of Treatment of Pharmacological Diseases

The present invention also relates to methods of using the compounds or compositions described herein in the treatment or prevention of a hyperproliferative disease in mammals or in the manufacture of a medicament for the treatment or prophylaxis. Such methods include administering to a patient (or mammal) in need thereof, including a human, an amount of a compound, a pharmaceutically acceptable salt or ester thereof, or a composition of the invention effective for the treatment or prevention of a disease.

Hyperproliferative diseases include, but are not limited to, solid tumors such as breast, respiratory, brain, genital, digestive, urinary, eye, liver, skin, head and neck, thyroid, parathyroid, and their metastasized cancers. These diseases may include lymphomas, sarcomas, and leukemias.

The invention also relates to methods of using the compounds of the invention as prophylactic or anticancer agents for preventing the hyperproliferative diseases of mammals described herein. Such methods include administering to a mammal, including a human, a compound of the present invention or a pharmaceutically acceptable salt or ester thereof that is effective in delaying or reducing the onset of a certain amount of disease.

Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, coronary carcinoma, lobular epithelial carcinoma.

Examples of cardiovascular hyperproliferative diseases include, but are not limited to restenosis.

Examples of circulatory cancers include, but are not limited to, small cell and non-small cell lung carcinoma, bronchial adenoma and pleural and pulmonary blastoma.

Examples of brain cancers include, but are not limited to, hypopoptalmic glioma, astrocytoma of the cerebellum and cerebrum, medulloblastoma, epithelial cell tumor and ectoderm and pineal tumors.

Tumors of the nervous system include but are not limited to glioblastoma.

Tumors of the male genitalia include but are not limited to prostate and testicular cancer. Tumors of the female genital organs include, but are not limited to, endometrium, cervix, ovary, vagina, vulvar cancer and uterine sarcoma.

Tumors of the digestive system include, but are not limited to, anus, colon, esophagus, gallbladder, stomach, pancreas, rectum, small intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to, bladder, penis, kidney, renal pelvis, ureter, and urethral cancer.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinoma with or without fibrous lamellar variant), cholangiocarcinoma (hepatic biliary carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell cancer, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head and neck cancers include, but are not limited to, laryngeal / hypopharyngeal / nasopharyngeal / oropharyngeal cancer and lip and oral cancer.

Lymphomas include, but are not limited to, AIDS-related lymphomas, non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, Hodgkin's disease, and lymphomas of the central nervous system.

Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lympharcoma, and rhabdomyosarcoma.

Leukemias include but are not limited to acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia and hairy cell leukemia.

Such diseases have been well characterized in humans and exist with similar etiology in other mammals that can be treated by the administration of a compound of the invention and / or pharmaceutical composition.

The use of the compounds of the present invention can be illustrated, for example, by their in vitro activity in the in vitro tumor cell proliferation test described below. The relationship between activity in tumor cell proliferation in vitro and antitumor activity in clinical trials has been very well established in the art. For example, Taxol (Silvestrini et al. Stem Cells 1993 , 11 (6), 528-35), Taxotere (Bissery et al. Anti Cancer Drugs 1995 , 6 (3), 339) and Therapeutic uses of topoisomerase inhibitors (Edelman et al. Cancer Chemother. Pharmacol. 1996 , 37 (5), 385-93) are illustrated with the use of in vitro tumor cell proliferation tests.

The compounds and compositions herein exhibit anti-proliferative activity and are therefore useful for treating the symptoms described above, ie, symptoms mediated by hyperproliferative diseases. Symptoms mediated by a hyperproliferative disease refer to a disease or condition in which progression continues at least in part through proliferation. The following test is one of the methods by which the activity of a compound associated with the treatment of a disease specified herein can be determined.

In vitro tumor model examination

Anti-proliferative activity measurements can be measured as follows. Human tumor cell lines such as HCT-116 were cultured under conditions recommended by the supplier (CCL-247, American Type Culture Collection, Masassas, VA, USA). To prepare the test plates, cells were removed from the culture dish in the form of a single cell suspension and plated at 5000 cells / well in 96-well plates. The test compounds exemplified by Formula 1 were dissolved in 100% dimethyl sulfoxide at a concentration of 10 mmol / L and diluted to an appropriate concentration in which the final dimethyl sulfoxide concentration in the medium did not exceed 0.25%. The day after cell plate culture, the test compound was added to the medium in the appropriate dilution form, and the cells with the test compound were brought into contact with normal cell culture conditions for 72 hours. Inhibitor activity was measured using the CellTiter-Glo test kit using the instructions provided by the manufacturer (Promega, Madison, Wis., USA). % Growth inhibition was calculated using the formula% inhibition = (value with test compound / value without test compound) × 100.

Representative compounds of the invention were tested in this test and found to be active.

In addition, the compounds of the present invention are useful for the treatment or prevention of angiogenic dependent diseases, or in the manufacture of a medicament for the treatment or prophylaxis. Several diseases include, for example, ocular neovascular disease, angiogenic glaucoma, diabetic retinopathy, phacofibrosis, hemangioma, hemangiofioma, psoriasis, age-related hypertrophic degeneration, hemangioblastoma, hemangioma, and rheumatoid It is known to be associated with pain and inflammatory diseases such as rheumatoid disease or rheumatoid inflammation including arthritis, and tumor diseases including liquid tumors such as, for example, so-called solid tumors and leukemia. In the case of angiogenesis inhibitors, the compounds of the present invention are also useful for controlling the development of solid tumors, such as cancer of the breast, prostate, lung, pancreas, kidney, colon and cervical canal, as well as melanoma and tumor metastasis. Well known in the industry.

Tumors smaller than about 1-2 mm in diameter can also be supplied with oxygen and nutrients directly into tumor cells through dispersion. However, angiogenesis is considered an absolute requirement for tumors that grow to larger diameters. The main mechanism of action, which acts as an important inhibitor of tumor angiogenesis, includes the inhibition of growth of blood vessels, especially capillaries, into avascular nonproliferative tumors, resulting in a net increase in tumors due to the balance obtained between itself and proliferation. do. Another method of treatment is to reduce or prevent migration of the tumor into the body through the blood stream due to inhibition of tumor-associated angiogenesis. In addition, growth of vascular endothelial cells may be inhibited to prevent lateral secretory growth-promoting effects exerted on surrounding tissue by vascular endothelial cells that normally align blood vessels.

Anti-angiogenic activity can be measured as follows.

Genograph Tumor Model Trial:

On day 0, 5 × 10 6 MDA-MB-231 breast cancer cells (NCI, MD) were subcutaneously inoculated subcutaneously from female Ncr nude mice (Taconic Laboratories, NY). When tumors reached about 75-150 mm ³ , animals with tumors were randomly divided into several groups of 10 mice per group to be treated with vehicle or test compound. All test compounds were formulated in PEG 400: ethanol: 50 mM methanesulfonic acid (40:10:50, v / v / v) vehicle and administered orally for 14 days. Dose volume was 0.1 ml-test product / 10 g body weight or 10 ml / kg. In the course of the study, the length and width of each tumor were measured every 2 to 3 days with an electronic caliper, and the size of the tumor was measured based on the formula [length (mm) x width (mm) 2] / 2. Calculated at Animal weights were also recorded at the same time. Clinical signs after all compound administrations were observed. At the end of the treatment period, tumors from control animals and animals treated with the test compound were cut out, fixed in 10% buffered formalin and embedded in paraffin. Tissue sections are prepared for immunochemical staining and stained with anti-CD31 antibody (sc-1506, Santa Cruz, CA), and according to the manufacturer's instructions, an ABC kit (Burlingame, CA). Development). The amount of CD31 staining as a percentage of the total area for untreated tumors was determined from the images of the sections using ImagePro Plus (Media Cybernetics, Silver Spring, MD) software.

Representative compounds of the invention have been tested in this test and found to be active in reducing tumor size and inhibiting angiogenesis.

Described above by a standard toxicity test and standard pharmacological test for the determination of the prevention and / or treatment of the symptoms identified above for a mammal and a comparison of these results with the results of known agents used to treat these symptoms. Based on the above and other standard experimental techniques known to evaluate compounds useful for the prophylaxis and / or treatment of a disease or condition, effective dosages of the compounds of the present invention are in addition to the prevention and / or treatment of each desired symptom. Can be easily determined. The amount of active ingredient administered in the prophylaxis and / or treatment of one of these symptoms depends on the particular compound and the dosage unit used, the method of administration, the duration of treatment (including prophylactic treatment), the age and sex of the patient being treated, and (Or) may vary widely depending on considerations such as the nature and extent of the condition to be treated.

The total amount of active ingredient administered is generally about 0.001 mg / kg to 300 mg / kg, preferably about 0.10 mg / kg to about 150 mg / kg body weight per day. The unit dosage may comprise from about 0.5 mg to about 1500 mg of the active ingredient and may be administered one or more times per day. The daily injection dosage, including intravenous, intramuscular, subcutaneous and parenteral injection, and the use of infusion solutions, is preferably 0.01 to 200 mg / kg of total body weight. The daily rectal dose is preferably 0.01 to 200 mg / kg of total body weight. The daily vaginal dosage is preferably 0.01 to 200 mg / kg of total body weight. The daily topical dose is preferably between 0.01 and 200 mg / kg of total body weight administered between 1 and 4 times daily. Transdermal concentrations preferably require maintaining a daily dosage of 0.01 to 200 mg / kg. The daily inhalation dose is preferably 0.01 to 100 mg / kg of total body weight.

Of course, the specific initial and sustained doses to each patient may depend on the nature and severity of the symptoms as determined by the attending physician, the activity of the specific compound used, the age and general condition of the patient, the time of administration, route of administration, rate of excretion of the drug, Will change depending on the drug combination and the like. Preferred methods of administration and frequency of administration of a compound of the invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by one skilled in the art using conventional prophylactic and / or therapeutic tests.

The compounds of the present invention may be administered in combination with one or more other pharmacological agents so long as a single pharmacological agent or combination does not cause unacceptable adverse effects. For example, the compounds of the present invention can be combined with other anti-hyperproliferative or other indicator agents and the like, mixtures and combinations thereof.

For example, any anti-hyperproliferative agent that can be added to the composition is a compound as listed in the Cancer Chemotherapy Drug Administration in Merck Index 11th Edition (1996), Asparaginase, Bleomycin, Carbople Latin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5- Fluorouracil, hexamethylmelamine, hydroxyurea, iphosphamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, Prednisone, procarbazine, raloxifene, streptozosin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine and vindesine, and the like, which are incorporated herein by reference It was included.

Other anti-hyperproliferative agents suitable for use in the compositions of the present invention are described in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., Publ. by McGraw-Hill, pages 125-1287 (1996), aminoglutetimides, L-asparaginase, azathioprine, 5-azacity, compounds recognized for use in the treatment and / or prevention of tumor diseases. Dean cladribine, busulfan, diethylstilbestrol, 2 ', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethynyl estradiol, 5-fluorodeoxyuridine, 5 Fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, hydroxyprogesterone acetate, megestrol acetate, melphalan, mito Tan, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartame (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine and vinorelbine The inclusion is not limited to one, all of which are included herein by reference.

Other anti-hyperproliferative agents suitable for the use of the compositions of the present invention include, but are not limited to, other anticancer agents such as epothilones, irinotecan, raloxifene and topotecan.

It is believed that one skilled in the art will be able to utilize the present invention to the maximum extent possible using the prior art and techniques available in the art.

Modifications or manipulations to the invention will be apparent to those of ordinary skill in the art without departing from the spirit or scope of the invention set forth herein.

This application is directed to US Provisional Application No. 60/425490, filed November 12, 2002, and US Provisional Application No. 60 / 460,915, filed April 7, 2003, and US Provisional Application No. 60, filed June 30, 2003. / 484,202 claim priority.

Claims (14)

A compound of formula (I) or a pharmaceutically acceptable salt or ester thereof. <Formula I> here, Represents a 6-membered aromatic ring containing 0, 1 or 2 N atoms; R ¹ and R ² are H; Halo; CF ₃ ; C (O) R ⁹ ; ; (C ₁ -C ₆ ) alkyl optionally substituted with up to 2 substituents selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl; And N [(C ₁ -C ₃₎ alkyl] ₂ a (wherein alkyl is twice or less each independently (C ₁ -C ₃₎ are optionally substituted with alkoxy) each independently optionally substituted with substituents selected from 1 or 2, (C ₁ -C ₆ ) alkoxy; OH, F, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , NH (C ₁ -C ₃ ) alkyl, phenyl, pyrrolidinyl, and NH (C ₁ -C ₃ ) alkyl having alkyl optionally substituted with up to 2 substituents each independently selected from; OH, F, phenyl, and (C ₁ -C ₃ ) alkoxy, where alkoxy N [(C ₁ -C ₃ ) alkyl] ₂ having alkyl independently optionally substituted with up to 2 substituents independently selected from each other; N [(C ₁ -C ₃₎ alkyl] ₂ less than twice an optionally substituted pyrrolidinyl; Phenyl optionally substituted with up to 2 substituents each independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN Are each independently selected from If it contains 1 or 2 N atoms, R ¹ and R ² must each be H, R ¹ and R ² together with the adjacent C atoms to which they are attached, Conditionally that the ring is formed only when it does not contain this N atom, a ring selected from benzo, dioxo and imidazo, wherein the imidazo is optionally substituted no more than twice with (C ₁ -C ₃ ) alkyl. Forming; R ³ is H, (C ₁ -C ₄ ) alkyl, OH, NO ₂ , NH ₂ , NH (C ₁ -C ₄ ) alkyl, NHC (O) (C ₁ -C ₄ ) alkyl and NHC (O) phenyl Wherein said phenyl is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN); R ⁴ is H; OH; Halo; CN; C (O) R ⁶ ; S (O) ₂ R ⁷ ; OSi [(C ₁ -C ₄₎ alkyl] _3; Tetrazolyl; Thienyl; Pyrrolyl; Pyrimidinyl; Oxazolyl; Furanyl; Each optionally OH, F, OC (O) NHphenyl, NHC (O) (C ₁ -C ₃ ) alkyl, C (O) NH ₂ , C (O) NH (C ₁ -C ₃ ) alkyl, C (O _{) N [(C 1 -C 3} ) alkyl] _2, , (C ₁ -C ₃ ) alkoxy optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy, NHC (O) NH (C ₁ -C ₃ ) alkyl (the alkyl is optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F and phenyl), NHC (O) NHphenyl (The phenyl is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , CN, and Optionally substituted with up to 2 substituents independently selected from NHC (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is optionally substituted independently up to two times with (C ₁ -C ₃ ) alkoxy, NH-phenyl (the phenyl is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CN, and Optionally substituted with up to 2 substituents independently selected from N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CN, CF ₃ , and Phenyl optionally substituted with up to 2 substituents independently selected from N [(C ₁ -C ₃₎ alkyl] ₂ less than twice an optionally substituted pyrrolidinyl (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₂ -C ₆ ) alkynyl substituted with; (C ₁ -C ₃ ) alkoxy, pyrrolidinyl, , And N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted with up to 2 substituents independently selected from OH, F, (C ₁ -C ₃ ) alkoxy and phenyl) (C ₁ -C ₆ ) alkoxy optionally substituted with up to 2 substituents independently selected from; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each of said alkyl groups is 2 or less independently selected from OH, (C ₁ -C ₃ ) alkyl, F, (C ₁ -C ₃ ) alkoxy, and phenyl Is optionally substituted independently with a substituent of; Oxadiazolyl optionally substituted up to twice with (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy, CN, (C ₁ -C ₃ ) alkyl, halo, , , C (O) (C ₁ -C ₃ ) alkyl (optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkoxy, OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl) , And C (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each said alkyl group is independently optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy Phenyl optionally substituted with up to 2 substituents independently selected from; Pyridyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl; C (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each said alkyl group is optionally substituted independently up to two times with (C ₁ -C ₃ ) alkoxy; And O-pyridyl optionally substituted with up to 2 substituents independently selected from CF ₃ , halo, and (C ₁ -C ₃ ) alkyl Is selected from; R ⁵ is selected from H, halo, CN, (C ₁ -C ₆ ) alkoxy, and (C ₁ -C ₆ ) alkyl; R ⁶ is OH; NHR ¹⁰ ; O- (C ₃ -C ₆ ) cycloalkyl; (C ₁ -C ₃ ) alkoxy; O- (C ₂ -C ₆ ) alkenyl; O- (C ₃ -C ₆ ) alkynyl; (C ₁ -C ₆ ) alkyl optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each said alkyl group is OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₃ ) alkoxy, S (O) Independently with up to 2 substituents independently selected from ₂ -phenyl, S (O) ₂ (C ₁ -C ₃ ) alkyl, phenyl, furyl, tetrahydrofuryl, (C ₃ -C ₆ ) cycloalkyl, and pyridyl Optionally substituted); N [(C ₁ -C ₃ ) alkyl] R ⁸ , wherein [(C ₁ -C ₃ ) alkyl] is optionally substituted no more than twice with (C ₁ -C ₃ ) alkoxy; N [(C ₃ -C ₆ ) cycloalkyl] (C ₁ -C ₃ ) alkyl, wherein said alkyl is (C ₁ -C ₃ ) alkoxy, OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ Up to ₂ independently selected from S (O) ₂ -phenyl, S (O) ₂ (C ₁ -C ₃ ) alkyl, phenyl, furyl, tetrahydrofuryl, (C ₅ -C ₆ ) cycloalkyl, and pyridyl Is substituted with a substituent of; NH ₂ , NH (C ₁ -C ₃ ) alkyl, N [(C ₁ -C ₄ ) alkyl] ₂ , C (O) NH ₂ , NHC (O) (C ₁ -C ₃ ) alkyl, NHS (O) ₂ (C ₁ -C ₃ ) alkyl, pyridyl, N [(C ₁ -C ₃ ) alkyl] C (O) NH (C ₁ -C ₃ ) alkyl, N [(C ₁ -C ₃ ) alkyl] C Independent from (O) (C ₁ -C ₃ ) alkyl, and (C ₁ -C ₃ ) alkyl (N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₃ ) alkoxy, and pyrrolidinyl Optionally substituted with up to 2 substituents selected from: pyrrolidinyl optionally substituted with up to 2 substituents independently selected; (C ₁ -C ₃₎ optionally less than two times substituted with alkyl know morpholinyl; (C ₁ -C ₃₎ the double or less of alkyl optionally substituted thiomorpholinyl; Pyrazinyl, C (O) NH ₂ , C (O) NH-phenyl, C (O) -furanyl, C (O) (C ₁ -C ₃ ) alkyl, C (O) NH (C ₁ -C ₃ ) Alkyl, C (O) N [(C ₁ -C ₃ ) alkyl] R ⁸ , S (O) ₂ (C ₁ -C ₃ ) alkyl, S (O) ₂ -phenyl, , Pyridyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN and CF ₃ , Phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN, halo, CF ₃ , and (C ₁ -C ₃ ) alkoxy, OH, F, phenyl, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , pyrrolidinyl, C (O) -pyrrolidinyl, , And (C ₁ -C ₃ ) alkyl optionally substituted with up to 2 substituents independently selected from pyridyl (optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy) Piperazinyl optionally substituted with up to 2 substituents independently selected from; And Piperidinyl optionally substituted with up to 2 substituents independently selected from phenyl, pyridyl, pyrrolidinyl and oxo-dihydrobenzimidazolyl Is selected from; R ⁷ is NH ₂ ; Pyrrolidinyl; ; NH (C ₁ -C ₃ ) alkyl, wherein said alkyl is optionally substituted up to two times with (C ₁ -C ₃ ) alkoxy; NH-phenyl (the phenyl is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN, (C ₁ -C ₄ ) alkoxy, halo and CF ₃ ); N [(C ₁ -C ₃₎ alkyl] _2, (wherein each alkyl is optionally substituted with twice or less independently alkoxy (C ₁ -C _4)); And Phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ and CN Is selected from; R ⁸ is (C ₁ -C ₃ ) alkoxy; Pyridyl; Piperidinyl; Selected from pyranyl and phenyl, each ring moiety optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkoxy, and (C ₁ -C ₃ ) alkyl; R ⁹ is (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy; OH; ; Phenyl optionally substituted with (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each said alkyl group is OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₄ ) alkoxy, S (O) _{2-phenyl, S (O) 2 (C} 1 -C 3) alkyl, it is optionally independently substituted with phenyl, furyl, tetrahydrofuryl, (C ₃ -C ₆₎ cycloalkyl, and pyridyl); And N [(C ₁ -C _{3) alkyl],} optionally substituted pyrrolidinyl as Is selected from, Only when is not containing N atoms, R ⁹ is also selected from pyridyl, thienyl, and NHR ¹⁰ ; R ¹⁰ is H; Indolyl; OH, F, phenyl, (C ₁ -C ₄ ) alkoxy, NHC (O) (C ₁ -C ₃ ) alkyl, S- (C ₁ -C ₃ ) alkyl, benzimidazolyl, indolyl, thienyl, Pyrazolyl, , N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl), (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, CN, halo, CF ₃ , S (O) ₂ (C ₁ -C ₃ ) alkyl, S (O) ₂ phenyl, and phenyl optionally substituted with up to 2 substituents independently selected from S (O) ₂ NH ₂ , Pyridyl optionally substituted up to twice with CF ₃ , Imidazolyl optionally substituted up to twice with (C ₁ -C ₃ ) alkyl, Furyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl, and Optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkoxy, (O), and (C ₁ -C ₄ ) alkyl (OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl Pyrrolidinyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkyl optionally substituted with up to 2 substituents independently selected from; S (O) ₂ -phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₃ ) alkyl, halo, and CN; (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, and phenyl (the phenyl is (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, halo, CF ₃ , and CN Optionally substituted with up to 2 substituents independently selected from pyrazolyl optionally substituted with up to 2 substituents independently selected from; Benzothiazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl; Thiazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl; Thiadiazolyl optionally substituted with up to 2 substituents independently selected from CF ₃ , (C ₃ -C ₆ ) cycloalkyl, and (C ₁ -C ₆ ) alkyl; CN, _{halo, CF 3, N [(C} 1 -C 4) alkyl] _2, indolyl, , O-pyridyl optionally substituted with C (O) NH (C ₁ -C ₄ ) alkyl, Pyridyl, Optionally, OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl, and (C ₁ -C ₄ ) alkoxy (N [(C ₁ -C ₄ ) alkyl] ₂ where one alkyl group is optionally substituted with phenyl Substituted), or With an optionally substituted (C ₁ -C ₄₎ alkoxy optionally in the substituents selected independently 2 or less substituted (C ₁ -C ₄₎ alkyl Phenyl optionally substituted with up to 2 substituents independently selected from; Pyridyl optionally substituted with phenoxy, wherein the phenoxy is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkyl and (C ₁ -C ₄ ) alkoxy; And Indazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl Is selected from; R ¹¹ And R ¹² are independently selected from H, F and Cl, provided that one of R ¹¹ and R ¹² is F or Cl, the other must be H; X is selected from O, S, CH ₂ , and NH, When X is NH, H on NH is pyridyl, pyrazinyl, phenyl, Or OH, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , C (O) -pyrrolidinyl, N [(C ₁ -C ₄ ) alkyl] ₂ , and phenyl ( Said phenyl is optionally substituted with up to 2 substituents independently selected from CN and (C ₁ -C ₃ ) alkoxy) (C ₁ -C ₄ ) alkyl optionally substituted with up to 2 substituents independently selected from Is replaced by When X is O, S, or CH ₂ , Part Optionally substituted by replacing any H atoms on the moiety with (C ₁ -C ₄ ) alkyl. The method of claim 1, Is a 6-membered ring containing no N atoms. The compound of claim 2, wherein R ¹ and R ² are each independently selected from H, (C ₁ -C ₃ ) alkoxy, F, and CF ₃ ; R ³ is selected from H, NH ₂ , and NHC (O) (C ₁ -C ₃ ) alkyl; R ⁴ is H, halo, (C ₁ -C ₃ ) alkoxy, CN, COR ⁶ , S (O) ₂ R ⁷ , N [(C ₁ -C ₃ ) alkyl] ₂ , optionally substituted phenyl and optionally substituted (C ₁ -C ₄ ) alkyl; And R ⁵ is selected from H, (C ₁ -C ₃ ) alkoxy, F and CN. The compound of claim 3, wherein R ⁵ is selected from H and F; And R ⁴ is H, halo, (C ₁ -C ₃ ) alkoxy, CN, COR ⁶ , S (O) ₂ R ⁷ , N [(C ₁ -C ₃ ) alkyl] ₂ , and optionally substituted (C ₁ -C ₄ ) alkyl. The compound of claim 4, wherein R ¹ and R ² are each H; R ³ is NH ₂ ; R ⁴ is COR ⁶ , S (O) ₂ R ⁷ , and N [(C ₁ -C ₃ ) alkyl] ₂ and N [(C ₃ -C ₆ ) cycloalkyl] [(C ₁ -C ₃ ) alkyl] (C ₁ -C ₄ ) alkyl optionally substituted with; R ⁵ is H; R ⁶ is N [(C ₁ -C ₃ ) alkyl] ₂ and N [(C ₃ -C ₆ ) cycloalkyl] [(C ₁ -C ₃ ) alkyl]; R ⁷ is N [(C ₁ -C ₃ ) alkyl] ₂ ; And R ¹¹ and R ¹² are each H. The method of claim 1, Is a 6 membered aromatic ring containing 1 or 2 N atoms. The compound of claim 6, wherein R ³ is selected from H, NH ₂ , and NHC (O) (C ₁ -C ₃ ) alkyl; R ⁴ is H, halo, (C ₁ -C ₃ ) alkoxy, CN, COR ⁶ , S (O) ₂ R ⁷ , N [(C ₁ -C ₃ ) alkyl] ₂ , optionally substituted phenyl and optionally substituted (C ₁ -C ₄ ) alkyl; And R ⁵ is selected from H, (C ₁ -C ₃ ) alkoxy, F and CN. A method of treating a hyperproliferative disease comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof. <Formula I> here, Represents a 6-membered aromatic ring containing 0, 1 or 2 N atoms; R ¹ and R ² are H; Halo; CF ₃ ; C (O) R ⁹ ; ; (C ₁ -C ₆ ) alkyl optionally substituted with up to 2 substituents selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl; And N [(C ₁ -C ₃₎ alkyl] ₂ a (wherein alkyl is twice or less each independently (C ₁ -C ₃₎ are optionally substituted with alkoxy) each independently optionally substituted with substituents selected from 1 or 2, (C ₁ -C ₆ ) alkoxy; OH, F, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , NH (C ₁ -C ₃ ) alkyl, phenyl, pyrrolidinyl, and NH (C ₁ -C ₃ ) alkyl having alkyl optionally substituted with up to 2 substituents each independently selected from; OH, F, phenyl, and (C ₁ -C ₃ ) alkoxy, where alkoxy N [(C ₁ -C ₃ ) alkyl] ₂ having alkyl independently optionally substituted with up to 2 substituents independently selected from each other; N [(C ₁ -C ₃₎ alkyl] ₂ less than twice an optionally substituted pyrrolidinyl; Phenyl optionally substituted with up to 2 substituents each independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN Are each independently selected from If it contains 1 or 2 N atoms, R ¹ and R ² must each be H, R ¹ and R ² together with the adjacent C atoms to which they are attached, Conditionally that the ring is formed only when it does not contain this N atom, a ring selected from benzo, dioxo and imidazo, wherein the imidazo is optionally substituted no more than twice with (C ₁ -C ₃ ) alkyl. Forming; R ³ is H, (C ₁ -C ₄ ) alkyl, OH, NO ₂ , NH ₂ , NH (C ₁ -C ₄ ) alkyl, NHC (O) (C ₁ -C ₄ ) alkyl and NHC (O) phenyl Wherein said phenyl is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN); R ⁴ is H; OH; Halo; CN; C (O) R ⁶ ; S (O) ₂ R ⁷ ; OSi [(C ₁ -C ₄₎ alkyl] _3; Tetrazolyl; Thienyl; Pyrrolyl; Pyrimidinyl; Oxazolyl; Furanyl; Each optionally OH, F, OC (O) NHphenyl, NHC (O) (C ₁ -C ₃ ) alkyl, C (O) NH ₂ , C (O) NH (C ₁ -C ₃ ) alkyl, C (O _{) N [(C 1 -C 3} ) alkyl] _2, , (C ₁ -C ₃ ) alkoxy optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy, NHC (O) NH (C ₁ -C ₃ ) alkyl (the alkyl is optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F and phenyl), NHC (O) NHphenyl (The phenyl is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , CN, and Optionally substituted with up to 2 substituents independently selected from NHC (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is optionally substituted independently up to two times with (C ₁ -C ₃ ) alkoxy, NH-phenyl (the phenyl is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CN, and Optionally substituted with up to 2 substituents independently selected from N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CN, CF ₃ , and Phenyl optionally substituted with up to 2 substituents independently selected from N [(C ₁ -C ₃₎ alkyl] ₂ less than twice an optionally substituted pyrrolidinyl (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₂ -C ₆ ) alkynyl substituted with; (C ₁ -C ₃ ) alkoxy, pyrrolidinyl, , And N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted with up to 2 substituents independently selected from OH, F, (C ₁ -C ₃ ) alkoxy and phenyl) (C ₁ -C ₆ ) alkoxy optionally substituted with up to 2 substituents independently selected from; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each of said alkyl groups is 2 or less independently selected from OH, (C ₁ -C ₃ ) alkyl, F, (C ₁ -C ₃ ) alkoxy, and phenyl Is optionally substituted independently with a substituent of; Oxadiazolyl optionally substituted up to twice with (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy, CN, (C ₁ -C ₃ ) alkyl, halo, , , C (O) (C ₁ -C ₃ ) alkyl (optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkoxy, OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl) , And C (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each said alkyl group is independently optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy Phenyl optionally substituted with up to 2 substituents independently selected from; Pyridyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl; C (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each said alkyl group is optionally substituted independently up to two times with (C ₁ -C ₃ ) alkoxy; And O-pyridyl optionally substituted with up to 2 substituents independently selected from CF ₃ , halo, and (C ₁ -C ₃ ) alkyl Is selected from; R ⁵ is selected from H, halo, CN, (C ₁ -C ₆ ) alkoxy, and (C ₁ -C ₆ ) alkyl; R ⁶ is OH; NHR ¹⁰ ; O- (C ₃ -C ₆ ) cycloalkyl; (C ₁ -C ₃ ) alkoxy; O- (C ₂ -C ₆ ) alkenyl; O- (C ₃ -C ₆ ) alkynyl; (C ₁ -C ₆ ) alkyl optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each said alkyl group is OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₃ ) alkoxy, S (O) Independently with up to 2 substituents independently selected from ₂ -phenyl, S (O) ₂ (C ₁ -C ₃ ) alkyl, phenyl, furyl, tetrahydrofuryl, (C ₃ -C ₆ ) cycloalkyl, and pyridyl Optionally substituted); N [(C ₁ -C ₃ ) alkyl] R ⁸ , wherein [(C ₁ -C ₃ ) alkyl] is optionally substituted no more than twice with (C ₁ -C ₃ ) alkoxy; N [(C ₃ -C ₆ ) cycloalkyl] (C ₁ -C ₃ ) alkyl, wherein said alkyl is (C ₁ -C ₃ ) alkoxy, OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ Up to ₂ independently selected from S (O) ₂ -phenyl, S (O) ₂ (C ₁ -C ₃ ) alkyl, phenyl, furyl, tetrahydrofuryl, (C ₅ -C ₆ ) cycloalkyl, and pyridyl Is substituted with a substituent of; NH ₂ , NH (C ₁ -C ₃ ) alkyl, N [(C ₁ -C ₄ ) alkyl] ₂ , C (O) NH ₂ , NHC (O) (C ₁ -C ₃ ) alkyl, NHS (O) ₂ (C ₁ -C ₃ ) alkyl, pyridyl, N [(C ₁ -C ₃ ) alkyl] C (O) NH (C ₁ -C ₃ ) alkyl, N [(C ₁ -C ₃ ) alkyl] C Independent from (O) (C ₁ -C ₃ ) alkyl, and (C ₁ -C ₃ ) alkyl (N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₃ ) alkoxy, and pyrrolidinyl Optionally substituted with up to 2 substituents selected from: pyrrolidinyl optionally substituted with up to 2 substituents independently selected; (C ₁ -C ₃₎ optionally less than two times substituted with alkyl know morpholinyl; (C ₁ -C ₃₎ the double or less of alkyl optionally substituted thiomorpholinyl; Pyrazinyl, C (O) NH ₂ , C (O) NH-phenyl, C (O) -furanyl, C (O) (C ₁ -C ₃ ) alkyl, C (O) NH (C ₁ -C ₃ ) Alkyl, C (O) N [(C ₁ -C ₃ ) alkyl] R ⁸ , S (O) ₂ (C ₁ -C ₃ ) alkyl, S (O) ₂ -phenyl, , Pyridyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN and CF ₃ , Phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN, halo, CF ₃ , and (C ₁ -C ₃ ) alkoxy, OH, F, phenyl, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , pyrrolidinyl, C (O) -pyrrolidinyl, , And (C ₁ -C ₃ ) alkyl optionally substituted with up to 2 substituents independently selected from pyridyl (optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy) Piperazinyl optionally substituted with up to 2 substituents independently selected from; And Piperidinyl optionally substituted with up to 2 substituents independently selected from phenyl, pyridyl, pyrrolidinyl and oxo-dihydrobenzimidazolyl Is selected from; R ⁷ is NH ₂ ; Pyrrolidinyl; ; NH (C ₁ -C ₃ ) alkyl, wherein said alkyl is optionally substituted up to two times with (C ₁ -C ₃ ) alkoxy; NH-phenyl (the phenyl is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN, (C ₁ -C ₄ ) alkoxy, halo and CF ₃ ); N [(C ₁ -C ₃₎ alkyl] _2, (wherein each alkyl is optionally substituted with twice or less independently alkoxy (C ₁ -C _4)); And Phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ and CN Is selected from; R ⁸ is (C ₁ -C ₃ ) alkoxy; Pyridyl; Piperidinyl; Selected from pyranyl and phenyl, each ring moiety optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkoxy, and (C ₁ -C ₃ ) alkyl; R ⁹ is (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy; OH; ; Phenyl optionally substituted with (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each said alkyl group is OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₄ ) alkoxy, S (O) _{2-phenyl, S (O) 2 (C} 1 -C 3) alkyl, it is optionally independently substituted with phenyl, furyl, tetrahydrofuryl, (C ₃ -C ₆₎ cycloalkyl, and pyridyl); And N [(C ₁ -C _{3) alkyl],} optionally substituted pyrrolidinyl as Is selected from, Only when is not containing N atoms, R ⁹ is also selected from pyridyl, thienyl, and NHR ¹⁰ ; R ¹⁰ is H; Indolyl; OH, F, phenyl, (C ₁ -C ₄ ) alkoxy, NHC (O) (C ₁ -C ₃ ) alkyl, S- (C ₁ -C ₃ ) alkyl, benzimidazolyl, indolyl, thienyl, Pyrazolyl, , N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl), (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, CN, halo, CF ₃ , S (O) ₂ (C ₁ -C ₃ ) alkyl, S (O) ₂ phenyl, and phenyl optionally substituted with up to 2 substituents independently selected from S (O) ₂ NH ₂ , Pyridyl optionally substituted up to twice with CF ₃ , Imidazolyl optionally substituted up to twice with (C ₁ -C ₃ ) alkyl, Furyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl, and Optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkoxy, (O), and (C ₁ -C ₄ ) alkyl (OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl Pyrrolidinyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkyl optionally substituted with up to 2 substituents independently selected from; S (O) ₂ -phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₃ ) alkyl, halo, and CN; (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, and phenyl (the phenyl is (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, halo, CF ₃ , and CN Optionally substituted with up to 2 substituents independently selected from pyrazolyl optionally substituted with up to 2 substituents independently selected from; Benzothiazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl; Thiazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl; Thiadiazolyl optionally substituted with up to 2 substituents independently selected from CF ₃ , (C ₃ -C ₆ ) cycloalkyl, and (C ₁ -C ₆ ) alkyl; CN, _{halo, CF 3, N [(C} 1 -C 4) alkyl] _2, indolyl, , O-pyridyl optionally substituted with C (O) NH (C ₁ -C ₄ ) alkyl, Pyridyl, Optionally, OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl, and (C ₁ -C ₄ ) alkoxy (N [(C ₁ -C ₄ ) alkyl] ₂ where one alkyl group is optionally substituted with phenyl Substituted), or With an optionally substituted (C ₁ -C ₄₎ alkoxy optionally in the substituents selected independently 2 or less substituted (C ₁ -C ₄₎ alkyl Phenyl optionally substituted with up to 2 substituents independently selected from; Pyridyl optionally substituted with phenoxy, wherein the phenoxy is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkyl and (C ₁ -C ₄ ) alkoxy; And Indazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl Is selected from; R ¹¹ And R ¹² are independently selected from H, F and Cl, provided that one of R ¹¹ and R ¹² is F or Cl, the other must be H; X is selected from O, S, CH ₂ , and NH, When X is NH, H on NH is pyridyl, pyrazinyl, phenyl, Or OH, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , C (O) -pyrrolidinyl, N [(C ₁ -C ₄ ) alkyl] ₂ , and phenyl ( Said phenyl is optionally substituted with up to 2 substituents independently selected from CN and (C ₁ -C ₃ ) alkoxy) (C ₁ -C ₄ ) alkyl optionally substituted with up to 2 substituents independently selected from Is replaced by When X is O, S, or CH ₂ , Part Optionally substituted by replacing any H atoms on the moiety with (C ₁ -C ₄ ) alkyl. The method of claim 8, wherein the hyperproliferative disease is selected from breast cancer, lung cancer, colon cancer, pancreatic cancer, prostate cancer, skin cancer, leukemia, lymphoma, glioblastoma and head and neck cancer. The method of claim 9, wherein the hyperproliferative disease is selected from breast cancer, lung cancer, colon cancer, and pancreatic cancer. A method of treating angiogenic diseases comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof. <Formula I> here, Represents a 6-membered aromatic ring containing 0, 1 or 2 N atoms; R ¹ and R ² are H; Halo; CF ₃ ; C (O) R ⁹ ; ; (C ₁ -C ₆ ) alkyl optionally substituted with up to 2 substituents selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl; And N [(C ₁ -C ₃₎ alkyl] ₂ a (wherein alkyl is twice or less each independently (C ₁ -C ₃₎ are optionally substituted with alkoxy) each independently optionally substituted with substituents selected from 1 or 2, (C ₁ -C ₆ ) alkoxy; OH, F, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , NH (C ₁ -C ₃ ) alkyl, phenyl, pyrrolidinyl, and NH (C ₁ -C ₃ ) alkyl having alkyl optionally substituted with up to 2 substituents each independently selected from; OH, F, phenyl, and (C ₁ -C ₃ ) alkoxy, where alkoxy N [(C ₁ -C ₃ ) alkyl] ₂ having alkyl independently optionally substituted with up to 2 substituents independently selected from each other; N [(C ₁ -C ₃₎ alkyl] ₂ less than twice an optionally substituted pyrrolidinyl; Phenyl optionally substituted with up to 2 substituents each independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN Are each independently selected from If it contains 1 or 2 N atoms, R ¹ and R ² must each be H, R ¹ and R ² together with the adjacent C atoms to which they are attached, Conditionally that the ring is formed only when it does not contain this N atom, a ring selected from benzo, dioxo and imidazo, wherein the imidazo is optionally substituted no more than twice with (C ₁ -C ₃ ) alkyl. Forming; R ³ is H, (C ₁ -C ₄ ) alkyl, OH, NO ₂ , NH ₂ , NH (C ₁ -C ₄ ) alkyl, NHC (O) (C ₁ -C ₄ ) alkyl and NHC (O) phenyl Wherein said phenyl is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN); R ⁴ is H; OH; Halo; CN; C (O) R ⁶ ; S (O) ₂ R ⁷ ; OSi [(C ₁ -C ₄₎ alkyl] _3; Tetrazolyl; Thienyl; Pyrrolyl; Pyrimidinyl; Oxazolyl; Furanyl; Each optionally OH, F, OC (O) NHphenyl, NHC (O) (C ₁ -C ₃ ) alkyl, C (O) NH ₂ , C (O) NH (C ₁ -C ₃ ) alkyl, C (O _{) N [(C 1 -C 3} ) alkyl] _2, , (C ₁ -C ₃ ) alkoxy optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy, NHC (O) NH (C ₁ -C ₃ ) alkyl (the alkyl is optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F and phenyl), NHC (O) NHphenyl (The phenyl is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , CN, and Optionally substituted with up to 2 substituents independently selected from NHC (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is optionally substituted independently up to two times with (C ₁ -C ₃ ) alkoxy, NH-phenyl (the phenyl is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CN, and Optionally substituted with up to 2 substituents independently selected from N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CN, CF ₃ , and Phenyl optionally substituted with up to 2 substituents independently selected from N [(C ₁ -C ₃₎ alkyl] ₂ less than twice an optionally substituted pyrrolidinyl (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₂ -C ₆ ) alkynyl substituted with; (C ₁ -C ₃ ) alkoxy, pyrrolidinyl, , And N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted with up to 2 substituents independently selected from OH, F, (C ₁ -C ₃ ) alkoxy and phenyl) (C ₁ -C ₆ ) alkoxy optionally substituted with up to 2 substituents independently selected from; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each of said alkyl groups is 2 or less independently selected from OH, (C ₁ -C ₃ ) alkyl, F, (C ₁ -C ₃ ) alkoxy, and phenyl Is optionally substituted independently with a substituent of; Oxadiazolyl optionally substituted up to twice with (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy, CN, (C ₁ -C ₃ ) alkyl, halo, , , C (O) (C ₁ -C ₃ ) alkyl (optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkoxy, OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl) , And C (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each said alkyl group is independently optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy Phenyl optionally substituted with up to 2 substituents independently selected from; Pyridyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl; C (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each said alkyl group is optionally substituted independently up to two times with (C ₁ -C ₃ ) alkoxy; And O-pyridyl optionally substituted with up to 2 substituents independently selected from CF ₃ , halo, and (C ₁ -C ₃ ) alkyl Is selected from; R ⁵ is selected from H, halo, CN, (C ₁ -C ₆ ) alkoxy, and (C ₁ -C ₆ ) alkyl; R ⁶ is OH; NHR ¹⁰ ; O- (C ₃ -C ₆ ) cycloalkyl; (C ₁ -C ₃ ) alkoxy; O- (C ₂ -C ₆ ) alkenyl; O- (C ₃ -C ₆ ) alkynyl; (C ₁ -C ₆ ) alkyl optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each said alkyl group is OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₃ ) alkoxy, S (O) Independently with up to 2 substituents independently selected from ₂ -phenyl, S (O) ₂ (C ₁ -C ₃ ) alkyl, phenyl, furyl, tetrahydrofuryl, (C ₃ -C ₆ ) cycloalkyl, and pyridyl Optionally substituted); N [(C ₁ -C ₃ ) alkyl] R ⁸ , wherein [(C ₁ -C ₃ ) alkyl] is optionally substituted no more than twice with (C ₁ -C ₃ ) alkoxy; N [(C ₃ -C ₆ ) cycloalkyl] (C ₁ -C ₃ ) alkyl, wherein said alkyl is (C ₁ -C ₃ ) alkoxy, OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ Up to ₂ independently selected from S (O) ₂ -phenyl, S (O) ₂ (C ₁ -C ₃ ) alkyl, phenyl, furyl, tetrahydrofuryl, (C ₅ -C ₆ ) cycloalkyl, and pyridyl Is substituted with a substituent of; NH ₂ , NH (C ₁ -C ₃ ) alkyl, N [(C ₁ -C ₄ ) alkyl] ₂ , C (O) NH ₂ , NHC (O) (C ₁ -C ₃ ) alkyl, NHS (O) ₂ (C ₁ -C ₃ ) alkyl, pyridyl, N [(C ₁ -C ₃ ) alkyl] C (O) NH (C ₁ -C ₃ ) alkyl, N [(C ₁ -C ₃ ) alkyl] C Independent from (O) (C ₁ -C ₃ ) alkyl, and (C ₁ -C ₃ ) alkyl (N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₃ ) alkoxy, and pyrrolidinyl Optionally substituted with up to 2 substituents selected from: pyrrolidinyl optionally substituted with up to 2 substituents independently selected; (C ₁ -C ₃₎ optionally less than two times substituted with alkyl know morpholinyl; (C ₁ -C ₃₎ the double or less of alkyl optionally substituted thiomorpholinyl; Pyrazinyl, C (O) NH ₂ , C (O) NH-phenyl, C (O) -furanyl, C (O) (C ₁ -C ₃ ) alkyl, C (O) NH (C ₁ -C ₃ ) Alkyl, C (O) N [(C ₁ -C ₃ ) alkyl] R ⁸ , S (O) ₂ (C ₁ -C ₃ ) alkyl, S (O) ₂ -phenyl, , Pyridyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN and CF ₃ , Phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN, halo, CF ₃ , and (C ₁ -C ₃ ) alkoxy, OH, F, phenyl, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , pyrrolidinyl, C (O) -pyrrolidinyl, , And (C ₁ -C ₃ ) alkyl optionally substituted with up to 2 substituents independently selected from pyridyl (optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy) Piperazinyl optionally substituted with up to 2 substituents independently selected from; And Piperidinyl optionally substituted with up to 2 substituents independently selected from phenyl, pyridyl, pyrrolidinyl and oxo-dihydrobenzimidazolyl Is selected from; R ⁷ is NH ₂ ; Pyrrolidinyl; ; NH (C ₁ -C ₃ ) alkyl, wherein said alkyl is optionally substituted up to two times with (C ₁ -C ₃ ) alkoxy; NH-phenyl (the phenyl is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN, (C ₁ -C ₄ ) alkoxy, halo and CF ₃ ); N [(C ₁ -C ₃₎ alkyl] _2, (wherein each alkyl is optionally substituted with twice or less independently alkoxy (C ₁ -C _4)); And Phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ and CN Is selected from; R ⁸ is (C ₁ -C ₃ ) alkoxy; Pyridyl; Piperidinyl; Selected from pyranyl and phenyl, each ring moiety optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkoxy, and (C ₁ -C ₃ ) alkyl; R ⁹ is (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy; OH; ; Phenyl optionally substituted with (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each said alkyl group is OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₄ ) alkoxy, S (O) _{2-phenyl, S (O) 2 (C} 1 -C 3) alkyl, it is optionally independently substituted with phenyl, furyl, tetrahydrofuryl, (C ₃ -C ₆₎ cycloalkyl, and pyridyl); And N [(C ₁ -C _{3) alkyl],} optionally substituted pyrrolidinyl as Is selected from, Only when is not containing N atoms, R ⁹ is also selected from pyridyl, thienyl, and NHR ¹⁰ ; R ¹⁰ is H; Indolyl; OH, F, phenyl, (C ₁ -C ₄ ) alkoxy, NHC (O) (C ₁ -C ₃ ) alkyl, S- (C ₁ -C ₃ ) alkyl, benzimidazolyl, indolyl, thienyl, Pyrazolyl, , N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl), (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, CN, halo, CF ₃ , S (O) ₂ (C ₁ -C ₃ ) alkyl, S (O) ₂ phenyl, and phenyl optionally substituted with up to 2 substituents independently selected from S (O) ₂ NH ₂ , Pyridyl optionally substituted up to twice with CF ₃ , Imidazolyl optionally substituted up to twice with (C ₁ -C ₃ ) alkyl, Furyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl, and Optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkoxy, (O), and (C ₁ -C ₄ ) alkyl (OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl Pyrrolidinyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkyl optionally substituted with up to 2 substituents independently selected from; S (O) ₂ -phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₃ ) alkyl, halo, and CN; (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, and phenyl (the phenyl is (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, halo, CF ₃ , and CN Optionally substituted with up to 2 substituents independently selected from pyrazolyl optionally substituted with up to 2 substituents independently selected from; Benzothiazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl; Thiazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl; Thiadiazolyl optionally substituted with up to 2 substituents independently selected from CF ₃ , (C ₃ -C ₆ ) cycloalkyl, and (C ₁ -C ₆ ) alkyl; CN, _{halo, CF 3, N [(C} 1 -C 4) alkyl] _2, indolyl, , O-pyridyl optionally substituted with C (O) NH (C ₁ -C ₄ ) alkyl, Pyridyl, Optionally, OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl, and (C ₁ -C ₄ ) alkoxy (N [(C ₁ -C ₄ ) alkyl] ₂ where one alkyl group is optionally substituted with phenyl Substituted), or With an optionally substituted (C ₁ -C ₄₎ alkoxy optionally in the substituents selected independently 2 or less substituted (C ₁ -C ₄₎ alkyl Phenyl optionally substituted with up to 2 substituents independently selected from; Pyridyl optionally substituted with phenoxy, wherein the phenoxy is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkyl and (C ₁ -C ₄ ) alkoxy; And Indazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl Is selected from; R ¹¹ And R ¹² are independently selected from H, F and Cl, provided that one of R ¹¹ and R ¹² is F or Cl, the other must be H; X is selected from O, S, CH ₂ , and NH, When X is NH, H on NH is pyridyl, pyrazinyl, phenyl, Or OH, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , C (O) -pyrrolidinyl, N [(C ₁ -C ₄ ) alkyl] ₂ , and phenyl ( Said phenyl is optionally substituted with up to 2 substituents independently selected from CN and (C ₁ -C ₃ ) alkoxy) (C ₁ -C ₄ ) alkyl optionally substituted with up to 2 substituents independently selected from Is replaced by When X is O, S, or CH ₂ , Part Optionally substituted by replacing any H atoms on the moiety with (C ₁ -C ₄ ) alkyl. The method of claim 11, wherein the angiogenic disease is selected from diabetic retinopathy, macular degeneration, angiofibroma, rheumatic inflammatory disease, neoplastic disease, and solid tumor growth. The method of claim 12, wherein the angiogenic disease is selected from breast cancer, lung cancer, colon cancer, prostate cancer and pancreatic cancer. A pharmaceutical composition comprising a compound of formula (I): or a pharmaceutically acceptable salt or ester thereof. <Formula I> here, Represents a 6-membered aromatic ring containing 0, 1 or 2 N atoms; R ¹ and R ² are H; Halo; CF ₃ ; C (O) R ⁹ ; ; (C ₁ -C ₆ ) alkyl optionally substituted with up to 2 substituents selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl; And N [(C ₁ -C ₃₎ alkyl] ₂ a (wherein alkyl is twice or less each independently (C ₁ -C ₃₎ are optionally substituted with alkoxy) each independently optionally substituted with substituents selected from 1 or 2, (C ₁ -C ₆ ) alkoxy; OH, F, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , NH (C ₁ -C ₃ ) alkyl, phenyl, pyrrolidinyl, and NH (C ₁ -C ₃ ) alkyl having alkyl optionally substituted with up to 2 substituents each independently selected from; OH, F, phenyl, and (C ₁ -C ₃ ) alkoxy, where alkoxy N [(C ₁ -C ₃ ) alkyl] ₂ having alkyl independently optionally substituted with up to 2 substituents independently selected from each other; N [(C ₁ -C ₃₎ alkyl] ₂ less than twice an optionally substituted pyrrolidinyl; Phenyl optionally substituted with up to 2 substituents each independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN Are each independently selected from If it contains 1 or 2 N atoms, R ¹ and R ² must each be H, R ¹ and R ² together with the adjacent C atoms to which they are attached, Conditionally that the ring is formed only when it does not contain this N atom, a ring selected from benzo, dioxo and imidazo, wherein the imidazo is optionally substituted no more than twice with (C ₁ -C ₃ ) alkyl. Forming; R ³ is H, (C ₁ -C ₄ ) alkyl, OH, NO ₂ , NH ₂ , NH (C ₁ -C ₄ ) alkyl, NHC (O) (C ₁ -C ₄ ) alkyl and NHC (O) phenyl Wherein said phenyl is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN); R ⁴ is H; OH; Halo; CN; C (O) R ⁶ ; S (O) ₂ R ⁷ ; OSi [(C ₁ -C ₄₎ alkyl] _3; Tetrazolyl; Thienyl; Pyrrolyl; Pyrimidinyl; Oxazolyl; Furanyl; Each optionally OH, F, OC (O) NHphenyl, NHC (O) (C ₁ -C ₃ ) alkyl, C (O) NH ₂ , C (O) NH (C ₁ -C ₃ ) alkyl, C (O _{) N [(C 1 -C 3} ) alkyl] _2, , (C ₁ -C ₃ ) alkoxy optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy, NHC (O) NH (C ₁ -C ₃ ) alkyl (the alkyl is optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F and phenyl), NHC (O) NHphenyl (The phenyl is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , CN, and Optionally substituted with up to 2 substituents independently selected from NHC (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is optionally substituted independently up to two times with (C ₁ -C ₃ ) alkoxy, NH-phenyl (the phenyl is (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CN, and Optionally substituted with up to 2 substituents independently selected from N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CN, CF ₃ , and Phenyl optionally substituted with up to 2 substituents independently selected from N [(C ₁ -C ₃₎ alkyl] ₂ less than twice an optionally substituted pyrrolidinyl (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₂ -C ₆ ) alkynyl substituted with; (C ₁ -C ₃ ) alkoxy, pyrrolidinyl, , And N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted with up to 2 substituents independently selected from OH, F, (C ₁ -C ₃ ) alkoxy and phenyl) (C ₁ -C ₆ ) alkoxy optionally substituted with up to 2 substituents independently selected from; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each of said alkyl groups is 2 or less independently selected from OH, (C ₁ -C ₃ ) alkyl, F, (C ₁ -C ₃ ) alkoxy, and phenyl Is optionally substituted independently with a substituent of; Oxadiazolyl optionally substituted up to twice with (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy, CN, (C ₁ -C ₃ ) alkyl, halo, , , C (O) (C ₁ -C ₃ ) alkyl (optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkoxy, OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl) , And C (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each said alkyl group is independently optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy Phenyl optionally substituted with up to 2 substituents independently selected from; Pyridyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl; C (O) N [(C ₁ -C ₃ ) alkyl] ₂ , wherein each said alkyl group is optionally substituted independently up to two times with (C ₁ -C ₃ ) alkoxy; And O-pyridyl optionally substituted with up to 2 substituents independently selected from CF ₃ , halo, and (C ₁ -C ₃ ) alkyl Is selected from; R ⁵ is selected from H, halo, CN, (C ₁ -C ₆ ) alkoxy, and (C ₁ -C ₆ ) alkyl; R ⁶ is OH; NHR ¹⁰ ; O- (C ₃ -C ₆ ) cycloalkyl; (C ₁ -C ₃ ) alkoxy; O- (C ₂ -C ₆ ) alkenyl; O- (C ₃ -C ₆ ) alkynyl; (C ₁ -C ₆ ) alkyl optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each said alkyl group is OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₃ ) alkoxy, S (O) Independently with up to 2 substituents independently selected from ₂ -phenyl, S (O) ₂ (C ₁ -C ₃ ) alkyl, phenyl, furyl, tetrahydrofuryl, (C ₃ -C ₆ ) cycloalkyl, and pyridyl Optionally substituted); N [(C ₁ -C ₃ ) alkyl] R ⁸ , wherein [(C ₁ -C ₃ ) alkyl] is optionally substituted no more than twice with (C ₁ -C ₃ ) alkoxy; N [(C ₃ -C ₆ ) cycloalkyl] (C ₁ -C ₃ ) alkyl, wherein said alkyl is (C ₁ -C ₃ ) alkoxy, OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ Up to ₂ independently selected from S (O) ₂ -phenyl, S (O) ₂ (C ₁ -C ₃ ) alkyl, phenyl, furyl, tetrahydrofuryl, (C ₅ -C ₆ ) cycloalkyl, and pyridyl Is substituted with a substituent of; NH ₂ , NH (C ₁ -C ₃ ) alkyl, N [(C ₁ -C ₄ ) alkyl] ₂ , C (O) NH ₂ , NHC (O) (C ₁ -C ₃ ) alkyl, NHS (O) ₂ (C ₁ -C ₃ ) alkyl, pyridyl, N [(C ₁ -C ₃ ) alkyl] C (O) NH (C ₁ -C ₃ ) alkyl, N [(C ₁ -C ₃ ) alkyl] C Independent from (O) (C ₁ -C ₃ ) alkyl, and (C ₁ -C ₃ ) alkyl (N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₃ ) alkoxy, and pyrrolidinyl Optionally substituted with up to 2 substituents selected from: pyrrolidinyl optionally substituted with up to 2 substituents independently selected; (C ₁ -C ₃₎ optionally less than two times substituted with alkyl know morpholinyl; (C ₁ -C ₃₎ the double or less of alkyl optionally substituted thiomorpholinyl; Pyrazinyl, C (O) NH ₂ , C (O) NH-phenyl, C (O) -furanyl, C (O) (C ₁ -C ₃ ) alkyl, C (O) NH (C ₁ -C ₃ ) Alkyl, C (O) N [(C ₁ -C ₃ ) alkyl] R ⁸ , S (O) ₂ (C ₁ -C ₃ ) alkyl, S (O) ₂ -phenyl, , Pyridyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN and CF ₃ , Phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN, halo, CF ₃ , and (C ₁ -C ₃ ) alkoxy, OH, F, phenyl, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , pyrrolidinyl, C (O) -pyrrolidinyl, , And (C ₁ -C ₃ ) alkyl optionally substituted with up to 2 substituents independently selected from pyridyl (optionally substituted up to twice with (C ₁ -C ₃ ) alkoxy) Piperazinyl optionally substituted with up to 2 substituents independently selected from; And Piperidinyl optionally substituted with up to 2 substituents independently selected from phenyl, pyridyl, pyrrolidinyl and oxo-dihydrobenzimidazolyl Is selected from; R ⁷ is NH ₂ ; Pyrrolidinyl; ; NH (C ₁ -C ₃ ) alkyl, wherein said alkyl is optionally substituted up to two times with (C ₁ -C ₃ ) alkoxy; NH-phenyl (the phenyl is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, CN, (C ₁ -C ₄ ) alkoxy, halo and CF ₃ ); N [(C ₁ -C ₃₎ alkyl] _2, (wherein each alkyl is optionally substituted with twice or less independently alkoxy (C ₁ -C _4)); And Phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ and CN Is selected from; R ⁸ is (C ₁ -C ₃ ) alkoxy; Pyridyl; Piperidinyl; Selected from pyranyl and phenyl, each ring moiety optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₃ ) alkoxy, and (C ₁ -C ₃ ) alkyl; R ⁹ is (C ₁ -C ₃ ) alkyl; (C ₁ -C ₃ ) alkoxy; OH; ; Phenyl optionally substituted with (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, halo, CF ₃ , and CN; N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each said alkyl group is OH, CN, N [(C ₁ -C ₄ ) alkyl] ₂ , (C ₁ -C ₄ ) alkoxy, S (O) _{2-phenyl, S (O) 2 (C} 1 -C 3) alkyl, it is optionally independently substituted with phenyl, furyl, tetrahydrofuryl, (C ₃ -C ₆₎ cycloalkyl, and pyridyl); And N [(C ₁ -C _{3) alkyl],} optionally substituted pyrrolidinyl as Is selected from, Only when is not containing N atoms, R ⁹ is also selected from pyridyl, thienyl, and NHR ¹⁰ ; R ¹⁰ is H; Indolyl; OH, F, phenyl, (C ₁ -C ₄ ) alkoxy, NHC (O) (C ₁ -C ₃ ) alkyl, S- (C ₁ -C ₃ ) alkyl, benzimidazolyl, indolyl, thienyl, Pyrazolyl, , N [(C ₁ -C ₄ ) alkyl] ₂ , wherein each alkyl is independently optionally substituted with up to 2 substituents independently selected from OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl), (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy, CN, halo, CF ₃ , S (O) ₂ (C ₁ -C ₃ ) alkyl, S (O) ₂ phenyl, and phenyl optionally substituted with up to 2 substituents independently selected from S (O) ₂ NH ₂ , Pyridyl optionally substituted up to twice with CF ₃ , Imidazolyl optionally substituted up to twice with (C ₁ -C ₃ ) alkyl, Furyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl, and Optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkoxy, (O), and (C ₁ -C ₄ ) alkyl (OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl Pyrrolidinyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkyl optionally substituted with up to 2 substituents independently selected from; S (O) ₂ -phenyl optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₃ ) alkyl, halo, and CN; (C ₁ -C ₄ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, and phenyl (the phenyl is (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, halo, CF ₃ , and CN Optionally substituted with up to 2 substituents independently selected from pyrazolyl optionally substituted with up to 2 substituents independently selected from; Benzothiazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl; Thiazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl; Thiadiazolyl optionally substituted with up to 2 substituents independently selected from CF ₃ , (C ₃ -C ₆ ) cycloalkyl, and (C ₁ -C ₆ ) alkyl; CN, _{halo, CF 3, N [(C} 1 -C 4) alkyl] _2, indolyl, , O-pyridyl optionally substituted with C (O) NH (C ₁ -C ₄ ) alkyl, Pyridyl, Optionally, OH, (C ₁ -C ₃ ) alkoxy, F, and phenyl, and (C ₁ -C ₄ ) alkoxy (N [(C ₁ -C ₄ ) alkyl] ₂ where one alkyl group is optionally substituted with phenyl Substituted), or With an optionally substituted (C ₁ -C ₄₎ alkoxy optionally in the substituents selected independently 2 or less substituted (C ₁ -C ₄₎ alkyl Phenyl optionally substituted with up to 2 substituents independently selected from; Pyridyl optionally substituted with phenoxy, wherein the phenoxy is optionally substituted with up to 2 substituents independently selected from (C ₁ -C ₄ ) alkyl and (C ₁ -C ₄ ) alkoxy; And Indazolyl optionally substituted up to twice with (C ₁ -C ₄ ) alkyl Is selected from; R ¹¹ And R ¹² are independently selected from H, F and Cl, provided that one of R ¹¹ and R ¹² is F or Cl, the other must be H; X is selected from O, S, CH ₂ , and NH, When X is NH, H on NH is pyridyl, pyrazinyl, phenyl, Or OH, (C ₁ -C ₃ ) alkoxy, N [(C ₁ -C ₃ ) alkyl] ₂ , C (O) -pyrrolidinyl, N [(C ₁ -C ₄ ) alkyl] ₂ , and phenyl ( Said phenyl is optionally substituted with up to 2 substituents independently selected from CN and (C ₁ -C ₃ ) alkoxy) (C ₁ -C ₄ ) alkyl optionally substituted with up to 2 substituents independently selected from Is replaced by When X is O, S, or CH ₂ , Part Optionally substituted by replacing any H atoms on the moiety with (C ₁ -C ₄ ) alkyl.