ES2367268T3 - PIRROLOTRIAZINE COMPOUNDS USEFUL AS QUINASA INHIBITORS. - Google Patents

Abstract

A compound of Formula (I) ** Formula ** or pharmaceutically acceptable salts thereof, wherein: R1 is or R2 is H or an alkyl group containing from 1 to 4 carbon atoms; R3 and R4 are independently selected from H, an alkyl group containing 1 to 4 carbon atoms, a substituted alkyl group containing 1 to 4 carbon atoms substituted at any available position and substitutable with at least one alkyl, an alkyl substituted in any available position and substitutable with at least one substituent, including alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyloxy, alkanoyl, alkanoyl, alkanoyloxy, amino, aminoalkyl, aminoalkyl, alkylamino, alkylamino, hydroxyalkyl, amino, amide, amide, carbamate, carbamate, ureido, cyano, sulfonamide, sulfonamide, alkylsulfone, heterocycloalkyl, heterocycloalkyl, cycloalkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkylalkyl, tioalkyloyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkyloxy alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, -NRcc (C = O) Rdd, alkenyl, alkenyl, alkynyl, alkynyl, aryl, aryl, heteroaryl, heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle, alkylcarbonyl, heteroalkyl, heteroalkenyl, heteroalkenyl, heteroalkynyl, heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino, arilalcanoilamino, arylthio, arylalkylthio, arylsulfonyl, arylalkyl sulfonyl, alkylsulfonyl, arylcarbonylamino or alkylaminocarbonyl, -OR9 and NR10R11; n is 2, 3, 4, 5 or 6; R5 and R6 are independently selected from alkyl, and substituted alkyl, substituted at any available position and substitutable with at least one substituent, including hydrogen, alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl , arylalkyloxy, alkanoylo, alkanoyloxy, amino, aminoalkyl, alkylamino, hydroxyalkyl, amide, carbamate, ureido, cyano, sulfonamide, alkylsulfone, heterocycloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, alkylthio, alkylthio, alkyloyl, thioyl, alkylthio, alkyloyl, thioyl, alkylalkyl, thio, alkylthio, alkylalkyl, thio, alkylalkyl, thio, alkyloyl, thio, alkyloyl, thio, alkyloyl, thio, alkylalkyl, thio, alkyloyl, thio, alkyloyl, thio, alkyloyl, thio, alkyloyl, thio, alkyloyl, thio, alkyloyl, thio, alkyloyl, tio, alkyl , alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, -NR c C (C = O) Rdd, alkenyl, alkynyl, aryl, heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle, alkylcarbonyl, heteroalkyl, heteroalkenyl, heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino, arylalkanoylamino, arylthio, arylalk ilium, arylsulfonyl, arylalkyl sulfonyl, alkylsulfonyl, arylcarbonylamino or alkylaminocarbonyl, or taken together with the N to which they are attached to form a 4, 5, 6, 7 membered heterocyclic ring or a substituted heterocyclic ring, substituted at any position of the available ring and substitutable, or in which the valence allows any ring condensed or attached thereto, with at least one aryl, hydrogen; alkyl, hydroxyalkyl, hydroxy (-OH), alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyaryl, halogen, haloalkyl, haloalkoxy, aryloxy, arylalkyl, arylalkyl, alkanoyl, alkanoyloxy, alkanoylamino, amino, aminoalkyl, alkylamino, aminocarbonylalkyl, arylamino, arylamino, arylamino, arylamino, arylamino, arylamino, arylamino ureido, cyano, sulfonamide, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, carboxyalkyl, carboalkoxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, alkenyl, alkynyl, aryl, heteroarylthio, heteroaryloxy, heteroarylalkenyl, heteroarylheteroaryl, heteroarylalkylthio, heteroaryloxyalkyl, alkylcarbonyl, aminocarbonylalkyl, aminocarbonylalkyl, arylazo, alkoxycarbonylalkoxy, arylcarbonyl, alkylaminocarbonyl, aminoalkylcarbonyl, arylaminocarbonyl, arylaminocarbonyl, alkylarylcarbonylalkylcarbonylalkylcarbonyl, arylaminocarbonyl, alkylarylcarbonylaminocarbonyl sulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, arylsulfinyl, alkylsulfinyl, arylsulfinylalkyl and arylsulfonylaminocarbonyl, said heterocyclic or heterocyclic ring optionally containing at least two heteroatoms; R7 and R8 are independently selected from H, alkyl, and substituted alkyl, substituted at any available position and substitutable with at least one substituent, including hydrogen, alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy , arylalkyl, arylalkyloxy, alkanoyl, alkanoyloxy, amino, aminoalkyl, alkylamino, hydroxyalkyl, amide, carbamate, ureido, cyano, sulfonamide, alkylsulfone, heterocycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy, alkyloyl alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyls alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, NRCC (C = O) Rdd, alkenyl, alkynyl, aryl, heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle, alkylcarbonyl, heteroalkyl, heteroalkenyl, heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino, arylalkanoylamino, aryl thio, arylalkylthio, arylsulfonyl, arylalkyl sulfonyl, alkylsulfonyl, arylcarbonylamino or alkylaminocarbonyl; m is 0, 1, 2 or 3; L is OC (= O) NH-, -O-, -C (= O) NH-, -NHC (= O) - or -NHS (= O) 2-; R9 is H, alkyl, substituted alkyl, substituted in any available position and substitutable with at least one substituent, including hydrogen, alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylakyloxy, alkanoyl alkanoyloxy, amino, aminoalkyl, alkylamino, hydroxyalkyl, amide, carbamate, ureido, cyano, sulfonamide, alkylsulfone, heterocycloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy , carbamoyl, -NRcc (C = O) Rdd, alkenyl, alkynyl, aryl, heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkyl, aryloxyalkyl, aryloxyaryl, heterocycle, alkylcarbonyl, heteroalkylamino, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl arylamino, arylalkanoylamino, arylthio, arylalkylthio, arylsulfonyl, arylalkyl sulfonyl , alkylsulfonyl, arylcarbonylamino, alkylaminocarbonyl, alkylamino; R10 and R11 are independently selected from H, alkyl, and substituted alkyl, substituted in any available position and substitutable with at least one substituent, including hydrogen, alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy , arylalkyl, arylalkyloxy, alkanoyl, alkanoyloxy, amino, aminoalkyl, alkylamino, hydroxyalkyl, amide, carbamate, ureido, cyano, sulfonamide, alkylsulfone, heterocycloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkyl, t-alkyloxy, nitroalkyloxy, nitroalkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, nitro-alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkyloxyloxy , alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, -NRcc (C = O) Rdd, alkenyl, alkynyl, aryl, heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkyl, aryloxyalkyl, aryloxyalkyl, aryloxyalkyl, alkyloxycarbonyl heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino, arylalkanoylamino, arylthio, ar ilalkylthio, arylsulfonyl, arylalkyl sulfonyl, alkylsulfonyl, arylcarbonylamino or alkylaminocarbonyl; and Ar1 is aryl, substituted aryl, substituted with at least one substituent in any position of the available and substitutable ring, or in which the valence allows any ring condensed or bonded thereto, including hydrogen; alkyl, substituted alkyl, hydroxy (-OH), alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyarylthio, halogen, haloalkyl, haloalkoxy, aryloxy, arylalkyl, arylalkyl, alkanoylo, alkanoyloxy, alkanoylamino, amino, aminoalkyl, alkylamino, aminocarbonylalkyl, arylamino, arylamino, arylamino , ureido, cyano, sulfonamide, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, carboxyalkyl, alkylaryloxycarbonylalkyl, alkyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkyl , arylalkenyl, aryloxycarbonyl, arylthio, arylthioalkyl, arylalkylthio, sulfonic acid, heteroaryl, heteroarylthio, heteroaryloxy, heteroarylalkenyl, heteroarylheteroaryl, heteroarilalquilotio heteroaryloxy, alkylcarbonyl, aminocarbonylaryl, aminocarbonyl, arylazo, alkoxycarbonylalkoxy, arylcarbonyl, alquilaminocarbon ilo, aminoalkylcarbonyl, arylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, arylsulfinyl, alkylsulfinyl, arylsulfinylalkyl and arylsulfonylamino, the substituted or substituted heteroaryl, the heteroaryl-substituted ring that the valence allows any ring condensed or attached thereto, with at least one aryl, hydrogen, alkyl, hydroxy (-OH), alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyarylthio, halogen, haloalkyl, haloalkoxy, aryloxy, arylalkyl, arylalkyl, alkanoyl, alkanoyloxy, alkanoylamino, amino, aminoalkyl, alkylamino, aminocarbonyl, arylamino, arylalkylamino, arylalkoxy, ureido, cyano, sulfonamide, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl alkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, nitroalkyloxy, alkyloxy, alkyloxy, alkyl lo, carboxy, carboxy alkyl, carboxy alkoxy, alkoxycarbonyl, al

Description

Field of the Invention

At least one pyrrolotriazine derivative is disclosed herein, at least one pharmaceutical composition comprising at least one pyrrolotriazine derivative described herein, and at least one pyrrolotriazine derivative disclosed herein for use in a process to treat at least one condition associated with kinase.

Background of the invention

Hyperproliferative diseases, such as, for example, cancer are generally characterized by uncontrolled cell proliferation and / or alteration of programmed cell death. Loss of a cell's ability to control cell proliferation often results from a genetic alteration in the cell pathways responsible for the regulation of cell functions including, but not limited to, for example, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis and angiogenesis. As a result, an approach to treat hyperproliferative diseases has involved targeting at least one protein involved in the regulation of these cellular functions.

Protein kinases are at least one class of proteins that have been identified as proteins that play an important role in the regulation of cellular functions. In fact, many diseases are associated with abnormal cellular responses triggered by protein-mediated kinase events. Such diseases include, but are not limited to, autoimmune diseases, bone diseases, inflammatory diseases, metabolic diseases, proliferative and neurodegenerative neurological diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases.

Protein kinases are a large and diverse group of enzymes that are divided into groups based on the particular amino acids (serine / threonine, tyrosine, lysine and histidine) to which a particular kinase is directed. For example, receptor and non-receptor tyrosine kinases target tyrosine kinase and cyclin-dependent kinases (CDK) and mitogen-activated protein kinases (MAPK) target both tyrosine and serine / threonine.

Exemplary protein kinases include, but are not limited to, for example, receptor tyrosine kinases (RTK) such as, for example, growth factors including, for example, type III receptor tyrosine kinases (Flt3); non-receptor tyrosine kinases such as, for example, Src kinases, including, for example, Src kinases, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk, Btk kinases, Csk kinases, ZAP70 kinases and Kak kinases; serine / threonine kinases such as, for example, p90 ribosomal S6 kinases (RSK), including, for example, RSK1 / p90Rsk, RSK2, RSK3 and RSK4, control point protein kinases, including, for example, CHK1 and CHK2, AURORA kinases, including, for example, aurora-A, aurora-B and aurora-C, and glycogen synthase kinase 3 (GSK3); Cyclin-dependent kinases (CDK) including, for example, CDK1, CDK2, CDK4, CDK5, CDK6, CDK 7, and cell division control protein 2 (CDC2); and mitogen-activated protein kinase (MAPK), such as, for example, mitogen-activated protein kinase 1 (ERK), MAPK3, MAPK7, mitogen-activated protein kinase 8 (JNK1), mitogen-activated protein kinase 14 (p38 alpha) , MAPK 10, JNK 3 alpha protein kinase, JNK 2 stress-activated protein kinase, and MAPK 14.

More recently, it was discovered that Aurora kinases are involved in the growth of various types of cancer cells, and as a result they are being set as a target to develop potential treatments for cancers. Consequently, efforts have been made to develop Aurora kinase inhibitors that are therapeutically effective against cancer cells. Kinase inhibitors such as the compounds described in PCT application No. WO 2004/009784, which inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1 are known.

summary of the invention

Compounds of Formula (I) are described herein: or a pharmaceutically acceptable salt thereof, wherein: R1 is

image 1

image2

R2 is H or lower alkyl;

R3 and R4 are independently selected from H, lower alkyl, substituted lower alkyl, -OR9 and NR10R11;

n is 2, 3, 4, 5 or 6;

R5 and R6 are independently selected from alkyl and substituted alkyl, or taken together with the N to which they are attached form a substituted 4, 5, 6 or 7-membered heterocyclic or heterocyclic ring which optionally contains

10 at least two heteroatoms;

R7 and R8 are independently selected from H, alkyl and substituted alkyl;

m is 0, 1, 2 or 3;

L is -OC (= O) NH-, -O-, -C (= O) NH-, -NHC (= O) - or -NHS (= O) 2-;

R9 is H, alkyl, substituted alkyl, alkylamino or substituted alkylamino;

R10 and R11 are independently selected from H, alkyl and substituted alkyl; Y

Ar1 is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

Additionally, at least one pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I) is described herein; optionally at least one pharmaceutically acceptable carrier and / or diluent; and optionally at least one different anti-cancer agent.

Additionally, at least one compound of Formula (I) for use in a method for the treatment of at least one proliferative disease is still described herein, said procedure usually comprising the steps of administering to a patient in need thereof. a therapeutically effective amount of at least one compound of Formula (I); optionally administering simultaneously or sequentially at least one different anti-cancer agent; and administering simultaneously or sequentially at least one

25 different anticancer treatment.

Additionally, at least one compound of Formula (I) selected from (i) 3-chloro-4-fluoro-N- (5 - {[6 - ({3- [4- (hydroxymethyl) ) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1f] [1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; 3-Chloro-4-fluoro-N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) pyrrolidin-1yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; 3-chloro-4-fluoro-N- (5 - {[6 - ({3 - [(2S) -2

30 (hydroxymethyl) morpholin-4-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; 3-Chloro-4fluoro-N- (5 - {[6 - ({3- [3- (hydroxymethyl) morpholin-4-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2 , 4] triazin-4-yl] amino} pyrimidin-2yl) benzamide; N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4] triazin-4 -yl] amino} pyrimidin2-yl) benzamide; N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4 ] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; 3-fluoro-N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1

35 f] [1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; 3-fluoro-N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] propyl} oxy) -5methylpyrrolo [2,1-f] [1,2 , 4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; and N- (3-fluorophenyl) -2 - {[6 - ({3- [4 (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2, 4] triazin-4-yl] amino} -1,3-thiazol-5-carboxamide; and (ii) pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The features and advantages of the invention can be more readily appreciated by those skilled in the art after reading the following detailed description. It will be appreciated that certain features of the invention which, for reasons of clarity, have been described above and then in the context of separate embodiments, can also be combined to form a single embodiment. On the contrary, various features of the invention which, for reasons of brevity, are described in the context of a single embodiment, can also be combined in order to form sub-combinations thereof.

The embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.

Unless otherwise indicated herein, references made in the singular may also be included in the plural. For example, "a" and "a" may refer to one or one, or one or one or more.

The definitions set forth herein have priority over the definitions set forth in any patent, patent application and / or patent application publication.

Definitions of terms used to describe the invention are set forth hereinbelow. Unless otherwise indicated, the initial definition provided for a group or term is applied each time that group or term is used individually or as part of another group.

Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.

Unless otherwise indicated, it is assumed that any heteroatom with unmet valences has sufficient hydrogen atoms to satisfy the valencies.

The terms "alkyl" and "alk" refer to a saturated straight chain or branched chain hydrocarbon radical containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" and / or "alk" groups include, but are not limited to, for example, methyl, ethyl, propyl, isopropyl, 1-methylpropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, diethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.

The term "substituted alkyl" refers to an alkyl group substituted at any available position and substitutable with at least one substituent. Exemplary substituents include, but are not limited to, for example, hydrogen, alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyloxy, alkanoyl, substituted alkanoyl, alkanoyloxy, amino, aminoalkyl, substituted aminoalkyl, alkylamino, substituted alkylamino, hydroxyalkyl, disubstituted amino, amide, substituted amide, carbamate, substituted carbamate, ureido, cyano, sulfonamide, substituted sulfonamide, alkylsulfone, heterocycloalkyl, substituted heterocycloalkyl, cycloalkyl, substituted cycloalkyl, substituted cycloalkyl, substituted cycloalkenyl , cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, -NRcc (C = O) Rdd, alkenyl, substituted alkenyl, alkynyl, substituted arynyl, substituted alkynyl , substituted heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroaryl alkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle, substituted heterocycle, alkylcarbonyl, substituted heteroalkyl, heteroalkenyl, heteroalkenyl, substituted heteroalkynyl, heteroalkynyl, substituted arylamino, arylalkylamino, alkanoylamino, arylamino, arilalcanoilamino, arylthio, arylalkylthio, arylsulfonyl, arylalkylsulfonyl, alkylsulfonyl, arylcarbonylamino or alkylaminocarbonyl.

The term "lower alkyl" refers to an alkyl group containing from 1 to 4 carbon atoms. It is important to appreciate that although the term "lower alkyl" is included within the definition of "alkyl", the use of the term "lower alkyl" is not intended to limit the definition of the term "alkyl" explicitly or implicitly to a hydrocarbon radical saturated linear or branched chain optionally substituted containing 5 to 7 carbon atoms. Exemplary lower alkyl groups include, but are not limited to, for example, methyl; ethyl; propyl; isopropyl; n-butyl; t-butyl; isobutyl; pentyl; and isopentyl.

The term "substituted lower alkyl" refers to a lower alkyl substituted at any available position and substitutable with at least one alkyl, substituted alkyl or substituent described above in defining the term "substituted alkyl" as an exemplary alkyl substituent.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon rings having 6 to 12 carbon atoms in the ring portion. Exemplary aryl groups include but are not limited to, for example, phenyl groups; naphthalenyl; biphenyl; and diphenyl. When two aromatic rings are present, the aromatic rings of the aryl group may be attached at a single point (for example, biphenyl), or be condensed (for example, naphthalenyl).

The term "substituted aryl" refers to an aryl substituted with at least one substituent at any position of the available and substitutable ring, or in which the valence allows any ring fused or attached thereto. Exemplary substituents include, but are not limited to, for example, hydrogen; I rent; substituted alkyl, hydroxy (-OH), alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyarylthio, halogen, haloalkyl, haloalkoxy, aryloxy, arylalkyl, arylalkyloxy, alkanoyl, substituted alkanoyl, alkanoyloxy, alkanoylamino, amino, aminoalkyl, substituted alkyl alkylamino , disubstituted amino, aminocarbonyl, arylamino, arylalkylamino, arylalkoxy, ureido, cyano, sulfonamide, substituted sulfonamide, heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl , carboxy, carboxy alkyl, carboxy-alkoxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, 10 alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylsulfonylamino, arylalkenyl, aryloxycarbonyl, arylthio, arylthioaryl, arylthiaryl the substituted heteroarylthio, heteroaryloxy, heteroarylalkenyl, heteroarylheteroaryl, heteroarilalquilotio heteroaryloxy, alkylcarbonyl, aminocarbonylaryl, aminocarbonyl, arylazo, alkoxycarbonylalkoxy, arylcarbonyl, alkylaminocarbonyl, aminoalkylcarbonyl, arylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,

Arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, arylsulfinyl, alkylsulfinyl, arylsulfinylalkyl and arylsulfonylaminocarbonyl.

The terms "aryloxy", "arylamino", "arylalkylamino", "arylthio", "arylalkanoylamino", "arylsulfonyl", "arylalkoxy", "arylsulfinyl", "arylheteroaryl", "arylalkylthio", "arylcarbonyl", "arylalkenyl" or "arylalkyl sulfonyl" refers to an aryl or substituted aryl attached to an oxygen; an amino; an alkylamino; an uncle; an alkanoylamino; a sulfonyl; an alkoxy; a

Sulfinyl; a heteroaryl or substituted heteroaryl; an alkylthio; a carbonyl; an alkenyl; or an alkylsulfonyl, respectively

The term "arylsulfonylaminocarbonyl" refers to an arylsulfonyl attached to an aminocarbonyl.

The terms "aryloxyalkyl", "aryloxycarbonyl" or "aryloxyaryl" refer to an aryloxy attached to an alkyl or substituted alkyl; a carbonyl; or a substituted aryl or aryl, respectively.

The term "arylalkyl" refers to an alkyl or substituted alkyl in which at least one of the hydrogen atoms bonded to at least one of the carbon atoms is replaced by a substituted aryl or aryl. Typical arylalkyl include, but is not limited to, for example, benzyl, 2-phenylethane-1-yl, 2-phenyleten-1-yl, naphthylmethyl, 2-naphthyletan-1-yl, 2naphthyleten-1-yl, naphthobenzyl and 2- naphtophenylethan-1-yl.

The term "arylalkyloxy" refers to an arylalkyl linked through an oxygen bond (-O-arylalkyl).

The terms "arylthioalkyl" or "arylsulfinylalkyl" refer to an arylthio or an arylsulfinyl, respectively, attached to a substituted alkyl or alkyl.

The term "heteroaryl" refers to aromatic cyclic groups, such as, for example, 5 to 6 membered monocyclic ring systems, 7 to 11 member bicyclics or 10 to 16 member tricyclics that have at least one heteroatom in at least a ring that contains carbon atoms. The ring containing atoms of

Carbon may contain 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur. The heteroaryl group may be attached to another moiety at any available point of attachment.

Exemplary monocyclic heteroaryl groups include, but are not limited to, for example, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thiazolyl, isoxazolyl, thiazolyl, pyridyl [ie,

40], pyridazinyl [ie,

], pyrimidinyl [that is,

image 1

], pyrazinyl [that is,

image 1

] and triazinyl. Unless reference is made to a specific point of attachment, for example, as in pyrid-2-yl, pyridazin-3-yl, it is intended that said heteroaryl groups may be attached to another moiety at any available point of attachment .

Exemplary bicyclic heteroaryl groups include, but are not limited to, for example, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, chromenyl, indolyl, indazolyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzofuryl, benzopurazylpyrazinylpyrazinyl pyrinoxynidyl pyrinoxyrazinyl pyrinoxyrazinyl pyrinoxynzanyl , furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,2-b] pyridinyl] or furo [2,3-b] pyridinyl) and triazinylazepinyl.

The term "substituted heteroaryl" refers to a substituted heteroaryl at any position of the available and replaceable ring, or in which the valence allows any ring fused or attached thereto, with at least one aryl, substituted aryl or a substituent that has been described above when defining the term "substituted aryl" as an exemplary aryl substituent.

The terms "heteroaryloxy", "heteroarylalkenyl", "heteroarylheteroaryl", "heteroarylalkyl", "heteroarylalkoxy", "heteroarylthio", "heteroarylsulfonyl" or "heteroarylalkylthio" refer to a substituted heteroaryl or heteroaryl attached to an oxygen; a substituted alkenyl or alkenyl; a heteroaryl or substituted heteroaryl; an alkyl or substituted alkyl; an alkoxy; an uncle; a sulfonyl; or an alkylthio, respectively.

The term "heteroaryloxyalkyl" refers to a heteroaryloxy attached to an alkyl or substituted alkyl.

The term "heterocyclic ring" refers to a stable, fully saturated or partially unsaturated monocyclic ring system of 4, 5, 6 or 7 members, containing at least one heteroatom. In one embodiment, the at least one heteroatom is selected from nitrogen, sulfur and / or oxygen. In another embodiment, the heterocyclic ring is a monocyclic ring of 4, 5, 6 or 7 members containing one, two or three heteroatoms selected from nitrogen, oxygen and / or sulfur. In yet another embodiment, the heterocyclic ring is a monocyclic ring of 4, 5, 6 or 7 members containing one or two heteroatoms selected from nitrogen and oxygen. In a further embodiment, the heterocyclic ring is a 5 or 6 membered monocyclic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and / or sulfur. In yet another embodiment, the heterocyclic ring is a 5 or 6 membered monocyclic ring containing one or two heteroatoms selected from nitrogen and oxygen.

Exemplary heterocyclic rings include, but are not limited to, for example, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl and homopiperazinyl.

The term "substituted heterocyclic ring" refers to a heterocyclic ring substituted at any position of the available and replaceable ring, or in which the valence allows any ring fused or attached thereto, with at least one aryl, substituted aryl or a substituent that described above when defining the term "substituted aryl" as an exemplary aryl substituent.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 3 rings and 3 to 8 carbons per ring. Exemplary cycloalkyls include, but are not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term "substituted cycloalkyl" refers to a cycloalkyl substituted with at least one substituent, preferably 1 to 4 substituents, more preferably 1 to 2 substituents, at any point of attachment available in the cycloalkyl ring, or in which the valence allow any ring condensed or attached to it. Exemplary substituents include, but are not limited to, for example, alkyl, substituted alkyl, and substituents that have been described in defining the term "substituted alkyl" as exemplary alkyl substituents.

Exemplary cycloalkyl includes, but is not limited to, for example, The term "heterocycloalkyl" refers to a saturated or unsaturated cycloalkyl in which one or more carbons (and any associated hydrogen atom) are independently replaced by at least a heteroatom selected from O and N.

image3

The term "substituted heterocycloalkyl" refers to a heterocycloalkyl substituted at any available ring position and substitutable with at least one alkyl, substituted alkyl or a substituent described above in defining the term "substituted alkyl" as an exemplary alkyl substituent.

The terms "heterocycloalkylalkyl" or "heterocycloalkylsulfonyl" refer to a substituted heterocycloalkyl or heterocycloalkyl attached to a substituted alkyl or alkyl or to sulfonyl, respectively.

The term "heterocycle" refers to an optionally substituted, completely saturated or unsaturated, aromatic or non-aromatic cyclic group, for example, which is a 4 to 7 membered monocyclic ring system, 7 to 11 membered bicyclic or 10 to 3 cyclic ring system. to 15 members, which has at least one heteroatom in at least one ring containing carbon atoms. Each ring of the heterocycle containing a heteroatom can have 1, 2 or 3 heteroatoms selected from N, O and S, in which the heteroatoms N and S can be optionally oxidized and the heteroatom N can optionally quaternize. The heterocycle can be attached to any hetero atom or carbon atom.

Monocyclic heterocycles for example include, but not limited to, for example pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, homopiperazinyl, 2-oxohomopiperazinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, pyridyl, oxidinyl, pyridyl, pyridyl pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thienyl, thiazoyl, trianyl and thiazyl thiazyl.

Exemplary bicyclic heterocycles include, but are not limited to, for example, 2,3-dihydro-2-oxo-1 Hindolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,1-b] pyridinyl] or furo [2,3- b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl , indazolyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thieno pyridyl and thienothienyl.

The term "substituted heterocycle" refers to a substituted heterocycle at any available point of attachment, or in which the valence allows any ring fused or bonded thereto, with at least one alkyl, substituted alkyl, or a substituent described above. above when defining the term "substituted alkyl" as an exemplary alkyl substituent.

The terms "heteroalkyl", "heteroalkenyl" and "heteroalkynyl" refer to an alkyl, alkenyl and alkynyl, respectively, in which one or more of the carbon atoms (and any of the associated hydrogen atoms) are each replaced by the same or different heteroatom. Typical heteroatoms include, but are not limited to, for example, -O-, -S-, -OO-, -SS-, -OS-, -NRa-, = NN =, -N = N-, -N = N -NRa, -PH-, -P (O) 2-, -OP (O) 2-, S (O) -, -S (O) 2-, a -SnH2-, in which Ra is hydrogen, alkyl , substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl or substituted aryl.

The terms "substituted heteroalkyl", "substituted heteroalkenyl" or "substituted heteroalkynyl" refer to a heteroalkyl, heteroalkenyl or heteroalkynyl, respectively, substituted with at least one alkyl, substituted alkyl, or a substituent described above when defining the term "substituted alkyl" as an exemplary alkyl substituent.

The term "hydroxyalkyl" refers to a -RbOH, wherein Rb is an alkyl or substituted alkyl.

The term "amino" refers to -NH2.

The term "aminoalkyl" refers to an alkyl substituted with an amino having at least one hydrogen replaced by a group selected from alkyl, alkenyl and cycloalkyl. Therefore, aminoalkyl refers to the group -RcNRdRe, in which Rc is an alkyl and Rd and Re are independently selected from hydrogen, alkyl, alkenyl and cycloalkyl, with the proviso that Rd and Re are not both hydrogen.

The term "substituted aminoalkyl" refers to an aminoalkyl in which at least one of the alkyl, alkenyl or cycloalkyl moieties is substituted with at least one, preferably 1 to 4, more preferably 1 to 2 groups selected from which indicated herein as appropriate for the remainder indicated. Therefore, for example, a substituted aminoalkyl refers to the group -RcNRdRe, in which Re is an alkyl or substituted alkyl and Rd and Re are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl and cycloalkyl substituted, with the proviso that Rd and Re are not both hydrogen, since in this case the group is amino and unsubstituted aminoalkyl.

The term "alkylamino" refers to an amino having at least one hydrogen replaced by a group selected from alkyl, alkenyl and cycloalkyl. Therefore, "alkylamino" refers to the group NRfRg, in which Rf and Rg are independently selected from H, alkyl, alkenyl and cycloalkyl, with the proviso that at least one of Rf or Rg is an alkyl.

The term "substituted alkylamino" refers to an alkylamino in which at least one of the alkyl, alkenyl or cycloalkyl moieties is substituted with at least one, preferably 1 to 4, more preferably 1 to 2 groups selected from which indicated herein as appropriate for the remainder indicated. Therefore, for example, a substituted alkylamino refers to the group -NRfRg, in which Rf and Rg are independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl and substituted cycloalkyl, with the proviso that at less one of Rf or Rg is an alkyl and at least one of Rf or Rg is a substituted moiety.

The term "disubstituted amino" refers to an amino having both hydrogens replaced by a group selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl and substituted cycloalkyl. Therefore, for example, a disubstituted amino refers to the group -NRhRi, in which Rh and Ri are independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl and substituted cycloalkyl.

The terms "halogen" and "halo" refer to chlorine, bromine, fluorine and iodine.

The terms "haloalkyl" or "haloalkoxy" refer to an alkyl or substituted alkyl; or an alkoxy, respectively, attached to a single halogen or multiple halogens. Exemplary haloalkyls containing multiple halogens include, but are not limited to, for example, -CHCl2 and -CF3. Exemplary haloalkoxy containing multiple halogens include, but are not limited to, for example, trifluoromethoxy (-OCF3).

The term "alkoxy" refers to an alkyl, substituted alkyl, alkanoyl, substituted alkanoyl, cycloalkyl or substituted cycloalkyl linked through an oxygen bond (-O-alkyl, -O-substituted alkyl, -O-alkanoyl, -O- substituted alkanoyl, -O-cycloalkyl or -O-substituted cycloalkyl). Exemplary alkoxy groups include, but are not limited to, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, t-butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, heptoxy, pentoxy, decanoxy, undecanoxy and dodecanoxy.

The terms "alkoxyalkyl" or "alkoxyarylthio" refer to an alkyl or substituted alkyl; or an arylthio, respectively, attached to an alkoxy.

The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary alkenyls include, but are not limited to, for example, ethenyl and allyl.

The term "substituted alkenyl" refers to an alkenyl substituted with at least one substituent, preferably 1 to 4 substituents, more preferably 1 to 2 substituents at any available point of attachment. Exemplary substituents include, but are not limited to, for example, alkyl, substituted alkyl, and the substituents described above in defining the term "substituted alkyl" as alkyl substituents.

5 by way of example.

The term "cycloalkenyl" refers to a cyclic alkenyl.

The term "substituted cycloalkenyl" refers to a cycled substituted alkenyl.

The term "alkanoyl" refers to an alkyl linked through a carbonyl (ie - C (= O) Rj, wherein Rj is an alkyl).

The term "substituted alkanoyl" refers to an alkanoyl substituted with at least one substituent, preferably 1 to 4 substituents, more preferably 1 to 2 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, for example, alkyl, substituted alkyl, and the substituents described above in defining the term "substituted alkyl" as exemplary alkyl substituents.

The terms "alkanoylamino", "arylcarbonylamino", "alkylcarbonylamino" or "arylsulfonylamino" refer to a substituted alkanoyl or alkanoyl; an arylcarbonyl; an alkylcarbonyl; or an arylsulfonyl, respectively, attached to an amino.

The term "alkanoyloxy" refers to an alkanoyl or substituted alkanoyl attached to an oxygen.

The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12

20 carbon atoms and at least one triple carbon-carbon bond. Exemplary alkyls include, but are not limited to, for example, ethynyl; propynyls, such as, for example, prop-1-in-1-yl and prop-2-in-1-yl; and butynyl, such as, for example, but-1-in-1-yl, but-1-in-3-yl and but-3-in-1-yl.

The term "substituted alkynyl" refers to an alkynyl substituted with at least one substituent, preferably 1 to 4 substituents, more preferably 1 to 2 substituents at any available point of attachment. The

Exemplary substituents include, but are not limited to, for example, alkyl, substituted alkyl, and the substituents described above in defining the term "substituted alkyl" as exemplary alkyl substituents.

The term "alkylsulfone" refers to -RkS (= O) 2Rk, in which Rk is an alkyl or substituted alkyl.

The term "oxo" refers to the divalent radical = O.

30 The term "carbamate" refers to the group -OC (= O) NH2.

The term "amide" refers to the group -C (= O) NH2.

The term "sulfonamide" refers to the group -SO2NH2.

The terms "substituted amide", "substituted sulfonamide" or "substituted carbamate" refer to an amide, sulfonamide or carbamate, respectively, which has at least one hydrogen replaced by a chosen group

Between alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl and substituted cycloalkyl.

A substituted amide, for example, refers to the group -C (= O) NRmRn, in which Rm and Rn are independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl and substituted cycloalkyl, with the condition of that at least one of Rm or Rn is a substituted moiety.

A substituted sulfonamide, for example, refers to the group -SO2NRoRp, in which Ro and Rp are selected

Independently between alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl and substituted cycloalkyl, with the proviso that at least one of Ro or Rp is a substituted moiety.

A substituted carbamate, for example, refers to the group -OC (= O) NRqRr, in which Rq and Rr are independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl and substituted cycloalkyl, with the proviso that at minus one of Rq or Rr is a substituted residue.

The term "ureido" refers to the group NHC (= O) NH2.

The term "cyano" refers to the group -CN.

The terms "cycloalkylalkyl" or "cycloalkylalkoxy" refer to a substituted cycloalkyl or cycloalkyl attached to a substituted alkyl or alkyl; or an alkoxy, respectively.

The term "nitro" refers to the group -N (O) 2.

The term "uncle" refers to the group -SH.

The term "thioalkyl" refers to the group -SRs, wherein Rs is an alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl.

The term "alkylthio" refers to the RtS group, in which Rt is an alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl.

The term "alkylsulfonyl" refers to the group -S (= O) 2Ru, wherein Ru is an alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl.

The term "alkylsulfinyl" refers to the group -S (= O) Rv, wherein Rv is an alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl.

The term "carboxy" refers to the group -C (= O) OH.

The terms "carboxy alkoxy" or "alkoxycarbonylalkoxy" refer to a carboxy, or an alkoxycarbonyl, respectively, attached to an alkoxy.

The term "alkoxycarbonyl" refers to the group -C (= O) ORw, wherein Rw is an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

The term "arylalkoxycarbonyl" refers to a substituted aryl or aryl attached to an alkoxycarbonyl.

The terms "alkylcarbonyloxy" or "arylcarbonyloxy" refer to the group -OC (= O) Rz, wherein Rx is a substituted alkyl or alkyl, or a substituted aryl or aryl, respectively.

The term "carbamoyl" refers to the groups -OC (= O) NH2, -OC (= O) NHRy and / or -OC (= O) NRyRz, in which Ry and Rz are independently selected from alkyl and substituted alkyl .

The group -NRaa (C = O) Rbb refers to a group in which Raa is selected from hydrogen and lower alkyl, and Rbb is selected from hydrogen, alkyl, substituted alkyl, alkoxy, aminoalkyl, substituted aminoalkyl, alkylamino, substituted alkylamino , aryl and substituted aryl.

The term "carbonyl" refers to a -C (= O).

The terms "alkylcarbonyl", "aminocarbonyl", "alkylaminocarbonyl", "aminoalkylcarbonyl" or "arylaminocarbonyl" refer to a substituted alkyl or alkyl; an amino; a substituted alkylamino or alkylamino; a substituted aminoalkyl or aminoalkyl; or an arylamino, respectively, attached to a carbonyl.

The terms "aminocarbonylalkyl" or "aminocarbonylalkyl" refer to an aminocarbonyl attached to a substituted aryl or aryl; or an alkyl or substituted alkyl, respectively.

The term "sulfonyl" refers to the group S (= O) 2.

The term "sulfinyl" refers to an S (= O).

The term "carboxy alkyl" refers to an alkyl or substituted alkyl attached to a carboxy.

As used herein, the term "patient" includes all mammalian species. A species of mammals includes, but is not limited to, for example, humans and pets, such as, for example, dogs, cats and horses.

The terms "salt" or "salts", as used herein, represent acidic and / or basic salts formed with organic and inorganic acids and / or bases, and such terms, as used herein, additionally include zwitterions ("internal salts").

The term "zwitterions", as used herein, represents compounds that contain both a basic moiety, including, but not limited to, for example, pyridine and imidazole; as an acidic moiety, including, but not limited to, for example, a carboxylic acid.

The term "pharmaceutically acceptable", as used herein, indicates that the subject matter to be identified as "pharmaceutically acceptable" is suitable and physiologically acceptable for administration to a patient. For example, the term "pharmaceutically acceptable salt or salts" represents suitable and physiologically acceptable salt or salts.

The compounds of Formula (I) can also form salts. As a result, when reference is made to a compound of Formula (I) herein, said reference includes, unless otherwise indicated, salts thereof. In one embodiment, the compounds of Formula (I) form pharmaceutically acceptable salts. In another embodiment, the compounds of Formula (I) form salts that can, for example, be used to isolate and / or purify the compounds of Formula (I). The salts of the compounds of Formula (I) can be formed, for example, by reacting a compound of Formula (I) with, for example, an equivalent amount of acid or base in a medium that allows the salt formed in this way to withdraw. by precipitation, or isolated by lyophilization.

Exemplary acid salts that the compounds of Formula (I) may form with inorganic and / or organic acids include, but are not limited to, for example, acetates, such as those formed with acetic or trihaloacetic acid; adipates; alginates; ascorbates; aspartates; benzoates; benzenesulfonates; bisulfates; borates; butyrates; citrates; canforates; camphorsulfonates; cyclopentanepropionates; digluconate; dodecyl sulfates; ethanesulfonates; smokers; glucoheptanoates; glycerophosphates; hemisulfates; heptanoates; hexanoates; hydrochlorides; hydrobromides; iohydrates; hydroxyethanesulfonates, such as, for example, 2-hydroxyethanesulfonates; lactates; maleates; methanesulfonates; naphthalenesulfonates, such as, for example, 2-naphthalenesulfonates; nicotinates; nitrates; oxalates; pectinates; persulfates; phenylpropionate, such as, for example, 3-phenylpropionate; phosphates; picrates; pivalates; propionates; salicylates; succinates; sulfates, such as, for example, those formed with sulfuric acid; sulfonates; tartrates; thiocyanates; and toluenesulfonates, such as, for example, tosylates and undecanoates. Said salts may be formed according to procedures known to a person skilled in the art.

Exemplary basic salts that the compounds of Formula (I) may form with inorganic and / or organic bases include, but are not limited to, for example, ammonium salts; alkali metal salts, such as, for example, sodium, lithium and potassium salts: alkaline earth metal salts, such as, for example, calcium and magnesium salts; salts formed with organic bases, such as, for example, benzathines, dicyclohexylamines, hydrabamines (such as, for example, N, N-bis (dehydroabiethyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-Dglylamides or t -butyl amines; salts formed with amino acids, such as, for example, arginine and lysine; and salts formed using agents, such as, for example, lower alkyl halides (for example, chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (for example, dimethyl, diethyl, dibutyl sulfates and diamyl), long chain halides (for example, chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl), and aralkyl halides (for example, benzyl and phenethyl bromides) to quaternize groups containing basic nitrogen. Said salts may be formed according to procedures known to a person skilled in the art.

All stereoisomers and geometric isomers of the compounds of Formula (I), in admixture or in pure or substantially pure form are also contemplated herein. Specifically, all enantiomers, tautomers and diastereomers of the compounds of Formula (I), as well as mixtures, compounds, racemic compounds, racemic mixtures and racemates produced therefrom are contemplated herein. Even more particularly, all optically active isomers of the compounds of Formula (I) that include pure or substantially pure optically active isomers, that is, optically active isomers free of other isomers.

When a compound containing an individual enantiomer of a compound of Formula (I) is desired, said compound can be obtained by resolution of the final product or by stereospecific synthesis from isomerically pure starting materials, or any convenient intermediate. The resolution of the final product, an intermediate,

or a starting material can be made by any suitable method known in the art, including, for example, physical procedures, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, and separation by chiral column chromatography. The individual optical isomers can be obtained from racemates by, for example, conventional procedures, such as, for example, salt formation with an optically active acid followed by crystallization. The chiral centers of the compounds described herein may have the S or R configuration as defined by the 1974 IUPAC Recommendations.

Additionally, prodrugs and / or solvates of the compounds of Formula (I) are contemplated herein.

The term "prodrug", as used herein, represents a compound that, upon administration to a subject, undergoes chemical conversion through metabolic and / or chemical processes in vivo to produce a compound and / or derivative of Formula (I), or a salt and / or solvate thereof. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 112, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs", by H. Bundgaard, p. 113-191 (1991); Y

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992).

The term "solvate", as used herein, represents a compound produced by the chemical interaction of at least one solvent with at least one solute comprising at least one compound of Formula (I). Exemplary solvates include, but are not limited to, for example, hydrates.

All numbers that express quantities of ingredients, properties, such as molecular weight, reaction conditions and so on that are preceded by the word "approximately" will be understood only as approximations so that slight upper and lower variations of the indicated number can be used to achieve substantially the same results as the indicated number. Therefore, unless

5 indicate otherwise, the numerical parameters preceded by the word "approximately" are approximations that may vary depending on the desired properties intended to be obtained by the invention. At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter must be interpreted based on the number of significant digits indicated and applying conventional rounding techniques.

10 It should be noted that each of the various intervals indicated is intended to be continuous to include each numerical parameter between the minimum and maximum values indicated for each interval. It will be further appreciated that, although not intended to limit the applicability of the doctrine of equivalents to the scope of the claims, each numerical parameter must be interpreted in a manner consistent with the indicated number of significant figures for each numerical parameter and applying conventional rounding techniques . In addition, it will even be appreciated that,

15 although without the intention of limiting the applicability of the doctrine of equivalents to the scope of the claims, even if a number may be included within a numerical range in which at least one of the minimum and maximum numbers of the interval is or is not preceded by the word "approximately", each numerical value included in the interval may or may not be preceded by the word "approximately". For example, a range of about 1 to about 10 includes about 1, about 2.2,

20 about 3.3, about 4.4, about 5, 5, about 6, 6, about 7.7, about 8.8, about 9.9 and about 10; a range of about 1.1 to about 3.2 includes about 1.1, about 1.2, 1.2, about 1.3, 1.3, about 1.4, 1.4, about 1.5 , 1.5, about 1.6, 1.6, about 1.7, 1.7, about 1.8, 1.8, about 1.9, 1.9, about 2.0, 2.0, about 2.1, 2.1,

25 about 2.2, 2.2, about 2.3, 2.3, about 2.4, 2.4, about 2.5, 2.5, about 2.6, 2.6, about 2.7 , 2.7, about 2.8, 2.8, about 2.9, 2.9, about 3.0, 3.0, about 3.1, 3.1, and about 3.2; and a range of about 1 to 4 includes about 1, 2, about 2, 3, about 3, and 4.

In addition, when an amount, concentration or other value or parameter is given as a list of the values

30 higher and lower values, said lists are intended to include all intervals formed by matching any higher value with any lower value, regardless of whether the intervals are disclosed separately.

Compounds of Formula (I) are described herein:

image 1

35 or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n, m and Ar1 are as defined hereinbefore.

In one embodiment, R1 is

image 1

in which Ar1 and L are as previously defined herein. 40 In another embodiment, R1 is

image 1

wherein R7, R8, m, L and Ar1 are as defined hereinbefore. In one embodiment, R5 and R6 are taken together with the nitrogen to which they are attached to form a heterocyclic ring of 4, 5, 6 or 7 members or substituted heterocyclic.

In another embodiment, R5 and R6 are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heterocyclic ring or substituted heterocyclic. In yet another embodiment, R5 and R6 are taken together with the nitrogen to which they are attached to form a ring.

5 or 6-membered substituted heterocyclic substituted with at least one substituent selected from alkyl and hydroxyalkyl.

In yet another embodiment, R5 and R6 are taken together with the nitrogen to which they are attached to form a 4, 5, 6 or 7 membered heterocyclic ring or substituted heterocyclic containing at least two heteroatoms selected from O, S and N.

In yet another embodiment, R5 and R6 are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heterocyclic ring or substituted heterocyclic ring containing a heteroatom more selected from 0 to 15 N. In a further embodiment, R5 and R6 are taken together with the nitrogen to which they are attached to form a morpholinyl. In yet another embodiment, R2 is hydrogen or lower alkyl. In yet another embodiment, R2 is methyl, ethyl or isopropyl. In yet another embodiment, R3, R4, R7 and R8 are independently selected from hydrogen and lower alkyl. In yet another embodiment, each of R3, R4, R7 and R8 is hydrogen. In yet another embodiment, L is -C (= O) NH- or NHC (= O) -.

In yet another embodiment, Ar1 is aryl or substituted aryl. In yet another embodiment, Ar1 is a substituted aryl, substituted with at least one substituent selected from halogen, cyano, lower alkyl and OR12, wherein R12 is a lower alkyl.

25 In yet another embodiment, Ar1 is

image 1

wherein R13 and R14 are independently selected from H, halogen and methyl. In one more embodiment, Ar2 is

image 1

30 in which R13 and R14 are independently selected from hydrogen and halogen.

In another embodiment, Ar2 is

image 1

wherein R13 is hydrogen or halogen. In one more embodiment, Ar2 is

image 1

5

wherein R13 and R14 are independently selected from hydrogen and halogen.

In one more embodiment, m is 0.

In yet another embodiment, n is 3.

In addition, at least one pharmaceutical composition comprising at least one

10 a compound according to Formula (I), optionally at least one pharmaceutically acceptable carrier and / or diluent, and optionally at least one different anti-cancer agent.

Also described herein is at least one compound of Formula (I) for use in a method of treating at least one proliferative disease, said procedure usually comprising the steps of administering to a patient in need thereof an effective amount of at least a compound according

15 with Formula (I), optionally administering simultaneously or sequentially at least one other anti-cancer agent, and optionally administering simultaneously or sequentially at least one other anti-cancer treatment.

The term "anti-cancer treatment" includes, but is not limited to, for example, radiotherapy and surgery.

The term "another anticancer agent" includes any known agent useful for treating cancer. The examples of

Such other anticancer agents include, but are not limited to, for example, antiangiogenic agents such as, for example, linomide, inhibitors of the function of integrin v3, angiostatin and razoxane; antiestrogens such as, for example, tamoxifen, toremifene, raloxifene, droloxifene and iodoxifene; progestogens such as, for example, megestrol acetate, hydroxyprogesterone and medroxyprogesterone; aromatase inhibitors such as, for example, anastrozole, testolactone, letrozole, borazol and exemestane; antihormones such as, for example,

25 aminoglutethimide; synthetic estrogens such as, for example, chlorotrianisen, diethylstilbestrol and 17-ethylestradiol; synthetic androgens such as, for example, dromostanolone propionate, fluoxymesterone, and methyltestosterone; antiprogestogens; antiandrogens such as, for example, flutamide; nilutamide, bicalutamide and cyproterone acetate; androgens such as, for example, testosterone; synthetic glucocorticoids such as, for example, methylprednisolone, triamcinolone, prednisolone and prednisone; LHRH agonists and antagonists such

30 such as goserelin acetate and leuprolide; testosterone 5-dihydroreductase inhibitors such as, for example, finasteride; farnesyltransferase inhibitors; anti-invasion agents such as, for example, metalloproteinase inhibitors such as marimastat and inhibitors of the urokinase type plasminogen activator receptor function; VEGF inhibitors such as, for example, anti-VEGF antibodies (Avastin) and small molecules such as, for example, ZD6474, SU6668, Vatalanib, BAY-43-9006, SU11248, CP-547632 and

35 CEP-7055; Her 1 and Her 2 inhibitors including, for example, anti-Her 2 antibodies (Herceptin); EGFR inhibitors such as, for example, gefitinib, erlotinib, ABX-EGF, EMD72000, 11F8 and cetuximab; Eg5 inhibitors such as, for example, SB-715992, SB-743921 and MKI-833; Her bread inhibitors such as, for example, canertinib, EKB-569, CI-1033, AEE-788, XL-647, mAb 2C4 and GW-572016; Src inhibitors such as, for example, Gleevac and Dasatinib; MEK-1 inhibitors; MAPK inhibitors; PI3 kinase inhibitors; Met inhibitors; others

40 Aurora kinase inhibitors; PDGF inhibitors such as, for example, imatinib; IGF1R inhibitors such as, for example, those disclosed in US Patent Application No. 2004/0044203 A1; other receptor and non-receptor tyrosine kinase inhibitors; other serine / threonine kinase inhibitors; CDK inhibitors; antimetabolites such as, for example, methotrexate, idatrexate, trimetrexate, 5-fluorouracil, tegafur, cytarabine, fludarabine, 6-thioguanine, DON (d-oxo-norleucine or AT-125) and 6-mercaptopurine; antibiotics

Intercalating antitumor agents such as, for example, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mitoxantrone and mitramycin; platinum derivatives such as, for example, cisplatin, oxaliplatin and carboplatin; alkylating agents such as, for example, nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoureas, dacarbazine, hexamethyl melamine, estramustine and thiotepa; antimitotic agents such as, for example, vinblastine, vinflunine, Taxol (paclitaxel), Taxotere (docetaxel), 7-Omethylthiomethylpaclitaxel, 4-deacetyl-4-methylcarbonatepaclitaxel, 3'-tert-butyl-3'-N-tert butyloxycarbonyl-4-deacetyl-3'desphenyl-3'-N-desbenzoyl-4-O-methoxycarbonyl-paclitaxel, C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, epothilone analogues, ie , ixabepilone and derivatives thereof; integrin signaling inhibitors; topoisomerase inhibitors such as, for example, etoposide, teniposide, amsacrine, doxorubicin, daunorubicin, irinotecan and topotecan; cell cycle inhibitors such as, for example, flavopyridols; biological response modifiers such as, for example, interferon alfa; monoclonal antibodies such as, for example, rituximab and gemtuzumab ozogamicin; proteosome inhibitors such as, for example, Velcade® (bortezomib); SN-8; procarbazine; L-asparaginase; pyridobenzoindole derivatives; ribonucleotide reductase inhibitors; mTOR inhibitors; leucovorin; VM-26; interleukins; and hematopoietic growth factors.

Proliferative diseases that can be treated according to the compounds of Formula (I) of the invention include, but are not limited to, for example, diseases associated with Aurora kinase such as, for example, cancer, bone diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, viral diseases, fungal diseases, proliferative and neurodegenerative neurological disorders, Alzheimer's disease, allergies and asthma, cardiovascular diseases and hormone-related diseases.

In one embodiment, at least one compound of Formula (I) is used to treat cancer.

Cancers in whose treatment the compounds of Formula (I) can be used include, but are not limited to, for example, carcinoma, including, for example, bladder, breast, colon, kidney, liver, lung (including small cell lung cancer). ), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin (including squamous cell carcinoma); hematopoietic tumors of the lymphoid lineage such as, for example, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodking lymphoma, non-Hodking lymphoma, hair cell lymphoma and Burkett lymphoma; hematopoietic tumors of myeloid lineage such as, for example, acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including, for example, fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including, for example, astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors such as, for example, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer and Kaposi's sarcoma.

Compounds according to Formula (I) are also described herein further including, but not limited to, for example, 3-chloro-4-fluoro-N- (5 - {[6 - ({3- [4 - (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; 3-Chloro-4-fluoro-N- (5 - {[6 - ({3 - [(2S) -2 (hydroxymethyl) pyrrolidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; 3-Chloro-4fluoro-N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) morpholin-4-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4] triazin-4-yl] amino} pyrimidin-2yl) benzamide; 3-Chloro-4-fluoro-N- (5 - {[6 - ({3- [3- (hydroxymethyl) morpholin-4-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1 , 2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4] triazin4-il ] amino} pyrimidin-2-yl) benzamide; N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1f] [1,2,4] triazin -4-yl] amino} pyrimidin-2-yl) benzamide; 3-fluoro-N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5methylpyrrolo [2,1-f] [1,2,4] triazin -4-yl] amino} pyrimidin-2-yl) benzamide; 3-fluoro-N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) pyrrolidin1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2 , 4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; N- (3-fluorophenyl) -2 - {[6 - ({3- [4 (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4 ] triazin-4-yl] amino} -1,3-thiazol-5-carboxamide; and pharmaceutically acceptable salts thereof.

Due to the key role that protein kinases play in regulating cell proliferation in general, inhibitors of said kinases can act as reversible cytostatic agents, thereby making said inhibitors useful for treating any disease process characterized by abnormal cell proliferation. For example, benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glumerulonephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, endotoxic shock fungal infections

The compounds of Formula (I) may modulate apoptosis and, therefore, may be useful for treating cancers, including, but not limited to, for example, cancers already mentioned hereinbefore; treat viral infections, including, but not limited to, for example, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus; prevent the development of AIDS in HIV-infected individuals; treat autoimmune diseases including, but not limited to, for example, systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus; treat neurodegenerative disorders including, but not limited to, for example, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; treat myelodysplastic syndromes; treat aplastic anemia; treat ischemic lesions associated with myocardial infarction, stroke and reperfusion injury; treat arrhythmias; treat atherosclerosis; treat alcohol-related or toxin-induced liver diseases; treat hematological diseases including, but not limited to, for example, chronic anemia and aplastic anemia; treat degenerative diseases of the musculoskeletal system including, but not limited to, for example, osteoporosis and arthritis; treat aspirin-sensitive rhinosinusitis; treat cystic fibrosis; treat multiple sclerosis; treat kidney diseases; and treat cancer pain.

The compounds of Formula (I) can also modulate the level of synthesis of cellular RNA and DNA and, as a result, could be useful in the treatment of viral infections, including, but not limited to, for example, HIV; human papilloma virus; herpesvirus, poxvirus; Epstein-Barr virus; Sindbis virus; and adenovirus.

The compounds of Formula (I) may also be useful in cancer chemoprevention. Chemoprevention is defined as the inhibition of the development of an invasive cancer by blocking the onset of the mutagenic event or blocking the progression of premalignant cells that have already experienced an injury, or by inhibiting tumor relapse.

The compounds of Formula (I) may also be useful for inhibiting tumor angiogenesis and metastasis.

The compounds of Formula (I) can be additionally used as an adjuvant to surgery. For example, at least one compound according to Formula (I) can be used in combination with antibody therapy, or together with a vaccine / immune modulating agents used to treat cancer.

In one embodiment the patient is an animal.

In another embodiment the patient is a human being.

The compounds of Formula (I) can be administered by any means suitable for the condition to be treated, which may depend on the need for the site-specific treatment or the amount of drug to be delivered.

A pharmaceutical composition comprising at least one compound according to Formula (I) can be supplied, for example, orally through any acceptable and suitable oral form including, but not limited to, for example, tablets; troches dragees; aqueous or oily suspensions; dispersible powders or granules; emulsions; soft or hard capsules; syrups; and elixirs. Pharmaceutical compositions intended for oral use can be prepared according to any method known in the art for manufacturing pharmaceutical compositions. To provide pharmaceutically elegant and palatable preparations, a pharmaceutical composition according to the invention may contain at least one agent selected from sweetening agents, flavoring agents, coloring agents and preservatives.

A tablet may be prepared, for example, by mixing at least one compound according to Formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets including, but not limited to, for example, inert diluents such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulating and disintegrating agents such as, for example, microcrystalline cellulose, croscarmellose sodium, corn starch and alginic acid; binding agents such as, for example, starch, gelatin, polyvinylpyrrolidone and gum arabic; and lubricating agents such as, for example, magnesium stearate, stearic acid and talc. In addition, a tablet can be left uncoated or coated by known techniques to mask the bad taste of a drug of unpleasant taste, or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract thereby maintaining the effects of the active ingredient during a longer period. For example, water soluble taste masking materials may be used including, but not limited to, for example, hydroxypropyl methylcellulose and hydroxypropyl cellulose, or time lag materials including, but not limited to, for example, ethyl cellulose and cellulose acetate butyrate .

Hard gelatin capsules can be prepared, for example, by mixing at least one compound according to Formula (I) with at least one inert solid diluent including, but not limited to, for example, calcium carbonate; calcium phosphate; and kaolin. Soft gelatin capsules can be prepared by mixing at least one compound according to Formula (I) with at least one water soluble carrier including, but not limited to, for example, polyethylene glycol; and oily media such as, for example, peanut oil, liquid paraffin and olive oil.

An aqueous suspension can be prepared by mixing at least one compound according to Formula (I) with at least one excipient suitable for the manufacture of an aqueous suspension, including, but not limited to, for example, suspending agents such as, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum arabic; dispersing agents or humectants such as, for example, a natural phosphatide, such as, for example, lecithin; condensation products of alkylene oxide with fatty acids such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols such as, for example, heptadecaethylene-oxyethanol; condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as, for example, polyethylene sorbitan monooleate. An aqueous suspension may also contain at least one preservative such as, for example, ethyl p-hydroxybenzoate and n-propyl; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent including, but not limited to, for example, sucrose, saccharin and aspartame.

The oil suspensions may be prepared, for example, by suspending at least one compound according to Formula (I) in a vegetable oil such as, for example, peanut oil; olive oil; Sesame oil; and coconut oil, or in mineral oil such as, for example, liquid paraffin. An oily suspension may also contain a thickening agent such as, for example, beeswax; hard paraffin; and cetyl alcohol. To provide an appetizing oily suspension, at least one of the sweetening agents already described herein, and / or at least one flavoring agent may be added to the oily suspension. An oily suspension may also contain a preservative including, but not limited to, for example, an antioxidant such as, for example, butylated hydroxyanisole and alpha-tocopherol.

The dispersible powders and granules can be prepared by mixing at least one compound according to Formula (I) with at least one dispersing and / or wetting agent; at least one suspending agent; and / or at least one preservative. Suitable dispersing agents, wetting agents and suspending agents are as previously described. In addition, dispersible powders and granules may also contain excipients including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents, and / or preservatives including, but not limited to, for example, antioxidants such as, for example, ascorbic acid.

An emulsion of at least one compound according to Formula (I) can be prepared as an oil-in-water emulsion. The oil phase can be provided, but not limited, for example, by a vegetable oil such as, for example, olive oil and peanut oil; a mineral oil such as, for example liquid paraffin; and mixtures thereof. Suitable emulsifying agents include, but are not limited to, for example, natural phosphatides such as, for example, soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide such as, for example, polyoxyethylene sorbitan monooleate. An emulsion may also contain a sweetening agent, a flavoring agent, a preservative and / or an antioxidant.

Syrups and elixirs may contain a sweetening agent including, but not limited to, for example glycerol; propylene glycol; sorbitol and sucrose. Syrups and elixirs may also contain a demulcent, a preservative, a flavoring agent, a coloring agent and / or an antioxidant.

A pharmaceutical composition comprising at least one compound according to Formula (I) can also be supplied, for example, intravenously, subcutaneously and / or intramuscularly through any acceptable and suitable injectable form including, but not limited to, for example. , sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution and isotonic sodium chloride solution; sterile microemulsions of oil in water; and aqueous or oleaginous suspensions.

A sterile injectable oil-in-water microemulsion can be prepared 1) by dissolving at least one compound according to Formula (I) in an oil phase, such as, for example, a mixture of soybean oil and lecithin; combining the compound containing the oil phase with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion.

A compound according to Formula (I) can be introduced into the bloodstream of a patient by administering an injectable solution and / or microemulsion containing the compound of Formula (I) such as, for example, a local injection in embolate . If it is desired to maintain a constant circulating concentration of the compound of Formula (I), a continuous intravenous release device such as, for example, a Deltec CADD-PLUS.TM intravenous pump can be used. 5400 model.

A sterile aqueous or oleaginous suspension can be prepared according to procedures known in the art. For example, a sterile aqueous solution or suspension can be prepared with a diluent or solvent acceptable for the non-toxic parenteral route such as, for example, 1,3-butanediol; and a sterile oil suspension can be prepared with a sterile non-toxic acceptable suspension or solvent medium such as, for example, sterile fixed oils including, but not limited to, for example, synthetic mono- or diglycerides; and fatty acids including, but not limited to, for example, oleic acid.

A pharmaceutical composition comprising at least one compound according to Formula (I) can be additionally administered, for example, through any acceptable and suitable rectal form including, but not limited to, for example, a suppository. A suppository can be prepared by mixing at least one compound of Formula (I) with a suitable non-irritating excipient that is liquid at the rectal temperature but solid at least at a temperature below the rectal temperature. Non-irritating excipients by way of example include, but are not limited to, for example, cocoa butter; glycerinated gelatin; hydrogenated vegetable oils; mixtures of polyethylene glycols of various molecular weights; and fatty acid esters of polyethylene glycol.

A compound according to Formula (I) can be additionally administered by any acceptable and suitable topical route including, but not limited to, for example, creams; ointments; jellies; solutions; suspensions, transdermal patches; intranasal inhalers, etc. For the purposes of this application, the topical application will include mouthwashes and gargles.

Exemplary compositions for administration by nasal spray or inhalation include solutions that may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to improve absorption and / or bioavailability and / or other solubilizing or dispersing agents. such as those known in the art.

An "effective amount" of a compound according to Formula (I) can be determined by one skilled in the art and includes exemplary dosage amounts for a mammal of about 0.05 to 100 mg / kg body weight of active compound per day, which can be administered in a single dose or in the form of individual divided doses, such as 1 to 4 times a day.

The specific dosage level and dosage frequency for any particular subject, however, can be varied and generally depends on a variety of factors that include, but are not limited to, for example, the bioavailability of the specific compound or compounds of Formula (I). in the administered form; the metabolic stability and duration of action of the specific compound or compounds of Formula (I); the species, age, body weight, general health, sex and diet of the subject; the mode and timing of administration; the rate of excretion; the combination with drugs; and the severity of the particular condition.

If formulated as a fixed dose, a combination product may use, for example, a dosage of the compound of Formula (I) within the dosage range described above and the dosage of another anticancer agent / treatment within the approved dosage range for said known anticancer agent / treatment. If a combination product is inappropriate, the compound of Formula (I) and the other anticancer agent / treatment can be administered, for example, simultaneously or sequentially. If administered sequentially, the invention is not limited to any particular administration sequence. For example, the compounds of Formula (I) can be administered before or after administration of the known anticancer agent or treatment.

The compounds of Formula (I) can also be formulated or co-administered with other therapeutic agents that are selected for their particular utility in the administration of therapies associated with the conditions mentioned above. For example, the compounds of the invention can be formulated with agents to prevent nausea, hypersensitivity and / or gastric irritation, such as, for example, anti-emetics and antihistamines H1 and H2.

The other therapeutic agents above, when used in combination with the compounds of Formula (I), can be used, for example, in the amounts indicated in the Physicians Desk Reference (PDR) (vademecum of pharmaceutical specialties of the United States) or as otherwise determined by an expert in the field.

In general, the compounds of Formula (I) can be prepared according to Schemes I and II and the general knowledge of one skilled in the art. Tautomers and solvates (e.g., hydrates) of the compounds of Formula (I) are also within the scope of the invention. Solvation procedures are generally known in the art. Accordingly, the compounds of the invention may be in the free or hydrate form, and may be obtained by the procedures illustrated in Schemes I and II. The abbreviations used in Stages 1-4 of Scheme I and Stages 1-5 of Scheme II are as defined in the Examples set forth hereinbelow.

Scheme I

image 1

X = halogen

Step 1: Compound III can be obtained by treating compound II with a base, such as, for example, cesium carbonate in an appropriate solvent, such as, for example, acetonitrile, followed by an additional reaction with an alkylating agent corresponding to High temperature.

Step 2: Compound IV can be obtained by treating compound III with a chlorination reagent, such as, by

example POCl3, in the presence of a base, such as, for example, N, N-diisopropylethylamine.

Step 3: Compound VI can be obtained by coupling the appropriately constituted compound IV V in the presence of a solvent such as, for example, DMA. 10

an aniline

Step 4: A compound according to Formula (I) is obtained by treating compound VI with

 an amine

primary or secondary properly functionalized in the presence of a catalyst, such as, for example, tetrabutylammonium iodide.

Scheme 20

image 1

X = halogen

R17 = lower alkyl

Step 1: Compound VIII can be obtained by treating compound VII with a base, such as, for example, cesium carbonate in an appropriate solvent, such as, for example, acetonitrile, followed by an additional reaction with a corresponding alkylating agent. at high temperature.

Step 2: Compound IX can be obtained by treating compound VIII with a chlorination reagent, such as, for example POCl3, in the presence of a base, such as, for example, N, N-diisopropylethylamine.

Step 3: Compound XI can be obtained by coupling compound IX with an appropriately substituted aminothiazole carboxylate X in the presence of a reagent, such as, for example, DMT; a drying agent, such as, for example, 60% NaH in mineral oil; and a solvent, such as, for example, acetic acid.

Step 4: Compound XII can be obtained by hydrolyzing compound XI to give the carboxylic acid

Corresponding under conventional conditions, for example lithium hydroxide in THF / MeOH / water, followed by subsequent treatment with an appropriate aniline in the presence of a base, such as, for example, diisopropylethylamine.

Step 5: A compound according to Formula (I) can be obtained by treating compound XII with, for example, a properly functionalized primary or secondary amine in the presence of a catalyst, such as,

20 for example, tetrabutylammonium iodide.

It is important to appreciate that other compounds of Formula (I) can be easily prepared using procedures generally known to one skilled in the art, including, but not limited to, for example, the various preparation procedures used in the Examples set forth hereinbelow. .

ESSAYS

At least one compound of Formula (I), including the compounds described in the examples thereof, have been tested in at least one assay described below and the activity shown as an inhibitor of at least one of Aurora kinase A, B and / or C.

Cell Based Assay for Histone H3 Phosphorylation

To determine the ability of compounds to inhibit the function of Aurora kinases in human cells, the phosphorylation status of Histone H3 (HH3) in Serine 10 was analyzed. HH3 is a phosphorylated chromatin protein in at least two serine residues. including Ser-10 and Ser-28. Ser-10 in the centromeric HH3 is phosphorylated in the G2 phase of the cell cycle and by mitosis. Ser-10 is phosphorylated on the entire chromosome. Phosphorylation at this site in HH3 regulates the onset of chromatin condensation and seems to require Aurora kinases.

Using this knowledge, a western cell assay was created to measure the degree of phosphorylation of HH3 by Aurora kinases in cells arrested in mitosis. Specifically, HCT-116 colorectal cancer cells were cultured in a 96-well plate and allowed to grow for 6 hours. After 6 hours, Nocodazole was added to the wells at a final concentration of 15 ug / ml, and the cells were incubated for an additional 16 hours. Nocodazole treatment caused the cells to stop in mitosis with maximum phosphorylation of HH3. At the end of the 16-hour Nocodazole treatment, the cells were treated with various concentrations of compounds within the scope of Formula (I) for approximately 2 hours to determine the ability of said compounds of Formula (I) to reverse phosphorylation of HH3 Aurora kinase dependent. At the end of the experiment, cells treated with compound of Formula (I) and control were fixed in 4% formaldehyde and then stained with rabbit polyclonal antibody specific for the epitope containing phosphorylated Ser-10 (Upstate No. 06-570 ). At the same time, the cells were also stained using a monoclonal antibody against a constitutive protein (anti-actin, Chemicon 1501R) to control the number of cells in each well. Primary antibodies were detected using secondary antibodies labeled with Alexa dye (anti-mouse-800 (Rockland No. 610-131121), and anti-rabbit-680 (Molecular Probes No. A21076)). The test plates were subsequently analyzed for fluorescence in the two channels (800 and 680) using a Liquor Odyssey instrument. The phospho-HH3 specific fluorescence was normalized to actin specific fluorescence. The percent inhibition of HH3 phosphorylation with respect to vehicle treated cells was determined for each concentration of compound of Formula (I) tested. The concentration necessary to provide 50% inhibition of HH3 phosphorylation (IC50 of P-HH3) for each compound of Formula (I) tested was also determined.

Phenotypic analysis of cells treated with Aurora Kinase inhibitors

The role of Aurora kinases in the regulation of an appropriate cell division has been studied extensively. The genetic alteration of these kinases in model organisms and mammalian cells has demonstrated specific phenotypes associated with a loss of Aurora kinase function. Specifically, mitotic defects including the appearance of polyploid cells due to a failure in cytokinesis is a marked and measurable phenotype in cells that lack Aurora kinase activity. In addition, these polyploid cells undergo apoptosis after subsequent attempts at cell division. Based on these well characterized phenotypes, a functional assay was developed to simultaneously measure polyploidy and apoptosis in cells treated with Aurora kinase inhibitors.

The DNA content can be easily quantified by adding propidium iodide (IP) to fixed cells. Propidium iodide binds to cellular DNA and emits fluorescence when illuminated. The fluorescence is directly proportional to the cellular DNA content. As a result, the percentage of cells in a population in each phase of the cell cycle and also the percentage of cells with a DNA content greater than 4N (polyploid cells) can be determined using flow cytometry.

Numerous techniques are available to detect apoptosis in mammalian cells. An event that occurs in most cell types once the cell has been destined for apoptotic cell death is the specific proteolytic cleavage of the nuclear protein Poly-ADP Ribose Polymerase (PARP). This excision is performed by the effector of apoptosis caspasa, CASP-3 and CASP-7. Commercial antibodies are available that detect the 85 kDa fragment of the cleaved PARP (PARP-p85) present in apoptotic cells but not the full-length PARP present in living cells. These antibodies are useful for determining the fraction of apoptotic cells in a population at any given time.

Combining staining with PI for DNA content and staining for PARP-p85, an assay was created to track the induction of both polyploidy and apoptosis in treated cells with various concentrations of various compounds of Formula (I). The treated cells were analyzed according to said assay a variety of times after treatment. Using this assay, compounds of Formula (I) that induced polyploidy could be identified after 24 hours of treatment and apoptosis at 48 hours after treatment, and this was consistent with the specific inhibition of Aurora kinases.

Cellular Cytotoxicity Assays

To determine the long-term effects on cells treated with compounds according to Formula (I), a cytotoxicity assay was used to measure overall cell viability after 72 hours of exposure to the compound of Formula (I). The cytotoxicity assay uses soluble tetrazolium salts, MTS (Promega Corporation; Madison, WI) that are metabolically converted into a colored product in living cells but not in dead cells.

Cells were seeded in 96-well culture plates. After 24 hours, the compound of Formula was added

(I) and diluted in series. After 72 hours of exposure, the percentage of MTS conversion inhibition was determined with respect to vehicle treated cells for each concentration of compound of Formula (I) tested. The concentration necessary to provide a 50% inhibition of MTS conversion (IC50 of MTS) for each compound of Formula (I) tested was also determined.

The cytotoxicity assay was performed on at least 12 human cancer cell lines including breast (BT-549, DU4475, MDA-MB-468, MDA-MB-231), prostate (PC-3, DU145, LNCaP), lung ( NCI-H446, SHP-77), ovary (A2780), colon (HCT116), and hematologic (CCRF-CEM). This panel of cell lines allowed to determine the relative sensitivities of the various lines to cell destruction for each compound of Formula (I) tested.

Biochemical Murine Assay

A cDNA corresponding to the full length mouse Aurora A coding sequence (gi: 46391089, nucleotides 52-1305) was cloned into a baculovirus protein expression vector system that introduced a His6 purification marker at the amino terminus of the protein (His-mAurA). Five liters of Sf9 cells were grown up to 2 x 10 6 cells / ml and infected with the recombinant His-mAurA baculovirus using a multiplicity of infection of 3. The cells were collected 48 hours after infection. Two cell pellets, each containing x5 x 109 cells, were quickly frozen in dry ice and stored at -80 ° C.

To purify recombinant His-mAurA, cell pellets were thawed on ice and resuspended in 200 ml of Lysis Buffer containing: 50 mM Tris HCl pH 8, 300 mM NaCl, 5% Glycerol, 1X Protease Inhibitors with EDTA ( Complete Tabs, Roche Biochemicals), 1 mM DTT and 1 mM sodium orthovanadate. The cells were broken by a brief sonication. The insoluble material was pelleted by centrifugation at 4 ° C. The soluble material was removed to a clean container and the volume was adjusted to 200 ml with Lysis Buffer. The soluble fraction was applied twice to a pre-equilibrated Ni-Nta resin column in Lysis Buffer (without protease inhibitors). The resin was washed with 50 ml of Lysis Buffer (without protease inhibitors). The protein was eluted in Lysis Buffer (without protease inhibitors) containing increasing concentrations of Imidazole (25, 50, 75, 100, 150, 200, 250 and 300 mM). 24 ml fractions were collected and analyzed for His-mAurA protein content using SDS-PAGE. Fractions containing purified protein were pooled and 15% glycerol was added before storage at -80 ° C. The protein had a purity greater than 80% and the concentration was determined to be 0.15 mg / ml by the BioRad protein assay.

Purified murine Aurora A activity was assayed in a 96-well plate format using a peptide substrate with the amino acid sequence RRRRRRRRRRRISDELMDATFADQEAK (PAKtide). The reactions were performed at a final volume of 50 ul containing: 15 g of His-mAurA, 125 mM PAKtide, 10 uM ATP, 0.5 uCi / well of 33P-ATP, 40 mM Tris-HCl pH 7.4, 10 mM MgCl2, 0.5 mM DTT and 0.1 mg / ml BSA. After allowing the reaction to continue for 30 minutes at 30 ° C, 25 ul was transferred to a Millipore filter plate (Cat. No. MAPHNOB50). The filter plates were dried for 1 hour. After drying, 35 ul scintillation agent (Microscint20) was added and the level of radioactive phosphate (33-P) incorporated into the PAKtide substrate was measured by HismAurA in a TOPcount plate reader.

To test the ability of the compounds of Formula (I) to inhibit the activity of Aurora A, the assay described above was performed in the presence of a variety of concentrations of compound of Formula (I) ranging from about 0.001 µM to about 40 uM. Compound tests of Formula (I) were performed in the presence of DMSO at a final concentration of 1%. At least 3 individual wells were tested at each compound concentration and the percentage of average inhibition was determined with respect to vehicle treated wells. The concentration of compound of Formula (I) necessary to inhibit His-mAurA activity at 50% of the activity of vehicle-treated wells for each compound of Formula (I) (50% Inhibitory Concentration; IC50) was calculated.

IC50 values

At least one compound of Formula (I) showed activity in at least one of the tests mentioned above by means of an IC50 value between about 0.01 and about 100 µM. In one embodiment, at least one compound of Formula (I) showed activity in at least one of the aforementioned assays by means of an IC50 value of less than about 1.0 µM. In another embodiment, at least one compound of Formula (I) showed activity in at least one of the aforementioned tests through an IC50 value of less than about 0.5 µM.

Examples

The invention is further defined in the following Examples. It should be appreciated that these Examples are given by way of illustration only. From the above analysis and this Example, one skilled in the art can determine the basic characteristics of this invention, and without departing from the scope thereof, can do

5 various changes and modifications to the invention to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth hereinbelow, but is defined by the claims appended thereto.

All temperatures are in degrees Celsius (° C) unless otherwise indicated herein.

All reactions were performed with continuous magnetic stirring under an atmosphere of dry nitrogen or argon.

10 All evaporations and concentrations were performed in a rotary evaporator. Commercially available reagents that were received without further purification were used. The solvents were commercially available anhydrous grades and were used without drying or further purification. Flash chromatography was performed using silica gel (EMerck Kieselgel 60, 0.040-0.060 mm).

The following abbreviations were used herein: HCl: hydrochloric acid, TFA: acid

15 trifluoroacetic acid, CH3CN: acetonitrile, MeOH: methanol, MgSO4: magnesium sulfate, NaHCO3: sodium bicarbonate, DMA: dimethylamine, Cs2CO3: cesium carbonate, POCl3: phosphorus oxychloride, EtOH: ethanol, CH2Cl2: dichloromethane, dichloromethane, dichloromethane O- (7-azabenzotriazol-1-yl-N, N, N ', N'-tetramethyluronium, NaH: sodium hydride, HOAc: acetic acid, THF: tetrahydrofuran, DMF: dimethyl formamide, Bn: benzyl, Me: methyl, Et: ethyl, min: minute (s), h: hour (s), l: liter, ml: milliliter, :l: microliter, g: gram (s), mg: milligram (s), mol: moles, mmol : millimol or millimoles, mequiv .:

20 milliequivalent, TA or ta: room temperature, t. ret .: HPLC retention time (minutes), sat .: saturated, aqueous: aqueous, TLC: thin layer chromatography, HPLC: high performance liquid chromatography, RP HPLC: reverse phase HPLC, prep HPLC: HPLC reverse phase preparative, LC / MS: high performance liquid chromatography / mass spectrometry, MS: mass spectrometry, NMR: nuclear magnetic resonance, and mp: melting point.

25 HPLC Conditions:

In Examples 1-8 the t. ret. Inverse phase analytical HPLC was obtained with a Chromolith SpeedROD 4.6 x 50 mm column, 4 ml / min flow rate, 4 min linear gradient elution (unless otherwise indicated herein, all gradients started with 100% of solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 0% of solvent B, and finished with 100% of solvent B (90% MeOH, H2O at 10%, 0.1% TFA) and

30% solvent A). UV detection was performed at 220 nm.

The preparative reverse phase HPLC (RP) analysis was performed with a linear elution gradient using mixtures of H2O / MeOH buffered with 0.1% trifluoroacetic acid and detection at 220 nm in one of the following columns: Shimadzu S5 ODS- VP 20 x 100 mm (flow rate = 9 ml / min), or YMC S10 ODS 50 x 500 mm (flow rate = 50 ml / min), or YMC S10 ODS 30 x 500 mm (flow rate = 20 ml / min).

All final products were characterized by 1H NMR, RP HPLC, electrospray ionization mass spectrometry (EMI EM) or atmospheric pressure ionization (IPA EM). 1H NMR spectra were obtained on a 500 MHz JEOL instrument or a 400 MHz Bruker instrument. 13C NMR spectra were recorded at 100 or 125 MHz. Field intensities were expressed in units of  (parts per million, ppm) with respect to solvent peaks, and multiplicities of peaks were designated as indicated below. : s, singlet; d,

40 double; dd, double of doublets; dm, multiplet doublet; t, triplet; c, quadruplet; s a, wide singlet; m, multiplet.

Example 1

3-Chloro-4-fluoro-N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1 , 2,4] triazin-4

il] amino} pyrimidin-2-yl) benzamide

image4

1A. 6- (3-Chloropropoxy) -5-methylpyrrolo [1,2-f] [1,2,4] triazin-4 (3H) -one

image 1

A mixture of 6-hydroxy-5-methylpyrrolo [1,2-f] [1,2,4] triazin-4 (3H) -one (1.5 g, 9.08 mmol, which was prepared according to the procedure set out in the provisional patent application with serial number 60/583459), Cs2CO3 (3.0 g,

9.08 mmol) and 1-bromo-3-chloropropane (894 µL, 9.08 mmol) in H2O / CH3CN / MeOH (10 mL: 5 mL: 2 mL) was heated at 50 ° C for 18 h. 1-Bromo-3-chloropropane (300 µL, 3.05 mmol) was added to the reaction and heating continued at 50 ° C for 4 h. The reaction mixture was allowed to cool to rt and 10 ml of H2O was added. A solid precipitate was collected by filtration, rinsed with 10 ml of H2O / MeOH and dried under vacuum, giving 1.45 g (66%) of 1A. T. ret. HPLC RP: 2.38 min and (M + H) +: 242.

10 1B: 4-Chloro-6- (3-chloropropoxy) -5-methylpyrrolo [1,2-f] [1,2,4] triazine

image 1

POCl3 (2 ml, 23 mmol) and diisopropylethylamine (1 ml, 5.79 mmol) were added to a solution of 1A in toluene (15 ml) and the reaction mixture was heated at 110 ° C for 4 h. The reaction mixture was allowed to cool to rt and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed successively with cold 0.5 N HCl, aq NaHCO3. cold and brine. The

The organic phase was dried over MgSO4, filtered and concentrated to give 1.4 g (93% yield) of 1B. T. ret. HPLC RP: 3.26 min.

1 C. 3-Chloro-4-fluoro-N- (5-nitropyrimidin-2-yl) benzamide

image 1

To 5-nitropyrimidin-2-amine (1.0 g, 7.1 mmol) in pyridine (10 ml) was added 3-chloro-4-fluorobenzoic acid (1.7 g, 9.7

20 mmol). The reaction mixture was heated at 100 ° C for 4 h and allowed to cool to rt. 15 ml of H2O was added. A precipitate was collected by filtration and purified by chromatography on silica gel, eluting with CH2Cl2 followed by 10% EtOAc / CH2Cl2, giving 1.16 g (55% yield) of 1C. T. ret. HPLC RP: 2.22 min and (M + H) +: 297.

1D. N- (5-aminopyrimidin-2-yl) -3-chloro-4-fluorobenzamide

image 1

At 1C (1.16 g, 3.92 mmol) in a mixture of 60 ml of EtOH and 10 ml of MeOH, 10% Pt / C (300 mg) was added. The reaction was stirred under 1 hydrogen atmosphere for 1.5 h, filtered and concentrated, giving 850 mg (80% yield) of 1D. T. ret. HPLC RP: 1.58 min and (M + H) +: 267.

1E. 3-Chloro-N- (5- (6- (3-chloropropoxy) -5-methylpyrrolo [1,2-f] [1,2,4] triazin-4-ylamino) pyrimidin-2-yl) -4- fluorobenzamide

image 1

To 1B (500 mg, 1.9 mmol) in DMA (10 ml) 1D (520 mg, 1.9 mmol) was added. The reaction was stirred at 40 ° C and then 4N HCl in dioxane (0.48 ml, 1.9 mmol) was added dropwise. The reaction was heated at 70 ° C for 2 h and allowed to cool to rt. To the reaction was added diethyl ether and the resulting solid was filtered and washed with ether, giving 858 mg (80% yield) of 1E as a dihydrochloride salt. T. ret. HPLC RP: 3.31 min.

1F. 3-Chloro-4-fluoro-N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1 , 2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide

image 1

To the compound 1E (80 mg, 0.14 mmol) in DMA (0.7 ml) were added successively piperidin-4-ylmethanol (71 mg,

10 0.61 mmol), diisopropylethylamine (70 µL, 0.4 mmol) and tetrabutylammonium iodide (13 mg, 0.035 mmol). The reaction mixture was heated at 60 ° C for 4, allowed to cool to rt and purified by prep HPLC. The concentration of the appropriate fractions was followed by the addition of water and sat. Potassium carbonate. at pH 12. A precipitate was collected by filtration, rinsed with water and dried, giving 31.4 mg (40% yield) of 1F. T. ret. HPLC RP: 2.40 min and (M + H) +: 569.

15 Examples 2-8

Examples 2 to 8, which are set forth in Table 1 indicated hereinbelow, were prepared according to the procedure that has been used in the preparation of Example 1.

Table 1

Example

 Compound T. ret. HPLC (min) (M + H) +

2

hydroxymethyl) pyrrolidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide 2.4  555

(cont.) (cont.)

Example

Compound T. ret. HPLC (min) (M + H) +

3

3-Chloro-4-fluoro-N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) morpholin-4-yl] propyl} oxy) -5 methylpyrrolo [2,1-f] [1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide 2.29  571

4

3-Chloro-4-fluoro-N- (5 - {[6 - ({3- [3- (hydroxymethyl) morpholin-4-yl] propyl} oxy) -5 methylpyrrolo [2,1-f] [1,2 , 4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide 2.31  571

5

N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} -oxy) -5-methylpyrrolo [2,1f] [1,2,4] triazin-4- il] amimo} pyrimidin-2-yl) benzamide 1.92  517

6

N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1f] [1,2,4] triazin -4-yl] amino} pyrimidin-2-yl) benzamide 1.94  503

7

3-fluoro-N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1f] [1,2,4] triazin -4-yl] amino} pyrimidin-2-yl) benzamide 2.05  538

Example

Compound T. ret. HPLC (min) (M + H) +

8

3-fluoro-N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1f] [1,2 , 4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide 2.05  521

Example 9

N- (3-fluorophenyl) -2 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2, 4] triazin-4-yl] amino} 1,3-thiazol-5-carboxamide

image5

9A. 6- (3-Chloropropoxy) -5-methylpyrrolo [1,2-f] [1,2,4] triazin-4 (3H) -one

image 1

A mixture of 6-hydroxy-5-methylpyrrolo [1,2-f] [1,2,4] triazin-4 (3H) -one (1.5 g, 9.08 mmol, which was prepared according to the procedure set out in the provisional patent application with serial number 60/583459), Cs2CO3 (3.0 g,

10.08 mmol) and 1-bromo-3-chloropropane (894 µL, 9.08 mmol) in H2O / CH3CN / MeOH (10 mL: 5 mL: 2 mL) was heated at 50 ° C for 18 h. 1-Bromo-3-chloropropane (300 µL, 3.05 mmol) was added to the reaction and heating continued at 50 ° C for 4 h. The reaction mixture was allowed to cool to rt and 10 ml of water was added. The solid precipitate was collected by filtration, rinsed with 10 ml of H2O / MeOH and dried under vacuum, giving 1.45 g (66%) of 9A. T. ret. HPLC RP: 2.38 min and (M + H) +: 242.

15 9B: 4-chloro-6- (3-chloropropoxy) -5-methylpyrrolo [1,2-f] [1,2,4] triazine

image 1

POCl3 (2 ml, 23 mmol) and diisopropylethylamine (1 ml, 5.79 mmol) were added to a solution of compound 9A in toluene (15 ml) and the reaction mixture was heated at 110 ° C for 4 h. The reaction mixture was allowed to cool to rt and concentrated in vacuo. The residue was dissolved in dichloromethane and washed successively with cold 0.5 N HCl, aq NaHCO3. cold and brine. The organic phase was dried over MgSO4, filtered and concentrated, giving 1.4 g (93% yield) of 9B. T. ret. HPLC RP: 3.26 min.

9C. Methyl 2- (6- (3-Chloropropoxy) -5-methylpyrrolo [1,2-f] [1,2,4] triazin-4-ylamino) thiazol-5-carboxylate

image 1

To a mixture of 9B (780 mg, 3 mmol) and methyl 2-aminothiazol-5-carboxylate (470 mg, 3 mmol) in DMF (7 ml) was added 60% NaH in mineral oil (340 mg, 8.5 mmol) at 0 ° C. The reaction mixture was stirred for 2 h at rt and 1 ml of HOAc was added. Subsequently, water was added, yielding 1.03 g of 9C (90% yield) as a yellow precipitate. The precipitate was subsequently collected by filtration, rinsed with water and dried. T. ret. HPLC RP: 3.74 min and (M + H) +: 382.

10 9D. 2- (6- (3-Chloropropoxy) -5-methylpyrolo [1,2-f] [1,2,4] triazin-4-ylamino) thiazole-5-carboxylic acid

image 1

A mixture of 9C (1.03 g, 2.71 mmol) and LiOH · H2O (300 mg, 7.14 mmol) in THF / MeOH / H2O (8 ml: 8 ml: 4 ml) was heated at 70 ° C for 2 h. The reaction mixture was concentrated and water was added followed by 2N HCl, yielding 856 mg of 9D (86% yield) as a yellow solid. The yellow solid was collected

15 subsequently by filtration. T. ret. HPLC RP: 3.35 min. and LC / MS (M + H) +: 368.

9E. N- (3-fluorophenyl) -2 - {[6 - ({3- [4-hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4 ] triazin-4-yl] amino} -1,3thiazol-5-carboxamide

image 1

To a solution of 9D (54 mg, 0.147 mmol), 3-fluoroaniline (21 mg, 0.189 mmol) and diisopropylethylamine (78 µL, 0.448

20 mmol) in DMA (0.8 ml) HATU (114 mg, 0.300 mmol) was added. After 4 h of stirring at 60 ° C, piperidin-4-ylmethanol (120 mg, 1.04 mmol) and tetrabutylammonium iodide (20 mg, 0.05 mmol) were added. The reaction mixture was heated at 100 ° C for 16 h and allowed to cool to rt. Water was added and the precipitated solid was collected by filtration. Purification by prep HPLC. provided 11.5 mg (12% yield) of the 9E TFA salt as a yellow solid. T. ret. HPLC RP: 2.95 min and LC / MS (M + H) +: 540.

25

Claims (20)

1. A compound of Formula (I) image 1 or pharmaceutically acceptable salts thereof, wherein: R1 is image2 R2 is H or an alkyl group containing from 1 to 4 carbon atoms; R3 and R4 are independently selected from H, an alkyl group containing from 1 to 4 carbon atoms, a substituted alkyl group containing from 1 to 4 carbon atoms substituted in any available position and substitutable with at least one alkyl, an alkyl substituted in any available position and substitutable with at least a substituent, including alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyloxy, alkanoyl, alkanoyl, alkanoyloxy, amino, aminoalkyl, aminoalkyl, alkylamino, alkylamino, hydroxyalkyl, amino, amide, amide, carbamate, carbamate, ureido, cyano, sulfonamide, sulfonamide, alkylsulfone, heterocycloalkyl, heterocycloalkyl, cycloalkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, -NRcc (C = O) Rdd, alkenyl, alkenyl, alkynyl, alkynyl, aryl, aryl, heteroaryl, heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle, alkylcarbonyl, heteroalkyl, heteroalkenyl, heteroalkenyl, heteroalkynyl, heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino, arylalkanoylamino, arylthio, arylalkylthio, arylsulfonyl, arylalkyl sulfonyl, alkylsulfonyl, arylcarbonylamino or alkylaminocarbonyl, -OR9 and NR10R11; n is 2, 3, 4, 5 or 6; R5 and R6 are independently selected from alkyl, and substituted alkyl, substituted in any available position and substitutable with at least one substituent, including hydrogen, alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyl, 25 alkanoyl, alkanoyloxy, amino, aminoalkyl, alkylamino, hydroxyalkyl, amide, carbamate, ureido, cyano, sulfonamide, alkylsulfone, heterocycloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, -NRcc (C = O) Rdd, alkenyl, alkynyl, aryl, heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle, alkylcarbonyl, heteroalkyl, heteroalkenyl, heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino, arylalkylamino, arylthio, arylalkylthio, arylsulfonyl, arylalkyl sulfonyl, alkylsulfonyl, arylcarbonylamino or alkylaminocarbonyl, or taken together with the N to which they are attached to form a 4, 5, 6, 7-membered heterocyclic ring or a substituted heterocyclic ring, substituted at any position of the available and replaceable ring, or in which the valence allows any condensed ring or attached thereto, with at least one aryl, hydrogen; alkyl, hydroxyalkyl, hydroxy (-OH), alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyarylthio, halogen, haloalkyl, haloalkoxy, aryloxy, arylalkyl, arylalkyl, alkanoyl, alkanoyloxy, alkanoylamino, amino, aminoalkyl, alkylamino, arylamino, arylamino , ureido, cyano, sulfonamide, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, carboxyalkyl, alkyloxycarbonyloxy, alkyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkyloxycarbonyloxycarbonyl, alkoxycarbonyloxycarbonyl, alkyloxycarbonyl 40 arylsulfonylamino, arylalkenyl, aryloxycarbonyl, arylthio, arylthioalkyl, arylalkylthio, sulfonic acid, heteroaryl, heteroarylthio, heteroaryloxy, heteroarylalkenyl, heteroarylheteroaryl, heteroarilalquilotio heteroaryloxy, alkylcarbonyl, aminocarbonylaryl, aminocarbonyl, arylazo, alkoxycarbonylalkoxy, arylcarbonyl, alkylaminocarbonyl, aminoalkylcarbonyl, arylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, arylsulfinyl, alkylsulfinyl, arylsulfinylalkyl and arylsulfonylaminocarbonyl, optionally containing said heterocyclic or heterocyclic substituted ring; R7 and R8 are independently selected from H, alkyl, and substituted alkyl, substituted in any available position and substitutable with at least one substituent, including hydrogen, alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyl, alkanoyl, alkanoyloxy, amino, aminoalkyl, alkylamino, hydroxyalkyl, amide, carbamate, ureido, cyano, sulfonamide, alkylsulfone, heterocycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, NRCC (C = O) Rdd, alkenyl, alkynyl, aryl, heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle, alkylcarbonyl, heteroalkyl, heteroalkenyl, arylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino , arylalkylthio, arylsulfonyl, arylalkyl sulfonyl, alkyl lsulfonyl, arylcarbonylamino or alkylaminocarbonyl; m is 0, 1, 2 or 3; L is OC (= O) NH-, -O-, -C (= O) NH-, -NHC (= O) - or -NHS (= O) 2-; R9 is H, alkyl, substituted alkyl, substituted in any available position and substitutable with at least one substituent, including hydrogen, alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyl, alkanoyl, alkanoyloxy, amino, aminoalkyl , alkylamino, hydroxyalkyl, amide, carbamate, ureido, cyano, sulphonamide, alkylsulfone, heterocycloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carbonyl, carbonyl C = O) Rdd, alkenyl, alkynyl, aryl, heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkyl, aryloxyalkyl, aryloxyaryl, heterocycle, alkylcarbonyl, heteroalkyl, heteroalkenyl, arylamino, arylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino, arylaminoylamino arylalkylthio, arylsulfonyl, arylalkyl sulfonyl, alkylsulfonyl, arylcarbonylamino, alkylaminocarbonyl, alkylamino; R10 and R11 are independently selected from H, I rent, and substituted alkyl, substituted in any available position and substitutable with at least one substituent, including hydrogen, alkyl, hydroxy (-OH), alkoxy, halogen, haloalkyl, haloalkoxy, oxo, aryloxy, arylalkyl, arylalkyl, alkanoyl, alkanoyloxy, amino, aminoalkyl, alkylamino, hydroxyalkyl, amide, carbamate, ureido, cyano, sulfonamide, alkylsulfone, heterocycloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thio-alkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, -NR c C (C = O) Rdd, alkenyl, alkynyl, aryl, heteroaryl, heteroaryloxy, arylheteroaryl, arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, heterocycle, alkylcarbonyl, heteroalkyl, heteroalkenyl, heteroalkynyl, arylamino, arylalkylamino, alkanoylamino, arylamino, arilalcanoilamino , arylthio, arylalkylthio, arylsulfonyl, arylalkyl sulfonyl, alkylsulfoni lo, arylcarbonylamino or alkylaminocarbonyl; Y Ar1 is aryl, substituted aryl, substituted with at least one substituent in any position of the available and substitutable ring, or in which the valence allows any ring condensed or attached thereto, including hydrogen; alkyl, substituted alkyl, hydroxy (-OH), alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyarylthio, halogen, haloalkyl, haloalkoxy, aryloxy, arylalkyl, arylalkyl, alkanoylo, alkanoyloxy, alkanoylamino, amino, aminoalkyl, alkylamino, aminocarbonylalkyl, arylamino, arylamino, arylamino , ureido, cyano, sulfonamide, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, carboxyalkyl, alkylaryloxycarbonylalkyl, alkyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonyloxycarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkyl , arylalkenyl, aryloxycarbonyl, arylthio, arylthioalkyl, arylalkylthio, sulfonic acid, heteroaryl, heteroarylthio, heteroaryloxy, heteroarylalkenyl, heteroarylheteroaryl, heteroarilalquilotio heteroaryloxy, alkylcarbonyl, aminocarbonylaryl, aminocarbonyl, arylazo, alkoxycarbonylalkoxy, arylcarbonyl, alquilaminocarbon yl, aminoalkylcarbonyl, arylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, arylsulfinyl, alkylsulfinyl, arylsulfinyl alkyl and arylsulfonylaminocarbonyl, heteroaryl, substituted heteroaryl, in which it is substituted in any position of the available and replaceable ring, or in which the valence allows any ring condensed or attached thereto, with at least one aryl, hydrogen, alkyl, hydroxy (-OH), alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyarylthio, halogen, haloalkyl, haloalkoxy, aryloxy, arylalkyl, arylalkyl, alkanoyl, alkanoyloxy, alkanoylamino, amino, aminoalkyl, alkylamino, aminocarbonyl, arylamino, arylalkylamino, arylalkoxy, ureido, cyano, sulfonamide, heterocycloalkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkoxy, nitro, thio, thioalkyl, alkylthio, alkylsulfonyl, alkylsulfinyl, carboxy, carboxy alkyl, carboxy alkoxy, alkoxycarbonyl, alkylcarbonyloxy, carbamoyl, alkenyl, alkynyl, 5 aryl, arylsulfonylamino, arylalkenyl, aryloxycarbonyl, arylthio, arylthioalkyl, arylalkylthio, sulfonic acid, heteroaryl, heteroarylthio, heteroaryloxy, heteroarylalkenyl, heteroarylheteroaryl, heteroarylalkylthio, heteroaryloxyalkyl, alkylcarbonyl, aminocarbonylaryl, aminocarbonylalkyl, arylazo, alkoxycarbonylalkoxy, arylcarbonyl, alkylaminocarbonyl, aminoalkylcarbonyl, arylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfonyl, heteroarylsulfonyl, heterocycloalkylsulfonyl, arylsulfinyl, alkylsulfinyl, arylsulfinylalkyl 10 and arylsulfonylaminocarbonyl. 2. A compound according to claim 1, wherein R5 and R6 are taken together with the N to which they are attached to form a 4, 5, 6 or 7 membered heterocyclic ring or substituted heterocyclic containing at least two heteroatoms selected from O, S and N; and wherein the substituted heterocyclic is substituted as defined in claim 1. 3. A compound according to claim 1, wherein R5 and R6 are taken together with the N to which they are attached to form a 5- or 6-membered heterocyclic ring or substituted heterocyclic containing at least two heteroatoms selected from O and N; and wherein the substituted heterocyclic is substituted as defined in claim 1.

Four.

 A compound according to claim 3, wherein R5 and R6 are taken together with the N to which they are attached to form a morpholinyl.

5.

 A compound according to claim 1, wherein R2 is H or an alkyl group containing from 1 to 4 carbon atoms.

6.

 A compound according to claim 5, wherein R2 is methyl, ethyl or isopropyl.

7.

 A compound according to claim 1, wherein R3, R4, R7 and R8 are independently selected from H and an alkyl group containing from 1 to 4 carbon atoms.

8. A compound according to claim 7, wherein each of R3, R4, R7 and R8 is independently H. 9. A compound according to claim 1, wherein R5 and R6 are taken together with the N to which they are attached to form a 5- or 6-membered heterocyclic ring or substituted heterocyclic; 30 and wherein the substituted heterocyclic is substituted as defined in claim 1.

10.

 A compound according to claim 1, wherein R5 and R6 are taken together with the N to which they are attached to form a 5- or 6-membered substituted heterocyclic ring, substituted with at least one substituent selected from alkyl and hydroxyalkyl.

eleven.

 A compound according to claim 1, wherein L is -C (= O) NH- or -NHC (= O) -.

12. A compound according to claim 1, wherein Ar1 is aryl or substituted aryl; and wherein the substituted aryl is substituted as defined in claim 1. 13. A compound according to claim 12, wherein Ar1 is a substituted aryl, substituted with at least one substituent selected from H, halogen, cyano, an alkyl group containing 1 to 4 carbon atoms, and OR12, wherein R12 is an alkyl group containing 1 to 4 carbon atoms. A compound according to claim 1, wherein n is 3. 15. A compound according to claim 1, wherein Ar1 is image 1 wherein R13 and R14 are independently selected from H, halogen and methyl.

16.

 A compound according to claim 1, wherein m is 0.

17.

 A compound according to claim 1, which has the formula

image 1 or pharmaceutically acceptable salts thereof, wherein R2, R3, R4, R5, R6, R7, R8, R9, m, n, L and Ar1 are as defined hereinbefore. 18. A compound according to claim 1, having the formula image 1 or pharmaceutically acceptable salts thereof, wherein R2, R3, R4, R5, R6, n, L and Ar1 are as defined hereinbefore. 10 19. A pharmaceutical composition comprising a) at least one compound according to claim 1; b) optionally at least one pharmaceutically acceptable carrier and / or diluent; Y c) optionally at least one different anti-cancer agent. 20. A compound according to any one of claims 1 to 18 for use in a method for treating at least one kinase associated condition.

twenty-one.

 A compound according to claim 20, wherein said kinase associated condition is a proliferative disease.

22

 A compound according to claim 20 or 21, wherein said method comprises the steps of administering to a patient in need thereof a therapeutically effective amount of at least one compound.

20 according to any of claims 1 to 18; optionally administer at least one different anti-cancer agent simultaneously or sequentially, and optionally simultaneously or sequentially administer at least one different anti-cancer treatment. 23. A compound according to any one of claims 20 to 22, wherein the kinase associated condition is selected from cancer, bone disease, inflammatory disease, disease 25 autoimmune, metabolic disease, viral disease, fungal disease, neurological and degenerative disorders, Alzheimer's disease, allergies and asthma, cardiovascular disease and hormone-related disease. 24. A compound according to claim 1 selected from (i) 3-Chloro-4-fluoro-N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f ] [1,2,4] triazin-4-il 30 amino} pyrimidin-2-yl) benzamide; 3-Chloro-4-fluoro-N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1- f] [1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; 3-Chloro-4-fluoro-N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) morpholin-4-yl] propyl} oxy) -5-methylpyrrolo [2,1- f] [1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; 3-Chloro-4-fluoro-N- (5 - {[6 - ({3- [3- (hydroxymethyl) morpholin-4-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [ 1,2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4] triazin-4 -yl] amino} pyrimidin-2yl) benzamide; N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2,4 ] triazin-4-yl] amino} pyrimidin2-yl) benzamide; 5 3-fluoro-N- (5 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2, 4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; 3-fluoro-N- (5 - {[6 - ({3 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1 , 2,4] triazin-4-yl] amino} pyrimidin-2-yl) benzamide; and N- (3-fluorophenyl) -2 - {[6 - ({3- [4- (hydroxymethyl) piperidin-1-yl] propyl} oxy) -5-methylpyrrolo [2,1-f] [1,2 , 4] triazin-4-yl] amino} 10,3-thiazol-5-carboxamide; Y (ii) a pharmaceutically acceptable salt thereof.