ES2362421T3 - QUINASA AZAINDOL INHIBITORS. - Google Patents

Abstract

A compound of formula (I): ~ ** Formula ** in which: Z is selected from O or S, and R41 is absent; X and Y are independently selected from O, OCO, S, SO, SO2, CO, CO2, NR10, NR11CO, NR12CONR13, NR14CO2, NR15SO2, NR16SO2NR17, SO2NR18, CONR19, halogen, nitro, cyano, or X or Y are absent; R1 is hydrogen, CH3, OH, OCH3, SH, SCH3, OCOR21, SOR22, SO2R3, SO2NR24R24, CO2R26, CONR27R28, NH2 NR29SO2NR30R31, NR32SO2R33, NR34COR35, NR36CO2R37, halogen, nitro or cyano; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl, substituted alkynyl, aryl, substituted aryl, heterocycle, substituted heterocycle, aralkyl, substituted aralkyl, heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; with the proviso that when X is halo, nitro or cyano, R2 is absent, and when Y is halo, nitro or cyano, R3 is absent; R6 is H, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, NR7R8, OR9 or halogen; R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R21, R24, R25, R26, R27, R28, R29, R30, R31, R32, R34, R35, R36, R38, R39 and R40 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocycle or substituted heterocycle; R22, R23, R33 and R37 are independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocycle or substituted heterocycle; R42 is (R43) n in which n is equal to 0, 1 or 2 and each R43 is independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl; and R44 is methyl or hydrogen, with the additional condition that a. R2 cannot be hydrogen if X is SO, SO2, NR13CO2 or NR14SO2; and b. R3 cannot be hydrogen if Y is SO, SO2, NR13CO2 or NR14SO2; or one of its enantiomers, diastereomers, or one of its pharmaceutically acceptable salts or solvates, in which the term "substituted alkyl" refers to an alkyl group substituted by one to four substituents selected from halo, hydroxyl, alkoxy, oxo, alkanoyl , aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, substituted thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl selected from CONH (alkyl), CONH (aryl), CONH (aralkyl) or cases in which there are two substituents in the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles, and in which when the substituent is also substituted, it will be with alkyl, alkoxy, aryl or aralkyl; the term "substituted aryl" refers to an aryl group substituted by one to four substituents selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, alralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxyl, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthio, arylthiono, arylsulfonylamine, sulfonic acid, alkylsulfonyl, sulfonamido and aryloxy, and in which the substituent may also be substituted by hydroxyl, alkyl, alkoxy aryl, substituted aryl, substituted alkyl or aralkyl; the term "substituted alkenyl" refers to an alkenyl group substituted by one to two substituents selected from halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthio, alkylsulfonyl, sulfonamido, nitro , cyano, carboxyl, carbamyl, substituted carbamyl, guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl and pyrimidyl; The term "substituted alkynyl" refers to an alkynyl group substituted by a substituent selected from halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthio, alkylsulfonyl, sulfonamido, nitro, cyano, carboxyl, carbamyl, substituted carbamyl, guanidino and heterocycle; the term "substituted heterocycle" refers to a saturated or unsaturated aromatic or non-aromatic cyclic group selected from a system of monocyclic rings of 4 to 7 members, bicyclics of 7 to 11 members or tricyclics of 10 to 15 members, which has at least a heteroatom in at least one ring containing a carbon atom, in which each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, in the that the nitrogen and sulfur heteroatoms may also be optionally oxidized and the nitrogen heteroatoms may also be optionally quaternized, wherein the substituents are selected from one or more alkyl or aralkyl groups as described above, or between one or more groups described formerly as alkyl substituents.

Description

The present invention relates to compounds that inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1, thereby making them useful as anti-cancer agents. The compounds are also useful in the treatment of diseases, other than cancer, that are associated with signal transduction pathways that function through growth factors and anti-angiogenesis receptors such as VEGFR-2.

Normal angiogenesis plays an important role in a variety of processes that include embryonic development, wound healing, obesity and various components of female reproductive function. Pathological or unwanted angiogenesis has been linked to pathological conditions, including diabetic retinopathy, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma, asthma, cancer and metastatic disease (Fan et al., 1995, Trend Pharmacol.-Sci. 16: 57–66; Folkman, 1995, Nature Medicine 1: 27–31). It is believed that the alteration of vascular permeability plays a role in both normal and pathological physiological processes (Cullinan – Bove et al, 1993, Endocrinology 133: 829–837; Senger et al, 1993 Cancer and Metastasis Reviews, 12: 303– 324).

The tyrosine kinase receptors (RTK) are important in the transmission of biochemical signals through the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand binding domain connected through a segment of the plasma membrane to an intracellular tyrosine kinase domain. Binding of the ligand to the receptor causes the stimulation of the tyrosine kinase activity associated with the receptor that leads to phosphorylation of the tyrosine residues of both the receptor and other intracellular proteins, leading to a variety of cellular responses. To date, at least nineteen different subfamilies of RTK have been identified, defined by the homology of the amino acid sequences. One of these subfamilies is currently composed of the fms tyrosine kinase receptor, Flt or Flt1 (VEGFR-1), the receptor that contains the kinase insert domain, KDR (also called Flk-1 or VEGFR-2) or another receptor fms tyrosine kinase, Flt4 (VEGFR-3). It has been observed that two of these related RTKs, Flt and KDR, bind to vascular endothelial growth factor (VEGF) with high affinity (De Vries et al, 1992, Science 255: 989-991; Terman et al, 1992 , Biochem. Biophys. Res. Comm. 1992,187: 1579-1586). VEGF binding to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation state of cellular proteins and calcium fluxes. It has been identified that VEGF, together with the acid and basic fibroblast growth factor (aFGF and bFGF), have a growth promoting activity of endothelial cells in vitro. It should be noted that aFGF and bFGF bind and activate the tyrosine kinase receptor called FGFR-1. By virtue of the restricted expression of its receptors, the growth factor activity of VEGF, unlike that of FGF, is relatively specific for endothelial cells. Recent evidence indicates that VEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, "Breast Cancer Research and Treatment", 36: 139–155) and vascular permeability (Connolly et al., 1989, J. Biol. Chem. 264: 20017–20024).

In adults, endothelial cells have a low rate of proliferation, except in cases of tissue regeneration, such as wound healing and the female reproductive cycle, as well as adipogenesis. However, in pathological conditions such as cancer, hereditary vascular diseases, endometriosis, psoriasis, arthritis, retinopathies and atherosclerosis, endothelial cells actively proliferate and organize themselves in the vessels. After exposure to angiogenic stimuli with growth factors, such as VEGF and bFGF, endothelial cells re-enter the cell cycle, proliferate, migrate and organize into a three-dimensional network. Currently, there is a generalized assumption that the ability of tumors to expand and produce metastases depends on the formation of this vascular network.

The union of VEGF or bFGF with its corresponding receptor produces dimerization, autophosphorylation in tyrosine residues and enzymatic activation. These phosphotyrosine residues serve as "coupling" sites for downstream specific signaling molecules and enzymatic activation results in EC activation. Disruption of these routes should inhibit the activation of endothelial cells. The disruption of the FGFR-1 pathway should also affect the proliferation of tumor cells, as this kinase is activated in many types of tumors, in addition to proliferating endothelial cells. Finally, there is recent evidence that also suggests that disruption of VEGF signaling inhibits the emigration of endothelial cells, a fundamental process in the formation of the vascular network.

Overexpression and activation of VEGFR-2 and FGFR-1 in the vasculature associated with tumors have suggested a role for these molecules in tumor angiogenesis. Angiogenesis and subsequent tumor growth is inhibited by antibodies directed against the VEGF ligand and VEGF receptors, and by truncated soluble VEGFR-2 (which lack a transmembrane sequence and a cytoplasmic kinase domain). Dominant mutations introduced either in VEGFR-2 or in FGFR-1 that result in a loss of enzyme activity inhibit tumor growth in vivo. The antisense direction of these receptors or their related ligands also inhibits angiogenesis and tumor growth. Recent tests have elucidated, in part, the temporal requirements of these receptors in tumor growth. It seems that VEGF signaling is critical in early tumor growth and that bFGF is more important at a later time linked to tumor expansion.

In WO00 / 71129, compounds that inhibit VEGF have been disclosed. Other documents citing compounds close to the present are US2003 / 0069244 and Tetrahedron 1996, 52 (8) 3037-3048.

According to the present invention, the compounds of formula I:

image 1

its enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates, inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2. In formula I and throughout memory, the above symbols are defined as explained below:

Z is selected from O or S, with the proviso that when Z is O or S, R41 is absent;

X and Y are independently selected from O, OCO, S, SO, SO2, CO, CO2, NR10, NR11CO, NR12CONR13, NR14CO2, NR15SO2, NR16SO2NR17, SO2NR18, CONR19, halogen, nitro, cyano, or X or Y are absent;

R1 is hydrogen, CH3, OH, OCH3, SH, SCH3, OCOR21, SOR22, SO2R23, SO2NR24R25, CO2R26, CONR27R28, NH2NR29SO2NR30R31 NR32SO2R33 NR34COR35, NR36CO2R37, NR38CONR39R40, halogen, nitro or c;

R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocycle, substituted heterocycle, aralkyl, substituted aralkyl, heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; with the proviso that when X is halo, nitro or cyano, R2 is absent, and when Y is halo, nitro or cyano, R3 is absent;

R6 is H, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, NR7R8, OR9 or halogen;

R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R21, R24, R25, R26, R27, R28, R29, R30, R31, R32, R34, R35, R36, R38, R39 and R40 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocycle or substituted heterocycle;

R22, R23, R33 and R37 are independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocycle or substituted heterocycle;

R42

is:

image 1

(R43) n in which n is equal to 0, 1 or 2 and each R43 is independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl; Y R44 is methyl or hydrogen, with the additional condition that:

5

10

fifteen

twenty

25

30

35

40

Four. Five

to.

R2 may not be hydrogen if X is SO, SO2, NR13CO2 or NR14SO2; Y

b.

R3 may not be hydrogen if Y is SO, SO2, NR13CO2 or NR14SO2.

In a preferred embodiment, R1 is hydrogen or methyl; R6 is hydrogen; R3 is lower alkyl; and Z is oxygen or nitrogen.

In another preferred embodiment, R1 is hydrogen; R3 is lower alkyl; And it is absent; X is oxygen or nitrogen; R43 is fluorine or hydrogen; and R44 is hydrogen or methyl.

In yet another preferred embodiment, X is oxygen; R2 is a substituted alkyl and R43 is fluorine.

Preferred compounds of the invention include:

4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methyl – pyrrolo [2,1 – f] [1,2,4] triazin – 6 – ol,

(R) –1– [4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methylpyrrolo [2,1 – f] [1,2,4] triazin– 6 – iloxi] –propan – 2 – ol,

(S) –1– [4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methyl – pyrrolo [2,1 – f] [1,2,4] triazin – 6 – yloxy] –propan – 2 – ol,

(R) –1– [4– (4 – Fluoro – 2 – methyl – 1 H –pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methyl – pyrrolo [2,1 – f] [1, 2,4] triazin – 6 – yloxy] –propan – 2– ol,

(R) –2– [4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methylpyrrolo [2,1 – f] [1,2,4] triazin– 6-yloxy] –1-methylethylamine,

(R) –2– [4– (4 – Fluoro – 2 – methyl – 1 H –pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methylpyrrolo [2,1 – f] [1,2, 4] triazin – 6-yloxy] –1– methylethylamine,

2– [4– (4 – Fluoro-1H – pyrrolo [2,3-b] pyridin-5-yloxy) –5-methylpyrrolo [2,1-f] [1,2,4] triazin-6-yloxy] –Ethylamine,

(4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5-yl) - [5 – isopropyl – 6– (3-methyl– [1,2,4] oxadiazol – 5-yl) –pyrrolo [ 2,1 – f] [1,2,4] triazin– 4-yl] –amine,

(4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5-yl) - [5 – isopropyl – 6– (5-methyl– [1,3,4] oxadiazol – 2-yl) –pyrrolo [ 2,1 – f] [1,2,4] triazin– 4-yl] –amine,

(4-Fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) - [5-isopropyl-6– (5-methyl- [1,3,4] oxadiazol-2-yl ) –Pirrolo [2,1– f] [1,2,4] triazin – 4-yl] –amine and

[5 – Isopropyl – 6– (5 – methyl– [1,3,4] oxadiazol – 2-yl) –pyrrolo [2,1 – f] [1,2,4] triazin – 4-yl] - (2 –Methyl – 1H – pyrrolo [2,3 – b] pyridin – 5– yl) –amine.

The invention also provides a pharmaceutical composition comprising a compound of formula I or II and a pharmaceutically acceptable carrier.

The invention also provides a pharmaceutical composition comprising a compound of formula I or II in combination with a pharmaceutically acceptable carrier and an anti-carcinogenic or cytotoxic agent. In a preferred embodiment, said anti-carcinogenic or cytotoxic agent is selected from the group consisting of linomide; αvβ3 integrin function inhibitors; angioestatin; razoxane; tamoxifen; toremifene; raloxifene; droloxifene; yodoxifene; megestrol acetate; anastrozole; letrozole; borazol; exemestane; flutamide; nilutamide; bicalutamide; cyproterone acetate; goserelin acetate; leuprolide; finasteride; metalloproteinase inhibitors; inhibitors of the urokinase type plasminogen activator receptor function; antibodies against growth factors; antibodies against growth factor receptors, such as Avastin® (bevacizumab) and Erbitux® (cetuximab); tyrosine kinase inhibitors; serine / threonine kinase inhibitors; methotrexate; 5– fluorouracil; purine; adenosine analogues, cytosine arabinoside; doxorubicin; daunorubicin; epirubicin; idarubicin; mitomycin-C; dactinomycin; mitramycin; cisplatin; carboplatin; nitrogen mustard; melphalan; chlorambucil; busulfan; cyclophosphamide; ifosfamide; nitrosoureas; thiotepa; vincristine; Taxol® (paclitaxel); Taxotere® (docetaxel); epothilone analogs; discodermolide analogs; eleuterobin analogs; etoposide; teniposide; amsacrine; topotecan; flavopyridoles; biological response modifiers and proteasome inhibitors, such as Velcade® (bortezomib).

A method is also disclosed for inhibiting the protein kinase activity of growth factor receptors comprising administering to a mammalian species in need thereof a therapeutically effective protein kinase inhibitor amount of a compound of formula I.

In addition, a method for inhibiting the tyrosine kinase activity of at least one growth factor receptor is disclosed, such as that comprising administering to a mammalian species in need thereof a therapeutically effective amount of a compound of formula I or II . In a preferred embodiment, said growth factor receptor is selected from the group consisting of VEGFR-2 and FGFR-1.

Finally, a method for treating a proliferative disease is disclosed, comprising administering to a mammalian species in need thereof a therapeutically effective amount of a compound of formula

I. In a preferred embodiment, the proliferative disease is cancer.

The definitions of terms and expressions that can be used herein are presented below. The initial definition provided for a group, a term or an expression herein applies to that group, term or expression throughout this report individually or as part of another group, unless otherwise indicated.

The term "alkyl" refers to unsubstituted straight or branched chain hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The term "lower alkyl" refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.

The term "substituted alkyl" refers to an alkyl group substituted by, for example, one to four substituents, such as halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, disubstituted amines wherein the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, substituted thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SO2NH2, substituted sulfonamido, nitro, cyano , carboxyl, carbamyl, e.g., CONH2, substituted carbamyl, e.g., CONH (alkyl), CONH (aryl), CONH (aralkyl) or cases in which there are two nitrogen substituents selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. When indicated above, when the substituent is also substituted, it will be with alkyl, alkoxy, aryl or aralkyl.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring part, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.

The term "aralkyl" refers to an aryl group directly linked by an alkyl group, such as benzyl.

The term "substituted aryl" refers to an aryl group substituted by, for example, one to four substituents such as alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, alralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxyl, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthio, arylthiono, arylsulfonylamine, sulfonic acid, alkylsulfonyl, sulfonamido, aryloxy and the like. The substituent may also be substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.

The term "heteroaryl" refers to an optionally substituted aromatic group, for example, which is a 4 to 7 membered monocyclic ring system, 7 to 11 membered bicyclic or 10 to 15 membered tricyclic ring, having at least one heteroatom and at least one ring containing a carbon atom, for example, pyridine, tetrazole, indazole, indole.

The term "alkenyl" refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably, 2 to 15 carbon atoms and, most preferably, 2 to 8 carbon atoms, with one to Four double bonds.

The term "substituted alkenyl" refers to an alkenyl group substituted by, for example, one to two substituents, such as halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthio, alkylsulfonyl , sulfonamido, nitro, cyano, carboxyl, carbamyl, substituted carbamyl, guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.

The term "alkynyl" refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably, 2 to 15 carbon atoms and, most preferably, 2 to 8 carbon atoms, with one to Four triple bonds.

The term "substituted alkynyl" refers to an alkynyl group substituted by, for example, a substituent such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthio, alkylsulfonyl, sulfonamido , nitro, cyano, carboxyl, carbamyl, substituted carbamyl, guanidino and heterocycle, eg, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.

The term "cycloalkyl" refers to optionally substituted saturated cyclic hydrocarbon ring systems, preferably, containing 1 to 3 rings and 3 to 7 carbons per ring which may also be fused with an unsaturated C3-C7 carbocyclic ring. Examples of groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl and adamantyl. Examples of substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.

The terms "heterocycle" and "heterocyclic" refer to a fully saturated or unsaturated and optionally substituted cyclic aromatic or non-aromatic group that is, for example, a 4 to 7 membered, bicyclic 7 to 11 membered monocyclic ring system or 10 to 15 member tricyclics, which has at least one heteroatom in at least one ring containing a carbon atom. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, the optionally oxidized nitrogen and sulfur heteroatoms and optionally quaternized nitrogen heteroatoms being also possible. The heterocyclic group may be attached to any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl , piperacinyl, 2– oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinylmorphinophthalophonylophonylaphonylophonylophonylophonylaphonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonylophonyl pipeline of thiamorpholinyl, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thienyl, thiranyl, triazinyl and triazolyl, and the like.

Examples of bicyclic heterocyclic groups include 2,3-dihydro-2-oxo-1H-indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopinyl, benzopyryloyl, benzopinyl cycloyl , 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, benzimidazolyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, indolyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofu Ryl, thienopyridyl, thienothienyl and the like.

Examples of substituents include one or more alkyl or aralkyl groups as described above, or one

or more groups described above as alkyl substituents. Smaller heterocycles, such as epoxides and aziridines, are also included.

The term "heteroatoms" will include oxygen, sulfur and nitrogen.

The compounds of formula I can form salts that also belong to the scope of the present invention. Pharmaceutically acceptable salts (ie, physiologically acceptable non-toxic) are preferred, although other salts are also useful, eg, in the isolation or purification of compounds of the present invention.

The compounds of formula I can form salts with alkali metals, such as sodium, potassium and lithium; with alkaline earth metals, such as calcium and magnesium; with organic bases, such as dicyclohexylamine, tributylamine, pyridine and amino acids, such as arginine, lysine and the like. Such salts can be formed by those skilled in the art.

The compounds for formula I can form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various other compounds (eg, nitrates, phosphates , borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts can be formed by those skilled in the art.

In addition, zwitterions can be formed ("internal salts").

All stereoisomers of the compounds of the present invention, whether mixed or in pure or substantially pure form, are contemplated. The definition of the compounds according to the invention encompasses all possible stereoisomers and mixtures thereof. It particularly encompasses racemic forms and isolated optical isomers that have the specified activity. The racemic forms can be resolved by physical procedures, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates obtained by conventional procedures, such as, for example, salt formation with an optically active acid followed by crystallization.

The compounds of formula I may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula I) is a prodrug of the compounds of the invention.

There are various forms of prodrugs that are 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. 42, p. 309–396, edited by K. Widder, et al. (Acamedic 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);

c) H. Bundgaard, "Advanced Drug Delivery Reviews", 8, 1–38 (1992);

It should also be understood that the solvates (eg, hydrates) of the compounds of formula I also belong to the scope of the present invention. Dissolution procedures are generally known in the art.

Use and utility

The present invention is based on the discovery that certain pyrrolotriazines are inhibitors of protein kinases. More specifically, they inhibit the effects of VEGF, a valuable property in the treatment of pathological conditions associated with angiogenesis and / or increased vascular permeability, such as cancer. The invention relates to a pharmaceutical composition of the compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier in the treatment of a hyperproliferative disorder in a mammal. Specifically, said pharmaceutical composition is expected to inhibit the growth of those primary or recurrent solid tumors that are associated with VEGF, especially, those tumors that depend significantly on VEGF for growth and spread, including, for example, bladder cancers, squamous cells, head, colorectal, esophageal, gynecological (such as ovarian), pancreas, breast, prostate, lung, vulva, skin, brain, genitourinary tract, lymphatic system (such as thyroid), stomach, larynx and lung. In another embodiment, the compounds of the present invention are also useful in the treatment of non-carcinogenic disorders, such as diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis, obesity, Kaposi's sarcoma, hemangioma, acute and chronic nephropathies (including proliferative glomerulonephritis and diabetes-induced renal disease), atheroma, arterial restenosis, autoimmune diseases, acute inflammation and eye diseases with proliferation of the retinal vessels, diabetic retinopathy of prematurity and macular degeneration. The compounds of the invention are also useful in the prevention of blast implantation in a mammal, the treatment of atherosclerosis, eczema, sclerodemia, hemangioma. The compounds of the present invention possess good activity against the VEGF tyrosine kinase receptor, while they possess some activity against other tyrosine kinases.

Therefore, according to another aspect of the invention, the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided in the manufacture of a medicament for use in the production of an antiangiogenic effect and / or a reducing effect of vascular permeability in a mammalian animal, such as a human being.

A method for producing an antiangiogenic effect and / or a reducing effect of vascular permeability in a mammalian animal, such as a human being, is revealed, in need of such treatment comprising administering to said animal an effective amount of a compound of formula I or one of its pharmaceutically acceptable salts as defined hereinbefore.

The compounds described herein also inhibit other tyrosine kinase receptors, including HER1 and HER2, and are therefore useful in the treatment of proliferative disorders, such as psoariasis and cancer. It has been observed that the HER1 kinase receptor is expressed and activated in many solid tumors including non-small cell lung cancer, colorectal cancer and breast cancer. Similarly, it has been observed that the HER2 receptor kinase is overexpressed in breast, ovarian, lung and gastric cancer. Monoclonal antibodies that infra-regulate the abundance of the HER2 receptor or inhibit the signaling produced by the HER1 receptor have demonstrated antitumor efficacy in preclinical and clinical studies. Therefore, HER1 and HER2 kinase inhibitors are expected to be effective in treating tumors that depend on signaling from either of the two receptors. The ability of these compounds to inhibit HER1 is further added to their use as antiangiogenic agents. See the following documents and references cited in such reports: Cobleigh, MA, Vogel, CL, Tripathy, D., Robert, NJ, Scholl, S., Fehrenbacher, L., Wolter, JM, Paton, V., Shak, S ., Lieberman, G. and Slamon, DJ, "Multinational study of the efficacy and safety of humanized anti – HER2 monoclonal antibody in women who have HER2 – overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease", J. of Clin . Oncol. 17 (9), p. 2639-2848 (1999); Baselga, J., Pfister, D., Cooper, MR, Cohen, R., Burtness, B., Bos, M., D'Andrea, G., Seidman, A., Norton, L., Gunnett, K. , Falcey, J., Anderson, V., Waksal, H. and Mendelsohn, J., "Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin", J. Clin. Oncol. 18 (4), p. 904-914 (2000).

The antiproliferative, antiangiogenic and / or reducing vascular permeability treatment defined hereinbefore may be applied as a single therapy or may involve, in addition to a compound of the invention, one or more other substances and / or treatments. Such joint treatment can be performed by simultaneous, consecutive or separate administration of the individual components of the treatment. The compounds of the present invention may also be useful in combination with anti-cancer and cytotoxic agents and treatments, including radiation. If formulated as a fixed dose, such combination products employ the compounds of the present invention in the dose range described below and the other pharmaceutically active agent in their authorized dose range. The compounds of formula I may be used consecutively with anticancer or cytotoxic agents and treatment, including radiation, when a combination formulation is not appropriate.

In the field of medical oncology, normal practice is to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology, the or other components of such joint treatment, in addition to the antiproliferative, antiangiogenic and / or vascular permeability reduction treatment defined hereinbefore, may be: surgery, radiotherapy or chemotherapy. Such chemotherapy can address three main categories of therapeutic agent:

(i)

antiangiogenic agents that work by mechanisms other than those defined hereinbefore (eg, linomide, inhibitors of the function of integrin αvβ3, angioestatin, razoxane);

(ii)

cytostatic agents, such as antiestrogens (for example, tamoxifen, toremifene, raloxifene, droloxyphene, iodoxifene), progestogens (for example, megestrol acetate), aromatase inhibitors (for example, anastrozole, letrozole, borazol, exemestane), antihormones, antiprogestogens , antiandrogens (e.g., flutamide, nilutamide, bicalutamide, cyproterone acetate), agonists and LHRH antagonists (e.g., goserelin acetate, leuprolide), testosterone 5α-dihydroreductase inhibitors (e.g., finasteride), farnesyltransferase inhibitors , anti-invasive agents (for example, metalloproteinase inhibitors such as marimastat and inhibitors of urokinase-like plasminogen activator receptor function) and inhibitors of growth factor function (such growth factors include, for example, EGF, FGF, platelet derived growth factor and hepatocyte growth factor, and including such inhibited other growth factor antibodies, growth factor receptor antibodies, such as Avastin® (bevacizumab) and Erbitux® (cetuximab); tyrosine kinase inhibitors and serine / threonine kinase inhibitors); Y

(iii) antiproliferative / antineoplastic drugs and combinations thereof, such as those used in medical oncology, such as antimetabolites (for example, antifolates, such as methotrexate, fluoropyrimidines type 5 - fluorouracil, purine and adenosine analogues, cytosine arabinoside ); intercalating antitumor antibiotics (for example, anthracyclines such as doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mitramycin); platinum derivatives (for example, cisplatin, carboplatin); alkylating agents (for example, nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa; antimitotic agents (for example, vinca alkaloids, such as vincristine and taxoids such as Taxol® (paclitaxel), Taxotere® ( docetaxel) and more recent microtubular agents, such as epothilone analogs, discodermolide analogs and eleuterobin analogs); topoisomerase inhibitors (e.g. epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan); cell cycle inhibitors (by example, flavopyridols); biological response modifiers and proteasome inhibitors, such as Velcade® (bortezomib).

As stated above, the compounds of formula I of the present invention are of interest because of their antiangiogenic and / or vascular permeability reducing effects. Such compounds of the invention are expected to be useful in a wide selection of pathological conditions, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, obesity, acute and chronic kidney disease, atheroma, arterial restenosis, autoimmune diseases, inflammation acute and eye diseases associated with the proliferation of retinal vessels, such as diabetic retinopathy.

More specifically, the compounds of formula I are useful in the treatment of a variety of cancers, including (but not limited to) the following:

-carcinoma, including bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, including carcinoma of squamous cells;

5

10

fifteen

twenty

25

30

35

40

Four. Five

Hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy lymphoma and Burkett lymphoma.

- hematopoietic myeloid lineage tumors, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;

-Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;

-tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schawanomas; Y

-other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenodermia pigmentosa, keratoctantoma, toroid follicular cancer and Kaposi's sarcoma.

Due to the key role of kinases in the regulation of cell proliferation in general, inhibitors can act as reversible cytostatic agents that may be useful in the treatment of any pathological process characterized by abnormal cell proliferation, e.g. eg, benign prostatic hyperplasia, familial adenomatous polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, graft rejection, endotoxic shock e fungal infections

The compounds of formula I can induce or inhibit apoptosis. The apoptotic response is anomalous in a variety of human diseases. The compounds of formula I, as modulators of apoptosis, will be useful in the treatment of cancer (including, but not limited to those types mentioned herein above), viral infections (including, but not limited to herpes virus, virus of smallpox, Epstein – Barr virus, Sindbis virus and adenovirus), prevention of the development of AIDS in HIV-infected individuals, autoimmune diseases (including, but not limited to systemic lupus erythematosus, autoimmune mediating glomerulonephritis, rheumatoid arthritis, psoriasis , inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, vertebral muscular atrophy and cerebellar degeneration), syndromes myelodysplastic, aplastic anemia, ischemic injury associated with myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis, alcohol-related or toxin-induced liver diseases, hematological diseases (including, but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system ( including, but not limited to osteoporosis and arthritis), acetylsalicylic acid sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

The compounds of formula I are especially useful in the treatment of tumors that have a high incidence of tyrosine kinase activity, such as colon, lung and pancreatic tumors. By administering a composition (or a combination) of the compounds of the present invention, tumor growth in a mammalian host is reduced.

Compounds of formula I may also be useful in the treatment of diseases, other than cancer, that may be associated with signal transduction pathways that function through growth factor receptors such as VEGFR-2 and FGFR -one.

The compounds of the present invention may be formulated with a pharmaceutical carrier or diluent for oral, intravenous or subcutaneous administration. The pharmaceutical composition can be formulated in a classical manner using solid or liquid carriers, diluents and additives appropriate for the desired mode of administration. Orally, the compounds can be administered in the form of tablets, capsules, granules, powders and the like. The compounds can also be administered as suspensions using vehicles appropriate for this mode of administration. The compounds may be administered in a dose range of about 0.05 to 800 mg / kg / day, preferably, less than 500 mg / kg / day, in a single dose or in 2 to 4 divided doses.

Biological analysis

VEGFR – 2 and FGFR – 1 kinase analysis:

Reagents Final concentration

Stock solution VEGFR – 2 FGFR – 1 5

10

fifteen

twenty

25

30

35

(continuation)

Reagents

Final concentration

Stock solution

VEGFR – 2 FGFR – 1

ASB 10 mg / ml MnCl2 (1M) MgCl2 (1M) DTT (1M) Enzymatic stock solution mg / ml)

in 10% glycerol (1 25 µg / ml 1.5mM 0.5mM 7.5 ng / rxn 25 µg / ml 0.5mM 0.5mM 0.5mM 30 ng / rxn

Poly (glu / tyr) (10 mg / ml) ATP (1mM) γ – ATP (10µCi / µl)

7.5 µg / ml 2.5µM 0.5µCi / ml 30 µg / ml 1.0µM 0.5µCi / ml

The incubation mixtures used for the analysis of VEGFR-2 or FGFR-1 contain synthetic substrate poly (glu / tyr), (4: 1), ATP, ATP-γ-32P and buffer containing Mn ++ and / or Mg ++, DTT , ASB and Tris buffer. The reaction is initiated by the addition of enzyme and, after 60 minutes at room temperature, it is terminated by the addition of 30% TCA to a final concentration of 15% TCA. Inhibitors are carried up to 10mM in 100% DMSO. The analyzes are prepared in a 96-well format in quadruplicate. The compounds are diluted 1: 500 in 100% DMSO and then 1:10 in water for a final DMSO concentration of 10%. 10 µl are added to the B-H rows in a 96-well format of 10% DMSO. 20 µl of compound are added to row A at a concentration 5 times higher than the processing conditions. 10 µl is transferred to each row followed by six serial dilutions with mixing and 10 µl is discarded in row F. Row G is a control without compound and row H is a control without compound and without enzyme. The enzyme and the substrate are administered using a Tomtec Quadra station.

The plates are covered with adhesive plate covers, incubated at 27˚C for 60 minutes and then precipitated in acid with TCA for 20 minutes on ice. The precipitate is transferred to UniFilter-96 GF / C microplates using either a Tomtec or FilterMate Packard harvester. Activity is determined by quantifying the incorporated radioactivity using a Packard Top-Count microplate scintillation counter, after the addition of a Microscint-20 cocktail in each dry well of the UniFilter microplates.

The present compounds inhibit VEGFR-2 and FGFR-1 kinases with IC50 values between 0.001 to 10µM. Preferred compounds have IC50 values of less than 0.3 µM versus VEGFR-2.

These compounds are selective against the enzymes kinases of VEGFR-2 and FGFR-1. They have minimal activity against HER – 2, CDK kinases, LCK and Src kinases.

Preparation Procedures

Certain compounds of formula I can be prepared according to the following schemes and those skilled in the art.

All temperatures are in degrees Celsius (° C) unless otherwise indicated. Purifications by preparative reverse phase CLAR were performed on: 21 x 100 mm HC 18 C Premisphere® column with the solvent system (1) or (2). Solvent system (1): solvent A: 10% acetonitrile - 90% water + 5mM NH4OAc; solvent B: 90% acetonitrile - 10% water + 5mM NH4OAc. Solvent system (2): solvent A: 10% acetonitrile - 90% water + 0.05% TFA; solvent B: 90% acetonitrile - 10% water + 0.05% TFA. The gradient was with 20% B to 100% B. For LC / MS the conditions used were solvent system

(1) or (2) with 0% B to 100% B in a 2 minute gradient. Column: 4.6 x 30 mm HC of 18 C Premisphere®, at 220nM. Flow rate: 4 ml / minute. For the analytical CLAR, the conditions used were (solvent A: 10% acetonitrile - 90% water + 5mM NH4OAc; solvent B: 90% acetonitrile - 10% water + 5mM NH4OAc, with 0% B to B at 100% in a 30-minute gradient Column: YMC ODS-A 18 C, 6.0 x 150 mm, at 220nM Flow rate: 4 ml / minute All synthesized compounds were characterized by at least proton NMR and LC / MS (Micromass ZMD 2000, HEI) During the reactions, the organic extract was dried over anhydrous sodium sulfate (Na2SO4), unless otherwise mentioned.

For commonly used reagents, the following abbreviations are used. NMM: N-methylmorpholine; DIBAL: diisobutylaluminum hydride; BOP reagent: benzotriazol-1-yloxy-tris (trimethylamin) phosphonium hexaflurophosphate; DCE: dichloroethane; K2CO3: potassium carbonate; KOH: potassium hydroxide: DCC: dicyclohexyl carbodiimide; EDCI: 1– (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; T.A .: room temperature; HOBt: hydroxybenzotriazole; DCM: dichloromethane; CbzCl: chlorobenzoyl chloride; mCPBA: meta-chloroperbenzoic acid; NaHCO3: sodium bicarbonate; HCl: hydrochloric acid; TFA: trifluoroacetic acid; NH4Cl: ammonium chloride; DIPEA: diisopropylamine; Et3N: triethylamine. Na2SO4: sodium sulfate; DEAD: diethyl azodicarboxylate; DPPA: diphenylphosphorylazide; DMF: dimethylformamide; THF: tetrahydrofuran; DBU: 1.8 – diazabicyclo [5.4.0] undec – 7 – eno; T.A .: room temperature;

10 min: minutes; h: hour.

image2

Stage 1

This step is carried out by the reaction of two optionally substituted aldehyde equivalents (1), such as isobutyraldehyde, with alkyl isocyanate in the presence of a soft DBU type base to obtain Compound 3.

Stage 2

The product 3 of this scheme is reacted with an amination reagent, such as hydroxylamin-O-sulfonic acid or O-2,4-dinitrophenylhydroxamate, in the presence of a base such as KOH or sodium hydride to form Compound 4.

35 Stage 3

Compound 4 of this scheme is subjected to cyclization by treatment with formamide in the presence of a base, such as sodium methoxide in MeOH with heating to provide Compound 5.

Stage 4

Compound 5 of this scheme is halogenated, for example, with phosphorus oxychloride at an elevated temperature 40 to provide Compound 6.

Stage 5

Compound 6 is reacted with an amine, such as an aniline or a phenol, in an organic solvent, such as acetonitrile or DMF, to provide Compound 7.

image 1

Stage 1

The pyrrolotriazine ester can be treated with an N-hydroxyacetamidine to obtain Compound 1.

Stage 2

Compound 2 of this scheme can then be treated with a halogenating agent, such as phosphorous oxychloride, to obtain an intermediate chloroimidate.

Stage 3

The chloroimidate obtained above can be treated with an appropriate aniline or phenol and can provide Compound 3 of this scheme as described in scheme 1.

image 1

Stage 1

The pyrrolotriazine ester can be treated with a hydrazine hydrate to provide Compound 1.

Stage 2

Then Compound 1 can be converted to Compound 2 as described in Scheme 1.

image 1

Stage 1

This step is performed by reacting 4-chloro-7-azaindole with an amine, such as allylamine, in the presence of a catalyst, such as palladium (0), followed by deprotection of the aniline to obtain Compound 1, in the one that R is a proton.

Stage 2

Compound 1 of this scheme is reacted with sodium nitrite to form a diazonium salt that can be displaced by fluorine to form Compound 2.

Stage 3

Compound 2 of this scheme is then protected, such as with a silyl protecting group, to form Compound 3 of Scheme 4.

Stage 4

Compound 3 of this scheme is subjected to lithiation, for example, with sec-butyllithium at low temperature, by treatment with an electrophile, such as azide or oxirane, to form Compound 4 of Scheme 4. When used the azide, the compound can also be treated with palladium on carbon in the presence of hydrogen to obtain an aniline.

Stage 5

Compound 4 is deprotected to form Compound 5 of Scheme 4.

image 1

Stage 1

This step is performed by reacting 7-azaindole-N-oxide with a brominating agent, such as tetramethylammonium bromide, in the presence of methanesulfonic anhydride to obtain Compound 1.

Stage 2

Compound 1 of this scheme is protected with a protecting group, such as triisopropylsilane, to obtain Compound 2 of this scheme.

Stage 3

Compound 2 of this scheme is then subjected to lithiation by the exchange of halogens followed by treatment with a fluorination agent, such as N-fluorobenzenesulfonimide, to obtain Compound 3 of Scheme 5.

Stage 4

Compound 3 of this scheme can then be converted to Compound 4 as described in the Scheme

Four.

image 1

Stage 1

This step is performed by 5-lithiation of 4-chloro-7-azaindole with, for example, sec-butyl-lithium at a low temperature, followed by cooling with an azide, such as 4-azido-toluene, to obtain Compound 1.

Stage 2

Compound 1 of this scheme is reduced with hydrogen in the presence of a palladium catalyst, preferably palladium on carbon, to obtain Compound 2 of this scheme.

Stage 3

Compound 2 of this scheme can then be reduced with an delogenating agent, such as zinc powder, in the presence of acetic acid to obtain Compound 3 of this scheme.

image 1

Stage 1

4-Fluoro-7-azaindole is protected by an appropriate protecting group, such as phenylsulfonamide, to form Compound 1 of Scheme 7.

Stage 2

Compound 1 of this scheme is subjected to lithiation, for example, with n-butyllithium at low temperature, followed by treatment with an electrophile, such as iodomethane, to form Compound 2 of Scheme 7.

Stage 3

Compound 2 of this scheme is then deprotected with a reagent, such as tetrabutylammonium fluoride, to form Compound 3 of Scheme 7.

Stage 4

Then Compound 3 of this scheme can be converted to obtain Compound 4 as described above.

In addition, other compounds of formula I can be prepared using procedures generally known to those skilled in the art. Specifically, the following examples provide more procedures for preparing compounds of the present invention.

The invention will now be described in greater depth by the following working examples, which are preferred embodiments of the invention. These examples are illustrative rather than restrictive, and it is to be understood that there may be other embodiments belonging to the spirit and scope of the invention as defined by the appended claims herein.

Example 1

image 1

5-methyl-4– (1H-pyrrolo [2,3-b] pyridin-5-yloxy) -pyrrolo [2,1-f] [1,2,4] triazin-6-carboxylic acid ethyl ester

At 0 ° C, sodium hydride (14 mg; 0.36 mmol; 60% in oil) was added to a solution of 5-hydroxy-7-azaindole (48 mg; 0.36 mmol) in DMF (1.5 ml) , then 4-chloro-5-methylpyrrolo [2,1-f] [1,2,4] triazine-6-carboxylic acid ethyl ester (76 mg; 0.32 mmol, WO 0071129) was added and the mixture was stirred to TA for 16 h, it was stopped with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layers were washed with brine (50 ml), dried, filtered and concentrated. The residue was purified by preparative CLAR (retention time = 7.12 min). 1H-NMR (400 MHz, CDCl3) δ8.10 (1H, s), 7.91 (1H, sa), 7.82 (1H, s), 7.31 (1H, s), 6.85 (1H , sa) 4.31 (2H, c, J = 7.3 Hz), 2.79 (3H, s), 1.33 (3H, t, J = 7.3 Hz). m / z 338 (M + H) +, 379 (M + AcCN) +.

The intermediate indole compound, 5-hydroxy-7-azaindole, was prepared as explained below:

image 1

Under argon in a flask covered with aluminum foil, a solution of 5-methoxy-7-azaindole (60 mg; 0.4 mmol, for preparation, see Heterocycles 1999, 50 (2), 1065-1080) was added in dichloromethane to a solution of boron tribromide (890 µl, 1M) in dichloromethane at 78 ° C. The mixture was allowed to warm to T.A. and stirred for a further 2 h. Then, a 10% solution of sodium bicarbonate was added and the separated aqueous layer was extracted with dichloromethane (3 x 25 ml). The combined organic layers were washed with brine (30 ml), dried, filtered and concentrated to provide 50 mg of an oil that was used directly without further purification. m / z 135 (M + H) +.

Example 2

image 1

5-Methyl-4– (2-methyl-1 H -pyrrolo [2,3-b] pyridin-5-yloxy) -pyrrolo [2,1-f] [1,2,4] triazin-6– carboxylic

The procedure described above was applied for the preparation of Example 1 using 5-hydroxy-2-methyl-7–

intermediate azaindole. 1H-NMR (400 MHz, CDCl3) δ8.87 (1H, sa), 8.09 (1H, s), 8.06 (1H, sa), 7.82 (1H, s), 7.60 (1H , sa), 6.14 (1H, sa), 4.31 (2H, c, J = 7.0 Hz), 2.79 (3H, s), 2.43 (3H, s), 1.33 (3H, t, J = 7.0 Hz). CL / MEM; (M + H) + =

352. (M + AcCN) = 393.

The intermediate compound, 5-hydroxy-2-methyl-7-azaindole, was prepared as explained below:

image 1

A. To a solution of 5-methoxy-7-azaindole (240 mg; 1.62 mmol) in THF (10 ml), a 60% suspension of sodium hydride in oil (71 mg; 1.78 mmol) was added to TA under argon. The mixture was stirred at T.A. for 5 minutes and phenylsulfonyl chloride (250 µl; 1.95 mmol) was added and the mixture was stirred for 16 h, stopped with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 25 ml ). The combined organic layers were washed with brine (50 ml), dried, filtered and concentrated. The residue was purified by flash chromatography (1% MeOH in dichloromethane + 0.5% triethylamine) to provide N-phenylsulfonyl-5-methoxy-7-azaindole (325 mg; 70%) as a solid.

1H-NMR (400 MHz, CDCl3) δ8.12 (3H, m), 7.65 (1H, dd, J = 3.8), 7.54 (1H, m), 7.45 (2H, m) , 7.28 (1H, d, J = 2.8 Hz), 6.51 (1H, d, J = 3.8 Hz), 3.82 (3H, s). (M + H) + = 289.

B. A solution (2.7M) of n-butyllithium in hexanes (0.48 ml; 1.30 mmol) was added to a solution of N-phenylsulfonyl-5-methoxy-7-azaindole (220 mg; 0 , 76 mmol) in THF (7.0 ml) at -78˚C under argon. The resulting solution was stirred at -78 ° C for 1 h and methyl iodide (120 µl; 1.91 mmol) was added. The resulting mixture was stirred at -78 ° C for 2 h, stopped with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layers were washed with brine (50 ml), dried, filtered and concentrated. The residue was purified by flash chromatography (1% MeOH in dichloromethane + 0.1% triethylamine) to provide (170 mg; 73%) of a mixture (5: 1) of N-phenylsulfonyl-5-methoxy– 2-methyl-7-azaindole, m / z 303 (M + H +), retention time of analytical CLAR = 1.83 min and N-tolylsulfonyl-5-methoxy-2-methyl-7-azaindole, m / z 317; retention time = 1.97 min.

C. To a solution of the above compound mixture in THF-methanol (3: 1) (4 ml), a 10% solution of sodium hydroxide in water (3 ml) was added at room temperature. The mixture was heated to 65 ° C for 1 h, cooled to room temperature, neutralized to pH 7 with a solution of saturated ammonium chloride and extracted with ethyl acetate (3 x 15 ml). The combined organic layers were washed with brine (50 ml), dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel (1% MeOH in dichloromethane + 0.1% triethylamine) to provide 5-methoxy-2-methyl-7-azaindole (35 mg; 66%) . (M + H) + = 163.

D. The procedure described above for the preparation of hydroxy-indole from methoxy-indole of Example 1 was applied to 5-methoxy-2-methyl-7-azaindole (35 mg; 0.2 mmol) to provide 5-hydroxy –2 – methyl – 7 – azaindole (32 mg; 100%) that was used directly without further purification. LC / MS; (M + H) + = 135.

Example 3

image 1

6-Benzyloxy-5-methyl-4– (2-methyl-1H-pyrrolo [2,3-b] pyridin-5-yloxy) -pyrrolo [2,1-f] [1,2,4] triazine

5-Hydroxy-2-methyl-7-azaindole was treated with 6-benzyloxy-4-chloro-5-methyl-pyrrolo [2,1-f] [1,2,4] triazine (see WO 0071129) by a procedure similar to the preparation of Example 1. 1H-NMR (400 MHz, DMSO-d6) δ8.02 (1H, sa), 7.85 (1H, s), 7.83 (1H, s), 7 , 70 (1H, sa), 7.41 (6H, m), 6.15 (1H, sa), 5.12 (2H, s), 2.92 (3H, s), 2.42 (3H, s). m / z 386 (M + H) +, 427 (M + + AcCN).

Example 4

image 1

6-Benzyloxy-4– (4-fluoro-1H-pyrrolo [2,3-b] pyridin-5-yloxy) -5-methyl-pyrrolo [2,1-f] [1,2,4] triazine

To a solution of 4-fluoro-1H-pyrrolo [2,3-b] pyridin-5-ol (53.5 mg; 0.35 mmol) in DMF (2 ml) at -78˚C, hydride of sodium (60% in oil, 14 mg; 0.35 mmol) and the mixture was heated to 0 ° C. After 30 minutes, the flask was cooled to -78˚C, 6-benzyloxy-4-chloro-5-methyl-pyrrolo [2,1-f] [1,2,4] triazine (80 mg; 0, 29 mmol) and the mixture was allowed to reach RT for 30 min. A saturated ammonium chloride solution was added, the solution was extracted with ethyl acetate (3 x 15 ml)), the combined organic layers were washed with water (30 ml), brine (30 ml), dried and concentrated. under vacuum The crude material was purified by titration with acetonitrile to give the title compound (90 mg; 80%) of a bone-colored solid. 1H – NMR (400 MHz, DMSO – d6) δ12.17 (1H, s), 8.30 (1H, d, J = 9.6 Hz), 8.00 (1H, s), 7.94 (1H , s), 7.61 (1H, t, J = 3.0 Hz), 7.49 (2H, d, J = 7.1 Hz), 7.41 (2H, t, J = 7.1 Hz ), 7.34 (1H, t, J = 7.3 Hz), 6.59 (1H, dd, J = 2.0; 3.5 Hz), 5.16 (2H, s), 2.43 (3H, s). LC / MS; (M + H) + = m / z 390.

The intermediate compound, 4-fluoro-1H-pyrrolo [2,3-b] pyridin-5-ol, was prepared as explained below:

image 1

A. The procedure described in J. Org. Chem., 2000, 65, 1158-1174. A 350 ml flask was dried in the oven dried and covered with a rubber partition, and filled with argon. The flask was charged with 4-chloro-1H-pyrrolo [2,3-b] pyridine [20 g, 131 mmol, for preparation, see Benoît, S .; Gingras, S., “Processes for the preparation of antiviral 7– azaindole derivatives”. U.S. Provisional Patent 60 / 367,401, 2003], sodium tert-butoxide (35.2 g; 367 mmol), Pd (OAc) 2 (589 mg; 2.62 mmol), (o-biphenyl) PCy2 (1.83 g; 5.24 mmol) and emptied and filled with argon. 1,4-dioxane (0.25 L) and N-allylamine (29 ml; 393 mmol) were added and argon was bubbled through the mixture for 20 minutes. The partition was replaced with a Teflon® screw cap, the flask was sealed and the mixture was heated at 100 aC for 16 h. The mixture was cooled to room temperature, diluted with ether (0.5 L), filtered through Celite® and concentrated in vacuo. The resulting oil was dissolved in dichloromethane (0.25 L), washed twice with water, dried, filtered and concentrated in vacuo to give allyl- (1 H -pyrrolo [2,3-b] pyridin-4– il) –amine like a brown gum. 1H – NMR (400 MHz, DMSO – d6) δ 11.10 (1H, sa), 7.78 (1H, d, J = 5.3 Hz), 7.03 (1H, s), 6.73 (1H , t, J = 5.8 Hz), 6.53 (1H, d, J = 2.5 Hz), 6.04 (1H, t, J = 5.5 Hz), 5.96– 5.87 (1H, m), 5.22 (1H, ddd, J = 1.8; 3.4; 17.2 Hz), 5.11 (1H, ddd, J = 0.7; 1.8; 10, 4 Hz), 3.86 (2H, m). LC / MS: m / z 174 (M + H) +.

B. The procedure described in Tetrahedron Letters, 1998, 39, 1313-1316 was used. A 0.5 ml rounded bottom flask was dried in the oven equipped with a condenser and filled with argon. The flask was charged with allyl– (1 H -pyrrolo [2,3-b] pyridin-4-yl) -amine (22.69 g; 131 mmol), ethanol (262 ml), 10% palladium on carbon (15 g) and methanesulfonic acid (8.5 ml; 131 mmol). The mixture was heated at 105 ° C for 72 h. The mixture was cooled to room temperature, filtered through Celite® and concentrated in vacuo. The resulting oil was purified by a SCX silica column (300 g), eluting with methanol (3 x 500 ml) followed by a solution of 2M ammonia in methanol (3 x 500 ml) to give 1H-pyrrolo [2,3– b] pyridin-4-ylamine (13.15 g; 75% in two stages) as a light yellow oil. 1H – NMR (400 MHz, DMSO – d6) δ11.02 (1H, sa), 7.69 (1H, d, J = 5.3 Hz), 7.01 (1H, d, J = 3.3 Hz ), 6.46 (1H, d, J = 3.3 Hz), 6.10 (1H, d, J = 5.3 Hz), 6.07 (2H, s). LC / MS: m / z 134 (M + H) +.

C. 1H-pyrrolo [2,3-b] pyridin-4-ylamine (10.3 g; 77 mmol) was dissolved in a 48% by weight solution of tetrafluoroboric acid in water (155 ml). The mixture was cooled to 0 ° C and sodium nitrite (5.87 g; 85.1 mmol) in water (15 ml) was added dropwise. The mixture was allowed to reach T.A. and stirred for 22 h. Ethyl acetate (500 ml) was added, the mixture was cooled to 0 ° C, neutralized with sodium hydrogen carbonate and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 300 ml), the organic layers were combined and concentrated in vacuo. The resulting solid was triturated with 250 ml of ethyl acetate, filtered and the filtrate was washed with a 1N sodium hydroxide solution (2 x 200 ml). The organic layer was dried, filtered and concentrated in vacuo to give 4-fluoro-1H-pyrrolo [2,3-b] pyridine (4.67 g; 44%) as a brown solid. 1H – NMR (400 MHz, DMSO – d6) δ12.00 (1H, sa), 8.20 (1H, dd, J = 5.3; 8.4 Hz), 7.51 (1H, t, J = 3.1 Hz), 6.94 (1H, dd, J = 5.3; 10.4 Hz), 6.51 (1H, dd, J = 2.1; 3.6 Hz), 6.07

5

10

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twenty

25

30

35

40

Four. Five

(2H, s). LC / MS: m / z 134 (M + H) +.

D. 4-Fluoro-H-pyrrolo [2,3-b] pyridine (2 g; 14.7 mmol) was dissolved in THF (50 ml) and sodium hydride (60% in oil, 881 mg; 22 , 0 mmol) in small portions. After 30 minutes, chlorotriisopropylsilane (4.71 ml; 22.0 mmol) was added and stirred at 65 ° C for 16 h. Ethyl acetate (100 ml) was added, the mixture was cooled to 0 ° C, neutralized with saturated ammonium chloride solution and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (2 x 100 ml) and the organic layers were combined, washed with water (150 ml), brine (150 ml), dried and concentrated in vacuo. The crude material was purified by flash chromatography eluting with 1% ethyl acetate in hexane to give 4-fluoro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine (2.16 g; 50%) Like a colorless oil. 1H – NMR (400 MHz, DMSO – d6) δ8.22 (1H, dd, J = 5.6; 8.3 Hz), 7.51 (1H, d, J = 3.6 Hz), 6.98 (1H, dd, J = 4.1; 10.1 Hz), 6.69 (1H, d, J = 3.5 Hz), 1.86 (3H, m), 1.06 (9H, s) , 1.04 (9H, s). LC / MS: m / z 293 (M + H) +.

E. The procedure described in J. Med Chem., 1997, 40, 2674 was modified. 4-Fluoro-1-triisopropylsilanyl-1 H -pyrrolo [2,3-b] pyridine (213 mg; 0.73 mmol) was dissolved. in THF (4.9 ml) and the mixture was cooled to -78˚C. Sec-Butyllithium solution (1.10M in THF; 1.46 ml; 1.61 mmol) was added dropwise, and after 30 minutes, (R) -camforsulfonyl-oxaziridine (418 mg; 1, 82 mmol) in tetrahydrofuran (2.5 ml). After 25 h, a saturated ammonium chloride solution was added and the mixture was allowed to reach T.A. The solution was extracted with ethyl acetate (3 x 15 ml) and the combined organic layers were washed with water (30 ml), brine (30 ml), dried and concentrated in vacuo. The crude material was purified by flash chromatography eluting with a mixture of 5% ethyl acetate in toluene to give the desired product. LC / MS: m / z 309 (M + H) +.

F. 4-Fluoro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridin-5-ol (207 mg; 0.67 mmol), THF (3.4 ml) and a fluoride solution of tetrabutylammonium (1.0M in THF; 1.01 ml; 1.01 mmol) and the mixture was stirred for 90 min. A saturated ammonium chloride solution was added, the mixture was extracted with ethyl acetate (3 x 15 ml), the combined organic layers were washed with water (30 ml), brine (30 ml), dried and concentrated to empty. The crude material was purified by flash chromatography eluting with a mixture of 1% NH4OH: 7% methanol: 92% dichloromethane to provide 4-fluoro-1H-pyrrolo [2,3-b] pyridin-5-ol (60 mg; 59%) as a light yellow solid. 1H – NMR (400 MHz, DMSO – d6) δ11.62 (1H, s), 9.34 (1H, s), 7.95 (1H, d, J = 10.3 Hz), 7.39 (1H , d, J = 2.8 Hz), 6.38 (1H, dd, J = 2.0; 3.2 Hz). LC / MS: m / z 153 (M + H) +.

Example 5

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4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methyl – pyrrolo [2,1 – f] [1,2,4] triazin – 6 – ol

To a solution of Example 4 (84 mg; 0.22 mmol) in DMF (1.1 ml), 10% Pd on charcoal (10 mg) and ammonium formate (68 mg; 1.08 mmol) were added . The mixture was stirred at T.A. for 20 h and then filtered through Celite® and concentrated in vacuo. The resulting solid was dissolved in methanol and purified by a SCX silica column (18 g) by washing with methanol (2 x 8 ml) and then eluting with a solution of 2M ammonia in methanol (2 x 8 ml) to give the compound of the title (60 mg; 93%) as a beige solid. 1H – NMR (400 MHz, DMS O – d6) δ12.16 (1H, s), 9.53 (1H, s), 8.29 (1H, d, J = 9.6 Hz), 7.88 ( 1H, s), 7.61 (1H, t, J = 3.0 Hz), 7.55 (1H, s), 6.59 (1H, dd, J = 2.0; 3.5 Hz), 2.40 (3H, s). LC / MS: m / z 300 (M + H) +.

Example 6

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(R) –1– [4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methylpyrrolo [2,1 – f] [1,2,4] triazin– 6 – iloxi] –propan – 2 – ol

An oven-dried sealed tube was loaded with 4– (4-fluoro-1H-pyrrolo [2,3-b] pyridin-5-yloxy) -5-methylpyrrolo [2,1–

f] [1,2,4] triazin-6-ol (Example 5) (7.5 mg; 0.025 mmol), t-BuOH (0.25 ml), 0.5M of a solution of triethylamine in t-BuOH (5 µl; 0.0025 mmol) and R - (+) - propylene oxide (21 µl; 0.300 mmol). The tube was sealed and the mixture was stirred at 80 ° C for 1 h. The reaction mixture was cooled and concentrated in vacuo. The crude material was purified by preparative CLAR to give the title compound (5 mg; 56%) as a bone-colored solid. 1H – NMR (400 MHz, DMSO – d6) δ12.17 (1H, s), 8.31 (1H, d, J = 9.6 Hz), 7.95 (1H, s), 7.93 (1H , s), 7.61 (1H, t, J = 3.0 Hz), 6.59 (1H, dd, J = 1.9; 3.4 Hz), 4.91 (1H, d, J = 4.8 Hz), 4.02–3.94 (1H, m), 3.92–3.83 (2H, m), 2.42 (3H, s), 1.16 (3H, d, J = 6.3 Hz). LC / MS: (M + H) + 358. (MH) = 356.

Example 7

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(S) –1– [4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methyl – pyrrolo [2,1 – f] [1,2,4] triazin – 6 – iloxy] –propan – 2– ol

A. A 150 ml tube was loaded with 5-methyl-4-phenoxy-pyrrolo [2,1-f] [1,2,4] triazin-6-ol (5.93 g; 24.6 mmol), THF (2 ml) and sodium methanethiol (5.17 mg; 73.7 mmol). The tube was sealed and the mixture was heated at 80 ° C for 4 h. The mixture was cooled to T.A., water (100 ml) was added and the solution was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with water (200 ml), 1N aqueous solution of sodium hydroxide (2 x 200 ml), brine (200 ml), dried and concentrated in vacuo to provide (3.2 g; 67% ) of 5-methyl-4-methylsulfanylpyrrolo [2,1-f] [1,2,4] triazin-6-ol as a beige solid. 1H – NMR (400 MHz, DMSO – d6) δ9.49 (1H, s), 8.11 (1H, s), 7.39 (1H, s), 2.58 (3H, s), 2.34 (1H, s). m / z 196 (M + H +).

B. A 10 ml tube was loaded with 5-methyl-4-methylsulfanylpyrrolo [2,1-f] [1,2,4] triazin-6-ol (75 mg; 0.38 mmol), tert-butyl alcohol ( 2 ml), (S) -propylene oxide (0.134 ml; 1.92 mmol) and triethylamine (5 µl; 0.04 mmol). The tube was sealed and the mixture was heated at 80 ° C for 17 h. The mixture was cooled to T.A. and concentrated in vacuo. The crude material was purified by flash chromatography eluting with a mixture of 50% ethyl acetate in hexane to give (56 mg, 58%) of (S) –1– (5-methyl-4-methylsulfanylpyrrolo [2, 1-f] [1,2,4] triazin-6-yloxy) -propan-2-ol as a white solid. 1H – NMR (400 MHz, DMSO – d6) δ8.16 (1H, s), 7.78 (1H, s), 4.88 (1H, m), 3.95 (m, 1H), 3.82 (2H, m), 2.59 (3H, s), 2.36 (3H, s), 1.13 (3H, d, J = 6.3 Hz). m / z 254 (M + H +).

C. To a solution of (S) -5-methyl-4-methylsulfanyl-pyrrolo [2,1-f] [1,2,4] triazin-6-ol (20 mg; 0.08 mmol) in chloroform ( 1.0 ml) at 0 ° C, a solution of peracetic acid in acetic acid (51 µl; 0.24 mmol; 32% solution by weight) was added. The mixture was allowed to reach T.A. and stirred for an additional 2.0 h. A saturated solution of ammonium chloride was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (2 x 50 ml) and the organic layers were combined, washed with water (100 ml), brine (100 ml), dried and concentrated in vacuo. The resulting sulfone was used without any purification.

D. At –78˚C, sodium hydride (60% in oil; 3.1 mg; 0.08 mmol) was added to a solution of 4-fluoro-1H-pyrrolo [2,3-b] pyridine-5 -Ol (13 mg; 0.09 mmol, see Example 4) in dimethyl formamide (1 ml). The mixture was stirred at 0˚C for 30 min and cooled again to –78˚C. Then (S) –1– (4-methanesulfonyl-5-methylpyrrolo [2,1- f] [1,2,4] triazin-6-yloxy) -propan-2-ol (22 mg; 0.08) mmol) and the mixture was stirred at RT for 2 h, it was stopped with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4), filtered and evaporated. The residue was purified by preparative CLAR to produce (10 mg; 36%) of the title compound. 1H – NMR (400 MHz, DMSO – d6) δ12.17 (1H, s), 8.31 (1H, d, J = 9.3 Hz), 7.95 (1H, s), 7.93 (1H , s), 7.61 (1H, t, J = 3.1 Hz), 6.59 (1H, dd, J = 1.98; 3.3 Hz), 4.01– 3.97 (1H, m), 3.92-3.83 (2H, m), 2.42 (3H, s), 1.16 (3H, d, J = 6.3 Hz), m / z 358 (M + H +) .

The intermediate azaindole, 4-Fluoro-1H-pyrrolo [2,3-b] pyridin-5-ol, was prepared as explained below.

image 1

E. 1H-pyrrolo [2,3-b] pyridin-7-oxide (50 g; 1 eq.) And tetramethylammonium bromide (86 g; 1.5 eq.) Were placed in DMF (500 ml). The mixture was cooled to 0 ° C and methanesulfonic anhydride (130 g; 2 eq.) Was added in small

portions. The suspension was allowed to reach 23˚C and stirred for 4 h. The mixture was poured into water (1 L) and the solution was neutralized with a 50% aqueous solution of sodium hydroxide (pH = 7). Water (2 L) was added and the mixture was cooled to 10 ° C for 30 min. The solid formed was filtered and washed with cold water (1 L). The solid was dissolved in a dichloromethane / methanol mixture (4: 1), dried over MgSO4, concentrated in vacuo until

5 provide 4-bromo-1H-pyrrolo [2,3-b] pyridine (40 g; 54%). 1H – NMR (400 MHz, DMSO – d6) δ12.05 (1H, sa), 8.08 (1H, d, J = 5.3 Hz), 7.59 (1H, m), 7.33 (1H , d, J = 5.05 Hz), 6.41 (1H, d, J = 3.5 Hz). LC / MS; m / z 197 (M + H) +

F. A 500 ml flask dried in the oven covered with a rubber partition was emptied and refilled with argon. The flask was charged with 4-bromo-1H-pyrrolo [2,3-b] pyridine (40 g; 1 eq.) And THF (400 ml). The mixture was cooled to 0 ° C and sodium hydride (60% in oil; washed with hexanes; 8.9 g; 1 eq.) Was added in small portions. After 15 minutes, chlorotriisopropylsilane (443.4 ml; 1 eq.) Was added, the tube was sealed and stirred at 80˚C for 3 h. The reaction mixture was cooled again, neutralized with saturated ammonium chloride (50 ml) and extracted twice with hexanes (2 x 800 ml). The combined organic layers were dried and concentrated in vacuo to provide 4-bromo-1-triisopropylsilanyl-1 H -pyrrolo [2,3- b] pyridine (71.1 g; 99%). 1H – NMR (400 MHz, DMSO – d6) δ8.09 (1H, d, J = 5.1 Hz), 7.60 (1H, d, J = 3.5 Hz), 7.37 (1H, d , J = 5.3 Hz), 6.59 (1H, d, J = 3.5 Hz), 1.85 (3H, Sept. J

15 = 7.6 Hz), 1.04 (9H, d, J = 7.6 Hz). CL-MS; m / z 353 (M + H +).

G. A 250 ml round bottom flask dried in the oven was emptied and refilled with argon. The flask was charged with 4-bromo-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine (1.4 g; 1 eq), THF (25 ml) and the mixture was cooled to -78˚C. Tert-butyllithium (1.7M in pentane; 4.66 ml; 2 eq.) Was added dropwise and after 5 minutes, N-fluorobenzenesulfonimide (1.25 g; 1 eq.) Was added. After 45 min, a saturated ammonium chloride solution (20

20 ml) and the mixture was allowed to reach T.A. Water (40 ml) was added and the solution was extracted with hexanes (3 x 100 ml), the combined organic layers were washed with water, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography eluting with a mixture of 100% hexanes to give 4-fluoro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine (970 mg; 84%).

H. Then, the procedures described in Example 4E and 4F were followed to obtain the title compound.

The following examples were prepared using a procedure similar to that described for the preparation of Example 7, using the appropriate hidoxiazaindole and the appropriate pyrrolotriazine which, in turn, was prepared using the three step sequence (A → B → C) described above. with the appropriate modification of step B. In the following Table 1, the compounds are shown.

image 1

Table 1:

Ex.

R2 R3 Name LC / MS (M + H) + Performance (%)

8

(R) –MeCH (OH) CH2O I (R) –1– [4– (4 – Fluoro – 2 – methyl – 1H– pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5– methyl – pyrrolo [2,1 – f] [1, 2,4] triazin – 6– iloxy] –propan – 2 – ol 372 25

9

(S) –MeCH (OH) CH2O H (S) –1– [4– (4 – Fluoro – 1H– pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5– methylpyrrolo [2,1 – f] [1,2,4] triazin– 6– iloxi] –propan – 2 – ol 388 36

10

(S) –MeCH (OH) CH2O I (S) –1– [4– (4 – Fluoro – 2 – methyl – 1H– pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5– methylpyrrolo [2,1 – f] [1,2, 4] triazin – 6– iloxy] –propan – 2 – ol 372 37

(continuation)

Ex.

R2 R3 Name LC / MS (M + H) + Performance (%)

eleven

(R) –MeCH (OBn) CH2O H (R) –6– (2 – Benzyloxy-propoxy) –4– (4– fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5– yloxy) –5 – methylpyrrolo [2,1– f] [1 , 2,4] triazine 448 61

12

(R) –MeOCH2CH (OH) CH2O H (R) –1– [4– (4 – Fluoro – 1H– pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5– methylpyrrolo [2,1 – f] [1,2,4] triazin– 6– iloxy] –3 – methoxypropan – 2 – ol 388 64

12

(R) –MeOCH2CH (OH) CH2O I (R) –1– [4– (4 – Fluoro – 2 – methyl – 1H– pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5– methylpyrrolo [2,1 – f] [1,2, 4] triazin – 6– iloxy] –3 – methoxypropan – 2 – ol 402 14

13

(S) –MeOCH2CH (OH) CH2O H (S) –1– [4– (4 – Fluoro – 1H– pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5– methylpyrrolo [2,1 – f] [1,2,4] triazin– 6– iloxy] –3 – methoxypropan – 2 – ol 358 33

14

(S) –MeOCH2CH (OH) CH2O I (S) –1– [4– (4 – Fluoro – 2methyl – 1H– pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5– methylpyrrolo [2,1 – f] [1,2,4] triazin – 6– iloxy] –3 – methoxypropan – 2 – ol 402 28

fifteen

NH2SO2NH (CH2) 2O H N– {2– [4– (4 – Fluoro – 1H – pyrrolo [2,3– b] pyridin – 5 – yloxy) –5– methylpyrrolo [2,1 – f] [1,2,4] triazin – 6 - yloxy] –ethyl} –sulfamide 422 48

16

MeSO2NH (CH2) 2O H N– {2– [4– (4 – Fluoro – 1H – pyrrolo [2,3– b] pyridin – 5 – yloxy) –5 – methyl– pyrrolo [2,1 – f] [1,2,4] triazin –6 – iloxy] - ethyl} –methanesulfonamide 421 40

17

MeSO2NH (CH2) 2O I N– {2– [4– (4 – Fluoro-2-methyl-1H– pyrrolo [2,3-b] pyridin-5-yloxy) –5– methyl-pyrrolo [2,1 – f] [1,2 , 4] triazin – 6– yloxy] –ethyl} –methanesulfonamide 435 fifteen

The 4-fluoro-2-methyl-5-hydroxy-1H-pyrrolo [2,3-b] pyridine needed for Examples 8, 10, 12, 14 and 17 was prepared from 4-fluoro-2-methyl- 1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine as described in the Example

4. This last compound was prepared as explained below.

Preparation of 4-fluoro-2-methyl-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine

image 1

A. To a solution of 4-fluoro-1H-pyrrolo [2,3-b] pyridine (408 mg; 3.0 mmol) in THF (5 ml), sodium hydride (60% in oil; 120 mg) was added ; 3.0 mmol) in small portions. After 30 min, benzenesulfonyl chloride (0.42 ml; 3.3 mmol) was added and stirred at 23˚C for 21 h. Ethyl acetate (25 ml) was added, the

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mixture at 0 ° C, neutralized with a saturated ammonium chloride solution and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (2 x 25 ml), the organic layers were combined, washed with water (100 ml), brine (100 ml), dried and concentrated in vacuo. The crude material was purified by flash chromatography eluting with 25% ethyl acetate in hexane to give 1-benzenesulfonyl-4-fluoro-1H-pyrrolo [2,3-b] pyridine (683 g; 82%). 1H – NMR (400 MHz, DMSO – d6) δ8.40 (1H, dd, J = 5.8; 7.8 Hz), 8.12 (2H, dd, J = 1.0; 6.3 Hz) , 7.98 (1H, d, J = 4.3 Hz), 7.73 (1H, tt, J = 1.3; 6.9 Hz), 7.63 (3H, t, J = 7.3 Hz), 7.25 (1H, dd, J = 5.6; 9.9 Hz), 6.93 (1H, d, J = 4.1 Hz). LC / MS; m / z 277 (M + H) +

B. To a solution of 1-benzenesulfonyl-4-fluoro-1H-pyrrolo [2,3-b] pyridine (683 mg; 2.47 mmol) in THF (12.0 ml) at -78˚C, was added n-butyllithium solution (2.36M in hexanes; 2.30 ml; 5.44 mmol) in drops. After 90 min, iodomethane (0.31 ml; 4.95 mmol) was added quickly. After 15 min, a saturated ammonium chloride solution was added and the mixture was allowed to reach T.A. The solution was extracted with ethyl acetate (3 x 15 ml) and the combined organic layers were washed with water (30 ml), brine (30 ml), dried and concentrated in vacuo. The crude material was placed in THF (12 ml) and a solution of tetrabutylammonium fluoride (1.0M in THF, 3.7 ml; 3.7 mmol) was added. The mixture was heated at 65 ° C for 16 h. The mixture was cooled to T.A., concentrated in vacuo and the residue was purified by preparative CLAR to provide 4-fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridine (300 mg; 80%). 1H – NMR (400 MHz, CDCl3) δ 10.70 (1H, s), 8.13 (1H, t, J = 5.8 Hz), 6.77 (1H, dd, J = 5.3; 9, 6 Hz), 6.25 (1H, s) 2.51 (3H, s). LC / MS; m / z 151 (M + H +).

C. To a solution of 4-fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridine (300 mg; 2.0 mmol) in THF (6 ml), sodium hydride (60% in oil; 84 mg; 2.1 mmol) in small portions. After 30 minutes, chlorotriisopropylsilane (0.45 ml; 2.1 mmol) was added and the mixture was stirred at 65 ° C for 16 h. Ethyl acetate (25 ml) was added, the mixture was cooled to 0 ° C, neutralized with a saturated ammonium chloride solution and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (2 x 25 ml) and the organic layers were combined, washed with water (100 ml), brine (100 ml) and concentrated in vacuo. The crude material was purified by flash chromatography eluting with hexanes to give 4-fluoro-2-methyl-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine (400 mg; 65%) as a colorless oil. LC / MS; m / z 307 (M + H +).

Example 18

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(R) –2– [4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methylpyrrolo [2,1 – f] [1,2,4] triazin– 6-yloxy] –1– methylethylamine

A. The procedures offered in Tetrahedron Lett, 1977, 1977 and JACS, 1999, 3633–39 were modified. Thus, a 10 ml flask was charged with 1– (5-methyl-4-methylsulfanylpyrrolo [2,1-f] [1,2,4] triazin-6-yloxy) -propan-2-ol (249 mg ; 0.98 mmol) and tetrahydrofuran (4.91 ml) and cooled to 0 ° C. Triphenylphosphine (516 mg; 1.96 mmol), diethyl azodicarboxylate (310 µl; 1.96 mmol) and diphenylphosphoryl azide (424 µl; 1.96 mmol) were added. The mixture was stirred at 23 ° C for 15 h and then concentrated in vacuo. The crude material was purified by flash chromatography eluting with a mixture of 20% ethyl acetate in hexane to give (156 mg; 57%) of 6– (2-azidopropoxy) -5-methyl-4-methyl sulfanylpyrrolo [2 , 1 – f] [1,2,4] triazine as a white solid. 1H – NMR (400 MHz; DMSO – d6) δ8.19 (1H, s), 7.85 (1H, s), 4.16 (1H, dd, J = 2.8; 9.6 Hz), 4 , 05–3.96 (m, 2H), 2.60 (3H, s), 2.37 (3H, s), 1.21 (3H, d, J = 6.3 Hz). LC / MS; m / z 254 (M + H +)

B. 6– (2-azido-propoxy) -5-methyl-4-methylsulfanyl-pyrrolo [2,1-f] [1,2,4] triazine and 4-fluoro-1H-pyrrolo [2 , 3 – b] pyridin – 5 – ol according to the procedure described in Example 7 to provide 6– (2– azido-propoxy) –4– (4-fluoro-1H – pyrrolo [2,3 – b] pyridin – 5 -Yloxy) -5-methyl-pyrrolo [2,1-f] [1,2,4] triazine. The crude material was purified by preparative CLAR. 1H – NMR (400 MHz, DMSO – d6) δ12.18 (1H, s), 8.32 (1H, d, J = 9.6 Hz), 8.02 (1H, s) 7.96 (1H, s), 6.60 (1H, d, J = 3.6 Hz), 4.21 (1H, d, J = 7.0 Hz), 4.09-4.02 (2H, m), 2, 42 (3H, s), 1.23 (3H, d, J = 6.3 Hz). LC / MS; m / z 382 (M + H +).

C. A solution of 6– (2-azido-propoxy) -4- (4-fluoro-1H-pyrrolo [2,3-b] pyridin-5-yloxy) -5-methyl-pyrrolo [2,1] was stirred - f] [1,2,4] triazine (20 mg; 0.05 mmol) in ethyl acetate (2.0 ml) in the presence of hydrogen (96.53 kPa) and 10% Pd / C (10 mg ) for 12 h. Excess hydrogen was removed, and the mixture was filtered through Celite® and evaporated. The residue was purified by preparative CLAR to produce (10 mg; 54%) of the title compound. LC / MS: m / z 357 (M + H +). Hydrochloride salt: 1H-NMR (400 MHz, DMSO-d6) δ12.19 (1H, s), 8.31 (1H, d, J = 8.9 Hz), 8.16 (2H, sa), 8, 05 (1H, s), 7.97 (1H, s), 7.60 (1H, s), 6.60 (1H, s), 4.19 (2H, m), 4.03 (2H, m ), 3.65 (1H, m), 1.30 (3H, d, J = 6.8 Hz).

Example 19

image 1

(R) –2– [4– (4 – Fluoro – 2 – methyl – 1 H –pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methylpyrrolo [2,1 – f] [1,2, 4] triazin – 6-yloxy] –1– methyl-ethylamine

Compound A of Example 18 was treated with 4-fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridin-5-ol, after which the azide reduction as described in the preparation of Example 18 provided the title compound. The product was purified by preparative CLAR. LC / MS: m / z 371 (M + H +). Hydrochloride salt: 1H-NMR (400 MHz, DMSO-d6) δ7.97 (1H, d, J = 8.9 Hz), 7.71 (1H, s), 7.64 (1H, s), 6, 20 (1H, s), 4.09 (1H, dd, J = 10.1; 3.8 Hz), 3.93 (1H, dd, J = 10.1; 3.8 Hz), 3.59 (1H, m), 3.21 (2H, m), 2.43 (3H, s), 1.81 (3H, s), 1.30 (3H, d, J = 6.8 Hz).

Example 20

image 1

2– [4– (4 – Fluoro-1H – pyrrolo [2,3-b] pyridin-5-yloxy) –5-methylpyrrolo [2,1-f] [1,2,4] triazin-6-yloxy] –Ethylamine

A. A 25 ml flask was charged with 5-methyl-4-phenoxypyrrolo [2,1-f] [1,2,4] triazin-6-ol (450 mg; 1.87 mmol, WO0071129), tert- butyl ester of (2-hydroxyethyl) -carbamic acid (577 µl; 3.73 mmol), tetrahydrofuran (9.3 ml) and cooled to 0 ° C. Then triphenylphosphine (978 mg; 3.73 mmol) and diethyl azodicarboxylate (310 µl; 1.96 mmol) were added. The mixture was stirred at 23 ° C for 15 h and then concentrated in vacuo. The crude material was purified by flash chromatography eluting with a mixture of 20% ethyl acetate in hexane to give tert-butyl ester of acid [2– (5-methyl-4-phenoxypyrrolo [2,1-f] [1 , 2,4] triazin-6-yloxy) -ethyl] -carbamic. 1H – NMR (400 MHz, DMSO – d6) δ8.98 (1H, s), 7.93 (1H, s), 7.89 (1H, s), 7.46 (2H, t, J = 4, 5 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.04 (1H, t, J = 5.6 Hz), 4.05–3.98 (4H, m), 2 , 36 (3H, s), 1.38 (9H, s). LC / MS; m / z 385 (M + H +).

B. The procedure described in Step A of Example 7 was applied starting from (865 mg; 2.25 mmol) of tert-butyl ester of acid [2– (5-methyl-4-phenoxypyrrolo [2,1-f] [ 1,2,4] triazin-6-yloxy) -ethyl] -carbamic to provide tert-butyl ester of [2– (5-methyl-4-methylsulfanyl-pyrrolo [2,1-f] [1,2,4 ] triazin-6-yloxy) -ethyl] -carbamic (652.7 mg; 86%). 1H – NMR (400 MHz, DMSO – d6) δ8.98 (1H, s), 8.17 (1H, s), 7.79 (1H, s), 7.02 (1H, t, J = 5, 6 Hz), 4.02 (2H, c, J = 7.3 Hz), 3.96 (2H, t, J = 5.6 Hz), 2.59 (3H, s), 2.35 (3H , s), 1.37 (9H, s). LC / MS; m / z 339 (M + H +).

C. The procedure described in Example 7 was used starting from (100 mg; 0.30 mmol) of tert-butyl ester of acid [2– (5-methyl-4-methylsulfanylpyrrolo [2,1-f] [1,2 , 4] triazin-6-yloxy) -ethyl] -carbamic to provide tert-butyl ester of {2– [4– (4-fluoro-1H-pyrrolo [2,3-b] pyridin-5-yloxy) –5 -Methyl-pyrrolo [2,1-f] [1,2,4] triazin-6-yloxy] -ethyl} -carbamic (42 mg; 73%). 1H – NMR (400 MHz, DMSO – d6) δ12.17 (1H, s), 8.31 (1H, d, J = 9.3 Hz), 7.96 (1H, s), 7.94 (1H , s), 7.62 (1H, s), 7.05 (1H, m), 6.60 (1H, s), 4.02 (2H, m), 3.32 (2H, m), 2 , 40 (3H, s), 1.38 (9H, s). LC / MS; m / z 443 (M + H +).

D. To a solution of tert-butyl ester of acid {2– [4– (4-fluoro-1H-pyrrolo [2,3-b] pyridin-5-yloxy) –5-methylpyrrolo [2,1– f] [ 1,2,4] triazin-6-yloxy] -ethyl} -carbamic (30 mg; 0.068 mmol) in dichloromethane (1.4 ml), trifluoroacetic acid (0.14 m) was added at RT After 160 min, the mixture was concentrated and the residue was purified by preparative CLAR and, after concentration, the hydrochloride salt was formed using a 1N aqueous solution of HCl in acetonitrile, and the salt was lyophilized to provide 2– [4– ( 4-fluoro-1H-pyrrolo [2,3-b] pyridin-5-yloxy) -5- methylpyrrolo [2,1-f] [1,2,4] triazin-6-yloxy] -ethylamine (14,1 mg; 53%) as a white lyophilized product. 1H – NMR (400 MHz, DMSO – d6) δ12.19 (1H, s), 8.31 (1H, d, J = 9.6 Hz), 8.13 (3H, sa), 8.05 (1H , s), 7.97 (1H, s), 7.62 (1H, t, J = 3.0 Hz), 6.59 (1H, dd, J = 1.8; 3.5 Hz), 4 , 24 (2H, t, J = 4.8 Hz), 3.26 (2H, c, J = 5.3 Hz), 2.47 (3H, s). LC / MS; m / z 343 (M + H +). HRMS calculated for C16H15FN6O2: 343.1318; Found: 343.1309.

The following examples were prepared using a procedure similar to that described for the preparation of Example 7, using the appropriate hidoxiazaindole. However, the sulfone of Example 7 of the following examples was replaced by the appropriate chloroimidate. See Example 25 for the preparation of the 5-isopropylpyrrolo [2,1-f] -triazine that is needed for Example 22.

image 1

Table 2:

Ex.

R1 R2 Name LC / MS (M + H) + Performance (%)

twenty-one

I COOEt 4– (4-Fluoro-1H- pyrrolo [2,3-b] pyridin-5-yloxy) -5- methyl-pyrrolo [2,1-f] [1,2,4] triazin-6– acid ethyl ester carboxylic 356 24

22

i – Pr COOMe Methyl ester of 4– (4-fluoro– 1H-pyrrolo [2,3-b] pyridin-5-yloxy) - 5-isopropylpyrrolo [2,1– f] [1,2,4] triazin-6-carboxylic acid 370 33

Example 23

image 1

(R) –1– [5 – Methyl – 4– (2 – methyl – 1 H –pyrrolo [2,3 – b] pyridin – 5 – yloxy) –pyrrolo [2,1 – f] [1,2,4] triazin – 6 – yloxy] –propan – 2 – ol

Sulfone 1– (4-methanesulfonyl-5-methyl-pyrrolo [2,1-f] [1,2,4] triazin-6-yloxy) -propan-2-ol with 4-fluoro-2–

15 methyl-1H-pyrrolo [2,3-b] pyridin-5-ol according to the procedure described in Example 4 (yield 55%). LC / MS; m / z 354 (M + H +), Hydrochloride salt: 1H-NMR (400 MHz, DMSO-d6) δ11.65 (1H, s), 8.04 (1H, s), 7.90 (1H, s) , 7.87 (1H, s), 7.75 (1H, s), 6.17 (1H, s), 4.33 (1H, m), 3.98 (1H, m), 3.85 ( 2H, m), 2.49 (3H, s), 2.40 (3H, s), 1.16 (3H, d, J = 6.8 Hz).

Example 24

twenty

image 1

(4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5-yl) - [5 – isopropyl – 6– (3-methyl– [1,2,4] oxadiazol – 5-yl) –pyrrolo [ 2.1– f] [1,2,4] triazin– 4-yl] –amine

A. To a solution of N-hydroxyacetamidine (315 mg; 4.25 mmol) in THF (10 ml) at 0 ° C, sodium hydride (60% in oil; 340 mg; 8.5 mmol) was added in small portions and the resulting mixture was stirred for 20 min. Then 5-isopropyl-4-oxo-3,4-dihydro-pyrrolo [2,1-f] [1,2,4] triazine-6-carboxylic acid methyl ester was added and the mixture was heated in a pressure vessel at 80˚C for 18 h. The reaction mixture was cooled again and the precipitate was filtered. The filtrate was diluted with ethyl acetate and washed with saturated ammonium chloride, brine (50 ml),

30 was dried (MgSO4), filtered and concentrated to provide 5-isopropyl-6- (3-methyl- [1,2,4] oxadiazol-5-yl) -3H- pyrrolo [2,1-f] [ 1,2,4] triazin-4-one (520 mg; 95%).

B. To a solution of the oxadiazole of the previous step (300 mg; 1.08 mmol) in toluene (7 ml), phosphorous oxychloride (122 µl; 1.29 mmol) and diisopropylethylamine (150 µl; 0.86 mmol) were added ), and the reaction mixture was heated to reflux for 3 days. The reaction mixture was cooled again and poured onto ice cold saturated sodium bicarbonate solution. The separated aqueous layer was extracted with ethyl acetate (2 x 25 ml) and the combined organic layers were washed with brine (50 ml), dried (MgSO4), filtered and evaporated to provide 4-chloro-5-isopropyl –6– (3-methyl– [1,2,4] oxadiazol-5-yl) -pyrrolo [2,1-f] [1,2,4] raw triazine that was used directly in the next stage (280 mg , 94%).

C. Diisopropylethylamine (0.1 ml; 0.5 mmol) was added to a solution of 4-chloro-5-isopropyl-6- (3-methyl- [1,2,4] oxadiazol-5-yl) -pyrrolo [2,1-f] [1,2,4] triazine (54 mg; 0.18 mmol; see Example 25) and 4-fluoro-1 H -pyrrolo [2,3- b] pyridine-5-ylamine ( 30 mg, 0.18 mmol) in DMF (1.0 ml). The mixture was stirred at T.A. for 16 h, it was stopped with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layers were washed with brine (50 ml), dried, filtered and concentrated. The residue was purified by preparative CLAR to provide the title compound (34 mg; 43%). LC / MS: m / z 393 (M + H) + Monohydrochloride salt: 1H-NMR (400 MHz, DMSO-d6) δ11.99 (1H, s), 8.12 (1H, s), 7.89 ( 1H, s), 7.50 (1H, s), 6.55 (1H, sa), 4.16 (1H, m), 2.43 (3H, s), 1.44 (6H, d, J = 7.3 Hz).

The intermediate compound, fluoro-1H-pyrrolo [2,3-b] pyridin-5-ylamine, was prepared as explained below:

D. A 100 ml round bottom flask was dried in the oven and refilled with argon. The flask was charged with 4-fluoro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine (763 mg; 2.61 mmol), THF (17.4 ml) and the mixture was cooled to -78˚ C. A solution of sec-butyllithium (1.10M in THF; 5.21 ml; 5.74 mmol) was added dropwise, and after 30 minutes, 1-sulfonylazido-4-methylbenzene (1.29 g) was quickly added ; 6.52 mmol) in THF (7.4 ml). After 25 h, a saturated ammonium chloride solution was added and the mixture was allowed to reach T.A. The mixture was extracted with ethyl acetate (3 x 50 ml) and the combined organic layers were washed with water (100 ml), brine (100 ml), dried and concentrated in vacuo. The crude material was stirred in hexanes to remove excess 1-azido-4-methylbenzene, and the filtrate was purified by flash chromatography eluting with a mixture of 2.5% ethyl acetate in hexanes to give 5– azido-4-fluoro-1-triisopropylsilanyl-1H-pyrrolo [2,3- b] pyridine (746 mg; 86%) as a colorless oil. 1H – NMR (400 MHz, DMSO – d6) δ8.16 (1H, d, J = 10.3 Hz), 7.56 (1H, d, J = 3.3 Hz), 6.71 (1H, d , J = 3.6 Hz) 1.84 (3H, m), 1.05 (9H, s), 1.03 (9H, s). LC / MS: m / z 334 (M + H +).

E. The procedure described for the desylation of Example 7 was applied to provide 5-azido-4-fluoro-1H-pyrrolo [2,3-b] pyridine. 1H – NMR (400 MHz, DMSO – d6) δ 12.10 (1H, s), 8.14 (1H, d, J = 10.1 Hz), 7.57 (1H, t, J = 2.5 Hz ), 6.53 (1H, dd, J = 1.8; 3.3 Hz). LC / MS; m / z 178 (M + H).

F. The procedure for the conversion of the azide group to the amine group described in Example 18 using 310.27 kPa of hydrogen was applied to 5-azido-4-fluoro-1H-pyrrolo [2,3-b] pyridine provide 4-fluoro-1H-pyrrolo [2,3-b] pyridin-5-ylamine (91% yield) as a tan solid. 1H – NMR (400 MHz, DMSO – d6) δ11.42 (1H, s), 7.84 (1H, d, J = 10.9 Hz), 7.30 (1H, t, J = 3.0 Hz ), 6.28 (1H, dd, J = 1.9; 3.6 Hz). LC / MS; m / z 152 (M + H +). HRMS calculated for C7H6FN3: 151.0545; Found: 151.0549.

Example 25

image 1

(4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5-yl) - [5 – isopropyl – 6– (5-methyl– [1,3,4] oxadiazol – 2-yl) –pyrrolo [ 2.1– f] [1,2,4] triazin – 4-yl] –amine

A. Ethyl isocyanoacetate (80 g; 0.71 mol) was dissolved in 1 L of dry tetrahydrofuran under nitrogen and 1,8-diazabicyclo [5.4.0] undec-7-ene (107.7 g; 0, 71 mol) to the solution. A solution of isobutyraldehyde (29.7 g; 0.41 mol) in 1.5 l of dry tetrahydrofuran was added dropwise at room temperature for 3 hours. The mixture was then stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo to obtain a brown oil. The concentrate was partitioned between 1.2 L of ethyl acetate and 0.5 L of water. The organic layer was then washed with 0.4 L of 0.1N hydrochloric acid followed by 0.3 L of saturated sodium bicarbonate solution and then 0.3 L of saturated brine. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo to obtain a brown oil. The residue was dissolved in toluene and added to a column of 1,600 ml (~ 800 g) of silica gel moistened with hexane. The product was eluted at a nitrogen pressure of 103.42 kPa first with 4.8 L of hexane followed by 5 L of 20% ethyl acetate in hexane. The eluent containing product observed was combined by TLC analysis and concentrated in vacuo to obtain a yellow oil. The concentrate was dry pumped under high vacuum to give product A, 3– (1-methyl ethyl) pyrrole-2,4-dicarboxylic acid diethyl ether (54 g; 60% yield) of yellow oil which solidified at rest at temperature ambient. TLC silica gel: Rf = 0.2; hexane / ethyl acetate (4/1) UV visualization and PMA staining. 1H-NMR: (CDCl3) δ1-1-1.5 (m, 12H), 4.2-4.3 (m, 1H), 4.3-4.3 (m, 4H), 7.5 ( d, 1H).

5

10

fifteen

twenty

25

30

35

40

B. To a suspension of NaH (13.9 g; 34 mmol, 60% in oil) in DMF (0.36 l) at 0˚C, a solution of Compound A (75 g; 29 mmol) in DMF was added (0.4 l). After stirring for 45 min, 2,4-dinitrohydroxylamine was added in small portions. Once the addition was complete, the cold bath was removed and the mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, 10% lithium chloride (LiCl) and brine, then dried and concentrated. The residue was purified to provide the desired 1-amino-3– (1-methyl ethyl) pyrrole-2,4-dicarboxylic acid diethyl ester compound as an oil (81 g) at 80% purity, which was used without major purification.

C. Compound B (77.7 g; 0.29 M) was mixed with formamide (0.5 L) and heated to 160 ° C. After 8 h, the mixture was allowed to cool to T.A., stirred for 2 days and then diluted with water (4 L). The product was extracted with ethyl acetate. The organic layer was concentrated, toluene was added to the residue and concentrated again. The brown solid was triturated with ether and dried under high vacuum to provide 5– (1-methyl ethyl) pyrrolo [2,1- f] [1,2,4] triazin-4 (3H) -one– ethyl ester 6-carboxylic as a light brown solid (45 g; 62%). LC / MS; (M + H) + = 250.1.

D. A 5-isopropyl-4-oxo-3,4-dihydro-pyrrolo [2,1- f] [1,2,4] triazine-6-carboxylic acid ethyl ester suspension was suspended in water (4 ml) and hydrazine hydrate (4 ml) was heated at 110˚C for 24 h. The reaction mixture was cooled again and the precipitate formed was isolated by filtration and air dried. The solid was suspended in ethyl acetate and acetyl chloride (853 µl; 12 mmol) was added. The mixture was stirred at T.A. for 2 days and the solid was isolated by filtration, washed with ethyl acetate and air dried to provide 5-isopropyl-6- (5-methyl- [1,3,4] oxadiazol-2-yl) -3H -Pyrrolo [2,1-f] [1,2,4] triazin-4-one (575 mg; 35%).

E. The procedure for the formation of chloroimidate described in Example 24 was used to convert 5-isopropyl-6- (5-methyl- [1,3,4] oxadiazol-2-yl) -3H-pyrrolo [2, 1-f] [1,2,4] triazin-4-one in 4-chloro-5-isopropyl-6– (5– methyl– [1,3,4] oxadiazol-2-yl) –pyrrolo [2, 1-f] [1,2,4] triazine in a quantitative yield that was used directly without any purification.

F. The procedure described in Example 24 of aniline coupling was used to react 4-chloro-5-isopropyl-6- (5-methyl- [1,3,4] oxadiazol-2-yl) -pyrrolo [2,1-f] [1,2,4] triazine and 4-fluoro-1 H -pyrrolo [2,3-b] pyridine-5-ylamine to provide the title compound (41% yield). Monohydrochloride salt: 1H-NMR (400 MHz, MeOD-d4) δ8.26 (1H, s), 8.00 (1H, s), 7.50 (1H, m), 6.69 (1H, m. ), 4.08 (1H, m), 2.51 (3H, s), 1.40 (6H, d, J = 7.1 Hz).

The following examples were prepared using the coupling procedure exemplified in the Example

24. Examples 26 and 27 were prepared using a procedure similar to that described for the preparation of Example 24 and 25, respectively, using the appropriate 5-aminoazaindole. Example 28 was done in a manner similar to that in Example 18.

image 1

Table 3:

Ex.

R1 R2 R3 Name LC / MS (M + H) + Yield (%)

26

i – Pr I (4 – Fluoro – 2 – methyl – 1H– pyrrolo [2,3-b] pyridin-5-yl) - [5– isopropyl-6– (5-methyl– [1,3,4] oxadiazol-2-yl ) - pirrolo [2,1 – f] [1,2,4] triazin – 4– il] –amine 407

26

(continuation)

Ex.

R1 R2 R3 Name LC / MS (M + H) + Yield (%)

27

i – Pr I (4 – Fluoro – 2 – methyl – 1H– pyrrolo [2,3-b] pyridin-5-yl) [5– isopropyl-6– (3-methyl– [1,2,4] oxadiazol-5-yl) - pirrolo [2,1 – f] [1,2,4] triazin – 4– il] –amine 407 9

28

I (R) –MeCH (NH2) CH2O H (R) - [6– (2-Amino-propoxy) - 5-methylpyrrolo [2,1– f] [1,2,4] triazin-4-yl] - (4– fluoro – 1H – pirrolo [2, 3– b] pyridin – 5 – yl) –amine 356 86

29

I NH2SO2NH (CH2) 2O H N– {2– [4– (4 – Fluoro – 1H– pyrrolo [2,3 – b] pyridin – 5– ylamino) –5 – methyl-pyrrolo [2,1– f] [1,2,4] triazin –6 – iloxy] –ethyl} - sulfamide 421 56

30

I (R) –MeCH (OH) CH2O H (R) –1– [4– (4 – Fluoro – 1H– pyrrolo [2,3 – b] pyridin – 5– ylamino) –5 – methyl-pyrrolo [2,1– f] [1,2,4] triazin – 6 – yloxy] - propan – 2 – ol 357 twenty

31

i – Pr COOMe H Methyl ester of 4– (4– Fluoro-1H-pyrrolo [2,3– b] pyridin-5-ylamino) –5– isopropylpyrrolo [2,1– f] [1,2,4] triazin-6-carboxylic acid 369 40

Example 32

image 1

1– [5-isopropyl-4– (1H-pyrrolo [2,3-b] pyridin-5-ylamino) -pyrrolo [2,1-f] [1,2,4] triazin-6-yloxy] –propan –2 – ol

1– (5-Isopropyl-4-methylsulfanylpyrrolo [2,1-f] [1,2,4] triazin-6-yloxy) -propan-2-ol (262 mg; 0.93 mmol,

10 obtained from Example 25 using the procedure of Step B of Example 7) and 1-triisopropylsilanyl-1H-pyrrolo [2,3- b] pyridine-5-ylamine (290 mg; 0.93 mmol) in chloroform and added m-chloroperbenzoic acid (60%, 535 mg, 1.86 mmol). The mixture was heated at 120˚C for 10 min in an Optimizer ™ microwave oven from Personal Chemistry Smith Enrys. The solution was evaporated in vacuo and the residue was purified by preparative CLAR. The isolated product was dissolved in THF (10 ml) and TBAF (1.0M; 0.2 ml; 0.2 mmol) was added. The mixture was stirred for 5 min. Be

15 evaporated the solvent in vacuo. The residue was purified by preparative CLAR to provide the title compound (34 mg; 1%).

The intermediate compound, 1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridin-5-ylamine, was prepared as explained below:

A. 4-Chloro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine (10 mg; 32.5 mmol) was dissolved in THF (250 ml) and cooled

20 to –78˚C. Then sec-butyllithium (54.8 ml; 1.3M / cyclohexane, 71.4 mmol) was added dropwise and the solution was stirred for 20 min. A solution of tosylazide (16 g; 81.2 mmol) in THF (100 ml) was added and the mixture was stirred for 1 h. The reaction mixture was stopped with saturated ammonium chloride (50 ml) and heated to

T.A. The mixture was extracted with hexanes (2 x 200 ml) and the combined organic layers were dried. The organic phase was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; 100% hexanes) to provide 5-azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine as a

5 mixture with starting material (10.2 g). This mixture was used directly in the next stage.

B. 5-azido-4-chloro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine (1.6 g; 4.6 mmol) was dissolved in ethyl acetate (100 ml) and Pd was added / C (10%, 100 mg). This suspension was stirred at T.A. and under 1 atmosphere of hydrogen for 18 h. The solid was removed by filtration over Celite® and the solution was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 95% hexanes, 5% ethyl acetate) to

10 provide 4-chloro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridin-5-ylamine (730 mg; 43.5%; 2 steps).

C. Dilute 4-chloro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridin-5-ylamine (10.2 g; 31.5 mmol) in ethyl acetate (200 ml) and acetic acid ( 100 ml) Zinc powder (50 g; 0.8 mol) was added in small portions to T.A. After shaking the suspension to T.A. for 4 h, the mixture was filtered over Celite and the filtrate was slowly neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (2 x 300 ml). The organic layers were dried

Combined, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, 5% ethyl acetate in hexanes) to provide 1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine-5-ylamine (6.38 g ).

Examples 33–35 were prepared as explained below. Example 33 was synthesized in a manner similar to the preparation of Example 32. Examples 34 and 35 were prepared in a manner similar to preparation 20 of Example 24.

image 1

25 Table 4:

Ex.

R1 R2 Name LC / MS (M + H) + Yield (%)

33

(R) - MeOCH2CH (OH) CH2O H (R) –1– [5 – Isopropyl – 4– (1H – pyrrolo [2,3– b] pyridin – 5 – ylamino) - pyrrolo [2,1– f] [1,2,4] triazin – 6– iloxy] - 3 – methoxypropan – 2 – ol 375

33

3. 4

COOMe H Methyl ester of 5– isopropyl-4– (1 H -pyrrolo [2,3-b] pyridin-5-ylamino) -pyrrolo [2,1– f] [1,2,4] triazine-6– carboxylic acid 351 36

35

I [5 – Isopropyl – 6– (5– methyl– [1,3,4] oxadiazol– 2-yl) –pyrrolo [2,1– f] [1,2,4] triazin – 4-yl] - (2 - methyl – 1H – pyrrolo [2,3– b] pyridin – 5-yl) –amine 389 86

Example 36

image 1

5-Isopropyl-4– [methyl- (1 H -pyrrolo [2,3-b] pyridin-5-yl) -amino] -pyrrolo [2,1-f] [1,2,4] triazine acid methyl ester 6-carboxylic

The title compound was prepared in a manner similar to the preparation of Example 24 using methyl- (1 H -pyrrolo [2,3-b] pyridin-5-yl) -amine and 4-chloro-5-isopropylpyrrolo [methyl] 2,1-f] [1,2,4] triazine-6-carboxylic. (25% yield). LC / MS; m / z 365 (M + H +). Monohydrochloride salt: 1H – NMR (400 MHz, DMSO – d6) δppm 11.73 (1H, s), 8.22 (1H, s), 8.00 (1H, s), 7.75 (1H, s) , 7.50 (1H, s), 6.40 (1H, s), 3.70 (3H, s), 3.26 (1H, m), 2.51 (3H, s), 0.54 ( 6H, d, J = 7.3 Hz).

The intermediate compound, methyl- (1 H -pyrrolo [2,3-b] pyridin-5-yl) -amine, was prepared as explained below:

A. 1-Triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridin-5-ylamine (375 mg; 1.3 mmol) and triethylamine (271 ml; 1.95 mmol) in dichloromethane (10 ml) were treated with di-tert-butyl dicarbonate (340 mg; 1.5 mmol) and the mixture was stirred at RT for 2.5 h, it was stopped with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4), filtered and concentrated. The residue was purified by preparative CLAR.

B. Then 1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridin-5-yl) -carbamic acid tert-butyl ester (250 mg, 0.6 mmol) was treated with sodium hydride (24 mg, oil 60%, 0.6 mmol) and methyl iodide (48 µl; 0.77 mmol) in DMF (2.0 mL). The mixture was stirred at T.A. for 16 h, it was stopped with saturated ammonium chloride (20 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4), filtered and concentrated. The residue, which was used without further purification, was then treated with TFA (1.0 ml) in dichloromethane (4.0 ml) and the mixture was stirred at T.A. for 10 h, it was concentrated and purified by preparative CLAR to provide methyl (1 H -pyrrolo [2,3-b] pyridin-5-yl) -amine (31 mg, 33%). m / z 148 (M + H) +.

Example 37

image 1

Ethyl– [5-isopropyl-6– (3-methyl– [1,2,4] oxadiazol-5-yl) -pyrrolo [2,1-f] [1,2,4] triazin-4-yl] - (1H – pyrrolo [2,3 – b] pyridin– 5-yl) –amine

The procedure described in Example 24 was used. Thus, when 4-chloro-5-isopropyl-6- (3-methyl- [1,2,4] oxadiazol-5-yl) -pyrrolo [2,1] -F] [1,2,4] triazine (86 mg; 0.31 mmol), ethyl - (1 H -pyrrolo [2,3-b] pyridin-5-yl) -amine (50 mg; 0.31 mmol ) and diisopropylethylamine (162 µl; 0.93 mmol) in DMF (2.0 mL), the title compound was obtained. LC / MS: m / z 403 (M + H) +. Monohydrochloride salt: 1H-NMR (400 MHz, DMSO-d6) δ9.70 (1H, s), 8.20 (1H, s), 8.02 (1H, s), 7.52 (1H, s), 7.29 (1H, s), 6.38 (1H, sa), 4.10 (2H, c, J = 6.8 Hz), 3.24 (1H, m), 2.30 (3H, s ), 1.19 (3H, t, J = 6.8 Hz), 0.59 (6H, d, J = 7.1 Hz), (1H, m), 2.30 (3H, s), 1 , 19 (3H, t, J = 6.8 Hz), 0.59 (6H, d, J = 7.1 Hz).

The intermediate compound, ethyl- (1 H -pyrrolo [2,3-b] pyridin-5-yl) -amine, was prepared as explained below:

A. Acetyl chloride (75 µl; 1.0 mmol) was added to a solution of 1-triisopropylsilanyl-1 H -pyrrolo [2,3-b] pyridine-5-ylamine (230 mg; 0.8 mmol) and 4 –Dimethylaminopyridine (5 mg) in pyridine (1.6 ml). The mixture was stirred at T.A. for 24 h, and a saturated solution of ammonium chloride (30 ml) and ethyl acetate (30 ml) were added. The separated aqueous layer was extracted with ethyl acetate (3 x 25 ml) and the combined organic layers were dried, filtered and concentrated to provide an oil that was purified by preparative CLAR to give N– (1– triisopropylsilanyl-1H– pyrrolo [2,3-b] pyridin-5-yl) -acetamide (140 mg, 53%) as an oil: LC / MS; m / z 332 (M + H +).

COAT. under argon, a solution of borane-dimethyl sulfide complex (665 µl; 6.6 mmol, 10M) was added to N-methyl-N- (1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine-5– il) -acetamide (110 mg; 0.33 mmol) in THF (3.0 ml). The mixture was heated to 65 ° C for 2 h, cooled again and a 6N hydrochloric acid solution was added slowly. The mixture was heated to 100 ° C and stirred vigorously for 12 h, cooled again and a 6N sodium hydroxide solution was added until pH 7 was reached. The mixture was extracted with ethyl acetate (3 x 15 ml) and the combined organic layers were dried, filtered and evaporated to provide an oil that was purified through a SCX column of silica gel (arylsulfonic acid with methanol washes and 2N NH3 in methanol) to give ethyl– (1H– pyrrolo [2,3-b] pyridin-5-yl) -amine. LC / MS; m / z 203 (M + AcCN), 162 (M + H) +.

Claims (12)

1. A compound of formula (I): image 1 in which: Z is selected from O or S, and R41 is absent; X and Y are independently selected from O, OCO, S, SO, SO2, CO, CO2, NR10, NR11CO, NR12CONR13, NR14CO2, NR15SO2, NR16SO2NR17, SO2NR18, CONR19, halogen, nitro, cyano, or X or Y are absent; R1 is hydrogen, CH3, OH, OCH3, SH, SCH3, OCOR21, SOR22, SO2R3, SO2NR24R24, CO2R26, CONR27R28, NH2 NR29SO2NR30R31, NR32SO2R33, NR34COR35, NR36CO2R37, halogen, nitro or cyano; R2 and R3 are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl, substituted alkynyl, aryl, substituted aryl, heterocycle, substituted heterocycle, aralkyl, substituted aralkyl, heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; with the proviso that when X is halo, nitro or cyano, R2 is absent, and when Y is halo, nitro or cyano, R3 is absent; R6 is H, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, NR7R8, OR9 or halogen; R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R21, R24, R25, R26, R27, R28, R29, R30, R31, R32, R34, R35, R36, R38, R39 and R40 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocycle or substituted heterocycle; R22, R23, R33 and R37 are independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heterocycle or substituted heterocycle; R42 is image 1 (R43) n in which n is equal to 0, 1 or 2 and each R43 is independently selected from the group consisting of hydrogen, fluorine, chlorine and methyl; and R44 is methyl or hydrogen, with the additional condition that

to.

R2 cannot be hydrogen if X is SO, SO2, NR13CO2 or NR14SO2; Y

b.

R3 cannot be hydrogen if Y is SO, SO2, NR13CO2 or NR14SO2;

or one of its enantiomers, diastereomers, or one of its pharmaceutically acceptable salts or solvates, in which the term "substituted alkyl" refers to an alkyl group substituted by one to four substituents selected from halo, hydroxyl, alkoxy, oxo, alkanoyl , aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralcanoylamino, substituted alkanoylamino, substituted arylamino, aralcanoylamino 5 10 fifteen twenty 25 30 35 40 Four. Five substituted, thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthio, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, substituted sulfonamido, nitro, cyano, carboxyl, carbamyl, substituted carbamyl selected from CONH (aryl), CONH (alkyl), CONH (aralkyl) or the cases in which there are two substituents in the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles, and in which when the substituent is also substituted, it will be with alkyl, alkoxy, aryl or aralkyl; the term "substituted aryl" refers to an aryl group substituted by one to four substituents selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, alralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxyl, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthio, arylthiono, arylsulfonylamine, sulfonic acid, alkylsulfonyl, sulfonamido and aryloxy, and in which the substituent may also be substituted by hydroxyl, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl; the term "substituted alkenyl" refers to an alkenyl group substituted by one to two substituents selected from halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthio, alkylsulfonyl, sulfonamido, nitro , cyano, carboxyl, carbamyl, substituted carbamyl, guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl and pyrimidyl; the term "substituted alkynyl" refers to an alkynyl group substituted by a substituent selected from halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthio, alkylsulfonyl, sulfonamido, nitro, cyano, carboxyl, carbamyl, substituted carbamyl, guanidino and heterocycle; the term "substituted heterocycle" refers to a saturated or unsaturated aromatic or non-aromatic cyclic group selected from a system of monocyclic rings of 4 to 7 members, bicyclic of 7 to 11 members or tricyclic of 10 to 15 members, which has at least a heteroatom in at least one ring containing a carbon atom, in which each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, in the that nitrogen and sulfur heteroatoms may also be optionally oxidized and nitrogen heteroatoms may also be optionally quaternized, wherein the substituents are selected from one or more alkyl or aralkyl groups as described above, or between one or more groups described formerly as alkyl substituents.

2.

A compound according to claim 1, wherein R1 is hydrogen or methyl; R6 is hydrogen; R3 is lower alkyl; and Z is oxygen.

3.

A compound according to claim 1, wherein R1 is hydrogen; R3 is lower alkyl; And it is absent; X is oxygen or nitrogen; R43 is fluorine or hydrogen; and R44 is hydrogen or methyl.

Four.

A compound according to claim 1, in the X is oxygen; R2 is a substituted alkyl and R43 is fluorine.

5.

A compound selected from the group consisting of:

(4-Fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) - [5-isopropyl-6– (3-methyl– [1,2,4,] oxadiazole-5– il) –pirrolo [2,1– f] [1,2,4] triazin – 4-il] –amina, (R) - [6– (2-Amino-propoxy) -5-methyl-pyrrolo [2,1-f] [1,2,4] triazin-4-yl] - (4-fluoro-1H-pyrrolo [ 2,3-b] pyridin-5-yl) -amine, N– {2– [4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – ylamino) –5 – methyl-pyrrolo [2,1 – f] [1,2,4] triazin –6 – iloxy] –ethyl} –sulfamide, (R) –1– [4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – ylamino) –5 – methyl – pyrrolo [2,1 – f] [1,2,4] triazin – 6 – yloxy] –propan – 2 – ol, Methyl-acid ester 4– (4-fluoro-1 H -pyrrolo [2,3-b] pyridin-5-ylamino) -5-isopropylpyrrolo [2,1-f] [1,2,4] triazin-6– carboxylic, 1– [5 – Isopropyl – 4– (1 H –pyrrolo [2,3 – b] pyridin – 5 – ylamino) –pyrrolo [2,1 – f] [1,2,4] triazin – 6-yloxy] –propan –2 – ol, (R) –1– [5 – Isopropyl – 4– (1 H –pyrrolo [2,3 – b] pyridin – 5 – ylamino) –pyrrolo [2,1 – f] [1,2,4] triazin – 6– iloxy] –3 – methoxy – propan – 2– ol, Methyl ester of 5-isopropyl-4– (1 H -pyrrolo [2,3-b] pyridin-5-ylamino) -pyrrolo [2,1-f] [1,2,4] triazine-6-carboxylic acid, 5-Isopropyl-4– [methyl- (1 H -pyrrolo [2,3-b] pyridin-5-yl) -amino] -pyrrolo [2,1-f] [1,2,4] triazin acid methyl ester 6– carboxylic and Ethyl– [5-isopropyl-6– (3-methyl– [1,2,4] oxadiazol-5-yl) -pyrrolo [2,1-f] [1,2,4] triazin-4-yl] - (1H-pyrrolo [2,3-b] pyridin-5-yl) -amine. 6. A compound selected from the group consisting of: 4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methyl – pyrrolo [2,1 – f] [1,2,4] triazin – 6 – ol, ( R) –1– [4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methylpyrrolo [2,1 – f] [1,2,4] triazin – 6 –Yloxy) –propan – 2 – ol, (S) –1– [4– (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5 – yloxy – 5 – methyl – pyrrolo [2,1 – f] [1,2,4] triazin –6 – iloxi] –propan – 2 – ol, (R) –1– [4– (4 – Fluoro – 2 – methyl – 1 H –pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methylpyrrolo [2,1 – f] [1,2, 4] triazin – 6 – yloxy] –propan – 2– ol, (R) –2– [4– (4 – Fluoro – 1H – pyrrolo (2,3 – b] pyridin – 5 – yloxy) –5 – methylpyrrolo [2,1 – f] [1,2,4] triazin– 6-yloxy] –1-methylethylamine, (R) –2– [4– (4 – Fluoro – 2 – methyl – 1 H –pyrrolo [2,3 – b] pyridin – 5 – yloxy) –5 – methylpyrrolo [2,1 – f] [1,2, 4] triazin-5-yloxy] -1-methyl-ethylamine, 2– [4– (4 – Fluoro-1H – pyrrolo [2,3-b] pyridin-5-yloxy) –5-methylpyrrolo [2,1-f] [1,2,4] triazin-6-yloxy] –Ethylamine, (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5-yl) - [5 – isopropyl – 6– (3-methyl– [1,2,4] oxadiazol – 5-yl) –pyrrolo [ 2,1 – f] [1,2,4] triazin– 4-yl] –amine, (4 – Fluoro – 1H – pyrrolo [2,3 – b] pyridin – 5-yl) - [5 – isopropyl – 6– (5-methyl– [1,3,4] oxadiazol – 2-yl) –pyrrolo [ 2,1 – f] [1,2,4] triazin– 4-yl] –amine, (4-Fluoro-2-methyl-1H-pyrrolo [2,3-b] pyridin-5-yl) - [5-isopropyl-6– (5-methyl- [1,3,4] oxadiazol-2-yl ) –Pirrolo [2,1– f] [1,2,4] triazin – 4-yl] –amine and [5 – Isopropyl – 6– (5 – methyl– [1,3,4] oxadiazol – 2-yl) –pyrrolo [2,1 – f] [1,2,4] triazin – 4-yl] - (2 –Methyl – 1H – pyrrolo [2,3 – b] pyridin – 5– yl) –amine.

7.

A pharmaceutical composition comprising at least one of the compounds of any one of claims 1 to 6 and a pharmaceutically acceptable carrier thereof.

8.

A pharmaceutical composition comprising at least one or more compounds of any one of claims 1 to 6 in combination with a pharmaceutically acceptable carrier and at least one additional anti-carcinogenic or cytotoxic agent.

9.

The pharmaceutical composition of claim 8, wherein said anti-carcinogenic or cytotoxic agent is selected from the group consisting of: linomide; αvβ3 integrin function inhibitors; angioestatin, razoxane, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrozole, borazol, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants, leuprodylectants of the receptor function of the plasminogen activator urokinase, antibodies against growth factors, antibodies against receptors of growth factors, bevacizumab, cetuximab, tyrosine kinase inhibitors, serine / threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine, analogs of adenosine, cytosine arabinoside, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mitramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulfan, thiophathosphamine, cyclophosphamidene, cyclophosphamidene, cyclophosphamidene, cyclophosphamidene, cyclophosphamidene, cyclophosphamidene, cyclophosphamidene, cyclophosphoramide docetaxel, epothilone analogues, discodermolide analogs, analogs of eleuterobin, etoposide, teniposide, amsacrine, topotecan, irrinotecan, flavopyridols, proteasome inhibitors, including bortezomib, and biological response modifiers.

10.

Use of at least one of the compounds of any one of claims 1 to 6 for the manufacture of a medicament intended to produce an antiangiogenic effect or a vascular permeability reducing effect,

or intended to inhibit the protein kinase activity of growth factor receptors or the tyrosine kinase activity of growth factor receptors in a mammalian species.

eleven.

Use of the composition of claim 7 for the manufacture of a medicament for the treatment of proliferative diseases or autoimmune diseases in a mammalian species.

12.

Use of at least one of the compounds of any one of claims 1 to 6 for the manufacture of a medicament intended to treat diseases associated with signal transduction pathways that function through the growth factor receptors in a species of mammalian