ZA200109577B - Pyrrolotriazine inhibitors of kinases. - Google Patents

Description

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PYRROLOTRIAZINE INHIBITORS OF KINASES

Related Applications

This application claims priority benefit under Title 35 § 119(e) of United

States provisional Application No. 60/135,265, filed May 21, 1999, and United States provisional Application No. 60/193,727, filed March 31, 2000.

Field of the Invention

This invention relates to compounds that inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2, FGFR-1, PDGFR, HERI, and HER2, thereby making them useful as anti-cancer agents. The compounds are also useful in the treatment of diseases, other than cancer, which are associated with signal transduction pathways operating through growth factor receptors such as VEGFR-2.

Background of the Invention : Normal angiogenesis plays an important role in a variety of processes ’ * including embryonic development, wound healing, obesity and several components of . 5 female reproductive function. Undesirable or pathological angiogenesis had been ¥ 20 associated with disease states including diabetic retinopathy, psoriasis, cancer, . rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, ; Trend Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31).

Alteration of vascular permeability is thought to play a role in both normal and pathophysiological processes (Cullinan-Bove et al, 1993,, Endocrinology 133: 829- 2% 83%: Scape cil, 1555 Cancer and Metwstasls Reviews, 12: 303-324).

Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine "30 kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity that leads to phosphorylation of tyrosine residues on both the receptor and other intracellular proteins, leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by

EE v5), . ' "WO 00/71129 PCT/US00/13420 amino acid sequence homology, have been identified. One of these subfamilies is presently comprised by the fms-like tyrosine kinase receptor, Flt or Fitl (VEGFR-1), the kinase insert domain-containing receptor, KDR (also referred to as Flk-1 or

VEGFR-2), and another fms-like tyrosine kinase receptor, Fit4 (VEGFR-3). Two of these related RTKSs, Flt and KDR, have been shown to bind 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). Binding of VEGF to these receptors expressed in heterologous cells had been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.

VEGF, along with acidic and basic fibroblast growth factor (aF GF & bFGF) have been identified as having in vitro endothelial cell growth promoting activity. By virtue of the restricted expression of its receptors, the growth factor activity of VEGF, in contrast to that of the FGFs, is relatively specific towards 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).

Lo In adults, endothelial cells have a low proliferation index except in cases of tissue remodeling, such as wound healing and the female reproductive cycle, and . 20 adipogenesis. However in pathological states such as cancer, inherited vascular diseases, endometriosis, psoriasis, arthritis, retinopathies and atherosclerosis, endothelial cells are actively proliferating and organizing into vessels. Upon 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

So © 7775 network. The ability of tumors to expand and metastasize 1s dependent upon the 000 formation of this vascular network.

Binding of VEGF or bFGF to their corresponding receptor results in dimerization, autophosphorylation on tyrosine residues and enzymatic activation.

These phosphotyrosine residues serve as “docking” sites for specific downstream signaling molecules and enzymatic activation results in proliferation of endothelial cells. Disruption of these pathways should inhibit endothelial cell proliferation.

Disruption of the FGFR-1 pathway should also affect tumor cell proliferation since this kinase is activated in many tumor types in addition to proliferating endothelial cells. Finally, recent evidence also suggests that disruption of VEGF signaling inhibits endothelial cell migration, a critical process in vascular network formation.

The over-expression and activation of VEGFR-2 and FGFR-1 in tumor- associated vasculature has suggested a role for these molecules in tumor angiogenesis.

Angiogenesis and subsequent tumor growth is inhibited by antibodies directed against

VEGF ligand and VEGF receptors, and by truncated (lacking a transmembrane sequence and cytoplasmic kinase domain) soluble VEGFR-2 receptors. Dominant mutations introduced into either VEGFR-2 or FGFR-1 which result in a loss of enzymatic activity inhibits tumor growth in vivo. Antisense targeting of these receptors or their cognate ligands also inhibits angiogenesis and tumor growth. Recent evidence has elucidated, in part, the temporal requirements of these receptors in tumor growth. It appears that VEGF signaling is critical in early tumor growth and bFGF is more important at a later time associated with tumor expansion.

Other RTKSs such as HER! and HER? are involved in cell proliferation and are associated with diseases such as psoriasis and cancer. Disruption of signal transduction by inhibition of these kinases would have an antiproliferative and therapeutic effect.

Description of the Invention

In accordance with the present invention, compounds of formula I }

Ry ZR*R® 2 S77

R“X

Nt A

R' I their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof inhibit the tyrosine kinase activity of growth factor receptors such as

VEGFR-2. In formula I and throughout the specification, the above symbols are defined as follows:

X and Y are independently selected from O, OCO, §, SO, SO,, CO, CO,, NR,

NR''CO, NR'2CONR'?, NR**CO,, NR'*S0,, NR'*SO,NR'’, SO,NR'%,

p ! - WO 00771129 PCT/US00/13420

CONR'®, halogen, nitro, cyano, or X or Y are absent;

Z is selected from 0, S, N, or CR;

R! is hydrogen, CH;, OH, OCH;, SH, SCH;, OCOR?', SORZ, SO,R?, SO,NR*R?,

CO,R*, CONR?’R?, NH,, NR¥SO,NR*R’’, NR*’SO;R*”, NR*COR>,

NR**CO,R*, NR®¥CONR¥R*, halogen, nitro, or cyano;

R? and R? are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, heterocycloalkyl or substituted heterocycloalkyl, or when X is halo, nitro or cyano R? is absent or when Y is halo, nitro or cyano R? is absent;

R* and R’ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, or R*and R’ may together form an optionally substituted monocyclic 5-7 membered saturated or unsaturated carbocyclic or heterocyclic ring, or an optionally substituted bicyclic 7-11 membered saturated or unsaturated carbocyclic or heterocyclic ring, except that when Z is O or §, R’ is absent, or when Z is : nitrogen, R* and R® are not both hydrogen;

Coe R® is H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted § heterocyclo, NR’R®, OR’ or halogen; } 20 R’ RE RS,RO R', RZ RZ RY RY RY RT RE RY RY, R* RS R¥ RY.

RZ R¥ R¥ R’' R%, R* R*¥ R* R® R* and R* are independently ; selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo;

R?, R? R* and R* are independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo; and

R? is selected from the group consisting of hydrogen, lower alkyl or substituted alkyl, or R? is absent if the carbon to which it is attached is part of an unsaturated aryl or heteroaryl ring; with the provisos that: a. R? may not be hydrogen if X is SO, SO,, NR'*CO;, or NR'*S0, b. R® may not be hydrogen if Y is SO, SO,, NR'>CO;, or NR"*SO0,.

Listed below are definitions of various terms used to describe this invention.

These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.

The term “alkyl” refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably | to 7 carbon atoms. The expression “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 in which the 2 amino substituents are selected from alkyl, ary! or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, ~~ alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SOoNH,, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. CONH,, substituted carbamyl e.g. CONHalkyl, CONHaryl, CONHaralky] or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as, , indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further 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 portion, such as phenyl, naphthyl, biphenyl and diphenyl! groups, each of which may be substituted.

The term “aralkyl” refers to an aryl group bonded directly through an alkyl group, such as benzyl. }

The term “substituted aryl” rcfers 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, aralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono,

. ‘ i. WO 00/71129 PCT/US00/13420 arylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, aryloxy and the like.

The substituent may be further substituted by hydroxy, 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, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom and at least one carbon atom-containing ring, for example, pyridine, tetrazole, indazole.

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, having 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, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, 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 § : carbon atoms, having one to four triple bonds. oo 20 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, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl oandthelike. A

The term “cycloalkyl” refers to an optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing | to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocylic ring.

Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include onc or more alkyl groups as described above, or one or more groups described above as alkyl substituents.

The terms “heterocycle”, “heterocyclic” and “heterocyclo” refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. 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, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.

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

Exemplary bicyclic hetrocyclic groups include 2,3-dihydro-2-oxo-1H-indolyl, } benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N- oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridiny! (such as furo[2,3-c]pyridinyl, furo{3,1-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4- oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazoly!, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryi, thienopyridyl, thienothieny!, and the like.

Exemplary substituents include one or more alkyl or aralkyl groups as described above or one or more groups described above as alkyl substituents.

1 5 WOO00/71129 PCT/US00/13420

Also included are smaller heterocyclos, such as, epoxides and aziridines.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

The compounds of formula I may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts arc also useful, e.g., in isolating or purifying the compounds of this invention.

The compounds of formula I may 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 as known to those skilled in the art.

The compounds for formula I may 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 others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts can be formed as known to those skilled in the ’ art. ; In addition, zwitterions (“inner salts”) may be formed. oo 20 All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly cmbraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by °° © © TTT 35 physical methods, such as, for example, fractional crystailization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

Compounds of the 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 formulas I) is a prodrug within the scope and spirit of the invention.

Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and

Methods in Enzvmology, 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 Deliverv Reviews, 8, 1-38 (1992);

It should further be understood that solvates (e.g., hydrates) of the compounds of formula 1 are also with the scope of the present invention. Methods of solvation 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 property of value in the treatment of disease states associated with angiogenesis . : and/or increased vascular permeability such as cancer. The invention relates to a pharmaceutical composition of compound of formula I, or pharmaceutically ] acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier in the treatment of hyperproliferative disorder in mammal. In particular, the said pharmaceutical composition is expected to inhibit the growth of those primary and recurrent solid tumors which are associated with VEGF, especially those tumors which are significantly dependent on VEGF for their growth and spread, including for example, cancers of the bladder, squamous cell, head, colorectal, oesophageal, 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 noncancerous disorders such as diabetes, diabetic retinopathy, psoriasis, rheumatoid arthritis, obesity, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies (including proliferative glomerulonephritis and diabetes-induced renal disease), atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ee

R ' a WO 00/71129 PCT/US00/13420 ocular diseases with retinal vessel proliferation, diabetic retinopathy, retinopathy of prematurity and macular degeneration. The invention also relates to prevention of blastocyte implantation in a mammal, treatment of atherosclerosis, excema, sclerodema, hemangioma. Compounds of the present invention posses good activity against VEGF receptor tyrosine kinase while possessing some activity against other tyrosine kinases.

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

According to a further feature of the invention there is provided a method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm- blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined herein before.

The compounds described herein also inhibit other receptor tyrosine kinases ) including HER1 and HER? and are therefore useful in the treatment of proliferative ; disorders such as psoriasis and cancer. The HER receptor kinase has been shown to . 20 be expressed and activated in many solid tumors including non-small cell lung, colorectal, and breast cancer. Similarly, the HER2 receptor kinase has been shown to : be overexpressed in breast, ovarian, lung and gastric cancer. Monoclonal antibodies that downregulate the abundance of the HER2 receptor or inhibit signaling by the

HERI receptor have shown anti-tumor effficacy in preclincal and clinical studies. It "© 735 is therefore expected that inhibitors of the HER and HER? kinases will have efficacy ~~ in the treatment of tumors that depend on signaling from either of the two receptors.

The ability of these compounds to inhibit HER further adds to their use as anti- angiogenic agents. See the following documents and references cited therein:

Cobleigh, M. A., Vogel, C. L., Tripathy, D., Robert, N. J, Scholl, S., Fehrenbacher,

L., Wolter, J. M., Paton, V., Shak, S., Lieberman, G., and Slamon, D. J., “Multinational study of the efficacy and safety of humanized anti-HHER2 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.

2639-2648 (1999); Baselga, J., Pfister, D., Cooper, M. R., Cahen, 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).

In addition, the formula I compounds of this invention may be used as contraceptives in mammals.

The antiproliferative, antiangiogenic and/or vascular permeability reducing treatment defined herein before may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.

The compounds of this invention may also be useful in combination with known anti- cancer and cytotoxic agents and treatments, including radiation. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formula I may be used sequentially : with known anticancer or cytotoxic agents and treatment, including radiation when a .

E combination formulation is inappropriate. ’ 20 In the field of medical oncology it is normal practice to use a combination of . different forms of treatment to treat each patient with cancer. In medical oncology the : other component(s) of such conjoint treatment in addition to the antiproliferative, antiangiogenic and/or vascular permeability reducing treatment defined herein before may be: surgery, radiotherapy or chemotherapy. Such chemotherapy may cover three main categories of therapeutic agent: 1) antiangiogenic agents that work by different mechanisms from those defined hereinbefore (for example, linomide, inhibitors of integrin avf33 function, angiostatin, razoxin); ’ (11) cytostatic agents such as antiestrogens (for example tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, borazole, exemestane), antiharmones, antiprogestogens, antiandrogens (for example flutamide, nilutamide,

ae ———— TT TTT TTT bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example gosereline acetate, luprolide), inhibitors of testosterone

Sa-dihydroreductase (for example finasteride), farnesyltransferase inhibitors, anti-invasion agents (for example metalloproteinase inhibitors like manimastat and inhibitors of urokinase plasminogen activator receptor function) and inhibitors of growth factor function, (such growth factors include for example EGF, FGF, platelet denved growth factor and hepatocyte growth factor such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors); and (ili) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as antimetabolites (for example antifolates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); Intercalating antitumour antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, : mithramycin); platinum derivatives (for example cisplatin, ) carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide : 20 nitrosoureas, thiotephan); antimitotic agents (for example vinca alkaloids like vincristine and taxoids like taxol, taxotere and newer : microbtubule agents such as epothilone analogs, discodermolide analogs, and eleutherobin analogs); topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, © 77735 topotecan); cell cycle inhibitors (for example flavopyridols); and biological response modifiers.

As stated above, the formula I compounds of the present invention are of interest for their antiangiogenic and/or vascular permeability reducing effects. Such compounds of the invention arc expected to be useful in a wide range of disease states including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, obesity, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and ocular diseases associated with retinal vessel proliferation such as diabetic retinopathy.

More specifically, the compounds of formula I are useful in the treatment of a vanety of cancers, including (but not limited to) the following: -carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; -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 cell lymphoma and Burkett's lymphoma; -hematopoietic tumors of myeloid lineage, 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 schwannomas; and -other tumors, including melanoma, seminoma, teratocarcinoma, : osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma. 3

Due to the key role of kinases in the regulation of cellular proliferation in general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.

Compounds of formula I may induce or inhibit apoptosis. The apoptotic response is aberrant in a variety of human diseases. Compounds of formula I, as modulators of apoptosis, will be useful in the treatment of cancer (including but not limited to those types mentioned hereinabove), viral infections (including but not limited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases

(including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel diseasc, 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, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related 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) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

The compounds of formula I are especially useful in treatment of tumors having a high incidence of tyrosine kinase activity, such as colon, lung, and pancreatic tumors. By the administration of a composition (or a combination) of the compounds of this invention, development of tumors in a mammalian host is reduced.

Compounds of formula I may also be useful in the treatment of diseases other

CT than cancer that may be associated with signal transduction pathways operating ; through growth factor receptors such as VEGFR-2. oo 20 The compounds of this invention may be formulated with a pharmaceutical vehicle or diluent for oral, intravenous or subcutaneous administration. The : pharmaceutical composition can be formulated in a classical manner using solid or liquid vehicles, diluents and additives appropriate to the desired mode of administration. Orally, the compounds can be administered in the form of tablets. 5 capsules, granules, powders and the like. The compounds may be administered ina ~~ dosage range of about 0.05 to 200 mg/kg/day, preferably less than 100 mg/kg/day, in a single dose or in 2 to 4 divided doses.

Biological assavs

VEGFR-2 and FGFR-1 Kinase assavs:

Reagents Final Concentration

Stock Solution VEGFR-2 FGFR-1

TrispH 7.0 20 mM 20mM

BSA 10 mg/ml 25 pg/ml 25ug/ml

MnCl, (1M) 1.5 mM 0.5 mM

MgCl; (1M) anna 0.5 mM

DTT(1M) 0.5 mM 0.5 mM

Enzyme Stock in 10%glycerol (1 mg/ml) Sng/rxn 20ng/rxn Polyglw/tyr (10 mg/ml) 80 pg/ml 30 ug/ml

ATP (1mM) 2.5 uM 1.0 uM y-ATP (10uCi/pul) 0.5 uCv/ml 0.5uCi

Incubation mixtures employed for VEGFR-2 or FGFR-1 assay contain the synthetic substrate polyGlu:Tyr, (4:1), ATP, ATP-y-**P and buffer containing Mn™— and/or Mg", DTT, BSA, and Tris buffer. The reaction is initiated by addition of enzyme and after 60 minutes is terminated by the addition of TCA to 30%. Inhibitors are brought to 10mM in 100% DMSO. Assays are prepared in a 96 well format.

Compounds are diluted 1:500 in 100% DMSO and then 1:10 in water for a final

DMSO concentration of 10%. 10 pL are added to rows B-H in a 96 well format of 10% DMSO. 20 pl of compound is added to row A at a concentration 5 fold higher than running conditions. Ten pL are transferred to each row with 10 pippetting : phases for mixing, and at row F 10 pL are discarded. Row G is a control with no . ; compound and row H is no compound and no enzyme control. Enzyme and substrate are delivered using a Tomtec Quadra station. }

Plates are covered with sticky plate tops, incubated at 27°C for 60 minutes, : and then acid precipitated with TCA for 20 minutes on ice. The precipitate is transferred to UniFilter-96, GF/C microplates using either a Tomtec or Packard

FilterMate harvester. Activity is determined by quantitating the incorporated radioactivity using a Packard TopCount Microplate Scintillation Counter following the addition of Microscint-20 cocktail into each dried well of the UniFilter microplates.

The instant compounds inhibit VEGFR-2 and FGFR-1 kinases with ICso values between 0.003 -25 pM.

HERI or HER? Kinase assavs:

Compounds of interest were assayed in a kinase buffer that contained 20 mM

Tris.HCI, pH 7.5, 10 mM MnCls, 0.5 mM dithiothreitol, bovine serum albumin at 0.1 mg/ml, poly(glu/tyr, 4:1) at 0.1 mg/ml, 1 pM ATP, and 4 pCi/ml [y-**PJATP.

Poly(glw/tyr, 4:1) is a synthetic polymer that serves as a phosphoryl acceptor and is purchased from Sigma Chemicals. The kinase reaction is initiated by the addition of enzyme and the reaction mixtures were incubated at 26 °C for 1 h. The reaction is terminated by the addition of EDTA to 50 mM and proteins are precipitated by the addition of trichloroacetic acid to 5%. The precipitated proteins are recovered by filtration onto Packard Unifilter plates and the amount of radioactivity incorporated is measured in a Topcount scintillation counter.

For the preparation of recombinant HER, the cytoplasmic sequence of the receptor were expressed in insect cells as a GST fusion protein, which was purified by affinity chromatography. The cytoplasmic sequence of HER2 was subcloned into the baculovirus expression vector pBlueBac4 (Invitrogen) and was expressed as an untagged protein in insect cells. The recombinant protein was partially purified by ion-exchange chromatography.

The instant compounds inhibit HER-1 and HER-2 kinases with ICso values between 0.003 -25 uM.

Methods of Preparation

Certain compounds of formula I may generally be prepared according to the ’ 20 following schemes and the knowledge of one skilled in the art.

Scheme 1

RX YR® H,NOSO,H RX YR? RX YR’

Dn STL GLI § §

R! N CHO sens FR N CN sen 2 R! N CONH,

NH, NH, 1 2 3

R¥X YR? RY 0

HCOH Pat NaOMe ] ~ NH

Step 3 R! N Cont, Step 4 ol

NHCHO Rg! 4 5 3 Br 3 ZR'R}

POBr; A L, 0 we oO wm LS

R' R' 6 7

Step 1

The first step is accomplished by the reaction of an optionally substituted 2- formylpyrrole (product 1) with an aminating reagent, such as hydroxylamine-O- 5S sulfonic acid, in an aqueous solvent at room temperature, followed by treatment under cooling with a base such as KOH. Compounds 1 may be obtained from substituted : pyrroles by formylation, for example by reaction with phosphorus oxychloride and

DMF. A methylpyrrole may be obtained by reduction of a formylpyrrole, for example by reaction with lithium aluminum hydride.

Step 2

The product 2 is reacted with an aqueous base such as KOH at room temperature to form the product 3 of Scheme 1.

Step 3

The compound 3 is reacted with an acylating agent, such as formic acid, in an aqueous solvent, to form the product 4 of Scheme 1.

Step 4

The compound 4 is cyclized with a base such as sodium methoxide in methanol with heating to form the product 5 of Scheme 1.

Step S

The compound 5 is halogenated, for example with phosphorus oxybromide at elevated temperature, to form the product 6 of Scheme 1.

Step 6 h) The compound 6 is reacted with an amine such as an aniline in an organic solvent, such as acetonitrile, to form the product 7 of Scheme 1.

The compound 7 of Scheme 1 where R; = 7-halogen can be prepared from the compound 7 of Scheme 1 where R; = hydrogen by reaction with a halogenating agent such as bromine in a suitable solvent such as acetic acid.

Scheme 2

A sC E YR? Lewis acid ( bY) N RY Base ), \ Acylating agent \ y + E » £ 3 ————— ~~ step 1 N step 2

H

1 ’ Base, E 3 Formamide, Ry a : E YR? Aminating agent —( YR heat , . Ua sO ee : N” "COOCH; step 3 N COOCH, step 4 N./% : . 1

H NH

; 2 3 ? 4 : RY x! PY ZR*R? halogenation Ae A

ES N == N 3 E \ J ————— E \ J i step § N. # step 6 N. =

N N

E = electron withdrawing group such as ester or nitro or ketone - Cl X'= halogen

Step 1

An anion of tosylmethyl isocyanide (TosMIC) is reacted with a Michael acceptor such as ethyl crotonate to obtain disubstituted pyrrole 1. An anion of

TosMIC could be made by treating a solution of it in dimethyl sulfoxide (DMSO) with a base such as sodium hydride (NaH) at rt or a solution of it in tetrahydrofuran (THF) with lithium hexamethyldisilazane at —78 °C.

Step 2

Treatment of pyrrole 1 with an acylating agent such as trichloroacetyl chloride in the presence of a Lewis acid such as aluminum chloride at from rt to 50 °C followed by treatment with sodium methoxide could afford trisubstituted pyrrole 2.

Alternatively, following the published procedure of (M. Suzuki, M. Miyoshi, K.

Matsumoto J. Org. Chem. 1974, 39, 1980) Compound 2 could be obtained by warming an aldehyde. such as acetaldehyde, with 2 equivalents of ethyl isocyanoacetate in the presence of a base, such as DBU, in an organic solvent, such as

THF.

Step 3

Pyrrole 2 could be aminated by an aminating reagent, such as diphenyl phosphoryl hydroxylamine, in the presence of a base, such as sodium hydride at rt in organic solvents, such as dimethyl formamide (DMF).

Step 4

N-Aminated pyrrole 3 upon heating at from 120 to 195 °C with formamide could undergo cyclization to afford 1,2,4-triazine 4.

Step 5

Compound 4 upon treatment with a halogenating agent, such as phosphorous oxybromide at from 60 to 115 °C, in the presence or absence of a co-solvent such as ; : 1,2-dichloroethane, compound 5 could be obtained.

Step 6 :

Compound 5 is reacted with amines. such as anilines in an organic solvent, such as DMF, to obtain compound 6. Alternatively, compound $5 is treated with an anion of a heterocyclic compound, such as oxindole, in an organic solvent such as

THF.

Scheme 3

. > : WO 00/71129 PCT/US00/13420 b wo-N_ coor” ma he Sil > - at b step 1 , N “SCOOR® step2 N COOR

R? R* 2

Alkylating agent, “ Deprotection Rooc, OR’

Taers ) \ oN COOR® step 4 > ) {coon

R H

Same as in Scheme II Ro, ZR'R} J RO ZR'R?

EE —_t SN —_— =r N 6 wherein R? = XR?, RP = R® described hereinbefore

Step 1

A suitably N-protected ester of glycine, such as with benzyl group, could be added to dialkyl methylene malonate at from rt to 80 °C to obtain compound 1. 5S Step2

Compound 1 could undergo cyclization to form pyrrole 2 upon treatment with ’ a strong base, such as lithium hexamethyldisilazane at from —78 °C to rt in an organic solvent such as THF. i Step 3

Compound 2 could be alkylated by treatment with an alkylating agent, such as iodomethane or dimethyl sulfate, in the presence of a base, such as potassium carbonate, in an organic solvent, such as acetone or DMF.

Step 4 77 Deprotection of compound 3 could be achieved, when optionally protected by groups such as benzyl, by hydrogenation over a catalyst, such as palladium, in the presence of ammonium formate.

Step 5

Compound 4 could be converted to compound 5 in an analogous manner to that described in Scheme 2.

Step 6

Hydrolysis of the ester group in compound 5 could be achieved by treatment with a base such as aqueous potassium hydroxide. The resulting acid could be coupled with an amine in the presence of a coupling agent, such as DCC or PyBrop.

Scheme 4

Rly IRE gly IRR wooed} rae H ~~ Deprotection _

N. 7 step 1 RON J step 2 0 1 } R}Y ZR*R? Ry ZRR? ~~" N ~~ SN es step 3 Wee 2 3 wherein X = NR'?, NR''cO, NR*?CONR*?, NR**C00,

NR'3s0,, NR'®SO,NR'7, as described hereinbefore.

Step 1

Compound 5 of Scheme 3 could be converted to carboxylic acid by treatment ; ! with a base such as aqueous potassium hydroxide. This acid could undergo Curtius rearrangement by treatment with diphenyl phosphoryl azide in the presence of an . alcohol, such as benzyl alcohol, in an organic solvent, such as 1,4-dioxane, to afford : compound 1.

Step 2

Deprotection of the carbamate group could be achieved, when optionally protected by groups such as carbobenzyloxy, by hydrogenation over a catalyst, such as palladium,

Step 3

The amino group of compound 2 could be acylated, for example by treatment with a carboxylic acid in the presence of a coupling agent such as DCC, or could be sulfonylated, for example by treatment with a sulfonyl chloride. Alternatively, the amino group of compound 2 may be alkylated with alkyl halides or could undergo reductive amination with aldehydes in the presence of a reducing agent, such as sodium cyanoborohydride.

Scheme 5

R® Dial oxalate, HO OH decarboxytation

N RY ii 2% —- EE

R°00C—/ ~~ C00 step | R°00C™ >” ~COOR® step 2 : 1 R 2

HO om R'0 op’ RO oR’

SUR GI — step 3 ! tep 4

RN coon’ ep R! N coor! °F A rR? R® H 3 4 455 5

R30 ZR'R —_— ~ . rere J 2 ~= N

R 0

Same as Scheme 11 Nn A

I

R 6 wherein R?= XR?; R®, R= R®; and R' = H or COOR® as described hereinbefore.

Step 1

Suitably protected compound 1 (imino dicarboxylate) could be cyclized by treatment with dialkyl oxalate in the presence of a base, such as sodium methoxide, in an organic solvent, such as methanol. - Step 2

Compound 2 upon selective deprotection, such as with trifluoro acetic acid (TFA) when optionally protected by tert-butyl ester, undergoes decarboxylation to afford Compound 3 where R'=H. Step 2 is omitted to form compound 3 where R'=

COOR*.

Step 3 oo oo

The hydroxy group of compound 3 could be etherified by reaction with an alkylating agent, such as dimethyl sulfate.

Step 4

Compound 4 could be deprotected by hydrogenation, when optionally protected as benzyl group, to obtain compound 5.

Step 5

Compound 5 could then be converted to compound 6 in an analogous manner to that described in step 4 of scheme 3 followed by steps 3 to 6 of Scheme 2.

Scheme 6

RY x! R}Y OPh Reducing e == ~ N e ~~ ~ N 9 =

RS00C~—( LJ stepd R'0OC—( |] step2

N 'N

From

Scheme 2 1

R3Y OPh RY OPh 1) m-CPBA vol on 2) OH = N I \ =" ~N > uo NN. 7 step 3 HN. ie step 4 2 3

Ry FR Alkylation Ry OFF pe bee ) wns mod TN Tepe

HO : ste \_N. J p RO NN J step 6

N 'N 4 5 3 OH 4p S

RY RY ZR'R

Ne SN —_— NN

CJ — wo)

N step 7 N.N7 . 6 7 : x!= halogen

R* = R® described hereinbefore ]

Step 1 . Compound 5 of Scheme 2 could be etherified at the 4-position, for example by treatment with phenoxide anion.

Step 2

Reduction with a reducing agent, such as DIBAL, in an organic solvent, such as toluene, could afford the alcohol 2.

Step 3

Oxidation of the alcohol could be achieved by treatment of compound 2, for example with MnO; at an elevated temperature in an organic solvent, such as toluene.

Step 4

Treatment of compound 3 with an oxidant, such as m-chloroperbenzoic acid (m-CPBA) in an organic solvent, such as dichloromethane, followed by aqueous hydrolysis with a base, such as potassium bicarbonate, could afford the hydroxy compound 4.

Step 5

Alkylation of the phenolic group in compound 4 with an agent, such as

S iodomethane, in the presence of a base, such as NaH, at from rt to 100 °C, could afford compound 5. - Step 6

Hydrolysis of Compound 5 could be achieved by treatment with an acid, such as aqueous HC], at an elevated temperature to afford compound 6.

Step 7

Compound 6 could be converted to compound 7 using procedures analogous to those described in Scheme 2.

Scheme 7 3 OPh : 8) OPh 0 RY Wittig reaction PN. RY

TY meg eS \ P step \

H Ng N. ie : Compound 3 1 ' of Scheme 6

X H, 0 RY OH Scheme2 Q RY bal a hy EE step 2 \ \ \ NA step 3 Ln. A : 2 3 ns

RY ZR'R 0

CL — RE K _ NE a _ ————— ; \ step 4 Rf I 4 wherein R', RS = R? as described hereinbefore - 15 Step 1

A compound 3 of Scheme 6 could undergo Wittig reaction, for example with phosphonates such as methyl diethylphosphonoacetate, in an organic solvent, such as dichlorethane, in the presence of a base, such as NaH to afford Compound 1.

Step 2

The double bond could be hydrogenated by treatment with hydrogen in the presence of a catalyst, such as palladium.

Step 3

Compound 2 could be converted to compound 3 by procedures described in

Scheme 2.

Step 4

Hydrolysis of the ester, as described hereinbefore, followed by coupling of the resulting acid with an amine in the presence of a coupling agent, such as DCC, could afford Compound 4.

In addition, other compounds of formula I may be prepared using procedures generally known to those skilled in the art. In particular, the following examples provide additional methods for the preparation of the compounds of this invention.

The invention will now be further described by the following working examples(s), which are preferred embodiments of the invention. All temperatures are in degrees Celsius (°C) unless otherwise indicated. HPLC purifications were done on C18 reverse phase (RP) columns using water methanol mixtures and trifluoroacetic acid as buffer solution. These examples are illustrative rather than limiting and it is to be understood that there may be other embodiments that fall within the spirit and scope of the invention as defined by the claims appended hereto. }

Example 1 cl pe 9 \ NP

N-(4-Chlerophenyl)pyrrolo[2,1-f]{1,2,4}triazin-4-amine

A. 4-Bromo-pyrrolo|2,1-f]{1,2,4]triazine : A mixture of 50 mg (0.37 mmol) of pyrrolo[2,1-f)[1,2,4}triazin-4(3H)-one [prepared as described in S.A. Patil, B.A. Otter and R.S. Klein, J. Het. Chem., 31, 781-786 (1994)] and 0.5 g of phosphorus oxybromide was heated at 60°C for 20 min., under argon. A clear orange melt was initially obtained which solidified to a yellow solid on continued heating. Ice was added with vigorous stirring to the solid. The mixture was extracted twice with ethyl acetate. The combined extracts were washed with sat.

NaHCO; and brine, dricd (MgSQ,), and the solvent removed to afford 63 mg of crude

Compound A as an orange oil which crystallized on standing. (M+H) =198",200"

B. 4-(4-Chiorophenyiamino)-pyrrolo[2,1-f}{1,2,4] triazine

A solution of 60 mg (0.3 mmol) of Compound A and 38 mg (0.3 mmol) of p- chloroaniline in 1.5 ml of acetonitrile was stirred overnight at rt and under argon. A white precipitate was obtained which was removed by filtration. The filter cake was suspended in ethyl acetate and sat. NaHCO: added and the mixture stirred until a solution was obtained. The organic layer was separated and washed with brine, dried (MgSO) and the solvent removed to yield 23 mg (0.094 mmol, 31 %) of Example 1 as a white solid. (M+H)" = 245"

Example 2

Mo

SL

9

Mn 2-Methyl-5-(pyrrolof2,1-f][1,2,4]triazin-4-ylamino)phenol ; The compound of Example 2 was prepared as a white solid in 49% yield from

Compound A of Example | and 3-hydroxy-4-methylaniline as described for

Compound B of Example 1. (M+H)" = 2417 oo _ . Exempley = ci ay \ Ne

N-(4-Chloro-2-flucrophenyl)pyrrolo{2,1-f}{1,2,4]triazin-4-amine

The compound of Example 3 was prepared as a white solid in 40% yield from

Compound A of Example 1 and 2-fluoro-4-chloroanilinc as described for Compound

B of Example 1. (M+H)™ = 263"

Example 4

Ct pe <7 SN 7-Bromo-N-{4-chlorophenyl)pyrrolo{2,1-f}[1,2.4]triazin-4-amine

To a solution of 26 mg (0.11 mmol) of Example 1 in | ml of acetic acid was added dropwise a solution of 19 mg of bromine in 100 m! of acetic acid. A white precipitate was obtained during the addition. Stirring was continued for 1 hr, under argon. The mixture was evaporated to dryness and the residue diluted with ethyi acetate and treated with sat NaHCO3. The clear colorless organic layer was washed with brine, dried (MgSO) and the solvent removed to give a white solid residue. This material was subjected to flash chromatography on a 15 cc column of silica gel. Elution with chloroform (100 %) afforded 18 mg (0.06 mmol, 50%) of Example 4 as a white solid. } : (M+H)" = 323, 3257

Example §

Me pee

CL

Me—GQ Ny 3 2-Methyl-5-[(6-methylpyrrolof2,1-f][1,2,4]triazin-4-yl)amino]phenol

A. 2-Formyl-3-methylpyrrole/2-formyl-4-methylpyrrole

To 3.15 ml (41 mmol) of DMF at 0°C under argon was added dropwise 3.81 mi (41 mmol) of phosphorus oxychloride. The cooling bath was removed and stirring was continued for 15 min. The solution was diluted with 9 ml of 1,2-dichloroethane and again cooled to 0°C. A solution of 3.0 g (37 mmol) of 3-methylpyrrole in 9 ml of 1,2- dichloroethane was added dropwise. The mixture was heated to reflux for 15 min,

SE

. * v WO 00/71129 PCT/US00/13420 cooled to 0°C and a solution of 16.2 g (203 mmol) of sodium acetate in 45 ml of water was added with vigorous stirring. The mixture was heated at reflux for 20 min and allowed to cool to room temperature. The aqueous layer was separated and extracted twice with methylene chloride. The combined organic layers were washed with sat

NaHCO; until pH 7, dried (MgS0s), and the solvent removed to yield a dark oily solid which was purified by flash chromatography (10% EtOAc:hexane) to afford 3.6 g (89%) of a 4:1 mixture of 2-formyl-3-methylpyrrole and 2-formyl-4-methylpyrrole as a pale yellow solid.

B. 1-Amino-2-aminocarbonyl-4-methyl-pyrrole

Compound A as an isomeric mixture was aminated as described in S.A. Patil, B.A.

Otter and R.S. Klein, J. Het. Chem., 31, 781-786 (1994) to form a 2:1 mixture of 1- amino-2-cyano-3-methylpyrrole and 1-amino-2-cyano-4-methylpyrrole in combined 20% yield. The mixture of nitriles was hydrolyzed as described in the reference to form Compound B as well as unreacted 1-amino-2-cyano-3-methylpyrrole, which were separated by flash chromatography (10% EtOAc:hexane).

C. 6-Methyl-pyrrolo|2,1-f]{1,2,4] triazin-4(3H)-one

Compound C was prepared from Compound B as described in S.A Patil, B.A. Otter

Co and R.S. Klein, J. Het. Chem., 31, 781-786 (1994). i D. 4-(3-Hydroxy-4-methyl-phenylamino)-6-methyl-pyrrolo[2,1- : - 20 f][1,2,4}triazine

Example 5 was prepared from Compound C using the 2 step sequence of Compound

R A of Example 1 and Compound B of Example 1, using 3-hydroxy-4-methylaniline. (M+H)" = 255.

Example 6 ew a

J ay

Nn,

N-(4-Bromo-2-fluorophenyl)pyrrolof2,1-f][1,2,4]triazin-4-amine

The title compound was prepared as a white solid in 57% yield from Compound A of

Example 1 and 2-fluoro-4-bromoaniline as described for Compound B of Example 1. (M+H)" = 307, 309.

Example 7

Me ow wT \ LN 2-Methyl-5-{(5-methylpyrrolo{2,1-f]{1,2 4]triazin-4-yl)amino} phenol

A. 1-Amino-2-aminocarbonyl-3-methyl-pyrrole

A solution of 290 mg (2.4 mmol) of 1-amino-2-cyano-3-methylpyrrole (prepared as described in Compound B of Example 5) and 3.5 g (62 mmol) of potassium hydroxide in 2 ml of water and 28 ml of ethanol was heated at reflux for 3 hr. The mixture was evaporated to near dryness, the residue diluted with additional water, and the mixture extracted with ethyl acetate (3x). The combined extracts were washed with brine, dried (MgSO,) and the solvent removed to yield 274 mg (82 %) of Compound A as a white solid.

B. 4-(3-Hydroxy-4-methyl-phenylamino)-5-methyl-pyrrolo[2,1- f]{1,2,4]triazine

Example 7 was prepared from Compound A as described for Compounds C and D of

Example 5. (M+H)" = 255. : 15 Example 8 : : Br ow ; Nn

N-(4-Bromo-2-fluorophenyl)-5-methylpyrrolo{2,1-f][1,2,4] triazin-4-amine

Example 8 was prepared as a white solid in 29% overall yield from 5-methyl- pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one using the 2 step sequence of Compounds A and B of Example 1, using 2-fluoro-4-bromo-aniline. (M+H)" = 321, 323.

Example 9

Br ne ¢

N

N-(4-Bromo-2-fluorophenyl)-6-methylpyrrolo[2,1-f][1,2,4]triazin~4-amine

; ’ ¢ WO 00/71129 PCT/US00/13420

Example 9 was prepared as a white solid in 20% overall yield from Compound C of

Example 5 using the 2 step sequence of Compound A and Compound B of Example 1, using 2-fluoro-4-bromo-aniline. The product was purified by flash chromatography on silica gel with 10% ethyl acetate/hexanes. (M+H)™ = 321, 323.

Example 10

SD

Cr ome \ nA 1-[2,3-Dihydro-6-(pyrrolo[2,1-f]{1,2,4]triazin-4-ylamino)-1H-indol-1-ylJethanone

Example 10 was prepared as a white solid in 4% yield from Compound A of Example 1 and 1-acetyl-6-aminoindoline as described for Compound B of Example 1, using 10% isopropanol/methylene chloride for extraction, and with purification by chromatography on silica gel with ethyl acetate. (M+H)" = 294,

Example 11

Me pes oo =v” SN ; \ NA . Me 2-Methyl-5-{(7-methylpyrrolo{2,1-f][1,2,4]triazin-4-yl)amino]phenol

A. 2-Methylpyrrole

To 80 ml of a 1 M solution of lithium aluminum hydride in ether (80 mmol), at rt and under argon, was added dropwise a solution of 4.0 g (40 mmol) of 2-formylpyrrole at ) © TTT sich arate as fo mamtain gentle reflux. Kcilux was continued for 6 hr. The excess hydride was hydrolyzed by the dropwise sequential addition of 3 ml of water (with cooling), 3 ml of 15% sodium hydroxide, and 9 ml of water. The resulting solids were removed by filtration and the filter cake washed well with additional ether. The filtrate was evaporated to dryness and the dark oil residue diluted with methylene chloride, dried (MgSOs) and the solvent removed. The resulting dark oil was distilled (kugelrohr, 700 mm, 190°C) to afford 1.13 g (35%) of Compound A as a clear colorless oil.

B. 2-Formyl-5-methyl-pyrrole

To 0.54 ml of DMF, with ice cooling and under argon. was added dropwise 0.64 mi of

POCI;. The reaction, which solidified during the addition, was warmed lightly with a warm water bath and the clear colorless solution stirred an additional 20 min after addition was completed. The mixture was diluted with 3 ml of 1,2-dichloroethane and, with cooling, a solution of 510 mg (6.3 mmol) of Compound A was added dropwise. The solution was heated at reflux for 15 min, ice cooled and a solution of 2.6g (31.5 mmol) of sodium acetate was added with vigorous stirring. The mixture was heated at 80 °C for 20 min, cooled to rt and extracted with methylene chloride.

The extracts were washed with brine, dried (MgSO.) and the solvent removed to give a dark oil residue. This material was subjected to flash chromatography on silica with 10% EtOAc:hexane to afford 126 mg (18%) of Compound B as a light tan solid.

C. 1-Amino-2-cyano-5-methyl-pyrrole

A solution of 140 mg (1.28 mmol) of Compound B in 2 ml of methylene chloride, at rt and under argon, was added rapidly dropwise to a solution of 290 mg (1.35 mmol) of MSH (O-mesitylenesulfonyl-hydroxylamine) in 2 ml of methylene chloride. A deep red solution was obtained which was stirred for an additional 0.5 hr. The mixture was washed twice with sat NaHCOs;, dried (MgSO,) and the solvent removed to give a deep red oil. A solution of this material in 5 ml of DMF was added : 4 dropwise to a suspension of 102 mg (2.56 mmol) of sodium hydride in 5 ml of DMF, : 20 at rt and under argon. The red color was consumed and the reaction became dark . yellow. Stirring was continued for an additional 0.5 hr. The mixture was ice cooled and a solution of 385 mg (1.8 mmol) of MSH in 5 ml of DMF was added. Stirring was continued for 1 hr with cooling. The dark solution was diluted with ethyl acetate and washed once with water. The aqueous layer was rextracted once with ethyl acetate.

The combined organic layers were dried (MgSO) and the solvents removed. The resulting dark red oil was subjected to flash chromatography on silica with 20%

EtOAc:hexane to afford 100 mg (65%) of Compound C as a yellow solid.

D. - 1-Amino-2-aminocarbonyl-5-methyl-pyrrole

To a solution of 1.1g (20 mmol) of KOH in 2.5 ml of water was added 100 mg (0.82 mmol) of Compound C. The suspension was stirred overnight at rt and heated at 50°C for 4 hrs. The resulting precipitate was removed by filtration. The filter cake was dissolved in ethyl! acetate, the solution was dried (MgSQ,) and the solvent removed to give 58 mg of Compound D as a yellow solid. The aqueous filtrate was extracted 3x with ethyl acetate. The combined extracts were dried (MgSO) and the solvent removed to give an additional 11 mg of Compound D as a yellow solid (total 69 mg, 60%).

E. 7-methyl-pyrrolo{2,1-f][1,2,4]triazin-4(3H)-one

A solution of 65 mg (0.47 mmol) of Compound D in 0.5 mi of formic acid was heated at 100°C for 4 hrs. After removal of the solvent, the residue was subjected to flash chromatography on silica with 50% EtOAc:hexane to afford 53 mg (76%) of

Compound E as a white solid.

F. 4-(3-Hydroxy-4-methyl-phenylamino)-7-methyl-pyrrolo[2,1- f][1,2,4] triazine

Example 11 was prepared as a white solid in 30% overall yield from Compound E using the 2 step sequence of Compound A of Example 1 and Compound B of

Example 1, using 3-hydroxy-4-methylaniline. The product was purified by flash chromatography on silica with 25% ethyl acetate/hexanes. (M+H)" 255. s Example 12

Br

AT

; =r” SN F

Me

N-(4-Bromo-2-fluorophenyl)-7-methylpyrrole[2,1-f] [1,2,4]triazin-4-amine

Example 12 was prepared as a white solid in 33% overall yield from Compound E of

Example 11 using the 2 step sequence of Compound A of Example | and Compound : Buf Exuiipit I, usirg 2-Nuviv=4-Uiomoatiiire: Tie prouet was puiiiicd uy Nasir chromatography on silica with 10% ethyl acetate/hexanes. (M+H)" = 321, 323.

Example 13 oT 5-[(5,7-Dimethylpyrrolo{2,1-f]{1,2,4]triazin-4-yl)amino]-2-methylphenol

A. 2-formyl-3,5-dimethylpyrrole

To dimethylformamide (4.5 mL, 57.8 mmol) under argon at 0°C was added phosphorus oxychloride (57.8 mmol) dropwise over 5 min. The cooling bath was removed and after 15 min. 1,2-dichloroethane (15 mL) was added. The reaction mixture was again cooled to 0°C and a solution of 2,4-dimethylpyrrole (52.6 mmol) in 1,2-dichloroethane (15 mL) was added dropwise over 15 min. The reaction was heated to reflux for 15 min, and then cooled to rt. A solution of sodium acetate (24 g) in water (75 mL) was added slowly to the reaction mixture and the resulting mixture was again heated to reflux for 20 min. After the reaction mixture was cooled to rt it was diluted with CH,Cl,, and the aqueous phase was washed with CHCl, (2x50 mL).

The combined organic fractions were washed with saturated NaHCO;, dried (Na;SOq, and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to provide 5.2 g (80%) of the desired compound 2-formyl-3,5-dimethylpyrrole. [M+H]=124.1, [M-

H]=122.0

B. 5,7-dimethylpyrrolo(2,1-f]{1,2,4]triazine-4(3H)-one

Compound B was prepared from A as described in [S.A.Patil, B.A. Otter and R.S.

Klein, J. Het. Chem., 31, 781-786 (1994)]. Thus, removal of formic acid after the ) reaction gave 5 mg (95%) of compound B. 'H NMR (CD:OD): 3 7.40 (s, 1H), 2.15 (s, 1H), 2.28 (s, 3H), 2.19 (s, 3H) :

C. 5,7-Dimethyl-4-(3-hydroxy-4-methylphenylamino)-pyrrolo(2,1- f111,2,4|triazine

The title compound was prepared by treating compound B with 3-hydroxy-4- methylaniline as described for compound B of Example 1. Thus, after purification by preparative HPLC, 14 mg (25 %) of 5,7-Dimethyl-4-(3-hydroxy-4- methylphenylamino)-pyrrolo[2,1-f][1,2,4]triazine was obtained as white solid. MS: [M+H]=269.2, ESI [M-H]=267.0, 'H NMR (CDCls): § 8.20 (br s, 1H), 7.81 (s, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.99 (s, 2H), 6.69 (dd, /=8.0, 5.7 Hz, 1H), 6.25 (s, 1H), 2.58 (s, 3H), 2.43 (s, 3H), 2.07 (s, 3H)

Example 14

. i ) WO 00/71129 PCT/US00/13420 ed ~~ Ny / 5-[(6-Ethyl-5,7-dimethylpyrrolo[2,1-f]{1,2,4]triazin-4-yl)amino}-2-methylphenol

The title compound was prepared from 2,4-dimethyl-3-ethylpyrrole in a manner similar to the preparation of Example 13 from 3,5-dimethylpyrrole. Thus, after purification by preparative HPLC, 19 mg (21 %) of 5,7-dimethyl-6-ethyl-4-(3- hydroxy-4-methylphenylamino)-pyrrolo[2,1-f}[ 1,2,4]triazine was obtained as white solid. MS: [M+H]" = 297.3, [M-H] = 295.1; 'H NMR (CDCl3): 8 9.67 (brs, 1H), 7.81 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.90 (br s, 1H), 6.70 (s, 1H), 6.64 (dd, /=8.3, 5.8 Hz, 1H), 2.64 (q, J/=7.5, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 2.08 (s, 3H), 1.13 (t, J=7.5, 3H)

Example 15 <0 oo or 5-[(5,6-Dimethylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino}-2-methylphenol

A. Preparation of 3,4-dimethylpyrrole

To a flask containing anhydrous diethyl ether (160 mL) was added slowly a solution of LiAlH4 in THF (1 M, 71.01 mmol). This mixture was stirred for 15 min. at rt. diethyl 3,4-pyrroledicarboxylate (5.0 g, 23.67 mmol) was added portion-wise as a om solid to tho solution over 15 mins Tho reaction mika Was thi licditd wi 45°C TT (reflux) overnight. The reaction mixture was cooled to 0°C and Na,S04.10 HO (15 g) was slowly added. The mixture was stirred for 30 min. and 15 mL of 10% aqueous : 20 NH,4Cl was added slowly and the mixture stirred for an additional 15 min. The mixture was filtered and the residue was rinsed with ethyl acetate (3 x 20 mL). The filtrate was dried over Na,SQ, and purified by chromatography on silica gel eluting with a gradient of 10-20% ethyl acetate in hexanes to provide 540 mg (24%) of 3.4- dimethylpyrrole. MS: [M-H] =94.0

B. 5,6-Dimethyl-4-(3-hydroxy-4-methylphenylamino)-pyrrolo|2,1- f111,2,4]triazine.

The compound A was converted to the title compound in a manner similar to the preparation of Example 13 from 3,5-dimethylpyrrolc. Thus, after purification by preparative HPLC. 19 mg (21 %) of 5,6-dimethyl-4-(3-hydroxy-4- methylphenylamino)-pyrrolo(2,1-f][1,2,4]triazine was obtained as white solid. [M+H]* = 269.2, [M-H] = 267.0; '"H NMR (CDCl): 6 8.30 (br s, 1H), 7.54 (s, 1H), 7.14 (s, 1H), 6.87 (d. J=7.9 Hz, 1H), 6.85 (s, 1H), 6.45 (dd, J=7.8, 1.9 Hz, 1H), 2.28 (s, 3H), 1.97 (s, 3H), 1.85 (s, 3H)

Example 16 (XL

AE

5-[(5-Ethylpyrrolof2,1-f]{1,2,4]triazin-4-yl)amino}-2-methylphenol : A. Preparation of 2-formyl-3-ethylpyrrole : 3-Ethylpyrrole was converted to a mixture of Compound A and 2-formyl-4- } ; 15 ethylpyrrole as described in the preparation of Compound A of Example 5. [M+H]" = 3 124.1

B. Preparation of S-ethyl-4-(3-hydroxy-4-methylphenyiamino)- : pyrroto|2,1-f][1,2,4}triazinc :

The mixture obtained above was converted to the title compound in a manner similar to the preparation of Example 5 from compound B of Example 5. Thus, after purification by preparative HPLC, 22 mg (26 %) of 5-ethyl-4-(3-hydroxy-4- methylphenylamino)-pyrrolo[2,1-f][1,2,4]triazine was obtained as white solid. MS: [M+H]™=269.2, [M-H]'=267.1; 'H NMR (CDCls): 5 8.80 (brs, 1H), 7.73 (s, 1H), 7.43 : (s, 1H), 6.99-6.89 (m, 2H), 6.60 (s, 1H), 6.55 (d, /=2.7 Hz, 1H), 2.45 (s, 1H), 2.87 (q, J=7.5 Hz, 2H), 2.00 (s, 3H), 1.31 (t, J=7.5 Hz, 3H)

Example 17

~

IJ

5-[[2-(Dimethylamino)pyrrolo{2,1-f][1,2,4]triazin-4-yl]amino}-2-methylphend

To a solution of 4-chloro-2-dimethylaminopyrrolo[2,1-f][1,2,4]triazin-2-amine (50 mg, 0.26 mmol) (Tetrahedron, 3037, 52, 1996, José Ma. Quintela, Maria J. Moreira and Carlos Peinador) in ethanol (2.5 mL) under argon was added 5-amino-o-cresol (35 mg, 0.28 mmol). The reaction mixture was stirred overnight at 75°C. Upon cooling, a solid precipitated which was recrystallized from warm ethanol to provide 52 mg (72 %) of the title compound as white solid. MS: [M+H]"= 284.2, ESI [M-H}" =282.1; '"H NMR (CDCl): § 7.52 (s, 1H), 7.13-6.98 (m, 4H), 6.58 (s, 1H), 3.15 (s, 6H), 2.19 (s, 3H).

Example 18

ETNA oo 4-[(3-Hydroxy-4-methylphenyl)amino]-5-phenylpyrrolo[2,1-f] [1,2,4]triazine-6- carboxylic acid ethyl ester

A. 3-carboethoxy-4-phenylpyrrole

To a 1.0 M solution of lithium hexamethyldisilazide in THF (41 mL, 41 mmol) at - 78°C was added dropwise over 45 min. a solution of tosylmethyl isocyanide (8.1 g,41 © mmol) in THF. After the reaction was stirred for an additional 45 min. a solutionof trans-ethyl cinnamate (7.3 g, 41 mmol) in THF (40 mL) was added over 40 min. Tte reaction was warmed to 25°C and stirred for 5 h. The reaction was diluted with ethyl acetate and washed with sat. aqueous NaHCO;. The aqueous layer was extracted three times with ethyl acetate, dried (N2,SO.), concentrated and purified by chromatography on silica gel eluting with a gradient of 20-30% ethyl acetate in hexancs to provide 3.4 g (41%) of 3-carboethoxy-4-phenylpyrrole as an off-white solid. '"H NMR (CDCls): 5 8.62 (br s, 1H), 7.57-7.12 (m, 6H), 6.73 (s, 1H), 4.19 (q,

J=7.1 Hz, 2H), 1.23 (t, /=7.1 Hz, 3H)

B. 3-carboethoxy-4-phenyl-5-formylpyrrole

Compound A was converted to the title compound (74% yield) in a manner similar to the preparation of Compound A of Example 5 from 3-methylpyrrole. [M-H] = 242

C. 3-carboethoxy-4-phenyl-5-cyanopyrrole

S To a solution of Compound B (0.55 g, 2.4 mmol) in pyridine (10 mL) under argon at rt was added hydroxylamine hydrochloride (0.18 g, 2.6 mmol). The reaction mixture was stirred for 2 hrs. Acetic anhydride (0.25 mL, 2.6 mmol) was added and the mixture was heated at 95°C for 6 h. Water and ethyl acetate were added to quench the reaction and the mixture was extracted (3 X) with ethyl acetate. The combined cxtracts were washed with brine, dried (Na;SO,) and purified by chromatography on silica gel eluting with a gradient of 25-50% ethyl acetate in hexanes to provide 0.1 g (17%) of Compound C as a solid. '"H NMR (CDCl3): 6 9.92 (brs, 1H), 7.52-7.30 (m, 6H), 4.24 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H)

D. i-amine-3-carboethoxy-4-phenyl-5-cyanopyrroie

To a suspension of NaH (60% in oil, 33 mg, 0.83 mmol) in DMF (5 mL) at 0°C was added Compound C (0.1 g, 0.42 mmol) in DMF (3 mL). After 10 min. at 0°C, diphenyl phosphoryl hydroxylamine (0.19 g, 0.83 mmol) was added neat followed by

DMF (3 mL). The reaction mixture was stirred for 2 hrs at 25°C and then quenched with pH 7 phosphate buffer (15 mL). The mixture was extracted with ethyl acetate (4 x20 mL). The combined extracts were dried (Na;SO, ) and purified by ’ chromatography on silica gel eluting with 25-50% ethyl acetate in hexanes to provide 94 mg (85%) of Compound D. "H NMR (CDCl;): § 10.2 (br s, 1H), 7.55 (s, 1H), 7.47-7.35 (m, 5H), 5.12 (s, 2H), 4.27 (q, J=7.1 Hz, 2H), 1.22 (t, /=7.1 Hz, 3H)

E. 5-Phenyl-6-carboethoxy-pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one

To a solution of Compound D (94 mg, 0.4 mmol) in methanol (2 mL) and water (2 mL) was added sodium perborate tetrahydrate (0.28 g, 2 mmol). The reaction mixture was heated to 50°C for 15 hrs and then quenched with water (5 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed : with brine (10 mL), dried (N2;SO.), and concentrated in vacuo. The residue was heated with formic acid at 60° C for 5 hrs. The formic acid was removed and the crude material was purified by chromatography silica gel eluting with a gradient of 2- 5% methanol in chloroform to provide 26 mg (26%) of Compound E. [M-H] = 282

F. 5-phenyl-6-carboethoxy-4-(3-hydroxy-4-methylphenylamino)- pyrrolo[2,1-f][1,2,4] triazine

Phosphorus oxybromide (130 mg, 5 eq) was combined with Compound E (26 mg, 0.092 mmol) and heated to 60°C for 45 min. The melt was poured into ice water and extracted with ethyl acetate (4 x 5 mL). The extracts were washed with sat. NaHCO; dried (N2,SO4 ) and concentrated in vacuo. The residue was dissolved in CH,CN (1.0 mL) and DMF (0.2 mL) and 5-amino-o-cresol (16 mg, 0.13 mmol) was added.

The reaction mixture was stirred overnight under argon at 25°C. Solvent was removed in vacuo, and the crude material was purified first by radial chromatography ona! mmsilica gel plate eluting with a gradient of 2-5% methanol in chloroform, and then by preparative TLC (silica gel, 2% methanol in chloroform) to provide 6 mg (17 %) of the title compound as yellowish solid. [M+H]" = 389; 'H NMR (CDCl): & 8.05 (s, 1H), 7.98 (s, 1H), 7.47-7.44 (m, 5H), 7.14 (s, 1H), 6.88 (d, /=8.2 Hz, 1H), 6.87 (s, 1H), 6.28 (dd, J=8.2, 1.6 Hz, 1H), 5.47 (br 5, 1H), 4.11 (q, J=7.1 Hz, 2H), 2.08 (s, 3H), 1.10 (t, /=7.1 Hz, 3H).

Example 19 ) wa : . MeOOC \ th A : 4-[(3-Hydroxy-4-methylphenyl)amino|-5-methylpyrrolo|2,1- ) f][1.2,4]triazine-6-carboxylic acid methyl ester

A. 3-mcthylpyrrole-2,4-dicarboxylic acid dimethyl ester

A To asuspension of aluminum chloride (106 4 g. 798 mmol) in dichloroethane (700 mL) at —40°C under nitrogen was added dropwise trichloroacetyl chloride (89 mL, 798 mmol). A solution of 4-methylpyrrole-3-carboxylic acid methyl ester (37 g, 266 mmol, prepared by the procedure analogous to Compound A of Example 18 using methyl crotonate) in dichloroethane (200 mL) was added and the reaction mixture was gradually warmed to rt. and was stirred over the weekend (65 hr). A cold and pre- prepared aluminum chloride (53.2 g) and trichloroacetyl chloride (44.6 g)in dichloroethane (450 mL) was added to the reaction mixture. After an additional 24 hr, the mixture was carefully poured into an ice-water bath (2 L) and the pH of the solution was adjusted to 2.0. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extract was washed with 3 N HC], brine, then dried (Na;SQs), and concentrated in vacuo to give dark oil. This oil was dissolved in methanol (400 mL), and the resulting solution was cooled 0°C under nitrogen. To this solution was added sodium methoxide (25 % in methanol) until the pH of the solution was 10. After | hr, the mixture was concentrated and then diluted with ice water (1 L) and the pH of the mixture was adjusted to 6. The mixture was extracted with dichlormethane (3 x 1 L). The combined extracts were washed with NaHCO, brine, dried (Na,S0,) and concentrated in vacuo. The brown solid obtained was purified by chromatography on silica gel eluting with ethyl acetate in hexanes to provide 44.3 g (84%) of Compound A. MS: [M+H] = 196

B. 1-Amino-3-methylpyrrole-2,4-dicarboxylic acid dimethyl ester

Compound B was prepared from compound A (46 g, 213 mmol) in a manner similar to Compound D of Example 18 except most of the solvent was removed prior to the addition of water. Thus, after purification by chromatography on silica gel eluting : with 25-30% ethyl acetate in hexanes, 38 g (84%) of Compound B was obtained as ; white solid. ESI [M+H]"=213.1

C. 5-Methylpyrrolo[2,1-f][1,2,4)triazin-4(3H)-one-6-carboxylic acid ) 3 methyl] ester

Compound B (38 g, 179 mmol) was combined with formamide (400 mL) and heated . to 165°C for 6 hr. The reaction was diluted with water (5 mL), extracted with ethyl

B acetate (3 x 10 mL), dried (Na;SOs) and concentrated. The crude material was purified by washing with ether/hexanes (7/3) to provide 33.4 g (90%) of Compound C as a white solid. ESI MS: [M-H] = 206.0

D. 4-[(3-Hydroxy-4-methylphenyl)amino|-5-methylpyrrolo[2,1- f][1,2,4]triazine-6-carboxylic acid methyl ester

The title compound was prepared in a manner similar to the preparation of compound

F of example 18. Thus, after purification by preparative HPLC, 13.5 mg (42 %) of the title compound was obtained as yellowish solid. ESI [M+H)]" = 313.2; 'H NMR (CDCl,): § 7.97 (s, 1H), 7.92 (s, 1H), 7.36 (s, 1H), 7.12 (d, /=8.1 Hz, 1H), 6.88 (d,

J=8.1 Hz, 1H), 3.86 (s, 2H), 2.90 (s, 3H), 2.21 (s, 3H).

Example 20

: i * WO 00/71129 PCT/US00/13420 rT XN

Nan NY Pp 4-[(3-Hydroxy-4-methylphenyl)amino]-5-methylpyrrolo|2,1-f] [1,2,4]triazine-6- carboxylic acid

A 1.0 M aqueous LiOH solution (0.16 mmol) was added to Example 19 (26 mg, 0.083 mmol) in a mixture of THF (0.6 mL), methanol (0.2 mL), and water (0.2 mL) at 0°C.

The reaction mixture was warmed to 25°C and stirred for 2 hrs. An additional solution of LiOH (0.5 mL) was added and the reaction was warmed to 50°C for 1.25 hr. The reaction was brought to pH 7 with 5% aqueous HCI solution and extracted with ethyl acetate (4 x 7 mL). The organic extracts were dried (MgSOs ) and concentrated in vacuo to provide 16 mg (67%) of the title compound as off-white solid. MS: [M+H]" =299.2;: '"H NMR (CD;0D): & 7.87 (s, 1H), 7.68 (s, 1H), 7.27 (s, 1H), 6.99 (d, /=8.2

Hz, 1H), 6.81 (s, 1H), 2.76 (s, 3H), 2.09 (s, 3H) : Example 21 - LX

B , o

OL nS 1-][4-[(3-Hydroxy-4-methylphenyl)amino|-5-methylpyrrolo|2,1-f][1,2,4]triazin-6- yljcarbonyl}-4-methylpiperazine

To a solution of Example 20 (7 mg, 0.023 mmol) in DMF (0.4 mL) at 25°C was © added N-methyl piperazine (3.5 pL. 0.03 mmol), I-hydroxybenzotriazole (3 mg, 0.023 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7 mg, 0.05 mmol). After 24 hrs., the mixture was concentrated, diluted with water (2 mL), and extracted with ethyl acetate (5 x 2 mL). The combined organic extracts were washed with saturated aqueous NaHCOs (2 x 5 mL). The crude material was purified by chromatography on silica gel eluting with a gradient of 5-10% methanol in chloroform to provide 6.23 mg (70%) of the title compound as white solid. MS: [M+H]"=381.3; '"H NMR (CDCl;): 8 7.76 (s, 1H), 7.48 (s, 1H), 7.08 (s, 1H), 7.02 (d,

J=8.2 Hz, 1H), 6.69 (d, J/=8.2 Hz, 1H), 3.82-3.44 (m, 2H), 2.54 (s, 3H), 2.53-2.28 (m, 6H), 2.27 (s, 3H), 2.10 (s, 3H)

Example 22 1 LX [Tm on

SNA

4-{(3-Hydroxy-4-methyvlphenyl)amino}-5-methyl-N-{2-(1- pyrrolidinyl)ethyl}pvrrolo|2,1-f][1,2,4]triazine-6-carboxamide

Example 20 (7 mg, 0.023 mmol) was converted to 6 mg (65%) of the title compound as white solid in a manner similar to the preparation of Example 21 from Example 20.

MS: [M+H]" = 395.3; 'H NMR (DMF-d;): 8 9.56 (s, 1H), 8.40 (s, 1H), 7.42 (br s, 1H), 7.10-7.05 (m, 2H), 3.49-3.47 (m. 12H), 2.49 (s, 3H), 2.14 (s, 3H)

Example 23

LX wo 0” \ ~, 4-[(3-Methoxy-4-methylphenyl)amino}-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester

To a solution of Example 19 (10.8 mg, 0.04 mmol) in CHiCN (0.5 mL) and methanol (0.1 mL) was added trimethylsilyl diazomethane (21 pL of 2.0 M solution in THF).

After 24 hrs. TLC indicated no reaction had occurred. DMF (0.2 mL) and additional trimethylsilyl diazomethane (0.1 mL) were added and the reaction mixture was stirred for additional 24 hrs. After the addition of additional 1.1 eq. of trimethylsilyl diazomethane, LC/MS indicated the disappearance of starting alcohol. Acetic acid (2 drops) was added and the reaction mixture concentrated in vacuo. The crude matenal was purified first by chromatography on silica gel eluting with a gradient of 2-5% methanol in chloroform and then by preparative HPLC to provide 2.8 mg (25%) of

Example 23 as white solid. [M+H]=327.2; '"H NMR (CDCl): 87.92 (s, 1H), 7.87 (s, 1H), 7.26 (s, 1H), 7.07 (d, J/=8.1 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.87 (s, 3H), 2.15 (s. 3H).

Example 24

Nr J 4-[(3-Hydroxy-4-methyiphenyl)amino]-5-methylpyrrolo|2,1-f][1,2,4]triazine-6- methanol

To a suspension of Example 19 (23 mg, 0.08 mmol) in CHCl; (1 mL) at —=78°C under argon was added diisobutyl aluminum hydride (1.0 M in toluene, 0.15 mL). The reaction mixture was gradually warmed to 0°C over 45 min. TLC indicated that starting material remained and an additional 1 equivalent of diisobuty! aluminum hydride was added at 0°C. After 20 min. the reaction mixture was pourcd into aqueous potassium sodium tartrate and stirred for 30 min. The mixture was extracted with CH,Cl, (4 x 5 mL), dried (Na,S0,), and purified by chromatography on silica gel eluting with a gradient of 5-10% methanol in chloroform to provide 8 mg (38%) . of Example 24 as a solid. MS: [M+H] =285.2; 'H NMR (CD;0D): § 7.70 (s, 1H), . } 7.56 (s, 1H), 7.19 (s, 1H), 7.08 (d, /=8.0 Hz, 1H), 6.89 (d, /=8.0 Hz, 1H), 4.68 (s, . 15S 2H), 2.62 (s, 3H), 2.20 (s, 3H) : ; Example 25

JL

Ty

RN

4-|(3-Hydroxy-4-methylphenyl)methylaminoj-5-methylpyrrolo(2,1- f1[1,2,4]triazine-6-carboxylic acid methyl ester

A. 5-methyl-6-carbomethoxy-4-(3-tert-butyldimethylsilyloxy-4- methylphenylamino)-pyrrolo[2,1-f][1,2,4] triazine

To a solution of Example 19 (31 mg, 0.1 mmol) in DMF (1 mL) at 25°C under argon was added t-butyldimethylsilyl chloride (19 mg, 0.13 mmol) and imidazole (11 mg, 0.15 mmol). The reaction mixture was stirred 5 hrs at ambient temperature and then stored at —40°C overnight. Water was added and the mixture was extracted with ethyl acetate (3 x 5 mL). The organic extracts were washed with brine (10 mL), dried (Na,S0,), and purified by chromatography on silica gel eluting with 25% ethyl acetate in hexanes to provide 42 mg (100%) of Compound A. MS: (M+H)" =427.4

B. 5-Methyl-6-carbomethoxy-4-(3-methoxy-4-methylphenyl-N- methylamino)-pyrrolo[2,1-f][1,2,4]triazine

To a solution of Compound A (29 mg, 68 umol) in THF (0.7 mL) at 0°C was added

NaH (5.5 mg, 0.14 mmol). After stirring for 10 min. methyl iodide (17 pL, 0.27 mmol) was added followed by DMF (80 uL) and the reaction mixture was allowed to warm to 25°C over 1 hr. After cooling to 0°C the reaction was quenched with pH 7 phosphate buffer (1 mL) and extracted with ethyl acetate (3 x 2 mL). The combined organic extracts were dried (Na,SO,) and purified by chromatography on silica gel eluting with a gradient of 25-50% ethyl acetate in hexancs. The residue was taken up in THF (1 mL) and cooled to 0°C. Tetrabutylammonium fluoride (0.1 mL) was added and the reaction was stirred under argon at 0°C for 45 min. The mixture was quenched with pH 7 phosphate buffer and extracted with ethyl acetate (3 x 2 mL).

The organic extracts were dried (Na;SO4) and purified by rotary chromatography on a | mm silica gel plate eluting with 2% methanol in chloroform to provide 10 mg (50%) of the title compound as a white solid. MS: [M+H]=327.3; "HNMR (CD;0D): 6 7.58 (s, L1H), 7.51 (s, 1H), 6.87 (d, /=7.7 Hz, 1H), 6.24 (s, 1H), 6.22 (d,

J=7.7 Hz, 1H), 3.69 (s, 3H), 3.26 (s, 3H), 2.09 (s, 3H), 1.79 (s, 3H)

Example 26

LX

ON on

Ty \ Ny JP 2-Methyl-5-[S-methyl-6-(1H-1,2,4-triazol-1-ylmethyl)pyrrolo[2,1- f1{1,2,4]triazin-4-yl]amino]phenol

A. S-methyl-6-hydroxymethyl-4-(3-tert-butyldimethylsilyloxy-4- methylphenylamino)-pyrrolo(2,1-f][1,2,4]triazine

To a solution of Compound A of Example 24 (42 mg, 0.1 mmol) in CH,Cl; (1 mL) at —78°C under argon was added diisobutyl aluminum hydride (1.0 M in toluene, 0.30 mL). After 45 min. the reaction mixture was poured into aqueous potassium sodium tartrate and stirred for 40 min at 25°C. The mixture was extracted with ethyl acetate (3 x 5mL). The combined organic extracts were washed with brine (10 mL), dried (Na,S0O.) and concentrated to provide compound A which was used directly for the next step without further purification.

B. 5-(1,2,4-pyrazole)methyl-6-hydroxy-4-(3-methoxy-4- methylphenylamino)-pyrrolo[2,1-f][1,2,4] triazine

To a solution of Compound A (20 mg, 50 pmol) in CH,Cl; (1mL) at 0°C was added triethylamine (75 pmol) and methane sulfonyl chloride (55 pmol). The reaction mixture was warmed to 25°C and stirred for 1 hr. The mixture was concentrated in vacuo. In a separate vial 1,2,4-triazole (10 mg, 0.15 mmol) was added to NaH (6 mg, 0.15 mmol) in DMF (1 mL) at 0°C under argon. This mixture was warmed to 25°C : 15 and stirred for 15 min. and then cooled back to 0°C. The mesylate was dissolved in ) 0.5 mL of DMF and added to the second vial. The reaction was warmed to 25°C and to stirred for 3 hrs. Water (2 mL) was added and the mixture was extracted with cthyl p acetate(3 x 5 mL). The combined organic extracts were dried (Na;SOs), and purified k by preparative TLC on a 1 mm silica gel plate eluting with 5% methanol in chloroform. The material obtained was dissolved in THF and cooled to 0°C. ; Tetrabutyl ammonium fluoride (2.0 eq) was added and the mixture was stirred under argon at 0°C for 30 min. The material was concentrated and purified directly by preparative TLC on a 1 mm silica gel plate eluting twice with 5% methanol in © ~ ©chioroform io provide 2.1 mg {1U%] of the title compound. MS: [M+H] = 336.2,’H

NMR (CD;OD): 6 8.36 (s, 1H), 7.89 (s, 1H), 7.62 (s, 1H), 7.55 (s, IH), 7.07 (s, 1H), 6.96 (d, J=7.9 Hz, 1H), 6.78 (d, /=7.9 Hz, 1H), 5.39 (s, 2H), 2.48 (s, 3H), 2.08 (s, 3H)

Example 27 a

TN A

4-chloro-5-methyl-6-carbomethoxypyrrolo|2,1-f][1,2,4]triazine

Phosphorous oxychloride (2.5 mL) was combined with Compound C of Example 19 (100 mg, 0.483 mmol) and heated at 100°C overnight. The melt was allowed to cool to rt and dissolved in ethyl acetate. The mixture was neutralized with aqueous

NaHCO; and extracted twice with ethyl acetate. The combined organic washes were dried (N2,;SO,) and concentrated to provide 101 mg (93%) of Example 27. MS: (M+H)" = 226.6

Example 28 \ .

Dee

TN A

4-(2,3-Dihydro-1H-indol-1-yl)-5-methylpyrrolo[2,1-f][1,2,4] triazine-6-carboxylic acid methyl ester

A mixture of Example 27 (20 mg, 0.09 mmol) and indoline (21 mg, 0.177 mmol) in

CH;CN (1 mL) was shaken for 4 hrs. DMF (0.2 mL) was added, and the crude mixture was purified by preparative HPLC to provide 12.2 mg (45 %) of Example 28 ) as a white solid. [M+H]*=309.2; 'H NMR (CDCl;): 5 8.06 (s, 1H), 7.91 (s, 1H), 7.20 d 15 (m, 1H), 7.01 (m, 1H), 6.93-6.91 (m, 2H), 4.15 (t, /=7.8 Hz, 2H), 3.81 (s, 3H), 3.09 (t,

J=17.8 Hz, 2H), 2.35 (s, 3H).

Example 29

LL -

Meo A 4-](3-Carboxyphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester

A mixture of Example 27 (20 mg, 0.09 mmol), triethylamine (0.1 mL), and 3-amino benzoic acid (24 mg, 0.177 mmol) in CH;CN (1 mL) was shaken for 4 hrs. The mixture was filtered, washing with CH;CN, and the crude material was purified by preparative HPLC to provide Example 29 as a solid. [M+H]'=327.1; 'H NMR

(CDCl): 8 9.24 (br s, 1H), 8.11 (s, 1H), 7.91 (m, 1H), 7.73-7.58 (m, 4H), 3.80 (s. 3H), 2.83 (s, 3H).

Example 30

HN ie

MeO,C \ Ng 5 4-(1H-Indazol-6-ylamino)-5-methylpyrrolo{2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester

A mixture of Example 27 (20 mg, 0.09 mmol) and 6-aminoindazole (18 mg, 0.13 mmol) in CH3;CN (1 mL) and DMSO (0.5 mL) was shaken for 4 hrs. The mixture was filtered, washed with CH;CN, and the crude material was purified by preparative

HPLC to provide Example 30 as a white solid ( 13 mg, 45 %). [M+H]'=323.1; 'H

NMR (CDCl): & 8.37 (s, 1H), 7.99 (s, 1H), 7.94 (d, /=7.4 Hz, 1H), 7.68 (d, J=4.2 Hz, 1H), 7.00 (dd, J=7.4, 4.2 Hz, 1H), 3.83 (s, 3H), 2.91 (s, 3H).

Example 31

Ne Va

LC

HN oH <1

TN

4-[[3-Hydroxy-4-|{(phenylsulfonyl)amino]phenyl]amino]-5-methyipyrrolo(2,I- ______ _ __ __fu1.24]triazine-6-carbnxylic acid methyl ecter I

A mixture of Example 27 (20 mg, 0.09 mmol) and 4’-amino-2’- hydroxybenzenesulfonanilide (18 mg, 0.13 mmol) in DMF (1 mL) was shaken for4 hrs. The mixture was purified by preparative HPLC to provide Example 31 as a solid (7 mg, 18%). [M+H]"=454.2; '"H NMR (CDCl): 5 7.92 (s, 1H), 7.76 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.51-7.40 (m, 6H), 6.85 (m, 2H), 6.37 (s, 1H), 3.84 (s, 3H), 2.81 (s, 3H).

Example 32

A

Re

MeO,C \ A 4-(2-Benzothiazolylamino)-5-methylpyrroio(2,1-f}[1,2,4]triazine-6-carboxylic acid methyl ester

To a 0°C mixture of NaH (60%, 5 mg, 0.106 mmol) in DMF (0.5 mL) was added 2- aminobenzothiazole (16 mg, 0.106 mmol). The reaction mixture was stirred for 10 min. at 0°C. Example 27 (20 mg, 0.09 mmol) was added in DMF (1 mL). The reaction mixture was stirred for 45 min. at 25°C and then quenched with pH 7 phosphate buffer. The mixture was extracted with ethyl acetate. The combined extracts were dried (N2;SOy ) and purified by preparative HPLC to provide Example 32 asasolid (12 mg, 40%). [M+H]"=340.2; 'H NMR (CDCl): § 8.41 (s, 1H), 8.28 (s,

K 1H), 7.28 (d, J=7.2 Hz, 1H), 7.08 (m, 2H), 6.57 (d, /=7.2 Hz, 1H), 3.82 (s, 3H), 2.38 (s, 3H). : Example 33 . NH Nn ~

MeO,C \ A 5-Methyl-4-[[3-[(methylsulfonyl)amino]phenyl}amino]pyrrolo(2,1- f1{1,2,4]triazine-6-carboxylic acid methyl ester

Phosphorus oxychloride was combined with Example 19 (30 mg, 0.14 mmol) and heated to 100°C for 15 hrs. The melt was cooled and concentrated to remove excess reagent, then extracted with ethyl acetate (20 mL). The extract was washed with sat aqueous NaHCO;, (10 mL) dried over MgSO, and concentrated in vacuo to provide chlorinated compound Example 27. The residue was dissolved in DMF (2 mL) and 3- (methylsulfonylamino)aniline (54 mg, 0.3 mmol) was added. The reaction mixture was stirred for 4 hrs under argon at 25°C. The crude reaction mixture was purified by preparative HPLC. The material obtained appeared to be a salt of the desired compound. The material was dissolved in ethyl acetate and washed with saturated aqueous NaHCO;. Evaporation of the solvent gave 24 mg (40 %) of Example 33. MS: [M+H]" = 376.2; '"H NMR (d-DMSO): 5 8.89 (s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.38 (s, 1H), 7.34-7.32 (m, 2H), 7.01 (d, J=8.0 Hz, 1H), 3.81 (s, 3H), 3.02 (s, 3H), 2.82 (s, 3H).

Example 34

Dee N .

Me0,C \ A 4-([3-(Hydroxysuifonyl)phenyljamino}-5-methylpyrrolo[2,1-f][1,2,4] triazine-6- carboxylic acid methyl ester

Example 27 (20 mg, 0.09 mmol) was dissolved in DMF (1 mL) and 3- aminobenzenesulfonic acid (23 mg, 0.13 mmol) was added. After 5 hr at rt, the crude : reaction mixture was purified by preparative HPLC. The material obtained appeared to be a salt of the desired compound. The material was dissolved in ethyl acetate and : 15 washed with saturated aqueous NaHCO;. Evaporation of the solvent gave 9.7 mg (30 %) of Example 34. MS: [M+H]"= 363.2; 'H NMR (CDCl;/CD30D): § 8.04 (s, 1H), 7.82 (d, J=7.1 Hz, 1H), 7.65 (s, 1H), 7.52-7.42 (m, 1H), 7.31-7.26 (m, 2H), 3.73 (s, * 3H), 2.75 (s, 3H).

Example 35

CL a 5

MeO,C = ’ \ LA : 4-[[3-(Hydrazinocarbonyl)phenyljamino]-S-methylpyrrolo[2,1-f][1,2,4] triazine-6- carboxylic acid methyl ester

Example 35 was prepared from 3-aminobenzhydrazide (30 mg, 0.2 mmol) and

Example 27 (30 mg, 1 mmol) in a manner similar to the preparation of Example 28 to afford 6 mg (18 %) of solid. MS: [M+H]" = 341.2; 'H NMR (d-DMSO): § 7.79 (s, 1H), 7.58 (s, 1H), 7.11-7.05 (m, 3H), 6.72 (d, J= 8.1 Hz, 1H), 5.23 (brs, 2H), 3.76 (s, 3H), 2.67 (s, 3H)

Example 36

POW ee 0

MeO,C \ A 4-[[3-(Aminosulfonyl)phenyljamino}-5-methylpyrrolo{2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester

Example 27 (20 mg, 0.09 mmol) was treated with 3-aminobenzenesulfonamide (23 mg, 0.13 mmol) in a manner similar to that described for Example 31. Evaporation of the extracting solvent gave 18.6 mg (58 %) of solid. MS: [M+H]" = 362; '"H NMR (d-

DMSO): 6 9.08 (s, 1H), 8.18 (s, 2H), 7.98 (s, 1H), 7.91-7.89 (m, 1H), 7.62-7.58 (m, 2H), 7.42 (s, 2H), 3.81 (s, 3H), 2.84 (s, 3H)

Example 37 3 Oo.

IN,

ST Ny 4-[[3-[(Butylamino)sulfonyl]phenyljamino|-S-methylpyrrolo(2,1-f]{1,2,4]triazine- 6-carboxylic acid methyl ester

Example 27 (20 mg, 0.09 mmol) was treated with N-butyl-3-amino-benzene- sulfonamide (30 mg, 0.13 mmol) in a manner similar to that described for Example 31. Evaporation of the extracting solvent gave 31 mg (89 %) of solid. MS: [M+H]™ = 418.2; 'H NMR (CDCl;): § 8.07 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.84-7.82 (m, 1H), 7.58 (d, /=8.0 Hz, 1H), 7.49-7.45 (m, 2H), 3.82 (s, 3H), 2.93-2.89 (m, 2H), 2.81 (s, 3H), 1.44-1.18 (m, 4H), 0.84 (t, /=7.4 Hz, 3H)

Example 38

— OS ] ¥ 4 WO 00/71129 PCT/US00/13420

Jo

NH x "

De®

E0,C \ A 4-[(6-Methoxy-3-pyridinyl)amino]-5-methylpyrrolo{2,1-f]{1,2,4]triazine-6- carboxylic acid ethyl ester

Example 27 (20 mg, 0.09 mmol) was dissolved in DMF (1 mL) and 5-amino-2- methoxypyridine (16 mg, 0.13 mmol) was added. The reaction mixture was stirred for 2.5 hrs under argon at 25°C. The crude reaction mixture was concentrated and purified directly by chromatography on silica gel eluting with a gradient of 25-50% ethyl acetate in hexanes. The material obtained was dissolved in ethanol (2 mL) and sodium ethoxide (20%, 0.3 g, 10 eq) was added. The mixture was stirred at 75°C for 3 hrs. The crude material was purified directly by preparative HPLC to provide 4.3 mg (15%) of an off-white solid. MS: [M+H]=314.2; '"H NMR (CDCl,): & 8.25 (d, J=2.7

Hz, 1H), 7.93 (s, 1H), 7.85 (d, /=8.8 Hz, 1H), 7.82 (s, IH), 7.09 (br s, 1H), 6.74 (d,

J=8.8 Hz, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 2.86 (5, 3H)

Example 39

Bee

MeO,C Pp \ " 4-[(3-Cyanophenyl)amino}-5-methylpyrrolo[2,1-f]{1,2,4]triazine-6-carboxylic acid methyl ester -

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 3- aminobenzonitrile (21 mg, 0.177 mmol) by the procedure analogous to Example 28.

MS: [M+H]" = 308.2; 'H NMR (CDCl): § 8.23 (s, 1H), 7.97 (s, IH), 7.93 (s, 1H), 7.75 (d, J=6.3 Hz, 1H), 7.46-7.36 (m, 3H), 3.82 (s, 3H), 2.89 (s, 3H)

Example 40

4 BN

R 3

JQ ni AS A \ H

Des or \ A 4-[3-(Acetylamino)phenyljamino]-S-methylpyrrolo[2,1-f][1,2,4])triazine-6- carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 3°- aminoacetanilide (27 mg, 0.177 mmol) by the procedure analogous to Example 28.

MS: [M+HJ" = 340.2; '"H NMR (CDCl): § 7.81 (s, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.20-7.07 (m, 3H), 3.80 (s, 3H), 2.84 (5, 3H), 1.90 (s, 3H) :

Example 41 : ee:

MeO,C \ LA 4-[(3-Fluoro-4-methylphenyl)amino}-S-methylpyrrolo[2,1-f]{1,2,4]triazine-6- carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 3-fluoro- 4-methylaniline (17 mg, 0.13 mmol) by the procedure analogous to Example 28. MS: ) [M+H] = 315.2; '"H NMR (CDCl): § 7.92 (s, 1H), 7.87 (s, 1H), 7.57 (d, J=2.8 Hz, 1H), 7.19-7.09 (m, 3H), 3.81 (s, 3H), 2.87 (s, 3H), 2.20 (s, 3H)

Example 42

LO

MeO,C: \ NA . 5-Methyl-4-[(4-methyl-3-nitrophenyl)amino]pyrrolo(2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 3-nitro- 4-methylaniline (20 mg, 0.13 mmol) by the procedure analogous to Example 28. MS:

a EUR } SE : i oo [M+H]" = 342.2; '"H NMR (CDCl): & 8.39 (s, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.30 (d,

J=6.5 Hz, 1H), 7.19 (d, J=6.5 Hz, 1H), 3.83 (s, 3H), 2.89 (s, 3H), 2.54 (s, 3H)

Example 43 ped

Bee

MeO,C \ ho 4-[(3-Cyano-4-methylphenyl)amino]-5-methylpyrrolo|2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 3-cyano- 4-methylaniline (18 mg, 0.13 mmol) by the proccdure analogous to Example 28. MS: [M+H]"=323.2; '"H NMR (CDCl): 8 8.08 (s, 1H), 7.96 (s, 1H), 7.90 (s, 1H), 7.61 (d,

J=8.2 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 3.82 (s, 3H), 2.87 (s, 3H), 2.48 (s, 3H)

Example 44

I~

Bee

MeO,C \ A 4-[(1-Acetyl-2,3-dihydro-1H-indol-6-yl)amino]-5-methylpyrrolo[2,1- f][1,2,4]triazine-6-carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 1-acetyl- © b-aminomndoline (£3 Tg, U.13 Hol) by iiie protediit didiuguus tv Campie 28: ME: [M+H]* = 366.2; '"H NMR (CDCly): 5 8.14 (d, J= 8.6 Hz, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.51 (s, 1H), 7.12 (d, J= 8.6 Hz, 1H), 4.03 (t, J= 7.8 Hz, 2H), 3.81 (5, 3H), 3.18 (1, J=7.8 Hz, 2H), 2.67 (s, 3H), 2.19 (s, 3H)

Example 45 a B .

LX

NM AY NH,

Dee pn EP 4-[(3-Amino-4-methylphenyl)amino}-5-methylpyrrolo{2,1-f]{1,2,4}triazine-6- carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 3-amino- 4-methylaniline (16 mg, 0.13 mmol) by the procedure analogous to Example 28. MS: [M+H]" = 312.2; 'H NMR (CDCl): & 7.92 (s, 1H), 7.90 (s, L1H), 7.11 (s, 1H), 6.96 (d,

J=8.2 Hz, 1H), 6.74 (d, J=8.2 Hz, 1H), 3.81 (s, 3H), 2.85 (s, 2H), 2.18 (s, 3H)

Example 46

Br es

De® = TX

MeO,C \ A 4-[(4-Bromo-2-fluorophenyl)amino]-5-methylpyrrolo({2,1-f]{1,2,4]triazine-6- . . carboxylic acid methyl ester : The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 2-fluoro- 4-bromoaniline (25.1 mg, 0.13 mmol) by the procedure analogous to Example 28. : MS: [M+H]"= 379.1; 'H NMR (CDCl;): 8 8.52 (t, /=8.8 Hz, 1H), 7.95 (s, 1H), 7.92 (s, LH), 7.60 (br s, 1H), 7.30 (m, 2H), 3.82 (s, 3H), 2.86 (s, 3H)

Example 47 \ 4

Ysohd

Me0,C N A 4-(5-isoquinolinylamino)- 5-Methylpyrrolo[2,1-f]{1,2,4]triazine-6-carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 5-amino isoquinoline (19 mg, 0.13 mmol) by the procedure analogous to Example 28. MS:

[M+H]"= 334.2; 'H NMR (CDCl): § 8.12 (s, 1H), 8.09 (s, 1H), 7.10 (t, J/=7.6 Hz, 1H), 6.83 (d, /=7.6 Hz, 1H), 6.70 (d, J/=7.6 Hz, 1H), 6.59 (dd, J=7.7, 4.2 Hz, 1H), 6.01 (d, /=8.2 Hz, 1H), 3.82 (s, 3H), 2.71 (s, 3H)

Example 48

LX

. NH x

See = Ty

TN A

4-{(3,4-Dimethylphenyl)amino}-5-methylpyrrolo[2,1-f]{1,2,4]triazine-6- carboxylic acid methyl ester ‘

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 3,4- dimethylaniline (16 mg, 0.13 mmol) by the procedure analogous to Example 28. MS: [M+H]"=310.2; '"H NMR (CDCls): & 7.90 (s, 1H), 7.84 (s, tH), 7.31 (s, 1H), 7.20(d,

J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 3.80 (s, 3H), 2.84 (s, 3H), 2.22 (s, 3H), 2.18 (s, : 3H) oo Example 49 to To. ~~

NA

4-[[5-(Hydroxymethyl)-2-methylphenyl]amino}-5-methylpyrrolo|2,1-

Tmo To oo 7 GZ mz iie=G-uar bux vic atid methyl ester TT ’

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 3-amino- 5-(hydroxymethyl)-2-methylaniline(18 mg, 0.13 mmol) by the procedure analogous to

Example 28. MS: [M+H]"= 327.2; '"H NMR (CDCl): § 7.93 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.36-7.21 (m, 3H), 4.65 (s, 2H), 3.80 (s, 3H), 2.87 (s, 3H), 2.28 (s, 3H)

Example 50 ar

LX

\ = TX 4-{(4-Bromo-3-methylphenyl)amino]-5-methylpyrrolo(2,1-1][1,2,4] triazine-6- carboxylic acid methyl ester } The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 4-bromo- 3-methylaniline (25 mg, 0.13 mmol) by the procedure analogous to Example 28. MS: [M+H] = 376.2; '"H NMR (CDCl): 5 7.91 (s, 1H), 7.89 (s, 1H), 7.45 (m, 1H), 7.34 (m, 1H), 7.20 (m, 1H), 3.81 (s, 3H), 2.84 (s, 3H), 2.35 (s, 3H)

Example 51 er

ENA

: 10 4-[(4-Chloro-3-nitrophenyl)amino]-5-methylpyrrolo[2,1-f][1,2 4]triazine-6- : j carboxylic acid methyl ester : The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 4-chloro- } 3-nitroaniline (23 mg, 0.13 mmol) by the procedure analogous to Example 28. MS: : [M+H] = 362.7; 'H NMR (CDCl,): 5 8.48 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.75 1S (dd,J=8.7, 2.5 Hz, 1H), 7.48 (d, J/=8.6 Hz, 1H), 7.38 (s, 1H), 3.83 (s, 3H), 2.89 (s, 3H)

Example 52

QO. ree)

Me0,C \ A 4-{(2,3-Dihydro-1,4-benzodioxin-6-yl)amino}-5-methylpyrrolo|2,1- f}[1,2,4]triazine-6-carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and (2,3- dihydro-1,4-benzodioxin-6-yl)amine (20 mg, 0.13 mmol) by the procedure analogous to Example 28. MS: [M+H]™ = 340.3: '"H NMR (CDCl): § 7.90 (s, 1H), 7.84 (s, 1H), 7.24 (s, 1H), 7.14 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.81 (dd , J= 8.4, 2.4 Hz, 1H), 420 (m, 4H), 3.80 (s, 3H), 2.83 (s, 3H)

Example 53

TL Nr . NH Nn \ = Nw 5-Methyl-4-[[2-methyl-5-{(methylsulfonyl)amino]phenyl)amino]pyrrolo[2,1- f]{1,2,4]triazine-6-carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 2- methyl-5-(methylisulfonyl)aniline (27 mg, 0.13 mmol) by the procedure analogousto

Example 28. MS: [M+H] = 390.2; 'H NMR (CDCl3): 6 8.04 (brs, 1H), 7.95 (s, 1H), : 7.87 (s, 1H), 7.09-6.99 (m, 2H), 3.82 (s, 3H), 3.00 (s, 3H), 2.89 (s, 3H), 2.28 (s, 3H)

Example 54

JOEY i" ON \ N

Sp Xn

S5-Methyl-4-[[4-methyl-3-[(methylsulfonyl)amino|phenyl]amino]pyrrolo[2,1- f]{1,2,4]triazine-6-carboxylic acid methyl ester © To asolution of Example 53 (16 mg, 51 umoi) in pyridine (I mL) at 0°C was added ~~ 4-methyl-3-[(methylsulfonyl)aniline (4.4 pul, 87 pmol). The reaction mixture was stirred for 1 hr at 0°C and then warmed to 25°C and stirred for 4 hrs. Water (5 mL) was added and the mixture was extracted with ethyl acetate 3 Xx 5S mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL) and dried (Na,;S0,). The crude material was purified by chromatography on silica gel eluting with 2% methanol in chloroform to provide 6.9 mg (30%) of solid. MS: [M+H] = 390.2; '"H NMR (CDCl): & 7.93 (s, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.35 (d, J=8.2 Hz, -S6-

1H), 7.27 (s, 1H), 7.18 (d, /=8.2 Hz, 1H), 6.25 (s, 1H). 3.82 (s, 3H), 3.03 (s, 3H), 2.86 (s, 3H), 2.24 (s, 3H)

Example 55

Poy eS ua0se—( J 4-[(3-Hydroxyphenyl)amino}-5-methylpyrrolo[2,1-f}[1,2,4]triazine-6-carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 3- hydroxyaniline (14 mg, 0.13 mmol) by the procedure analogous to Example 28. MS: [M+H]" = 299.1; '"H NMR (CDCl): 6 7.93 (s, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.30 (br 10s, 1H), 6.97 (d, J= 8.5 Hz, 1H), 6.60 (dd, J=8.4,2.3 Hz, 1H), 3.82 (s, 3H), 2.68 (s, 3H).

Example 56 ed

NH

: pa EN 4-{[2-(Aminosulfonyl)phenyljamino]-5-methylpyrrolo{2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and 3- (aminosulfonyl)aniline (23 mg, 0.13 mmol) by the procedure analogous to Example 28. MS: [M+H]" = 362.1; '"H NMR (CDCl): 5 8.97 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.56 (t, J=8.2 Hz, 1H), 7.52 (t,

J=8.2 Hz, 1H), 5.53 (s, 2H), 3.80 (s, 3H), 2.73 (s, 3H)

Example 57 .

Ie

NH oH mee , J

. ' N WO 00/71129 PCT/US00/13420 4-{(3-Hydroxy-4-methoxyphenyl)amino|-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester

The title compound was prepared from Example 27 (28 mg, 0.124 mmol) and 5- amino-2-methoxy-phenol (20 mg, 0.148 mmol) by the procedure analogous to

Example 28. MS: [M+H]" =329.2; 'H NMR (CDCl3): 8 7.90 (s, 1H), 7.84 (s, 1H), 7.19 (d, J= 8.1 Hz, 1H), 7.18 (s, 1H), 7.02 (d, J= 8.1 Hz, 1H), 5.73 (s, 1H), 3.83 (5, 3H), 3.78 (s, 3H), 2.84 (s, 3H).

Example 58 == Ty ’ ~<A 4-[(3-Hydroxy-2-methylphenyl)amino|-5-methylpyrrolo[2,1-f}{1,2.4]triazine-6- carboxylic acid methyl ester

The title compound was preparcd from Example 27 (28 mg, 0.124 mmol) and 3- amino-2-methylphenol (18 mg, 0.148 mmol) by the procedure analogous to Example 28. MS: [M+H]"=313.2; 'H NMR (CD;0D): 5 7.90 (s, 1H), 7.76 (s, 1H), 6.97 (1, J= 7.6 Hz, 1H), 6.80 (d, J= 7.4 Hz, 1H), 6.68 (d, J= 7.4 Hz, 1H), 3.80 (s, 3H), 2.66 (s, 3H), 2.55 (s, 3H).

Example 59 lll meoe—( 1] :

NAN : : 4-[(2,3-Dihydro-1H-indol-6-yl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester

The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and (2,3- dihydro- 1 H-indol-6-yl)amine (27 mg, 0.13 mmol) by the procedure analogous to

Example 29. MS: [M+H]™ = 324.2; 'H NMR (CDCls): 8 8.05 (s, 1H), 7.91 (s, 1H), 6.97 (d, J= 7.8 Hz, 1H), 6.31 (s, 1H), 6.23 (d, /=7.8 Hz, 1H), 4.22 (1, J= 7.7 Hz, 2H), 3.84 (s, 3H), 2.84 (t, /=17.7 Hz, 2H), 2.55 (s, 3H).

Example 60

VY

NS

~ wT 5-Methyl-4-|(5-methyl-2-pyridinyl)amino|pyrrolo(2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester Thetitle compound was prepared from Example 27 (20 mg, 0.09 mmol) and (5- methyl-2-pyridinyl)aminc (14 mg, 0.13 mmol) by the procedure analogous to

Example 30. MS: [M+H]" = 298.2; '"H NMR (CDCl): 8 8.33 (s, 1H), 8.22 (s, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.68 (s, 1H), 6.37 (d, /=8.7 Hz, 1H), 3.81 (s, 3H), 2.44 (s, 3H), 1.92 (s, 3H)

Example 61 a \ i 7 Nw : 4-{(1H-Benzotriazol-5-yl)amino}-5-methyipyrrolo{2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester p The title compound was prepared from Example 27 (20 mg, 0.09 mmol) and (1H- Benzotriazol-5-yl)amine (14 mg, 0.13 mmol) by the procedure analogous to Example 30. MS: [M+H]"= 324.2; 'H NMR (CDCl): & 8.61 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 7.67 (d, J= 8.1 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J= 8.1 Hz, 1H), 3.85 (s, 3H), 2.49 (s, 3H).

Example 62

ANA, 2 MeO,C \ ho

Claims (41)

SE, LL a. : . oo Claims What is claimed is:

1. A compound of formula 1] Ry ZRORS 1 N R2X \ PY NE RS R I its enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein X and Y are independently selected from O, OCO, §, SO, SO,, CO, CO,, NR'C, NR''CO, NR'’CONR"*, NR"*CO;, NR"*SO;, NR'*SO,NR"’, SO;NR", CONR", halogen, nitro, cyano, or X or Y are absent; . Z is selected from O, S, N, or CR’; ] R! is hydrogen, CHs, OH, OCHs, SH, SCHi, OCOR?, SOR%, SO,R”, SO,NR*R”, : 15 CO;R*, CONRYR?, NH,, NR®SO;NR™R’', NR*SO,R*, NR**COR®, . NR*CO,RY, NR*®CONR’? SRY halogen, nitro, or cyano; R? and R® are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted : alkenyl, alkynyl, substituted alkynyl. aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, heterocycloalkyl or substituted heterocycloalkyl, or when X is halo, nitro or cyano R? is absent or ~~ whenYishalo, nitro or cyano R® isabsent; R* and R’ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, or R*and R® may together form an optionally substituted monocyclic 5-7 membered saturated or unsaturated carbocyclic or heterocyclic ring, or an optionally substituted bicyclic 7-11 membered saturated or unsaturated carbocyclic or heterocyclic ring, except that when Z is O or S, R’ is absent, or when Z is nitrogen, R* and R? are not both hydrogen; R® is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted

- PCT/US00/13420 heterocyclo, NR'R?, OR’ or halogen; R’, RE, R®, R'%, R!!, R'2, RR RY, R'S, R'7, R!S, RY, R?!, R¥ R®, R¥, RY, 1%, R”, R*, R*, R%, R*, R®, R*, R*, R¥ and R* are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo, except that when R’ and R?® are both methyl, then either R* or R’ must independently be substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, or substituted aralkyl; R*, R®, R* and R*’ are independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo; and R® is selected from the group consisting of hydrogen, lower alkyl or substituted alkyl, or R? is absent if then carbon to which it is attached is part of an unsaturated aryl or heteroaryl ring; with the provisos that:

a. R? may not be hydrogen if X is SO, SO,, NR"“CO,, or NR*S0,,

b. R® may not be hydrogen if Y is SO, SO,, NR'>CO,, or NR*SO,. oT

2. The compound according lo Claim 1, selected from the group consisting of: N-(4-Chlorophenyl)pyrrolo[2,1-}[1,2,4]triazin-4-amine; 2-Methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-4-ylamino)phenol; 7-Bromo-N-(4-chlorophenyl)pyrrolo(2, 1-f][1 2,4]triazin-4-amine; N-(4-Chloro-2-fluorophenyl)pyrrolo[2, 1-f][1,2,4}triazin4-amine; 2-Methyl-5-[(6-methylpyrrolo{2,1-f][1,2,4}triazin-4-yl)amino]phenol; : N-(4-Bromo-2-fluorophenyl)pyrrolo[2, 1 fl 1 2,4]triazin-4-aminc; E 2-Methyl-5-[(5-methylpyrrélo[2,1-f]{1,2,4]triazin-4-yl)amino]phenol; 5-[[2-(Dimethylamino)pyrrolo[2,1-f][1 ,2,4]triazin-4-yl]Jamino]-2-methylphenol; 5-[(5,7-Dimethylpyrrolo[2,1-f][ 1,2,4)triazin-4-yl)amino]-2-methylphenol; 5-[(6-Ethyl-5,7-dimethylpyrrolo[2,1-f][1 ,2,4]triazin-4-yl)amino]-2-methylphenot; 5-[(5,6-Dimethylpyrrolo[2,1-f][1,2,4]triazin-4-yl)Jamino}-2-methylphenol; 2-Methyl-5-[(7-methylpyrrolo(2,1-f][1,2,4]triazin-4-yl)amino]phenol; N-(4-Bromo-2-fluorophenyl)-5-methylpyrrolo[2, 1-f][1,2,4]triazin-4-amine; N-(4-Bromo-2-fluorophenyl)-7-methylpyrrolo{2,1-f][1,2,4]triazin-4-amine; 1-[2.

3-Dihydro-6-(pyrrolo[2,1-f}{1,2,4]triazin-4-ylamino)- 1 H-indol-1-ylJethanone; N-(4-Bromo-2-fluorophenyl)-6-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine; -111- AMENDED SHEET i . ‘ WO 00/71129 PCT/US00/13420 5-[(5-Ethylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]-2-methylphenol: 4-[(3-Hydroxy-4-methylphenyl)amino]-5-methylpyrrolo{2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester; 4-[(3-Hydroxy-4-methylphenyl)amino]-3-methylpyrrolo[2,1-f][1,2,4]triazinc-6-

methanol; 4-[(3-Hydroxy-4-methylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid; 1-[[4-[(3-Hydroxy-4-methylphenyl)amino}-5-methylpyrrolo[2,1-f][1,2,4]triazin-6- yl]carbonyl}-4-methylpiperazine;

4-[(3-Hydroxy-4-methylphenyl)amino]-5-methyl-N-[2-(1- pyrrolidinyl)ethyl}pyrrolo[2,1-f][1,2,4]}triazine-6-carboxamide; 4-[(3-Hydroxy-4-methylphenyl)amino)-S-phenylpyrrolo(2,1-f][ 1.2,4]triazine-6- carboxylic acid ethyl ester: 4-[(3-Methoxy-4-methylphenyl)amino]-5-methylpyrrolo[2.1-f][ 1,2,4]triazine-6-

carboxylic acid methyl ester; 2-Methyl-5-[5-methyl-6-(1H-1,2,4-triazol- 1-ylmethyl)pyrrolo{2,1-f][1,2,4]triazin-4-

yl]Jamino]phenol;

© 4-[(3-Cyanophenyl)amino]-5-methylpyrrolo{2,1-f][1,2,4]triazine-6-carboxylic acid

} methyl ester;

) 20 4-[(3-Carboxyphenyl)amino]}-5-methylpyrrolo{2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-[3-(Acetylamino)phenyl}amino]-5-methylipyrrolo[2.1-f][1,2,4 ]Jtriazine-6-carboxyl ic acid methyl ester; 4-[(3-Fluoro-4-methylphenyl)amino]-5-methylpyrrolo{2,1-f][ 1,2 ,4]triazine-6-

CTArBoRyilt dtid methyl ester; } 5-Methyl-4-[(4-methyl-3-nitrophenyl)amino]pyrrolof2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester; 5-Methyl-4-[[4-methyl-3-[(methylsulfonyl)amino]phenyl]amino]pyrrolo[2,1- f]{1,2,4]triazine-6-carboxylic acid methyl ester;

4-[(3-Cyano-4-methylphenyl)amino]-5-mcthylpyrrolo(2,1-f](1,2,4]triazine-6- carboxylic acid methyl ester;

4-[(1-Acetyl-2,3-dihydro-1H-indol-6-yl)amino]-5-methylpyrrolo[2,1-f}{1,2,4]triazine- 6-carboxylic acid methyl ester;

+ .

4-(2,3-Dihydro-1H-indol-1-y1)-5-methylpyrrolo[2,1-f][ 1,2,4]triazine-6-carboxylic acid methyl ester; 4-{(3-Amino-4-methylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester;

4-[(4-Bromo-2-fluorophenyl)amino]-5-methylpymolo[2,1-f]{ 1,2,4]triazine-6- carboxylic acid methyl ester; 4-[(2,3-Dihydro-1H-indol-6-yl)amino}-5-methylpyrrolo[2,1-][1,2,4]triazine-6- carboxylic acid methyl ester;

S-Mcthyl-4-(5-quinolinylamino)pyrrolo[2,1-f][ 1,2,4]triazine-6-carboxylic acid methyl ester; 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-[(3,4-Dimethylphenyl)amino}-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxyiic acid methyl ester;

4-[[5-(Hydroxymethyl)-2-methylphenyl]amino}-5-methylpyrrolo[2,1- f][1,2,4]triazine-6-carboxylic acid methyl ester;

4-(1H-Indazol-6-ylamino)-5-methylpyrrolo[2,1-f}[1,2,4]triazine-6-carboxylic acid methyl ester; . : 4-[(4-Bromo-3-methylphenyl)amino}-5-methylpyrrolo[2,1-f)[1,2,4]triazine-6- B : 20 carboxylic acid methyl ester; 4-[(4-Chloro-3-nitrophenyl)amino}-5-methylpyrrolo[2,1-f][1,2.4]}triazine-6-carboxylic acid methyl ester; 4-[(2,3-Dihydro-1,4-benzodioxin-6-yl)amino]-5-methylpyrrolo{2,1-f][ 1,2,4]triazine- 6-carboxylic acid methyl ester;

5-Methyl-4-[(5-methyl-2-pyridinyl)amino]pyrrolo[2,1-f}[ 1,2,4]triazine-6-carboxylic acid methyl ester; 4-[(1H-Benzotriazol-5-yl)amino]-5-methylpyrrolo[2,1-f][ 1,2,4]triazine-6-carboxylic acid methyl ester; : 5-Methyl-4-[[2-methyl-5-[(methylsulfonyl)amino}phenylJamino]pyrrolo[2,1-

f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-[(1,2-Dihydro-4-methyl-2-o0xo0-7-quinolinyl)amino]-5-methylpyrrolof2,1- f1[1,2,4]triazine-6-carboxylic acid methyl ester;

4.[(3-Hydroxy-4-methylphenyl)methylamino]}-5-methylpyrrolo[2,1-f][ 1,2,4]triazine- 6-carboxylic acid methyl ester: 4-[(3-Hydroxyphenyl)amino]-5-methylpyrrolo[2,1-f]{1,2,4]triazine-6-carboxylic acid methyl ester;

5S 4-[[2-(Aminosulfonyl)phenyljamino]-5-methylpyrrolo[2,1-f][1,2.4]triazine-6- carboxylic acid methyl! ester; {4-[(3-Hydroxy-4-methylphenyl)amino}-5-methyipyrrolo[2,1-f][ 1,2,4]triazin-6- yllcarbamic acid phenylmethyl ester; 4-(2,3-Dihydro-2-oxo- 1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-

carboxylic acid methyl ester; 4-[(3-Hydroxy-4-methoxyphenyl)amino}-5-methylipyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester; 4-[(3-Hydroxy-2-methylphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester:

4-(2-Benzothiazolylamino)-5-methylpyrrolo(2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-[[3-Hydroxy-4-[(phenylsulfonyl)amino]phenyl]amino}-5-methylpyrrolo[2,1 - f][1,2,4]triazine-6-carboxylic acid methyl ester, 4-[[3-(Aminosulfonyl)-4-methylphenyl}amino}-5-methylpyrrolo(2,1-f][1,2,4]triazine-

6-carboxylic acid methyl ester; 4-[(2,3-Dihydro-1,3-dioxo-1H-isoindol-5-yl)amino]-5-methylpyrrolo[2,1- f](1,2,4]triazine-6-carboxylic acid methyl ester; 4-[[3-(Hydroxymethyl)phenyl]amino]-5-mcthylpyrrolo{2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester;

35 #iiEndol-G-yiamino)-S-methylpyreic[2;l i124 triazine € carboxylic acid methyl ester; 5-[(6-Amino-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]-2-methylphenol; 4-[(3-Carboxy-4-hydroxyphenyl)amino]-5-methylpyrrolo[2,1-f]{1,2,4]triazine-6- carboxylic acid methyl ester;

4-(3-Hydroxyphenoxy)-5-methylpyrrolo[2,1-f]{1,2,4]triazine-6-carboxylic acid methyl ester; 5-Methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazine-6-carbox ylic acid methyl ester;

5-Methyl-4-{(1,2,3,4-tetrahydro-1,4-dioxo-6-phthalazinyl)amino]pyrrolo[2,1- f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-[[3-(Hydroxysulfonyl)phenyl]amino]-5-methylpyrrolo[2,1-f](1,2,4]triazine-6- carboxylic acid methyl ester;

4-[[3-[(Butylamino)sulfonyljphenyliJamino]-5-methylipyrrolo(2,1-f}[ 1,2,4]triazine-6- carboxylic acid methyl ester; 4-{[3-(Aminosulfonyl)phenyl]amino}-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester; 4-[{(3-Hydroxy-4-methylphenyl)amino]-5-methoxypyrrolo{2,1-f][1,2,4]triazine-6-

carboxylic acid ethyl ester; 4-[[3-(Hydrazinocarbonyl)phenyl]Jamino}-5-methylpyrrolo{2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester; 5-Methyl-4-[[3-[(methylsulfonyl)amino]phenyljamino]pyrrolo{2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester;

5-Ethyl-4-{(3-hydroxy-4-methylphenyl)amino]pyrrolo[2,1-f][ |,2,4]triazine-6- carboxylic acid ethyl ester;

: 5-Ethyl-4-[(6-methoxy-3-pyridinyl)amino]pyrrolo(2,1-f][1,2,4]triazine-6-carboxylic : acid ethyl ester; i 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-ethylpyrrolo[2,1-f][ 1,2,4]triazine-6- : 20 carboxylic acid ethyl ester;

4-{(4-Bromo-2-fluorophenyl)amino]-5-methoxypyrrolo[2,1-f}[ 1,2,4]triazine-6- i carboxylic acid ethyl ester; 4-[(4-Bromo-2-fluorophenyl)amino]-5-methoxy-N-[2-(1-

pyrrolidinyl)ethyl]}pyrrolo[2,1-f][ 1,2,4]triazine-6-carboxamide;

4-[(4-Bromo-2-fluorophenyl)amino}-5-methoxy-N-methyl-N-[2-(1- pyrrolidinyl)ethyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[(6-Methoxy-3-pyridinyl)amino]-5-methylpyrrolo{2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester; : 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methoxypyrrolo[2,1-f][1,2,4]triazine-6-

carboxylic acid ethyl ester; 5-Methoxy-4-[(6-methoxy-3-pyridinyl)amino]pyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid ethyl ester;

5-Ethyl-4-[(4-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester; 4-[(3-Amino-4-mcthylphenyl)amino]-5-ethylpyrrolo{2,1-f][1,2,4]triazine-6- carboxylic acid ethyl ester;

4-[(3-Hydroxy-4-methylphenyl)amino]pyrrolo[2,1-f][1,2,4]triazine-5.6-dicarboxylic acid diethyl ester; 5-Ethyl-4-[[4-methyl-3-[(methylsulfonyl)amino]phenyl]amino]jpyrrolo[2,1- fl[1,2,4]tnnazine-6-carboxylic acid ethyl ester; 5-Ethyl-4-[(6-methoxy-3-pyridinyl)amino]pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid; 5-Ethyl-4-[(6-methoxy-3-pyridinyl)amino]pyrrolo[2,1-f]{ 1,2,4]triazine-6-carboxylic acid methyl ester; 4-(2,3-Dihydro-2-oxo- 1 H-benzimidazol-1-yl)-5-methylpyrrolo{2,1-f][ 1,2,4]triazine- 6-carboxylic acic methyl ester;

5-Methyl-4-(1,2,3,4-tetrahydro-3-oxo-1-quinoxalinyl)pyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl! ester; 5-Methyl-4-[[ 1-(phenylmethyl)-1H-indazol-5-yl]amino]pyrrolo[2,1-f][1,2,4]triazine- 6-carboxylic acid methyl ester; 4-[[6-(Acetylamino)-3-pyridinyl]Jamino]-3-methylpyrrolo[2,1-f]{1,2,4]triazine-6-

carboxylic acid methyl ester; 5-Ethyl-4-[(6-methoxy-3-pyridinyl)amino]-N-[2-(1-pyrrolidinyl)ethyl}pyrrolo{2,1- fl[1,2,4]triazine-6-carboxamide; 5-Ethyl-4-[(6-methoxy-3-pyridinyl)amino]-N-methy!l-N-{2-(1- pyrrolidinyl)ethyl]pyrrolo[2,1-f]{1,2,4]triazine-6-carboxamide;

#F[{G-Ciiviu-d-pynining amino -5-cihyipyiroro] 2; 1 F524 Jirtazine-6-carboxylic acid ethyl ester; 5-Ethyl-4-(1H-indazol-6-ylamino)pyrrolo[2,1-f]{1,2,4]triazine-6-carboxylic acid ethyl ester; 4-[(6-Methoxy-3-pyridinyl)amino]-S-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester; [4-[(6-Methoxy-3-pyridinyl)amino]-5-ethylpyrrolo[2,1-f][1,2,4]triazin-6-yl}carbamic acid phenylmethyl ester;

\ co oo 4-(2,3-Dihydro-2-o0xo0-1H-indol-3-yl)-5-methylpyrrolo[2,1-f}{ 1,24 ]triazine-6- carboxylic acid; 4-Hydroxy-5-methoxypyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester; 4-[2,3-Dihydro-5-[(methylsuifonyl)amino]-2-oxo- 1 H-indol-3-yl]-5- methylpyrrolo{2,1-f]{1,2,4]triazine-6-carboxylic acid methyl ester; 5-Ethyl-4-[(4-hydroxyphenyl)amino]pyrrolo{2,1-f][ 1,2,4]triazine-6-carboxylic acid ethyl ester; 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)pyrrolo[2,1-f]{1,2,4)triazine-6-carboxylic acid methyl ester; 5-Methyl-4-(1H-pyrazol-3-ylamino)pyrrolo{2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-[(4-Mcthoxyphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-[(3,4-Dimethoxyphenyl)amino]-5-methylpyrrolo[2,1-f][ 1,2,4]triazine-6-carboxylic 1S acid methyl! ester; 5-Methyl-4-[(5-methyl- | H-pyrazol-3-yl)amino]pyrrolo[2,1-f]{ 1,2,4]triazine-6- carboxylic acid methyi ester; 4-(2,3-Dihydro-3-o0x0-1H-indazol-2-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- . carboxylic acid methyl ester; ‘ 20 4-(2,3-Dihydro-3-oxo-1H-indazol-1-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester;

. 4-[6-Fluoro-2-hydroxy-1H-indol-3-yl}-5-methylipyrrolo[2,1-f][ 1,2,4]triazine-6- carboxylic acid methyl ester; 4-[6-Bromo-2-hydroxy-1H-indol-3-yl]-5-methylpyrrolo[2,1-f][ 1,2,4]triazine-6- carboxylic acid methyl cster; 4-[5-(Aminosulfonyl)-2,3-dihydro-2-oxo-1H-indol-3-yl]-5-methylpyrrolo[2,1- f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-[2,3-Dihydro-5-[[[2-(4-morpholinyl)ethyl}Jamino]sulfonyl]}-2-oxo- 1 H-indol-3-yl}-5- methylpyrrolo[2,1-f]{1,2,4]triazine-6-carboxylic acid methyl ester; 4-[2,3-Dihydro-2-ox0-5-[[[2-(1-pyrrolidinyl)ethyl)amino}sulfonyl}-1H-indol-3-yl]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-(5-Fluoro-2,3-dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-carboxylic acid methyl ester;

4 : WO 00/71129 PCT/US00/13420 4-[2,3-Dihydro-2-oxo0-6-(trifluoromethyl)- 1 H-indol-3-yl]-5-methylpyrrolo[2, 1- f][1,2,4]triazine-6-carboxylic acid methyl cstcr, 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)pyrrolo[2,1-f][ 1,2 ,4]triazine-5,6-dicarboxylic acid diethyl ester;

4-[2,3-Dihydro-6-(methylsulfonyl)-2-oxo-1H-indol-3-yl]-5-methylpyrrolo[2,1- f]{1,2,4]triazine-6-carboxylic acid methyl ester; 4-[5-[(Dimethylamino)sulfonyl]-2,3-dihydro-2-oxo-1H-indol-3-yl]-5- methylpyrrolo[2,1-f}[1,2,4]triazine-6-carboxylic acid methyl ester; 4-[5-(Aminocarbonyl)-2,3-dihydro-2-oxo-1H-indol-3-yl]-5-methylpyrrolo[2,1-

f)[1,2,4]triazine-6-carboxylic acid methyl ester;

[4-(2,3-Dihydro-2-oxo- 1H-indol-3-yl)-5-methylpyrroio(2,1-f][ 1,2,4 |triazin-6- yl]carbamic acid phenyimethyl ester; 4-(5-Cyano-2,3-dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-carboxylic acid methyl ester;

4-(2,3-Dihydro-6-methyl-2-oxo-1H-pyrazolo[2,3-d]pyrimidin-3-yl)-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-(2,3-Dihydro-2-oxo-1H-pyrazolo[2,3-b]pyridin-3-yl)-5-methylpyrrolo[2,1-

= f}[1,2,4]triazine-6-carboxylic acid methyl ester; 4-(2,3-Dihydro-2-oxo-1H-indol-3-y1)-N,5-dimethyl-N-{2-(1- . 20 pyrrolidinyl)ethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-S-methyl-N-{2-(1- pyrrolidinyl)ethyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-(2,3-Dihydro-2-oxo- | H-indol-3-yl)-5-methyl-N-[3-(4- morpholinyl)propylpyrrolo(2,1-f]{1,2,4]triazine-6-carboxamide;

4-{2;3-Dihydio-2-0%0- 1 i -indol-3-yi-S-meiny-N-{2-(3- - morpholinyl)ethyl]pyrrolo[2,1-f][1,2 4]triazine-6-carboxamide; 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-N-[[[3- (dimethylamino)propyl}aminojcarbonyl]-N-ethyl-5-methylpyrrolo(2,1- f](1,2,4]triazine-6-carboxamide;

4-[2,3-Dihydro-5-[[(2-hydroxyethyl)amino]sulfonyl]-2-oxo-1H-indol-3-yl]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester; 4-[2,3-Dihydro-5-(4-morpholinylsulfonyl)-2-o0xo-1H-indol-3-yl]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester;

4-[2,3-Dihydro-5-[(methylamino)sulfonyl}-2-oxo-1H-indol-3-yl]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester: 4-{(3-Bromophenyl)amino]-5-ethylpyrrolo[2,1-f][ 1 ,2,4]triazine-6-carboxylic acid ethyl ester;

5-Ethyl-4-[(4-phenoxyphenyl)amino]pyrrolo(2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester; 5-Ethyl-4-[[1-(phenylmethyl)- 1 H-indazol-4-yl]Jamino]pyrrolo(2,1-f][1,2,4]triazine-6- carboxylic acid ethyl ester; 4-(6-Cyano-2,3-dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][ 1,2 4]triazine-

6-carboxylic acid methyl ester; 4-(2,5-Dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-5-methylpyrroio[2,1- f](1,2,4]triazine-6-carboxylic acid methyl ester; 3-(6-Amino-5-methylpyrrolo[2,1-f][ 1,2,4]triazin-4-yl)-1,3-dihydro-2H-indol-2-one: 3-(6-Amino-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,3-dihydro-2H-indol-2-one:

4-[(3-Hydroxy-4-methylphenyl)amino]-5-methyl-N-[3-(4- morpholinyl)propyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide;

N-[4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]- : N'-[2-(4-morpholinyl)ethyl]urea; E N-[4-(2,3-Dihydro-2-oxo-1H-indol-3-yl}-5-methylpyrrolo{2, 1-f]{ 1,2,4]triazin-6-yl]-

N'-[3-(4-morpholinyl)propyljurca; ) N-[4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methyipyrrolo[2, 1-f][ I,2,4]triazin-6-yl]- N'-[4-(4-morpholinyl)butyl]jurea; 5-Ethyl-4-[[1-(phenylmethyl)- 1H-indazol-5-ylJamino]pyrrolo[2,1-f][1,2,4]triazine-6- methanol;

4-(2,3-Dihydro-1-methyl-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-carboxylic acid methyl ester; 5-Ethyl-4-[(6-methoxy-3-pyridinyl)amino]-N-[2-(1-pyrrolidinyl)ethyl]pyrrolo[2,1- f][1,2,4]triazine-6-carboxamide; 5-Ethyl-4-[(6-methoxy-3-pyridinyl)amino}-N-methyl-N-[2-(1-

pyrrolidinyl)ethyl]pyrrolo(2,1-f][1,2,4]triazine-6-carboxamide; S-Ethyl-N-[3-(1H-imidazol-1-yl)propyl]-4-[[1-(phenylmethyl)- 1 H-indazol-5- ylJamino]pyrrolo[2,1-f]{1,2,4]triazine-6-carboxamide;

PCT/US00/13420 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methyl-N-[3-(1- pyrrolidinyl)propyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamde; 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methyl-N-[3-(4-methyl-1- : piperazinyl)propyl]pyrrolo{2,1-f}[1,2,4]triazine-6-carboxamide;

4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methyl-N-[3-(1H-1,2,3-triazol-1- yl)propyllpyrrolo[2,1-f}{1,2,4]triazine-6-carboxamide; 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methyl-N-{3-(2H-1,2,3-triazol-2-

yl)propyllpyrrolo{2,1-f][1,2 4]triazine-6-carboxamide; 4-(2,3-Dihydro-2-o0xo-1H-indol-3-yl)-5-methyl-N-[3-(1H-1,2 4-triazol-1- yl)propyllpyrrolo{2,1-f}[1,2,4]triazine-6-carboxamide; : 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methyl-N-[3-(2-methyl-1H-imidazol-1- yDpropyllpyrrolo[2,1-f]{ 1,2,4]triazine-6-carboxamide; © 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methyl-N-[4-(4- : morpholinyl)butyljpyrrolo(2,1-f][1,2,4]triazine-6-carboxamide; 4-23 -Dihydro-2-oxo- 1H-indol-3-yI)-N,5-dimethyl-N-[3-(4- : morpholinyl)propyl]pyrrolo{2,1-f}{1,2,4]riazine-6-carboxamide; Co 4-(6-F luoro-2,3-dihydro-2-oxo- 1H-indol-3-yl)-5-methy}-N-[3-(4- : morpholiny!)propyl]pyrrolo[2, 1-f][ 1,2,4]triazine-6-carboxamide; 5-Ethyl-N-[2-(4-morpholinyl)ethyl}-4-[[ 1-(phenylmethyl)-1H-indazol-5- ylJamino]pyrrolo{2,1-f]{1,2 4]triazine-6-carboxamide; 5-Ethyl-N-[6-[3-(1H-imidazol-] -ylypropyl}-2-pyridinyl}-4-{[1 -(phenylmethyl)-1H- ’ indazol-5-yljamino]pyrrolo(2,1-f][ 1,2 4]triazine-6-carboxamide; ~ 4-(5-Fluoro-2,3-dihydro-2-oxo-1 H-indol-3-yl)-5-methyl-N-[3-(4- morpholinyl)propyl]pyrrolo(2, 1-f][1,2,4]triazine-6-carboxamide;

4-(3-Hydroxy-4-methoxyphenyl)-5-methyl-N-{3-(4-morpholinyl)propyl]pyrrolof2,i- f][1,2,4]triazine-6-carboxamide; : 7-Bromo-5-ethyl-4-{{ 1-(phenylmethyl)-1 H-indazol-5-ylJamino]pyrrolo{2,1 - f][1,2,4]triazine-6-carboxylic acid ethyl ester; 7-Bromo-5-ethyl-4-[[1-(phenylmethy!)-1H-indazol-5-ylJamino]pyrrolof2,1- f][1,2,4)triazine-6-methanol; N-[4-(2,3-Dihydro-2-oxo-1H-indol-3-y1)-5-methylpyrrolo[2,1-f]{1 ,2,4)triazin-6-yl}-4- morpholinebutanamide; : -120- CLEAN COPY

" CL PCT/US00/13420 5-Ethyl-6-[[2-(4-morpholinyl)ethoxy]methyl]-N-] 1-(phenylmethyl)-1H-indazol-5- yllpyrrolo[2,1-f]{1,2,4]triazin-4-amine; 7-Bromo-5-ethyl-N-[2-(4-morpholinylethyl}4-[[ 1-(phenyimethyl)-1H-indazol-5- yllamino]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide;

4-(2,3-Dihydro-2-0x0-1H-indol-3-y1)-5-methyipyrrolof2, 1-f]{1,2,4]triazine-6- carboxamide; ) 4-(2,3-Dihydro-2-ox0-1H-indol-3 -yD-N,5-dimethylpyrrolo[2,1-f][1,2,4]triazine-6- carboxamide; 4-(2,3-Dihydro-2-ox0-1H-indol-3-yl)-5-methoxy-N-[3-(1H-1,2,4-triazol-1- :

: 10 yDpropyllpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; Coo 4-(2,3-Dihydro-2-ox0-1H-indol-3-yl)-5-methoxy-N-[3-(4- morpholinyl)propyllpyrrolo[2,1-£][1,2,4]triazine-6-carboxamide; 4-[(4-Bromophenyl)amino]-5-methyl-N-[3-(4-morpholinyl)propyl]pyrrolo[2, 1-

: fj[1,2,4]triazine-6-carboxamide;

N-[4~(2,3-Dihydro-2-ox0-1H-indol-3-yl)-5-methylpyrrolo[2, 1-f][ 1 2,4]triazin-6-yl]-2- methylpropanamide; : 3-[6-(Dimethylamino)-7-(hydroxymethyl)-5-methylpyrrolo[2, 1-f]{1,2,4]triazin-4-yl1}- 1,3-dihydro-2H-indol-2-one; N-{4-(2,3-Dihydro-2-ox0-1H-indol-3-y1)-5-methylpyrrolo[2,1-f][1 ,2,41triazin-6-

yllmethanesulfonamide; 3~(5,6-Dimethoxypyrrolo[2,1-f][1,2,4]triazin-4-yl)- 1 ;3-dihydro-2H-indol-2-one; N-{4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1 .2,4]triazin-6-yl]4- morpholinepropanesulfonamide;

~ [4-(2,3-Dibydro-Z-oxo-1H-indol-3-yi)-5-methoxypyrrolo[2, 1-f][1,2,4]triazin-6-

yl]carbamic acid phenylimethyl ester; 4-[5-{Aminosulfonyl)-2,3-dihydro-2-o0x0-1 H-indol-3-yl]-5-methyl-N-[3-(4- morpholinyl)propylipyrrolo{2,1-f][1,2,4]triazine-6-carboxamide;

1,3-Dihydro-3-[5-methoxy-6-[[4-(4-methyl-1 -piperazinyl)butyljamino]pyrrolo[2,]- f][1,2,4}triazin-4-v1]-2H-indol-2-one;

3-(6-Amino-5-methoxypyrrolo[2,1-f}{1,2,4]mazin4-v1)-1 ,3-dihydro-2H-indol-2-one; 1,3-Dihydro-3-[5-methoxy-§-[[4-(4-morpholinyl)butyl]aminolpyrrolo]2,1- f[1,2,4]wriazin-4-yl}-2H-indol-2-one;

-121- CLEAN COPY

) PCT/US00/13420 4-[(3-Hydroxy-5-methylphenyl)amino}-5-methylpyrrolof2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester; 4-[(4-Ethyl-3-hydroxyphenyl)amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methy] ester;

1,3-Dihydro-3-[5-methyl-6-[2-(1H-1 ,2,4-triazol-1-yl)ethoxy]pyrrolo[2,1- . fi{1,2,4]triazin-4-yl]-2H-indol-2-one; 5-[(5,6-Dimethoxypyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]-2-methylphenol; : 4-[(4-Bromo-3-hydroxyphenyl)amino}-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester; :

4-[[3-Hydroxy-4-(1-methylethyl)phenyl]amino}-5-methylpyrrolo[2,1- - + f][1,2,4]triazine-6-carboxylic acid methyl ester; i 4-(2,3-Dihydro-2-oxo0-1H-indol-3-yl)-5-methylpyrrolo[2,1-f]{1,2,4 triazine-6- : propanoic acid methyl ester; 4-{(4-Hydroxy-2-naphthalenyl)amino}-5-methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester; 4-[(4-Carboxy-3-hydroxyphenyl)amino]-5 -methylpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid methyl ester; 4-[(3-Chloro-4-fluorophenyl)amino]-5-methylpyrro lo [2,1-f][1,2.,4]triazine-6- carboxylic acid methyl ester; 4-[(3-Chloro-4-fluorophenyl)amino]-5-ethylpyrrolo[2,1-f}{1,2,4]triazine-6-carboxylic : acid ethyl ester; : 1,3-Dihydro-3-(6-methoxy-5-methylpyrrolo{2,1-f][1,2,4]triazin-4-y1)-2H-indol-2-one; G-{{(=Clitutu= Ruut uplreily uimuupyu oii] 2, 1-13] 1,2 4 u faze -G-uar bux sic auid methyl ester; 4-[3-{4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6- v1}-1-oxopropylimorphcline; 1-[3-[4~(2,3-Dihydro-2-oxo- 1 H-indol-3-yl)-5-methylpyrmrolo[2,1-f][ 1,2 ,4]triazin-6-

yl]-1-oxopropyli-4-methylipiperazine; : 4-[{1-(Pbenylmethy!)-1H-indazol-5-yljaminc]-5-ethylpyrrolo[2,1-f] 1,2,4]triazine-6-

= carboxylic acid ethyl ester; 4-[[1-(Phenylmethyl)-1H-indazol-5-yl}Jamino]- 5-propylpyrroio{2,1-f]{1,2,4]triazine- 6-carboxylic acid ethyl ester; -122- CLEAN COPY ’

} _ PCT/US00/13420 Sa 4-[(4-Bromophenyl)amino]-3-cthylpyrrolo[2,1-f][ 2,4 ]triazine-6-carboxylic acid : ethyl ester; 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5,6-dimethoxypyrrolo[2,1-f}[1,2,4]triazine-7- carboxylic acid methyl ester;

. 5 4-[(4-Butyl-3-hydroxyphenyl)amino]-5-methylpyrrolo[2, 1-f){1,2,4]triazine-6- carboxylic acid methyl ester; oo 4-[(3-Hydroxy-4-propylphenyl)amino}-5-methylpyrrolo[2, 1-f][1,2,4]triazine-6- carboxylic acid methyl ester; ’ 4-[(3-Hydroxy-4-methylphenyl)amino]-5-propylpyrrolo[2,1-f]{1,2,4}triazine-6- : carboxylic acid ethyl ester; | : 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-N-(2-methoxyethyl)-5-methylpyrrolo{2,1- ) f1(1,2,4]triazine-6-carboxamide; ~ 4~(2,3-Dihydro-2-oxo-1H-indol-3-yl)-N-(3-methoxypropyl)-5-methylpyrrolo[2,1- f}{1,2,4]triazine-6-carboxamidc; 4-(2,3-Dihydro-2-oxo-1H-indol-3-yl)-5-methyi-N-[(tetrahydro-2- furanyl)methyl]pyrrolo[2, 1-f][1 ,2,4]triazine-6-carboxamide; 5-Ethoxy-4-[(3-hydroxy-4-methylphenyl)amino]pyrrolo[2,1-f][1,2,4]triazine-6- : carboxylic acid ethyl ester; 4-[(4-Ethyl-3-hydroxyphenyl)amino]-5-methyl-N-[3-(4- morpholinyl)propyljpyrrolo[2,1-f]] 1,2,4]triazinie~6-carboxamide; 4-[(4-Bromo-3-hydroxyphenyl)amino]-5-methyl-N-[3-(4- morpholinyl)propyllpyrrolo[2,1-f]{1,2,4]triazine-6-carboxamide; A-[(3-Hydroxy-4-methylphenyl)amino}-5-methyl-N-{3-(2H-1,2,3-triazol-2- yl)propyllpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 5-Ethyl-4-(phenylamino)pyrrolo[2,1-f][ 1,2,4]triazine-6-carboxylic acid ethyl ester; 5-Ethyl-4-(methylphenylamino)pyrrolo[2;1-f][1,2,4]triazine-6-carboxylic acid ethyl ester; 5-Ethyl-4-(1,2,3,4-tetrahydro-2-isoquinolinyl)pyrrolo(2,1-f]{ 1,2,4 Jtriazine-6- : carboxylic acid ethyl ester; 4-[(3-Hydroxy-4-methylphenyl)amino]-N-(3-methoxypropyl)-5-methylpyrrolo{2,1- £][1,2.4]triazine-é-carboxamide; 4-[(3-Hydroxy-4-methylphenyl)amino]-5-methyl-N-[3-(4-methyl-1- piperazinyl)propyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; oo -123- CLEAN COPY eT . + ” WO 00/71129 PCT/US00/13420 4-[(3-Hydroxy-4-methylphenyl)amino]-N,5-dimethylpyrrolo[2,1-f][ 1,2,4]triazine-6- carboxamide; N-[2-(Dimethylamino)ethyl]-4-[(3-hydroxy-4-methylphenyl)amino}-5- methylpyrrolo[2,1-f]{1,2,4)triazine-6-carboxamide; 5-Ethyl-4-(1,2,3,4-tetrahydro-1-quinolinyl)pyrrolo{2,1-f][ 1,2,4]triazine-6-carboxylic acid ethyl ester; 5-Ethyl-4-[(phenylmethyl)amino]pyrrolo[2,1-f][1,2,4]}trnazine-6-carboxylic acid ethyl ester; 4-(2,3-Dihydro-2-oxo0-1H-indol-3-yl)-5-ethoxypyrrolo[2,1-f]{ 1,2,4]triazine-6- carboxylic acid ethyl ester; 4-[(3-Hydroxy-4-methylphenyl)amino}-5-methyl-N-[3-(1- pyrrolidinyl)propyl]pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 5-Ethyl-4-[(2-phenylethyl)amino]pyrrolo(2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester; N-[4-(Dimethylamino)butyl]-4-[(3-hydroxy-4-methylphenyl)amino]-5- methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[(3-Hydroxy-4-methylphenyl)amino]}-5-(1-methylethyl)pyrrolo[2,1- fo f]{1,2,4]triazine-6-carboxylic acid ethyl cster; : 4-[(3-Hydroxy-4-methylphenyl)amino}-5-methyl-N-[3-

. 20 (methylsulfonyl)propyljpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide; 4-[(3-Chloro-4-fluorophenyl)methyl]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine- ; 6-carboxylic acid cthyl ester; [4-[(3-Chloro-4-fluorophenyl)amino}-5-ethylpyrrolo[2,1-f][1,2,4]triazin-6- yl}carbamic acid phenylmethyl ester; 23 3-{i-Mewyieinyi-4-{{ 1 -(pireny ime iiyiF 1 H-iidzui-3=y1janinupynoiv{ 2, i - f][1,2,4]triazinc-6-carboxylic acid ethyl ester; 4-(Butylamino)-5-ethylpyrrolo(2,1-f](1,2 4]triazine-6-carboxylic acid ethyl ester 5-Ethyl-4-[(2-methoxyethyl)amino]pyrrolo[2,1-f](1,2,4]triazine-6-carboxylic acid cthyl ester; 5-Ethyl-4-(4-morpholinyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester; 5-Ethyl-4-[[3-(1H-imidazol-1-yl)propyl]aminojpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid ethyl ester;

~

© 2-Methyl-5-{[5-methyl-6-[3~(2H-1,2,3-triazol-2-yl)propoxy]pyrrolo[2,1-

f][1,2,4]triazin-4-yl]Jamino}phenol;

1,3-Dihydro-3-[5-methoxy-6-(phenylmethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-y1]-2H-

indol-2-one;

5-Ethyl-4-[[(1S)-]1-phenylethyl]amino]pyrrolo{2,1-f][1,2,4])triazine-6-carboxylic acid ethyl ester;

5-Ethyl-4-[[(1R)-1-phenylethyl]amino]pyrrolo[2,1-f]{1,2,4]triazine-6-carboxylic acid ethyl ester;

5-Ethyl-4-[[2-(2-pyridinyl)ethyl]amino]pyrrolo[2,1-f]{1,2,4]triazine-6-carboxylic acid ethyl ester;

4-[(4-Cyano-3-hydroxyphenyl)amino]-5-methylpyrrolo{2,1-f}[1,2,4]triazine-6-

carboxylic acid methyl ester;

4-[(Cyclohexylmethyl)amino]-5-ethylpyrrolo{2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester;

4-[[(4-Cyanocyclohexyl)methyl]amino]-5-ethylpyrrolo{2,1-f][1,2,4]triazine-6-

carboxylic acid ethyl ester; 4-[(3-Chloro-4-fluorophenyl)amino]-5-(phenylmethyl)pyrrolo[2,1-f}[1,2,4]triazine-6- : carboxylic acid ethyl ester; . 4 5-(Phenylmethyl)-4-[{ 1-(phenylmethyl)-1H-indazol-5-ylJamino]pyrrolo[2,1- : 20 f][1,2,4]triazine-6-carboxylic acid ethyl ester;

4-[(3-Hydroxy-4-methylphenyl)amino]-5-(phenylmethyl)pyrrolo[2,1-f][1,2,4]triazine- : 6-carboxylic acid ethyl ester; 4-[[(4-Bromophenyl)methyl]amino}-5-cthylpyrrolo[2,1-f]{1,2,4]triazine-6-carboxylic acid ethyl ester;

5-Ethyl-4-[(trans-4-hydroxycyclohexyl)aminolpyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid ethyl ester; N-(3-Bromophenyl)-5-methyl-6-[3-(2H-1,2,3-triazol-2-yl)propoxy]pyrrolo[2,1- f}[1,2,4)triazin-4-amine; : N-(4-Bromo-2-fluorophenyl)-5-methyl-6-[3-(2H-1,2,3-triazol-2-

ylpropoxylpyrrolo[2,1-f][1,2,4]triazin-4-amine; 1,3-Dihydro-3-[5-methyl-6-[3-(2H-1,2,4-triazol-2-yl)propoxy]pyrrolo(2,1- f][1,2.4]triazin-4-yl]-2H-indol-2-one;

. J “ WO 00/71129 PCT/US00/13420 5-Ethyl-4-[[(1-hydroxycyclohexyl)methyl]amino}pyrrolo[2,1-f][1,2,4]triazine-6- carboxylic acid ethyl ester, 4-[[(3-Bromophenyl)methyljamino}-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester, 4-[[(2-Bromophenyl)methyl)amino]-5-ethylpyrrolo(2,1-f}[1,2,4]triazine-6-carboxylic acid ethyl ester; 5-Ethyl-N,N-dimethy!-4-[{ 1-(phenyimethyl)- 1 H-indazol-5-yl]Jamino]pyrrolo{2,1- f](1,2,4]triazine-6-carboxamide; 4-[(3-Hydroxy-4-methylphenyl)amino}-N-[3-(4-morpholinyl)propyl}-5- propylpyrrolo[2,1-f]{1,2,4]triazinc-6-carboxamidc; 4-[(3-Hydroxy-4-methylphenyl)amino}-5-propyl-N-{3-(1- pyrrolidinyl)propyllpyrrolof2,1-f][1,2,4]triazine-6-carboxamide; N-(3-Bromophenyl)-5-methyl-6-[3-(4-morpholinyl)propyllpyrrolo[2,1- f][1,2,4]triazin-4-amine; 4-[(3-Chloro-4-fluorophenyl)amino}-5-[3-(phenylmethoxy)propyl]pyrrolo[2,1- f][1,2,4]triazine-6-carboxylic acid methyl ester; and 4-[[1-(Phenylmethyl)-1H-indazol-5-ylJamino]pyrrolo[2,1-f][ 1,2,4]triazine-6- " carboxylic acid methyl ester; and pharmaceutically acceptable salts thereof.

3. A pharmaceutical composition comprising a compound of Claim | and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising a compound of Claim 1 in combination with piaiiidceuiivdily dauitpiduic Callie dif df dii=tdrter Of tyoioRic agent formulated as a fixed dose.

5. The pharmaceutical composition as recited in claim 4, wherein said anti- cancer or cytotoxic agent is selected from the group consisting of: tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene, megestrol acetate, anastrozole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate,

PCT/US00/13420 5-fluorouracil, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotephan, vincristine, taxol, taxotere, etoposide, teniposide, amsacrine, irinotecan, topotecan and an epothilone.

6. A method for producing an antiangiogenic effect which comprises administering to a warm-blooded species, an effective antiangiogenic producing amount of a compound of Claim 1.

7. A method for producing a vascular permeability reducing effect which comprises administering to a warm-blooded species, an effective vascular permeability reducing amount of a compound of Claim 1.

8. A method of inhibiting protein kinase activity of growth factor receptors which comprises administering to a warm-blooded species, an effective protein kinase inhibiting amount of a compound of Claim 1.

9. A method of inhibiting tyrosine kinase activity of growth factor receptors which comprises administering to a warm-blooded species, an effective tyrosine kinase inhibiting amount of a compound of Claim 1.

10. Use of a compound of Claim 1 in the manufacture of a medicament for treating proliferative diseases in a warm-blooded species.

11. Use of a compound of Claim 1 in the manufacture of a medicament for treating cancer in a warm-blooded species.

12. Use of a compound of Claim 1 in the manufacture of a medicament for treating inflammation in a warm-blooded species. -127- AMENDED SHEET

) PCT/US00/13420

13. Use of a compound of Claim 1 in the manufacture of a medicament for treating autoimmune disease in a mammalian species. :

14. Use of a compound of Claim 1 and an anti-cancer or cytotoxic agent in the manufacture of a medicament for treating proliferative diseases in a warm- blooded species.

15. Use of a compound of Claim 1 and an anti-cancer or cytotoxic agent in the manufacture of a medicament for treating cancer in a warm-blooded species.

16. Use of a compound of Claim 1 and an anti-cancer or cytotoxic agent in the manufacture of a medicament for treating inflammation in a mammalian species.

17. Use of a compound of Claim 1 and an anti-cancer or cytotoxic agent in the manufacture of a medicament for treating autoimmune diseases in a mammalian species.

18. Use of a compound of Claim 1 in the manufacture of a medicament for treating diseases associated with signal transduction pathways operating through growth factor receptors in a warm-blooded species.

19. Use of a compound of Claim 1 in the manufacture of a medicament for producing an antiangiogenic effect in warm-blooded species.

20. Use of a compound of Claim 1 in the manufacture of a medicament for producing a vascular permeability reducing effect in warm-blooded species.

21. Use of a compound of Claim 1 in the manufacture of a medicament for inhibiting protein kinase activity of growth factor receptors in warm-blooded species. -128- AMENDED SHEET

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22. Use of a compound of Claim 1 in the manufacture of a medicament for inhibiting tyrosine kinase activity of growth factor receptors in warm-blooded species.

23. A substance or composition for use in a method for producing an antiangiogenic effect, said substance or composition comprising a compound of Claim 1, and said method comprising administering to a warm-blooded species in need thereof, an effective antiangiogenic producing amount of said substance or composition.

24. A substance or composition for use in a method for producing a vascular permeability reducing effect, said substance or composition comprising a compound of Claim 1, and said method comprising administering to a warm- blooded species in need thereof an effective vascular permeability reducing amount of said substance or composition.

25. A substance or composition for use in a method of inhibiting protein kinase activity of growth factor receptors, said substance or composition comprising a compound of Claim 1, and said method comprising administering to CE WaIIIEDIO0U0U SPOtics in iced ther, Gn CHCCHVE Protcin Kinass inhi oiing —— = amount of said substance or composition.

26. A substance or composition for use in a method of inhibiting tyrosine kinase activity of growth factor receptors, said substance or composition comprising a compound of Claim 1, and said method comprising administering to a warm-blooded species in need thereof, an effective tyrosine kinase inhibiting amount of said substance or composition. -129- AMENDED SHEET

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27. A substance or composition for use in a method for treating proliferative diseases, said substance or composition comprising a compound of Claim 1, and said method comprising administering to a warm-blooded species in need thereof, an effective amount of said substance or composition.

28. A substance or composition for use in a method for treating cancer, said substance or composition comprising a compound of Claim 1, and said method comprising administering to a warm-blooded species in need thereof, a therapeutically effective amount of said substance or composition.

29. A substance or composition for use in a method for treating inflammation, said substance or composition comprising a compound of Claim 1, and said method comprising administering to a warm-blooded species in need thereof, a therapeutically effective amount of said substance or composition.

30. A substance or composition for use in a method for treating autoimmune disease, said substance or composition comprising a compound of Claim 1, and said method comprising administering to a mammalian species in need thereof, a therapeutically effective amount of said substance or composition.

31. A substance or composition for use in a method for treating proliferative diseases, said substance or composition comprising a compound of So __ Claim 1 and an anti-cancer or cytotoxic agent and said method comprising —— ——— administering to a warm-blooded species in need thereof, a therapeutically effective amount of said substance or composition.

32. A substance or composition for use in a method for treating cancer, said substance or composition comprising a compound of Claim 1 and an anti- cancer or cytotoxic agent, and said method comprising administering to a warm- blooded species in need thereof, a therapeutically effective amount of said substance or composition. -130- AMENDED SHEET

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33. A substance or composition for use in a method for treating inflammation, said substance or composition comprising a compound of Claim 1 and an anti-cancer or cytotoxic agent, and said method comprising administering to a mammalian species in need thereof, a therapeutically effective amount of said substance or composition.

34. A substance or composition for use in a method for treating autoimmune diseases, said substance or composition comprising a compound of Claim 1 and an anti-cancer or cytotoxic agent, and said method comprising administering to a mammalian species in need thereof, a therapeutically effective amount of said substance or composition.

35. A substance or composition for use in a method for treating diseases associated with signal transduction pathways operating through growth factor receptors, said substance or composition comprising a compound of Claim 1, and said method comprising administering to a warm-blooded species in need thereof, a therapeutically effective amount of said substance or composition.

36. A compound according to Claim 1 or Claim 2, substantially as herein described and illustrated. )

C37. A composition according to Claim 3 or Claim 4 or Claim 5, oo substantially as herein described and illustrated.

38. A method according to any one of Claims 6 - 9, substantially as herein described and illustrated.

39. Use according to any one of Claims 10 - 22, substantially as herein described and illustrated. -131- AMENDED SHEET

) « PCT/US00/13420

40. A substance or composition for use in a method of treatment according to any one of Claims 23 - 29, substantially as herein described and illustrated.

41. A new compound; a new composition; a new non-therapeutic method of treatment; a new use of a compound of Claim 1, or of a compound of Claim 1 and an anti-cancer or cytotoxic agent; or a substance or composition for a new use in a method of treatment, substantially as herein described. -132- AMENDED SHEET