NZ625073B2 - Disubstituted benzothienyl-pyrrolotriazines and their use as fgfr kinase inhibitors - Google Patents

Abstract

Provided are disubstituted 5-(1-benzothiophen-2-yl) pyrrolo[2,1-f][1,2,4]triazin-4-amine compounds of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include 4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl} piperazin-2-one and 4-{[ 4-Amino-7-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl} piperazin-2-one. The compounds are FGFR kinase inhibitors. The compounds may be useful in the treatment of cancer. o[2,1-f][1,2,4]triazin-7-yl]methyl} piperazin-2-one and 4-{[ 4-Amino-7-(ethoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl]methyl} piperazin-2-one. The compounds are FGFR kinase inhibitors. The compounds may be useful in the treatment of cancer.

Description

DISUBSTITUTED BENZOTHIENYL - PYRROLOTRIAZINES AND THEIR USE AS FGFR KINASE INHIBITORS This invention relates to novel substituted 5—(1-benzothiophen—2-yl)pyrrolo[2,l-f][1,2,4]triazin amine derivatives having protein tyrosine kinase tory activities, to processes for the ation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or itions for treating proliferative disorders, in particular cancer and tumor diseases.

Cancer is a leading cause of death worldwide and accounted for 7.6 million deaths d 13% of all deaths) in 2008. Deaths from cancer are projected to continue to rise worldwide to over 1 1 million in 2030 (WHO source, Fact Sheet No. 297, February 2011). 10 There are many ways how cancers can arise which is one of the reasons why their therapy is diffi- cult. One way that transformation of cells can occur is following a genetic alteration. The completion of the human genome project showed genomic instability and heterogeneity of human cancer genes.

Recent strategies to identify these genetic alterations sped up the s of cancer-gene discovery.

Gene abnormality can, for instance, lead to the overexpression of proteins, and hence to a non- 15 physiological activation of these proteins. One family of proteins from which a number of onco— proteins derive are tyrosine kinases and in ular receptor tyrosine kinases (RTKs). In the past two decades, numerous avenues of research have demonstrated the importance of RTK-mediated ling in adverse cell growth leading to cancer. In recent years, promising results have been ed in the clinic with selective small-molecule inhibitors of tyrosine kinases as a new class of 20 anti-tumorigenic agents [Swinney and Anthony, Nature Rev. Drug Disc. 10 (7), 9 (2011)].

Fibroblast growth factors (FGFs) and their receptors (FGFRs) form part of a unique and diverse signalling system which plays a key role in a variety of biological processes which ass various aspects of embryonic pment and adult pathophysiology [Itoh and Ornitz, J. Biochem. 149 (2), 121-130 (2011)]. In a spatio-temporal manner, FGFs stimulate h FGFR binding a 25 wide range of cellular functions including migration, proliferation, differentiation, and survival.

The FGF family ses 18 secreted polypeptidic growth factors that bind to four highly con- served receptor tyrosine kinases (FGFR-l to —4) expressed at the cell surface. In addition, FGFR-5 can bind to FGFs but does not have a kinase domain, and therefore is devoid of intracellular signal- ling. The specificity of the ligand/receptor interaction is enhanced by a number of transcriptional and 30 translational processes which give rise to multiple isoforms by alternative transcriptional initiation, ative splicing, and C-terminal truncations. Various heparan sulfate proteoglycans (e.g. ans) can be part of the FGF/FGFR complex and strongly influence the ability of FGFs to ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena _2_ induce ling responses [Polanska et al., Developmental Dynamics 238 (2), 277-293 (2009)].

FGFRs are cell surface receptors consisting of three extracellular immunoglobulin—like domains, a single-pass transmembrane domain, and an intracellular dimerized tyrosine kinase domain. Binding of FGF bring the intracellular kinases into close proximity, enabling them to transphosphorylate each other. Seven phosphorylation sites have been identified (e.g., in FGFR-l Tyr463, Tyr583, , Tyr653, Tyr654, , and Tyr766).

Some of these phosphotyrosine groups act as docking sites for downstream signalling molecules which themselves may also be directly phosphorylated by FGFR, leading to the activation of multiple signal transduction pathways. Thus, the MAPK signalling cascade is ated in cell 10 growth and differentiation, the PI3K/Akt signalling cascade is involved in cell survival and cell fate ination, while the PI3K and PKC signalling cascades have a function in the l of cell polarity. Several feedback tors of FGF signalling have now been identified and include members of the Spry (Sprouty) and Sef (similar expression to FGF) families. Additionally, in certain conditions, FGFR is released from pre-Golgi membranes into the cytosol. The receptor and its 15 ligand, FGF-2, are co-transported into the s by a mechanism that involves importin, and are engaged in the CREE-binding protein (CBP) complex, a common and essential transcriptional co— activator that acts as a gene activation gating factor. Multiple correlations between the immuno- histochemical expression of FGF-2, FGFR—1 and FGFR-2 and their cytoplasmic and nuclear tumor cell localizations have been ed. For instance, in lung adenocarcinomas this association is also 20 found at the r level, emphasizing an active role of the complex at the nucleus [Korc and Friesel, Carr. Cancer Drags Targets 5, 639-651 (2009)].

FGFs are widely expressed in both developing and adult tissues and play important roles in a y of normal and ogical processes, including tissue development, tissue regeneration, angio- s, stic transformation, cell migration, ar differentiation, and cell survival. 25 Additionally, FGFs as pro-angiogenic s have also been implicated in the ng phenomenon of resistance to ar endothelial growth factor receptor-2 (VEGFR-2) inhibition [Bergers and Hanahan, Nat. Rev. Cancer 8, 592-603 (2008)].

Recent oncogenomic profiles of signalling networks demonstrated an important role for aberrant FGF signalling in the emergence of some common human cancers [Wesche et al., Biochem. J. 437 30 (2), 199-213 (2011)]. Ligand-independent FGFR constitutive signalling has been described in many human cancers, such as brain cancer, head and neck cancer, gastric cancer and ovarian cancer. gR—mutated forms as well as FGFR—intragenic translocations have been identified in gnancies such as myeloproliferative diseases. Interestingly, the same mutations discovered to be [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _3_ the cause of many developmental disorders are also found in tumor cells (e.g., the mutations found in achondroplasia and thanatophoric sia, which cause dimerization and thus constitutive activation of FGFR-3, are also frequently found in bladder cancer). A mutation that promotes dimerization is just one mechanism that can increase ligand-independent signalling from FGFRs.

Other mutations located inside or outside of the kinase domain of FGFRs can change the conformation of the domain giving rise to permanently active kinases.

Amplification of the chromosomal region 8p11—12, the genomic location of FGFR-I , is a common focal amplification in breast cancer and occurs in approximately 10% of breast cancers, predomi— nantly in oestrogen receptor-positive cancers. FGFR-1 amplifications have also been reported in non- 10 small cell lung us carcinoma and are found at a low incidence in ovarian cancer, bladder cancer and rhabdomyosarcoma. Similarly, approximately 10% of gastric cancers show FGFR-2 amplification, which is associated with poor prognosis, diffuse-type cancers. Moreover, multiple single nucleotide polymorphisms (SNPs) located in FGFR-l to -4 were found to ate with an increased risk of developing ive cancers, or were reported to be associated with poor prognosis 15 (e.g., FGFR-4 G388R allele in breast cancer, colon cancer and lung adenocarcinoma). The direct role of these SNPs to promote cancer is still controversial.

In y, a great number of in vitro and in vivo studies have been performed that validate FGFR-l to -4 as important cancer targets, and comprehensive reviews have summarized these findings [see, for example, Heinzle et al., Expert Opin. Ther. Targets 15 (7), 829-846 (2011); 20 Wesche et al., Biochem. J. 437 (2), 199-213 (2011); Greulich and Pollock, Trends in Molecular Medicine 17 (5), 283-292 (2011); Haugsten et al., M01. Cancer Res. 8 (11), 1439-1452 (2010)].

Several strategies have been followed to attenuate aberrant FGFR-l to -4 signalling in human tumors including blocking antibodies and small-molecule tors, amongst others. A number of selective small—molecule FGFR inhibitors are currently in al development, such as AZD-4547 — 25 Zeneca) and BIG-398 (Novartis).

Notwithstanding the significant advancements that have generally been ed in cancer therapy in recent years, there is a uing need to identify new anti-cancer compounds with improved properties, such as higher potency, greater selectivity, d toxicity and/or better tolerability.

Therefore, the technical m to be solved according to the present invention may be seen in pro- 30 viding alternative nds having inhibitory ty on the FGFR kinases, thus offering new therapeutic options for the ent of ediated diseases, in particular cancer and other pro- bative disorders.

[Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena _4_ Fused hetero-5,6-bicyclic kinase tors bearing a 9- or a 10-membered bicyclic heteroaryl substituent have been sed in WC 2007/061737-A2 and WO 2005/097800—Al, respectively.

These compounds were stated to be useful for the treatment of cancer and other diseases owing to their inhibitory action on the mTOR (mammalian target of Rapamycin) and/or lGF-lR (typel insulin-like growth factor receptor) kinases. Further hetero-5,6-bicyclic template structures asso- ciated with the inhibition of kinases have been described in, inter alia, WO 01/19828-A2, WO 2007/079164-A2 and WO 2010/051043—A1. 4—Aminopyrrolo[2,1-f][l,2,4]triazine derivatives with differing inhibition profiles against a number of protein kinases have been disclosed in, inter alia, WO 00/71129-A1, WO 2007/0561?0-A2, 10 W0 2007/061882-A2, WO 2007/064932—A2, W0 2009/136966-A1, and WO 2010/126960—A1.

In WO 2005/121147-Al, WO 2007/064883—A2 and WO 2007/06493l-A2, opyrrolo[2,l-f]— [1,2,4]triazine derivatives containing a substituted diarylurea group in 5-position were described as having FGFR-l inhibiting activity. However, other receptor tyrosine kinases, y the VEGFR, PDGFR and Tie-2 kinases, are also significantly inhibited by this particular class of compounds. As 15 it was hypothesized that such multi-kinase activity might lead to an augmentation of potential side effects during treatment, it was the aim of the present invention to identify new agents having an improved selectivity for the FGFR kinases, thus providing new s for a more tolerable cancer y.

Surprisingly, it has now been found that certain 4-aminopyrrolo[2,l-f][l,2,4]triazine derivatives 20 bearing a specifically tuted benzothiophen—Z-yl e in 5-position exhibit potent and selec- tive tion of FGFR kinases, notably of the FGFR-l and FGFR-3 kinases, which renders these compounds particularly useful for the treatment of proliferative disorders, such as cancer and tumor es.

Thus, in one aspect, the present invention relates to 6,7-disubstituted 5-(1-benzothiophenyl)- 25 pyrrolo[2, l -f] [l ,2,4]triazin—4-amine derivatives of the general formula (I) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena (I), wherein R1 is hydrogen, chloro, methyl or methoxy, R2 is hydrogen or y, with the proviso that at least one of R1 and R2 is other than hydrogen, represents , (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl, 5-membered teroaryl, or the group -CH2-OR3, -CH2—NR4R5 or —C(=O)—NR4R6, wherein R3 is hydrogen, (C1-C4)-alkyl, (C3—C6)-cycloalkyl or phenyl, wherein (i) said (C1-C4)-alkyl is optionally substituted with hydroxy, (C1-C4)-alkoxy, 10 hydroxycarbonyl, (C1—C4)-alkoxycarbonyl, amino, arninocarbonyl, mono- )-alkylaminocarbonyl, di-(C1-C4)-alkylaminocarbonyl, (C3—C6)—cycloalkyl or up to three fluoro atoms, and (ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two substituents 15 independently selected from the group consisting of (C1-C4)-alkyl, hydroxy and amino, and (iii) said phenyl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoro- 20 , romethoxy, (C1-C4)-alky1 and (C1-C4)-alkoxy, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena is hydrogen or (C1-C4)-a]kyl, is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6- ed heterocycloalkyl, wherein (Z) said (C1-C4)-alkyl is optionally substituted with hydroxy, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)—alkoxycarbonyl, arbonyl, Cl—C4)-alkyl- arninocarbonyl, —C4)—alkylaminocarbonyl or (C3-C6)-cycloalkyl, and (ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy and 10 amino, and (iii) said 4- to 6-membered heterocycloalkyl is optionally tuted with one or two substituents independently selected from the group consisting of (C1-C4)- alkyl, hydroxy, 0x0 and amino, 15 is hydrogen, (C1-C4)-alky1, (C3—C6)-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein (Z) said (C1-C4)-alkyl is optionally substituted with hydroxy, (C1-C4)-alkoxy, hydroxycarbonyl, (C1—C4)-alkoxycarbonyl, amino, arninocarbonyl, mono- (C1-C4)-alkylarninocarbonyl, di-(C1-C4)-alkylaminocarbonyl or (C3—C6)—cyclo- 20 alkyl, and (ii) said (C3-C6)-cycloalkyl is ally substituted with one or two substituents independently selected from the group consisting of (C1-C4)-alkyl, hydroxy and amino, 25 and (iii) said 4- to 6-membered heterocycloalkyl is optionally tuted with one or two substituents independently selected from the group consisting of (C1-C4)- alkyl, hydroxy, oxo and amino, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 01‘ R4 and R5, or R4 and R6, respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered hetero- cycloalkyl ring which may contain a second ring heteroatom selected from N(R7) 5 and O, and which may be substituted on ring carbon atoms with one or two sub- stituents independently selected from the group consisting of )—alkyl, 0X0, y, amino and arbonyl, and wherein R7 is hydrogen, (C1-C4)-alkyl, formyl or (C1-C4)-alkylcarbonyl, and 10 G2 represents chloro, cyano, (C1-C4)-alkyl, or the group -CR8AR8B-OH, -CH2—NR9R1°, -C(=O)-NR11R12 or -CH2-OR15, wherein R8A and R813 are independently selected from the group consisting of hydrogen, (C1—C4)—alkyl, cyclopropyl and cyclobutyl, is hydrogen or (C1-C4)-alkyl, 15 is en, (C1-C4)-alkyl, (C1-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6- membered cycloalkyl, wherein (i) said (C1-C4)-alkyl is optionally substituted with hydroxy, amino, aminocarbo- nyl, mono-(C1-C4)-alkylaminocarbonyl or di-(C1-C4)-alkylaminocarbonyl, and 20 (ii) said (C3-C5)-cycloalkyl is optionally substituted with one or two substituents ndently selected from the group consisting of (C1-C4)—alkyl, hydroxy and amino, and (iii) said 4- to ered heterocycloalkyl is optionally substituted with one or 25 two substituents independently selected from the group consisting of (C1—C4)- alkyl, hydroxy, oxo and amino, is hydrogen or (C1-C4)-alkyl, [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _ 8 _ is hydrogen, (C1-C4)-alkyl, )-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein (i) said (C1-C4)-alkyl is optionally substituted with y, amino, aminocarbo- nyl, mono-(C1-C4)-alkylaminocarbonyl or di-(C1-C4)-alkylaminocarbonyl, and (ii) said (C3-C6)-cycloalkyl is ally substituted with one or two substituents independently ed from the group consisting of (C1-C4)-alkyl, hydroxy and amino, and 10 (iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group ting of (C1-C4)- alkyl, hydroxy, oxo and amino, 01' R9 and R10, or R11 and R12, respectively, are joined and, taken together with the nitrogen 15 atom to which they are attached, form a monocyclic, ted 4- to 7—membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R13), O, S and S(O)2, and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (C1- C4)-alkyl, 0X0, hydroxy, amino and arbonyl, and wherein 20 R13 is hydrogen, (C1—C4)—alkyl, (C3-C6)-cycloalkyl, formyl or (C1—C4)—alkyl— carbonyl, and R15 is (C1-C4)-alkyl, with the proviso that G1 is not chloro when G2 is chloro or cyano. 25 The compounds according to this invention can also be present in the form of their salts, solvates and/or solvates of the salts.

D [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na _9_ Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds included in the formula (I) of the ae (l—A), (LB), (1- C), (I-D) and (I-E) mentioned in the following and their salts, solvates and solvates of the salts, and the compounds ed in the formula (I) and mentioned in the following as process products and/or embodiment examples and their salts, solvates and solvates of the salts, where the compounds included in the formula (I) and mentioned in the following are not already salts, solvates and solvates ofthe salts.

Sa_lts for the purposes ofthe present invention are preferably ceutically acceptable salts ofthe com— pounds according to the invention (for example, see S. M. Berge er al., "Pharmaceutical , J. 10 Pharm. Sci. 1977, 66, 1-19). Salts which are not lves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds ing to the invention are also included.

Pharmaceutically acceptable salts include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric 15 acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, nic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid.

Pharmaceutically acceptable salts also e salts of ary bases, such as for example and preferably alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for 20 example calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines, such as illustratively and preferably ethylamine, lamine, triethylamine, N,N—diiso- propylethylamine, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, ne, dicyclohexylamine, dibenzylamine, N—methylmorpholine, N— methylpiperidine, arginine, lysine, and 1,2-ethylenediamine. 25 Solvates in the context of the invention are ated as those forms of the compounds according to the invention which form a complex in the solid or liquid state by stoichiometric coordination with solvent les. Hydrates are a specific form of es, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.

The compounds of this invention may, either by nature of asymmetric centers or by restricted 30 rotation, be present in the form of isomers (enantiomers, diastereomers). Any isomer may be present Dhich the asymmetric center is in the (R)-, (S), or (R,S)-configuration.

[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _10_ It will also be appreciated that when two or more asymmetric centers are present in the compounds of the invention, several diastereomers and enantiomers of the exemplified structures Will often be le, and that pure diastereomers and pure omers represent preferred ments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the invention.

Geometric s by nature of substituents about a double bond or a ring may be present in cis (= Z—) or trans (= E—) form, and both ic forms are encompassed within the scope of this invention.

All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this 10 invention are encompassed within the scope of this ion. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art. For example, diastereomeric mixtures can be separated into the individual isomers by chromato- graphic processes or crystallization, and racemates can be separated into the respective enantiomers either by chromatographic processes on chiral phases or by tion. 15 In addition, all possible tautomeric forms of the compounds described above are included according to the present invention.

The present ion also asses all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is tood to mean a compound in which at least one atom within the compound according to the invention has been 20 exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound ing to the invention are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, ”O, 18’O, 18’F, 36Cl, 82Br, 1231, 124I, 129I and 1311. Particular isotopic variants of a compound according 25 to the invention, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Due to comparatively easy preparability and detectability, especially compounds labelled with 3H or 14C isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular eutic benefits as a 30 consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. Such modifications of the compounds Drding to the invention may ore in some cases also constitute a preferred ment of the present ion. Isotopic ts of the compounds according to the invention can be prepared by [Annotation] kirstena None set by kirstena [Annotation] na ionNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena _11_ processes known to those skilled in the art, for example by the methods described below and the methods described in the working examples, by using corresponding isotopic ations of the particular reagents and/or starting compounds therein.

In the context of the present invention, the tuents and residues have the following meaning, unless specified otherwise: 1C1—C4)-Allgvl in the context of the invention represents a straight-chain or ed alkyl radical having 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.

)-Alkoxy in the context of the invention represents a straight-chain or branched alkoxy radical 10 having 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, toxy, sec-butoxy, and tert—butoxy.

Mono-1C1-C42-allgylamino in the context of the invention represents an amino group with a straight- chain or branched alkyl substituent Which contains 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methylamino, ethylamino, n-propylamino, isopropylamino, n— 15 butylamino, and tert-butylamino.

-C4)-allgylamino in the context of the invention ents an amino group with two identical or different ht-chain or branched alkyl substituents which each contain 1 to 4 carbon atoms.

There may be mentioned by way of example and preferably: N,N—dimethylamino, MN—diethylamino, N—ethyl-N—methylamino, N—methyl-N—n-propylamino, N—isopropyl-N—methylamino, N—isopropyl-N—n- 20 propylamino, sopropylamino, N—n-butyl—N—methylamino, and N-tert—butyl-N—methylamino. 1C1—C4l—Alfllcarbonyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is bonded to the rest of the molecule Via a carbonyl group [—C(=O)-]. There may be mentioned by way of example and preferably: acetyl, propionyl, ryl, iso—butyryl, n-pentanoyl, and pivaloyl. 25 C1-C4 -Alkox carbon 1 in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms which is bonded to the rest of the molecule via a carbonyl group [-C(=O)-]. There may be mentioned by way of e and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, and tert-butoxycarbo- nyl.

D [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _12_ Mono- C1-C4 -alk laminocarbon 1 in the context of the invention represents an amino group which is bonded to the rest of the molecule Via a carbonyl group [-C(=O)-] and which has a straight-chain or branched alkyl substituent having 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, iso- propylaminocarbonyl, n-butylaminocarbonyl, and tert—butylaminocarbonyl.

Di—(C1-CQ-alkylaminocarbonyl in the context of the ion represents an amino group which is bonded to the rest of the le via a carbonyl group [-C(=O)-] and which has two identical or different straight-chain or branched alkyl substituents having in each case 1 to 4 carbon atoms.

There may be mentioned by way of example and preferably: N,N—dimethylaminocarbonyl, 10 MN—diethylaminocarbonyl, N—ethyl-N—methylaminocarbonyl, N—methyl-N—n-propylaminocarbonyl, N—isopropyl-N—methylaminocarbonyl, isopropylaminocarbonyl, N—n-butyl-N—methylamino- carbonyl, and N-tert—butyl-N—methylaminocarbonyl.

C3-C6 -C cloalk l in the context of the invention represents a monocyclic, saturated carbocycle having 3 to 6 ring carbon atoms. There may be mentioned by way of example: cyclopropyl, cyclo- 15 butyl, cyclopentyl, and cyclohexyl. Preferred are cyclopropyl and utyl. 4- to ered heterocycloalkyl and 4- to 6-membered heterocycloalkyl in the context of the invention represent a clic, saturated heterocycle with 4 to 7 or, respectively, 4 to 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O, S and S(O)2, and which can be bonded via a ring carbon atom or via a ring nitrogen atom (if present). 4- to 20 6-membered heterocycloalkyl containing one ring nitrogen atom and optionally one filrther ring heteroatom from the series N, O or S(O)2 is preferred. 5- or 6-membered heterocycloalkyl containing one ring nitrogen atom and optionally one further ring heteroatom from the series N or O is particularly preferred. There may be mentioned by way of e: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, thiolanyl, oxidothiolanyl, 25 azolidinyl, 1,3-oxazolidinyl, 1,3—thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4—dioxanyl, azinanyl, morpholinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl, azepanyl, l,4-diazepanyl, and l,4-oxazepanyl. red are inyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, piperidinyl, piperazinyl, 1,2-oxazinanyl, morpholinyl, and thiomorpholinyl. Particularly preferred are pyrroli- 30 dinyl, piperidinyl, piperazinyl, and morpholinyl. 5—membered aza-heteroa l in the context of the ion represents an aromatic cyclic radical Daroaromatic) having 5 ring atoms in total, which contains at least one ring nitrogen atom and optionally one or two further ring heteroatoms from the series N, O and/or S, and which is bonded [Annotation] na None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena _13_ via a ring carbon atom or ally via a ring nitrogen atom (when allowed by valency). 5—membered aza-heteroaryl containing one ring nitrogen atom and one or two fithher ring hetero- atoms from the series N and/or 0 is preferred. There may be mentioned by way of example: pyrrolyl, pyrazolyl, imidazolyl, yl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl. Preferred are pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and oxadiazolyl.

An oxo substituent in the context of the invention represents an oxygen atom, which is bonded to a carbon atom Via a double bond.

In the context of the present invention, for all the radicals which occur several times, the meaning thereof is independent of each other. If radicals in the compounds according to the invention are 10 substituted, the radicals can be mono- or polysubstituted, unless specified ise. tution by one or by two or three identical or different substituents is preferred. Substitution by one or by two identical or different substituents is particularly preferred.

In a preferred embodiment, the t invention relates to compounds of general formula (I), wherein 15 R1 is chloro, methyl or methoxy, R2 is hydrogen or methoxy, G1 represents chloro, (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl or 5-membered aza—heteroaryl selected from the group consisting of pyrazolyl, olyl, oxazolyl, isoxazolyl and oxa- diazolyl, or represents the group -CH2-OR3 or -CH2-NR4R5, wherein 20 R3 is hydrogen, (C1-C4)-a1kyl or (C3—C6)-cycloalkyl, wherein said (C1-C4)-alkyl is optionally substituted with y, )-alkoxy, hydroxycarbonyl, (C1—C4)—all<oxycarbonyl, amino, aminocarbonyl, (C3—C6)—cyclo- alkyl or up to three fluoro atoms, R4 is hydrogen or (C1-C4)-alkyl, 25 R5 is hydrogen, (C1-C4)-a1kyl, (C1-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 5- or 6- membered heterocycloalkyl, wherein (i) said (C1-C4)-alkyl is ally substituted with hydroxy, hydroxycarbonyl or D (C3-C6)-cycloalkyl, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _14_ and (ii) said 5- or ered heterocycloalkyl is ally substituted with 0x0, 01‘ R4 and R5 are joined and, taken together with the nitrogen atom to which they are attached, 5 form a monocyclic, saturated 4— to 6-membered cycloalkyl ring which may contain a second ring heteroatom selected from N(R7) and O, and which may be substituted on a ring carbon atom with oxo or hydroxy, and wherein R7 is hydrogen or (C1—C4)—a]kyl, and 10 G2 represents chloro, cyano, (C1-C4)-alkyl, or the group -CR8AR8B-OH, -CH2-NR9R10, -C(=O)-NR11R12 or -CH2-OR15, wherein RSA and R813 are independently selected from the group consisting of hydrogen, )—alkyl and cyclopropyl, is hydrogen or methyl, 15 R10 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 5— or 6- membered heterocycloalkyl, wherein (i) said (C1-C4)-alkyl is ally substituted with hydroxy or aminocarbonyl, and (ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with 0x0, 20 is hydrogen or methyl, R12 is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl or 5- or 6-membered heterocyclo- alkyl, wherein (i) said (C1-C4)-alkyl is optionally substituted with hydroxy, and 25 (ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with 0x0, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena _15_ 01‘ R9 and R10, or R11 and R12, respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 6—membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R13), O, S and S(O)2, and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (C1- C4)-alkyl, 0X0, hydroxy, amino and aminocarbonyl, and wherein R13 is en, (C1-C4)-alkyl, cyclopropyl, cyclobutyl, formyl or (C1-C4)-alkyl- carbonyl, 10 and R15 is methyl or ethyl, with the proviso that G1 is not chloro when G2 is chloro 0r cyano.

In a particularly preferred embodiment, the present invention relates to nds of general for— mula (I), wherein 15 R1 is methyl, R2 is methoxy, G1 represents methyl, oxazol-S-yl or the group R3 or -CH2-NR4R5, wherein R3 is hydrogen, (C1-C4)-alky1, cyclopropyl or cyclobutyl, wherein said (C1-C4)-alkyl is optionally substituted with y, methoxy, ethoxy, 20 hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, amino, aminocarbonyl, cyclopropyl, cyclobutyl or up to three fluoro atoms, is hydrogen, methyl or ethyl, is hydrogen, (C1-C4)-alkyl, acetyl, cyclopropyl, cyclobutyl or 2-oxopyrrolidinyl, wherein said )-alkyl is optionally substituted with hydroxy, hydroxycarbonyl, 25 ropyl or cyclobutyl, or ation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —16— R4 and R5 are joined and, taken together with the nitrogen atom to which they are attached, form a clic, saturated 5- or 6-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from NH and O, and which may be sub- stituted on a ring carbon atom with oxo or hydroxy, 5 and G2 represents methyl or the group gB—OH, -CH2-NR9R10 or -C(=O)-NR“R12, n R8A and R813 are independently hydrogen or methyl, R9 is en, R10 is hydrogen, (C1-C4)-alkyl, acetyl, cyclopropyl, cyclobutyl or 2-oxopyrrolidinyl, 10 wherein said (C1-C4)-alkyl is ally substituted with hydroxy or aminocarbonyl, R11 is hydrogen or methyl, R12 is hydrogen, (C1-C4)-alkyl, cyclopropyl, cyclobutyl or 2-oxopyrrolidin-3—yl, wherein said (C1-C4)—a]l<yl is optionally substituted with hydroxy, or 15 R9 and R10, or R11 and R12, respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 6—membered heterocycloalkyl ring which may n a second ring heteroatom selected from N(R13), O and S(O)2, and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, methyl, 20 0X0, hydroxy, amino and aminocarbonyl, and wherein R13 is hydrogen, formyl or acetyl.

In a distinct embodiment, the present invention relates to compounds of general formula (I), n R1 is methyl, and 25 D is methoxy.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena _17_ In a further distinct embodiment, the present invention relates to compounds of general formula (I), wherein G1 represents the group -CH2-OR3, n R3 is hydrogen or (C1-C4)-a1kyl optionally substituted with hydroxy, methoxy, amino, aminocarbonyl or up to three fluoro atoms.

In another distinct embodiment, the present invention relates to nds of general formula (I), wherein Gl represents the group -CH2-NR4R5, wherein R4 is hydrogen or methyl, 10 R5 is (C1-C4)-alkyl, acetyl, ropyl, cyclobutyl or 2-oxopyrrolidinyl, wherein said (C1-C4)-a1kyl is optionally substituted with hydroxy, or R4 and R5 are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 5- or 6-membered heterocycloalkyl ring which may 15 contain a second ring heteroatom selected from NH and O, and which may be sub- stituted on a ring carbon atom with oxo or hydroxy.

In r distinct embodiment, the present invention relates to nds of general formula (I), n G2 represents the group -CH2—NR9R1°, wherein 20 R9 is hydrogen, R10 is acetyl or yrrolidin—3—yl, or R9 and R10 are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 5— or 6-membered heterocycloalkyl ring which may 25 D contain a second ring heteroatom selected from N(R13) and O, and which may be [Annotation] kirstena None set by na ation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena ed set by kirstena —18— substituted on ring carbon atoms with up to two substituents independently selected from the group consisting of methyl, OX0, hydroxy and amino, and wherein R13 is hydrogen, formyl or acetyl.

In yet another distinct embodiment, the present invention relates to compounds of general formula 5 (I), wherein G2 represents the group -C(=O)-NR“R12, n R11 is hydrogen, R12 is (C1-C4)-alkyl or 2-oxopyrrolidinyl, wherein said (C1-C4)-alkyl is optionally substituted with hydroxy, 10 or R11 and R12 are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, ted 4— to 6—membered heterocycloalkyl ring which may contain a second ring heteroatom selected from NH and O, and which may be substituted on a ring carbon atom with 0x0 or hydroxy. 15 In an especially preferred embodiment, the present invention relates to compounds of l formula (I), wherein R1 is methyl, R2 is methoxy, G1 represents the group -CH2-OR3, wherein 20 R3 is )-alkyl optionally substituted with hydroxy, amino or aminocarbonyl, represents the group -CH2-NR9R10 or —C(=O)-NR”R12, wherein R9 is hydrogen, R10 is 2-oxopyrrolidinyl, [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena _19_ 01‘ R9 and R10 are joined and, taken together with the nitrogen atom to which they are attached, form a piperazin— l -yl, 3 perazin— l -yl or 4-acetylpiperazin— l -yl ring, R11 is hydrogen, 5 R12 is 2-oxopyrrolidin—3-yl, or R11 and R12 are joined and, taken together with the nitrogen atom to which they are ed, form a 3 -hydroxyazetidin— l —yl, 4-hydroxypiperidin— l -yl or 3 -oxopiperazin— 1 —yl ring.

The definitions of residues indicated specifically in the respective combinations or preferred com- 10 binations of residues are also replaced as d by definitions of es of other combinations, irrespective of the particular combinations indicated for the residues. Combinations of two or more of the abovementioned preferred ranges are particularly preferred.

The compounds of the general formula (I) can be prepared by various synthetic routes which are primarily governed by the nature of the particular G1 and G2 groups chosen (see definitions above). 15 Thus, in another embodiment, the present invention s to a process for preparing the compounds ofthe general formula (1), characterized in that [A] a 6-substituted 4-aminopyrrolo[2,l-f][1,2,4]triazine of formula (II) N H 2 3 O R N / / K ,N / N (11), wherein R3 has the meaning described above, 20 is at first reacted with formaldehyde and an amine of formula (III) 9 HN/R \Rm (111), D wherein R9 and R10 have the gs described above, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _20_ in the presence of an acid to give a compound of formula (IV) wherein R3, R9 and R10 have the meanings described above, then brominated to a compound of formula (V) wherein R3, R9 and R10 have the meanings described above, and subsequently coupled with a benzothiophen—Z-yl boronate of formula (VI) 1 14 R O—R \ / B\ S O_R14 R2 (v1), wherein R1 and R2 have the gs described above, 10 and R14 represents en or (C1-C4)-alkyl, or both R14 residues are linked together to form a -(CH2)2-, -C(CH3)2-C(CH3)2-, 3-, -CH2-C(CH3)2-CH2- OI‘ -C(=O)-CH2-N(CH3)- CH2-C(=O)- bridge, Din the presence of a ium catalyst and a base to yield the target compound of formula (I-A) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena (I-A), wherein R1, R2, R3, R9 and R10 have the meanings described above, or [B] a 6-substituted 4-aminopyrrolo[2,l-f][1,2,4]triazine of a (II) N H 2 o—R3 N / / K /N / N 5 (11), wherein R3 has the meaning described above, is at first formylated with MN—dimethylformamide in the ce of phosphoryl chloride to an aldehyde of a (VII) (VII), 10 wherein R3 has the meaning described above, then brominated to a compound of formula (VIII) D [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] na Unmarked set by kirstena (VIII), wherein R3 has the meaning described above, and subsequently coupled with a benzothiophen-Z-yl boronate of formula (VI) 1 14 R O—R \ / B\ S O_R14 R2 (VI), wherein R1, R2 and R14 have the meanings described above, in the presence of a palladium catalyst and a base to give a compound of formula (IX) (1X), wherein R1, R2 and R3 have the meanings described above, which then is either 10 [B-l] reacted with an amine of formula (III) 9 /R HN \R10 (111), ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _23_ wherein R9 and R10 have the meanings described above, in the presence of an acid and a reducing agent to yield the target compound of formula (I-A) (I-A), wherein R1, R2, R3, R9 and R10 have the meanings described above, or [B-2] oxidized to a carboxylic acid of formula (X) (X): wherein R1, R2 and R3 have the meanings bed above, 10 and finally coupled with an amine of formula (XI) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na _24_ 11 HN< R12 (X1), wherein R11 and R12 have the meanings described above, in the presence of a condensing agent to yield the target compound of formula (I—B) (1-3), wherein R1, R2, R3, R11 and R12 have the meanings described above, [C] a 6-substituted 4-aminobromopyrrolo[2,l-f][l ,2,4]triazine of formula (XII) NH2 Br OH N / / R /N / N (XII) is at first d with a benzothiophen—2—yl te of formula (VI) R1 O_R14 \ / B\ S O_R14 R2 (v1), in R1, R2 and R14 have the meanings described above, [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _25_ in the presence of a palladium catalyst and a base to give a nd of a (XIII) (XIII), wherein R1 and R2 have the meanings described above, and then reacted with formaldehyde and an amine of formula (III) 9 R HN< 10 R 5 (111), wherein R9 and R10 have the meanings described above, in the presence of an acid to yield the compound of formula (I-C) (1—C)7 wherein R1, R2, R9 and R10 have the meanings described above, 10 which subsequently is either D [C-l] ed to an aldehyde of formula (XIV) [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na (XIV), wherein R1, R2, R9 and R10 have the meanings described above, and treated with an amine of formula (XV) 4 R HN< R5 (XV), wherein R4 and R5 have the meanings described above, in the presence of an acid and a reducing agent to yield the target compound of formula (1-D) (1-D), wherein R1, R2, R4, R5, R9 and R10 have the meanings described above, D 10 01‘ [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena _27_ [C-2] converted into the corresponding 6-(halomethyl) tive of formula (XVI) (XV1), wherein R1, R2, R9 and R10 have the meanings described above, and X is chloro, bromo or iodo, and treated With an l of formula (XVII) R3A—OH (XVII), wherein R3A has the meaning of R3 as described above except for hydrogen, in the presence of a base to yield the target compound of formula (I-E) (LE): [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —28— wherein R1, R2, R”, R9 and R10 have the meanings described above, optionally followed, where appropriate, by (i) separating the compounds of formula (I) thus obtained into their respective enantiomers and/or diastereomers, preferably using chromatographic methods, and/or (ii) ting the nds of formula (I) into their respective hydrates, es, salts and/or hydrates or solvates of the salts by treatment with the corresponding solvents and/or acids or bases.

The compounds of the ae (I-A), (I—B), (I—C), (1—D) and (LE), which can be prepared by the processes described above, each represent a particular subset of the compounds of the general for- mula (I). 10 Process steps [A] (II) —> (IV) and [C] (XIII) —> (I-C), representing Mannich—type aminomethylation reactions, are carried out in the usual way by treating the respective starting compound with a mixture of aqueous formaldehyde and amine component (III) in the presence of an acid catalyst such as formic acid or acetic acid. Preferably, acetic acid is used both as catalyst and solvent. The reaction is usually performed at a temperature ranging from +20°C to +80°C. 15 As the brominating agent for process steps [A] (IV) —> (V) and [B] (VII) —> (VIII), preferably N—bromosuccinirnide (NBS), 1,3-dibromo—5,5—dimethylhydantoin (DBDMH) or elemental bromine are used. The ons are generally carried out in an inert solvent, such as dichloromethane, chloro- form, ydrofuran, acetonitrile or ethylformamide (DMF), within a temperature range from -78°C to +20°C. 20 The coupling reactions [A] (V) + (VI) —> (LA), [B] (VIII) + (VI) —> (IX) and [C] (XII) + (VI) —> (XIII) [”Suzuki-Miyaura coupling"] are generally carried out in an inert solvent with the aid of a palladium catalyst and an aqueous base. Palladium catalysts suitable for this purpose include, for example, palladium(II) acetate, palladium(II) chloride, iphenylphosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) de, [1,l'-bis(diphenylphosphino)ferrocene]palladium(II) 25 chloride, tetrakis(triphenylphosphine)palladium(0), benzylideneacetone)palladium(0), and His- (dibenzylideneacetone)dipalladium(0), optionally in ation with other phosphine ligands such as, for example, 2-dicyclohexylphosphino-2',4‘,6'-triisopropylbiphenyl (X-Phos), 2-dicyclohexyl- phosphino-Z',6'-dimethoxybiphenyl (S-Phos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), or 4-(di-tert—butylphosphino)—N,N—dimethylaniline. Also, palladium pre-catalysts from 30 which the catalytically active species is generated under the reaction ions, such as (2'—aminobi— Dyl-Z-y1)(chloro)palladium-dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine, can be used [see, for example, S. Kotha et al., Tetrahedron 58, 9633-9695 (2002); T. E. Barder er £11., J. Am.

[Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na _29_ Chem. Soc. 127 (13), 4685-4696 ; S. L. ld et al., J. Am. Chem. Soc. 132 (40), 14073-14075 (2010), and further nces cited therein].

Suitable bases for these coupling ons are in particular alkali carbonates, such as sodium, potassium or caesium carbonate, alkali phosphates, such as sodium or potassium phosphate, or alkali fluorides, such as potassium or caesium fluoride. Usually, these bases are ed as aqueous solutions. The reactions are carried out in organic solvents that are inert under the reaction conditions. Preferably, water-miscible organic solvents, such as 1,2-dimethoxyethane, tetrahydro- furan, oxane, acetonitrile, MN-dimethylformamide (DMF) or dimethylsulfoxide (DMSO), are employed but other inert solvents, such as dichloromethane or toluene, may also be used. 10 Process step [B] (11) —> (V11) ["Vilsmeier—Haack formylation"] is d out in the usual manner by ng the pyrrolotriazine (11) in N,N—dimethylformamide (DMF) solvent With phosphoryl chloride.

The reaction is usually performed at a temperature from 0°C to +80°C.

Reducing agents suitable for the reductive amination reactions [B-l] (1X) + (111) —> (I-A) and [C-1] (XIV) + (XV) —> (I-D) are customary alkali borohydrides, such as lithium borohydride, sodium 15 borohydride, potassium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.

The transformations are generally carried out in the presence of an acid, preferably acetic acid, in an alcohol or ether solvent, such as methanol, ethanol, isopropanol, tetrahydrofuran or 1,4—di0xane, within a ature range from 0°C to +80°C, depending on the reactivity of the amine components (111) and (XV), respectively, and/or the particular borohydride used. 20 For the oxidation reaction in process step [B—2] (1X) —> (X), oxidation With sodium chlorite in the presence of a hypochlorite scavenger such as 2—methylbutene represents the method of choice [cf.

H. W. Pinnick et al., edron 37, 2091—2096 (1981); A. Raach and O. Reiser, J. Pmkt. Chem. 342 (6), 605-608 (2000), and references cited therein]. The reaction is usually carried out in a tetrahydrofuran/water mixture at a temperature between 0°C and ambient temperature. 25 Condensing agents suitable for s step [B-2] (X) + (X1) —> (I-B) [amide formation] e, for example, carbodiirnides such as N,N’-diethyl-, N,N’-dipropyl-, N,N’-diisopropyl-, N,N'—dicyclo- hexylcarbodiimide (DCC) or N—(3-dimethylaminopropyl)-N’-ethylcarbodiimide (EDC), phosgene derivatives such as MN’-carbonyldiimidazole (CD1) or isobutyl chloroformate, oc-chloroenamines such as 1-chloromethyldimethy1amino—1—propene, phosphorus compounds such as propane- 30 phosphonic anhydride, l cyanophosphonate, bis(2-oxooxazolidinyl)phosphoryl chloride, Dotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) or benzotriazol- 1—yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), and m compounds such [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena _30_ as 0-(benzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), 0-(benzotriazol- 1—yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo—l—(2H)—pyridyl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), 0-(7-azabenzotriazol-l-yl)-N,N,N',N'—tetra- uronium hexafluorophosphate (HATU) or 0-(1I-I—6-chlorobenzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TCTU), if appropriate in ation With further auxiliaries, such as l-hydroxybenzotriazole (HOBt) or oxysuccinimide (HOSu), and/or bases such as alkali carbonates, for example sodium or potassium carbonate, or organic amine bases, such as tri- ethylamine, N—methylpiperidine, N—methylmorpholine (NMM), MN—diisopropylethylamine (DIPEA), pyridine or 4-]\/',N-dimethylaminopyridine (DMAP). Preference is given to using 0-(7-azabenzotria- 10 zol—l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) or 0—(benzotriazol—1-yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU) in combination With NN—diisopropylethyl- amine (DIPEA) and optionally l-hydroxybenzotriazole (HOBt).

Inert solvents for process step [B-2] (X) + (XI) —> (I-B) are, for example, ethers such as diethyl ether, tert—butyl methyl ether, tetrahydrofuran, l,4-dioxane or 1,2-dimethoxyethane, hydrocarbons 15 such as e, e, xylene, hexane or cyclohexane, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, itrile, ethyl acetate, ne, dimethyl- sulfoxide (DMSO), MN—dimethylformamide (DMF), N,N’-dimethylpropylene urea (DMPU) or N—methylpyrrolidinone (NMP). It is also possible to use mixtures of these solvents. Preference is 20 given to using romethane, tetrahydrofuran, N,N—dimethylformamide or mixtures thereof. The reactions are generally carried out at a temperature ranging from 0°C to +60°C, preferably at +10°C to +40°C.

Oxidizing agents that are capable of converting the primary alcohol (l-C) into the de (XIV) (process [C-l]) under mild conditions e 1,1,1—triacetoxy—1,1-dihydro-l,2-benziodoxol—3(1H)— 25 one ("Dess-Martin periodinane"), 2,2,6,6-tetramethylpiperidin-l-oxyl (TEMPO) in combination with secondary oxidants such as iodosobenzene—I,I—diacetate or sodium hypochlorite, and yl- sulfoxide (DMSO)-based ion systems such as DMSO/trifluoroacetic anhydride or DMSO/N,N’-dicyclohexylcarbodiimide (DCC). Preference is given to l,1,l-triacetoxy—1,1-dihydro- l,2-benziodoxol-3(lH)-one. The reaction is generally carried out in an inert solvent, preferably using 30 dichloromethane, For the hydroxy—to-halogen ormation in s step [C-2] (l-C) —> (XVI), various standard gods and reagents that are well known in the art may be employed. Reagents of choice are thionylc oride [for X = C1], tetrabromomethane/triphenylphosphine [for X = Br], and iodine/triphenyl- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _31_ phosphine [for X = I]. The preparation of 6-(chloromethyl) derivatives (XVI) [X = Cl] is preferred for reasons of convenience of work-up and nd stability.

Bases suitable for the process step [C-2] (XVI) + (XVII) —> (I-E) [ether formation] are in particular alkali carbonates such as lithium, sodium, potassium or caesium ate, alkali acetates such as sodium or potassium e, or customary tertiary amine bases such as triethylamine, N—methylmorpholine, N—methylpiperidine, MN—diisopropylethylamine or ne. Preference is given to MN—diisopropylethylamine (DIPEA). The reaction (XVI) + (XVII) —> (I-E) is performed in an inert solvent, such as ydrofuran, or without solvent, using an excess of alcohol (XVII), at a temperature g from +20°C to +200°C, preferably at +50°C to . Advantageously, the IO conversion is carried out by means of a microwave reactor device.

The reaction ce (I-C) —> (XVI) —> (I—E) may be d out in two separate steps, i.e. with isolation and purification of the intermediate compound (XVI), or it may be performed using a one- pot procedure, i.e. employing the crude intermediate (XVI) as ed in the preparation reaction.

In cases Where a primary or ary amine moiety forms part of the G1 or G2 group in the target 15 compounds of formula (I), it may sometimes be appropriate in the preparation reactions described above to use a protected derivative of this amine as on component instead of the free amine.

For this purpose, conventional temporary amino—protecting groups, such as acyl groups (e.g., acetyl or trifluoroacetyl) or carbamate-type protecting groups (e. g., a Boc-, Cbz- or Fmoc-group), may be employed. A Boc (tert—butoxycarbonyl) group is preferably used. Similarly, a hydroxy function 20 being part of the G1 or G2 group may arily be blocked in sor nds and process intermediates, for example as a tetrahydropyranyl (THP) ether or as a silyl ether derivative, such as a trimethylsilyl or tert—butyldimethylsilyl ether.

These protecting groups may then be cleaved off concomitantly during aqueous work-up and puri- fication procedures, or they are removed in a subsequent, separate reaction step using standard 25 methods well known in the art. The preparation of such protected intermediates from the corres- ponding free amines or alcohols is likewise readily accomplished following general procedures described in the literature [see, for example, T. W. Greene and P. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].

Certain types of protected (i.e. acylated) amine derivatives exert significant FGFR-inhibiting activity 30 by their own. Accordingly, such compounds are also encompassed by the general formula (I) as de— Di above.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _32_ The preparation of the compounds of the invention may be illustrated by means of the following on schemes: Scheme 1 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _33_ Scheme 2 R1 OR \ / B \ 14 3 9 OR /R 2 HN\ 10 R R \ N / Pd-catalyst/base NaBHSCN Or NaBH(OAc)3 AcOH NaClO2 MeZC=CHMe NaH2P04 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena _34_ Scheme 3 OH Dess-Martin periodinane NaBH(OAc)3 ACOH [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _35_ Scheme 4 RBA—OH RSA—OH base base 6—substituted 4-arrfinopyrrolo[2,l-f][l,2,4]triazines of formula (II) can, for example, be pre— pared by two different routes which are depicted in Scheme 5 below. In the first route, 4—amino [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _36_ cyanopyrrolo[2,1-f][l,2,4]triazine (XVIII) is converted into the ester (XIX) by acid-mediated alco- s and then reduced to the roxymethyl) compound (IIa) [R3 in (II) = H] using lithium tri- ethylborohydride. rd transformation into the ponding 6-(halomethyl)pyrrolotriazine, such as the chloro compound (XX), followed by treatment with an alcohol of a (XVII) in the presence of a base readily provides the ether tives of formula (IIb) [R3 in (II) 72 H]. The preparation of the ng compound (XVIII) has been described previously [see Int. Pat. Appl. WC 2007/ 064883 (Intermediate AX/ Step 3)].

The second route starts from the protected 1-aminobromocyanopyrrole (XXI) [preparation given in Int. Pat. Appl. WO 2007/064883 (Intermediate AAE, Step 3)]. Deprotonation of the ure- 10 thane nitrogen, subsequent metalation in 4—position and reaction With dehyde affords the 4-(hydroxymethyl) derivative (XXII). Treatment with hydrogen chloride followed by addition of alcohol (XVII) and condensation with formamidine using a one-pot procedure then provides the target compound of formula (IIb). This route is especially suited for the preparation of alkyl ether derivatives [R3A in (IIb) = (C1-C4)-alkyl] in that the alcohol reactant (XVII) may also serve as the 15 reaction t in these cases.

Scheme5 NH2 NH2 NH2 O N/ / EtOH N/ / LiBHEt3 N/ / |\\N/N / CN —> k / —> k / conc.HZSO4 \N/N OEt \N/N OH (XVIII) (XIX) (IIa) NH2 NH2 SOCI2 N/ / R3A—OH (XVII) N/ / N / \N/ N / CI base K\N/ O—R3A XHCI (XX) (IIb) 1. HCI 2. RsA—OH (XVII) 3. HC(=NH)NH2 NC NC 1. MeMgBr v Br Boc\N/N67 / / 2. n-BuLi Boc\N/N OH H 3. H2C=O H D (XXI) (XXII) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _37_ The 4-aminobromopyrrolo[2,1-f][1,2,4]triazine derivative of formula (XII) is readily available from 4-amino(hydroxymethyl)pyrrolo[2,1—f][1,2,4]triazine (Ila) (cf. Scheme 5) by initial 5,7- dibromination using 1,3-dibromo-5,5-dimethylhydantoin and subsequent selective 7-debromination via a halogen-metal exchange with n-butyllithium followed by methanol quenching (see Scheme 6 below).

Scheme 6 2 Br N/ / o N/ / 1. n-BuLi,-78°C K /N / / —> OH \N/N OH 2. MeOH Br (Ha) (XXIII) N/ / K/N/ N OH (XII) The benzothiophen—Z-yl boronates of formula (VI) can conveniently be prepared starting from the substituted thiophenol derivatives of formula (XXIV) (see Scheme 7 below). Alkylation with bromo- 10 acetal (XXV) and uent polyphosphoric acid-mediated cyclization provides the benzothiophene intermediates of formula ) which are then metalated in 2-position and reacted with a yl borate. Alkaline work-up s the free (benzothiophen—Z-yl)boronic acids of formula (VIa) which may be ormed, if desired, into cyclic boronates, e. g. so-called MIDA boronates of formula (VIb), by standard procedures known in the art [see, for e, D. M. Knapp er al., J. Am. Chem. 15 Soc. 131 (20), 6961-6963 (2009)].

[Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _38_ Scheme 7 R1 Br/YOEt R1 EtO OEt (XXV) OEt PPA —> —> SH S C32C03 R2 R2 (XXIV) (XXVI) R1 R1 OH \ 1. n-BuLi, B(OiPr)3 \ —> B: S 8 OH 2. aq. NaOH R2 R2 (XXVII) (VIa) 0 /—COOH HaC—N LCOOH \ water trap S 8::N—CH (VIb) [cf. P. A. Plé and L. J. Mamett, J. Heterocyclic Chem. 25 (4), 1271-1272 ; A. Venturelli et al, J. Med. Chem. 50 (23), 5644-5654 (2007)].

The compounds of the formulae (III), (XI), (XV), , (XXIV) and (XXV) are either commer- cially available, known from the literature, or can be prepared from readily available starting materials by adaptation of standard methods described in the literature. Detailed procedures and literature references for preparing the starting materials can also be found in the Experimental Part in the section on the preparation of the starting materials and intermediates. 10 The preparation of finther subgroups of the compounds of general formula (I) is illustrated in the following reaction schemes 8—14. The required pyrrolotriazine precursors can be readily synthesized by customary methods well known in the art, and r synthetic ormations, in most instances, follow the preparation routes that have been outlined in the process section above, using r types of reactions, such as, for e, bromination, boronate coupling, aminomethylation, 15 reductive amination, oxidation and/or ether or amide forming reactions. Further details are provided in the Experimental Part on the preparation of the exemplary ments and their respective Dursor compounds.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _39_ Scheme8 NH2 Br NHZ Br OH N/ 0TBD'V'S / tBuMeZSiCI N/ / 1. n-BuLi K /N / —> —> ole K /N / N N R8A R83 2' Br Br \n/ O (XXIII) Dess-Martin HN/R perlodlnane. . \ 5 R —> —> NaBH(OAc)3 AcOH [R8A, R813 = (C1-C4)-alkyl, ropyl 0r cyclobutyl].

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na ation] kirstena Unmarked set by kirstena _40_ Scheme 9 [R8A = (C1-C4)-alkyl, cyclopropyl 0r cyclobutyl; X = Cl, Br or 1].

Scheme 10 [R = (C1-C4)-alkyl].

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _41_ M NH2 N / / KN» / R (XXVIII) NH2 Br N / / KN» / R / N\ R10 [R = chloro or (C1-C4)-a1kyl; for the preparation of the starting al (XXVIII), see Int. Pat.

Appl. WO 2007/064883 and WO 2007/056170, respectively].

[Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na _42_ Scheme [2 NH2 NH2 OTBD'V'S N/ OTBDMS / MeZZn k\N/N / Pd--cata|yst LN/N// Br CH3 tBuMeZSiCI slilyl etherC eavage imidazole C|3H3 ’3\ NH2 I (I) NH2 /B\ OH / \ N/ OH / H3C 0 CH3 N / / k\N/N / Pd-catalyst KN/N / Br (XXIX) CH3 NBS 1 14 R [OR \ B NH 3 \OR14 2 Br R2 OH N/ / <—— Pd-catalystfbase KN/N / CH3 Dess-Martin periodinane R4 / HN\R5 —> NaBH(OAc)3 AcOH [for the preparation of the starting compound (XXIX), see Scheme 14 below].

O [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] na Unmarked set by kirstena _43_ Scheme 13 H2 NH2 NH2 N/ 0TBDMS OTBDMS / OHtBuMeZSiCI N/ / NCS N/ / |\\N/N / _> KN/N / —> / imidazole \N/N (Ha) NH2 Br OTBDMS NBS N / / —> Dess-Martin aQ- HCI periodinane —> —> /R HN \R5 —> NaBH(OAc)3 AcOH [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na _44_ Scheme 14 OH 0” N/ OTBDMS / NBS N/ / tBuMeZSiCI N/ / |\\ —’ _> N / \ N / -Imldazole- K N / N/ N/ N/ CH3 0 H30 NH2 Br/NTN\Br NH2 Br Zn(CN)2 OTBDMS OTBDMS N / / o N / / k N / k N / Pd-catalyst \N/ \N/ ON ON R OR \ B’ 3 \OR14 R2 OTBDMS N / / Pd-catalyst / base K R4 Dess-Martin HN/ periodlnane- - \ 5 R —> —> NaBH(OAc)3 AcOH The compounds of the present invention have valuable pharmacological properties and can be used for the tion and treatment of disorders in humans and other mammals.

The compounds of the present invention are potent inhibitors of the ty or expression of receptor tyrosine kinases, particularly of the FGFR kinases, and most notably of the FGFR-l and FGFR-3 s. ingly, in another embodiment, the present invention provides a method of treating Drders relating to or mediated by the ty of FGFR kinases in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of formula (I) [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _45_ as defined above. In certain embodiments, the disorders ng to the activity of FGFR kinases are proliferative disorders, in particular cancer and tumor diseases.

In the context of the present invention, the term ment” or ”treating" includes inhibiting, delaying, relieving, mitigating, arresting, reducing, or causing the sion of a disease, disorder, condition, or state, the development and/or progression thereof, and/or the ms thereof. The term ntion” or "preventing” includes reducing the risk of having, contracting, or experiencing a disease, disorder, condition, or state, the development and/or progression thereof, and/or the symptoms thereof The term prevention includes prophylaxis. Treatment or prevention of a disorder, disease, condition, or state may be partial or te. 10 The term "proliferative disorder" es disorders involving the undesired or uncontrolled pro- liferation of a cell. The compounds of the present ion can be utilized to prevent, inhibit, block, reduce, decrease, control, etc., cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a subject in need thereof, including a mammal, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, 15 polymorph, metabolite, hydrate or solvate thereof which is effective to treat or prevent the disorder.

Throughout this document, for the sake of simplicity, the use of singular language is given preference over plural language, but is generally meant to include the plural language if not other- wise stated. For example, the expression "A method of treating a disease in a patient, comprising administering to a patient an effective amount of a compound of formula (1)” is meant to include the 20 aneous treatment of more than one disease as well as the administration of more than one compound of formula (I).

Proliferative disorders that can be treated and/or prevented with the compounds of the present invention ularly include, but are not limited to, the group of cancer and tumor diseases. These are tood as g, in particular, the following diseases, but t being d to them: 25 mammary carcinomas and mammary tumors l and lobular forms, also in Situ), tumors of the respiratory tract (small cell and all cell lung carcinoma, parvicellular and non-parvicellular carcinoma, bronchial oma, bronchial adenoma, pleuropulmonary blastoma), cerebral tumors (e.g. of the brain stem and of the alamus, astrocytoma, glioblastoma, medulloblastoma, ependymoma, and neuro-ectodermal and pineal tumors), tumors of the digestive organs (oesophagus, 30 h, gall bladder, small intestine, large intestine, rectum, anus), liver tumors (inter alia hepatocellular carcinoma, cholangiocellular carcinoma and mixed hepatocellular and cholangio— Dllar carcinoma), tumors of the head and neck region (larynx, hypopharynx, nasopharynx, oro- pharynx, lips and oral cavity), skin tumors (squamous epithelial carcinoma, Kaposi sarcoma, [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena —46— malignant melanoma, Merkel cell skin cancer and lanomatous skin cancer), tumors of soft tissue (inter alia soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lympho- sarcomas and myosarcomas), tumors of the eyes (inter alia intraocular melanoma, uveal melanoma and retinoblastoma), tumors of the endocrine and exocrine glands (e.g. d and para- thyroid glands, pancreas and salivary gland), tumors of the urinary tract (tumors of the bladder, penis, kidney, renal pelvis and ureter), tumors of the reproductive organs (carcinomas of the endo- metrium, cervix, ovary, vagina, vulva and uterus in women, and omas of the prostate and testicles in men), as well as distant metastases thereof. These disorders also include proliferative blood diseases in solid form and as circulating blood cells, such as lymphomas, leukaemias and 10 myeloproliferative diseases, e.g. acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenic and hairy cell leukaemia, and AIDS-related mas, Hodgkin's lymphomas, non- Hodgkin's lymphomas, cutaneous T-cell mas, Burkitt's lymphomas, and lymphomas in the central nervous system.

Due to their activity and selectivity profile, the compounds of the present invention are believed to be 15 particularly suitable for the treatment of breast (mammary), lung, stomach (gastric), bladder and ovary cancer and tumor diseases. rmore, the nds of the present invention may be especially suited for the prevention or suppression of tumor metastasis in general.

Other proliferative disorders that can be treated and/or prevented With the compounds and methods of the present invention include sis, keloids and other hyperplasias affecting the skin, bullous 20 disorders associated With dermal blister ion including bullous goid, ma multiforme and dermatitis herpetiformis, fibrotic disorders such as lung s, atherosclerosis, restenosis and hepatic cirrhosis, renal diseases including mesangial cell erative disorders, glomerulopathies, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis and poly- cystic kidney disease, benign prostate hyperplasia (BPH), angiogenic or blood vessel proliferative 25 disorders, and thrombotic microangiopathy syndromes.

The nds of the present invention are also useful for the treatment and/or prevention of ophthalmological diseases such as, for example, age-related macular degeneration (AMD), dry macular degeneration, ischemic retinal vein occlusion, diabetic macula edema, diabetic retinopathy, retinopathy of prematurity, and other retinopathies. 30 Other conditions that may be treated and/or prevented by administering a compound of the present invention include gynaecological diseases such as endometriosis, myoma and ovarian cysts, meta— D: disorders related to adipogenesis, bile lism, phosphate metabolism, calcium metabolism and/or bone lization, skeletal disorders such as, for example, dwarfism, achondrodysplasia [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _47_ and Pfeiffer syndrome, cartilage diseases such as osteoarthritis and polyarthritis, rheumatoid arthritis, calvities, and transplant rejection.

The diseases mentioned above have been well characterized in , but also exist with a com- parable aetiology in other mammals, and can be treated in those with the compounds and methods of the present invention.

Thus, the present invention r relates to the use of the compounds according to the invention for the treatment and/or prevention of disorders, especially of the aforementioned disorders.

The present invention further relates to the use of the compounds according to the ion for preparing a pharmaceutical composition for the treatment and/or tion of disorders, especially 10 ofthe aforementioned disorders.

The present invention further relates to the use of the compounds according to the invention in a method for the ent and/or prevention of disorders, especially of the aforementioned disorders.

The present invention further relates to a method for the treatment and/or tion of disorders, especially of the aforementioned disorders, by using an effective amount of at least one of the com— 15 pounds according to the invention.

Compounds of the t invention may be administered as the sole pharmaceutical agent or in combination with one or more additional therapeutic agents as long as this ation does not lead to undesirable and/or unacceptable side effects. Such combination therapy includes administration of a single pharmaceutical dosage ation which contains a compound of formula (I), as defined 20 above, and one or more additional therapeutic , as well as administration of a compound of formula (I) and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, a compound of a (I) and a therapeutic agent may be administered to the patient together in a single (fixed) oral dosage ition such as a tablet or capsule, or each agent may be administered in separate dosage formulations. 25 Where separate dosage formulations are used, the compound of formula (I) and one or more additional therapeutic agents may be administered at essentially the same time (i.e., concurrently) or at separately staggered times (i.e., sequentially).

In particular, the compounds of the present invention may be used in fixed or separate combination 30 Qother anti-cancer agents such as ting agents, anti-metabolites, plant-derived anti—tumor ts, hormonal y agents, topoisomerase inhibitors, tubulin tors, kinase inhibitors, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —48— targeted drugs, antibodies, antibody-drug conjugates (ADCs), immunologicals, biological response rs, anti-angiogenic compounds, and other anti-proliferative, cytostatic and/or cytotoxic sub- stances. In this regard, the following is a non—limiting list of examples of secondary agents that may be used in combination With the compounds of the t invention: AbareliX, abiraterone, aclarubicin, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, alpharadin, amine, aminoglutethimide, amonafide, amrubicin, amsacrine, anastrozole, andro- mustine, arglabin, asparaginase, ib, 5—azacitidine, basiliximab, can, bendamustine, bevacizumab, bexarotene, bicalutamide, rene, cin, bortezomib, bosutinib, ib alaninate, buserelin, busulfan, cabazitaxel, CAL-101, m folinate, calcium linate, 10 camptothecin, capecitabine, latin, carmofur, carmustine, catumaxomab, cediranib, celmo- , mab, chlorambucil, chlormadinone, chlormethine, cidofovir, cisplatin, cladribine, clodronic acid, clofarabine, combretastatin, crisantaspase, crizotinib, cyclophosphamide, cypro- terone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, darinaparsin, dasatinib, dauno- rubicin, decitabine, degarelix, denileukin diftitox, mab, deslorelin, dibrospidium chloride, 15 docetaxel, dovitinib, doxifluridine, doxorubicin, dutasteride, eculizumab, edrecolomab, eflornithine, elliptinium acetate, eltrombopag, endostatin, enocitabine, epimbicin, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epothilone, eptaplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exatecan, exemestane, exisulind, fadrozole, inide, filgrastim, finasteride, ridol, fludarabine, 5-fluorouracil, fluoxymesterone, flutamide, foretinib, formestane, fotemu- 20 stine, fulvestrant, ganirelix, gefitinib, gemcitabine, gemtuzumab, can, gimeracil, glufosfamide, glutoxim, lin, histrelin, hydroxyurea, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, intedanib, interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma, interleukin-2, ipilimumab, irinotecan, ixa- bepilone, lanreotide, lapatinib, xifene, lenalidomide, lenograstim, an, lenvatinib, 25 lestaurtinib, letrozole, leuprorelin, levamisole, linifanib, linsitinib, lisuride, lobaplatin, lomustine, lonidamine, lurtotecan, mafosfamide, mumab, masitinib, masoprocol, medroxyprogesterone, rol, oprol, melphalan, mepitiostane, topurine, methotrexate, methyl aminolevulinate, methyltestosterone, mifamurtide, mifepristone, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, molgramostim, motesanib, nandrolone, 30 nedaplatin, nelarabine, neratinib, nilotinib, nilutamide, zumab, nimustine, nitracrine, nola- trexed, ofatumumab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronic acid, panitumumab, pazopanib, pegaspargase, peg-epoetin beta, pegfilgastrim, peg-interferon alpha-2b, pelitrexol, bnbicin,emetrexed, pemtumomab, pentostatin, peplomycin, perfosfamide, perifosine, pertuzumab, picibanil,pirarubicin, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, ponatinib, 35 porfimer sodium, pralatrexate, prednimustine, procarbazine, procodazole, PX—866, quinagolide, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na _49_ fene, raltitrexed, ranibizumab, ranimustine, razoxane, regorafenib, onic acid, rituximab, romidepsin, romiplostim, rubitecan, saracatinib, sargramostim, satraplatin, selumetinib, sipuleucel- T, mus, sizofiran, sobuzoxane, sorafenib, streptozocin, sunitinib, talaporfm, tamibarotene, tamoxifen, inib, tasonermin, teceleukin, tegafur, telatinib, temoporfin, temozolomide, temsirolimus, teniposide, testolactone, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, tioguanine, tipifamib, tivozanib, toceranib, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, ne, trilostane, trimetrexate, triptorelin, trofosfamide, ubenimex, icin, vandetanib, vapreotide, varlitinib, nib, vemurafenib, vidarabine, vinblastine, vincristine, Vindesine, Vinflunine, lbine, volociximab, vorinostat, 10 zinostatin, zoledronic acid, and zorubicin.

Generally, the following aims may be pursued with the combination of compounds of the present invention with other anti-cancer agents: 0 improved activity in slowing down the growth of a tumor, in reducing its size or even in its com- plete elimination compared with treatment with a single active compound; 15 0 possibility of ing the herapeutics used in a lower dosage than in monotherapy; o possibility of a more tolerable y with few side effects compared with individual administra- tion; 0 possibility of treatment of a r spectrum of cancer and tumor diseases; 0 achievement of a higher rate of response to therapy; 20 0 longer survival time of the patient compared with standard therapy.

Thus, in a further embodiment, the present invention relates to pharmaceutical compositions com- prising at least one of the compounds according to the invention and one or more additional thera- peutic agents for the treatment and/or tion of disorders, especially of the aforementioned dis- orders. 25 In cancer treatment, the compounds of the present invention may also be employed in conjunction with radiation therapy and/or surgical intervention.

Furthermore, the compounds of a (I) may be utilized, as such or in compositions, in research adiagnostics, or as analytical reference standards, and the like, which are well known in the art.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _50_ When the compounds of the present invention are administered as pharmaceuticals, to humans and other mammals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more ably, 0.5% to 90%) of active ingredient in ation with one or more pharmaceutically acceptable excipients.

Thus, in another aspect, the present invention relates to pharmaceutical compositions sing at least one of the compounds according to the invention, conventionally together with one or more inert, non-toxic, pharmaceutically le excipients, and to the use thereof for the treatment and/or tion of ers, especially of the aforementioned disorders.

The compounds ing to the invention can act systemically and/or locally. For this purpose, they 10 can be administered in a suitable way such as, for example, by the oral, parenteral, pulmonary, nasal, lingual, sublingual, buccal, rectal, dermal, ermal, conjunctival, otic or topical route, or as an implant or stent.

For these application routes, the nds of the invention can be administered in suitable application forms. 15 Suitable for oral administration are application forms which function according to the prior art and deliver the compounds according to the invention rapidly and/or in modified fashion, and which contain the compounds according to the invention in crystalline, ous and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example having enteric coatings or coatings which are insoluble or dissolve with a delay and control the release of the compound 20 according to the invention), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), sugar-coated s, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. eral application can be d out with avoidance of an absorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or with inclusion of an absorption 25 (intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). UsefiJl parenteral application forms include injection and infusion ations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

Forms suitable for other application routes include, for example, inhalatory pharmaceutical forms (e.g. powder rs, nebulizers), nasal drops, solutions or sprays, tablets or capsules to be adminis- 30 tered lingually, sublingually or buccally (e.g. troches, lozenges), suppositories, ear and eye ns (e.g. drops, ointments), vaginal capsules, aqueous suspensions (lotions, shaking mix- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _51_ tures), lipophilic suspensions, ointments, creams, milks, pastes, foams, dusting s, transderrnal eutic systems (e.g. patches), implants and stents.

In a preferred embodiment, the pharmaceutical ition comprising a compound of a (I) as defined above is provided in a form suitable for oral administration. In another preferred embodi- ment, the pharmaceutical ition comprising a compound of formula (I) as defined above is provided in a form suitable for intravenous stration.

The compounds according to the ion can be converted into the recited application forms in a manner known per se by mixing with inert, non-toxic, pharmaceutically le excipients. These excipients include, inter alia, carriers (e.g. microcrystalline ose, e, mannitol), solvents 10 (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), surfactants (e.g. polyoxysorbitan oleate), sants (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e. g. antioxidants such as, for example, ascorbic acid), colorants (e.g. nic pigments such as, for example, iron oxides), and taste and/or odour masking agents.

A preferred dose of the compound of the present invention is the maximum that a patient can tolerate 15 and not develop serious side effects. Illustratively, the compound of the t invention may be administered parenterally at a dose of about 0.001 mg/kg to about 1 mg/kg, preferably of about 0.01 mg/kg to about 0.5 mg/kg of body weight. On oral administration, an exemplary dose range is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg, and more preferably about 0.1 to 10 mg/kg of body . Ranges intermediate to the above-recited values are also ed to be part of the 20 invention.

Nevertheless, actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient. It may therefore be 25 necessary where appropriate to deviate from the stated s, in particular as a function of age, gender, body weight, diet and general health status of the patient, the bioavailability and pharmacodynamic characteristics of the particular compound and its mode and route of administra- tion, the time or interval over which administration takes place, the dose regimen selected, the response of the individual patient to the active ingredient, the specific disease ed, the degree of 30 or the involvement or severity of the disease, the kind of concurrent treatment (i.e., the interaction of the compound of the invention with other co—administered therapeutics), and other relevant Dimstances.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by na _52_ Thus, it may be satisfactory in some cases to manage with less than the aforementioned minimum amount, Whereas in other cases the stated upper limit must be exceeded. Treatment can be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small ents until the optimum effect under the circumstances is reached.

For convenience, the total daily dosage may be divided and administered in individual portions spread over the day.

The following exemplary embodiments illustrate the invention. The invention is not restricted to the examples.

The percentages in the following tests and examples are, unless stated otherwise, by weight; parts 10 are by weight. Solvent ratios, dilution ratios and concentrations ed for liquid/liquid ons are each based on volume.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _53_ A. es Abbreviations and Acronyms: Ac acetyl A020 acetic anhydride AcOH acetic acid aq. aqueous (solution) Boc tert—butoxycarbonyl br. broad (lH-NMR signal) Bu butyl cat. catalytic conc. trated d t (lH-NMR signal) DBDMH l,3-dibromo-5,5—dimethylhydantoin DCI direct al ionization (MS) DCM dichloromethane Dess-Martin periodinane 1,1,l-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(lH)-one DIPEA NN—diisopropylethylamine DMF MN—dimethylformamide DMSO dimethylsulfoxide EI electron impact ionization (MS) eq. equivalent(s) ESI electro-spray ionization (MS) Et ethyl EtOAc ethyl acetate GC-MS gas chromatography-coupled mass spectroscopy h hour(s) Hal halogen lH-NMR proton nuclear ic resonance spectroscopy HPLC high performance liquid chromatography iPr isopropyl LC—MS liquid chromatography-coupled mass spectroscopy Me methyl DH methanol min minute(s) ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _54_ MS mass spectroscopy m/z mass-to-charge ratio (MS) NBS N—bromosuccinimide n—Bu n-butyl NCS N—chlorosuccinimide ofth. of theory (chemical yield) Pd/C palladium on charcoal PdC12(dppf) [l , l '—bis(diphenylphosphino)ferrocene] dichloropalladiumfll) Pd(dba)2 bis(dibenzylideneacetone)pa11adium Ph phenyl PPA polyphosphoric acid quartet (IH-NMR signal) quant. quantitative (yield) rac racemic TLC retention factor reverse phase (HPLC) room temperature retention time (HPLC) singlet (lH—NMR ) ted ion) triplet (IH-NMR signal) tetra-n-butylammonium fluoride tert—butyldimethylsilyl N- [( lH-benzotriazol— l -yloxy)(dimethylamin0)methylene] -N—methyl— methanaminium tetrafluoroborate tBu tert—butyl tert tertiary TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _55_ LC-MS and GC-MS methods: Method 1 (LC-MS ): Instrument: Micromass Quattro r with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9u, 50 mm X 1 mm; eluent A: 1 L water + 0.5 mL 50% aq. formic acid, eluent B: 1 L acetonitrile + 0.5 ml 50% aq. formic acid; gradient: 0.0 min 90% A —> 0.1 min 90% A —> 1.5 min 10% A —> 2.2 min 10% A; temperature: 50°C; flow rate: 0.33 ; UV detection: 210 nm.

Method 2 gLC-MS ): Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8u, 50 mm X 1 mm; eluent A: 1 L water + 0.25 mL 99% formic acid, eluent B: 1 L acetonitrile + 10 0.25 mL 99% formic acid; gradient: 0.0 min 90% A —> 1.2 min 5% A —> 2.0 min 5% A; oven: 50°C; flow rate: 0.40 mL/min; UV detection: 210-400 nm.

Method 3 (LC-MS ): Instrument: Micromass Quattro Micro with HPLC Agilent 1100 Series; : YMC—Triart C18 3”, 50 mm X 3 mm; eluent A: 1 L water + 0.01 mol ammonium carbonate, eluent B: 1 L acetonitrile; 15 gradient: 0.0 min 100% A —> 2.75 min 5% A —> 4.5 min 5% A; oven: 40°C; flow rate: 1.25 mL/min; UV detection: 210 nm.

Method 4 (LC-MS ): Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8u, 30 mm X 2 mm; eluent A: 1 L water + 0.25 mL 99% formic acid, eluent B: 1 L acetonitrile + 20 0.25 mL 99% formic acid; gradient: 0.0 min 90% A —> 1.2 min 5% A —> 2.0 min 5% A; oven: 50°C; flow rate: 0.60 mL/min; UV detection: 208—400 nm.

Method 5 (LC-MS ): Instrument: Micromass o Premier with Waters UPLC y; column: Thermo il GOLD 1.9u, 50 mm X 1 mm; eluent A: 1 L water + 0.5 mL 50% aq. formic acid, eluent B: 1 L 25 itrile + 0.5 ml 50% aq. formic acid; gradient: 0.0 min 97% A —> 0.5 min 97% A —> 3.2 min 5% A —> 4.0 min 5% A; temperature: 50°C; flow rate: 0.3 mL/min; UV detection: 210 mm.

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —56— Method 6 gGC-MS ): Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15 m x 200 um x 0.33 um; constant flow with helium: 0.88 mL/min; oven: 70°C; inlet: 250°C; gradient: 70°C, 30°C/min —> 310°C (maintain for 3 min). 5 Method 7 (LC-MS ): Instrument MS: Waters Micromass QM; Instrument HPLC: Agilent 1100 series; column: Agilent ZORBAX Extend-C18 3.0 mm x 50 mm, 3.5u; eluent A: 1 L water + 0.01 mol um carbo— nate, eluent B: 1 L itrile; gradient: 00 min 98% A —> 0.2 min 98% A —> 3.0 min 5% A —> 4.5 min 5% A; temperature: 40°C; flow rate: 1.75 mL/min; UV ion: 210 nm. 10 Method 8 (LC-MS ): Instrument MS: Waters Micromass ZQ; Instrument HPLC: Agilent 1100 series; column: Agilent ZORBAX Extend-C18 3.0 mm X 50 mm, 3.5u; eluent A: 1 L water + 0.01 mol ammonium carbo- nate, eluent B: 1 L itrile; gradient: 0.0 min 98% A —> 0.2 min 98% A —> 3.0 min 5% A —) 4.5 min 5% A; temperature: 40°C; flow rate: 1.75 mL/min; UV ion: 210 nm. 15 General purification methods (see Table I and II below): Method P1: PreParative RP-HPLC ReProsil C18, gradient acetonitrile/0.2% aq. trifluoroacetic acid).

Method P2: Preparative RP-HPLC (XBridge C18, gradient acetonitrile/water + 0.1% aq. ammonia). 20 Method P3: Preparative RP-HPLC (Sunfire C18, gradient itrile/water).

Method P4: Preparative C ge C18, gradient acetonitrile/water + 0.05% aq. ammonia).

Method P5: 25 The product obtained from the preceding RP—HPLC purification is dissolved in methanol and filtered figh an anion exchange cartridge (Stratospheres SPE, PL-HC03 MP-resin). The cartridge is d with ol, and the filtrate is evaporated.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _ 57 _ Method P6: A on of the product in ethyl acetate is washed with sat. aq. sodium hydrogencarbonate on followed by sat. aq. sodium chloride solution, dried over magnesium sulfate, filtered and evaporated.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na _ 58 _ Starting Materials and Intermediates: Intermediate 1A oxy—4-methylaniline HC NH 0 H30’ A mixture of 5-methylnitroanisol (265 g, 1.58 mol) and 10% Pd/C (39.75 g) in THF (1.32 L) was stirred overnight at rt under 1 atm of hydrogen. Filtration over kieselguhr and evaporation afforded 216.1 g of the crude product which was used in the next step without further purification.

LC-MS (method 3): R = 2.39 min; MS (ESIpos): m/z = 138 (M+H)+ ‘H—NMR (400 MHz, DMSO-ds): 5 = 6.45—6.63 (m, 3H), 4.46 (s, 2H), 3.72 (s, 3H), 2.16 (s, 3H) 10 Intermediate 2A 2—Methoxy—4-methylbenzenethiol HC SH H30 Method 1: 15 A solution of sodium nitrite (7 g, 101.4 mmol) in water (25 ml) was added dropwise to a cooled (0°-5°C) solution of ediate 1A (13.7 g, 100 mmol) in concentrated hloric acid (30 ml) and water (85 ml). After stirring at 0°C for 10 min, sodium acetate (15 g, 182.8 mmol) was added.

The resulting mixture was added dropwise to a hot solution (70°-80°C) of potassium 0-ethyl dithio- carbonate (30 g, 187.1 mmol) in water (140 ml), stirred between 70°C and 80°C for 1 h and then 20 (1 to rt. The mixture was ted twice with ethyl acetate, and the ed organic extracts were dried over sodium sulfate and evaporated. The residue was taken up in a 1.3 M solution of [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _59_ potassium hydroxide in ethanol (300 m1). Glucose (8 g) was added, and the resulting mixture was d for 3 h. Then, the ethanol solvent was evaporated, and the residue was diluted with water and acidified with 6 N aqueous sulfuric acid. Zinc powder (15 g) was added carefully, and the resulting e was heated to 50°C for 30 min. The mixture was then cooled to rt, diluted with dichloromethane and filtered. The filtrate was extracted twice with dichloromethane, and the combined c extracts were dried over sodium sulfate and evaporated affording 14.3 g of the crude product which was used in the next step without further purification.

Method 2: To 2.9 L of THF was added a warm solution of 355 ml (6.67 mol) concentrated sulfuric acid in 10 1.1 L of water. At 50°C, 293 g (1.33 mol) oxy—4-methylbenzenesulfonyl chloride were added under stirring. Then, 521 g (7.97 mol) of zinc powder were added carefully in portions (foaming), and the slightly exothermic reaction was cooled in a water bath to maintain a temperature of 50°- 55°C. The e was subsequently stirred at 55°C for 3 h. The progress of the reaction was monitored by TLC (silica gel, petrolether/ethyl acetate 95:5). The reaction mixture was poured into 15 13.6 L of water, 6.8 L dichloromethane were added, and the mixture was stirred for 5 min. After decanting from remaining zinc and phase separation, the s phase was extracted once more with 6.8 L dichloromethane. The combined organic phases were washed with 10% brine, dried and ated at 40°C under reduced pressure yielding 237 g of crude product. This material was used in the next step without r purification. An analytical sample was obtained by silica gel 20 chromatography with petrolether/ethyl acetate (97:3) as eluent.

LC-MS (method 1): R = 1.21 min; MS (ESIneg): m/z = 153 (M-H)’ 1H-NMR (400 MHz, DMSO-da): 8 = 7.17 (d, 1H), 6.81 (s, 1H), 6.66 (d, 1H), 4.63 (br. s, 1H), 3.80 (s, 3H), 2.26 (s, 3H) ppm.

Intermediate 3A 25 1 — [(2,2-Diethoxyethyl)sulfanyl] methoxy—4—methylbenzene H3C S/YOVCHs H C’0 OVCH3 3 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena _60_ 237 g crude material from Intermediate 2A, 287 g (1.46 mol) bromoacetaldehyde-diethylacetal and 862 g (2.65 mol) caesium carbonate were suspended in 2 L DMF. The reaction temperature in- creased initially to 40°C, then stirring was continued overnight at ambient temperature. The reaction mixture was partitioned between 10 L of water and 2.7 L of ethyl acetate. The aqueous phase was ted with another n of 2.7 L ethyl acetate. The combined organic phases were washed with 10% brine, dried and evaporated. The resulting oily residue was purified by silica gel chromatography with petrolether/ethyl acetate (95:5) as .

Yield: 236 g of an oil (66% ofth.) GC—MS (method 6): R: = 6.03 min; MS (EIpos): m/z = 270 (M)+ 10 ‘HTWMKMOONHE,DMSO«@:8=7J6(¢1HL682(&1HL673(¢1HL4550,HD,380@, 3H), 3.52-3.64 (m, 2H), 3.39—3.51 (m, 2H), 2.96 (d, 2H), 2.33 (s, 3H), 1.09 (t, 6H) ppm.

Intermediate 4A 7—Methoxy—5-methyl- 1 thiophene H30 H C’0 3 15 To a refluxing mixture of 13 g polyphosphoric acid and 150 ml benzene was added dropwise a solution of 5.2 g (19.2 mmol) of Intermediate 3A, and refluxing was continued overnight. After cooling, the organic layer was ed, and the residue and flask were rinsed twice with DCM. The combined organic phases were evaporated at reduced pressure. The e (3.76 g) was chromato- graphed on silica gel with isohexane/0—10% ethyl acetate as eluent. 20 Yield: 1.69 g of an oil (49% ofth.) GC-MS (method 6): R = 5.20 min; MS (EIpos): rn/z = 178 (M)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 7.68 (d, 1H), 7.34 (d, 1H), 7.28 (s, 1H), 6.78 (s, 1H), 3.93 (s, 3H), 2.43 (s, 3H) ppm.

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena ed set by na —61— Intermediate 5A (7—Methoxy—5-methylbenzothiophen—2—yl)bor0nic acid H3C OH \ / B\ S OH O H C’ 3 Under argon atmosphere, 26.7 g (150 mmol) of ediate 4A were dissolved in 270 ml of THF and cooled to -70°C. Between -70°C and —65°C, 66 ml (165 mmol) of a 2.5 N solution of n—butyl- lithium in hexane were added dropwise within 20 min, resulting in formation of a white precipitate.

After stirring for 1 h at -70°C, 41.5 ml (180 mmol) triisopropyl borate were added at this tem- perature within 10 min (resulting in a thick suspension). Stirring was continued for 1 h at -70°C, before the reaction mixture was allowed to warm up to rt overnight. Then, 400 m1 of saturated aq. 10 um chloride solution were added, the layers were separated, and the s layer was extracted once more with THF. The ed organic phases were evaporated under reduced pressure. To the e thus obtained, 200 ml of water and 86 m1 of 2 N aq. sodium hydroxide solution were added. The solution was washed twice with DCM, then acidified with 35 ml of 3 M sulfuric acid, and the resulting suspension was stirred vigorously for 1 h. The precipitate was filtered 15 offby suction and dried overnight at 45°C in vacuo.

Yield: 28.25 g of a colorless solid (94% pure by LC-MS, 80% of th.) LC—MS (method 2): R. = 0.87 min; MS (ESIpos): rn/z = 223 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 6 = 7.17 (d, 1H), 6.81 (s, 1H), 6.66 (d, 1H), 4.63 (br. s, 1H), 3.80 (s, 3H), 2.26 (s, 3H) ppm. 20 Intermediate 6A 2—(7-Methoxy—5-methyl-1 -benzothiophen—2-yl)—6-methyl- 1 ,3 ,6,2-dioxazaborocane-4, 8-dione [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena —62— O H3C \ /OAR B\ N—CH3 S 0% H 0’0 0 3 6.3 g (28.4 mmol) of Intermediate 5A and 4.2 g (28.4 mmol) 2,2'-(methylimino)diacetic acid were dissolved in a mixture of 45 ml DMSO and 400 ml toluene and refluxed for 16 h using a Dean—Stark trap. After evaporation, the residue was taken up in ethyl acetate and washed three times with water 5 and once with brine. The organic phase was dried over magnesium sulfate and evaporated to a volume of about 200 ml. A white solid precipitated which was filtered, washed with ethyl acetate and dried in vacuo to give a first crop (5.52 g) of the title compound. A second crop (3.32 g) was ob- tained after ation of the mother liquor and flash-chromatography over a layer of silica gel using cyclohexane/0-100% ethyl acetate as the . 10 Yield: 8.84 g (overall purity 92.5% by LC—MS, 87% of th.) LC-MS (method 2): R. = 0.93 min; MS (ESIpos): m/z = 334 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): 8 = 7.42 (s, 1H), 7.26 (s, 1H), 6.76 (s, 1H), 4.40 (d, 2H), 4.17 (d, 2H), 3.92 (s, 3H), 2.63 (s, 3H), 2.42 (s, 3H) ppm.

Intermediate 7A 15 Ethyl 4-aminopyrrolo[2,1 -f] [1 ,2,4]triazine—6—carboxylate NH2 O N/ / K» / N 0—\ CH3 A solution of 4-aminopyrrolo[2,1-f][1,2,4]triazine—6-carbonitrile (3.9 g, 24.5 mmol; preparation described in PCT Int. Pat. Appl. WO 2007/064883) in ethanol (124.8 ml) was stirred with con- centrated sulfuric acid (62.4 ml) at 80°C ght. After cooling to rt, the reaction mixture was 20 ged onto 800 g of ice and brought to pH 6—7 with concentrated aq. sodium hydroxide solution.1 acetate (500 ml) and romethane (500 ml) were added to the sion, and the resulting [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _63_ mixture was filtered over kieselguhr. The organic layer was ted from the aqueous layer. The solid was dissolved in hot water (1 L), and the aqueous layer was ted twice with ethyl acetate.

The combined organic layers were dried over sodium sulfate and ated. The residue was triturated with an isopropanol/diethylether mixture, and the solid was filtered off yielding 2.5 g (49% ofth.) of the title compound.

LC-MS (method 2): R = 0.59 min; MS s): m/z = 206 (M+H)+ lH—NMR (400 MHz, DMSO-dg): 5 = 8.11—7.97 (m, 3H), 7.88 (s, 1H), 7.34 (br. s, 1H), 4.27 (q, 2H), 1.30 (t, 3H) ppm.

Intermediate 8A 10 (4-Aminopyrrolo [2, l -f] [l ,2,4]triazin—6-yl)methanol NH2 N / / b / \N/N OH An ice-cooled solution of Intermediate 7A (3.0 g, 14.5 mmol) in THF (30 ml) was treated with a 1 M solution of lithium triethylborohydride in THF (58 ml) and d at rt for 45 min. The reaction mixture was then cooled to 0°C, quenched with methanol, warmed slowly to rt and adsorbed on 15 kieselguhr. Purification by column chromatography over silica gel (dichloromethane/methanol 20:1 —> 4:1 gradient) afforded 2.21 g (92.5% of th.) of the title compound.

LC—MS (method 3): R = 1.46 min; MS (ESIpos): m/z = 164 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 7.75 (s, 1H), 7.64 (br. s, 2H), 7.50 (br. (1, 1H), 6.79 (br. d, 1H), 5.01 (t, 1H), 4.50 (d, 2H) ppm. 20 Intermediate 9A lert—Butyl [2-cyano(hydroxymethyl)- lH—pyrrol- l -yl] carbamate D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena 0 CH3 JL JVCHs Hi 0 CH, N CN \/ HO Under argon, a 1 M solution of methylmagnesiurn bromide in THF (13.3 ml) was added over 15 min to a solution of tert—butyl (4-bromo-2—cyano—1H—pyrrolyl)carbamate (3.7 g, 12.09 mmol; preparation described in PCT Int. Pat. Appl. WO 2007/064883, Intermediate AAE, Step 3) in THF 5 (37 ml) cooled to -60°C. After 30 min, a 1.6 M solution of n-butyllithium in hexane (15.1 ml, 242 mmol) was added over 10 min to the reaction, and the ing mixture was stirred between -60°C and -40°C for 1 h. Then, paraformaldehyde (1.09 g, 36.3 mmol) was added to the reaction, and the on mixture was slowly warmed to rt and stirred overnight. After quenching with sat. aq. ammonium chloride solution, the aqueous layer was ted twice with ethyl e. The com- 10 bined organic phases were washed with sat. aq. sodium chloride solution, dried over sodium sulfate and evaporated. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate 2:1 —> 1:1) afforded 2.04 g (69% of th.) of the title compound.

LC—MS (method 4): R. = 0.70 min; MS (ESIpos): m/z = 238 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 10.79 (br. s, 1H), 7.09 (d, 1H), 6.86 (d, 1H), 4.97 (t, 1H), 15 4.28 (d, 2H), 1.45 (s, 9H) ppm.

Intermediate 10A 6—(Methoxymethyl)pyrrolo [2, 1 -f] [1 ,2,4]triazin—4—amine NH2 N/ / K N / N/ O—CH3 Method I.‘ 20 A solution of Intermediate 8A (1.3 g, 7.9 mmol) in THF (25 ml) was treated with thionyl chloride i115 m1, 15.8 mmol) and stirred at rt for 2 h. After ation, the residue was dissolved in anol (25 m1) and treated with sodium acetate (1.3 g, 15.8 mmol). The mixture was stirred for [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _65_ 3 h at 65°C and then evaporated again. Purification by column chromatography on silica gel oromethane/methanol 100:2) afforded 787 mg (55% of th.) of the title compound.

Method 2: A solution of ediate 9A (6.14 g, 25.88 ) in a 4 M on of hydrogen chloride in 1,4- dioxane (15 ml) was stirred at rt for 5 h. After dilution with methanol (73 ml), stirring at rt was continued overnight. Then, potassium phosphate (54.9 g, 258.65 mmol) and formamidinium acetate (13.46 g, 129.32 mmol) were added, and the resulting mixture was stirred at 65°C for 17 h. The reaction mixture was evaporated, sat. aq. sodium chloride solution was added, and the mixture was extracted with dichloromethane followed by ethyl acetate. The combined organic phases were dried 10 over sodium e and evaporated. Purification by column chromatography on silica gel (dichloro- methane/methanol 40:1 —> 20:1) afforded 2.36 g (49% of th.) of the title compound.

LC-MS (method 3): R. = 1.72 min; MS (ESIpos): m/z = 179 (M+H)+ 1H—NMR (400 MHz, DMSO-ds): 8 = 7.77 (s, 1H), 7.69 (br. s, 2H), 7.57 (s, 1H), 6.81 (s, 1H), 4.42 (s, 2H), 3.25 (s, 3H) ppm. 15 Intermediate 11A o(methoxymethyl)pyrrolo[2, 1 —f] [1 riazinecarbaldehyde Phosphoryl de (13.7 ml, 147.18 mmol) was added to a solution of Intermediate 10A (5.24 g, 29.43 mmol) in DMF (80 ml) at 0°C. The resulting mixture was d at 60°C for 8 h, then care- 20 fully quenched with water and neutralized with 4 M aq. sodium hydroxide solution. The aqueous layer was extracted with ethyl e. The combined organic phases were washed with sat. aq. sodium chloride solution, dried over magnesium sulfate and evaporated. A solution of the residue in methanol (50 ml) was treated with sodium acetate (2.41 g, 29.43 mmol) and refluxed overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic 25 Des were washed with sat. aq. sodium chloride solution, dried over magnesium sulfate and [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena _66_ evaporated, affording 2.66 g of the crude product which was used in the next step without further purification.

LC-MS (method 4): R = 0.50 min; MS (ESIpos): m/z = 207 (M+H)+ 1H-NMR (400 MHz, s): 8 = 10.35 (s, 1H), 8.20 (br. s, 2H), 8.07 (s, 1H), 7.06 (s, 1H), 4.72 (s, 2H), 3.39 (s, 3H) ppm.

Intermediate 12A 4-Aminobromo(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazinecarbaldehyde A solution of Intermediate 11A (crude, 2.66 g) in DMF (30 ml), cooled to -30°C, was treated with a 10 solution of N—bromosuccinimide (NBS; 2.52 g, 14.19 mmol) in DMF (14 ml). The resulting mixture was slowly warmed to 0°C. After 1 hour, the mixture was warmed to rt, stirred for further 15 min and then quenched with 1 M aq. sodium thiosulfate solution. The precipitate was filtered off and washed with ethyl acetate, affording 1.1 g (100% purity, 30% of th.) as a first crop of the title com- pound. The remaining filtrate was extracted with ethyl acetate. The combined organic phases were 15 washed with sat. aq. sodium chloride solution, dried over sodium e and evaporated. Purification of the residue by column chromatography on silica gel (cyclohexane/ethyl acetate 1:1 —> 1:3) affor- ded further 1.39 g (70% , 26% of th.) of the title nd.

LC—MS (method 2): R: = 0.67 min; MS (ESIpos): m/z = 283/285 (M+H)+ 1H-NMR (400 MHz, DMSO-da): 5 = 10.36 (s, 1H), 8.63 (br. s, 1H), 8.13 (s, 1H), 7.23 (br. s, 1H), 20 4.64 (s, 2H), 3.26 (s, 3H) ppm. ediate 13A 4—Amino(methoxymethyl)(7-methoxy—5—methylbenzothiophen—2-yl)pyrrolo [2, 1 -f] [1 ,2,4] — triazine—7—carbaldehyde [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Under argon, a degassed 0.5 M aq. potassium phosphate solution (9.9 ml) was added to a solution of Intermediate 12A (710 mg, 2.49 mmol), Intermediate 5A (921 mg, 3.73 mmol) and ino- biphenylyl)(chloro)palladium—dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine (1:1; 196 mg, 249 umol; see S.L. Buchwald et al., J. Am. Chem. Soc. 132 (40), 14073-14075 (2010)) in ed THF (28.4 ml). The resulting mixture was stirred at 60°C for 2 h and then evaporated.

Purification of the residue by column chromatography on silica gel (cyclohexane/ethyl actetate 5:1 —> 121) afforded 550 mg (51% of th.) of the title compound.

LC—MS d 2): R. = 1.06 min; MS (ESIpos): m/z = 383 (M+H)+ 10 ‘H-NMR (400 MHz, DMSO-ds): 5 = 10.50 (s, 1H), 8.43 (br. s, 1H), 8.21 (s, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 6.87 (s, 1H), 6.09 (br. s, 1H), 4.58 (s, 2H), 3.96 (s, 3H), 3.19 (s, 3H), 2.46 (s, 3H) Intermediate 14A 6-(Ethoxymethyl)pyrrolo [2, 1 -f] [1 ,2,4]triazinamine NH2 N/ / kw / 01 CH 15 3 Method 1 .' D1 suspension of 2 g (12.2 mmol) of Intermediate 8A in 40 ml THF were added 1.78 ml (24.4 mmol) thionyl chloride at rt within 20 sec. The mixture was stirred for 1.5 h, then evaporated to ation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —68— dryness, and the residue was dissolved in 40 ml ethanol. 2 g (24.4 mmol) sodium acetate were added, and the mixture was stirred at 70°C for 1 h 45 min. The reaction mixture was evaporated again, and sat. aq. sodium hydrogencarbonate solution was added. The mixture was extracted five times with ethyl acetate. The ed organic phases were washed with sat. aq. sodium chloride solution, dried with magnesium sulfate and evaporated to dryness, giving 2.02 g of crude product which was purified by column chromatography on silica gel with dichloromethane/methanol (0-2%) as the .

Yield: 1.37 g (58% ofth.).

Method 2: 10 Step 1: A solution of ediate 9A (2.3 g, 9.69 mmol) in 1,4-dioxane (5 ml) was treated with a 4 M solution of hydrogen chloride in 1,4-dioxane (24 m1, 96.9 mmol) and stirred at rt for 130 min.

Then, the suspension was filtered, and the precipitate was washed with 1,4-dioxane (5 ml) and dried in vacuo yielding 1.01 g (54% of th.) of the intermediate compound 1-amino(chloromethyl)-1H- pyrrole—2-carbonitrile hydrochloride. 15 Step 2: Freshly prepared 1-amino(chloromethyl)-lH-pyrrole-Z-carbonitrile hydrochloride from Step 1 (0.3 g, 1.82 mmol) was dissolved in ethanol (10 m1) and stirred at rt for 5 min. The clear solution was treated with idine acetate (813 mg, 7.81 mmol) and potassium phosphate (1.66 g, 7.81 mmol) and stirred first at rt for 3 days, then at 80°C for 10.5 h. More formamidine acetate (488 mg, 4.69 mmol) was added, and the mixture was stirred for further 18 h at 80°C. The 20 mixture was then cooled to rt, and water and ethyl acetate were added. The organic phase was sepa- rated, and the aqeous phase was extracted twice with ethyl e. The combined organic phases were washed with sat. aq. sodium chloride solution, dried with magnesium sulfate and evaporated.

The residue was dissolved in a mixture of methanol and dichloromethane, ed on diatomaceous earth, dried in vacuo and finally purified by chromatography on silica gel ent 0-10% 25 methanol/dichloromethane) yielding 260 mg (78% of th.) of the title compound.

LC-MS (method 3): R = 2.02 min; MS (ESIpos): m/z = 193 (M+H)+ lH-NMR (400 MHz, DMSO-ds): 5 = 7.77 (s, 1H), 7.59-7.74 (br. s, 2H), 7.56 (s, 1H), 6.82 (s, 1H), 5.76 (s, 1H), 4.46 (s, 2H), 3.46 (q, 2H), 1.13 (t, 3H) ppm.

Intermediate 15A 30 unino(ethoxymethyl)pyrrolo [2,1 -f] [1 ,2,4]triazinecarba1dehyde [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by na —69— To a solution of 2.1 g (10.9 mmol) of Intermediate 14A in 40 ml dry DMF, 5.1 ml (54.6 mmol) phosphoryl chloride were added dropwise at 0°C under an argon atmosphere. The mixture was stirred at 60°C for 10 h. Then, water was added carefully, and the mixture was stirred at t ature until all reactive intermediates were destroyed (HPLC control). The acidic solution was neutralized with 1 M aq. sodium hydroxide on and extracted three times with ethyl acetate. The combined organic phases were washed with sat. aq. sodium de solution, dried over magnesium sulfate and evaporated at reduced pressure.

Yield: 1.94 g (purity 90%, 81% of th.) 10 LC—MS (method 5): R1 = 1.49 min; MS (ESIpos): m/z = 221 (M+H)+ ‘H-NMR (400 MHZ, DMSO-ds): 5 = 10.35 (s, 1H), 8.14-8.26 (m, 2H), 8.07 (s, 1H), 7.07 (s, 1H), 4.76 (s, 2H), 3.58 (q, 2H), 1.20 (t, 3H) ppm.

Intermediate 16A 4-Aminobromo(ethoxymethyl)pyrrolo[2, 1 -f] [1 ,2,4]triazinecarbaldehyde 15 To a solution of 73 g (0.33 mol) of Intermediate 15A in 1.9 L DMF was added dropwise a solution of 65 g (0.37 mol) NBS in 200 ml DMF at —15°C. The mixture was d to warm to 0°C and stirred for 3 h at this temperature. The reaction mixture was poured into 2% aq. sodium thiosulfate solution under stirring, and the precipitate was filtered off, washed with water and dried over 20 aphorous pentoxide in vacuo.

Yield: 85.6 g (86% ofth.) [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _70_ LC-MS (method 2): R = 0.76 min; MS s): m/z = 299/301 (M+H)+ ‘H-NMR (400 MHz, DMSO-ds): 6 = 10.36 (s, 1H), 8.62 (br. s, 1H), 8.13 (s, 1H), 7.22 (br. s, 1H), 4.68 (s, 2H), 3.49 (q, 2H), 1.10 (t, 3H) ppm.

Intermediate 17A 4—Amino(ethoxymethyl)(7-methoxy—5—methyl- l -benzothiophen—2-yl)pyrrolo[2, 1 -f] [1 ,2,4]— ne—7-carbaldehyde Under an argon atmosphere, 714 mg (purity 85%, 2.03 mmol) of Intermediate 16A, 946 mg (2.84 mmol) of Intermediate 6A and 160 mg (0.2 mmol) (2'-aminobiphenylyl)(chloro)palladium— 10 dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine (1:1; see S.L. Buchwald et al., J. Am.

Chem. Soc. 132 (40), 14073-14075 (2010)) were suspended in 15.5 ml THF. Then, 15.5 ml of a ed 0.5 M aq. potassium phosphate on were added, and the mixture was stirred at 50°C for 16 h. After addition of water, the mixture was extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The 15 residue was purified by column chromatography on silica gel (100 g) with 10—50% ethyl acetate/ cyclohexane as the eluent.

Yield: 452 mg (75% pure by HPLC, 42% of th.) LC-MS (method 5): R = 2.38 min; MS (ESIpos): m/z = 397 (M+H)+ ‘H—NMR (400 MHz, DMSO-ds): 6 = 10.50 (s, 1H), 8.42 (br. s, 1H), 8.21 (s, 1H), 7.43 (s, 1H), 20 7.33 (s, 1H), 6.87 (s, 1H), 6.07 (br. s, 1H), 4.63 (s, 2H), 3.96 (s, 3H), 3.40 (q, 2H), 2.46 (s, 3H), D (t, 3H) ppm.

[Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _71_ Intermediate 18A (4—Amino-5,7-dibromopyrrolo[2,1-f] [1 riazin—6-yl)methanol NH2 Br N / / Br A solution of Intermediate 8A (5 g, 30.4 mmol) in THF (100 ml) was treated with 1,3-dibromo-5,5- dimethylhydantoin (9.58 g, 33.5 mmol) and stirred at rt for 2 h. The precipitate was filtered off and dried in vacuo to afford 6.60 g (64% of th.) of the title compound.

LC-MS (method 2): R. = 0.56 min; MS (ESIpos): m/z = 321/323/325 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.23 (br. s, 1H), 7.96 (s, 1H), 6.94 (br. s, 1H), 5.09 (br. s, 1H), 4.43 (s, 2H) ppm. 10 ediate 19A (4—Aminobromopyrrolo[2, 1 -f] [1 ,2,4]triazin—6—yl)methanol NH2 Br N / / k\N/N OH A suspension of Intermediate 18A (3.7 g, 11.5 mmol) in THF (800 ml) was heated under stirring until complete dissolution. The mixture was then cooled to -78°C, and a 1.6 M solution of n-butyl- 15 lithium in hexanes (20 ml, 32.1 mmol) was added dropwise. After 5 min, a further portion of 1.6 M n-butyllithium solution (1.5 ml, 2.29 mmol) was added. The resulting mixture was stirred at -78°C for 5 min, then quenched with methanol (5 ml) and warmed to rt. The reaction mixture was d with sat. aq. um chloride solution, sat. aq. sodium hydrogencarbonate solution, sat. aq. sodium chloride solution and ethyl acetate. After phase separation, the organic layer was washed 20 with sat. aq. sodium chloride solution. The combined s phases were re-extracted with ethyl acetate. The combined organic phases were washed again with sat. aq. sodium chloride solution, Di over magnesium sulfate and evaporated to afford 2.87 g of the crude product which was used in subsequent steps without fithher purification.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] na None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _72_ LC-MS (method 3): R = 1.73 min; MS (ESIpos): m/z = 243/245 (M+H)+ 1H—NMR (400 MHz, DMSO-da): 5 = 8.41—7.89 (br. s, 1H), 7.82 (s, 1H), 7.66 (s, 1H), 7.13-6.48 (br. s, 1H), 5.11 (t, 1H), 4.45 (d, 2H) ppm.

Intermediate 20A [4—Amino(7-methoxymethylbenzothiophen—2-yl)pyrrolo [2, 1 -f] [1 ,2,4]triazin—6-yl]methanol A suspension of Intermediate 19A (70% purity, 2.52 g, 7.26 mmol), Intermediate 6A (3.63 g, 10.9 mmol) and caesium fluoride (5.51 g, 36.3 mmol) in a THF/water mixture (10:1; 80 ml) was degassed under argon. tert—butylphosphino)-N,N—dimethylaniline-dichloropalladium (2:1; 10 176 mg, 0.248 mmol) was added, and the resulting mixture was degassed again and stirred at 50°C for 16 h. The reaction mixture was then washed with sat. aq. sodium chloride on, and the organic layer was separated, dried over ium sulfate, filtered and evaporated. The residue was suspended in methanol, and the resulting solid was filtered off and dried in vacuo to afford 1.97 g (90% purity, 72% of th.) of the title compound. 15 LC-MS (method 2): R: = 0.85 min; MS (ESIpos): m/z = 340 (M+H)+ lH—NMR (400 MHz, DMSO-ds): 5 = 7.91 (s, 1H), 7.5-8.1 (br. s, 1H), 7.72 (s, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 5.5-6.0 (br. s, 1H), 5.06 (t, 1H), 4.49 (d, 2H), 3.95 (s, 3H), 2.45 (s, 3H) Intermediate 21A 20 6—(Methoxymethyl)(7-methoxymethyl— 1 —benzothiophen—2-yl)pyrrolo [2, 1 -f] [1 ,2,4]triazin—4— amine D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena A solution of Intermediate 20A (400 mg, 1.17 mmol) in dichloromethane (12 ml) was treated with thionyl chloride (128 pl, 1.76 mmol) and stirred at It for 15 min. After evaporation, the e was taken up in methanol (12 ml) and treated with DIPEA (409 ul, 2.35 mmol). The mixture was refluxed overnight and then evaporated again. ation by column chromatography on silica gel (dichloromethane/methanol 98:2 —> 95:5) ed 388 mg (93% of th.) of the title compound.

LC—MS d 2): R = 1.00 min; MS (ESIpos): m/z = 355 (M+H)+ ‘H-NMR (400 MHz, DMSO-ds): 8 = 7.93 (s, 1H), 7.82 (s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 4.38 (s, 2H), 3.95 (s, 3H), 3.22 (s, 3H), 2.45 (s, 3H) ppm. 10 Intermediate 22A 6—(Ethoxymethyl)(7-methoxymethylbenzothiophen—2-yl)pyrrolo [2, 1 -f] [1 ,2,4]triazin—4-amine Intermediate 20A (200 mg, 587 umol) in dichloromethane (5 ml) was treated with thionyl chloride (64 ul, 881 umol) and stirred at It for 15 min. After evaporation, the residue was refluxed in ethanol 15 D11) for 1 h, then treated with DIPEA (204 ul, 1.17 mmol) and refluxed again ght. The reaction mixture was evaporated, and the crude product was purified by column chromatography on [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _74_ silica gel (dichloromethane/methanol 98:2 —> 95:5) affording 202 mg (90% of th.) of the title com- pound.

LC-MS (method 5): R = 2.32 min; MS (ESIpos): m/z = 369 (M+H)+ 1H-NMR (400 MHz, DMSO-da): 5 = .59 (br. s, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 6.20-5.50 (br. s, 1H), 4.41 (s, 2H), 3.95 (s, 3H), 3.41 (q, 2H), 2.45 (s, 3H), 1.08 (t, 3H) ppm.

Intermediate 23A tert—Butyl 4- ino(hydroxymethyl)—5—(7—methoxymethylbenzothiophen—2—yl)pyrrolo- [2,1-f][1,2,4]triazin—7-yl]methyl}piperazine—1—carboxylate 10 A solution of Intermediate 20A (9.5 g, 27.9 mmol) in acetic acid (136.8 ml) was treated with tert- butyl zine-l-carboxylate (6.24 g, 33.49 mmol) and 37% aq. formaldehyde solution (2.5 ml, 33.49 mmol). The mixture was stirred at 60°C for 2.5 h. After evaporation, the residue was taken up in ethyl acetate, and the e was washed twice with sat. aq. sodium hydrogencarbonate solution, 15 dried over sodium sulfate and evaporated. The residue was triturated in boiling ethanol (100 ml).

The solid was filtered off and washed with ethanol and diethylether affording 9.70 g (58% of th.) of the title compound.

LC—MS (method 2): R: 0.88 min; MS (ESIpos): m/z = 539 (M+H)+ D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena _75_ 1H-NMR (400 MHz, CDC13)I 6 = 7.94 (s, 1H), 7.13-7.35 (m, 2H, overlap with CHC13 peak), 6.67 (s, 1H), 5.86 (br. s, 1H), 5.54 (br. s, 2H), 4.68 (s, 2H), 4.08 (s, 2H), 4.00 (s, 3H), 3.45 (br. s, 4H), 2.59-2.48 (m, 7H), 1.45 (s, 9H) ppm.

Intermediate 24A tert—Butyl 4-( no(7-methoxymethyl— 1 -benzothiophen—2-yl) [(2-methoxyoxoethoxy)- methyl]pyrrolo[2, 1 -f] [1 ,2,4]triazin—7-yl}methyl)piperazinecarboxylate A on of Intermediate 23A (300 mg, 556 umol) in dichloromethane (12 ml) was d with thionyl chloride (81 ul, 1.11 mmol) and stirred at rt for 15 min. After evaporation, the residue was 10 dissolved in freshly distilled methylglycolate (2.5 ml) and treated with DIPEA (485 pl, 2.78 mmol).

The mixture was stirred at 70°C for 2 h, then evaporated again, and excess methylglycolate was removed by distillation. Purification of the residue by column chromatography on silica gel (cyclohexane/ethyl acetate 1:5) afforded 136 mg (33% of th.) of the title compound.

LC-MS d 2): R. = 0.88 min; MS (ESIpos): m/z = 611 (M+H)+ 15 1H-NMR (400 MHz, DMSO-ds): 8 = 7.99 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 4.58 (s, 2H), 4.11 (s, 2H), 3.96 (s, 3H), 3.93 (s, 2H), 3.57 (s, 3H), 3.30-3.24 (m, 4H), 2.45-2.38 (m, 7H), 1.39 (s, 9H) ppm.

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena —76— Intermediate 25A tert—Butyl 4- {[4-aminoformyl(7-methoxy—5-methylbenzothiophen—2-yl)pyrrolo[2, 1 —f] [1 ,2,4] - triazin—7-yl]methyl }piperazinecarboxylate A solution of ediate 23A (300 mg, 556 umol) in dichloromethane (4.2 ml) was treated with Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one; 307 mg, 724 umol) and stirred at rt for 2 h. The reaction e was quenched With sat. aq. sodium hydrogen- carbonate on and sat. aq. sodium thiosulfate solution (1:1) and stirred at rt for 30 min. The aqueous layer was extracted three times with dichloromethane, and the ed organic layers were 10 dried over magnesium sulfate and evaporated. Purification by column tography on silica gel (cyclohexane/ethyl acetate 1:1 —> 100% ethyl acetate) afforded 273 mg (87% of th.) of the title compound.

LC—MS (method 2): R = 0.87 min; MS (ESIpos): m/z = 537 (M+H)+ 1H—NMR (400 MHZ, DMSO-ds): 8 = 10.02 (s, 1H), 8.44-8.18 (br. s, 1H), 8.08 (s, 1H), 7.51 (s, 15 1H), 7.32 (s, 1H), 6.88 (s, 1H), 6.01-5.74 (br. s, 1H), 4.16 (s, 2H), 3.96 (s, 3H), 3.30—3.22 (m, 4H), 2.48-2.40 (m, 7H), 1.38 (s, 9H) ppm.

Intermediate 26A 4—Amino(7-methoxy—5-methylbenzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo [2, 1 —f] — [1 ,2,4]triazinecarbaldehyde bis(formiate) D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _77_ X 2 HCOOH A solution of ediate 23A (80 mg, 148 umol) in THF (3.9 ml) was treated with Dess—Martin periodinane (1,1,l-triacetoxy-l,1-dihydro-1,2—benziodoxol-3(1H)-one; 94 mg, 222 umol) and stirred at rt for 30 min. The on mixture was quenched with sat. aq. sodium hydrogencarbonate solution and sat. aq. sodium thiosulfate solution (1 :1). The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried over magnesium sulfate and evaporated. The residue was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (4 m1) and stirred at rt for 1 h. After evaporation, the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) ing 34 mg (52% of th.) of 10 the title compound.

LC—MS (method 2): R. = 0.78 min; MS (ESIpos): m/z = 437 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 10.02 (s, 1H), 8.29 (br. s, 2H), 8.09 (s, 1H), 7.50 (s, 1H), 7.33 (s, 1H), 6.88 (s, 1H), 4.17 (s, 2H), 3.96 (s, 3H), 2.90-2.81 (m, 4H), 2.63-2.56 (m, 4H), 2.46 (s, 3H) ppm. 15 Intermediate 27A tert—Butyl 4-( {4-amino(7-methoxy—5-methyl— 1 -benzothiophen—2-yl) [(3 -oxopiperazin— 1 —yl)- methyl]pyrrolo [2, 1 -f] [1 riazin—7-yl}methyl)piperazinecarboxylate [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —78— A solution of Intermediate 25A (185 mg, 344 umol) in THF (4.6 ml) was treated With 2-oxo- piperazine (344 mg, 3.4 mmol), sodium triacetoxyborohydride (365 mg, 1.7 mmol) and acetic acid (39 ul, 689 umol). The resulting mixture was stirred at rt for 2 h, then adsorbed on kieselguhr and purified by column chromatography on silica gel (dichloromethane —> dichloromethane/methanol 100:8) affording 221 mg (quant.) of the title nd.

LC-MS (method 4): R. = 0.77 min; MS (ESIpos): m/z = 621 (M+H)+.

Intermediate 28A N—Ethylethanaminium o {[4-(tert—butoxycarbonyl)piperazin— 1 -yl]carbonyl} (7-methoxy- 10 5—methylbenzothiophen—2-yl)pyrrolo[2,1—f][1 ,2,4]triazinecarboxylate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _79_ A on of Intermediate 25A (70 mg, 130 umol) in THF/water (10:1, 4.85 ml) was treated with a 2 M solution of 2-methylbuten in THF (521 pl, 1.04 mmol) and sodium dihydrogenphosphate (107 mg, 783 umol) and stirred at rt for 5 min. Sodium chlorite (70 mg, 783 umol) was added, and the resulting mixture was stirred at rt overnight. After dilution with water, the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated, and the residue was purified by preparative RP-HPLC (XBridge C18, gradient 5- 50% itrile/water + 0.05% lamine) affording 18 mg (21% of th.) of the title nd.

LC-MS (method 1): R = 1.14 min; MS (ESIpos): m/Z = 567 (M+H)+ 1H—NMR (400 MHz, DMSO-ds): inter al. 8 = 8.26-7.89 (br. s, 1H), 7.94 (s, 1H), 7.33 (s, 1H), 7.28 10 (s, 1H), 6.83 (s, 1H), 5.64-5.33 (br. s, 1H), 3.95 (s, 3H), 2.80 (q, 4H), 2.45 (s, 3H), 1.40 (s, 9H), 1.09 (t, 6H) ppm.

Intermediate 29A tert—Butyl 4- { [4-amino(azidomethyl)(7—methoxy—5-methylbenzothiophen—2-yl)pyrrolo— ][1,2,4]triazin—7-yl]methyl}piperazine—1—carboxylate 15 A solution of Intermediate 23A (150 mg, 0.278 mmol) in dichloromethane (7.5 ml) was treated with thionyl chloride (40 ul, 0.56 mmol) and stirred at rt for 15 min. After evaporation, the residue was dissolved in DMF (6 ml) and treated with sodium azide (362 mg, 5.57 mrnol) and sodium iodide 6% times with ethyl acetate. The combined organic layers were washed with water and with sat.mg, 1.39 mmol). The mixture was heated to 80°C for 1 h, then d with water and extracted 20 aq. sodium chloride solution, dried over magnesium sulfate and evaporated. Purification by column [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _80_ chromatography on silica gel hexane/ethyl acetate 98:2 —> 100% ethyl acetate) afforded 95.8 mg (57% of th.) of the title compound.

LC-MS (method 4): R. = 0.99 min; MS (ESIpos): m/z = 564 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.20-7.80 (br. s, 1H), 8.01 (s, 1H), 7.39 (s, 1H), 7.33 (s, 1H), 6.86 (s, 1H), 6.05-5.55 (br. s, 1H), 4.50 (s, 2H), 3.96 (s, 3H), 3.94 (s, 2H), 3.32-3.25 (m, 4H), 2.45 (s, 3H), 2.43-2.36 (m, 4H), 1.39 (s, 9H) ppm.

Intermediate 30A tert—Butyl 4- {[6-(acetamidomethyl)-4—amino—5—(7-methoxy—5-methylbenzothiophen—2—yl)pyrrolo- [2,1-f] [1,2,4]triazin—7-yl]methyl}piperazine—1—carboxylate 10 A e of Intermediate 29A (320 mg, 567 umol), 10% Pd/C (320 mg) and acetic anhydride (106 pl, 1.13 mmol) in methanol (32 ml) was stirred for 90 min under 1 atm of hydrogen at It. The mixture was then filtered through kieselguhr, and the filtrate was evaporated. Purification by column chromatography on silica gel hexane/ethyl acetate 1:1 —> 100% ethyl acetate) afforded 440 mg 15 (quant.) of the title compound.

LC-MS (method 2): R. = 0.91 min; MS (ESIpos): m/z = 580 (M+H)+ 1H—NMR (400 MHz, DMSO-ds): 8 = 8.02—7.97 (m, 2H), 7.38 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), (br. (1, 2H), 3.95 (s, 3H), 3.89 (s, 2H), .24 (m, 4H), 2.45 (s, 3H), 2.43-2.36 (m, 4H), 1.74 (s, 3H), 1.39 (s, 9H) ppm.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —81— Intermediate 31A 7— etylpiperazin— 1 -yl)methyl] arnjno—5—(7—methoxymethylbenzothiophen—2—yl)pyrrolo- [2,1 -f] [1 ,2,4]triazinecarbaldehyde A solution of Example 55 (678 mg, purity 89%, 1.26 mmol) in dichloromethane (4 ml) containing molecular sieves (4A) was treated with Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2- benziodoxol-3(1H)-one; 623 mg, 1.47 mmol) and stirred at rt for 5 min. The reaction e was then adsorbed on diatomaceous earth and purified by column chromatography on silica gel (gradient of 30-100% ethyl acetate/cyclohexane, then 0-10% methanol/dichloromethane) ng 449 mg 10 (49% of th.) of the title compound.

LC-MS (method 4): R = 0.70 min; MS (ESIpos): m/z = 479 (M+H)+.

Intermediate 32A 4- {[4-Amino(azidomethyl)(7-methoxymethylbenzothiophen—2-y1)pyrrolo[2, 1 -f] [1 ,2,4] - triazin—7-yl]methyl}piperazin—2-one [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena A solution of Example 13 (59 mg, 130 umol) in dichloromethane (3.5 ml) was treated with thionyl chloride (19 ul, 261 umol) and stirred at rt for 15 min. After ation, the residue was dissolved in DMF (2.8 ml) and treated with sodium iodide (97 mg, 652 umol) and sodium azide (169 mg, 2.6 mmol). The mixture was stirred at 80°C for 1 h. After on with sat. aq. sodium chloride solution, the aqueous phase was extracted four times with ethyl acetate, and the combined organic layers were dried over magnesium sulfate and evaporated. Purification by column chromatography on silica gel oromethane/methanol 98:2 —> 90:10) ed 35 mg (56% of th.) of the title compound. 10 LC-MS (method 5): R = 2.04 min; MS (ESIpos): m/z = 478 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.02 (s, 1H), 7.75 (br. s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 6.86 (s, 1H), 4.51 (s, 2H), 4.01 (s, 2H), 3.96 (s, 3H), 3.16-3.08 (m, 2H), 3.04-2.98 (m, 2H), 2.65—2.58 (m, 2H), 2.45 (s, 3H) ppm.

Intermediate 33A 15 4—Amino(7-methoxy—5-methylbenzothiophen—2-yl)(morpholinylmethyl)pyrrolo[2, 1 —f] - [1,2,4]triazinecarbaldehyde [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na A solution of Example 50 (710 mg, purity 70%, 1.13 mmol) in dichloromethane (5 ml) containing molecular sieves (4A) was treated with Dess—Martin periodinane (1,1,1-triacetoxy—1,1-dihydro-1,2- benziodoxol-3(lH)-one; 623 mg, 1.47 mrnol) and stirred at rt for 5 min. The reaction mixture was then adsorbed on diatomaceous earth and purified by column chromatography on silica gel (gradient of 30—100% ethyl acetate/cyclohexane) yielding 386 mg (72% of th.) of the title compound.

LC-MS d 2): R: = 0.76 min; MS (ESIpos): m/z = 438 (M+H)+.

Intermediate 34A (4—Aminobromopyrrolo[2, 1 -f] [1 ,2,4]triazin—6-yl)methanol NH2 OH N/ / K N / N/ Br 10 A solution of 1,3-dibromo-5,5-dimethylhydantoin (87 mg, 0.305 mmol) in THF (1 ml) was added dropwise to a solution of Intermediate 8A (100 mg, 0.609 mmol) in THF (4 ml) and methanol (2 ml) at -78°C. The mixture was stirred at -78°C for 16 h, then d with water and extracted with ethyl acetate. The combined organic layers were washed with sat. aq. sodium chloride solution, dried over 15 magnesium sulfate and evaporated. Purification by column chromatography on silica gel (dichloromethane/methanol 20:1 —> 10:1) afforded 55 mg (32% of th.) of the title compound.

Dws (method 3): Rt = 1.71 min; Ms (ESIpos): m/z = 243/245 (M+H)+ [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena —84— ‘H-NMR (400 MHz, DMSO-ds): 8 = 7.74-7.94 (m, 3H), 7.04 (s, 1H), 5.12 (t, 1H), 4.48 (d, 2H) ediate 35A 7—Bromo( { [tert—butyl(dimethyl)silyl]oxy}methyl)pyrrolo [2, 1 -f] [1 ,2,4]triazin—4-amine NHZ (In—I3 CH3 N/ / O_?i+CH3 K ,N / CH .

N Br 5 A solution of Intermediate 34A (885 mg, 3.64 mmol) in DMF (11 ml) was treated with tert—butyl- dimethylsilyl de (823 mg, 5.46 mmol) and imidazole (743 mg, 10.92 mmol) and stirred at rt for 2 h. The reaction mixture was combined with the reaction mixture of a 100 mg test run, d with water and extracted twice with ethyl e. The combined organic phases were washed with water 10 and sat. aq. sodium chloride solution, dried over magnesium sulfate and evaporated. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate 2:1 —> 100% ethyl acetate) afforded 1.36 g (93% of th.) of the title compound.

LC-MS (method 2): R. = 1.13 min; MS (ESIpos): m/z = 357/359 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 7.98-7.68 (m, 3H), 7.04 (s, 1H), 4.68 (s, 2H), 0.89 (s, 9H), 15 0.09 (s, 6H) ppm.

Intermediate 36A 4-Amino( {[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolo[2,1 -f] [1 ,2,4]triazinecarb0nitrile NH2 C|:H3 CH3 N / / O—?i CH3 KN/N / CH CH 3 3 CN Under argon, a mixture of ediate 35A (880 mg, 2.46 mmol), bis(diphenylphosphino)- 20 fil), bis(dibenzy1ideneacetone)palladium [Pd(dba)2] (135 mg, 0.148 mmol), zinc cyanide (578 mg,cene]dichloropalladium(II)-dichloromethane complex [PdC12(dppf) x DCM] (120 mg, 0.148 4.92 mmol), zinc powder (64 mg, 0.985 mmol) and zinc acetate (180 mg, 0.985 mmol) in degassed ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena _85_ DMF/water (100:1, 9.2 ml) was stirred at 160°C overnight. The reaction mixture was then combined with the reaction mixture of a 100 mg test run, and the combined mixtures were adsorbed on kieselguhr, filtered over another layer of kieselguhr and eluted with tert—butyl methyl ether. The filtrate was washed with sat. aq. sodium hydrogencarbonate solution, and the aqueous layer was re- extracted three times with tert—butyl methyl ether. The combined organic phases were dried over sodium sulfate and evaporated. ation by column chromatography on silica gel (cyclo- /ethyl acetate 1:1) afforded 453 mg (44% of th.) of the title nd.

LC—MS (method 2): R: = 1.09 min; MS (ESIpos): m/z = 304 (M+H)+ lH—NMR (400 MHz, DMSO-d6): 8 = 8.22-8.35 (m, 2H), 8.06 (s, 1H), 6.95 (s, 1H), 4.83 (s, 2H), 10 0.91 (s, 9H), 0.11 (s, 6H) ppm.

Intermediate 37A 4-Aminobromo( { [tert—butyl(dimethyl)silyl]oxy}methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazine—7—carbo- nitrile ”“2 Br ('ng CH3 N / / O—?i CH3 KN/N / CH CH 3 3 ON 15 A solution of 1,3-dibromo-5,5-dimethylhydantoin (621 mg, 2.17 mmol) in THF (20 ml) was added dropwise to a solution of Intermediate 36A (1.1 g, 3.62 mmol) in THF (80 ml) at —50°C. The resulting mixture was slowly warmed to rt, stirred for 2 h and then quenched with 10% aq. sodium lfate solution and sat. aq. sodium hydrogencarbonate solution. The aqueous phase was extracted three times with ethyl acetate. A solid itating from the ethyl acetate solution was 20 filtered off and washed with ethyl acetate, affording 508 mg (100% purity, 36% of th.) as a first crop of the title compound. The remaining filtrate was dried over sodium sulfate and evaporated. The residue was precipitated from DMSO and washed with DMSO and ethyl acetate affording further 498 mg (85% purity, 26% of th.) of the title compound.

LC—MS (method 5): R = 2.70 min; MS (ESIpos): m/z = 382/384 (M+H)+ 25 lH-NMR (400 MHz, DMSO-d5): 5 = 8.10 (s, 1H), 4.76 (s, 2H), 0.90 (s, 9H), 0.12 (s, 6H) ppm.

[Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena _86_ Intermediate 38A 4—Amino( { [tert—butyl(dimethyl)silyl] oxy} methyl)(7-methoxymethylbenzothiophen—2-yl)- pyrrolo[2,1 -f] [1 ,2,4]triazinecarbonitrile Under argon, a solution of Intermediate 37A (459 mg, 1.29 mmol) in degassed THF (14.8 ml) was added to (2'-aminobiphenylyl)(chloro)palladium—dicyclohexyl(2',4',6'-triisopropylbiphenyl—2-yl)- phosphine (1:1; 152 mg, 0.19 mmol; see S. L. ld et al., J. Am. Chem. Soc. 132 (40), 14073— 14075 (2010)) and Intermediate 6A (647 mg, 1.94 mmol). Degassed 0.5 M aq. potassium phosphate solution (5.1 ml) was added dropwise, and the resulting mixture was stirred at 60°C for 2 h. The 10 reaction mixture was then combined with the reaction mixtures of us 70 mg, 90 mg and 500 mg test runs and evaporated. Purification of the residue by column chromatography on silica gel (cyclohexane/ethyl acetate 3:1 —> 100% ethyl acetate) afforded 1.0 g (58% of th.) of the title compound.

LC—MS d 2): R = 1.49 min; MS (ESIpos): m/z = 480 (M+H)+ 15 1H-NMR (400 MHZ, DMSO-ds): 5 = 8.57-8.35 (br. s, 1H), 8.18 (s, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 6.86 (s, 1H), 6.28-6.03 (br. s, 1H), 4.74 (s, 2H), 3.95 (s, 3H), 2.44 (s, 3H), 0.83 (s, 9H), 0.00 (s, 6H) ppm.

Intermediate 39A oformyl(7-methoxymethyl-1—benzothiophen—2-yl)pyrrolo[2,1 -f] [1 ,2,4]triazine—7- 20 carbonitrile D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena ed set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena A solution of Example 68 (250 mg, 0.684 mmol) in dichloromethane (5 ml) was treated with Dess- Martin periodinane (1,1,1-triacetoxy—1,1-dihydro-1,2-benziodoxol-3(1H)-one; 377 mg, 0.889 mmol) and stirred at rt for 1 h. The reaction mixture was combined with the reaction mixture from a 50 mg test run, quenched with sat. aq. sodium hydrogencarbonate solution and sat. aq. sodium lfate solution (1 :1) and stirred at rt for 30 min. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate and evaporated. ation by column chromatography on silica gel (cyclohexane/25% ethyl acetate —> 100% ethyl acetate) afforded 102 mg (24% of th.) of the title nd. 10 LC—MS (method 2): R1 = 1.02 min; MS (ESIpos): m/z = 364 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 9.86 (s, 1H), 8.78 (br. s, 1H), 8.30 (s, 1H), 7.62 (s, 1H), 7.36 (s, 1H), 6.91 (s, 1H), 6.51 (br. s, 1H), 3.97 (s, 3H), 2.46 (s, 3H) ppm.

Intermediate 40A 4—Amino—6-(azidomethyl)(7-methoxy-5—methyl— 1 —benzothiophen—2-yl)pyrrolo[2, 1 -f] [1 ,2,4]— 15 triazinecarbonitrile [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _88_ A solution of Example 68 (100 mg, 273 umol) in dichloromethane (5 ml) was d with thionyl chloride (39 pl, 547 umol) and stirred at rt for 15 min. After evaporation, the e was dissolved in DMF (6 ml) and treated with sodium iodide (205 mg, 1.36 mmol) and sodium azide (355 mg, 5.47 . The mixture was stirred at 80°C overnight, then diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water, followed by sat. aq. sodium chloride solution, dried over sodium sulfate and evaporated affording 91 mg of the crude product which was used in the next step t further purification.

LC—MS (method 2): R = 1.13 min; MS (ESIpos): m/z = 391 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): d = 8.65—8.45 (br. s, 1H), 8.23 (s, 1H), 7.46 (s, 1H), 7.34 (s, 1H), 10 6.88 (s, 1H), 6.41-6.10 (br. s, 1H), 4.57 (s, 2H), 3.96 (s, 3H), 2.46 (s, 3H) ppm.

Intermediate 41A 5,7-Dibromo( { [tert—butyl(dimethyl)silyl]oxy}methyl)pyrrolo [2, 1 -f] [1 ,2,4]triazin—4-amine NH2 Br N/ / K /N CH / O—?i—€CH3I 3 CH3 N Br CH3 CH3 A on of Intermediate 18A (2 g, 6.21 mrnol) in DMF (20 ml) was treated with imidazole 15 (846 mg, 12.4 mmol) and tert—butyldimethylsilyl chloride (1.12 g, 7.45 mmol) and stirred at rt for 20 h. The reaction mixture was then diluted with water (200 ml) and stirred at rt for fithher 2 h. tion of the solid ed 2.46 g (88% of th.) of the title compound.

LC-MS (method 2): R = 1.37 min; MS (ESIpos): m/z = 437 (M+H)+ 1H-NMR (400 MHz, DMSO-da): 5 = 8.49—8.05 (br. s, 1H), 7.96 (s, 1H), 7.15-6.76 (br. s, 1H), 4.64 20 (s, 2H), 0.87 (s, 9H), 0.09 (s, 6H) ppm.

Intermediate 42A 2—[4—Aminobromo( { [tert—butyl(dimethyl)silyl]oxy}methyl)pyrrolo [2, 1 -f] [1 ,2,4]triazin—7—yl] - propan—2-ol D [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na _89_ CH3 Under argon, a solution of Intermediate 41A (1 g, 2.29 mmol) in THF (40 ml) was cooled to —78°C and treated with a 1.6 M solution of methyllithiurn in diethylether (1.5 ml, 2.40 mmol). After stirring for 10 min at -78°C, a 1.6 M solution of n-butyllithium in hexanes (1.58 ml, 2.52 mmol) was added, and stirring was continued for 10 min. Acetone (1.68 ml, 22.92 mmol) was added, and the resulting mixture was slowly warmed to rt and stirred at rt for 18 h. The reaction was then quenched with water, and the aqueous phase was ted twice with ethyl acetate. The combined organic phases were washed with sat. aq. sodium chloride solution, dried over magnesium sulfate and ated.

Purification by flash chromatography on silica gel (cyclohexane/ethyl acetate 2:1) afforded 306 mg 10 (30% of th.) of the title compound.

LC-MS d 4): R = 1.39 min; MS (ESIpos): m/z = 415/417 (M+H)+ 1H—NMR (400 MHz, DMSO-ds): 5 = .85 (br. s, 1H), 7.89 (s, 1H), 7.05-6.82 (br. s, 1H), 5.49 (s, 1H), 4.88 (s, 2H), 1.66 (s, 6H), 0.87 (s, 9H), 0.08 (s, 6H) ppm.

Intermediate 43A 15 2—[4-Aminobromo(hydroxymethyl)pyrrolo[2, l -f] [l ,2,4]triazin—7-yl]propan—2-ol A solution of Intermediate 42A (304 mg, 0.732 mmol) in THF (15 ml) was treated with a l M solution of tetra-n-butylammonium fluoride in THF (768 pl, 768 umol) and stirred at rt for 2 min.

The reaction mixture was diluted with itrile (20 ml), then evaporated, and the residue was 20 Died by preparative RP-HPLC (Reprosil C18, nt 10-30% acetonitrile/0.2% aq. TFA). The product thus obtained was dissolved in methanol and filtered through an anion exchange cartridge [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _90_ (Stratospheres SPE, PL-HC03 MP-resin). The cartridge was eluted with methanol, and the filtrate was ated affording 180 mg (67% of th.) of the title compound.

LC-MS (method 2): R = 0.55 min; MS (ESIpos): m/z = 301/303 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.21-7.90 (m, 1H), 7.87 (s, 1H), 7.09-6.60 (br. s, 1H), 5.90 (br. s, 1H), 5.03 (br. s, 1H), 4.63 (s, 2H), 1.66 (s, 6H) ppm. ediate 44A 4-Amino(2-hydroxypropanyl)(7-methoxymethy1benzothiophenyl)pyrrolo[2, 1 -f] - [1 ,2,4]t1iazinecarbaldehyde 10 A solution of Example 73 (135 mg, purity 89%, 302 umol) in dichloromethane (7 ml) was treated with Dess-Martin inane -triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one; 166 mg, 392 umol) and stirred at rt for 70 min. The reaction mixture was combined with the reaction mixture of a 18 mg (45 umol) test run and quenched with sat. aq. sodium hydrogencarbonate solution and sat. aq. sodium thiosulfate solution (1:1). The aqueous phase was extracted three times with 15 dichloromethane. The combined c phases were washed with sat. aq. sodium chloride solution, dried over magnesium sulfate and evaporated yielding 143 mg (purity 77%, 92% of th.) of the title compound.

LC-MS (method 2): R = 1.08 min; MS (ESIpos): m/z = 397 (M+H)+.

Intermediate 45A 20 D[tert-Butyl(dimethyl)silyl] oxy} methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazinamine [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _91_ NH? (EH3 CH3 N/ / 0—?i+CH3 K /N / CH3 CH 3 N A solution of 1.5 g (9.14 mmol) of Intermediate 8A in 15 ml dry DMF was treated with 1.65 g (10.96 mmol) tert—butyldimethylsilyl chloride and 1.24 g (18.27 mmol) imidazole and stirred at rt overnight. The reaction mixture was poured into 250 ml water and stirred for 5 min. The resulting precipitate was filtered off and dried in vacuo at 45°C. Yield: 2.28 g (90% of th.).

LC—MS (method 5): R1 = 2.12 min; MS s): m/z = 279 (M+H)+.

Intermediate 46A 6-( { [tert—Butyl(dimethyl)silyl]oxy}methyl)-7—chloropyrrolo[2, 1 -f] [1 ,2,4]triazin—4-amine NHz ('le CH3 K /N / CH CH 3 N Cl 10 A solution of 2 g (7.18 mmol) of Intermediate 45A in 20 ml THF was treated with 893 mg (6.47 mmol) rosuccinimide in 6 portions over 60 min at -10°C. Stirring was continued for 15 min at —10°C, then the mixture was allowed to warm to rt. Another 192 mg (1.44 mrnol) N—chloro- imide were added at rt, and stirring was continued overnight. About nth of the reaction mixture was evaporated to dryness, and the residue was purified by preparative RP-HPLC (Reprosil 15 C18, nt 10-95% acetonitrile/0.1% aq. formic acid) furnishing 94 mg (4% of th.) of the title compound. The major part of the reaction mixture was adsorbed on silica gel and subjected to chromatography on silica gel with isohexane/ethyl acetate 5-66% as eluent, yielding 899 mg (40% of th.) of the title compound. Total yield: 993 mg (44% of th.).

LC-MS (method 5): R1 = 2.45 min; MS (ESIpos): m/z = 313 (M+H)+ 20 1H—NMR (400 MHz, DMSO-ds): 8 = 7.69—8.04 (m, 3H), 7.0 (s, 1H), 4.70 (s, 2H), 0.88 (s, 9H), 0.08 (s, 6H) ppm.

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by na _92_ Intermediate 47A o( { [tert—butyl(dimethyl)silyl] oxy} methyl)chloropyrrolo[2, 1 -f] [1 ,2,4]triazin—4—amine ““2 Br €st CH3 K /N / CH3 H 3 N Cl A solution of 890 mg (2.85 mmol) of Intermediate 46A in 20 ml DMF was treated with 506 mg (2.85 mmol) N—bromosuccinimide in portions over 1 h at -10°C. Stirring was ued for 3 h at —10°C and then overnight at rt. Water (200 ml) was added, and the mixture was stirred for 2 h. The precipitated solid was filtered off, washed with water and dried in vacuo at 45°C. Yield: 997 mg (89% of th.).

LC—MS (method 5): R = 2.82 min; MS (ESIpos): m/z = 391/393/395 (M+H)+ 10 1H-NMR (400 MHz, DMSO-ds): 6 = 8.32 (br. s, 1H), 7.97 (s, 1H), 6.97 (br. s, 1H), 4.66 (s, 2H), 0.87 (s, 9H), 0.09 (s, 6H) ppm.

Intermediate 48A 6—( { [tert—Butyl(dimethyl)silyl]oxy}methyl)-7—chloro(7-methoxymethylbenzothiophen—2-yl)- pyrrolo[2,1-f] [1,2,4]triazin—4-amine 15 Under an argon atmosphere, a flask was d with 800 mg (2.04 mmol) of Intermediate 47A, Dmg (2.04 mmol) of Intermediate 6A, 80 mg (0.1 mmol) (2'-aminobiphenylyl)(chloro)- palladium—dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine (1:1; see S. L. Buchwald er al., [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena _93_ J. Am. Chem. Soc. 132 (40), 14073-14075 ) and 1.3 g (6.13 mmol) potassium phosphate.

Then, 30 ml of a degassed 1,4-dioxane/water mixture (5:1) were added, and the solution was stirred at 70°C for l h. Further 680 mg (2.04 mmol) of Intermediate 6A and 32 mg (0.04 mmol) (2'—amino- biphenylyl)(chloro)palladium—dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine (1:1) were added, and stirring at 70°C was continued for another 1 h. This procedure was repeated three times until the ng material was consumed (control by . With the last n of reagents, also 1.6 ml of 5 M aq. sodium ide solution were added to achieve a pH value of 8-9. At the end of the reaction period, 30 ml water and 5 M aq. formic acid were added (pH 3-4) whereupon an oil separated. A part of this oil was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% 10 acetonitrile/0.1% aq. formic acid). Two fractions of the title compound were obtained: 103 mg of a solid (89% purity by LC-MS, 9% of th.), and 23 mg of a solid (100% purity by LC-MS, 2% of th.).

The rest of the oil and the supernatant were diluted with water, adjusted to pH 8-9 with sat. aq. sodium hydrogencarbonate solution and extracted three times with dichloromethane. The combined organic phases were washed with water, dried and evaporated under reduced re, yielding 2.1 g 15 of an oil. This material was purified by column chromatography on silica gel with dichloromethane/0-5% methanol as eluent to afford further 709 mg (43% purity by LC—MS, 31% of th.) of the title nd. Total yield: 42% of th.

LC—MS (method 2): R: = 1.57 min; MS (ESIpos): m/z = 489 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 5 = 8.08 (s, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 6.88 (s, 1H), 4.66 (s, 20 2H), 3.98 (s, 3H), 2.47 (s, 3H), 0.84 (s, 9H), —0.03 (s, 6H) ppm.

Intermediate 49A 4—Aminochloro(7-methoxymethy1—1 —benzothiophen—2-yl)pyrrolo[2, l -f] [ l ,2,4]triazine—6— carbaldehyde [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena _94_ To a suspension of 166 mg (0.44 mmol) of Example 79 and molecular sieves (3A) in 3 ml dichloro- methane were added 207 mg (0.49 mmol) Dess-Martin periodinane (1,1,l-triacetoxy-l,l-dihydro- 1,2-benziodoxol-3(1H)-one) at 0-5°C. The mixture was stirred for 10 min at this temperature, then fithher 56 mg (0.13 mmol) Dess-Martin periodinane were added, and stirring was ued for 15 min at 5°C and 10 min at ambient temperature. After this, the e was adsorbed on diatomaceous earth and purified by column tography on silica gel with dichloromethane/ 0—10% ol as eluent. Yield: 100 mg of a solid (92.7% pure by LC-MS, 56% of th.).

LC-MS (method 2): R = 1.08 min; MS (ESIpos): m/z = 373 (M+H)+ 1H—NMR (400 MHz, DMSO-ds): 8 = 9.90 (s, 1H), 8.46 (br. s, 1H), 8.15 (s, 1H), 7.54 (s, 1H), 7.34 10 (s, 1H), 6.89 (s, 1H), 6.07 (br. s, 1H), 3.96 (s, 3H), 2.46 (s, 3H) ppm.

Intermediate 50A 7-Chloro(chloromethyl)(7-methoxymethylbenzothiophen—2-yl)pyrrolo[2, 1 -f] [1,2,4]- triazin—4-amine 15 The title compound was isolated as a by-product in the preparation of Example 79 (see below).

Yield: 9.2 mg (10% ofth.).

LC-MS (method 3): R. = 2.98 min; MS (ESIpos): m/z = 393/395 .

Intermediate 51A 6—( { [tert—Butyl(dimethyl)silyl] oxy}methyl)—7—methylpyrrolo [2, 1 -f] [1 ,2,4]triazin—4-amine D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na _95_ NH2 CIZH3 CH3 N/ / O—?i CH3 K ,N / C“3 CH 3 N CH 3 To a solution of 3 g (8.4 mmol) of Intermediate 35A in 60 ml 1,4-dioxane under an argon atmo- sphere were added 171 mg (0.21 mmol) of PdC12(dppf) x DCM and then dropwise over 10 min 16.8 ml of a 2 M solution of dimethylzinc in toluene (causing a rise in temperature from 22°C to 31°C). Stirring was continued first for 10 min at ambient temperature, then for 13 h at 90°C. After this, water (10 ml) was added to the reaction mixture at rt, and the suspension was stirred for l h.

The mixture was evaporated under reduced pressure, and the residue was taken up in water and ethyl acetate and stirred for another 1 h. The precipitate was d off and discarded, the phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic 10 phases were dried and evaporated affording 2.45 g (92% purity by LC-MS, 92% of th.) of the title compound.

LC-MS d 5): R = 2.18 min; MS (ESIpos): m/z = 293 (M+H)+ 1H—NMR (400 MHz, DMSO-ds): 8 = 7.98—7.78 (m, 3H), 7.04 (s, 1H), 4.68 (s, 2H), 0.89 (s, 9H), 0.09 (s, 6H) ppm. 15 Intermediate 52A (4-Aminomethylpyrrolo[2,1 -f] [1 ,2,4]triazin—6-yl)methanol NH2 OH N / / R N / N/ Method I.‘ To a solution of 100 mg (0.28 mmol) of Intermediate 35A in 2 ml 1,4-dioxane under an argon 20 atmosphere were added 6 mg (0.01 rnmol) PdC12(dppf) x DCM and then se over 10 min 0.56 ml of a 2 M solution of ylzinc in toluene. The mixture was stirred at 90°C overnight, D evaporated, and the residue was treated with acetonitrile and 5 M aq. formic acid. The pre- cipitate was d off, the filtrate was evaporated, and the residue was taken up in DMSOXaceto- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena _96_ nitrile and d by preparative C (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid). Yield: 33 mg (66% of th.). 1H-NMR (400 MHz, DMSO-ds): 8 = 7.79 (s, 1H), 7.47 (br. s, 2H), 6.80 (s, 1H), 4.84 (t, 1H), 4.49 (d, 2H), 2.36 (s, 3H) ppm.

Method 2.‘ Under an argon atmosphere, a microwave reaction vessel was charged with 750 mg (3.1 mmol) of Intermediate 34A, 515 pl (3.7 mmol) trimethylboroxine, 786 mg (3.7 mmol) potassium phosphate and 73 mg (0.09 mmol) (2'-aminobiphenylyl)(chloro)palladium-dicyclohexyl(2',4',6'-triisopropyl- biphenylyl)phosphine (1:1; see S. L. Buchwald et al., J. Am. Chem. Soc. 132 (40), 14075 10 (2010)). Then, 13 ml of a degassed 1,4—dioxane/water mixture (5:1) were added, the vessel was sealed, and the mixture was heated to 140°C for 20 min in the microwave (4 bar, 50 watt). Further 50 mg (2'-aminobiphenylyl)(chloro)palladium—dicyclohexyl(2',4',6'-triisopropylbiphenylyl)- phosphine (1:1) were added, and the mixture was heated again to 140°C for 20 min in the microwave. Another portion of 515 pl hylboroxine was added, and the vessel was heated again 15 to 140°C for 20 min. The latter procedure was repeated two more times with heating s of 30 min each until LC-MS showed only minor amounts of starting material left. The mixture was filtered over guhr, washed with 1,4-dioxane, and the combined filtrates were evaporated to dryness.

This e was combined with a previous 100 mg test run and purified by preparative RP—HPLC (XBridge C18, gradient 5-42% acetonitrile/0.05% aq. ammonium hydroxide solution). Yield: 238 20 mg (38% ofth.).

LC-MS (method 5): R = 0.51 min; MS (ESIneg): m/z = 177 (M-H)’ lH—NMR (400 MHz, DMSO-ds): 5 = 7.79 (s, 1H), 7.48 (br. s, 2H), 6.80 (s, 1H), 4.84 (t, 1H), 4.49 (d, 2H), 2.36 (s, 3H) ppm.

Intermediate 53A 25 nobromomethylpyrrolo [2, 1 -f] [l ,2,4]triazin—6-yl)methanol NH2 Br OH N/ / K N / N/ D CH3 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena _97_ A solution of 245 mg (1.38 mmol) of Intermediate 52A in 8.8 ml DMF was treated with 288 mg (1.62 mmol) osuccinimide in portions over 2 h at -10°C. Stirring was continued at —10°C for 30 min and then for 2 h at ambient temperature. The mixture was poured into 50 ml water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The residue was flash-chromatographed on silica gel with dichloromethane/0-15% methanol as eluent. Yield: 148 mg (42% of th.).

LC—MS (method 4): R. = 0.42 min; MS (ESIpos): m/z = 257/259 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 7.85 (s, 1H), 6.14-8.22 (broad, 2H), 4.88 (t, 1H), 4.45 (d, 2H), 2.43 (s, 3H) ppm. 10 Intermediate 54A 4-Amino(7-methoxy—5-methylbenzothiophen—2-yl)methylpyrrolo[2, 1 -f] [1 ,2,4]triazine—6- carbaldehyde To a suspension of 175 mg (0.49 mmol) of Example 75 and molecular sieves (3A) in 3.5 m1 15 dichloromethane were added 230 mg (0.54 mmol) Dess-Martin inane (1,1,1—triacetoxy—1,1- dihydro-l,2-benziodoxol-3(1H)-one) at 0—5°C. The e was d for 5 min at this temperature, followed by 30 min at rt. After this, the mixture was adsorbed on diatomaceous earth and purified by flash-chromatography on silica gel with isohexane/10-100% ethyl acetate as . Yield: 139 mg of a solid (79% of th.). 20 LC—MS (method 5): R. = 2.34 min; MS (ESIpos): m/z = 353 (M+H)+ fivMR (400 MHz, DMSO-ds): 8 = 9.93 (s, 1H), 8.06 (s, 1H), 7.50 (s, 1H), 7.33 (s, 1H), 6.88 (s, 3.96 (s, 3H), 2.71 , (s, 3H), 2.46 (s, 3H) ppm.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena _98_ ediate 55A tert—Butyl 4-[(4-arninomethylpyrrolo[2, 1 —f] [1 ,2,4]triazin—7-yl)methyl]piperazinecarboxylate A solution of ylpyrrolo[2,1-fj[1,2,4]triazin—4-arnine (500 mg, 3.3 mmol; ation described in PCT Int. Pat. Appl. WO 2007/056170) in acetic acid (8 ml) was treated with 37% aq. formaldehyde solution (328 pl, 4.04 rnrnol) and tert—butyl piperazine-l-carboxylate (754 mg, 4.04 mmol). The mixture was stirred at 60°C overnight. After evaporation, the residue was taken up in ethyl acetate and washed with sat. aq. sodium hydrogencarbonate solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate 10 and evaporated affording 1.2 g of the crude product which was used in the next step without fiirther ation.

LC—MS (method 2): R. = 0.56 min; MS (ESIpos): m/z = 347 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 7.79 (s, 1H), 7.51 (br. s, 2H), 6.67 (s, 1H), 3.76 (br. s, 2H), 3.29—3.17 (m, 4H), 2.36-2.29 (m, 4H), 2.22 (s, 3H), 1.37 (s, 9H) ppm. 15 Intermediate 56A utyl 4- [(4-arninobromomethylpyrrolo [2, 1 -f] [1 ,2,4]triazin—7-yl)methyl]piperazine— 1 — carboxylate [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena _99_ NH2 Br N / / kw / CH3 N/\\N o \\/ \/( CH3 0new.

CH3 A solution of Intermediate 55A (1.17 g, 3.37 mmol) in THF (20 ml) was cooled to -60°C and treated with 1,3-dibromo-5,5-dimethylhydantoin (5.78 mg, 2.02 mmol). The mixture was stirred for 4 h at —60°C to -20°C. After this, the reaction mixture was quenched with 10% aq. sodium thiosulfate solution. Most of the THF solvent was evaporated whereupon a solid precipitated. Filtration and recrystallization from acetone afforded 862 mg (59% of th.) of the title compound.

LC—MS (method 2): R. = 0.66 min; MS (ESIpos): m/z = 425/427 (M+H)+ lH-NMR (400 MHz, DMSO-ds): 5 = 8.29—7.62 (br. s, 1H), 7.85 (s, 1H), .44 (br. s, 1H), 3.80 (s, 2H), .22 (m, 4H), 2.37-2.27 (m, 4H), 2.16 (s, 3H), 1.37 (s, 9H) ppm. 10 Intermediate 57A tert—Butyl 4- {[4-amino(7-methoxymethyl—1 -benzothiophen—2-yl)methylpyrrolo [2, 1 —f] [1 ,2,4] - triazin—7-yl]methyl }piperazinecarboxylate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —100— A solution of Intermediate 56A (100 mg, 235 umol) in degassed 1,4-dioxane (3 ml) was treated with Intermediate 6A (93 mg, 282 umol), dicyclohexyl(2',6'-dimethoxybiphenylyl)phosphine (S—Phos; 9.6 mg, 23 umol) and palladium diacetate (2.6 mg, 11 umol). Degassed 3 M aq. potassium phosphate solution (588 ul) was added, and the resulting mixture was stirred at 60°C for 1 h. A further portion of Intermediate 6A (78 mg, 235 umol) was added, and stirring at 60°C was continued overnight. The reaction mixture was quenched with 2 M aq. sodium hydroxide solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with sat. aq. sodium chloride solution, dried over ium sulfate and evaporated. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate 3:2) afforded 82 mg (62% of th.) of the title 10 nd.

LC-MS (method 2): R = 0.97 min; MS (ESIpos): m/z = 523 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 7.94 (s, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 3.95 (s, 3H), 3.84 (s, 2H), 3.30-3.23 (m, 4H, p with water peak), 2.45 (s, 3H), 2.42-2.33 (m, 4H), 2.19 (s, 3H), 1.39 (s, 9H) ppm. 15 Intermediate 58A tert—Butyl 4-[(4-aminochloropyrrolo[2,1—f][1,2,4]triazin—7-yl)methyl]piperazine—1—carboxylate Following the procedure of ediate 55A, 4 g (23.7 mmol) 6-chloropyrrolo[2,1—f][1,2,4]triazin— 4-amine (preparation described in PCT Int. Pat. Appl. WO 2007/064883) were reacted to give 11.2 20 g of the title compound as crude material which was used in the next step without further ation.

LC—MS (method 5): R = 0.74 min; MS (ESIpos): m/z = 367 (M+H)+ fimple of 67 mg of the corresponding formiate salt, tert—butyl aminochloropyrrolo[2,1—f]—4]triazinyl)methyl]piperazinecarboxylate formiate, was isolated after preparative RP- [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —101— HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) of 100 mg of the crude material obtained above. 1H-NMR (400 MHz, DMSO-ds): inter al. 8 = 8.14 (s, 1H), 7.91 (s, 1H), 7.83 (br. s, 2H), 6.95 (s, 1H), 3.80 (s, 2H), 3.17 (s, 2H), 2.38 (br. s, 4H), 1.37 (s, 9H) ppm.

Intermediate 59A utyl 4- [(4-aminobromochloropyrrolo[2, 1 —f] [1 riazin—7-yl)methyl]piperazine— 1 — ylate NH2 Br N/ / K Cl N / N/ Following the procedure of Intermediate 56A, 11 g (30 mmol) of Intermediate 58A were reacted to 10 give 1.17 g (9% of th.) of the title nd after flash-chromatography on silica gel (dichloro- methane/methanol 10:1) and subsequent ative RP-HPLC (Daiso C18, gradient 40—65% aceto- nitrile/water).

LC-MS (method 2): R = 0.74 min; MS (ESIpos): m/z = 445/447/449 (M+H)+ 1H—NMR (400 MHz, DMSO-ds): inter al. 8 = 7.96 (s, 1H), 3.84 (s, 2H), 2.37 (br. s, 4H), 1.37 (s, 15 9H) ppm.

Intermediate 60A tert—Butyl 4- {[4-aminochloro(7-methoxy—5—methylbenzothiophen—2-yl)pyrrolo[2, l —f] [l ,2,4] - triazin—7-yl]methyl }piperazinecarboxylate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] na Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena —102— Under an argon atmosphere, a flask was charged with 140 mg (0.31 mmol) of Intermediate 59A, 102 mg (0.46 mmol) of Intermediate 5A, 16 mg (0.02 mmol) PdC12(dppf) X DCM and 122 mg (1.15 mmol) sodium carbonate. After addition of 3 ml degassed l,2-dimethoxyethane/water (3:1), the suspension was stirred at 60°C for 2.5 h. Further portions of Intermediate 5A (50 mg, 0.23 mmol) and PdC12(dppf) X DCM (8 mg, 0.01 mmol) were added, and stirring was continued at 40°C for 2.5 h. The latter procedure was repeated once more until the starting material was consumed. Then, the reaction e was partially evaporated under reduced re, water was added, and the mixture was extracted with dichloromethane. The combined organic phases were washed with water 10 and sat. aq. sodium chloride solution, dried and evaporated under reduced pressure. The residue (322 mg) was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.l% aq. formic acid) to give 49 mg of a mixture of the title compound and the Boc-deprotected derivative, 6- chloro(7-methoxymethylbenzothiophen—2-yl)(piperazin— l -ylmethyl)pyrrolo [2, 1 — f][1,2,4]triazin—4-amine. This mixture was used as such in the next reaction step (see e 85). 15 LC-MS (method 2): R = 1.00 min; MS (ESIpos): m/z = 543 (M+H)+, and R = 0.81 min; MS (ESI- pos): m/z = 443 .

Intermediate 61A 4- {[4-Amino(methoxymethyl)pyrrolo[2,1-f] [l ,2,4]triazin—7-yl]methyl}piperazin—2-one D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena —103— NH2 N / / O—CH3 KN» / A solution of Intermediate 10A (5 g, 28.1 mmol) and piperazin-Z-one (3.09 g, 30.9 mmol) in acetic acid (85 ml) was treated with 37% aq. formaldehyde solution (3.15 ml, 42.1 mmol) and d at 60°C for 16 h. The les were evaporated under reduced pressure, and the residue was dissolved in methanol and adsorbed on diatomaceous earth. Purification by column chromatography on silica gel (5-10% methanol/dichloromethane) afforded 3.91 g (46% of th.) of the title compound.

LC-MS (method 3): R = 1.68 min; MS (ESIpos): m/z = 291 (M+H)+.

Intermediate 62A 4- {[4-Aminobromo(methoxymethyl)pyrrolo[2,1-f] [1 ,2,4]triazinyl]methyl}piperazin-Z-one NH2 Br N / / ()_CH3 KN» / 10 A solution of Intermediate 61A (3.9 g, 13.4 mmol) in DMF (50 ml) was cooled to 0°C and d with a solution of N—bromosuccinimide (2.63 g, 14.8 mmol) in DMF (6 ml). The mixture was stirred at 0°C for 1 h. Then, the solvent was evaporated, and the residue was dissolved in methanol and ed on aceous earth. Purification by column chromatography on silica gel (5-10% 15 methanol/dichloromethane) afforded 1.99 g (39% of th.) of the title compound.

LC—MS (method 3): R. = 1.86 min; MS (ESIpos): m/z = 369/371 (M+H)+ D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —104— 1H-NMR (400 MHZ, DMSO-ds): 8 = 7.96-8.23 (br. s, 1H), 7.90 (s, 1H), 7.71 (s, 1H), .98 (br. s, 1H), 4.45 (s, 2H), 3.91 (s, 2H), 3.27 (s, 3H), 3.07 (br. s, 2H), 2.96 (s, 2H), 2.56 (br. s, 2H) Intermediate 63A 7—(Chloromethyl)(ethoxymethyl)(7-methoxymethylbenzothiophen—2-yl)pyrrolo[2, l -f] - [1 ,2,4]triazin—4-amine hydrochloride A suspension of Example 86 (1 g, 2.51 mmol) in toluene (60 ml) was treated dropwise with l chloride (1.83 ml, 25.1 mmol), and the mixture was stirred at rt overnight. The volatiles were evapo- 10 rated under d pressure. The residue was co-evaporated with toluene under d pressure for three times affording 0.85 g (74% of th.) of the title compound which was ately used for the next step without further purification.

Intermediate 64A 4-Amino(ethoxymethyl)(7-methoxymethylbenzothiophenyl)pyrrolo [2, 1 -f] [1 ,2,4]- 15 triazinecarboxylic acid [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —105— A suspension of Intermediate 17A (5 g, 12.6 mmol) in THF/water (10:1, 220 ml) was treated with a 2 M solution of 2-methylbutene in THF (31.5 ml, 63.1 mmol) and with sodium dihydrogen— phosphate (6.96 g, 50.4 mmol). The e was stirred at rt for 5 min. Then, sodium chlorite (4.56 g, 50.44 mmol) was added, and the resulting mixture was stirred at rt for 20 h. The suspension was filtered, and the resulting solid was washed with water affording 4.24 g (74% of th.) of the title compound which was used in the next step without further purification.

LC-MS (method 4): R = 1.06 min; MS (ESIpos): m/z = 413 (M+H)+ 1H—NMR (400 MHz, DMSO-da): 5 = 13.22 (br. s, 1H), 8.53-8.00 (br. s, 1H), 8.14 (s, 1H), 7.41 (s, 10 1H), 7.33 (s, 1H), 6.86 (s, 1H), 6.28-5.65 (br. s, 1H), 4.61 (s, 2H), 3.96 (s, 3H), 3.36 (q, 2H), 2.46 (s, 3H), 1.01 (t, 3H) ppm.

Intermediate 65A 5,7—Dimethoxy- l -benzothiophene 15 To a solution of othiophene-5,7-diol (1.16 g, 6.98 mmol) in acetone (20 ml) under argon were added ium carbonate (2.89 g, 20.9 mmol) and iodomethane (912 pl, 14.6 mmol). The resulting mixture was d under reflux for 18 h. After cooling to rt, the mixture was treated with a 7 M Dtion of ammonia in methanol (10 ml) for 30 min and then adsorbed on silica gel. Purification by [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena —106— column chromatography over silica gel (cyclohexane/ethyl acetate 40:1) afforded 0.52 g (32% of th.) of the title compound.

LC-MS (method 4): R1 = 1.02 min; MS (ESIpos): m/z = 195 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 7.69 (d, 1H), 7.35 (d, 1H), 7.02 (d, 1H), 6.57 (d, 1H), 3.92 (s, 3H), 3.81 (s, 3H) ppm.

Intermediate 66A (5,7-Dimethoxybenzothiophenyl)boronic acid HO O\ \ CH B / 3 / HO 8 0\ CH3 Under an argon here, a 1.6 M solution of n—butyllithium in hexane (1.84 ml, 2.95 mmol) was 10 added dropwise to a on of Intermediate 65A (520 mg, 2.68 mmol) in dry THF (5 ml) at -70°C.

After 1 h at -70°C, triisopropyl borate (742 pl, 3.21 mmol) was added, and the mixture was stirred for 16 h while slowly warming up to rt. Dichloromethane and sat. aq. ammonium chloride solution were added, and the pH value was adjusted to 6 by addition of 1 M hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The ed 15 organic phases were dried with magnesium sulfate, d and evaporated. The resulting residue was purified by column chromatography over silica gel (at first eluting with dichloro- methane/methanol 40:1, then ol, finally methanol/4 M hydrogen chloride in 1,4-dioxane 10:1) yielding 631 mg (71% purity, 71% of th.) of the title compound.

LC—MS (method 4): R: = 0.83 min; MS (ESIpos): m/z = 239 (M+H)+. 20 Intermediate 67A 4-Amino(chloromethyl)pyrrolo[2,1 -f] [1 ,2,4]triazinecarbaldehyde D [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena —107— Intermediate 67A was isolated as a side-product of the synthesis of Intermediate 11A after column tography on silica gel (dichloromethane/acetone 8:2 —) 7:3).

LC—MS (method 2): R = 0.6 min; MS (ESIpos): m/z = 211/213 (M+H)+.

Intermediate 68A 4-Amino [(3 -oxopiperazin—1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazinecarbaldehyde A solution of Intermediate 67A (11.03 g, 52.4 mmol) and iperazine (6.82 g, 68.1 nnnol) in 331 ml DMF was treated at rt with DIPEA (13.7 ml, 78.6 mmol) and stirred ovemight. The 10 precipitate was filtered off, washed with DMF and diethylether and then dried in vacuo to yield 11.64 g of the title compound (89% purity, 72% of th.).

LC-MS d 7): R = 1.30 min; MS (ESIpos): m/z = 275 (M+H)+.

Intermediate 69A 4- {[4-Amino(hydroxymethyl)pyrrolo[2,1-f] [1 ,2,4]triazin—6-yl]methyl}piperazin—2-one [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena —108— H N NH2 <foN N/ / h N N/ OH To a solution of Intermediate 68A (10.17 g, 89% purity, 33.01 mmol) in 1 M hydrochloric acid (370 ml) and methanol (370 ml) at rt was added zinc dust (12.1 g, 185 mmol), and the mixture was stirred at rt for 18 h. Silica gel (100 g) was added, and the volatiles were ated under reduced pressure. The residue was suspended in methanol, the volatiles were evaporated under reduced pressure again, and the residue was dried in vacuo. The solid was subjected to column chromato- graphy on silica gel (gradient dichloromethane/7 M ammonia in methanol 10:1 —> 3:1) to yield 6.39 g of the title compound (60% of th.).

LC—MS d 8): R1 = 1.12 min; MS (ESIpos): m/z = 277 (M+H)+ 10 1H-NMR (400 MHz, DMSO-ds): 6 = 7.83 (s, 1H), 7.76 (br. s, 1H), 7.64 (br. s, 2H), 6.83 (s, 1H), 5.01 (br. s, 1H), 4.74 (s, 2H), 3.64 (br. s, 2H), 3.14 (br. s, 2H), 2.95 (br. s, 2H), 2.58 (br. s, 2H) ediate 70A 4- { [4-Aminobromo(hydroxymethyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin—6-yl]methyl}piperazinone 15 trifluoroacetate H N NH2 Br < _)=O N N / / KN/N x CF3COOH OH A suspension of Intermediate 69A (1 g) in methanol/water (10:1, 33 ml) was treated with trifluoro- acetic acid (0.56 ml, 7.24 mmol) to result in a clear solution. A solution of N—bromosuccinimide (708 mg, 3.98 mmol) in methanol (30 ml) was added se at 0°C, and the mixture was stirred at 20 Dfor 1 h. The formed precipitate was filtered off and dried in vacuo to yield 700 mg of the title compound (41% of th.).

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena —109— LC-MS d 7): R = 1.38 min; MS (ESIpos): m/z = 355/357 (M+H)+ 1H-NMR (400 MHZ, D20): 8 = 7.90 (s, 1H), 5.00 (s, 2H), 4.44 (s, 2H), 3.85 (s, 2H), 3.58 (br. t, 2H), 3.50 (br. t, 2H) ppm. 5 Preparation es: Example 1 4- {[4-Amino(methoxymethyl)-5—(7—methoxy—5—methyl- l -benzothiophenyl)pyrrolo[2,1 —f]— [l ,2,4]triazin—7-yl]methyl}piperazin—2-one 10 Method 1 .' A solution of Intermediate 13A (3 g, 7.84 mmol) in methanol (87 ml) was treated with acetic acid (0.898 ml, 15.68 mmol), 2-oxopiperazine (1.17 g, 11.76 mmol) and sodium triacetoxyborohydride (4.98 g, 23.53 mmol). The mixture was d at It for 4.5 h. Further portions of 2—oxopiperazine (392 mg, 3.9 mmol) and sodium triacetoxyborohydride (3.3 g, 15.68 mmol) were added, and the 15 resulting mixture was stirred at 60°C overnight. After evaporation, the e was taken up in sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The combined c phases were dried over sodium sulfate and evaporated, and the residue was purified by column chromatography on silica gel (dichloromethane/methanol 40:1 —> 10:1). The product thus obtained 20 fianolictriturated in methanol and filtered off affording 540 mg (14% of th.) of the title compound. Themother liquor was evaporated and the residue purified by two-fold RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.l% aq. formic acid). The fractions containing pure product [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —110— were ed and neutralized with sat. aq. sodium hydrogencarbonate solution. The acetonitrile solvent was evaporated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated affording 395 mg (13% of th.) as a second batch of the title compound. 5 Method 2.‘ A solution of Intermediate 21A (291 mg, 0.82 mmol) in acetic acid (2.9 ml) was treated with 37% aq. formaldehyde on (104 pl, 1.39 mmol) and 2—oxopiperazine (139 mg, 1.39 mmol). The mix— ture was stirred at 60°C for 3 h and then evaporated. Purification by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. formic acid) afforded 184 mg (44% of th.) of 10 the title compound.

LC-MS (method 4): R = 0.77 min; MS (ESIpos): m/z = 467 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.00 (s, 1H), 7.73 (br. s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 4.41 (s, 2H), 3.97 (s, 2H), 3.96 (s, 3H), 3.20 (s, 3H), 3.15-3.08 (br. s, 2H), 3.01 (s, 2H), 2.64 (br. t, 2H), 2.45 (s, 3H) ppm. 15 Example 2 4— { [4-Amino(methoxymethyl)(7-methoxy—5-methylbenzothiophen—2-yl)pyrrolo [2, l —f] — [1 ,2,4]triazin—7-yl]methyl}piperazin—2-one ochloride fiution of Example 1 (100 mg, 214 umol) in 1,4—dioxane (2 ml) was treated with a 4 M solution 20 drogen de in 1,4-dioxane (2 ml, 8 mmol). The t was evaporated g 130 mg (quant) of the title compound.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —111— LC-MS (method 2): R = 0.79 min; MS (ESIpos): m/z = 467 (M+H)+ 1H-NMR (400 MHz, DMSO-da): 8 = 8.39 (br. s, 1H), 8.31-8.53 (br. s, 1H), 8.17 (s, 1H), 7.38 (s, 1H), 7.34 (s, 1H), 6.87 (s, 1H), 6.21-6.42 (br. s, 1H), 4.81 (br. s, 2H), 4.52 (br. s, 2H), 3.96 (s, 3H), 3.57 (s, 2H), .72 (m, 4H), 3.26 (s, 3H), 2.46 (s, 3H) ppm. 5 Example 3 (3R)—3 —( { [4-Amino(methoxymethyl)(7—methoxy—5-methylbenzothiophen—2-yl)pyrrolo[2, l —f] — [1 ,2,4] triazinyl]methyl} amino)pyrrolidinone ochloride NH A solution of Intermediate 13A (520 mg, 1.36 mmol) in methanol (15 ml) and acetic acid (156 pl, 10 27 mmol) was treated with (R)arninopyrrolidin—2-one (503 mg, 5.0 mmol) and triacetoxyboro- hydride (1.06 g, 5.0 mmol). The mixture was stirred at rt overnight and then ated. Purification by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.l% aq. formic acid) and lyophilization of the product thus obtained from a 4 M on of hydrogen de in 1,4—dioxane afforded 272 mg (36% of th.) of the title compound. 15 LC-MS (method 2): R. = 0.70 min; MS (ESIpos): m/z = 467 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): d = 9.62 (br. s, 1H), 9.46 (br. s, 1H), 8.56-8.22 (br. s, 1H), 8.44 (s, 1H), 8.19 (s, 1H), 7.38 (s, 1H), 7.34 (s, 1H), 6.87 (s, 1H), 6.54-6.12 (br. s, 1H), 4.89—4.65 (m, 2H), 4.58-4.46 (m, 2H), .07 (br. s, 1H, overlap With water peak), 3.96 (s, 3H), 3.36—3.16 (m, a 3.25 (s, 3H), 2.48-2.39 (m, 1H), 2.46 (s, 3H), 2.23-2.06 (m, 1H) ppm.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena e 4 (3R)-3 -( { [4-Arnino(methoxymethyl)-5—(7—methoxymethylbenzothiophen—2-yl)pyrrolo[2, 1 -f] - [1 ,2,4]triazin—7-y1]methy1} amino)pyrrolidin—2—one NH A solution of Intermediate 13A (2.0 g, 5.2 mmol) in methanol (58 ml) and acetic acid (0.6 ml) was treated with (R)aminopyrrolidin—2—one (785 mg, 7.8 mrnol) and triacetoxyborohydride (3.32 g, 15.6 mmol). The mixture was stirred at rt overnight. After this, the reaction mixture was diluted with sat. aq. sodium hydrogencarbonate solution and ted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. The residue was purified 10 by two-fold column chromatography on silica gel (dichloromethane/methanol 40:1 to 10:1) to afford 957 mg (37% of th.) of the title compound.

LC—MS (method 4): R: 0.72 min; MS (ESIpos): m/z = 467 (M+H)+ lH—NMR (400 MHz, DMSO-ds): 5 = 8.01 (s, 1H), 7.75 (s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 4.46-4.34 (m, 2H), 4.24—4.02 (m, 2H), 3.96 (s, 3H), .04 (m, 3H), 3.21 (s, 3H), 2.45 (s, 15 3H), 2.40—2.27 (m, 1H), 1.80-1.65 (m, 1H) ppm.

Example 5 4— { [4-Amino(ethoxymethyl)(7-methoxy—5—methylbenzothiophen—2-y1)pyrrolo [2, 1 —f] [1 ,2,4] - triazin—7-yl]methyl}piperazin—Z-one D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —113— Method 1: A solution of Intermediate 17A (2 g, 5.05 mmol) in THF (100 ml) was d at 0°C with 2—oxopiperazine (1.01 g, 10.1 mmol), sodium triacetoxyborohydride (1.07 g, 5.04 mmol) and acetic acid (0.29 ml, 5.04 mmol). The resulting mixture was stirred at 0°C for 30 min. Four additional portions of sodium triacetoxyborohydride (1.07 g, 5.04 mmol) and of acetic acid (0.29 ml, 5.04 mmol) were added every 30 s, and the ing mixture was d for further 30 min at 0°C, then for 25 min at 35°C and finally at rt overnight. The on was quenched with 10% aq. sodium chloride solution and extracted twice with ethyl acetate. The combined organic layers were 10 evaporated. The residue was purified by column chromatography over silica gel (dichloromethane/ methanol 95:5 —> 90:10) affording 360 mg (17% of th.) of the compound described in Example 86 (see below) and 1.82 g of the title compound in separate fractions. The title product thus obtained was suspended in ethanol (20 ml), refluxed for 2 h and then cooled to 15°C. The solid was filtered off and washed with ethanol affording 1.63 g (67% of th.) of the pure title compound. 15 Method 2: A solution of Example 13 (930 mg, 1.9 mmol) in dichloromethane (18 ml) was d with thionyl chloride (210 pl, 2.8 mmol) and stirred at rt for 15 min. After evaporation, the residue was dissolved in ethanol (18 ml) and treated with DIPEA (670 ul, 3.8 mmol). The mixture was stirred at 70°C for 2 h and then evaporated. The residue was purified by column chromatography on silica gel 20 oromethane/methanol 98:2 —> 90:10). The product thus obtained was triturated in an aceto- nitrile/diethylether mixture and filtered. The filtrate was evaporated, and the residue was re—purified Dolumn chromatography on silica gel (dichloromethane/methanol 98:2 —> . Again, the product thus obtained was ated in acetonitrile/diethylether and filtered. This procedure was [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —114— repeated one more time. The three batches of solids obtained in this way were combined, triturated in acetonitrile/diethylether once again and finally filtered off affording 600 mg (62% of th.) of the title compound.

Method 3.‘ A solution of ediate 22A (720 mg, purity 89%, 1.74 mmol) in acetic acid (10 ml) was stirred with piperazin—2-one (261 mg, 2.61 mmol) at 60°C. To this, 37% aq. formaldehyde solution (260 pl, 3.48 mmol) was added in three portions after 0, 3 and 12 h, respectively, and the mixture was stirred at 60°C for a total of 24 h. Then, the volatiles were removed under reduced pressure, and the e was partitioned n ethyl acetate and sat. aq. sodium hydrogencarbonate solution. The organic 10 phase was washed with sat. aq. sodium de solution, dried with magnesium sulfate and evaporated. The residue was dissolved in a mixture of methanol and dichloromethane, adsorbed on diatomaceous earth, dried in vacuo and purified by flash-chromatography on silica gel (gradient 0-6% methanol/dichloromethane). The product ons were combined, evaporated and re-purified by preparative RP-HPLC (Reprosil C18, nt 30-50% acetonitrile/0.2% aq. TFA). The product 15 fractions were combined again, diluted with sat. aq. sodium hydrogencarbonate solution and ted with ethyl acetate. The organic phase was washed with sat. aq. sodium chloride solution, dried with magnesium sulfate and evaporated yielding 281 mg (31% of th.) of the title compound.

LC—MS (method 2): R. = 0.86 min; MS (ESIpos): m/z = 481 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.01 (s, 1H), 7.8-8.05 (br. s, 1H), 7.74 (br. s, 1H), 7.38 (s, 20 1H), 7.31 (s, 1H), 6.85 (s, 1H), 5.6-5.9 (br. s, 1H), 4.45 (s, 2H), 3.97 (s, 2H), 3.94 (s, 3H), 3.41 (q, 2H), 3.09-3.13 (m, 2H), 3.02 (s, 2H), 2.63—2.69 (br. s, 2H), 2.45 (s, 3H), 1.07 (t, 3H) ppm.

Example 6 4- {[4-Amino(ethoxymethyl)(7-methoxymethylbenzothiophenyl)pyrrolo[2,1-f][1 ,2,4] - n—7-yl]methyl}piperazin—2-one dihydrochloride [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena —115— A solution of ediate 17A (60 mg, purity 69%, 104 umol) in methanol (6 ml) was treated with iperazine (22 mg, 209 umol), sodium orohydride (33 mg, 522 mmol) and acetic acid (12 ul, 209 umol). The mixture was stirred at 60°C for 16 h and then filtered. The filtrate and the residue were purified separately by preparative RP-HPLC (Reprosil C18, gradient 40—60% aceto- nitrile/0.2% aq. TFA). The product fractions were combined, diluted with 1 M hydrochloric acid (3 ml) and evaporated to dryness yielding 46 mg (79% of th.) of the title compound.

LC-MS (method 2): R = 0.87 min; MS (ESIpos): m/z = 481 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.37 (br. s, 1H), 8.31 (br. s, 1H), 8.14 (s, 1H), 7.38 (s, 1H), 10 7.33 (s, 1H), 6.87 (s, 1H), 6.13 (br. s, 1H), 4.80 (br. s, 2H), 4.52 (s, 2H), 3.96 (s, 3H), 3.86 (br. s, 2H), 3.36-3.51 (m, 5H), 2.46 (s, 3H), 1.11 (t, 3H) ppm.

Example 7 (3R)-3 -( {[4-Amino(ethoxymethyl)(7-meth0xymethy1benzothiophenyl)pyrrolo[2, 1 -f] - [1 ,2,4]triazin—7-yl]methyl} amino)pyrrolidin—2—one dihydrochloride [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —116— NH A solution of Intermediate 17A (60 mg, purity 69%, 104 umol) in ol (3 ml) was treated with (R)aminopyrrolidin—2-one (22 mg, 209 umol), sodium cyanoborohydride (33 mg, 522 umol) and acetic acid (12 pl, 209 umol). The mixture was stirred at 60°C for 4 h and then filtered. The filtrate was purified by ative C (Reprosil C18, gradient 40-60% acetonitrile/ 0.2% aq. TFA).

The product fractions were combined, diluted with 1 M hydrochloric acid and evaporated to s yielding 46 mg (79% of th.) of the title nd.

LC-MS (method 4): R = 0.74 min; MS (ESIpos): m/z = 481 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 9.58-9.75 (m, 1H), 9.33-9.54 (m, 1H), 8.44 (s, 1H), 8.27-8.71 10 (br. s, 1H), 8.19 (s, 1H), 7.38 (s, 1H), 7.34 (s, 1H), 6.87 (s, 1H), 6.18-6.48 (br. s, 1H), 4.68-4.87 (m, 2H), 4.49-4.62 (q, 2H), 3.96 (s, 3H), 3.45 (q, 2H), 3.18-3.35 (m, 2H), 2.46 (s, 4H), 2.08-2.22 (m, 1H), 1.10 (t, 3H) ppm.

Example 8 (3R)-3 -( { [4-Amino(ethoxymethyl)-5—(7—methoxymethylbenzothiophen—2-yl)pyrrolo[2, 1 -fl - 15 [1 ,2,4]triazin—7-yl]methyl} amino)pyrrolidin—2—one [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —ll7— NH A solution of Intermediate 17A (226 mg, purity 75%, 428 umol) in methanol (4 ml) was treated with aminopyrrolidin—2-one (85 mg, 855 umol), sodium cyanoborohydride (134 mg, 2.14 mmol) and acetic acid (49 pl, 855 umol). The mixture was stirred at rt for 1.5 h. After this, the mixture was directly separated by preparative RP-HPLC (Reprosil C18, gradient 40-60% acetonitrile/0.2% aq.

TFA). The product fractions were combined, diluted with sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The combined organic phases were washed with sat. aq. sodium chloride solution, dried over magnesium sulfate and evaporated to s yielding 180 mg (88% of th.) of the title compound. 10 LC-MS (method 4): R = 0.74 min; MS (ESIpos): m/z = 481 (M+H)+ 1H—NMR (400 MHz, s): 8 = 8.00 (s, 1H), 7.76 (s, 1H), 1 (br. s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 5.6-5.9 (br. s, 1H), 4.39-4.49 (m, 2H), 4.04-4.23 (m, 2H), 3.96 (s, 3H), 3.41 (q, 2H), 3.05-3.23 (m, 3H), 2.45 (s, 3H), 2.31—2.40 (m, 1H), 1.68-1.79 (m, 1H), 1.08 (t, 3H) ppm. 15 Example 9 N2- { [4-Amino(ethoxymethyl)(7-methoxy—5-methylbenzothiophen—2-yl)pyrrolo [2, l -f] — [1 ,2,4]triazin—7-yl]methyl} amide dihydrochloride D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —118— NH2 A solution of Intermediate 17A (60 mg, purity 69%, 104 umol) in ol (3 ml) was treated with glycinamide hloride (23 mg, 209 umol), sodium cyanoborohydride (32 mg, 522 mmol) and acetic acid (12 pl, 209 umol). The e was stirred at 60°C for 16 h. After filtration, the e 5 was separated by preparative RP-HPLC (Reprosil C18, nt 20-40% acetonitrile/O.2% aq.

TFA). The product fractions were combined, d with 1 M hydrochloric acid, evaporated to dryness and combined with the residue from the filtration step. This material was re-purified by two- fold preparative RP-HPLC (Reprosil C18, gradient 20-40% acetonitrile/0.2% aq. TFA). The pro- duct fractions were combined again, diluted with 1 M hydrochloric acid and evaporated to dryness 10 yielding 7.4 mg (13% of th.) of the title compound.

LC-MS (method 2): R = 0.80 min; MS (ESIpos): m/z = 455 (M+H)+ 1H—NMR (500 MHz, DMSO-da): 8 = 9.33 (br. s, 2H), 9.05 (br. s, 1H), 8.31 (s, 1H), 7.93 (br. s, 1H), 7.58 (br. s, 1H), 7.40 (s, 1H), 7.35 (s, 1H), 7.05 (br. s, 1H), 6.88 (s, 1H), 4.65 (br. m, 2H), 4.56 (s, 2H), 3.96 (s, 3H), 3.74 (br. m, 2H), 3.46 (q, 2H), 2.46 (s, 3H), 1.10 (t, 3H) ppm. 15 e 10 6—(Ethoxymethyl)(7-methoxy—5-methylbenzothiophen—2-yl)(morpholinylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin—4-amine D [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —119— A solution of Intermediate 17A (55 mg, purity 73%, 101 umol) in methanol (3 ml) was treated with line (18 mg, 202 umol), sodium cyanoborohydride (19 mg, 303 mmol) and acetic acid (18 ul, 304 umol). The mixture was stirred at 60°C for 18 h. r s of line (18 mg, 202 umol), sodium cyanoborohydride (19 mg, 303 mmol) and acetic acid (18 ul, 304 umol) were added, and stirring at 60°C was continued for another 3 h. The resulting mixture was diluted with THF to dissolve precipitates and separated by preparative RP—HPLC (Reprosil C18, gradient 20—40% itrile/O.2% aq. TFA). The t fractions were combined and ated to dryness. The residue was dissolved in methanol and filtered through an anion exchange cartridge (Stratospheres 10 SPE, PL-HC03 MP-resin). The cartridge was eluted with methanol, and the filtrate was evaporated yielding 32 mg (68% of th.) of the title compound.

LC-MS (method 2): R = 0.78 min; MS (ESIpos): m/z = 468 (M+H)+ ‘H—NMR (400 MHz, DMSO-ds): 5 = 7.98 (s, 1H), 7.9 (br. s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 5.75 (br. s, 1H), 4.45 (s, 2H), 3.95 (s, 3H), 3.88 (s, 2H), 3.51-3.56 (m, 4H), 3.40 (q, 2H), 15 2.4—2.5 (m, 4H), 2.45 (s, 3H), 1.06 (t, 3H) ppm.

Example 11 1 —(4- {[4-Amino(ethoxymethyl)(7-methoxymethylbenzothiophen—2-yl)pyrrolo[2, 1 —f]— [1 ,2,4]triazin—7-yl]methyl}piperazin— 1 -yl)ethanone dihydrochloride D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l20— A solution of Intermediate 17A (130 mg, 0.328 mmol) in methanol (8 ml) was treated with N—acetylpiperazine (63 mg, 0.492 mmol), sodium cyanoborohydride (103 mg, 1.63 mmol) and acetic acid (37 ul, 0.655 mmol). The mixture was stirred at 60°C for 3 h. It was then combined with the reaction mixture of a 30 mg test run, evaporated and purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid). The product thus obtained was lyophilized from 1,4-dioxane, then ved in ethyl acetate and washed with sat. aq. sodium en- carbonate on. The organic layer was dried over magnesium sulfate, evaporated and lyophilized again from 1,4-dioxane. Re-purification by preparative RP-HPLC (Reprosil C18, gradient 10-95% 10 acetonitrile/0.1% aq. formic acid), followed by two-fold column chromatography on silica gel (dichloromethane/methanol 98:2 —> 4:1) and lyophilization from a 4 M solution of hydrogen chloride in 1,4-dioxane afforded 49 mg (18% of th.) of the title nd.

LC—MS d 2): R = 0.82 min; MS (ESIpos): m/z = 509 (M+H)+ 1H—NMR (400 MHZ, DMSO-ds): inter a]. 8 = .26 (br. s, 1H), 8.17 (s, 1H), 7.38 (s, 1H), 7.34 15 (s, 1H), 6.87 (s, 1H), 6.53-6.05 (br. s, 1H), 4.75 (br. s, 2H), 4.56 (br. s, 2H), 3.96 (s, 3H), 3.45 (q, 2H, overlap with water peak), 2.46 (s, 3H), 2.03 (s, 3H), 1.09 (t, 3H) ppm.

Example 12 [4-Amino(7-methoxymethylbenzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo[2, l -f] - [1 ,2,4] triazin—6-yl]methanol bis(formiate) D ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena —l2l— x2 HCOZH A solution of Intermediate 23A (95 mg, 152 umol) in a 4 M solution of hydrogen chloride in 1,4- dioxane (3.7 ml) was stirred at rt for 2 h. After evaporation, the residue was purified by ative RP-HPLC (Reprosil C18, gradient 10-95% itrile/0.1% aq. formic acid) affording 44 mg (62% ofth.) of the title compound.

LC—MS (method 2): R: 0.63 min; MS (ESIpos): m/z = 439 (M+H)+ 1H-NMR (400 MHZ, DMSO-ds): 8 = 8.28 (br. s, 2H), 7.98 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 4.50 (s, 2H, overlap with water peak), 3.98 (s, 2H, overlap With water peak), 3.95 (s, 3H, overlap With water peak), 2.95-2.84 (m, 4H), 2.61-2.55 (m, 4H, overlap With DMSO peak), 2.45 (s, 10 3H) ppm.

Example 13 4— {[4—Amino(hydroxymethyl)(7-methoxy—5—methyl- l -benzothiophen—2-yl)pyrrolo [2, 1 —f] [l ,2,4] - triazin—7—y1]methyl}piperazin—2-one ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na —122— A solution of Intermediate 20A (1.34 g, 3.96 rmnol) in acetic acid (13.9 ml) was treated with 37% aq. formaldehyde solution (501 ul, 6.6 mrnol) and 2-oxopiperazine (670 mg, 6.6 mmol). The mixture was d at 50°C for 2 h and then evaporated. Purification by column chromatography on silica 5 gel (dichloromethane/methanol 98:2 —> 90:10) afforded 942 mg (49% of th.) of the title compound.

LC-MS (method 2): R: = 0.67 min; MS (ESIpos): m/z = 453 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 7.99 (s, 1H), 7.76 (br. s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 4.51 (s, 2H), 4.03 (br. s, 2H), 3.95 (s, 3H), 3.18-3.13 (m, 2H), 3.07-2.98 (m, 2H), 2.72- 2.60 (m, 2H), 2.45 (s, 3H) ppm. 10 Example 14 7— { [(3S)-3 -Amino-3 -methylpyrrolidin— 1 -yl]methyl} —6-(methoxymethyl)(7-methoxymethyl— 1 — benzothiophen—2-yl)pyrrolo[2, 1 -f] [1 riazin—4—amine trihydrochloride ation] na None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l23— A solution of Intermediate 21A (100 mg, 0.28 mmol) in acetic acid (1 ml) was treated with 37% aq. formaldehyde on (25 ul, 0.33 mmol) and tert—butyl [(3S)methylpyrrolidin—3—yl]carbamate (Yoshida et al., Chem. Pharm. Bull. 1996, 44 (7), 1376-1386; 67 mg, 0.33 mmol). The mixture was stirred at rt for 3 h and then evaporated. The residue was diluted with sat. aq. sodium hydrogencarbonate solution, and solid potassium carbonate was added until no more gas generation occurred. The s phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. The residue was dissolved in a 4 M solution of hydrogen de in oxane (2 ml) and stirred at rt for 2 h. After evaporation, the residue was purified by two-fold preparative RP-HPLC (first Reprosil C18, gradient 10-95% aceto- 10 nitrile/0.1% aq. formic acid; then Shield RP18, gradient 5-50% methanol + 0.1% aq. TFA/0.1% aq.

TFA). The t thus obtained was lyophilized from a 4 M solution of hydrogen chloride in 1,4- dioxane affording 14 mg (8% of th.) of the title compound.

LC-MS (method 2): R. = 0.67 min; MS (ESIpos): m/z = 467 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): inter al. 8 = 8.50-8.22 (br. s, 1H), 8.14 (s, 1H), 7.36 (s, 1H), 7.34 15 (s, 1H), 6.87 (s, 1H), 6.36-6.01 (br. s, 1H), 4.88 (br. s, 2H), 4.56 (br. s, 2H), 3.96 (s, 3H, overlap with water peak), 3.26 (s, 3H), 2.46 (s, 3H), 1.52 (s, 3H) ppm.

Example 15 7— { [(3S)-3 -Amino-3 -methylpyrrolidin— 1 -yl]methyl} (ethoxymethyl)(7-methoxy—5-methyl—1 - hiophen—2-yl)pyrrolo[2, 1 -f] [1 ,2,4]triazin—4-amine 20 A solution of ediate 17A (100 mg, 271 umol) in acetic acid (1 ml) was treated with 37% aq. naldehyde solution (24 pl, 326 umol) and tert-butyl [(315)methylpyrrolidinyl]carbamate (Yoshida et al., Chem. Pharm. Bull. 1996, 44 (7), 1376-1386; 65 mg, 326 umol). The mixture was [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na —124— stirred at 60°C for 4 h. Then, further amounts of 37% aq. formaldehyde solution (10 pl, 136 umol) and tert—butyl [(3S)methylpyrrolidin—3—yl]carbamate (27 mg, 136 umol) were added, and stirring at 60°C was continued ght. After evaporation, the residue was ioned between ethyl acetate and sat. aq. sodium hydrogencarbonate solution. Solid potassium carbonate was added until 5 no more gas generation occurred. The aqueous phase was extracted three times with ethyl acetate.

The combined organic phases were dried over sodium sulfate, evaporated and purified by preparative RP—HPLC (Reprosil C18, nt 10-95% acetonitrile/O.1% aq. formic acid). The product thus obtained was dissolved in a 4 M on of hydrogen chloride in 1,4-dioxane (2 ml) and stirred at rt for 1 h. After evaporation, the residue was purified by ative RP-HPLC (Reprosil C18, 10 nt 10-95% acetonitrile/0.1% aq. formic acid) affording 24 mg (18% of th.) of the title compound.

LC-MS (method 4): R. = 0.70 min; MS (ESIpos): m/z = 481 (M+H)+ lH-NMR (400 MHz, DMSO-da): inter al. 6 = 8.19 (s, 1H), 7.38 (s, 1H), 7.34 (s, 1H), 6.87 (s, 1H), 4.90 (br. s, 2H), 3.96 (s, 3H), 3.46 (q, 3H), 2.46 (s, 3H), 1.54 (s, 3H), 1.14—1.05 (m, 3H) ppm. 15 Example 16 1 -(4- {[4-Amino(methoxymethyl)—5—(7—methoxy—5-methy1— 1 -benzothiophenyl)pyrrolo[2, 1 —f] - [1 ,2,4] triazin—7-yl]methyl}piperazin— 1 -yl)ethanone dihydrochloride A solution of Intermediate 21A (50 mg, 141 umol) in acetic acid (1 ml) was treated with 37% aq. 20 formaldehyde on (4.6 pl, 169 umol) and ylpiperazine (21.6 mg, 169 umol). The mixture Dstirred at 75°C for 3 h. After evaporation, the residue was purified by preparative RP-HPLC [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —125— (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. formic acid). Lyophilization from a 4 M on ofhydrogen de in 1,4-dioxane afforded 34 mg (39% of th.) of the title compound.

LC-MS (method 5): R = 1.78 min; MS (ESIpos): m/z = 495 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): inter al. 8 = 8.70-8.35 (br. s, 1H), 8.18 (s, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 6.86 (s, 1H), 6.61-6.19 (br. s, 1H), 4.74 (br. s, 2H), 4.54 (br. s, 2H), 3.96 (s, 3H), 3.25 (s, 3H), 2.46 (s, 3H), 2.03 (s, 3H) ppm.

Example 17 6—(Methoxymethyl)(7-methoxymethyl— 1 —benzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin—4-arnine formiate X HCOOH 10 A solution of ediate 23A (110 mg, 204 umol) in dichloromethane (2.2 ml) was d with thionyl chloride (29 pl, 408 umol) and stirred at rt for 15 min. After evaporation, the residue was dissolved in methanol (2.2 ml) and d with DIPEA (39 pl, 224 umol). The mixture was stirred at 70°C for l h and then evaporated. The residue was taken up in a 4 M solution of hydrogen 15 chloride in oxane (2.2 ml) and stirred at rt for 2 h. Evaporation and purification by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) afforded 44.9 mg (46% of th.) of the title compound.

LC-MS (method 2): R = 0.73 min; MS (ESIpos): m/z = 453 (M+H)+ lH-NMR (400 MHz, s): 5 = 8.28 (br. s, 1H), 8.00 (s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 6.85 20 DH), 4.41 (s, 2H), 4.00-3.90 (m, 5H), 3.00-2.90 (m, 4H), 2.65-2.56 (m, 4H), 2.45 (s, 3H) ppm. ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —126— Example 18 6—(Ethoxymethyl)(7-methoxymethyl— 1 —benzothiophen—2-yl)(piperazin— 1 hyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin—4-arnine A solution of Intermediate 23A (80 mg, 317 umol) in dichloromethane (2 ml) was treated with thionyl chloride (22 pl, 297 umol) and stirred at rt for 15 min. After ation, the residue was dissolved in ethanol (2 m1) and treated with DIPEA (28 pl, 163 umol). The mixture was stirred at 70°C for 1 h and then evaporated. The residue was taken up in a 4 M on of hydrogen chloride in 1,4-dioxane (2 m1) and stirred at rt for 1 h. Evaporation and purification by preparative RP—HPLC 10 (Reprosil C18, gradient 10-95% itrile/0.1% aq. formic acid) afforded 35 mg (50% of th.) of the title compound.

LC-MS (method 2): R = 0.82 min; MS (ESIpos): m/z = 467 (M+H)+ 1H—NMR (400 MHz, DMSO-da): infer a}. 8 = 8.09 (br. s, 1H), 7.36 (s, 1H), 7.32 (s, 1H), 6.86 (s, 1H), 4.50 (br. s, 2H), 3.96 (s, 3H), 3.42 (q, 2H, overlap with water peak), 2.45 (s, 3H), 1.05 (t, 3H) 15 ppm.

Example 19 6-(Ethoxymethyl)(7-methoxymethylbenzothiophen—2-yl)(piperazin— 1 -y1methy1)pyrrolo- [2,1 -f] [1 ,2,4]triazin—4-arnine dihydrochloride D [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —127— A solution of Example 18 (50 mg, 107 umol) in a 4 M on of hydrogen de in 1,4—dioxane (1 ml) was stirred at rt for 15 min. After evaporation 55 mg (93% of th.) of the title compound were obtained.

LC—MS (method 4): R = 0.74 min; MS (ESIpos): m/z = 467 (M+H)+ ‘H-NMR (400 MHz, DMSO-ds): inter a7. 5 = 8.18 (s, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 6.87 (s, 1H), 4.76 (br. s, 2H), 4.60 (br. s, 2H), 3.96 (s, 3H), 3.45 (q, 2H), 2.46 (s, 3H), 1.09 (1:, 3H) ppm.

Example 20 1 -(4- {[4-Amino(ethoxymethyl)(7-methoxymethylbenzothiophen—2-yl)pyrrolo[2, 1 —f]— 10 [1 ,2,4] triazin—7-yl]methyl} piperazin— 1 -yl)ethanone [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —128— A solution of Example 18 (70 mg, 150 umol) in romethane (2 ml) and THF (08 ml) was treated with acetyl de (21 pl, 300 umol) and sodium ate (127 mg, 1.2 mmol). The mix- ture was stirred at rt overnight. After evaporation, the residue was ed by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) affording 27 mg (31% of th.) of the title compound.

LC-MS (method 4): R. = 0.77 min; MS (ESIpos): m/z = 509 (M+H)+ 1H—NMR (400 MHz, g): 5 = 7.98 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 4.45 (s, 2H), 3.95 (s, 3H), 3.92 (s, 2H), 3.45-3.36 (m, 6H), 2.48-2.38 (m, 7H, overlap with DMSO peak), 1.97 (s, 3H), 1.06 (t, 3H) ppm. 10 Example 21 4-( {4-Amino [(2-hydroxyethoxy)methyl]-5—(7-methoxymethylbenzothiophen—2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin—7-yl}methyl)piperazin—2—one formiate X HCOOH A solution of Example 13 (60 mg, 132 umol) in dichloromethane (2 ml) was treated with thionyl 15 chloride (14 pl, 198 umol). The mixture was stirred at rt for 15 min and then evaporated. The resi- due was dissolved in ethylene glycol (500 pl) and stirred at 100°C for 90 min. Purification by pre- parative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) afforded 34 mg (47% of th.) of the title compound.

LC—MS d 2): R = 0.69 min; MS (ESIpos): m/z = 497 (M+H)+ D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —129— 1H-NMR (400 MHz, DMSO-ds): 8 = 8.14 (s, 1H), 8.00 (s, 1H), 7.74 (br. s, 1H), 7.42 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 4.49 (s, 2H), 3.99 (s, 2H), 3.96 (s, 3H), 3.50-3.43 (m, 2H), 3.42—3.36 (m, 2H, overlap with water peak), 3.15-3.07 (m, 2H), 3.03 (s, 2H), 2.69-2.61 (m, 2H), 2.45 (s, 3H) ppm. e 22 2— { [4-Amino(7-methoxy—5-methylbenzothiophen—2-yl)(piperazin— 1 hyl)pyrrolo[2, 1 -f] - [1 ,2,4] triazin—6-yl]methoxy} ethanol dihydrochloride X2 HCI A solution of Intermediate 23A (100 mg, 185 umol) in dichloromethane (4 ml) was treated with thionyl chloride (27 ul, 371 umol). The mixture was stirred at rt for 20 min and then evaporated. 10 The residue was dissolved in ethylene glycol/THF (2:1, 1.5 ml) and d at 100°C for 2 h. After evaporation, the residue was purified by ative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. formic acid), followed by column chromatography on silica gel (dichloro- methane/methanol + 0.1% aq. ammonia 98:2 —> 90:10). Lyophilization from a 4 M solution of hydrogen chloride in 1,4-dioxane ed 67 mg (64% of th.) of the title nd. 15 LC—MS (method 2): R. = 0.66 min; MS (ESIpos): m/z = 483 (M+H)+ ‘H-NMR (400 MHz, DMSO-ds): 8 = 8.16 (s, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 6.98 (s, 1H), 4.86 (s, 2H), 4.69 (s, 2H), 4.03 (s, 3H), 3.81-3.49 (m, 12H), 2.50 (s, 3H) ppm.

Example 23 6—(Butoxymethyl)(7-methoxy—5-methyl— 1 —benzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo— 20 Df] [1 ,2,4]triazinamine forrniate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l30— X HCOOH A solution of Intermediate 23A (100 mg, 185 umol) in dichloromethane (2 ml) was treated with thionyl chloride (27 pl, 371 umol). The mixture was stirred at rt for 15 min and then ated.

The residue was dissolved in l-butanol (2 ml) and heated to 70°C for 1 h. After evaporation, the residue was taken up in a 4 M solution of hydrogen chloride in l,4-dioxane (2 ml) and stirred at rt for 2 h. Evaporation and purification by preparative RP-HPLC (Reprosil C18, gradient 10—95% acetonitrile/0.1% aq. formic acid) afforded 22 mg (24% of th.) of the title compound.

LC—MS (method 2): Rt = 0.82 min; MS s): m/z = 495 (M+H)+ lH-NMR (400 MHz, DMSO-ds): 5 = 8.29 (s, 1H), 7.99 (s, 1H), 7.35 (s, 1H), 7.29 (s, 1H), 6.84 (s, 10 1H), 4.43 (s, 2H), 3.95 (s, 3H), 3.92 (s, 2H), 3.35 (t, 2H), 2.90—2.79 (m, 4H), 2.45 (s, 3H), 1.47— 1.37 (m, 2H), 1.31-1.18 (m, 2H), 0.80 (t, 3H) ppm.

Example 24 5—(7—Methoxymethyl- 1 thiophen-2—yl)—7—(piperazin— 1 -ylmethyl)(propoxymethyl)pyrrolo— [2,1-f] [1,2,4]triazin—4-amine bis(fonniate) ation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena —l3l— A solution of Intermediate 23A (100 mg, 185 umol) in dichloromethane (2 ml) was treated with thionyl chloride (27 pl, 371 umol). The mixture was stirred at rt for 15 min and then evaporated.

The residue was dissolved in l-propanol (2 ml), treated with DIPEA (48 ul, 278 umol) and stirred at rt for l h. After evaporation, the residue was taken up in a 4 M solution of hydrogen chloride in 1,4- dioxane (2 ml) and stirred at rt for 2 h. Evaporation and purification by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. formic acid) afforded 15 mg (16% of th.) of the title compound.

LC-MS (method 2): R = 0.78 min; MS (ESIpos): m/z = 481 (M+H)+ 10 1H-NMR (400 MHz, DMSO-da): 5 = 8.26 (br. s, 2H), 7.98 (s, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 4.44 (s, 2H), 3.95 (s, 3H), 3.92 (s, 2H), 3.32 (t, 2H), 2.87-2.79 (m, 4H), 1.52-1.39 (m, 2H), 0.81 (t, 3H) ppm.

Example 25 6-[(Cyclopropylmethoxy)methyl] (7-methoxymethylbenzothiophen—2-yl)(piperazinyl- 15 methyl)pyrrolo [2, 1 -f] [1 ,2,4]triazin—4—amine bis(formiate) ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l32— X 2 HCOOH A on of Intermediate 23A (100 mg, 185 umol) in dichloromethane (2 ml) was treated with thionyl chloride (27 pl, 371 umol). The mixture was stirred at rt for 15 min and then evaporated.

The residue was dissolved in cyclopropylmethanol (2 ml), treated with DIPEA (48 ul, 278 umol) and stirred at 70°C for 2 h. After evaporation, the residue was taken up in a 4 M solution of hydrogen de in l,4-dioxane (2 ml) and stirred at rt for 2 h. Evaporation and purification by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. formic acid) afforded 29 mg (30% of th.) of the title compound.

LC-MS (method 2): R = 0.78 min; MS (ESIpos): m/z = 493 (M+H)+ 10 lH-NMR (400 MHz, DMSO-da): 8 = 8.28 (br. s, 2H), 7.99 (s, 1H), 7.37 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 4.45 (s, 2H), 3.95 (s, 3H), 3.93 (s, 2H), 3.21 (d, 2H), 2.95—2.83 (m, 4H), 2.61—2.56 (m, 4H), 2.45 (s, 3H), 1.01—0.91 (m, 1H), 0.46—0.37 (m, 2H), 0.15-0.08 (m, 2H) ppm. e 26 6-[(Cyclobutyloxy)methyl] (7-methoxymethyl- 1 thiophen—2-yl)(piperazinyl- 15 methyl)pyrrolo[2,1-f] [1 ,2,4]triazin—4—amine [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena —l33— A solution of Intermediate 23A (85 mg, 157 umol) in dichloromethane (1.7 ml) was d with thionyl chloride (23 pl, 315 umol). The mixture was stirred at rt for 15 min and then ated.

The residue was dissolved in cyclobutanol (1.7 ml), treated with DIPEA (41 ul, 236 umol) and stirred at 70°C for 2 h. After evaporation, the residue was taken up in a 4 M solution of hydrogen chloride in l,4-dioxane (1.7 ml) and stirred at rt for 2 h. Evaporation and purification by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. formic acid) afforded 23 mg (28% of th.) of the title compound.

LC-MS (method 2): R = 0.82 min; MS (ESIpos): m/z = 493 (M+H)+ 10 ‘H-NMR (400 MHz, DMSO-ds): 5 = 8.01 (s, 1H), 7.37 (s, 1H), 7.32 (s, 1H), 6.85 (s, 1H), 4.37 (s, 2H), 4.06-3.86 (m, 6H), 3.14—2.97 (m, 4H), 2.80-2.62 (m, 4H), 2.45 (s, 3H), 2.10-1.96 (1n, 2H), 1.83-1.69 (m, 2H), 1.65-1.52 (m, 1H), 1.49—1.33 (m, 1H) ppm.

Example 27 6-(Isopropoxymethyl)(7-methoxymethyl-1 -benzothiophenyl)(piperazin-1 -ylmethyl)- 15 pyrrolo[2,1-f] ]t1iazinamine forrniate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] na Unmarked set by na —134— X HCOOH A solution of Intermediate 23A (65 mg, 120 umol) in dichloromethane (1.3 ml) was treated with thionyl chloride (17 pl, 241 umol). The mixture was stirred at rt for 15 min and then evaporated.

The residue was dissolved in 2-propanol (1.3 ml), treated with DIPEA (23 ul, 132 umol) and stirred at 70°C for 1 h. Further DIPEA (23 ul, 132 umol) was added, and the mixture was stirred again at 70°C for 1 h. Then, another portion of DIPEA (63 ul, 362 umol) was added, and stirring was continued at 90°C for 3 h. After evaporation, the residue was taken up in a 4 M solution of hydrogen chloride in 1,4-dioxane (1.3 m1) and stirred at rt for 2 h. Evaporation and ation by ative RP—HPLC (Reprosil C18, nt 10—95% acetonitrile/O.1% aq. formic acid) afforded 23 mg (34% 10 of th.) of the title compound.

LC-MS (method 4): R = 0.74 min; MS (ESIpos): m/z = 481 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.30 (s, 1H), 7.98 (s, 1H), 7.37 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 4.43 (s, 2H), 3.95 (s, 3H), 3.90 (s, 2H), 3.57 (m, 1H, overlap with water peak), 2.88—2.78 (m, 4H), 2.45 (s, 3H), 1.04 (d, 6H) ppm. 15 Example 28 6—[(2-Methoxyethoxy)methyl] (7-methoxy—5—methylbenzothiophen—2-yl)(piperazin— 1 —yl- methyl)pyrrolo [2, 1 -f] [1 ,2,4]triazin—4-amine formiate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l35— A solution of Intermediate 23A (100 mg, 185 umol) in dichloromethane (2 ml) was treated with thionyl chloride (27 pl, 371 umol). The mixture was stirred at rt for 15 min and then evaporated.

The residue was ved in 2-methoxyethanol (2 ml), d with DIPEA (35 ul, 204 umol) and stirred at 70°C for l h. After evaporation, the residue was taken up in a 4 M solution of hydrogen chloride in l,4-dioxane (2 ml) and stirred at rt for 2 h. Evaporation and purification by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. formic acid) afforded 50 mg (50% of th.) of the title compound.

LC-MS d 2): R. = 0.75 min; MS (ESIpos): m/z = 497 (M+H)+ 10 1H-NMR (400 MHz, DMSO-d5): 8 = 8.26 (br. s, 1H), 7.99 (s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 4.48 (s, 2H), 3.95 (s, 3H), 3.94 (s, 2H), 3.52-3.46 (m, 2H, overlap with water peak), 3.44- 3.37 (m, 2H, overlap with water peak), 3.20 (s, 3H), 2.94-2.84 (m, 4H), 2.61-2.54 (m, 4H, overlap with DMSO peak), 2.45 (s, 3H) ppm. e 29 15 5—(7-Methoxymethylbenzothiophen—2—yl)—7—(piperazin— 1 -ylmethyl) [(2,2,2-trifluoroethoxy)- methyl]pyrrolo [2, l -f] [l ,2,4]triazin—4-amine formiate [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l36— A solution of Intermediate 23A (100 mg, 185 umol) in romethane (2 ml) was treated with thionyl chloride (27 pl, 371 umol). The mixture was stirred at rt for 15 min and then evaporated.

The residue was dissolved in 2,2,2-trifluoroethanol (2 ml), treated with DIPEA (35 ul, 204 umol) and stirred at 70°C for 1 h. Further DIPEA (35 ul, 204 umol) was added, and stirring was continued at rt for l h. After ation, the residue was taken up in a 4 M solution of hydrogen chloride in 1,4—dioxane (2 ml) and stirred at rt for 2 h. Evaporation and purification by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. formic acid) afforded 23 mg (23% of th.) of the title compound. 10 LC-MS (method 2): R. = 0.79 min; MS (ESIpos): m/z = 521 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.28 (br. s, 1H), 8.00 (s, 1H), 7.37 (s, 1H), 7.30 (s, 1H), 6.85 (s, 1H), 4.66 (s, 2H), 4.08 (q, 2H), 3.95 (s, 3H), 3.92 (s, 2H), .75 (m, 4H), 2.45 (s, 3H) ppm.

Example 30 Aminoethoxy)methyl] (7-methoxymethylbenzothiophen—2-yl)(piperazin- l -ylmethyl)- 15 pyrrolo[2,l-f] [1,2,4]t1iazinamine trihydrochloride ation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena ed set by kirstena —137— X3HC| A solution of Intermediate 23A (150 mg, 278 umol) in dichloromethane (5 ml) was treated with thionyl chloride (40 pl, 556 umol). The mixture was stirred at rt for 15 min and then evaporated.

The residue was dissolved in THF (0.5 ml) and treated with tert—butyl (2-hydroxyethyl)carbamate (1 ml) and DIPEA (242 ul, 1.39 mrnol). The mixture was stirred at 100°C overnight. After evapo- ration, the residue was taken up in 1,4-dioxane (10 ml), treated with a 4 M on of en chloride in 1,4-dioxane (10 ml) and stirred at rt for 1 h. The volatiles were d under reduced pressure, and the e was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid). Further purification by preparative RP-HPLC (Shield RP18, 25% 10 acetonitrile/75% 0.01% aq. TFA) followed by lyophilization from a 4 M solution of hydrogen chloride in 1,4-dioxane afforded 10 mg (6% of th.) of the title compound.

LC-MS (method 2): R = 0.58 min; MS (ESIpos): m/z = 482 (M+H)+ 1H-NMR (400 MHz, D20): 8 = 8.12 (s, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 6.99 (s, 1H), 4.61 (s, 2H), 4.04 (s, 3H), 3.88-3.80 (m, 1H), 3.70-3.60 (m, 3H), 3.52-3.46 (m, 4H), 3.40-3.34 (m, 4H), 3.07 (t, 15 2H), 2.51 (s, 3H) ppm.

Example 31 Methyl { [4-amino(7-methoxy—5-methyl- 1 —benzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin—6-yl]methoxy} acetate D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —138— A solution of Intermediate 23A (50 mg, 92 umol) in dichloromethane (2 ml) was treated with thionyl chloride (13 pl, 186 umol). The mixture was stirred at rt for 15 min and then evaporated. The e was dissolved in glycolate (1 ml), treated with DIPEA (80 ul, 464 umol) and stirred at 70°C for 2 h. After evaporation, the e was taken up in romethane (1.6 ml), treated with trifluoroacetic acid (400 pl, 5.19 mrnol) and stirred at rt for 1 h. Then, the mixture was evaporated, and the residue was purified by preparative RP—HPLC (Reprosil C18, gradient 10—95% acetonitrile/O.1% aq. TFA). Fractions containing the title compound were lized with sat. aq. sodium hydrogencarbonate solution and evaporated. The residue was taken up in water, and the 10 mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated ing 21 mg (43% of th.) of the title compound.

LC-MS (method 2): R. = 0.72 min; MS (ESIpos): m/z = 511 (M+H)+ ‘H—NMR (400 MHz, DMSO-ds): 5 = 7.99 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 4.59 (s, 2H), 4.11 (s, 2H), 3.95 (s, 3H), 3.90 (s, 2H), 3.57 (s, 3H), 2.81-2.69 (m, 4H), 2.48-2.39 (m, 7H) 15 Example 32 { [4-Amino(7-methoxymethylbenzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo[2, 1 -f] - [1 ,2,4]triazin—6-yl]methoxy} acetic acid D [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l39— A on of Intermediate 24A (200 mg, 327 umol) in THF (14 ml) was treated with 2.5 M aq. lithium hydroxide solution (16 ml) and stirred at 80°C for 2 h. The mixture was then ed with the reaction mixture of a 27 mg test run. The aqueous phase was extracted twice with THF, and the combined organic phases were evaporated. The residue was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (2 ml) and d at rt for 3 h. After evaporation, the residue was purified by preparative RP-HPLC (Reprosil C18, nt 10—95% acetonitrile/O.1% aq. TFA). Lyophilization from a 4 M solution of hydrogen chloride in 1,4-dioxane and re-purification by preparative RP- HPLC (XBridge C18, gradient 5-95% acetonitrile/O.1% aq. ammonium hydroxide solution) afforded 10 13 mg (7% of th.) of the title nd.

LC—MS (method 2): R = 0.69 min; MS (ESIpos): m/z = 497 (M+H)+ ‘H-NMR (400 MHz, DMSO-ds): 8 = 8.00 (s, 1H), 7.38 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 4.54 (s, 2H), 4.08 (s, 2H), 3.95 (s, 3H), 3.79 (s, 2H), 2.99-2.89 (m, 4H), 2.73-2.63 (m, 4H), 2.44 (s, 3H) 15 Example 33 2— { [4-Amino(7-methoxy—5-methylbenzothiophen—2-yl)(piperazin— 1 hyl)pyrrolo[2, 1 -f] - [1 ,2,4]triazin—6-yl]methoxy} acetamide [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —140— Intermediate 24A (200 mg, 327 umol) was treated with a 7 M solution of ammonia in methanol (10 ml) and stirred at rt overnight. The mixture was then combined with the reaction mixture of a 20 mg test run, and the solvents were evaporated. The residue was treated with a 4 M solution of hydrogen de in l,4-dioxane (2 ml) and stirred at rt for 2 h. Evaporation and subsequent ations by preparative RP-HPLC (first Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. TFA; then XBridge C18, nt 5-95% itrilefO.1% aq. ammonium hydoxide solution) afforded 5.5 mg (3% of th.) of the title compound.

LC-MS (method 2): R. = 0.69 min; MS s): rn/z = 496 (M+H)+ 10 1H-NMR (400 MHz, DMSO-da): 5 = 8.14-7.59 (br. s, 1H), 7.99 (s, 1H), 7.39 (s, 1H), 7.35-7.22 (m, 3H), 6.85 (s, 1H), 4.54 (s, 2H), 3.95 (s, 3H), 3.90 (s, 2H), 3.79 (s, 2H), 2.73-2.66 (m, 4H), 2.45 (s, 3H), 2.43-2.35 (m, 4H) ppm. e 34 2-( {7- [(4-Acetylpiperazin— 1 -yl)methyl]amino(7-methoxymethyl-1 -benzothiophenyl)- 15 pyrrolo [2, l -f] [l ,2,4]triazin—6-yl}methoxy)acetamide [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —141— A solution of Example 33 (105 mg, 68% purity, 144 umol) in THF/dichloromethane (125, 3.9 ml) was d With sodium carbonate (179 mg, 1.6 mmol) and stirred at rt for 30 min. Acetyl chloride (30 ul, 424 umol) was added, and the resulting mixture was stirred at rt for 30 min, then quenched with methanol (2 ml) and evaporated. Purification by preparative C (Reprosil C18, gradient 10—95% acetonitrile/O.1% aq. formic acid) afforded 30 mg (85% purity, 34% of th.) of the title compound.

LC-MS (method 5): R = 1.67 min; MS (ESIpos): m/z = 538 (M+H)+ ‘H-NMR (400 MHz, DMSO-ds): 5 = 7.99 (s, 1H), 7.40 (s, 1H), 7.33—7.19 (m, 3H), 6.85 (s, 1H), 10 4.55 (s, 2H), 3.96 (s, 5H), 3.80 (s, 2H), 3.43-3.36 (m, 4H), 2.47-2.38 (m, 7H), 1.97 (s, 3H) ppm.

Example 35 5—(7—Methoxymethylbenzothiophen-2—yl)—6—(phenoxymethyl)(piperazin— 1 hyl)pyrrolo— [2,1-f] [1 ,2,4]triazinamine bis(f01miate) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —142— H30 0H X 2 HCOOH A solution of Intermediate 23A (100 mg, 185 umol) in dichloromethane (2 ml) was treated with thionyl chloride (27 pl, 371 umol). The e was stirred at rt for 15 min and then evaporated.

The residue was dissolved in THF (2 ml), treated with phenol (174 mg, 1.85 mmol) and DIPEA (48 ul, 278 umol) and d at 70°C for 2 h. Further amounts of phenol (174 mg, 1.85 mmol) and DIPEA (64 ul, 371 umol) were added, and ng was continued at 70°C overnight. After evapo- ration, the residue was taken up in a 4 M solution of hydrogen chloride in 1,4-dioxane (2 ml) and stirred at rt for 2 h. Evaporation and purification by preparative RP-HPLC (Reprosil C18, gradient 10—95% acetonitrile/0.1% aq. formic acid) ed 8 mg (8% of th.) of the title compound. 10 LC-MS (method 2): R = 0.84 min; MS (ESIpos): m/z = 515 (M+H)+ ‘H-NMR (400 MHz, DMSO-ds): 8 = 8.26 (s, 2H), 8.02 (s, 1H), 7.36 (s, 1H), 7.30—7.22 (m, 3H), 6.99-6.89 (m, 3H), 6.81 (m, 1H), 5.04 (s, 2H), 3.93 (s, 5H), 2.78-2.71 (m, 4H), 2.42 (s, 3H) ppm.

Example 36 5-(7-Methoxymethylbenzothiophenyl)[(methylamino)methyl] (piperazinylmethyl)- 15 pyrrolo[2,1-f] [1,2,4]t1iazin—4-amine trihydrochloride [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —143— ediate 25A (150 mg, 279 umol) in THF (3 ml) was d with acetic acid (32 pl, 559 umol), a 2 M solution of methylamine in THF (698 pl, 1.39 mmol) and sodium triacetoxyborohydride (296 mg, 1.39 mmol). The mixture was stirred at 60°C for 2 h and then evaporated. The residue was dissolved in a 4 M solution of hydrogen de in 1,4-dioxane (1.87 ml) and stirred at rt for 2 h.

After evaporation, the e was purified by preparative RP-HPLC sil C18, gradient 10- 95% acetonitrile/O.1% aq. TFA). Lyophilization from a 4 M solution of hydrogen chloride in 1,4— dioxane afforded 79 mg (49% of th.) of the title compound.

LC-MS (method 2): R = 0.56 min; MS (ESIpos): rn/z = 452 (M+H)+ 10 lH-NMR (400 MHz, D20): 5 = 8.17 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.01 (s, 1H), 4.52 (s, 2H), 4.46 (s, 2H), 4.04 (s, 3H), 3.48-3.39 (m, 4H), 3.25-3.15 (m, 4H), 2.59 (s, 3H), 2.51 (s, 3H) ppm.

Example 37 6—[(Dimethylamino)methyl] (7-methoxy—5—methyl— 1 —benzothiophen—2-yl)(piperazin- 1 —ylmethyl)— pyrrolo[2, 1 -f] [1 ,2,4]triazinamine trihydrochloride [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —144— A solution of Intermediate 25A (150 mg, 279 umol) in THF (3 ml) was treated with acetic acid (32 pl, 559 umol), a 2 M on of ylamine in THF (698 pl, 1.39 mmol) and sodium triacetoxyborohydride (296 mg, 1.39 mmol). The mixture was stirred at 60°C for 2 h and then evaporated.

The residue was dissolved in a 4 M solution of en chloride in 1,4-dioxane (1.88 ml) and stirred at rt for 2 h. After evaporation, the residue was d by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. TFA). Lyophilization from a 4 M solution of hydrogen chloride in 1,4-dioxane afforded 83 mg (50% of th.) of the title compound.

LC-MS (method 4): R. = 0.50 min; MS (ESIpos): m/z = 466 (M+H)+ 10 ‘H-NMR (400 MHz, D20): 5 = 8.17 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.01 (s, 1H), 4.57 (s, 2H), 4.50 (s, 2H), 4.04 (s, 3H), 3.47-3.36 (m, 4H), 3.21-3.12 (m, 4H), 2.80 (s, 6H), 2.51 (s, 3H) ppm.

Example 38 6—[(Ethylamino)methyl] (7-methoxymethyl— 1 —benzothiophen—2-yl)(piperazinylmethyl)— pyrrolo[2,1-f] [1,2,4]triazinamine trihydrochloride [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —145— A solution of Intermediate 25A (60 mg, 111.8 umol) in THF (1 ml) was treated with a 2 M solution of ethylamine in THF (83 ul, 167 umol), sodium triacetoxyborohydride (118 mg, 559 umol) and acetic acid (83 ul, 167 umol). The mixture was stirred at 60°C for 90 min. Further amounts of 2 M ethylamine solution (83 ul, 167 umol) and sodium triacetoxyborohydride (71 mg, 335 umol) were added, and stirring at 60°C was ued for another 2 h. After evaporation, the residue was ved in a 4 M solution of hydrogen chloride in 1,4—dioxane (3 ml) and stirred at rt overnight.

The mixture was evaporated, and the residue was purified by preparative RP-HPLC sil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) and lyophilized from a 4 M solution of hydrogen 10 chloride in oxane. Re-purification by preparative RP-HPLC (Sunfire C18, 20% aceto- nitrile/80% 0.02% aq. TFA) and re-lyophilization from a 4 M solution of en chloride in 1,4- dioxane afforded 19 mg (29% of th.) of the title compound.

LC-MS (method 2): R = 0.56 min; MS (ESIpos): m/z = 466 (M+H)+ lH-NMR (400 MHz, D20): 5 = 8.14 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.01 (s, 1H), 4.45 (s, 4H), 15 4.04 (s, 3H), .32 (m, 4H), 3.18-3.05 (m, 4H), 2.99 (q, 2H), 2.51 (s, 3H), 1.10 (t, 3H) ppm.

Example 39 2—( { [4-Amino(7-methoxy—5-methylbenzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo[2, 1 -f] - [1 ,2,4]triazin—6-yl]methyl} amino)ethanol trihydrochloride D ation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena -146— A solution of Intermediate 25A (150 mg, 279 umol) in THF (3 ml) was treated with 2-aminoethanol (84 ul, 1.39 mmol), sodium triacetoxyborohydride (296 mg, 1.39 mmol) and acetic acid (32 pl, 559 umol). The mixture was stirred at 60°C for 2 h and then evaporated. The residue was ved in a 4 M solution of hydrogen chloride in 1,4—dioxane (1.87 ml) and stirred at rt for 2 h. After ation, the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10—95% acetonitrile/0.1% aq. TFA). Lyophilization from a 4 M on of hydrogen chloride in 1,4—dioxane afforded 140 mg (80% of th.) of the title compound.

LC-MS (method 2): R = 0.54 min; MS (ESIpos): m/z = 482 (M+H)+ 10 1H-NMR (400 MHz, D20): 8 = 8.15 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.00 (s, 1H), 4.47 (s, 2H), 4.37 (s, 2H), 4.04 (s, 3H), 3.79-3.71 (m, 2H), 3.42-3.34 (m, 4H), 3.19-3.12 (m, 2H), 3.06—2.97 (m, 4H), 2.51 (s, 3H) ppm.

General Procedure for reductive amination reactions with Intermediate 25A (GPl): A 0.1 M solution of Intermediate 25A in THF was d with 5 eq. of the respective amine com- 15 ponent, 5 eq. of sodium triacetoxyborohydride and 2 eq. of acetic acid. The resulting mixture was stirred at 60°C for 2 h and then evaporated. A 0.15 M solution of the residue thus obtained in a 4 M solution of hydrogen chloride in 1,4-dioxane was stirred at rt for 1-2 h. After evaporation, the residue was purified as described below.

Example 40 20 rac— 1 — {[4-Amino(7-methoxy—5-methyl- 1 —benzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo— at] [1 ,2,4]triazinyl]methyl}piperidinol trihydrochloride [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena —147— According to GPl, Intermediate 25A (150 mg, 279 umol) was reacted With 3-hydroxypiperidine (141 mg, 1.39 mmol). Purification by preparative RP-HPLC (Reprosil C18, gradient 10-95% aceto- nitrile/O.1% aq. TFA) and lyophilization from a 4 M solution of hydrogen chloride in 1,4-dioxane afforded 178 mg (quant) of the title compound.

LC—MS (method 2): R: 0.54 min; MS s): m/z = 522 (M+H)+ lH-NMR (400 MHz, D20): 6 = 8.16 (s, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 7.01 (s, 1H), 4.66-4.16 (m, 5H), 4.04 (s, 3H), 3.55-2.71 (m, 11H), 2.51 (s, 3H), 1.96-1.42 (m, 4H), .50 (m, 1H) ppm.

Example 41 10 1 - { no(7-methoxymethylbenzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo[2, 1 -f] - [1 ,2,4]triazin—6-yl]methyl}piperidin—4-ol trihydrochloride [Annotation] na None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na ation] kirstena Unmarked set by kirstena -148— ing to GP], Intermediate 25A (150 mg, 279 umol) was reacted with 4-hydroxypiperidine (141 mg, 1.39 mmol). Purification by preparative RP-HPLC (Reprosil C18, gradient 10—95% aceto- nitrile/0.1% aq. TFA) and lization from a 4 M solution of en chloride in 1,4—dioxane afforded 162 mg (91% of th.) of the title compound.

LC-MS (method 4): R1 = 0.48 min; MS (ESIpos): m/Z = 522 (M+H)+ lH-NMR (400 MHz, D20): 5 = 8.16 (s, 1H), 7.58 (br. s, 1H), 7.46 (s, 1H), 7.01 (s, 1H), 4.67—4.48 (m, 4H), 4.04 (s, 4H), 3.59-2.78 (m, 12H), 2.51 (s, 3H), 2.14-1.38 (m, 4H) ppm.

Example 42 rac— 1 - { [4-Amino(7-methoxy—5-methyl- 1 —benzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo- 10 [2,1 -f] [1 ,2,4]triazin—6-yl]methyl} pyrrolidin—3 —ol trihydrochloride According to GPl, Intermediate 25A (150 mg, 279 umol) was reacted With 3-hydroxypyrrolidine (113 111, 1.39 mmol). Purification by preparative RP-HPLC (Reprosil C18, gradient 10-95% aceto- nitrile/0.1% aq. TFA) and lyophilization from a 4 M solution of hydrogen chloride in 1,4—dioxane 15 afforded 148 mg (85% of th.) of the title compound.

LC-MS (method 4): R = 0.46 min; MS (ESIpos): m/z = 508 (M+H)+ 1H—NMR (400 MHz, D20): 5 = 8.18 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 7.01 (s, 1H), 4.71—4.30 (m, 5H), 4.04 (s, 3H), 3.70-2.95 (m, 12H), 2.51 (s, 3H), 2.32—2.14 (m, 1H), 2.03-1.87 (m, 1H) ppm.

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —149— Example 43 6—[(Diethylamino)methyl] (7-methoxy—5—methylbenzothiophen—2-yl)(piperazin— 1 —ylmethyl)- o[2,1-f] [1 ,2,4]triazin—4-arnine trihydrochloride X3HC| ing to GP1, Intermediate 25A (150 mg, 279 umol) was reacted With diethylamine (144 pl, 1.39 mmol). Purification by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/ 01% aq. TFA) and lyophilization from a 4 M solution of hydrogen chloride in oxane afforded 12? mg (69% of th.) of the title compound.

LC-MS (method 2): R = 0.55 min; MS (ESIpos): m/z = 494 (M+H)+ 10 1H-NMR (400 MHZ, D20): 8 = 8.19 (s, 1H), 7.61 (s, 1H), 7.47 (s, 1H), 7.01 (s, 1H), 4.59 (s, 2H), 4.51 (s, 2H), 4.04 (s, 3H), 3.47-3.35 (m, 4H), 3.29-3.00 (m, 8H), 2.51 (s, 3H), 1.07 (t, 6H) ppm.

Example 44 6-[(Cyclobutylamino)methyl] (7-methoxymethylbenzothiophenyl)(piperazin- 1 hyl )pyrrolo [2, 1 -f] [1 ,2,4]triazin—4-amjne trihydrochloride [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —150— X3HC| According to GPl, Intermediate 25A (150 mg, 279 umol) was reacted With cyclobutylamine (119 pl, 1.39 mmol). Purification by ative RP-HPLC sil C18, gradient 10-95% aceto- nitrile/0.1% aq. TFA) and lyophilization from a 4 M solution of hydrogen chloride in oxane 5 afforded 127 mg (72% of th.) of the title compound.

LC—MS (method 2): R: 0.58 min; MS s): m/z = 492 (M+H)+ 1H-NMR (400 MHZ, D20): 5 = 8.16 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 7.00 (s, 1H), 4.40 (s, 2H), 4.37 (s, 2H), 4.04 (s, 3H), 3.69-3.58 (m, 1H), 3.44-3.33 (m, 4H), 3.21-3.12 (m, 4H), 2.51 (s, 3H), 2.02-1.87 (m, 4H), 1.81-1.62 (m, 2H) ppm. 10 Example 45 5—(7-Methoxymethylbenzothiophen—2-yl)—7-(piperazin— 1 -ylmethyl)(pyrrolidin— 1 -ylmethyl)- o[2,1-f] [1 ,2,4]triazin—4-amine trihydrochloride [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by na —151— According to GP], Intermediate 25A (150 mg, 279 umol) was reacted with pyrrolidine (116 pl, 1.39 mmol). Purification by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/ 0.1% aq.

TFA) and lyophilization from a 4 M solution of hydrogen chloride in 1,4-dioxane ed 112 mg (64% of th.) of the title compound.

LC-MS (method 2): R. = 0.54 min; MS (ESIpos): m/z = 492 (M+H)+ 1H-NMR (400 MHz, D20): 8 = 8.19 (s, 1H), 7.60 (s, 1H), 7.46 (s, 1H), 7.01 (s, 1H), 4.70—4.61 (m, 4H), 4.04 (s, 3H), 3.55-3.40 (m, 6H), 3.35—3.26 (m, 4H), 3.02-2.87 (m, 2H), 2.51 (s, 3H), 1.97— 1.83 (m, 4H) ppm.

Example 46 10 6—[(Cyclopropylamino)methyl] (7-methoxy—5—methyl- 1 thiophen—2-yl)(piperazin— 1 —yl- methyl)pyrrolo[2,1 -f] [1 ,2,4]triazin—4-amine trihydrochloride According to GP], Intermediate 25A (200 mg, 372 umol) was reacted with cyclopropylamine (129 pl, 1.86 mmol). Purification by preparative RP-HPLC (Reprosil C18, gradient 10—95% aceto- 15 nitrile/0.1% aq. TFA) and lization from a 4 M solution of hydrogen chloride in 1,4—dioxane afforded 140 mg (62% of th.) of the title compound.

LC-MS (method 5): R. = 1.42 min; MS (ESIpos): m/z = 478 (M+H)+ 1H—NMR (400 MHz, D20): 8 = 8.16 (s, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 7.01 (s, 1H), 4.57 (s, 2H), 4.47 (s, 2H), 4.04 (s, 3H), 3.46-3.34 (m, 4H), 3.19—3.07 (m, 4H), 2.61-2.54 (m, 1H), 2.51 (s, 3H), 20 D-0.64 (m, 4H) ppm.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena —152— Example 47 6— {[(Cyclopropylmethyl)amino]methyl} —5—(7—methoxymethylbenzothiophen—2-y1)—7—(piperazin— 1 —ylmethy1)pyrrolo [2, 1 -f] [1 ,2,4]triazin—4-amine trihydrochloride According to GPl, Intermediate 25A (200 mg, 372 umol) was reacted With cyclopropylmethylamine (161 pl, 1.86 mmol). Purification by preparative RP—HPLC (Reprosil C18, gradient 10—95% acetonitrile/0.1% aq. TFA) and lyophilization from a 4 M solution of hydrogen chloride in 1,4- e afforded 163 mg (69% of th.) of the title compound.

LC-MS d 2): R. = 0.60 min; MS (ESIpos): m/z = 492 (M+H)+ 10 1H-NMR (400 MHZ, D20): 8 = 8.14 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.00 (s, 1H), 4.50 (s, 2H), 4.44 (s, 2H), 4.04 (s, 3H), 3.42-3.34 (m, 4H), 3.16-3.07 (m, 4H), 2.86 (d, 2H), 2.50 (s, 3H), 0.89- 0.76 (m, 1H), 0.55-0.45 (m, 2H), 0.23-0.14 (m, 2H) ppm.

Example 48 N— { [4-Amino(7-methoxymethyl— 1 —benzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo[2, 1 -fl - 15 [1 ,2,4]triazin—6-y1]methy1} e trihydrochloride [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —153— X3HC| A solution of Intermediate 25A (161 mg, 300 umol) in THF (3.2 ml) was treated with 2—aminoacetic acid (112 mg, 1.5 mmol), sodium triacetoxyborohydride (317 mg, 1.5 mmol) and acetic acid (34 ul, 600 umol). The resulting mixture was stirred at 60°C for 2 h and then ated. The residue was purified by preparative RP-HPLC sil C18, gradient 10-95% acetonitrile/O.l% aq. TFA). The product thus obtained was ved in a 4 M solution of hydrogen chloride in 1,4-dioxane (2 ml) and stirred at rt for 1 h. After evaporation, the residue was purified by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. TFA). Subsequent lyophilization from a 4 M on ofhydrogen chloride in 1,4-dioxane afforded 18 mg (9% of th.) of the title nd. 10 LC-MS (method 2): R = 0.63 min; MS (ESIpos): m/z = 496 (M+H)+ lH-NMR (400 MHz, D20): 5 = 8.14 (s, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 6.99 (s, 1H), 4.42 (s, 2H), 4.36 (s, 2H), 4.03 (s, 3H), 3.64 (s, 2H), 3.42—3.33 (m, 4H), 3.07-2.96 (m, 4H), 2.50 (s, 3H) ppm.

Example 49 4- {[4-Amino(7-methoxy—5-methyl-1 thiopheny1)(piperazin-1 -ylmethyl)pyrrolo- 15 [2,1-t] [1 ,2,4]triazin—6-yl]methyl}piperazin—2—one trihydrochloride [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena —154— A solution of Intermediate 27A (220 mg, 354 umol) in a 4 M solution of hydrogen chloride in 1,4- e (2 ml) was stirred at rt for 2 h. Then, the mixture was evaporated leaving 235 mg of the crude product which was used in the next step without further purification. 5 LC—MS (method 4): R = 0.60 min; MS (ESIpos): m/z = 521 (M+H)+.

Example 50 [4—Amino(7-methoxymethyl- 1 —benzothiophen—2-yl)(morpholinylmethyl)pyrrolo— [2, 1 -fl [1 ,2,4]triazin—6-yl]methanol 10 A solution of Intermediate 20A (500 mg, purity 87%, 1.28 mmol) and 4-methylenemorpholin—4-ium de (347 mg, 2.56 mmol) in DMF (28 ml) was stirred at 70°C for 1.5 h. The mixture was fled with ethyl acetate and washed with sat. aq. sodium hydrogencarbonate solution and sat. aq.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —155— sodium chloride solution. The organic layer was dried with magnesium sulfate and evaporated under reduced pressure yielding 710 mg (purity 78%, 99% of th.) of the title compound.

LC-MS (method 2): R = 0.65 min; MS (ESIpos): m/z = 440 .

Example 51 (3S)-3 -( { [4-Amino(7-methoxy—5-methyl— 1 —benzothiophen—2-yl)(morpholin—4-ylmethyl)— o[2,1 -f] [1 ,2,4]triazin—6-yl]methyl} amino)pyrrolidin—2-one A solution of Intermediate 33A (65 mg, 149 umol) in methanol (2 ml) was treated with (3S) aminopyrrolidin—2-one (45 mg, 446 umol), sodium cyanoborohydride (47 mg, 743 umol) and acetic 10 acid (26 pl, 446 umol). After stirring at 60°C for 16 h, the resulting mixture was separated by ative RP-HPLC (Reprosil C18, gradient 20-40% acetonitrile/0.2% aq. TFA). The t thus obtained was dissolved in ol and filtered through an anion exchange cartridge (Strato- spheres SPE, PL-HC03 MP-resin). The cartridge was eluted with methanol, and the filtrate was eva— porated yielding 49 mg (63% of th.) of the title nd. 15 LC-MS (method 2): R = 0.71 min; MS (ESIpos): m/z = 522 (M+H)+ 1H-NMR (400 MHz, DMSO-da): 5 = 7.96 (s, 1H), 7.66 (s, 1H), 7.5-8.1 (br. s, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 5.4-6.0 (br. s, 1H), 3.95 (s, 3H), 3.91 (s, 2H), 3.75 (d, 2H), 3.50-3.66 (m, 4H), 3.06-3.19 (m, 3H), 2.94-3.05 (m, 1H), 2.61 (t, 1H), 2.45 (t, 3H), 2.38-2.44 (m, 4H), 1.89- 1.99 (m, 1H), 1.49-1.60 (m, 1H) ppm.

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —156— Example 52 4— { [4-Amino(7-methoxymethylbenzothi0phen—2-yl)(morpholin—4-ylmethyl)pyrrolo— [2,1 -1] [1 ,2,4]triazin—6-yl]methyl}piperazin—2—one 5 A solution of Intermediate 33A (65 mg, 149 umol) in methanol (2 ml) was treated with 2—oxo- piperazine (45 mg, 446 umol), sodium cyanoborohydride (47 mg, 743 umol) and acetic acid (26 ul, 446 umol). After stirring at 60°C for 16 h, the resulting mixture was separated by ative RP- HPLC (Reprosil C18, nt 20-40% acetonitrile/0.2% aq. TFA). The product thus obtained was dissolved in methanol and d through an anion exchange cartridge (Stratospheres SPE, PL- 10 HC03 MP-resin). The cartridge was eluted with methanol, and the filtrate was evaporated ng 41 mg (53% of th.) of the title compound.

LC-MS (method 2): R = 0.70 min; MS (ESIpos): m/z = 522 (M+H)+ lH-NMR (400 MHz, DMSO-ds): 8 = 7.97 (s, 1H), 7.67 (br. s, 1H), 7.55-8.05 (br. s, 1H), 7.38 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 5.29-5.88 (br. s, 1H), 3.95 (s, 3H), 3.92 (s, 2H), 3.58 (s, 2H), 3.51- 15 3.56 (m, 4H), 3.00-3.06 (m, 2H), 2.85 (s, 2H), 2.45 (s, 3H), 2.43-2.48 (m, 5H) ppm.

Example 53 rac— 1 -( { no(7-methoxymethylbenzothiophen—2-yl)(morpholin—4-y1methyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin—6-yl]methyl} amino)propanol D [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —157— A solution of Intermediate 33A (64 mg, 146 umol) in methanol (2 ml) was treated with rac—l—amino- propan—2-ol (33 mg, 439 umol), sodium cyanoborohydride (46 mg, 731 umol) and acetic acid (25 u], 439 umol). After stirring at 60°C for 16 h, the resulting mixture was separated by preparative RP-HPLC (Reprosil C18, gradient 20-40% acetonitrile/O.2% aq. TFA). The product thus obtained was dissolved in methanol and filtered through an anion exchange dge (Stratospheres SPE, PL- HC03 MP—resin). The cartridge was eluted with methanol, and the e was ated yielding 42 mg (57% of th.) of the title compound.

LC-MS (method 5): R = 1.63 min; MS (ESIpos): m/z = 497 (M+H)+ 10 ‘H-NMR (400 MHz, DMSO-ds): 6 = 7.96 (s, 1H), 7.47—7.92 (br. s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 6.84 (s, 1H), 5.36-5.92 (br. s, 1H), 4.36 (d, 1H), 3.95 (s, 3H), 3.90 (s, 2H), 3.64-3.75 (1n, 2H), 3.49—3.61 (m, 5H), 2.45 (s, 3H), 2.39—2.47 (1n, 4H), 2.31-2.38 (m, 2H), 0.97 (d, 3H) ppm.

Example 54 1 -( { [4-Amino(7-methoxymethyl-1 -benzothiopheny1)(morpholinylmethyl)pyrrolo- 15 [2,1-1] [1 ,2,4]triazin—6-yl]methyl} amino)—2—methylpropan—2-ol [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —158— A solution of Intermediate 33A (80 mg, 183 umol) in methanol (2 ml) was treated with 1—amino propan—2-ol (34 mg, 274 umol), sodium cyanoborohydride (57 mg, 914 umol) and acetic acid (21 pl, 366 umol). After stirring at 60°C for 16 h, the resulting mixture was separated by pre- parative RP-HPLC (Reprosil C18, gradient 20-40% itrile/O.2% aq. TFA). The product thus obtained was ved in methanol and filtered through an anion ge cartridge (Stratospheres SPE, PL—HC03 MP-resin). The cartridge was eluted with methanol, and the filtrate was evaporated yielding 29 mg (31% of th.) of the title compound.

LC-MS (method 2): R = 0.65 min; MS (ESIpos): m/z = 511 (M+H)+ 10 ‘H-NMR (400 MHz, DMSO-ds): 5 = 7.96 (s, 1H), 7.50-8.02 (br. s, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 6.84 (s, 1H), 5.4-6.0 (br. s, 1H), 4.11 (s, 1H), 3.95 (s, 3H), 3.90 (s, 2H), 3.70 (d, 2H), 3.51-3.58 (m, 4H), 2.45 (s, 3H), 2.39-2.46 (m, 4H), 2.33 (d, 2H), 1.83-1.92 (m, 1H), 1.03 (s, 6H) ppm.

Example 55 1 -(4- {[4-Amino(hydroxymethyl)(7-methoxymethy1benzothiophenyl)pyrr010[2, 1 -f] - 15 [1 ,2,4] triazin—7-yl]methyl}piperazin— 1 —yl)e1:han0ne [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —159— A solution of Intermediate 20A (345 mg, 1.01 mmol) in acetic acid (5 ml) was treated with 37% aq. formaldehyde solution (91 ul, 1.22 mmol) and l-acetylpiperazine (160 mg, 1.22 mmol). The mixture was stirred at 60°C for 6 h and then ated. The residue was dissolved in a mixture ofTHF/l M aq. lithium hydroxide solution (1:1, 10 ml) and stirred at rt for 2 h. The mixture was then combined with the reaction mixture of a 100 mg test run, and sat. aq. ammonium de solution was added.

The mixture was ted with ethyl acetate, and the c phase was washed with sat. aq. sodium chloride solution, dried over magnesium sulfate and evaporated under d pressure yielding 678 mg (purity 87%, 94% of th.) of the title nd. 10 LC-MS (method 2): R. = 0.71 min; MS (ESIpos): m/z = 481 (M+H)+.

Example 56 (3R)—3 - [( {7- [(4-Acetylpiperazin— 1 -yl)methyl]—4—amino(7-methoxy—5-methylbenzothiophen— 2—yl)pyrrolo[2,1-f] [1 ,2,4]triazin—6-yl} methyl)amino]pyrrolidin—2-one [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l60— NH CH3 A solution of Intermediate 31A (80 mg, 167 umol) in methanol (1.4 ml) was treated with (3R) aminopyrrolidin—2-one (21 mg, 251 umol), sodium cyanoborohydride (52 mg, 836 umol) and acetic acid (19 pl, 334 umol). After stirring at 60°C for 16 h, the resulting mixture was separated by pre- parative RP-HPLC (Reprosil C18, gradient 20—40% acetonitrile/0.2% aq. TFA). The product thus obtained was dissolved in ol and filtered through an anion exchange cartridge (Stratospheres SPE, PL-HC03 MP-resin). The cartridge was eluted with methanol, and the filtrate was evaporated yielding 46 mg (49% of th.) of the title nd.

LC-MS d 2): R. = 0.70 min; MS (ESIpos): m/z = 563 (M+H)+ 10 1H-NMR (400 MHz, DMSO-da): 5 = 8.42 (s, 1H), 8.05 (s, 1H), 7.93-8.24 (br. s, 1H), 7.51 (s, 1H), 7.34 (s, 1H), 6.88 (s, 1H), .07 (br. s, 1H), 4.21-4.37 (m, 2H), 4.19 (s, 2H), 4.10 (t, 1H), 3.96 (s, 3H), 3.56-3.66 (m, 2H), 3.44-3.54 (m, 4H), .27 (m, 4H), 2.47 (s, 4H), 2.16-2.25 (m, 1H), 2.00 (s, 3H), 1.86-1.95 (m, 1H) ppm. e 57 15 1 —(4- {[4-Amino {[(2-hydroxymethylpr0pyl)amino]methyl} (7-methoxymethyl— 1 —benzo- thiophen—2-yl)pyrrolo[2, 1 -f] [1 ,2,4]triazin—7—yl]methyl}piperazin— 1 -yl)ethanone [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena —161— A on of Intermediate 31A (80 mg, 183 umol) in methanol (2 ml) was treated with 1—amino methylpropan—2-ol (31 mg, 251 umol), sodium cyanoborohydride (53 mg, 836 umol) and acetic acid (19 ul, 334 umol). After stirring at 60°C for 16 h, the resulting mixture was separated by pre- 5 parative RP-HPLC (Reprosil C18, nt 20—40% acetonitrile/O.2% aq. TFA). The product thus obtained was dissolved in methanol and filtered through an anion exchange cartridge (Stratospheres SPE, PL-HC03 MP-resin). The cartridge was eluted with methanol, and the filtrate was evaporated yielding 29 mg (31% of th.) of the title compound.

LC-MS (method 2): R = 0.71 min; MS (ESIpos): m/z = 552 (M+H)+ 10 ‘H-NMR (400 MHz, DMSO-ds): 5 = 7.96 (s, 1H), 7.59-8.02 (br. s, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 6.84 (s, 1H), 5.45—5.93 (br. s, 1H), 4.13 (br. s, 1H), 3.95 (s, 3H), 3.93 (s, 2H), 3.71 (s, 2H), 3.37— 3.44 (m, 4H), 2.45 (s, 3H), 2.32—2.43 (m, 6H), 1.97 (s, 3H), 1.03 (s, 6H) ppm.

Example 58 4—( {4-Amino(7-meth0xymethyl— 1 —benzothiophen—2-yl) [(3 -0xopiperazin— 1 —yl)methyl]pyrrolo- 15 [2, 1 -t] [1 ,2,4]triazin—7-yl}methyl)piperazine— 1 —carbaldehyde formiate [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —162— X HCOOH Acetic acid anhydride (498 ul, 5.17 mmol) and formic acid (237 pl, 6.28 mmol) were stirred first 2 h at 50°C and then overnight at rt. uently, the mixture was diluted with dichloromethane (5.1 ml), and 1.16 ml of this solution were added to a solution of Example 49 (233 mg, 370 umol) in pyridine (89 ul). After stirring at rt for 2 h, the mixture was diluted with methanol and then eva- porated. The residue was purified by ative RP—HPLC (Reprosil C18, nt 10—95% aceto— nitrile/O. 1% aq. formic acid) affording 77 mg (35% of th.) of title compound.

LC—MS (method 4): R. = 0.62 min; MS (ESIpos): m/z = 549 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): inter al. 8 = 8.14 (s, 1H), 7.97 (s, 2H), 7.67 (s, 1H), 7.38 (s, 1H), 10 7.30 (s, 1H), 6.84 (s, 1H), 3.96 (s, 2H), 3.95 (s, 3H), 3.58 (s, 2H), 3.04 (br. t, 2H), 2.86 (s, 2H), 2.45 (s, 3H), 2.42 (br. t, 2H) ppm.

Example 59 4-( {7- [(4-Acetylpiperazin— 1 -yl)methyl] amino(7-methoxymethylbenzothiophenyl)- pyrrolo[2,1-f] [1 ,2,4]triazinyl}methyl)piperazin—2-one [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena —163— A suspension of Example 49 (310 mg, 522 umol) in dichloromethane/THF (2.5:1, 9.64 ml) was treated with sodium carbonate (442 mg, 4.17 mmol) and stirred at rt for 30 min. Acetyl chloride (74 ul, 1.04 mmol) was added, and the resulting mixture was stirred at rt for 2 h. After quenching with methanol, the mixture was evaporated, and the residue was purified by preparative RP—HPLC sil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) affording 133 mg (45% of th.) of the title compound.

LC—MS (method 2): R. = 0.69 min; MS (ESIpos): m/z = 563 (M+H)+ 1H-NMR (400 MHz, methanol-d4): 5 = 7.89 (s, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 6.79 (s, 1H), 4.13 10 (s, 2H), 3.98 (s, 3H), 3.74 (s, 2H), 3.59 (t, 2H), 3.54 (t, 2H), 3.18 (t, 2H), 3.02 (s, 2H), 2.68-2.55 (m, 6H), 2.48 (s, 3H), 2.08 (s, 3H) ppm.

Example 60 Methyl 4-amino(7-methoxy—5-methylbenzothiophenyl)(piperazinylcarbonyl)pyrrolo- [2,1-f][1,2,4]t1iazinecarboxylate bis(formiate) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —164- X 2 HCOOH To a solution of Intermediate 28A (15 mg, 26 umol) in a thanol mixture (5:1, 180 pl), cooled to 0°C, was added (trimethylsilyl)diazomethane (2 M solution in hexane, 15 pl, 32 umol).

The resulting mixture was slowly warmed to rt over 30 min and then evaporated. The residue was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 ml) and stirred at rt for 1 h.

After ation, the residue was purified by preparative C (Reprosil C18, gradient 10- 95% itrile/0.1% aq. formic acid) affording 4.8 mg (35% of th.) of the title nd.

LC—MS (method 2): Rt = 0.66 min; MS (ESIpos): m/z = 481 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): inter a]. 8 = 8.17 (s, 2H), 8.38-8.23 (br. s, 1H), 8.04 (s, 1H), 7.43 10 (s, 1H), 7.31 (s, 1H), 6.86 (s, 1H), 5.71-5.58 (br. s, 1H), 3.96 (s, 3H), 3.60 (s, 3H, overlap with water peak), 2.46 (s, 3H) ppm.

Example 61 5—(7—Methoxy—5-methylbenzothiophen-2—yl)—6—(1 ,3 —oxazolyl)(piperazinylmethyl)pyrrolo— [2,1-f] [1,2,4]triazin—4-amine trihydrochloride [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena —l65— A solution of Intermediate 25A (100 mg, 0.19 mmol) in methanol (3.33 ml) was treated with (4-toluenesulfonyl)methylisocyanide (36 mg, 0.19 mmol) and potassium carbonate (25 mg, 186 umol). The mixture was refluxed for 6 h. It was then ed with the ons mixtures from three 30 mg test runs and evaporated. The residue was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (10 ml) and stirred at rt for 2 h. After evaporation, the residue was purified by two—fold preparative RP-HPLC (Reprosil C18, nt 10-95% acetonitrile/O.1% aq. TFA).

Further purification by column chromatography on silica gel (dichloromethane/methanol 5:1 with 0.5% aq. ammonia) and lyophilization from a 4 M solution of hydrogen chloride in 1,4—dioxane 10 afforded 75 mg (34% of th.) of the title compound.

LC—MS (method 4): R. = 0.69 min; MS (ESIpos): m/z = 476 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): inter al. 8 = 8.40 (s, 1H), 8.20 (s, 1H), 7.46 (s, 1H), 7.35 (s, 1H), 6.96 (s, 1H), 6.89 (s, 1H), 3.95 (s, 3H), 2.46 (s, 3H) ppm.

Example 62 15 6—(Aminomethyl)(7-methoxy—5-methyl— 1 thiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo- [2, l -f] [l ,2,4]triazin—4-amine trihydrochloride [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena —166— X3HC| A suspension of Intermediate 29A (76 mg, 134 umol) and 10% Pd/C (60 mg) in a 0.5 M solution of hydrogen chloride in methanol (20 ml) was stirred at rt for 3 h under 1 atm of hydrogen. The mixture was then filtered through kieselguhr, the filtrate was evaporated, and the residue was purified by preparative RP-HPLC (Reprosil C18, nt 10-95% acetonitrile/0.1% aq. TFA). The product thus obtained was lyophilized from a 4 M solution of hydrogen chloride in 1,4-dioxane affording 34 mg (46% of th.) of the title compound.

LC—MS (method 2): R = 0.55 min; MS (ESIpos): m/z = 438 (M+H)+ 1H-NMR (400 MHz, DMSO-da): inter al. 8 = 8.24 (br. s, 3H), 8.12 (s, 1H), 7.52 (s, 1H), "L34 (s, 10 1H), 6.89 (s, 1H), 3.96 (s, 3H), 3.76-3.63 (m, 1H), 3.52-3.42 (m, 1H), 2.47 (s, 3H) ppm.

Example 63 N— { [4—Amino(7-methoxymethylbenzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo— [2, 1 —f] [1 ,2,4]triazin—6-yl]methyl} ide bis(trifluoroacetate) [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena —167— H30 [CH3 0 CH3 N / / \< K ,N / O x 2 CFscOOH N/\\ \\/NH A solution of Intermediate 30A (210 mg, 362 umol) in dichloromethane (26 ml) was treated With trifluoroacetic acid (5.2 ml) and stirred at rt for 1 h. After evaporation at rt, the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. TFA) affording 163 mg (63% of th.) of the title compound.

LC—MS (method 3): R: 2.42 min; MS (ESIpos): m/z = 480 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): inter a]. 8 = .75 (br. s, 1H), 8.30-8.16 (br. s, 1H), 8.08 (s, 1H), 7.38 (s, 1H), 7.33 (s, 1H), 6.87 (s, 1H), 4.32 (br. d, 2H), 3.96 (s, 3H), 3.40-2.98 (m, 8H), 2.46 (s, 3H), 1.77 (s, 3H) ppm. 10 Example 64 N— { [4-Amino(7-methoxymethylbenzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo— [2, 1 —f] [1 ,2,4]triazin—6-yl]methyl} acetamide dihydrochloride [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —168— A solution of Intermediate 30A (80 mg, 0.14 mmol) in dichloromethane (10 ml) and trifluoroacetic acid (2 ml) was stirred at rt for 1 h and then evaporated. Purification by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) and lyophilization from a mixture ofmethanol and 4 M solution of hydrogen chloride in oxane afforded 39 mg (50% of th.) of the title compound.

LC-MS (method 5): R = 1.56 min; MS (ESIpos): m/z = 480 (M+H)+ 1H-NMR (400 MHz, DMSO-da): inter al. 8 = 8.12 (s, 1H), 7.38 (s, 1H), 7.33 (s, 1H), 6.87 (s, 1H), 4.37 (br. d, 2H), 3.96 (s, 3H), 3.85-3.20 (m, 8H, overlap with water peak), 2.46 (s, 3H), 1.76 (s, 3H) ppm. 10 Example 65 N-( {4-Amino [(4-formylpiperazin— 1 -yl)methyl](7-methoxy—5-methylbenzothiophen—2-yl)- o [2, 1 -f] [1 ,2,4]triazin—6-yl}methyl)acetamide formiate Acetic acid anhydride (304 pl, 3.16 mmol) and formic acid (145 pl, 3.16 mmol) were stirred first 2 h 15 at 50°C and then overnight at rt. Subsequently, the mixture was diluted with dichloromethane (3.1 ml), and 663 pl of this on were added to a solution of Example 63 (160 mg, 226 umol) in pyridine (54 ul). The e was d at rt for 2 h, then diluted with methanol (1 ml), and stirring was continued at 40°C for another 2 h. After evaporation, the residue was purified by preparative RP—HPLC sil C18, gradient 10-95% itrile/0.1% aq. formic acid) affording 74 mg (61% 20 of th.) of title compound.

EMS (method 4): R = 0.65 min; MS (ESIpos): m/z = 508 (M+H)+ [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na —169— ‘H-NMR (400 MHz, DMSO-ds): 5 = 8.13 (s, 1H), 8.06-7.89 (m, 3H), 7.38 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 4.28 (d, 2H), 4.01-3.88 (m, 5H), 2.47—2.34 (m, 7H), 1.75 (s, 3H) ppm.

Example 66 N-( {7- [(4-Acetylpiperazin— 1 -yl)methyl] amino(7-methoxymethylbenzothiophen—2-yl)- 5 o[2, 1 -f] [1 ,2,4]triazin—6-yl} methyl)acetamide A solution of Example 63 (110 mg, 229 umol) and acetyl chloride (32 pl, 458 umol) in THF/ dichloromethane (1 :2, 3 ml) was treated with sodium ate (194 mg, 1.83 mmol) and stirred at rt overnight. Then, the mixture was diluted with methanol (2 ml) and water (1 ml) and stirred at rt 10 for 1 h. After evaporation, the residue was purified by preparative RP-HPLC (Reprosil C18, gra- dient 10-95% acetonitrile/0.1% aq. formic acid). Lyophilization from 1,4-dioxane and re-purification by column chromatography on silica gel (dichloromethane/methanol 50:1 —> 100% ol) affor- ded 35 mg (28% of th.) of the title compound.

LC—MS (method 2): R: = 0.70 min; MS (ESIpos): m/z = 522 (M+H)+ 15 1H-NMR (400 MHz, a): 5 = .98 (m, 2H), 7.38 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 4.27 (d, 2H), 3.95 (s, 3H), 3.91 (s, 2H), 3.44—3.36 (m, 4H), 2.48-2.35 (m, 7H), 1.98 (s, 3H), 1.75 (s, 3H) ppm.

Example 67 — 4—Amino(7-methoxymethylbenzothiophen—2—yl) [(3 -oxopiperazin— 1 -yl)methyl]— 20 lo[2, l-f] [1,2,4]triaziny1}methyl)acetamide [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —170— A suspension of ediate 32A (35 mg, 73 umol) in methanol (4.1 ml) was treated with acetic anhydride (13 pl, 146 umol) and 10% Pd/C (41 mg) and stirred at rt for 1 h under 1 atm of hydro- gen. Filtration over kieselguhr and evaporation of the filtrate afforded 30 mg (79% of th.) of the title 5 compound.

LC-MS d 5): R: = 1.65 min; MS (ESIpos): m/z = 494 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 7.99 (s, 2H), 7.75 (br. s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 4.27 (s, 1H), 4.26 (s, 1H), 3.95 (s, 5H), .08 (m, 2H), 3.05-2.96 (m, 2H), 2.66-2.57 (m, 2H), 2.45 (s, 3H), 1.72 (s, 3H) ppm. 10 Example 68 4—Amino(hydroxymethyl)(7-methoxy—5—methylbenzothiophen—2-yl)pyrrolo[2, 1 -f] [1 ,2,4] — triazine—7—carbonitrile [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena ation] na None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l71— A solution of Intermediate 38A (1 g, 2.08 mmol) in THF (10 n11) was treated with a 1 M solution of tetra-n-butylammonium fluoride in THF (12 ml, 12 mmol). The mixture was d at rt overnight and then evaporated. The residue was taken up in water and extracted three times with ethyl acetate.

The combined organic phases were dried over ium sulfate and evaporated. The residue was triturated in tert—butyl methyl ether, and the solid was filtered off affording 680 mg (78% of th.) of the title compound.

LC—MS (method 2): R. = 0.95 min; MS (ESIpos): m/z = 366 (M+H)+ 1H—NMR (400 MHz, DMSO-ds): 6 = 8.61-8.29 (br. s, 1H), 8.18 (s, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 6.87 (s, 1H), 6.32-6.03 (br. s, 1H), 5.46 (t, 1H), 4.55 (d, 2H), 3.96 (s, 3H), 2.45 (s, 3H) ppm. 10 Example 69 4-Amino(methoxymethyl)(7-methoxy—5—methylbenzothiophen—2-yl)pyrrolo [2, 1 -f] [1 ,2,4] - triazinecarbonitrile A solution of Example 68 (60 mg, 164 umol) in dichloromethane (5 ml) was treated with thionyl 15 chloride (18 ul, 246 umol). The mixture was stirred at rt for 15 min and then evaporated. The resi- due was dissolved in methanol (2 ml) and treated with DIPEA (57 pl, 328 umol). The mixture was stirred first 2 h at 60°C, then refluxed overnight and finally heated to 150°C for 30 min in a micro- wave device. After this, the mixture was evaporated, and the residue was purified by preparative RP- HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. TFA). The product thus obtained was 20 dissolved in methanol and filtered h an anion exchange cartridge (Stratospheres SPE, PL- HC03 in). The cartridge was eluted with methanol, and the filtrate was evaporated affording 18 mg (28% of th.) of the title compound.

D LC—MS (method 4): R. = 1.12 min; MS (ESIpos): m/z = 379 (M+H)+ [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —172— ‘H-NMR (400 MHz, DMSO-ds): 5 = 8.61-8.40 (br. s, 1H), 8.21 (s, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 6.8? (s, 1H), 6.34-6.09 (br. s, 1H), 4.47 (s, 2H), 3.96 (s, 3H), 3.26 (s, 3H), 2.45 (s, 3H) ppm.

Example 70 4-Amino(ethoxymethyl)(7-methoxymethylbenzothiophen—2-yl)pyrrolo[2, 1 -f] [1,2,4]- triazinecarbonitrile A solution of e 68 (60 mg, 164 umol) in dichloromethane (5 ml) was treated with thionyl chloride (18 pl, 246 umol). The mixture was stirred at It for 15 min and then evaporated. The resi- due was dissolved in ethanol (2 ml) and treated with DIPEA (57 pl, 328 umol). The mixture was 10 stirred at 60°C overnight and then heated to 150°C for 30 min in a microwave device. After this, the mixture was evaporated, and the residue was d by ative C (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. TFA). The product thus obtained was dissolved in ethanol (2 ml) and again heated to 150°C for 30 min in the microwave oven. DIPEA (57 ul, 328 umol) was added, and heating to 150°C in the microwave oven was continued for further 30 min. After eva- 15 poration, the residue was purified by column chromatography on silica gel (dichloromethane/ methanol 95:5) affording 16 mg (23% ofth.) of the title nd.

LC—MS (method 2): R = 1.18 min; MS s): rn/Z = 393 (M+H)+ 1H-NMR (400 MHz, DMSO-da): 5 = 8.61-8.38 (br. s, 1H), 8.20 (s, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 6.87 (s, 1H), 6.33-6.08 (br. s, 1H), 4.51 (s, 2H), 3.96 (s, 3H), 3.45 (q, 2H), 2.45 (s, 3H), 1.10 (t, 20 3H) ppm.

D ation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —173— Example 71 4—Amino(7-methoxymethylbenzothiophen—2-yl) [(3 -oxopiperazin— 1 -y1)methy1]pyrrolo [2, 1 - f][1,2,4]triazinecarbonitri1e A solution of Intermediate 39A (20 mg, 55 umol) in THF (0.73 ml) was treated with acetic acid (6 pl, 110 umol), 2-oxopiperazine (27 mg, 275 umol) and sodium triacetoxyborohydride (58 mg, 275 umol). After stirring at rt for 3 h, further amounts of THF (1 ml), acetic acid (6 u], 110 umol), 2-0xopiperazine (27 mg, 275 umol) and sodium triacetoxyborohydride (58 mg, 275 umol) were added, and stirring at rt was continued overnight. After evaporation, the residue was purified by pre- 10 parative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. TFA). The product thus obtained was dissolved in methanol and filtered through an anion exchange cartridge ospheres SPE, PL-HC03 MP-resin). The dge was eluted with methanol, and the filtrate was evaporated affording 13 mg (52% of th.) of the title compound.

LC-MS d 2): R = 0.86 min; MS (ESIpos): m/z = 447 (M+H)+ 15 1H-NMR (400 MHz, DMSO-ds): 5 = 8.60—8.31 (br. s, 1H), 8.19 (s, 1H), 7.74 (s, 1H), 7.44 (s, 1H), 7.33 (s, 1H), 6.87 (s, 1H), 6.25-5.98 (br. s, 1H), 3.96 (s, 3H), 3.62 (s, 2H), 3.13-3.07 (m, 2H), 2.91 (s, 2H), 2.45 (s, 3H) ppm.

Example 72 N,N’— {[4-Amino(7-methoxymethy1— 1 —benzothiophen—2-y1)pyrrolo[2,1 -f] [1 ,2,4]triazine— 20 6,7—diyl]bis(methylene) } diacetamide D [Annotation] na None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —174— A suspension of Intermediate 40A (crude, 85 mg), 10% Pd/C (115 mg) and acetic ide (40 ul, 435 umol) in methanol (12 ml) was stirred at rt under 1 atm of hydrogen. After 4 h, further s of 10% Pd/C (115 mg) and acetic anhydride (40 ul, 435 umol) were added, and stirring at rt under 1 atm of hydrogen was continued for 2 h. The resulting mixture was filtered through kieselguhr, the filtrate was evaporated, and the residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. TFA). The product thus obtained was dissolved in methanol and filtered h an anion exchange cartridge (Stratospheres SPE, PL-HC03 MP—resin). The cartridge was eluted with methanol, and the filtrate was evaporated affording 18 mg (18% of th.) of 10 the title compound.

LC-MS (method 2): R. = 0.73 min; MS (ESIpos): m/z = 452 (M+H)+ 1H-NMR (400 MHz, DMSO-da): 8 = 8.29 (br. t, 1H), 8.04 (br. t, 1H), 8.00 (s, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 4.58 (d, 2H), 4.26 (d, 2H), 3.95 (s, 3H), 2.45 (s, 3H), 1.81 (s, 3H), 1.74 (s, 3H) ppm. 15 Example 73 2— [4-Amino(hydroxymethyl)(7-methoxy—5—methylbenzothiophen—2-yl)pyrrolo [2, 1 —f] [1 ,2,4] - triazin—7-yl]propan—2-ol [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —175— A flask containing a suspension of Intermediate 43A (180 mg, 598 umol), Intermediate 6A (299 mg, 897 umol) and caesium fluoride (454 mg, 2.99 mmol) in THF/water (10:1, 11 ml) was degassed under d pressure and then refilled with argon. 4-(Di-tert—butylphosphino)-N,N- dimethylaniline-dichloropalladium (2:1; 13 mg, 18 umol) was added. The resulting mixture was degassed again and stirred under argon at 50°C for 16 h. After this, the reaction mixture was sepa- rated by preparative RP-HPLC (Reprosil C18, gradient 30-50% acetonitrile/O.2% aq. TFA). The t fractions were diluted with a 7 M solution of ammonia in methanol and then concentrated under reduced pressure. The precipitate was d off, washed with water and dried in vacuo 10 yielding 99 mg (42% of th.) of the title compound.

LC-MS (method 2): R = 0.89 min; MS (ESIpos): m/z = 399 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 7.96 (s, 1H), 7.51-8.02 (br. s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 6.86 (s, 1H), 5.99 (s, 1H), 5.23-5.82 (br. s, 1H), 5.04 (t, 1H), 4.53 (d, 2H), 3.96 (s, 3H), 2.45 (s, 3H), 1.73 (s, 6H) ppm. 15 Example 74 4— { [4-Amino(2-hydroxypropan—2-yl)-5—(7—methoxymethylbenzothiophen—2-yl)pyrrolo— [2,1 -f] [1 ,2,4]triazin—6-yl]methyl}piperazin—2—one [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena -176— A solution of Intermediate 44A (50 mg, 73% purity, 92 umol) in methanol (4 ml) was treated with 2—oxopiperazine (28 mg, 276 umol), sodium cyanoborohydride (23 mg, 368 umol) and acetic acid (21 pl, 368 umol). The mixture was stirred first 18 h at 60°C and then 3 days at rt. After this, the e was separated by preparative C (Reprosil C18, gradient 20-40% acetonitrile/0.2% aq. TFA). The product fractions were diluted with a 7 M solution of ammonia in methanol and evaporated under d pressure. The residue was dissolved in ethyl acetate and washed with water. The organic phase was dried with sodium sulfate and concentrated under reduced re.

The residue was dissolved in 1,4-dioxane and lyophilized yielding 24 mg (52% of th.) of the title 10 compound.

LC-MS (method 5): R = 1.85 min; MS (ESIpos): m/z = 481 (M+H)+ 1H-NMR (400 MHz, s): 8 = 7.99 (s, 1H), 7.73-8.01 (br. s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 6.87 (s, 1H), 5.2-5.7 (br. s, 1H), 3.95 (s, 3H), 3.57 (s, 2H), 3.14 (br. s, 2H), 2.60 (br. s, 4H), 2.46 (s, 3H), 1.70 (br. s, 6H) ppm. 15 Example 75 [4—Amino(7-methoxymethylbenzothiophen—2-yl)methylpyrrolo [2, 1 -f] [1 ,2,4]triazin—6-yl] - methanol [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na —177— Under an argon atmosphere, a flask was charged with 165 mg (0.64 mmol) of ediate 53A, 143 mg (0.64 mmol) of Intermediate 5A, 25 mg (0.03 mrnol) (2'-aminobiphenylyl)(chloro)palladium— dicyclohexyl(2',4',6'-t1iisopropylbiphenylyl)phosphine (1 :1; see S. L. Buchwald et al., J. Am.

Chem. Soc. 132 (40), 14073-14075 ) and 409 mg (1.93 mmol) potassium phosphate. Then, 7 ml of a degassed mixture of 1,4-dioxane and water (5:1) were added, and the solution was stirred at 70°C for 1 h. Another portion of Intermediate 5A (142 mg, 0.64 mmol) and of (2'-aminobiphenyl yl)(chloro)palladium—dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine (10 mg, 0.012 mmol) were added, and stirring was continued for 1 h. After this, the reaction mixture was partially 10 evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were evaporated under reduced pressure, and the residue was triturated with acetonitrile. The precipitate was filtered off and dried in vacuo yielding 180 mg (92% purity by LC-MS, 73% of th.) of the title compound. From the filtrate a second batch (41 mg, 18% of th.) was obtained by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/O.1% aq. 15 formic acid). Total yield: 91% of th.

LC-MS d 5): R. = 1.92 min; MS (ESIpos): m/z = 355 (M+H)+ 1H—NMR (400 MHz, DMSO-ds): 8 = 7.95 (s, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 6.83 (s, 1H), 4.82 (t, 1H), 4.44 (d, 2H), 3.95 (s, 3H), 2.45 (s, 3H) ppm.

Example 76 20 4- { no(7-methoxy—5-methylbenzothiophen—2-yl)methylpyrrolo [2, 1 -f] [1 ,2,4]triazin—6- yl]methyl}piperazin—2-one D [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na -178— A suspension of 55 mg (0.16 mmol) of Intermediate 54A in THF (1.5 ml) was treated with 78 mg (0.78 mmol) piperazin—2-one, 18 pl (0.31 mmol) acetic acid and 166 mg (0.78 mmol) triacetoxy- dride. The mixture was stirred at ambient temperature overnight. Then, 1.5 ml water were added, and most of the THF solvent was evaporated under d pressure. The remaining mixture was diluted with more water, and the precipitated solid was filtered off and dried (35 mg). This material was further purified by preparative RP—HPLC (Reprosil C18, gradient 10—95% aceto— nitrile/0.1% aq. formic acid). The product fractions were adjusted to pH 9 with solid potassium carbonate and partially concentrated under reduced pressure. The itated solid was filtered off 10 and dried at 45°C in vacuo to afford 16 mg (24% of th.) of the title compound.

LC-MS (method 5): R = 1.74 min; MS (ESIpos): m/z = 437 (M+H)+ lH-NMR (400 MHz, DMSO-da): 8 = 7.95 (s, 1H), 7.66 (br. s, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 6.83 (s, 1H), 3.95 (s, 3H), 3.50 (s, 2H), 3.05 (m, 2H), 2.84 (s, 2H), 2.45 (m, 5H) ppm.

Example 77 15 1 —( { [4-Amino(7-methoxymethyl— 1 —benzothiophen—2-yl)methylpyrrolo[2, 1 —f] [1 ,2,4]triazin—6- yl]methyl} amino)-2—methylpropan—2-ol formiate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —179— H3C ICH3 0 CH N/ 3 / 3C k / OH \ ,N N H CH3 xHCOOH A suspension of 55 mg (0.16 mmol) of Intermediate 54A in THF (1.5 ml) was d with 98 mg (0.78 mmol) 1-aminomethylpropan—2-ol hydrochloride, 39 mg (0.47 mmol) sodium acetate and 166 mg (0.78 mmol) sodium triacetoxyborohydride. The mixture was stirred at ambient temperature overnight. Then, 1.5 ml water were added, and the mixture was evaporated under reduced pressure.

The residue was purified by preparative RP-HPLC (Reprosil C18, gradient 10-95% aceto- nitrile/O. 1% aq. formic acid) to afford 38 mg (52% of th.) of the title compound.

LC-MS (method 5): R = 1.68 min; MS (ESIpos): m/z = 426 (M+H)+ lH—NMR (400 MHz, DMSO-dg): 5 = 8.19 (s, 1H), 7.94 (s, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 6.84 (s, 10 1H), 3.95 (s, 3H), 2.45 (s, 3H), 2.34 (s, 2H), 1.02 (s, 6H) ppm.

Example 78 1 —( { [4-Amino(7-methoxymethylbenzothiophen—2-yl)methylpyrrolo [2, 1 -f] [1 ,2,4]triazin—6- hyl} amino)methylpropan—2-ol [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l80— A solution of 29 mg (0.06 mmol) of Example 77 in 3 ml of methanol was run through a Strato- spheres SPE PL-HC03 MP-resin cartridge, preconditioned with 2 ml of methanol. The cartridge was washed with 4 ml of ol, and the eluate was evaporated to afford 21.5 mg (82% of th.) of the title nd.

LC-MS (method 4): R. = 0.68 min; MS (ESIpos): m/z = 426 (M+H)+ ‘H—NMR (400 MHz, DMSO-ds): 8 = 7.94 (s, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 6.83 (s, 1H), 4.07 (s, 1H), 3.95 (s, 3H), 3.63—3.75 (m, 2H), 2.45 (s, 3H), 2.32 (m, 3H), 1.42-1.56 (m, 1H), 1.02 (s, 6H) Example 79 10 nochloro(7-methoxy—5-methyl-1—benzothiophen—2-yl)pyrrolo[2,1 -f] [1 ,2,4]triazin—6-yl] - methanol A solution of Intermediate 48A (117 mg, 0.24 mmol) in 5 ml THF was treated with 5 ml conc. hydrochloric acid and stirred at ambient ature overnight. Then, 12 ml of 5 M aq. sodium 15 hydroxide solution as well as ethyl acetate were added, the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with sat. aq. sodium chloride solution, dried and evaporated. The residue was purified by preparative RP—HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) to afford 30 mg (34% of th.) of the title nd. 20 LC-MS (method 2): R. = 0.90 min; MS (ESIpos): m/z = 375 (M+H)+ ‘H-NMR (400 MHz, DMSO-da): 8 = 8.04 (s, 1H), 7.43 (s, 1H), 7.32 (s, 1H), 6.85 (s, 1H), 5.02 (t, 4.43 (d, 2H), 3.96 (s, 3H), 2.45 . (s, 3H) ppm.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na —181— 9.2 mg (10% of th.) of 7-chloro(chloromethyl)(7-methoxymethylbenzothiophenyl)- pyrrolo[2,1-f] [1,2,4]triazin—4-amine were ed as a by-product (cf. Intermediate 50A). e 80 4- { [4-Aminochloro(7-methoxymethyl-1 -benzothiophen—2-yl)pyrrolo [2, 1 -f] [1 riazin— 6—yl]methyl }piperazin—2-one The title compound was prepared according to the procedure of Example 76 starting from 40 mg (0.11 mmol) of Intermediate 49A. Yield: 27 mg (55% of th.).

LC-MS (method 2): R = 0.86 min; MS (ESIpos): m/z = 457 (M+H)+ 10 1H-NMR (400 MHz, DMSO-ds): 8 = 8.05 (s, 1H), 7.68 (br. s, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 3.96 (s, 3H), 3.52 (s, 2H), 3.05 (br. s, 2H), 2.86 (s, 2H), 2.45 (s, 3H) ppm.

Example 81 1—({[4-Aminochlor0(7-methoxy—5—methyl—1-benzothiophen—2-yl)pyrrolo[2,1—f] [1 ,2,4]t1iazin—6- yl]methyl} amino)methylpropan—2-ol formiate [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na —l82— The title compound was prepared according to the procedure of Example 77 starting from 40 mg (0.11 mmol) of Intermediate 49A. Yield: 24 mg (45% of th.).

LC-MS (method 2): R = 0.73 min; MS (ESIpos): m/z = 446 (M+H)+ ‘H—NMR (400 MHz, DMSO-ds): 5 = 8.15 (s, 1H), 8.04 (s, 1H), 7.45 (s, 1H), 7.30 (s, 1H), 6.85 (s, 1H), 3.96 (s, 3H), 3.73 (s, 2H), 2.45 (s, 3H), 2.32 (s, 2H), 1.00 (s, 6H) ppm.

Example 82 1—( { [4-Aminochloro(7-methoxymethyl— l -benzothiophen—2-yl)pyrrolo[2, l -f] [1,2,4]triazin yl]methyl} amino)methylpropan—2-ol 10 The title nd was prepared from e 81 according to the procedure of Example 78.

EMS (method 2): R = 0.72 min; MS (ESIpos): m/z = 446 (M+H)+ [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena _ 183 — ‘H-NMR (400 MHz, DMSO-ds): 8 = 8.04 (s, 1H), 7.45 (s, 1H), 7.30 (s, 1H), 6.85 (s, 1H), 4.09 (br. s, 1H), 3.95 (s, 3H), 3.71 (s, 2H), 2.45 (s, 3H), 2.31 (s, 2H), 1.44-1.64 (m, 1H), 1.00 (s, 6H) ppm.

Example 83 7-Chloro(ethoxymethyl)(7-methoxymethyl- l -benzothiophen—2-yl)pyrrolo[2, l -f] [1,2,4]- triazin—4-amine 8.2 mg (0.02 mmol) of Intermediate 50A were suspended in 1 ml of ethanol, treated with 41 ul (0.11 mmol) of a 2.68 M on of sodium ethanolate in ethanol and refluxed for 1 min. The clear solu- tion was then evaporated, and the crude product was purified by preparative C (Reprosil 10 C18, gradient 10-95% acetonitrile/0.l% aq. formic acid) to afford 5 mg (56% of th.) of the title compound.

LC-MS (method 4): R1 = 1.25 min; MS (ESIpos): m/z = 402 (M+H)+ 1H—NMR (400 MHz, DMSO-da): 8 = 8.06 (s, 1H), 7.40 (s, 1H), 7.32 (s, 1H), 6.86 (s, 1H), 4.40 (s, 2H), 3.96 (s, 3H), 3.40 (q, 2H), 2.45 (s, 3H), 1.06 (t, 3H) ppm. 15 e 84 5—(7-Methoxymethylbenzothiophen—2—yl)—6-methyl(piperazin— l -ylmethyl)pyrrolo[2, l —f] - [1,2,4]triazinamine formiate [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —184- A solution of ediate 57A (100 mg, 191 umol) in a 4 M solution of hydrogen chloride in 1,4- dioxane (2 ml) was stirred at rt for 3 h and then evaporated. Purification by two-fold preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.1% aq. formic acid) afforded 71 mg (67% 5 ofth.) of the title compound.

LC—MS (method 2): R: 0.81 min; MS (ESIpos): m/z = 423 (M+H)+ 1H-NMR (400 MHZ, CDCl3)Z 6 = 8.46 (br. s, 1H), 7.89 (s, 1H), 7.27 (s, 1H, overlap with CHC13 peak), 7.18 (s, 1H), 6.67 (s, 1H), 4.01 (s, 3H), 3.97 (s, 2H), .09 (m, 4H), .73 (m, 4H), 2.50 (s, 3H), 2.24 (s, 3H) ppm. 10 Example 85 ro(7-methoxymethylbenzothiophen—2-yl)(piperazin— 1 -ylmethyl)pyrrolo[2, 1 —f] - [1 ,2,4]triazin—4-amine trihydrochloride [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena —l85— Intermediate 60A (65 mg, 0.12 mmol) was stirred in 1 ml of a 4 M solution of hydrogen chloride in 1,4-dioxane for 2 h at rt. The suspension was evaporated to s, and the crude product was puri- fied by preparative RP-HPLC (Reprosil C18, gradient 10-95% acetonitrile/0.l% aq. hydrochloric acid) affording 49 mg (74% of th.) of the title compound.

LC-MS (method 2): R. = 0.81 min; MS (ESIpos): m/z = 443 (M+H)+ 1H—NMR (400 MHz, DMSO-da): inter al. 8 = 9.56 (br. s, 1H), 8.45 (br. s, 1H), 8.19 (s, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 6.89 (s, 1H), 6.30 (br. s, 1H), 4.63 (br. s, 1H), 3.40 (br. s, 8H), 2.46 (s, 3H) Example 86 10 [4-Amino(ethoxymethyl)(7-methoxy—5—methyl- l -benzothiophen—2-yl)pyrrolo [2, 1 -f] [1 ,2,4] - triazin—7-yl]methanol The title compound (360 mg) was obtained as a side product in the ation of Example 5 by preparation method 1. 15 LC—MS (method 2): R. = 0.99 min; MS (ESIpos): m/z = 399 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = .72 (br. s, 1H), 7.99 (s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 6.05-5.48 (br. s, 1H), 5.04 (br. s, 1H), 4.81 (d, 2H), 4.47 (s, 2H), 3.96 (s, 3H), 3.39 (q, 3H), 2.45 (s, 3H), 1.05 (t, 3H) ppm.

Example 87 20 D4-Amino(ethoxymethyl)(7-methoxymethyl-1 -benzothiophenyl)pyrrolo[2, l -f] [1 ,2,4] - triazin—7-yl]methyl}imidazolidin—2—one [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —186— A suspension of Intermediate 63A (100 mg, 0.221 mmol) in THF (5 ml) was treated with imidazolidin—2-one (57 mg, 0.662 mmol) and N,N—diisopropylethylamine (153 pl, 0.926 mmol), and the mixture was heated to 150°C for 90 min in a microwave oven. After this, the reaction mixture 5 was purified by preparative RP-HPLC (Reprosil C18, gradient 40-60% acetonitrile/0.2% aq. trifluoroacetic acid). The product thus obtained was dissolved in ol and filtered through an anion exchange cartridge (Stratospheres SPE, PL-HC03 MP-resin). The cartridge was eluted with ol, and the filtrate was evaporated. The product was purified once again by preparative thin layer chromatography over silica gel (cyclohexane/ethyl acetate 3:1) affording 24 mg (22% of th.) of 10 the title compound.

LC-MS (method 2): R. = 0.99 min; MS (ESIpos): m/z = 467 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.21—7.65 (br. s, 1H), 7.99 (s, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 6.38 (s, 1H), .56 (br. s, 1H), 4.65 (s, 2H), 4.46 (s, 2H), 3.95 (s, 3H), 3.38 (q, 2H), 3.31-3.10 (m, 4H), 2.45 (s, 3H), 1.06 (t, 3H) ppm. 15 Example 88 4— { [4-Amino(7-methoxybenzothiophen—2—yl)(methoxymethyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin—7- yl]methyl}piperazin—2-one [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by na [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —187— To a solution of Intermediate 62A (72.6 mg, 197 umol), (7-methoxybenzothiophen—2—yl)boronic acid (45 mg, 216 umol) and caesium fluoride (149 mg, 983 umol) in degassed THF/water (10:1, 2.2 ml) under argon was added (2'-aminobiphenylyl)(chloro)palladium—dicyclohexyl(2',4',6'—triiso- propylbiphenylyl)phosphine (1 :1; 7.7 mg, 9.8 umol; see S. L. Buchwald et al., J. Am. Chem. Soc. 132 (40), 14073-14075 (2010)). The resulting mixture was degassed again and stirred under argon at 60°C for 3 h. After this, the mixture was separated by preparative RP-HPLC (Reprosil C18, gradient 20-40% acetonitrile/0.1% aq. TFA). The product fractions were combined and evaporated to s. The residue was dissolved in methanol and filtered through an anion exchange cartridge 10 (Stratospheres SPE, PL-HC03 MP-resin). The cartridge was eluted with methanol, and the e was evaporated affording 31 mg (35% of th.) ofthe title compound.

LC-MS (method 2): R. = 0.71 min; MS (ESIpos): m/z = 453 (M+H)+ 1H-NMR (400 MHz, DMSO-ds): 8 = 8.00 (s, 1H), 7.72 (s, 1H), 7.61-8.23 (br. s, 1H), 7.51 (d, 1H), 7.46 (s, 1H), 7.40 (t, 1H), 6.99 (d, 1H), .11 (br. s, 1H), 4.42 (s, 2H), 3.98 (s, 5H), 3.20 (s, 15 3H), 3.11 (br. m, 2H), 3.01 (s, 2H), 2.62-2.67 (m, 2H) ppm.

Example 89 4— { [4-Amino(methoxymethyl)(5-methyl— 1 —benzothiophen—2-yl)pyrrolo[2, 1 -f] [1 ,2,4]triazin— 7-yl]methyl}piperazin—2-one D ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l88— To a on of Intermediate 62A (50 mg, 135 umol), (5-methylbenzothiophen—2-yl)boronic acid (28.6 mg, 149 umol) and caesium fluoride (103 mg, 677 umol) in degassed THF/Water (10:1, 4.4 ml) under argon was added (2'-aminobiphenylyl)(chloro)palladium—dicyclohexyl(2',4',6'—triiso- propylbiphenylyl)phosphine (1:1; 5.3 mg, 6.8 umol; see S. L. Buchwald et al., J. Am. Chem. Soc. 132 (40), 14073-14075 (2010)). The resulting mixture was degassed again and stirred under argon at 60°C for 16 h. After this, the mixture was separated by preparative RP-HPLC (Reprosil C18, gradient 30-50% acetonitrile/0.1% aq. TFA). The product fractions were combined and evaporated to dryness. The residue was dissolved in methanol and filtered h an anion exchange cartridge 10 (StratoSpheres SPE, PL-HC03 MP-resin). The cartridge was eluted with methanol, and the e was evaporated ing 27 mg (45% of th.) ofthe title compound.

LC-MS d 2): R = 0.79 min; MS (ESIpos): m/z = 437 (M+H)+ 1H—NMR (400 MHz, DMSO-dg): 5 = 8.00 (s, 1H), 7.89 (d, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.58— 8.18 (br. s, 1H), 7.40 (s, 1H), 7.24 (dd, 1H), 5.58-6.03 (m, 1H), 4.42 (s, 2H), 3.97 (s, 2H), 3.21 (s, 15 3H), 3.11 (br. t, 2H), 3.01 (s, 2H), 2.64 (t, 2H), 2.44 (s, 3H) ppm.

Example 90 l - [4-Amino(ethoxymethyl)(7-methoxy-5—methylbenzothiophen—2-yl)pyrrolo [2, l -f] [1 ,2,4] - triazin—7-yl]ethanol D ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l89— Under argon, a 1 M solution of methylmagnesium e in THF (630 pl, 630 umol) was added dropwise at rt to a solution of Intermediate 17A (100 mg, 252 umol) in THF (10 ml). The mixture was stirred at rt for 3 h and then treated with another portion of methylmagnesiurn bromide in THF (177 pl, 177 umol). The reaction e was stirred for r 16 h, then quenched with sat. aq. ammonium chloride solution and extracted with ethyl acetate. The ed organic layers were washed with brine, dried with magnesium sulfate, filtered and ated. The residue was purified by preparative RP-HPLC (Reprosil C18, nt 40-60% acetonitrile/O.1% aq. TFA). The product fractions were diluted with sat. aq. sodium hydrogencarbonate solution and extracted with ethyl 10 acetate. The organic phase was washed with sat. aq. sodium chloride solution, dried with magnesium sulfate, filtered and evaporated yielding 39 mg (36% of th.) of the title compound.

LC-MS (method 4): R. = 1.07 min; MS (ESIpos): m/z = 413 (M+H)+ lH-NMR (400 MHz, DMSO-ds): 5 = 7.95 (s, 1H), 7.56-8.07 (br. s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 5.46-5.54 (m, 1H), 5.37-5.95 (br. s, 1H), 5.26 (d, 1H), 4.67 (d, 1H), 4.38 (d, 1H), 15 3.95 (s, 3H), 3.38 (q, 2H), 2.45 (s, 3H), 1.52 (d, 3H), 1.05 (t, 3H) ppm.

Example 91 [4—Amino(ethoxymethyl)(7-methoxy—5—methylbenzothiophenyl)pyrrolo [2, 1 -f] [l ,2,4] - triazinyl](cyclopropyl)methanol [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena —190— Under argon, a 0.5 M solution of cyclopropylmagnesium bromide in THF (1.26 ml, 630 umol) was added se at rt to a solution of Intermediate 17A (100 mg, 252 umol) in THF (5 ml). The mixture was stirred at rt for 1 h, then quenched with sat. aq. ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and evaporated. The residue was purified by preparative RP—HPLC (Reprosil C18, gradient 50-70% itrile/O. 1% aq. TFA). The product fractions were diluted with sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase was washed with sat. aq. sodium chloride solution, dried with magnesium e, d and evaporated 10 yielding 10 mg (10% of th.) of the title compound.

LC-MS (method 2): R1 = 1.13 min; MS (ESIpos): m/z = 439 (M+H)+ lH-NMR (400 MHz, DMSO-da): 8 = 7.94 (s, 1H), 7.68—8.04 (br. s, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 5.47—5.89 (br. s, 1H), 5.30 (d, 1H), 4.64 (d, 1H), 4.59-4.67 (m, 1H), 4.39 (d, 1H), 3.96 (s, 3H), 3.38 (q, 2H), 2.45 (s, 3H), 1.54-1.64 (m, 1H), 1.04 (t, 3H), 0.51—0.59 (m, 1H), 0.40— 15 0.47 (m, 1H), 0.28-0.38 (m, 2H) ppm.

Example 92 (3S)-3 -( { [4-Amino(methoxymethyl)(7-methoxy—5-methylbenzothiophen—2-yl)pyrrolo[2, 1 -f] - [1 ,2,4]triazin—7-yl]methyl} amino)pyrrolidin—2—one D ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena —191— A suspension of Intermediate 13A (100 mg, 0.233 mmol) in THF (2 ml) was treated with (S) aminopyrrolidin—2-one (35 mg, 0.349 mrnol), sodium triacetoxyborohydride (148 mg, 0.698 mmol) and acetic acid (26.6 ul, 0.465 mrnol). The resulting mixture was stirred at rt for 3 h and then directly purified by preparative RP-HPLC sil C18, nt 40-60% acetonitrile/O.2% aq. trifluoroacetic acid). The product fractions were combined and evaporated to dryness. The residue was dissolved in methanol and filtered through an anion exchange cartridge (Stratospheres SPE, PL- HC03 in). The cartridge was eluted with methanol, and the filtrate was evaporated ing 56 mg (51% of th.) of the title nd. 10 LC-MS (method 4): R. = 0.72 min; MS (ESIpos): m/z = 467 (M+H)+ 1H-NMR (400 MHz, DMSO-da): 5 = 8.01 (s, 1H), 7.76 (s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 4.48 (d, 2H), 4.43 (d, 2H), 4.24-4.02 (m, 2H), 3.96 (s, 3H), 3.26-2.99 (m, 6H), 2.45 (s, 3H), 2.40—2.27 (m, 1H), 1.82-1.64 (m, 1H) ppm.

Example 93 15 (3S)-3 -( { [4-Amino(ethoxymethyl)(7-methoxymethyl-1 -benzothiophen—2-yl)pyrrolo[2, 1 -f] - [1 ,2,4]triazin—7-yl]methyl} amino)pyrrolidin—2—one [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —l92— A suspension of Intermediate 17A (100 mg, 0.252 mmol) in THF (2 ml) was treated with (S) yrrolidin—2-one (38 mg, 378 umol), sodium toxyborohydride (160 mg, 757 umol) and acetic acid (30 pl, 504 umol). The resulting e was d at rt for 3 h and then directly purified by preparative RP-HPLC (Reprosil C18, gradient 30-50% acetonitrile/0.2% aq. trifluoro- acetic acid). The product fractions were ed and evaporated to dryness. The residue was dissolved in methanol and filtered through an anion exchange cartridge (Stratospheres SPE, PL- HC03 MP-resin). The cartridge was eluted with methanol, and the filtrate was evaporated affording 84 mg (69% of th.) of the title compound. 10 LC-MS (method 4): R = 0.75 min; MS (ESIpos): m/z = 481 (M+H)+ 1H—NMR (400 MHz, DMso-d6): 8 = 8.00 (s, 1H), 7.75 (s, 1H), 7.67-8.11 (br. s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 6.85 (s, 1H), 5.5-6.0 (br. s, 1H), 4.44 (q, 2H), 4.14—4.21 (m, 1H),4.02-4.11 (m, 1H), 3.38—3.45 (q, 2H), 3.16-3.24 (m, 1H), 3.05—3.16 (m, 2H), 2.45 (s, 3H), .40 (m, 1H), 1.67— 1.79 (m, 1H), 1.08 (t, 3H) ppm. 15 General ure for the preparation of Examples 94—105 in Table 1: A 0.13 M suspension of Intermediate 17A in THF was treated with 1.5 eq. of the tive amine component, 3 eq. of sodium triacetoxyborohydride and 1.5 eq. of acetic acid. The resulting mixture was stirred at 60°C for 3—20 h. After this, purification was carried out according to the methods indicated.

D ation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —193— Table I Example Structure Purification LC-MS data No. method(s) 94 P1,P5 Method 4: R1 = 1.22 min; MS (ESIpos): m/z = 468 (M+H)+ P6, P3 Method 2: R = 0.92 min; MS (ESIpos): m/Z = 509 (M+H)+ P1,P5 Method 4: R = 0.83 min; MS (ESIpos): m/Z = 452 (M+H)+ P1,P5 Method 5: R1 = 1.84 min; MS (ESIpos): m/z = 454 (M+H)+ [Annotation] na None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —194— Example Structure Purification LC-MS data No. method(s) 98 P1,P5 Method 5: R1 = 1.82 min; MS (ESIpos): m/z = 482 (M+H)+ 99 P1,P5 Method 5: R1 = 2.21 min; MS (ESIpos): m/z = 516 (M+H)+ 100 P1,P5 Method 2: R = 0.86 min; MS (ESIpos): m/z = 507 (M+H)+ 101 P1,P5 Method 2: R1 = 0.81 min; MS (ESIpos): m/z = 468 (M+H)+ [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —195— Example Structure ation LC-MS data No. method(s) 102 P1, P5, P4 Method 2: R1 = 1.03 min; MS (ESIpos): m/z = 474 (M+H)+ 103 P1, P5, P2 Method 2: R1 = 1.05 min; MS (ESIpos): m/z = 460 (M+H)+ 104 P1,P6 Method 2: R = 0.91 min; MS (ESIpos): m/z = 467 (M+H)+ 105 P1,P6 Method 2: R = 0.89 min; MS (ESIpos): m/z = 495 (M+H)+ [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena Example 106 4—Amino(ethoxymethyl)(7-methoxy—5—methy1— 1 thiophen—2-y1)-N— [(3R)oxopyrrolidin— 3—y1]pyrrolo[2,1-f][1,2,4]triazinecarboxamide NH A stirred solution of Intermediate 64A (50 mg, 121 umol) in DMF (2 ml) was treated at rt with N—[(1H—benzotriazolyloxy)(dimethylamino)methylene] -N—methylmethanaminium tetrafluoroborate (TBTU) (43 mg, 133 umol) and DIPEA (53 pl, 303 umol). After 15 min, (3R)arnjnopyrrolidin one (24 mg, 242 umol) was added, and the resulting mixture was stirred at rt for further 2 h. After this, the mixture was separated by preparative RP-HPLC (Reprosil C18, gradient 30-50% 10 acetonitrile/0.2% aq. trifluoroacetic acid). The product fractions were combined and evaporated to s. The residue was dissolved in methanol and filtered through an anion exchange cartridge (Stratospheres SPE, PL-HC03 MP-resin). The cartridge was eluted with methanol, and the filtrate was evaporated affording 36 mg (60% of th.) of the title compound.

LC—MS (method 2): R: = 0.91 min; MS (ESIpos): m/z = 495 (M+H)+ 15 1H-NMR (400 MHz, DMSO-da): 5 = 9.50 (d, 1H), 8.21-8.45 (br. s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 6.86 (s, 1H), 5.84—6.09 (br. s, 1H), 4.74 (dd, 2H), 4.47-4.56 (m, 1H), 3.96 (s, 3H), 3.37 (q, 2H), 3.22-3.29 (m, 2H), .61 (m, 1H), 2.46 (s, 3H), 1.90-2.03 (m, 1H), 1.00 (t, 3H) ppm. e 107 20 Q4-Amino(ethoxymethyl)(7-methoxymethylbenzothiophenyl)pyrrolo[2,1-f][1 ,2,4] - triazin—7-y1]carbonyl}piperazin—2-one [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na —l97— A stirred solution of Intermediate 64A (50 mg, 121 umol) in DMF (2 ml) was treated at rt with TBTU (43 mg, 133 umol) and DIPEA (53 u], 303 umol). After 15 min, piperazin—2-one (24 mg, 242 umol) was added, and the resulting mixture was stirred at rt for further 16 h. After this, the mixture was separated by preparative C (Reprosil C18, gradient 40-60% acetonitrile/O.2% aq. trifluoroacetic acid). The product fractions were ed and evaporated to dryness. The resi— due was dissolved in methanol and filtered through an anion exchange dge (Stratospheres SPE, PL—HC03 MP-resin). The cartridge was eluted with ol, and the filtrate was evaporated affording 45 mg (68% of th.) of the title compound. 10 LC—MS (method 2): R. = 0.92 min; MS (ESIpos): rn/z = 495 (M+H)+ lH-NMR (400 MHz, DMSO-da): 8 = 8.14 (br. s, 1H), 7.99-8.01 (m, 1H), 7.9-8.3 (br. s, 1H), 7.41 (d, 1H), 7.32 (s, 1H), 6.86 (s, 1H), 5.78—6.05 (br. s, 1H), 4.30—4.49 (m, 2H), 4.13—4.23 (m, 1H), 4.03—4.10 (m, 1H), 3.96 (s, 3H), 3.76-3.87 (m, 1H), 3.57—3.74 (m, 1H), 3.35—3.43 (m, 2H), 3.14— 3.25 (m, 1H), 2.45 (s, 3H), 0.96-1.05 (m, 3H) ppm. 15 General procedure for the ation of Examples 108—123 in Table 11: A 0.13 M solution of Intermediate 64A in DMF was treated with 1.1 eq. TBTU and 2.5 eq. DIPEA and stirred at rt for 15 min. 2 eq. of the respective amine were added, and the resulting mixture was stirred at rt for further 18 h. After this, purification was carried out according to the methods indicated.

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na —198— Table 11 Example Structure Purification LC-MS data No. method(s) 108 P1 Method 2: R1 = 1.02 min; MS (ESIpos): m/z = 456 (M+H)+ 109 P1 Method 4: Rt = 0.97 min; MS (ESIpos): m/Z = 412 (M+H)+ 110 P1, P5 Method 2: R1 = 1.01 min; MS (ESIpos): m/z = 426 (M+H)+ 111 P1,P5 Method 4: R = 1.11 min; MS (ESIpos): m/z = 440 (M+H)+ ation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —199— Example Structure ation LC-MS data No. method(s) P1 Method 4: R1 = 1.07 min; MS (ESIpos): m/z = 482 (M+H)+ P1,P5 Method 2: R = 0.84 min; MS (ESIpos): m/z = 523 (M+H)+ P1,P5 Method 2: R = 0.96 min; MS (ESIpos): m/z = 440 (M+H)+ P1,P5 Method 2: R = 1.09 min; MS (ESIpos): m/z = 452 (M+H)+ [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —200— Example Structure Purification LC-MS data No. method(s) 116 P1,P5 Method 4: R = 0.95 min; MS (ESIpos): m/z = 495 (M+H)+ 117 P1,P5 Method 4: R = 0.93 min; MS (ESIpos): m/z = 481 (M+H)+ 118 P1,P5 Method 2: R = 0.93 min; MS (ESIpos): m/z = 482 (M+H)+ 119 P1,P5 Method 2: R1 = 1.04 min; MS (ESIpos): m/z = 516 (M+H)+ [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —201— e Structure Purification LC-MS data No. method(s) P1,P5 Method 4: R = 0.88 min; MS (ESIpos): m/z = 468 (M+H)+ P1,P5 Method 4: R = 0.91 min; MS (ESIpos): m/z = 496 (M+H)+ P1,P5 Method 4: R = 1.09 min; MS s): m/z = 488 (M+H)+ P1,P5 Method 4: RI = 0.98 min; MS (ESIpos): m/z = 530 (M+H)+ [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 124 4— { [4-Amino-5 -(5 1 —f] [1 ,2,4] - , 7-dimethoxy-1 -benzothiophen—2-yl)(methoxymethyl)pyrrolo [2, triazin—7-yl]methy1}piperazin—2-one To a solution of Intermediate 62A (100 mg, 271 umol), Intermediate 66A (77 mg, 325 umol) and caesium fluoride (206 mg, 1.35 mmol) in degassed THF/water (10:1; 5 m1) under argon was added (2'—arninobipheny1—2-y1)(chloro)palladium—dicyclohexy1(2',4',6'-triisopropylbiphenyly1)phosphine (1:1; 42.6 mg, 54 umol; see S. L. Buchwald et al., J. Am. Chem. Soc. 132 (40), 14073—14075 (2010)). The ing mixture was degassed again and d under argon at 60°C for 6 h. Then, 10 another portion of Intermediate 66A (39 mg, 162 umol) was added, and stirring at 60°C was con- tinued for 10 h. After this, the reaction mixture was separated by preparative RP-HPLC sil C18, gradient 30-50% acetonitrile/0.1% aq. TFA). The product ons were combined and evapo- rated to dryness. The residue was dissolved in methanol and filtered through an anion exchange cartridge (Stratospheres SPE, PL—HC03 MP—resin). The dge was eluted with methanol, and the 15 filtrate was ated affording 40 mg (28% of th.) of the title compound.

LC-MS (method 2): R. = 0.78 min; MS (ESIpos): m/z = 483 (M+H)+ 1H-NMR (500 MHz, DMSO-ds): 8 = 7.99 (s, 1H), 7.68 (br. s, 1H), 7.49-8.17 (br. s, 1H), 7.37 (s, 1H), 7.05 (d, 1H), 6.63 (d, 1H), 5.5-6.0 (br. s, 1H), 4.42 (s, 2H), 3.97 (s, 2H), 3.94 (s, 3H), 3.84 (s, 3H), 3.20 (s, 3H), 3.09-3.14 (m, 2H), 3.01 (s, 2H), 2.62-2.67 (m, 2H) ppm.

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na Example 125 4— { [4-Amino(hydroxymethyl)(7-methoxy—5—methylbenzothiophen—2-yl)pyrrolo [2, 1 —f] [1 ,2,4] - triazin—6-yl]methyl}piperazin—2-one To a suspension of Intermediate 70A (700 mg, 1.49 mmol), Intermediate 5A (497 mg, 2.24 mmol) and caesium fluoride (1.36 g, 8.95 mmol) in degassed THF/water (2:1, 90 ml) under argon was added (2'-aminobiphenylyl)(chloro)palladium—dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phos- phine (1:1; 117 mg, 0.149 mmol; see S. L. Buchwald et al., J. Am. Chem. Soc. 132 (40), 14073- 14075 (2010)). The resulting mixture was degassed again and stirred under argon at 60°C overnight. 10 Another portion of Intermediate 5A (231 mg, 1.04 mmol) and (2'-aminobiphenylyl)- (chloro)palladium—dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine (1:1; 117 mg, 0.149 mmol) were added, and stirring was continued at 60°C for 3 h. The itate was filtered off, washed with THF and dried in vacuo. The solid was suspended in mixture of DMF and 1 M aq. trifluoroacetic acid and filtered. The filtrate was separated by preparative C (Reprosil C18, 15 gradient 20-40% acetonitrile/0.2% aq. trifluoroacetic acid). The product fractions were combined and then alkalized by addition of sat. aq. sodium bicarbonate solution. The solution was extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated to yield 88 mg of the title nd (13% of th.).

LC-MS (method 2): R. = 0.70 min; MS (ESIpos): m/z = 453 (M+H)+ 20 1H—NMR (400 MHz, s): inter al. 8 = 7.6-8.0 (br. s, 1H), 7.98 (s, 1H), 7.71 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 5.4-5.8 (br. s, 1H), 5.19 (t, 1H), 4.85 (d, 2H), 3.95 (s, 3H), 3.58 DH), 3.04 (br. m, 2H), 2.88 (s, 2H), 2.45 (s, 3H) ppm.

[Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena Example 126 4— { [4-Arnino(methoxymethyl)(7-methoxy—5-methy1— 1 -benzothiophen—2-yl)pyrrolo [2, 1 —f] — [1 ,2,4]triazin—6-yl]methyl}piperazin—2-one A suspension of Example 125 (88 mg, 194 umol) in dichloromethane (5 ml) was treated with thionyl chloride (29 pl, 389 umol), and the mixture was stirred at rt for 65 min. r portion of thionyl chloride (29 pl, 389 umol) was added, and stirring was continued for 1.5 h. An excess of ol was then added, followed by dropwise addition of a 5.4 M on of sodium methylate in methanol (84 mg, 1.56 mmol) until pH 8 was reached. After stirring for 3 days, the volatiles were evaporated 10 under reduced pressure, and the residue was separated by preparative RP-HPLC (Reprosil C18, gradient 20-40% acetonitrile/O.2% aq. trifluoroacetic acid). The product fractions were evaporated to yield 19 mg of the title nd (21% of th.).

LC—MS (method 2): R = 0.77 min; MS (ESIpos): m/z = 466 (M+H)+ 1H—NMR (400 MHZ, DMSO-ds): 8 = 7.99 (s, 1H), 7.75-8.11 (br. s, 1H), 7.68 (s, 1H), 7.38 (s, 1H), 15 7.31 (s, 1H), 6.84 (s, 1H), 5.51-5.82 (m, 1H), 4.77 (s, 2H), 3.95 (s, 3H), 3.55 (s, 2H), 3.31 (s, 3H), 3.04 (br. s, 2H), 2.85 (s, 2H), 2.42-2.48 (m, 5H) ppm.

Example 127 4— { [4-Amino(ethoxymethyl)(7-methoxy—5—methylbenzothiophen—2-y1)pyrrolo [2, 1 —f] [1 ,2,4] - triazin—6-yl]methyl}piperazin—2-one D [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —205— A suspension of Example 125 (100 mg, 221 umol) in dichloromethane (10 ml) was treated with thionyl chloride (161 pl, 2.21 mmol), and the e was stirred at rt for 30 min. Ethanol was added, and the volatiles were evaporated under reduced pressure. The residue was dissolved in ethanol (10 ml), sodium ethylate (30 mg, 442 umol) was added, and the e was d at rt for 1 h. The mixture was then directly separated by preparative RP-HPLC (Reprosil C18, gradient 20— 40% acetonitrile/O.2% aq. roacetic acid). The product fractions were combined and alkalized by addition of sat. aq. sodium bicarbonate solution. The solution was extracted with ethyl acetate, and the c layer was washed with brine, dried over magnesium sulfate and evaporated to yield 10 57 mg of the title compound (54% of th.).

LC-MS (method 2): R. = 0.85 min; MS (ESIpos): m/z = 480 (M+H)+ ‘H—NMR (400 MHz, DMSO-da): 5 = 7.99 (s, 1H), 7.75-8.09 (br. s, 1H), 7.64-7.71 (m, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 6.84 (s, 1H), 5.38-5.91 (br. s, 1H), 4.81 (s, 2H), 3.95 (s, 3H), 3.49—3.59 (m, 4H), 2.99-3.08 (m, 2H), 2.86 (s, 2H), 1.12 (t, 3H) ppm. 15 ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —206— B. Evaluation of Biological Activifl Abbreviations and Acronyms: AhX 6-amin0hexanoic acid ATP adenosine triphosphate BSA bovine serum albumin CREB CAMP-response element-binding protein DMSO dimethylsulfoxide EDTA ethylenediaminetetraacetic acid EGTA ethyleneglycol—bis(2—aminoethylether)-N,N,N’, ’-tetraacetic acid FBS fetal bovine serum FGF fibroblast growth factor FGFR fibroblast growth factor receptor GFP green fluorescent protein GST glutathione S-transferase HEPES 4-(2-hydroxyethyl)piperazine- l -ethansulf0nic acid HRTF homogeneous time-resolved fluorescence MOPS 3-(N—morpho1ino)propanesulfonic acid mTOR mammalian target of cin PBS phosphate buffered saline PI3K phosphatidylinositol 3-kinase RTK receptor tyrosine kinase SNP single nucleotide polymorphism TR—FRET time-resolved fluorescence resonance energy transfer VEGF vascular endothelial growth factor VEGFR vascular endothelial growth factor or tration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to trate the activity of the compounds of the present invention, the following assays may be used.

D [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —207— B-l. FGFR-l high ATP kinase assay FGFR-l inhibitory activity at high ATP concentration of the compounds of the present invention after their pre-incubation with FGFR-l was quantified employing the TR-FRET based FGFR-l high ATP assay as described in the following paragraphs: A recombinant tagged FGFR-l fusion protein [fusion of glutathione-S—transferase (GST) (N-ter- minally), ag, thrombin cleavage site, and the intracellular part of human FGFR-l from amino acids G400 to R800 as in GenBank entry NM_015850], expressed in SF9 insect cells using — virus sion system and purified via glutathione-agarose y chromatography, was pur- chased from Proqinase (product no. 0101—0000—1) and used as enzyme. As substrate for the kinase 10 reaction, the biotinylated peptide -Ahx—AAEEEYFFLFAKKK (C-terminus in amide form) was used which can be purchased, e. g., from Biosyntan (Berlin-Buch, Germany).

Usually, test compounds were tested on the same iter plate at 11 different concentrations in the range of 20 uM to 0.1 nM (e.g. 20 nM, 5.9 uM, 1.7 uM, 0.51 nM, 0.15 nM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM, and 0.1 nM) in duplicates for each concentration. The dilution series was 15 prepared separately prior to the assay as 100—fold concentrated stock solutions in DMSO; exact concentrations could vary ing on the pipettor used. For the assay, 50 n1 of each stock solution of the test compound in DMSO was pipetted into a black, low-volume ll microtiter plate (Greiner Bio-One, Frickenhausen, Germany). 2 ul of a solution of the above FGFR-l fusion protein in aqueous assay buffer [8 mM MOPS pH 7.0, 10 mM magnesium acetate, 1.0 mM dithiothreitol, 20 0.05% (w/v) bovine serum albumin (B SA), 0.07% (v/v) Tween-20, 0.2 mM EDTA] was added, and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compound to the . Then, the kinase reaction was started by the on of 3 ul of a solution of adenosine triphosphate (ATP, 3.3 mM; final concentration in the 5 ul assay volume = 2 mM) and substrate (0.16 uM; final tration in the 5 ul assay volume = 0.1 nM) in assay buffer, and the resulting 25 mixture was incubated for a reaction time of 15 min at 22°C. The concentration of FGFR—l fusion protein was adjusted depending on the activity of the enzyme lot and was chosen appropriately to have the assay in the linear range (typical concentrations were in the range of 0.05 ug/ml). The reaction was d by the addition of 5 ul of a solution of HTRF detection reagents [25 nM streptavidin—XL665 (Cis Biointemational) and 1 nM PT66-Eu-chelate, an europium—chelate labelled 30 anti-phosphotyrosine antibody n-Elmer; PT66-Tb-cryptate from Cis emational may be used instead), in an aqueous EDTA solution (50 mM EDTA, 0.1% (w/v) BSA in 50 mM EDES/NaOH pH 7.5)].

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —208— The resulting mixture was incubated for 1 h at 22°C to allow formation of the x n the phosphorylated biotinylated peptide and the detection reagents. Subsequently, the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu-chelate to the streptavidin—XL665. For this, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured in a TR-FRET reader [e.g. Rubystar (BMG Labtech— nologies, Offenburg, Germany) or Viewlux (Perkin-Elmer)]. The ratio of the emissions at 665 nm and at 620 nm was taken as the measure for the amount of phosphorylated substrate. Data were normalised e reaction without inhibitor = 0% inhibition, all other assay components but no enzyme = 100% tion), and ICso values were calculated by a 4-parameter fit using an se 10 re.

ICso values for individual compounds of the invention from this assay are listed in Table 1A below: Table 1A Example N0. FGFR-l (high ATP) Example N0. FGFR-l (high ATP) IC50 [nM] ICso [nM] 1 12.2 15 1.0 16 12.5 17 0.9 18 0.7 19 0.5 20 25.0 21 4.2 22 0.9 23 17.9 24 1.3 25 0.7 26 0.9 27 1.3 28 2.1 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by kirstena —209— Example No. FGFR—l (high ATP) Example No. FGFR—l (high ATP) IC50 [nM] IC50 [nM] 1.6 56 2.4 2.8 57 3.2 1.5 58 6.8 5.2 59 3.8 1.0 60 16.2 61 0.5 62 3.1 64 1.0 65 5.6 66 1.6 67 5.0 68 27.0 69 55.3 70 39.1 71 2.7 72 1.4 73 4.4 74 4.0 75 4.1 76 2.8 77 1.4 78 1.7 79 12.6 80 1.3 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] na Unmarked set by kirstena —210— Example No. FGFR—l (high ATP) Example No. FGFR—l (high ATP) IC50 [nM] IC50 [nM] 1.9 105 8.7 3.4 106 6.4 107 9.4 108 3.9 109 8.4 110 17.5 111 27.0 112 42.1 113 52.7 114 11.2 115 24.9 116 3.7 117 8.8 118 6.8 119 9.0 120 6.8 121 8.2 122 18.9 123 25.1 124 27.3 125 5.0 126 3.9 127 8.0 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] na Unmarked set by kirstena —211— Selected 8-amino-l-(benzothiophen—2-yl)imidazo[1,5-a]pyrazine derivatives and related compounds which were regarded to be representative of t prior art (see Int. Pat. Appl. WO 2007/061737- A2 and example compounds described therein) were synthesized ing the published procedures and also tested in the FGFR-l high ATP assay for comparative purposes. ICso values that were obtained for these compounds are listed in Table 1B below: Table 1B Structure of Example No. in FGFR—l (high ATP) comparative compound WO 2007/061737 ICso [nM] S 4 12000 \ [Annotation] na None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —212— Structure of e No. in FGFR-l (high ATP) comparative nd WO 2007/061737 ICso [nM] 205 20000 ICHZ} O \ NHZ o N/ / RN?“ 210 456 HSC \ NH2 S N/ / Rwy/N 233 4600 CI \ NH2 s N/ / g? The ICso values specified in Table 1A and 1B demonstrate that the compounds of the present inven- tion are about five to a thousand times more potent in inhibiting FGFR-l kinase activity than the selected prior art nds.

B-2. FGFR—3 kinase assay FGFR-3 inhibitory activity of the compounds of the present invention after their pre—incubation with FGFR-3 was quantified employing the TR—FRET based FGFR-3 assay as described in the following paragraphs: A recombinant tagged FGFR-3 fusion protein [fusion of hione-S-transferase (GST) (N—ter- 10 minally), ag, thrombin cleavage site, and the intracellular part of human FGFR-3 from amino acids R397 to T806 as in NCBI/Protein entry 133.1], expressed in SF9 insect cells using alovirus expression system and purified via glutathione-S-transferase affinity chromatography, was purchased from Proqinase (product no. 10681) and used as enzyme. As substrate for the [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —213— kinase reaction, the biotinylated peptide -Ahx-AAEEEYFFLFAKKK (C-terminus in amide form) was used which can be purchased, e.g., from Biosyntan (Berlin-Buch, y).

Usually, test compounds were tested on the same microtiter plate at 11 different concentrations in the range of 20 uM to 0.1 nM (e.g. 20 uM, 5.9 uM, 1.7 uM, 0.51 uM, 0.15 uM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM, and 0.1 nM) in duplicates for each concentration. The dilution series was prepared tely prior to the assay as 100—fold concentrated stock solutions in DMSO; exact concentrations could vary depending on the pipettor used. For the assay, 50 n1 of each stock on of the test compound in DMSO was pipetted into a black, low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). 2 pl of a solution of the above FGFR-3 fusion protein 10 in aqueous assay buffer [8 mM MOPS pH 7.0, 10 mM magnesium acetate, 1.0 mM dithiothreitol, 0.05% (w/v) bovine serum albumin (BSA), 0.07% (v/v) Tween-20, 0.2 mM EDTA] was added, and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compound to the enzyme. Then, the kinase reaction was started by the addition of 3 ul of a solution of adenosine triphosphate (ATP, 16.7 HM; final concentration in the 5 ul assay volume = 10 nM) and substrate 15 (0.8 uM; final concentration in the 5 ul assay volume = 0.5 nM) in assay buffer, and the resulting e was incubated for a reaction time of 60 min at 22°C. The tration of FGFR—3 fusion n was adjusted depending on the activity of the enzyme lot and was chosen appropriately to have the assay in the linear range (typical concentrations were in the range of 0.03 ug/ml). The reaction was stopped by the on of 5 ul of a solution of HTRF detection reagents [100 nM 20 streptavidin—XL665 (Cis Biointernational) and 1 nM PT66-Tb-cryptate, a terbium—cryptate labelled hosphotyrosine antibody (Cis Biointernational; PT66-Eu-chelate from Perkin-Elmer may be used instead), in an aqueous EDTA solution (50 mM EDTA, 0.1% (w/v) BSA in 50 mM HEPES/NaOH pH 7.5)].

The resulting mixture was incubated for 1 h at 22°C to allow formation of the complex between the 25 phosphorylated biotinylated peptide and the detection reagents. Subsequently, the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the late to the streptavidin—XL665. For this, the fluorescence emissions at 620 nm and 665 nm after tion at 350 nm were measured in a TR-FRET reader [e.g. Rubystar (BMG Labtech— nologies, Offenburg, y) or Viewlux (Perkin-Elmer)]. The ratio of the emissions at 665 nm 30 and at 620 nm was taken as the measure for the amount of phosphorylated substrate. Data were normalised (enzyme reaction without inhibitor = 0% tion, all other assay components but no enzyme = 100% inhibition), and ICso values were calculated by a meter fit using an in—house a...

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena —214— IC50 values for individual compounds of the invention from this assay are listed in Table 2A below: Table 2A Example N0. FGFR-3 IC50 [nM] Example N0. FGFR-3 ICso [nM] 1 24.8 24 5.7 2 29.4 25 5.2 3 46.6 26 4.9 27 12.6 28 9.7 29 2.5 30 6.4 31 13.3 32 52.3 33 7.2 34 10.5 35 65.4 36 9.8 37 34.6 38 18.8 39 4.9 40 7.9 41 7.2 42 18.4 43 32.4 44 6.1 45 9.7 23 41.9 46 8.1 [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —215— Example N0. FGFR-3 ICso [nM] Example No. FGFR-3 ICso [nM] 47 3.4 77 3.8 48 78 2.0 51 79 17.9 52 80 0.2 53 81 0.5 82 16.0 83 2.1 84 16.5 85 26.0 86 6.8 87 28.1 90 11.0 91 31.1 93 8.7 95 28.7 98 26.5 99 36.9 102 39.8 106 7.1 107 17.4 108 7.7 114 9.6 117 5.3 119 4.5 121 24.6 [Annotation] kirstena None set by na ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —216— Selected 8-amino-l-(benzothiophen—2-yl)imidazo[1,5-a]pyrazine derivatives and related compounds which were regarded to be representative of closest prior art (see Int. Pat. Appl. WO 2007/061737- A2 and example compounds described therein) were synthesized following the published ures and also tested in the FGFR-3 assay for comparative purposes. ICso values that were obtained for these compounds are listed in Table 2B below: Table 2B Structure of e No. in FGFR-3 comparative compound WO 2007/061737 ICso [nM] S 4 2400 \ [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena —217— Structure of Example No. in FGFR-3 ative compound WO 2007/061737 ICso [nM] 205 20000 ICHZ} O \ NH, o N/ / RN?“ 210 554 HSC \ NH2 S N/ / e? 233 10000 CI \ NH, s N/ / g? The ICso values specified in Table 2A and 2B demonstrate that the compounds of the present inven- tion are about three to a thousand times more potent in inhibiting FGFR-3 kinase activity than the selected prior art compounds.

B-3. FGFR—4 high ATP kinase assay FGFR-4 inhibitory activity at high ATP concentration of the compounds of the t invention after their pre-incubation with FGFR-4 was fied employing the TR-FRET based FGFR—4 high ATP assay as described in the following paragraphs: A recombinant tagged FGFR-4 fusion protein [fusion of glutathione-S-transferase (GST) (N—ter- 10 minally), His6-tag, thrombin cleavage site, and the intracellular part of human FGFR-4 from amino acids R391 to T802 as in GenBank entry NM_002011], sed in SF9 insect cells using baculo- Dexpression system and purified via glutathione-agarose y chromatography, was pur- chased from Proqinase (product no. 0127—0000—3) and used as enzyme. As substrate for the kinase [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —218— reaction, the biotinylated peptide biotin-Ahx-AAEEEYFFLFAKKK (C-terminus in amide form) was used which can be purchased, e. g., from Biosyntan (Berlin-Buch, Germany).

Usually, test compounds were tested on the same microtiter plate at 11 different concentrations in the range of 20 uM to 0.1 nM (e.g. 20 ”M, 5.9 uM, 1.7 ”M, 0.51 ”M, 0.15 ”M, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM, and 0.1 nM) in duplicates for each concentration. The on series was prepared separately prior to the assay as 100—fold concentrated stock solutions in DMSO; exact concentrations could vary depending on the pipettor used. For the assay, 50 n1 of each stock solution of the test compound in DMSO was pipetted into a black, low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). 2 ul of a solution of the above FGFR-4 fusion protein 10 in aqueous assay buffer [8 mM MOPS pH 7.0, 10 mM magnesium acetate, 1.0 mM dithiothreitol, 0.05% (w/v) bovine serum albumin (BSA), 0.07% (v/v) Tween-20, 0.2 mM EDTA] was added, and the e was incubated for 15 min at 22°C to allow nding of the test compound to the . Then, the kinase reaction was started by the addition of 3 ul of a solution of adenosine triphosphate (ATP, 3.3 mM; final concentration in the 5 ul assay volume = 2 mM) and substrate 15 (0.8 uM; final concentration in the 5 ul assay volume = 0.5 nM) in assay buffer, and the resulting e was incubated for a reaction time of 60 min at 22°C. The tration of FGFR—4 fusion n was adjusted depending on the activity of the enzyme lot and was chosen appropriately to have the assay in the linear range (typical concentrations were in the range of 0.03 ). The reaction was stopped by the addition of 5 pl of a solution of HTRF detection reagents [100 nM 20 streptavidin—XL665 (Cis Biointernational) and 1 nM PT66-Tb-cryptate, a terbium—cryptate labelled anti-phosphotyrosine antibody (Cis Biointernational; PT66-Eu-chelate from Perkin-Elmer may be used instead), in an aqueous EDTA solution (50 mM EDTA, 0.1% (w/v) BSA in 50 mM HEPES/NaOH pH 7.5)].

The resulting mixture was incubated for 1 h at 22°C to allow formation of the complex between the 25 phosphorylated biotinylated peptide and the ion reagents. uently, the amount of phosphorylated substrate was evaluated by measurement of the resonance energy er from the Tb-chelate to the streptavidin—XL665. For this, the fluorescence ons at 620 nm and 665 nm after excitation at 350 nm were measured in a TR-FRET reader [e.g. Rubystar (BMG Labtech— es, Offenburg, Germany) or Viewlux (Perkin-Elmer)]. The ratio of the emissions at 665 nm 30 and at 620 nm was taken as the measure for the amount of phosphorylated substrate. Data were normalised (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme = 100% inhibition), and ICso values were calculated by a 4-parameter fit using an in—house awe.

[Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —219— B-4. mTOR kinase assay (tor comQarative gurgosest mTOR inhibitory activity of the compounds of the present invention was fied employing the TR-FRET based mTOR assay as described in the following paragraphs: inant fusion tagged mTOR protein [glutathione-S—transferase (GST) fused to human mTOR amino acids from 1360 to 2549], expressed in insect cells and purified by glutathione—sepharose affinity chromatography, was purchased fiom Invitrogen (Cat-No. 4753) and used as enzyme. As ate for the kinase on, a recombinant fusion protein of GFP and 4E-BP1 (purchased from Invitrogen, . PV4759) was used.

Test compounds were dissolved in DMSO to generate 10 mM stock solutions. These solutions were 10 first 10-fold diluted by 100% DMSO to get 1 mM solutions in 100% DMSO, then 100—fold diluted by 50% DMSO to get 10 uM solutions in 50% DMSO.

For the assay, 0.5 ul of a 10 uM solution of the test compound in 50% DMSO was pipetted into a black, low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). 2 ul of a solution of the above mTOR fusion n in s assay buffer [50 mM NaOH pH 7.5, 15 5 mM magnesium chloride, 1.0 mM dithiothreitol, 1 mM EGTA, 0.01% (v/v) Triton-X100, 0.01% (wfv) bovine serum albumin (BSA)] was added, and the mixture was incubated for 15 min at 22°C to allow pre-binding of the test compound to the enzyme. Then, the kinase reaction was started by the addition of 2.5 ul of a solution of adenosine triphosphate (ATP, 80 uM; final concentration in the 5 ul assay volume = 40 nM) and substrate (0.6 uM; final concentration in the 5 ul assay volume 20 = 0.3 nM) in assay buffer, and the resulting mixture was incubated for a reaction time of 60 min at 22°C. The concentration of mTOR fusion protein was chosen appropriately to have the assay in the linear range (a typical final concentration in the 5 ul assay volume was 1.25 ng/ul). The reaction was stopped by the addition of 5 ul of 30 mM EDTA (final concentration in the 10 ul assay volume = 15 mM) and 2 nM Tb-chelate labelled anti-4E-BP1 [pT46] phosphospecific antibody rogen 25 Cat-No. PV4755] (final concentration in the 10 ul assay volume = 1 nM) in FRET buffer.

The resulting e was incubated for 1 h at 22°C to allow formation of the complex between the phosphorylated substrate and the Tb-chelate labelled dy. Subsequently, the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer fiom the Tb—chelate to the GFP. For this, the fluorescence emissions at 495 nm and 520 nm after excitation at 30 340 nm was measured in an Envision 2104 multilabel reader (Perkin-Elmer). The ratio of the Dsions at 520 nm and at 495 nm was taken as the measure for the amount of phosphorylated ate. Data were normalised (enzyme reaction without inhibitor = 0% inhibition, all other assay ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —220— components but no enzyme = 100% inhibition), and either mean values (if tested in replicates at a single tration) or ICso values (by a 4—parameter fit using an in—house software) were calculated.

Mean inhibition values at 1 uM for individual compounds of the present invention are listed in Table 3 below: Table 3 Example No. mTOR Example No. mTOR % tion @ 1 ”M % inhibition @ 1 ”M 1 8.7 22 17.6 2 7.2 23 11.6 3 8.2 24 6.3 5 9.7 25 3.5 6 0.3 26 6.8 3.1 27 5.9 7.8 28 no inhib. effect detect. no inhib. effect detect. 29 28.5 6.0 30 21.1 31 16.3 32 1.6 33 0.9 34 25.9 35 1.4 6.7 36 14.4 no inhib. effect detect. 37 8.6 17.6 38 20.8 31.3 39 11.5 40 0.1 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena ed set by na —221— Example No. mTOR Example No. mTOR % inhibition @ 1 ”M % inhibition @ l ”M no inhib. effect detect. 69 8.7 no inhib. effect detect. 70 5.8 10.1 71 0.1 13.3 72 8.2 15.5 73 18.5 74 18.6 75 10.2 76 8.5 77 0.7 78 5.8 79 14.7 80 3.9 81 4.1 82 7.1 83 6.3 84 9.1 85 0.9 87 12.7 88 5.3 89 no inhib. effect detect. 93 12.5 98 no inhib. effect detect. 99 5.3 103 no inhib. eflect detect.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena —222— Example No. mTOR Example No. mTOR % inhibition @ 1 uM % inhibition @ 1 nM no inhib. effect detect. 119 no inhib. effect detect. 8.5 121 no inhib. effect detect. (no inhib. effect detect. = no inhibitory effect detectable at 1 uM).

The data in Table 3 show that the compounds of the present invention only have a weak, if any, inhibitory effect on mTOR kinase which is not considered to contribute to the pharmacological activity observed with these compounds.

B-5. Inhibition of growth factor-mediated cell proliferation Human cal vein endothelial cells (HUVEC) were obtained from Cellsystems (FC-0003) and grown in Vasculife VEGF complete medium (Cellsystems, LL-1020) containing 2% fetal bovine serum (FBS) at 37°C and 5% C02. The cells were used for proliferation assays up to passage 7.

The HUVEC cells were harvested using accutase (PAA, L11-007) and seeded in columns 2 to 12 of 10 96-well plates n EST tissue culture plate 96-well flat bottom, BD 353075, or ”CLEAR-PLATE, black, 96-well, r Bio-One, No. 655090) at a cell density of 2500 cells/ well in 100 pl ife VEGF complete medium with column 1 remaining empty as blank. Cells were allowed to incubate at 37°C and 5% CO2 for at least 6 h. Then, the cells were washed once with PBS and starved overnight in Vasculife basal medium (Cellsystems, LM-0002) containing 15 heparin, ate and L-glutamine (components of the Vasculife Life Factors Kit, Cellsystems, LL- 1020) as well as 0.2% FBS.

After about 18 h, the starving medium was discarded, and the cells were exposed for 72 h to 9 consecutive log or half-log concentrations of test compound in the range of 10 pM to 30 11M and to 5, 10 or 20 ng/ml hFGF-2 (recombinant human FGF basic, R&D Systems, 233—FB) in 100 pl 20 starving medium. 10 mM stock solutions of test compounds in DMSO were diluted to 200 X final concentration in DMSO ing in a final DMSO concentration of 0.5% in all wells. Controls con- sisted of cells grown in starving medium only and of cells grown in hFGF-2 containing starving medium with 0.5% DMSO. To determine cell proliferation, 5 ul Alamar Blue solution (Biosource, DALl 100) was added to each well (1 :20 dilution), and the cells were d to incubate for further 25 4h at 37°C and 5% C02 before measuring cence (ex. 535 nm, em. 595 nm) with a atrafluor Plus Tecan plate reader (XFLUOR4 version 4.20). In some experiments, an ATP Determination Kit (BIAFFIN GmbH, LBR—T100) was used according to the manufacturer's in- ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —223— structions. In each experiment, samples were d in triplicate, and the standard deviations were determined. GraphPad Prism 5 software was used to analyze the data and to obtain IC50 values. All test compounds were assayed 2 to 10 times in ndent experiments and similar results were obtained.

The data listed in Table 4 below represent the IC50 values for representative compounds of the invention resulting from the corresponding averaged pIC50 : Table 4 Example N0. hFGF—2 mediated Example N0. hFGF—2 mediated HUVEC proliferation, HUVEC proliferation, IC50 [nM] IC50 [nM] 16.4 48 360.0 17.5 51 1.2 5.3 52 4.0 9.7 53 3.3 54 2.2 56 18.1 57 3.2 59 51.1 60 250.0 64 4.5 67 12.1 68 14.4 71 5.4 72 1.6 73 5.5 74 0.2 46 84.5 75 1.5 [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena ation] kirstena Unmarked set by kirstena —224— Example No. hFGF—Z mediated Example No. hFGF—2 mediated HUVEC eration, HUVEC proliferation, IC50 [nM] ICso [nM] 1.5 84 46.6 3.2 85 126.0 3.5 1.6 Most compounds of the t invention displayed about ten— to hundred-fold reduced inhibitory activity in this proliferation assay when vascular endothelial growth factor (VEGF-Ams isoform) was used as mediating growth factor (instead of FGF-Z), indicating a significant selectivity of these compounds for FGFR versus VEGFR kinases.

B-6. Human xenograft and syngeneic tumor models Different tumor models have been conducted in order to profile compounds of the present invention in viva. Human, rat or mouse tumor cells were ated in vitro and implanted into either immunodeficient or competent mice, or immunodeficient rats. Treatment started after tumor 10 establishment, and tumor-bearing animals were treated with substances via different routes (per os, intravenously, intraperitoneally or subcutaneously). Substances were tested as mono-therapy or in combination therapy with other cological substances. Treatment of the tumor—bearing s was conducted until the tumors reached an average size of 120 m2. Tumors were measured in two dimensions using a caliper, and tumor volume was calculated ing to the formula (length 15 x width2)/2. Substance efficacy was evaluated at the end of the experiment using the T/C ratio [T = final tumor weight in the d group; C = final tumor weight in the control group]. Statistical significance of the efficacy between control and treated groups was determined using the ANOVA variance test. All animal studies were conducted according to the German regulatory guidelines.

Although the invention has been disclosed with reference to specific embodiments, it is apparent that 20 other embodiments and variations of the invention may be devised by others skilled in the art t fining from the true spirit and scope of the invention. The claims are intended to be construed tode all such embodiments and equivalent variations.

[Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena ation] kirstena Unmarked set by kirstena —225— C. Examples relating to Pharmaceutical Compositions Pharmaceutical compositions according to the present invention can be illustrated as follows: Sterile i.V. solution: A 5 mg/mL solution of the d compound of the invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1—2 mg/mL with sterile 5% dextrose and is administered as an iv. infusion over about 60 minutes.

Lyophilized powder for i.v. administration: A sterile preparation can be prepared with (1') 100—1000 mg of the desired compound of the inven- tion as a lyophilized powder, (ii) 32—327 mg/mL sodium citrate, and (iii) 300—3000 mg Dextran 40. 10 The formulation is tituted with sterile, injectable saline or 5% dextrose to a concentration of 10 to 20 mg/mL, which is r diluted with saline or 5% dextrose to 0.2 to 0.4 mg/mL, and is administered either as iv. bolus or by iv. infusion over 15—60 minutes.

Intramuscular sion: The following solution or suspension can be prepared for intramuscular injection: 15 50 mg/mL of the d, water-insoluble compound of the invention; 5 mg/mL sodium carboxy— methylcellulose; 4 mg/mL Tween 80; 9 mg/mL sodium chloride; 9 mg/mL benzyl alcohol.

Hard shell capsules: A large number of unit capsules are prepared by filling rd two-piece hard n capsules each with 100 mg of the desired, powdered compound of the invention, 150 mg of lactose, 50 mg of 20 cellulose and 6 mg ofmagnesium stearate.

Soft gelatin capsules: A mixture of the desired compound of the invention in a ible oil, such as soybean oil, cotton- seed oil or olive oil, is prepared and ed by means of a positive cement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are 25 washed and dried. The d compound of the invention can be dissolved in a mixture of poly- ethylene glycol, glycerin and sorbitol to prepare a water-miscible medicine mix.

D [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —226— Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of the desired compound of the invention, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. riate s and non-aqueous gs may be applied to increase palatability, improve elegance and stability, or delay absorption.

Solution or suspension for topical application to the eye (eye drops): A sterile formulation can be prepared with 100 mg of the desired compound of the invention as a lyophilized powder reconstituted in 5 mL of sterile saline. As vative, benzalkonium chloride, 10 thimerosal, phenylmercuric nitrate, or the like may be used in a range of about 0.001% to 1% by weight.

[Annotation] kirstena None set by kirstena ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —227—

Claims (15)

We claim:

1. A compound of a (I) (I), wherein R1 is hydrogen, chloro, methyl or methoxy, R2 is hydrogen or methoxy, with the o that at least one of R1 and R2 is other than hydrogen, represents chloro, (C1-C4)—alkyl, (C1-C4)-alkoxycarbonyl, 5-membered aza—heteroaryl , or the group -CH2-OR3, —CH2—NR4R5 or -C(=O)-NR4R6, n 10 R3 is hydrogen, (C1-C4)—alkyl, (C3-C6)-cycloalkyl or phenyl, (i) said (C1-C4)—alkyl is ally substituted with hydroxy, (C1—C4)- alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, amino, amino- carbonyl, mono—(C1-C4)-alkylaminocarbonyl, di—(Cl—C4)—alkylamino- carbonyl, (C3—C6)—cycloalkyl or up to three fluoro atoms, 15 and (ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two sub- stituents independently selected from the group consisting of (C1-C4)- alkyl, hydroxy and amino, and [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —228— (iii) said phenyl is optionally substituted with one or two substituents inde- pendently selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, (C1-C4)-alkyl and (C1-C4)- alkoxy, is hydrogen or )-alkyl, is hydrogen, )—alkyl, (C1-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein (Z) said (C1—C4)—alkyl is ally substituted with hydroxy, (C1-C4)- alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, arninocarbonyl, 10 mono-(C1-C4)—alkylarninocarbonyl, di-(C1-C4)-alkylaminocarbonyl or )-cycloalkyl, and (ii) said )—cycloalkyl is optionally substituted with one or two sub- stituents independently selected from the group consisting of (C1—C4)— 15 alkyl, y and amino, and (iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group con- sisting of )—alkyl, hydroxy, 0X0 and amino, 20 is hydrogen, (C1-C4)—alkyl, (C3-C6)-cycloalkyl or 4- to 6-membered hetero— cycloalkyl, wherein (Z) said (C1—C4)—alkyl is optionally substituted with hydroxy, (C1-C4)- alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, amino, amino- carbonyl, mono—(C1-C4)-alkylarninocarbonyl, -C4)-alkylarnino- 25 carbonyl or (C3—C6)-cycloalkyl, and (ii) said (C3-C6)—cycloalkyl is optionally substituted with one or two sub— stituents independently selected from the group consisting of )- alkyl, hydroxy and amino, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by na [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —229— and (iii) said 4- to 6—membered cycloalkyl is optionally substituted with one or two substituents independently selected from the group con- sisting of (C1-C4)—alkyl, hydroxy, oxo and amino, or R4 and R5, or R4 and R6, respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring atom ed from N(R7) and O, and which may be substituted on 10 ring carbon atoms with one or two substituents independently ed from the group consisting of (C1-C4)-alkyl, oxo, hydroxy, amino and amino- carbonyl, and wherein R7 is hydrogen, (C1—C4)-alkyl, formyl or (C1-C4)-alkylcarbonyl, and 15 represents chloro, cyano, (C1—C4)-alkyl, or the group -CR8AR8B-OH, —CH2—NR9R10, -C(=O)-NR11R12 or -CH2—OR15, wherein R8A and R813 are independently selected from the group consisting of hydrogen, (C1- C4)-alkyl, cyclopropyl and cyclobutyl, R9 is hydrogen or (C1—C4)—alkyl, 20 R10 is hydrogen, )—alkyl, )-alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein (i) said (C1-C4)—alkyl is optionally tuted with hydroxy, amino, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl or di-(Cl—C4)-alkyl- aminocarbonyl, 25 and (ii) said (C3-C6)—cycloalkyl is optionally substituted with one or two sub— stituents independently selected from the group consisting of (C1-C4)- alkyl, hydroxy and amino, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] na Unmarked set by kirstena [Annotation] kirstena None set by kirstena ation] kirstena ionNone set by kirstena [Annotation] na Unmarked set by kirstena —230— and (iii) said 4- to 6—membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group con- sisting of (C1-C4)—alkyl, y, oxo and amino, R11 is hydrogen or (C1-C4)—alkyl, R12 is hydrogen, (C1-C4)—alkyl, (C3-C6)-cycloalkyl or 4- to 6-membered hetero- cycloalkyl, wherein (i) said (C1—C4)—alkyl is optionally substituted with hydroxy, amino, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl or di-(Cl—C4)—alkyl- 10 aminocarbonyl, and (ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two sub- nts ndently selected from the group consisting of (C1—C4)- alkyl, hydroxy and amino, 15 and (iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group con- g of (C1-C4)—alkyl, hydroxy, oxo and amino, or 20 R9 and R10, or R11 and K”, respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R13), O, S and S(O)2, and which may be sub- stituted on ring carbon atoms with up to three substituents independently 25 selected from the group consisting of fluoro, (C1-C4)-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein R13 is hydrogen, (C1—C4)—a1kyl, (C3-C6)-cycloalkyl, formyl or (C1—C4)— alkylcarbonyl, [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by na [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] na MigrationNone set by kirstena [Annotation] na Unmarked set by kirstena —231— and R15 is (C1-C4)-alkyl, with the proviso that G1 is not chloro when G2 is chloro or cyano, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

2. The compound of formula (1) according to Claim 1, wherein R1 is chloro, methyl or y, R2 is hydrogen or methoxy, G1 represents chloro, (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl or 5-membered aza—hetero- aryl selected from the group consisting of lyl, imidazolyl, yl, isoxazolyl 10 and oxadiazolyl, or represents the group -CH2-OR3 or -CH2-NR4R5, wherein R3 is hydrogen, (C1-C4)—alkyl or (C3-C6)-cycloalkyl, wherein said (C1-C4)-alkyl is optionally substituted with hydroxy, (C1-C4)- alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, amino, aminocarbonyl, (C3-C6)-cycloalky1 or up to three fluoro atoms, 15 R4 is hydrogen or (C1-C4)—alkyl, R5 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 5- or 6-membered heterocycloalkyl, wherein (i) said (C1-C4)—alkyl is optionally tuted with hydroxy, hydroxy— carbonyl or (C3-C6)-cycloalkyl, 20 and (ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with oxo, or R4 and R5 are joined and, taken together with the nitrogen atom to which they are 25 D attached, form a monocyclic, ted 4- to 6-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R7) and [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —232— O, and which may be tuted on a ring carbon atom with 0x0 or hydroxy, and wherein R7 is hydrogen or (C1-C4)-alkyl, and G2 represents chloro, cyano, (C1—C4)-alkyl, or the group -CR8ARgB-OH, -CH2—NR9R1°, -C(=O)-NR11R12 or -CH2-OR15, wherein R8A and R813 are independently ed from the group consisting of hydrogen, (C1- C4)-alkyl and ropyl, is hydrogen or methyl, 10 R10 is hydrogen, (C1-C4)-alkyl, (C1-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 5- or 6-membered cycloalkyl, wherein (i) said (C1-C4)—alkyl is optionally substituted with y or amino- carbonyl, and 15 (ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with oxo, is hydrogen or methyl, is hydrogen, (C1-C4)—alkyl, (C3-C6)-cycloalkyl or 5- or 6-membered hetero- cycloalkyl, wherein 20 (i) said (C1—C4)—alkyl is ally substituted with hydroxy, and (ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with oxo, 01' 25 R9 and R10, or R11 and K”, tively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to [Annotation] kirstena None set by na ation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by na ation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —233— 6-membered heterocycloalkyl ring which may contain a second ring heteroatom ed from N(R13), O, S and S(O)2, and which may be sub- stituted on ring carbon atoms with up to three tuents independently selected from the group consisting of fluoro, (C1-C4)-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein R13 is en, (C1-C4)-alkyl, cyclopropyl, cyclobutyl, formyl or (C1-C4)-a1kylcarbonyl, and R15 is methyl or ethyl, 10 with the proviso that G1 is not chloro when G2 is chloro or cyano, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

The compound of formula (1) according to Claim 1 or 2, wherein is methyl, is methoxy, 15 represents methyl, oxazol-S—yl or the group -CH2-OR3 or -CH2-NR4R5, wherein R3 is hydrogen, (C1-C4)—alkyl, cyclopropyl or cyclobutyl, wherein said (C1-C4)—alkyl is optionally substituted with hydroxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, amino, amino- carbonyl, cyclopropyl, cyclobutyl or up to three fluoro atoms, 20 is hydrogen, methyl or ethyl, is hydrogen, (C1-C4)—alkyl, acetyl, cyclopropyl, cyclobutyl or 2—oxopyrroli- dinyl, wherein said (C1-C4)—alkyl is optionally tuted with hydroxy, hydroxy— carbonyl, cyclopropyl or cyclobutyl, 01‘ [Annotation] kirstena None set by kirstena [Annotation] kirstena MigrationNone set by kirstena [Annotation] kirstena Unmarked set by kirstena ation] kirstena None set by kirstena [Annotation] kirstena ionNone set by kirstena [Annotation] kirstena Unmarked set by kirstena —234— R4 and R5 are joined and, taken er with the nitrogen atom to which they are attached, form a monocyclic, saturated 5- or 6-membered heterocycloalkyl ring which may n a second ring heteroatom selected from NH and O, and which may be substituted on a ring carbon atom with oxo or hydroxy, and represents methyl or the group —CR8AR8B-OH, -CH2-NR9R10 or —NRHR12, wherein RSA and R813 are independently hydrogen or methyl, R9 is en, 10 R10 is hydrogen, (C1-C4)—alkyl, acetyl, cyclopropyl, cyclobutyl or 2-oxopyrroli- dinyl, wherein said (C1-C4)—alkyl is optionally substituted with hydroxy or amino- carbonyl, R11 is hydrogen or methyl, 15 is hydrogen, (C1-C4)—alkyl, cyclopropyl, utyl or 2-oxopyrrolidinyl, wherein said (C1-C4)—alkyl is optionally substituted with hydroxy, 01‘ R9 and R10, or R11 and R12, respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 20 6-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R13), O and S(O)2, and which may be substi- tuted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, , oxo, hydroxy, amino and aminocarbonyl, and wherein 25 R13 is hydrogen, formyl or acetyl, D or a pharmaceutically acceptable salt, hydrate and/or e thereof.

4. The compound of formula (1) according to Claim 1, 2 or 3, wherein R1 is methyl, R2 is methoxy, G1 represents the group -CH2-OR 3, wherein R3 is (C1-C4)-alkyl optionally substituted with y, amino or aminocarbo- 5 nyl, and G2 represents the group -CH2-NR 9R10 or -C(=O)-NR11 R12 , wherein R9 is hydrogen, R10 is 2-oxopyrrolidinyl, 10 or R9 and R10 are joined and, taken together with the nitrogen atom to which they are attached, form a piperazinyl, 3-oxopiperazinyl or 4-acetylpiperazin- 1-yl ring, R11 is hydrogen, 15 R12 is 2-oxopyrrolidinyl, or R11 and R12 are joined and, taken together with the en atom to which they are attached, form a oxyazetidinyl, 4-hydroxypiperidinyl or iperazinyl ring, 20 or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

5. The compound of formula (I) according to any one of claims 1 to 4, wherein the compound is 4-{[4-amino(methoxymethyl)(7-methoxymethylbenzothiophen yl)pyrrolo[2,1-f][1,2,4]triazinyl]methyl}piperazinone, 7915464_1 (GHMatters) P97075.NZ H C 3 CH 3 O NH S 2 O CH N 3 N N N NH O or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

6. The compound of formula (I) according to any one of Claims 1 to 4, wherein the 5 compound is 4-{[4-amino(methoxymethyl)(7-methoxymethylbenzothiophen yl)pyrrolo[2,1-f][1,2,4]triazinyl]methyl}piperazinone, H C 3 CH 3 O NH S 2 O CH N 3 N N N NH O .

7. s for preparing a compound of formula (I) as defined in any one of Claims 1 to 6, 10 characterized in that [A] a tituted 4-aminopyrrolo[2,1-f][1,2,4]triazine of formula (II) 7915464_1 (GHMatters) P97075.NZ NH 2 O R3 N N N (II), wherein R3 has the meaning indicated in any one of Claims 1 to 4, is at first reacted with formaldehyde and an amine of formula (III) R9 HN R10 (III), 5 wherein R9 and R10 have the meanings ted in any one of Claims 1 to 4, in the presence of an acid to give a compound of formula (IV) NH 2 O R3 N N N R9 N R10 (IV), wherein R3, R9 and R10 have the meanings indicated in any one of Claims 1 to 4, then brominated to a compound of formula (V) NH 2 Br O R3 N N N R9 N R10 (V), 10 wherein R3, R9 and R10 have the meanings indicated in any one of Claims 1 to 4, and subsequently coupled with a benzothiophenyl boronate of formula (VI) 4_1 (GHMatters) P97075.NZ R1 O R14 B S O R14 R2 (VI), wherein R1 and R2 have the meanings indicated in any one of Claims 1 to 4, and R14 ents hydrogen or (C1-C4)-alkyl, or both R14 residues are linked together to 5 form a -(CH2)2-, -C(CH3)2-C(CH3)2-, -(CH2)3-, (CH3)2-CH2- or -C(=O)-CH2-N(CH3)-CH2-C(=O)- bridge, in the presence of a palladium catalyst and a base to yield the target compound of formula (I-A) R1 R2 NH S 2 O R3 N N N R9 N R10 (I-A), 10 wherein R1, R2, R3, R9 and R10 have the meanings indicated in any one of Claims 1 to 4, or [B] a 6-substituted 4-aminopyrrolo[2,1-f][1,2,4]triazine of formula (II) NH 2 O R3 N N N (II), 7915464_1 (GHMatters) P97075.NZ wherein R3 has the g indicated in any one of Claims 1 to 4, is at first formylated with N,N-dimethylformamide in the presence of phosphoryl chloride to an aldehyde of formula (VII) NH 2 O R3 N N N O H (VII), 5 wherein R3 has the meaning indicated in any one of Claims 1 to 4, then brominated to a compound of formula (VIII) NH 2 Br O R3 N N N O H (VIII), wherein R3 has the meaning indicated in any one of Claims 1 to 4, and subsequently coupled with a hiophenyl boronate of formula (VI) R1 O R14 B S O R14 10 R2 (VI), wherein R1, R2 and R14 have the meanings indicated above, in the presence of a palladium catalyst and a base to give a compound of formula (IX) 7915464_1 (GHMatters) P97075.NZ R1 R2 NH S 2 O R3 N N N O H (IX), wherein R1, R2 and R3 have the meanings indicated in any one of Claims 1 to 4, which then is either [B-1] reacted with an amine of formula (III) R9 HN R10 (III), 5 wherein R9 and R10 have the meanings indicated in any one of Claims 1 to 4, in the presence of an acid and a reducing agent to yield the target compound of formula (I-A) R1 R2 NH S 2 O R3 N N N R9 N R10 (I-A), 10 n R1, R2, R3, R9 and R10 have the meanings indicated in any one of Claims 1 to 4, 7915464_1 (GHMatters) P97075.NZ or [B-2] oxidized to a carboxylic acid of formula (X) R1 R2 NH S 2 O R3 N N N OH O (X), wherein R1, R2 and R3 have the gs indicated in any one of Claims 1 to 4, 5 and finally coupled with an amine of formula (XI) R11 HN R12 (XI), wherein R11 and R12 have the meanings indicated in any one of Claims 1 to 4, in the presence of a condensing agent to yield the target compound of formula (I-B) R1 R2 NH S 2 O R3 N N N R11 N O 10 R12 (I-B), 7915464_1 (GHMatters) P97075.NZ wherein R1, R2, R3, R11 and R12 have the meanings ted in any one of Claims 1 to 4, or [C] a 6-substituted 4-aminobromopyrrolo[2,1-f][1,2,4]triazine of formula (XII) NH 2 Br OH N N N (XII) 5 is at first coupled with a benzothiophenyl boronate of formula (VI) R1 O R14 B S O R14 R2 (VI), wherein R1, R2 and R14 have the meanings indicated above, in the presence of a palladium catalyst and a base to give a compound of formula 10 (XIII) R1 R2 NH S 2 OH N N N (XIII), wherein R1 and R2 have the meanings indicated in any one of Claims 1 to 4, and then reacted with formaldehyde and an amine of formula (III) R9 HN R10 (III), 4_1 (GHMatters) P97075.NZ n R9 and R10 have the gs indicated in any one of Claims 1 to 4, in the presence of an acid to yield the compound of formula (I-C) R1 R2 NH S 2 OH N N N R9 N R10 (I-C), wherein R1, R2, R9 and R10 have the meanings indicated in any one of Claims 1 to 4, 5 which subsequently is either [C-1] oxidized to an aldehyde of formula (XIV) R1 R2 NH S 2 O N N N H N R9 R10 (XIV), wherein R1, R2, R9 and R10 have the meanings indicated in any one of Claims 1 to 4, 10 and treated with an amine of formula (XV) R4 HN R5 (XV), 7915464_1 (GHMatters) P97075.NZ wherein R4 and R5 have the meanings indicated in any one of Claims 1 to 4, in the presence of an acid and a reducing agent to yield the target compound of formula (I-D) R1 R2 NH S 2 R4 N N R5 N N R9 N R10 (I-D), 5 wherein R1, R2, R4, R5, R9 and R10 have the meanings indicated in any one of Claims 1 to 4, or [C-2] converted into the corresponding 6-(halomethyl) tive of formula (XVI) R1 R2 NH S 2 X N N N R9 N R10 (XVI), 10 wherein R1, R2, R9 and R10 have the meanings indicated in any one of Claims 1 to 4, and 7915464_1 ters) P97075.NZ X is chloro, bromo or iodo, and treated with an alcohol of formula (XVII) R3A OH (XVII), wherein R3A has the meaning of R3 as indicated in any one of Claims 1 to 4, 5 except for hydrogen, in the presence of a base to yield the target compound of a (I-E) R1 R2 NH S 2 O R3A N N N R9 N R10 (I-E), wherein R1, R2, R3A, R9 and R10 have the meanings indicated above, optionally followed, where appropriate, by (i) separating the compounds of formula (I) 10 thus obtained into their respective enantiomers and/or diastereomers, and/or (ii) converting the compounds of formula (I) into their respective hydrates, solvates, salts and/or hydrates or solvates of the salts by treatment with the corresponding solvents and/or acids or bases.

8. Compound as defined in any one of Claims 1 to 6 for the treatment and/or prevention of es. 15

9. Compound as defined in any one of Claims 1 to 6 for use in a method for the treatment and/or prevention of cancer and tumor es.

10. Use of a compound as defined in any one of Claims 1 to 6 for the manufacture of a ceutical composition for the treatment and/or prevention of cancer and tumor diseases. 4_1 (GHMatters) P97075.NZ

11. Pharmaceutical composition comprising a compound as defined in any one of Claims 1 to 6 and one or more pharmaceutically acceptable excipients.

12. The pharmaceutical composition of Claim 11 further comprising one or more additional therapeutic agents. 5

13. The pharmaceutical composition as defined in Claim 11 or 12 for the treatment and/or prevention of cancer and tumor diseases.

14. Method for the treatment and/or tion of cancer and tumor diseases in a non-human mammal, comprising administering to a non-human mammal in need thereof a therapeutically effective amount of one or more compounds as defined in any one of Claims 1 10 to 6, or of a ceutical composition as defined in any one of Claims 11 to 13.

15. The compound of formula (I) according to Claim 1, the process for preparing a compound of formula (I) ing to Claim 7, the use according to Claim 10, the ceutical composition according to Claim 11, or the method according to Claim 14, substantially as herein described with reference to the es. 15 7915464_1 (GHMatters) P97075.NZ