WO2014048878A1 - Phenyl- or pyridyl- pyrrolo[2,3b]pyrazine derivatives useful in the treatment or prevention of proliferative disorders or dysplasia - Google Patents

Abstract

The invention relates to compounds of formula (I), wherein X¹, X², X³, R¹, R², R^2a, R³ have the meaning as cited in the description and the claims. Said compounds are useful as FGFR inhibitors. The invention also relates to pharmaceutical compositions, such compounds for use as medicament, especially in the treatment or prevention of one or more proliferative disorders or dysplasia.

Description

PHENYL- OR PYRIDYL- PYRROLO[2,3B]PYRAZINE DERIVATIVES USEFUL IN THE TREATMENT OR PREVENTION OF PROLIFERATIVE DISORDERS OR DYSPLASIA

The present invention relates to pyrrolo[2,3b]pyrazine and pyridine compounds useful as FGFR inhibitors. The invention also relates to pharmaceutical compositions, such as compounds for use as medicaments, especially in the treatment or prevention of one or more proliferative disorders or dysplasia.

Protein kinases are a family of proteins responsible for the regulation of multiple cellular functions, including proliferation, replication, differentiation, metabolism, death and motility. Such kinases work as enzymes to post-translationally modify serine, threonine and tyrosine residues on target proteins through the addition of a phosphate group. The uncontrolled activation of kinase activity has been observed in many diseases, such as proliferative disorders, where kinase inhibitors have been used to treat the disease in vivo.

Fibroblast growth factors (FGF) are important regulators of many physiological processes, such as wound healing, morphogenesis during development and angiogenesis (reviewed in Turner and Grose, Nature Reviews Cancer, 2010, 10, pi 16-129). FGFs activate the fibroblast growth factor receptor (FGFR) family (FGFR1, 2, 3 and 4) through binding of the extracellular immunoglobulin (Ig)-like domains, induction of FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signalling pathways. FGFs and FGFRs therefore function as central components of the FGFR signalling pathway. Aberrant FGFR signalling can drive directly cancer cell proliferation and survival, as well as angiogenesis, leading to tumour development and maintenance. Similarly, aberrant FGFR signalling can drive directly dysplasia of e.g. skeletal tissue. Aberrant FGFR signalling can result from, without being limited to, abnormal expression of FGFs, amplification of the FGFR locus or mutation of FGFR.

Vascular endothelial growth factor receptors (VEGFRs) are important regulators of angiogenesis. Of the three family members, VEGFR2/kinase insert domain receptor (KDR) is a key driver as it is largely expressed on endothelial cells. Through binding of its ligand, vascular endothelial growth factor (VEGF), VEGFR2/KDR dimerizes and activates downstream signalling pathways. VEGF and VEGFR2 therefore function as central components of the VEGFR2/KDR signalling pathway. Aberrant VEGFR2/KDR signalling can drive cancer cell-associated angiogenesis, sustaining tumour growth. Inhibition of VEGFR2/KDR and tumour-associated angiogenesis has been clinically validated with bevacizumab, a monoclonal antibody against vascular endothelial growth factor. However, bevacizumab has associated on-target toxicities, including hypertension (Martel et al, Community Oncology, 2006, 3, p90-93). Furthermore, FGFR and VEGFR families have high sequence similarity in the kinase domain, indicating FGFR inhibitors are likely to also target VEGFR (Bamborough et al, J Med Chem, 2008, 51, p7898-7914). As a result, it is considered highly desirable to obtain selectivity against VEGFR2/KDR to avoid the associated on-target toxicities.

WO 2012/073017 Al discloses substituted benzopyrazin derivatives for the treatment of various diseases resulting from FGF/FGFR mutation and/or overexpression.

However, there is a continuing need for new compounds useful as selective FGFR inhibitors with good pharmacokinetic properties.

Thus, an object of the present invention is to provide a new class of compounds as FGFR inhibitors which may be effective in the treatment of FGFR related diseases, especially for treatment of proliferative disorders, such as cancer or lung fibrosis, and particularly in disorders mediated by FGFR pathway dysregulation such as hypophosphatemic rickets or Pfeiffer syndrome, and may show improved pharmaceutically relevant properties including activity, selectivity, ADMET properties and/or reduced side effects.

Accordingly, the present invention provides compounds of formula (I)

or a pharmaceutically acceptable salt thereof, wherein X¹ is CH₂ and X² is CH₂; O; or N(R°), or

X¹ and X² are CH (resulting in a group -CH=CH- for -X^!-X²- in formula (I));

R° is H; or Ci_₄ alkyl, wherein Ci_₄ alkyl is optionally substituted with one or more halogen, which are the same or different;

X³ is N; or CH;

R¹ is phenyl; naphthyl; 5 to 6 membered aromatic heterocyclyl; or 9 to 10 membered aromatic heterobicyclyl, wherein R¹ is optionally substituted with one or more R⁴, which are the same or different;

R⁴ is halogen; CN; C(0)OR⁵; OR⁵; C(0)R⁵; C(0)N(R⁵R^5a); S(0)₂N(R⁵R^5a); S(0)N(R⁵R^5a); S(0)₂R⁵; S(0)R⁵; N(R⁵)S(0)₂N(R^5aR^5b); SR⁵; N(R⁵R^5a); N0₂; OC(0)R⁵; N(R⁵)C(0)R^5a; N(R⁵)S(0)₂R^5a; N(R⁵)S(0)R^5a; N(R⁵)C(0)OR^5a; N(R⁵)C(0)N(R^5aR^5b); OC(0)N(R⁵R^5a); T¹; Ci_6 alkyl; C₂_₆ alkenyl; or C₂_₆ alkynyl, wherein Ci_₆ alkyl; C₂_₆ alkenyl; and C₂_₆ alkynyl are optionally substituted with one or more R⁶, which are the same or different;

R⁵, R^5a, R^5b are independently selected from the group consisting of H; T¹; Ci_₆ alkyl; C₂_₆ alkenyl; and C₂_₆ alkynyl, wherein Ci_₆ alkyl; C₂_₆ alkenyl; and C₂_₆ alkynyl are optionally substituted with one or more R⁶, which are the same or different;

R⁶ is halogen; CN; C(0)OR⁷; OR⁷; C(0)R⁷; C(0)N(R⁷R^7a); S(0)₂N(R⁷R^7a); S(0)N(R⁷R^7a); S(0)₂R⁷; S(0)R⁷; N(R⁷)S(0)₂N(R^7aR^7b); SR⁷; N(R⁷R^7a); N0₂; OC(0)R⁷; N(R⁷)C(0)R^7a; N(R⁷)S0₂R^7a; N(R⁷)S(0)R^7a; N(R⁷)C(0)N(R^7aR^7b); N(R⁷)C(0)OR^7a; OC(0)N(R⁷R^7a); or T¹ ;

R⁷, R^7a, R^7b are independently selected from the group consisting of H; T¹; Ci_₆ alkyl; C₂_₆ alkenyl; and C₂_₆ alkynyl, wherein Ci_₆ alkyl; C₂_₆ alkenyl; and C₂_₆ alkynyl are optionally substituted with one or more halogen, which are the same or different;

T¹ is phenyl; C3-7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T¹ is optionally substituted with one or more R⁸, which are the same or different; R⁸ is halogen; CN; C(0)OR⁹; OR⁹; C(0)R⁹; C(0)N(R⁹R^9a); S(0)₂N(R⁹R^9a); S(0)N(R⁹R^9a); S(0)₂R⁹; S(0)R⁹; N(R⁹)S(0)₂N(R^9aR^9b); SR⁹; N(R⁹R^9a); N0₂; OC(0)R⁹; N(R⁹)C(0)R^9a; N(R⁹)S(0)₂R^9a; N(R⁹)S(0)R^9a; N(R⁹)C(0)OR^9a; N(R⁹)C(0)N(R^9aR^9b); OC(0)N(R⁹R^9a); oxo (=0), where the ring is at least partially saturated; Ci_₆ alkyl; C₂_₆ alkenyl; or C₂_₆ alkynyl, wherein Ci_₆ alkyl; C₂_₆ alkenyl; and C₂_₆ alkynyl are optionally substituted with one or more halogen, which are the same or different;

R⁹, R^9a, R^9b are independently selected from the group consisting of H; Ci_₆ alkyl; C₂_₆ alkenyl; and C₂_₆ alkynyl, wherein Ci_₆ alkyl; C₂_₆ alkenyl; and C₂_₆ alkynyl are optionally substituted with one or more halogen, which are the same or different;

R²; R^2a; R³ are independently selected from the group consisting of H; and halogen.

In case a variable or substituent can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.

Within the meaning of the present invention the terms are used as follows: The term "optionally substituted" means unsubstituted or substituted. Generally -but not limited to-, "one or more substituents" means one, two or three, preferably one or two substituents and more preferably one substituent. Generally these substituents can be the same or different. "Alkyl" means a straight-chain or branched hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified.

"Alkenyl" means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent as further specified.

"Alkynyl" means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent as further specified. "Ci_3 alkyl" means an alkyl chain having 1 - 3 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, or e.g. -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂- CH₂-CH₂-, -CH(C₂H₅)-, -C(CH₃)₂-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_₃ alkyl carbon may be replaced by a substituent as further specified.

"Ci_4 alkyl" means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g. - CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂-CH₂-CH₂-, -CH(C₂H₅)-, -C(CH₃)₂-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_₄ alkyl carbon may be replaced by a substituent as further specified.

"Ci_6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_₄ alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, n-hexyl, or e.g. -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂-CH₂-CH₂-, -CH(C₂H₅)-, - C(CH₃)₂-, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent as further specified. "C₂_6 alkenyl" means an alkenyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -CH=CH₂, -CH=CH-CH₃, -CH₂-CH=CH₂, -CH=CH-CH₂-CH₃, -CH=CH- CH=CH₂, or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkenyl group. Each hydrogen of a C₂_₆ alkenyl carbon may be replaced by a substituent as further specified. "C₂_6 alkynyl" means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -C≡CH, -CH₂-C≡CH, CH₂-CH₂-C≡CH, CH₂-C≡C-CH₃, or e.g. -C≡C- when two moieties of a molecule are linked by the alkynyl group. Each hydrogen of a C₂_₆ alkynyl carbon may be replaced by a substituent as further specified. "C₃_7 cycloalkyl" or "C₃_7 cycloalkyl ring" means a cyclic alkyl chain having 3 - 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Preferably, cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified herein. The term "C₃_5 cycloalkyl" or "C₃_5 cycloalkyl ring" is defined accordingly. "Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro. "3 to 7 membered heterocyclyl" or "3 to 7 membered heterocycle" means a ring with 3, 4, 5, 6 or 7 ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(0)₂-), oxygen and nitrogen (including =N(0)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a 3 to 7 membered heterocycles are aziridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. The term "5 to 6 membered heterocyclyl" or "5 to 6 membered heterocycle" is defined accordingly.

"Saturated 4 to 7 membered heterocyclyl" or "saturated 4 to 7 membered heterocycle" means fully saturated "4 to 7 membered heterocyclyl" or "4 to 7 membered heterocycle".

"4 to 7 membered at least partly saturated heterocyclyl" or "4 to 7 membered at least partly saturated heterocycle" means an at least partly saturated "4 to 7 membered heterocyclyl" or "4 to 7 membered heterocycle".

"5 to 6 membered aromatic heterocyclyl" or "5 to 6 membered aromatic heterocycle" means a heterocycle derived from cyclop entadienyl or benzene, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, - S(0)₂-), oxygen and nitrogen (including =N(0)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine. "5 membered aromatic heterocyclyl" or "5 membered aromatic heterocycle" means a heterocycle derived from cyclo entadienyl, where at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(0)₂-), oxygen and nitrogen (including =N(0)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole.

"7 to 11 membered heterobicyclyl" or "7 to 11 membered heterobicycle" means a heterocyclic system of two rings with 7 to 11 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(0)₂-), oxygen and nitrogen (including =N(0)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for a 7 to 11 membered heterobicycle are indole, indoline, benzo furan, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 7 to 11 membered heterobicycle also includes spiro structures of two rings like 6-oxa-2-azaspiro[3,4]octane, 2- oxa-6-azaspiro[3.3]heptan-6-yl or 2,6-diazaspiro[3.3]heptan-6-yl or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octan-2-yl or 3,8- diazabicyclo[3.2.1 Joctane. "Saturated 7 to 11 membered heterobicyclyl" or "saturated 7 to 11 membered heterobicycle" means fully saturated 7 to 11 membered heterobicyclyl or 7 to 11 membered heterobicycle.

"7 to 11 membered at least partly saturated heterobicyclyl" or "7 to 11 membered at least partly saturated heterobicycle" means an at least partly saturated "7 to 11 membered heterobicyclyl" or "7 to 11 membered heterobicycle".

"9 to 11 membered aromatic heterobicyclyl" or "9 to 11 membered aromatic heterobicycle" means a heterocyclic system of two rings, wherein at least one ring is aromatic and wherein the heterocyclic ring system has 9 to 11 ring atoms, where two ring atoms are shared by both rings and that may contain up to the maximum number of double bonds (fully or partially aromatic) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(0)₂-), oxygen and nitrogen (including =N(0)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for an 9 to 11 membered aromatic heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The terms "9 to 10 membered aromatic heterobicyclyl" or "9 to 10 membered aromatic heterobicycle" are defined accordingly.

Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention. With respect to all preferred compounds of the formula (I) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts.

In preferred embodiments of the present invention, the substituents mentioned below independently have the following meaning. Hence, one or more of these substituents can have the preferred or more preferred meanings given below.

In one embodiment of the present invention, X³ is N. In another embodiment X³ is CH. Preferably, R¹ is phenyl; or pyridyl, wherein R¹ is unsubstituted or substituted with one or more R⁴, which are the same or different.

Preferably, R¹ is substituted with one or more R⁴, which are the same or different. Preferably, R¹ in formula (I) is selected to give formula (la)

wherein X° is N; or CH; and X¹, X², X³, R², R^2a, R³, R⁴ have the meaning as indicated above. In one embodiment, X° is CH. In another embodiment, X° is N.

Preferably, R⁴ is T¹; or Ci_₆ alkyl, substituted with T¹. More preferably, R⁴ is T¹; or Ci_₃ alkyl, substituted with T¹. In particular, R⁴ is T¹; or CH₂-T¹. Preferably, T¹ is saturated 4 to 7 membered heterocyclyl, wherein T¹ is unsubstituted or substituted with one or more R⁸, which are the same or different. More preferably, T¹ is piperazinyl; piperidinyl; or morpholinyl, wherein T¹ is unsubstituted or substituted with one or more R⁸, which are the same or different. Preferably, R⁸ is Ci_₆ alkyl; or oxo, where the ring is at least partially saturated. More preferably, R⁸ is Ci_₃ alkyl; or oxo, where the ring is at least partially saturated. Even more preferably, R⁸ is Ci_₆ alkyl. Even more preferably, R⁸ is Ci_₃ alkyl.

Preferably, R⁴ is piperazin-1 -ylmethyl; 4-methylpiperazin-l-yl; 4-ethylpiperazin-l-yl; morpholin-4-yl; (4-methylpiperazin-l-yl)methyl; (4-ethylpiperazin-l-yl)methyl; morpholin-4- ylmethyl; or (2-oxo-piperazin-4-yl)methyl. More preferably, R⁴ is piperazin-1 -ylmethyl; 4- methylpiperazin-l-yl; 4-ethylpiperazin-l-yl; morpholin-4-yl; (4-methylpiperazin-l-yl)methyl;

(4-ethylpiperazin-l-yl)methyl; or morpholin-4-ylmethyl; More preferably, R⁴ is 4- methylpiperazin-l-yl; 4-ethylpiperazin-l-yl; morpholin-4-yl; (4-methylpiperazin-l-yl)methyl; morpholin-4-ylmethyl; or (2-oxo-piperazin-4-yl)methyl. Even more preferably, R⁴ is 4- methylpiperazin-l-yl; 4-ethylpiperazin-l-yl; morpholin-4-yl; (4-methylpiperazin-l-yl)methyl; or morpholin-4-ylmethyl.

Preferably, R³ is H. Preferably, R², R^2a are independently selected from the group consisting of H; F; and CI.

Compounds of the formula (I) in which some or all of the above-mentioned groups have the preferred or more preferred meanings are also an object of the present invention.

Preferred specific compounds of the present invention are selected from the group consisting of l-(4-{2-[2-(3,5-dimethoxyphenyl) ethyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl)-4- methylpiperazine;

l-(4-{2-[(E)-2-(3,5-dimethoxyphenyl) ethenyl] 5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl)4- methylpiperazine;

l-(4-{2-[2-(3,5-dimethoxyphenyl) ethyl]-5H-pyrrolo [2, 3-b] pyrazine-6-yl} phenyl) piperazine;

1- (4-{2-[(E)-2-(3,5-dimethoxyphenyl) ethenyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine;

N-[(3,5-dimethoxyphenyl) methyl] -6- [4-(4-methylpiperazin-l-yl) phenyl]-5H-pyrrolo [2, 3-b] pyrazin-2-amine;

N-[(2, 6-dichloro-3,5-dimethoxyphenyl) methyl]-6-[4-(4-methylpiperazin-l-yl) phenyl]-5H- pyrrolo [2, 3-b] pyrazin-2-amine;

N-[(3,5-dimethoxyphenyl) methyl]-6-[4-(piperazin-l-yl) phenyl]-5H-pyrrolo [2, 3-b] pyrazin-

2- amine; and

1- (4-{5-[(2,6-dichloro-3,5-dimethoxyphenyl) methoxy]-lH-pyrrolo [2, 3-b] pyridin-2-yl} phenyl)-4-methylpiperazine.

Further preferred specific compounds of the present invention are selected from the group consisting of N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-{5-[(4-methylpiperazin-l-yl)methyl] pyridin-2-yl}-5H-pyrrolo[2, 3-b]pyrazin-2-amine;

N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-{5-[(4-ethylpiperazin-l-yl)methyl]pyridin-

2- yl}-5H-pyrrolo[2,3-b]pyrazin-2-amine; N- [(2,6-dichloro-3 ,5 -dimethoxyphenyl)methyl] -6- [5 -(morpholin-4-ylmethyl)pyridin-2-yl] -

5H-pyrrolo[2,3-b]pyrazin-2-amine; and

N-[(2,6-dichloro-3,5-dimethoxyphenyl)mem^

pyrrolo[2,3-b]pyrazin-2-amine.

Where tautomerism, like e.g. keto-enol tautomerism, of compounds of formula (I) may occur, the individual forms, like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio. Same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like.

Especially, when enantiomeric or diastereomeric forms are given in a compound according to formula (I) each pure form separately and any mixture of at least two of the pure forms in any ratio is comprised by formula (I) and is a subject of the present invention. Isotopic labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S. Solvates of compounds of formula (I) are also within the scope of the present invention. If desired, isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials, reagents and/or catalysts.

In case the compounds according to formula (I) contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

As shown in Table 1 below compounds of the present invention have FGFR inhibiting or modulating activity. Furthermore compounds display negligible VEGFR2/KDR inhibiting or modulating activity. Certain compounds of the present invention are therefore selective against VEGFR2/KDR. Certain compounds of the present invention offer the opportunity to display a differentiated side-effect and toxicity profile, namely to avoid hypertension, the primary on-target toxicity associated with VEGFR2/KDR inhibitors.

The present invention provides compounds of the formula (I) in free or pharmaceutically acceptable salt form to be used in the treatment of, but not limited to, proliferative disorders or dysplasia.

Thus a further aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use as a medicament. In particular, cancer or tumour diseases, including benign or malignant tumours, can be treated where a dysregulation of the FGFR pathway exists. These cancers include, but are not limited to, breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bone sarcoma, colon cancer, multiple myeloma, leukemia, lymphoma, liver cancer, melanoma, head and neck cancer, oral cancer, esophageal cancer, thyroid cancer, pituitary cancer, retinoblastoma, renal cell cancer, brain cancer, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer and testicular cancer. More particularly, the cancers are selected from the group consisting of breast carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, rhabdomyosarcoma, bone cancer, colon cancer, multiple myeloma, acute myeloid leukemia (AML), 8pl l myeloproliferative syndrome (EMS) / stem cell leukemia/lymphoma (SCLL), myeloproliferative disorders (MPD), head and neck cancer, thyroid cancer, astrocytoma, glioblastoma, endometrial cancer and testicular cancer. Most particularly the cancer is bladder cancer. Most particularly the cancer is multiple myeloma. Most particularly the cancer is glioblastoma. In particular, aberrant tumour- associated angiogenesis can be treated where a dysregulation of the FGFR pathway exists. In particular, non-cancer diseases can be treated where a dysregulation of the FGFR pathway exists. These diseases include, but are not limited to, Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Jackson- Weiss syndrome, Beare-Stevenson cutis gyrata, hypochondroplasia, hypophosphatemic rickets, fibrous dysplasia, osteomalacia and lung fibrosis (e.g. COPD, IPF).

Thus, a further aspect of the present invention is a compound or a pharmaceutical salt thereof of the present invention for use in a method of treating and preventing one or more proliferative disorders or dysplasia. Preferred, more preferred and even more preferred disorders are cited below.

Preferred disorders are cancer or tumour diseases, including benign or malignant tumours. More preferred are cancer or tumour diseases, including benign or malignant tumours. Even more preferred are breast cancer, lung cancer, bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bone sarcoma, colon cancer, multiple myeloma, leukemia, lymphoma, liver cancer, melanoma, head and neck cancer, oral cancer, esophageal cancer, thyroid cancer, pituitary cancer, retinoblastoma, renal cell cancer, brain cancer, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer and testicular cancer. Even more preferred are breast carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bladder cancer, gastric cancer, pancreatic cancer, prostate cancer, rhabdomyosarcoma, bone cancer, colon cancer, multiple myeloma, acute myeloid leukemia (AML), EMS/SCLL, myeloproliferative disorders (MPD), head and neck cancer, thyroid cancer, astrocytoma, glioblastoma, endometrial cancer and testicular cancer. Even more preferred is bladder cancer. Even more preferred is multiple myeloma. Even more preferred is glioblastoma. Even more preferred is aberrant tumour-associated angiogenesis where a dysregulation of the FGFR pathway exists. Preferred non-cancer diseases are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Jackson- Weiss syndrome, Beare-Stevenson cutis gyrata, hypochondroplasia, hypophosphatemic rickets, fibrous dysplasia, osteomalacia and lung fibrosis (e.g. COPD, IPF).

FGFRs and FGFs are frequently over-expressed and/or hyperactivated in cancers, where it is believed they contribute to the malignant phenotype through aberrant activation of the FGFR pathways. Similarly, over-expression and/or hyperactivation of certain family members has been linked to poorer patient prognosis. Activation of the FGFR pathway can be achieved through a variety of mechanisms, including gene amplifications, activating mutations, chromosomal translocations leading to novel fusion proteins, and single nucleotide polymorphisms (SNPs). Therefore, cancers displaying aberrant FGFR pathway activation would benefit from FGFR inhibitor therapy. There is a large body of literature to support the presence of FGFR alterations in cancer affecting each individual family member. For FGFR1, these include, but are not limited to, genomic amplification in breast, ovarian, bladder and lung cancer, activating mutations in lung cancer, melanoma and glioblastoma, and multiple fusion events in EMS/SCLL. For FGFR2, these include, but are not limited to, genomic amplification in gastric and breast cancer, activating mutations in endometrial cancer, lung cancer, and gastric cancer, and non-coding SNPs linked to an increased incidence of breast cancer. For FGFR3, these include, but are not limited to, activating mutations in bladder, prostate, cervical and head and neck cancer, and fusion events in multiple myeloma, glioblastoma and EMS/SCLL. For FGFR4, these include, but are not limited to, activating mutations in lung, breast and rhabdomyosarcoma, and coding SNPs linked to poor prognosis in breast, lung and colon cancer. Furthermore, FGF alterations are also observed e.g. amplification of FGF 1 in ovarian cancer or overexpression of various FGF ligands by cancer cells to promote autocrine signalling e.g. FGF2 and FGF6 in prostate cancer. Furthermore, the FGFR pathway is a key regulator of angiogenesis, especially during tumor growth, and is up- regulated in reponse to anti-angiogenic or chemo -therapies. Furthermore, the FGFR pathway can activate cancer associated fibroblasts to support tumour growth. Finally, more selective small molecular weight inhibitors of FGFR display tumour suppressive properties in preclinical tumour models and are being tested in the clinic. In summary, the FGFR pathway is essential to several important cellular processes in cancer cells. For those reasons, therapies targeting the FGFR pathway may inhibit directly both the growth and survival of tumour cells and tumour angiogenesis, and therefore act as an anti-tumourigenic therapy.

The FGFR pathway has also been shown to be dysregulated in non-cancer disorders. Although the FGFR pathway is normally involved in the proper development and functioning of e.g. lung or bone tissue, FGFR pathway dysregulation can lead to severe disorders. Activating mutations and/or over-expression of FGFR family members lead to dysplasia and/or aberrant cell growth. Therefore, disorders displaying aberrant FGFR pathway activation would benefit from FGFR inhibitor therapy. There is also a large body of literature to support the presence of FGFR and/or FGF alterations in non-cancer disorders. These include, but are not limited to, skeletal disorders such as Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Jackson- Weiss syndrome, Beare-Stevenson cutis gyrata, hypochondroplasia and achondroplasia caused by e.g. mutations in FGFR2. These also include, but are not limited to, disorders in phosphate homeostasis such as hypophosphatemic rickets, fibrous dysplasia of the bone or tumour-induced osteomalacia e.g. missense mutations in FGF23. These also include, but are not limited to, lung fibrosis disorders such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), hypertrophy of the airway smooth muscle (ASM) or viral infection leading to these, or other, disorders e.g. respiratory syncytial virus (RSV) caused by e.g. increased expression of various FGF ligands. In summary, the FGFR pathway is essential to several important cellular processes in normal tissues of e.g. lung or bone. For those reasons, therapies targeting the FGFR pathway may reverse and/or stabilize symptoms, and therefore act as a therapy for the aforementioned disorders. Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of one or more proliferative disorders or dysplasia. Preferred, more preferred and even more preferred disorders are cited above. Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more proliferative disorders or dysplasia, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Preferred, more preferred and even more preferred disorders are cited above.

The therapeutic method described may be applied to mammals such as dogs, cats, cows, horses, rabbits, monkeys and humans. Preferably, the mammalian patient is a human patient.

Yet another aspect of the present invention is a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of the present invention together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

Preferably, the one or more bioactive compounds are FGFR inhibitors other than the compounds of formula (I).

"Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like a mixture of compounds of formula (I) in the composition or other FGFR inhibitors.

The active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions). The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In practical use, the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, for example, as liquid drops or spray. The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (I) are administered orally. The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

Starting materials for the synthesis of preferred embodiments of the invention may be purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR or can be synthesized using known methods by one skilled in the art. In general, several methods are applicable to prepare compounds of the present invention. In some cases various strategies can be combined. Sequential or convergent routes may be used. Exemplary synthetic routes are described below.

Examples

Experimental procedures:

The following Abbreviations and Acronyms are used:

aq aqueous

Brine saturated solution of sodium chloride in water

BINAP (+) (R)-(+)-2, 2^*-Bis (diphenylphosphino)- 1 , 1 '-binaphthyl

Cul copper (II) iodide

DCM dichloromethane

DME dimethoxyethane

DMF dimethyl formamide

EtOAc ethylacetate

Et₂0 diethyl ether

EtOH ethanol

HC1 hydrochloric acid

h hour(s)

K₂CC"3 potassium carbonate

MeOH methanol

mL millilitre (s)

MW Microwave

NH₄CI ammonium chloride NH₄OH.HCI hydroxyl amine hydrochloride

NH₃ aqueous ammonia

Na₂S0₄ sodium sulphate

NaHC0₃ sodium bicarbonate

NaOH sodium hydroxide

NaOMe sodium methoxide

NBS N-Bromo succinamide

NMR Nuclear Magnetic Resonance

Na₂C0₃ sodium dicarbonate

Pd (OAc) ₂ Palladium acetate

Pd ₂(dba) 3 tries (dibenzilidineacetone) dipalladium

Pd (PPh₃)₂ Cl₂ Bis (triphenylphosphine) palladium (II) dichloride

PTSA p-toluenesulphonic acid.

R_f Retention factor

TBAF tetrabutylammonium fluoride

TEA triethyl amine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC Thin layer chromatography

t-BuOH tert-butyl alcohol

t-BuOK potassium-tert-butoxide

tR time of retention

w/w weight/ weight

Analytical LCMS conditions are as follows:

System 1: ACIDIC IPC METHOD: Linear gradient 5-100 % solvent B in 1.5 mins + 0.2 mins 100 % solvent B, flow rate 0.6ml/min. Column HSS T3 (50 X 2.1 mm). Solvent A = 0.1 % Formic acid in water: 0.1 % Formic acid in Acetonitrile (90: 10), Solvent B = 0.1 % Formic acid in Acetonitrile: 0.1 % Formic acid in water (90: 10)

System 2: ACIDIC FINAL METHOD: Linear gradient 5-100 % solvent B in 5.30 mins + 0.5 mins 100 % solvent B, flow rate 0.6ml min. Column HSS T3 (100 X 2.1 mm). Solvent A = 0.1 % Formic acid in water: 0.1 % Formic acid in Acetonitrile (90: 10), Solvent B = 0.1 % Formic acid in Acetonitrile: 0.1 % Formic acid in water (90: 10) System 3: ACIDIC METHOD: 5 % Solvent B for 1 min and then Linear gradient 5-100 % solvent B in 5.5 mins + 2.5 mins 100 % solvent B , flow rate 1.0 ml/min. Column ATLANTIS dC18 (50 X 3.0 mm). Solvent A = 0.1 % Formic acid in water, Solvent B = 0.1 % Formic acid in Acetonitrile

Following synthetic schemes are provided wherein

Scheme 1 relates to examples 1- 4;

Scheme 2 relates to examples 5-7;

Scheme 3 relates to example 8;

Scheme A relates to examples A - C;

Scheme D relates to example D.

Scheme la:

Scheme lb:

Scheme 2a:

Scheme 3:

Scheme A:

Scheme D:

Example 1: l-(4-{2-[2-(3, 5-dimethoxyphenyl) ethyl] -5H-pyrrolo [2, 3-b] pyrazin-6-yl} henyl)-4-methylpiperazine:

A mixture of l-(4-{2-[(E)-2-(3, 5-dimethoxyphenyl) ethenyl]-5H-pyrrolo [2, 3-b] pyrazin-6- yl} phenyl)-4-methylpiperazine (40 mg, 0.09 mmol) and Pd/C (10 mg, 20%) in MeOH (50 mL) was stirred at room temperature under hydrogen at 1 atmospheric pressure for 16h. The resulting mixture was filtered through a celite pad, and washed with MeOH (3* 20 mL). The combined filtrate was concentrated under reduced pressure and purified by prep TLC using DCM: MeOH (98:2) system to afford l-(4-{2-[2-(3, 5-dimethoxyphenyl) ethyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl)-4-methylpiperazine (18 mg) as a solid.

1H NMR (400 MHz, CDC1₃) δ 9.69 (s, 1H), 7.96 (s, 1H), 7.66 (d, J= 8.7 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 2.0 Hz, 1H), 6.41 (d, J = 2.3 Hz, 2H), 6.32 (t, J = 2.2 Hz, 1H), 3.76 (s, 6H), 3.36 - 3.32 (m, 4H), 3.19 (dd, J = 9.7, 5.7 Hz, 2H), 3.07 (dd, J = 9.7, 5.8 Hz, 2H), 2.63 - 2.59 (m, 4H), 2.38 (s, 3H). M/Z: 457.57, M+l : 458, t_R= 2.05 min. (System 2) Example 2: 1-(4-{2-[(Ε)-2-(3, 5-dimethoxyphenyl) ethenyl] 5H-pyrrolo [2, 3-b] pyrazin- 6-yl} phenyl) 4-methylpiperazine:

l-(4-{2-bromo-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl)-4-methylpiperazine (200 mg, 0.54 mmol), l-ethenyl-3, 5-dimethoxybenzene (105.73 mg, 0.64 mmol), tri O-tolyl phosphine (16.33 mg, 5 mol %) , Pd(OAc)₂ (12.03 mg, 5 mol %) and K₂C0₃ (148.28 mg, 1.07 mmol) was dissolved in DMA (15 mL), purged with Argon for 15 min. and stirred at 150°C for 16h. The reaction mixture was filtered through a celite pad and the pad rinsed with EtOAc (3* 15 mL). The combined filtrate was washed with water (3* 20 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was triturated with n-pentane (2* 2 mL) and dried under high vacuo to afford l-(4-{2-[(E)-2-(3, 5- dimethoxyphenyl) ethenyl] 5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) 4-methylpiperazine (70 mg) as a yellow solid.

1H NMR (400 MHz, DMSO) δ 12.24 (s, 1H), 8.24 (s, 1H), 7.83 (d, J= 8.1 Hz, 2H), 7.55 (d, J = 15.8 Hz, 1H), 7.40 (d, J= 15.8 Hz, 1H), 7.01 (d, J= 8.1 Hz, 2H), 6.84 (d, J= 19.9 Hz, 3H), 6.40 (s, 1H), 3.75 (s, 6H), 3.28 (s, 4H), 3.22 (s, 4H), 2.19 (s, 3H).M/Z: 455.5, M+l : 456, t_R= 2.25 min. (System 2) Step 2.1: l-(4-{2-bromo-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) -4-methylpiperazine:

To a solution of 5-bromo-3-{2-[4-(4-methylpiperazin-l-yl) phenyl] ethynyl} pyrazin-2-amine (1.0 g, 2.68 mmol) in DMF (10 ml) was added tBuOK (0.301 g, 2.68 mmol). The reaction mixture was allowed to stir at room temperature overnight, quenched with crushed ice and the product extracted with EtOAc (4* 25 mL). The combined organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel column using DCM: MeOH: NH₃ aq. (93:6: 1%) as eluent to afford l-(4-{2-bromo-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) -4- methylpiperazine as a brown solid.

1H NMR (400 MHz, DMSO) δ 12.55 (s, 1H), 8.20 (s, 1H), 7.86 (d, J= 8.4 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.94 (s, 1H), 3.26 (s, 4H), 2.44 (s, 4H), 2.21 (s, 3H). M/Z: 371.07, M+l : 372.3, t_R= 1.88 min. (System 2)

Step 2.2: 5-bromo-3-{2-[4-(4-methylpiperazin-l-yl) phenyl] ethynyl} pyrazin-2-amine:

A round bottom flask was charged with 3, 5-dibromopyrazin-2-amine (1.39 g, 5.41 mmol), Pd (PPh₃)₄ (0.577 g, 8 mol %), Cul (0.095 mg, 8 mol %) and Acetonitrile (25 mL) under argon. To the reaction mixture l-(4-ethynylphenyl)-4-methylpiperazine (1 g, 4.99 mmol) and TEA (2.52 g, 4.99 mmol) were added. The reaction mixture was allowed to stir at room temperature overnight, filtered through celite pad and the pad rinsed with EtOAc (3* 15 mL). The combined filtrate was concentrated under reduced pressure. The crude product was triturated with n-pentane (2* 2 mL) and dried under high vacuo to afford 5-bromo-3-{2-[4-(4- methylpiperazin-l-yl) phenyl] ethynyl} pyrazin-2-amine (1 g) as a sticky solid, which was used as such in the next step without further purification. M/Z: 371.07, M+l : 372.3, t_R= 1.94 min.

H NMR (400 MHz, DMSO) δ 7.86 (s, 1H), 7.43 (d, J= 8.9 Hz, 2H), 6.84 (d, J= 9.0 Hz, 2H), 3.14 (s, 8H), 2.47 (s, 3H). (Note: ^!HNMR contain TEA solvent).

Step 2.3: 3, 5-dibromopyrazin-2-amine:

To a solution of pyrazine-2-amine (10 g, 105.26 mmol) in Chloroform (300 mL) was added pyridine (17.46 g, 221.05 mmol). A solution of bromine (35.32 g, 221.05 mmole) was in chloroform (100 mL) and added to the reaction mixture drop-wise at 30-35°C over a period of 30 min. After complete addition, the reaction mixture was stirred at room temperature. After 5 h the reaction mixture was poured on to water and the aqueous layer extracted with DCM (2* 250 mL). The combined organic layers were washed with water (2* 250 mL) followed by brine solution (250 mL), dried over anhydrous Na₂S0₄, filtered and evaporated under reduced pressure. The resulting crude product was further purified by triturating with n-pentane to afford a 3, 5-dibromopyrazin-2-amine (12.6 g) as a brownish solid.

M/Z: 252.8, M+l :253.8, t_R= 2.26 min. (System 2) Step 2.4: l-(4-ethynylphenyl)-4-methylpiperazine:

A well stirred solution of TMS-diazomethane (5.37 g, 46.99 mmol) in dry THF (100 mL) was treated drop wise with n-BuLi (3.01 g, 46.99 mmol) (24 mL of 2M solution in hexane) at - 78°C under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 45 min. A solution of 4-(4-methylpiperazin-l-yl) benzaldehyde (8 g, 39.16 mmol) in dry THF (25 mL) was added slowly over a period of 30 min. The reaction mixture was stirred at -78°C for lh and then warmed up to 25°C. Stirring was continued for 2h before quenching with saturated aqueous NH₄C1 solution (100 mL). The reaction mixture was diluted with DCM (200 mL). The organic phase was separated and the aqueous phase was further extracted with DCM (3* 50 mL). The combined organic extracts were dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel column using Hexane: Acetone (7:3) as eluent to afford l-(4- ethynylphenyl)-4-methylpiperazine (5 g) as a yellow solid.

1H NMR (400 MHz, CDC13) δ 7.41 - 7.36 (m, 2H), 6.86 - 6.81 (m, 2H), 3.29 - 3.22 (m, 4H), 2.99 (s, 1H), 2.59 - 2.53 (m, 4H), 2.35 (s, 3H). M/Z: 200.2, M+l : 201, t_R = 1.59 min. (System 2) Step 2.5: 4-(4-methylpiperazin-l-yl) benzaldehyde:

A mixture of 4-fluorobenzaldehyde (26.5 g, 214 mmol), N-Methylpiperazine (36.36 g, 363 m mol) and Na₂C0₃ (38.47 g, 363 mmol) in water (lOOmL) was heated at 100 °C for 5h. The reaction mixture was cooled to room temperature and additional water (500 mL) was added and extracted with DCM (3* 100 mL). The combined extracts were washed with brine dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to afford the title compound as oil which solidified on cooling. The compound was triturated in n-pentane to afford 4-(4-methylpiperazin-l-yl) benzaldehyde (41 g) as a tan solid.

1H NMR (400 MHz, CDC1₃) δ 9.78 (s, 1H), 7.76 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 3.46- 3.38 (m, 4H), 2.59 - 2.53 (m, 4H), 2.36 (s, 3H). M/Z: 204, M+l : 205.3, t_R= 0.87min. (System 2)

Example 3: l-(4-{2-[2-(3, 5-dimethoxyphenyl) ethyl] -5H-pyrrolo [2, 3-b] pyrazine -6-yl} phenyl) piperazine hydrochloride salt:

To a clear solution of tert-butyl 4-(4-{2-[2-(3, 5-dimethoxyphenyl) ethyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine- 1-carboxylate (30 mg, 0.05 mmol) in THF (2 ml) was added Dioxane/HCl (4 M, 9.24 mg, 0.26 mmol) at 0°C. The reaction mixture was allowed to stir at room temperature overnight then concentrated under reduced pressure to get a sticky solid which was triturated with EtOAc (2* 10 mL) followed by Et₂0 (2 mL) and n-pentane (2 mL). Residual solid was dried under high vacuo to afford l-(4-{2-[2-(3, 5-dimethoxyphenyl) ethyl]-5H-pyrrolo [2, 3-b] pyrazine -6-yl} phenyl) piperazine hydrochloride salt (20 mg) as a brown solid.

1H NMR (400 MHz, DMSO) δ 9.30 (s, 2H), 8.22 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.9 Hz, 2H), 7.08 (s, 1H), 6.44 (d, J = 2.1 Hz, 2H), 6.32 (d, J = 2.1 Hz, 1H), 3.70 (s, 6H), 3.57 (s, 4H), 3.21 (m, 6H), 3.05 - 2.98 (m, 2H). M/Z: 443, M+l : 444.5, t_R= 2.12 min. (System 2)

Step 3.1: tert-butyl 4-(4-{2-[2-(3, 5-dimethoxyphenyl) ethyl] -5H-pyrrolo [2, 3-b] pyrazin- 6-yl} phenyl) piperazine-l-carboxylate:

Pd/C (10%) (0.05 mg, 10 %, w/w) was added to a solution of tert-butyl 4-(4-{2-[(E)-2-(3, 5- dimethoxyphenyl) ethenyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine-l- carboxylate (300 mg, 0.47 mmol) in DCM: MeOH (1 : 1, 50 mL), and agitated in a par shaker apparatus under a hydrogen at a pressure of 40 psi for 24h. The reaction mixture was filtered through celite pad and the pad rinsed with DCM (3* 20 mL) followed by MeOH (2* 20 mL). The combined filtrate was concentrated under reduced pressure and the crude product purified by column chromatography on silica gel column using DCM: MeOH (95:5) as an eluent to afford tert-butyl 4-(4-{2-[2-(3, 5-dimethoxyphenyl) ethyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine-l-carboxylate (70 mg) as a brown solid.

1H NMR (400 MHz, CDC1₃) δ 10.47 (s, 1H), 7.96 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H), 6.84 (s, 1H), 6.40 (d, J = 2.1 Hz, 2H), 6.32 (d, J = 2.1 Hz, 1H), 3.75 (s, 6H), 3.65 - 3.61 (m, 4H), 3.28 (s, 4H), 3.20 (dd, J= 9.5, 6.0 Hz, 2H), 3.11 - 3.05 (m, 2H), 1.50 (s, 9H). M/Z: 543.66, M+l : 544.5, t_R= 3.42 min. (System 2)

Step 3.2: tert-butyl 4-(4-{2-[(E)-2-(3, 5-dimethoxyphenyl) ethenyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine-l-carboxylate:

A microwave tube was charged with tert-butyl 4-(4-{2-bromo-5H-pyrrolo [2, 3-b] pyrazin-6- yl} phenyl) piperazine-l-carboxylate (500 mg, 1.091 mmol), l-ethenyl-3, 5- dimethoxybenzene (214.9 mg, 1.309 mmol), Cul (20.77 mg, 10 mol %), tri(O-tolyl) phosphine (33.2 mg, 10 mol %), Pd (OAc)₂ (24.49 mg, 10 mol %) and triethyl amine (220 mg, 2.181 mmol) in dry DMF (5 mL). The mixture was purged with Argon and the cap sealed. The reaction mixture was irradiated at 90°C for lh in a microwave then the reaction mixture was filtered through celite and the pad rinsed with EtOAc (3* 15 mL). The combined filtrate was concentrated under reduced pressure. The resulting product was washed with n-pentane (2* 2 mL) and dried under high vacuo to afford tert-butyl 4-(4-{2-[(E)-2-(3, 5- dimethoxyphenyl) ethenyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine-l- carboxylate (100 mg) as a yellow solid.

M/Z: 541.64, M+l : 542.5, t_R= 3.66 min. (System 2) Example 4: l-(4-{2-[(E)-2-(3, 5-dimethoxyphenyl) ethenyl]-5H-pyrrolo [2, 3-b] pyrazin- 6-yl} phenyl) piperazine:

To a clear solution of tert-butyl 4-(4-{2-[(E)-2-(3, 5-dimethoxyphenyl) ethenyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine-l-carboxylate (100 mg, 0.184 mmol) in DCM (100 mL) was added TFA (42 mg, 0.369 mmol) at 10°C. The reaction mixture was allowed to stir at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in minimum amount of water and basified with IN NaOH to pH 10. The product was extracted with EtOAc (3* 20 mL) and the combined organic extracts were dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was triturated with Et₂0 (2 mL), dried under high vacuo to afford l-(4-{2-[(E)-2-(3, 5-dimethoxyphenyl) ethenyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine (10 mg) as a brown solid. 1H NMR (400 MHz, DMSO) δ 12.27 (s, 1H), 8.28 (s, 1H), 7.87 (d, J= 8.6 Hz, 2H), 7.59 (d, J = 16.0 Hz, 1H), 7.44 (d, J = 16.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.93 - 6.83 (m, 3H), 6.44 (s, 1H), 3.79 (s, 6H), 3.20 (s, 4H), 2.87 (s, 4H), 1.22 (s, 1H).M/Z: 441.52, M+l : 442.4, t_R= 2.3 min. (System 2) Step 4.1: tert-butyl 4-(4-{2-bromo-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine- 1-carboxylate:

To a solution of tert-butyl 4-{4-[2-(3-amino-6-bromopyrazin-2-yl) ethynyl] phenyl} piperazine- 1-carboxylate (3.7 g, 7.911 mmol) in DMF (30 ml) was added t-BuOK (1.775 g, 15.82 mmol). The reaction mixture was heated at 90°C overnight. The reaction mixture was cooled to 0°C and quenched with water. The resulting precipitate was filtered off, washed with water and dried under high vacuo to afford tert-butyl 4-(4-{2-bromo-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine- 1-carboxylate (3 g) as a dark brown solid.

1H NMR (400 MHz, DMSO) δ 12.58 (s, 1H), 8.21 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.66 - 7.51 (m, 2H), 7.06 (d, J = 8.5 Hz, 1H), 6.96 (s, 1H), 3.46 (s, 4H), 3.29 (d, J = 28.4 Hz, 4H), 1.42 (s, 9H).

Step 4.2: tert-butyl 4-{4-[2-(3-amino-6-bromopyrazin-2-yl) ethynyl] phenyl} piperazine- 1-carboxylate:

A round bottom flask was charged with 3, 5-dibromopyrazin-2-amine (2.46 g, 9.25 mmol), Pd₂ (PPh₃)₄ (0.49 g, 5 mol %), Cul (0.16 g, 10 mol %) and Acetonitrile (25 mL) under argon. Tert-butyl l-(4-ethynylphenyl) piperidine-4-carboxylate (2.4 g, 8.41 mmol) and triethylamine (5.9 mL, 42.09 mmol) were added and the reaction mixture stirred at room temperature for 3h then filtered through a celite pad and the pad rinsed with EtOAc (3* 15 mL). The combined filtrate was concentrated under reduced pressure and the crude product purified by triturating with n-pentane: DCM (8:2) and dried under high vacuo to afford tert-butyl 4-{4-[2-(3-amino- 6-bromopyrazin-2-yl) ethynyl] phenyl} piperazine-l-carboxylate (3.5 g) as a brown solid. 1H NMR (400 MHz, CDC13) δ 8.01 (s, 1H), 7.47 (d, J= 8.6 Hz, 2H), 6.86 (d, J= 8.8 Hz, 2H), 5.10 (s, 2H), 3.63 - 3.53 (m, 4H), 3.26 (d, J = 5.0 Hz, 4H), 1.49 (s, 9H). M/Z: 457.1, M+l : 458.3, t_R= 3.56 min. (System 2)

Step 4.3: tert-butyl 4-(4-ethynylphenyl) piperazine-l-carboxylate

TBAF (13.13 g, 0.05 mmol) was added drop wise to a solution of tert-butyl 4-{4-[2- (trimethylsilyl) ethynyl] phenyl} piperazine-l-carboxylate (3.6 g, 0.01 mmol) in THF (50 mL) at 0°C. The reaction mixture was allowed to stir at room temperature overnight and then the solvent removed under reduced pressure. The crude product was dissolved in water and extracted with EtOAc (3* 150 mL). The combined organic layers were washed with brine solution (150 mL), dried over anhydrous Na₂S0₄, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel column using Hexane: EtOAc (95:5) as eluent to afford tert-butyl 4-(4-ethynylphenyl) piperazine-1- carboxylate (2.4 g) as a white solid.

1H NMR (400 MHz, CDC13) δ 7.43 - 7.37 (m, 2H), 6.85 - 6.80 (m, 2H), 3.60 - 3.54 (m, 4H), 3.22 - 3.16 (m, 4H), 2.99 (s, 1H), 1.48 (s, 9H); M/Z: 281.3, M+l : 182.1 (Fragment of De- BOC), t_R= 2.04 min. (System 2)

Step 4.4: tert-butyl 4-{4-[2-(trimethylsilyl) ethynyl] phenyl} piperazine-l-carboxylate:

A 250mL round bottom flask was charged with tert-butyl 4-(4-iodophenyl) piperazine-l- carboxylate (5.1 g, 13.14 mmol), Pd (PPh₃)₄ (759 mg, 5 mol %), Cul (250 mg, 10 mol %) and Acetonitrile (50 mL) under argon. To the reaction mixture, TEA (9.2 ml, 66.05 mmol), followed by ethynyl (trimethyl) silane (2.58 g, 26.27 mmol) were added and the mixture purged again for a further 15 min. The reaction mixture was allowed to stir at room temperature overnight then the solvent removed under reduced pressure. Water was added to the crude residue and extracted with EtOAc (3* 150 mL). The combined organic extracts were washed with brine solution (150 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column using Hexane: EtOAc (9: 1) as eluent to afford tert-butyl 4-{4-[2-(trimethylsilyl) ethynyl] phenyl} piperazine-l-carboxylate (3.6 g) as a yellow solid.

1H NMR (400 MHz, CDC13) δ 7.37 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 3.59 - 3.53 (m, 4H), 3.21 - 3.15 (m, 4H), 1.48 (s, 9H), 0.27 - 0.20 (m, 9H). M/Z: 358.6, M+l : 359.4, t_R= 4.14 min. (System 2)

Step 4.5: tert-butyl 4-(4-iodophenyl) piperazine-l-carboxylate:

To a stirred, cooled (0°C) solution of KHSO₄ (6.8 g, 50.48 mmol) in water, was added tert- butyl- 4-(4-aminophenyl) piperazine-l-carboxylate (7 g, 25.25 mmol) portion wise while maintaining the temperature at 0°C. After 30 minutes, a solution of NaN0₂ (3.4 g, 50.48 mmol) in water was added drop wise at 0°C. After 15 min a solution of KI (14.66 g, 88.33 mmol) in water was added drop wise. Brown fumes were evolved and the reaction mixture allowed to stir at room temperature overnight. EtOAc (200 mL) was added and the organic phase was separated. The aqueous phase was further extracted with EtOAc (2* 200 mL). Combined organic extracts were dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel column Hexane: EtOAc (9: 1) as eluent to afford tert-butyl 4-(4-iodophenyl) piperazine-l- carboxylate (5.1 g) as a white solid.

M/Z: 388.2, M+l : 389.3, t_R= 3.62 min. (System 2)

Example 5: N-[(3, 5-dimethoxyphenyl) methyl]-6-[4-(4-methylpiperazin-l-yl) phenyl]- 5H-pyrrolo [2, 3-b] pyrazin-2-amine:

To a solution of N-[(3, 5-dimethoxyphenyl) methyl]-6-[4-(4-methylpiperazin-l-yl) phenyl]-5- {[2-(trimethylsilyl) ethoxy] methyl} -5H-pyrrolo [2, 3-b] pyrazin-2-amine (30 mg, 0.05 mmol) in MeOH (1 mL) was added 4 M MeOH/ HC1 (1 mL) at 5°C. The reaction mixture was allowed to stir at room temperature for overnight. The solvent was removed under reduced pressure and the crude product purified by column chromatography on silica gel column using DCM: MeOH: NH₃ aq. (97:2: 1%) as eluent to afford N-[(3, 5-dimethoxyphenyl) methyl]-6- [4-(4-methylpiperazin-l-yl) phenyl]-5H-pyrrolo [2, 3-b] pyrazin-2-amine (11 mg) as a brown solid.

1H NMR (400 MHz, CDC13) δ 9.79 (s, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.52 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.60 (dd, J = 11.9, 2.0 Hz, 3H), 6.38 (t, J = 2.2 Hz, 1H), 4.70 (d, J = 5.6 Hz, 1H), 4.57 (d, J = 5.1 Hz, 2H), 3.78 (s, 6H), 3.33 - 3.28 (m, 4H), 2.62 - 2.58 (m, 4H), 2.37 (s, 3H). M/Z: 458.56, M+l : 459.4, t_R= 1.96 min. (System 2)

Step 5.1: N-[(3, 5-dimethoxyphenyl) methyl]-6-[4-(4-methylpiperazin-l-yl) phenyl] -5- {[2- (trimethylsilyl) ethoxy] methyl}-5H-pyrrolo [2, 3-b] pyrazin-2-amine:

In a microwave tube, BINAP (7.43 mg, 8 mol %), Pd₂(dba)₃(0) (2.91 mg, 3 mol %) were taken in a mixture of solvent, Toluene: t-BuOH (5: 1), purged with argon for few minutes then l-[4-(2-bromo-5-{[2-(trimethylsilyl) ethoxy] methyl} -5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] -4-methylpiperazine (200 mg, 0.4 mmol), (3, 5-dimethoxyphenyl) methanamine (86.51 mg, 0.52 mmol) and t- BuOK (38.21 mg, 0.4 mmol) were added to the reaction mixture, purged again with argon, sealed the tube with cap. The reaction mixture was irradiated at 130°C for 1 h in MW. The reaction mixture was filtered through celite pad and aid with EtOAc (3* 5 mL). Combined filtrate was concentrated under reduced pressure. Crude product was purified by column chromatography on silica gel column DCM: MeOH: N¾ aq. (95:4: 1%) as an eluent to afford N-[(3, 5-dimethoxyphenyl) methyl] -6- [4-(4-methylpiperazin- 1-yl) phenyl] -5 -{[2-(trimethylsilyl) ethoxy] methyl} -5H-pyrrolo [2, 3-b] pyrazin-2-amine (60 mg) as a yellow solid. 1H NMR (400 MHz, CDC1₃) δ 7.71 (d, J= 8.8 Hz, 2H), 7.61 (s, 1H), 7.04 (d, J= 8.9 Hz, 2H), 6.61 (d, J = 2.3 Hz, 2H), 6.52 (s, 1H), 6.40 (t, J = 2.2 Hz, 1H), 5.56 (s, 2H), 4.80 (t, J = 5.7 Hz, 1H), 4.60 (d, J= 5.6 Hz, 2H), 3.80 (s, 6H), 3.78 - 3.71 (m, 2H), 3.38 - 3.33 (m, 4H), 2.67 - 2.61 (m, 4H), 2.41 (s, 3H), 1.03 - 0.96 (m, 2H), 0.01 (s, 9H).M/Z: 588.82, M+l : 589.6, t_R= 2.7 min. (System 2)

Step 5.2: l-[4-(2-bromo-5-{[2-(trimethylsilyl) ethoxy] methyl}-5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] -4-methylpiperazine:

NaH (60 %, 25 mg, 1.04 mmol) was added portion wise to a cooled (0°C) solution of l-(4-{2- bromo-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl)-4-methylpiperazine (0.3 g, 0.804 mmol) in DMF (0.5 mL). Stirring was continued for 30 minutes at 0°C then (2-Chloromethoxy-ethyl)- trimethyl-silane (0.17 g, 0.104 mmol) was added and the reaction mixture stirred at room temperature overnight and then quenched with water. The aqueous layer was extracted with Et₂0 (3* 5 mL) and the combined organic extracts dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was washed with n-pentane (1 mL) and dried under high vacuo to afford l-[4-(2-bromo-5-{[2-(trimethylsilyl) ethoxy] methyl}- 5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] -4-methylpiperazine (250 mg) as a solid.

1H NMR (400 MHz, CDC1₃) δ 8.27 (s, 1H), 7.73 (d, J= 8.9 Hz, 2H), 7.04 (d, J= 8.9 Hz, 2H), 6.68 (s, 1H), 5.62 (s, 2H), 3.78 - 3.73 (m, 2H), 3.38 - 3.34 (m, 4H), 2.64 - 2.60 (m, 4H), 2.39 (s, 3H), 0.90 (t, J = 7.1 Hz, 2H), 0.01 - -0.01 (m, 9H). M/Z: 502.52, M+H: 504.4, t_R = 2.71 mm.

Example 6: N-[(2, 6-dichloro-3, 5-dimethoxyphenyl) methyl]-6-[4-(4-methylpiperazin-l- yl) phenyl] -5H-pyrrolo [2, 3-b] pyrazin-2-amine:

To a solution of N-[(2,6-dichloro-3, 5-dimethoxyphenyl) methyl] -6- [4-(4-methylpiperazin-l- yl) phenyl] -5 -{[2-(trimethylsilyl) ethoxy] methyl} -5H-pyrrolo [2, 3-b] pyrazin-2-amine (120 mg, 0.182 mmol) in THF was added drop wise TBAF (1M in THF, 44 mg, 0.364 mmol) and ethylene diamine (5.0 mg, 0.182 mmol). The reaction mixture was stirred at 80°C for 15h, and then concentrated. Water was added to the resulting residue and extracted with EtOAc (2* 50 mL), dried over anhydrous Na₂S0₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel column using DCM: MeOH: N¾ aq. (95:4: 1%) as eluent to afford N-[(2, 6-dichloro-3, 5-dimethoxyphenyl) methyl] -6- [4-(4-methylpiperazin-l- yl) phenyl]-5H-pyrrolo [2, 3-b] pyrazin-2-amine (12 mg) as a brown solid.

1H NMR (400 MHz, DMSO) δ 11.68 (s, 1H), 7.74 (d, J= 8.4 Hz, 2H), 7.57 (s, 1H), 6.99 (d, J = 8.6 Hz, 2H), 6.93 (s, 1H), 6.62 (s, 1H), 6.47 (s, 1H), 4.66 (s, 2H), 3.92 (s, 6H), 3.29 (d, J = 19.3 Hz, 4H), 3.22 (s, 4H), 2.24 (s, 3H). M/Z: 526.1, M+H: 527.4 t_R = 2.21 min. (System 2)

Step 6.1: N-[(2, 6-dichloro-3, 5-dimethoxyphenyl) methyl]-6-[4-(4-methylpiperazin-l-yl) phenyl] -5- {[2-(trimethylsilyl) ethoxy] methyl}-5H-pyrrolo [2, 3-b] pyrazin-2-amine:

The title compound was prepared in analogy to the procedure described in step 5.1 using l-[4- (2-bromo-5-{[2-(trimethylsilyl)ethoxy] methyl} -5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl]-4- methylpiperazine and (2, 6-dichloro-3, 5-dimethoxyphenyl) methanamine which in turn was prepared by the chlorination of (3, 5-dimethoxyphenyl) methanamine using sulfuryl chloride in diethyl ether. Obtained N-[(2, 6-dichloro-3, 5-dimethoxyphenyl) methyl] -6- [4-(4- methylpiperazin-l-yl) phenyl] -5 -{[2-(trimethylsilyl) ethoxy] methyl} -5H-pyrrolo [2, 3-b] pyrazin-2-amine (150 mg) as yellow solid.

The title compound: M/Z: 656.1, M+H: 657.4, t_R = 2.71 min. (System 2)

Step 6.2: (2, 6-dichloro-3, 5-dimethoxyphenyl) methanamine:

Sulfuryl chloride (2. 42 mL , 11.96 mmol) was added drop wise to a cold (5°C) solution of (3, 5-dimethoxyphenyl) methamine (1 g, 5.98 mmol) in Et₂0 (10 mL). Yellow precipitate formed. The reaction mixture was stirred at room temperature for lh, quenched by addition of water and concentrated, made pH of solution neutral with 5 % NaHC0₃ solution and extracted with EtOAc (3* 15 mL). The organic phase was washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The compound was purified by silica gel column chromatography using DCM as an eluent to afford title compound (2.7 g) as an off white solid.

The title compound: 1H NMR (400 MHz, DMSO) δ 6.49 (s, 1H), 4.13 (s, 2H), 3.91 (s, 6H).

Example 7: N-[(3, 5-dimethoxyphenyl) methyl]-6-[4-(piperazin-l-yl) phenyl] -5H-pyrrolo

[2, 3-b] pyrazin-2-amine:

To a clear solution of tert-butyl 4-[4-(2-{[(3, 5-dimethoxyphenyl) methyl] amino} -5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] piperazine-l-carboxylate (50 mg, 0.092 mmol) in THF (2 ml) was added Dioxane/HCl (4 M, 6.4 mg, 0.184 mmol) at 0°C. The reaction mixture was allowed to stir at room temperature for 8h and then concentrated under reduced pressure and a sticky solid was obtained which was triturated in Et₂0 (2* 10 mL) followed by n-pentane (2 mL). Drying under high vacuo afforded N-[(3, 5-dimethoxyphenyl) methyl] -6- [4-(piperazin- 1-yl) phenyl]-5H-pyrrolo [2, 3-b] pyrazin-2-amine hydrochloride salt (15 mg) as a brown solid.

1H NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.64 (s, 1H), 6.51 (d, J= 2.2 Hz, 2H), 6.38 (t, J= 2.2 Hz, 1H), 4.48 (s, 2H), 3.69 (s, 6H), 3.49 - 3.45 (m, 4H), 3.32 - 3.28 (m, 4H). M/Z: 444.5, M+H: 445.5, t_R = 1.86 min. (System 2)

Step 7.1: tert-butyl 4-[4-(2-{[(3, 5-dimethoxyphenyl) methyl] amino}-5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] piperazine-l-carboxylate:

To a solution of tert-butyl 4-[4-(2-{[(3, 5-dimethoxyphenyl) methyl] amino}-5-{[2- (trimethylsilyl) ethoxy] methyl} -5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] piperazine-l- carboxylate in THF was added TBAF in THF 1M soln. (55.79 mg, 0.21 mmol) followed by ethylene diamine (10.69 mg, 0.18 mmol) at room temperature. The reaction mixture was refluxed for 24 h, then cooled to room temperature and quenched with water (1.5 mL) and product was extracted with EtOAc (3 * 15 mL). Combined organic phase was dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. Crude product was purified by column chromatography on silica gel DCM: MeOH: NH₂ aq. (96: 3: 1%) as an eluent to afford tert-butyl 4-[4-(2-{[(3, 5-dimethoxyphenyl) methyl] amino} -5H-pyrrolo [2, 3- b] pyrazin-6-yl) phenyl] piperazine-l-carboxylate (52 mg) as a brown solid.

M/Z: 544.6, M+H: 545.5, t_R = 3.02 min (System 2)

Step 7.2: tert-butyl 4-[4-(2-{[(3, 5-dimethoxyphenyl) methyl] amino}-5-{[2- (trimethylsilyl) ethoxy] methyl}-5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] piperazine-l- carboxylate:

The title compound was prepared in analogy to the procedure described in step 5.1 using tert- butyl 4-[4-(2-bromo-5-{[2-(trimethylsilyl) ethoxy] methyl} -5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] piperazine-l-carboxylate and (3, 5-dimethoxyphenyl) methanamine to afford tert- butyl 4-[4-(2-{[(3, 5-dimethoxyphenyl) methyl] amino}-5-{[2-(trimethylsilyl) ethoxy] methyl} -5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] piperazine-l-carboxylate (120 mg) as a brown solid.

The title compound: M/Z: 674.3, M+H: 675.3, t_R = 4.12 min. (System 2) Step 7.3: tert-butyl 4-[4-(2-bromo-5-{[2-(trimethylsilyl) ethoxy] methyl}-5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] piperazine-l-carboxylate:

The title compound was prepared in analogy to the procedure described in step 5.2 using tert- butyl 4-(4-{2-bromo-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl) piperazine-l-carboxylate to afford tert-butyl 4-[4-(2-bromo-5-{[2-(trimethylsilyl) ethoxy] methyl} -5H-pyrrolo [2, 3-b] pyrazin-6-yl) phenyl] piperazine-l-carboxylate (150 mg) as a yellow solid.

1H NMR (400 MHz, CDC1₃) δ 8.27 (s, 1H), 7.74 (d, J= 8.8 Hz, 2H), 7.03 (d, J= 8.8 Hz, 2H), 6.69 (s, 1H), 5.62 (s, 2H), 3.79 - 3.73 (m, 2H), 3.66 - 3.61 (m, 4H), 3.30 (d, J = 4.7 Hz, 4H), 1.51 (s, 9H), 1.03 - 0.97 (m, 2H), 0.00 (s, 9H).

Example 8: l-(4-{5-[(2, 6-dichloro-3, 5-dimethoxyphenyl) methoxy]-lH-pyrrolo [2, 3-b] pyridin-2-yl} phenyl)-4-methylpiperazine :

To a solution of 2-[4-(4-methylpiperazin-l-yl) phenyl] -lH-pyrrolo [2, 3-b] pyridin-5-ol (25 mg, 0.076 mmol) in DMF (2 mL) was added 3-(bromomethyl)-2, 4-dichloro-l, 5- dimethoxybenzene (27.43 mg, 0.09 mmol) [Step-6.2] and K₂C0₃ (15.8 mg, 0.1 1 mmol) under argon. The reaction mixture was stirred at room temperature overnight and then water was added. The mixture was extracted with EtOAc (3* 10 mL), combined organic layers washed with brine solution, dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to give the crude product which was purified by prep TLC using DCM: MeOH (9: 1) as mobile phase to afford the title compound l-(4-{5-[(2, 6-dichloro-3, 5-dimethoxyphenyl) methoxy]-lH- pyrrolo [2, 3-b] pyridin-2-yl} phenyl)-4-methylpiperazine (10 mg) as a tan solid.

1H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 2.3 Hz, 1H), 7.04 - 6.96 (m, 3H), 6.65 (s, 1H), 5.28 (s, 2H), 3.94 (s, 6H), 3.26 (d, J= 47.3 Hz, 8H), 2.23 (s, 3H).M/Z: 526, M+H: 527.3, t_R = 2.43 min. (System 2)

Step 8.1: 2-[4-(4-methylpiperazin-l-yl) phenyl]-lH-pyrrolo [2, 3-b] pyridin-5-ol:

A dry microwave tube was charged with l-(4-{5-methoxy-lH-pyrrolo [2, 3-b] pyridin-2-yl} phenyl)-4-methylpiperazine (240 mg, 0.7 mmol) and freshly prepared pyridine. HC1 and irradiated in microwave at 170°C for 3h. After cooling, MeOH (5 mL) was added, the mixture adsorbed on to silica gel and purified by column chromatography using DCM: MeOH (96: 4) as eluent to afford title compound 2-[4-(4-methylpiperazin-l-yl) phenyl] -lH-pyrrolo [2, 3-b] pyridin-5-ol (65 mg) as tan solid.

M/Z: 308.3, M-H: 307.4, t_R = 1.41 min. (System 2)

Step 8.2: l-(4-{5-methoxy-lH-pyrrolo [2, 3-b] pyridin-2-yl} phenyl)-4-methylpiperazine:

A round bottom flask was charged with 3-bromo-5-methoxypyridin-2-amine (600 mg, 2.95 mmol), Pd (PPh₃)₂Cl₂ (0.103 mg, 0.148 mmol), copper iodide (28.7 mg, 0.148 mmol) and DMF (6 mL) under argon. To the reaction mixture l-(4-ethynylphenyl)-4-methylpiperazine (710 mg, 3.56 mmol) and TEA (0.45 mL, 3.25 mmol) were added. The reaction mixture was purged again with argon, allowed to stir at 120°C overnight, filtered through a celite pad and the pad rinsed with the aid of EtOAc (2* 20 mL). The combined filtrate was concentrated under reduced pressure and the residue purified by silica gel column chromatography using DCM: MeOH (97: 3) as eluent to afford the title compound as a brown solid.

1H NMR (400 MHz, DMSO) δ 11.62 (s, 1H), 7.74 (s, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.29 (t, J = 4.2 Hz, 1H), 6.85 (d, J = 9.0 Hz, 2H), 6.49 (d, J = 2.0 Hz, 1H), 3.67 (d, J = 4.8 Hz, 3H), 3.09 - 3.03 (m, 4H), 2.34 - 2.28 (m, 4H), 2.08 (s, 3H).M/Z: 322.4, M+H: 323.3 t_R = 1.73 min. (System 2)

Step 8.3: 3-bromo-5-methoxypyridin-2-amine:

To a solution of 3-bromo-2-(2, 5 -dimethyl- lH-pyrrol-l-yl)-5-methoxypyridine (12 g, 442.68 mmol) in EtOH (100 mL) was added NH₄OH.HCl (20.76 g, 298.77 mmol) dissolved in water followed by TEA (17.28 g, 170.72 mmol). The reaction mixture was stirred at 80°C overnight. The reaction mixture was cooled to room temperature and made alkaline by adding 10% NaOH solution (200 mL) and extracted with DCM (4* 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated to afford the crude product which was purified by silica gel chromatography using Hexane: EtOAc (6: 4) as eluent to afford the title compound (4.3 g) brown solid.

1H NMR (400 MHz, CDC1₃) δ 7.77 (d, J= 2.7 Hz, 1H), 7.35 (d, J= 2.7 Hz, 1H), 4.67 (s, 2H), 3.77 (s, 3H). M/Z: 201.97, M+H: 203.1, t_R = 1.3 min. (System 2)

Step 8.4: 3-bromo-2-(2, 5-dimethyl-lH-pyrrol-l-yl)-5-methoxypyridine:

Sodium metal (4.46 g, 193.9 mmol) was added to MeOH (100 mL) in a round bottom flask, and stirred for 30 minutes. Anhydrous DMF (40 mL) was added followed by Cul (1.38 g, 7.27 mmol) and 3, 5-dibromo-2-(2, 5-dimethyl-lH-pyrrol-l-yl) pyridine (16 g, 48.48 mmol). The reaction mixture was heated at 80°C for 2h. The reaction mixture was cooled to room temperature, water (100 mL) added and the reaction mixture filtered over a celite bed and the bed was washed with Et₂0 (3* 100 mL). The filtrate was extracted with Et₂0 (4* 100 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give crude product which was pure enough to carry forward for the next reaction. M/Z: 281.15, M+H: 283.2, t_R = 3.07 min. (System 3)

Step 8.5: 3, 5-dibromo-2-(2, 5-dimethyl-lH-pyrrol-l-yl) pyridine:

A round bottom flask fitted with a Dean Stark apparatus was charged with a solution of 3, 5- dibromo-2-amine (16 g, 63.51 mmol) in dry Toluene (250 mL). To the reaction mixture 2, 5- hexanedione (7.97 g, 69.86 mmol) and PTSA (1.81 g, 66.82 mmol) were added and the reaction mixture heated at 120°C for 2h. The reaction mixture was cooled to room temperature and washed with saturated NaHC0₃ solution followed by brine and dried over anhydrous Na₂S0₄, filtered and concentrated to give crude product which was used without further purification.

1H NMR (400 MHz, CDC1₃) δ 8.62 (d, J= 2.2 Hz, 1H), 8.22 (d, J= 2.2 Hz, 1H), 5.92 (s, 2H), 2.00 (s, 6H).

Step 8.6: 3, 5-dibromopyridin-2-amine:

NBS (198.5 g, 1115.6 mmol) was added portion wise over a period of 10 min to a cooled solution (0°C) of pyridine-2-amine (50 g, 531.27 mmol) in Acetonitrile (500 mL). A significant exotherm was obtained. The reaction mixture was allowed to stir at room temperature for 2h then the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography using Hexane: EtOAc (8: 2) as eluent to afford title compound (98 g) as a reddish solid.

M/Z: 251.91, M+H: 253, t_R = 0.96 min. (System 1) Step 8.7: 3-(bromomethyl)-2, 4-dichloro-l, 5-dimethoxybenzene:

To a solution of (2, 6-dichloro-3, 5-dimethoxyphenyl) methanol (600 mg, 2.53 mmol) in DCM (10 mL) was added carbon tetrabromide (0.84 g, 2.53 mmol) followed by triphenylphosphine (0.66 g, 2.53 mmol). Reaction mixture was allowed to stir at room temperature for lh. Then reaction mixture was concentrated and crude mass was purified by silica gel column chromatography using Hexane: EtOAc (80:20) as an eluent to afford title compound as white solid.

1H NMR (400 MHz, CDC13) δ 6.54 (s, 1H), 4.79 (s, 2H), 3.92 (s, 6H).

Ste 8.8: (2, 6-dichloro-3, 5-dimethoxyphenyl) methanol:

Sulfuryl chloride (3. 21 g , 23.78 mmol) was added drop wise to a cold (5°C) solution of (3, 5- dimethoxyphenyl) methanol (2 g, 11.89 mmol) in Et₂0 (20 mL). The reaction mixture was stirred at room temperature for lh, quenched by addition of water (3 mL) and concentrated, made pH of solution neutral with 5 % NaHC0₃ solution and extracted with DCM (3* 25 mL). The organic phase was washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The compound was purified by triturating in n-pentane to afford (2.7 g) of title compound as white solid.

H NMR (400 MHz, CDC13) δ 6.55 (s, 1H), 5.00 - 4.98 (d, 2H), 3.92 (s, 6H).

Example A: N-[(2, 6-dichloro-3, 5-dimethoxyphenyl) methyl]-6-{5-[(4-methylpiperazin- 1-yl) methyl] pyridin-2-yl}-5H-pyrrolo [2, 3-b] pyrazin-2-amine:

To a solution of N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-{5-[(4-methylpiperazin-l- yl)methyl]pyridin-2-yl}-5-{[2-(trim

amine (280 mg, 0.416 mmol) in DCM was added drop wise SnCL, (1M in DCM, 325.05 mg, 1.249 mmol). The reaction mixture was stirred at 0°C for lh, and then at room temperature for lh. DCM was removed and basified with 4N NaOH solution, extracted with DCM (2* 50 mL) dried over anhydrous Na₂S0₄, filtered and concentrated. The crude product was purified by column chromatography on silica gel column using DCM: MeOH: NH₃ aq. (95:4: 1%) as an eluent to afford N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-{5-[(4-methylpiperazin- l-yl)methyl]pyridin-2-yl}-5H-pyrrolo[2,3-b]pyrazin-2-amine (150 mg) as a brown solid.

1H NMR (300 MHz, CDC1₃) δ 9.72 (s, IH), 8.55 (s, IH), 7.76 (s, 3H), 6.93 (d, J = 1.9 Hz, IH), 6.57 (s, IH), 4.97 (d, J = 5.7 Hz, 2H), 4.65 (s, IH), 3.95 (s, 6H), 3.57 (s, 2H), 2.53 (s, 8H), 2.32 (s, 3H). M/Z: 541.17, M+H: 542.3 t_R = 1.92 min. (System 2)

Step A.1: N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-{5-[(4-methylpiperazin-l- yl)methyl]pyridin-2-yl}-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-

2-amine

The title compound was prepared in analogy to the procedure described in step 5.1 using 1- {[6-(2-bromo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-6-yl)pyridin-3- yl]methyl}-4-methylpiperazine( 600mg, 1.027mmol) and (2, 6-dichloro-3, 5- dimethoxyphenyl) methanamine (277mg, 1.73mmol). Reaction was carried out by conventional heating in a sealed tube at 130°C for 2h instead of MW as mentioned in step 5.1. Obtained N-[(2,6-dichloro-3,5-diethylphenyl)methyl]-6-{5-[(4-methylpiperazin-l- yl)methyl]pyridin-2-yl}-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-2- amine (350 mg) as yellow solid.

M/Z: 671.25, M+H: 672.7, t_R = 1.36 min. (System 2)

Step A.2 : 1- { [6-(2-bromo-5- { [2-(trimethylsilyl)ethoxy] methyl}-5H-pyrrolo [2,3-b] razin-6-yl)pyridin-3-yl]methyl}-4-methylpiperazine

To a round bottom flask was added 5-bromo-3-(2-{5-[(4-methylpiperazin-lyl)methyl]pyridin- 2-yl}ethynyl)pyrazin-2-amine (400 mg, 0.103 mmol) , DMF (30 mL) and NaH (60% in mineral oil) (124 mg, 0.31mmol)The reaction mixture was stirred at room temperature for 2 h and then 2-(trimethylsilyl)ethoxymethyl chloride (194.22 mg, 0.12 mmol) was added drop wise. The reaction mixture was stirred at rt for 2 h. To the reaction mixture again added NaH (60% in mineral oil) (0.041 g, O.lmmol) and was stirred for 24 h at rt. The reaction mixture was quenched with water (40mL) and extracted with EtOAc (3x25 mL). The organic layer was washed with brine (25 mL), dried with Na2S04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography using DCM/MeOH 95:5 as eluent to afford the title compound (300mg) as a solid.

M/Z: 517.54, M+H: 519.5 t_R = 1.23 min. (System 2)

Step A.3 : 5-bromo-3-(2- {5- [(4-methylpiperazin- l-yl)methyl] pyridin-2- yl}ethynyl)pyrazin-2-amine

The title compound was prepared in analogy to the procedure described in step 2.2 using 3, 5- dibromopyrazin-2-amine and l-[(6-ethynylpyridin-3-yl) methyl] -4-methylpiperazine to afford 5-bromo-3-(2- {5-[(4-methylpiperazin- 1 -yl) methyl] pyridin-2-yl} ethynyl)pyrazin-2-amine (170 mg) as brown solid.

1H NMR (400 MHz, DMSO) δ 2.32 (s, 3H), 2.48 (s, 4H), 2.58 (m, 4H), 3.56 (s, 2H), 7.07 (s, 2H), 7.79 (dd, J= 2.13, 8.03 Hz, 1H), 7.88 (m, 1H), 8.16 (s, 1H), 8.55 (d, J= 1.43 Hz, 1H).

Step A.4: l-[(6-ethynylpyridin-3-yl) methyl] -4-methylpiperazine

DIPEA(4.17mL, 30mmol) was added to a cooled solution of (6-ethynylpyridin-3-yl) methanol( 2 g, 15,02 mol) in dry THF(25 mL), cooled further to 0°C and methane sulfonyl chloride(2.064g, 18.02mmol) was added dropwise and the reaction mixture stirred at room temperature for 2h. TLC showed complete conversion of SM to (6-ethynylpyridin-3-yl) methyl methanesulfonate, then to the reaction mixture again DIPEA (2.08mL, 15.02mmol) was added followed by the addition of 1-Methylpiperazine( 1.65g, 16.52mmol) and the reaction mixture was stirred at room temperature for 12h. Reaction was quenched by adding sat. Sodium bicarbonate solution( 5 mL) and extracted with ethyl acetate( 3*50mL), dried over anhydrous Na₂S0₄, filtered and evaporated under reduced pressure. The resulting crude product was further purified by column chromatography using on silica gel column using DCM: MeOH (95:5) as eluent to afford l-[(6-ethynylpyridin-3-yl) methyl]-4- methylpiperazine as a pale brown solid.

M/Z: 215.29, M+l : 216.4, t_R= 0.28 min.

'H NMR (400 MHz, CDCls) δ 2.31 (s, 3H), 2.51 (dd, 8H), 3.14 (s, 1H), 3.53 (s, 2H), 7.45 (d, J= 7.93 Hz, 1H), 7.65 (dd, J = 2.19, 7.95 Hz, 1H), 8.52 (d, J= 1.56 Hz, 1H). Step A.5: (6-ethynylpyridin-3-yl) methanol

To a solution of Ethyl 6-ethynylpyridine-3-carboxylate (5.4 g,0.031 mol) in dry THF (20 mL) at 0°C was added a 2 M solution of LiAlH₄ in THF 1.41g (0.0372 mol, 18.6 mL). The mixture was stirred at room temperature for 2 h and excess LiAlH4 was quenched by adding IN NaOH (4 mL) followed by water (12 mL). Reaction mixture was filtered over celite bed, the bed was washed with EtOAc( 2*25mL). The combined filtrate was concentrated under reduced pressure and the crude material was purified by flash chromatography using a 4-6% gradient of EtOAc/n-Hexane to give (6-ethynylpyridin-3-yl) methanol as a pale yellow solid (3g).

The title compound: M/Z: 133.15, M+H: 134.2, t_R = 0.44 min. (System 2)

1H NMR (400 MHz, CDC1₃) δ 3.14 (s, 1H), 4.74 (d, 2H), 7.46 (d, J= 7.97 Hz, 1H), 7.70 (dd, J= 2.22, 7.99 Hz, 1H), 8.51 (dd, J= 0.66, 1.45 Hz, 1H).

Example B: N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-{5-[(4-ethylpiperazin-l- l)methyl]pyridin-2-yl}-5H-pyrrolo[2,3-b]pyrazin-2-amine

The title compound was prepared in analogy to the procedure described in example A using N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-{5-[(4-ethylpiperazin-lyl)methyl]pyridin- 2-yl}-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-2-amine (400 mg, 0.582 mmol) to afford N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-{5-[(4- ethylpiperazin-l-yl)methyl]pyridin-2-yl}-5H-pyrrolo[2,3-b]pyrazin-2-amine (150 mg) as a brown solid. 1H NMR (400 MHz, CDC1₃) δ 1.10 (t, , 3H), 2.46 (m, 4H), 2.55 (s, 6H), 3.56 (s, 2H), 3.93 (s, 6H), 4.95 (d, 2H), 6.55 (s, 1H), 6.91 (d, J= 2.04 Hz, 1H), 7.74 (m, 3H), 8.53 (s, 1H), 9.76 (s, 1H). M/Z: 555.19, M+H: 556.48, t_R = 3.45 min. (System 2) Step B.l: N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-{5-[(4-ethylpiperazin-l- yl)methyl]pyridin-2-yl}-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin- 2-amine

The title compound was prepared in analogy to the procedure described in step 5.1 using 1- {[6-(2-bromo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-6-yl)pyridin-3- yl]methyl}-4-ethylpiperazine( lg, 1.73mmol) and (2, 6-dichloro-3, 5-dimethoxyphenyl) methanamine ( 450mg, 1.904mmol). Reaction was carried out by conventional heating in a sealed tube at 130°C for 2h instead of MW as mentioned in step 5.1. Obtained N-[(2,6- dichloro-3,5-diethylphenyl)methyl]-6-{5-[(4-ethylpiperazin-l-yl)methyl]pyridin-2-yl}-5-{[2- (trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-2-amine (800 mg) as yellow solid. The title compound: M/Z: 685.27, M+H: 686.7, t_R = 1.36 min. (System 2)

1H NMR (400 MHz, CDC13) δ 0.23( s, 9H), 1.18 (t, 2H), 1.50 (t, 3H), 2.89 (m, 10H), 3.85 (t, 2H), 3.97 (s, 2H), 4.32 (s, 6H), 5.35 (d, , 2H), 6.55 (s,2H), 6.95 (s, 1H), 7.66 (s, 1H), 8.16 (m, 3H), 9.01 (s, 1H).

Step B.2: l-{[6-(2-bromo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin- 6-yl)pyridin-3-yl]methyl}-4-ethylpiperazine

The title compound was prepared in analogy to the procedure described in example A.2 using 5-bromo-3-(2- {5-[(4-ethylpiperazin- lyl)methyl]pyridin-2-yl} ethynyl)pyrazin-2-amine (2.5g, 6.23 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride to afford l-{[6-(2-bromo-5-{[2- (trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-6-yl)pyridin-3-yl]methyl}-4-ethyl piperazine (1.3g) as yellow solid. M/Z: 531.5, M+H: 533.6 t_R = 1.23 min. (System 2)

1H NMR (400 MHz, CDC13) δ 0.08 (s, 9H), 1.04 (t, 2H), 1.36 (t, 3H), 2.72 (m, 4H), 2.82 (s, 6H), 3.72 (t, 2H), 3.85 (s, 2H), 6.45 (s, 2H), 7.51 (s, 1H), 8.07 (m, 2H), 8.59 (s, 1H), 8.92 (s, 1H).

Step B.3 : 5-bromo-3-(2-{5-[(4-ethylpiperazin-l-yl)methyl]pyridin-2-yl}ethynyl)pyrazin- 2-amine

The title compound was prepared in analogy to the procedure described in step 2.2 using 3, 5- dibromopyrazin-2-amine and l-[(6-ethynylpyridin-3-yl) methyl] -4-ethylpiperazine to afford 5-bromo-3-(2- {5-[(4-ethylpiperazin- 1 -yl) methyl]pyridin-2-yl} ethynyl)pyrazin-2-amine(2.5g) as a yellow solid

The title compound: M/Z: 401.3, M+H: 403.5, t_R = 0.68 min. (System 2) 1H NMR (400 MHz, DMSO) δ 1.10 (broad s, 3H), 2.47 (m, 4H), 2.79 (s, 4H), 3.60 (s, 2H), 7.06 (s, 2H), 7.81 (m, 1H), 7.90 (d, J= 8.00 Hz, 1H), 8.17 (s, 1H), 8.57 (s, 1H).

Step B.4: l-ethyl-4-[(6-ethynylpyridin-3-yl) methyl] piperazine

The title compound was prepared in analogy to the procedure described in example A.4 using (6-ethynylpyridin-3-yl) methanol and methane sulfonyl chloride to afford (6-ethynylpyridin- 3-yl)methyl methanesulfonate which upon further reaction with 1-Ethylpiperazine afforded l-ethyl-4-[(6-ethynylpyridin-3-yl) methyljpiperazine (2.3 g) as a brown solid.

1H NMR (400 MHz, CDC13) δ 1.35 (d, 3H), 2.79 (m, 10H), 3.15 (s, 1H), 3.60 (s, 2H), 7.45 (d, J= 7.94 Hz, 1H), 7.60 (dd, J= 1.98, 7.97 Hz, 1H), 8.53 (d, J= 1.60 Hz, 1H

Example C : N- [(2,6-dichloro-3,5-dimethoxyphenyl)methyl] -6- [5-(morpholin-4- ylmethyl)pyridin-2-yl] -5H-pyrrolo [2,3-b] pyrazin-2-amine

The title compound was prepared in analogy to the procedure described in example A using N- [(2,6-dichloro-3 ,5 -dimethoxyphenyl)methyl] -6- [5 -(morpholin-4-ylmethyl)pyridin-2-yl] -5 - {[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-2-amine (140 mg, 0.021 mmol) to afford N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-[5-(morpholin-4- ylmethyl)pyridin-2-yl]-5H-pyrrolo[2,3-b]pyrazin-2-amine( 25 mg) as a brown solid. M/Z: 528.14, M-H: 527.6, t_R = 0.87 min. (System 2) 1H NMR (400 MHz, CDC1₃) δ 2.49 (s, 4H), 3.55 (s, 2H), 3.73 (m, 4H), 3.93 (s, 6H), 4.65 (t, 1H), 4.95 (d, 2H), 6.56 (s, 1H), 6.92 (d, J= 2.01 Hz, 1H), 7.76 (m, 3H), 8.54 (s, 1H), 9.74 (s, 1H). Step C.l: N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-[5-(morpholin-4- ylmethyl)py ridin-2-yl] -5- { [2-(trimethylsilyl)ethoxy] methyl}-5H-pyrrolo [2,3-b] pyrazin-2- amine

The title compound was prepared in analogy to the procedure described in step 5.1 using 6-[5- (morpholin-4-ylmethyl)pyridin-2-yl]-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3- b]pyrazin-2-amine( 300mg, 0.547mmol) and (2, 6-dichloro-3, 5-dimethoxyphenyl) methanamine ( 142.8mg, 0.602 mmol). Reaction was carried out by conventional heating in a sealed tube at 130°C for 2h instead of MW as mentioned in step 5.1. Obtained N-[(2,6- dichloro-3 ,5-dimethoxyphenyl)methyl] -6- [5 -(morpho lin-4-ylmethyl)pyridin-2-yl] -5 - { [2-

(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-2-amine (150 mg) as yellow solid. The title compound: M/Z: 658.2, M+H: 659.7, t_R = 1.30 min. (System 2)

Step C.2: Synthesis of 4-{[6-(2-bromo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H- pyrrolo [2,3-b] pyrazin-6-yl)pyridin-3-yl] methyl} morpholine

The title compound was prepared in analogy to the procedure described in example A.2 using 5-bromo-3-{2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]ethynyl}pyrazin-2-amine (500 mg, 1.33 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride to afford 4-{[6-(2-bromo-5-{[2- (trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-6-yl)pyridin-3-yl]methyl} morpholine (560 mg) as a yellow solid. M/Z: 504.5, M+H: 506.5 t_R = 1.18 min. (System 2) 1H NMR (400 MHz, CDC13) δ 0.08(s, 9H),1.04(t, 2H),2.74(t, 4H), 3.71 (t, 2H), 3.82 (s, 2H), 3.97 (t, 4H), 6.45 (s, 2H), 7.50 (s, 1H), 8.08 (m, 2H), 8.59 (s, 1H), 8.92 (s, 1H). Corrected Step C.3: 5-bromo-3-{2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]ethynyl}pyrazin-2-amine

The title compound was prepared in analogy to the procedure described in step 2.2 using 3, 5- dibromopyrazin-2-amine and 4-[(6-ethynylpyridin-3-yl)methyl]morpholine to afford 5- bromo-3-{2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]ethynyl}pyrazin-2-amine (540mg) as a brown solid.

The title compound: M/Z: 374.24, M+H: 376.4, t_R = 0.66 min. (System 2) Step C.4: 4-[(6-ethynylpyridin-3-yl) methyl] morpholine

The title compound was prepared in analogy to the procedure described in example A.4 using (6-ethynylpyridin-3-yl) methanol and methane sulfonyl chloride to afford (6-ethynylpyridin- 3-yl)methyl methanesulfonate which upon further reaction with morpholine afforded 4-[(6- ethynylpyridin-3-yl)methyl]morpholine(2.7g) as a brown solid. M/Z: 202.25, M+H: 203.3 tR = 0.26 min. (System 2) 1H NMR (400 MHz, CDC1₃) δ 2.44 (m, 4H), 3.14 (s, 1H), 3.51 (s, 2H), 3.70 (m, 4H), 7.45 (d, J= 7.95 Hz, 1H), 7.66 (dd, J= 2.17, 7.95 Hz, 1H), 8.52 (d, J= 1.57 Hz, 1H).

Example D: N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-[5-(piperazin-l- lmethyl)pyridin-2-yl] -5H-pyrrolo [2,3-b] pyrazin-2-amine

To a solution of tert-butyl 4-{[6-(2-{[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]amino}-5- {[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-6-yl)pyridin-3- yl]methyl}piperazine-l-carboxylate (400 mg, 0.582 mmol) in DCM was added drop wise SnC14 (1M in DCM, 325.05 mg, 1.747 mmol). The reaction mixture was stirred at 0°C for lh, and then at room temperature for lh. Reaction was monitored by TLC/ LCMS which showed complete deprotection of SEM group and partial deprotection of boc observed so DCM removed and basified with 4N NaOH solution, extracted with DCM (2* 50 mL) dried over anhydrous Na₂S0₄, filtered and concentrated. To the crude product Dioxane/ HC1 (4M, 10 mL) was added at 0°C and allowed to stir at room temperature for 2h and then concentrated under reduced pressure and a sticky solid was obtained which was basified with 2N NaOH, extracted with DCM( 2*50 mL) dried over anhydrous Na₂S0₄, filtered and concentrated. The sticky mass obtained was purified by column chromatography on silica gel column using DCM: MeOH: NH₃ aq. (95:4: 1%) as eluent to afford N-[(2,6-dichloro-3,5- dimethoxyphenyl)methyl] -6- [5 -(piperazin- 1 -ylmethyl)pyridin-2-yl] -5H-pyrrolo [2,3 - b]pyrazin-2-amine (18 mg) as a brown solid.

1H NMR (400 MHz, CDC1₃) δ 2.47 (s, 4H), 2.93 (s, 4H), 3.53 (s, 2H), 3.92 (d, 6H), 4.95 (d, ,2H), 6.55 (s, 1H), 6.91 (s, 1H), 7.75 (m, 3H), 8.54 (s, 1H), 10.01 (s, 1H)

M/Z: 527.16, M+H: 528.5, t_R = 0.77 min. (System 2)

Step D.l: tert-butyl 4-{[6-(2-{[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]amino}-5-{[2- (trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-6-yl)pyridin-3- yl]methyl}piperazine-l-carboxylate

The title compound was prepared in analogy to the procedure described in step 5.1

tert-butyl 4-{[6-(2-bromo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-6- yl)pyridin-3-yl]methyl}piperazine-l-carboxylate(250mg, 0.381mmol)and (2, 6-dichloro-3, 5- dimethoxyphenyl) methanamine (98.96mg, 0.419 mmol). The reaction was carried out by conventional heating in a sealed tube at 130°C for 2h instead of MW as mentioned in step 5.1. tert-butyl 4-{[6-(2-{[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]amino}-5-{[2- (trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3-b]pyrazin-6-yl)pyridin-3- yl]methyl}piperazine-l-carboxylate (130 mg) was obtained as a yellow solid.

The title compound: M/Z: 757.81, M+H: 758.7, t_R = 1.54 min. (System 2)

Step D.2: tert-butyl 4-{[6-(2-bromo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3- b]pyrazin-6-yl)pyridin-3-yl]methyl}piperazine-l-carboxylate

The title compound was prepared in analogy to the procedure described in example A.2 using tert-butyl 4-( {6-[2-(3-amino-6-bromopyrazin-2-yl)ethynyl]pyridin-3-yl}methyl)piperazine- 1 - carboxylate (1.9 g, 4.014 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride to afford tert- butyl 4-{[6-(2-bromo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[2,3- b]pyrazin-6-yl)pyridin-3-yl]methyl}piperazine-l -carboxylate (280 mg) as a brown solid. M/Z: 603.6, M+H: 605.6 t_R = 1.54 min. (System 2)

Step D.3: tert-butyl 4-({6-[2-(3-amino-6-bromopyrazin-2-yl)ethynyl]pyridin-3- yl}methyl)piperazine-l-carboxylate

The title compound was prepared in analogy to the procedure described in step 2.2 using 3, 5- dibromopyrazin-2-amine and tert-butyl 4-[(6-ethynylpyridin-3-yl)methyl]piperazine-l- carboxylate to afford tert-butyl 4-({6-[2-(3-amino-6-bromopyrazin-2-yl)ethynyl]pyridin-3- yl}methyl)piperazine-l -carboxylate (2.4g) as a yellow solid.

The title compound: M/Z: 473.37, M+H: 475.5, t_R = 0.87 min. (System 2)

Step D.4: tert-butyl 4-[(6-ethynylpyridin-3-yl)methyl]piperazine-l-carboxylate

The title compound was prepared in analogy to the procedure described in example A.4 using (6-ethynylpyridin-3-yl) methanol and methane sulfonyl chloride to afford (6-ethynylpyridin- 3-yl)methyl methanesulfonate which upon further reaction with tert-butyl piperazine-1- carboxylate afforded tert-butyl 4-[(6-ethynylpyridin-3-yl)methyl]piperazine-l -carboxylate as a brown solid. M/Z: 301.38, M+H: 302.5 t_R = 0.62 min. (System 2) Exemplified compounds were tested as described below in the FGFR3 Enzyme Assay (FRET), the Ba/F3-FGFR3 cellular viability assay (ATP quantitation) and the Ba/F3-KDR cellular viability assay (ATP quantitation), to demonstrate they are FGFR inhibitors selective over KDR.

Biological Assay FGFR3 enzymatic assay

Kinase profiling was performed by Invitrogen/Life Technologies using their Z'-LYTE® Biochemical Kinase Profiling Service (Kupcho et al, Current Chemical Genomics, 2008, 1, p43-53). More specifically, 10 point titrations using 3-fold dilutions were prepared of compound and added to the reaction in 1% DMSO (final). The final 10 kinase reaction consisted of 2.25 - 20 ng FGFR3, 2 μΜ Tyr 04 peptide and compound in kinase buffer (75 μΜ ATP, 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl₂, 2 mM MnCl₂, 1 mM EGTA, 1 mM DTT), combined in low volume NBS, black 384-well plates. The plates were shaken for 30 seconds, incubated for 1 hour at room temperature, and 5 of a 1 :64 dilution of Development Reagent B was added. The plates were again shaken for 30 seconds, incubated for 1 hour at room temperature, and the plate read on a fluorescent plate reader using an excitation wavelength of 400nm and emission wavelengths of 445nm and 520nm. The data was analyzed for extent of phosphorylation of the FRET peptide using the emission ratio. Inhibition of proliferation was determined using a compound concentration range (10 μΜ to 0.5 nM) to calculate an IC₅₀ value.

Ba/F3-FGFR3 cellular viability assay To assess cellular activity on FGFR3, Ba/F3-FGFR3 cells in logarithmic-phase growth were harvested and 5,000 cells were distributed into each well of a 384-well plate in 50 μΐ, of growth media (RPMI-1640, 10% FBS, 2mM L-Glutamine, 500 μg/mL Puromycin and antibiotics). Fifty nanoliters diluted compound were added to appropriate wells, in duplicate, and the cells were cultured for 48 hours at 37°C in a humidified 5%> C0₂ atmosphere. Viability was determined by adding 15 CellTiter-Glo® and measuring luminescence according to the manufacturer's instructions. Inhibition of proliferation was determined using a compound concentration range (10 μΜ to 3 nM) to calculate an IC₅₀ value. Ba/F3-KDR cellular viability assay

To assess cellular activity on KDR, Ba/F3-KDR cells in logarithmic-phase growth were harvested and 5,000 cells were distributed into each well of a 384-well plate in 50 μΙ_, of growth media (RPMI-1640, 10% FBS, 2mM L-Glutamine, 500 μg/mL Puromycin and antibiotics). Fifty nano liters diluted compound were added to appropriate wells, in duplicate, and the cells were cultured for 48 hours at 37°C in a humidified 5% C0₂ atmosphere. Viability was determined by adding 15 μί CellTiter-Glo® and measuring luminescence according to the manufacturer's instructions. Inhibition of proliferation was determined using a compound concentration range (10 μΜ to 3 nM) to calculate an IC₅₀ value.

Parental Ba/F3 cellular viability assay

To assess non-selective cytotoxic activity in the parental cell line as a counterscreen, Ba/F3 cells in logarithmic-phase growth were harvested and 5,000 cells were distributed into each well of a 384-well plate in 50 μΐ, of growth media (RPMI-1640, 10% FBS, 10 ng/ml murine IL-3, 2mM L-Glutamine, 500 μg/mL Puromycin and antibiotics). Fifty nano liters diluted compound were added to appropriate wells, in duplicate, and the cells were cultured for 48 hours at 37°C in a humidified 5% C0₂ atmosphere. Viability was determined by adding 15 μΐ_^ CellTiter-Glo® and measuring luminescence according to the manufacturer's instructions. Inhibition of proliferation was determined using a compound concentration range (10 μΜ to 3 nM) to calculate an IC₅₀ value.

Biological Data

Table 1:

ND = not determined

Claims

Patent Claims

A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X¹ is CH₂ and X² is CH₂; O; or N(R°), or

X¹ and X² are CH;

R° is H; or Ci_₄ alkyl, wherein Ci_₄ alkyl is optionally substituted with one or more halogen, which are the same or different;

X³ is N; or CH;

R¹ is phenyl; naphthyl; 5 to 6 membered aromatic heterocyclyl; or 9 to 10 membered aromatic heterobicyclyl, wherein R¹ is optionally substituted with one or more R⁴, which are the same or different;

R⁴ is halogen; CN; C(0)OR⁵; OR⁵; C(0)R⁵; C(0)N(R⁵R^5a); S(0)₂N(R⁵R^5a); S(0)N(R⁵R^5a); S(0)₂R⁵; S(0)R⁵; N(R⁵)S(0)₂N(R^5aR^5b); SR⁵; N(R⁵R^5a); N0₂; OC(0)R⁵; N(R⁵)C(0)R^5a; N(R⁵)S(0)₂R^5a; N(R⁵)S(0)R^5a; N(R⁵)C(0)OR^5a; N(R⁵)C(0)N(R^5aR^5b); OC(0)N(R⁵R^5a); T¹; Ci_₆ alkyl; C₂_₆ alkenyl; or C₂_₆ alkynyl, wherein Ci_₆ alkyl; C₂_₆ alkenyl; and C₂_₆ alkynyl are optionally substituted with one or more R⁶, which are the same or different; R⁵, R^5a, R^5b are independently selected from the group consisting of H; T¹; Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R⁶, which are the same or different;

R⁶ is halogen; CN; C(0)OR⁷; OR⁷; C(0)R⁷; C(0)N(R⁷R^7a); S(0)₂N(R⁷R^7a); S(0)N(R⁷R^7a); S(0)₂R⁷; S(0)R⁷; N(R⁷)S(0)₂N(R^7aR^7b); SR⁷; N(R⁷R^7a); N0₂; OC(0)R⁷; N(R⁷)C(0)R^7a; N(R⁷)S0₂R^7a; N(R⁷)S(0)R^7a; N(R⁷)C(0)N(R^7aR^7b); N(R⁷)C(0)OR^7a; OC(0)N(R⁷R^7a); or T¹;

R⁷, R^7a, R^7b are independently selected from the group consisting of H; T¹; Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

T¹ is phenyl; C3-7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T¹ is optionally substituted with one or more R⁸, which are the same or different;

R⁸ is halogen; CN; C(0)OR⁹; OR⁹; C(0)R⁹; C(0)N(R⁹R^9a); S(0)₂N(R⁹R^9a); S(0)N(R⁹R^9a); S(0)₂R⁹; S(0)R⁹; N(R⁹)S(0)₂N(R^9aR^9b); SR⁹; N(R⁹R^9a); N0₂; OC(0)R⁹; N(R⁹)C(0)R^9a; N(R⁹)S(0)₂R^9a; N(R⁹)S(0)R^9a; N(R⁹)C(0)OR^9a; N(R⁹)C(0)N(R^9aR^9b); OC(0)N(R⁹R^9a); oxo (=0), where the ring is at least partially saturated; Ci_₆ alkyl; C₂-6 alkenyl; or C₂-6 alkynyl, wherein Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R⁹, R^9a, R^9b are independently selected from the group consisting of H; Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_₆ alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R²; R^2a; R³ are independently selected from the group consisting of H; and halogen.

The compound of claim 1, wherein X³ is N.

The compound of claim 1, wherein X³ is CH. The compound of any one of claims 1 to 3, wherein is R¹ phenyl; or pyridyl, wherein R¹ is unsubstituted or substituted with one or more R⁴, which are the same or different.

The compound of any one of claims 1 to 4, wherein R¹ is substituted with one or more R⁴, which are the same or different.

The compound of any one of claims 1 to 5, wherein R¹ in formula (I) is selected to give formula (la)

wherein X° is N; or CH; and X¹, X², X³, R², R^2a, R³, R⁴ have the meaning as indicated in claim 1.

7. The compound of claim 6, wherein X is CH.

8. The compound of claim 6, wherein X is N.

9. The compound of any one of claims 1 to 8, wherein R⁴ is T¹; or Ci_₆ alkyl, substituted with T¹.

10. The compound of any one of claims 1 to 9, wherein T¹ is saturated 4 to 7 membered heterocyclyl, wherein T¹ is unsubstituted or substituted with one or more R⁸, which are the same or different.

1 1. The compound of any one of claims 1 to 10, wherein T¹ is piperazinyl; piperidinyl; or morpholinyl, wherein T¹ is unsubstituted or substituted with one or more R⁸, which are the same or different. The compound of any one of claims 1 to 11, wherein R is Ci_₆ alkyl; or oxo, where the ring is at least partially saturated.

The compound of any one of claims 1 to 12, wherein R⁴ is piperazin-l-ylmethyl; 4- methylpiperazin- 1 -yl; 4-ethylpiperazin- 1 -yl; morpho lin-4-yl; (4-methylpiperazin- 1 - yl)methyl; (4-ethylpiperazin- l-yl)methyl; morpho lin-4-ylmethyl; or (2-oxo-piperazin- 4-yl)methyl.

The compound of any one of claims 1 to 13, wherein R³ is H.

The compound of any one of claims 1 to 14, wherein R², R^2a are independently selected from the group consisting of H; F; and CI.

The compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 15 selected from the group consisting of l-(4-{2-[2-(3,5-dimethoxyphenyl) ethyl]-5H-pyrrolo [2, 3-b] pyrazin-6-yl} phenyl)-4- methylpiperazine;

l-(4-{2-[(E)-2-(3,5-dimethoxyphenyl) ethenyl] 5H-pyrrolo [2,3-b] pyrazin-6-yl} phenyl)4-methylpiperazine;

l-(4-{2-[2-(3,5-dimethoxyphenyl) ethyl]-5H-pyrrolo [2,3-b] pyrazine

-6-yl} phenyl) piperazine;

l-(4-{2-[(E)-2-(3,5-dimethoxyphenyl) ethenyl]- 5 H-pyrrolo [2,3-b] pyrazin-6-yl} phenyl) piperazine;

N-[(3,5-dimethoxyphenyl) methyl]-6-[4-(4-methylpiperazin-l-yl) phenyl]-5H-pyrrolo [2,3-b] pyrazin-2-amine;

N-[(2, 6-dichloro-3,5-dimethoxyphenyl) methyl]-6-[4-(4-methylpiperazin-l-yl) phenyl]-5H-pyrrolo [2,3-b] pyrazin-2-amine;

N-[(3,5-dimethoxyphenyl) methyl]-6-[4-(piperazin-l-yl) phenyl]-5H-pyrrolo [2,3-b] pyrazin-2-amine;

l-(4-{5-[(2,6-dichloro-3,5-dimethoxyphenyl) methoxy]-l H-pyrrolo [2,3-b] pyridin-2- yl} phenyl)-4-methylpiperazine;

N-[(2, 6-dichloro-3, 5-dimethoxyphenyl) methyl]-6-{5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-yl}-5H-pyrrolo [2, 3-b] pyrazin-2-amine; N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-{5-[(4-ethylpiperazin-l- yl)methyl]pyridin-2-yl}-5H-pyrrolo[2,3-b]pyrazin-2-amine;

N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-[5-(morpholin-4-ylmethyl)pyridin- 2-yl]-5H-pyrrolo[2,3-b]pyrazin-2-amine; and

N-[(2,6-dichloro-3,5-dimethoxyphenyl)methyl]-6-[5-(piperazin-l-ylmethyl)pyridin-2- yl]-5H-pyrrolo[2,3-b]pyrazin-2-amine.

17. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 16 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

18. A compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 16 for use as a medicament.

19. A compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 16 for use in a method of treating or preventing one or more proliferative disorders or dysplasia.

20. Use of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 16 for the manufacture of a medicament for the treatment or prophylaxis of one or more proliferative disorders or dysplasia.

21. A method for treating, controlling, delaying or preventing one or more proliferative disorders or dysplasia in a mammalian patient in need of the treatment, wherein the method comprises administration to said patient a therapeutically effective amount of a compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.