WO2014044846A1

WO2014044846A1 - 3-(aryl- or heteroaryl-amino)-7-(3,5-dimethoxyphenyl)isoquinoline derivatives as fgfr inhibitors useful for the treatment of proliferative disorders or dysplasia

Info

Publication number: WO2014044846A1
Application number: PCT/EP2013/069721
Authority: WO
Inventors: Clive MC CARTHY; Matthew Mills
Original assignee: Evotec UK Ltd
Current assignee: Evotec UK Ltd
Priority date: 2012-09-24
Filing date: 2013-09-23
Publication date: 2014-03-27
Anticipated expiration: 2015-03-24

Description

3-(ARYL- OR HETEROARYL-AMINO)-7-(3,5-DIMETHOXYPHENYL)ISOQUINOLINE DERIVATIVES AS FGFR INHIBITORS USEFUL FOR THE TREATMENT OF PROLIFERATIVE DISORDERS OR DYSPLASIA

The present invention relates to 7-substituted phenyl isoquinoline 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.

7-Phenyl isoquino lines are known in the art from, e.g. WO 2006/039718 A2, WO 2007/125405 A2, US 2010/0197688 Al, WO 2012/080284 A2 and L. Ren et al, Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 10, 15 May 2012, Pages 3387-3391. 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

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_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 heterocycle 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 cyclop 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 1 1 membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazolme, 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 1 1 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 1 1 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, benzimidazolme, 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.

Preferably, R¹ is phenyl; pyrazolyl; pyridazinyl; or pyridyl, wherein R¹ is unsubstituted or substituted with one or more R⁴, which are the same or different. More, 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 R², R^2a, R³, R⁴ have the meaning as indicated above. In one embodiment, X° is N. In another embodiment, X° is CH.

Preferably, R⁴ is T¹; or Ci_₆ alkyl, substituted with T¹. More preferably, R⁴ is T¹; or Ci_₄ 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 methyl; ethyl; n-propyl; isopropyl; or oxo, where the ring is at least partially saturated. Preferably, R⁴ is 4-methylpiperazin-l-yl; 4-ethylpiperazin-l-yl; morpholin-4-yl; (4- methylpiperazin-l-yl)methyl; morpholin-4-ylmethyl; (2-oxo-piperazin-4-yl)methyl; (1- methyl-2-oxo-piperazin-4-yl)methyl; piperidin-4-yl; l-methylpiperidin-4-yl; lH-l,2,4-triazol- 1-ylmethyl; or piperazin-l-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.

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

7-(3, 5-dimethoxyphenyl)-N-[4-(4-methylpiperazin-l-yl) phenyl] isoquinolin-3 -amine;

7-(3,5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl) pyridin-2-yl] isoquinolin-3-amine; 7-(3,5-dimethoxyphenyl)-N-[5-(4-ethylpiperazin-l-yl) pyridin-2-yl] isoquinolin-3 -amine; 7-(3,5-dimethoxyphenyl)-N-[5-(morpholin-4-yl) pyridin-2-yl] isoquinolin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl) pyridin-2-yl] isoquino lin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(4-ethylpiperazin-l-yl) pyridin-2-yl] isoquino lin- 3 -amine; 7-(2,6-dichloro-3 ,5 -dimethoxyphenyl)-N- [5 -(morpho lin-4-yl) pyridin-2-yl] isoquino lin-3 - amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-{5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-yl} isoquino lin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2-yl] isoquino lin-3 -amine;

4-[(6-{[7-(2,6-dichloro-3,5-dimethoxyphenyl) isoquino lin-3 -yl] amino} pyridin-3-yl) methyl] piperazin-2-one;

7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-{5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-yl} isoquino lin-3-amine;

7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2-yl]

isoquinolin-3-amine; and

7-(2-fiuoro-3 ,5 -dimethoxyphenyl)-N- [5 -(morpho lin-4-ylmethyl) pyridin-2-yl] isoquino lin-3 - amine.

Further preferred specific compounds of the present invention are selected from the group consisting of

7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-[5-(piperidin-4-yl) pyridin-2-yl] isoquino lin-3 - amine;

7-(2,6-dichloro-3 ,5 -dimethoxyphenyl)-N- [6-(morpho lin-4-yl)pyridin-3 -yl] isoquino lin-3 - amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-{6-[(4- methylpiperazin-l-yl)methyl]pyridin-3-yl}isoquinolin-3-amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[4-(lH-l,2,4-triazol-l-ylmethyl)phenyl]isoquinolin- 3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l-ylmethyl)pyridin-2-yl]isoquinolin- 3 -amine; 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N- {5-[(4- ethylpiperazin- 1 -yl)methyl]pyridin-2-yl} isoquino lin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[l-(l-methylpiperidin-4-yl)-lH-pyrazol-4- yl]isoquino lin-3 -amine; 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(l-meth^

3 - amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[6-(4-ethylpiperazin-l-yl)pyridazin-3- yl]isoquino lin-3 -amine;

4- [(6- { [7-(2,6-dichloro-3 ,5 -dimethoxyphenyl)isoquino lin-3 -yl] amino } pyridin-3 -yl)methyl] - 1 - methylpiperazin-2-one;

7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(4-em^

amine;

7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl)pyridin-2-yl]isoquinolin- 3 -amine;

4- [(6- { [7-(2,6-difluoro-3 ,5 -dimethoxyphenyl)isoquino lin-3 -yl] amino } pyridin-3 - yl)methyl]piperazin-2-one;

7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l-ylmethyl)pyridin-2-yl]isoquino lin-3- amine;

7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl)-N-{5-[(4-methylpiperazin-l-yl) methyl] pyridin- 2-yl} isoquinolin-3-amine;

7-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-N-[5-(4-ethylpiperazin-l-yl)pyridin-2- yl]isoquino lin-3 -amine;

7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl) pyridin-2-yl] isoquino lin-3 -amine;

7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2-yl] isoquino lin-3 -amine;

4-[(6-{[7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl) isoquino lin-3 -yl] amino}

pyridin-3 -yl) methyl] piperazin-2-one; and

7-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l-ylmethyl)pyridin-2- yl]isoquino lin-3 -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 pharmaceutically acceptable 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 NaCl in water

BINAP 2, 2'-bis (diphenylphosphino)-l, l '-binaphthalene

DCM dichloromethane

DME dimethoxyethane

DMSO dimethylsulfoxide

DIPEA diisopropylethylamine

DMF dimethyl formamide

EtOAc ethylacetate

equiv equivalent(s)

Et₂0 diethyl ether

H₂0 Water

HC1 Hydrochloric acid

h hour(s)

K₂CC"3 potassium carbonate

LAH lithium aluminium hydride

LiHMDS lithiumbis (trimethyl) silylamide

MeOH methanol

mL millilitre (s)

NH3 aqueous ammonia

Na₂SC"4 sodium sulphate

NaHC03 sodium bicarbonate

NaOH sodium hydroxide

NMR Nuclear Magnetic Resonance

Na₂CC"3 sodium dicarbonate

O/N overnight Pd (OAc) 2 Palladium acetate

Pd ₂(dba) 3 tries (dibenzilidineacetone) dipalladium

Pd (PPh₃)₄ tetrkis (triphenylphospine) palladium (0)

Selectfluor l-chloromethyl-4-fluoro-l, 4-diazobicyclo [2.2.2] octane

Bis (tetrafluoroborate)

S-Phos dicyclohexyl (2, 6-dimethoxybiphenyl)-2-yl) phosphane

THF tetrahydrofuran

TLC Thin layer chromatography

t-BuOH tert-butyl alcohol

R_f Retention factor

tR time of retention

X-Phos 2-dicyclohexylphosphino-2, 4, 6'-triisopropyl biphenyl

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 dC 18 (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 1-10, A, L-T;

Scheme 2 relates to examples 11-13, H-K;

Scheme 3 relates to examples B-G.

Scheme 3:

Example 1: 7-(3, 5-dimethoxyphenyl)-N-[4-(4-methylpiperazin-l-yl) phenyl] isoquinolin- -amine:

An oven-dried sealed tube containing a stir bar was charged with Pd(OAc)₂ (2 mg, 5 mol %), X-Phos (4 mg, 5 mol %), 3-chloro-(3, 5-dimethoxy phenyl) isoquinoline (50 mg, 0.166 mmol), 4-(4-methylpiperazin-l-yl) aniline (31 mg, 1.66 mmol) and cesium carbonate (62 mg, 0.209 mmol). The tube was evacuated and backfilled with argon, then 5ml of a (5: 1) mixture of Toluene: t-BuOH (5:1) was added. The tube was sealed and heated with stirring at 120°C overnight. The resulting mixture was allowed to cool to room temperature and filtered through a pad of Celite and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and purified by chromatography on a silica gel column using DCM: MeOH: N¾ aq. (96:4: 1%) as an eluent. The isolated compound was triturated in n-pentane to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDC1₃) δ 8.96 (s, 1H), 7.96 (s, 1H), 7.74 (dd, J = 8.7, 1.8 Hz, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.02 - 6.99 (m, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.97 (d, J = 3.2 Hz, 1H), 6.81 (d, J = 2.2 Hz, 2H), 6.51 - 6.46 (m, 2H), 3.88 (s, 6H), 3.26 - 3.19 (m, 4H), 2.66 - 2.58 (m, 4H), 2.38 (s, 3H).M/Z: 454, M+l : 455.5, t_R= 2.34 min. (System 2)

Ste 1.1: 3-chloro-7-(3, 5-dimethoxy phenyl) isoquinoline:

To a solution of 7-bromo-3-chloroisoquinoline (500 mg, 2.0 mmol) and 3,5- dimethoxyphenylboronic acid (364 mg, 2.0 mmol) in DME and water (1 : 1) in a sealed tube was added S-Phos (42 mg, 5 mole %) followed by Pd(OAc)₂ (23 mg, 5 mole %) and disodium carbonate (262 mg, 2.47 mmol). The reaction mixture was purged with Argon, then heated at 90°C for O/N, allowed to cool to room temperature, diluted with EtOAc and water, filtered through a pad of celite and extracted with EtOAc. The organic phase was washed with brine, dried over Na₂S0₄, filtered and concentrated in vacuo. The crude product was purified by Flash chromatography (n-Hexane: EtOAc (9: 1) to afford 0.5 g of the title compound as white solid.

1H NMR (400 MHz, CDC1₃) δ 9.12 (s, 1H), 8.15 - 8.11 (m, 1H), 7.96 (dd, J = 8.6, 1.8 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.75 (s, 1H), 6.82 (d, J = 2.2 Hz, 2H), 6.53 (t, J = 2.2 Hz, 1H), 3.89 (s, 6H). M/Z: 299.7, M+l : 300.3, t_R= 3.44 min. (System 2)

Example 2: 7-(3,5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl) pyridin-2-yl] isoquinolin-3-amine:

A solution of 3-chloro-7-(3, 5-dimethoxyphenyl) isoquinoline (220 mg, 0.73 mmol) , 5-(4- methylpiperazin-l-yl) pyridine-2-amine (141.11 mg, 0.73 mmol), X-Phos ( 8.75 mg, 2.5 mol % ) and cesium carbonate (286.96 mg, 0.88 mmol) in Toluene (4 mL) and t-BuOH (1 mL) was purged with argon for 20 min. Pd(OAc)₂ (4.12 mg, 2.5 mol %) was added and the mixture purged again with argon for 5 min. The reaction mixture was heated at 90°C for O/N. The reaction mixture was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated under reduced pressure and purified by chromatography using a silica gel column using DCM: MeOH: NH₃ aq. (94:6: 1%) as eluent to afford 7-(3, 5-dimethoxyphenyl)- N-[5-(4-methylpiperazin-l-yl) pyridin-2-yl] isoquinolin-3 -amine (150 mg) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 8.88 (s, 1H), 7.98 (d, J = 9.9 Hz, 2H), 7.87 (d, J = 2.9 Hz, 1H), 7.75 (dd, J = 8.7, 1.8 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.32 (dd, J = 9.0, 3.0 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 6.75 (d, J = 2.2 Hz, 2H), 6.40 (t, J = 2.2 Hz, 1H), 3.75 (s, 6H), 3.06 (dd, J = 11.5, 6.4 Hz, 4H), 2.57 - 2.50 (m, 4H), 2.26 (s, 3H).M/Z: 455.2, M+l : 456.5, t_R= 2.01 min. (System 2)

Step 2.1: 5-(4-methylpiperazin-l-yl) pyridin-2-amine:

A solution of l-methyl-4-(6-nitro-pyridin-3-yl) piperazine (1.5 g, 6.83 mmol) in MeOH (75 mL) was hydrogenated in the presence of 10% Pd/C (0.3 g) using an H2 balloon. After 12 h, the reaction mixture was filtered through a pad of Celite and rinsed with MeOH (2 x 15 mL). The filtrate was concentrated and purified by triturating in n-pentane to afford the title compound (1.0 g) as a brown solid. 1H NMR (400 MHz, CDC1₃) δ 7.78 (d, J = 2.6 Hz, 1H), 7.18 (dd, J = 8.8, 2.9 Hz, 1H), 6.49 (dd, J= 8.8, 0.6 Hz, 1H), 3.10 - 3.03 (m, 4H), 2.59 (dd, J= 11.9, 6.9 Hz, 4H), 2.35 (s, 3H).

Step 2.2: l-Methyl-4-(6-nitro-pyridin-3-yl) piperazine: To 5-Bromo-2-nitro-pyridine (2 g, 9.85 mmol) in DMSO (10 mL) was added potassium carbonate (2.04 g, 15.0 mmol), 1-methylpiperazine (1.73 g, 17.0 mmol), and tetrabutylammonium iodide (70 mg, 0.197 mmol) and was heated at 120°C for 18 h. The mixture was made acidic with 1M aq. HCl and was partitioned between DCM and water. The aqueous layer was made basic with 2M aq. sodium carbonate and was extracted with DCM. The organic layer was dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo, and was triturated with water to yield l-Methyl-4-(6-nitro-pyridin-3-yl)-piperazine (1.5 g) as a yellow solid. 1H NMR (400 MHz, CDC13) 5 8.15 (dd, J= 11.6, 6.1 Hz, 2H), 7.20 (dd, J= 9.2, 3.1 Hz, 1H), 3.53 - 3.45 (m, 4H), 2.60 (dd, J= 12.7, 7.5 Hz, 4H), 2.37 (d, J= 6.0 Hz, 3H).

Example 3: 7-(3, 5-dimethoxyphenyl)-N-[5-(4-ethylpiperazin-l-yl) pyridin-2-yl] isoquinolin-3-amine:

To a solution of 3-chloro-7-(3, 5-dimethoxyphenyl) isoqinoline (50 mg, 0.167 mmol) , 5-(4- ethylpiprazine-l-yl) pyridine-2-amine (38 mg , 0.183 mmol), X-Phos ( 8 mg, 10 mol% ) and cesium carbonate (108.4 mg, 0.334 mmol) in Toluene (4 mL) and t-BuOH (1 mL) (4: 1) argon was purged for 20 min. Then was added Pd(OAc)₂ (3.76 mg, 10 mol%) again argon was purged for 5 min. The reaction mixture was heated at 120°C for O/N. The reaction mixture was cooled to room temperature and filtered through celite pad and filtrate was concentrated under reduced pressure. Product was purified by column chromatography on silica gel column using DCM: MeOH: NH₃ aq. (94:6: 1%) as an eluent to afford 7-(3,5-dimethoxyphenyl)-N-[5- (4-ethylpiperazin-l-yl)pyridin-2-yl]isoquinolin-3 -amine (20 mg) as a brown solid.

1H NMR (400 MHz, CDC1₃) δ 9.00 (s, 1H), 8.14 (s, 1H), 8.06 (d, J = 2.5 Hz, 1H), 8.00 (s, 1H), 7.79 (dd, J = 19.3, 8.6 Hz, 2H), 7.42 (s, 1H), 7.31 (dd, J = 8.9, 2.7 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 1.9 Hz, 2H), 6.49 (s, 1H), 3.88 (s, 6H), 3.25 - 3.14 (m, 4H), 2.66 (d, J = 4.4 Hz, 4H), 2.50 (q, J = 7.1 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H).M/Z: 469.58, M+l : 470.4, t_R= 2.1 min. (System 2) Step 3.1: 5-(4-ethylpiperazin-l-yl) pyridin-2-amine:

The title compound was prepared in analogy to the procedure described in step 2.1 using 1- ethyl-4-(6-nitro-pyridin-3-yl) piperazine which in turn was prepared in analogy to the procedure described in step 2.2 using 5-Bromo-2-nitro-pyridine and 1-ethylpiperazine.

The title compound: 1H NMR (400 MHz, CDC1₃) δ 7.78 (d, J = 2.7 Hz, 1H), 7.22 - 7.15 (m, 1H), 6.49 (dd, J = 8.8, 0.4 Hz, 1H), 4.19 (s, 2H), 3.10 - 3.05 (m, 4H), 2.65 - 2.59 (m, 4H), 2.48 (q, J = 7.2 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H).M/Z: 206.29, M+l : 207.3, t_R= 0.37 min. (System 3 )

Example 4: 7-(3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-yl) pyridin-2-yl] isoquinolin-3- amine:

To a solution of 3-chloro-7-(3, 5-dimethoxyphenyl) isoqinoline (50 mg, 0.167 mmol), 5- (morpholin-4-yl) pyridin-2-amine (32.8 mg, 0.183 mmol), X-Phos (9.54 mg, 10 mol %) and cesium carbonate (108.4 mg, 0.334 mmol) in Toluene (4 mL) and t-BuOH (1 mL) (4: 1) argon was purged for 20 min. Then was added Pd(OAc)₂ (3.73 mg, 10 mol %) again argon was purged for 5 min. The reaction mixture was heated at 120°C for O/N. The reaction mixture was cooled to room temperature and filtered through celite pad and filtrate was concentrated under reduced pressure. Product was purified by column chromatography on silica gel column using DCM: MeOH: NH₃aq (94:6: 1%) as an eluent to afford 7-(3, 5-dimethoxyphenyl)-N-[5- (morpholin-4-yl) pyridin-2-yl] isoquinolin-3 -amine (20 mg) as a brown solid.

1H NMR (400 MHz, CDC1₃) δ 9.01 (s, 1H), 8.15 (d, J = 2.9 Hz, 1H), 8.06 - 7.99 (m, 2H), 7.81 (dt, J = 18.0, 5.2 Hz, 2H), 7.31 (dd, J = 8.9, 3.0 Hz, 1H), 7.14 (d, J = 9.1 Hz, 1H), 6.83 (d, J = 2.2 Hz, 2H), 6.50 (t, J = 2.2 Hz, 1H), 3.93 - 3.86 (m, 10H), 3.13 (dd, J = 5.6, 3.9 Hz, 4H). M/Z: 442.51, M+l : 443.4, t_R= 2.6 min. (System 2) Step 4.1: 5-(morpholin-4-yl) pyridin-2-amine:

The title compound was prepared in analogy to the procedure described in step 2.1 using 4-(6- nitropyridin-3-yl) morpholine which in turn was prepared in analogy to the procedure described in step 2.2 using 5-bromo-2-nitro-pyridines and morpholine.

The title compound: 1H NMR (400 MHz, CDC1₃) δ 7.77 (d, J= 2.8 Hz, 1H), 7.16 (dd, J= 8.8, 2.9 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 4.06 (dd, J= 32.5, 27.7 Hz, 2H), 3.85 (dt, J = 11.7, 5.0 Hz, 4H), 3.06 - 2.98 (m, 4H). M/Z: 179.22, M+l : 180.3, t_R= 0.60 min. (System 3)

Example 5: 7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl) pyridin-2-yl] isoquinolin-3-amine :

A solution of 3-chloro-7-(2, 6-dichloro-3, 5-dimethoxyphenyl) isoquinoline (25 mg, 0.068 mmol), 5-(4-methylpiprazine-l-yl) pyridine-2-amine (step 2.1) (14.3 mg, 0.075 mmol), X- Phos (3.23 mg, 10 mol %) and cesium carbonate (44.2 mg, 0.136 mmol) in Toluene (2 mL) and t-BuOH (0.5 mL) (4: 1) was purged with argon for 20 min. Pd₂(dba)₃ was added (6.21 mg, 10 mol %) and the mixture was purged again with argon for 5 min then heated at 120°C overnight. The reaction mixture was cooled to room temperature, filtered through a celite pad and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using DCM: MeOH: NH₃ aq. (95:5: 1%) as an eluent to afford 7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl) pyridin-2-yl] isoquinolin-3 -amine (18 mg) as a tan solid.

1H NMR (400 MHz, CDC1₃) δ 8.97 (s, 1H), 8.12 (d, J = 11.1 Hz, 1H), 8.04 (d, J = 2.7 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.42 (dd, J = 8.5, 1.7 Hz, 1H), 7.32 (dd, J = 9.0, 2.9 Hz, 1H), 7.18 (d, J = 8.9 Hz, 1H), 6.65 (s, 1H), 3.99 (s, 6H), 3.26 - 3.16 (m, 4H), 2.72 - 2.62 (m, 4H), 2.41 (s, 3H).M/Z: 523.5, M+l : 524.3, t_R= 2.08 min. (System 2) Ste 5.1: 3-chloro-7-(2, 6-dichloro-3, 5-dimethoxy phenyl) isoquinoline:

Sulfuryl chloride (491.42 mg , 3.486 mmol) was added drop wise to a cold (5°C) solution of 3-chloro-(3, 5-dimethoxy phenyl) isoquinoline (1 g, 3.169 mmol) in Et₂0 (150 mL). The reaction mixture was stirred at room temperature for lh, quenched by addition of water, concentrated, neutralised with 5 % NaHC0₃ solution and extracted with DCM (3 x 25 mL). The organic phase was washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The compound was purified by trituration in n-pentane to afford (950 mg) of title compound as white solid.

1H NMR (400 MHz, CDC1₃) δ 9.10 (s, 1H), 7.89 - 7.84 (m, 2H), 7.79 (s, 1H), 7.58 (dd, J = 8.6, 1.5 Hz, 1H), 6.67 (s, 1H), 3.99 (s, 6H). M/Z: 367, M+l : 368.4, t_R= 1.75 min. (System 1)

Example 6: 7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-[5-(4-ethylpiperazin-l-yl) pyridin- -yl] isoquinolin-3-amine:

To a solution of 3-chloro-7-(2, 6-dichloro-3, 5-dimethoxyphenyl) isoqinoline (600 mg, 1.628 mmol), 5-(4-ethylpiprazine-l-yl) pyridine-2-amine (step 3.1) (376 mg, 1.82 mmol), X-Phos (77.60 mg, 10 mol %) and cesium carbonate (1.06 g, 1.25 mmol) in Toluene (15 mL) and t- BuOH (5 mL) (4: 1) argon was purged for 20 min. Then was added Pd₂ (dba)₃ (149 mg, 10 mol %) again argon was purged for 5 min. The reaction mixture was heated at 120°C overnight. The reaction mixture was cooled to room temperature and filtered through celite pad and filtrate was concentrated under reduced pressure. Product was purified by column chromatography on silica gel column using DCM: MeOH: NH₃ aq. (95:5: 1%) as an eluent to afford 7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-[5-(4-ethylpiperazin-l-yl) pyridin-2-yl] isoquinoline-3 -amine (600 mg) as a pale yellow solid. 1H NMR (400 MHz, CDC1₃) δ 8.97 (s, 1H), 8.09 (dd, J = 25.7, 7.3 Hz, 2H), 7.82 - 7.68 (m, 2H), 7.41 (dd, J = 8.5, 1.6 Hz, 1H), 7.32 (dd, J = 8.9, 2.9 Hz, 1H), 7.17 - 7.10 (m, 1H), 6.65 (s, 1H), 3.99(s, 6H), 3.26 - 3.16 (m, 4H), 2.71 - 2.62 (m, 4H), 2.51 (q, J = 7.2 Hz, 2H), 1.15 (t, J= 7.2 Hz, 3H). M/Z: 537.1, M+l : 538.6, t_R= 0.81 min. (System 1)

Example 7: 7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-yl) pyridin-2-yl] isoquinolin-3-amine:

To a solution of 3-chloro-7-(2, 6-dichloro-3, 5-dimethoxyphenyl) isoqinoline (50 mg, 0.136 mmol), 5-(morpholine-4-yl) pyridine-2-amine (26.74 mg , 0.149 mmol) (step 4.1), X-Phos ( 6.46 mg, 10 mol %) and cesium carbonate (88.4 mg, 0.271 mmol) in Toluene (2 mL) and t- BuOH (0.5 mL) (4: 1) argon was purged for 20 min. Then was added Pd₂ (dba)₃ (12.42 mg, 10 mol %) again argon was purged for 5 min. The reaction mixture was heated at 120°C overnight. The reaction mixture was cooled to room temperature and filtered through celite pad and filtrate was concentrated under reduced pressure. Product was purified by column chromatography on silica gel column DCM: MeOH: NH3 aq. (96:4: 1%) as an eluent to afford 7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-yl) pyridin-2-yl] isoquinolin-3- amine (25 mg) as a yellow solid.

1H NMR (400 MHz, DMSO) δ 9.67 (s, 1H), 9.08 (s, 1H), 8.41 (s, 1H), 8.00 (d, J = 2.7 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.48 (s, 1H), 7.40 (d, J= 8.6 Hz, 1H), 7.27 (d, J= 9.1 Hz, 1H), 7.03 (s, 1H), 3.99 (s, 6H), 3.79 - 3.74 (m, 4H), 3.11 - 3.06 (m, 4H). M/Z: 510.1, M+l : 511.3, t_R= 2.57 min. (System 2)

Example 8: 7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-{5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-yl} isoquinolin-3-amine:

To a solution of 3-chloro-7-(2, 6-dichloro-3, 5-dimethoxyphenyl) isoqinoline (50 mg, 0.136 mmol), 5-[(4-methylpiperazin-l-yl) methyl]pyridin-2-amine (28.68 mg, 0.149 mmol), X-Phos ( 6.21 mg, 10 mol %) and cesium carbonate (88.38 mg, 0.271 mmol) in Toluene (2 mL) and t- BuOH (0.5 mL) (4: 1) argon was purged for 20 min. Then was added Pd₂(dba)₃ ( 6.21 mg, 10 mol %) again argon was purged for 5 min. The reaction mixture was heated at 120°C for O/N. The reaction mixture was cooled to room temperature and filtered through celite pad and filtrate was concentrated under reduced pressure. Product was purified by column chromatography on silica gel column using DCM: MeOH: NH3 aq. (94:6:0.1%) as an eluent to afford 7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-{5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-yl} isoquinolin-3 -amine (15mg) as an off white solid.

1H NMR (400 MHz, CDC1₃) δ 9.00 (s, 1H), 8.26 - 8.20 (m, 2H), 7.83 (d, J = 8.6 Hz, 1H), 7.74 (s, 1H), 7.60 (dd, J= 8.5, 2.3 Hz, 1H), 7.45 (dd, J= 8.5, 1.7 Hz, 1H), 7.27 (t, J= 4.2 Hz, 2H), 6.66 (s, 1H), 3.99 (s, 6H), 3.52 (s, 2H), 2.97 - 2.52 (m, 8H), 2.49 (s, 3H). M/Z: 537, M+l : 537.9, t_R= 4.22 min. (System 2)

Step 8.1: 5-(4-Methyl-piperazin-l-ylmethyl) pyridin-2-ylamine:

Step 8.1a: A mixture of [5-(4-Methyl-piperazin-l-ylmethyl) pyridin-2-yl] carbamic acid tert- butyl ester (0.80 g, 2.61 mmol) and a 4 N solution of HC1 in Dioxane (20 mL) was stirred for 12 h at room temperature and concentrated. The residue was dissolved in MeOH, ambersep resin was added and the mixture shaken for 30 min. The mixture was filtered and evaporated to afford 5-(4-methyl-piperazin-l-ylmethyl) pyridin-2-yl-amine (0.480 g) as a brown solid. Hexane: EtOAc (5:5) M/Z: 206, M+H: 207.3 t_R = 0.54 min. (System 1) Step 8.1b: [5-(4-Methyl-piperazin-l-ylmethyl) pyridin-2-yl] carbamic acid tert-butyl ester.

A mixture of methanesulfonic acid 6-tert-butoxycarbonylamino-pyridin-3-ylmethyl ester (Step 8.2) (0.8 g, 2.6 mmol), N-Methylpiperazine (0.29 mL, 2.9 mmol, 1.1 equiv), K₂C0₃ (0.728 g, 5.2 mmol, 2 equiv), and Acetonitrile (10 mL) was stirred for 6 h at room temperature, diluted with EtOAc and water and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na₂S0₄), filtered and concentrated to provide a yellow solid (0.75g). Triturating in Et₂0 afforded [5-(4-Methyl-piperazin-l-ylmethyl) pyridin-2-yl] carbamic acid tert-butyl ester as a yellow solid. M/Z: 306.1, M+H: 307.5, t_R = 0.56 min. (System 1) Step 8.2: Methanesulfonic acid 6-tert-butoxycarbonylamino-pyridin-3-yl-methyl ester:

Methanesulfonic anhydride (0.490 g, 4.28 mmol, 1.21 equiv) was added portion wise to a cold (5°C) mixture of (5-hydroxymethyl-pyridin-2-yl) carbamic acid tert-butyl ester (Step 8.3) (0.8 g, 3.5 mmol) and DIPEA (1.3 mL, 10.7 mmol, 3 equiv) in DCM (10 mL), under an argon atmosphere. The reaction mixture was allowed to stir for 1 h at 5°C, diluted with EtOAc and water and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na₂S0₄), filtered and concentrated and used as such for the next step without further purification.

Step 8.3: (5-hydroxymethyl-pyridin-2-yl) carbamic acid tert-butyl ester:

Lithium aluminiumhydride (251 mg, 6.61 mmol, 1.1 equiv) was added portion wise to a cold (5°C) solution of 6-tertbutoxycarbonylamino nicotinic acid ethyl ester (Step 8.4) (1.6 g, 6.01 mmol) in THF (25 mL), under an argon atmosphere. The reaction mixture was stirred for 1 h at 5°C and quenched by sequential addition of water (0.4 mL), 15 % NaOH aqueous solution (0.4 mL) and water (1.2 mL). The resulting mixture was filtered through a pad of celite and concentrated. The residue was diluted with EtOAc and water and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na₂S0₄), filtered and concentrated. The residue was purified by trituration in Et₂0 to provide the title compound (0.85 g) as a solid. M/Z: 224.2, M+H: 225.4, t_R = 0.63 min. (System 1)

Step 8.4: 6-tert-Butoxycarbonylamino nicotinic acid ethyl ester:

A solution of di-tert-butyl dicarbonate (1.7 g, 7.8 mmol, 1.3 equiv) in Acetonotrile (20 mL) is added drop wise to a suspension of ethyl 6-aminonicotinate (1 g, 6.0 mmol) and DMAP (73 mg, 0.6 mmol, 0.1 equiv) in Acetonitrile (10 mL) at room temperature. The reaction mixture was stirred for 4h at room temperature and concentrated. The residue was diluted with EtOAc and water, and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na₂S0₄), filtered and concentrated. The residue was purified by silica gel column chromatography (Hexane: EtOAc, 4: 1) to afford the title compound (1.18 g) as a white solid. 1H NMR (400 MHz, CDC13) δ 9.25 (s, 1H), 8.96 (dd, J = 2.3, 0.7 Hz, 1H), 8.30 - 8.24 (m, 1H), 8.09 (dd, J= 8.9, 0.5 Hz, 1H), 4.42 - 4.35 (m, 2H), 1.59 (d, J= 11.9 Hz, 10H). Example 9: 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin- 2-yl] isoquinolin-3-amine:

To a solution of 3-chloro-7-(2, 6-dichloro-3, 5-dimethoxyphenyl) isoqinoline (50 mg, 0.136 mmol), 5-(morpholin-4-ylmethyl) pyridin-2-amine (28.87 mg , 0.149 mmol), X-Phos ( 6.46 mg, 5 mol %) and cesium carbonate (88.4 mg, 0.271 mmol) in Toluene (2 mL) and t-BuOH (0.5 mL) (4: 1) argon was purged for 20 min. Then was added Pd₂(dba)₃ (12.42 mg, 5 mol %) again argon was purged for 5 min. The reaction mixture was heated at 120°C for O/N. The reaction mixture was cooled to room temperature and filtered through celite pad and filtrate was concentrated under reduced pressure. Product was purified by column chromatography on silica gel column using DCM: MeOH: NH₃ aq. (94:6: 1%) as an eluent to afford 7-(2, 6- dichloro-3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2-yl] isoquinolin-3- amine (15mg) as an off white solid.

1H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 9.12 (d, J = 4.6 Hz, 1H), 8.55 (s, 1H), 8.21 (d, J = 1.9 Hz, 1H), 7.91 - 7.82 (m, 2H), 7.60 (dd, J = 8.5, 2.3 Hz, 1H), 7.42 (dd, J = 8.5, 1.7 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.03 (s, 1H), 3.99 (s, 6H), 3.62 - 3.55 (m, 4H), 3.42 (s, 2H), 2.37 (s, 4H).

M/Z: 524, M+l : 525.6, t_R= 1.92 min. (System 2) Step 9.1: 5-(morpholin-4-ylmethyl) pyridin-2-amine:

The title compound was prepared in analogy to the procedure described in (step 8.1a) using 4- ({6-[(tert-butoxy) nitroso] pyridin-3-yl} methyl) morpholine which in turn was prepared in analogy to the procedure described in (step 8.1b) using Methanesulfonic acid 6-tert- butoxycarbonylamino pyridin-3-yl-methyl ester (step 8.2) and morpholine.

Title compound: M/Z: 193. 12, M+l : 194. 2, t_R= 0.58 min. (System 1)

Example 10: 4-[(6-{[7-(2, 6-dichloro-3, 5-dimethoxyphenyl) isoquinolin-3-yl] amino} pyridin-3-yl) methyl] piperazin-2-one:

A solution of 3-chloro-7-(2, 6-dichloro-3, 5-dimethoxyphenyl)isoqinoline (200 mg, 0.54 mmol), 4-[(6-aminopyridin-3-yl) methyl] piperazin-2-one (167mg, 0.81 mmol), Pd(PPh₃)4 (31 mg, 5 mol %) and BINAP ( 16.89 mg, 5 mol %) and cesium carbonate (351 mg, 1.08 mmol) in Toluene (5 mL) and t-BuOH (1 mL) (5: 1) was purged with argon for 20 min. The reaction mixture was heated at 120°C overnight. The reaction mixture was cooled to room temperature, filtered through a celite pad and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel column using DCM: MeOH: NH₃ aq. (94:6: 1%) as eluent to afford 7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-[5- (morpholin-4-ylmethyl) pyridin-2-yl] isoquinolin-3-amine (35mg) as a pale yellow solid. 1H NMR (400 MHz, CDC1₃) δ 9.00 (s, 1H), 8.31 - 8.23 (m, 2H), 7.84 (d, J = 8.7 Hz, 1H), 7.74 (s, 1H), 7.60 (dd, J = 8.5, 2.3 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.16 (d, J = 8.6 Hz, 1H), 6.66 (s, 1H), 5.80 (s, 1H), 3.96 (s, 6H), 3.55 (s, 2H), 3.37 (t, J = 4.3 Hz, 2H), 3.22 (s, 2H), 2.70 - 2.64 (m, 2H). M/Z 537.1, M+l 538.3, t_R= 2.30 min. (System 2)

Example A: 7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-[5-(piperidin-4-yl) pyridin-2-yl] isoquinolin-3-amine:

Dioxane/ HCl(g) (4M solution, 5 mL) was added to a solution of tert-butyl 4-(6-{[7-(2,6- dichloro-3,5-dimethoxyphenyl)isoquinolin-3-yl]amino}pyridin-3-yl)piperidine-l-carboxylate (28mg, mmol) in dioxane (2mL) and stirred at RT for lh. The solvent was evaporated and the residue triturated with n-pentane to afford title compound as a white solid (22mg).

1H NMR (400 MHz, MeOD) δ 9.32 (s, 1H), 8.24 - 8.18 (m, 2H), 8.01 (s, 2H), 7.61 (s, 2H), 7.44 (d, J = 9.8 Hz, 1H), 6.94 (s, 1H), 4.00 (s, 6H), 3.66 (s, 1H), 3.57 (d, J = 13.1 Hz, 2H), 3.16 (ddd, J= 15.8,13.6, 11.6 Hz, 4H), 2.20 (d, J= 13.4 Hz, 2H), 1.96 (d, J= 9.5 Hz, 2H). M/Z: 509, M+l : 509.5, t_R= 1.81 min (system 2)

Step Al: tert-butyl 4-(6-{[7-(2,6-dichloro-3,5-dimethoxyphenyl)isoquinolin-3- yl]amino}pyridin-3-yl)piperidine-l-carboxylate:

The title compound was prepared in analogy to the procedure described in example 5 using tert-butyl 4-(6-aminopyridin-3-yl)piperidine-l-carboxylate and 3-chloro-7-(2, 6-dichloro-3, 5- dimethoxyphenyl) isoquinoline. tert-butyl 4-(6-{[7-(2,6-dichloro-3,5- dimethoxyphenyl)isoquino lin-3 -yl] amino } pyridin-3 -yl)piperidine- 1 -carboxylate was obtained as a pale yellow solid (28 mg).

M/Z: 609.54, M+l : 609.7-612.7, t_R= 1.26 min. (system 2)

Example L: 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N- [6-(morpholin-4-yl)pyridin-3- yl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 5 using 6- (morpholin-4-yl)pyridin-3 -amine and 3-chloro-7-(2, 6-dichloro-3, 5 -dimethoxyphenyl) isoquinoline. 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[6-(morpholin-4-yl)pyridin-3- yl]isoquino lin-3 -amine was obtained as a pale yellow solid (20 mg).

1H NMR (500 MHz, Chloroform-d) δ 8.91 (s, 1H), 8.29 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.37 (dd, J = 8.6, 1.4 Hz, 1H), 6.86 (s, 1H), 6.74 (d, J = 9.0 Hz, 1H), 6.67 - 6.61 (m, 2H), 3.98 (s, 6H), 3.89 - 3.85 (m, 4H), 3.57 - 3.50 (m, 4H). M/Z: 511.0, M+l : 511.0- 513.0, t_R= 2.83 min. (system 2)

Example M: 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-{6-[(4- methylpiperazin-l-yl)methyl]pyridin-3-yl}isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 5 using 6- [(4-methylpiperazin-l-yl)methyl]pyridin-3 -amine and 3-chloro-7-(2, 6-dichloro-3, 5- dimethoxyphenyl) isoquinoline. 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N- {6-[(4- methylpiperazin-l-yl)methyl]pyridin-3-yl}isoquinolin-3-amine was obtained as a pale yellow solid (20 mg).

1H NMR (500 MHz, Chloroform-d) δ 8.99 (s, 1H), 8.60 (d, J = 2.6 Hz, 1H), 7.81 - 7.76 (m, 1H), 7.73 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 8.5, 1.6 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.18 (s, 1H), 6.65 (s, 1H), 6.61 (s, 1H), 3.99 (s, 6H), 3.68 (s, 2H), 2.79 - 2.43 (m, 8H), 2.37 (s, 3H). M/Z: 538.1, M+l : 538.1 , t_R= 1.95 min. (system 2)

Example N: 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[4-(lH-l,2,4-triazol-l- ylmethyl)phenyl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 5 using 4- (lH-l,2,4-triazol-l-ylmethyl)aniline and 3-chloro-7-(2, 6-dichloro-3, 5-dimethoxyphenyl) isoquinoline. 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[4-(lH-l,2,4-triazol-l- ylmethyl)phenyl]isoquinolin-3 -amine was obtained as a pale yellow solid (20 mg). 1H NMR (500 MHz, Chloroform-d) δ 8.97 (s, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.72 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.5, 1.6 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.26 (s, 1H), 6.93 (s, 1H), 6.65 (s, 1H), 5.33 (s, 2H), 3.98 (s, 6H).

M/Z: 506.0, M+l : 506.0 , t_R= 3.49 min. (system 2)

Example O: 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l-ylmethyl)pyridin- 2-yl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 5 using 5- (piperazin-l-ylmethyl)pyridin-2-amine and 3-chloro-7-(2, 6-dichloro-3, 5-dimethoxyphenyl) isoquinoline. 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(piperazin- 1 -ylmethyl)pyridin-2- yl]isoquinolin-3 -amine was obtained as a pale yellow solid (170 mg).

1H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 9.09 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.56 (dd, J = 8.5, 2.3 Hz, 1H), 7.41 (dd, J = 8.5, 1.7 Hz, 1H), 7.27 (d, J = 8.5 Ηζ,ΙΗ), 7.01 (s, 1H), 4.05 - 3.79 (m, 6H), 3.38 (s, 2H), 2.69 (dd, J = 14.1, 9.5 Hz, 4H), 2.31 (s, 4H). M/Z: 524.3, M+l : 524.3- 527.3, t_R= 3.68 min. (system 2)

Example P: 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-{5-[(4- ethylpiperazin-l-yl)methyl]pyridin-2-yl}isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 5 using 5- [(4-ethylpiperazin-l-yl)methyl]pyridin-2-amine and 3-chloro-7-(2, 6-dichloro-3, 5- dimethoxyphenyl) isoquinoline. 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N- {5-[(4- ethylpiperazin-l-yl)methyl]pyridin-2-yl}isoquinolin-3-amine was obtained as a pale yellow solid (160 mg). ^lU NMR, δ 9.85 (s, 1H), 9.09 (s, 1H), 8.53 (s, 1H), 8.17 (d, 1H), 7.84 (m, 2H), 7.56 (dd, 1H), 7.41 (dd, 1H), 7.28 (d, 1H), 7.01 (s, 1H), 3.97 (s, 6H), 3.39 (s, 2H), 2.31 (m, 10H), 0.96 (t, 3H). M/Z: 552.3, M+l : 552.3-555.3, t_R= 4.05 min. (system 2)

Example Q: 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[l-(l-methylpiperidin-4-yl)-lH- pyrazol-4-yl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 5 using 1- (l-methylpiperidin-4-yl)-lH-pyrazol-4-amine and 3-chloro-7-(2, 6-dichloro-3, 5- dimethoxyphenyl) isoquinoline. 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[l-(l- methylpiperidin-4-yl)-lH-pyrazol-4-yl]isoquinolin-3 -amine was obtained as a pale yellow solid (120 mg).

1H NMR, δ 8.97 (s, 1H), 8.64 (s, 1H), 7.93 (s, 1H), 7.69 (d, 2H), 7.50 (s, 1H), 7.28 (m, 1H), 7.00 (s, 1H), 6.90 (s, 1H), 4.08 (m, 1H), 3.96 (s, 6H), 2.85 (d, 2H), 2.20 (s, 3H), 2.01 (m, 6H). M/Z: 512.3, M+l : 513.3, t_R= 2.33 min (system 2)

Example R: 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N- [5-(l-methylpiperidin-4-yl)pyridin- 2-yl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 5 using 5- (l-methylpiperidin-4-yl)pyridin-2-amine and 3-chloro-7-(2, 6-dichloro-3, 5- dimethoxyphenyl) isoquinoline. 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(l- methylpiperidin-4-yl)pyridin-2-yl]isoquinolin-3 -amine was obtained as a pale yellow solid (120 mg).

1H NMR (400 MHz, DMSO) δ 9.76 (s, 1H), 9.08 (s, 1H), 8.51 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.56 (dd, J = 8.6, 2.4 Hz, 1H), 7.39 (dd, J = 8.5, 1.7 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.01 (s,lH), 3.89 (d, J = 60.0 Hz, 6H), 2.86 (d, J = 11.3 Hz, 2H), 2.42 (dd, J= 13.8, 9.7 Hz, 1H), 2.18 (s, 3H), 1.95 (dd, J= 11.5, 8.6 Hz, 2H), 1.80 - 1.50 (m, 4H). M/Z: 522, M+l : 523, t_R= 4.47 min. (system 2)

Example S: 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[6-(4-ethylpiperazin-l-yl)pyridazin- 3-yl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 5 6-(4- ethylpiperazin-l-yl)pyridazin-3 -amine and 3-chloro-7-(2, 6-dichloro-3, 5 -dimethoxyphenyl) isoquinoline. 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[6-(4-ethylpiperazin-l-yl)pyridazin-3- yl]isoquinolin-3 -amine was obtained as a pale yellow solid (140 mg).

1H NMR, δ 9.75 (s, 1H), 9.09 (s, 1H), 8.57 (s, 1H), 7.88 (d, 1H), 7.82 (s, 1H), 7.41(m, 3H), 7.01 (s, 1H), 3.97 (s, 6H), 3.46 (s, 4H), 3.31 (s, 4H), 2.38 (d, 2H), 1.04 (t, 3H).

M/Z: 539.3, M+l : 539.3-542.3, t_R= 3.93 min. (system 2)

STEP S.l: 6-(4-ethylpiperazin-l-yl)pyridazin-3-amine:

In a clean dry sealed tube 6-chloropyridazin-3-amine (1000 mg, 7.72 mmol) and 1- ethylpiperazine (2644.32 mg, 23.16 mmol) are taken and heated the reaction mixture at 160°C for 2 h. Reaction mixture cooled to room temperature. TLC shows complete conversion of starting material. The reaction mixture was triturated with ethyl acetate (200 ml) followed by n-pentane, filtered and dried to obtain the title compound as a brown solid (900 mg).

1H NMR (400 MHz, DMSO) δ 7.13 (d, J= 9.6 Hz, 1H), 6.73 (d, J= 9.6 Hz, 1H), 5.73 (d, J = 17.0 Hz, 2H), 3.34 - 3.26 (m, 4H), 2.52 (dd, J = 9.6, 5.0 Hz, 4H), 2.42 (q, J = 7.2 Hz, 2H), 1.11 - 0.97 (m, 3H).

M/Z: 207.28 , M+l :208.4 , t_R= 0.23min. (system 1)

Example T: 4- [(6-{ [7-(2,6-dichloro-3,5-dimethoxyphenyl)isoquinolin-3- yl]amino}pyridin-3-yl)methyl]-l-methylpiperazin-2-one:

The title compound was prepared in analogy to the procedure described in example 5 using 4- [(6-aminopyridin-3-yl)methyl]-l-methylpiperazin-2-one and 3-chloro-7-(2, 6-dichloro-3, 5- dimethoxyphenyl) isoquinoline. 4-[(6- {[7-(2,6-dichloro-3,5-dimethoxyphenyl)isoquinolin-3- yl]amino}pyridin-3-yl)methyl]-l-methylpiperazin-2-one was obtained as a pale yellow solid (20 mg).

1H NMR, δ 9.00 (s, 1H), 8.26 (d, 2H), 7.82 (d, 1H), 7.73 (s, 1H), 7.58 (dd, 1H), 7.44 (dd, 1H), 7.14 (d, 1H), 6.65 (s, 1H), 4.55 (s, 2H), 3.98 (s, 6H), 3.28 (m, 2H), 3.17 (s, 2H), 2.61 (m, 2H), 2.32 (s, 3H).

Title compound: M/Z: 552.45 M+l : 552.3-555.3, t_R= 3.57 min. (System 1)

Example 11: 7-(2, 6-difluoro-3, 5-dimethoxyphenyl)-N-{5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-yl} isoquinolin-3-amine:

To a solution of 3-chloro-7-(2, 6-difluoro-3, 5-dimethoxyphenyl) isoqinoline (step 14.1) (50 mg, 0.149 mmol), 5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-amine (step 8.1) (33.78 mg , 0.164 mmol), X-Phos (6.46 mg, 10 mol % ) and cesium carbonate (96.8 mg, 0.298 mmol) in Toluene (2 mL) and t-BuOH (0.5 mL) (4: 1) argon was purged for 20 min. Then was added Pd₂(dba)₃ (12.42 mg, 10 mol %) again argon was purged for 5 min. The reaction mixture was heated at 120°C for O/N. The reaction mixture was cooled to room temperature and filtered through celite pad and filtrate was concentrated under reduced pressure. Product was purified by column chromatography on silica gel column DCM: MeOH: NH₃ aq. (94:6: 1%) as an eluent to afford 7-(2, 6-difluoro-3, 5-dimethoxyphenyl)-N-{5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-yl} isoquinolin-3 -amine (15 mg) as an off white solid.

1H NMR (400 MHz, CDC1₃) δ 9.02 (d, J = 12.3 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 7.97 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.66 (dd, J = 8.6, 1.6 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 6.69 (t, J = 8.0 Hz, 1H), 3.94 (d, J = 3.2 Hz, 6H), 3.48 (s, 2H), 2.46 (dd, J= 83.1, 25.8 Hz, 8H), 2.31 (s, 3H).M/Z: 505.2, M+l : 506.6, t_R= 0.72 min. (System

1)

Step 11.1: 3-chloro-7-(2-fluoro-3, 5-dimethoxyphenyl) isoquinoline and 3-chloro-7-(2, 6- ifluoro-3, 5-dimethoxyphenyl) isoquinoline:

Selectfluor (1.181 g, 3.33 mmol, 2 equiv) was added portion wise to solution of 3-chloro-7-(3, 5-dimethoxyphenyl) isoquinoline (500 mg, 1.66 mmol) in Acetonitrile (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h, quenched by the addition of water and concentrated to remove acetonitrile. The resulting mixture was partitioned between EtOAc and water. Filtered to provide a white solid (batch 1). The filtrate was extracted with EtOAc. The organic phase was washed with water and brine, dried (Na₂S0₄), filtered and concentrated to afford (batch 2). The two batches were combined and purified by column chromatography on silica gel column (Hexane: EtOAc, 7:3) to afford a sample of 3-chloro-7-(2-fluoro-3, 5 -dimethoxyphenyl) isoquinoline (110 mg) and 3-chloro-7- (2, 6-difluoro-3, 5 -dimethoxyphenyl) isoquinoline (150 mg) as white solid.

3-chloro-7-(2-fluoro-3, 5-dimethoxyphenyl) isoquinoline:

1H NMR (400 MHz, CDC1₃) δ 9.12 (s, 1H), 8.13 (s, 1H), 7.92 (dt, J = 8.6, 1.8 Hz, 1H), 7.83 (d, J= 8.7 Hz, 1H), 7.76 (s, 1H), 6.58 (ddd, J= 8.1, 6.0, 2.9 Hz, 2H), 3.94 (d, J= 4.5 Hz, 3H), 3.86 (s, 3H). M/Z: 317.06, M+l : 318.4, t_R= 1.66 min. (System 1)

3-chloro-7-(2, 6-difluoro-3, 5-dimethoxyphenyl) isoquinoline:

1H NMR (400 MHz, CDC1₃) 5 9.11 (s, 1H), 8.09 (s, 1H), 7.87 - 7.84 (m, 1H), 7.83 - 7.78 (m, 1H), 7.77 (d, J = 4.4 Hz, 1H), 6.72 (t, J = 8.0 Hz, 1H), 3.94 (d, J = 4.4 Hz, 6H). M/Z: 335.73, M+l : 336.4, t_R= 1.62 min. (System 1)

Example H: 7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(4-ethylpiperazin-l-yl)pyridin-2- yl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 11 using 5-(4-ethylpiperazin-l-yl)pyridin-2-amine and 3-chloro-7-(2, 6-difluoro-3, 5- dimethoxyphenyl) isoquinoline. 7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(4- ethylpiperazin-l-yl)pyridin-2-yl]isoquinolin-3 -amine was obtained as an off white solid (105 mg).

1H NMR (400 MHz, CDC1₃) δ 8.98 (s, 1H), 8.13 (s, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.94 (s, 1H), 7.78 (d, J= 8.7 Hz, 1H), 7.65 (s, 1H), 7.31 (d, J= 3.0 Hz, 2H), 7.14 (s, 1H), 6.69 (s, 1H), 3.94 (s, 6H), 3.21 (d, J = 4.8 Hz, 4H), 2.69 (s, 4H), 2.54 (d, J = 7.1 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H). M/Z: 505.56, M+l : 506.31, t_R= 1.89 min. (System 1)

Example I: 7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl)pyridin- 2-yl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 11 using 5-(4-methylpiperazin-l-yl)pyridin-2-amine and 3-chloro-7-(2, 6-difluoro-3, 5- dimethoxyphenyl) isoquinoline. 7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(4- methylpiperazin-l-yl)pyridin-2-yl]isoquinolin-3 -amine was obtained as an off white solid (100 mg). 1H NMR (400 MHz, CDC1₃) δ 8.98 (s, 1H), 8.13 (s, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.94 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.63 (dd, J = 8.6, 1.6 Hz, 1H), 7.32 (dd, J = 8.9, 3.0 Hz, 1H), 7.24 (s, 1H), 7.12 (d, J = 8.9 Hz, 1H), 6.69 (s, 1H), 3.94 (s, 6H), 3.22 - 3.15 (m, 4H), 2.67 - 2.58 (m, 4H), 2.38 (s, 3H). M/Z: 491.5, M+l : 492.6, t_R= 0.84 min. (System 1) Example J: 4-[(6-{[7-(2,6-difluoro-3,5-dimethoxyphenyl)isoquinolin-3-yl]amino}pyridin- 3-yl)methyl]piperazin-2-one:

The title compound was prepared in analogy to the procedure described in example 11 using 4-[(6-aminopyridin-3-yl)methyl]piperazin-2-one and 3-chloro-7-(2, 6-difluoro-3, 5- dimethoxyphenyl) isoquinoline. 4-[(6- {[7-(2,6-difluoro-3,5-dimethoxyphenyl)isoquinolin-3- yl]amino}pyridin-3-yl)methyl]piperazin-2-one was obtained as a pale yellow solid (105 mg).

1H NMR, δ 9.01 (s, 1H), 8.27 (d, 2H), 7.98 (s, 1H), 7.84 (d, 1H), 7.65 (dd, 2H), 7.18 (s, 1H), 6.70 (t, 1H), 5.79 (s, 1H), 3.95 (s, 6H), 3.55 (s, 2H), 3.37 (s, 2H), 3.22 (s, 2H), 2.67 (m, 2H). M/Z: 505.5, M+l : 506.6, t_R= 0.87 min. (System 1) Example K: 7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l-ylmethyl)pyridin-2- yl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example 11 using 5-(piperazin-l-ylmethyl)pyridin-2-amine and 3-chloro-7-(2, 6-difluoro-3, 5- dimethoxyphenyl) isoquinoline. 7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l- ylmethyl)pyridin-2-yl]isoquinolin-3 -amine was obtained as a pale yellow solid (140 mg).

1H NMR (400 MHz, CDC1₃) δ 9.01 (s, 1H), 8.30 (s, 1H), 8.25 (d, J = 1.9 Hz, 1H), 7.97 (s, 1H), 7.82 (d, J= 8.6 Hz, 1H), 7.66 (dd, J= 8.6, 1.5 Hz, 1H), 7.60 (d, J= 2.3 Hz, 1H), 7.41 (s, 1H), 7.12 (d, J =8.4 Hz, 1H), 6.69 (s, 1H), 3.94 (s, 6H), 3.46 (s, 2H), 2.91 (t, J= 4.8 Hz, 4H), 2.46 (s, 4H). M/Z: 491.53, M+l : 492.6, t_R= 0.89 min. (System 1) [Since the HNMR spectrum was recorded in CDCI₃, one labile proton of -NH is missing.]

Example 12: 7-(2, 6-difluoro-3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2-yl] isoquinolin-3-amine:

To a solution of 3-chloro-7-(2, 6-difluoro-3, 5-dimethoxyphenyl) isoqinoline (step 14.1 ) (50 mg, 0.149 mmol) , 5-(morpholin-4-ylmethyl) pyridin-2-amine (step 9.1) (32 mg, 0.164 mmol), X-Phos ( 6.46 mg, 10 mol %) and cesium carbonate (96.8 mg, 0.298 mmol) in Toluene (2 mL) and t-BuOH (0.5 mL) (4: 1) argon was purged for 20 min. Then was added Pd₂(dba)₃ (12.42 mg, 10 mol %) again argon was purged for 5 min. The reaction mixture was heated at 120°C for O/N. The reaction mixture was cooled to room temperature, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel DCM: MeOH: NH₃ aq. (94:6: 1%) as eluent to afford 7- (2, 6-difluoro-3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2- yl] isoquinolin- 3 -amine (15mg) as an off white solid.

1H NMR (400 MHz, CDC1₃) 1H NMR (400 MHz, CDC13) δ 9.01 (s, 1H), 8.30 (s, 1H), 8.26 (d, J= 1.9 Hz, 1H), 7.97 (s, 1H), 7.83 (d, J= 8.7 Hz, 1H), 7.67 (dd, J= 8.6, 1.6 Hz, 1H), 7.62 (dd, J = 8.5, 2.2 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.69 (t, J = 8.0 Hz, 1H), 3.94 (s, 6H), 3.75 - 3.70 (m, 4H), 3.47 (s, 2H), 2.47 (s, 4H).M/Z: 492.5, M+l : 493.6, t_R= 0.79 min. (System 1)

Example 13: 7-(2-fluoro-3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2- yl] isoquinolin-3-amine:

A solution of 3-chloro-7-(2-fluoro-3, 5-dimethoxyphenyl) isoquinoline (50 mg, 0.167 mmol), 5-(morpholin-4-ylmethyl) pyridin-2-amine (step 9.1) (35 mg, 0.184 mmol) X-Phos ( 6.46 mg, 10 mol %) and cesium carbonate (108 mg, 0.334 mmol) in Toluene (2 mL) and t-BuOH (0.5 mL) (4: 1) was purged with argon for 20 min. Pd₂(dba)₃ (12.42 mg, 10 mol %) was added and the mixture again purged with argon for 5 min. The reaction mixture was heated at 120°C overnight. The reaction mixture was cooled to room temperature, filtered through a celite pad and the filtrate concentrated under reduced pressure. The rsidue was purified by column chromatography on silica gel DCM: MeOH: NH₃ aq. (94:6: 1%) as eluent to afford 7-(2- fluoro-3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2-yl] isoquinolin-3- amine (15 mg) as a yellow solid.

1H NMR (400 MHz, CDC1₃) δ 9.02 (s, 1H), 8.34 - 8.23 (m, 2H), 8.02 (s, 1H), 7.87 - 7.75 (m, 2H), 7.62 (dd, J = 8.4, 2.3 Hz, 1H), 7.42 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.62 - 6.54 (m, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.77 - 3.69 (m, 4H), 3.48 (d, J = 9.6 Hz, 2H), 2.47 (s, 4H). M/Z: 474.2, M+l : 476.7, t_R= 1.78 min. (System 2)

Example B: 7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl)-N-{5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-yl} isoquinolin-3-amine:

An oven-dried sealed tube containing a stir bar was charged with 3-chloro-7-(2-chloro-6- fluoro-3,5- (125 mg, 0.35 mmol), 5-[(4-methylpiperazin-l-yl)methyl]pyridin-2-amine (80.54 mg, 0.39 mmol), X-phos (16.94 mg, 10mol%), Cesium carbonate (230.7 mg, 0.71 mmol) and Pd₂(dba)₃ (32.47 mg, 10mol%). The tube was evacuated and backfilled with argon and then 5 mL mixture of Toluene: t-BuOH (5:1) was added. The tube was sealed and heated with stirring at 120°C overnight. The resulting mixture was allowed to cool to room temperature and filtered through a pad of Celite and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and purified by chromatography on a silica gel column using DCM: MeOH: NH3 aq. (94:5: 1%) as an eluent. The isolated compound was triturated in n-pentane to afford the title compound 7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl)-N-{5-[(4- methylpiperazin-l-yl) methyl] pyridin-2-yl} isoquinolin-3 -amine as an off white solid (110 mg).

1H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 9.17 (s, 1H), 8.60 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.61 (ddd, J = 9.5, 8.6, 1.7 Hz, 2H), 7.35 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 7.8Hz, 1H), 4.02 (t, J = 6.9 Hz, 6H), 3.46 (s, 2H), 2.55 - 2.23 (m, 8H), 2.20 (s, 3H). M/Z: 522.01, M+l : 522.6, t_R= 3.72 min (system 2)

Ste B.1 3-chloro-7-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)isoquinoline:

Sulfuryl chloride (16.35 mg, 2.077 mmol, 1.1 equiv) diluted with acetonitrile (10 mL) was added drop wise to a solution of 3-chloro-7-(2-fluoro-3,5-dimethoxyphenyl)isoquinoline (600 mg, 1.88 mmol) in Acetonitrile (100 mL) at -30°C. The reaction mixture was stirred at same temperature for 1 h, quenched by the addition of sodium bicarbonate solution and concentrated to remove acetonitrile. The resulting mixture was extracted EtOAc ( 3* 50 mL) the EtOAc layer dried over anhy. Na₂S0₄, the solvent filtered and removed to get a crude compound which was purified by chromatography on silicagel column using EtOAc: Hexane (5:95) as an eluent. The isolated compound was triturated in n-pentane to afford the title compound 3-chloro-7-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)isoquinoline as white solid(610 mg).

M/Z: 352.19, M+l : 352.3-355.4 t_R= 1.65 min (system 1) Example C: 7-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-N-[5-(4-ethylpiperazin-l- yl)pyridin-2-yl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example B using 5-[(4-ethylpiperazin-l-yl)pyridin-2-amine and 3-chloro-7-(2-chloro-6-fluoro-3,5- dimethoxyphenyl)isoquinoline. 7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l- ylmethyl)pyridin-2-yl]isoquinolin-3 -amine was obtained as a colourless solid (145 mg).

1H NMR (400 MHz, CDC1₃) δ 8.97 (s, 1H), 8.12 (s, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.32 (dd, J = 8.9, 3.0 Hz, 1H), 7.22 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H),6.67 (d, J = 7.5 Hz, 1H), 3.95 (t, J = 7.3 Hz, 6H), 3.24 - 3.14 (m, 4H), 2.71 - 2.61 (m, 4H), 2.50 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H) M/Z: 522.01, M+l : 522.6, t_R= 0.77 min (system 1)

Example D: 7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl) pyridin-2-yl] isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example B using 5-[(4-methylpiperazin-l-yl)pyridin-2-amine and 3-chloro-7-(2-chloro-6-fluoro-3,5- dimethoxyphenyl)isoquinoline. 7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l- ylmethyl)pyridin-2-yl]isoquinolin-3 -amine was obtained as a pale yellow solid (165 mg).

1H NMR (400 MHz, CDC1₃) δ 8.98 (d, J= 6.7 Hz, 1H), 8.12 (d, J= 3.3 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.80 (dd, J = 19.5, 4.7 Hz, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.31 (dd, J = 9.0, 3.0 Hz, 2H), 7.13 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 4.00 - 3.91 (m, 6H), 3.21 - 3.15 (m, 4H), 2.66 - 2.59 (m, 4H), 2.38 (s, 3H). M/Z: 507.21, M+l : 508.3, t_R= 1.93 min. (system 2)

Example E: 7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2-yl] isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example B using 5-(morpholin-4-ylmethyl)pyridin-2-amine and 3-chloro-7-(2-chloro-6-fluoro-3,5- dimethoxyphenyl)isoquinoline. 7-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-N-[5- (morpholin-4-ylmethyl)pyridin-2-yl]isoquinolin-3-amine was obtained as a pale yellow solid (114 mg).

1H NMR (400 MHz, CDC1₃) δ 9.01 (d, J = 6.4 Hz, 1H), 8.30 - 8.23 (m, 2H), 7.87 - 7.80 (m, 2H), 7.61 (dd, J = 8.5, 2.2 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 16.1 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.68 (d, J= 7.5 Hz, 1H), 3.95 (t, J = 7.1 Hz, 6H), 3.75 - 3.70 (m, 4H), 3.47 (s, 2H), 2.48 (d, J = 4.0 Hz, 4H).

M/Z: 508.97, M-l : 507.3, t_R= 2.08 min. (system 2)

Example F: 4-[(6-{[7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl) isoquinolin-3-yl] amino} pyridin-3-yl) methyl] piperazin-2-one:

The title compound was prepared in analogy to the procedure described in example B using 4-[(6-aminopyridin-3-yl)methyl]piperazin-2-one and 3-chloro-7-(2-chloro-6-fluoro-3,5- dimethoxyphenyl)isoquinoline. 4-[(6- {[7-(2-chloro-6-fluoro-3, 5 -dimethoxyphenyl) isoquinolin-3-yl] amino} pyridin-3-yl) methyl] piperazin-2-one was obtained as a colourless solid (120 mg).

1H NMR (400 MHz, CDC1₃) δ 2.71 - 2.64 (m, 2H), 3.22 (s, 2H), 3.37 (s, 2H), 3.55 (s, 2H), 3.96 (s, 3H), 3.97 (s, 3H), 5.79 (s, 1H), 6.68 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.56 (d, J = 9.0 Ηζ, ΙΗ), 7.60 (dd, J = 8.5, 2.3 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.86 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 9.01 (s, 1H).

M/Z: 521.57, M+l : 522.3, t_R= 2.37 min. (system 2)

Example G: 7-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l- ylmethyl)pyridin-2-yl]isoquinolin-3-amine:

The title compound was prepared in analogy to the procedure described in example B using 5-(piperazin-l-ylmethyl) pyridin-2-amine and 3-chloro-7-(2-chloro-6-fluoro-3,5- dimethoxyphenyl)isoquinoline. 7-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-N-[5-(piperazin- l-ylmethyl)pyridin-2-yl]isoquinolin-3 -amine was obtained as a pale yellow solid (90 mg).

^!H NMR, δ 9.01 (s, 1H), 8.27 (d, 2H), 7.83 (m, 2H), 7.58 (m, 3H), 7.13 (d, 1H), 6.67 (d, 1H), 3.95 (t,

6H), 3.46 (s, 2H), 2.90 (t, 4H), 2.44 (s, 4H).

M/Z: 507.98, M-l : 506.1 , t_R= 1.87 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 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.

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 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 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 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 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:

Example No. FGFR3 Ba/F3-FGFR3 Ba/F3-KDR Ba/F3 Parental enzymatic assay cellular viability cellular viability cellular viability

IC o fnjVn assay IC (nM) assay IC (nM) assay IC (nM)

1 1,100 ND ND ND

2 195 ND ND ND

3 928 ND ND ND

4 2520 ND ND ND

5 17 10.5 1075 3095

6 15 31 1011 1397

7 103 ND ND ND 8 4 20 2623 2607

9 23 35 1000 10000

10 21 6 1535 10000

11 9.5 <10 419 2608

12 7.5 <10 304 >3160

13 45 83 2499 3160

A 6.1 32.4 2658 3160

B 5.8 37 215 2300

C 24.8 61 209 1908

D 7.2 50 256 3160

E 12.2 54 459 1000

F 9 37 105 10000

G 6 110 315 2591

H 57 20.3 658 1000

I 30 17.5 400 2459

J 8 3 264 3160

K 7.5 3.2 461 3282

L 486 49.3 10000 10000

M 22 15 2705 2513

N 87 28.9 3160 10000

O 6.7 6 719 1404

P 5.5 8 626 1105

Q 21.3 39.3 731 1305

R 4.8 4.3 543 553

S 3.9 5.2 635 1351

T 8 ND ND ND ot determined

Claims

Patent Claims

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

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;

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;

The compound of claim 1, wherein is R¹ phenyl; pyrazolyl; pyridazinyl; or pyridyl, wherein R¹ is unsubstituted or substituted with one or more R⁴, which are the same or different.

The compound of claim 1 or 2, wherein R¹ is substituted with one or more R⁴, which are the same or different.

The compound of any one of claims 1 to 3, wherein R¹ in formula (I) is selected to give formula (la) wherein X° is N; or CH; and R², R^2a, R³, R⁴ have the meaning as indicated in claim 1.

5. The compound of claim 4, wherein X° is N.

6. The compound of claim 4, wherein X° is CH.

7. The compound of any one of claims 1 to 6, wherein R⁴ is T¹; or Ci_₆ alkyl, substituted with T¹.

8. The compound of any one of claims 1 to 7, 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.

9. The compound of any one of claims 1 to 8, wherein T¹ is piperazinyl; piperidinyl; or morpholinyl, wherein T¹ is unsubstituted or substituted with one or more R⁸, which are the same or different.

10. The compound of any one of claims 1 to 9, wherein R⁸ is Ci_₆ alkyl; or oxo, where the ring is at least partially saturated.

1 1. The compound of any one of claims 1 to 10, wherein R⁴ is 4-methylpiperazin-l-yl; 4- ethylpiperazin- 1 -yl; morpho lin-4-yl; (4-methylpiperazin- 1 -yl)methyl; morpholin-4- ylmethyl; (2-oxo-piperazin-4-yl)methyl; ( 1 -methyl-2-oxo-piperazin-4-yl)methyl; piperidin-4-yl; l-methylpiperidin-4-yl; lH-l ,2,4-triazol-l-ylmethyl; or piperazin-1- ylmethyl.

12. The compound of any one of claims 1 to 1 1 , wherein R³ is H. The compound of any one of claims 1 to 12, 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 13 selected from the group consisting of

7-(3, 5-dimethoxyphenyl)-N-[4-(4-methylpiperazin-l-yl) phenyl] isoquinolin-3 -amine; 7-(3 ,5-dimethoxyphenyl)-N- [5 -(4-methylpiperazin- 1 -yl) pyridin-2-yl] isoquino lin-3 - amine;

7-(3 ,5-dimethoxyphenyl)-N- [5 -(4-ethylpiperazin- 1 -yl) pyridin-2-yl] isoquino lin-3 - amine;

7-(3,5-dimethoxyphenyl)-N-[5-(morpholin-4-yl) pyridin-2-yl] isoquino lin-3 -amine; 7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl) pyridin-2-yl] isoquino lin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(4-ethylpiperazin-l-yl) pyridin-2-yl] isoquino lin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(morpholin-4-yl) pyridin-2-yl] isoquino lin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-{5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-yl} isoquino lin-3-amine;

7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2-yl] isoquino lin-3 -amine;

7-(2-fluoro-3,5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2-yl] isoquino lin-3 -amine;

7-(2, 6-dichloro-3, 5-dimethoxyphenyl)-N-[5-(piperidin-4-yl) pyridin-2-yl]

isoquino lin-3 -amine; 7-(2,6-dichloro-3 ,5 -dimethoxyphenyl)-N- [6-(morpho lin-4-yl)pyridin-3 -yl] isoquino lin-

3- amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[4-(lH-l,2,4-triazol-l- ylmethyl)phenyl]isoquino lin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l-ylmethyl)pyridin-2- yl]isoquino lin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-{5-[(4- ethylpiperazin- 1 -yl)methyl]pyridin-2-yl} isoquino lin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[l-(l-methylpiperidin-4-yl)-lH-pyrazol-4- yl]isoquino lin-3 -amine;

7-(2,6-dichloro-3,5-dimethoxyphenyl)-N-[5-(l-methylpiperidin-4-yl)pyridin-2- yl]isoquino lin-3 -amine;

4- [(6- { [7-(2,6-dichloro-3 ,5 -dimethoxyphenyl)isoquino lin-3 -yl] amino } pyridin-3 - yl)methyl] - 1 -methylpiperazin-2-one;

7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(4-ethylpiperazin-l-yl)pyridin-2- yl]isoquino lin-3 -amine;

7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl)pyridin-2- yl]isoquino lin-3 -amine;

7-(2,6-difluoro-3,5-dimethoxyphenyl)-N-[5-(piperazin-l-ylmethyl)pyridin-2- yl]isoquino lin-3 -amine;

7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl)-N-{5-[(4-methylpiperazin-l-yl) methyl] pyridin-2-yl} isoquino lin-3 -amine;

7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl)-N-[5-(4-methylpiperazin-l-yl) pyridin-2- yl] isoquino lin-3 -amine;

7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl)-N-[5-(morpholin-4-ylmethyl) pyridin-2- yl] isoquino lin-3 -amine; 4-[(6-{[7-(2-chloro-6-fluoro-3, 5-dimethoxyphenyl) isoquinolin-3-yl] amino} pyridin-3-yl) methyl] piperazin-2-one; and

7-(2-chloro-6-fluoro-3 ,5 -dimethoxyphenyl)-N- [5 -(piperazin- 1 -ylmethyl)pyridin-2- yl]isoquino lin-3 -amine.

15. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 14 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

16. A compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 14 for use as a medicament.

17. A compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 14 for use in a method of treating or preventing one or more proliferative disorders or dysplasia.

18. Use of a compound or a pharmaceutically acceptable salt thereof of any one of the claims 1 to 14 for the manufacture of a medicament for the treatment or prophylaxis of one or more proliferative disorders or dysplasia.

19. 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 14 or a pharmaceutically acceptable salt thereof.