WO2017162611A1

WO2017162611A1 - Quinoline-3-carboxamide compounds and their use in treating cancer

Info

Publication number: WO2017162611A1
Application number: PCT/EP2017/056599
Authority: WO
Inventors: Bernard Christophe Barlaam; Kurt Gordon Pike; Richard Ducray; Sebastien Louis Degorce; Gilles Ouvry
Original assignee: Astrazeneca Ab
Priority date: 2016-03-21
Filing date: 2017-03-20
Publication date: 2017-09-28

Abstract

This specification generally relates to compounds of Formula (I): (I) and pharmaceutically acceptable salts thereof, where R^1, R², R³, R⁴ and R⁵ have any of the meanings defined herein. The specification also relates to the use of such compounds and salts thereof to treat or prevent ATM kinase mediated disease, including cancer. The specification further relates to crystalline forms of compounds of Formula (I) and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds and salts thereof; kits comprising such compounds and salts thereof; methods of manufacture of such compounds and salts thereof; intermediates useful in the manufacture of such compounds and salts thereof; and to methods of treating ATM kinase mediated disease, including cancer, using such compounds and salts thereof alone or in combination with other therapies.

Description

Quinoline-3-carboxamide Compounds and Their Use in Treating Cancer

FIELD OF INVENTION

This specification generally relates to substituted quinoline-3-carboxamide compounds and pharmaceutically acceptable salts thereof. These compounds selectively modulate ataxia telangiectasia mutated ("ATM") kinase, and the specification therefore also relates to the use of such compounds and salts thereof to treat or prevent ATM kinase mediated disease, including cancer. The specification further relates to crystalline forms of substituted quinoline-3-carboxamide compounds and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds and salts thereof; kits comprising such compounds and salts thereof; methods of manufacture of such compounds and salts thereof; intermediates useful in the manufacture of such compounds and salts thereof; and to methods of treating ATM kinase mediated disease, including cancer, using such compounds and salts thereof alone or in combination with other therapies.

BACKGROUND

ATM kinase is a serine threonine kinase originally identified as the product of the gene mutated in ataxia telangiectasia. Ataxia telangiectasia is located on human

chromosome 1 lq22-23 and codes for a large protein of about 350 kDa, which is characterized by the presence of a phosphatidylinositol ("PI") 3-kinase-like

serine/threonine kinase domain flanked by FRAP-ATM-TRRAP and FATC domains which modulate ATM kinase activity and function. ATM kinase has been identified as a major player of the DNA damage response elicited by double strand breaks. It primarily functions in S/G2/M cell cycle transitions and at collapsed replication forks to initiate cell cycle checkpoints, chromatin modification, HR repair and pro-survival signalling cascades in order to maintain cell integrity after DNA damage (Lavin, 2008).

ATM kinase signalling can be broadly divided into two categories: a canonical pathway, which signals together with the Mrel 1-Rad50-NBS1 complex from double strand breaks and activates the DNA damage checkpoint, and several non-canonical modes of activation, which are activated by other forms of cellular stress (Cremona et al., 2013). ATM kinase is rapidly and robustly activated in response to double strand breaks and is reportedly able to phosphorylate in excess of 800 substrates (Matsuoka et al., 2007), coordinating multiple stress response pathways (Kurz and Lees Miller, 2004). ATM kinase is present predominantly in the nucleus of the cell in an inactive homodimeric form but autophosphorylates itself on Serl981 upon sensing a DNA double strand break (canonical pathway), leading to dissociation to a monomer with full kinase activity (Bakkenist et al., 2003). This is a critical activation event, and ATM phospho-Serl981 is therefore both a direct pharmacodynamic and patient selection biomarker for tumour pathway dependency.

ATM kinase responds to direct double strand breaks caused by common anti-cancer treatments such as ionising radiation and topoisomerase-II inhibitors (for example doxorubicin or etoposide) but also to topoisomerase-I inhibitors (for example irinotecan or topotecan) via single strand break to double strand break conversion during replication. ATM kinase inhibition can potentiate the activity of any these agents, and as a result ATM kinase inhibitors are expected to be of use in the treatment of cancer.

SUMMARY OF INVENTION

Briefly, this specification describes, in part, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, where:

R¹ is methoxymethyl or hydroxymethyl;

R² is hydro or fluoro;

R³ is hydro, fluoro or methyl;

R⁴ is hydro or methyl; and R⁵ is hydro or fluoro.

This specification also describes, in part, a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier.

This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

This specification also describes, in part, a method for treating cancer in a warm blooded animal in need of such treatment, which comprises administering to said warmblooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

This specification further describes, in part, a compound of Formula (IA):

or a pharmaceutically acceptable salt thereof, where:

R¹ is methoxymethyl or hydroxymethyl;

R² is hydro or fluoro;

R³ is hydro, fluoro or methyl;

R⁴ is hydro or methyl; and

R⁵ is hydro or fluoro. This specification also describes, in part, a pharmaceutical composition which comprises a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier.

This specification also describes, in part, a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in therapy.

This specification also describes, in part, a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

This specification also describes, in part, a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

This specification also describes, in part, a method for treating cancer in a warm blooded animal in need of such treatment, which comprises administering to said warmblooded animal a therapeutically effective amount of a compound of Formula (IA), or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: X-Ray Powder Diffraction Pattern of Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide.

Figure 2: DSC Thermogram of Form I of 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4- {[(liS)-l-(l -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } quino line-3 -carboxamide.

Figure 3: X-Ray Powder Diffraction Pattern of Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide.

Figure 4: DSC Thermogram of Form J of 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4- {[(liS)-l-(l -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } quino line-3 -carboxamide. Figure 5: TGA Thermogram of Form J of 7-Fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4- {[(liS)-l-(l -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } quino line-3 -carboxamide.

Figure 6: Comparison of Experimental VCD Spectrum of the Compound Prepared in Example 1 with Simulated VCD Spectra of 7-Fluoro-6-[6-(methoxymethyl)pyridin-3-yl]- 4-{[l-(l-methyl-lH-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide R and S

Enantiomers.

Figure 7: Tumour Growth Inhibition in the Mouse Xenograft Model by 7-Fluoro-6-[6-

(methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide (Example 1) in Combination with Irinotecan.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Many embodiments are detailed throughout the specification and will be apparent to a reader skilled in the art. The invention is not to be interpreted as being limited to any particular embodiment.

In the first embodiment there is provided a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, where:

R¹ is methoxymethyl or hydroxymethyl;

R² is hydro or fluoro;

R³ is hydro, fluoro or methyl;

R⁴ is hydro or methyl; and

R⁵ is hydro or fluoro. Compounds and salts described in this specification may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms. The invention includes any optically active or racemic form of a compound of Formula (I) which possesses ATM kinase inhibitory activity, as for example measured using the tests described herein. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis using optically active materials or by resolution of a racemic form.

Therefore, in one embodiment there is provided a compound of Formula (IA):

or a pharmaceutically acceptable salt thereof, where:

R¹ is methoxymethyl or hydroxymethyl;

R² is hydro or fluoro;

R³ is hydro, fluoro or methyl;

R⁴ is hydro or methyl; and

R⁵ is hydro or fluoro.

In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, which is in an enantiomeric excess (%ee) of >95%, > 98% or > 99%. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, which is in an enantiomeric excess (%ee) of > 99%.

In one embodiment there is provided a compound of Formula (IB):

or a pharmaceutically acceptable salt thereof, where:

R¹ is methoxymethyl or hydroxymethyl;

R² is hydro or fluoro;

R³ is hydro, fluoro or methyl;

R⁴ is hydro or methyl; and

R⁵ is hydro or fluoro.

In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, which is in an enantiomeric excess (%ee) of >95%, > 98% or > 99%. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, which is in an enantiomeric excess (%ee) of > 99%.

The term "pharmaceutically acceptable" is used to specify that an object (for example a salt, dosage form, diluent or carrier) is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors,

Weinheim/Zurich:Wiley-VCH/VFICA, 2002. A suitable pharmaceutically acceptable salt of a compound of Formula (I), (IA) or (IB) is, for example, an acid-addition salt. An acid addition salt of a compound of Formula (I), (IA) or (IB) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person. An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid. An acid addition salt may also for example be formed using an organic acid selected from trifluoro acetic acid, citric acid, maleic acid, oxalic acid, fumaric acid, tartaric acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and /?ara-toluenesulfonic acid. It is to be understood that it it may be possible to form salts with acids not specifically listed above, and that as a result the broadest definition of "pharmaceutically acceptable" is not to be limited to only salts formed with the specifically recited acids.

Therefore, in one embodiment there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoro acetic acid, citric acid, maleic acid, oxalic acid, fumaric acid, tartaric acid, pyruvic acid,

methanesulfonic acid, benzenesulfonic acid or /?ara-toluenesulfonic acid salt. In one embodiment there is provided a compound of Formula (IA) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoro acetic acid, citric acid, maleic acid, oxalic acid, fumaric acid, tartaric acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or /?ara-toluenesulfonic acid salt. In one embodiment there is provided a compound of Formula (IB) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoro acetic acid, citric acid, maleic acid, oxalic acid, fumaric acid, tartaric acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or para- toluenesulfonic acid salt.

A further embodiment provides any of the embodiments defined herein (for example the embodiment of claim 1) with the proviso that one or more specific Examples (for instance one, two or three specific Examples) selected from Examples 1.1, 2, 2.1, 2.2, 3, 3.1, 4, 4.1, 5, 5.1, 6, 6.1, 7, 8, 8.1, 9, 10, 11, 11.1, 12, 13, 14, 14.1, 15, 16, 16.1 and 17 is individually disclaimed.

Some values of variable groups in Formulae (I), (IA) and (IB) are as follows. Such values may be used in combination with any of the definitions, claims (for example claim 1 or claim 15), or embodiments defined herein to provide further embodiments.

a) R¹ is methoxymethyl.

b) R¹ is hydroxymethyl.

c) R² is hydro.

d) R² is fluoro.

e) R³ is hydro or fluoro.

f) R³ is hydro or methyl. g) R³ is fluoro or methyl.

h) R³ is hydro.

i) R³ is fluoro.

j) R³ is methyl,

k) R⁴ is hydro.

1) R⁴ is methyl,

m) R⁵ is hydro,

n) R⁵ is fluoro.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, where:

R¹ is methoxymethyl;

R² is hydro or fluoro;

R³ is hydro, fluoro or methyl;

R⁴ is methyl; and

R⁵ is hydro or fluoro.

In one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, where the compound is selected from:

7-fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

7-fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( IR)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

7-fluoro-6-[2-fluoro-6-(methoxymethyl)pyridin-3-yl]-4- {[(15)-l-(l-methyl-lH- pyrazo 1-3 -yl)ethyl] amino } quino line-3 -carboxamide;

4- {[(liS)-l-(l ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[2-fiuoro-6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(liS)-l-(l ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[2-fluoro-6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- { [( 1 S)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- { [( lR)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide; 7-fiuoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -( 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

7-fiuoro-6-[6-(methoxymethyl)pyridin-3-yl]-4- {[(li?)-l-(lH-pyrazol-3- yl)ethyl] amino } quino line-3 -carboxamide;

7-fiuoro-4- { [( 1 S)- 1 -(4-fiuoro- 1 -methyl- 1 H-pyrazol-3 -yl)ethyl] amino } -6- [6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

7-fiuoro-4- { [( IR)- 1 -(4-fiuoro- 1 -methyl- 1 H-pyrazo l-3-yl)ethyl] amino } -6-[6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

7-fiuoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -(4-methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

7-fiuoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( IR)- 1 -(4-methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

7-fiuoro-6- [6-(hydroxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- { [( 1 S)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- { [( IR)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

6- [2-fiuoro-6-(methoxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- {[(IS)- l-(l,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino} -6- [2-fluoro-6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- { [( IR)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -6- [6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(IS)- l-(l,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino} -6- [2-fluoro-6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

6- [6-(hydroxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- {[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide; 4- { [( 1R) - 1 - ( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -6- [6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(IS)- 1 -(4-fluoro - 1 -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino} -6- [6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

6-[6-(methoxymethyl)pyridin-3-yl]-4- {[(15)- 1 -(1 -methyl- 1 H-pyrazo 1-3- yl)ethyl] amino } quino line-3 -carboxamide;

6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( IR)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide; and

6- [2-fiuoro-6-(methoxymethyl)-3-pyridyl]-4-[[(15)- 1 -(4-fiuoro- 1 -methyl-pyrazol-3- yl)ethyl] amino] quino line-3 -carboxamide

In one embodiment there is provided a compound of Formula (IA), or a

pharmaceutically acceptable salt thereof, where the compound is selected from:

7- fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- {[(liS)-l-(l ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[2-fluoro-6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

7-fluoro-6- [6-(methoxymethyl)pyridin-3-yl] -4- {[(15)- 1-(1 H-pyrazo 1-3- yl)ethyl] amino } quino line-3 -carboxamide;

7-fluoro-4- { [( 1 S)- 1 -(4-fluoro- 1 -methyl- 1 H-pyrazol-3 -yl)ethyl] amino } -6- [6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

7-fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -(4-methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

7-fluoro-6- [6-(hydroxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- { [( 1 S)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide; 6- [2-fiuoro-6-(methoxymethyl)pyridin-3 -yl] -4- { [( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- {[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(IS)- 1 -(4-fiuoro- 1 -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino} -6- [6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

6-[6-(methoxymethyl)pyridin-3-yl]-4- {[(15)- 1 -(1 -methyl- 1 H-pyrazo 1-3- yl)ethyl] amino } quino line-3 -carboxamide; and

6- [2-fiuoro-6-(methoxymethyl)-3-pyridyl]-4-[[(15)- 1 -(4-fiuoro- 1 -methyl-pyrazol-3- yl)ethyl] amino] quino line-3 -carboxamide.

In one embodiment there is provided a compound of Formula (IB), or a

pharmaceutically acceptable salt thereof, where the compound is selected from:

7- fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( IR)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- { [( IR)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4- {[(li?)-l-(lH-pyrazol-3- yl)ethyl] amino } quino line-3 -carboxamide;

7-fluoro-4- { [( IR)- 1 -(4-fluoro- 1 -methyl- 1 H-pyrazo l-3-yl)ethyl] amino } -6-[6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

7-fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( IR)- 1 -(4-methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- { [( IR)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide; 4- { [( 1R) - 1 - ( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -6- [6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- { [( 1R) - 1 - ( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -6- [6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide; and

6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( IR)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide.

In one embodiment there is provided 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]- 4- {[(liS)-l-(l -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } quino line-3 -carboxamide, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]- 4- {[(liS)-l-(l -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } quino line-3 -carboxamide.

In one embodiment there is provided a pharmaceutically acceptable salt of 7- fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide.

In one embodiment there is provided 4- {[(15)- l-(l,4-dimethyl- 1 H-pyrazo 1-3- yl)ethyl] amino } -7-fluoro-6-[6-(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided 4- {[(15)- l-(l,4-dimethyl- 1 H-pyrazo 1-3- yl)ethyl] amino } -7-fluoro-6-[6-(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide.

In one embodiment there is provided a pharmaceutically acceptable salt of 4- {[(liS)-l-(l ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide.

In one embodiment there is provided 6-[6-(methoxymethyl)pyridin-3-yl]-4- {[(15)- 1-(1 -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino} quino line-3 -carboxamide, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided 6-[6-(methoxymethyl)pyridin-3-yl]-4- {[(15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } quino line-3 -carboxamide.

In one embodiment there is provided a pharmaceutically acceptable salt of 6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide. In one embodiment there is provided 4-{[(15)-l-(l,4-dimethyl-lH-pyrazol-3- yl)ethyl] amino } -6- [6-(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide, or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided 4-{[(15)-l-(l,4-dimethyl-lH-pyrazol-3- yl)ethyl] amino } -6- [6-(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide.

In one embodiment there is provided a pharmaceutically acceptable salt of 4- {[(liS)-l-(l ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -6- [6-(methoxymethyl)pyridin-3 - yl] quino line-3 -carboxamide.

Compounds and salts described in this specification may exist in solvated forms and unsolvated forms. For example, a solvated form may be a hydrated form, such as a hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or an alternative quantity thereof. The invention encompasses all such solvated and unsolvated forms of compounds of Formula (I), (IA), or (IB), particularly to the extent that such forms possess ATM kinase inhibitory activity, as for example measured using the tests described herein.

Atoms of the compounds and salts described in this specification may exist as their isotopes. The invention encompasses all compounds of Formula (I), (IA), or (IB) where an atom is replaced by one or more of its isotopes (for example a compound of Formula (I), (IA), or (IB) where one or more carbon atom is an ⁿC or ¹³C carbon isotope, or where one or more hydrogen atoms is a ²H or ³H isotope).

Compounds and salts described in this specification may exist as a mixture of tautomers. "Tautomers" are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom. The invention includes all tautomers of compounds of Formula (I), (IA), or (IB) particularly to the extent that such tautomers possess ATM kinase inhibitory activity.

Compounds and salts described in this specification may be crystalline, and may exhibit one or more crystalline forms. The invention encompasses any crystalline or amorphous form of a compound of Formula (I), (IA), or (IB), or mixture of such forms, which possesses ATM kinase inhibitory activity.

It is generally known that crystalline materials may be characterised using conventional techniques such as X-Ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

The specific crystalline forms described herein provide XRPD patterns

substantially the same as the XRPD patterns shown in the Figures, and have the various 2- theta values as shown in the Tables included herein. One skilled in the art will understand that an XRPD pattern or diffractogram may be obtained which has one or more

measurement errors depending on the recording conditions, such as the equipment or machine used. Similarly, it is generally known that intensities in an XRPD pattern may fluctuate depending on measurement conditions or sample preparation as a result of preferred orientation. Persons skilled in the art of XRPD will further realise that the relative intensity of peaks can also be affected by, for example, grains above 30μιη in size and non-unitary aspect ratios. The skilled person understands that the position of reflections can be affected by the precise height at which the sample sits in the

diffractometer, and also the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect.

As a result of these considerations, the diffraction pattern data presented are not to be taken as absolute values (Jenkins, R & Snyder, R.L. 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons 1996; Bunn, C.W. (1948), 'Chemical

Crystallography ', Clarendon Press, London; Klug, H. P. & Alexander, L. E. (1974), ⁱX- Ray Diffraction Procedures '). It should correspondingly be understood that the crystalline forms embodied herein are not limited to those that provide XRPD patterns that are identical to the XRPD pattern shown in the Figures, and any crystals providing XRPD patterns substantially the same as those shown in the Figures fall within the scope of the corresponding embodiment. A person skilled in the art of XRPD is able to judge the substantial identity of XRPD patterns. Generally, a measurement error of a diffraction angle in an XRPD is approximately plus or minus 0.2° 2-theta, and such degree of a measurement error should be taken into account when considering the X-ray powder diffraction pattern in the Figures and when reading data contained in the Tables included herein.

A person skilled in the art also understands that the value or range of values observed in a particular compound's DSC Thermogram will show variation between batches of different purities. Therefore, whilst for one compound the range may be small, for others the range may be quite large. Generally, a measurement error of a diffraction angle in DSC thermal events is approximately plus or minus 5°C, and such degree of a measurement error should be taken into account when considering the DSC data included herein. TGA thermograms show similar variations, such that a person skilled in the art recognises that measurement errors should be taken into account when judging substantial identity of TGA thermograms.

The compound of Example 1 exhibits crystalline properties, and two crystalline form are characterised herein.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide, which has an X-ray powder diffraction pattern comprising at least one specific peak at about 2-theta = 9.4°.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide, which has an X-ray powder diffraction pattern comprising at least one specific peak at about 2-theta = 12.1°.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide, which has an X-ray powder diffraction pattern comprising at least two specific peaks at about 2-theta = 9.4 and 12.1°.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide, which has an X-ray powder diffraction pattern comprising specific peaks at about 2-theta = 7.0, 9.4, 12.1, 16.1, 19.3, 19.6, 20.5, 21.4, 20.5 and 24.0°.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 1. In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide, which has an X-ray powder diffraction pattern comprising at least one specific peak at 2-theta = 9.4 plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide, which has an X-ray powder diffraction pattern comprising at least one specific peak at 2-theta = 12.1° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide, which has an X-ray powder diffraction pattern comprising at least two specific peaks at 2-theta = 9.4 and 12.1° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide, which has an X-ray powder diffraction pattern comprising specific peaks at 2-theta = 7.0, 9.4, 12.1, 16.1, 19.3, 19.6, 20.5, 21.4, 20.5 and 24.0° plus or minus 0.2° 2-theta.

DSC analysis of Form I of 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(15)-l- (l-methyl-lH-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide shows a melting endo therm with an onset of about 149.1°C and a peak at about 150.8°C (Figure 2).

Therefore, in one embodiment there is provided a crystalline form, Form I of 7- fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram comprising an endo therm with an onset of melting at about 149.1°C and a peak at about 150.8°C.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram comprising an endotherm with an onset of melting at 149.1°C plus or minus 5°C and a peak at 150.8°C plus or minus 5°C.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram comprising an endotherm with an onset of melting at 149.1°C and a peak at 150.8°C.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram substantially as shown in Figure 2.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide, which has an X-ray powder diffraction pattern comprising at least one specific peak at about 2-theta = 12.7°.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide, which has an X-ray powder diffraction pattern comprising at least one specific peak at about 2-theta = 13.6°.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide, which has an X-ray powder diffraction pattern comprising at least two specific peaks at about 2-theta = 12.7 and 13.6°.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide, which has an X-ray powder diffraction pattern comprising specific peaks at about 2-theta = 3.5, 6.7, 7.0, 7.3, 7.8, 10.4, 12.7, 13.6, 19.2 and 20.1°.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 3.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide, which has an X-ray powder diffraction pattern comprising at least one specific peak at 2-theta = 12.7° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide, which has an X-ray powder diffraction pattern comprising at least one specific peak at 2-theta = 13.6° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form I of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide, which has an X-ray powder diffraction pattern comprising at least two specific peaks at 2-theta = 12.7 and 13.6° plus or minus 0.2° 2- theta.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide, which has an X-ray powder diffraction pattern comprising specific peaks at 2-theta = 3.5, 6.7, 7.0, 7.3, 7.8, 10.4, 12.7, 13.6, 19.2 and 20.1° plus or minus 0.2° 2-theta.

DSC analysis of Form J of 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(15)-l- (l-methyl-lH-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide shows a melting endotherm with an onset of about 72°C and a peak of about 85°C followed by a subsequent melting endotherm with an onset of about 141.9°C and a peak at about 146.0°C (Figure 4).

Therefore, in one embodiment there is provided a crystalline form, Form J of 7- fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram comprising an endotherm with an onset of melting at about 72°C and a peak at about 85°C.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram comprising an endotherm with an onset of melting at 72°C plus or minus 5°C and a peak at 85°C plus or minus 5°C.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram comprising an endotherm with an onset of melting at 72°C and a peak at 85°C.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram comprising an endotherm with an onset of melting at about 72°C and a peak at about 85°C and an endotherm with an onset of melting at about 141.9°C and a peak at about 146.0°C.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram comprising an endotherm with an onset of melting at 72°C plus or minus 5°C and a peak at 85°C plus or minus 5°C and an endotherm with an onset of melting at 141.9°C plus or minus 5°C and a peak at 146.0°C plus or minus 5°C.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram comprising an endotherm with an onset of melting at 72°C and a peak at 85°C and an endotherm with an onset of melting at 141.9°C and a peak at 146.0°C .

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a DSC thermogram substantially as shown in Figure 4.

TGA analysis of Form J of 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(15)-l- (l-methyl-lH-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide indicated a weight loss of approximately 7.8% which suggests a dihydrated form.

Therefore, in one embodiment there is provided a crystalline form, Form J of 7- fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which shows a weight loss of about 7.8% when subjected to thermal gravimetric analysis.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which shows a weight loss of 7.8% when subjected to thermal gravimetric analysis.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which has a TGA Thermogram substantially as shown in Figure 5.

In one embodiment there is provided a crystalline form, Form J of 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide which is a dihydrate.

When it is stated that an embodiment relates to a crystalline form, the degree of crystallinity may vary. Therefore, in one embodiment there is provided a crystalline form where the degree of crystallinity is greater than about 60%. In one embodiment the degree of crystallinity is greater than about 80%. In one embodiment the degree of crystallinity is greater than about 90%. In one embodiment the degree of crystallinity is greater than about 95%. In one embodiment the degree of crystallinity is greater than about 98%.

Compounds of Formula (I) may for example be prepared by the reaction of a compound of Formula (II):

(Π)

Or a salt thereof, where R³, R⁴ and R⁵ are as defined in any of the embodiments herein and X is an iodine, bromine, or chlorine atom or a triflate group, or alternatively a bromine atom, with a compound of formula (III):

(III)

Or a salt thereof, where R¹ and R² are as defined in any of the embodiments herein and Y is a boronic acid, boronic ester or potassium trifluoroborate group (for example boronic acid, boronic acid pinacol ester, or potassium trifluoroborate). The reaction may be performed under standard conditions well known to those skilled in the art, for example in the presence of a palladium source (for example tetrakis triphenylphosphine palladium or palladium(II) acetate), optionally a phosphine ligand (for example Xantphos or S-phos), and a suitable base (for example cesium carbonate or triethylamine).

Compounds of Formula (II) are therefore useful as intermediates in the preparation of the compounds of Formula (I) and provide a further embodiment.

In one embodiment there is provided a compound of Formula (II), or a salt thereof, where:

R³ is hydro, fluoro or methyl;

R⁴ is hydro or methyl;

R⁵ is hydro or fluoro; and

X is an iodine, bromine, or chlorine atom or a triflate group. In one embodiment X is a bromine atom.

Compounds of Formula (IA) may for example be prepared by the reaction of a compound of Formula (IIA):

(IIA)

(III)

Compounds of Formula (IIA) are therefore useful as intermediates in the preparation of the compounds of Formula (IA) and provide a further embodiment.

In one embodiment there is provided a compound of Formula (IIA), or a salt thereof, where:

R³ is hydro, fluoro or methyl;

R⁴ is hydro or methyl;

R⁵ is hydro or fluoro; and

Compounds of Formula (IB) may for example be prepared by the reaction of a compound of Formula (IIB):

(IIB) Or a salt thereof, where R³, R⁴ and R⁵ are as defined in any of the embodiments herein and X is an iodine, bromine, or chlorine atom or a triflate group, or alternatively a bromine atom, with a compound of formula (III):

(III)

Compounds of Formula (IIB) are therefore useful as intermediates in the preparation of the compounds of Formula (IB) and provide a further embodiment.

In one embodiment there is provided a compound of Formula (IIB), or a salt thereof, where:

R³ is hydro, fluoro or methyl;

R⁴ is hydro or methyl;

R⁵ is hydro or fluoro; and

In one embodiment there is provided 6-bromo-7-fluoro-4-{[(lS)-l-(l -methyl- 1H- pyrazo 1-3 -yl)ethyl] amino } quino line-3 -carboxamide.

Compounds of Formula (I) may also be prepared by the reaction of a compound of Formula (IV):

(IV)

Or a salt thereof, where R¹, R² and R⁵ are as defined in any of the embodiments herein and X¹ is a leaving group (for example a halogen atom or a triflate group, conveniently a chlorine atom) with a compound of formula (V):

(V)

Or a salt thereof, where R³ and R⁴ are as defined in any of the embodiments herein. The reaction may be performed under standard conditions well known to those skilled in the art, for example in the presence of a palladium source (for example tetrakis

triphenylphosphine palladium or palladium(II) acetate), optionally a phosphine ligand (for example Xantphos or S-phos), and a suitable base (for example cesium carbonate or triethylamine). The reaction can alternatively proceed by nucleophilic aromatic substitution using a suitable base (for example diisopropylethylamine) as catalyst.

Compounds of Formula (IA) may also be prepared by the reaction of a compound of Formula (IV):

(IV)

Or a salt thereof, where R¹, R² and R⁵ are as defined in any of the embodiments herein and X¹ is a leaving group (for example a halogen atom or a triflate group, conveniently a chlorine atom) with a compound of formula (VA):

(VA)

triphenylphosphine palladium or palladium(II) acetate), optionally a phosphine ligand (for example Xantphos or S-phos), and a suitable base (for example cesium carbonate or triethylamine). The reaction can alternatively proceed by nucleophilic aromatic substitution using a suitable base (for example diisopropylethylamine) as a promoter.

Compounds of Formula (IB) may also be prepared by the reaction of a compound of Formula (IV):

(IV)

Or a salt thereof, where R¹, R² and R⁵ are as defined in any of the embodiments herein and X¹ is a leaving group (for example a halogen atom or a triflate group, conveniently a chlorine atom) with a compound of formula (VB):

(VB)

triphenylphosphine palladium or palladium(II) acetate), optionally a phosphine ligand (for example Xantphos or S-phos), and a suitable base (for example cesium carbonate or triethylamine). The reaction can alternatively proceed by nucleophilic aromatic substitution using a suitable base (for example diisopropylethylamine) as catalyst. Compounds of Formula (IV) are therefore useful as intermediates in the preparation of the compounds of Formula (I), (IA) and (IB) and provide a further embodiment.

In one embodiment there is provided a compound of Formula (IV), or a salt thereof, where:

R¹ is methoxymethyl or hydroxymethyl;

R² is hydro or fluoro;

R⁵ is hydro or fluoro; and

X¹ is a leaving group. In one embodiment X¹ is a chlorine atom.

In one embodiment there is provided 4-chloro-7-fluoro-6-(6- (methoxymethyl)pyridin-3 -yl)quino line-3 -carboxamide.

In any of the embodiments where a compound of Formula (II), (IIA) or (IIB) or a salt thereof or a compound of Formula (IV) or a salt thereof is mentioned it is to be understood that such salts do not need to be pharmaceutically acceptable salts. A suitable salt of a compound of Formula (II), (IIA), (IIB) or (IV) is, for example, an acid-addition salt. An acid addition salt of a compound of Formula (II), (IIA), (IIB) or (IV) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person. An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid. An acid addition salt may also be formed using an organic acid selected from trifluoro acetic acid, citric acid, maleic acid, oxalic acid, fumaric acid, tartaric acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para- toluenesulfonic acid.

Therefore, in one embodiment there is provided a compound of Formula (II) or a salt thereof, where the salt is a hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoro acetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid or /?ara-toluenesulfonic acid salt.

As a result of their ATM kinase inhibitory activity, the compounds of Formula (I), (IA), or (IB), and pharmaceutically acceptable salts thereof are expected to be useful in therapy, for example in the treatment of diseases or medical conditions mediated at least in part by ATM kinase, including cancer. Where "cancer" is mentioned, this includes both non-metastatic cancer and also metastatic cancer, such that treating cancer involves treatment of both primary tumours and also tumour metastases.

"ATM kinase inhibitory activity" refers to a decrease in the activity of ATM kinase as a direct or indirect response to the presence of a compound of Formula (I), or pharmaceutically acceptable salt thereof, relative to the activity of ATM kinase in the absence of compound of Formula (I), (IA), or (IB), and pharmaceutically acceptable salts thereof. Such a decrease in activity may be due to the direct interaction of the compound of Formula (I), (IA), or (IB), and pharmaceutically acceptable salts thereof with ATM kinase, or due to the interaction of the compound of Formula (I), (IA), or (IB), and pharmaceutically acceptable salts thereof with one or more other factors that in turn affect ATM kinase activity. For example, the compound of Formula (I), (IA), or (IB), and pharmaceutically acceptable salts thereof may decrease ATM kinase by directly binding to the ATM kinase, by causing (directly or indirectly) another factor to decrease ATM kinase activity, or by (directly or indirectly) decreasing the amount of ATM kinase present in the cell or organism.

The term "therapy" is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology. The term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

The term "prophylaxis" is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

The term "treatment" is used synonymously with "therapy". Similarly the term "treat" can be regarded as "applying therapy" where "therapy" is as defined herein.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in therapy. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in therapy. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in therapy.

In one embodiment there is provided the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. In one embodiment there is provided the use of the compound of Formula (IA), or a

pharmaceutically acceptable salt thereof, for the manufacture of a medicament. In one embodiment there is provided the use of the compound of Formula (IB), or a

pharmaceutically acceptable salt thereof, for the manufacture of a medicament.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by ATM kinase. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by ATM kinase. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by ATM kinase. In any embodiment, said disease mediated by ATM kinase is cancer. In any embodiment, said cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In any embodiment, said cancer is colorectal cancer.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

In one embodiment there is provided the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease mediated by ATM kinase. In one embodiment there is provided the use of the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease mediated by ATM kinase. In one embodiment there is provided the use of the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease mediated by ATM kinase. In any embodiment, said disease mediated by ATM kinase is cancer. In any embodiment, said cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In any embodiment, said cancer is colorectal cancer.

In one embodiment there is provided the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. In one embodiment there is provided the use of the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. In one embodiment there is provided the use of the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.

In one embodiment there is provided a method for treating a disease in which inhibition of ATM kinase is beneficial in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method for treating a disease in which inhibition of ATM kinase is beneficial in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (IA), or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method for treating a disease in which inhibition of ATM kinase is beneficial in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (IB), or a pharmaceutically acceptable salt thereof. In any embodiment, said disease mediated by ATM kinase is cancer. In any embodiment, said cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In any embodiment, said cancer is colorectal cancer.

The term "therapeutically effective amount" refers to an amount of a compound of Formula (I), (IA), or (IB), or corresponding pharmaceutically acceptable salts thereof which is effective to provide "therapy" in a subject, or to "treat" a disease or disorder in a subject. In the case of cancer, the therapeutically effective amount may cause any of the changes observable or measurable in a subject as described in the definition of "therapy", "treatment" and "prophylaxis" above. For example, the effective amount can reduce the number of cancer or tumour cells; reduce the overall tumour size; inhibit or stop tumour cell infiltration into peripheral organs including, for example, the soft tissue and bone; inhibit and stop tumour metastasis; inhibit and stop tumour growth; relieve to some extent one or more of the symptoms associated with the cancer; reduce morbidity and mortality; improve quality of life; or a combination of such effects. An effective amount may be an amount sufficient to decrease the symptoms of a disease responsive to inhibition of ATM kinase activity. For cancer therapy, efficacy in-vivo can, for example, be measured by assessing the duration of survival, time to disease progression (TTP), the response rates (RR), duration of response, and/or quality of life. As recognized by those skilled in the art, effective amounts may vary depending on route of administration, excipient usage, and co- usage with other agents. For example, where a combination therapy is used, the amount of the compound of Formula (I), (IA), or (IB), or corresponding pharmaceutically acceptable salts thereof and the amount of the other pharmaceutically active agent(s) are, when combined, jointly effective to treat a targeted disorder in the animal patient. In this context, the combined amounts are in a "therapeutically effective amount" if they are, when combined, sufficient to decrease the symptoms of a disease responsive to inhibition of ATM activity as described above. Typically, such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound of Formula (I), (IA), or (IB), or corresponding

pharmaceutically acceptable salts thereof and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).

"Warm-blooded animals" include, for example, humans.

In one embodiment there is provided a method for treating cancer in a

warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (IA), or a pharmaceutically acceptable salt thereof. In one embodiment there is provided a method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (IB), or a pharmaceutically acceptable salt thereof. In any embodiment, said cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In any embodiment, said cancer is colorectal cancer.

The anti-cancer treatment described in this specification may be useful as a sole therapy, or may involve, in addition to administration of the compound of Formula (I), (IA), or (IB), or corresponding pharmaceutically acceptable salts thereof conventional surgery, radiotherapy or chemotherapy; or a combination of such additional therapies. Such conventional surgery, radiotherapy or chemotherapy may be used simultaneously, sequentially or separately to treatment with the compound of Formula (I), (IA), or (IB), or corresponding pharmaceutically acceptable salts thereof.

Radiotherapy may include one or more of the following categories of therapy: i. External radiation therapy using electromagnetic radiation (for example focal external beam radiotherapy ["EBRT"]), and intraoperative radiation therapy using electromagnetic radiation;

ii. Internal radiation therapy or brachytherapy; including interstitial radiation therapy or intraluminal radiation therapy; or

iii. Systemic radiation therapy, including but not limited to iodine 131 and strontium 89.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof is used simultaneously, separately or sequentially with radiotherapy. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof is used simultaneously, separately or sequentially with

radiotherapy. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof is used simultaneously, separately or sequentially with radiotherapy. In any embodiment the cancer is glioblastoma. In any embodiment the radiotherapy is focal external beam radiotherapy.

In one embodiment there is provided a method of treating cancer in a warmblooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof and radiotherapy, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof and radiotherapy are jointly effective in producing an anti-cancer effect. In one embodiment there is provided a method of treating cancer in a warm-blooded animal who is in need of such treatment, which comprises administering to said warmblooded animal a compound of Formula (IA), or a pharmaceutically acceptable salt thereof and radiotherapy, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof and radiotherapy are jointly effective in producing an anti-cancer effect. In one embodiment there is provided a method of treating cancer in a warm-blooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (IB), or a pharmaceutically acceptable salt thereof and

radiotherapy, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof and radiotherapy are jointly effective in producing an anti-cancer effect. In any embodiment the cancer is glioblastoma. In any embodiment the radiotherapy is focal external beam radiotherapy.

In one embodiment there is provided a method of treating cancer in a warmblooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof and simultaneously, separately or sequentially administering radiotherapy, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof and

radiotherapy are jointly effective in producing an anti-cancer effect. In one embodiment there is provided a method of treating cancer in a warm-blooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (IA), or a pharmaceutically acceptable salt thereof and simultaneously, separately or sequentially administering radiotherapy, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof and radiotherapy are jointly effective in producing an anti-cancer effect. In one embodiment there is provided a method of treating cancer in a warm-blooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (IB), or a

pharmaceutically acceptable salt thereof and simultaneously, separately or sequentially administering radiotherapy, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof and radiotherapy are jointly effective in producing an anti-cancer effect. In any embodiment the cancer is glioblastoma.

In any embodiment the radiotherapy is selected from one or more of the categories of radiotherapy listed under points (i) - (iii) above.

Chemotherapy may include one or more of the following categories of anti-tumour substance:

i. Antineoplastic agents and combinations thereof, such as DNA alkylating agents (for example czs-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustards like ifosfamide, bendamustine, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas like carmustine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); anti- tumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, liposomal doxorubicin, pirarubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, amrubicin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, irinotecan, topotecan and camptothecin); inhibitors of DNA repair mechanisms such as CHK kinase; DNA-dependent protein kinase inhibitors; inhibitors of poly (ADP-ribose) polymerase (PARP inhibitors, including olaparib); and Hsp90 inhibitors such as tanespimycin and retaspimycin, inhibitors of ATR kinase (such as AZD6738); and inhibitors of WEE 1 kinase (such as AZD1775/MK- 1775);

ii. Ant iangio genie agents such as those that inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), sorafenib, vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and cediranib (AZD2171); compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354; and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ανβ3 function and angiostatin), or inhibitors of angiopoietins and their receptors (Tie-1 and Tie-2), inhibitors of PLGF, inhibitors of delta-like ligand (DLL-4);

iii. Immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor; approaches to decrease T-cell anergy or regulatory T-cell function; approaches that enhance T-cell responses to tumours, such as blocking antibodies to CTLA4 (for example ipilimumab and tremelimumab), B7H1, PD-1 (for example BMS-936558 or AMP-514), PD-L1 (for example MEDI-4736) and agonist antibodies to CD 137; approaches using transfected immune cells such as cytokine-transfected dendritic cells; approaches using cytokine -transfected tumour cell lines, approaches using antibodies to tumour associated antigens, and antibodies that deplete target cell types (e.g., unconjugated anti-CD20 antibodies such as Rituximab, radiolabeled anti-CD20 antibodies Bexxar and Zevalin, and anti-CD54 antibody Campath); approaches using anti-idiotypic antibodies;

approaches that enhance Natural Killer cell function; and approaches that utilize antibody-toxin conjugates (e.g. anti-CD33 antibody Mylotarg); immunotoxins such as moxetumumab pasudotox; agonists of toll-like receptor 7 or toll-like receptor 9; iv. Efficacy enhancers, such as leucovorin.

Therefore, in one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof is used simultaneously, separately or sequentially with at least one additional anti-tumour substance. Therefore, in one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof is used simultaneously, separately or sequentially with at least one additional anti-tumour substance. Therefore, in one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof is used simultaneously, separately or sequentially with at least one additional anti-tumour substance. In any embodiment there is one additional anti-tumour substance. In any embodiment there are two additional anti-tumour substances. In any embodiment there are three or more additional anti-tumour substances.

In one embodiment there is provided a method of treating cancer in a warmblooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof and at least one additional anti-tumour substance, where the amounts of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect. In one embodiment there is provided a method of treating cancer in a warm-blooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (IA), or a pharmaceutically acceptable salt thereof and at least one additional anti-tumour substance, where the amounts of the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect. In one embodiment there is provided a method of treating cancer in a warm-blooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (IB), or a pharmaceutically acceptable salt thereof and at least one additional anti-tumour substance, where the amounts of the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect.

In one embodiment there is provided a method of treating cancer in a warmblooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional anti-tumour substance to said warm-blooded animal, where the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect. In one embodiment there is provided a method of treating cancer in a warm-blooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional anti-tumour substance to said warmblooded animal, where the amounts of the compound of Formula (IA), or pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect. In one embodiment there is provided a method of treating cancer in a warm-blooded animal who is in need of such treatment, which comprises administering to said warm-blooded animal a compound of Formula (IB), or a

pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional anti-tumour substance to said warm-blooded animal, where the amounts of the compound of Formula (IB), or pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anticancer effect.

In any embodiment, said cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In any embodiment, said cancer is colorectal cancer.

In any embodiment the additional anti-tumour substance is selected from one or more of the anti-tumour substances listed under points (i) - (iv) above.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof is used

simultaneously, separately or sequentially with at least one anti-neoplastic agent. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof is used simultaneously, separately or sequentially with at least one anti-neoplastic agent. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof is used simultaneously, separately or sequentially with at least one anti-neoplastic agent. In any embodiment the anti-neoplastic agent is selected from the list of antineoplastic agents in point (i) above. In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from cz^'s-platin, oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, AZD1775 and AZD6738. In one embodiment there is provided a compound of Formula

(IA) , or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from cz^'s-platin, oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, AZD1775 and AZD6738. In one embodiment there is provided a compound of Formula

(IB) , or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from cz^'s-platin, oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, AZD1775 and AZD6738. In any embodiment, said cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In any embodiment, said cancer is colorectal cancer.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin. In any embodiment, said cancer is selected from colorectal cancer,

glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In any embodiment, said cancer is colorectal cancer.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with irinotecan. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with irinotecan. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with irinotecan. In any embodiment the cancer is colorectal cancer. In any embodiment the cancer is gastric cancer.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with FOLFIRI. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with FOLFIRI. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with FOLFIRI. In any embodiment the cancer is colorectal cancer. In any embodiment the cancer is gastric cancer.

"FOLFIRI" is a dosage regime involving a combination of leucovorin, 5- fluorouracil and irinotecan.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with a taxoid. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with a taxoid. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with a taxoid. In any embodiment the taxoid is paclitaxel or docetaxel. In any embodiment the taxoid is docetaxel. In any embodiment the cancer is gastric cancer.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with topotecan. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with a taxoid. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with topotecan. In any embodiment the cancer is lung cancer. In any embodiment the cancer is small cell lung cancer.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with etoposide. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with etoposide. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with etoposide. In any embodiment the cancer is lung cancer. In any embodiment the cancer is small cell lung cancer.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with etoposide and a platin. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with etoposide and a platin. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with etoposide and a platin. In any embodiment the cancer is small cell lung cancer. In any embodiment the platin is czs-platin, oxaliplatin or carboplatin. In any embodiment the platin is czs-platin. In any embodiment the cancer is lung cancer. In any embodiment the cancer is small cell lung cancer.

In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with olaparib. In one embodiment there is provided a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IA), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with olaparib. In one embodiment there is provided a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, where the compound of Formula (IB), or a pharmaceutically acceptable salt thereof, is used simultaneously, separately or sequentially with olaparib. In any embodiment the cancer is gastric cancer.

In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I) and at least one additional anti-tumour substance. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I A) and at least one additional anti-tumour substance. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IB) and at least one additional anti-tumour substance. In any embodiment the pharmaceutical composition also comprises at least one pharmaceutically acceptable diluent or carrier. In any embodiment the anti-tumour substance is an anti-neoplastic agent.

In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I) and at least one additional anti-tumour substance, for use in the treatment of cancer. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IA) and at least one additional anti-tumour substance, for use in the treatment of cancer. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IB) and at least one additional anti- tumour substance, for use in the treatment of cancer. In any embodiment the

pharmaceutical composition also comprises at least one pharmaceutically acceptable diluent or carrier. In any embodiment the anti-tumour substance is an anti-neoplastic agent.

In one embodiment there is provided a kit comprising:

a) A compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a first unit dosage form;

b) A further additional anti-tumour substance in a further unit dosage form;

c) Container means for containing said first and further unit dosage forms; and optionally

d) Instructions for use. In one embodiment there is provided a kit comprising: a) A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, in a first unit dosage form;

b) A further additional anti-tumour substance in a further unit dosage form;

d) Instructions for use. In one embodiment there is provided a kit comprising: a) A compound of Formula (IB), or a pharmaceutically acceptable salt thereof, in a first unit dosage form;

b) A further additional anti-tumour substance in a further unit dosage form;

d) Instructions for use. In any embodiment the anti-tumour substance comprises an anti-neoplastic agent.

In any embodiment where an anti-neoplastic agent is mentioned, the anti-neoplastic agent is one or more of the agents listed under point (i) above.

The compounds of Formula (I), (IA) or (IB) or corresponding corresponding pharmaceutically acceptable salts thereof, may be used as pharmaceutical compositions, comprising one or more pharmaceutically acceptable diluents or carriers.

Therefore, in one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier. Therefore, in one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier. Therefore, in one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier.

The compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or

intramuscular dosing), or as a suppository for rectal dosing. The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in therapy. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in therapy. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in therapy.

In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, and at least one

pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, and at least one

pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer. In any embodiment, the cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In any embodiment, the cancer is colorectal cancer.

In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer, where the pharmaceutical composition is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from cis-platin, oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, AZD1775 and AZD6738. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer, where the pharmaceutical composition is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from cis-platin, oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, AZD1775 and AZD6738. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer, where the pharmaceutical composition is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from cis-platin, oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil,

cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, AZD1775 and AZD6738. In any embodiment, the cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In any embodiment, the cancer is colorectal cancer.

In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer, where the pharmaceutical composition is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin. In one embodiment there is provided a

pharmaceutical composition comprising a compound of Formula (IA), or a

pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer, where the pharmaceutical composition is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IB), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer, where the pharmaceutical composition is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin. In any embodiment, the cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In any embodiment, the cancer is colorectal cancer.

In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer, where the pharmaceutical composition is used simultaneously, separately or sequentially with irinotecan. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer, where the pharmaceutical composition is used simultaneously, separately or sequentially with irinotecan. In one embodiment there is provided a pharmaceutical composition comprising a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer, where the pharmaceutical composition is used simultaneously, separately or sequentially with irinotecan. In one embodiment, the cancer is selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer. In one embodiment, the cancer is colorectal cancer.

In any embodiment where cancer is mentioned in a general sense, the cancer may be selected from colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma and lung cancer.

In any embodiment where cancer is mentioned in a general sense the following embodiments may apply:

In one embodiment the cancer is colorectal cancer.

In one embodiment the cancer is glioblastoma.

In one embodiment the cancer is gastric cancer.

In one embodiment the cancer is ovarian cancer.

In one embodiment the cancer is diffuse large B-cell lymphoma.

In one embodiment the cancer is chronic lymphocytic leukaemia.

In one embodiment the cancer is head and neck squamous cell carcinoma.

In one embodiment the cancer is lung cancer. In one embodiment the cancer is small cell lung cancer. In one embodiment the cancer is non-small cell lung cancer.

In one embodiment the cancer is metastatic cancer.

In one embodiment the cancer is non-metastatic cancer.

The compound of Formula (I), (IA), (IB) or corresponding pharmaceutically acceptable salts thereof will normally be administered to a warm-blooded animal at a unit dose within the range 0.005-5000mg/m² body area of the animal, or alternatively approximately 0.001-lOOmg/kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 0.1-250mg of active ingredient. The daily dose will necessarily be varied depending upon the host treated, the particular route of administration, any therapies being co -administered, and the severity of the illness being treated. Accordingly the practitioner who is treating any particular patient may determine the optimum dosage.

EXAMPLES

The various embodiments are illustrated by the following Examples. The invention is not to be interpreted as being limited to the Examples. During the preparation of the Examples, generally:

i. Operations were carried out at ambient temperature, i.e. in the range of about 17 to 30°C and under an atmosphere of an inert gas such as nitrogen unless otherwise stated;

ii. Evaporations were carried out by rotary evaporation or utilising Genevac

equipment in vacuo and work-up procedures were carried out after removal of residual solids by filtration;

iii. Flash chromatography purifications were performed on an automated Armen Glider Flash : Spot II Ultimate (Armen Instrument, Saint -Ave, France) or automated Presearch combifiash companions using prepacked Merck normal phase Si60 silica cartridges (granulometry : 15-40 or 40-63 μιη) obtained from Merck, Darmstadt, Germany, silicycle silica cartridges or graceresolv silica cartridges;

iv. Preparative chromatography was performed on a Waters instrument (600/2700 or 2525) fitted with a ZMD or ZQ ESCi mass spectrometers and a Waters X-Terra or a Waters X-Bridge or a Waters SunFire reverse-phase column (C-18, 5 microns silica, 19mm or 50mm diameter, 100mm length, flow rate of 40mL / minute) using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN or decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents;

v. Yields, where present, are not necessarily the maximum attainable;

vi. Structures of end-products of Formula (I) were confirmed by nuclear magnetic resonance (NMR) spectroscopy, with NMR chemical shift values measured on the delta scale. Proton magnetic resonance spectra were determined using a Bruker advance 700 (700MHz), Bruker Avance 500 (500 MHz), Bruker 400 (400 MHz) or Bruker 300 (300 MHz) instrument; 19F NMR were determined at 282 MHz or 376 MHz; 13C NMR were determined at 75 MHz or 100 MHz; measurements were taken at around 20 - 30°C unless otherwise specified; the following abbreviations have been used: s = singlet; d = doublet; t = triplet; q = quartet; p = pentet/quintet; m = multiplet; dd = doublet of doublets; ddd = doublet of doublet of doublet; dt = doublet of triplets; td = triplet of doublets; qd = quartet of doublets; bs = broad signal;

vii. End-products of Formula (I) were also characterised by mass spectroscopy

following liquid chromatography (LCMS); LCMS was carried out using an Waters Alliance HT (2790 & 2795) fitted with a Waters ZQ ESCi or ZMD ESCi mass spectrometer and an X Bridge 5μΜ C-18 column (2.1 x 50mm) at a flow rate of 2.4mL/min, using a solvent system of 95% A + 5% C to 95% B + 5% C over 4 minutes, where A = water, B = MeOH, C = 1 : 1 MeOF water (containing 0.2% ammonium carbonate); or by using a Shimadzu UFLC or UHPLC coupled with DAD detector, ELSD detector and 2020 EV mass spectrometer (or equivalent) fitted with a Phenomenex Gemini-NX CI 8 3.0x50mm, 3.0μΜ column or equivalent (basic conditions) or a Shim pack XR - ODS 3.0 x 50mm, 2.2μΜ column or Waters BEH CI 8 2.1 x 50mm, 1.7μΜ column or equivalent using a solvent system of 95% D + 5% E to 95% E + 5% D over 4 minutes, where D = water (containing 0.05% TFA), E = MeCN (containing 0.05% TFA) (acidic conditions) or a solvent system of 90% F + 10% G to 95% G + 5% F over 4 minutes, where F = water (containing 6.5mm ammonium hydrogen carbonate and adjusted to pHIO by addition of ammonia), G = MeCN (basic conditions);

viii. Intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, mass spectral, HPLC and/or NMR analysis;

ix. X-ray powder diffraction spectra were determined (using a Panlytical Cubix

instrument) by mounting a sample of the crystalline material on a Panalytical single silicon crystal (SSC) wafer mount and spreading out the sample into a thin layer with the aid of a microscope slide. The sample was spun at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a copper long-fine focus tube operated at 45kV and 40mA with a wavelength of 1.5418 angstroms. The X-ray beam was passed through a 0.04rad so Her slit, then an automatic variable divergence slit set at 20mm and finally a 20mm beam mask. The reflected radiation was directed through a 20mm antiscatter slit and a 0.04rad so Her slit. The sample was exposed for 1.905 seconds per 0.0025067° 2-theta increment (continuous scan mode) over the range 2 degrees to 40 degrees 2-theta in theta-theta mode. The instrument was equipped with an X-Celerator detector. Control and data capture was by means of a Dell Pentium 4HT Workstation operating with X'Pert Industry software;

x. Differential Scanning Calorimetry was performed on a TA Instruments Q1000 DSC. Typically, less than 5mg of material contained in a standard aluminium pan fitted with a lid was heated over the temperature range 25°C to 300°C at a constant heating rate of 10°C per minute. A purge gas using nitrogen was used at a flow rate 50mL per minute;

xi. Thermal Gravimetric Analysis was performed on a TA Instruments Q5000 TGA.

Typically less than 5mg of material contained in a 100 platinum pan was heated to 200°C from ambient temperature at a constant heating rate of 10°C per minute. A purge gas using nitrogen was used - flow rate 25ml per minute;

xii. The following abbreviations have been used: h = hour(s); r.t. = room temperature (~17-30°C); C0₂ = carbon dioxide; CuS0₄ = copper(II) sulphate; FCC = flash column chromatography using silica; CS2CO3 = cesium carbonate; DCM = dichloromethane; DBU = l,8-Diazabicyclo[5.4.0]undec-7-ene; DEA =

diethylamine; DIPEA = diisopropylethylamine; DMA = N,N-dimethylacetamide; DMAP = 4-dimethylaminopyridine; DMF = NN-dimethylformamide; DMSO = dimethylsulphoxide; Et₂0 = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; HATU = l-[¾z5(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate; HC1 = hydrogen chloride; IPA = isopropyl alcohol; K2CO3 = potassium carbonate; MeOH = methanol; MeCN = acetonitrile; MTBE = methyltertbutyl ether; MgS0₄ = anhydrous magnesium sulphate; NaOH = sodium hydroxide; Na₂S0₄ = anhydrous sodium sulphate; NBS = N-bromosuccinimide; NH3 = ammonia; NH₄OH = aqueous ammonia solution; Pd(PPh₃)₄ =

tetrakis(triphenylphosphine)palladium(0); PdCl₂(dppf) = Ι,Γ- 5z^'5(diphenylphosphino)ferrocene-palladium(II) dichloride; SCX

Strong Cation Exchange; sat. = saturated aqueous solution; THF = tetrahydrofuran; tR = retention time; and

xiii. IUPAC names were generated using 'Canvas', a proprietary naming program. Example 1

7-Fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(lS)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

To a vial charged with sodium tetrachloropalladate(II) (0.900g, 3.06mmol) and 3-(di-tert- butylphosphino)propane-l -sulfonic acid (1.642g, 6.12mmol) under nitrogen was added water (40mL) at r.t. The resulting solution was stirred at r.t. for 10 minutes and was added in one portion to 6-bromo-7-fluoro-4-{[(15)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino }quinoline-3-carboxamide (60g, 153mmol), 2-(methoxymethyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (79g, 184mmol) and CS2CO3 (100g, 306mmol) in dioxane (1200mL) and water (250mL) at 25°C under nitrogen. The resulting mixture was stirred at 100°C for 16 h. The solvent was evaporated and EtOAc (2000mL) was added. The organic phase was washed with water (500mL) and dried over Na₂S04, filtered and evaporated. The crude product was purified by FCC, elution gradient 0 to 7% MeOH in DCM. Pure fractions were evaporated to dryness to afford 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide (50. Og, 75%) as a yellow foam, which was combined with additional batches. The resulting compound was purified by crystallisation from MeCN (1 L) to afford 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(15)-l-(l- methyl-lH-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (49. Og, 66%) as a white solid ("Form A"). 'HNMR Spectrum (300 MHz, DMSO-d6): 1.54 (3H, d), 3.42 (3H, s), 3.76 (3H, s), 4.58 (2H, s), 5.20-5.35 (1H, m), 6.18 (1H, d), 7.40-7.70 (4H, m), 7.66 (1H, d), 8.02 (1H, br s), 8.49 (1H, d), 8.69 (1H, s), 8.81 (1H, s), 9.78 (1H, d). Mass Spectrum: m/z [M+H]⁺= 435. Analytical chiral HPLC: Column, Chiralcel OD-H 5μΜ, 0.46x15 cm; mobile phase, 40% MeOH (0.1% DEA) in Super Critical C0₂; flow rate 4mL/min; t_R 1.44 min (i?-isomer, tR 1.13 min). [α]ϋ'. -72° in MeCN (c~2mg/mL). The configuration of Example 1 was determined using vibrational circular dichroism ("VCD", see He, Yanan et al. "Determination of absolute configuration of chiral molecules using vibrational optical activity: A review", Appl. Spectrosc. 2011, 65, 699-723). A solution of 15.4mg of Example 1 in 150

of DMSO-d6 was transferred to a 0.100mm BaF₂ cell and the VCD spectrum was acquired for 7 h in a BioTools ChirallR instrument (Bio Tools Inc. Jupiter, Florida, USA) equipped with dual source and dual photoelastic modulator. The resolution was 4 cm^"1. A Monte Carlo molecular mechanics search for low energy geometries was conducted for the truncated structures of the two enantiomers of Example 1 shown below.

Truncated Structures of Example 1 used for Molecular Mechanics Search

MacroModel within the Maestro graphical interface (Schrodinger Inc.) was used to generate starting coordinates for conformers. All conformers within 5 kcal/mole of the lowest energy conformer were used as starting points for density functional theory (DFT) minimizations within Gaussian09. Optimized structures, harmonic vibrational

frequencies/intensities, VCD rotational strengths, and free energies at STP (including zero- point energies) were determined for each conformer. In these calculations, the functional B3LYP and the basis set 6-31G* were used. Simulations of infrared and VCD spectra for each conformation were generated using an in-house built program to fit Lorentzian line shapes (12 cm^"1 line width) to the computed spectra thereby allowing direct comparisons between simulated and experimental spectra. On the basis of the comparison results between the experimental and predicted spectra (shown in Figure 6), Example 1 was assigned the (S) configuration.

Experiments were carried out to develop solid forms of Example 1. Solid material obtained as described above ("Form A") was placed in a vial with a magnetic stirrer bar, and approximately 2mL of acetonitrile was added. The vial was then sealed tightly with a cap and left to stir on a magnetic stirrer plate at 50°C. After approximately 13 days, the sample was removed from the plate, the cap taken off and the slurry left to dry under ambient conditions before the resultant solid was analysed by XRPD and DSC. This form ("Form I") was determined to be crystalline by XRPD, with a melting point of 149.1°C (onset). Characteristic XRPD peaks for Example 1 Form I are shown in Table 1.

Table 1: Characteristic X-Ray powder diffraction peaks for Form I of 7-Fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4-{[(lS)-l-(l -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide

In a further experiment approximately 40mg of Form A material obtained as described above was placed in a vial with a magnetic stirrer bar, and approximately 2mL of water added. The vial was then sealed tightly with a cap and left to stir on a magnetic stirrer plate. After approximately 3 days, the sample was removed from the plate, the cap taken off and the slurry left to dry under ambient conditions. The resultant solid was then analysed by XRPD, DSC and TGA. The solid ("Form J") was determined to be crystalline by XRPD, with a melting point of 149.1°C (onset). The Form J material showed a loss of weight by TGA of 7.8%, indicating that it was a dihydrate. Characteristic XRPD peaks for Example 1 Form J are shown in Table 2. Table 2: Characteristic X-Ray powder diffraction peaks for Form J of 7-Fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4-{[(lS)-l-(l -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide

Intermediate 1.1: 6-Bromo-7-fluoro-4-{[(lS)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

DIPEA (92mL, 527.16mmol) was added dropwise to 6-bromo-4-chloro-7-fluoroquinoline- 3 -carboxamide (40g, 131.8mmol) and (15)-l-(l-methylpyrazol-3-yl)ethylamine hydrochloride (lOg, 50.48mmol) in DMA (lOOmL) at 20°C over a period of 10 minutes. The resulting mixture was stirred at 100°C for 4 h and cooled down. The resulting solution was poured into water (500mL). The precipitate was filtered to give a white solid, which was washed with water (3 x 500mL) then crystallized in MeOH (200mL). The solid was collected and dried under vacuum to give 6-bromo-7-fluoro-4-{[(15)-l-(l-methyl-lH- pyrazo 1-3 -yl)ethyl] amino} quino line-3 -carboxamide (38. Og, 73.5%) as white solid H NMR Spectrum (300 MHz, DMSO-d6): 1.54 (3H, d), 3.79 (3H, s), 5.05-5.25 (1H, m), 6.17 (1H, d), 7.55 (1H, br s), 7.60 (1H, d), 7.68 (1H, d), 8.15 (1H, br s), 8.70 (1H, d, 8.75 (1H, s), 9.34 (1H, d). Mass Spectrum: m/z [M+H]⁺= 392.

Intermediate 1.2: 6-bromo-4-chloro-7-fluoro uinoline-3-carboxamide

DMF (0.5mL) was added to a stirred suspension of 6-bromo-7-fluoro-4-oxo-lH-quinoline- 3-carboxylic acid (22.5g, 78.7mmol) in thionyl chloride (140g, 1180mmol) and the mixture heated to reflux for 2 h. The reaction was allowed to cool, concentrated in vacuo and the residue azeotroped twice with toluene to afford a yellow solid. This solid was added portionwise to an aqueous solution of ammonium hydroxide (147mL, 1180mmol) at 0°C. The white suspension was stirred for 15 minutes, then the solid was filtered, washed with water and dried under vacuum to afford 6-bromo-4-chloro-7-fluoroquinoline-3- carboxamide (23.80g, 100%) as a white powder. ^!H NMR Spectrum (400 MHz, DMSO- d6): 8.92 (1H, s), 8.59 (1H, d), 8.21 (1H, s), 8.09 (1H, d), 7.98 (1H, s). Mass Spectrum: m/z [M+H]⁺= 305.

Intermediate 1.3: 6-bromo-7-fluoro-4-oxo-lH- uinoline-3-carboxylic acid

A solution of sodium hydroxide (18.3g, 458mmol) in water (lOOmL) was added to a stirred suspension of ethyl 6-bromo-7-fluoro-4-oxo-lH-quinoline-3-carboxylate (28.8g,

91.7mmol) in EtOH (500mL) at ambient temperature. The reaction mixture was then stirred at 75°C for 2 h, allowed to cool and the pH adjusted to 4 using 2N hydrochloric acid. The precipitate was collected by filtration, washed with water and dried under vacuum to afford 6-bromo-7-fluoro-4-oxo-lH-quinoline-3-carboxylic acid (23.30g, 89%>) as a white powder. 'HNMR Spectrum (400 MHz, DMSO-d6): 14.78 (1H, s), 13.45 (1H, s), 8.93 (1H, s), 8.46 (1H, d), 7.70 (1H, d). Mass Spectrum: m/z [M+H]⁺= 288 Intermediate 1.4: ethyl 6-bromo-7-fluoro-4-oxo-lH-quinoline-3-carboxylate

A solution of diethyl 2-[[(4-bromo-3-fluorophenyl)amino]methylidene]propanedioate (90g, 249.88mmol) in diphenyl ether (600mL, 3.79mol) was stirred at 240°C for 2.5 h. The mixture was allowed to cool to 70°C. The solids were collected by filtration and dried in a oven under vacuum to afford ethyl 6-bromo-7-fluoro-4-oxo-lH-quinoline-3-carboxylate (50g, 64%) as a white solid which was used without further purification. Ή NMR

Spectrum (500 MHz, DMSO-d6, 100°C): 1.26 - 1.33 (3H, m), 4.25 (2H, q), 7.52 (1H, d), 8.37 (1H, d), 8.48 (1H, s), 12.05 (1H, s). Mass Spectrum: m/z [M+H]⁺= 314.

Intermediate 1.5: diethyl 2-[[(4-bromo-3- fluorophenyl)amino] methylidene propanedioate

A solution of 4-bromo-3-fluoroaniline (56.6g, 299mmol) and 1,3-diethyl 2- (ethoxymethylidene)propanedioate (72.5g, 335mmol) in EtOH (560mL) was stirred at 80°C for 4 h. The reaction mixture was allowed to cool, the solids collected by filtration and dried in an oven to afford diethyl 2-[[(4-bromo-3- fluorophenyl)amino]methylidene]propanedioate (90g, 84%) as an off-white solid which was used without further purification. 'HNMR Spectrum (400 MHz, DMSO-d6): 1.26 (6H, q), 4.14 (2H, q), 4.22 (2H, q), 7.18 - 7.25 (1H, m), 7.57 (1H, dd), 7.64 - 7.7 (1H, m), 8.33 (1H, d), 10.62 (1H, d). Mass Spectrum: m/z [M+H]⁺= 360. Intermediate 1.6: 2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine

A stirred mixture of 5-bromo-2-(methoxymethyl)pyridine (60g, 297mmol),

4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (94g, 371mmol), potassium acetate (87g, 891mmol) and PdCl2(dppf) (0.217g, 0.30mmol) in dioxane (1 L) under nitrogen was stirred at 100°C for 16 h. The mixture was concentrated and filtered through a Celite pad, eluted with hexane (1 L) and evaporated to give 2-(methoxymethyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (180g, 162%) as a brown oil, which was used without further purification. Mass Spectrum: m/z [M+H]⁺= 250.

Intermediate 1.7: 5-bromo-2-(methox methyl)pyridine

Sodium hydride (4.98g, 207mmol) was added portionwise to (5-bromopyridin-2- yl)methanol (30g, 160mmol) in THF (450mL) at 0°C over a period of 10 minutes under nitrogen. The resulting solution was stirred at 25°C for 0.5 h. Methyl iodide (12.97mL, 207mmol) was added dropwise to the solution at 0°C. The resulting mixture was stirred at 25°C for 16 h. The reaction mixture was diluted with MeOH (20mL). The crude product was purified by FCC, eluting with a gradient of 10% to 60%> EtOAc in heptane. Pure fractions were evaporated to dryness to afford 5-bromo-2-(methoxymethyl)pyridine (30. Og, 93%) as a yellow liquid. 'HNMR Spectrum (300 MHz, CDC1₃): 3.48 (3H, s), 4.54 (2H, s), 7.34 (1H, dd), 7.83 (1H, dd), 8.61 (1H, d). Intermediate 1.8: (lS)-l-(l-methylpyrazol-3- l ethylamine hydrochloride

To a clear solution of (i?)-2-methyl-N-[(15)-l-(l-methylpyrazol-3-yl)ethyl]propane-2- sulfinamide (9.73g, 42.43mmol) in dry dioxane (lOOmL) at r.t. was added hydrogen chloride (4M in dioxane, 53mL, 212mmol) dropwise, giving a free flowing fine white precipitate. This solution was stirred overnight at r.t. After evaporation of the solvent, the resulting white solid was stirred in Et₂0 (60mL) for 3 h. This solution was filtered and the solid was washed with further Et₂0 before drying overnight in vacuo to give (15)-1-(1- methyl-lH-pyrazol-3-yl)ethylamine hydrochloride (7.65g, 91%) as a white solid.

'HNMR Spectrum (400 MHz, DMSO-d6): 1.49 (3H, d), 3.82 (3H, s), 4.2 - 4.42 (1H, m), 6.38 (1H, d), 7.67-7.71 (1H, m), 8.51 (3H, s).

(1 S)- 1-(1 -methyl- lH-pyrazo 1-3 -yl)ethylamine hydrochloride was derivatised for enantiopurity analysis as follows. Benzoyl chloride (0.087mL, 0.75mmol) was added to clear a solution of (1 S)- 1-(1 -methyl- lH-pyrazo 1-3 -yl)ethylamine hydrochloride (0.1 lOg, 0.68mmol) and DIPEA (0.256mL, 1.50mmol) in DCM (5mL) at r.t. under nitrogen. The reaction mixture was stirred at r.t. overnight. The reaction mixture was diluted with DCM (20mL), washed with water (lOmL) and brine (lOmL) and dried over MgS0₄. After evaporation of the solvent, the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μΜ silica, 50mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as an eluent.

Fractions containing the desired compound were evaporated to dryness to afford N-[(lS)-l- (l-methylpyrazol-3-yl)ethyl]benzamide (0.080g, 63.1%) as a beige solid. 'HNMR

Spectrum (500 MHz, DMSO-d6): 1.52 (3H, d), 3.84 (3H, s), 5.2 - 5.34 (1H, m), 6.21 (1H, d), 7.48 - 7.54 (2H, m), 7.54 - 7.6 (1H, m), 7.62 (1H, d), 7.89 - 7.97 (2H, m), 8.64 (1H, d). Mass Spectrum: m/z [M+H]⁺= 230; Analytical chiral HPLC: Column, Chiralpak AS 3μΜ 4.6x50mm; mobile phase, Heptane/IPA/TEA 50/50/0.1; flow rate, 2mL/min: tR 0.71 min (R-isomer, tR 0.48 min). Intermediate 1.9: (R)-2-methyl- V-[(lS)-l-(l-methylpyrazol-3-yl)ethyl]propane-2- sulfinamide

To a suspension of (i?)-2-methyl-N-(l-(l-methyl-lH-pyrazol-3-yl)ethylidene)propane-2- sulfinamide (11.07g, 48.68mmol) in 2-methyltetrahydrofuran (110 mL) at -78°C under nitrogen was added, dropwise lithium tri-sec-butylboro hydride (1M in THF, 122mL, 122mmol). The reaction mixture was stirred at -78°C for 160 minutes. Further lithium tri- sec-butylhydroborate (1M in THF, 24.4mL, 24.4mmol). The mixture was stirred for 90 minutes at -78°C, then overnight, warming to r.t. The reaction mixture was quenched by addition of MeOH (90mL) followed by the addition of sat. aqueous NH₄C1 (90mL). After concentration of the reaction mixture, water (90mL) was added. The mixture was extracted with EtOAc (3 x 360mL), the organic layers were combined, washed with brine (lOOmL), dried with MgS0₄ and evaporated. The crude product was purified by FCC, eluting with a gradient of 0% to 7% MeOH in DCM to afford (R)-2-methyl-N-[(lS)-l-(l-methylpyrazol- 3-yl)ethyl]propane-2-sulfinamide (9.73g, 87%) as a white waxy solid. Ή NMR Spectrum (400 MHz, CDCb): 1.20 (9H, s), 1.61 (3H, d), 3.39 (1H, d), 3.86 (3H, s), 4.62 (1H, p), 6.15 (1H, d), 7.26 (1H, d). Mass Spectrum: m/z [M+H]⁺= 230

Intermediate 1.10: (R)-2-methyl- V-(l-(l-methyl-lH-pyrazol-3-yl)ethylidene)propane- 2-sulfinamide

To a solution of l-(l-methyl-lH-pyrazol-3-yl)ethanone (1.38g, 11.12mmol) in 2- methyltetrahydrofuran (20mL) was added (i?)-2-methylpropane-2-sulfinamide (3.37g, 27.79mmol) and tetraisopropoxytitanium (8.23mL, 27.79mmol). The mixture was stirred at reflux for 18 h and cooled at r.t. The product was poured into water (300mL) and the resulting solid was filtered off and was washed with EtOAc. The water filtrate was extracted with EtOAc (2x 250mL). The organic layers were combined, washed with brine (200mL), dried with MgS0₄ and evaporated to dryness to afford a yellow oil which solidified upon standing. Further purification by FCC eluting with 25% EtOAc in heptane afforded ( ?)-2-methyl-N-( 1 -( 1 -methyl- 1 H-pyrazo 1-3 -yl)ethylidene)propane-2-sulfinamide (2.04g, 81%) as a white crystalline solid. 'HNMR Spectrum (400 MHz, CDC1₃): 1.29 (9H, s), 2.75 (3H, s), 3.95 (3H, s), 6.77 (1H, d), 7.34 (1H, d).

Intermediate 1.11: l-(l-methyl-lH-pyrazol-3- l)ethanone

To a stirred solution of N-methoxy-N, 1 -dimethyl- 1 H-pyrazo le-3-carboxamide (3.62g, 20.33mmol) in dry THF (20mL) was added methyl magnesium bromide (43.6mL, 60.98mmol, 1.4 M in 25% THF in toluene) dropwise at -40°C. The resulting mixture was warmed to 0°C slowly for about 2 h. Saturated aqueous ammonium chloride (50mL) was added dropwise to the reaction mixture at 0°C. Water (50mL) was added and the mixture was extracted with EtOAc (200mL). The organic phase was washed with water (50mL) and brine (lOOmL), dried over Na₂S0₄ and filtered. After concentration, the crude oil was purified by FCC, eluting with 10%> MeOH in DCM. Collected fractions were evaporated to dryness to afford 1-(1 -methyl- 1 H-pyrazo 1-3 -yl)ethanone (1.38g, 54.7%) as a clear oil which crystallized upon standing. ^!H NMR Spectrum (400 MHz, CDCI3): 2.57 (3H, s), 3.97

(3H, s), 6.78 (1H, d), 7.37 (1H, d). Intermediate 1.12: V-methoxy- V,l-dimethyl-lH-pyrazole-3-carboxamide

1,1 '-Carbonyldiimidazole (0.707g, 4.36mmol) was added in portions to a solution of 1- methyl-lH-pyrazole-3-carboxylic acid (0.5g, 3.96mmol) and triethylamine (0.553mL, 3.96mmol) in DCM (lOmL). After formation of the activated ester was complete, N,0- dimethylhydroxylamine hydrochloride (0.425g, 4.36mmol) was added in portions. The mixture was stirred at r.t. until completion of the reaction. After evaporation of the solvent to dryness, water (50mL) was added, followed by the addition of EtOAc (150mL). The organic layer was extracted, washed with brine and dried over MgS0₄. After evaporation of the solvent, the residue was purified by FCC, eluting with 10% MeOH in DCM to afford N-methoxy-N, 1 -dimethyl- lH-pyrazole-3-carboxamide (0.520g, 78%>) as a colourless gum. 'HNMR Spectrum (400 MHz, CDC1₃): 3.43 (3H, s), 3.75 (3H, s), 3.96 (3H, s), 6.76 (1H, d), 7.36 (1H, d).

(15)-l-(l-methylpyrazol-3-yl)ethylamine hydrochloride (Intermediate 1.8) was also prepared by the following method.

A solution of (5)-2-methyl-N-[(15)-l-(l-methylpyrazol-3-yl)ethyl]propane-2-sulfinamide (115g, 501mmol) in MeOH (350mL) was added dropwise to a stirred solution of hydrogen chloride in MeOH (2.75M, 1823mL, 5014mmol) at 0°C over a period of 2 h. The resulting solution was stirred at 25°C for 2 h. The reaction mixture was evaporated to afford the crude product, which was combined with additional batches. The crude product was washed with MTBE (2 x 400mL) to afford (15)-l-(l-methylpyrazol-3-yl)ethylamine (120g, 82%>) as a white solid (analytical data consistent with material produced by previous method). Intermediate 1.13: (S)-2-methyl- V-[(lS)-l-(l-methylpyrazol-3-yl)ethyl]propane-2- sulfinamide

Methyl magnesium bromide (88g, 740.74mmol) was added to a stirred solution of (5)-2- methyl-N-[(l-methylpyrazol-3-yl)methylene]propane-2-sulfinamide (158g, 741mmol) in DCM (1.4 L) cooled to -65°C. The resulting solution was stirred at -65°C for 4 h. The reaction mixture was quenched with saturated aqueous NH₄C1 (800mL). The organic layer was dried over Na₂S04, filtered and evaporated. This reaction was combined with others. The resulting crude material was purified by FCC, eluting with 0% to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford (5)-2-methyl-N-[(15)-l-(l- methylpyrazol-3-yl)ethyl]propane-2-sulfinamide (240g, 141%) as a colourless oil contaminated with a minor amount of (5)-2-methyl-N-[(li?)-l-(l-methylpyrazol-3- yl)ethyl]propane-2-sulfinamide (ratio 87: 13). The mixture of diastereoisomers was separated by preparative chiral HPLC on a Chiralpak IC-3 column, eluting isocratically with 0.1% DEA in MeOH. The fractions containing the desired compound were evaporated to dryness to afford (S)-2-methyl-N-[(lS)-l-(l-methylpyrazol-3- yl)ethyl]propane-2-sulfinamide (170g, 70.8%>) as a colourless liquid. Ή NMR Spectrum (300MHz, CDCb): 1.25 (9H, s), 1.52 (3H, d), 3.83-3.84 (1H, m), 3.86 (3H, s), 4.61-4.64 (1H, m), 6.20 (1H, d), 7.28 (1H, d). Mass Spectrum: m/z [M+H]⁺= 230. Analytical chiral HPLC: Column, Chiralpak-IC 5μΜ, 0.46x10cm; mobile phase, 10% MeOH(0.1%DEA) in Super Critical C0₂; flow rate, 4mL/min: tR 1.75 min (other diastereoisomer tR 2.38 min).

Intermediate 1.14: (S)-2-methyl- V-[(l-methylpyrazol-3-yl)methylene]propane-2- sulfinamide

Tetraethoxytitanium (528g, 2315.78mmol) was added in one portion to 1-methyl-lH- pyrazole-3-carbaldehyde (170g, 1543.86mmol) and (5)-2-methylpropane-2-sulfinamide (225g, 1852mmol) in THF (1 L) at 25°C under air. The resulting solution was stirred at 80°C for 17 h. The reaction mixture was quenched with water (50mL). The mixture was filtered through a Celite pad, eluted with EtOAc (2 L). The filtrate was dried over Na₂S0₄, filtered and evaporated to afford (5)-2-methyl-N-[(l-methylpyrazol-3- yl)methylene]propane-2-sulfinamide (280g, 85%) as a yellow solid, which was used in the next step directly without further purification. 'HNMR Spectrum (300 MHz, CDCb): 1.25 (9H, s), 3.99 (3H, s), 6.77 (1H, d), 7.40 (1H, d), 8.63 (1H, s). Mass Spectrum: m/z

[M+H]⁺= 214.

Alternatively, 7-fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H- pyrazo 1-3 -yl)ethyl] amino }quinoline-3-carboxamide (Example 1) was made as follows.

DIPEA (89mL, 509mmol) was added to (1 S)- 1-(1 -methyl- lH-pyrazo 1-3 -yl)ethylamine hydrochloride (25.2g, 127mmol) and 4-chloro-7-fluoro-6-(6-(methoxymethyl)pyridin-3- yl)quinoline-3-carboxamide (40g, 115,69mmol) in dioxane (400mL) at 20°C under nitrogen. The resulting solution was stirred at 100°C for 17 h. The same reaction was repeated starting from (15)-l-(l-methyl-lH-pyrazol-3-yl)ethylamine hydrochloride (6.30g, 31.81mmol) and the two reaction mixtures were combined. The solvent was evaporated and EtOAc (2 L) was added, washed with water (500mL). The organic phase was dried over Na₂S0₄, filtered and evaporated. The crude product was purified by two FCCs, eluting with a gradient of 0% to 7% MeOH in DCM. Pure fractions were evaporated to dryness. Crystallisation in MeCN (500mL) to afford 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide (44. Og, 70% yield) as a white solid.

Intermediate 1.15: 4-chloro-7-fluoro-6-(6-(methoxymethyl)pyridin-3-yl)quinoline-3- carboxamide

2-(Methoxymethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (25.3g, 65.89mmol, 65% wt) was added in one portion to 6-bromo-4-chloro-7-fluoroquinoline-3- carboxamide (20g, 65.89mmol), cesium carbonate (64.4g, 197.68mmol) and Pd(PPli3)4 (7.61g, 6.59mmol) in thoroughly degassed dioxane (527mL) and water (132mL) under nitrogen. The reaction mixture was then heated to 95°C for 30 minutes. The reaction mixture was added slowly to stirred water (2 L), and the resulting precipitate was collected by filtration. The crude solid was slurried in MeCN (500mL), collected by filtration and dried under vacuum to afford 4-chloro-7-fluoro-6-(6-(methoxymethyl)pyridin-3- yl)quinoline-3-carboxamide (14.18g, 62.2%) as a beige solid. Ή NMR Spectrum (400 MHz, DMSO-d6): 3.43 (3H, s), 4.60 (2H, s), 7.60 (IH, d), 7.96 (IH, s), 8.08 (IH, d), 8.17 (IH, dt), 8.20 (IH, s), 8.41 (IH, d), 8.85 (IH, s), 8.94 (IH, s). Mass Spectrum: m/z

[M+H]⁺= 346.

The preparations of 2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine and 6-bromo-4-chloro-7-fluoroquinoline-3-carboxamide have already been described. 4-Chloro-7-fluoro-6-(6-(methoxymethyl)pyridin-3-yl)quinoline-3-carboxamide (Intermediate 1.15) was also made as follows.

Thionyl chloride (250mL, 3425mmol) and catalytic DMF were added in one portion to 7- fluoro- 1 -(4-methoxybenzyl)-6-(6-(methoxymethyl)pyridin-3-yl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid (80g, 178.40mmol) at 25°C. The resulting mixture was stirred at 70°C for 3 h. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene and dissolved in MeCN (500mL). The solution was added dropwise to aqueous ammonia (250mL) at 0°C. The solid was collected to give crude 4-chloro-7-fiuoro-6-(6-(methoxymethyl)pyridin-3-yl)quinoline-3-carboxamide (50. Og). The reaction was repeated starting with 7-fluoro-l-(4-methoxybenzyl)-6-(6- (methoxymethyl)pyridin-3-yl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid (46g, 103mmol). The two batches were combined and triturated with DCM/MeOH (1 :1) to give 4-chloro-7-fluoro-6-(6-(methoxymethyl)pyridin-3-yl)quinoline-3-carboxamide (50g). Intermediate 1.16: 7-fluoro- l-(4-methoxybenzyl)-6-(6-(methoxymethyl)py ridin-3-yl)- 4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid

A solution of sodium hydroxide (42. Og, 1049mmol) in water (750mL) was added in one portion to a stirred solution of ethyl 7-fluoro- l-(4-metho xybenzyl)-6-[6- (methoxymethyl)pyridin-3 -yl] -4-oxo- 1 ,4-dihydroquino line-3 -carboxylate

(lOOg, 210mmol) in THF (1.5 L) at 25°C. The resulting mixture was stirred at 60°C for 2 h. The reaction mixture was acidified with 0.1M hydrochloric acid to pH 3. The solids were filtered and dried under vacuum to afford 7-fluoro- l-(4-metho xybenzyl)-6-(6- (methoxymethyl)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (80g, 85%) as a brown solid. 'HNMR Spectrum (300 MHz, DMSO-d6): 3.41 (3H, s), 3.73 (3H , s), 4.57 (2H, s), 5.78 (2H, s),6.95 (2H, d),7.33 (2H, d), 7.56 (IH, d), 8.02 (IH, d), 8.10 (IH, d), 8.49 (IH, d), 8.77 (IH, s), 9.27 (IH, s), 14.81 (IH, br s). Mass Spectrum: m/z [M+H]⁺= 449.

Intermediate 1.17: ethyl 7-fluoro-l-(4-methoxybenzyl)-6-[6-(methoxymethyl)pyridin- 3-yl] -4-oxo- 1 ,4-dihydroquinoline-3-carboxylate

To a vial charged with sodium tetrachloropalladate (II) (0.630g, 2.14mmol) and 3-(di-tert- butylphosphino)propane-l -sulfonic acid (1.149g, 4.28mmol) under nitrogen was added water (20mL) at r.t. The resulting solution was stirred at r.t. for 10 minutes and was added in one portion to ethyl 6-bromo-7-fluoro-l-(4-methoxybenzyl)-4-oxo-l,4- dihydroquinoline-3-carboxylate (93g, 214.mmol), 2-(methoxymethyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (107g, 257mmol) and K2CO3 (89g,

642mmol) in dioxane (1200mL) and water (150mL) at 25°C under nitrogen. The resulting mixture was stirred at 80°C for 16 h. The reaction was poured into water (1.5 L) and the solid was collected and dried under vacuum to give ethyl 7-fluoro-l-(4-methoxybenzyl)-6- [6-(methoxymethyl)pyridin-3-yl]-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate (95g, 93%) Mass Spectrum: m/z [M+H]⁺= 477.

Intermediate 1.18: ethyl 6-bromo-7-fluoro-l-(4-methoxybenzyl)-4-oxo-l,4- dihydroquinoline-3-carboxylate

DBU (83mL, 550mmol) was added to ethyl 2-(5-bromo-2,4-difluorobenzoyl)-3-((4- methoxybenzyl)amino)acrylate (250g, 550mmol) in acetone (lOOOmL). The resulting solution was stirred at r.t. for 16 h. The reaction mixture was filtered, washed with Et₂0 (1 L) and the solid was collected to give ethyl 6-bromo-7-fluoro-l-(4-methoxybenzyl)-4-oxo- l,4-dihydroquinoline-3-carboxylate (150g, 62.8%) as a light yellow solid. Ή NMR Spectrum (300 MHz, DMSO-d6) δ 1.29 (3H, t), 3.72 (3H, s), 4.25 (2H, q), 5.56 (2H, s), 6.85-6.95 (2H, d), 7.25 (2H, d), 7.81 (1H, d), 8.41 (1H, d), 8.90 (1H, s). Mass Spectrum: m/z [M+H]⁺= 434, 436. Intermediate 1.19: ethyl 2-(5-bromo-2,4-difluorobenzoyl)-3-((4- methoxybenzyl)amino)acrylate

Ethyl 3-(dimethylamino)acrylate (86g, 603mmol) was added to 5-bromo-2,4- difluorobenzoyl chloride (140g, 548.5mmol) and DIPEA (144mL, 823mmol) in toluene (500mL) at 25 °C. The resulting solution was stirred at 25 °C for 21 h and used without isolation. 4-Methoxybenzylamine (75g, 549mmol) was added dropwise to the reaction mixture diluted with toluene (800mL) at 25°C over a period of 20 minutes. The resulting solution was stirred at r.t. for 3 h. The reaction mixture was diluted with DCM (2 L), and washed sequentially with water (3 x 500mL) and brine (200mL). The organic layer was dried over Na₂SC"4, filtered and evaporated to afford ethyl 2-(5-bromo-2,4- difluorobenzoyl)-3-((4-methoxybenzyl)amino)acrylate (250g, 100%) as a brown oil used without further purification. Mass Spectrum: m/z [M+H]⁺= 454.

Intermediate 1.20: 5-bromo-2,4-difluorobenzoyl chloride

Thionyl chloride (60.1mL, 822.79mmol) was added dropwise to a stirred solution of 5- bromo-2,4-difluorobenzoic acid (130g, 549mmol) in toluene (lOOOmL) and DMF (lOmL) at r.t. The temperature was increased slowly to 70°C and the reaction mixture was stirred for 16 h. After cooling down to r.t., the resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford crude 5-bromo-2,4-difluorobenzoyl chloride (140g, 100%), used in the next step without further purification. Ή NMR Spectrum (400 MHz, CDC1₃): 6.95-7.05 (1H, m), 8.30-8.45 (1H, m). Intermediate 1.21: 5-bromo-2,4-difluorobenzoic acid

NBS (214g, 1205mmol) was added dropwise to 2,4-difluorobenzoic acid (200g,

1265mmol) in sulfuric acid (800mL) cooled to 0°C. The resulting solution was stirred at 0°C for 4 h. The reaction mixture was stirred for a further 12 h at 25 °C. The reaction mixture was poured into ice water (1500mL) and the precipitate was collected by filtration, washed with water (500mL) and dried under vacuum to afford crude 5-bromo-2,4- difluorobenzoic acid, which was purified by crystallisation from hot MeOH/water to afford 5-bromo-2,4-difluorobenzoic acid (234g, 82%) as a white solid. Ή NMR Spectrum

(300MHz, DMSO-d6): 7.59-7.66 (IH, m), 7.93-8.16 (IH, m).

Example 1.1

7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(lR)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

4-Chloro-7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]quinoline (lOOmg, 0.29mmol), {\R)- 1-(1 -methyl- lH-pyrazo 1-3 -yl)ethylamine hydrochloride (46.7mg, 0.29mmol) and DIPEA (0.115mL, 0.67mmol) were heated to 90°C overnight in DMA (lmL). After cooling, the reaction mixture was purified by preparative HPLC (Waters XBridge Prep CI 8 OBD column, 5 μιη silica, 30mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as eluents. The fractions containing the desired compound were evaporated to dryness to afford the title compound (32.0mg, 25.5%) as a solid. 'HNMR Spectrum (500 MHz, DMSO-d6): 1.61 (3H, d), 3.48 (3H, s), 3.82 (3H, s), 4.64 (2H, s), 5.19 - 5.49 (IH, m), 6.24 (IH, d), 7.61 (2H, d), 7.66 (IH, d), 7.73 (IH, d), 8.08 (2H, dt), 8.26 (IH, br s), 8.56 (IH, d), 8.75 (IH, s), 8.87 (IH, s), 9.85 (IH, d). Mass Spectrum: m/z [M+H]⁺= 435. Analytical chiral HPLC: see Example 1. 4-Chloro-7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]quinoline was prepared as described previously.

Intermediate 1.1.1: (lR)-l-(l-methyl-lH- razol-3-yl)ethylamine hydrochloride

To a solution of (i?)-2-methyl-N-[(li?)-l-(l-methylpyrazol-3-yl)ethyl]propane-2- sulfinamide (1 lOg, 0.480mol) in EtOAc (1 L) was added a solution of HC1 in EtOAc (1L, 4M) in portions at r.t. The mixture was heated to 35 °C and stirred for 12 h. The mixture was filtered and the filter cake was dried to give (lR)-l-(l-methyl-lH-pyrazol-3- yl)ethylamine (80g, 100%) as the hydrochloride salt. 'HNMR Spectrum (400MHz, DMSO-d6): 1.47-1.49 (3H, d), 3.81 (3H, s), 4.28-4.31 (1H, m), 6.39-6.40 (1H, d), 7.69- 7.70 (1H, d), 8.58 (3H, s). Mass Spectrum: m/z [M+H]⁺= 126. For enantiopurity analysis see Example 1.

Intermediate 1.1.2: (R)-2-methyl- V- [(1R)- l-(l-methylpy razol-3-yl)ethyl] propane-2- sulfinamide

To a solution of (i?)-2-methyl-N-[(l-methylpyrazol-3-yl)methylene]propane-2-sulfinamide (190g, 0.890mol) in dry DCM (1.2 L) was added dropwise MeMgBr (470mL, l . lmol) at - 60°C over a period of 1 h. The resulting mixture was stirred at -60°C for 4 hrs, warmed to r.t. and stirred for 12 hrs. The reaction mixture was quenched by saturated aqueous NH4CI (1 L). The organic layer was separated and the aqueous layer was extracted with DCM (5 x 200mL). The combined organic layers were dried over Na₂S04, filtered and concentrated to give the crude product. Purification by FCC, eluting with 1% to 10% MeOH in DCM afforded ( ?)-2-methyl-N- [( \R)- 1 -( 1 -methylpyrazo 1-3 -yl)ethyl]propane-2-sulfinamide (1 lOg, 53.9%) as a yellow oil. Intermediate 1.1.3: (R)-2-methyl- V-[(l-methylpyrazol-3-yl)methylene]propane-2- sulfinamide

To a stirred solution of 1 -methyl- lH-pyrazole-3-carbaldehyde (200g, 1.8mol) in dry DCM (1.6 L) was added anhydrous CUSC (661g, 4.14mol), followed by (i?)-2-methylpropane-2- sulfinamide (229g, 1.89mol) at r.t. The resulting mixture was stirred at r.t. for 24 hrs. The reaction mixture was filtered though a pad of Celite, and washed with DCM, the filtrate was concentrated and purified by FCC, eluting with a gradient of EtOAc in petroleum ether (0% to 50%) to give pure (i?)-2-methyl-N-[(l-methylpyrazol-3- yl)methylene]propane-2-sulfinamide (190g, 51.2%) as a white solid.

Example 2

7-fluoro-6-[2-fluoro-6-(methoxymethyl)pyridin-3-yl]-4-{[(lS)-l-(l-methyl-lH- pyrazol-3-yl)ethyl] amino} quinoline-3-carboxamide

Pd(PPh₃)4 (22.21mg, 0.02mmol) was added in one portion to 6-bromo-7-fluoro-4- {[(15)-l- (l-methyl-lH-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (377mg, 0.96mmol), 2- fluoro-6-(methoxymethyl)-3-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)pyridine (385mg, 1.15mmol) and cesium carbonate (783mg, 2.40mmol) in degassed dioxane (6 mL) : water (0.750 mL) under nitrogen. The resulting mixture was stirred at 90°C for 18 h. The reaction mixture was diluted with EtOAc (50 mL), and washed with water (2 x 50 mL). The organic layer was dried over MgS04, filtered and evaporated to afford crude product. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH₃/MeOH. The fractions containing the desired material were evaporated, dissolved in DMA (3mL) and further purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μΜ silica, 30mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 7-fluoro-6-[2-fluoro-6-(methoxymethyl)pyridin-3-yl]-4-{[(15)-l-(l- methyl-lH-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (26.0mg, 6.0%) as a solid. 'HNMR Spectrum (400 MHz, DMSO-d6) 1.58 (3H, d), 3.5 (3H, s), 3.77 (3H, s), 4.61 (2H, s), 5.25 - 5.32 (1H, m), 6.21 (1H, s), 7.54 (1H, s), 7.58 - 7.62 (2H, m), 7.72 (1H, d), 8.13 (1H, t), 8.22 (1H, s), 8.54 (1H, d), 8.90 (1H, s), 9.78 (1H, d). Mass Spectrum: m/z [M+H]⁺ = 453. [a]_D: -43° in EtOH (c~2mg/mL).

2-Fluoro-6-(methoxymethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine used as starting material was made as follows:

Intermediate 2.1: 2-fluoro-6-(methoxymethyl)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine

3-Bromo-2-fluoro-6-(methoxymethyl)pyridine (2.2g, lO.OOmmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.79g, l l.OOmmol), potassium acetate (2.94g, 30mmol) and {l, -¾z5(diphenylphosphino)ferrocene}palladium chloride complex in CH2CI2 (0.243g, 0.30mmol) were suspended in degassed dioxane (30mL). The reaction was heated at 80°C for 5 h under a nitrogen atmosphere. The crude mixture was filtered over celite and washed with MeCN, then EtOAc. The filtrate was concentrated in vacuo to provide 2-fluoro-6-(methoxymethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (3.79g, 142%) as a black solid which was used without further purification.

HNMR Spectrum (400 MHz, DMSO-d6): 1.30 (12H, s), 3.58 (3H, s), 4.45 (2H, d), 7.36 (1H, dd), 8.16 (lH, t). Intermediate 2.2: 3-Bromo-2-fluoro-6- methoxymethyl)pyridine

Sodium methoxide (25% in MeOH, 2.472mL, 10.81mmol) was added dropwise over 15 minutes at -30°C to a stirred solution of 3-bromo-6-(bromomethyl)-2-fluoropyridine (3.06g, 11.38mmol) in dry DMF (20mL) under an inert atmosphere. Additional sodium methoxide (0.15mL) was added and the mixture was stirred until completion of the reaction. Saturated aqueous sodium bicarbonate (ca. 4mL) was added at -30°C and the mixture was stirred at r.t. The mixture was extracted with DCM. After evaporation of the solvent, the residue was purified by FCC using 1% to 1.5% EtOAc in hexane as an eluent to provide 3-bromo-2-fluoro-6-(methoxymethyl)pyridine (1.86g, 74%) as a colourless solid. 'HNMR Spectrum (400 MHz, DMSO-d6): 3.37 (3H, s), 4.43 (2H, s), 7.31 (1H, d), 8.30 (lH, t).

Intermediate 2.3: 3-bromo-6-(bromomethyl)-2-fluoropyridine

In the dark, 3-bromo-2-fluoro-6-methylpyridine (1.5g, 7.89mmol), NBS (1.62g, 9.08mmol) and benzoyl peroxide (0.191g, 0.79mmol) in carbon tetrachloride (15mL) were stirred at 80°C for 6 h in a sealed vessel. The mixture was cooled to r.t. and filtered. The filtrate was concentrated in vacuo. Purification by FCC eluting with 2% to 10% DCM in hexane afforded 3-bromo-6-(bromomethyl)-2-fluoropyridine (1.2g, 56%) as a yellow oil, contaminated with 22% starting material. 'HNMR Spectrum (400 MHz, DMSO-d6) 4.68 (2H, s), 7.48 (1H, dd), 8.32 (1H, dd). Mass Spectrum: m/z [M-H]^" = 268. Example 2.1

4-{[(lS)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-7-fluoro-6-[2-fluoro-6- (methoxymethyl)pyridin-3-yl] uinoline-3-carboxamide

6-Bromo-4-[ [( 1 S)- 1 -( 1 ,4-dimethylpyrazo 1-3 -yl)ethyl] amino] -7-fluoro-quino line-3 - carboxamide (230mg, 0.40mmol), 2-fluoro-6-(methoxymethyl)-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine (159mg, 0.48mmol), cesium carbonate (387mg,

1.19mmol) and tetrakis(triphenylphosphine)palladium(0) (32.1mg, 0.03mmol) were suspended in dioxane (4mL) and water (0.44mL). The resulting mixture was degassed and purged with nitrogen several times. The mixture was heated at 90°C for 4 h under a nitrogen atmosphere then cooled to r.t. and left overnight. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NFb/MeOH. The fractions containing the desired material were evaporated and further purified by preparative HPLC (Waters XBridge Prep CI 8 OBD column, 5μ silica, 50mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1% NF ) and MeCN as eluents. Fractions containing the desired compounds were further purified by FCC, elution gradient 0 to 5% 7N NFb/MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-{[(15)-l-(l,4-dimethyl-lH- pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6- [2-fluoro-6-(methoxymethyl)pyridin-3 -yl] quino line- 3-carboxamide (32.0mg, 17.3%) as a white solid. ^!H NMR Spectrum (400 MHz, DMSO- d6): 1.54 (3H, d), 1.83 (3H, s), 3.43 (3H, s), 3.61 (3H, s), 4.55 (2H, s), 5.27 (1H, p), 7.30 (1H, s), 7.45 (1H, s), 7.55 (1H, d), 7.62 (1H, d), 8.12 (2H, dd), 8.41 (1H, d), 8.81 (1H, s), 10.03 (1H, d). Mass Spectrum: m/z [M+H]⁺= 467. Intermediate 2.1.1: 6-Bromo-4- [ [(lS)-l-(l,4-dimethylpyrazol-3-yl)ethyl] amino] -7- fluoro-quinoline-3-carboxamide

DIPEA (0.342mL, 1.98mmol) was added to 6-bromo-4-chloro-7-fluoroquinoline-3- carboxamide (300mg, 0.99mmol) and (15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (231mg, 1.09mmol) in DMA (5mL). The resulting mixture was stirred at 100°C for 4 h and allowed to cool to r.t. The crude product was purified by ion exchange chromatography, using an SCX column, eluting with 7M NHs/MeOH. The desired fractions were evaporated to dryness and were further purified by FCC, eluting with a gradient of 0% to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-bromo-4- [ [( 15)- 1 -( 1 ,4-dimethylpyrazo 1-3 -yl)ethyl] amino] -7-fluoro-quino line-3 - carboxamide (238mg, 59.3%) as a yellow solid. H NMR Spectrum (400 MHz, DMSO-d6): 1.54 (3H, d), 1.95 (3H, s), 3.72 (3H, s), 5.19 (IH, p), 7.37 (IH, s), 7.47 (IH, bs), 7.65 (IH, d), 8.11 (IH, br s), 8.57 (IH, d), 8.76 (IH, s), 9.72 (IH, d). Mass Spectrum: m/z [M+H]⁺= 406.

Intermediate 2.1.2: (lS)-l-(l,4-dimeth l-lH-pyrazol-3-yl)ethylamine hydrochloride

(i?)-N-[(15)-l-(l,4-dimethylpyrazol-3-yl)ethyl]-2-methyl-propane-2-sulfinamide (0.27g, 1.1 lmmol) was treated with 4M HC1 in dioxane (1.387mL, 5.55mmol) at ambient temperature. The mixture was stirred for 1.3 h. The mixture was filtered and the solid washed with Et₂0 and dried to give (15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (0.195g, 100%) as a white solid. ^!H NMR Spectrum (400 MHz, DMSO-d6) 1.47 (3H, d), 2.02 (3H,s), 3.78 (3H, s), 4.35 (IH, q), 7.49 (IH, d), 8.38 (2H, br s). Intermediate 2.1.3: (R)- V-[(lS)-l-(l,4-dimethylpyrazol-3-yl)ethyl]-2-methyl-propane- 2-sulfinamide

Titanium isopropoxide (0.737mL, 2.48mmol) and (i?)-2-methylpropane-2-sulfinimide (375mg, 3.09mmol) were added to a stirred solution of l-(l,4-dimethyl-lH-pyrazol-3- yl)ethanone (171mg, 1.24mmol) in 2-methyltetrahydrofuran (5mL) at ambient temperature under nitrogen. The resulting solution was heated at 70°C overnight and then cooled to - 78°C. Lithium tri-sec-butyl borohydride (3.72mL, 3.72mmol) was added dropwise to this stirred solution under a nitrogen atmosphere. The solution was stirred at -78 ^c for approximately 1 h then allowed to warm to ambient temperature for 2 h. The reaction was quenched by the addition of MeOH (lOmL) and concentrated. The resulting gum was dissolved in Et₂0 (20mL). Water (20mL) was added, followed by EtOAc (lOOmL). The mixture was filtered to remove the salts. The filtrate was dried over MgS0₄, filtered and concentrated. The resulting gum was purified by FCC with isocratic elution using 10: 1 :0.1 (DCM/MeOH/triethylamine). Pure fractions were evaporated to dryness to afford (R)-N- [(15)-l-(l,4-dimethylpyrazol-3-yl)ethyl]-2-methyl-propane-2-sulfinamide (270mg, 89%) as a colourless gum. 'HNMR Spectrum (400 MHz, DMSO-d6) 1.09 (9H, s), 1.48 (3H, d), 1.97 (3H, d), 3.71 (3H, s), 7.33 (1H, s). Mass Spectrum: m/z [M+H]⁺= 244.

Intermediate 2.1.4: l-(l,4-dimethyl-lH- razol-3-yl)ethanone

Methyl magnesium bromide (3M in Et₂0) (4.71mL, 14.13mmol) was added dropwise to a stirred solution ofN-methoxy-N,l,4-trimethyl-lH-pyrazole-3-carboxamide (1.903g, 7.06mmol) in THF (20mL) at ambient temperature under nitrogen. The resulting solution was stirred overnight. The reaction mixture was diluted with EtOAc (75 mL) and washed sequentially with sat. aqueous NH₄C1 (30mL) and brine (30mL). The aqueous layer was extracted with EtOAc and the combined organic layers were dried over MgS0₄, filtered and concentrated. The resulting crude product was purified by FCC on silica gel, eluting with a gradient of 10% to 40% EtOAc in heptane. Pure fractions were evaporated to dryness to afford l-(l,4-dimethyl-lH-pyrazol-3-yl)ethanone (0.171g, 17.5%) as a pale yellow oil. 'HNMR Spectrum (400 MHz, DMSO-d6): 2.17 (3H, d), 2.43 (3H, s), 3.87 (3H, s), 7.51 - 7.69 (lH, m).

Intermediate 2.1.5: 7V-methoxy-7V, 1 ,4-trimeth l- lH-pyrazole-3-carboxamide

N, O-Dimethylhydroxylamine hydrochloride (48. lg, 493mmol) was added to 1 ,4-dimethyl- lH-pyrazole-3-carboxylic acid hydrochloride (58g, 328mmol), HATU (150g, 394mmol) and DIPEA (172mL, 985mmol) in DMF (300mL) at 25°C. The resulting solution was stirred at 25°C for 3 h. The reaction mixture was poured into water (500mL), extracted with EtOAc (3 x 500mL). The organic layer was dried over Na₂S04, filtered and evaporated to afford a brown residue. This crude product was purified by FCC, eluting with a gradient of 0% to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford N-methoxy-N,l,4-trimethyl-lH-pyrazole-3-carboxamide (60. Og, 100%) as a yellow oil. 'HNMR Spectrum (400 MHz, CDC1₃): 2.19 (3H, s), 2.82 (3H, s), 3.41 (3H, s), 3.87 (3H, s), 7.15 (1H, s). Mass Spectrum: m/z [M+H]⁺= 184.

(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (Intermediate 2.1.2) was alternatively prepared as follows.

Hydrogen chloride (6N in 2-propanol, 1.045mL, 6.27mmol) was added to tert- vXy\ [(15)- l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]carbamate (50mg, 0.21mmol) in MeOH (0.5mL) and the reaction was stirred for 18 h. The resulting mixture was evaporated to dryness and the resulting solid was triturated with ether (2x) to afford (15)-l-(l,4-dimethyl-lH-pyrazol- 3-yl)ethylamine hydrochloride (39.0mg, 106%) as a white solid. Intermediate 2.1.6: tert-butyl [(lS)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]carbamate

tert-butyl [(15)-l-(4-bromo-l-methyl-lH-pyrazol-3-yl)ethyl]carbamate (50mg, 0.16mmol) in degassed toluene (0.5mL) and water (0.050mL) was added to a mixture of

dicyclohexyl(2',6'-diisopropoxy-[ 1 , 1 '-biphenyl]-2-yl)phosphine (7.67mg, 0.02mmol), diacetoxypalladium (1.845mg, 8.22 μηιοΐ), methylboronic acid (39.4mg, 0.66mmol) and K2CO3 (68.2mg, 0.49mmol) under an atmosphere of nitrogen. The reaction was heated at 100°C for 2 h. The reactions were combined, diluted with EtOAc and washed with water (2x), brine, dried with MgS0₄, and concentrated. The resulting crude product was purified by FCC, eluting with a gradient of 0% to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl [(15)-l-(l,4-dimethyl-lH-pyrazol-3- yl)ethyl] carbamate (14.0mg, 71.2%) as a yellow oil. 'HNMR Spectrum (400 MHz, DMSO-d6): 1.30 (3H, d), 1.36 (9H, s), 1.93 (3H, s), 3.68 (3H, s), 4.56 - 4.71 (1H, m), 6.83 (1H, d), 7.30 (1H, s). Mass Spectrum: m/z [M+H]⁺= 240.

Intermediate 2.1.7: terf-butyl [(lS)-l-(4-bromo-l-methyl-lH-pyrazol-3- yl)ethyl] carbamate

N-Bromosuccinimide (406mg, 2.28mmol) was added to a solution of tert-butyl [(15)-1-(1- methyl-lH-pyrazo 1-3 -yl)ethyl] carbamate (343mg, 1.52mmol) in MeCN (1.75mL). The reaction was stirred at r.t. for 1.5 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHC03 solution (3x), dried with MgS0₄. The crude product was dissolved in EtOAc, washed with IN aqueous NaOH (2x) and water, dried with MgS0₄, and concentrated to yield tert-butyl [(15)-l-(4-bromo-l-methyl-lH-pyrazol- 3 -yl)ethyl] carbamate (429mg, 93%) as a yellow oil. 'HNMR Spectrum (400 MHz, DMSO-d6): 1.30 (3H, d), 1.36 (9H, s), 3.76 (3H, s), 4.58 - 4.72 (1H, m), 6.94 (1H, d), 7.82 (1H, s). Mass Spectrum: m/z [M-tBu]⁺ = 248, 250.

DIPEA (1.077mL, 6.18mmol) was added to (1 S)- 1-(1 -methyl- lH-pyrazo 1-3 -yl)ethylamine hydrochloride (500mg, 1.77mmol) and di-tert-butyl dicarbonate (463mg, 2.12mmol) in DCM (5mL). The resulting solution was stirred at r.t. for 80 minutes. The mixture was diluted with DCM, washed with water and dried with MgS0₄. Evaporation of the solvent afforded tert-butyl [(1 S)- 1-(1 -methyl- lH-pyrazo 1-3 -yl)ethyl] carbamate (455mg, 114%) as a yellow oil, used without further purification. ^!HNMR Spectrum (400 MHz, DMSO-d6): 1.34 (3H, d), 1.43 (9H, s), 3.81 (3H, s), 4.61-4.73 (1H, m), 6.12 (1H, d), 7.07 (1H, d), 7.57 (1H, d). Mass Spectrum: m/z [M+Na]⁺ = 248.

Example 2.2

4-{[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-7-fluoro-6-[2-fluoro-6- (hydroxymethyl)pyridin-3-yl]quinoline-3-carboxamide

Under an inert atmosphere of nitrogen, a solution of 6-bromo-4-[[(15)-l-(l,4- dimethylpyrazol-3-yl)ethyl]amino]-7-fluoro-quinoline-3-carboxamide (130mg, 0.32mmol), 6-fluoro-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]methanol (122mg,

0.48mmol), cesium carbonate (313mg, 0.96mmol), Pd(PPh₃)₄ (40mg, 0.03mmol) in dioxane (5mL) - water(lmL) was stirred for 2 h at 80°C. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD

Column, 5μιη, 19x150mm; mobile phase, water with 0.03%> NH₄OH and MeCN (gradient from 10% MeCN up to 40% in 10 min) to afford 4-{[(15)-l-(l,4-dimethyl-lH-pyrazol-3- yl)ethyl] amino } -7-fluoro-6-[2-fluoro-6-(hydroxymethyl)pyridin-3 -yl] quino line-3 - carboxamide (9.7mg, 7%) as a off-white solid. ^!HNMR Spectrum (300 MHz, DMSO-d6): 1.67 (3H, d), 1.92 (3H, s), 3.70 (3H, s), 4.72 (2H, s), 5.31 (1H, p), 7.25 (1H, s), 7.54-7.61 (2H, m), 8.79-8.81 (1H, m), 8.38 (1H, d), 8.79 (1H, s). Mass Spectrum: m/z [M+H]⁺= 453.

Intermediate 2.2.1: (5-bromo-6-fluoropyridin-2-yl)methanol

A mixture of (5-bromo-6-fluoropyridin-2-yl)methanol (l .OOg, 4.85mmol),

4,4,4^,,4^,,5,5,5^*,5^*-octamethyl-2,2^,-bi(l,3,2-dioxaborolane) (1.48g, 5.82mmol), Pd(dppf)Cl₂ (107mg, 0.15mmol), potassium acetate (1.43g, 14.6mmol) in dioxane (50mL) was stirred for 4 h at 80°C. The resulting mixture was concentrated under vacuum, then diluted with petroleum ether (50mL). The solids were filtered off and rinsed with MeCN (5mL) and petroleum ether (50mL). The filtrate were combined and concentrated to give [6-fluoro-5- (tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]methanol (lg, 81%) as a brown oil, without further purification. Mass Spectrum: m/z [M+H]⁺= 254.

Intermediate 2.2.1: 6-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl] methanol

3-Bromo-6-(bromomethyl)-2-fluoropyridine (2.3 lg, 8.59mmol) and K₂C0₃ (2.37g, 17.18mmol) were dissolved in dioxane (15mL):water (15mL) and sealed into a microwave tube. The reaction was heated to 60°C for 1 h in a microwave reactor and cooled to r.t. The reaction mixture was diluted with EtOAc (25mL) and washed with water (2 x 20mL). The organic layer was dried over MgSC^, filtered , evaporated and purified by FCC, eluting with a gradient of 0% to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (5-bromo-6-fluoropyridin-2-yl)methanol (1.22g, 69.1%) as a colourless liquid. 'HNMR Spectrum (400 MHz, DMSO-d6): 4.48 (2H, d), 5.59 (1H, t), 7.32 - 7.46 (1H, m), 8.26 (1H, dd). Mass Spectrum: m/z [M-H] - 204.

Example 3

4-{[(lS)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-7-fluoro-6-[6- (methoxymethyl)pyridin-3-yl uinoline-3-carboxamide

(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (0.471g, 2.22mmol), 4- chloro-7-fluoro-6-(6-(methoxymethyl)pyridin-3-yl)quinoline-3-carboxamide (0.640g, 1.85mmol) and DIPEA (1.290mL, 7.40mmol) were dissolved in DMA (12mL). The reaction was heated to 120°C for 75 minutes and cooled to r.t. After purification by ion exchange chromatography with an SCX column, eluting with 0.35M NH₃/MeOH, the material was further purified twice by flash CI 8 silica chromatography, eluting with a gradient of 15% to 40% MeCN in water containing 1% NH₄OH. Pure fractions were evaporated to dryness to afford 4-{[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-7- fluoro-6-[6-(methoxymethyl)pyridin-3-yl]quinoline-3-carboxamide (0.833g, 100%) as a dry film.

HNMR Spectrum (400 MHz, CDC1₃): 1.64 (3H, d), 1.85-1.9 (3H, m), 2.53 (2H, s), 3.53 (3H, s), 3.80 (3H, s), 4.66 (2H, s), 5.19 (1H, p), 7.09 (1H, s), 7.42 (1H, d), 7.49 - 7.54 (1H, m), 7.92 (1H, dt), 8.21 (1H, d), 8.66 (1H, s), 8.75 (1H, s), 9.98 (1H, d). Mass Spectrum: m/z [M+H]⁺= 449. Analytical chiral HPLC: Column, Chiralpak IC-3 3μΜ, 0.46x 5 cm; mobile phase, MeOH - hexane (3:7); flow rate, 1.5mL/min; tR 3.27 min (R- isomer, tR 1.77 min.). Example 3.1

4-{[(lR)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl] amino}-7-fluoro-6-[6- (methoxymethyl)pyridin-3-yl uinoline-3-carboxamide

A mixture of 4-chloro-7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]quinoline-3- carboxamide (1.059g, 2.60mmol), (li?)-l-(l ,4-dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (0.607g, 2.86mmol) and DIPEA (2.027mL, 1 1.72mmol) in DMA (lOmL) was heated at 100°C for 5 h and stirred at ambient temperature overnight. Water (lOmL) was added and the mixture was triturated. The resulting solid was collected by filtration and washed with water. The liquors were loaded onto a 50g SCX column and eluted sequentially with MeOH and 2M NH₃/MeOH. The basic fractions were concentrated and combined with the filter cake already isolated to provide the crude product as a brown gum (1.762g) which formed crystals upon standing. A portion (~700mg) was dissolved in MeOH and purified by preparative HPLC (Waters XBridge Prep CI 8 OBD column, 5μΜ silica, 50mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1% NH₃) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (238mg) as a cream amorphous solid. 'HNMR Spectrum (500 MHz, DMSO-d6): 1.56 (3H, d), 1.87 (3H, s), 3.42 (3H, s), 3.66 (3H, s), 4.59 (2H, s), 5.32 (1H, p), 7.33 (1H, s), 7.49 (1H, br s), 7.56 (1H, d), 7.63 (1H, d), 8.04 (1H, dt), 8.16 (1H, br s), 8.43 (1H, d), 8.75 (1H, s), 8.81 (1H, s), 10.08 (1H, d). Mass Spectrum: m/z [M+H]⁺= 449.

[OJD: -20.5° in MeOH (c~lmg/mL). Analytical chiral HPLC: see Example 3.

Intermediate 3.1.1: (lR)-l-(l,4-dimeth l-lH-pyrazol-3-yl)ethylamine hydrochloride

Using a similar procedure as for Intermediate 2.1.2, (S)-N-[(lR)-l-(l ,4-dimethylpyrazol-3- yl)ethyl]-2-methyl-propane-2-sulfinamide (403mg) was treated with 4M HCl in dioxane to give (li?)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (323mg). Ή NMR Spectrum (400 MHz, DMSO-d6): 1.47 (3H, d), 1.97 - 2.06 (3H, m), 3.78 (3H, s), 4.35 (1H, p), 6.46 (1H, s), 8.37 (1H, s).

Intermediate 3.1.2: (S)- V-[(lR)-l-(l,4-dimethylpyrazol-3-yl)ethyl]-2-methyl-propane- 2-sulfinamide

Using similar procedures as for Intermediate 2.1.3, reaction of (5)-2-methylpropane-2- sulfinimide (502mg, 4.14mmol) and l-(l,4-dimethyl-lH-pyrazol-3-yl)ethanone (229mg, 1.66mmol), followed by reduction with lithium tri-sec-butyl borohydride gave (5)-N-[(li?)- l-(l,4-dimethylpyrazol-3-yl)ethyl]-2-methyl-propane-2-sulfinamide (403mg), which was used without further purification. Mass Spectrum: m/z [M+H]⁺= 244.

Example 4

7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(lS)-l-(lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

(15)-l-(lH-pyrazol-3-yl)ethylamine hydrochloride (32.1mg, 0.29mmol), 4-chloro-7- fluoro-6-(6-(methoxymethyl)pyridin-3 -yl)quino line-3 -carboxamide ( 1 OOmg, 0.29mmo 1) and DIPEA (0.165mL, 0.95mmol) were suspended in DMA (lmL) and the resulting mixture was heated at 110°C overnight. The mixture was allowed to cooled to ambient temperature and was loaded onto a 20g SCX column. The column was eluted sequentially with MeOH and 2M NH₃/MeOH. The material was further purified by preparative HPLC (Waters SunFire column, 5μΜ silica, 19mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 7-fluoro-6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 H-pyrazol-3 -yl)ethyl] amino } quino line-3 - carboxamide (9.3mg, 8%). 'HNMR Spectrum (500 MHz, DMSO-d6): 1.56 (3H, d), 3.41 (3H, s), 4.56 (2H, s), 5.3-5.39 (1H, m), 6.17 (1H, d), 7.53 (2H, d), 7.65 (1H, d), 7.96 (1H, d), 8.26 (1H, s), 8.45 (1H, d), 8.71 (1H, s), 8.78 (1H, s). Mass Spectrum: m/z [M+H]⁺= 421.

Intermediate 4.1: (15)-l-(lH-pyrazol-3-yl)ethylamine hydrochloride

To a solution of (5)-2-methyl-N-[(15)-l-(lH-pyrazol-3-yl)ethyl]propane-2-sulfinamide (64.4g, 0.30mol) in EtOAc (1L) was added dropwise hydrogen chloride in EtOAc (1L, 4N). After the addition, the resulting mixture was stirred at 25 °C for 10 h. The reaction mixture was filtrated and washed with EtOAc (1.5L) to afford compound (15)-1-(1H- pyrazol-3-yl)ethylamine hydrochloride (51g, 92.7%>) as a white solid. Ή NMR Spectrum (400 MHz, DMSO-d6) 1.51 (3H, d), 4.37-4.40 (1H, m), 6.42 (1H, d), 7.74 (1H, d), 8.54 (2H, s), 8.90 (1H, s).

Intermediate 4.2: (S)-2-methyl- V-[(lS)-l-(lH-pyrazol-3-yl)ethyl]propane-2- sulfinamide

To a stirred solution of tert-butyl 3-[(15)-l-{[(5)-tert-butylsulfinyl]amino}ethyl]-lH- pyrazole-l-carboxylate (300g, 0.93mol) in MeOH (2.5L) was added K2CO3 (250g, 1.86mol) in portions. The resulting mixture was heated to reflux overnight. The reaction mixture was filtrated and washed with EtOAc (1.5L). The filtrate was dried with anhydrous Na₂S0₄ and then concentrated. Purification by FCC eluting with 0.6% MeOH DCM gave (5)-2-methyl-N-[(15)-l-(lH-pyrazol-3-yl)ethyl]propane-2-sulfinamide (64g, 34.8%) as a light yellow solid. No analytical data recorded.

Intermediate 4.3: tert-butyl 3-[(lS)-l-{[(S)-te^butylsulfinyl]amino}ethyl]-lH- pyrazole-l-carboxylate

To a stirred solution of tert-butyl 3-[[(5)-tert-butylsulfinyl]iminomethyl]pyrazole-l- carboxylate (299g, 0.93mol) in THF (2.5L) was added methyl magnesium bromide (401mL, 1.2mol, 3N in ether) dropwise at -60°C over a period of 30 minutes. The mixture was stirred at this temperature for 2 h, warmed to r.t. and stirred for another 2 h. Water (300mL) was added to the reaction and the resulting suspension was filtered. The filtered cake was washed with MeOH and the solution was concentrated to give tert-butyl 3-[(lS)- l-{[(5)-tert-butylsulfinyl]amino} ethyl]- lH-pyrazole-l-carboxylate (300g) which was used straight to the next step.

Intermediate 4.4: tert-butyl 3-[[(S)-tert-butylsulfinyl]iminomethyl]pyrazole-l- carboxylate

To a solution of crude (5)-2-methyl-N-(lH-pyrazol-3-ylmethylene)propane-2-sulfinamide from above (about 800g, 4.02mol) in dry DCM (4L) was added triethylamine (36 lg, 3.57mol). Then, di-tert-butyl dicarbonate (599g, 2.75mol) was added dropwise, followed by addition of DMAP (5g). The resulting mixture was stirred at r.t. overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc, washed with brine, dried over anhydrous Na₂S04, concentrated and purified by FCC, eluting with a gradient of 0-20% EtOAc in petroleum ether to afford tert-butyl 3-[[(S)-tert- butylsulfinyl]iminomethyl]pyrazole-l-carboxylate (277g, 33.7%). No analytical data recorded.

Intermediate 4.5: (S)-2-methyl- V-(lH-pyrazol-3-ylmethylene)propane-2-sulfinamide

To a stirred solution of lH-pyrazole-3-carbaldehyde (264g, 2.75mol) in dry DCM (4L) was added anhydrous CUSC (101 lg, 6.33mol), followed by (5)-2-methylpropane-2- sulfinamide (350g, 2.90mol) at r.t. The resulting mixture was stirred at 60°C for 9 h. The reaction mixture was filtered though a pad of Celite, and washed with DCM (1.5L). The combined filtrate was concentrated to give (5)-2-methyl-N-(lH-pyrazol-3- ylmethylene)propane-2-sulfinamide (about 800g), which was used in the next step without further purification. No analytical data recorded.

Example 5

7-fluoro-4-{[(lS)-l-(4-fluoro-l-methyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6- (methoxymethyl)pyridin-3-yl uinoline-3-carboxamide

(15)-l-(4-Fluoro-l-methyl-lH-pyrazol-3-yl)ethylamine (0.159g, l. l lmmol), 4-chloro-7- fluoro-6-[6-(methoxymethyl)pyridin-3-yl]quinoline-3-carboxamide (0.350g, 1.Olmmol) and DIPEA (0.705mL, 4.05mmol) were dissolved in DMA (5mL). The reaction was heated to 120°C for 45 minutes and cooled to r.t. The reaction was heated to 120°C for 75 minutes and cooled to r.t. After purification by ion exchange chromatography on an SCX column, eluting with 0.35M NH₃/MeOH, the material was further purified by flash CI 8 silica chromatography, eluting with a gradient of 15% to 40% MeCN in water containing 1% NH4OH. Pure fractions were evaporated to dryness to afford 7-fluoro-4-{[(15)-l-(4-fluoro- 1 -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -6- [6-(methoxymethyl)pyridin-3 -yl] quino line-3 - carboxamide (0.058g, 13%) as a cream solid. ^!H NMR Spectrum (400 MHz, CDC1₃): 1.71 (3H, d), 3.53 (3H, s), 3.74 (3H, s), 4.66 (2H, s), 5.24-5.37 (IH, m), 5.86 (2H, s), 7.17 (IH, d), 7.53 (IH, d), 7.65 (IH, d), 7.99 (IH, dt), 8.41 (IH, d), 8.73 (IH, s), 8.78 (IH, s), 9.54 (IH, d). Mass Spectrum: m/z [M+H]⁺= 453.

Intermediate 5.1: (15)-l-(4-Fluoro-l-meth l-lH-pyrazol-3-yl)ethylamine

1 -(Chloromethyl)-4-fluoro- 1 ,4-diazabicyclo[2.2.2]octane- 1 ,4-diium tetrafluoroborate (1.905g, 5.38mmol) was added to tert- vXy\ [( IS)- 1-(1 -methyl- lH-pyrazo 1-3- yl)ethyl] carbamate (0.932g, 4.14mmol) in MeCN (18mL). The resulting mixture was stirred at r.t. for 30 minutes and then at 80°C for 30 minutes and cooled over 60 h. More 1 -(chloromethyl)-4-fluoro- 1 ,4-diazabicyclo[2.2.2]octane- 1 ,4-diium tetrafluoroborate (1.905g) was added and the mixture stirred for another 3 h. The mixture was evaporated and the crude product was purified by ion exchange chromatography using an SCX column, eluting with 0.35M NHs/MeOH. Further purification by FCC, eluting with a gradient of 2% to 10% MeOH in DCM containing NH₄OH afforded (15)-l-(4-fiuoro-l- methyl-lH-pyrazol-3-yl)ethylamine (0.150g, 25.3%) as a brown liquid. Ή NMR Spectrum (400 MHz, CDCls): 1.45-1.48 (3H, m), 3.77 (3H, s), 4.17 (IH, q), 7.16 (IH, d).

Example 5.1

7-fluoro-4-{[(lR)-l-(4-fluoro-l-methyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6- (methoxymethyl)pyridin-3-yl uinoline-3-carboxamide

Using a similar procedure as in Example 5, (li?)-l-(4-fluoro-l-methyl-lH-pyrazol-3- yl)ethylamine (0.056g, 0.39mmol) and 4-chloro-7-fluoro-6-[6-(methoxymethyl)pyridin-3- yl]quinoline-3-carboxamide (0.150g, 0.43mmol) were reacted to afford the title compound (0.030g, 15%). 'HNMR Spectrum (500 MHz, DMSO-d6): 1.58 (3H, d), 3.43 (3H, s), 3.68 (3H, s), 4.60 (2H, s), 5.27 - 5.39 (IH, m), 7.51 (IH, s), 7.57 (IH, d), 7.69 (IH, d), 7.75 (IH, d), 8.08 (IH, dt), 8.16 (IH, s), 8.47 (IH, d), 8.79 (IH, s), 8.83 (IH, s), 9.65 (IH, d). Mass Spectrum: m/z [M+H]⁺= 453.

Intermediate 5.1.1: (1R)- l-(4-Fluoro- 1-meth l- 1 H-pyrazol-3-yl)ethylamine

1 -(Chloromethyl)-4-fluoro- 1 ,4-diazabicyclo[2.2.2]octane- 1 ,4-diium tetrafluoroborate (1.585g, 4.47mmol) and tert-butyl [(li?)-l-(l-methyl-lH-pyrazol-3-yl)ethyl]carbamate (0.96g, 4.26mmol) were reacted using a similar procedure as in Example 5, starting material to afford (li?)-l-(4-fluoro-l-methyl-lH-pyrazol-3-yl)ethylamine (0.200g, 33%) as a beige liquid. 'HNMR Spectrum (400 MHz, CDC1₃): 1.51 (3H, d), 3.76 (3H, s), 3.93 (2H, s), 4.27 (IH, q), 7.18 (IH, d).

Intermediate 5.1.2: terf-butyl [(lR)-l-(l-methyl-lH-pyrazol-3-yl)ethyl]carbamate

DIPEA (0.193mL, 1.1 lmmol) was added to (li?)-l-(l -methyl- lH-pyrazo 1-3 -yl)ethylamine hydrochloride (0.1 OOg, 0.50mmol) and di-tert-butyl dicarbonate (0.116g, 0.53mmol) in DCM (2mL). The resulting solution was stirred at r.t. for 1 h. The mixture was washed with water, dried and evaporated to give tert-butyl [(li?)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] carbamate (0.120g, quantitative). 'HNMR Spectrum (400 MHz, CDCI3): 1.45 (9H, s), 1.47 (3H, d), 1.53 (IH, s), 3.85 (3H, s), 4.82 (IH, s), 6.10 (IH, d), 7.25 (IH, d).

Mass Spectrum: m/z [M+H]⁺= 170. Examples 6 and 6.1

7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(lS)-l-(4-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide (Example 6)

7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(lR)-l-(4-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide (Example 6.1)

4-Chloro-7-fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide (3 OOmg, 0.87mmol, 1.00 equiv), l-(4-methyl-lH-pyrazol-3-yl)ethylamine hydrochloride (258mg, 1.60mmol, 1.50 equiv, mixture of enantiomers, ratio unknown) and DIPEA (335mg, 2.59mmol) were dissolved in DMA (5mL). The resulting solution was stirred for 12 h at 100°C. The reaction mixture was cooled. The product was precipitated by the addition of water. After collection by filtration, the solid was dried in an oven under reduced pressure. The crude product was purified by preparative HPLC with the following conditions:

Column, XBridge Shield RP18 OBD Column, 5μΜ, 19x150mm; mobile phase, water with 0.03% NH₄OH and MeCN (gradient from 30% to 70% MeCN). The racemic mixture was separated by Chiral Preparative HPLC with the following conditions: Column, Chiralpak AD-H, 2 x 25 cm; mobile phase, 50% IPA (0.1% DEA) in hexane (0.1% DEA) to give 7- fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- { [( IR)- 1 -(4-methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide (67.3mg , 18%) as a white solid and 7-fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- { [( 1 S)- 1 -(4-methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino} quino line-3 -carboxamide (23.2mg, 6%) as a white solid.

HNMR Spectrum (400 MHz, DMSO-d6): 1.56 (3H, d), 1.87 (3H, s), 3.42 (3H, s), 4.58 (2H, s), 5.37-5.41 (1H, m), 7.18-7.68 (4H, m), 8.00 (1H, s), 8.17 (1H, s), 8.39 (1H, s), 8.74-8.79 (2H, m), 9.99 (1H, br s),12.33 (1H, br s). Mass Spectrum: m/z [M+H]⁺= 435. Analytical chiral HPLC: Column, Chiralpak AD-H 5μΜ, 0.46x15cm; mobile phase, 50% IPA (0.1% DEA) in hexane (0.1% DEA); flow rate, lmL/min : S-isomer, t_R2.85 min; R- isomer, tR 4.67 min.

Intermediate 6.1: l-(4-Methyl-lH-pyrazol-3-yl)ethylamine hydrochloride

Acetyl chloride (2.5g, 31.85mmol) was added dropwise to a stirred solution of MeOH (30mL) over 10 minutes. After stirring at r.t. for 30 minutes, (5)-2-methyl-N-[-l-(4- methyl-lH-pyrazol-3-yl)ethyl]propane-2-sulfinamide (750mg, 3.27mmol) was added to this solution and the resulting solution was stirred for 12 h at r.t. The resulting mixture was concentrated under vacuum. After addition of EtOAc, the resulting precipitate was collected by filtration and dried in an oven under reduced pressure to give l-(4-methyl- lH-pyrazol-3-yl)ethylamine hydrochloride (450mg, 85%, mixture of enantiomers, ratio unknown) as a white solid. ^!H NMR Spectrum (400 MHz, DMSO-d6): 1.41-1.49 (3H, m), 2.03 (3H, s), 4.40 (1H, m), 7.52 (1H, m), 8.34 (1H, m br). Mass Spectrum: m/z [M+H]⁺= 126.

Intermediate 6.2: (S)-2-methyl- V-[-l-(4-methyl-lH-pyrazol-3-yl)ethyl]propane-2- sulfinamide

To a solution of (5)-2-methyl-N-[l-(4-methyl-lH-pyrazol-3-yl)ethylidene]propane-2- sulfinamide (l . lg, 4.84mmol, 1.00 equiv) in MeOH (lOmL) was added sodium

borohydride (336mg, 8.88mmol). The resulting solution was stirred for 2 h at r.t. The reaction was then quenched by the addition of water (3 OmL). The resulting solution was extracted with EtOAc (2x5 OmL) and the organic layers were combined, washed with brine (30mL), dried over anhydrous sodium sulphate and concentrated under vacuum to give (S)- 2-methyl-N-[-l-(4-methyl-lH-pyrazol-3-yl)ethyl]propane-2-sulfinamide (750mg, 68%, undefined mixture of diastereoisomers) as a colourless oil. Mass Spectrum: m/z [M+H]⁺=

230.

Intermediate 6.3: (S)-2-methyl- V-[l-(4-methyl-lH-pyrazol-3-yl)ethylidene]propane-2- sulfinamide

A mixture of l-(4-methyl-lH-pyrazol-3-yl)ethan-l-one (l. lg, 8.86mmol), (S)- 2- methylpropane-2-sulfinamide (2.2g, 18.15mmol), tetraethoxytitanium (4g, 17.54mmol) in THF (50mL) was stirred for 12 h at 75°C. The reaction mixture was cooled and the resulting mixture was concentrated under vacuum. The residue was purified by FCC, eluting with EtO Ac/petroleum ether (1 : 1) to give (5)-2-methyl-N-[l-(4-methyl-lH- pyrazol-3-yl)ethylidene]propane-2-sulfinamide (1.8g, 89%) as a light yellow oil.

'HNMR Spectrum (400 MHz, CDC1₃): 1.84 (9H, s), 2.32 (3H, s), 2.87 (3H, s), 7.39 (1H, m). Mass Spectrum: m/z [M+H]⁺= 228.

Intermediate 6.4: l-(4-methyl-lH-pyrazol-3-yl)ethan-l-one

To a stirred solution of tert-butyl 3-[methoxy(methyl)carbamoyl]-4-methyl-lH-pyrazole- 1-carboxylate (4g, 14.85mmol) in dry THF (30mL) cooled at -78°C under an atmosphere of nitrogen was added methyl lithium (1.6M in Et₂0, 14mL) drop wise over 10 minutes. The resulting solution was allowed to warm to r.t. and stirred for 12 h at 25 °C. The reaction was then quenched by the addition of aqueous NH4CI (50mL). The resulting solution was extracted with EtO Ac (2xl00mL) and the organic layers were combined. The resulting mixture was washed with brine (50mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by FCC, eluting with

EtO Ac/petroleum ether (1 :4), to give l-(4-methyl-lH-pyrazol-3-yl)ethan-l-one (l . lg , 60%) as a colourless oil. 'HNMR Spectrum (400 MHz, CDCI3) 2.33 (3H, s), 2.62 (3H, s), 7.42 (1H, m), 8.75 (1H, s). Mass Spectrum: m/z [M+H]⁺ = 125.

Intermediate 6.5:

3-[methoxy(methyl)carbamoyl]-4-methyl-lH-pyrazole-l- carboxylate

A mixture of N-methoxy-N,4-dimethyl-lH-pyrazole-3-carboxamide (5.3g, 31.33mmol), di-tert-butyl dicarbonate (13.5g, 61.86mmol), TEA (6.3g, 62.26mmol) and 4- dimethylaminopyridine (378mg, 3.09mmol) in DCM (300mL) was stirred for 12 h at r.t. The reaction was then quenched by the addition of 200mL of water. The resulting solution was extracted with 2x300mL of DCM. The organic layers were combined, dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by FCC, eluting with EtO Ac/petroleum ether (1 :8) to give tert-bvXy\ 3-

[methoxy(methyl)carbamoyl]-4-methyl-lH-pyrazole-l-carboxylate (4g, 47%) as colourless oil. 'HNMR Spectrum (400 MHz, CDC1₃) 1.64 (9H, s), 2.19 (3H, s), 3.41 (3H, s), 3.82 (3H, s), 7.83 (1H, m). Mass Spectrum: m/z [M+H]⁺= 270.

Intermediate 6.6: V-methoxy- V,4-dimethyl-lH-pyrazole-3-carboxamide

To a stirred solution of 4-methyl-lH-pyrazole-3-carbonyl chloride (4.5g), N, 0- dimethylhydroxylamine hydrochloride (4.5g, 46mmol) in DCM (lOOmL) at r.t. was added TEA (9.5g, 94mmol) drop wise in 5 minutes. The resulting solution was stirred for 2 h at r.t. The resulting mixture was concentrated under vacuum to give N-methoxy-N,4- dimethyl-lH-pyrazole-3-carboxamide (5. lg) as a yellow oil. Mass Spectrum: m/z [M+H]⁺= 170. Intermediate 6.7: 4-methyl-lH-pyrazole-3-carbonyl chloride

4-Methyl-lH-pyrazole-3-carboxylic acid hydrochloride (5g, 30.76mmoL), DCM (lOOmL), oxalyl chloride (8g, 63.03mmol), DMF (50mg, 0.68mmol) and TEA (lOOmg, 0.99mmol) was stirred for 5 h at 25 °C. The resulting mixture was concentrated under vacuum to give 4-methyl-lH-pyrazole-3-carbonyl chloride (4.1g) used without further purification.

Intermediate 6.8: 4-methyl-lH-pyrazole-3-carboxylic acid hydrochloride

A mixture of ethyl 4-methyl-lH-pyrazole-3-carboxylate (5g, 32.43mmol) and 4N aqueous hydrochloric acid (80mL) was stirred for 4 h at 100°C in an oil bath. The reaction mixture was cooled. The resulting mixture was concentrated under vacuum to give 4-methyl-lH- pyrazole-3-carboxylic acid hydrochloride (5g) as a white solid. Mass Spectrum: m/z

[M+H]⁺= 127

Example 7

7-fluoro-6-[6-(hydroxymethyl)pyridin-3-yl]-4-{[(lS)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

6- [6-( { [tert-butyl(dimethyl)silyl]oxy } methyl)pyridin-3 -yl] -4-chloro-7-fluoroquino line-3 - carboxamide (0.2g, 0.45mmol), (15)-l-(l-methyl-lH-pyrazol-3-yl)ethylamine

hydrochloride (0.087g, 0.54mmol) and DIPEA (0.272mL, 1.57mmol) were suspended in DMA (2mL) and heated at 100°C for 6 h. The reaction mixture was kept at ambient temperature for 2 days. The mixture was acidified with acetic acid and the crude product was purified by ion exchange chromatography using an SCX column, eluting with 7M NIH /MeOH. After evaporation of the solvent, the resulting solid was stirred in 4M HCl in dioxane (5mL) for 1 h. After evaporation of the solvent to dryness, the crude product was purified by preparative HPLC (Waters XBridge Prep CI 8 OBD column, 5 μιη silica, 30mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1% N¾) and MeCN as an eluent to afford 7-fluoro-6-[6-(hydroxymethyl)pyridin-3-yl]-4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } quino line-3 -carboxamide (0.15 Og, 80%) as a white solid. 'HNMR Spectrum (500 MHz, DMSO-d6): 1.60 (3H, d), 3.82 (3H, s), 4.70 (2H, d), 5.32 (1H, p), 5.53 (1H, t), 6.23 (1H, d), 7.54 (1H, br s), 7.61 -7.74 (3H, m), 8.05 (1H, dt), 8.21 (1H, br s), 8.53 (1H, d), 8.71 (1H, s), 8.87 (1H, s), 9.81 (1H, d). Mass Spectrum: m/z [M+H]⁺= 421.

Intermediate 7.1: 6-[6-({[tei"i-butyl(dimethyl)silyl]oxy}methyl)pyridin-3-yl]-4-chloro- 7-fluoroquinoline-3-carboxamide

6-Bromo-4-chloro-7-fluoroquinoline-3-carboxamide (1.2g, 3.95mmol), 2-({[tert- butyl(dimethyl)silyl]oxy}methyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.657g, 4.74mmol), cesium carbonate (3.86g, 11.86mmol) and

tetrakis(triphenylphosphine)palladium(0) (0.320g, 0.28mmol) were suspended in degassed dioxane (20mL) and water (2.2mL) at ambient temperature. The resulting mixture was degassed, purged with nitrogen and heated at 90°C for 4 h. The mixture was allowed to cool, and was filtered, washing sequentially with water and Et₂0. The resulting pale beige material was dried to provide 6-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-3-yl]-4- chloro-7-fluoroquinoline-3-carboxamide (1.850g, 105%) as a cream solid. 'HNMR

Spectrum (400 MHz, DMSO-d6): 0.00 (6H, s), 0.76 - 0.83 (9H, s), 4.71 (2H, s), 7.45-7.52 (1H, m), 7.81 (1H, s), 7.94 (1H, d), 8.05 (2H, dd), 8.27 (1H, d), 8.68 (1H, s), 8.79 (1H, s). Mass Spectrum: m/z [M+H]⁺= 446. Intermediate 7.2: 2-({[terf-butyl(dimethyl)silyl] oxy}methyl)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine

To a solution of 5-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (3.15g, 10.42mmol) in dioxane (30mL) under an atmosphere of argon were added

4,4,4^*,4^*,5,5,5^*,5^*-octamethyl-2,2^,-bi(l,3,2-dioxaborolane) (5.29g, 20.84mmol), [Ι,Γ- ¾z^'5(diphenylphosphino)ferrocene]palladium(II) chloride (0.600g, 0.73mmol), and potassium acetate (3.07g, 31.26mmol) sequentially. The reaction mixture was heated to 90°C for 2 h. The mixture was cooled down to r.t., diluted with EtOAc and washed with water and brine. The organic layer was collected, dried on MgS0₄, filtered and purified by FCC using a mixture of heptane/EtOAc (from 0% to 40% EtOAc) as an eluent. The fractions containing the product were pooled together, co-evaporated to yield 2-({[tert- butyl(dimethyl)silyl]oxy}methyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (3.33g, 91%) as a brown oil.

'HNMR Spectrum (400 MHz, DMSO-d6): 0.00 (6H, s), 0.98 (6H, s), 1.08 (6H, s), 1.22 (9H, s), 4.67 (2H, s), 7.36 (1H, dd), 7.94 (1H, dd), 8.59 (1H, s). Mass Spectrum: m/z

[M+H]⁺= 350.

Intermediate 7.3: 5-bromo-2-({[tei"i-but l(dimethyl)silyl]oxy}methyl)pyridine

To a solution of (5-bromopyridin-2-yl)methanol (2g, 10.6mmol) in DMF (20mL) was added imidazole (1.086g, 15.96mmol) under an atmosphere of argon. The mixture was cooled down to 0 °C and tert-butylchlorodimethylsilane (1.924g, 12.76mmol) was added at 0 °C. The reaction mixture was allowed to warm up to r.t. for 1 h. The crude mixture was diluted with EtOAc, and washed with water and brine. The organic layer was collected, dried on Na₂S04, filtered and purified by FCC eluting with DCM. The fractions containing the product were pooled, co-evaporated to yield 5-bromo-2-({[tert- butyl(dimethyl)silyl]oxy}methyl)pyridine (3.15g, 98%) as a transparent oil. Ή NMR Spectrum (400 MHz, DMSO-d6): 0.00 (6H, s), 0.82 (9H, s), 4.62 (2H, s), 7.31 (1H, dd), 7.97 (1H, dd), 8.47 - 8.56 (1H, m). Mass Spectrum: m/z [M+H]⁺= 302, 304.

Example 8

4-{[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-7-fluoro-6-[6- (hydroxymethyl)pyridin-3-yl]quinoline-3-carboxamide

6- [6-( { [tert-butyl(dimethyl)silyl]oxy } methyl)pyridin-3 -yl] -4-chloro-7-fluoroquino line-3 - carboxamide (0.2g, 0.45mmol), (15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (0.079g, 0.45mmol) and DIPEA (0.272mL, 1.57mmol) were suspended in DMA (2mL) and heated at 100°C for 6 h. The reaction mixture was kept at ambient temperature for 2 days. The mixture was acidified with acetic acid and the crude product was purified by ion exchange chromatography, using an SCX column eluting with 7M NF /MeOH and pure fractions were evaporated to dryness. The resulting solid was stirred in 4M HCl in dioxane (5mL) for 1 h. After evaporation of the solvent to dryness, the crude product was purified by preparative HPLC (Waters XBridge Prep CI 8 OBD column, 5μΜ silica, 30mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1% NH₃) and MeCN as eluents to afford 4-{[(lS)-l-(l,4-dimethyl-lH-pyrazol- 3 -yl)ethyl] amino } -7-fluoro-6- [6-(hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide

(0.150g, 77%) as a solid. H NMR Spectrum (500 MHz, DMSO-d6): 1.61 (3H, d), 1.92 (3H, s), 3.71 (3H, s), 4.71 (2H, d), 5.36 (1H, p), 5.54 (1H, t), 7.38 (1H, s), 7.51 (1H, s), 7.63 - 7.71 (2H, m), 8.08 (1H, dt), 8.20 (1H, s), 8.47 (1H, d), 8.76 (1H, s), 8.85 (1H, s), 10.10 (1H, d). Mass Spectrum: m/z [M+H]⁺= 435. Example 8.1

4-{[(lR)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-7-fluoro-6-[6- (hydroxymethyl)pyridin-3-yl]quinoline-3-carboxamide

Using a similar procedure as in Example 8, 6-[6-({[tert- butyl(dimethyl)silyl]oxy}methyl)pyridin-3-yl]-4-chloro-7-fluoroquinoline-3-carboxamide (O. lg, 0.22mmol) and (li?)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (0.039g, 0.22mmol) were reacted to afford the title compound (0.080g, 82%) as a solid. 'HNMR Spectrum (500 MHz, DMSO-d6): 1.61 (3H, d), 1.92 (3H, s), 3.71 (3H, s), 4.71 (2H, d), 5.32 - 5.41 (1H, m), 5.54 (1H, t), 7.39 (1H, s), 7.52 (1H, s), 7.64 - 7.7 (2H, m), 8.08 (1H, d), 8.20 (1H, s), 8.47 (1H, d), 8.76 (1H, s), 8.85 (1H, s), 10.10 (1H, d). Mass Spectrum: m/z [M+H]⁺= 435.

Example 9

6-[2-fluoro-6-(methoxymethyl)pyridin-3-yl]-4-{[(lS)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

Tetrakis(triphenylphosphine)palladium(0) (46.6mg, 0.04mmol) was added in one portion to a mixture of 6-bromo-4-{[(15)-l-(l-methyl-lH-pyrazol-3-yl)ethyl]amino}quinoline-3- carboxamide (754mg, 2.01mmol), 2-fluoro-6-(methoxymethyl)-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine (774mg, 2.32mmol) and cesium carbonate (1641mg, 5.04mmol) in degassed dioxane (10mL):water (1.25mL) under nitrogen. The resulting mixture was stirred at 90°C for 18 h. The reaction mixture was diluted with EtOAc (50mL), and washed with water (2 x 50mL). The organic layer was dried over MgSC^, filtered and evaporated. The resulting crude product was purified by ion exchange chromatography using an SCX column, eluting from the column using 7M NH₃/MeOH. After further purification by FCC, eluting with a 0% to 10% gradient of MeOH in DCM, the pure fractions were evaporated to dryness, slurried with MeCN overnight and filtered to afford 6-[2-fluoro-6-(methoxymethyl)pyridin-3-yl]-4-{[(15)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino }quinoline-3-carboxamide (217mg, 24.8%) as a cream solid.

'HNMR Spectrum (400 MHz, DMSO-d6): 1.56 (3H, d), 3.43 (3H, s), 3.75 (3H, s), 4.52 (2H, s), 5.17-5.33 (1H, m), 6.18 (1H, d), 7.51 (2H, d), 7.58 (1H, d), 7.91 (2H, s), 8.17 (2H, dd), 8.51 (1H, s), 8.83 (1H, s), 9.51 (1H, d). Mass Spectrum: m/z [M+H]⁺= 435. [a]_D: -33° in EtOH (c~2mg/mL).

Intermediate 9.1: 6-Bromo-4-{[(lS)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

6-bromo-4-chloroquinoline-3-carboxamide (750mg, 2.63mmol), ( IS)- 1-(1 -methyl- 1H- pyrazol-3-yl)ethylamine hydrochloride (467mg, 2.89mmol) and DIPEA (1.373mL, 7.88mmol) were dissolved in DMA (8mL). The reaction was heated to 100°C for 18 h, then cooled to r.t. The resulting mixture was diluted with MeOH and was purified by ion exchange chromatography, using an SCX column eluting using 7M NH₃/MeOH. Pure fractions were evaporated to dryness to afford (5)-6-bromo-4-((l-(l-methyl-lH-pyrazol-3- yl)ethyl)amino)quinoline-3-carboxamide (754mg, 77%) as a tan solid. Ή NMR Spectrum (400 MHz, DMSO-d6) 1.51 (3H, d), 1.88-2.00 (3H, m), 3.69 (3H, d), 5.15 (1H, dd), 7.35 (1H, s), 7.47 (1H, s), 7.66 - 7.80 (2H, m), 8.08 (1H, s), 8.39 (1H, d), 8.74 (1H, s), 9.40 (1H, d). Mass Spectrum: m/z [M+H]⁺= 376. Intermediate 9.2: 6-bromo-4-chloro uinoline-3-carboxamide

DMF (1.506mL, 19.4mmol) was added to 6-bromo-4-oxo-lH-quinoline-3-carboxylic acid (51.93g, 193.7mmol) and thionyl chloride (353mL, 4843mmol) at ambient temperature and the resulting solution stirred at 70°C for 2 h under an inert atmosphere. The resulting solution was evaporated to dryness and the residue was azeotroped with toluene to afford 6-bromo-4-chloroquinoline-3-carbonyl chloride (62.13g). The 6-bromo-4- chloroquinoline-3-carbonyl chloride was dissolved in DCM (420mL) and added

portionwise to aqueous ammonium hydroxide (251mL, 1937mmol, 7.7 N) at 0°C over 15 minutes. The organic solvent was removed under reduced pressure and the solid collected by filtration, washed with water, ether and then dried to afford 6-bromo-4-chloroquinoline- 3-carboxamide (52.8g, 95%) as a white solid. ^!H NMR Spectrum (500MHz, DMSO-d6): 8.00-8.11 (3H, m), 8.24 (1H, s), 8.45 (1H, s), 8.92 (1H, s). Mass Spectrum: m/z [M+H]⁺= 287.

Intermediate 9.3: 6-bromo-4-oxo-lH-quinoline-3-carboxylic acid

2N Sodium hydroxide (506mL, 101 lmmol) was added to a stirred suspension of ethyl 6- bromo-4-oxo-lH-quinoline-3-carboxylate (59.9g, 202mmol) in EtOH (590mL) and the resulting solution was stirred at 75 °C for 1.5 h. Water (1L) was added and the mixture cooled to 0°C. The pH of the solution was adjusted to 3 using hydrochloric acid and the precipitate collected by filtration. The solid was washed with water, EtOH/water (1 : 1) then Et₂0 and dried to afford 6-bromo-4-oxo-lH-quinoline-3-carboxylic acid (51.9g, 96%) as a beige solid. 'HNMR Spectrum (500MHz, DMSO-d6): 7.80 (1H, d), 8.05 (1H, d), 8.37 (1H, s), 8.93 (1H, s). Mass Spectrum: m/z [M+H]⁺= 268, 270. Intermediate 9.4: ethyl 6-bromo-4-oxo-lH-quinoline-3-carboxylate

Diphenyl ether (870mL) was heated to 240°C then diethyl {[(4- bromophenyl)amino]methylidene}propanedioate (75 g, 219.18mmol) added portionwise. The mixture was stirred at 240°C for 60 minutes in a flask fitted with Dean-Stark apparatus. After cooling ,the mixture was diluted with Et₂0 and the solid was collected by filtration, washed with Et₂0 and dried to afford ethyl 6-bromo-4-oxo-lH-quinoline-3- carboxylate (59.9g) as a beige crystallized solid, which was used without purification or characterisation.

Intermediate 9.5: diethyl {[(4-bromophenyl)amino]methylidene}propanedioate

Diethyl 2-(ethoxymethylene)malonate (71.5mL, 354mmol) was added to 4-bromoaniline (42g, 244mmol) in EtOH (420mL) and the resulting mixture stirred at 80°C overnight. After cooling to 10°C, the white solid was collected by filtration, washed with heptane and dried to afford diethyl {[(4-bromophenyl)amino]methylidene}propanedioate (75g, 90%) as a white crystalline solid. ^!H NMR Spectrum (500MHz, DMSO-d6): 1.25 (6H, s), 4.10 - 4.27 (4H, m), 7.38 (2H, d), 7.57 (2H, d), 8.37 (1H, br s). Mass Spectrum: m/z [M+H]⁺= 342, 344. Example 10

4-{[(lS)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[2-fluoro-6- (methoxymethyl)pyridin-3-yl uinoline-3-

In an analogous procedure as in Example 9, 6-bromo-4-{[(15)-l-(l,4-dimethyl-lH- pyrazo 1-3 -yl)ethyl] amino }quinoline-3-carboxamide (256mg, 0.66mmol) and 2-fluoro-6- (methoxymethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (264mg, 0.79mmol) were reacted to afford 4-{[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}- 6-[2-fluoro-6-(methoxymethyl)pyridin-3-yl]quinoline-3-carboxamide (137mg, 46%) as a solid. 'HNMR Spectrum (500 MHz, DMSO-d6): 1.54 (3H, d), 1.83 (3H, s), 3.41 (3H, s), 3.64 (3H, s), 4.51 (2H, s), 5.22-5.33 (1H, m), 7.32 (1H, s), 7.44 (1H, s), 7.51 (1H, d), 7.87 (2H, s), 8.12 (1H, s), 8.19 (1H, dd), 8.44 (1H, s), 8.80 (1H, s), 9.75 (1H, d). Mass

Spectrum: m/z [M+H]⁺= 449.

Intermediate 10.1: 6-bromo-4-{[(lS)-l-(l,4-dimethyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

The 6-bromo-4- { [( 15)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } quino line-3 - carboxamide (256mg, 94%) used as starting material was made in a similar way to that described in Intermediate 9.1. ^!HNMR Spectrum (400 MHz, DMSO-d6): 1.51 (3H, d), 1.88-2.0 (3H, m), 3.69 (3H, d), 5.15 (1H, dd), 7.35 (1H, s), 7.47 (1H, s), 7.66-7.8 (2H, m), 8.08 (1H, s), 8.39 (1H, d), 8.74 (1H, s), 9.40 (1H, d). Mass Spectrum: m/z [M-H]^" = 386. Example 11

4-{[(lS)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6-(methoxymethyl)pyridin- 3-yl] quinoline-3-carboxamide

In an analogous procedure to that described in Example 2.2, 6-bromo-4-{[(15)-l-(l,4- dimethyl-lH-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (280mg, 0.72mmol) and

2- (methoxymethyl)-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (269mg, 1.08mmol) were reacted, except that the reaction mixture was heated at 100°C for 18 h, to give 4- {[(liS)-l-(l ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -6- [6-(methoxymethyl)pyridin-3 - yl]quinoline-3-carboxamide (162mg, 52%) as a white solid. Ή NMR Spectrum (400 MHz, CD3OD): 1.56 (3H, d), 1.90 (3H, s), 3.41 (3H, s), 3.70 (3H, s), 4.56 (2H, s), 5.32 (IH, p), 7.36 (IH, s), 7.49 (IH, br s), 7.53 (IH, d), 7.88 (IH, d), 8.02 (IH, d), 8.16 (IH, br s), 8.18 (IH, dd), 8.50 (IH, d), 8.78 (IH, s), 8.93 (IH, d), 9.85 (IH, d). Mass Spectrum: m/z

[M+H]⁺= 431.

Example 11.1

4-{[(lR)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl] amino}-6-[6-(methoxymethyl)pyridin-

3- yl] quinoline-3-carboxamide

Under an atmosphere of nitrogen, a mixture of 6-bromo-4-{[(li?)-l-(l,4-dimethyl-lH- pyrazo 1-3 -yl)ethyl] amino }quinoline-3-carboxamide (280mg, 0.72mmol), 2- (methoxymethyl)-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (449mg, 1.80mmol), Pd(PPh₃)₄ (84mg, 0.07mmol) and Cs₂C0₃ (470mg, 1.44mmol) in dioxane (20mL) - water (5mL) was stirred for 3 h at 90°C. After cooling, the resulting mixture was concentrated under vacuum and purified by FCC, eluting with DCM/MeOH (10: 1). The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5μιη, 19x150mm; mobile phase, water with 0.03% NH₄OH and MeCN (22.% MeCN up to 40%) to give the title compound (125mg, 40%) as a white solid. Ή NMR Spectrum (300 MHz, DMSO-d6): 1.56 (3H, d), 1.90 (3H, s), 3.41 (3H, s), 3.70 (3H, s), 4.56 (2H, s), 5.30-5.36 (1H, m), 7.36 (1H, s), 7.53 (1H, d), 7.87 (1H, d), 8.02 (1H, d), 8.17 (1H, d), 8.50 (1H, s), 8.78 (1H, m), 8.92 (1H, m), 9.82-9.85 (1H, m). Mass Spectrum: m/z [M+H]⁺= 431.

Intermediate 11.1.1: 6-Bromo-4- { [(1R)- 1-(1 ,4-dimethyl- lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

A mixture of 6-bromo-4-chloroquinoline-3-carboxamide (600mg, 2.10mmol), (1R)-1-(1,4- dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (536mg, 3.05mmol) and DIPEA (l . lmL, 6.28mmol) in DMA (lOmL) was stirred for 12 h at 100°C. After cooling, water (50mL) was added and the resulting solution was extracted with DCM (3x50mL). The organic layers combined and washed with brine (50mL), dried over anhydrous sodium sulphate and concentrated under vacuum to give 6-bromo-4-{[(li?)-l-(l,4-dimethyl-lH- pyrazo 1-3 -yl)ethyl] amino }quinoline-3-carboxamide (800mg, 98%>) as a brown oil. Mass Spectrum: m/z [M+H]⁺= 388, 390.

Example 12

4-{[(lS)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[2-fluoro-6- (hydroxymethyl)pyridin-3-yl]quinoline-3-carboxamide

In an analogous procedure as in Example 2.2, 6-bromo-4-{[(15)-l-(l,4-dimethyl-lH- pyrazo 1-3 -yl)ethyl] amino }quinoline-3-carboxamide (130mg, 0.33mmol) and [6-fluoro-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]methanol (127mg, 0.50mmol) were reacted, except that the mixture was purified by preparative HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5μΜ, 19x150mm; mobile phase, water with 0.1%formic acid / MeCN to give 4-{[(lS)-l-(l,4-dimethyl-lH-pyrazol-3- yl)ethyl] amino } -6- [2-fluoro-6-(hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide, formate salt (16.4mg, 10%) as an off-white solid. 'HNMR Spectrum (400 MHz, CD₃OD): 1.73 (3H, d), 1.97 (3H, s), 3.74 (3H, s), 4.7 (2H, s), 5.4-5.5 (1H, m), 7.32 (1H, s), 7.55-7.65 (1H, m), 7.92 (1H, d), 8.03-8.12 (2H, m), 8.50 (1H, d), 8.81 (1H, s). Mass Spectrum: m/z [M+H]⁺= 435

Example 13

6-[6-(hydroxymethyl)pyridin-3-yl]-4-{[(lS)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

In an analogous procedure as in Example 7, 6-[6-({[tert- butyl(dimethyl)silyl]oxy } methyl)pyridin-3 -yl] -4-chloroquino line-3 -carboxamide (0.2g, 0.47mmol) and (15)-l-(l-methyl-lH-pyrazol-3-yl)ethylamine hydrochloride (0.091g, 0.56mmol) were reacted to afford 6-[6-(hydroxymethyl)pyridin-3-yl]-4-{[(15)-l-(l- methyl-lH-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (0.150g, 80%) as a solid. 'HNMR Spectrum (500 MHz, DMSO-d6): 1.57 (3H, d), 3.82 (3H, s), 4.64 (2H, d), 5.23- 5.3 (1H, m), 5.45 (1H, t), 6.23 (1H, d), 7.49 (1H, s), 7.58 (1H, d), 7.62 (1H, d), 7.91 (1H, d), 8.05 (1H, dd), 8.13 (2H, dd), 8.56 (1H, d), 8.81 (1H, s), 8.84 (1H, d), 9.54 (1H, d). Mass Spectrum: m/z [M+H]⁺= 403.

Intermediate 13.1: 6- [6-({ [7¾f"f-butyl(dimethyl)silyl] oxy} methyl)pyridin-3-yl] -4- chloroquinoline-3-carboxamide

6-Bromo-4-chloroquinoline-3-carboxamide (l . lg, 3.85mmol) and 2-({[tert- butyl(dimethyl)silyl]oxy}methyl)-5-(4_^

(1.61g, 4.62mmol) were reacted according to the same procedure as Intermediate 7.1 to give 6- [6-( { [tert-butyl(dimethyl)silyl]oxy } methyl)pyridin-3 -yl] -4-chloroquino line-3 - carboxamide (l .Og, 100%). 'HNMR Spectrum (400 MHz, DMSO-d6): 0.00 (6H, s), 0.80 (9H, s), 4.71 (2H, s), 7.47 (2H, d), 7.81 (1H, s), 8.02 - 8.22 (3H, m), 8.38 (1H, d), 8.75 (1H, s), 8.86 (1H, d). Mass Spectrum: m/z [M+H]⁺= 428.

Example 14

4-{[(lS)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6-(hydroxymethyl)pyridin- 3-yl] quinoline-3-carboxamide

In an analogous procedure as in Example 7, 6-[6-({[tert- butyl(dimethyl)silyl]oxy } methyl)pyridin-3 -yl] -4-chloroquino line-3 -carboxamide (0.2g, 0.47mmol) and (15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (0.082g, 0.47mmol) were reacted to afford 4-{[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}- 6-[6-(hydroxyrnethyl)pyridin-3-yl]quinoline-3-carboxamide (0.150g, 77%) as a solid. 'HNMR Spectrum (500 MHz, DMSO-d6): 1.62 (3H, d), 1.97 (3H, s), 3.77 (3H, s), 4.70 (2H, d), 5.33 - 5.41 (1H, m), 5.51 (1H, t), 7.42 (1H, s), 7.50 (1H, s), 7.64 (1H, d), 7.94 (1H, d), 8.08 (1H, dd), 8.23 (2H, dd), 8.55 (1H, d), 8.85 (1H, s), 8.94 (1H, d), 9.86 (1H, d). Mass Spectrum: m/z [M+H]⁺= 417.

Example 14.1

4-{[(lR)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl] amino}-6-[6-(hydroxymethyl)pyridin- 3-yl] quinoline-3-carboxamide

In an analogous procedure as in Example 7, 6-[6-({[tert- butyl(dimethyl)silyl]oxy } methyl)pyridin-3 -yl] -4-chloroquino line-3 -carboxamide

(O. lg, 0.23mmol), (li?)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethylamine hydrochloride (0.04 lg, 0.23mmol) were reacted to afford the title compound (0.080g, 82%) as a solid. 'HNMR Spectrum (500 MHz, DMSO-d6): 1.62 (3H, d), 1.97 (3H, s), 3.77 (3H, s), 4.70 (2H, d), 5.35 - 5.41 (1H, m), 5.51 (1H, t), 7.42 (1H, s), 7.51 (1H, s), 7.65 (1H, d), 7.95 (1H, d), 8.08 (1H, dd), 8.23 (2H, dd), 8.56 (1H, d), 8.85 (1H, s), 8.95 (1H, d), 9.86 (1H, d). Mass Spectrum: m/z [M+H]⁺= 417.

Example 15

4-{[(15)-l-(4-fluoro-l-methyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6- (methoxymethyl)pyridin-3-yl uinoline-3-carboxamide

In an analogous procedure to that described in Example 5, (15)-l-(4-fluoro-l-methyl-lH- pyrazol-3-yl)ethylamine (0.052g, 0.37mmol) and 4-chloro-6-[6-(methoxymethyl)pyridin- 3-yl]quinoline-3-carboxamide (O. lOOg, 0.31mmol) were reacted to afford 4-{[(15)-l-(4- fluoro- 1 -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -6- [6-(methoxymethyl)pyridin-3 - yl]quinoline-3-carboxamide (8.0mg, 6%). ^!H NMR Spectrum (500 MHz, DMSO-d6) 1.59 (3H, d), 3.42 (3H, s), 3.73 (3H, s), 4.58 (2H, s), 5.26 - 5.4 (IH, m), 7.50 (IH, s), 7.55 (IH, d), 7.78 (IH, d), 7.94 (IH, d), 8.07 (IH, dd), 8.15 (IH, s), 8.22 (IH, dd), 8.55 (IH, d), 8.83 (IH, s), 8.97 (IH, d), 9.43 (IH, d). Mass Spectrum: m/z [M+H]⁺= 435.

Intermediate 15.1: 4-chloro-6- [6-(methoxy methyl)py ridin-3-yl] quinoline-3- carboxamide

Sodium tetrachloropalladate(II) (0.907g, 3.08mmol) and 3-(di-tert- butylphosphino)propane-l -sulfonic acid (16.54g, 61.64mmol) dissolved in water (50.0mL) under an atmosphere of nitrogen were added to 6-bromo-4-chloroquinoline-3-carboxamide (17.6g, 61.64mmol), 2-(methoxymethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (21.94g, 61.64mmol) and potassium phosphate (39.3g, 184.92mmol) in thoroughly degassed dioxane (200mL) under nitrogen. The resulting mixture was stirred at 85°C for 2 h then allowed to cool to r.t. The reaction mixture was diluted with EtOAc (250mL), and washed sequentially with water (250mL) and brine (250mL). The organic layer was dried over Na₂SC"4, filtered and evaporated. Purification by preparative HPLC (column packed with silica) using a gradient from heptane/EtOAc 50/50 to EtOAc over 20 minutes afforded 4-chloro-6-[6-(methoxymethyl)pyridin-3-yl]quinoline-3-carboxamide

(6.1g, 30%). HNMR Spectrum (400 MHz, DMSO-d6) 3.48 (3H, s), 4.65 (2H, s), 7.61 - 7.68 (IH, m), 8.04 (IH, s), 8.29 (IH, s), 8.31 (IH, s), 8.34 - 8.4 (2H, m), 8.58 (IH, d), 8.96 (IH, s), 9.06 - 9.11 (IH, m). Mass Spectrum: m/z [M+H]⁺= 328. Example 16

6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(lS)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

In an analogous procedure as in Example 3, 4-chloro-6-[6-(methoxymethyl)pyridin-3- yl]quinoline-3-carboxamide (85mg, 0.26mmol) and ( IS)- 1-(1 -methyl- lH-pyrazo 1-3- yl)ethylamine hydrochloride (59mg, 0.36mmol) were reacted to provide 6-[6- (methoxymethyl)pyridin-3 -yl] -4- { [( 15)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide (51.9mg, 48%) as a pale yellow solid.

'HNMR Spectrum (400 MHz, DMSO-d6): 1.55 (3H, d), 3.41 (3H, s), 3.81 (3H, s), 4.56 (2H, s), 5.27 (IH, p), 6.22 (IH, d), 7.52 (IH, d), 7.62 (IH, d), 7.91 (IH, d), 8.04 (IH, d), 8.15 - 8.25 (2H, m), 8.57 (IH, s), 8.80 (IH, s), 8.87 (IH, d), 9.55 (IH, d); Mass Spectrum: m/z [M+H]⁺ = 417. [a]_D: -23° in EtOH (c~2mg/mL).

Example 16.1

6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(lR)-l-(l-methyl-lH-pyrazol-3- yl)ethyl] amino} quinoline-3-carboxamide

In an analogous procedure as in Example 3, 4-chloro-6-[6-(methoxymethyl)pyridin-3- yl]quinoline-3-carboxamide (81mg, 0.25mmol) and ( li?)-l-(l -methyl- 1 H-pyrazo 1-3- yl)ethylamine hydrochloride (56mg, 0.35mmol) were reacted to provide 6-[6-

(methoxymethyl)pyridin-3 -yl] -4- { [( li?)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino }quinoline-3-carboxamide (49mg, 48%) as a white solid.

'HNMR Spectrum (400 MHz, DMSO-d6): 1.55 (3H, d), 3.41 (3H, s), 3.81 (3H, s), 4.56 (2H, s), 5.27 (IH, p), 6.22 (IH, d), 7.52 (IH, d), 7.62 (IH, d), 7.91 (IH, d), 8.04 (IH, d), 8.15 - 8.25 (2H, m), 8.57 (IH, s), 8.80 (IH, s), 8.87 (IH, d), 9.55 (IH, d)

Mass Spectrum: m/z [M+H]⁺ = 417. [a]_D: +20° in EtOH (c~2mg/mL).

Example 17

6-[2-fluoro-6-(methoxymethyl)-3-pyridyl]-4-[[(lS)-l-(4-fluoro-l-methyl-pyrazol-3- yl)ethyl] amino] quinoline-3-carboxamide

In an analogous procedure as in Example 5, (15)-l-(4-fluoro-l-methyl-lH-pyrazol-3- yl)ethylamine (0.075g, 0.52mmol), 4-chloro-6-[2-fluoro-6-(methoxymethyl)pyridin-3- yl]quinoline-3-carboxamide (0.150g, 0.43mmol) were reacted to afford 6-[2-fiuoro-6- (methoxymethyl)-3 -pyridyl] -4- [ [( 1 S)- 1 -(4-fluoro- 1 -methyl-pyrazo 1-3 - yl)ethyl]amino]quinoline-3-carboxamide (0.03 lg, 16%). 'HNMR Spectrum (500 MHz, DMSO-d6): 1.58 (3H, d), 3.43 (3H, s), 3.68 (3H, s), 4.53 (2H, s), 5.23 - 5.34 (IH, m), 7.53 (2H, d), 7.75 (IH, d), 7.93 (2H, d), 8.16 (IH, s), 8.25 (IH, dd), 8.49 (IH, s), 8.85 (IH, s), 9.45 (IH, d). Mass Spectrum: m/z [M+H]⁺= 452.

Intermediate 17.1: 4-chloro-6-[2-fluoro-6-(methoxymethyl)pyridin-3-yl]quinoline-3- carboxamide

Tetrakis(triphenylphosphine)palladium(0) (0.202g, 0.18mmol) was added to 6-bromo-4- chloroquinoline-3-carboxamide (0.5g, 1.75mmol), 2-fluoro-6-(methoxymethyl)-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.608g, 2.28mmol) and cesium carbonate (1.141g, 3.50mmol) in dioxane (5mL) and water (lmL) under nitrogen. The resulting suspension was stirred at 100°C for 3 h. After cooling, the mixture was diluted with EtOAc (15mL) and water (15mL). A precipitated solid was collected by filtration to afford 4- chloro-6-[2-fluoro-6-(methoxymethyl)pyridin-3-yl]quinoline-3-carboxamide (0.477g, 79%) as a cream solid. 'HNMR Spectrum (400 MHz, DMSO-d6): 3.42 (3H, s), 4.53 (2H, s), 7.54 (IH, dd), 7.98 (IH, s), 8.15 (IH, dt), 8.21 (IH, s), 8.24 (IH, d), 8.35 (IH, dd), 8.48 (IH, s), 8.92 (IH, s). Mass Spectrum: m/z [M+H]⁺= 346.

Biological Assays

An ATM cellular potency assay was used to measure the effects of the compounds of the present invention. During the description of the assay, generally:

i. The following abbreviations have been used: Ab = Antibody; BSA = Bovine Serum Albumin; C0₂ = Carbon Dioxide; DMEM = Dulbecco's Modified Eagle Medium; DMSO =Dimethyl Sulphoxide; EMEM = Eagle's Minimal Essential Medium; FBS = Foetal Bovine Serum; h = hour(s); PBS = Phosphate buffered saline.

ii. IC50 values were calculated using a smart fitting model in Genedata. The IC50 value was the concentration of test compound that inhibited 50% of biological activity.

Assay a): ATM Cellular Potency

Rationale:

Cellular irradiation induces DNA double strand breaks and rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell.

The rationale of the pATM assay is to identify inhibitors of ATM in cells. HT29 cells are incubated with test compounds for lhr prior to X-ray- irradiation, lh later the cells are fixed and stained for pATM (Serl981). The fluorescence is read on the arrayscan imaging platform. Method details:

HT29 cells (ECACC #85061109) were seeded into 384 well assay plates (Costar #3712) at a density of 3500 cells / well in 40 μΐ EMEM medium containing 1% L glutamine and 10% FBS and allowed to adhere overnight. The following morning compounds of Formula (I) in 100%) DMSO were added to assay plates by acoustic dispensing. After lh incubation at 37°C and 5% C0₂, plates (up to 6 at a time) were irradiated using the X-RAD 320 instrument (PXi) with equivalent to ~600cGy. Plates were returned to the incubator for a further lh. Then cells were fixed by adding 20 μΐ of 3.7% formaldehyde in PBS solution and incubating for 20 minutes at r.t. before being washed with 50μ1 / well PBS, using a Biotek EL405 plate washer. Then 20μ1 of 0.1 % Triton X100 in PBS was added and incubated for 20 minutes at r.t., to permeabalise cells. Then the plates were washed once with 50μ1 / well PBS, using a Biotek EL405 plate washer.

Phospho-ATM Serl981 antibody (Millipore #MAB3806) was diluted 10000 fold in PBS containing 0.05%> polysorbate/Tween and 3% BSA and 20μ1 was added to each well and incubated over night at r.t. The next morning plates were washed three times with 50μ1 / well PBS, using a Biotek EL405 plate washer, and then 20μ1 of secondary Ab solution, containing 500 fold diluted Alexa Fluor® 488 Goat anti-rabbit IgG (Life Technologies, Al 1001) and 0.002mg/ml Hoeschst dye (Life technologies #H-3570), in PBS containing 0.05%> polysorbate/Tween and 3% BSA, was added. After lh incubation at r.t., the plates were washed three times with 50μ1 / well PBS, using a Biotek EL405 plate washer, and plates were sealed and kept in PBS at 4°C until read. Plates were read using an ArrayScan VTI instrument, using an XF53 filter with 10X objective. A two laser set up was used to analyse nuclear staining with Hoeschst (405nm) and secondary antibody staining ofpSerl981 (488nm).

The results of testing the Examples in assay a) are shown in Table 3. Table 3: Potency Data for Examples 1 - 17 in Assay a)

Example Assay a) ATM Cell ICso (μΜ)

1 0.0289

1.1 1.26

2 0.0734

2.1 0.0278

2.2 0.163

3 0.01

3.1 2.81

4 0.0772

4.1 0.209

5 0.0192

5.1 1.89

6 0.0113

6.1 0.214

7 0.114

8 0.0157

8.1 2.18

9 0.0625

10 0.0456

11 0.0175

11.1 1.23

12 0.29

13 0.214

14 0.0832

14.1 3.87

15 0.0624

16 0.0281

16.1 2.25

17 0.0458 Assay b) : Mouse Xenograft Model

Male nude mice were transplanted s.c. with SW620 cells (ATCC - CCL-227) to determine the in-vivo anti-tumour activity of ATM inhibitors. 1 x 10^A6 cells in 50% matrigel (BD Bioscience) were injected s.c. on the left flank of the animals. Animals were randomised into groups of 10-15 when tumours reached a volume of ~200-300mm³ and treatment commenced. Animals received 3 weekly cycles of treatment with compound. Animals were dosed once weekly with Irinotecan by i.p., and then 24 h post Irinotecan animals received a twice daily dose at 12h intervals on 3 consecutive days by peroral route with a compound of Formula (I). Tumours were measured twice weekly by caliper and volume of tumours calculated using elliptical formula (π/6 x width x width x length). Irinotecan was formulated in a 7.5% DMSO/ 92.5% water for injection solution.

Compounds of Formula (I) were formulated in a 10% DMSO/90% Captisol (30%w/v) solution. Captisol was sourced from Cydex Pharmaceuticals (Trademarked) β-cyclodextrin suitable for in vivo use and formulations.

The results of testing Example 1 in assay b) are shown in Figure 7. "Q7D" Means a once weekly dose. "Q1D" is a once daily dose.

Claims

1. A compound of Formula (I) :

or a pharmaceutically acceptable salt thereof, where:

R¹ is methoxymethyl or hydroxymethyl;

R² is hydro or fluoro;

R³ is hydro, fluoro or methyl;

R⁴ is hydro or methyl; and

R⁵ is hydro or fluoro.

2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , where R¹ is methoxymethyl.

3. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or claim 2, where R² is hydro.

4. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, where R³ is hydro.

5. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, where R⁴ is methyl.

6. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, where R⁵ is fluoro.

7. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , where the compound is selected from:

7-fiuoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- { [( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

7-fiuoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- {[( IR)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- {[(liS)-l-(l ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fiuoro-6-[2-fiuoro-6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(liS)-l-(l ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fiuoro-6-[2-fiuoro-6-

(hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- { [( 1 S)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6-

(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- { [( IR)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6-

(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

7-fiuoro-6- [6-(methoxymethyl)pyridin-3-yl] -4- {[(15)- 1-(1 H-pyrazo 1-3- yl)ethyl] amino } quino line-3 -carboxamide;

7-fiuoro-6- [6-(hydroxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide; 4- { [( 1 S)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- { [( 1R)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(IS)- l-(l,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino} -6- [2-fluoro-6-

(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6-

(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- { [( 1R)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -6- [6-

(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(IS)- l-(l,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino} -6- [2-fluoro-6-

(hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6-

(hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- { [( 1R)- 1 -( 1 ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -6- [6-

(hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(IS)- 1 -(4-fiuoro- 1 -methyl- 1 H-pyrazo 1-3 -yl)ethyl] amino} -6- [6-

(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

6-[2-fiuoro-6-(methoxymethyl)-3-pyridyl]-4-[[(15)- 1 -(4-fiuoro- 1 -methyl-pyrazol-3- yl)ethyl] amino] quino line-3 -carboxamide.

8. A pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, and at least one pharmaceutically acceptable diluent or carrier.

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use in therapy.

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use in the treatment of cancer.

The compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer as claimed in claim 10, where the compound of Formula (I) is used simultaneously, separately or sequentially with radiotherapy.

The compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer as claimed in claim 10, where the compound of Formula (I) is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin.

Use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for the manufacture of a medicament for the treatment of cancer.

A method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7.

15. A compound of Formula (IA) :

or a pharmaceutically acceptable salt thereof, where:

R¹ is methoxymethyl or hydroxymethyl;

R² is hydro or fluoro;

R³ is hydro, fluoro or methyl;

R⁴ is hydro or methyl; and

R⁵ is hydro or fluoro.

16. The compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in claim 15, where R¹ is methoxymethyl.

17. The compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in claim 15 or claim 16, where R² is hydro.

18. The compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 15 to 17, where R³ is hydro.

19. The compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 15 to 18, where R⁴ is methyl.

20. The compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 15 to 19, where R⁵ is fluoro.

21. The compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in claim 15, where the compound is selected from:

7-fluoro-6- [6-(methoxymethyl)pyridin-3 -yl] -4- { [( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- {[(liS)-l-(l ,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino } -7-fluoro-6-[2-fluoro-6-

(hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

6- [2-fluoro-6-(methoxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide;

4- {[(IS)- l-(l,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino} -6- [2-fluoro-6-

(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6-

(methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(IS)- l-(l,4-dimethyl- 1 H-pyrazo 1-3 -yl)ethyl] amino} -6- [2-fluoro-6-

(hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

6- [6-(hydroxymethyl)pyridin-3 -yl] -4- {[( 1 S)- 1 -( 1 -methyl- 1 H-pyrazo 1-3 - yl)ethyl] amino } quino line-3 -carboxamide; 4-{[(15)-l-(l,4-dimethyl-lH-pyrazol-3-yl)ethyl]amino}-6-[6- (hydroxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

4- {[(IS)- 1 -(4-fluoro- 1 -methyl- lH-pyrazo 1-3 -yl)ethyl] amino} -6- [6- (methoxymethyl)pyridin-3 -yl] quino line-3 -carboxamide;

6-[6-(methoxymethyl)pyridin-3-yl]-4- {[(15)- 1 -(1 -methyl- 1 H-pyrazol-3- yl)ethyl] amino } quino line-3 -carboxamide; and

6-[2-fluoro-6-(methoxymethyl)-3-pyridyl]-4-[[(15)- 1 -(4-fluoro- 1 -methyl-pyrazol-3- yl)ethyl] amino] quino line-3 -carboxamide.

22. A pharmaceutical composition which comprises a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 15 to 21, and at least one pharmaceutically acceptable diluent or carrier.

23. A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 15 to 21, for use in therapy.

24. A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 15 to 21, for use in the treatment of cancer.

25. The compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer as claimed in claim 24, where the compound of Formula (IA) is used simultaneously, separately or sequentially with radiotherapy.

26. The compound of Formula (IA), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer as claimed in claim 24, where the compound of Formula (IA) is used simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin.

27. Use of a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 15 to 21, for the manufacture of a medicament for the treatment of cancer. A method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 15 to 21.