WO2019057757A1

WO2019057757A1 - 1,3-dihydroimidazo[4,5-c]cinnolin-2-one compounds and their use in treating cancer

Info

Publication number: WO2019057757A1
Application number: PCT/EP2018/075327
Authority: WO
Inventors: Kurt Gordon Pike; Bernard Christophe Barlaam
Original assignee: Astrazeneca Ab
Priority date: 2017-09-20
Filing date: 2018-09-19
Publication date: 2019-03-28
Also published as: CN111344293A

Abstract

The specification generally relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, where R1-R4, A and X have the meanings defined herein. The specification also relates to the use of compounds of Formula (I) and salts thereof to treat or prevent ATM mediated disease, including cancer. The specification further relates to pharmaceutical compositions comprising substituted 1,3-dihydroimidazo[4,5-c]cinnolin-2-one compounds and pharmaceutically acceptable salts thereof; and kits comprising such compounds and salts.

Description

l,3-dihydroimidazo[4,5-c]cinnolin-2-one Compounds and Their Use in Treating

Cancer

FIELD

This specification relates to l,3-dihydroimidazo[4,5-c]cinnolin-2-one compounds and pharmaceutically acceptable salts thereof. These compounds and salts selectively modulate ataxia telangiectasia mutated ("ATM") kinase, and the specification therefore also relates to the use of l,3-dihydroimidazo[4,5-c]cinnolin-2-one compounds and salts thereof to treat or prevent ATM mediated disease, including cancer. The specification further relates to pharmaceutical compositions comprising l,3-dihydroimidazo[4,5- c]cinnolin-2-one compounds and pharmaceutically acceptable salts thereof; and kits comprising such compounds and salts.

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, M. F.; Rev. Mol. Cell Biol. 2008, 759-769).

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. , Oncogene 2013, 3351-3360). 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., Science 2007, 1160-1166), coordinating multiple stress response pathways (Kurz and Lees Miller, DNA Repair 2004, 889-900). 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., Nature 2003, 499-506). This is a critical activation event, and ATM phospho-Serl981 is therefore both a direct

pharmacodynamic and patient selection biomarker for tumour pathway dependency.

The antitumoral effects of ATM inhibitor monotherapy have been reported in a mouse model of acute myeloid leukemia (Fernandez-Capetillo et al., Science Signalling, 2016, 9 (445), ra91). Moreover, ATM kinase responds to direct double strand breaks caused by common anti-cancer treatments such as ionising radiation and topoisomerase-II inhibitors (doxorubicin, etoposide) and also to topoisomerase-I inhibitors (for example irinotecan and topotecan) via single strand break to double strand break conversion during replication. As a result, ATM kinase inhibition can potentiate the activity of any these agents. ATM kinase inhibitors are therefore expected to be of use in the treatment of cancer.

It is desirable for medicinal compounds to have pharmacokinetic properties which allow them to be dosed at tolerable levels to patients. Poor pharmacokinetic properties can be a cause of failure of drug candidates in clinical development. An example of poor pharmacokinetic properties is rapid metabolism which may cause a drug to be cleared rapidly from the body, thus reducing its therapeutic benefit. Although it may be possible to overcome rapid drug clearance by more frequent or higher dosing of the drug, such approaches may decrease patient compliance and/or expose patients to risks of increased side effects. Another approach to addressing problems of rapid metabolism is to substitute one or more atoms in a drug molecule that are suseptible to metabolism with atoms that are less suseptible. The resulting increased stability can impact the pharmacokinetic properties of a drug, for example, by retarding certain pathways of its metabolism.

The compounds described herein are expected to demonstrate pharmacokinetic properties that would be indicative of a profile suitable for administration to patients. WO 2015/170081, WO 2017/046216, WO 2017/076895 and WO 2017/076898 describe imidazo[4,5-c]quinolin-2-one compounds that have activity as ATM kinase modulators. However, there exists a need for new compounds which act against certain kinase enzymes, like ATM kinase, in a highly selective fashion (i.e. by modulating ATM more effectively than other biological targets).

As demonstrated elsewhere in the specification (for example in the cell based assays described in the experimental section), the compounds of the present specification generally possess very potent ATM kinase inhibitory activity, but much less potent activity against other tyrosine kinase enzymes, such as PI 3-kinase a, mTOR kinase and ataxia telangiectasia and Rad3-related protein ("ATR") kinase. As such, the compounds of the present specification not only inhibit ATM kinase, but can be considered to be highly selective inhibitors of ATM kinase.

As a result of their highly selective nature, the compounds of the present specification are expected to be particularly useful in the treatment of diseases in which ATM kinase is implicated (for example, in the treatment of cancer), but where it is desirable to minimise off-target effects or toxicity that might arise due to the inhibition of other tyrosine kinase enzymes, such as class PI 3-kinase a, mTOR kinase and ATR kinase.

SUMMARY

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

(I)

or a pharmaceutically acceptable salt thereof, wherein

A is N or CR⁴;

X is -OR⁵ or -NR⁶R⁷; R¹ is (Ci-C6)alkyl, cycloalkyl or heterocycloalkyl;

R² is H or methyl, wherein methyl is optionally substituted with 1, 2, or 3 halo substituents;

R³ is H, (Ci-C₆)alkyl or halo;

R⁴ is H, (Ci-C₆)alkyl or halo;

R⁵ is -(CH₂)_n-NR⁸R⁹;

R⁶ and R⁷ together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered non-aromatic monocyclic ring comprising carbon which is substituted with - NR¹⁰R^U;

R⁸ and R⁹ are independently selected from H and (Ci-Ce)alkyl; or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered non- aromatic monocyclic ring comprising carbon which can be optionally substituted with halo;

R¹⁰ is H or (Ci-C₃)alkyl;

R¹¹ is (Ci-C )alkyl;

n is 2, 3 or 4;

alkyl is a linear or branched saturated hydrocarbon;

alkoxy is a linear or branched O-linked saturated hydrocarbon;

cycloalkyl is a 3, 4, 5 or 6 membered aliphatic carbocyclic ring, which can be optionally substituted with 1 or 2 substituents selected from (Ci-C₃)alkyl, (Ci-C₃)alkoxy and -OH;

halo is F, CI or Br;

heterocycloalkyl is a 4, 5 or 6 membered non-aromatic monocyclic ring comprising carbon and 1 or 2 heteroatoms selected from nitrogen and oxygen; wherein

heterocycloalkyl can be optionally substituted with 1 or 2 substituents selected from (Ci- C )alkyl, (Ci-C )alkoxy and -OH.

An aspect of this specification includes compounds of formula (I), as defined above, tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof. In another aspect the specification provides a prodrug of a compound of formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.

In yet another aspect, the specification provides an N-oxide of a compound of formula (I) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.

It will be understood that certain compounds of formula (I) may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the specification encompasses all such solvated forms.

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 excipient.

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, the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in 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.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

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

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

(I)

or a pharmaceutically acceptable salt thereof, wherein

A is N or CR⁴;

X is -OR⁵ or -NR⁶R⁷;

R¹ is (Ci-C6)alkyl, cycloalkyl or heterocycloalkyl;

R³ is H, (Ci-C₆)alkyl or halo;

R⁴ is H, (Ci-C₆)alkyl or halo;

R⁵ is -(CH₂)_n-NR⁸R⁹;

R¹⁰ is H or (Ci-C₃)alkyl;

R¹¹ is (Ci-C )alkyl;

n is 2, 3 or 4;

alkyl is a linear or branched saturated hydrocarbon;

alkoxy is a linear or branched O-linked saturated hydrocarbon;

cycloalkyl is a 3, 4, 5 or 6 membered aliphatic carbocyclic ring, which can be optionally substituted with 1 or 2 substituents selected from (Ci-C₃)alkyl, (Ci-C₃)alkoxy and -OH; halo is F, CI or Br;

heterocycloalkyl can be optionally substituted with 1 or 2 substituents selected from (Ci- C₃)alkyl, (Ci-C )alkoxy and -OH.

In an embodiment, there is provided a compound of formula (la)

or a pharmaceutically acceptable salt thereof, wherein

A is N or CH;

X is -OR⁵ or -NR⁶R⁷;

R¹ is (Ci-C₃)alkyl, cycloalkyl, heterocycloalkyl;

R² is H or methyl, wherein methyl is optionally substituted with 1, 2, or 3 fluoro substituents;

R³ is H, methyl, chloro or fluoro;

R⁴ is H, methyl, chloro or fluoro;

R⁵ is -(CH₂)_n-NR⁸R⁹;

R⁸ and R⁹ are independently selected from H and (Ci-C₃)alkyl; or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered non- aromatic monocyclic ring comprising carbon which can be optionally substituted with fluoro;

R¹⁰ is H or (Ci-C )alkyl;

R¹¹ is (Ci-C )alkyl; n is 2, 3 or 4;

alkyl is a linear or branched saturated hydrocarbon;

cycloalkyl is a 3, 4, 5 or 6 membered aliphatic carbocyclic ring, which can be optionally substituted with 1 or 2 substituents selected from methyl, methoxy and -OH; heterocycloalkyl is a 4, 5 or 6 membered non-aromatic monocyclic ring comprising carbon and a heteroatom selected from oxygen; wherein heterocycloalkyl can be optionally substituted with 1 or 2 substituents selected from methyl, methoxy and -OH.

In an embodiment, there is provided a compound of formula (lb)

or a pharmaceutically acceptable salt thereof, wherein

A is N or CH;

R¹ is (Ci-C3)alkyl, cycloalkyl, heterocycloalkyl;

R³ is H, methyl or fluoro;

R⁴ is H, methyl or fluoro;

R⁸ and R⁹ are independently selected from H and (Ci-C3)alkyl; or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 5 or 6 membered non- aromatic monocyclic ring comprising carbon which can be optionally substituted with fluoro;

alkyl is a linear or branched saturated hydrocarbon;

cycloalkyl is a 3, 4, 5 or 6 membered aliphatic carbocyclic ring, which can be optionally substituted with 1 or 2 substituents selected from methyl, methoxy and -OH; heterocycloalkyl is a 5 or 6 membered non-aromatic monocyclic ring comprising carbon and a heteroatom selected from oxygen; wherein heterocycloalkyl can be optionally substituted with 1 or 2 substituents selected from methyl, methoxy and -OH.

embodiment, there is provided a compound of formula (Ic)

or a pharmaceutically acceptable salt thereof, wherein

A is N or CH;

R¹ is (Ci-C3)alkyl, cycloalkyl, heterocycloalkyl;

R³ is H, methyl or fluoro;

R⁴ is H, methyl or fluoro;

R⁶ and R⁷ together with the nitrogen atom to which they are attached form a 5 or 6 membered non-aromatic monocyclic ring comprising carbon which is substituted with -NR¹⁰Rⁿ;

R¹⁰ is H or (Ci-C₃)alkyl;

R¹¹ is (Ci-C₃)alkyl;

alkyl is a linear or branched saturated hydrocarbon;

cycloalkyl is a 3, 4, 5 or 6 membered aliphatic carbocyclic ring, which can be optionally substituted with 1 or 2 substituents selected from methyl, methoxy and -OH; heterocycloalkyl is a 5 or 6 membered non-aromatic monocyclic ring comprising carbon and a heteroatom selected from oxygen; wherein heterocycloalkyl can be optionally substituted with 1 or 2 substituents selected from methyl, methoxy and -OH. The following embodiments of moieties A, X, R^-R¹¹, n and halo may be applied, alone or in combination, to the descriptions of the compounds of Formula (I), (la), (lb) or (Ic) provided above:

A is N or CR⁴.

A is N or CH.

A is N.

A is CH.

X is -OR⁵ or -NR⁶R⁷.

X is -OR⁵.

X is -NR⁶R⁷.

X is selected from the following fragments:

wherein designates the point of attachment of the fragment to the remainder of the molecule. X is selected from the following fragments:

and wherein *" designates the point of attachment of the fragment to the remainder of the molecule.

X is selected from the following fragments:

R¹ is (Ci-C6)alkyl, cycloalkyl or heterocycloalkyl.

R¹ is (Ci-C3)alkyl, cycloalkyl or heterocycloalkyl.

R¹ is methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tertrahydropyranyl; wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tertrahydropyranyl can be optionally substituted with 1 or 2 substituents selected from (Ci-C3)alkyl, (Ci-C3)alkoxy and -OH.

R¹ is n-propyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tertrahydropyranyl; wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tertrahydropyranyl can be optionally substituted with 1 or 2 substituents selected from methyl, methoxy and -OH.

R¹ is iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, tertrahydropyran-3-yl or tertrahydropyran-4-yl; wherein cyclopropyl, cyclobutyl, cyclopentyl, tertrahydropyran-3-yl or tertrahydropyran-4-yl can be optionally substituted with 1 or 2 substituents selected from methyl and methoxy.

R¹ is iso-propyl, cyclopropyl, cyclobutyl or tertrahydropyranyl; wherein

cyclopropyl, cyclobutyl or tertrahydropyranyl can be optionally substituted with 1 or 2 substituents selected from methyl or methoxy. R¹ is selected from the following fragments:

, and ; wherein *· designates the point of attachment of the fragment to the remainder of the molecule.

R¹ is selected from the following fragments:

R¹ is selected from the followin fragments:

and ; wherein *^■ designates the point of attachment of the fragment to the remainder of the molecule.

R¹ is iso-propyl.

R¹ is cyclopropyl, optionally substituted with methyl.

R¹ is cyclobutyl, optionally substituted with methoxy.

R¹ is tertrahydropyranyl, optionally mono or di substituted with methyl. R² is H or methyl, wherein methyl is optionally substituted with 1, 2, or 3 halo substituents.

R² is H or methyl, wherein methyl is optionally substituted with 1, 2, or 3 fluoro substituents.

R² is methyl optionally substituted with 1 , 2, or 3 fluoro substituents.

R² is methyl or CHF₂.

R² is methyl.

R³ is H, (Ci-C₆)alkyl or halo.

R³ is H, (Ci-C3)alkyl, chloro or fluro.

R³ is H, methyl, chloro or fluoro.

R³ is H, methyl or fluoro.

R³ is H or fluoro.

R³ is fluoro.

R³ is H.

R⁴ is H, (Ci-C₆)alkyl or halo.

R⁴ is H, (Ci-C₃)alkyl, chloro or fluro.

R⁴ is H, methyl, chloro or fluoro.

R⁴ is H, methyl or fluoro.

R⁴ is H or fluoro.

R⁴ is H or methyl.

R⁴ is H.

R⁵ is -(CH₂)₃-NR¾⁹.

R⁶ and R⁷ together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered non-aromatic monocyclic ring comprising carbon which is substituted with - NR¹⁰Rⁿ . R⁶ and R⁷ together with the nitrogen atom to which they are attached form a 5 or 6 membered non-aromatic monocyclic ring comprising carbon which is substituted with - NR¹⁰R^U

R⁶ and R⁷ together with the nitrogen atom to which they are attached form a 5 or 6 membered non-aromatic monocyclic ring comprising carbon which is substituted with - N(CH₃)₂.

R⁶ and R⁷ together with the nitrogen atom to which they are attached form a fragment selected from:

wherein ·* designates the point of attachment of the fragment to the aromatic ring containing A.

R⁸ and R⁹ are independently selected from H and (Ci-Ce)alkyl; or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered non- aromatic monocyclic ring comprising carbon which can be optionally substituted with halo.

R⁸ and R⁹ are independently selected from H and (Ci-C3)alkyl; or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 5 or 6 membered non- aromatic monocyclic ring comprising carbon which can be optionally substituted with fluoro.

R⁸ and R⁹ are independently selected from H and methyl; or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 5 or 6 membered non-aromatic monocyclic ring comprising carbon which can be optionally substituted with fluoro.

R⁸ and R⁹ are methyl; or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 5 or 6 membered non-aromatic monocyclic ring comprising carbon which can be optionally substituted with fluoro.

R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 6 membered non-aromatic monocyclic ring comprising carbon which can be optionally substituted with fluoro.

R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 5 membered non-aromatic monocyclic ring comprising carbon which can be optionally substituted with fluoro.

R⁸ and R⁹ together with the nitrogen atom to which they are attached form a fragment selected from:

, and , wherein ** designates the point of attachment of the fragment to the remainder of the molecule.

, wherein ** designates the point of attachment of the fragment to the remainder of the molecule.

wherein »· designates the point of attachment of the fragment to the remainder of the molecule.

R⁸ is H and R⁹ is methyl.

R⁸ and R⁹ are methyl.

R is H or (Ci-C₃)alkyl.

R¹⁰ is H or methyl.

R¹⁰ is methyl.

R¹¹ is (Ci-C₃)alkyl.

R¹¹ is methyl. n is 2, 3 or 4.

n is 2 or 3.

n is 3. halo is F, CI or Br.

halo is F or CI. halo is F.

In an embodiment, the compound of Formula (I) is selected from:

8- [6-[3 -(Dimethylamino)propoxy] -3 -pyridyl] -3 -methyl- 1 -tetrahydropyran-4-yl- imidazo[4,5-c]cinnolin-2-one;

8- [6-[3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -(cis-3 -methoxycyclobutyl)-3 - methyl-imidazo[4,5-c]cinnolin-2-one;

8- [6-[3 -(Dimethylamino)propoxy] -3 -pyridyl] -3 -methyl- 1 - [(3 S)-tetrahydropyran-3 - yl]imidazo[4,5-c]cinnolin-2-one;

8- [6-[3 -(Dimethylamino)propoxy] -3 -pyridyl] -3 -methyl- 1 - [(3R)-tetrahydropyran-3 - yl]imidazo[4,5-c]cinnolin-2-one;

3 -Methyl-8-[6- [3 -( 1 -piperidyl)propoxy] -3 -pyridyl] - 1 -tetrahydropyran-4-yl- imidazo[4,5-c]cinnolin-2-one;

8- [4-[3 -(dimethylamino)propoxy]phenyl] - 1 -isopropyl-3 -methyl-imidazo [4,5 - c]cinnolin-2-one;

l-Isopropyl-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3-pyridyl]imidazo[4,5- c]cinnolin-2-one;

8- [6-[3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -isopropyl-3 -methyl-imidazo [4,5 - c]cinnolin-2-one;

l-Isopropyl-3-methyl-8-[4-(3-pyrrolidin-l-ylpropoxy)phenyl]imidazo[4,5- c]cinnolin-2-one;

l-isopropyl-3-methyl-8-(4-(3-(piperidin-l-yl)propoxy)phenyl)-l,3-dihydro-2H- imidazo[4,5-c]cinnolin-2-one;

8- [6-[3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -(trans-3 -methoxycyclobutyl)-3 - methyl-imidazo[4,5-c]cinnolin-2-one;

8-[6-[3-(4-Fluoro-l -piperidyl)propoxy] -3 -pyridyl]- 1 -isopropyl-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

8- [6-[3 - [(3R)-3 -Fluoropyrrolidin- 1 -yl]propoxy] -3 -pyridyl] - 1 -isopropyl-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

l-isopropyl-3-methyl-8-[2-methyl-6-[3-(l-piperidyl)propoxy]-3- pyridyl]imidazo[4,5-c]cinnolin-2-one; 1 -(trans-3 -Methoxycyclobutyl)-3 -methyl-8-[4- [3 -( 1 - piperidyl)propoxy]phenyl]imidazo[4,5-c]cinnolin-2-one;

8- [4-[3 -(Dimethylamino)propoxy]phenyl] - 1 -(trans-3 -methoxycyclobutyl)-3 - methyl-imidazo [4,5 -c] cinnolin-2-one;

8- [6-[3 -(4-Fluoro- 1 -piperidyl)propoxy] -3 -pyridyl] - 1 -(trans-3 -methoxycyclobutyl)- 3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[6-[3-(4-Fluoro-l-piperidyl)propoxy]-3-pyridyl]-l-(cz5-3-methoxycyclobutyl)-3- methyl-imidazo[4,5-c]cinnolin-2-one;

1 -(cis-3 -methoxycyclobutyl)-3 -methyl-8-[4- [3 -( 1 - piperidyl)propoxy]phenyl]imidazo[4,5-c]cinnolin-2-one;

8-[6-[3-[(3R)-3-Fluoropyrrolidin-l-yl]propoxy]-3-pyridyl]-l-(cz5-3- methoxycyclobutyl)-3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8- [4-[3 -(Dimethylamino)propoxy]phenyl] -3 -methyl- 1 - [(3R)-tetrahydropyran-3 - yl]imidazo[4,5-c]cinnolin-2-one;

3-Methyl-8-[4-[3-(l-piperidyl)propoxy]phenyl]-l-[(3R)-tetrahydropyran-3- yl]imidazo[4,5-c]cinnolin-2-one;

8-[6-[3-(4-Fluoro-l -piperidyl)propoxy] -3 -pyridyl] -3 -methyl- 1 -[(3R)- tetrahydropyran-3 -yl] imidazo [4,5 -c] cinnolin-2-one;

8- [4-[3 -(Dimethylamino)propoxy]phenyl] -3 -methyl- 1 -( 1 - methylcyclopropyl)imidazo[4,5-c]cinnolin-2-one;

3-Methyl- 1 -(1 -methylcyclopropyl)-8-[4-[3-(l - piperidyl)propoxy]phenyl]imidazo[4,5-c]cinnolin-2-one;

8- [6-[3 -(4-Fluoro- 1 -piperidyl)propoxy] -3 -pyridyl] -3 -methyl- 1 -(1 - methylcyclopropyl)imidazo[4,5-c]cinnolin-2-one;

3-Methyl- 1 -(1 -methylcyclopropyl)-8-[6-[3-(l -piperidyl)propoxy]-3- pyridyl]imidazo[4,5-c]cinnolin-2-one;

8- [4-[3 -(dimethylamino)propoxy]phenyl] - 1 - [( 1 R,3R)-3 -methoxy cyclop entyl] -3 - methyl-imidazo[4,5-c]cinnolin-2-one;

l-[(lS,3S)-3-methoxycyclopentyl]-3-methyl-8-[4-[3-(l- piperidyl)propoxy]phenyl]imidazo[4,5-c]cinnolin-2-one; 8- [4-[3 -(Dimethylamino)propoxy]phenyl] - 1 - [( 1 S ,3 S)-3 -methoxycyclopentyl] -3 - methyl-imidazo [4,5 -c] cinnolin-2-one;

l-[(lR,3R)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3- pyridyl]imidazo[4,5-c]cinnolin-2-one;

8-[6-[3-[(3S)-3-Fluoropyrrolidin-l-yl]propoxy]-3-pyridyl]-l-[(lR,3R)-3- methoxycyclopentyl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

l-[(l S,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3- pyridyl]imidazo[4,5-c]cinnolin-2-one;

8- [4-[3 -(Dimethylamino)propoxy]phenyl] - 1 -(cis-3 -methoxycyclobutyl)-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

l-(cz^'5-3-Methoxycyclobutyl)-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3- pyridyl] imidazo [4,5 -c] cinnolin-2-one;

8-[6-[3-[(3S)-3-Fluoropyrrolidin-l-yl]propoxy]-3-pyridyl]-l-(tra/75-3- methoxycyclobutyl)-3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-l-[(4S)-3,3-dimethyltetrahydropyran- 4-yl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8- [6-[3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -[(4R)-3 ,3 -dimethyltetrahydropyran- 4-yl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one

1 - [3 ,3 -dimethyltetrahydropyran-4-yl] -3 -methyl-8- {4-[3 -( 1 - piperidinyl)propoxy]phenyl} -l ,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one;

8-[4-[3-(dimethylamino)propoxy]phenyl]-l-[(4S)-3,3-dimethyltetrahydropyran-4- yl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8- [4-[3 -(dimethylamino)propoxy]phenyl] - 1 - [(4R)-3 ,3 -dimethyltetrahydropyran-4- yl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[4-[3-(dimethylamino)propoxy]phenyl]-7-fluoro-l-isopropyl-3-methyl- imidazo[4,5-c]cinnolin-2-one;

8- [6-[3 -(Dimethylamino)propoxy] -3 -pyridyl] -7-fluoro- 1 -isopropyl-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

7-Fluoro-l -isopropyl-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3- pyridyl]imidazo[4,5-c]cinnolin-2-one; 7- fluoro-l-isopropyl-3-methyl-8-[4-[3-(l-piperidyl)propoxy]phenyl]imidazo[4,5- c]cinnolin-2-one;

8- [4-[3-(dimethylamino)propoxy]phenyl]-l-isopropyl-3,7-dimethyl-imidazo[4,5- c]cinnolin-2-one;

l-isopropyl-3,7-dimethyl-8-[6-[3-(l-piperidyl)propoxy]-3-pyridyl]imidazo[4,5- c]cinnolin-2-one;

8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-l-isopropyl-3,7-dimethyl- imidazo[4,5-c]cinnolin-2-one;

l-Isopropyl-3,7-dimethyl-8-[4-[3-(l-piperidyl)propoxy]phenyl]imidazo[4,5- c]cinnolin-2-one;

3 -(difluoromethyl)-8- [6-[3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -isopropyl- imidazo[4,5-c]cinnolin-2-one;

8-[6-[(3R)-3-(Dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl]- 1 -isopropyl-3 -methyl- imidazo^, 5-c]cinnolin-2-one;

8-[6-[4-(Dimethylamino)-l -piperidyl] -3 -pyridyl]- 1 -isopropyl-3 -methyl - imidazo[4,5-c]cinnolin-2-one;

8- [6-[(3R)-3 -(dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl] -3 -methyl- 1 - [(3R)- tetrahydropyran-3 -yl] imidazo [4,5 -c] cinnolin-2-one;

8-[6-[4-(dimethylamino)- 1 -piperidyl] -3 -pyridyl]- 1 -[3,3-dimethyltetrahydropyran-4- yl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8- [6-[(3R)-3 -(dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl] - 1 - [3 ,3 - dimethyltetrahydropyran-4-yl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[6-[(3R)-3-(Dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl]- 1 -(trans-3- methoxycyclobutyl)-3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[6-[(3R)-3-(Dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl]- 1 -(cis-3- methoxycyclobutyl)-3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8- [6-[3 -(dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl] -3 -methyl- 1 -tetrahydropyran-4- yl-imidazo[4,5-c]cinnolin-2-one;

8-[6-[(3R)-3-(Dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl]- 1 -[(lR,3R)-3- methoxycyclopentyl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one; 8-[6-[(3R)-3-(Dimethylamino)pyrrolidin- 1 -yl]-3-pyridyl]- 1 -[(1 S,3S)-3- methoxycyclopentyl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8- [6-[4-(Dimethylamino)- 1 -piperidyl] -3 -pyridyl] - 1 -(cis-3 -methoxycyclobutyl)-3 - methyl-imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(Dimethylamino)-l-piperidyl]phenyl]-l-isopropyl-3-methyl-imidazo[4,5- c]cinnolin-2-one;

8- [4-[4-(dimethylamino)- 1 -piperidyl]phenyl] - 1 - [3 ,3 -dimethyltetrahydropyran-4- yl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[4-[4-(Dimethylamino)- 1 -piperidyl]phenyl] - 1 -[( 1 R,3R)-3-methoxycyclopentyl] - 3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[4-[4-(Dimethylamino)-l-piperidyl]phenyl]-l-[(lS,3S)-3-methoxycyclopentyl]-3- methyl-imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(Dimethylamino)-l-piperidyl]phenyl]-3-methyl-l-[(3R)-tetrahydropyran-3- yl]imidazo[4,5-c]cinnolin-2-one;

8- [6-[(3R)-3 -(Dimethyl amino)pyrro lidin- 1 -yl] -3 -pyridyl] -7-fluoro- 1 -isopropyl-3 - methyl-imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(Dimethylamino)-l-piperidyl]phenyl]-7-fluoro-l-isopropyl-3-methyl- imidazo[4,5-c]cinnolin-2-one;

8-[6-[(3R)-3-(dimethylamino)pyrrolidin-l-yl]-3-pyridyl]-l-isopropyl-3,7-dimethyl- imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(dimethylamino)- 1 -piperidyl]phenyl] - 1 -isopropyl-3 ,7-dimethyl- imidazo[4,5-c]cinnolin-2-one;

8- [6-[3 -(dimethylamino)propoxy] -2-fluoro-3 -pyridyl] - 1 -isopropyl-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

and pharmaceutically acceptable salts thereof.

In an embodiment, the compound of Formula (I) is selected from:

8- [6-[3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -isopropyl-3 -methyl-imidazo [4,5 - c]cinnolin-2-one; l-Isopropyl-3-methyl-8-[4-(3-pyrrolidin-l-ylpropoxy)phenyl]imidazo[4,5- c]cinnolin-2-one;

8- [6-[3 - [(3R)-3 -Fluoropyrrolidin- 1 -yljpropoxy] -3 -pyridyl] - 1 -isopropyl-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

8- [4-[3 -(Dimethylamino)propoxy]phenyl] - 1 - [( 1 S ,3 S)-3 -methoxycyclopentyl] -3 - methyl-imidazo[4,5-c]cinnolin-2-one;

8- [6-[3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -[(4R)-3 ,3 -dimethyltetrahydropyran- 4-yl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-{4-[3-(dimethylamino)propoxy]phenyl}-l-[(4R)-3,3-dimethyltetrahydro-2H- pyran-4-yl] -3 -methyl- 1 ,3 -dihydro-2H-imidazo [4,5 -c] cinnolin-2-one;

7- Fluoro-l-isopropyl-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3- pyridyl]imidazo[4,5-c]cinnolin-2-one;

8- [6-[(3R)-3-(Dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl]- 1 -isopropyl-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

and pharmaceutically acceptable salts thereof.

In substituents such as -OR⁵ and -NR⁶R⁷, "-" denotes the point of attachment of the substituent to the remainder of the molecule.

The term "O-linked" such as in "O-linked saturated hydrocarbon", means that the hydrocarbon residue is joined to the remainder of the molecule via an oxygen atom.

The term "pharmaceutically acceptable" is used to specify that an object (for example a salt, dosage form or excipient) 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/VHCA, 2002. A suitable pharmaceutically acceptable salt of a compound of Formula (I) is, for example, an acid-addition salt. An acid addition salt of a compound of Formula (I) 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 the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid. An acid addition salt may also be formed using an organic acid selected from the group consisting of 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 and /?ara-toluenesulfonic acid.

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, trifluoroacetic 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. In one embodiment there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a methanesulfonic acid salt. In one embodiment there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, where the pharmaceutically acceptable salt is a mono-methanesulfonic acid salt, i.e. the stoichiometry of the compound of the compound of Formula (I) to methanesulfonic acid is 1 : 1.

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

pharmaceutically acceptable salt thereof.

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

In one embodiment there is provided a pharmaceutically acceptable salt of a compound of Formula (I).

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. All such solvated and unsolvated forms of compounds of Formula (I) are encompassed herein, 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. All compounds of Formula (I) where an atom is replaced by one or more of its isotopes (for example a compound of Formula (I) where one or more carbon atom is an ^UC or ¹³C carbon isotope, or where one or more hydrogen atoms is a ²H or ³H isotope) are encompassed herein.

Compounds of the application may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including, but not limited to, cis- and trans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers can be prepared by the application or adaptation of known methods (e.g.

asymmetric synthesis).

For exam ncludes the racemic form of this fragment

as well as the R

and S enantiomers thereof. Similarly, the

fragment

includes the cis and trans forms thereof.

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

pharmaceutically acceptable salt thereof, which is a single optical isomer being in an enantiomeric excess (%ee) of > 95%, > 98% or > 99%. In one embodiment, the single optical isomer is present in an enantiomeric excess (%ee) of > 99%.

Compounds and salts described in this specification may be crystalline, and may exhibit one or more crystalline forms. Any crystalline or amorphous form of a compound of Formula (I), or mixture of such forms, which possesses ATM kinase inhibitory activity are encompassed herein.

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 crystalline materials may be determined by Karl Fischer analysis.

As a result of their ATM kinase inhibitory activity, the compounds of Formula (I), 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), or pharmaceutically acceptable salt thereof. Such a decrease in activity may be due to the direct interaction of the compound of Formula (I), or pharmaceutically acceptable salt thereof with ATM kinase, or due to the interaction of the compound of Formula (I), or pharmaceutically acceptable salt thereof with one or more other factors that in turn affect ATM kinase activity. For example, the compound of Formula (I), or pharmaceutically acceptable salt 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 (I), or a

pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by ATM kinase.

In one embodiment, said disease mediated by ATM kinase is cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer and lung cancer. In one embodiment, said cancer is colorectal cancer. In another embodiment, said 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.

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

pharmaceutically acceptable salt thereof, for use in the treatment of Huntington's disease. In one embodiment there is provided a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, for use as a neuroprotective agent.

A "neuroprotective agent" is an agent that aids relative preservation of neuronal structure and/or function.

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, said disease mediated by ATM kinase is 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 (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Huntington's disease.

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 use as a neuroprotective agent.

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, said disease is cancer.

In any embodiment, a disease in which inhibition of ATM kinase is beneficial may be Huntington' disease.

In one embodiment there is provided a method of treatment for aiding relative preservation of neuronal structure and/or function 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.

The term "therapeutically effective amount" refers to an amount of a compound of Formula (I) as described in any of the embodiments herein 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) or pharmaceutcially acceptable salt described in this specification 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) or pharmaceutcially acceptable salt 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 any embodiment where cancer is mentioned in a general sense, said cancer may be selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, hepatocellular carcinoma, small cell lung cancer and non-small cell lung cancer. Said cancer may also be selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma, breast cancer, prosate cancer 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 or gastric cancer.

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 oesophageal cancer.

In one embodiment the cancer is ovarian cancer.

In one embodiment the cancer is endometrial cancer.

In one embodiment the cancer is cervical 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 acute myeloid leukaemia.

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

In one embodment the cancer is prostate cancer.

In one embodiment the cancer is breast cancer. In one embodiment the cancer is triple negative breast cancer.

"Triple negative breast cancer" is any breast cancer that does not express the genes for the oestrogen receptor, progesterone receptor and Her2/neu.

In one embodiment the cancer is hepatocellular carcinoma.

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

In one embodiment the cancer is metastatic cancer. In one embodiment the metastatic cancer comprises metastases of the central nervous system. In one embodiment the metastases of the central nervous system comprise brain metastases. In one

embodiment the metastases of the central nervous system comprise leptomeningeal metastases.

"Leptomeningeal metastases" occur when cancer spreads to the meninges, the layers of tissue that cover the brain and the spinal cord. Metastases can spread to the meninges through the blood or they can travel from brain metastases, carried by the cerebrospinal fluid (CSF) that flows through the meninges. In one embodiment the cancer is non-metastatic 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), conventional surgery, radiotherapy or chemotherapy; or a combination of such additional therapies. Such conventional surgery, radiotherapy or chemotherapy may be administered simultaneously, sequentially or separately to treatment with the compound of Formula (I).

Radiotherapy may include one or more of the following categories of therapy: i. External radiation therapy using electromagnetic radiation, 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.

Therefore, in one embodiment there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and radiotherapy, for use in the treatment of cancer. In one embodiment the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment the metastatic cancer comprises metastases of the central nervous system. In one embodiment the metastases of the central nervous system comprise brain metastases. In one embodiment the metastases of the central nervous system comprise leptomeningeal metastases.

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 administered in combination with radiotherapy. In one embodiment the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment the metastatic cancer comprises metastases of the central nervous system. In one embodiment the metastases of the central nervous system comprise brain metastases. In one embodiment the metastases of the central nervous system comprise leptomeningeal metastases.

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

pharmaceutically acceptable salt thereof, and radiotherapy, for use in the simultaneous, separate or sequential treatment of 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 administered simultaneously, separately or sequentially with 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. In one embodiment, 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 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. In one embodiment, 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 the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment the metastatic cancer comprises metastases of the central nervous system. In one embodiment the metastases of the central nervous system comprise brain metastases. In one embodiment the metastases of the central nervous system comprise leptomeningeal metastases.

In any embodiment comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof and radiotherapy, where cancer is mentioned in a general sense, said cancer may be selected from the group consisting of glioblastoma, lung cancer (for example small cell lung cancer or non-small cell lung cancer), breast cancer (for example triple negative breast cancer), head and neck squamous cell carcinoma, oesophageal cancer, cervical cancer and endometrial cancer. In one embodiment the cancer is glioblastoma. In one embodiment, the cancer is metastatic cancer. In one embodiment the metastatic cancer comprises metastases of the central nervous system. In one embodiment the metastases of the central nervous system comprise brain metastases. In one

In any embodiment the radiotherapy is selected from the group consisting of 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 cisplatin, 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, valrubicin, 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 (such as VX-984, M3814, KU-0060648); 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);

Antiangio 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);

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 MEDI4736) 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; Efficacy enhancers, such as leucovorin.

Therefore, in one embodiment there is provided a compound of Formula (I), or a armaceutically acceptable salt thereof, and at least one additional anti -tumour substance, for use in the treatment of 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 administered in combination with an additional anti-tumour substance. In one embodiment there is one additional anti-tumour substance. In one embodiment there are two additional anti-tumour substances. In one embodiment there are three or more additional anti-tumour substances.

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

pharmaceutically acceptable salt thereof, and at least one additional anti -tumour substance for use in the simultaneous, separate or sequential treatment of 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 administered simultaneously, separately or sequentially with an additional anti-tumour substance.

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 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 any embodiment the additional anti-tumour substance is selected from the group consisting of 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, and at least one anti-neoplastic agent for use in the treatment of 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 administered in combination with at least one anti-neoplastic agent. In one 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, and at least one anti-neoplastic agent for use in the simultaneous, separate or sequential treatment of 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 administered simultaneously, separately or sequentially with at least one anti-neoplastic agent. In one embodiment the antineoplastic 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, and at least one additional anti -tumour substance selected from the group consisting of cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, MEDI4736, AZD1775 and AZD6738, for use in the treatment of cancer.

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

pharmaceutically acceptable salt thereof, and at least one additional anti -tumour substance selected from the group consisting of cisplatin, oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, AZD1775 and AZD6738, for use in the treatment of 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 administered in combination with at least one additional anti-tumour substance selected from the group consisting of cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, MEDI4736, AZD1775 and AZD6738.

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

pharmaceutically acceptable salt thereof, and at least one additional anti -tumour substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin and olaparib for use in the treatment of 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 administered in combination with at least one additional anti-tumour substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin and olaparib.

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

pharmaceutically acceptable salt thereof, and at least one additional anti -tumour substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin, for use in the treatment of 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 administered in combination with at least one additional anti-tumour substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin.

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 administered in combination with at least one additional anti-tumour substance selected from the group consisting of doxorubicin, pirarubicin, amrubicin and epirubicin. In one embodiment the cancer is acute myeloid leukaemia. In one embodiment the cancer is breast cancer (for example triple negative breast cancer). In one embodiment the cancer is hepatocellular carcinoma.

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

pharmaceutically acceptable salt thereof, and irinotecan, for use in the treatment of 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 administered in combination with irinotecan. In one embodiment the cancer is colorectal cancer.

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

pharmaceutically acceptable salt thereof, and FOLFIRI, for use in the treatment of 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 administered in combination with FOLFIRI. In one embodiment the cancer is colorectal 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 administered in combination with olaparib. In one embodiment the cancer is selected from gastric cancer, triple negative breast cancer, prostate cancer, small cell lung cancer and ovarian cancer. In one embodiment the cancer is gastric cancer. In one embodiment the cancer is triple negative breast cancer. In one embodiment the cancer is prostate cancer. In one embodiment the cancer is small cell lung cancer. In one embodiment the cancer is ovarian 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 administered in combination with topotecan. In one 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 administered in combination with immunotherapy. In one embodiment the immunotherapy is one or more of the agents listed under point (iii) above. In one embodiment the immunotherapy is an anti-PD-Ll antibody (for example MEDI4736).

According to a further 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 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), and pharmaceutically acceptable salts thereof, may be administered as pharmaceutical compositions, comprising one or more pharmaceutically acceptable excipients.

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 excipient.

The excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

The pharmaceutical 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 well known in the art.

Compositions intended for oral use may contain additional components, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

The compound of Formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range 2.5-5000 mg/m² body area of the animal, or approximately 0.05-100 mg/kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 0.1-250 mg 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.

The pharmaceutical compositions described herein comprise compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and are therefore expected to be useful in therapy.

As such, in one embodiment there is provided a pharmaceutical composition for use in therapy, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In one embodiment there is provided a pharmaceutical composition for use in the treatment of a disease in which inhibition of ATM kinase is beneficial, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In one embodiment there is provided a pharmaceutical composition for use in the treatment of cancer, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In one embodiment there is provided a pharmaceutical composition for use in the treatment of a cancer in which inhibition of ATM kinase is beneficial, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In one embodiment there is provided a pharmaceutical composition for use in the treatment of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, hepatocellular carcinoma, small cell lung cancer or non-small cell lung cancer, comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

EXAMPLES

The various embodiments of the specification are illustrated by the following Examples. The specification 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 suitable automated systems.

Examples of such systems include Armen Glider Flash: Spot II Ultimate (Armen Instrument, Saint-Ave, France) or automated Presearch combiflash companions using prepacked Merck normal phase Si60 silica cartridges (granulometry : 15-40 or 40-63 μηι) obtained from Merck, Darmstad, Germany, silicycle silica cartridges or graceresolv silica cartridges;

Preparative chromatography was performed on a suitable system. Examples of suitable systems include 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, 19 mm or 50 mm diameter, 100 mm length, flow rate of 40 mL / minute) using decreasingly polar mixtures of water (containing 1% ammonia) and acetonitrile or decreasingly polar mixtures of water (containing 0.1% formic acid) and acetonitrile as eluents;

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

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; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; bs, broad signal;

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 5μιη C-18 column (2.1 x 50 mm) at a flow rate of 2.4 mL/min, using a solvent system of 95% A + 5% C to 95% B + 5% C over 4 minutes, where A = water, B = methanol, C = 1 : 1 methanol: 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 3.0x50 mm, 3.0 μΜ column or equivalent (basic conditions) or a Shim pack XR - ODS 3.0 x 50 mm, 2.2 μΜ column or Waters BEH CI 8 2.1 x 50 mm, 1.7 μΜ 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 = Acetonitrile (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 6.5 mM ammonium hydrogen carbonate and adjusted to pHIO by addition of ammonia), G = Acetonitrile (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. Supercritical fluid chromatography was carried out using a suitable system such as either a Sepiatec Prep SFCIOO machine or a Waters SFC Prep 100 machine;

x. The following abbreviations have been used: h = hour(s); r.t. = room temperature (~18-25°C); cone. = concentrated; FCC = flash column chromatography using silica; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMA = N,N- dimethylacetamide; DMF = N,N-dimethylformamide; DMSO = dimethylsulfoxide; Et₂0 = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; K₂C0₃ = potassium carbonate; MeOH = methanol; MeCN = acetonitrile; MTBE =

Methyltertbutylether; MgS0₄ = anhydrous magnesium sulphate; Na₂S0₄ = anhydrous sodium sulphate; THF = tetrahydrofuran; sat. = saturated aqueous solution; SFC = supercritical fluid chromatography; and

xi. IUPAC names were generated using ACD Name 14 (Advanced Chemistry

Development, Inc., Toronto, Ontario, Canada) or OEChem 2 (OpenEye, Santa Fe, NM 87508, USA) software. In cases where the software was unable to distinguish between cis/trans isomers the cis or trans definitition was added manually to the software-generated IUPAC name.

Example 1 : 8- [6- [3-(Dimethylamino)propoxy] -3-pyridyl] -3-methyl-l- tetrahydropyran-4-yl-imidazo [4,5-c] cinnolin-2-one

8-Bromo-3-methyl-l etrahydropyran-4-yl-imidazo[4,5-c]cinnolin-2-one (180 mg, 0.50 mmol) was added to A ,N-dimethyl-3-[[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- pyridyl]oxy]propan-l -amine (182 mg, 0.59 mmol), CS2CO3 (484 mg, 1.49 mmol) and Pd(Pli3P)4 (57.3 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (1 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 2 hours, the mixture concentrated and purified by preparative HPLC to afford the desired material (20 mg) as a yellow solid. NMR Spectrum: ^lH NMR (300MHz, DMSO) δ 1.8-2.0 (4H, m), 2.1-2.2 (6H, m), 2.3-2.4 (2H, m), 2.5-2.7 (2H, m), 3.5-3.7 (2H, m), 4.0-4.1 (2H,m), 4.3-4.4 (2H, m), 5.0-5.2 (lH,m), 6.95-7.05 (1H, m), 8.0-8.8 (5H, m).

Mass Spectrum: m/z (ES+)[M+H]+ = 463

The following compounds were synthesised in an analogous fashion using N,N-dimethyl- 3-[[5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]propan-l -amine and the appropriate bromo intermediate.

Example 2: Isolated as a formic acid salt NMR Spectrum: ^lH NMR (300MHz, DMSO) δ 1.8-2.0 (2H, m), 2.1-2.2 (6H, m), 2.35-2.45 (2H, m), 2.7-3.1 (4H, m), 3.2 (3H, s), 3.6 (3H, s), 3.8-4.0 (1H, m), 4.3-4.4 (2H,m), 5.0-5.2 (1H, m), 6.9-7.1 (1H, m), 8.0-8.8 (5H, m). Mass Spectrum: m/z (ES+)[M+H]+ = 463 Example 3: NMR Spectrum: ¾ NMR (300MHz, DMSO) δ 1.7-2.0 (4H, m), 2.1-2.3 (7H, m), 2.35-2.5 (2H, m), 2.55-2.7 (lH,m), 3.3-3.5 (1H, m), 3.56 (1H, s), 3.9-4.0 (lH,m), 4.1- 4.2 (2H,m), 4.3-4.4 (2H, m), 4.8-5.0 (lH,m), 6.9-7.1 (1H, m), 8.0-8.5 (4H, m), 8.7 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+ = 463

Example 4: NMR Spectrum: ¾ NMR (300MHz, DMSO) δ 1.7-2.0 (4H, m), 2.1-2.3 (7H, m), 2.34-2.43 (2H, m), 2.5-2.7 (lH,m), 3.3-3.5 (1H, m), 3.6 (3H, s), 3.85-3.95 (lH,m), 4.1- 4.2 (2H,m), 4.3-4.4 (2H, m), 4.8-5.0 (lH,m), 6.95-7.05 (1H, m), 8.0-8.8 (5H, m). Mass Spectrum: m/z (ES+)[M+H]+ = 463

The preparations of the bromo intermediates required for Examples 1 - 4 are described below:

8-Bromo-3-methyl-l-tetrahvdropyran-4-yl-imidazor4,5-c1cinnolin-2-one

l,l-Dimethoxy-N,N-dimethylmethanamine (2.99 mL, 22.51 mmol) was added to 8-bromo- l-tetrahydropyran-4-yl-3H-imidazo[4,5-c]cinnolin-2-one (0.786 g, 2.25 mmol) in DMF (1.5 mL) and the resulting slurry stirred at 80 °C for 4 hours. The precipitate was collected by filtration, washed with water and ether and dried under vacuum to afford the desired material (0.745 g) as a bright orange solid which was used without further purification. Mass Spectrum: m z (ES+)[M+H]+ = 365

8-Bromo-l-tetrahvdropyran-4-yl-3H-imidazor4,5-c1cinnolin-2-one

Diphenyl phosphorazidate (2.70 mL, 12.46 mmol) was added slowly to 6-bromo-4- (tetrahydro-2H-pyran-4-ylamino)-3-cinnolinecarboxylic acid (1.33 g, 3.78 mmol) and triethylamine (1.579 mL, 11.33 mmol) in DMF (3 mL) and the resulting slurry stirred at 60 °C for 3 hours. Water (5 mL) was added and the precipitate collected by filtration and dried under vacuum to afford the desired material (0.786 g) as a brown solid, which was used without further purification.

NMR Spectrum: ^!H NMR (500MHz, DMSO) δ 1.88 (2H, d), 2.61 (2H, ddt), 3.62 (2H, q), 4.01 (2H, dd), 4.91 (1H, td), 7.85 (1H, dd), 8.24 (1H, d), 8.48 (1H, d), 12.58 (1H, s).

Mass Spectrum: m/z (ES+)[M+H]+ = 351

6-Bromo-4-(tetrah dro-2H-pyran-4-ylamino)-3-cinnolinecarboxylic acid

2M Sodium hydroxide (1 1.70 mL, 23.41 mmol) was added in one portion to ethyl 6- bromo-4-(tetrahydropyran-4-ylamino)cinnoline-3-carboxylate (1.78 g, 4.68 mmol) in MeOH (3 mL) and the resulting mixture stirred at ambient temperature for 1 hour. The precipitate was collected by filtration, washed with Et₂0 (20 mL) and dried under vacuum to the desired material (1.33 g), which was used without further purification.

NMR Spectrum: ^lH NMR (500MHz, DMSO) δ 1.35 - 1.68 (2H, m), 1.81 - 2.1 (2H, m), 3.42 - 3.59 (2H, m), 3.72 - 3.96 (2H, m), 4.11 - 4.41 (1H, m), 7.68 - 8.18 (2H, m), 8.26 (1H, s), 11.68 (1H, s).

Mass Spectrum: m/z (ES+)[M+H]+ = 352

Ethyl 6-bromo-4-(tetrahydropyran-4-ylamino)cinnoline-3-carboxylate

Tetrahydro-2H-pyran-4-amine (0.615 mL, 5.94 mmol) was added dropwise to ethyl 6- bromo-4-chloro-3-cinnolinecarboxylate (1.5 g, 4.75 mmol) and triethylamine (1.990 mL, 14.26 mmol) in THF (5 mL) and the reaction stirred at ambient temperature for 30 minutes. Ether (15 mL) was added and the solid was collected by filtration, washed with water (25 mL) and ether (20 mL) and dried under vacuum to afford the desired material (1.78 g) as a beige solid, which was used without further purification.

NMR Spectrum: ^!H NMR (400MHz, DMSO) δ 1.39 (3H, t), 1.63 - 1.76 (3H, m), 1.83 (1H, d), 1.94 (3H, d), 3.38 (3H, td), 4.45 (2H, q), 8.02 (2H, dd), 8.18 (1H, d), 8.68 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+ = 378

Ethyl 6-bromo-4-chloro-3 -cinnolinecarboxylate

Ethyl 6-bromo-4-oxo-lH-cinnoline-3-carboxylate (150 mg, 0.50 mmol) was suspended in thionyl dichloride (1357 μί, 18.68 mmol). N,N-dimethylformamide (3.89 μί, 0.05 mmol) was added and the mixture was stirred at 80°C for 5 hours under reflux. The mixture was evaporated to dryness and azeotroped three times with toluene. The residue was dissolved in DCM (15 mL) and washed with ice-cold aqueous NaHC0₃ solution (approximately 0.5M, 2 x 15 mL). The organic layer was dried over MgS0₄ and evaporated to afford the desired product (145 mg, 91 %) as a brown solid.

Mass Spectrum: m/z (ES+) [M+2H]+ = 315

Ethyl 6-bromo-4-oxo-lH-cinnoline-3-carboxylate

TFA (837 mL, 10.863 mol) was added slowly to ethyl 3-(5-bromo-2-pyrrolidin-l- yldiazenylphenyl)-3-oxopropanoate (160 g, 434.52 mmol) over a period of 30 minutes at 0°C under an inert atmosphere. The resulting solution was stirred at ambient temperature for 16 hours then the reaction mixture poured onto ice water (2 L). The precipitate was collected by filtration, washed with water (5 x 100 mL) and dried in the vacuum oven to afford the desired material (118 g, 91 %) as a pale yellow solid, which was used without further purification.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 1.30 (3H, t), 4.32 (2H, q), 7.64 (1H, d), 7.99 (1H, d), 8.18 (1H, s), 14.03 (1H, s).

Mass Spectrum: m/z (ES+)[M+H]+ = 297

Ethyl 3 -(5 -bromo-2-pyrrolidin- 1 -yldiazenylphenyl)-3 -oxopropanoate

Sodium hydride (55.3 g, 1382.68 mmol) was added portionwise to a solution of diethyl carbonate (467 g, 3.951 mol) in THF (800 mL) at ambient temperature under an inert atmosphere. A solution of l-(5-bromo-2-pyrrolidin-l-yldiazenylphenyl)ethanone

(117 g, 395.05 mmol) in THF (200 mL) was added slowly over a period of 60 minutes under an inert atmosphere and the resulting mixture stirred at 75 °C for 3 hours. The reaction mixture was allowed to cool then quenched with water (100 mL) and the resulting mixture concentrated under vacuum. The residue was diluted with water (500 mL), extracted with EtOAc (4 x 500 mL), the organic layer dried over Na₂S04, filtered and evaporated to afford the desired material (168 g, 115 %) as a brown solid, which was used without further purification.

NMR Spectrum: ^lH NMR (400MHz, DMSO) δ 1.11 (3H, t), 1.93 - 2.04 (4H, m), 3.60 (2H, t), 3.93 (2H, t), 4.03 (2H, q), 4.11 (2H, s), 7.41 (1H, d), 7.61 - 7.64 (2H, m).

Mass Spectrum: m/z (ES+)[M+H]+ = 368.1

1 -(5 -Bromo-2-pyrrolidin- 1 -yldiazenylphenyDethanone

l-(2-Amino-5-bromophenyl)ethanone (94.8 g, 442.87 mmol) was added to 2M

hydrochloric acid (700 mL, 1.40 mol), and the resulting mixture was stirred at 60°C for 2 hours. The mixture was cooled to 0°C and a solution of sodium nitrite (30.6 g, 442.87 mmol) in water (100 mL) was added dropwise. After 15 minutes the mixture was filtered, the solid discarded and the filtrate added to a stirred solution of pyrrolidine (31.5 g, 442.87 mmol) and sodium hydroxide (56.0 g, 1399.46 mmol) in water (500 mL) at 0°C. After 15 minutes the precipitate was collected by filtration, washed with water and dried in the vacuum oven to afford the desired material (117 g, 89 %) as a red solid, which was used without further purification.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 1.99 (4H, m), 2.54 (3H, s), 3.58 (2H, t),

3.91 (2H, t), 7.37 - 7.66 (3H, m).

Mass Spectrum: m/z (ES+)[M+H]+ = 298

8-Bromo-l-(cis-3-methoxycvclobutyl)-3-methyl-imidazor4,5-c1cinnolin-2-one

A solution of 8-bromo-l-(3-methoxycyclobutyl)-3H-imidazo[4,5-c]cinnolin-2-one (2 g, 5.73 mmol), iodomethane (1.22 g, 8.60 mmol), sodium hydroxide (344 mg, 8.60 mmol) and tetrabutylammonium bromide (192 mg, 0.60 mmol) in water (80 mL) and DCM (150 mL) was stirred at ambient temperature for 12 hours. The mixture was concentrated under vacuum and extracted with 3 x 100 mL of ethyl acetate. The organic layers were combined and concentrated then the residue purified by flash silica chromatography, eluting with DCM / MeOH (10: 1), to afford the desired material contaiminated with 8-bromo-2- methoxy-l-(cis-3-methoxycyclobutyl)imidazo[4,5-c]cinnoline (1.8 g). This mixture was taken forward into the next reaction without further purification.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 2.6-3.0 (7.2H, m), 3.2-3.3 (5.4H, m), 3.5- 3.6 (3.6H, m), 3.8-3.9 (1.8H, m), 4.2-4.4 (1.8H, m), 4.9-5.1 (1.8H, m), 7.6-8.7 (5.4H, m). Mass Spectrum: m/z (ES+)[M+H]+ = 363 8-Bromo-l-(cis-3-methoxycvclobutyl)-3H-imidazor4,5-c1cinnolin-2-one

A solution of 6-bromo-4-[(3-methoxycyclobutyl)amino]cinnoline-3-carboxylic acid (1.6 g, 4.54 mmol) and triethylamine (1.38 g, 13.64 mmol) in DMA (100 mL) was stirred for 1 h at ambient temperature then diphenyl phosphorazidate (3.75 g, 13.63 mmol) added. The resulting solution was stirred at ambient temperature for 1 h then at 60°C for 1 h before being allowed to cool and concentrated. The residue was diluted with water (100 mL) and the solid collected by filtration to afford the desired material (1.7 g) as a yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 349

6-Bromo-4- (cis-3-methoxycyclobutyl)aminolcinnoline-3-carboxylic acid

A solution of ethyl 6-bromo-4-[(3-methoxycyclobutyl)amino]cinnoline-3-carboxylate (3 g, 7.89 mmol) and sodium hydroxide (6.4 g, 160.01 mmol) in ethanol (120 mL) and water (80 mL) was stirred at ambient temperature for 2 h. The solids were filtered out and the resulting mixture concentrated under vacuum. The solids were collected by filtration and dried in an oven under reduced pressure to afford the desired material (2.05 g) as a grey solid which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 352

Ethyl 6-bromo-4- Γ(3 -methoxycvclobutvOaminol cinnoline-3 -carboxylate

A solution of ethyl 6-bromo-4-chloro-3-cinnolinecarboxylate (2 g, 6.34 mmol), cis-3- methoxycyclobutan-1 -amine hydrochloride (1.04 g, 7.56 mmol) and DIPEA (4.15 g, 32.11 mmol) in DMA (10 mL) was stirred for 12 h at 50°C in a sealed tube. The reaction as allowed to cool, diluted with EtOAc (100 mL) and the organics washed with water, dried over Na₂S04 then concentrated in vacuo to afford the desired material (3 g) as a brown solid which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 380

8-Bromo-3-meth l-l-[(3S)-tetrahydropyran-3-yllimidazo[4,5-clcinnolin-2-one

8-Bromo-l-[(3S)-tetrahydropyran-3-yl]-3H-imidazo[4,5-c]cinnolin-2-one (660 mg, 1.89 mmol) was added to a mixture of iodomethane (537 mg, 3.78 mmol), tetrabutylammonium bromide (60.9 mg, 0.19 mmol) and NaOH (113 mg, 2.84 mmol) in DCM (30 mL) and water (20 mL) and the resulting mixture stirred at ambient temperature for 12 hours. The reaction mixture was concentrated and diluted with EtOAc (100 mL). The organic layer was dried over Na₂S0₄, filtered and evaporated to afford the desired material (570 mg) as yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 363

8-Bromo-l-[(3S)-tetrahydropyran-3-yll-3H-imidazo[4,5-clcinnolin-2-one

A mixture of 6-bromo-4-[[(3S)-tetrahydropyran-3-yl]amino]cinnoline-3-carboxylic acid (438 mg, 1.24 mmol) and triethylamine (0.520 mL, 3.73 mmol) in DMF (10 mL) was stirred at ambient temperature for 1 hour. Diphenylphosphoryl azide (0.535 mL, 2.49 mmol) was added and the reaction stirred at 60°C for a further 1 hour. The reaction mixture was evaporated to dryness, redissolved in water (20 mL) and the solid collected by filtration to afford the desired material (660 mg) as yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 349

6-Bromo-4-r Γ(3 S)-tetrahvdropyran-3 -yll aminol cinnoline-3 -carboxylic acid

A mixture of ethyl 6-bromo-4-[[(3S)-tetrahydropyran-3-yl]amino]cinnoline-3-carboxylate (600 mg, 1.58 mmol) and NaOH (1600 mg, 40.00 mmol) in ethanol (30 mL) and water (20 mL) was stirred at 50 °C for 2 hours. The reaction mixture was evaporated, the pH adjusted to pH5 with 2M HC1 and the solid filtered to afford the desired material (438 mg) as light- yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 352 Ethyl 6-bromo-4- [ [(3 S)-tetrahydropyran-3 -yl] amino] cinnoline-3 -carboxylate

A mixture of ethyl 6-bromo-4-chloro-3-cinnolinecarboxylate (500mg, 1.58 mmol), (S)- tetrahydro-2H-pyran-3 -amine hydrochloride (327 mg, 2.38 mmol), and DIPEA (0.830 mL, 4.75 mmol) in DMA (2 mL) was stirred at 70 °C for 2 hours. The reaction mixture was diluted with water and the solids collected by filtration to afford the desired material (600 mg) as yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 380

8-Bromo-3 -meth l- 1 -[(3R)-tetrahydropyran-3 -yllimidazo[4,5 -clcinnolin-2-one

8-Bromo-l-[(3R)-tetrahydropyran-3-yl]-3H-imidazo[4,5-c]cinnolin-2-one (328 mg, 0.94 mmol) was added to a mixture of iodomethane (267 mg, 1.88 mmol), tetrabutylammonium bromide (30.3 mg, 0.09 mmol) and NaOH (56.4 mg, 1.41 mmol) in DCM (30 mL) and water (20 mL) and the resulting mixture stirred at ambient temperature for 12 hours. The reaction mixture was concentrated and diluted with EtOAc (100 mL). The organic layer was dried over Na₂S04, filtered and evaporated to afford the desired material (560 mg) as yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 363

8-Bromo-l-r(3R)-tetrahvdropyran-3-yl1-3H-imidazor4,5-c1cinnolin-2-one

A mixture of 6-bromo-4-[[(3R)-tetrahydropyran-3-yl]amino]cinnoline-3-carboxylic acid (382 mg, 1.08 mmol) and triethylamine (0.454 mL, 3.25 mmol) in DMF (10 mL) was stirred at ambient temperature for 1 hour. Diphenylphosphoryl azide (0.466 mL, 2.17 mmol) was added and the reaction stirred at 60°C for a further 1 hour. The reaction mixture was evaporated to dryness, redissolved in water (20 mL) and the solid collected by filtration to afford the desired material (328 mg) as yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 349

6-Bromo-4-r r(3R)-tetrahydrop yran-3 - yll aminol cinnoline-3 -carboxylic acid

A mixture of ethyl 6-bromo-4-[[(3R)-tetrahydropyran-3-yl]amino]cinnoline-3-carboxylate (600 mg, 1.58 mmol) and NaOH (1600 mg, 40.00 mmol) in ethanol (30 mL) and water (20 mL) was stirred at 50 °C for 2 hours. The reaction mixture was evaporated, the pH adjusted to pH5 with 2M HC1 and the solid filtered to afford the desired material (382 mg) as yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 352

Ethyl 6-bromo-4- Γ r(3R)-tetrahvdrop yran-3 -yll aminol cinnoline-3 -carboxylate

A mixture of ethyl 6-bromo-4-chloro-3-cinnolinecarboxylate (500mg, 1.58 mmol), (R)- tetrahydro-2H-pyran-3 -amine hydrochloride (327 mg, 2.38 mmol), and DIPEA (0.830 mL, 4.75 mmol) in DMA (2 mL) was stirred at 60 °C for 12 hours. The reaction mixture was diluted with water and the solids collected by filtration to afford the desired material (600 mg) as yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 380 The preparation of N,N-dimethyl-3-[[5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-2- pyridyl]oxy]propan-l -amine is described below. N,N-Dimethyl-3-[[5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]propan-l-amine is also available commercially, for example from Fluorochem Ltd, 14 Graphite Way, Hadfield, Glossop SKI 3 1QH, UK; catalogue number 213155-lg.

N,N-Dimethyl-3-[[5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-2-pyridylloxylpropan-

1 -amine

Butyllithium (2.5N, 4.8 mL, 50.96 mmol) was added to a solution of 3-(5-bromopyridin-2- yl)oxy-N,N-dimethylpropan-l -amine (2.07 g, 7.99 mmol) and 4,4,5, 5-tetramethyl-2-

(propan-2-yloxy)-l,3,2-dioxaborolane (2.79 g, 15.00 mmol) in THF (20 mL) at -78°C over 10 minutes under an inert atmosphere. The resulting solution was stirred for 4 hour at 18°C. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride then partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was concentrated in vacuo and the residue purified by flash column chromatography on silica, eluting with EtO Ac/petroleum ether (1 :3) to afford the desired material (270 mg, 11%) as a yellow solid.

Mass Spectrum: m/z (ES+)[M+H]+ = 225 3-(5-Bromopyridin-2-yl)oxy-N,N-dimethylpropan-l -amine

3-(Dimethylamino)propan-l-ol (3.09 g, 29.95 mmol) was added to a mixture of sodium hydride (2.4 g, 60.00 mmol) in DMF (50 mL) over a period of 20 min at ambient temperature. 5-Bromo-2-fluoropyridine (5.81 g, 33.01 mmol) was added and the resulting solution stirred for 4 hours at 30°C. The reaction was then quenched by the addition of a saturated aqueous solution of ammonium chloride and the resulting mixture concentrated under vacuum. The residue was purified by flash column chromatography on silica, eluting with DCM/MeOH ether (10: 1) to afford the desired material (5.2 g, 67%) as yellow oil. Mass Spectrum: m/z (ES+)[M+H]+ = 259

Example 5: 3-Methyl-8-[6-[3-(l-piperidyl)propoxy]-3-pyridyl]-l-tetrahydropyran-4- yl-imidazo [4,5-c] cinnolin-2-one

A solution of 3-(piperidin-l-yl)propan-l-ol (0.091 g, 0.63 mmol) in THF (2 mL) was added slowly to a stirred suspension of sodium hydride (0.051 g, 1.27 mmol) in THF (2 mL) and the mixture stirred at ambient temperature for 30 minutes. A solution of 8-(6- fluoro-3-pyridyl)-3-methyl-l-tetrahydropyran-4-yl-imidazo[4,5-c]cinnolin-2-one (0.12 g, 0.32 mmol) in DMF (2 mL) was added and the reaction stirred at 50°C for 3 hours. The reaction was cooled to ambient temperature and quenched with water. The reaction mixture was extracted with EtOAc (50 mL), and the organic layer washed twice with saturated brine (20 mL) and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% 1% NH₃ in MeOH in DCM, to afford the desired material (0.04 g) as a yellow solid.

NMR Spectrum: ^lH NMR (500MHz, DMSO) δ 1.40 (2H, d), 1.51 (4H, p), 1.74 - 1.81 (1H, m), 1.88 - 1.94 (2H, m), 1.93 - 2.01 (2H, m), 2.32 - 2.39 (3H, m), 2.41 (2H, t), 2.6 - 2.73 (2H, m), 3.58 - 3.65 (2H, m), 3.62 (3H, s), 4.07 (2H, dd), 4.38 (2H, t), 5.11 (1H, ddd), 7.01 (1H, dd), 8.10 (1H, dd), 8.25 (1H, dd), 8.37 - 8.47 (2H, m), 8.73 (1H, dd).

Mass Spectrum: m/z (ES+)[M+H]+ = 503 The synthesis of 8-(6-fluoro-3-pyridyl)-3-methyl-l-tetrahydropyran-4-yl-imidazo[4,5- c]cinnolin-2-one is described below:

8-(6-Fluoro-3 -pyridyl)-3 -methyl- 1 -tetrahydropyran-4-yl-imidazo [4,5 -c] cinnolin-2-one

8-Bromo-3-methyl-l-tetrahydropyran-4-yl-imidazo[4,5-c]cinnolin-2-one (0.745 g, 2.05 mmol), (6-fluoropyridin-3-yl)boronic acid (0.347 g, 2.46 mmol) and 2M potassium carbonate (3.08 ml, 6.15 mmol) were suspended in 1,4-dioxane (12 mL) and the mixture degassed before the addition of bis(triphenylphosphine)palladium(II) dichloride (0.043 g, 0.06 mmol). The reaction was heated to 120 °C for 6 hours under nitrogen then cooled to ambient temperature. The precipitate was collected by filtration and washed with water and ether to afford the desired material (0.812 g) as an orange solid which was used without further purification.

NMR Spectrum: ^!H NMR (500MHz, DMSO) δ 1.92 - 2.02 (2H, m), 2.58 - 2.75 (3H, m), 3.62 (3H, s), 4.03 (3H, dt), 5.11 (IH, ddd), 7.42 (IH, dd), 8.12 (IH, dd), 8.46 (IH, d), 8.47 - 8.5 (IH, m), 8.53 (IH, td), 8.81 (IH, d).

Mass Spectrum: m/z (ES+)[M+H]+ = 380

Example 6 : 8- [4- [3-(Dimethylamino)propoxy] phenyl] - l-isopropyl-3-methyl- imidazo [4,5-c] cinnolin-2-one

Dichlorobis(triphenylphosphine)palladium(II) (0.013 g, 0.02 mmol) was added to degassed solution of 8-bromo-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one 0.36 mmol) and N,N-dimethyl-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)propan-l -amine (0.116 g, 0.38 mmol), potassium carbonate (0.542 mL, 1.08 mmol) in 1,4-dioxane (8 mL) and heated in the microwave to 80 °C for 1 hour under nitrogen. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) and the organic layer was evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% (1% NH₃ in MeOH) in DCM. Pure fractions were evaporated to dryness and triturated with ether to afford the desired product (0.055 g, 36 %) as a pale brown solid.

NMR Spectrum: ^!H NMR (500 MHz, DMSO) δ 1.69 (6H, d), 1.89 (2H, p), 2.17 (6H, s), 2.39 (2H, t), 3.60 (3H, s), 4.10 (2H, t), 5.29 (1H, p), 7.13 (2H, d), 7.85 (2H, d), 8.05 (1H, dd), 8.31 (1H, d), 8.38 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 420

N,N-Dimethyl-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)propan-l -amine was prepared as described below.

N,N-Dimethyl-3-r4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy1-l-propanamine

Dichloro[l, -bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.063 g, 0.08 mmol) was added to 3-(4-bromophenoxy)-A ,N-dimethylpropan-l-amine (2g, 7.75 mmol), 4,4,4^*,4^*,5,5,5^*,5^*-octamethyl-2,2^,-bi(l,3,2-dioxaborolane) (2.36 g, 9.30 mmol) and potassium acetate (3.04 g, 30.99 mmol) in 1,4-dioxane (35 mL) and the mixture degassed for 15 minutes. The resulting suspension was stirred at 90 °C for 16 hours under an inert atmosphere. The reaction mixture was evaporated to dryness, redissolved in DCM (25 mL), washed with water (20 mL) and the organic layer was dried with a phase separating cartridge, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, to afford the desired material as a brown oil (1.000 g, 42.3 %) which solidified on standing. NMR Spectrum: ^lH NMR (400MHz, CDCb) δ 1.33 (12H, s), 1.96 - 2.07 (2H, m), 2.34 (6H, s), 2.52 - 2.65 (2H, m), 4.04 (2H, t), 6.83 - 6.94 (2H, m), 7.68 - 7.78 (2H, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 306

8-Bromo-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one was prepared as described below.

8-Bromo-l-isopropyl-3-methyl-imidazo[4,5-clcinnolin-2-one

l,l-Dimethoxy-N,N-dimethylmethanamine (0.623 mL, 4.69 mmol) was added to 8-bromo- l-isopropyl-3H-imidazo[4,5-c]cinnolin-2-one (0.144 g, 0.47 mmol) in DMF (2 mL and the resulting slurry was stirred at 80 °C for 4 hours. A precipitate formed which was collected by filtration, washed with water and ether and dried under vacuum to afford crude product as an orange solid. The filtrate was extracted with DCM (20 mL) and the organic layer combined with the above solid. The crude product was purified by flash silica

chromatography, elution gradient 0 to 5% MeOH in DCM . Pure fractions were evaporated to dryness to afford the desired product (0.106 g, 70.4 %) as a yellow solid.

NMR Spectrum: ^!H NMR (500 MHz, CDCb) δ 1.77 (6H, d), 3.75 (3H, s), 5.08 (1H, s), 7.72 (1H, dd), 8.28 (1H, d), 8.31 (1H, dd).

Mass Spectrum: m/z (ES+) [M+3H]+ = 323

8-Bromo-l-isopropyl-3H-imidazo[4,5-clcinnolin-2-one

Diphenyl phosphorazidate (1.948 mL, 8.99 mmol) was added slowly to 6-bromo-4- (isopropylamino)cinnoline-3-carboxylic acid (0.845 g, 2.72 mmol) and triethylamine (1.139 mL, 8.17 mmol) in DMF (3 mL) and stirred at 60 °C for 3 hours. The reaction was concentrated and redissolved in EtOAc (100 mL). The organic layer was washed with saturated ammonium chloride (30 mL) and brine (20 mL). The aqueous was extracted with EtOAc ( 2 x 30 mL) and the organic layers combined and evaporated to afford this desired product (0.3761 g, 45 %) as a pale yellow solid. Upon standing a precipitate crashed out of the aqueous solution. The solid was collected by filtration, washed with ether and dried under vacuum to give additional desired material (0.415 g, 50 %) as a yellow solid. The two crops were combined and used without further purification.

NMR Spectrum: ^lU NMR (500 MHz, DMSO) δ 1.61 (6H, d), 5.03 - 5.22 (1H, m), 7.83 (1H, dd), 8.22 (1H, d), 8.47 (1H, d), 12.50 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 307

6-Bromo-4-(isopropylamino)cinnoline-3-carboxylic acid

Sodium hydroxide (2.0 M) (5.91 mL, 11.81 mmol) was added in one portion to ethyl 6- bromo-4-(isopropylamino)cinnoline-3-carboxylate (0.799 g, 2.36 mmol) in MeOH (3 mL) and the resulting mixture stirred at 25 °C for 16 hours. A beige precipitate formed which was collected by filtration, washed with Et₂0 (20 mL) and dried under vacuum to afford the desired product (0.845 g, 115 %) as a cream solid, which was used without further purification.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.29 (6H, d), 4.14 - 4.47 (1H,

(1H, dd), 8.00 (1H, d), 8.29 (1H, d), 11.57 (1H, t).

Mass Spectrum: m/z (ES-) [M-H]- = 308

Ethyl 6-bromo-4-(isopropylamino)-3 -cinnolinecarboxylate

2-Propanamine (0.506 mL, 5.94 mmol) was added in one portion to ethyl 6-bromo-4- chlorocinnoline-3-carboxylate (1.5 g, 4.75 mmol) in THF (5 mL) and the reaction was stirred at room temperature for 40 minutes. A beige precipitate formed. Ether (20 mL) was added to the reaction mixture and the precipitate was collected by filtration and washed with water (20 mL) and ether (20 mL) and dried under vacuum to afford the desired product (1.049 g, 65.2 %) as a beige solid which was used without further purification. The filtrate was concentrated and extracted with DCM (50 mL). The organic layer was dried over MgS0₄, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the desired product (250 mg) as a pale yellow solid.

Mass Spectrum: m/z (ES-) [M-H]- = 336

Example 7: l-Isopropyl-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3- pyridyl] imidazo [4,5-c] cinnolin-2-one

A mixture of dichlorobis(triphenylphosphine)palladium(II) (12.68 mg, 0.02 mmol), 2-(3- (piperidin- 1 -yl)propoxy)-5-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridine (131 mg, 0.38 mmol), 8-chloro-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one (100 mg, 0.36 mmol) and 2M potassium carbonate solution (0.542 mL, 1.08 mmol) in 1,4-dioxane (3.07 mL) was heated in a microwave reactor at 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) and the organic layer evaporated to afford crude product as a brown solid residue. The crude product was purified by preparative HPLC to afford the desired material as a dry yellow film. Diethyl ether was added and the mixture evaporated to dryness to afford the desired material (80 mg) as a brown solid.

NMR Spectrum: ^!H NMR (400MHz, DMSO) δ 1.41 (2H, ddd), 1.53 (4H, dt), 1.71 (6H, d), 1.93 (2H, p), 2.38 - 2.47 (6H, m), 3.62 (3H, s), 4.42 (2H, t), 5.29 (IH, p), 6.96 (IH, dd), 8.02 (IH, dd), 8.18 (IH, dd), 8.35 (IH, d), 8.40 (IH, dd), 8.68 (IH, dd).

Mass Spectrum: m/z (ES+)[M+H]+ = 461

The following compounds were synthesised in an analogous fashion using between 1-2 equivalents of the appropriate boronic ester, between 5 - 10 mol% of catalyst and the appropriate chloro intermediate.

* 4 equivalents of base were used and the reaction stirred at 90°C for 2 days.

** The reaction was stirred at 90°C for 18 hours.

*** The reaction was stirred at 100°C for 90 minutes. Example 8: NMR Spectrum: ^lH NMR (400MHz, DMSO) δ 1.67 (6H, d), 1.84 - 1.93 (2H, m), 2.15 (6H, s), 2.35 (2H, q), 3.59 (3H, s), 4.37 (2H, t), 5.31 (1H, p), 6.98 (1H, d), 8.05 (1H, dd), 8.23 (1H, dd), 8.33 - 8.43 (2H, m), 8.71 (1H, d). Mass Spectrum: m/z (ES+) [M+H]+ = 421

Example 9: NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.69 (10H, t), 1.93 (2H, p), 2.43 - 2.48 (4H, m), 2.54 - 2.58 (2H, m), 3.60 (3H, s), 4.12 (2H, t), 5.28 (1H, p), 7.09 - 7.2 (2H, m), 7.79 - 7.91 (2H, m), 8.05 (1H, dd), 8.31 (1H, d), 8.38 (1H, d). Mass Spectrum: m/z (ES+) [M+H]+ = 446

Example 10: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.3 - 1.46 (2H, m), 1.45 - 1.62 (4H, m), 1.68 (6H, d), 1.89 (2H, h), 2.2 - 2.45 (6H, m), 3.60 (3H, s), 4.03 - 4.15 (2H, m), 5.28 (1H, hept), 7.06 - 7.17 (2H, m), 7.8 - 7.88 (2H, m), 8.04 (1H, dd), 8.31 (1H, d), 8.37 (1H, d). Mass Spectrum: m/z (ES+) [M+H]+ = 460

Example 10 can also be isolated as the methane sulfonic acid salt by taking the material as prepared above and subjecting to the following reaction conditions. l-Isopropyl-3-methyl-8-[4-[3-(l-piperidyl)propoxy]phenyl]imidazo[4,5-c]cinnolin-2-one (89 mg, 0.19 mmol) was dissolved in DCM (2 mL) and treated with 1M methanesulfonic acid (0.013 mL, 0.19 mmol) in DCM then the mixture evaporated to dryness. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1M NH₃/MeOH to afford the desired product (135 mg, 0.29 mmol) as a yellow solid. NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.55 - 1.67 (2H, m), 1.71 (6H, d), 1.76 - 1.84 (4H, m), 2.16 - 2.25 (2H, m), 3.17 - 3.32 (6H, m), 3.62 (3H, s), 4.20 (2H, t), 5.17 - 5.33 (1H, m), 6.77 - 7.36 (2H, m), 7.83 (2H, d), 8.02 (1H, dd), 8.30 (1H, d), 8.39 (1H, d). Mass Spectrum: m/z (ES+) [M+H]+ = 460

Example 11: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.93 (2H, p), 2.21 (6H, s), 2.4 - 2.45 (2H, m), 2.6 - 2.7 (2H, m), 3.19 - 3.3 (5H, m), 3.64 (3H, s), 4.27 - 4.36 (1H, m), 4.44 (2H, t), 5.55 (IH, ddd), 6.98 (IH, dd), 8.03 (IH, dd), 8.19 (IH, dd), 8.26 (IH, d), 8.40 (IH, dd), 8.69 (IH, dd). Mass Spectrum: m/z (ES+) [M+H]+ = 463

The preparations of the chloro intermediates and boronic esters required for examples 7 - 11 have either been described earlier or are described below.

8-Chloro- 1 -iso ropyl-3-methyl-imidazo[4,5-clcinnolin-2-one

A mixture of l,l-dimethoxy-N,N-dimethylmethanamine (21.75 mL, 163.69 mmol) and 8- chloro-l-isopropyl-3H-imidazo[4,5-c]cinnolin-2-one (4.3 g, 16.37 mmol) in DMF (60.1 mL) was stirred at 100 °C for 4 hours. The reaction was cooled and the precipitate collected by filtration to afford the desired material (2.6 g) as a pale orange solid which was used without further purification. On standing another crop of desired product was found to precipitate from the filtrate and was again collected (0.11 g) and used without further purification.

NMR Spectrum: ¾ NMR (300MHz, DMSO) δ 1.63 (6H, d), 3.58 (3H, s), 5.16 (IH, p), 7.74 (IH, dd), 8.35 - 8.39 (IH, m), 8.49 (IH, s).

Mass Spectrum: m/z (ES+)[M+H]+ = 276

8-Chloro-l-isopropyl-3H-imidazo[4,5-clcinnolin-2-one

l,3,5-Trichloro-l,3,5-triazinane-2,4,6-trione (1.80 g, 7.74 mmol) was added portionwise to a stirred suspension of 6-chloro-4-(isopropylamino)cinnoline-3-carboxamide (4.1 g, 15.49 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (4.63 mL, 30.98 mmol) in MeOH (60 mL) at 5°C then the solution was warmed to ambient temperature and stirred for lh 30. The reaction mixture was concentrated to dryness and partitioned between

EtOAc (50 mL) and sat aq. NH4C1 (50 mL). A precipitate was observed which was collected by filtration, washed with diethyl ether (3 x lOmL) and dried under vacuum at

45°C to afford the desired material (5.30 g) as a brown solid, which was used without further purification. Additional less pure material (1.3 g) was obtained from the organic phase following separation, drying (MgS0₄) and concentration in vacuo.

NMR Spectrum: ^!H NMR (400MHz, DMSO) δ 1.66 (6H, d), 5.10 (1H, hept), 7.69 (1H, dd), 8.27 (1H, d), 8.32 (1H, d).

Mass Spectrum: m/z (ES+)[M+H]+ = 262

6-Chloro-4-(isopropylamino)cinnoline-3-carboxamide

Propan-2-amine (1.775 mL, 20.66 mmol) was added to 4,6-dichloro-3- cinnolinecarboxamide (5 g, 20.66 mmol) and DIPEA (7.22 mL, 41.31 mmol) in acetonitrile (94 mL) and the resulting suspension stirred at 60 °C for 18 hours. The mixture was allowed to cool and diluted with water. The precipitate was collected by filtration, washed with water (20 mL) followed by acetonitrile (10 mL) and dried under vacuum to afford the desired material (4.06 g) as a brown solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 265

4,6-Dichloro-3-cinnolinecarboxamide

DMF (0.172 mL, 2.23 mmol) was added dropwise to a mixture of 6-chloro-4-hydroxy- cinnoline-3-carboxylic acid (5.00 g, 22.26 mmol) in thionyl chloride (32.5 mL, 445.24 mmol) at ambient temperature under an inert atmosphere. The resulting slurry was stirred at 80 °C for 18 hours then allowed to cool, concentrated to dryness and the residue azeotroped with toluene (3 x 100 mL) to afford the crude acid chloride. This crude material

(5 g, 19.12 mmol) was dissolved in acetone (41 mL), cooled to 0°C and ammonium hydroxide (54.6 mL, 1401.6 mmol) added dropwise over 10 minutes. The resulting mixture was stirred at ambient temperature for 1 hour and the precipitate collected by filtration.

The solid was washed with diethyl ether and dried under vacuum to afford the desired material (5 g) as a brown solid, which was used without further purification.

NMR Spectrum: ¾ NMR (400MHz, DMSO) δ 8.13 (1H, s), 8.15 (1H, dd), 8.37 (1H, dd),

8.42 (1H, s), 8.65 (1H, dd).

Mass Spectrum: m/z (ES+)[M+H]+ = 242

6-Chloro-4-hydroxy-cinnoline-3-carboxylic acid is available from commercial sources, for example from IChem LP, 5 walnut Hill Park, Suite 13, Woburn, MA, 01801, US; CAS Registry Number: 90272-08-5, or from Vijaya Pharmaceuticals, LLC (V-Pharma), 104 T. W. Alexander Drive, Building 5, PO Box 14547, Research Triangle Park, NC, 27709, US. The preparation is also described in the literature: Schofield, K.; Swain, T., Journal of the Chemical Society, (1949), 2393-9.

2-(3-(Piperidin-l-yl)propoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine

Butyllithium (139 mL, 347.59 mmol) was added dropwise to 5-bromo-2-(3-(piperidin-l- yl)propoxy)pyridine (80 g, 267.37 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (64.7 g, 347.59 mmol) in THF (400 mL) cooled to -78°C over a period of 10 minutes under an inert atmosphere. The resulting mixture was allowed to warm to ambient temperature and stirred for 12 hours. The reaction mixture was quenched with saturated aqueous solution of NH₄C1 (100 mL) and solvent was removed before the mixture was extracted with EtOAc (2 x 500 mL).Tthe organic layer was washed with saturated brine (2 x 100 mL), dried over Na₂S04, filtered and evaporated to afford the desired product (92 g, 99 %) as a yellow oil, which was used without further purification. NMR Spectrum: ^!H NMR (400 MHz, CDCb,) δ 1.34 (12H, s), 1.60 (5H, p), 1.93 - 2.08 (3H, m), 2.39 - 2.53 (6H, m), 4.34 (2H, dt), 6.67 - 6.77 (1H, m), 7.92 (1H, dd), 8.50 - 8.56 (lH, m).

Mass Spectrum: m/z (ES+), M-82 = 264.9 (decomposition to boronic acid observed)

5-Bromo-2-(3-(piperidin- 1 -yl)propoxy)pyridine

Sodium hydride (26.14 g, 653.46 mmol) was added portionwise to 3-(l-piperidinyl)-l- propanol (44.8 g, 312.52 mmol) in THF (400 mL) at 25°C under an inert atmosphere, then stirred at 50 °C for 30 minutes. 5-bromo-2-fluoropyridine (50.0 g, 284.11 mmol) was added at ambient temperature, then the solution was stirred at 50 °C for 2 hours. The mixture was poured into water/ice (1000 mL), the solvent removed under reduced pressure and extracted with DCM (3 x 150 mL). The organic layer was washed with saturated brine (3 x 150 mL), dried over Na₂S0₄, filtered and evaporated to afford the desired product (96 g, 113 %) as a brown oil, which was used without further purification.

NMR Spectrum: ^!H NMR (400MHz, DMSO) δ 1.36-1.50 (6H, m), 1.80-1.87 (2H, m), 2.29-2.36 (6H, m), 4.24 (2H, t), 6.79 (1H, d), 7.86-7.89 (1H, m), 8.26 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 299.0 l-[3-[4-(4,4,5,5-Tetramethyl-l ,3,2-dioxaborolan-2-yl)phenoxylpropyllpyrrolidine

Potassium acetate (1.036 g, 10.56 mmol) was added to l-(3-(4- bromophenoxy)propyl)pyrrolidine (1 g, 3.52 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (1.072 g, 4.22 mmol) and [Ι, - bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.129 g, 0.18 mmol) in 1,4- dioxane (1 mL) at 25°C under nitrogen. The resulting mixture was stirred at 100 °C for 3 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford the desired material as a brown oil (1.100 g, 94 %). Mass Spectrum: m/z (ES+)[M+H]+ 332

1 -(3 -(4-Bromophenoxy)propyl)pyrrolidine

A mixture of l-(3-chloropropyl)pyrrolidine, hydrochloride salt (1.5 g, 8.15 mmol), 4- bromophenol (1.410 g, 8.15 mmol) and potassium carbonate (4.50 g, 32.59 mmol) in DMF (15 mL) was heated to 90°C for 18 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (300 mL), washed with water (200 mL), saturated brine (200 mL), dried over a phase separator and the solvent was removed under reduced pressure to afford crude product. The crude product was purified by ion exchange chromatography, using an SCX column and eluting with 1M NH3/MeOH, to afford the desired material as a brown oil (1.97 g, 85 %).

NMR Spectrum: ^lH NMR (500MHz, CDC13) δ 1.73 - 1.85 (4H, m), 1.94 - 2.04 (2H, m), 2.49 - 2.56 (4H, m), 2.57 - 2.64 (2H, m), 3.99 (2H, t), 6.75 - 6.81 (2H, m), 7.31 - 7.39 (2H, m).

Mass Spectrum: m/z (ES+)[M+H]+ = 286 l-r3-r4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy1propyl1piperidine

Dichloro[l, -bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.11 g, 0.14 mmol) was added to l-(3-(4-bromophenoxy)propyl)piperidine (2.0 g, 6.71 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.044 g, 8.05 mmol) and potassium acetate (2.63 g, 26.83 mmol) in 1,4-dioxane (30.5 mL) and the mixture degassed for 15 minutes. The resulting suspension was stirred at 90 °C for 22 hours under an inert atmosphere. The reaction mixture was evaporated to dryness, redissolved in DCM (50 mL), washed with water (40 mL) and the organic layer was dried with a phase separating cartridge, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, to afford the desired material as a brown oil which solidified on standing.

NMR Spectrum: ^!H NMR (400MHz, CDCb) δ 1.33 (12H, s), 1.59 (2H, s), 1.88 (4H, q), 2.26 (2H, dq), 2.77 - 2.97 (6H, m), 4.06 (2H, t), 6.76 - 6.92 (2H, m), 7.64 - 7.8 (2H, m). Mass Spectrum: m/z (ES+) [M+H]+ = 346

Example 12: 8-[6-[3-(4-Fluoro-l-piperidyl)propoxy]-3-pyridyl]-l-isopropyl-3-methyl- imidazo 4,5-c] cinnolin-2-one

3-(4-Fluoropiperidin-l-yl)propan-l-ol (105 mg, 0.65 mmol) in THF (1.235 mL) was added dropwise to a stirred suspension of sodium hydride (52.2 mg, 1.30 mmol) in THF (1.235 mL) 0 °C. The resulting suspension was stirred at 0 °C for 10 minutes under an inert atmosphere before a solution of 8-(6-fluoro-3-pyridyl)-l-isopropyl-3-methyl-imidazo[4,5- c]cinnolin-2-one (110 mg, 0.33 mmol) in DMF (1.087 mL) was added and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (40 mL), washed three times with water (3 x 20 mL) and the organic layer was dried over MgS0₄, filtered and evaporated. The crude product was purified by preparative HPLC to afford the desired material (25 mg) as a yellow solid.

NMR Spectrum: ^!H NMR (400MHz, DMSO) δ 1.66 - 1.77 (8H, m), 1.79 - 1.97 (4H, m), 2.29 - 2.38 (3H, m), 2.55 - 2.62 (3H, m), 3.61 (3H, s), 4.42 (2H, t), 4.65 (IH, ddt), 5.28 (IH, p), 6.96 (IH, dd), 8.02 (IH, dd), 8.18 (IH, dd), 8.34 (IH, d), 8.39 (IH, dd), 8.67 (IH, dd). Mass Spectrum: m/z (ES+)[M+H]+ = 479

The preparation of 8-(6-fluoro-3-pyridyl)-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2- one is described below.

8-(6-Fluoro-3- yridyl)-l-isopropyl-3-methyl-imidazor4,5-c1cinnolin-2-one

Dichlorobis(triphenylphosphine)palladium (II) (31.7 mg, 0.05 mmol) was added to a degassed solution of (6-fluoropyridin-3-yl)boronic acid (134 mg, 0.95 mmol), 8-chloro-l- isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one (250 mg, 0.90 mmol) and 2M potassium carbonate solution (1.355 mL, 2.71 mmol) in 1,4-dioxane (3.16 mL) and the mixture heated in a microwave reactor at 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) then the organic layer evaporated to afford the desired material as a brown solid which was used in the subsequent steps without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 338

The preparation of 8-chloro-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one has been described previously.

3-(4-Fluoropiperidin-l-yl)propan-l-ol was prepared as described below. 3-(4-Fluoro iperidin- 1 -yPpropan- 1 -ol

To a solution of 4-fluoropiperidine (2.0 g, 19.39 mmol) in dry tetrahydrofuran (20 mL) at room temperature under nitrogen was added sodium hydride (1 g, 25.00 mmol) then stirred for thirty minutes. (3-Bromopropoxy)(tert-butyl)dimethylsilane (6.77 mL, 29.22 mmol) was added dropwise then allowed to stir for 24 h at ambient temperature. The reaction mixture was diluted with EtOAc (100 mL), and washed three times with water (3 x 50 mL). The organic layer was dried over MgS0₄, filtered and evaporated to afford crude product still bearing the silyl protecting group on the alcohol. This material was loaded onto 2 x 50g SCX columns washing with MeOH and the deprotected product eluted from the column using 2M NH3/MeOH to afford the desired material (2.226 g) as a yellow oil. NMR Spectrum: ^!H NMR (500MHz, CDCb) δ 1.63 - 1.77 (2H, m), 1.87 (4H, dq), 2.42 - 2.7 (6H, m), 3.74 - 3.87 (2H, m), 4.69 (1H, dt).

Example 13: 8- [6- [3-[(3R)-3-Fluoropyrrolidin-l-yl] propoxy]-3-pyridyl] -l-isopropyl-3- methyl-imidazo [4,5-c] cinnolin-2-one

3-[(3R)-3-Fluoro-l-pyrrolidinyl]-l-propanol (96 mg, 0.65 mmol) in THF (1.235 mL) was added dropwise to a stirred suspension of sodium hydride (52 mg, 1.30 mmol) in THF (1.2 mL) at 0 °C. The resulting suspension was stirred at 0 °C for 10 minutes under an inert atmosphere before a solution of 8-(6-fluoro-3-pyridyl)-l-isopropyl-3-methyl-imidazo[4,5- c]cinnolin-2-one (1 10 mg, 0.33 mmol) in DMF (1.0 mL) was added and the reaction mixture stirred at ambient temperature for 72 hours. The reaction mixture was diluted with ethyl acetate (40 mL), washed three times with water (3 x 20 mL) and the organic layer was dried over MgS0₄, filtered and evaporated. The crude product was purified by preparative HPLC to afford the desired product (4.7 mg) as a cream dry film.

NMR Spectrum: ^lH NMR (400MHz, CDCb) δ 1.79 (6H, d), 2.08 - 2.13 (2H, m), 2.75 (1H, td), 2.79 - 2.85 (2H, m), 2.89 - 3.12 (5H, m), 3.77 (3H, s), 4.46 (2H, t), 5.12 - 5.32 (2H, m), 6.91 (1H, dd), 7.84 (1H, dd), 7.92 (1H, dd), 8.20 (1H, d), 8.46 - 8.56 (2H, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 465 The preparation of 8-(6-fluoro-3-pyridyl)-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2- one has been described earlier.

The preparation of 3-[(3R)-3-fluoro-l-pyrrolidinyl]-l-propanol is described below. 3-IY3R)-3-Fluoro- 1 -pyrrolidinyll - 1 -propanol

To a suspension of (3R)-3-fluoropyrrolidine hydrochloride (0.92 g, 7.33 mmol) in dry tetrahydrofuran (22 mL) at room temperature under nitrogen was added sodium hydride (0.88 g, 21.98 mmol) then stirred for thirty minutes. (3-Bromopropoxy)(tert- butyl)dimethylsilane (2.55 mL, 10.99 mmol) was added dropwise then allowed to stir for 72 hours at ambient temperature. The reaction mixture was diluted with EtOAc (50 mL), and washed two times with water (2 x 25 ml). The organic layer was dried over MgS04, filtered and evaporated to afford crude product still bearing the silyl protecting group on the alcohol.

This material was loaded onto 2 x 20g SCX washing with MeOH and the deprotected product eluted from the column using 2M NFb/MeOH to afford the desired material (0.268 g) as a colourless solid.

NMR Spectrum: ^!H NMR (400MHz, DMSO) δ 1.77 (2H, dq), 2.06 - 2.44 (2H, m), 3.06 - 3.25 (3H, m), 3.39 (2H, d), 3.48 (2H, t), 3.51 - 3.86 (2H, m), 5.42 (1H, d).

Example 14: l-Isopropyl-3-methyl-8-[2-methyl-6-[3-(l-piperidyl)propoxy]-3- pyridyl] imidazo [4,5-c] cinnolin-2-one

A solution of 3 -(l-piperidinyl)-l -propanol (0.152 mL, 1.00 mmol) in THF (3.70 mL) was added slowly to a stirred suspension of sodium hydride (0.048 g, 2.00 mmol) in THF (3.7 mL) under an inert atmosphere and the reaction stirred at ambient temperature for 30 minutes. A solution of 8-(6-fluoro-2-methyl-3-pyridyl)-l-isopropyl-3-methyl-imidazo[4,5- c]cinnolin-2-one (0.176 g, 0.50 mmol) in THF (3.7 mL) was then added to the above reaction and the mixture stirred at ambient temperature for 2 hours. The reaction was diluted with EtOAc (50 mL), the organic layer washed with brine (2 x 20 mL), dried over MgS0₄, filtered and evaporated. The crude product was purified by preparative HPLC to afford the desired product (0.06 g, 25 %) as a white solid.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.40 (2H, d), 1.51 (4H, p), 1.63 (6H, d), 1.90 (2H, p), 2.34 (4H, dd), 2.40 (2H, t), 2.46 (3H, s), 3.61 (3H, s), 4.35 (2H, t), 5.21 (1H, dt), 6.79 (1H, d), 7.71 - 7.82 (2H, m), 8.21 (1H, d), 8.39 (1H, d).

Mass Spectrum: m/z ES+ [M+H]+ = 474

8-(6-Fluoro-2-methyl-3-pyridyl)-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one was prepared as described below.

8-(6-Fluoro-2-methyl-3-pyridyl)-l-isopropyl-3-methyl-imidazo[4,5-clcinnolin-2-one

Dichlorobis(triphenylphosphine)palladium(II) (22.19 mg, 0.03 mmol) was added to a degassed mixture of 8-chloro-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one (175 mg, 0.63 mmol), (6-fluoro-2-methyl-3-pyridinyl)boronic acid (108 mg, 0.70 mmol) and 2M aqueous potassium carbonate solution (0.949 mL, 1.90 mmol) in 1,4-dioxane (5.37 mL) and heated to 90 °C for 1 hour in a microwave reactor under an inert atmosphere. The reaction mixture was diluted with 10% methanol in DCM (40 mL) and water (15 mL). The aqueous phase was extracted with 10% methanol in DCM (2 x 20 mL), then the combined organic phases dried over a phase separating cartridge and concentrated to afford the desired product, which was used immediately without purification.

Mass Spectrum: m/z ES+ [M+H]+ = 352 Example 15: l-(frans-3-Methoxycyclobutyl)-3-methyl-8-[4-[3-(l- piperidyl)propoxy] phenyl] imidazo [4,5-c] cinnolin-2-one

l, -Bis(di-tert-butylphosphino)ferrocene palladium dichloride (10.22 mg, 0.02 mmol) was added to a degassed solution of l-[3-[4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)phenoxy]propyl]piperidine (1 14 mg, 0.33 mmol) and 8-chloro-l-(tra/?s-3- methoxycyclobutyl)-3-methyl-imidazo[4,5-c]cinnolin-2-one (100 mg, 0.31 mmol), 2M potassium carbonate solution (0.47 mL, 0.94 mmol) in 1 ,4-dioxane (1.1 mL) and the mixture was heated in a microwave reactor to 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), washed sequentially with water (10 mL), saturated brine (10 mL) and the organic layer was evaporated. The crude product was purified by preparative HPLC to afford the desired product (46.2 mg, 29 %) as a brown dry film.

NMR Spectrum: *H NMR (400 MHz, CDCb) 1.19 (lH, t), 1.44 (2H, p), 1.60 (3H, p), 1.97 - 2.06 (2H, m), 2.42 (4H, s), 2.47 - 2.54 (2H, m), 2.59 - 2.7 (2H, m), 3.34 (3H, s), 3.36 - 3.44 (2H, m), 3.73 (3H, s), 4.10 (2H, t), 4.34 (1H, tt), 5.43 - 5.54 (1H, m), 7.03 - 7.09 (2H, m), 7.6 - 7.66 (2H, m), 7.87 (1H, dd), 8.08 (1H, d), 8.42 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 502

* Reaction stirred for 2 hours at 80°C

Example 16: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.89 (2H, p), 2.16 (6H, s), 2.38 (2H, t), 2.56 - 2.67 (2H, m), 3.16 - 3.22 (2H, m), 3.24 (3H, s), 3.60 (3H, s), 4.10 (2H, t), 4.26 (IH, tt), 5.53 (IH, ddd), 7.1 - 7.16 (2H, m), 7.82 - 7.86 (2H, m), 8.04 (IH, dd), 8.19 (IH, d), 8.36 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 462

Example 17: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.62 - 1.78 (2H, m), 1.78 - 1.89 (2H, m), 1.89 - 1.96 (2H, m), 2.29 (IH, d), 2.44 (2H, d), 2.53 - 2.57 (IH, m), 2.63 (4H, td), 3.13 - 3.21 (2H, m), 3.23 (3H, s), 3.61 (3H, s), 4.29 (IH, ddd), 4.38 (2H, t), 4.67 (IH, ddt), 5.58 (IH, ddd), 6.95 - 7.07 (IH, m), 8.06 (IH, dd), 8.2 - 8.31 (2H, m), 8.39 (IH, d), 8.73 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 521 Example 18: NMR Spectrum: ^lH NMR (400 MHz, CDCb) δ 1.21 - 1.33 (IH, m), 1.84 - 1.97 (4H, m), 1.98 - 2.07 (2H, m), 2.34 - 2.49 (2H, m), 2.5 - 2.59 (2H, m), 2.62 (2H, d), 2.97 (2H, dddd), 3.10 (2H, tdd), 3.32 (3H, s), 3.77 (3H, s), 3.94 (IH, p), 4.44 (2H, t), 4.56 - 4.8 (IH, m), 4.98 - 5.15 (IH, m), 6.89 (IH, d), 7.86 (IH, dd), 8.00 (IH, dd), 8.41 (IH, d), 8.51 (IH, d), 8.57 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 521

Example 19: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.34 - 1.43 (2H, m), 1.52 (4H, p), 1.91 (2H, p), 2.39 (6H, s), 2.75 - 2.9 (2H, m), 2.94 - 3.02 (2H, m), 3.21 (3H, s), 3.59 (3H, s), 3.88 (IH, p), 4.10 (2H, t), 5.01 - 5.19 (IH, m), 7.12 (2H, d), 7.82 - 7.91 (2H, m), 8.04 (IH, dd), 8.19 (IH, s), 8.36 (2H, d). Mass Spectrum: m/z (ES+) [M+H]+ = 502

Example 20: NMR Spectrum: ^lH NMR (400 MHz, CDC13) δ 1.98 - 2.25 (4H, m), 2.49 (IH, q), 2.64 - 2.79 (3H, m), 2.85 (2H, dq), 2.93 - 3.03 (2H, m), 3.04 - 3.17 (2H, m), 3.32 (3H, s), 3.77 (3H, s), 3.94 (IH, p), 4.45 (2H, t), 4.98 - 5.3 (2H, m), 6.89 (IH, d), 7.86 (IH, d), 8.00 (IH, dd), 8.41 (IH, s), 8.51 (IH, d), 8.57 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 507

Example 21 : NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.88 (4H, td), 2.17 (6H, s), 2.22 (IH, s), 2.39 (2H, t), 2.54 - 2.66 (IH, m), 3.38 - 3.46 (IH, m), 3.58 (3H, s), 3.94 (IH, d), 4.10 (2H, t), 4.12 - 4.24 (2H, m), 4.90 (IH, tt), 7.1 1 - 7.17 (2H, m), 7.78 - 7.84 (2H, m), 8.05 (IH, dd), 8.23 (OH, s), 8.26 (IH, d), 8.38 (IH, d . Mass Spectrum: m/z (ES+) [M+H]+ = 462

Example 22: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.34 - 1.44 (2H, m), 1.51 (4H, p), 1.89 (4H, td), 2.08 (IH, s), 2.21 (IH, d), 2.29 - 2.38 (4H, m), 2.41 (2H, t), 3.39 - 3.47 (IH, m), 3.59 (3H, s), 3.95 (IH, d), 4.10 (2H, t), 4.13 - 4.24 (2H, m), 4.86 - 4.97 (IH, m), 7.1 1 - 7.19 (2H, m), 7.78 - 7.86 (2H, m), 8.06 (IH, dd), 8.27 (IH, d), 8.39 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 502

Example 23: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.72 (2H, d), 1.76 - 1.96 (6H, m), 2.19 (IH, d), 2.25 - 2.35 (3H, m), 2.43 - 2.47 (3H, m), 2.58 - 2.65 (IH, m), 3.36 - 3.45 (IH, m), 3.59 (3H, s), 3.94 (IH, d), 4.12 - 4.2 (2H, m), 4.38 (2H, t), 4.67 (IH, dt), 4.94 (IH, s), 7.02 (IH, d), 8.08 (IH, dd), 8.22 (IH, dd), 8.32 (IH, s), 8.42 (IH, d), 8.70 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 521

Example 24: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.25 (3H, d), 1.43 - 1.51 (IH, m), 1.65 (3H, s), 1.89 (2H, p), 2.16 (6H, s), 2.38 (2H, t), 3.58 (3H, s), 4.09 (2H, t), 7.1 - 7.17 (2H, m), 7.77 - 7.84 (2H, m), 8.07 (IH, dd), 8.36 (IH, d), 8.58 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 432

Example 25: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.26 (3H, s), 1.36 - 1.43 (2H, m), 1.49 (6H, dt), 1.65 (3H, s), 1.90 (2H, p), 2.36 (2H, s), 2.39 - 2.46 (2H, m), 3.58 (4H, s), 4.09 (2H, t), 7.14 (2H, d), 7.81 (2H, d), 8.08 (IH, dd), 8.37 (IH, d), 8.58 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 472

Example 26: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.18 - 1.33 (3H, m), 1.44 (IH, q), 1.65 (3H, s), 1.67 - 1.76 (2H, m), 1.77 - 1.96 (4H, m), 2.29 (2H, d), 2.45 (3H, t), 2.54 (IH, s), 3.59 (3H, s), 4.38 (2H, t), 4.56 - 4.79 (IH, m), 6.98 - 7.04 (IH, m), 8.10 (IH, dd), 8.19 (IH, dd), 8.40 (IH, d), 8.59 (IH, d), 8.67 (IH, d . Mass Spectrum: m/z (ES+) [M+H]+ = 491

Example 27: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.18 - 1.33 (3H, m), 1.33 - 1.44 (3H, m), 1.48 (5H, tt), 1.65 (3H, s), 1.91 (2H, p), 2.33 (2H, d), 2.39 (3H, t), 3.59 (3H, s), 4.37 (2H, t), 7.00 (IH, dd), 8.10 (IH, dd), 8.19 (IH, dd), 8.40 (IH, d), 8.59 (IH, d), 8.67 (IH, dd). Mass Spectrum: m/z (ES+) [M+H]+ = 473

Example 27 can also be isolated as the methane sulfonic acid salt by taking the material as prepared above and subjecting to the following reaction conditions.

3 -methyl- 1 -( 1 -methylcyclopropyl)-8- {6-[3-( 1 -piperidinyl)propoxy] -3 -pyridinyl} -1,3- dihydro-2H-imidazo[4,5-c]cinnolin-2-one (44 mg, 0.09 mmol) was dissolved in DCM (2 mL) and treated with 1M methanesulfonic acid (6.33 μί, 0.10 mmol) in DCM, stirred for 5 minutes, then the mixture evaporated to dryness. The residue was triturated with diethyl ether to afford the methane sulfonic acid salt (21.8 mg, 41.3 %) as a pale yellow solid. NMR Spectrum: *H NMR (400 MHz, DMSO) δ 1.19 - 1.34 (3H, m), 1.43 (2H, dd), 1.67 (6H, s), 1.84 (2H, d), 2.19 (2H, dt), 2.92 (2H, q), 3.24 (2H, dt), 3.50 (2H, d), 3.59 (3H, s),

4.44 (2H, t), 7.04 (IH, d), 8.13 - 8.31 (2H, m), 8.41 (IH, d), 8.61 (IH, s), 8.69 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 473

Example 28: NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.88 (2H, p), 2.16 (6H, s), 2.17 - 2.29 (3H, m), 2.33 (IH, dt), 2.38 (3H, t), 2.46 (IH, d), 3.28 (3H, s), 3.60 (3H, s), 4.10 (3H, q), 5.49 (IH, p), 7.1 - 7.16 (2H, m), 7.78 - 7.84 (2H, m), 8.05 (IH, dd), 8.25 (IH, d), 8.38 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 476

Example 29: NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.39 (2H, q), 1.50 (4H, p), 1.79 - 1.94 (3H, m), 2.14 - 2.29 (3H, m), 2.33 (4H, d), 2.37 - 2.43 (3H, m), 2.45 - 2.48 (IH, m), 3.28 (3H, s), 3.59 (3H, s), 4.04 - 4.16 (3H, m), 5.47 (IH, p), 7.03 - 7.19 (2H, m), 7.73 - 7.88 (2H, m), 8.03 (IH, dd), 8.22 (IH, d), 8.36 (IH, d . Mass Spectrum: m/z (ES+)

[M+H]+ =516

Example 30: NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.88 (3H, dt), 2.16 (6H, s), 2.17 - 2.46 (7H, m), 3.28 (3H, s), 3.60 (3H, s), 4.05 - 4.19 (3H, m), 5.50 (IH, q), 7.06 - 7.22 (2H, m), 7.75 - 7.86 (2H, m), 8.05 (IH, dd), 8.24 (IH, d), 8.37 (IH, d). Mass

Spectrum: m/z (ES+) [M+H]+ = 476

Example 31: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.4 - 1.48 (2H, m), 1.56 (4H, p), 1.83 - 2.02 (3H, m), 2.21 - 2.51 (11H, m), 3.33 (3H, s), 3.65 (3H, s), 4.20 (IH, p), 4.43 (2H, t), 5.58 (IH, p), 7.03 - 7.08 (IH, m), 8.12 (IH, dd), 8.26 (IH, dd), 8.38 (IH, d),

8.45 (IH, d), 8.73 - 8.78 (IH, m . Mass Spectrum: m/z (ES+) [M+H]+ = 517

Example 32: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.77 - 2.41 (l lH, m), 2.53 - 2.66 (3H, m), 2.77 - 2.88 (2H, m), 3.27 (3H, s), 3.60 (3H, s), 4.1 - 4.18 (IH, m), 4.40 (2H, t), 5.19 (IH, ddd), 5.52 (IH, p), 7.01 (IH, dd), 8.08 (IH, d), 8.21 (IH, dd), 8.33 (IH, d), 8.40 (IH, d), 8.69 - 8.76 (IH, m). Mass Spectrum: m/z (ES+) [M+H]+ = 521 Example 33: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.39 (2H, d), 1.50 (4H, p), 1.76 - 1.96 (3H, m), 2.14 - 2.48 (1 1H, m), 3.27 (3H, s), 3.59 (3H, s), 4.13 (IH, p), 4.36 (2H, t), 5.51 (IH, p), 6.96 - 7.05 (IH, m), 8.05 (IH, dd), 8.19 (IH, dd), 8.31 (IH, d), 8.38 (IH, d), 8.69 (IH, d . Mass Spectrum: m/z (ES+) [M+H]+ = 517

Example 34: NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.89 (2H, p), 2.18 (6H, s), 2.41 (2H, t), 2.84 (2H, td), 2.93 - 3.05 (2H, m), 3.21 (3H, s), 3.58 (3H, s), 3.88 (IH, p), 4.09 (2H, t), 5.07 (IH, p), 7.1 1 (2H, d), 7.85 (2H, d), 8.03 (IH, d), 8.34 (2H, d). Mass Spectrum: m/z (ES+) [M+H]+ = 462

Example 35: NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.39 (2H, d), 1.49 (4H, q), 1.91 (2H, p), 2.29 - 2.46 (6H, m), 2.78 - 2.87 (2H, m), 2.94 - 3.05 (2H, m), 3.21 (3H, s), 3.60 (3H, s), 3.89 (IH, p), 4.38 (2H, t), 5.06 - 5.18 (IH, m), 6.99 (IH, dd), 8.06 (IH, dd), 8.26 (IH, dd), 8.39 (IH, d), 8.45 (IH, d), 8.71 - 8.8 (IH, m . Mass Spectrum: m/z (ES+) [M+H]+ = 503

Example 36: NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.8 - 2.22 (5H, m), 2.29 - 2.33 (IH, m), 2.55 - 2.65 (4H, m), 2.77 - 2.88 (2H, m), 3.17 (2H, dd), 3.23 (3H, s), 3.61 (3H, s), 4.24 - 4.33 (IH, m), 4.40 (2H, t), 5.09 - 5.28 (IH, m), 5.54 - 5.65 (IH, m), 7.01 (IH, d), 8.06 (IH, dd), 8.21 - 8.32 (2H, m), 8.39 (IH, d), 8.73 (IH, d . Mass Spectrum: m/z (ES+) [M+H]+ = 507

The preparation of the chloro intermediates and boronic esters for Examples 15 - 36 have either been described earlier or are described below.

8-Chloro-l-(tra/? -3-methoxycvclobutyl)-3-methyl-imidazor4,5-c1cinnolin-2-one

l ,l-Dimethoxy-N,N-dimethylmethanamine (4.71 mL, 35.48 mmol) was added to 8-chloro- l-(trans-3-methoxycyclobutyl)-3H-imidazo[4,5-c]cinnolin-2-one (1.44 g, 4.73 mmol) in DMF (1 1 mL) and stirred at 100 °C for 2.5 hours. The mixture was cooled and the precipitate formed was collected by filtration, washing with water (30 mL) to afford desired product (0.5 g) as an orange solid. The aqueous layer was backextracted with DCM (2 x 25 mL), the combined organic layers washed with brine (3 x 25 mL), dried (MgS04) and concentrated to afford desired product (2.12 g) as a yellow solid (contaminated with a small quantity of DMF).

NMR Spectrum: *H NMR (400 MHz, DMSO) δ 2.52 - 2.63 (2H, m), 3.1 - 3.18 (2H, m), 3.23 (3H, d), 3.59 (3H, s), 4.25 (1H, dq), 5.43 (1H, tt), 7.73 (1H, dd), 8.24 (1H, d), 8.31 - 8.35 (lH, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 319

8-Chloro-l-(trans-3-methoxycyclobutyl)-3H-imidazo[4,5-clcinnolin-2-one

l ,3,5-Trichloro-l ,3,5-triazinane-2,4,6-trione (0.549 g, 2.36 mmol) was added portionwise to a solution of 6-chloro-4-[(tra/75-3-methoxycyclobutyl)amino]cinnoline-3-carboxamide (1.45 g, 4.73 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[l ,2-a]azepine (DBU) (1.414 ml, 9.45 mmol) in MeOH (22.22 ml) at 0 °C and the resulting solution allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was concentrated to dryness, then partitioned between EtOAc (50 mL) and saturated aqueous NH₄C1 (50 mL). A precipitated crashed out of solution which was collected by filtration, washed with diethyl ether (3 x lOmL) and azeotroped with MeCN (2 x 50 mL) to afford the desired material (1.79 g, 124 %) as a yellow solid.

Mass Spectrum: m/z (ES+) [M+H]+ = 305

6-Chloro-4-r(tra/? -3-methoxycvclobutyl)amino1cinnoline-3-carboxamide

7>a/?5-3-methoxycyclobutan-l -amine hydrochloride (0.719 g, 5.23 mmol) was added in one portion to 4,6-dichlorocinnoline-3-carboxamide (1.15 g, 4.75 mmol) and DIPEA (2.489 mL, 14.25 mmol) in acetonitrile (9.39 mL) and the resulting suspension was stirred at 90 °C for 18 hours. The reaction was allowed to cool, concentrated, diluted with water and the precipitate was collected by filtration, washed with water (20 mL) followed by acetonitrile (10 mL) and diethyl ether (10 mL) and dried under vacuum to afford the desired material (1.15 g, 79%) as an orange solid.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 2.27 - 2.35 (2H, m), 2.42 - 2.53 (2H, m), 3.19 (3H, s), 4.04 - 4.13 (1H, m), 4.65 - 4.75 (1H, m), 7.79 (1H, d), 7.86 - 7.9 (1H, m), 8.04 (1H, d), 8.21 (1H, d), 8.61 (1H, s), 10.80 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 307

8-Chloro-l-(c -3-methoxycyclobutyl)-3-methyl-imidazo[4,5-clcinnolin-2-one

l ,l-Dimethoxy-N,N-dimethylmethanamine (0.981 mL, 7.38 mmol) was added to 8-chloro- l-(cz5-3-methoxycyclobutyl)-3H-imidazo[4,5-c]cinnolin-2-one (0.3 g, 0.98 mmol) in DMF (2.3 ml) and stirred at 100 °C for 16 hours. The aqueous layer was backextracted with DCM (2 x 25 mL), the combined organic layers washed with brine (3 x 25 mL), dried (MgS0₄) and concentrated to afford desired product (0.744 g) as a yellow liquid. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane followed by 10% MeOH/EtOAc, to afford the desired product (0.110 g, 35.1 %) as a white solid.

NMR Spectrum: *H NMR (400 MHz, DMSO) δ 2.78 (2H, d), 2.97 (2H, q), 3.22 (3H, s), 3.58 (3H, s), 3.86 (IH, p), 4.98 (IH, p), 7.74 (IH, d), 8.34 (IH, d), 8.49 (IH, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 319 8-Chloro- 1 - cz5-3-methoxycyclobutyl)-3H-imidazo[4,5-c]cinnolin-2-one

l,3,5-Trichloro-l,3,5-triazinane-2,4,6-trione (0.824 g, 3.54 mmol) was added portionwise to a solution of 6-chloro-4-[(c 5-3-methoxycyclobutyl)amino]cinnoline-3-carboxamide (1.45 g, 4.73 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (DBU) (2.12 mL, 14.2 mmol) in MeOH (22.22 ml) at 0 °C at 0 °C and the resulting solution allowed to warm to ambient temperature and stirred for 72 hours. The reaction mixture was concentrated to dryness, then partitioned between EtOAc (50 mL) and saturated aqueous NH₄C1 (50 mL).

A precipitated crashed out of solution which was collected by filtration, washed with diethyl ether (3 x lOmL) and azeotroped with MeCN (2 x 50 mL) to afford the desired material (2.420 g, 168 %>) as a yellow solid.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 2.83 (2H, dddd), 2.98 (2H, dddt), 3.26 (3H, s), 3.90 (IH, p), 4.89 (IH, tt), 7.50 (IH, s), 7.68 (IH, dd), 8.30 (IH, d), 8.39 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 305

6-Chloro-4-r(c -3-methoxycvclobutyl)amino1cinnoline-3-carboxamide

Cis-3-methoxycyclobutan-l -amine hydrochloride (0.938 g, 6.82 mmol) was added in one portion to 4,6-dichlorocinnoline-3-carboxamide (1.65 g, 6.82 mmol) and DIPEA (3.57 mL, 20.45 mmol) in acetonitrile (13.47 mL) and the resulting suspension was stirred at 90 °C for 18 hours. The reaction was allowed to cool, concentrated, diluted with water and the precipitate was collected by filtration, washed with water (20 mL) followed by acetonitrile (10 mL) and diethyl ether (10 mL) to afford the desired material (1.450 g, 69.3 %) as a beige solid.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.77 - 2.1 (2H, m), 2.78 - 3.05 (2H, m), 3.21 (3H, s), 3.79 (1H, p), 4.26 (1H, h), 7.26 - 7.71 (1H, m), 7.85 (1H, dd), 8.15 (1H, d), 8.18 - 8.6 (2H, m), 10.19 - 10.57 (1H, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 307

8-Chloro-3-methyl-l-r(3R)-tetrahvdropyran-3-yl1imidazor4,5-c1cinnolin-2-one

l,l-Dimethoxy-N,N-dimethylmethanamine (2.285 mL, 17.20 mmol) was added to 8- chloro-l-[(3R)-tetrahydropyran-3-yl]-3H-imidazo[4,5-c]cinnolin-2-one (699 mg, 2.29 mmol) in DMF (5.36 mL) and the mixture stirred at 100 °C for 2.5 hours. The mixture was cooled and the precipitate formed was filtered, washed with water (10 mL) and diethyl ether (10 mL) to afford the desired product (560 mg, 77 %) as an orange solid which was used without further purification.

Mass Spectrum: m/z (ES+) [M+H]+ = 319

8-chloro-l-r(3R)-tetrahvdropyran-3-yl1-3H-imidazor4,5-c1cinnolin-2-one

l,3,5-Trichloro-l,3,5-triazinane-2,4,6-trione (0.480 g, 12.06 mmol) was added portionwise to a stirred suspension of 6-chloro-4-[[(3R)-tetrahydropyran-3-yl]amino]cinnoline-3- carboxamide (1.1612 g, 3.79 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (DBU) (1.234 mL, 8.82 mmol) in MeOH (18 mL) at 0 °C and warmed to ambient temperature for 90 minutes. A precipitate formed which was collected by filtration and washed with diethyl ether (3 x lOmL). The filtrate was adjusted to pH 7 with 2M HC1 and the precipitate formed was filtered, washed with water (10 mL), DCM:Et₂0 (1 : 1 ratio, 10 mL) and combined with the above solid to afford the desired material (0.837 g, 72.6 %) as a orange solid.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.57 - 1.72 (2H, m), 1.75 - 1.96 (2H, m), 3.45 - 3.58 (2H, m), 3.92 (1H, dd), 4.06 (1H, dd), 4.71 (1H, ddd), 7.70 (1H, dd), 8.21 (1H, d), 8.30 (1H, d), 11.47 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 305

6-Chloro-4- [(3R)-tetrahydropyran-3 -yl] amino] cinnoline-3 -carboxamide

(3R)-Tetrahydro-2H-pyran-3-amine hydrochloride (0.942 g, 9.32 mmol) was added in one portion to 4,6-dichlorocinnoline-3-carboxamide (1.5039 g, 6.21 mmol) and DIPEA (4.76 mL, 18.64 mmol) in acetonitrile (27.8 mL) and stirred at 80 °C for 3 hours. The reaction was allowed to cool, concentrated, diluted with water and the precipitate was collected by filtration, washed with water (20 mL) followed by acetonitrile (10 mL) and diethyl ether (10 mL) and dried under vacuum to afford the desired material (1.161 g, 60.9 %) as a beige solid.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.48 - 1.62 (1H, m), 1.75 (2H, tt), 2.07 (1H, q), 3.54 (1H, dd), 3.62 (2H, t), 3.87 (1H, dd), 4.24 (1H, dq), 7.75 (1H, s), 7.89 (1H, dd), 8.17 (1H, d), 8.24 (1H, d), 8.59 (1H, s), 10.45 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 307

8-Chloro-3-methyl- 1 -(1 -methylcyclopropyl)imidazo[4,5-clcinnolin-2-one

l,l-dimethoxy-N,N-dimethylmethanamine (3.23 ml, 24.30 mmol) was added to 8-chloro- l-(l-methylcyclopropyl)-3H-imidazo[4,5-c]cinnolin-2-one ( 0.89 g, 3.24 mmol) in DMF (7.57 ml) and the mixture stirred at 100 °C for 2.5 hours. The mixture was cooled and the precipitate formed was filtered, washed with water (10 mL) and diethyl ether (10 mL) to afford the desired product (0.57 g) as an orange solid. The aqueous layer was

backextracted with DCM (2 x 25 mL), the combined organic layers washed with brine (3 x 25 mL), dried (MgS04) and concentrated to afford desired product (0.25 g) as a red solid contaiminaed with a small quantity of DMF.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.09 - 1.29 (3H, m), 1.34 - 1.45 (1H, m), 1.60 (3H, s), 3.57 (3H, s), 7.75 (1H, dd), 8.33 - 8.39 (2H, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 289

8-Chloro- 1 -(1 -methylcyclopropyl)-3H-imidazo[4,5-clcinnolin-2-one

l,3,5-Trichloro-l,3,5-triazinane-2,4,6-trione (0.739 g, 3.18 mmol) was added portionwise to a stirred suspension of 6-chloro-4-((l-methylcyclopropyl)amino)cinnoline-3- carboxamide (1.76 g, 6.36 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (DBU) (1.902 mL, 12.72 mmol) in MeOH (29.9 mL) at 0 °C and warmed to ambient temperature for 90 minutes. A precipitate formed which was collected by filtration and washed with diethyl ether (3 x lOmL). The filtrate was adjusted to pH 7 with 2M HC1 and the precipitate formed was filtered, washed with water (10 mL), DCM:Et₂0 (1 : 1 ratio, 10 mL) and combined with the above solid to afford the desired material (0.992 g, 56.8 %) as a brown solid.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.07 - 1.25 (3H, m), 1.3 - 1.44 (1H, m), 1.58 (3H, s), 7.73 (1H, dd), 8.31 (1H, d), 8.36 (1H, d), 12.40 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 275

6-Chloro-4-((l-methylcyclopropyl)amino)cinnoline-3 -carboxamide

1-methylcyclopropanamine hydrochloride (1.23 g, 17.33 mmol) was added in one portion to 4,6-dichlorocinnoline-3-carboxamide (2.8 g, 11.57 mmol) and DIPEA (9 mL, 52.05 mmol) in acetonitrile (51.8 mL) and the resulting suspension was stirred at 80 °C for 16 hours. The reaction was allowed to cool, concentrated, diluted with water and the precipitate was collected by filtration, washed with water (20 mL) followed by acetonitrile (10 mL) and diethyl ether (10 mL) and dried under vacuum to afford the desired material (1.76 g, 55.0 %) as a brown solid.

Mass Spectrum: m/z (ES+) [M+H]+ = 277

8-Chloro-l-[(lR,3R)-3-methoxycyclopentyll-3-methyl-imidazo[4,5-clcinnolin-2-one

Sodium hydride (60% in mineral oil) (156 mg, 3.89 mmol) was added to 8-chloro-l- [(lR,3R)-3-hydroxycyclopentyl]-3-methyl-imidazo[4,5-c]cinnolin-2-one (496 mg, 1.56 mmol) in DMF (15.35 mL) at 0 °C and stirred for 30 minutes. Methyl iodide (0.214 mL, 3.42 mmol) was added and stirred at ambient temperature for 20 hours. The reaction was quenched with water and the precipitate formed was collected by filtration and rinsed with water (10 mL) to afford the desired product (336 mg, 65%) as a yellow solid.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.23 (1H, s), 1.73 - 1.87 (1H, m), 2.11 - 2.29 (4H, m), 3.27 (3H, s), 3.59 (3H, s), 4.13 (1H, s), 5.37 (1H, p), 7.74 (1H, d), 8.30 (1H, s), 8.35 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 333

8-Chloro-l-[(lR,3R)-3-hydroxycyclopentyll-3-methyl-imidazo[4,5-clcinnolin-2-one

Sodium hydride (60%> in mineral oil) (0.340 g, 8.50 mmol) was added to 8-chloro-l- [(lR,3R)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]cinnolin-2-one (1.0364 g, 3.40 mmol) in DMF (33.5 mL) at 0 °C and stirred for 20 minutes. Methyl iodide (0.468 ml, 7.48 mmol) was added and stirred to room temperature for 20 hours. The reaction was quenched with water and the precipitate formed was collected by filtration, rinsed with ether (10 mL) to afford the desired product (0.767 g, 71 %>) as a green solid.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.7 - 1.79 (1H, m), 2.02 - 2.12 (1H, m), 2.15 - 2.39 (4H, m), 3.61 (3H, s), 4.48 (2H, s), 5.43 (1H, p), 7.70 (1H, dd), 8.25 (1H, d), 8.32 - 8.39 (lH, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 319

8-Chloro-l-[(lR,3R)-3-hydroxycyclopentyll-3H-imidazo[4,5-clcinnolin-2-one

l,3,5-Trichloro-l,3,5-triazinane-2,4,6-trione (0.739 g, 3.18 mmol) was added portionwise to a stirred suspension of 6-chloro-4-[[(lR,3R)-3-hydroxycyclopentyl]amino]cinnoline-3- carboxamide (1.211 g, 3.95 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (DBU) (1.181 mL, 7.90 mmol) in MeOH (18.56 mL) at 0 °C and warmed to ambient temperature for 4 hours. A precipitate formed which was collected by filtration and washed with diethyl ether (3 x lOmL) to afford the desired product (1.036 g, 86 %) as a brown solid.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.58 - 1.74 (1H, m), 1.95 - 2.05 (1H, m), 2.1 - 2.3 (3H, m), 2.4 - 2.48 (1H, m), 4.43 (1H, s), 4.76 (1H, s), 5.40 (1H, p), 7.72 (1H, dd), 8.25 (1H, d), 8.31 (1H, d), 12.53 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 305

6-Chloro-4-rr(lR,3R)-3-hvdroxycvclopentyl1amino1cinnoline-3-carboxamide

(lR,3R)-3-aminocyclopentanol hydrochloride (0.910 g, 6.61 mmol) was added in one portion to 4,6-dichlorocinnoline-3-carboxamide (1.6 g, 6.61 mmol) and DIPEA (3.46 mL, 19.83 mmol) in acetonitrile (29.6 mL). The resulting suspension was stirred at 80 °C for 1 hour.

The reaction was allowed to cool, concentrated, diluted with water and the precipitate was collected by filtration, washed with water (20 mL) followed by acetonitrile (10 mL) and diethyl ether (10 mL) and dried under vacuum to afford the desired material (1.211 g, 59.7 %) as a beige solid. NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.60 (2H, tt), 1.72 - 1.9 (1H, m), 1.97 (1H, ddd), 2.06 - 2.18 (1H, m), 2.27 - 2.37 (1H, m), 4.29 (1H, d), 4.63 - 4.82 (2H, m), 7.74 (1H, s), 7.89 (1H, dd), 8.21 (1H, d), 8.31 (1H, d), 8.58 (1H, s), 10.60 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 307

8-Chloro-l-r(lS,3S)-3-methoxycvclopentyl1-3-methyl-imidazor4,5-c1cinnolin-2-one

Sodium hydride (60% in mineral oil) (201 mg, 5.02 mmol) was added to 8-chloro-l- [(lS,3S)-3-hydroxycyclopentyl]-3-methyl-imidazo[4,5-c]cinnolin-2-one (640 mg, 2.01 mmol) in DMF (19.8 mL) at 0 °C and stirred for 20 minutes. Methyl iodide (0.276 mL, 4.42 mmol) was added and stirred at ambient temperature for 20 hours. The reaction was quenched with water and the precipitate formed was collected by filtration and rinsed with water (10 mL) to afford the desired product (381 mg, 57 %) as an orange solid.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.76 - 1.88 (1H, m), 2.13 - 2.28 (4H, m), 3.27 (3H, s), 3.58 (3H, s), 4.11 (2H, m), 5.37 (1H, p), 7.74 (1H, dd), 8.29 (1H, d), 8.35 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 333

8-Chloro-l-r(lS,3S)-3-hvdroxycvclopentyl1-3-methyl-imidazor4,5-c1cinnolin-2-one

Sodium hydride (60% in mineral oil) (0.210 g, 5.25 mmol) was added to 8-chloro-l- [(lS,3S)-3-hydroxycyclopentyl]-3H-imidazo[4,5-c]cinnolin-2-one (0.640 g, 2.10 mmol) in DMF (20.71 mL) at 0 °C and stirred for 20 minutes. Methyl iodide (0.289 mL, 4.62 mmol) was added and stirred at ambient temperature for 20 hours. The reaction was quenched with water and the precipitate formed was collected by filtration, rinsed with ether (10 mL) to afford the desired product (0.516 g). The filtrate was extracted with ether (50 mL), washed with brine (30 mL), dried over MgS0₄ and concentrated to afford the desired product (0.263 g) as an orange solid. The material was used without further purification. Mass Spectrum: m/z (ES+) [M+H]+ = 319

8-Chloro-l-[(lS,3S)-3-hydroxycyclopentyll-3H-imidazo[4,5-clcinnolin-2-one

l,3,5-Trichloro-l,3,5-triazinane-2,4,6-trione (0.462 g, 1.99 mmol) was added portionwise to a stirred suspension of 6-chloro-4-[[(lS,3S)-3-hydroxycyclopentyl]amino]cinnoline-3- carboxamide (1.14 g, 3.72 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (1.19 mL, 7.95 mmol) in MeOH (17 mL) at 5°C then the solution was warmed to ambient temperature and stirred for 6 hours. A precipitate was observed which was collected by filtration, washed with diethyl ether (3 x lOmL) and dried under vacuum at 45°C to afford the desired material (5.94 g) as an orange solid, which was used without further purification.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.62 - 1.76 (1H, m), 1.97 - 2.07 (1H, m), 2.17 (1H, ddd), 2.2 - 2.3 (2H, m), 2.42 - 2.48 (1H, m), 4.43 (1H, s), 4.77 (1H, d), 5.40 (1H, p), 7.73 (1H, dd), 8.26 (1H, d), 8.32 (1H, d), 12.54 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 305

6-Chloro-4-rr(lS,3S)-3-hvdroxycvclopentyl1amino1cinnoline-3-carboxamide

(lS,3S)-3-aminocyclopentan-l-ol hydrochloride (0.953 g, 6.93 mmol) was added in one portion to 4,6-dichlorocinnoline-3-carboxamide (1.5 g, 6.20 mmol) and DIPEA (4.05 mL) in acetonitrile (27.7 ml) and the resulting suspension was stirred at 80 °C for 90 minutes. The mixture was allowed to cool and diluted with water. The precipitate was collected by filtration, washed with water (20 mL) followed by acetonitrile (10 mL) and dried under vacuum to afford the desired material (1.140 g, 60.0 %) as a grey solid, which was used without further purification.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.55 - 1.66 (2H, m), 1.76 - 1.86 (IH, m), 1.97 (IH, dq), 2.05 - 2.13 (IH, m), 2.25 - 2.35 (IH, m), 4.24 - 4.32 (IH, m), 4.66 - 4.78 (2H, m), 7.73 (IH, s), 7.89 (IH, dd), 8.21 (IH, d), 8.31 (IH, d), 8.58 (IH, s), 10.60 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 307

2-[3-(4-Fluoro-l-piperidyl)propoxyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- vDpyridine

Dichlorobis(tricyclohexylphosphine)palladium (II) (22.11 mg, 0.03 mmol) was added to 5- bromo-2-[3-(4-fluoro-l-piperidyl)propoxy]pyridine (95 mg, 0.30 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi-l,3,2-dioxaborolane (91 mg, 0.36 mmol) and potassium acetate (118 mg, 1.20 mmol) in 1,4-dioxane (3 mL) and the mixture degassed for 15 minutes. The resulting suspension was stirred at 90 °C for 16 hours under an inert atmosphere. The reaction mixture was evaporated to dryness, redissolved in DCM (50 mL), washed with water (40 mL) and the organic layer was dried with a phase separating cartridge, filtered and evaporated.

Mass Spectrum: m/z (ES+) [M+H]+ = 365 5-Bromo-2 3-(4-fluoro- 1 -piperidvQpropoxylpyridine

3-(4-Fluoro-l-piperidinyl)-l-propanol (0.302 g, 1.88 mmol) was added to a stirred suspension of sodium hydride (0.157 g, 3.92 mmol) in DMF (10 mL) at 25°C under nitrogen for 1 hour. 5-bromo-2-fluoropyridine (0.175 mL, 1.70 mmol) was added dropwise and the reaction was stirred at ambient temperature for 16 hours. Water (50 mL) was added portionwise to the mixture and the aqueous phase was extracted with DCM (3x50 mL). The organic phase was washed with water (50 mL), dried over a phase separator and evaporated.

The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1M NH3/MeOH to afford the desired product (0.300 g, 55.4 %) as a pale yellow oil.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.68 (2H, ddtd), 1.76 - 1.91 (5H, m), 2.22 - 2.32 (2H, m), 2.40 (2H, t), 2.50 (1H, m), 4.25 (2H, t), 4.66 (1H, dtt), 6.81 (1H, dd), 7.88 (1H, dd), 8.26 (1H, dd).

Mass Spectrum: m/z (ES+) [M+H]+ = 319

2-r3-r(3R)-3-Fluoropyrrolidin-l-yl1propoxy1-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yDpyridine

Dichlorobis(tricyclohexylphosphine)palladium (II) (48.7 mg, 0.07 mmol) was added to 5- bromo-2-[3-[(3R)-3-fluoropyrrolidin-l-yl]propoxy]pyridine (200 mg, 0.66 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (201 mg, 0.79 mmol) and potassium acetate (259 mg, 2.64 mmol) in dioxane (6.60 mL) was added and the reaction was heated to 90°C for 18 hours under an inert atmosphere. The reaction mixture was evaporated, redissolved in DCM (10 mL), washed with water (10 mL) and the organic layer dried with a phase separating cartridge and evaporated to afford crude product.

Mass Spectrum: m z (ES+) [M+H]+ = 351

5-Bromo-2-r3-r(3R)-3-fluoropyrrolidin-l-yl1propoxy1pyridine

3-[(3R)-3-Fluoro-l-pyrrolidinyl]-l-propanol (0.306 g, 2.08 mmol) was added to a stirred suspension of sodium hydride (0.174 g, 4.35 mmol) in DMF (10 mL) at 25 °C under nitrogen for 1 hour. 5-Bromo-2-fluoropyridine (0.195 mL, 1.89 mmol) was then added dropwise and the reaction was stirred at ambient temperature for 18 hours. Water (50 mL) was added portionwise to the mixture and the aqueous phase was extracted with DCM (3x50 mL). The organic phase was washed with water (50 mL), dried over a phase separator and evaporated. The crude product was purified by ion exchange

chromatography, using an SCX column, to afford the desired product (0.819 g, 143 %) as a pale yellow oil.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.78 - 1.91 (3H, m), 2.02 - 2.18 (1H, m), 2.28 (1H, tdd), 2.53 - 2.56 (1H, m), 2.61 (1H, dd), 2.72 - 2.84 (2H, m), 2.99 (1H, s), 4.26 (2H, t), 5.17 (1H, dddt), 6.81 (1H, dd), 7.87 (1H, dd), 8.26 (1H, dd).

Mass Spectrum: m/z (ES+) [M+H]+ = 305

2-[3-[(3S)-3-Fluoropyrrolidin-l-yllpropoxyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- vDpyridine

Dichlorobis(tricyclohexylphosphine)palladium (II) (97.4 mg, 0.14 mmol) was added to 5- bromo-2-[3-[(3S)-3-fluoropyrrolidin-l-yl]propoxy]pyridine (200 mg, 0.66 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (346 mg) and potassium acetate (259 mg, 2.64 mmol) in dioxane (6.60 mL) and the reaction was heated to 90°C for 24 hours under an inert atmosphere. The reaction mixture was evaporated, redissolved in DCM (10 mL), washed with water (10 mL) and the organic layer dried with a phase separating cartridge and evaporated to afford crude product, which was used without further purification.

Mass Spectrum: m/z (ES+) [M+H]+ = 351

5-Bromo-2-r3-r(3S)-3-fluoropyrrolidin-l-yl1propoxy1pyridine

3-[(3S)-3-Fluoro-l-pyrrolidinyl]-l-propanol (0.300 g, 2.04 mmol) was added to a stirred suspension of sodium hydride (0.170 g, 4.26 mmol) in DMF (10 mL) at 0°C under nitrogen, for 1 hour. 5-Bromo-2-fluoropyridine (0.191 mL, 1.85 mmol) was then added dropwise and the reaction was stirred at ambient temperature for 18 hours. Water (50 mL) was added portionwise to the mixture and the aqueous phase was extracted with DCM (3x50 mL). The organic phase was washed with water (50 mL), dried over a phase separator and evaporated. The crude product was purified by ion exchange

chromatography, using an SCX column, to afford the desired product (0.334 g, 60 %) as a pale yellow oil.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.78 - 1.95 (3H, m), 2.03 - 2.2 (1H, m), 2.28 (1H, q), 2.52 - 2.64 (2H, m), 2.74 - 2.85 (2H, m), 4.06 (1H, q), 4.26 (2H, t), 5.17 (1H, dtd), 6.81 (1H, d), 7.87 (1H, dd), 8.26 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 303

3-|Y3S)-3-Fluoro- 1 -pyrrolidinyll- 1 -propanol

To a suspension of (S)-3-fluoropyrrolidine hydrochloride (1.00 g, 7.96 mmol) in dry tetrahydrofuran (37.1 mL) at ambient temperature under nitrogen was added sodium hydride (0.956 g, 23.89 mmol) then stirred for 15 minutes. (3-Bromopropoxy)(tert- butyl)dimethylsilane (2.77 mL, 11.95 mmol) was added dropwise then allowed to stir for 72 hours at ambient temperature. The reaction mixture was diluted with EtOAc (50 mL), and washed two times with water (2 x 25 ml). The organic layer was dried over MgS0₄, filtered and evaporated to afford crude product still bearing the silyl protecting group on the alcohol. The crude product (silyl) was loaded onto a 50g SCX column washing with DCM and methanol and the deprotected product eluted from the column using 2M

NEb/MeOH to afford the desired material (0.550 g, 47 %) as a beige oil.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.52 - 1.62 (2H, m), 1.74 - 1.92 (1H, m), 2.01 - 2.18 (1H, m), 2.2 - 2.28 (1H, m), 2.44 (2H, dd), 2.7 - 2.83 (2H, m), 3.43 (2H, t), 4.41 (1H, s), 5.16 (1H, dddt).

Example 37: 1:1 mixture of 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-l-[(4S)-3,3- dimethyltetrahydropyr an-4-yl] -3-methyl-imidazo [4,5-c] cinnolin-2-one and 8- [6- [3- (dimethylamino)propoxy]-3-pyridyl]-l-[(4R)-3,3-dimethyltetrahydropyran-4-yl]-3- meth l-imidazo [4,5-c] cinnolin-2-one

Dichlorobis(triphenylphosphine)palladium (II) (20.24 mg, 0.03 mmol) was added to a degassed solution of N,N-dimethyl-3-[[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- pyridyl]oxy]propan-l -amine (185 mg, 0.61 mmol), a 1 : 1 mixture of 8-chloro-l-[(4R)-3,3- dimethyltetrahydropyran-4-yl] -3 -methyl-imidazo [4,5-c] cinnolin-2-one and 8-chloro- 1 - [(4S)-3,3-dimethyltetrahydropyran-4-yl]-3-methyl-imidazo[4,5-c]cinnolin-2-one (200 mg, 0.58 mmol) and 2M potassium carbonate solution (0.865 mL, 1.73 mmol) in 1,4-dioxane (4.90 mL) then the mixture heated in a microwave reactor at 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), washed sequentially with water (10 mL), saturated brine (10 mL) and the organic layer evaporated. The crude product was purified twice by preparative HPLC, using basic then acidic modifiers, to afford the desired material (22.5 mg) as a cream solid.

NMR Spectrum: ^!H NMR (400MHz, DMSO) δ 0.82 (3H, s), 1.18 (3H, s), 1.79 (IH, d),

2.19 (6H, s), 2.41 (2H, t), 3.38 (2H, d), 3.54 (2H, d), 3.61 (3H, s), 3.67 - 3.77 (2H, m), 4.06

(IH, dd), 4.39 (2H, t), 5.03 (IH, dd), 7.04 (IH, d), 8.07 (IH, dd), 8.19 - 8.22 (IH, m), 8.23

(IH, d), 8.42 (IH, d), 8.60 (IH, d), 8.69 (IH, d).

Mass Spectrum: m/z (ES+)[M+H]+ = 491

The racemic mixture described above could be separated to give the individual

enantiomeric components, Examples 38 and 39, as described below. The stereochemistry of these components is currently unknown so they are defined as isomer 1 and isomer 2 as the first and second eluting products respectively.

A 1 : 1 mixture of 8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-l-[(4S)-3,3- dimethyltetrahydropyran-4-yl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one and 8-[6- [3 - (dimethylamino)propoxy] -3 -pyridyl] - 1 -[(4R)-3 ,3 -dimethyltetrahydropyran-4-yl] -3 -methyl- imidazo[4,5-c]cinnolin-2-one was separated by preparative chiral-HPLC SFC (Chiralcel OJ-H Technologies IC column, 20 μιη silica, 250 mm length, 5 micron), eluting isocratically with 90% supercritical C0₂ in methanol (modified with ammonia) as eluent, to afford the first eluting product, Example 38, as solid (30 mg, 29%), and the second eluting product, Example 39, as a solid (39 mg, 38 %>).

Example 38: Isomer 1

NMR Spectrum: ^lU NMR (400 MHz, DMSO) δ 0.81 (3H, s), 1.17 (3H, s), 1.78 (IH, d), 1.89 (2H, p), 2.16 (6H, s), 2.37 (2H, t), 3.38 (IH, d), 3.45 (IH, dd), 3.53 (IH, d), 3.61 (3H, s), 3.65 - 3.77 (IH, m), 4.06 (IH, dt), 4.38 (2H, t), 5.02 (IH, dd), 7.03 (IH, dd), 8.06 (IH, dd), 8.22 (IH, dd), 8.41 (IH, d), 8.59 (IH, d), 8.67 - 8.7 (IH, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 491

Example 39: Isomer 2 NMR Spectrum: ^lH NMR (400 MHz, CDCb) δ 0.92 (3H, s), 1.33 (3H, s), 1.7 - 1.82 (1H, m), 1.97 - 2.07 (2H, m), 2.27 (6H, s), 2.44 - 2.53 (2H, m), 3.36 (1H, d), 3.57 (1H, dd), 3.65 - 3.72 (2H, m), 3.75 (3H, s), 4.24 - 4.32 (1H, m), 4.44 (2H, t), 4.82 (1H, dd), 6.92 (1H, dd), 7.82 (1H, dd), 7.88 (1H, dd), 8.34 (1H, d), 8.47 - 8.53 (2H, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 491

The preparation of N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)oxy)propan-l -amine has been described earlier.

The preparation of a 1 : 1 mixture of 8-chloro-l-[(4R)-3,3-dimethyltetrahydropyran-4-yl]-3- methyl-imidazo[4,5-c]cinnolin-2-one and 8-chloro-l-[(4S)-3,3-dimethyltetrahydropyran-4- yl]-3-methyl-imidazo[4,5-c]cinnolin-2-one is described below.

1 : 1 Mixture of 8-chloro-l-r(4R)-3,3-dimethyltetrahvdropyran-4-yl1-3-methyl-imidazor4,5- c] cinnolin-2-one and 8-chloro- 1 - |Y4S)-3 ,3 -dimethyltetrahydropyran-4-yl] -3 -methyl- imidazo[4,5-clcinnolin-2-one

l,l-Dimethoxy-N,N-dimethylmethanamine (10.38 mL, 78.12 mmol) was added to a 1 : 1 mixture of 8-chloro-l -[(4R)-3,3-dimethyltetrahydropyran-4-yl]-3H-imidazo[4,5- c]cinnolin-2-one and 8-chloro-l -[(4S)-3,3-dimethyltetrahydropyran-4-yl]-3H-imidazo[4, 5- c]cinnolin-2-one (2.6 g, 7.81 mmol) in DMF (20.9 mL) and the resulting slurry stirred at 100 °C for 22 hours. A precipitate formed which was collected by filtration, washed with diethyl ether (2 x 10 mL) and dried under vacuum to afford the desired material (1.48 g) as an orange solid. NMR Spectrum: ^lH NMR (400MHz, DMSO) δ 0.74 (3H, s), 1.13 (3H, s), 1.73 - 1.81 (1H, m), 3.45 (3H, d), 3.59 (3H, s), 3.67 - 3.77 (1H, m), 4.02 (1H, dd), 4.86 (1H, dd), 7.74 (1H, dd), 8.35 (1H, d), 8.58 (1H, d).

Mass Spectrum: m/z (ES+)[M+H]+ = 347

1 : 1 Mixture of 8-chloro-l-r(4R)-3,3-dimethyltetrahvdropyran-4-yll-3H-imidazor4,5- clcinnolin-2-one and 8-chloro-l-[(4S)-3,3-dimethyltetrahydropyran-4-yll-3H-imidazo[4,5- clcinnolin-2-one

l,3,5-Trichloro-l,3,5-triazinane-2,4,6-trione (1.059 g, 4.55 mmol) was added portionwise to a stirred suspension of a 1 : 1 mixture of 6-chloro-4-[[(4R)-3,3-dimethyltetrahydropyran- 4-yl] amino] cinnoline-3 -carboxamide and 6-chloro-4- [ [(4S)-3 ,3 -dimethyltetrahydropyran- 4-yl] amino] cinnoline-3 -carboxamide (3.05 g, 9.11 mmol) and 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (2.72 mL, 18.22 mmol) in MeOH (42.8 mL) at 5°C and the resulting solution allowed to warm to ambient temperature and stirred for 90 minutes. The reaction mixture was concentrated to dryness, then partitioned between EtOAc (50 mL) and saturated aqueous NH₄C1 (50 mL). A precipitated crashed out of solution which was collected by filtration, washed with diethyl ether (3 x 10 mL) and azeotroped with MeCN (2 x 50 mL) to afford the desired material (3.60 g) as a beige solid.

NMR Spectrum: ^lH NMR (400MHz, DMSO) δ 0.74 (3H, s), 1.14 (3H, s), 1.74 - 1.83 (1H, m), 3.38 - 3.52 (3H, m), 3.64 - 3.81 (1H, m), 4.02 (1H, dd), 4.80 (1H, dd), 7.71 (1H, dd), 8.31 (1H, d), 8.54 (1H, d).

Mass Spectrum: m/z (ES+)[M+H]+ = 332

1 : 1 Mixture of 6-chloro-4-[[(4R)-3,3-dimethyltetrahydropyran-4-yl]amino]cinnoline-3- carboxamide and 6-chloro-4- Γ IY4S)-3 ,3 -dimethyltetrahydropyran-4- yl] amino] cinnoline-3 - carboxamide

A 1 : 1 mixture of (lR)-3,3-dimethyltetrahydro-2H-pyran-4-amine hydrochloride and (1S)- 3,3-dimethyltetrahydro-2H-pyran-4-amine hydrochloride (2.26 g, 13.63 mmol) was added in one portion to 4,6-dichloro-3-cinnolinecarboxamide (3 g, 12.39 mmol) and DIPEA (6.5 mL, 37.18 mmol) in acetonitrile (24.49 mL) and the resulting suspension stirred at 90 °C for 18 hours. The reaction was allowed to cool, diluted with water and the precipitate was collected by filtration, washed with water (20 mL) followed by acetonitrile (10 mL) and dried under vacuum to afford the desired material (3.05 g) as a beige solid.

NMR Spectrum: ^!H NMR (400MHz, DMSO) δ 0.80 (3H, s), 1.10 (3H, s), 1.80 (1H, dtd), 1.96 (1H, dt), 3.25 (1H, d), 3.44 (1H, d), 3.52 (1H, td), 3.89 (1H, dt), 4.06 (1H, td), 7.83 (1H, s), 7.91 (1H, dd), 8.16 (1H, d), 8.26 (1H, d), 8.67 (1H, s), 10.40 (1H, d).

Mass Spectrum: m/z (ES+)[M+H]+ = 335

Example 40: 1:1 mixture of l-[(4S)-3,3-dimethyltetrahydropyran-4-yl]-3-methyl-8-[4- [3-(l-piperidyl)propoxy]phenyl]imidazo[4,5-c]cinnolin-2-one and l-[(4R)-3,3- dimethyltetrahydropyran-4-yl]-3-methyl-8-[4-[3-(l- pi eridyl)propoxy] phenyl] imidazo [4,5-c] cinnolin-2-one

Dichlorobis(triphenylphosphine)palladium (II) (14.3 mg, 0.02 mmol) was added to a degassed solution of l-(3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)propyl)piperidine (151 mg, 0.44 mmol) and a 1 : 1 mixture of 8-chloro-l-[(4R)- 3 ,3 -dimethyltetrahydropyran-4-yl] -3 -methyl-imidazo [4,5-c] cinnolin-2-one and 8-chloro- 1 - [(4S)-3,3-dimethyltetrahydropyran-4-yl]-3-methyl-imidazo[4,5-c]cinnolin-2-one (152 mg, 0.44 mmol), 2M potassium carbonate solution (0.66 mL, 1.31 mmol) in 1,4-dioxane (1.53 niL) then the mixture heated in a microwave reactor at 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), washed sequentially with water (10 mL), saturated brine (10 mL) and the organic layer evaporated. The crude product was purified by preparative HPLC to afford the desired material (81 mg) as a brown solid.

NMR Spectrum: ^!H NMR (400MHz, DMSO) δ 0.82 (3H, s), 1.18 (3H, s), 1.33 - 1.43 (2H, m), 1.50 (4H, p), 1.79 (1H, d), 1.90 (2H, p), 2.3 - 2.38 (2H, m), 2.40 (3H, t), 3.17 (1H, d), 3.35 (1H, d), 3.38 - 3.49 (1H, m), 3.56 (1H, d), 3.60 (3H, s), 3.62 - 3.7 (1H, m), 4.06 (1H, d), 4.10 (2H, t), 5.00 (1H, dd), 7.16 (2H, d), 7.79 - 7.86 (2H, m), 8.05 (1H, dd), 8.38 (1H, d), 8.52 - 8.56 (lH, m).

Mass Spectrum: m/z (ES+)[M+H]+ = 530

Example 41: 1:1 mixture of 8-[4-[3-(dimethylamino)propoxy]phenyl]-l-[(4S)-3,3- dimethyltetrahydropyr an-4-yl] -3-methyl-imidazo [4,5-c] cinnolin-2-one and 8- [4- [3- (dimethylamino)propoxy]phenyl]-l-[(4R)-3,3-dimethyltetrahydropyran-4-yl]-3- methyl-imidazo [4,5-c] cinnolin-2-one

Dichlorobis(triphenylphosphine)palladium (II) (71.6 mg, 0.10 mmol) was added to a degassed solution of N,N-dimethyl-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)propan-l -amine (179 mg, 0.59 mmol) and a 1 : 1 mixture of 8-chloro- 1-[(4R)- 3 ,3 -dimethyltetrahydropyran-4-yl] -3 -methyl-imidazo [4,5-c] cinnolin-2-one and 8-chloro- 1 - [(4S)-3,3-dimethyltetrahydropyran-4-yl]-3-methyl-imidazo[4,5-c]cinnolin-2-one (177 mg, 0.51 mmol), 2M potassium carbonate solution (0.77 mL, 1.53 mmol) in 1,4-dioxane (4.4 mL then the mixture heated in a microwave reactor at 100 °C for 90 minutes under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) and the organic layer was evaporated. The crude product was purified by preparative HPLC to afford the desired material (82 mg).

NMR Spectrum: *H NMR (400 MHz, DMSO) δ 0.83 (3H, s), 1.19 (3H, s), 1.80 (lH, d), 1.89 (2H, p), 2.17 (6H, s), 2.39 (2H, t), 3.32 - 3.5 (2H, m), 3.54 - 3.72 (5H, m), 4.04 - 4.15 (3H, m), 5.01 (1H, dd), 7.13 - 7.2 (2H, m), 7.8 - 7.87 (2H, m), 8.06 (1H, dd), 8.38 (1H, d), 8.54 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 490

The above material can also be isolated as the methane sulfonic acid salt by taking the material as prepared above and subjecting to the following reaction conditions.

A 1 : 1 mixture of 8-{4-[3-(dimethylamino)propoxy]phenyl}-l-[(4S)-3,3- dimethyltetrahydro-2H-pyran-4-yl] -3 -methyl- 1 ,3 -dihydro-2H-imidazo [4,5 -c] cinnolin-2- one and 8- {4-[3-(dimethylamino)propoxy]phenyl} - 1 -[(4R)-3,3-dimethyltetrahydro-2H- pyran-4-yl]-3-methyl-l,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one (20 mg, 0.04 mmol) was dissolved in DCM (2 mL) and treated with 1M methanesulfonic acid (0.003 mL, 0.04 mmol) in DCM then the mixture evaporated to dryness. The residue was triturated with diethyl ether to afford the methane sulfonic acid salt (18.9 mg, 79%) as a pale yellow solid. NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 0.88 (3H, s), 1.24 (3H, s), 1.82 - 1.9 (1H, m), 2.16 - 2.24 (2H, m), 2.39 (6H, s), 2.85 - 2.92 (3H, m), 3.27 - 3.38 (2H, m), 3.4 - 3.5 (1H, m), 3.58 - 3.67 (2H, m), 3.72 - 3.95 (1H, m), 4.1 - 4.16 (1H, m), 4.21 (2H, t), 4.95 - 5.04 (1H, m), 7.17 - 7.23 (2H, m), 7.81 - 7.87 (2H, m), 8.06 (1H, dd), 8.40 (1H, d), 8.53 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 490

The racemic mixture described above could be separated to give the individual

enantiomeric components, Examples 42 and 43, as described below. The stereochemistry of these components is currently unknown so they are defined as isomer 1 and isomer 2 as the first and second eluting products respectively. A 1 : 1 mixture of 8-{4-[3-(dimethylamino)propoxy]phenyl}-l-[(4S)-3,3- dimethyltetrahydro-2H-pyran-4-yl] -3 -methyl- 1 ,3 -dihydro-2H-imidazo [4,5 -c] cinnolin-2- one and 8- {4-[3-(dimethylamino)propoxy]phenyl} - 1 -[(4R)-3,3-dimethyltetrahydro-2H- pyran-4-yl]-3-methyl-l,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one was separated by preparative chiral-HPLC SFC (Phenomenex LUX CI column, 30 μιη silica, 250 mm length, 5 micron), eluting isocratically with 90% supercritical C02 in methanol (modified with ammonia) as eluent, to afford the first eluting product, Example 42, as solid (22 mg, 37%), and the second eluting product, Example 43, as a solid (24 mg, 40%>).

Example 42:Isomer 1

NMR Spectrum: *H NMR (400 MHz, DMSO) δ 0.83 (3H, s), 1.19 (3H, s), 1.81 (1H, d), 1.89 (2H, p), 2.17 (6H, s), 2.39 (2H, t), 3.35 (1H, d), 3.38 - 3.51 (1H, m), 3.57 (1H, d), 3.61 (3H, s), 3.63 - 3.72 (1H, m), 4.03 - 4.15 (3H, m), 5.01 (1H, dd), 7.12 - 7.23 (2H, m), 7.78 - 7.87 (2H, m), 8.06 (1H, dd), 8.38 (1H, d), 8.55 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 490

Example 43:Isomer 2

NMR Spectrum: ^lU NMR (400 MHz, DMSO) δ 0.83 (3H, s), 1.19 (3H, s), 1.81 (1H, d), 1.89 (2H, p), 2.17 (6H, s), 2.39 (2H, t), 3.35 (1H, d), 3.38 - 3.51 (1H, m), 3.57 (1H, d), 3.61 (3H, s), 3.63 - 3.72 (1H, m), 4.03 - 4.15 (3H, m), 5.01 (1H, dd), 7.12 - 7.23 (2H, m), 7.78 - 7.87 (2H, m), 8.06 (1H, dd), 8.38 (1H, d), 8.55 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 490

The preparation of a 1 : 1 mixture of 8-chloro-l-[(4R)-3,3-dimethyltetrahydropyran-4-yl]-3- methyl-imidazo[4,5-c]cinnolin-2-one and 8-chloro-l-[(4S)-3,3-dimethyltetrahydropyran-4- yl]-3-methyl-imidazo[4,5-c]cinnolin-2-one and the preparation of N,N-dimethyl-3-[4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]-l-propanamine has been described earlier. Example 44: 8-[4-[3-(Dimethylamino)propoxy]phenyl]-7-fluoro-l-isopropyl-3-methyl- imidazo [4,5-c] cinnolin-2-one

(2 ' -Amino-2-biphenylyl)(chloro)palladium - dicyclohexyl(2 ' ,4 ' ,6 ' -triisopropyl-2- biphenylyl)phosphine (1 : 1) (25.8 mg, 0.03 mmol) was added to N,N-dimethyl-3-[4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]-l-propanamine (lOOmg, 0.33 mmol), 8-bromo-7-fluoro-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one (111 mg, 0.33 mmol) and CS2CO3 (213 mg, 0.66 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) and the mixture was stirred at 80 °C for 2 hours. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford product as a brown oil. The crude product was purified by preparative HPLC to afford the desired product (50 mg, 35 %>) as a brown solid.

NMR Spectrum: ^!H NMR (300 MHz, DMSO) δ 1.65 (6H, d), 1.82-1.96 (2H, m), 2.20 (6H, s), 2.38-2.45 (2H, m), 3.60 (3H, s), 4.05-4.15 (2H, m), 5.15-5.25 (1H, m), 7.12 (2H, d), 7.68 (2H, d), 8.18 (1H, d), 8.25 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 438

8-Bromo-7-fluoro-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one was prepared as described below.

8-Bromo-7-fluoro-l-isopropyl-3-methyl-imidazor4,5-c1cinnolin-2-one

l,l-Dimethoxy-N,N-dimethylmethanamine (7.00 mL, 52.28 mmol) was added to 8-bromo- 7-fluoro-l-isopropyl-3H-imidazo[4,5-c]cinnolin-2-one (1.7 g, 5.23 mmol) in DMF (1 mL) and the mixture stirred at 100 °C for 3 hours. The reaction mixture was diluted with water.

The precipitate was collected by filtration, washed with water (100 mL) and dried under vacuum to afford the desired product (0.80 g, 45.1 %) as a red solid.

NMR Spectrum: ¾ NMR (300MHz, DMSO) δ 1.50-1.60 (6H, m), 3.50 (3H, s), 5.05-5.22

(1H, m),8.24 (1H, d), 8.72 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 339

8-Bromo-7-fluoro- 1 -isopropyl-3H-imidazo[4,5-clcinnolin-2-one

l,3,5-Trichloro-l,3,5-triazinane-2,4,6-trione (0.906 g, 3.90 mmol) was added to 6-bromo- 7-fluoro-4-(isopropylamino)cinnoline-3-carboxamide (2.55 g, 7.79 mmol) and

2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (2.350 mL, 15.59 mmol) in MeOH (1.5 mL) at 0°C and warmed to ambient temperature for 2 hours. The reaction mixture was evaporated and the crude solid triturated with diethyl ether and collected by filtration to afford the desired product (1.80 g, 71 %) as a light-brown solid, which was used without further purification.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 1.40-1.60 (6H, m), 3.40-3.50 (1H, m), 5.03-5.13 (1H, m), 8.07 (1H, d), 8.57 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 325

6-Bromo-7-fluoro-4-(isopropylamino)cinnoline-3-carboxamide

Propan-2-amine (0.563 g, 9.52 mmol) was added to 6-bromo-4-chloro-7-fluoro-cinnoline- 3-carboxamide (2.9 g, 9.52 mmol) and DIPEA (3.33 mL, 19.05 mmol) in acetonitrile (25 mL) at 20°C and stirred at 80 °C for 3 hours. The precipitate was collected by filtration, washed with diethyl ether (20 mL) and air dried to afford the desired product (2.60 g, 83 %) as a grey solid, which was used without further purification.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 1.20-1.30 (6H, m), 4.40-4.50 (1H, m), 7.80 (1H, s), 8.08 (1H, d), 8.50-8.60 (2H, m), 10.45 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 327

6-Bromo-4-chloro-7-fluoro-cinnoline-3-carboxamide

Ammonium hydroxide (17.31 g, 493.93 mmol) was added dropwise to 6-bromo-4-chloro- 7-fluoro-cinnoline-3-carbonyl chloride (3.2 g, 9.88 mmol) in acetonitrile (50 mL) at 0°C under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour and the precipitate was collected by filtration. The solid was washed with diethyl ether (20 mL) and air dried to afford the desired product (2.95 g, 98 %)as a grey solid, which was used without further purification.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 7.75 (2H, d), 8.50 (1H, s), 8.62-8.80 (1H, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 306

6-Bromo-4-chloro-7-fluoro-cinnoline-3-carbonyl chloride

DMF (0.081 mL, 1.05 mmol) was added dropwise to 6-bromo-7-fluoro-4-hydroxy- cinnoline-3-carboxylic acid (3 g, 10.45 mmol) in thionyl chloride (25 mL) over a period of 1 minute at ambient temperature under an inert atmosphere. The resulting solution was stirred at 80 °C for 90 minutes then allowed to cool, concentrated to dryness to afford the desired product (3.20 g, 95 %) as brown oil, which was used without further purification. NMR Spectrum: ^lH NMR (400MHz, CDCb) δ 8.37(1H, d), 8.74(1H, d).

Mass Spectrum: rM-2Cl+20C¾l+ = 315

6-Bromo-7-fluoro-4-h droxy-cinnoline-3-carboxylic acid

A solution of 4-amino-6-bromo-7-fluoro-cinnoline-3-carboxamide (36 g, 126.28 mmol) in DMSO/ 4M sulphuric acid (4 M) (400 mL/1000 mL) at ambient temperature. The solution was stirred for 8 days at 130 °C, cooled to ambient temperature and quenched with water/ice (3000 mL). The solids formed were collected by filtration, washed with water (2 x 500 mL) and oven dried. The crude product was purified by re-crystallization from DMSO to afford the desired product (18.4 g, 51%) as a light brown solid.

NMR Spectrum: ^!H NMR (300 MHz, DMSO) δ 7.68-7.71 (1H, d), 8.47-8.52 (1H, m), 13.79-14.76 (2H, br).

Mass Spectrum: m/z (ES+) [M+H]+ = 286.9 4-Amino-6-bromo-7-fluoro-cinnoline-3-carboxamide

Aluminium trichloride (54 g, 404.98 mmol) was added to a solution of 2-[(4-bromo-3- fluorophenyl)hydrazono]-2-cyanoacetamide (39 g, 136.81 mmol) in 1 ,2-dichlorobenzene (500 mL) under an inert atmosphere at ambient temperature. The solution was stirred for 2 days at 120 °C, then cooled and quenched with iced water (3000 mL). The solids formed were collected by filtration, washed with water (3 x 500 mL) and oven dried to afford the desired material (36 g, 92%) as a yellow solid.

Mass Spectrum: m/z (ES+) [M+2H]+ = 285

2-[(4-Bromo-3-fluorophenyl)hydrazonol-2-cyanoacetamide

4-Bromo-3-fluoroaniline (30 g, 157.88 mmol), concentrated hydrochloric acid (120 g, 3.29 mol), acetic acid (190 g, 3.16 mol) and water (500 g, 27.75 mol) were added to a round bottom flask under an inert atmosphere at ambient temperature. To the mixture was added a solution of sodium nitrite (12 g, 178.27 mmol) in H₂0 (300 mL) dropwise with stirring at 0-5 °C, then the solution was stirred for 2 hours at 0 °C. NaOAc (100 g, 1.22 mol) was added portionwise at 0 °C and the solution stirred for 30 minutes at 0 °C. 2- Cyanoacetamide (16 g, 194.47 mmol), EtOH (390 g, 8.47 mol), water (2500 g, 138 mol) were added to a second round bottom flask under an inert atmosphere at ambient temperature, then NaOAc (500 g, 6.10 mol, 6.10 equiv) was added at ambient temperature. To the mixture was added the solution in the first flask dropwise with stirring at 0-5 °C. The resulting solution was stirred for 2 hours at 0 °C. The solids were collected by filtration, and washed with water (3 x 1 L) and oven dried to afford the desired material (45 g) as a yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+) [M+H]+ = 282.9

Example 45: 8- [6- [3-(Dimethylamino)propoxy] -3-pyridyl] -7-fluoro-l-isopropyl-3- methyl-imidazo [4,5-c] cinnolin-2-one

(2 ' -Amino-2-biphenylyl)(chloro)palladium - dicyclohexyl(2 ' ,4 ' ,6 ' -triisopropyl-2- biphenylyl)phosphine (1 : 1) (23.20 mg, 0.03 mmol) was added to 8-bromo-7-fluoro-l- isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one_(100 mg, 0.29 mmol), N,N-dimethyl-3- ((5-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)propan- 1 -amine (117 mg, 0.38 mmol) and Cs₂C0₃ (240 mg, 0.74 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) and the mixture was stirred at 100 °C for 3 hours under an inert atmosphere. The crude product was purified by preparative HPLC to afford the desired product (21 mg, 16 %) as a yellow solid.

NMR Spectrum: ^lH NMR (400 MHz, CDCb) δ 1.78 (6H, d), 2.02-2.09 (2H, m), 2.33 (6H, s), 2.49-2.55 (2H, m), 3.78 (3H, s), 4.47 (2H, t), 5.17 (1H, t), 6.92 (1H, d), 7.91-7.94 (1H, m), 8.15(1H, t), 8.19 (1H, s), 8.44 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 439

Example 46 : 7-Fluoro- l-isopropyl-3-methyl-8- [6- [3-(l -piperidyl)propoxy] -3- p ridyl] imidazo [4,5-c] cinnolin-2-one

(2 ' -Amino-2-biphenylyl)(chloro)palladium - dicyclohexyl(2 ' ,4 ' ,6 ' -triisopropyl-2- biphenylyl)phosphine (1 : 1) (22.73 mg, 0.03 mmol) was added to 2-(3-(piperidin-l- yl)propoxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (lOOmg, 0.29 mmol), 8-bromo-7-fluoro-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one (98 mg, 0.29 mmol) and CS2CO3 (188 mg, 0.58 mmol) in 1 ,4-dioxane (0.2 mL) and water (0.04 mL) and the mixture was stirred at 80 °C for 2 hours. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, then further purified by preparative HPLC to afford desired product (20 mg, 14 %) as a white solid.

NMR Spectrum: ^lH NMR (300MHz. DMSO) δ 1.30-1.40 (2H, m), 1.45-1.55 (4H, m), 1.68 (6H, d), 1.85-1.98 (2H, m), 2.25-2.40 (6H, m), 3.60 (3H, s), 4.30-4.40 (2H, m), 5.20-5.30 (1H, m), 7.00 (1H, d), 8.08 (1H, s), 8.24 (1H, d), 8.36 (lH,d), 8.52 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 479

Example 47: 7-Fluoro-l-isopropyl-3-methyl-8-[4-[3-(l- piperidyl)propoxy] phenyl] imidazo [4,5-c] cinnolin-2-one

(2 ' -Amino-2-biphenylyl)(chloro)palladium - dicyclohexyl(2 ' ,4 ' ,6 ' -triisopropyl-2- biphenylyl)phosphine (1 : 1) (22.79 mg, 0.03 mmol) was added to l-[3-[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]propyl]piperidine (lOOmg, 0.29 mmol), 8- bromo-7-fluoro-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one (98 mg, 0.29 mmol) and CS2CO3 (189 mg, 0.58 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) and the mixture was stirred at 80 °C for 2 hours. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford crude product as a yellow oil. The crude product was purified by preparative HPLC to afford the desired product (10 mg, 7 %) as a white solid. NMR Spectrum: 1H NMR (300MHz, DMSO) δ 1.32-1.40 (2H, m), 1.48-1.55 (4H, m), 1.68 (6H, d), 1.85-1.98 (2H, m), 2.25-2.40 (6H, m), 3.60 (3H, s), 4.05-4.15 (2H, m), 5.15- 5.25 (1H, m), 7.12 (2H, d), 7.65 (2H, d), 8.15-8.26 (2H, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 478

Example 48: 8- [4- [3-(Dimethylamino)propoxy] phenyl] -l-isopropyl-3,7-dimethyl- imidazo 4,5-c] cinnolin-2-one

(2 ' -Amino-2-biphenylyl)(chloro)palladium - dicyclohexyl(2 ' ,4 ' ,6 ' -triisopropyl-2- biphenylyl)phosphine (1 : 1) (25.8 mg, 0.03 mmol) was added to N,N-dimethyl-3-[4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]-l-propanamine (lOOmg, 0.33 mmol), 8-bromo-l-isopropyl-3,7-dimethyl-imidazo[4,5-c]cinnolin-2-one (110 mg, 0.33 mmol) and CS2CO3 (213 mg, 0.66 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) and the mixture was stirred at 80 °C for 4 hours under an inert atmosphere. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, the further purified by preparative HPLC to afford the desired product (60 mg, 42 %) as a yellow solid.

NMR Spectrum: ^!H NMR (300 MHz, DMSO) δ 1.65 (6H, d), 1.85-1.96 (2H, m), 2.20 (6H, s), 2.38-2.45 (5H, m), 3.60 (3H, s), 4.03-4.13 (2H, m), 5.08-5.18 (1H, m), 7.08 (2H, d), 7.47 (2H, d), 7.98 (1H, s), 8.25 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 434

The preparation of 8-bromo-l-isopropyl-3,7-dimethyl-imidazo[4,5-c]cinnolin-2-one is described below.

8-Bromo-l-iso ropyl-3,7-dimethyl-imidazo[4,5-clcinnolin-2-one

l,l-Dimethoxy-N,N-dimethylmethanamine (10.42 mL, 77.84 mmol) was added to 8- bromo-l-isopropyl-7-methyl-3H-imidazo[4,5-c]cinnolin-2-one (2.5 g, 7.78 mmol) in DMF (20 mL) and the solution was stirred at 100 °C for 2 hours. The reaction mixture was diluted with water. The precipitate was collected by filtration, washed with water (50 mL) and dried under vacuum to afford the desired product (2.0 g, 77 %) as a red solid, which was used without further purification.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.62 (6H, d), 2.57 (3H, s), 3.67 (3H, s), 5.09-5.16 (1H, m), 8.28 (1H, s), 8.62 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 335

8-Bromo-l-isopropyl-7-methyl-3H-imidazo[4,5-clcinnolin-2-one

l,3,5-Trichloro-l,3,5-triazinane-2,4,6-trione (1.294 g, 5.57 mmol) was added portionwise to a stirred suspension of 6-bromo-4-(isopropylamino)-7-methylcinnoline-3-carboxamide (3.6g, 11.14 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (3.36 mL, 22.28 mmol) in MeOH (60 mL) at 0 °C, then the solution was warmed to ambient temperature and stirred for 90 minutes. The reaction mixture was diluted with water and the precipitate collected by filtration, washed with water (100 mL) and dried under vacuum to afford the desired product (3.20 g, 89 %) as a brown solid, which was used without further purification.

NMR Spectrum: ¾ NMR (300 MHz, DMSO) δ 1.62 (6H, d), 2.55 (3H, s), 5.03-5.12 (1H, m), 8.22 (1H, s), 8.49 (1H, s), 12.49 (1H, br).

Mass Spectrum: m/z (ES+) [M+2H]+ = 323

6-Bromo-4-(isopropylamino)-7-methylcinnoline-3-carboxamide

Propan-2-amine (0.767 g, 12.98 mmol) was added to 6-bromo-4-chloro-7-methyl- cinnoline-3-carboxamide (3.9 g, 12.98 mmol) and DIPEA (4.53 mL, 25.95 mmol) in acetonitrile (60 mL) and the resulting suspension stirred at 60 °C for 16 hours. The mixture was allowed to cool and diluted with water. The precipitate was collected by filtration, washed with water (50 mL) and dried under vacuum to afford the desired material (3.70 g, 88 %) as a brown solid, which was used without further purification.

NMR Spectrum: ^!H NMR (400Hz, DMSO) δ 1.33 (6H, d), 2.55 (3H, s), 4.32-4.40 (1H, m), 7.71 (1H, s), 8.15 (1H, s), 8.40 (1H, s), 8.57 (1H, s), 10.34 (1H, d).

Mass Spectrum: m/z (ES+) [M+2H]+ = 325

6-Bromo-4-chloro-7-methyl-cinnoline-3-carboxamide

DMF (0.164 mL, 2.12 mmol) was added to a mixture of 6-bromo-4-hydroxy-7-methyl- cinnoline-3-carboxylic acid (6.00 g, 21.20 mmol) in thionyl chloride (90 mL, 1233.2 mmol) at ambient temperature under an inert atmosphere. The resulting slurry was stirred at 80 °C for 2 hours then allowed to cool, concentrated to dryness and the residue azeotroped with toluene (3 x 100 mL) to afford the crude acid chloride. This crude material (6.78 g, 21.19 mmol) was dissolved in acetone (30 mL), cooled to 0 °C and ammonium hydroxide (50 mL, 321.01 mmol) added dropwise over 10 minutes. The resulting mixture was stirred at ambient temperature for 1 hour. The precipitate was collected by filtration, washed with water (100 mL) and dried under vacuum to afford the desired material (4.20 g, 66 %) as a yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+) [M+H]+ = 301

6-Bromo-4-hvdroxy-7-methyl-cinnoline-3-carboxylic acid

Potassium hydroxide (62 g, 1.11 mol) was added to a solution of 4-amino-6-bromo-7- methyl-cinnoline-3-carboxamide (31 g, 110.28 mmol) in DMSO/H₂0 (600 mL / 600 mL) under an inert atmosphere at ambient temperature. The solution was stirred for 2 days at 120 °C, cooled to ambient temperature and quenched with water/ice (3000 mL). The pH value of the solution was adjusted to 7 with 3M hydrochloric acid. The solids formed were collected by filtration, washed with water (2 x 500 mL) and dried. The crude product was purified by re-crystallization from DMSO to afford the desired product (11.5 g, 37%) as a light brown solid.

NMR Spectrum: ^!H NMR (300 MHz, DMSO) δ 2.50-2.57 (m, 3H), 7.78 (s, 1H), 8.35 (s, 1H), 14.28-14.33 (br, 1H), 14.70-14.75 (br, 1H).

Mass Spectrum: m/z (ES+) [M+H]+ = 282

4-Amino-6-bromo-7-methyl-cinnoline-3-carboxamide

Aluminium trichloride (59.4 g, 445.47 mmol) was added to a solution of (lE)-2-amino-N- (4-bromo-3-methyl-anilino)-2-oxo-acetimidoyl cyanide (42 g, 149.41 mmol) in 1,2- dichlorobenzene (500 mL) under an inert atmosphere at ambient temperature. The solution was stirred for 3 hours at 120 °C, then cooled to 40-50 °C and quenched with water/ice (3000 mL). The solids formed were collected by filtration and washed with water (2 x 500 mL) and oven dried to afford the desired material (31 g, 74%) as a yellow solid.

Mass Spectrum: m/z (ES+) [M+2H]+ = 283

(lE)-2-amino-N-(4-bromo-3-methyl-anilino)-2-oxo-acetimidoyl cyanide

4-Bromo-3-methylaniline (30 g, 161.25 mmol), concentrated hydrochloric acid (100 mL), acetic acid (200 mL), and water (500 mL) were added to a round bottom flask under an inert atmosphere at ambient temperature. To the mixture was added a solution of sodium nitrite (12.3 g, 178.27 mmol) in H₂0 (200 mL) dropwise with stirring at 0 °C, then the solution was stirred for 2 hours at 0 °C. NaOAc (100 g, 1.22 mol) was added portionwise at 0 °C and the solution stirred for 30 minutes at 0 °C. 2-Cyanoacetamide (16.35 g, 194.47 mmol), EtOH (500 mL) and water (2000 mL) were added to a second round bottom flask under an inert atmosphere at ambient temperature, then NaOAc (500 g, 6.10 mol, 38.00 equiv) was added at ambient temperature and then the mixture from the first flask added dropwise with stirring and the temperature maintained at 0-5 °C. The resulting solution was stirred for 2 hours at 0 °C. The solids were collected by filtration, and washed with water (3 x 1 L) and dried to afford the desired material (42 g, 93%) as a yellow solid, which was used without further purification.

Mass Spectrum: m/z (ES+) [M+H]+ = 281 Example 49: l-Isopropyl-3,7-dimethyl-8-[6-[3-(l-piperidyl)propoxy]-3- pyridyl] imidazo [4,5-c] cinnolin-2-one

(2 ' -Amino-2-biphenylyl)(chloro)palladium - dicyclohexyl(2 ' ,4 ' ,6 ' -triisopropyl-2- biphenylyl)phosphine (1 : 1) (22.73 mg, 0.03 mmol) was added to 2-[3-(l- piperidyl)propoxy] -5 -(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridine (1 OOmg, 0.29 mmol), 8-bromo-l-isopropyl-3,7-dimethyl-imidazo[4,5-c]cinnolin-2-one (97 mg, 0.29 mmol) and CS2CO3 (188 mg, 0.58 mmol) in 1,4-dioxane (0.2 mL) and water (0.04 mL) and the mixture was stirred at 80 °C for 2 hours under an inert atmosphere. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, then further purified by preparative HPLC to afford the desired product (20 mg, 15 %) as a white solid.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 1.30-1.40 (2H, m), 1.45-1.55 (4H, m), 1.68 (6H, d), 1.85-1.98 (2H, m), 2.25-2.4 (9H, m), 3.60 (3H, s), 4.30-4.40 (2H, m), 5.10-5.20 (lH,m), 6.95 (1H, d) ,7.90 (1H, m), 8.10 (1H, s), 8.28 (1H, s), 8.32 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 475

Example 50: 8- [6- [3-(Dimethylamino)propoxy] -3-pyridyl] -l-isopropyl-3,7-dimethyl- imidazo [4,5-c] cinnolin-2-one

(2 ' -Amino-2-biphenylyl)(chloro)palladium - dicyclohexyl(2 ' ,4 ' ,6 ' -triisopropyl-2- biphenylyl)phosphine (1 : 1) (23.47 mg, 0.03 mmol) was added to 8-bromo-l-isopropyl-3,7- dimethyl-imidazo[4,5-c]cinnolin-2-one (100 mg, 0.30 mmol), N,N-dimethyl-3-{[5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridinyl]oxy}-l-propanamine (110 mg, 0.36 mmol) and CS2CO3 (243 mg, 0.75 mmol) in 1,4-dioxane (0.8 mL) and water (0.16 mL) and the mixture was stirred at 100 °C for 3 hours under an inert atmosphere. The reaction mixture was evaporated to afford crude product. The crude product was purified by preparative HPLC to afford the desired product (39.8 mg, 31 %) as a pale yellow solid. NMR Spectrum: ^!H NMR (400MHz, CDCI3) δ 1.57 (6H, d), 2.12 (2H, s), 2.32-2.48 (9H, m), 2.65 (2H, s), 3.78 (3H, s), 4.47 (2H, t), 5.13 (1H, t), 6.89 (1H, d), 7.67-7.69 (1H, m), 7.93 (1H, s), 8.23 (1H, d), 8.35 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 435

Example 51: l-Isopropyl-3,7-dimethyl-8-[4-[3-(l- piperidyl)propoxy] phenyl] imidazo [4,5-c] cinnolin-2-one

(2 ' -Amino-2-biphenylyl)(chloro)palladium - dicyclohexyl(2 ' ,4 ' ,6 ' -triisopropyl-2- biphenylyl)phosphine (1 : 1) (22.79 mg, 0.03 mmol) was added to l-(3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)propyl)piperidine (100 mg, 0.29 mmol), 8- bromo-l-isopropyl-3,7-dimethyl-imidazo[4,5-c]cinnolin-2-one (97 mg, 0.29 mmol) and CS2CO3 (189 mg, 0.58 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) and the mixture was stirred at 80 °C for 4 hours under an inert atmosphere. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, then further purified by preparative HPLC to afford the desired product (20 mg, 14 %>) as a yellow solid.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 1.34-1.45 (2H, m), 1.48-1.55 (4H, m), 1.63 (6H, d), 1.85-1.98 (2H, m), 2.30-2.38 (4H, m), 2.45 (5H, s), 3.60 (3H, s), 4.05-4.15 (2H, m), 5.05-5.15 (1H, m), 7.07 (2H, d), 7.45 (2H, d), 8.00 (1H, s), 8.28 (1H, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 474

Example 52: 3-(Difluoromethyl)-8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-l- isopropyl-imidazo [4,5-c] cinnolin-2-one

Dichlorobis(triphenylphosphine)palladium(II) (0.999 mg, 1.42 μηιοΐ) was added to a degassed solution of A ,N-dimethyl-3-[[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- pyridyl]oxy]propan-l -amine (9.15 mg, 0.03 mmol) and 8-chloro-3-(difluoromethyl)-l- isopropyl-imidazo[4,5-c]cinnolin-2-one (8.9 mg, 0.03 mmol), 2M potassium carbonate solution (0.043 mL, 0.09 mmol) in 1,4-dioxane (0.527 mL) and heated in a microwave at 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (10 mL), and washed sequentially with water (7 mL), saturated brine (7 mL) and the organic layer was evaporated. The crude product was purified by preparative HPLC to afford the desired product (5.7 mg, 44 %) as a yellow dry film.

NMR Spectrum: ^!H NMR (400 MHz, CDCb) δ 1.81 (6H, d), 2.03 - 2.15 (2H, m), 2.43 (6H, s), 2.64 - 2.74 (2H, m), 4.46 (2H, t), 5.18 (1H, dt), 6.92 (1H, d), 7.60 (1H, t), 7.92 (2H, ddd), 8.15 - 8.25 (1H, m), 8.44 - 8.56 (1H, m), 8.59 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ 457

8-Chloro-3-(difluoromethyl)-l-isopropyl-imidazo[4,5-c]cinnolin-2-one was prepared as described below.

8-Chloro-3-(difluoromethyl)-l-isopropyl-imidazor4,5-c1cinnolin-2-one

8-Chloro-l-isopropyl-3H-imidazo[4,5-c]cinnolin-2-one (200 mg, 0.76 mmol) was dissolved in DMA (7.61 mL) under inert atmosphere. Sodium hydride (192 mg, 4.80 mmol) was added and the mixture was stirred for 20 minutes. Sodium

chloro(difluoro)acetate (824 mg, 5.41 mmol) was added and the mixture was heated to 90 °C for 2 hours. The reaction was cooled, diluted with EtOAc (20 mL) and water (20 mL), then the organic layer washed with water (2 x 20 mL), dried and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 60 % EtOAc in heptane, to afford the desired product (37 mg, 16%) as a beige solid.

NMR Spectrum: *H NMR (400 MHz, DMSO) δ 1.63 (6H, d), 5.11 - 5.23 (1H, m), 7.7 -

8.09 (2H, m), 8.43 (2H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 313

Example 53 : 8- [6- [(3R)-3-(Dimethylamino)pyrrolidin-l-yl]-3-pyridyl] -l-isopropyl-3- methyl-imidazo [4,5-c] cinnolin-2-one

8-(6-Fluoro-3-pyridyl)-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one (110 mg, 0.33 mmol), and (3R)-A ,N-dimethyl-3-pyrrolidinamine (37.2 mg, 0.33 mmol) were suspended in DMF (3.26 mL) and heated to 150 °C for 5 hours in a microwave reactor. The reaction mixture was diluted with DCM (20 mL), and washed twice with water (10 mL). The organic layer was dried over a phase separating cartridge, filtered and evaporated. The crude product was purified by preparative HPLC to afford the desired product (25.6 mg, 18 %) as a brown solid.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.67 (6H, d), 1.77 - 1.9 (1H, m), 2.22 (7H, s), 2.81 (1H, dt), 3.14 - 3.25 (1H, m), 3.41 (1H, td), 3.59 (3H, s), 3.67 (1H, t), 3.76 (1H, dd), 5.29 (1H, p), 6.64 (1H, d), 8.05 (2H, ddd), 8.27 (1H, d), 8.34 (1H, d), 8.69 (1H, d). Mass Spectrum: m/z (ES+) [M+H]+ = 432

The following compounds were synthesised in an analogous fashion using the appropriate amine and the appropriate fluoropyridine and a reaction time of between 3 and 6 hours at 150 °C:

* Purified twice by preparative HPLC

** 2 Equivalent of the amine were used in the reaction.

*** 3 Equvalents of the amine were used in the reaction and the material purified by flash silica chromatography eluting with 0 to 10% 1% N¾ in MeOH in DCM and the isolated product triturated with diethyl ether.

Example 54: NMR Spectrum: ^lH NMR (400 MHz, CDCb) δ 1.60 (2H, qd), 1.78 (6H, d), 2.02 (2H, d), 2.40 (6H, s), 2.61 (IH, dtd), 2.97 (2H, td), 3.76 (3H, s), 4.49 (2H, d), 5.22 (IH, p), 6.82 (IH, d), 7.84 (2H, ddd), 8.17 (IH, d), 8.43 - 8.55 (IH, m), 8.58 (IH, d).Mass Spectrum: m/z (ES+) [M+H]+ = 446

Example 55: NMR Spectrum: 'H NMR (400 MHz, DMSO) δ 1.78 - 1.9 (3H, m), 2.21 (2H, s), 2.22 (6H, s), 2.61 (IH, d), 2.80 (IH, dt), 3.20 (IH, dd), 3.41 (2H, td), 3.57 (3H, s), 3.67 (IH, t), 3.76 (IH, dd), 3.95 (IH, d), 4.15 (2H, d), 4.86 - 4.97 (IH, m), 6.67 (IH, d), 8.04 (2H, ddd), 8.22 (IH, d), 8.35 (IH, d), 8.64 (IH, d . Mass Spectrum: m/z (ES+)

[M+H]+ = 474

Example 56: NMR Spectrum: ¾ NMR (400 MHz, DMSO) δ 0.81 (3H, s), 1.17 (3H, s), 1.32 - 1.46 (2H, m), 1.82 (3H, dd), 2.23 (6H, s), 2.92 (3H, t), 3.36 (IH, d), 3.59 (3H, s), 3.66 - 3.75 (2H, m), 4.02 - 4.1 (IH, m), 4.43 (2H, d), 5.01 (IH, dd), 7.05 (IH, d), 8.04 (2H, dd), 8.19 (IH, s), 8.35 (IH, d), 8.51 (IH, s), 8.66 (IH, d . Mass Spectrum: m/z (ES+) [M+H]+ = 516

Example 57: NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 0.86 (3H, s), 1.22 (3H, s), 1.84 (IH, d), 1.88 - 1.96 (IH, m), 2.19 (IH, ddq), 2.27 (6H, s), 2.93 (2H, dt), 3.27 - 3.5 (3H, m), 3.62 (3H, s), 3.56 - 3.79 (4H, m), 4.11 (IH, d), 4.98 (IH, dd), 6.68 (IH, d), 8.00 (2H, td), 8.17 (IH, s), 8.36 (IH, d), 8.45 (IH, d), 8.64 (IH, d) (isolated as formate salt). Mass Spectrum: m/z (ES+)[M+H]+ = 502

Example 58: NMR Spectrum: 'H NMR (400 MHz, CDCb) δ 1.91 - 2.06 (IH, m), 2.22 - 2.31 (IH, m), 2.35 (6H, s), 2.57 - 2.69 (2H, m), 2.82 - 2.95 (IH, m), 3.32 - 3.45 (6H, m), 3.47 - 3.57 (IH, m), 3.75 (4H, s), 3.87 (IH, dd), 4.34 (IH, tt), 5.49 (IH, ddd), 6.49 - 6.54 (IH, m), 7.83 (2H, ddd), 8.06 (IH, d), 8.44 (IH, d), 8.58 (IH, dd). Mass Spectrum: m/z (ES+)[M+H]+ = 474

Example 59: NMR Spectrum: ^!H NMR (400 MHz, CDCb) δ 2.01 (IH, s), 2.26 - 2.35 (IH, m), 2.37 (5H, s), 2.96 (3H, ddd), 3.13 (2H, tdd), 3.33 (3H, s), 3.37 (IH, d), 3.45 - 3.57 (2H, m), 3.76 (4H, s), 3.85 - 3.99 (2H, m), 4.93 - 5.06 (IH, m), 6.51 (IH, d), 7.89 (2H, ddd), 8.30 (IH, d), 8.47 (IH, d), 8.63 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 474

Example 60: NMR Spectrum: ^lH NMR (500 MHz, DMSO) δ 1.79 - 1.89 (IH, m), 1.92 (IH, d), 1.94 - 2 (2H, m), 2.15 (2H, d), 2.23 (6H, s), 2.6 - 2.71 (IH, m), 2.76 - 2.85 (IH, m), 3.20 (IH, dd), 3.38 - 3.46 (IH, m), 3.61 (3H, s), 3.61 - 3.71 (2H, m), 3.74 - 3.82 (IH, m), 4.09 (2H, dd), 5.05 - 5.14 (IH, m), 6.67 (IH, d), 8.04 - 8.11 (2H, m), 8.32 (IH, s), 8.36 (IH, d), 8.67 - 8.71 (IH, m). Mass Spectrum: m/z (ES+) [M+H]+ = 474 Example 61: NMR Spectrum: ¾ NMR (400 MHz, DMSO) δ 1.77 - 1.9 (2H, m), 2.22 (1 IH, s), 2.34 - 2.42 (IH, m), 2.81 (IH, dt), 3.20 (IH, dd), 3.28 (3H, s), 3.41 (IH, td), 3.59 (3H, s), 3.65 - 3.8 (2H, m), 4.14 (IH, s), 5.50 (IH, p), 6.65 (IH, d), 8.03 (2H, ddd), 8.22 (IH, d), 8.35 (IH, d), 8.66 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 488

Example 62: NMR Spectrum: 'H NMR (400 MHz, DMSO) δ 1.24 (IH, s), 1.76 - 1.9 (2H, m), 2.15 - 2.3 (10H, m), 2.37 (IH, dd), 2.81 (IH, dt), 3.16 - 3.26 (IH, m), 3.28 (3H, s), 3.36 - 3.46 (IH, m), 3.59 (3H, s), 3.67 (IH, t), 3.76 (IH, dd), 4.15 (IH, d), 5.49 (IH, q), 6.65 (IH, d), 8.03 (2H, ddd), 8.22 (IH, d), 8.35 (IH, d), 8.66 (IH, d . Mass Spectrum: m/z (ES+) [M+H]+ = 488

The preparation of the fluoropyridine intermediates required for Examples 53 - 62 have either been described previously or are described below:

8-(6-Fluoro-3-pyridyl)-3-methyl-l-[(3R)-tetrahydropyran-3-yllimidazo[4,5-clcinnolin-2- one

l,l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (10.22 mg, 0.02 mmol) was added to a degassed solution of (6-fluoropyridin-3-yl)boronic acid (46.4 mg, 0.33 mmol)and 8-chloro-3-methyl- 1 -[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]cinnolin-2-one (100 mg, 0.31 mmol), 2M potassium carbonate solution (0.471 mL, 0.94 mmol) in 1,4- dioxane (1.098 mL) and the mixture was heated in a microwave reactor to 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) then the organic layer evaporated to afford the desired material as an orange dry film, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 380 1 : 1 mixture of l-[(4R)-33-dimethyltetrahydropyran-4-yll-8-(6-fluoro-3-pyridyl)-3-methy imidazo[4,5-clcinnolin-2-one and l-[(4S)-3,3-dimethyltetrahydropyran-4-yll-8-(6-fluoro- 3 -p yridvD-3 -methyl-imidazo f4,5-c1 cinnolin-2-one

Dichlorobis(triphenylphosphine)palladium (II) (16.19 mg, 0.02 mmol) was added to a degassed solution of (6-fluoropyridin-3-yl)boronic acid (68.3 mg, 0.48 mmol) and a 1 : 1 mixture of 8-chloro-l -[(4R)-3,3-dimethyltetrahydropyran-4-yl]-3-methyl-imidazo[4,5- c] cinnolin-2-one and 8-chloro- 1 - [(4S)-3 ,3 -dimethyltetrahydropyran-4-yl] -3 -methyl- imidazo[4,5-c]cinnolin-2-one (160 mg, 0.46 mmol), 2M potassium carbonate solution (0.692 mL, 1.38 mmol) in 1,4-dioxane (2.384 mL) and the mixture was heated in a microwave reactor to 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL), then the organic layer evaporated to afford the desired material as a brown solid, which was used without further purification.

Mass Spectrum: m/z (ES+) [M+H]+ = 408

8-(6-Fluoro-3-pyridyl)-l-(trans-3-methoxycyclobutyl)-3-methyl-imidazo[4,5-clcinnolin-2- one

l,l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (10.22 mg, 0.02 mmol) was added to a degassed solution of (6-fluoropyridin-3-yl)boronic acid (46.4 mg, 0.33 mmol) and 8-chloro- 1 -(trans-3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c]cinnolin-2-one (100 mg, 0.31 mmol), 2M potassium carbonate solution (0.471 mL, 0.94 mmol) in 1,4-dioxane (1.098 mL) and the mixture was heated in a microwave reactor to 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL), then the organic layer evaporated to afford the desired material as a brown solid, which was used without further purification.

Mass Spectrum: m/z (ES+)[M+H]+ = 380

8-(6-Fluoro-3-pyridyl)-l-(cis-3-methoxycvclobutyl)-3-methyl-imidazor4,5-c1cinnolin-2- one

Dichlorobis(triphenylphosphine)palladium (II) (39.6 mg, 0.06 mmol) was added to a degassed solution of (6-fluoropyridin-3-yl)boronic acid (167 mg, 1.19 mmol) and 8-chloro- l-(cis-3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c]cinnolin-2-one (360 mg, 1.13 mmol), 2M potassium carbonate solution (1.694 mL, 3.39 mmol) in 1,4-dioxane (4 mL) and the mixture was heated at 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL), then the organic layer evaporated. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents, to afford the desired product (1 15 mg) as a green solid.

Mass Spectrum: m/z (ES+)[M+H]+ = 380

8-(6-Fluoro-3 -pyridyD- 1 - |Y 1 R,3R)-3 -methoxycyclopentyl] -3 -methyl-imidazo [4,5 - clcinnolin-2-one

l,l '-Bis(di-tert-butylphosphino)ferrocene - dichloropalladium (1 : 1) (19.58 mg, 0.04 mmol) was added to a degassed solution of (6-fluoro-3-pyridinyl)boronic acid (89 mg, 0.64 mmol) and 8-chloro-l-[(lR,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]cinnolin-2-one (100 mg, 0.30 mmol), 2M potassium carbonate solution (0.451 mL, 0.90 mmol) in 1,4- dioxane (1.052 mL) the mixture was heated in a microwave reactor to 80 °C for 2 hours under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) and the organic layer evaporated to afford crude product as a brown solid residue, which was used immediately without further purification.

Mass Spectrum: m/z (ES+) [M+H]+ = 394

8-(6-Fluoro-3-pyridyl)-l-r(lS,3S)-3-methoxycvclopentyl1-3-methyl-imidazor4,5- clcinnolin-2-one

l,l '-Bis(di-tert-butylphosphino)ferrocene - dichloropalladium (1 : 1) (10.28 mg, 0.02 mmol) was added to a degassed solution of (6-fluoro-3-pyridinyl)boronic acid (46.7 mg, 0.33 mmol) and 8-chloro-l-[(lS,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]cinnolin- 2-one (105 mg, 0.32 mmol), 2M potassium carbonate solution (0.473 mL, 0.95 mmol) in 1,4-dioxane (1.104 mL) the mixture was heated in a microwave reactor to 80 °C for 1 hours under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) and the organic layer evaporated to afford crude product as a brown solid residue, which was used immediately without further purification. Mass Spectrum: m/z (ES+) [M+H]+ = 394

Example 63 : 8- [6- [4-(Dimethylamino)- 1-piperidyl] -3-pyridyl] -l-(cis-3- methoxycyclobutyl)-3-methyl-imidazo [4,5-c] cinnolin-2-one

8-Bromo-l -(cis-3-methoxycyclobutyl)-3-methyl-imidazo[4,5-c]cinnolin-2-one (0.09 g, 0.25 mmol) was added to N,N-dimethyl-l-(5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyridin-2-yl)piperidin-4-amine (0.246 g, 0.74 mmol), CS2CO3 (0.484 g, 1.49 mmol) and palladium - triphenylphosphine (1 :4) (0.057 g, 0.05 mmol) in 1 ,4-dioxane (6 mL) and water (1.2 mL), and the mixture was stirred at 80 °C for 2 hours under an inert atmosphere. The crude product was purified by preparative HPLC to afford the desired product.

Fractions containing the desired compound were evaporated to dryness to afford the desired product (0.12 g, 99 %) as a yellow solid.

NMR Spectrum: ^lH NMR (300 MHz, DMSO) δ 1.2-1.5 (2H, m), 1.7-1.9 (2H, m), 2.1-2.2 (6H, m), 2.3-2.4 (1H, m), 2.75-3.05 (6H, m), 3.2-3.3 (3H,m), 3.55 (3H,s),3.8-4.0 (lH,m), 4.3-4.5 (2H, m), 5.0-5.2 (lH,m), 6.95-7.05 (1H, m), 7.98-8.12 (2H, m), 8.28-8.4 (2H, m), 8.72 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 488

Example 64 : 8- [4- [4-(Dimethylamino)- l-piperidyl] phenyl] - l-isopropyl-3-methyl- imidazo [4,5-c] cinnolin-2-one

l, -Bis(di-tert-butylphosphino)ferrocene palladium dichloride (11.78 mg, 0.02 mmol) was added to a degassed solution of N,N-dimethyl-l-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-4-piperidinamine (119 mg, 0.36 mmol) and 8-chloro-l- isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one (100 mg, 0.36 mmol), 2M potassium carbonate solution (0.542 mL, 1.08 mmol) in 1,4-dioxane (3.07 mL). and the mixture heated in a microwave reactor at 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) then the organic layer evaporated. The crude product was purified twice by preparative HPLC to afford the desired product (16.30 mg, 10.15 %) as a yellow solid.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.42 - 1.54 (2H, m), 1.68 (6H, d), 1.85 (2H, d), 2.20 (6H, s), 2.22 - 2.31 (1H, m), 2.79 (2H, t), 3.59 (3H, s), 3.86 (2H, d), 5.27 (1H, dt), 7.10 (2H, d), 7.76 (2H, d), 8.04 (1H, dd), 8.27 (1H, d), 8.34 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 445

N,N-Dimethyl-l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-4-piperidinamine was prepared as described below.

N,N-Dimethyl-l-r4-(4^,5,5-tetramethyl-13,2-dioxaborolan-2-yl)phenyl1-4-piperidinamine

To l-(4-bromophenyl)-N,N-dimethyl-piperidin-4-amine (100 mg, 0.35 mmol),

4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (108 mg, 0.42 mmol) and potassium acetate (139 mg, 1.41 mmol) in dioxane (3.53 mL) under nitrogen was added dichlorobis(tricyclohexylphosphine)palladium (II) (26.1 mg, 0.04 mmol) and the reaction was heated to 90°C for 2 hours, then at 100°C for 16 hours. The reaction mixture was evaporated to dryness, redissolved in DCM (100 mL), and washed with water (100 mL). The organic layer was dried with a phase separating cartridge and evaporated to afford crude product, which was used without further purification. NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.26 (12H, s), 1.43 (2H, qd), 1.82 (2H, d), 2.23 (6H, s), 2.73 (2H, td), 3.76 - 3.99 (3H, m), 6.89 (2H, d), 7.49 (2H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 331 l-(4-Bromo henyl)-N,N-dimethyl-piperidin-4-amine

Sodium triacetoxyborohydride (1.251 g, 5.90 mmol) was added to a mixture of l-(4- bromophenyl)-4-piperidinone (1.00 g, 3.94 mmol), dimethylamine (2M in THF) (3.94 mL, 7.87 mmol) and acetic acid (0.901 mL, 15.74 mmol) in DCM (20 mL) and stirred at ambient temperature for 2 hours. The reaction mixture was quenched with saturated sodium hydrogen carbonate solution, extracted with DCM (50 mL) and the organic layer dried over a phase separating cartridge and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM to afford the desired material (0.853 g, 77 %) as an orange solid.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.43 (2H, qd), 1.74 - 1.86 (2H, m), 2.17 (7H, s), 2.66 (2H, td), 3.63 - 3.73 (2H, m), 6.85 - 6.92 (2H, m), 7.26 - 7.34 (2H, m).

Mass Spectrum: m/z (ES+) [M+2H]+ = 285

Example 65: 1:1 mixture of 8-[4-[4-(dimethylamino)-l-piperidyl]phenyl]-l-[(4S)-3,3- dimethyltetrahydropyr an-4-yl] -3-methyl-imidazo [4,5-c] cinnolin-2-one and 8- [4- [4- (dimethylamino)-l-piperidyl]phenyl]-l-[(4R)-3,3-dimethyltetrahydropyran-4-yl]-3- methyl-imidazo [4,5-c] cinnolin-2-one

l ,l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (42.10 mg, 0.06 mmol) was added to a degassed solution of N,N-dimethyl-l-[4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)phenyl]-4-piperidinamine (213 mg, 0.65 mmol) and a 1 : 1 mixture of 8- chloro-l-[(4R)-3,3-dimethyltetrahydropyran-4-yl]-3-methyl-imidazo[4,5-c]cinnolin-2-one and 8-chloro-l-[(4S)-3,3-dimethyltetrahydropyran-4-yl]-3-methyl-imidazo[4,5-c]cinnolin- 2-one (224 mg, 0.65 mmol), 2M potassium carbonate solution (0.969 mL, 1.94 mmol) in 1 ,4-dioxane (3.34 mL) and the mixture heated in a microwave reactor at 80 °C for 2 hours under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) then the organic layer evaporated. The crude product was purified twice by preparative HPLC to afford the desired product (29 mg, 9 %) as a yellow solid.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 0.83 (3H, s), 1.18 (3H, s), 1.47 (2H, qd), 1.75 - 1.89 (3H, m), 2.20 (6H, s), 2.26 (1H, ddt), 2.80 (2H, td), 3.33 - 3.46 (2H, m), 3.56 (1H, s), 3.59 (3H, s), 3.61 - 3.71 (1H, m), 3.89 (2H, d), 4.08 (1H, dd), 5.00 (1H, dd), 7.14 (2H, d), 7.75 (2H, d), 8.05 (1H, dd), 8.34 (1H, d), 8.50 (1H, d).

Mass Spectrum: m/z (ES+)[M+H]+ = 515

Example 66 : 8- [4- [4-(Dimethylamino)- 1-piperidyl] phenyl] - 1- [(lR,3R)-3- methox cyclopentyl] -3-methyl-imidazo [4,5-c] cinnolin-2-one

l ,l '-Bis(di-tert-butylphosphino)ferrocene - dichloropalladium (1 : 1) (1 1.16 mg, 0.02 mmol) was added to a degassed solution of N,N-dimethyl-l-[4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)phenyl]-4-piperidinamine (1 19 mg, 0.36 mmol) and 8-chloro-l- [(lR,3R)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]cinnolin-2-one (1 14 mg, 0.34 mmol), 2M potassium carbonate solution (0.514 mL, 1.03 mmol) in 1 ,4-dioxane (1.199 mL).The mixture was heated in a microwave reactor to 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) then the organic layer evaporated. The crude product was purified by preparative HPLC to afford the desired product (7.8 mg, 5 %) as a brown solid.

NMR Spectrum: ^!H NMR (400 MHz, DMSO) δ 1.24 (4H, s), 1.42 - 1.54 (3H, m), 1.85 (4H, d), 2.20 (8H, s), 2.22 - 2.28 (IH, m), 2.79 (2H, t), 3.59 (3H, s), 3.87 (2H, d), 4.13 (IH, s), 5.44 - 5.61 (IH, m), 7.1 1 (2H, d), 7.73 (2H, d), 8.05 (IH, dd), 8.21 (IH, s), 8.35 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 501

Example 67: 8-[4-[4-(Dimethylamino)-l-piperidyl]phenyl]-l-[(lS,35)-3- methox cyclopentyl] -3-methyl-imidazo [4,5-c] cinnolin-2-one

l ,l '-Bis(di-tert-butylphosphino)ferrocene - dichloropalladium (1 : 1) (1 1.75 mg, 0.02 mmol) was added to a degassed solution of N,N-dimethyl-l-[4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)phenyl]-4-piperidinamine (125 mg, 0.38 mmol) and 8-chloro-l- [(l S,3S)-3-methoxycyclopentyl]-3-methyl-imidazo[4,5-c]cinnolin-2-one (120 mg, 0.36 mmol), 2M potassium carbonate solution (0.541 mL, 1.08 mmol) in 1 ,4-dioxane (1.262 mL) and the mixture was heated in a microwave reactor to 80 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), washed sequentially with water (10 mL), saturated brine (10 mL) and the organic layer was evaporated. The crude product was purified by preparative HPLC to afford the desired product (19 mg, 1 1 %) as a brown solid.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.47 (2H, qd), 1.85 (3H, d), 2.20 (6H, s), 2.2 - 2.43 (6H, m), 2.79 (2H, td), 3.29 (3H, s), 3.59 (3H, s), 3.86 (2H, d), 4.09 - 4.16 (IH, m), 5.48 (IH, p), 7.10 (2H, d), 7.72 (2H, d), 8.04 (IH, dd), 8.20 (IH, d), 8.34 (IH, d). Mass Spectrum: m/z (ES+) [M+H]+ = 501

Example 68 : 8- [4- [4-(Dimethylamino)- 1-piperidyl] phenyl] -3-methyl- 1- [(3R)- tetrahydropyran-3-yl] imidazo [4,5-c] cinnolin-2-one

l, -Bis(di-tert-butylphosphino)ferrocene - dichloropalladium (1 : 1) (27.20 mg, 0.04 mmol) was added to a degassed solution of N,N-dimethyl-l-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]-4-piperidinamine (138 mg, 0.42 mmol) and 8-chloro-3-methyl- l-[(3R)-tetrahydropyran-3-yl]imidazo[4,5-c]cinnolin-2-one (133 mg, 0.42 mmol), 2M potassium carbonate solution (0.626 mL, 1.25 mmol) in 1,4-dioxane (3.55 mL) and the mixture was heated in a microwave reactor to 80 °C for 2 hours under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), washed sequentially with water (10 mL), saturated brine (10 mL) and the organic layer was evaporated. The crude product was purified by preparative HPLC to afford the desired product (9.8 mg, 5 %) as a yellow solid.

NMR Spectrum: ^lH NMR (400 MHz, CDCb) δ 1.66 (2H, qd), 1.95 (4H, dt), 2.24 (1H, t), 2.33 (7H, s), 2.72 - 2.92 (3H, m), 3.58 (1H, ddd), 3.73 (3H, s), 3.88 (2H, d), 4.05 (1H, d), 4.19 (1H, ddd), 4.42 - 4.53 (1H, m), 4.85 - 4.97 (1H, m), 7.07 (2H, d), 7.63 (2H, d), 7.92 (1H, dd), 8.17 - 8.22 (1H, m), 8.45 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 487

Example 69: 8-[6-[(3R)-3-(Dimethylamino)pyrrolidin-l-yl]-3-pyridyl]-7-fluoro-l- isopropyl-3-methyl-imidazo [4,5-c] cinnolin-2-one

(2 ' -Amino-2-biphenylyl)(chloro)palladium - dicyclohexyl(2 ' ,4 ' ,6 ' -triisopropyl-2- biphenylyl)phosphine (1 : 1) (34.7 mg, 0.04 mmol) was added to (3R)-N,N-dimethyl-l-[5- (4,4,5, 5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-2-pyridyl]pyrrolidin-3-amine (140mg, 0.44 mmol), 8-bromo-7-fluoro-l-isopropyl-3-methyl-l,3-dihydro-2H-imidazo[4,5-c]cinnolin-2- one (150 mg, 0.44 mmol) and CS2CO3 (288 mg, 0.88 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) and the solution heated at 80 °C for 2 hours. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, then by preparative HPLC to afford the desired product (80 mg, 40 %) as a yellow solid.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 1.59-1.73 (6H, m), 1.80-1.92 (1H, m), 2.15-2.35 (7H, m), 2.80-2.90 (1H, m), 3.15-3.25 (1H, m), 3.40-3.50 (1H, m), 3.60 (3H, s), 3.62-3.70 (1H, m), 3.72-3.82 (1H, m), 5.18-5.28 (1H, m), 6.65 (1H, d), 7.89 (1H, d), 8.15 (1H, d), 8.24 (1H, d), 8.48 (1H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 350 (3R)-N,N-Dimethyl-l-[5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-2- pyridyl]pyrrolidin-3 -amine was prepared as described below.

(3R -N.N-Dimethyl-l-r5-(4,4,5,5-tetramethyl-l ,3.2-dioxaborolan-2-vn-2- pyridyllp yrrolidin-3 -amine

Under an inert atmosphere, 4,4,5, 5-tetramethyl-l ,3,2-dioxaborolane (0.285 mL, 1.96 mmol) was added slowly to (3R)-l-(5-bromo-2-pyridyl)-A ,N-dimethyl-pyrrolidin-3-amine, triethylamine (0.342 mL, 2.45 mmol) and dichlorobis(triphenylphosphine)palladium (II) (68.8 mg, 0.10 mmol) in 1 ,4-dioxane (1 mL) at 0°C, and the resulting mixture was stirred at 100 °C for 16 hours. The precipitate was filtered and washed with hexane, and the filtrate was concentrated to afford the desired product (297 mg, 95 %>) as a brown oil, which was used without further purification.

Mass Spectrum: m/z (ES+) [M+H]+ = 318

(3R)- 1 -(5-Bromo-2-pyridyl)-N,N-dimethyl-pyrrolidin-3-amine

4-Methylbenzenesulfonic acid (0.080 g, 0.42 mmol) was added to 2,5-dibromopyridine (lg, 4.22 mmol) and (3R)-N,N-dimethyl-3-pyrrolidinamine (0.964 g, 8.44 mmol) and stirred at 1 10 °C for 1 hour under an inert atmosphere. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with saturated sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over Na₂S04, filtered and evaporated to afford the desired product (0.800 g, 70.1 %) as a brown oil.

NMR Spectrum: ^lH NMR (400MHz, DMSO) δ 1.65-1.80 (1H, m), 2.05-2.20 (8H, m) 2.60-2.72 (1H, m), 2.98-3.10 (1H, m), 3.49-3.60 (2H, m), 6.43 (1H, d), 7.61 (1H, d) 8.10 (1H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 270

Example 70 : 8- [4- [4-(Dimethylamino)- 1-piperidyl] phenyl] -7-fluoro- l-isopropyl-3- methyl-imid azo [4,5-c] cinnolin-2-one

[l , -Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31.0 mg, 0.04 mmol) was added to A ,N-dimethyl-l-[4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl]-4- piperidinamine (140 mg, 0.42 mmol), 8-bromo-7-fluoro-l-isopropyl-3-methyl- imidazo[4,5-c]cinnolin-2-one (144 mg, 0.42 mmol) and CS2CO3 (276 mg, 0.85 mmol) in 1 ,4-dioxane (2 mL) and water (0.4 mL) and stirred at 80 °C for 4 hours. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM then by preparative HPLC to afford the desired product (60 mg, 31 %) as a yellow solid. NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 1.50-1.65 (8H, m), 1.90-2.05 (2H, m), 2.55-2.65 (7H, m), 2.72-2.85 (2H, m), 3.60 (3H, s), 3.98 (2H, d), 5.15-5.25 (1H, m), 7.15 (2H, d), 7.62 (2H, d), 8.10-8.25 (2H, m).

Mass Spectrum: m/z (ES+) [M+H]+ = 463 Example 71: 8-[6-[(3R)-3-(Dimethylamino)pyrrolidin-l-yl]-3-pyridyl]-l-isopropyl- 3,7-dimethyl-imidazo [4,5-c] cinnolin-2-one

Dichloro[l, -bis(diphenylphosphino)ferrocene]palladium (II) (32.3 mg, 0.04 mmol) was added to (3R)-N,N-dimethyl- 1 -[5-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)-2- pyridyl]pyrrolidin-3 -amine (140mg, 0.44 mmol), 8-bromo-l-isopropyl-3,7-dimethyl- imidazo[4,5-c]cinnolin-2-one (148 mg, 0.44 mmol) and CS2CO3 (288 mg, 0.88 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) and the mixture was stirred at 80 °C for 4 hours under an inert atmosphere. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, then further purified by preparative HPLC to afford the desired product (100 mg, 51 %) as a yellow solid.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 1.80-1.95 (1H, m), 1.60 (6H, d), 2.28 (7H, s), 2.45-2.50 (3H, m), 2.90 (2H, s), 3.15-3.25 (1H, m), 3.35-3.45 (1H, m) 3.60 (3H, s), 3.63-3.73 (1H, m), 3.73-3.83 (1H, m), 5.10-5.20 (1H, m), 6.60 (1H, d), 7.73 (1H, d), 8.00 (1H, s), 8.25 (2H, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 446

Example 72: 8-[4-[4-(Dimethylamino)-l-piperidyl]phenyl]-l-isopropyl-3,7-dimethyl- imidazo 4,5-c] cinnolin-2-one

Dichloro[l, -bis(diphenylphosphino)ferrocene]palladium (II) (33.2 mg, 0.05 mmol) was added to A ,N-dimethyl-l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-4- piperidinamine (150mg, 0.45 mmol), 8-bromo-l-isopropyl-3,7-dimethyl-imidazo[4,5- c]cinnolin-2-one (152 mg, 0.45 mmol) and CS2CO3 (296 mg, 0.91 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) and the mixture was stirred at 80 °C for 4 hours under an inert atmosphere. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM, then further purified by preparative HPLC to afford the desired product (35 mg, 17 %) as a yellow solid.

NMR Spectrum: ^!H NMR (300MHz, DMSO) δ 1.42-1.52 (2H, d), 1.62 (6H, d), 1.87 (2H, d), 2.20 (7H, s), 2.46 (3H, s), 2.70-2.80 (2H, m) 3.60 (3H, s), 3.85 (2H, d), 5.06-5.16 (IH, m), 7.07 (2H, d), 7.39 (2H, d), 7.97 (IH, s), 8.23 (IH, s).

Mass Spectrum: m/z (ES+) [M+H]+ = 459

Example 73 : 8- [6- [3-(Dimethylamino)propoxy] -2-fluoro-3-pyridyl] -l-isopropyl-3- methyl-imidazo [4,5-c] cinnolin-2-one

l,l '-Bis(di-tert-butylphosphino)ferrocene - dichloropalladium (1 : 1) (47.10 mg, 0.08 mmol) was added to a degassed solution of 3-[[6-fluoro-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-pyridyl]oxy]-N,N-dimethyl-propan-l -amine (492 mg, 1.52 mmol) and 8-chloro-l-isopropyl-3-methyl-imidazo[4,5-c]cinnolin-2-one (200 mg, 0.72 mmol), 2M potassium carbonate solution (1.084 mL, 2.17 mmol) in 1,4-dioxane (2.53 mL) and the mixture was heated in a microwave reactor to 80 °C for 2 hours under an inert atmosphere. The reaction mixture was diluted with EtOAc (25 mL), and washed sequentially with water (10 mL), saturated brine (10 mL) then the organic layer evaporated. The crude product was purified by preparative HPLC to afford the desired product (88 mg, 28 %) as a brown solid.

NMR Spectrum: ^lH NMR (400 MHz, DMSO) δ 1.65 (6H, d), 1.88 (2H, p), 2.15 (6H, s), 2.36 (2H, t), 3.60 (3H, s), 4.32 (2H, t), 5.22 (IH, hept), 6.96 (IH, dd), 7.92 (IH, dd), 8.26 (IH, dd), 8.39 (2H, d).

Mass Spectrum: m/z (ES+) [M+H]+ = 439 3-[[6-Fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]-N,N- dimethyl-propan-1 -amine was prepared as described below.

3-[[6-Fluoro-5-(4^,5,5-tetramethyl-13,2-dioxaborolan-2-yl)-2-pyridylloxyl-N,N- dimethyl- ropan- 1 -amine

To 3-(5-Bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-l-amine (500 mg, 1.80 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (550 mg, 2.16 mmol) and potassium acetate (708 mg, 7.22 mmol) in dioxane (18.04 mL) under an inert atmosphere was added dichlorobis(tricyclohexylphosphine)palladium (II) (133 mg, 0.18 mmol) and the reaction was heated to 90°C for 18 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (10 mL), and washed with water (10 mL). The organic layer was dried with a phase separating cartridge and evaporated to afford crude product, which was used without further purification.

Mass Spectrum: m/z (ES+) [M+H]+ = 325

The preparation of 3-(5-Bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-l- known in the literature, for example in WO2015170081.A1.

BIOLOGICAL ASSAYS

The following assays were used to measure the effects of the compounds of Formula (I): a) ATM cellular potency assay; b) PI3K cellular potency assay; c) mTOR cellular potency assay; d) ATR cellular potency assay. During the description of the assays, generally:

i. The following abbreviations have been used: 4NQO = 4-Nitroquinoline N-oxide;

Ab = Antibody; BSA = Bovine Serum Albumin; C0₂ = Carbon Dioxide; DMEM = Dulbecco's Modified Eagle Medium; DMSO =Dimethyl Sulphoxide; EDTA = Ethylenediaminetetraacetic Acid; EGTA = Ethylene Glycol Tetraacetic Acid; ELISA = Enzyme-linked Immunosorbent Assay; EMEM = Eagle's Minimal Essential Medium; FBS = Foetal Bovine Serum; h = Hour(s); HRP = Horseradish Peroxidase; i.p. = intraperitoneal; PBS = Phosphate buffered saline; PBST = Phosphate buffered saline / Tween; TRIS = Tris(Hydroxymethyl)aminomethane; MTS reagent: [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4- sulfophenyl)-2H-tetrazolium, inner salt, and an electron coupling reagent

(phenazine methosulfate) PMS; s.c. = sub-cutaneously.

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 (Protocol 1 or 2 can be used):

(1) 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% CO2, 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 20μ1 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 XI 00 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 of pSerl981 (488nm).

(2) HT29 cells (ECACC #85061 109) were seeded into 384 well assay plates (Greiner # 781090) at a density of 3500 cells / well in 40μ1 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 Multi Rad 160 X-Ray Irradiation cabinet (Faxitron) with equivalent to ~600cGy. Plates were returned to the incubator for a further lh. Then cells were fixed by adding 20μ1 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 Bluewasher plate washer (Blue Cat Bio).

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 Bluewasher 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 Bluewasher plate washer, and plates were sealed and kept in PBS at 4°C until read. Plates were read using an Cell Insight imaging platform, 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 of pSerl981 (488nm).

Assay b): ATR Cellular Potency

Rationale:

ATR is a PI 3-kinase-related kinase which phosphorylates multiple substrates on serine or threonine residues in response to DNA damage during or replication blocks. Chkl, a downstream protein kinase of ATR, plays a key role in DNA damage checkpoint control. Activation of Chkl involves phosphorylation of Ser317 and Ser345 (the latter regarded as the preferential target for phosphorylation/activation by ATR). This was a cell based assay to measure inhibition of ATR kinase, by measuring a decrease in

phosphorylation of Chkl (Ser 345) in HT29 cells, following treatment with compound of Formula (I) and the UV mimetic 4NQO (Sigma #N8141).

Method details:

HT29 cells (ECACC #85061109) were seeded into 384 well assay plates (Costar #3712) at a density of 6000 cells / well in 40 μΐ EMEM medium containing 1% L glutamine and 10% FBS and allowed to adhere overnight. The following morning compound of Formula (I) in 100%) DMSO were added to assay plates by acoustic dispensing. After lh incubation at 37°C and 5% CO₂, 40nl of 3mM 4NQO in 100% DMSO was added to all wells by acoustic dispensing, except minimum control wells which were left untreated with 4NQO to generate a null response control. Plates were returned to the incubator for a further lh. Then cells were fixed by adding 20μ1 of 3.7% formaldehyde in PBS solution and incubating for 20 mins at r.t. Then 20μ1 of 0.1% Triton X100 in PBS was added and incubated for 10 minutes at r.t., to permeabalise cells. Then the plates were washed once with 50μ1 / well PBS, using a Biotek EL405 plate washer.

Phospho-Chkl Ser 345 antibody (Cell Signalling Technology #2348) was diluted 150 fold in PBS containing 0.05% polysorbate/Tween and 15μ1 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 (Molecular Probes #A- 11008) and 0.002mg/ml Hoeschst dye (Molecular Probes #H-3570), in PBST, was added. After 2h incubation at r.t., the plates were washed three times with 50μ1 / well PBS, using a Biotek EL405 plate washer, and plates were then sealed with black plate seals 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 of pChkl (488nm).

Assay c): PI3K Cellular Potency

Rationale:

This assay was used to measure PI3K-a inhibition in cells. PDKl was identified as the upstream activation loop kinase of protein kinase B (Aktl), which is essential for the activation of PKB. Activation of the lipid kinase phosphoinositide 3 kinase (PI3K) is critical for the activation of PKB by PDKl .

Following ligand stimulation of receptor tyrosine kinases, PI3K is activated, which converts PIP2 to PIP3, which is bound by the PH domain of PDKl resulting in recruitment of PDKl to the plasma membrane where it phosphorylates AKT at Thr308 in the activation loop.

The aim of this cell -based mode of action assay is to identify compounds that inhibit PDK activity or recruitment of PDKl to membrane by inhibiting PI3K activity. Phosphorylation of phospho-Akt (T308) in BT474c cells following treatment with compounds for 2h is a direct measure of PDKl and indirect measure of PI3K activity.

Method details: BT474 cells (human breast ductal carcinoma, ATCC HTB-20) were seeded into black 384 well plates (Costar, #3712) at a density of 5600 cells / well in DMEM containing 10% FBS and 1% glutamine and allowed to adhere overnight.

The following morning compounds in 100% DMSO were added to assay plates by acoustic dispensing. After a 2h incubation at 37°C and 5% C0₂, the medium was aspirated and the cells were lysed with a buffer containing 25mM Tris, 3mM EDTA, 3mM EGTA, 50mM sodium fluoride, 2mM Sodium orthovanadate, 0.27M sucrose, lOmM β- glycerophosphate, 5mM sodium pyrophosphate, 0.5%> Triton X-100 and complete protease inhibitor cocktail tablets (Roche #04 693 116 001, used 1 tab per 50ml lysis buffer).

After 20 minutes, the cell lysates were transferred into ELISA plates (Greiner # 781077) which had been pre-coated with an anti total- AKT antibody in PBS buffer and non-specific binding was blocked with 1% BSA in PBS containing 0.05% Tween 20. Plates were incubated over night at 4°C. The next day the plates were washed with PBS buffer containing 0.05% Tween 20 and further incubated with a mouse monoclonal anti- phospho AKT T308 for 2h. Plates were washed again as above before addition of a horse anti-mouse-HRP conjugated secondary antibody. Following a 2h incubation at r.t, plates were washed and QuantaBlu substrate working solution (Thermo Scientific #15169, prepared according to provider's instructions) was added to each well. The developed fluorescent product was stopped after 60 minutes by addition of Stop solution to the wells. Plates were read using a Tecan Safire plate reader using 325nm excitation and 420nm emission wavelengths respectively. Except where specified, reagents contained in the Path Scan Phospho AKT (Thr308) sandwich ELISA kit from Cell Signalling (#7144) were used in this ELISA assay.

Assay d): mTOR Cellular Potency

Rationale:

This assay was used to measure mTOR inhibition in cells. The aim of the phospho- AKT cell based mechanism of action assay using the Acumen Explorer is to identify inhibitors of either PI3Ka or mTOR-Rictor (Rapamycin insensitive companion of mTOR). This is measured by any decrease in the phosphorylation of the Akt protein at Ser473 (AKT lies downstream of ΡΒΚα in the signal transduction pathway) in the MDA-MB-468 cells following treatment with compound.

Method details:

MDA-MB-468 cells (human breast adenocarcinoma #ATCC HTB 132) were seeded at 1500 cells / well in 40μ1 of DMEM containing 10% FBS and 1% glutamine into Greiner 384 well black flat-bottomed plates. Cell plates were incubated for 18h in a 37°C incubator before dosing with compounds of Formula (I) in 100%) DMSO using acoustic dispensing. Compounds were dosed in a 12 point concentration range into a randomised plate map. Control wells were generated either by dosing of 100% DMSO (max signal) or addition of a reference compound (a ΡΙ3Κ-β inhibitor) that completely eliminated the pAKT signal (min control). Compounds were then tested by one of two assay protocols A or B:

Protocol A:

Plates were incubated at 37°C for 2h; cells were then fixed by the addition of ΙΟμΙ of a 3.7%) formaldehyde solution. After 30 minutes the plates were washed with PBS using a Tecan PW384 plate washer. Wells were blocked and cells permeabilised with the addition of 40μ1 of PBS containing 0.5%> Tween20 and 1% Marvel™ (dried milk powder) and incubated for 60 minutes at r.t. The plates were washed with PBS containing 0.5% (v/v) Tween20 and 20μ1 rabbit anti-phospho AKT Ser473 (Cell Signalling Technologies, #3787) in same PBS-Tween + 1% Marvel™ was added and incubated overnight at 4°C.

Plates were washed 3 times with PBS + 0.05%> Tween 20 using a Tecan PW384. 20μ1 of secondary antibody Alexa Fluor 488 anti-Rabbit (Molecular Probes, #A11008) diluted in PBS + 0.05%> Tween20 containing 1% Marvel™ was added to each well and incubated for lh at r.t. Plates were washed three times as before then 20μ1 PBS added to each well and plates sealed with a black plate sealer.

The plates were read on an Acumen plate reader as soon as possible, measuring green fluorescence after excitation with 488nm laser. Using this system IC50 values were generated and quality of plates was determined by control wells. Reference compounds were run each time to monitor assay performance. Protocol B:

The cell plates were then incubated for 2 h at 37°C before being fixed by the addition of 20μ1 3.7% formaldehyde in PBS/A (1.2% final concentration), followed by a 30 minute room temperature incubation, and then a 2x wash with 150μ1 PBS/A using a BioTek ELx406 platewasher. Cells were permeabilised and blocked with 20μ1 of assay buffer (0.1% Triton X-100 in PBS/A + 1% BSA) for lh at room temperature, and then washed lx with 50μ1 PBS/A. Primary phospho-AKT (Ser473) D9E XP® rabbit monoclonal antibody (#4060, Cell Signaling Technology) was diluted 1 :200 in assay buffer, 20μ1 added per well, and plates were incubated at 4°C overnight. Cell plates were washed 3x with 200μ1 PBS/T, then 20μ1 1 :750 dilution in assay buffer of Alexa Fluor® 488 goat anti -rabbit IgG secondary antibody (#A1 1008, Molecular Probes, Life

Technologies), with a 1 :5000 dilution of Hoechst 33342, was added per well. Following a 1 h incubation at room temperature, plates were washed 3x with 200μ1 PBS/T, and 40μ1 PBS w/o Ca, Mg and Na Bicarb (Gibco #14190-094) was added per well.

Stained cell plates were covered with black seals, and then read on the Cell Insight imaging platform (Thermo Scientific), with a lOx objective. The primary channel (Hoechst blue fluorescence 405nM, BGRFR 386 23) was used to Auto focus and to count number of events (this provided information about cytotoxicity of the compounds tested). The secondary channel (Green 488nM, BGRFR 485 20) measured pAKT staining. Data was analysed and ICsos were calculated using Genedata Screener^® software.

Table 1 shows the results of testing the Examples in tests a) b) c) and d). Results may be the geometric mean of several tests.

Table 1 : Potency Data for Example 1 in Assays a) - d)

0.0128 >30 12.8 >30

0.0155 >30 >30 >30

0.0218 >30 26.9 >10

0.00777 >30 14.5 >30

0.0102 >30 0.011, >30, >30

>30

0.0145 >30 >30 25

0.0325 >30 >30 >30

0.00918 >30 >30 >30

0.00547 >30 16.8 >30

0.00369 >10

0.0301 >30 >30 >30

0.0202 >30 >30 >30

0.0119 >30 >30 >30

0.017 >30 >30 >30

0.00344 >30 >30 >30

0.00541 >30 >30 >30

0.0173 >30 28.9 >30

0.0216 >30 >30 >30

0.0334 >10 >30 >30

0.0171 >30 >30 >30

0.0819 >30 5.1 >30

0.351 >30 >30 0.0044, >30,

>5.4

0.162 >30 >30 >30

0.0342 >30 6.64 >30

0.00357 >30 >30 >30

0.00424 >30 >30 >30

0.0102 >30 >30 >30

0.00357 >30 >30 >30

0.00461 >30 >30 >30

>30 4.25 >10

0.0163 >30 >30 >30

0.0042 >30 >30 >30

0.0255 >30 >30 >30

0.00603 >30 >30 2.17

0.141 >30 >25.2 >30

0.00281 >30 16.9 >30

0.0624 >30 >30 >30

0.0359 >30 >30 >30

0.333 >30 >3.12

0.00739 >30 25.6 >30 0.0525 >30 >30 >30

0.0475 >30 >30 >30

0.0189 >30 >30 >30

0.0608 >30 27.5 >30

0.247 >30 4.78 >30

0.182 >30 >30 >30

0.291 >30 >30 >30

0.407 >30 >30 >30

0.00781 >30 5.67 >30

0.0138 >30 >30 >30

0.0327 >30 >30 27.6

0.0189 >30 21.3 >30

0.0229 >30 >30 >30

0.00771 >30 >30 >30

0.0184 >30 >30 >30

0.0144 14.7

0.0362 >30 23.4 >30

0.0067 >30 >30 >30

0.0048 >30 >30 >30

0.0207 >30 >30 >30

0.0089 >30 >30 >30

0.0385 >30 >30 >30

0.0133 >30 0.99 >30

0.0223 >30 >30 >10

0.0444 >30 >30 >30

0.0369 >30 >30 >30

0.126 >30 >30 >30

0.359 >30 >30 >30

0.183 >30 >30 >30

0.0202 >30 >30 >30

Claims

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

A is N or CR⁴;

X is -OR⁵ or -NR⁶R⁷;

R¹ is (Ci-Ce)alkyl, cycloalkyl or heterocycloalkyl;

R³ is H, (Ci-C₆)alkyl or halo;

R⁴ is H, (Ci-C₆)alkyl or halo;

R⁵ is -(CH₂)_n-NR⁸R⁹;

R⁶ and R⁷ together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered non-aromatic monocyclic ring comprising carbon which is substituted with -

NR¹⁰R^U;

R⁸ and R⁹ are independently selected from H and (Ci-Ce)alkyl; or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered non-aromatic monocyclic ring comprising carbon which can be optionally substituted with halo;

R¹⁰ is H or (Ci-C₃)alkyl;

R¹¹ is (Ci-C )alkyl;

n is 2, 3 or 4;

alkyl is a linear or branched saturated hydrocarbon;

alkoxy is a linear or branched O-linked saturated hydrocarbon;

cycloalkyl is a 3, 4, 5 or 6 membered aliphatic carbocyclic ring, which can be optionally substituted with 1 or 2 substituents selected from (Ci-C₃)alkyl, (Ci-C₃)alkoxy and -OH; halo is F, CI or Br; heterocycloalkyl is a 4, 5 or 6 membered non-aromatic monocyclic ring comprising carbon and 1 or 2 heteroatoms selected from nitrogen and oxygen; wherein heterocycloalkyl can be optionally substituted with 1 or 2 substituents selected from (Ci-C3)alkyl, (Ci-C3)alkoxy and -OH.

2. A compound as claimed in claim 1, wherein said compound is a compound of formula (la)

or a pharmaceutically acceptable salt thereof, wherein

A is N or CH;

X is -OR⁵ or -NR⁶R⁷;

R¹ is (Ci-C3)alkyl, cycloalkyl, heterocycloalkyl;

R³ is H, methyl, chloro or fluoro;

R⁴ is H, methyl, chloro or fluoro;

R⁵ is -(CH₂)_n-NR⁸R⁹;

R⁸ and R⁹ are independently selected from H and (Ci-C3)alkyl; or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered non-aromatic monocyclic ring comprising carbon which can be optionally substituted with fluoro;

R¹⁰ is H or (Ci-C₃)alkyl;

R¹¹ is (Ci-C₃)alkyl;

n is 2, 3 or 4; alkyl is a linear or branched saturated hydrocarbon;

cycloalkyl is a 3, 4, 5 or 6 membered aliphatic carbocyclic ring, which can be optionally substituted with 1 or 2 substituents selected from methyl, methoxy and -OH;

heterocycloalkyl is a 4, 5 or 6 membered non-aromatic monocyclic ring comprising carbon and a heteroatom selected from oxygen; wherein heterocycloalkyl can be optionally substituted with 1 or 2 substituents selected from methyl, methoxy and -OH.

3. A compound as claimed in claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R¹ is n-propyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tertrahydropyranyl; wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tertrahydropyranyl can be optionally substituted with 1 or 2 substituents selected from methyl, methoxy and -OH.

4. A compound as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R² is methyl optionally substituted with 1, 2, or 3 fluoro substituents.

5. A compound as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ are independently selected from H, methyl and fluoro.

6. A compound as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X is -OR⁵ and R⁵ is -(CH₂)3-NR⁸R⁹.

7. A compound as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X is -NR⁶R⁷.

8. A compound as claimed in claim 6, or a pharmaceutically acceptable salt thereof, wherein R⁸ and R⁹ are methyl; or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 5 or 6 membered non-aromatic monocyclic ring comprising carbon which can be optionally substituted with fluoro.

9. A compound as claimed in claim 7, or a pharmaceutically acceptable salt thereof, wherein R⁶ and R⁷ together with the nitrogen atom to which they are attached form a 5 or 6 membered non-aromatic monocyclic ring comprising carbon which is substituted with - N(CH₃)₂.

10. A compound as claimed in claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, selected from:

8-[6- [3 -(Dimethylamino)propoxy] -3 -pyridyl] -3 -methyl- 1 -tetrahydropyran-4-yl- imidazo[4,5-c]cinnolin-2-one;

8-[6- [3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -(cis-3 -methoxycyclobutyl)-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

8-[6- [3 -(Dimethylamino)propoxy] -3 -pyridyl] -3 -methyl- 1 -[(3 S)-tetrahydropyran-3 - yl]imidazo[4,5-c]cinnolin-2-one;

8-[6- [3 -(Dimethylamino)propoxy] -3 -pyridyl] -3 -methyl- 1 -[(3R)-tetrahydropyran-3 - yl]imidazo[4,5-c]cinnolin-2-one;

3-Methyl-8-[6-[3-(l -piperidyl)propoxy] -3 -pyridyl]- 1 -tetrahydropyran-4-yl-imidazo[4,5- c]cinnolin-2-one;

8-[4- [3 -(dimethylamino)propoxy]phenyl] - 1 -isopropyl-3 -methyl-imidazo [4,5 -c] cinnolin-2- one;

1 -Isopropyl-3 -methyl-8 -[6- [3 -( 1 -piperidyl)propoxy] -3 -pyridyl] imidazo [4,5 -c] cinnolin-2- one;

8 - [6- [3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -isopropyl-3 -methyl-imidazo [4,5- c]cinnolin-2-one;

1 -Isopropyl-3-methyl-8-[4-(3-pyrrolidin- 1 -ylpropoxy)phenyl]imidazo[4,5-c]cinnolin-2- one;

8-[6- [3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -(trans-3 -methoxycyclobutyl)-3 -methyl - imidazo[4,5-c]cinnolin-2-one; 8-[6-[3-(4-Fluoro-l-piperidyl)propoxy]-3-pyridyl]-l-isopropyl-3-methyl-imidazo[4,5- c]cinnolin-2-one;

8-[6-[3-[(3R)-3-Fluoropyrrolidin-l-yl]propoxy]-3-pyridyl]-l-isopropyl-3-methyl- imidazo[4,5-c]cinnolin-2-one;

l-isopropyl-3-methyl-8-[2-methyl-6-[3-(l-piperidyl)propoxy]-3-pyridyl]imidazo[4,5- c]cinnolin-2-one;

1 -(tra/75-3-Methoxycyclobutyl)-3-methyl-8-[4-[3-(l - piperidyl)propoxy]phenyl]imidazo[4,5-c]cinnolin-2-one;

8-[4- [3 -(Dimethylamino)propoxy]phenyl] - 1 -(trans-3 -methoxycyclobutyl)-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

8-[6- [3 -(4-Fluoro- 1 -piperidyl)propoxy] -3 -pyridyl] - 1 -(trans-3 -methoxycyclobutyl)-3 - methyl-imidazo[4,5-c]cinnolin-2-one;

8-[6- [3 -(4-Fluoro- 1 -piperidyl)propoxy] -3 -pyridyl] - 1 -(cis-3 -methoxycyclobutyl)-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

1 -(cis-3 -methoxycyclobutyl)-3 -methyl-8- [4-[3 -( 1 -piperidyl)propoxy]phenyl]imidazo[4,5- c]cinnolin-2-one;

8-[6-[3-[(3R)-3-Fluoropyrrolidin-l-yl]propoxy]-3-pyridyl]-l-(cz^'5-3-methoxycyclobutyl)-3- methyl-imidazo[4,5-c]cinnolin-2-one;

8-[4-[3-(Dimethylamino)propoxy]phenyl]-3-methyl-l-[(3R)-tetrahydropyran-3- yl]imidazo[4,5-c]cinnolin-2-one;

3-Methyl-8-[4-[3-(l -piperidyl)propoxy]phenyl]- 1 -[(3R)-tetrahydropyran-3-yl]imidazo[4,5- c]cinnolin-2-one;

8-[6- [3 -(4-Fluoro- 1 -piperidyl)propoxy] -3 -pyridyl] -3 -methyl- 1 - [(3R)-tetrahydropyran-3 - yl]imidazo[4,5-c]cinnolin-2-one;

8-[4-[3-(Dimethylamino)propoxy]phenyl]-3-methyl- 1 -(1 -methylcyclopropyl)imidazo[4,5- c]cinnolin-2-one;

3-Methyl-l-(l-methylcyclopropyl)-8-[4-[3-(l-piperidyl)propoxy]phenyl]imidazo[4,5- c]cinnolin-2-one;

8-[6-[3-(4-Fluoro- 1 -piperidyl)propoxy]-3-pyridyl]-3-methyl-l -(1 - methylcyclopropyl)imidazo[4,5-c]cinnolin-2-one; 3-Methyl-l-(l-methylcyclopropyl)-8-[6-[3-(l-piperidyl)propoxy]-3-pyridyl]imidazo[4,5- c]cinnolin-2-one;

8-[4-[3-(dimethylamino)propoxy]phenyl]-l-[(lR,3R)-3-methoxycyclopentyl]-3-methyl- imidazo [4,5 -c] cinnolin-2-one;

l-[(lS,3S)-3-methoxycyclopentyl]-3-methyl-8-[4-[3-(l- piperidyl)propoxy]phenyl]imidazo[4,5-c]cinnolin-2-one;

8-[4- [3 -(Dimethylamino)propoxy]phenyl] - l-[(lS,3S)-3 -methoxycyclopentyl] -3 -methyl - imidazo[4,5-c]cinnolin-2-one;

l-[(lS,3S)-3-Methoxycyclopentyl]-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3- pyridyl]imidazo[4,5-c]cinnolin-2-one;

8-[4- [3 -(Dimethylamino)propoxy]phenyl] - 1 -(cis-3 -methoxycyclobutyl)-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

1 -(cis-3 -Methoxycyclobutyl)-3 -methyl-8-[6- [3 -( 1 -piperidyl)propoxy] -3 - pyridyl]imidazo[4,5-c]cinnolin-2-one;

8-[6-[3-[(3S)-3-Fluoropyrrolidin-l-yl]propoxy]-3-pyridyl]-l-(tra/75-3-methoxycyclobutyl)- 3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[6- [3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 - [(4S)-3 ,3 -dimethyltetrahydropyran-4-yl] -3 - methyl-imidazo[4,5-c]cinnolin-2-one;

8-[6- [3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 - [(4R)-3 ,3 -dimethyltetrahydropyran-4-yl] -3 - methyl-imidazo [4,5 -c] cinnolin-2-one

l-[3,3-dimethyltetrahydropyran-4-yl]-3-methyl-8-{4-[3-(l-piperidinyl)propoxy]phenyl}- l,3-dihydro-2H-imidazo[4,5-c]cinnolin-2-one;

8-[4- [3 -(dimethylamino)propoxy]phenyl] - 1 -[(4S)-3 ,3 -dimethyltetrahydropyran-4-yl] -3 - methyl-imidazo[4,5-c]cinnolin-2-one;

8-[4- [3 -(dimethylamino)propoxy]phenyl] - 1 -[(4R)-3 ,3 -dimethyltetrahydropyran-4-yl] -3 - methyl-imidazo [4,5 -c] cinnolin-2-one; 8-[4- [3 -(dimethylamino)propoxy]phenyl] -7-fluoro- 1 -isopropyl-3 -methyl-imidazo [4,5 - c]cinnolin-2-one;

8-[6- [3 -(Dimethylamino)propoxy] -3 -pyridyl] -7-fluoro- 1 -isopropyl-3 -methyl-imidazo [4, 5- c]cinnolin-2-one;

7-Fluoro-l-isopropyl-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3-pyridyl]imidazo[4,5- c]cinnolin-2-one;

7- fluoro- 1 -isopropyl-3 -methyl-8 -[4- [3 -( 1 -piperidyl)propoxy]phenyl]imidazo [4,5 - c]cinnolin-2-one;

1- isopropyl-3,7-dimethyl-8-[6-[3-(l-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]cinnolin

2- one;

8-[6- [3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 -isopropyl-3 ,7-dimethyl-imidazo [4,5 - c]cinnolin-2-one;

l-Isopropyl-3,7-dimethyl-8-[4-[3-(l-piperidyl)propoxy]phenyl]imidazo[4,5-c]cinnolin-2- one;

3- (difluoromethyl)-8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-l-isopropyl-imidazo[4,5 c]cinnolin-2-one;

8-[6- [(3R)-3 -(Dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl] - 1 -isopropyl-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

8-[6-[4-(Dimethylamino)- 1 -piperidyl] -3 -pyridyl]- 1 -isopropyl-3 -methyl-imidazo [4,5 - c]cinnolin-2-one;

8-[6-[(3R)-3-(dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl] -3 -methyl- 1 -[(3R)- tetrahydropyran-3 -yl] imidazo [4,5 -c] cinnolin-2-one;

8-[6- [4-(dimethylamino)- 1 -piperidyl] -3 -pyridyl] - 1 -[3 ,3 -dimethyltetrahydropyran-4-yl] -3 - methyl-imidazo[4,5-c]cinnolin-2-one;

8-[6-[(3R)-3-(dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl]- 1 -[3,3-dimethyltetrahydropyran-

4- yl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[6- [(3R)-3 -(Dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl] - 1 -(trans-3 -methoxycyclobutyl)- 3 -methyl-imidazo [4,5 -c] cinnolin-2-one; 8-[6- [(3R)-3 -(Dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl] - 1 -(cis-3 -methoxycyclobutyl)-3- methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[6-[3-(dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl] -3 -methyl- 1 -tetrahydropyran-4-yl- imidazo[4,5-c]cinnolin-2-one;

8-[6-[(3R)-3-(Dimethylamino)pyrrolidin-l-yl]-3-pyridyl]-l-[(lR,3R)-3- methoxycyclopentyl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[6-[(3R)-3-(Dimethylamino)pyrrolidin-l-yl]-3-pyridyl]-l-[(lS,3S)-3- methoxycyclopentyl] -3 -methyl-imidazo [4,5 -c] cinnolin-2-one;

8-[6-[4-(Dimethylamino)- 1 -piperidyl] -3 -pyridyl]- 1 -(czs-3-methoxycyclobutyl)-3 -methyl - imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(Dimethylamino)- 1 -piperidyl]phenyl]- 1 -isopropyl-3-methyl-imidazo[4,5- c]cinnolin-2-one;

8-[4-[4-(dimethylamino)- 1 -piperidyl]phenyl]- 1 -[3,3-dimethyltetrahydropyran-4-yl]-3- methyl-imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(Dimethylamino)- 1 -piperidyl]phenyl]- 1 -[(lR,3R)-3-methoxycyclopentyl]-3- methyl-imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(Dimethylamino)- 1 -piperidyl]phenyl]- 1 -[(1 S,3S)-3-methoxycyclopentyl]-3- methyl-imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(Dimethylamino)- 1 -piperidyl]phenyl] -3 -methyl- 1 -[(3R)-tetrahydropyran-3- yl]imidazo[4,5-c]cinnolin-2-one;

8-[6- [(3R)-3 -(Dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl] -7-fluoro- 1 -isopropyl-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(Dimethylamino)-l-piperidyl]phenyl]-7-fluoro-l-isopropyl-3-methyl-imidazo[4,5- c]cinnolin-2-one;

8-[6-[(3R)-3-(dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl]- 1 -isopropyl-3, 7-dimethyl- imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(dimethylamino)- 1 -piperidyl]phenyl]- 1 -isopropyl-3, 7-dimethyl -imidazo[4,5- c]cinnolin-2-one;

8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-l-isopropyl-3-methyl-imidazo[4,5- c]cinnolin-2-one.

11. A compound as claimed in claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, selected from:

1 -Isopropyl-3 -methyl-8 -[6- [3 -( 1 -piperidyl)propoxy] -3 -pyridyl]imidazo [4,5 -c] cinnolin-2- one;

8-[6-[3-(4-Fluoro-l-piperidyl)propoxy]-3-pyridyl]-l-isopropyl-3-methyl-imidazo[4,5- c]cinnolin-2-one;

8-[4-[3-(dimethylamino)propoxy]phenyl]-l-[(lR,3R)-3-methoxycyclopentyl]-3-methyl- imidazo[4,5-c]cinnolin-2-one;

8-[6- [3 -(dimethylamino)propoxy] -3 -pyridyl] - 1 - [(4R)-3 ,3 -dimethyltetrahydropyran-4-yl] -3 - methyl-imidazo[4,5-c]cinnolin-2-one;

8- {4-[3-(dimethylamino)propoxy]phenyl} - 1 -[(4R)-3,3-dimethyltetrahydro-2H-pyran-4-yl]- 3 -methyl- 1 ,3 -dihydro-2H-imidazo [4,5 -c] cinnolin-2-one;

7- Fluoro-l-isopropyl-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3-pyridyl]imidazo[4,5- c]cinnolin-2-one;

8- [6- [(3R)-3 -(Dimethylamino)pyrrolidin- 1 -yl] -3 -pyridyl] - 1 -isopropyl-3 -methyl- imidazo[4,5-c]cinnolin-2-one;

8-[4-[4-(Dimethylamino)- 1 -piperidyl]phenyl]- 1 -isopropyl-3-methyl-imidazo[4,5- c]cinnolin-2-one.

12. 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 11 , and at least one pharmaceutically acceptable excipient.

13. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11 , for use in therapy.

14. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11 , for use in the treatment of cancer.

15. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer according to claim 14, wherein the compound of Formula (I) is administered simultaneously, separately or sequentially with radiotherapy.

16. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer according to claim 14, where the compound of Formula (I) is administered simultaneously, separately or sequentially with at least one additional anti- tumour substance selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin.

17. Use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11 , in the manufacture of a medicament for the treatment of cancer.

18. 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 11.