WO2019138227A1

WO2019138227A1 - Pharmaceutical compounds

Info

Publication number: WO2019138227A1
Application number: PCT/GB2019/050058
Authority: WO
Inventors: Adam Piotr TREDER; Frank Burkamp
Original assignee: Almac Discovery Limited
Priority date: 2018-01-10
Filing date: 2019-01-10
Publication date: 2019-07-18
Also published as: GB201800378D0

Abstract

Compounds that are useful as inhibitors of the activity of Wee-1 kinase are provided. Also provided are pharmaceutical compositions comprising these compounds and to methods of using these compounds in the treatment of cancer and methods of treating cancer.

Description

PHARMACEUTICAL COMPOUNDS

The present invention relates to compounds that are useful as inhibitors of the activity of Wee-1 kinase. The present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds in the treatment of cancer and methods of treating cancer.

BACKGROUND TO THE INVENTION

Cells are continually challenged on a daily basis, resulting in multiple lesions forming in DNA. The lesions, if not repaired, can lead to mutations or cell death, thus complex signalling networks exist which ensure that lesions are detected and repaired to maintain the integrity of DNA.

Detection of DNA damage initiates a series of events which are key in maintaining the genome. Cell cycle checkpoints are designed to stop the cell cycle and allow repair of the lesion before allowing the cell to continue into mitosis.

Two key checkpoints have been identified, one at the end of the G1 phase and the second at G2, working in tandem to ensure all lesions are identified and repaired. In 50% of human cancers the G1 checkpoint is non-functional due to mutations in the tumour suppressor gene p53. However, the G2 check-point is seldom mutated and often found to be activated in cancer cells. Cancer cells exploit this to confer resistance to treatment modalities, including DNA damaging agents and radiation.

Three kinases have been identified as key regulators of the G2 checkpoint, namely Chk1 , Chk2 and Wee-1. Inhibitors for these kinases are currently being evaluated in clinical trials.

Wee-1 is a nuclear tyrosine kinase which negatively regulates entry into mitosis at the G2/M check-point by catalysing a phosphorylation of the cdc2 / cyclin B kinase complex. The phosphorylation occurs on the tyrosine-15 residue and leads to the inactivation of the cdc2 / cyclin B complex, ultimately preventing mitosis. Wee-1 function is intimately linked to that of Chk1 and Chk2 due to their phosphorylation and inactivation of cdc25 on serine- 216, as well as the reported activation of Wee-1 by Chk 1 & 2 (Ashwell, 2012, DNA Repair in Cancer Therapy, DOI: 10.1016/B978-0-12-384999-1.10010-1). Wee-1 is downstream of the Chk family and is a crucial component of the checkpoint signalling cascade as it prevents cells from entering mitosis if lesions are detected (Do et at., Cell Cycle 2013 12 (19) 3159-3164.

Commonly administered anti-cancer compounds induce DNA damage, including anti metabolites, platinum agents, topoisomerase inhibitors and alkylating agents. However, their efficacy is limited due to excessive toxicity, resistance and lack of tumour selectivity. Compounds which work in combination with these agents to prevent DNA repair selectively in tumour cells would be extremely beneficial. As the tumour suppressor gene p53 is commonly mutated in tumour cell lines, the administration of a Wee-1 kinase inhibitor, abrogating the G2 check point, may lead to increased sensitivity to DNA damaging agents. The potential for this has been reported, as silencing of Wee-1 activity was sufficient to sensitize HeLa cells to doxorubicin due to abrogation of G2 arrest. By contrast, in normal breast epithelium due to the fully competent p53 protein, the removal of Wee-1 function had little additional effect compared to doxorubicin alone (Wang et ai, 2004, Cancer Biology and Therapy, 3(3), 305-313).

It has been reported that cell lines harbouring mutations in the tumour suppressor gene p53 had increased sensitivity to DNA damaging agents when co-administered with Wee-1 small molecule inhibitors. Synergistic in vitro and in vivo efficacy has been reported when small molecule inhibitors were combined with gemcitabine, 5-fluorouracil, carboplatin, cisplatin (Hirai et ai. 2010, Cancer Biology & Therapy 9:7, 514-522), cytarabine (Tibes et ai., 2012, Blood, 119 (12), 2863-2872), Chk-1 inhibitors (Carrasa et ai., 2012 Cell Cycle 1 :11 (13):2507-2517, Russell et ai, 2013 Cancer Res. 15; 73 (2) 776-784) and Src inhibitors (Cozzi et ai., 2012, Cell Cycle 11 (5), 1029-1039). Single agent apoptotic efficacy, independent of p53 status, has been reported in sarcoma cell lines and in patient derived sarcoma samples (Kreahling et ai., 2012, Mol. Cancer Ther., 11 (1), 174-182) and efficacy demonstrated in a panel of cancer cell lines in vivo (Guertin et ai., 2013 Mol. Cancer Ther., 12 (8) 1442-1452).

Irradiation is known to increase phosphorylation of the Tyr15 and Thr14 residues of cdc2, leading to a radio-resistant phenotype. Inhibition of Wee-1 activity by small molecule inhibitors (Wang et ai., 2004, Cancer Biology and Therapy 3(3), 305-313), (Caretti et ai., 2013 Mol. Cancer Ther. 12 (2) 141-150) lead to a reduction in phosphorylation and radiosensitization, with the effect being more pronounced in p53 mutant cell lines. It has been reported in melanoma that over-expression of Wee-1 is correlated with poor clinical outcome (Magnussen et al., 2012 PLoS One 7; (6) e38254), indicating it may have a significant role as a biomarker and as a targeted therapy.

Compounds having a kinase inhibitory effect, for example a Wee-1 kinase inhibitory effect, are described in W02002/090360, WO2007/126122, US2007/0254892, W02008/115742, W02008/153207, WO2010/098367, US2012/0220572, WO2012/161812,

WO2013/0018045, WO2013/126656, WO2013/059485, WO2013/013031 ,

WO2014/167347, WO2015/019037, WO2015/092431.

It is one object of the present invention to overcome at least some of the disadvantages of the prior art or to provide a commercially useful alternative thereto.

It is a further object of the present invention to provide a compound having an enhanced or similar Wee-1 kinase inhibitory effect compared to known compounds or compositions.

It is a further object of the present invention to provide a compound which exhibits enhanced Wee-1 potency in cells compared to known compounds or compositions.

It is a further object of the present invention to provide a compound which exhibits an enhanced or similar kinetic solubility compared to known compounds or compositions.

It is a further object of the present invention to provide a compound which exhibits an enhanced or similar thermodynamic solubility compared to known compounds or compositions.

It is a further object of the present invention to provide a compound which exhibits an enhanced or similar stability in human microsomes compared to known compounds or compositions.

Furthermore, it is an object of the present invention to provide compounds which exhibit more than one, or two, or three, or four, or most preferably all, of the above properties, i.e. to provide compounds having an enhanced or similar Wee-1 kinase inhibitory effect, and/or enhanced or comparable Wee-1 potency in cells, and/or an enhanced or similar kinetic solubility, and/or an enhanced or similar thermodynamic solubility, and/or an enhanced or similar stability in human microsomes, compared to compounds known compounds or compositions.

SUMMARY OF THE INVENTION

In a first aspect the present invention provides a compound of Formula (a):

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R² is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group or a cycloalkoxy group;

R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2;

n is 0, 1 or 2; and

Y is

where R⁵ is a hydrogen atom, an alkyl group or a cycloalkyl group and where R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom, an alkyl group or a cycloalkyl group, or where R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4- membered ring; or

Y is

where a is 0 and b is 1 , or a is 1 and b is 0, and where R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group.

In a further aspect the present invention provides a compound of Formula (b)

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R³ is a hydrogen atom, a cyano group, an alkyl group or a cycloalkyl group; R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2; and

n is 0, 1 or 2;

with the proviso that R³ and R⁴ cannot both be a hydrogen atom.

In a further aspect the present invention provides a compound of Formula (c)

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R⁹ is a hydrogen atom, a cyano group, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group; and

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group.

In a further aspect the present invention provides a compound of Formula (d)

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R¹⁰ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2; and

n is 0, 1 or 2. In a further aspect the present invention provides a compound of Formula (e)

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R¹¹ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group;

X is CH₂ or O; and

p is 1 or 2.

Each aspect or embodiment as defined herein may be combined with any other aspect(s) or embodiment(s) unless clearly indicated to the contrary. In particular any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

In a further aspect the present invention provides the compound of Formula (a), or Formula (b), or Formula (c), or Formula (d), or Formula (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, and at least one pharmaceutically acceptable excipient.

In a further aspect the present invention provides a pharmaceutical composition comprising the compound of Formula (a), or Formula (b), or Formula (c), or Formula (d), or Formula (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, and at least one pharmaceutically acceptable excipient. In a further aspect the present invention provides the compound of Formula (a), or Formula (b), or Formula (c), or Formula (d), or Formula (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for use in therapy.

In a further aspect the present invention provides the compound of Formula (a), or Formula (b), or Formula (c), or Formula (d), or Formula (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for use as a medicament.

In a further aspect the present invention provides the compound of Formula (a), or Formula (b), or Formula (c), or Formula (d), or Formula (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for use in treating or preventing cancer.

In a further aspect the present invention provides the use of the compound of Formula (a), or Formula (b), or Formula (c), or Formula (d), or Formula (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for the manufacture of a medicament for treating or preventing cancer.

In a further aspect the present invention provides a method of treating or preventing cancer in a human or animal patient comprising administering to a patient in need thereof an effective amount of a compound of Formula (a), or Formula (b), or Formula (c), or Formula (d), or Formula (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein.

Other preferred embodiments of the compounds according to the invention appear throughout the specification and in particular in the examples. Particularly preferred are those named compounds having greater activity as tested. Compounds having higher activity are more preferred over those having lower activity.

The present inventors have surprisingly found that compounds of the present invention show an improved or similar Wee-1 kinase-inhibitory effect compared to known

compounds. The present inventors have also surprisingly found that compounds of the present invention show an improved or comparable Wee-1 potency in cells compared to known compounds.

The present inventors have also surprisingly found that compounds of the present invention show an enhanced or similar kinetic solubility compared to known compounds.

The present inventors have also surprisingly found that compounds of the present invention show an enhanced or similar thermodynamic solubility compared to known compounds.

The present inventors have also surprisingly found that compounds of the present invention show an enhanced or similar stability in human microsomes compared to known compounds.

In addition, the present inventors have surprisingly found that compounds of the present invention exhibit an enhanced or similar Wee-1 kinase inhibitory effect as well as displaying enhanced or comparable Wee-1 potency in cells, and/or an enhanced or similar kinetic solubility, and/or an enhanced or similar thermodynamic solubility, and/or an enhanced or similar stability in human microsomes, compared to known compounds.

Without wishing to be bound by theory, it is thought that the compounds of the present invention tend to show the advantageous effects discussed above due to their structure.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition.

As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:

The term“alkyl group” (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbyl substituent typically containing 1 to 15 carbon atoms, such as 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. A“C_n alky group refers to an aliphatic group containing n carbon atoms. For example, a C -C alkyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Attachment to the alkyl group occurs through a carbon atom. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl (branched or unbranched), hexyl (branched or unbranched), heptyl (branched or unbranched), octyl (branched or unbranched), nonyl (branched or unbranched), and decyl (branched or unbranched). The alkyl group can optionally be substituted with one or more substituents.

The term“alkynyl group” (alone or in combination with another term (s)) means a straight-or branched-chain hydrocarbon substituent containing one or more triple bonds and typically 2 to 15 carbon atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 carbon atoms. Examples of such substituents include ethynyl, 1-propynyl, 3-propynyl, 1-butynyl, 3-butynyl and 4- butynyl. The alkynyl group can optionally be substituted with one or more substituents.

The term“cycloalkyl group” (alone or in combination with another term(s)) means a saturated cyclic hydrocarbon substituent containing 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, which typically contains 3 to 8 carbon ring atoms and more typically 3 to 6 ring atoms. It is understood that attachment to a cycloalkyl group is via a ring atom of the cycloalkyl group. Examples of single-ring cycloalkyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclohexyl

(cyclohexanyl). The cycloalkyl group can optionally be substituted with one or more substituents.

A cycloalkyl may alternatively be partly unsaturated or be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic cycloalkyls. In a spirocyclic cycloalkyl, one atom is common to two different rings. An example of a spirocyclic cycloalkyl is spiropentanyl. In a bridged cycloalkyl, the rings share at least two common non-adjacent atoms. Examples of bridged cycloalkyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. In a fused-ring cycloalkyl system, two or more rings may be fused together, such that two rings share one common bond. Examples of two- or three-fused ring cycloalkyls include

tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl) and decalinyl.

The term“alkoxy group" refers to an -O-alkyl group. The alkoxy group can refer to linear, branched, saturated or unsaturated hydrocarbon chains, including, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and pentoxy. The alkoxy group can optionally be substituted with one or more substituents.

The term“cycloalkoxy group” refers to an -O-cycloalkyl group. The cycloalkoxy group refers to cyclic, saturated or unsaturated, hydrocarbon chains, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl and cyclohexyl. The cycloalkoxy group can optionally be substituted with one or more substituents.

The term“hydroxy" refers to an -OH group.

The term“halo group” refers to an atom selected from chlorine, fluorine, bromine and iodine. Examples of halo groups include a chlorine atom (a chloro group) and a fluorine atom (a fluoro group).

An alkyl, alkynyl, alkoxy, cycloalkyl or cycloalkoxy group can be optionally substituted with one or more substituents, which can be the same or different. A substituent can be attached through a carbon atom in the alkyl, alkynyl, alkoxy, cycloalkyl or cycloalkoxy group. The term“substituent (or“radical”) includes but is not limited to alkyl, substituted alkyl, aralkyl, substituted aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, cyano, amino, amido, alkylamino, arylamino, carbocyclyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, nitro, thio, alkanoyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl,

alkoxycarbonyl, oxo, alkylsulfonyl and arylsulfonyl.

If a group (for example an alkyl group) is“optionally substituted’, it is understood that the group has one or more substituents attached (substituted) or does not have any substituents attached (unsubstituted).

For completeness, it is also noted that certain chemical formulae used herein define delocalized systems. This definition is known in the art as a definition of aromaticity and may indicate the presence of, for example, a mono-, di- or tri-cyclic system that contains (4n+2) electrons where n is an integer. In other words, these systems may display Huckel aromaticity.

In whatever aspect, the compounds of the present invention may possess some aspect of stereochemistry. For example, the compounds may possess chiral centres and / or planes and / or axes of symmetry. As such, the compounds may be provided as single stereoisomers, single diastereomers, mixtures of stereoisomers or as racemic mixtures. Stereoisomers are known in the art to be molecules that have the same molecular formula and sequence of bonded atoms, but which differ in their spatial orientations of their atoms and / or groups.

In addition, the compounds of the present invention may possess tautomerism. Each tautomeric form is intended to fall within the scope of the invention.

In addition, the compounds of the present invention may be provided as a pro-drug. Pro drugs are transformed, generally in vivo, from one form to the active forms of the drugs described herein. For example, a prodrug may be formed by protecting any -N-H groups with a hydrolysable group that gives -NH on hydrolysis. Any -NH group within the compound may be protected as a physiological hydrolyzable amide.

In addition, it will be understood that the elements described herein may be the common isotope or an isotope other than the common isotope. For example, a hydrogen atom may be ¹H, ²H (deuterium) or ³H (tritium).

In addition, the compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts or as co-crystals. For example, the compounds may be provided having protonated amine groups.

The term“pharmaceutically acceptable salt’ refers to ionic compounds formed by the addition of an acid to a base. The term refers to such salts that are considered in the art as being suitable for use in contact with a patient, for example in vivo and pharmaceutically acceptable salts are generally chosen for their non-toxic, non-irritant characteristics.

The term“co-crystai refers to a multi- component molecular crystal, which may comprise non-ionic interactions.

Pharmaceutically acceptable salts and co-crystals may be prepared by ion exchange chromatography or by reacting the free base or acidic form of a compound with

stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in one or more suitable solvents, or by mixing the compound with another pharmaceutically acceptable compound capable of forming a co-crystal. Salts known in the art to be generally suitable for use in contact with a patient include salts derived from inorganic and / or organic acids, including the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate and tartrate. These may include cations based on the alkali and alkaline earth metals, such as sodium, potassium, calcium and magnesium, as well as ammonium, tetramethylammonium,

tetraethylammonium. Further reference is made to the number of literature sources that survey suitable pharmaceutically acceptable salts, for example the Handbook of pharmaceutical salts published by IUPAC.

In addition, the compounds of the present invention may sometimes exist as zwitterions, which are considered as part of the invention.

The present inventors have discovered that the compounds of the present invention are useful in the treatment of medical conditions associated with disordered cell growth, including, but not restricted to, cancer, in particular (but not restricted to) cancers associated with inactivation in the tumour suppressor gene p53. The compound may have utility and activity as a single agent exploiting synthetic or contextual lethality relationships as well as in diseases including cancers with enhanced susceptibility to increased replicative stress and impaired cell cycle progression. Wee1 inhibitors according to the invention may also be used in combination modalties including combinations with genotoxic agents, radiotherapy, targeted agents and immune-modulators including but not restricted to immune checkpoint inhibitors.

For example, cancers include cardiac cancers, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, hematologic cancers, skin cancers and adrenal gland cancers, and cancers such as adrenal tumors, bile duct, bladder, blood, bone and connective tissue, brain and central nervous system, breast, cervical, colon and rectal (colorectal), endometrial, esophageal, gallbladder, head and neck, Hodgkin's Lymphoma,

hypopharangeal, kidney, laryngeal, leukemias, liver, lung, lymphoma, mediastinal tumors, melanoma (malignant melanoma), mesothelioma, multiple myeloma, nasal cavity, nasopharyngeal, neuroendocrine tumors, non-Hodgkin’s lymphoma, oral, oesophagus, oropharyngeal, ovarian, pancreas, paranasal sinus, parathyroid, penis, pituitary tumors, prostate, salivary gland, sarcoma, skin, spine, stomach, testicular, thyroid, urethra, uterine, vaginal and vulvar. Preferably the cancer is selected from colon and rectal (colorectal) cancer, head and neck cancer, lung cancer, oesophagus cancer, ovarian cancer and pancreas cancer. More preferably, the cancer is colon and rectal (colorectal) cancer. Alternatively, preferably, the cancer is lung cancer, more preferably non-small cell lung cancer.

The compounds of the present invention are also useful in preparing a medicament that is useful in treating the diseases described above, in particular cancer.

The present invention is further directed to a method of inhibiting Wee-1 activity which comprises administering to a mammal, preferably a human, in need thereof a

pharmaceutically effective amount of the compound of the present invention.

The compounds of this invention may be administered to mammals, including humans, either alone or, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

The present invention also includes within its scope the use of the compounds of the present invention in combination with a second or further drug in the treatment of cancer. The second or further drug may be a drug that is already known in the art in the treatment of cancer.

The present invention also includes the use of the compounds of the invention in a regime including the step of radiotherapy. The radiotherapy may be an ordinary method of treatment by x-ray, g-ray, neutron, a-particle, proton or electron beam irradiation. The co administration of compounds contained in this invention may lead to the potentiation of the radiation therapy, thus classifying them as radio-sensitizers.

In particular, cancers often become resistant to therapy. The development of resistance may be delayed or overcome by the administration of a combination of drugs that includes the compounds of the present invention for example in cancers which are known to be resistant to DNA damaging agents, radiotherapy or any other form of treatment agents and modalities. For example, drugs that may be used in combination with the compounds of the present invention may target the same or a similar biological pathway to that targeted by the compounds of the present invention or may act on a different or unrelated pathway.

Depending on the disease to be treated, a variety of combination partners may be co administered with the compounds of the present invention, for example genotoxic agents, targeted agents and immune-modulators. The second active ingredient may include, but is not restricted to: alkylating agents, including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea and bendamustine; platinum derivatives, including cisplatin, oxaliplatin, carboplatin and satraplatin; antimitotic agents, including vinca alkaloids (vincristine, vinorelbine and vinblastine), taxanes (paclitaxel, docetaxel), epothilones and inhibitors of mitotic kinases including aurora and polo kinases;

topoisomerase inhibitors, including anthracyclines, epipodophyllotoxins, camptothecin and analogues of camptothecin; antimetabolites, including 5-fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, fludarabine, methotrexate and premetrexed; targeted therapies, for example protein kinase inhibitors, including imatinib, gefitinib, sorafenib, sunitinib, erlotinib, dasatinib, and lapatinib; proteasome inhibitors, including bortezomib; histone deacetylase inhibitors, including valproate and SAHA; cell cycle and checkpoint inhibitors, including CDK4 / 6, CHK1 and CHK2; DNA-repair- modulators, including but not restricted to inhibitors of PARP, DNA-PK, ATM, ATR;

antiangiogenic drugs, including bevacizumab; monoclonal antibodies, including

trastuzumab, rituximab, alemtuzumab, tositumomab, cetuximab, panitumumab; conjugates of myoclonal antibodies, including Gemtuzumab ozogamicin, Ibritumomab tiuxetan;

hormonal therapies, including antiestrogens (tamoxifen, raloxifen, anastrazole, letrozole, examestane) antiandrogens (flutamide, bicalutamide) and Luteinising Hormone analogues or antagonists.

With regard to combination therapy the compounds of the present invention may be administered separately, sequentially, simultaneously, concurrently or may be

chronologically staggered with one or more standard therapeutics such as any of those mentioned above.

Formula (a)

The present invention provides a compound of Formula (a):

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2;

n is 0, 1 or 2; and

Y is

Y is

where a is 0 and b is 1 , or a is 1 and b is 0, and where R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group. Preferably R¹ is a cyano group or an alkynyl group substituted by one or more alkoxy groups. More preferably R¹ is a cyano group or an alkynyl group substituted by an alkoxy group. More preferably R¹ is a cyano group or an alkynyl group substituted by a methoxy group. Most preferably, R¹ is a cyano group or a -CºC-CH₂-OMe group.

In one embodiment, preferably R¹ is a cyano group.

In an alternative embodiment, preferably, R¹ is an alkynyl group. More preferably still, R¹ is an alkynyl group substituted by one or more alkoxy groups. More preferably still, R¹ is an alkynyl group substituted by an alkoxy group. More preferably still, R¹ is an alkynyl group substituted by a methoxy group. More preferably still, R¹ is a -CºC-CH₂-OMe group.

Preferably R² is a hydrogen atom, an alkyl group or an alkoxy group. More preferably, R² is a hydrogen atom, a C_rC₂ alkyl group or a C_rC₂ alkoxy group. More preferably still, R² is a hydrogen atom, a methyl group or a methoxy group. Most preferably, R² is a hydrogen atom or a methoxy group.

Alternatively, preferably, R² is an alkoxy group, preferably a methoxy group.

Alternatively, preferably, R² is an alkyl group, preferably a methyl group.

Alternatively, preferably, R² is a methyl group or a methoxy group.

Preferably R⁶ is a chlorine atom.

Preferably, m is 0 or 1. More preferably m is 1. Alternatively, preferably, m is 0.

Preferably, n is 0 or 1. More preferably n is i . Alternatively, preferably, n is 0.

Preferably m is 1 and n is 1.

Alternatively, preferably, m is 0 and n is 0.

Alternatively, preferably, m is 1 and n is 0.

Alternatively, preferably, m is 0 and n is 1. In one preferable embodiment, Y is

where R⁵ is a hydrogen atom, an alkyl group or a cycloalkyl group and where R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom, an alkyl group or a cycloalkyl group, or where R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring.

Preferably R⁵ is a hydrogen atom or an alkyl group. More preferably R⁵ is a hydrogen atom or a CrC₆ alkyl group. More preferably still, R⁵ is a hydrogen atom or a C_rC₃ alkyl group. More preferably still, R⁵ is a hydrogen atom or a C_rC₂ alkyl group. More preferably still, R⁵ is a hydrogen atom or a methyl group. Most preferably, R⁵ is a hydrogen atom.

It is understood that when R⁵ is a‘hydrogen atom’, R⁵ may be the common isotope of hydrogen or an isotope other than the common isotope. For example, R⁵ may be ¹ H, ²H (deuterium) or ³H (tritium), preferably ¹ H or ²H (deuterium).

Preferably, R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom, an alkyl group or a cycloalkyl group. More preferably, R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a CrC₆ alkyl group. More preferably still, R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a C_rC₃ alkyl group. More preferably still, R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a C_rC₂ alkyl group. Most preferably, R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group.

Alternatively, preferably, R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring. Preferably, when R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring, R⁵ is a hydrogen atom.

Preferably the 4 membered ring contains three carbon atoms and one nitrogen atom. In a further preferable embodiment, Y is

Preferably a is 1 and b is 0. Alternatively, preferably a is 0 and b is 1.

Preferably R⁴ is a hydrogen atom or an alkyl group. More preferably R⁴ is a hydrogen atom or a CrC₆ alkyl group. More preferably still, R⁴ is a hydrogen atom or a C_rC₃ alkyl group. More preferably still, R⁴ is a hydrogen atom or a C_rC₂ alkyl group. More preferably still, R⁴ is a hydrogen atom or a methyl group.

Preferably R² is an alkoxy group, m is 1 and n is 1. More preferably, R² is a methoxy group, m is 1 and n is 1.

Alternatively, preferably, R² is an alkoxy group, m is 0 and n is 0. More preferably, R² is a methoxy group, m is 0 and n is 0.

Preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is a cyano group, R² is an alkoxy group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a cyano group, R² is a methoxy group, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is an alkoxy group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a - CºC-CH₂-OMe group, R² is a methoxy group, R⁶ is a chlorine atom, m is 1 and n is 1. Alternatively, preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is a cyano group, R² is an alkoxy group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a cyano group, R² is a methoxy group, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is an alkoxy group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a - CºC-CH₂-OMe group, R² is a methoxy group, R⁶ is a chlorine atom, m is 0 and n is 0.

Formula (a1)

In one preferable embodiment, there is provided a compound of Formula (a1):

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2; n is 0, 1 or 2;

R⁵ is a hydrogen atom, an alkyl group or a cycloalkyl group; and

R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom, an alkyl group or a cycloalkyl group, or R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring.

Preferably R¹ is a cyano group or an alkynyl group substituted by one or more alkoxy groups. More preferably R¹ is a cyano group or an alkynyl group substituted by an alkoxy group. More preferably R¹ is a cyano group or an alkynyl group substituted by a methoxy group. Most preferably, R¹ is a cyano group or a -CºC-CH₂-OMe group.

In one embodiment, preferably R¹ is a cyano group.

Alternatively, preferably, R² is an alkoxy group, preferably a methoxy group.

Alternatively, preferably, R² is an alkyl group, preferably a methyl group.

Alternatively, preferably, R² is a methyl group or a methoxy group.

Preferably R⁶ is a chlorine atom.

Preferably, n is 0 or 1. More preferably n is 1. Alternatively, preferably, n is 0.

Preferably m is 1 and n is 1. Alternatively, preferably, m is 0 and n is 0.

Alternatively, preferably, m is 1 and n is 0.

Alternatively, preferably, m is 0 and n is 1.

In embodiments wherein m is 0 and n is 2, preferably at least one of R⁷ and R⁸ is alkyl. Preferably, in such embodiments, at least one of R⁷ and R⁸ is methyl. Preferably in such embodiments both R⁷ and R⁸ are methyl.

It is understood that when R⁵ is a‘hydrogen atom’, R⁵ may be the common isotope of hydrogen or an isotope other than the common isotope. For example, R⁵ may be ¹H, ²H (deuterium) or ³H (tritium), preferably ¹H or ²H (deuterium).

In embodiments wherein R² is an alkoxy group, optionally a methoxy group, preferably R⁵, R⁷ and R⁸ are not all H.

In embodiments wherein R² is an alkoxy group, optionally a methoxy group, preferably one or more of R⁵, R⁷ and R⁸ is an alkyl group, preferably a CrC₆ alkyl group. Preferably, in embodiments wherein R² is an alkoxy group, optionally a methoxy group, one or more of R⁵, R⁷ and R⁸ is a methyl group. In embodiments wherein R² is an alkyl group, optionally a methyl group, preferably R⁵, R⁷ and R⁸ are not all H.

In embodiments wherein R² is an alkyl group, optionally a methyl group, preferably one or more of R⁵, R⁷ and R⁸ is an alkyl group, preferably a CrC₆ alkyl group. Preferably, in embodiments wherein R² is an alkyl group, optionally a methyl group, one or more of R⁵, R⁷ and R⁸ is a methyl group. Preferably, in embodiments wherein R² is an alkyl group, optionally a methyl group, R⁷ and R⁸ are each a methyl group.

In embodiments wherein R² is an alkyl group, for example a methyl group, preferably R¹ is an alkynyl group substituted by one or more alkoxy groups. More preferably, in such embodiments R¹ is an alkynyl group substituted by an alkoxy group. More preferably, in such embodiments R¹ is an alkynyl group substituted by a methoxy group. Most preferably, in such embodiments R¹ is a -CºC-CH₂-OMe group.

Alternatively, preferably, R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring. Preferably the 4 membered ring contains three carbon atoms and one nitrogen atom. Preferably, when R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring, R⁵ is a hydrogen atom. More preferably, when R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring, R⁵ is a hydrogen atom, m is 0 and n is 0.

Preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 , n is 1 and R⁷ and R⁸ are

independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 1 , n is 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. Alternatively, preferably, R¹ is a cyano group, R² is an alkoxy group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 , n is 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a cyano group, R² is a methoxy group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 1 , n is 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group.

Alternatively, preferably R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 , n is 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a -CºC-CH₂- OMe group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 1 , n is 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is an alkoxy group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 , n is 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 1 , n is 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group.

Alternatively, preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0, n is 0 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 0, n is 0 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group.

Alternatively, preferably, R¹ is a cyano group, R² is an alkoxy group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0, n is 0 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a cyano group, R² is a methoxy group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 0, n is 0 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. Alternatively, preferably R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0, n is 0 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a -CºC-CH₂- OMe group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 0, n is 0 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is an alkoxy group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0, n is 0 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 0, n is 0 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group.

Alternatively, preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 or 1 , n is 0 or 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 0 or 1 , n is 0 or 1 and R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring.

Alternatively, preferably, R¹ is a cyano group, R² is an alkoxy group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 or 1 , n is 0 or 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a cyano group, R² is a methoxy group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 0 or 1 , n is 0 or 1 and R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring.

Alternatively, preferably R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 or 1 , n is 0 or 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a -CºC- CH₂-OMe group, R² is a hydrogen atom or a methyl group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 0 or 1 , n is 0 or 1 and R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring. Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is an alkoxy group, R⁵ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 or 1 , n is 0 or 1 and R⁷ and R⁸ are independently selected from the group consisting of a hydrogen atom and a methyl group. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R⁵ is a hydrogen atom, R⁶ is a chlorine atom, m is 0 or 1 , n is 0 or 1 and R⁷ and R⁸, together with the nitrogen atom to which they are attached, form a 4-membered ring.

Preferably the compound according to Formula (a) or (a1) is selected from:

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(4-(methylamino)piperidin-1- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(4-(methylamino)piperidin-1- yl)phenyl)amino)-8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

(S)-2-((4-(3-Aminopyrrolidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-5- oxo-5, 6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

(S)-2-((4-(3-Aminopyrrolidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-8-

(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

(S)-6-(2,6-Dichlorophenyl)-2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-3- methylphenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

(S)-6-(2,6-Dichlorophenyl)-2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-3- methylphenyl)amino)-8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

2-((4-(4-Aminopiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)-8-(3- methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methoxyphenyl)amino)-8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

(S)-2-((4-(3-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-5- oxo-5, 6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

(S)-6-(2,6-Dichlorophenyl)-2-((4-(3-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

2-((4-(4-(Azetidin-1-yl)piperidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-

5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c(]pyrimidin-5(6/-/)-one;

2-((4-([1 ,3'-Biazetidin]-1 '-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-

5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile; 2-((4-([1 ,3'-Biazetidin]-1'-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)-8-(3- methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-

5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

2-((4-(4-Aminopiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-

5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2-chloro-6-methylphenyl)-5- oxo-5, 6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-8-(3- methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methoxyphenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(4-(methylamino)piperidin-1-yl)phenyl)amino)-

5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

2-((4-(4-Amino-4-methylpiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6- dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

2-((4-(4-Amino-4-methylpiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6- dichlorophenyl)-8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c(]pyrimidin-5(6/-/)-one;

6-(2,6-Dichlorophenyl)-2-((4-(3-(dimethylamino)azetidin-1-yl)-3- methoxyphenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

2-((4-(4-Amino-4-methylpiperidin-1-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-

5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)-4-methylpiperidin-1-yl)-3- methoxyphenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)-4-methylpiperidin-1- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(4-methyl-4-(methylamino)piperidin-1- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((4-(3-methylazetidin-3-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2-chloro-6-methylphenyl)-8-

(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one; 6-(2-Chloro-6-methylphenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

6-(2-Chloro-6-methylphenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile; and

6-(2-Chloro-6-methylphenyl)-2-((3-methyl-4-(4-(methylamino)piperidin-1- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile.

Formula (a2)

In one preferable embodiment, there is provided a compound of Formula (a2):

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2;

n is 0, 1 or 2; and

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group.

In one embodiment, preferably R¹ is a cyano group. ln an alternative embodiment, preferably, R¹ is an alkynyl group. More preferably still, R¹ is an alkynyl group substituted by one or more alkoxy groups. More preferably still, R¹ is an alkynyl group substituted by an alkoxy group. More preferably still, R¹ is an alkynyl group substituted by a methoxy group. More preferably still, R¹ is a -CºC-CH₂-OMe group.

Alternatively, preferably, R² is an alkoxy group, preferably a methoxy group.

Alternatively, preferably, R² is an alkyl group, preferably a methyl group.

Alternatively, preferably, R² is a methyl group or a methoxy group.

Preferably R⁶ is a chlorine atom.

Preferably m is 1 and n is 1.

Alternatively, preferably, m is 0 and n is 0.

Alternatively, preferably, R² is an alkoxy group, m is 0 and n is 0. More preferably, R² is a methoxy group, m is 0 and n is 0. Preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is a cyano group, R² is an alkoxy group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a cyano group, R² is a methoxy group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a hydrogen atom or a methyl group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is an alkoxy group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is a cyano group, R² is an alkoxy group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a cyano group, R² is a methoxy group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a hydrogen atom or a methyl group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is an alkoxy group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0.

Preferably, the compound according to Formula (a) or (a2) is selected from:

6-(2,6-dichlorophenyl)-2-((3-methoxy-4-(1 ,7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(1 ,6-diazaspiro[3.3]heptan-6- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(1 -methyl-1 , 7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

2-((4-(1 ,7-Diazaspiro[3.5]nonan-7-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-

5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(1 ,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-

5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((4-(1 -methyl-1 , 7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)- 5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile; and

6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(1 -methyl-1 , 7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile.

Formula (a3)

In one preferable embodiment, there is provided a compound of Formula (a3)

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R² is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group or a cycloalkoxy group; R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2;

n is 0, 1 or 2; and

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group.

In one embodiment, preferably R¹ is a cyano group.

Alternatively, preferably, R² is an alkoxy group, preferably a methoxy group.

Alternatively, preferably, R² is an alkyl group, preferably a methyl group.

Alternatively, preferably, R² is a methyl group or a methoxy group.

Preferably R⁶ is a chlorine atom.

Preferably m is 1 and n is 1. Alternatively, preferably, m is 0 and n is 0.

Preferably R¹ is a cyano group, R² is an alkoxy group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a cyano group, R² is a methoxy group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1.

Preferably the compound according to Formula (a) or (a3) is selected from:

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2,6-diazaspiro[3.3]heptan-2- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile; 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2,7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile; and

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile.

Formula (b)

The present invention provides a compound of Formula (b)

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R³ is a hydrogen atom, a cyano group, an alkyl group or a cycloalkyl group;

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2; and

n is 0, 1 or 2;

with the proviso that R³ and R⁴ cannot both be a hydrogen atom.

In one embodiment, preferably R¹ is a cyano group. In an alternative embodiment, preferably, R¹ is an alkynyl group. More preferably still, R¹ is an alkynyl group substituted by one or more alkoxy groups. More preferably still, R¹ is an alkynyl group substituted by an alkoxy group. More preferably still, R¹ is an alkynyl group substituted by a methoxy group. More preferably still, R¹ is a -CºC-CH₂-OMe group.

Preferably R² is a hydrogen atom, an alkyl group or an alkoxy group. More preferably, R² is a hydrogen atom, a C_rC₂ alkyl group or a C_rC₂ alkoxy group. More preferably still, R² is a hydrogen atom, a methyl group or a methoxy group. Most preferably, R² is a hydrogen atom or a methyl group.

Alternatively, preferably, R² is an alkoxy group, preferably a methoxy group.

Alternatively, preferably, R⁴ is an alkyl group. More preferably R⁴ is a CrC₆ alkyl group. More preferably still, R⁴ is a C_rC₃ alkyl group. More preferably still, R⁴ is a C_rC₂ alkyl group. More preferably still, R⁴ is a methyl group.

Preferably R⁶ is a chlorine atom.

Preferably R³ is a cyano group, an alkyl group or a cycloalkyl group. More preferably R³ is a cyano group or an alkyl group. More preferably still, R³ is a cyano group or a CrC₆ alkyl group. More preferably still, R³ is a cyano group or a C_rC₃ alkyl group. More preferably still, R³ is a cyano group or a C_rC₂ alkyl group. More preferably still, R³ is a cyano group or a methyl group optionally substituted with one or more halo groups. More preferably still, R³ is a cyano group, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group. More preferably still, R³ is a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group. Most preferably R³ is a methyl group.

Alternatively, preferably, R³ is a hydrogen atom, a cyano group or an alkyl group. More preferably R³ is a hydrogen atom, a cyano group or a CrC₆ alkyl group. More preferably still, R³ is a hydrogen atom, a cyano group or a C_rC₃ alkyl group. More preferably still, R³ is a hydrogen atom, a cyano group or a C_rC₂ alkyl group. More preferably still, R³ is a hydrogen atom, a cyano group or a methyl group optionally substituted with one or more halo groups. More preferably still, R³ is a hydrogen atom, a cyano group, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group. More preferably still, R³ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group. Most preferably R³ is a hydrogen atom or a methyl group.

It is understood that when R³ is a‘hydrogen atom’, R³ may be the common isotope of hydrogen or an isotope other than the common isotope. For example, R³ may be ¹ H, ²H (deuterium) or ³H (tritium), preferably ¹ H or ²H (deuterium).

Preferably m is 1 and n is 1.

Alternatively, preferably, m is 0 and n is 0.

Alternatively, preferably, m is 1 and n is 0.

Alternatively, preferably, m is 2 and n is 0.

Preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R³ is a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R³ is a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. Alternatively, preferably, R¹ is a cyano group, R² is a methoxy group, R³ is a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a cyano group, R² is a methoxy group, R³ is a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R³ is a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a hydrogen atom or a methyl group, R³ is a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a methoxy group, R³ is a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R³ is a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R³ is a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R³ is a methyl group, a -CF₃ group, a - CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is a cyano group, R² is a methoxy group, R³ is a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a cyano group, R² is a methoxy group, R³ is a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R³ is a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a hydrogen atom or a methyl group, R³ is a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a methoxy group, R³ is a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R³ is a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0.

Preferably, the compound according to formula (b) is selected from:

6-(2,6-Dichlorophenyl)-2-((4-(4-methylpiperidin-4-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((4-(1 ,4-dimethylpiperidin-4-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-8-(3-methoxyprop-1-yn-1-yl)-2-((4-(4-methylpiperidin-4- yl)phenyl)amino)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

6-(2,6-Dichlorophenyl)-2-((4-(1 ,4-dimethylpiperidin-4-yl)phenyl)amino)-8-(3- methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

6-(2,6-Dichlorophenyl)-2-((4-(3-methylpiperidin-3-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile; and

6-(2,6-Dichlorophenyl)-2-((4-(1 ,3-dimethylpiperidin-3-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile.

Formula (c)

The present invention provides a compound of Formula (c):

(C)

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R⁹ is a hydrogen atom, a cyano group, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group; and

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group.

In one embodiment, preferably R¹ is a cyano group.

Alternatively, preferably, R² is an alkoxy group, preferably a methoxy group.

Preferably R⁶ is a chlorine atom.

Preferably, R⁹ is a hydrogen atom, a cyano group or an alkyl group. More preferably R⁹ is a hydrogen atom, a cyano group or a CrC₆ alkyl group. More preferably still, R⁹ is a hydrogen atom, a cyano group or a C_rC₃ alkyl group. More preferably still, R⁹ is a hydrogen atom, a cyano group or a C_rC₂ alkyl group. More preferably still, R⁹ is a hydrogen atom, a cyano group or a methyl group optionally substituted with one or more halo groups. More preferably still, R⁹ is a hydrogen atom, a cyano group, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group. More preferably still, R⁹ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group. Most preferably R⁹ is a hydrogen atom or a methyl group.

It is understood that when R⁹ is a‘hydrogen atom’, R⁹ may be the common isotope of hydrogen or an isotope other than the common isotope. For example, R⁹ may be ¹H, ²H (deuterium) or ³H (tritium), preferably ¹H or ²H (deuterium).

Alternatively, preferably, R⁹ is a cyano group, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, more preferably a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group.

Preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁹ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group and R⁶ is a chlorine atom. More preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R⁹ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom and R⁶ is a chlorine atom.

Alternatively, preferably, R¹ is a cyano group, R² is a methoxy group, R⁹ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group and R⁶ is a chlorine atom. More preferably, R¹ is a cyano group, R² is a methoxy group, R⁹ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom and R⁶ is a chlorine atom.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R⁹ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group and R⁶ is a chlorine atom. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a hydrogen atom or a methyl group, R⁹ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom and R⁶ is a chlorine atom.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a methoxy group, R⁹ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group and R⁶ is a chlorine atom. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R⁹ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom and R⁶ is a chlorine atom.

Preferably, the compound according to Formula (c) is selected from:

2-((4-(Azetidin-3-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-c]pyrimidine-8-carbonitrile; and

6-(2,6-Dichlorophenyl)-2-((4-(3-methylazetidin-3-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile.

Formula (d)

The present invention provides a compound of Formula (d):

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R¹⁰ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group; m is 0, 1 or 2; and

n is 0, 1 or 2.

In one embodiment, preferably R¹ is a cyano group.

Alternatively, preferably, R² is an alkoxy group, preferably a methoxy group.

Preferably, R¹⁰ is a hydrogen atom, a cyano group or an alkyl group. More preferably R¹⁰ is a hydrogen atom, a cyano group or a CrC₆ alkyl group. More preferably still, R¹⁰ is a hydrogen atom, a cyano group or a C_rC₃ alkyl group. More preferably still, R¹⁰ is a hydrogen atom, a cyano group or a C_rC₂ alkyl group. More preferably still, R¹⁰ is a hydrogen atom, a cyano group or a methyl group optionally substituted with one or more halo groups. More preferably still, R¹⁰ is a hydrogen atom, a cyano group, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group. More preferably still, R¹⁰ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group. More preferably still, R¹⁰ is a hydrogen atom or a methyl group. Most preferably R¹⁰ is a hydrogen atom.

It is understood that when R¹⁰ is a‘hydrogen atom’, R¹⁰ may be the common isotope of hydrogen or an isotope other than the common isotope. For example, R¹⁰ may be ¹ H, ²H (deuterium) or ³H (tritium), preferably ¹ H or ²H (deuterium). Preferably R⁴ is a hydrogen atom or an alkyl group. More preferably R⁴ is a hydrogen atom or a CrC₆ alkyl group. More preferably still, R⁴ is a hydrogen atom or a C_rC₃ alkyl group. More preferably still, R⁴ is a hydrogen atom or a C_rC₂ alkyl group. More preferably still, R⁴ is a hydrogen atom or a methyl group.

Preferably R⁶ is a chlorine atom.

Preferably m is 1 and n is i .

Alternatively, preferably, m is 0 and n is 0.

Preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R¹⁰ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R¹⁰ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is a cyano group, R² is a methoxy group, R¹⁰ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a cyano group, R² is a methoxy group, R¹⁰ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R¹⁰ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a hydrogen atom or a methyl group, R¹⁰ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a methoxy group, R¹⁰ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 1 and n is 1. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R¹⁰ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, m is 1 and n is 1.

Alternatively, preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R¹⁰ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R¹⁰ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is a cyano group, R² is a methoxy group, R¹⁰ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a cyano group, R² is a methoxy group, R¹⁰ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R¹⁰ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a hydrogen atom or a methyl group, R¹⁰ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, m is 0 and n is 0.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a methoxy group, R¹⁰ is a hydrogen atom or a methyl group optionally substituted by one or more halo groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, m is 0 and n is 0. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R¹⁰ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, m is 0 and n is 0.

Formula (e)

The present invention provides a compound of Formula (e):

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R¹¹ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group;

X is CH₂ or O; and

p is 1 or 2.

Preferably p is 1. Preferably X is O (i.e. an oxygen atom).

Alternatively, preferably, X is CH₂.

Preferably R⁴ is a hydrogen atom or an alkyl group. More preferably R⁴ is a hydrogen atom or a CrC₆ alkyl group. More preferably still, R⁴ is a hydrogen atom or a C_rC₃ alkyl group. More preferably still, R⁴ is a hydrogen atom or a C_rC₂ alkyl group. More preferably still, R⁴ is a hydrogen atom or methyl group.

Preferably X is O, and R⁴ is preferably a hydrogen atom or a CrC₆ alkyl group, more preferably a hydrogen atom or a C_rC₃ alkyl group, more preferably a hydrogen atom or a CrC₂ alkyl group, more preferably a hydrogen atom or a methyl group, most preferably a hydrogen atom.

Alternatively, when X is CH₂, R⁴ is preferably a CrC₆ alkyl group, more preferably a C_rC₃ alkyl group, more preferably a C_rC₂ alkyl group, most preferably a methyl group.

Preferably R⁶ is a chlorine atom.

In one embodiment, preferably R¹ is a cyano group.

Preferably R^{1 1} is a hydrogen atom or an alkyl group. More preferably R^{1 1} is a hydrogen atom or a CrC₆ alkyl group. More preferably still, R^{1 1} is a hydrogen atom or a C_rC₃ alkyl group. More preferably still, R^{1 1} is a hydrogen atom or a C_rC₂ alkyl group. More preferably R^{1 1} is a hydrogen atom, a methyl group, or a methyl group substituted by one or more halo groups. More preferably still, R¹¹ is a hydrogen atom, a methyl group, a -CF₃ group, a -CHF₂ group or a -CH₂F group. More preferably still, R¹¹ is a hydrogen atom, a methyl group or a -CF₃ group. More preferably still, R¹¹ is a hydrogen atom or a methyl group. Most preferably, R¹¹ is a hydrogen atom.

It is understood that when R¹¹ is a‘hydrogen atom’, R¹¹ may be the common isotope of hydrogen or an isotope other than the common isotope. For example, R¹¹ may be ¹ H, ²H (deuterium) or ³H (tritium), preferably ¹ H or ²H (deuterium).

Alternatively, preferably, R² is an alkoxy group, preferably a methoxy group.

Preferably R² is an alkoxy group and p is 1. More preferably, R² is a methoxy group and p is 1.

Preferably, X is O, p is 1 and R¹¹ is a hydrogen atom, a methyl group, or a methyl group substituted by one or more fluoro groups. More preferably, X is O, p is 1 and R¹¹ is a hydrogen atom, a methyl group, or a -CF₃ group. Most preferably, X is O, p is 1 and R¹¹ is a hydrogen atom.

Preferably R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R¹¹ is a hydrogen atom or a methyl group optionally substituted by one or more fluoro groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, X is O and p is 1. More preferably, R¹ is a cyano group, R² is a hydrogen atom or a methyl group, R¹¹ is a hydrogen atom, a methyl group or a -CF₃ group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, X is O and p is 1.

Alternatively, preferably, R¹ is a cyano group, R² is a methoxy group, R¹¹ is a hydrogen atom or a methyl group optionally substituted by one or more fluoro groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, X is O and p is 1. More preferably, R¹ is a cyano group, R² is a methoxy group, R¹¹ is a hydrogen atom, a methyl group or a -CF₃ group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, X is O and p is 1. Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a hydrogen atom or a methyl group, R¹¹ is a hydrogen atom or a methyl group optionally substituted by one or more fluoro groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, X is O and p is 1. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a hydrogen atom or a methyl group, R¹¹ is a hydrogen atom, a methyl group or a -CFs group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, X is O and p is 1.

Alternatively, preferably, R¹ is an alkynyl group optionally substituted by a methoxy group, R² is a methoxy group, R¹¹ is a hydrogen atom or a methyl group optionally substituted by one or more fluoro groups, R⁴ is a hydrogen atom or a methyl group, R⁶ is a chlorine atom, X is O and p is 1. More preferably, R¹ is a -CºC-CH₂-OMe group, R² is a methoxy group, R¹¹ is a hydrogen atom, a methyl group or a -CF₃ group, R⁴ is a hydrogen atom, R⁶ is a chlorine atom, X is O and p is 1.

Preferably, the compound according to Formula (e) is rac-6-(2,6-Dichlorophenyl)-2-((4- (morpholin-2-yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile.

Further embodiments

Preferably, there is provided the compound of any of Formulae (a), (a1), (a2), (a3), (b), (c), (d), (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, and at least one pharmaceutically acceptable excipient.

Preferably, there is provided a pharmaceutical composition comprising the compound of any of Formulae (a), (a1), (a2), (a3), (b), (c), (d), (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, and at least one pharmaceutically acceptable excipient.

Suitable pharmaceutically acceptable excipients would be known by the person skilled in the art, for example, fats, water, physiological saline, alcohol (e.g., ethanol), glycerol, polyols, aqueous glucose solution, extending agent, disintegrating agent, binder, lubricant, wetting agent, stabilizer, emulsifier, dispersant, preservative, sweetener, colorant, seasoning agent or aromatizer, concentrating agent, diluent, buffer substance, solvent or solubilizing agent, chemical for achieving storage effect, salt for modifying osmotic pressure, coating agent or antioxidant, saccharides such as lactose or glucose; starch of corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; alcohols such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose; and other conventionally used additives such as gelatin, talc, plant oil and gum arabic.

Preferably the pharmaceutical composition as described herein comprises one or more further pharmaceutically active agents. In certain embodiments, the pharmaceutical composition further comprises an anti-cancer agent, for example as a combination therapy as described herein. In such embodiments, a suitable anti-cancer agent may be any one or more of a genotoxic agent, a targeted agent and an immune-modulator.

Preferably, there is provided the compound of any of Formulae (a), (a1), (a2), (a3), (b), (c), (d), (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for use in therapy.

Preferably, there is provided the compound of any of Formulae (a), (a1), (a2), (a3), (b), (c), (d), (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for use as a medicament.

Preferably, there is provided the compound of any of Formulae (a), (a1), (a2), (a3), (b), (c), (d), (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for use in treating or preventing cancer. Preferably the cancer is selected from colon and rectal (colorectal) cancer, head and neck cancer, lung cancer, oesophagus cancer, ovarian cancer and pancreas cancer. More preferably, the cancer is colon and rectal (colorectal) cancer. Alternatively, preferably, the cancer is lung cancer, more preferably non-small cell lung cancer.

Preferably, there is provided the use of the compound of any of Formulae (a), (a1), (a2), (a3), (b), (c), (d), (e), or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein, for the manufacture of a medicament for treating or preventing cancer. Preferably the cancer is selected from colon and rectal (colorectal) cancer, head and neck cancer, lung cancer, oesophagus cancer, ovarian cancer and pancreas cancer. More preferably, the cancer is colon and rectal (colorectal) cancer. Alternatively, preferably, the cancer is lung cancer, more preferably non-small cell lung cancer. Preferably, there is provided a method of treating or preventing cancer in a human or animal patient comprising administering to a patient in need thereof an effective amount of the compound of any of Formulae (a), (a1), (a2), (a3), (b), (c), (d), (e), or a

pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition as described herein. Preferably the cancer is selected from colon and rectal (colorectal) cancer, head and neck cancer, lung cancer, oesophagus cancer, ovarian cancer and pancreas cancer. More preferably, the cancer is colon and rectal (colorectal) cancer. Alternatively, preferably, the cancer is lung cancer, more preferably non-small cell lung cancer.

In preferred embodiments of all therapeutic uses and methods of the invention, the subject to be treated is a human subject.

Preferably, the compounds of the present invention have an IC₅₀ value for Wee-1 kinase of about 0.1 nM to about 1 ,000 nM, more preferably from about 0.1 nM to about 500 nM, or from about 0.1 nM to about 300 nM, or from about 0.1 nM to about 100 nM, or from about 0.1 nM to about 50 nM, or from about 0.1 nM to about 30 nM, or from about 0.1 nM to about 15 nM, or from about 0.1 nM to about 10 nM, or from about 0.1 nM to about 5 nM, or from about 0.1 nM to about 2 nM, or from about 0.1 nM to about 1 nM, or, preferably, less than 10nM, more preferably less than 5 nM, more preferably less than 2 nM, most preferably less than 1 nM. A method for determining the IC₅₀ value of a compound for Wee-1 kinase is described below (see examples).

When introducing elements of the present disclosure or the preferred embodiments(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

The foregoing detailed description has been provided by way of explanation and illustration, and is not intended to limit the scope of the appended claims. Many variations in the presently preferred embodiments illustrated herein will be apparent to one of ordinary skill in the art, and remain within the scope of the appended claims and their equivalents. EXPERIMENTAL SECTION

Abbreviations

Aq: aqueous; dba: dibenzylideneacetone; DCM: dichloromethane; DIPEA:

diisopropylethylamine (Hunig’s base); DMA: A/./V-dimethylacetamide; DMF: L/,L/- dimethylformamide; dppf: 1 ,T-bis(diphenylphosphino)ferrocene; EtOAc: ethyl acetate;

EtOH: ethanol; ESI: electrospray ionisation; HOAc: acetic acid; HPLC: high pressure liquid chromatography; LC: liquid chromatography; LCMS: liquid chromatography mass spectrometry; M: molar; m/z: mass-to-charge ratio; mCPBA: 3-chloroperbenzoic acid;

MeCN: acetonitrile; MeOH: methanol; min: minutes; MS: mass spectrometry; MTBE: methyl tert- butyl ether; NMR: nuclear magnetic resonance; R_T: retention time; RT: room

temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin layer

chromatography.

General Experimental Conditions

Solvents and reagents

Common organic solvents that were used in reactions (e.g. THF, DMF, DCM, IPA, and methanol) were purchased anhydrous from Sigma-Aldrich^® in Sure/Seal™ bottles and were handled appropriately under nitrogen. Water was deionised using an Elga PURELAB Option-Q. All other solvents used (i.e. for work-up procedures and purification) were generally HPLC grade and were used as supplied from various commercial sources.

Unless otherwise stated, all starting materials used were purchased from commercial suppliers and used as supplied.

Microwave synthesis

Unless quoted otherwise, microwave experiments were carried out using a CEM

Discover™/Explorer24™ system controlled by Synergy 1.5 software. In other cases a Biotage Initiator™ Eight was used. Both machines give good reproducibility and control at temperature ranges from 60-250°C and pressures of up to maximum of 20 bar.

Flash chromatography

Purification of compounds by flash chromatography was achieved using a Biotage Isolera Four system. Unless otherwise stated, Biotage KP-Sil SNAP cartridge columns (10-340 g) were used along with the stated solvent system and an appropriate solvent gradient depending on compound polarity (determined by TLC analysis). In the case of more polar and basic compounds, Biotage KP-NH SNAP cartridge columns (11 g) were used.

NMR spectroscopy

¹H NMR spectra were recorded at ambient temperature using a Bruker (500MHz) spectrometer or a Bruker (400MHz) spectrometer. All chemical shifts (d) are expressed in ppm. Residual solvent signals were used as an internal standard and the characteristic solvent peaks were corrected to the reference data outlined in J. Org. Chem., 1997, 62, p7512-7515; in other cases, NMR solvents contained tetramethylsilane, which was used as an internal standard.

High Pressure Liquid Chromatography

Liquid Chromatography Mass Spectrometry (LCMS) experiments to determine retention times (RT) and associated mass ions were performed using one of the following methods:

Method A: The system consists of an Agilent Technologies 6130 quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LC system with UV diode array detector and autosampler. The spectrometer consists of an electrospray ionization source operating in positive and negative ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Agilent Eclipse Plus C18 RRHD 1.8 micron 50 x 2.1 mm maintained at 40°C. Mobile phases: A) 0.1 % (v/v) formic acid in water; B) 0.1% (v/v) formic acid in acetonitrile.

Gradient Time (min) Flow (mL/min) %A %B

0.00 0.5 80 20

1.80 0.5 0 100

2.20 0.5 0 100

2.50 0.5 80 20

3.00 0.5 80 20

Method B: The system consists of an Agilent Technologies 6140 single quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LC system with UV diode array detector and autosampler. The spectrometer consists of a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax Eclipse Plus C18 RRHD 1.8 micron 50 x 2.1 mm maintained at 40°C. Mobile phases: A) 0.1% (v/v) formic acid in water; B) 0.1% (v/v) formic acid in acetonitrile.

Gradient Time (min) Flow (mL/min) %A %B

0.00 1.0 95 5

1.80 1.0 0 100

2.20 1.0 0 100

2.21 1.0 95 5

2.50 1.0 95 5 Intermediate A: 6-(2,6-Dichlorophenyl)-2-(methylthio)-5-oxo-5,6-dihvdropyridor4,3- dlpyrimidine-8-carbonitrile

Obtained as described in WO2018/011570 (Page: 38, Intermediate C).

Intermediate B: 6-(2,6-Dichlorophenyl)-8-(3-methoxyprop-1-vn-1-yl)-2-(methylthio)pyrido- r4,3-dlpyrimidin-5(6/-/)-one

Obtained as described in W02018/011570 (Page: 38-39, Intermediate D). Intermediate C: 2-Amino-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihvdropyridor4,3-dlpyrimidine-8- carbonitrile

To 25 mL microwave reactor was added Intermediate A (300 mg, 0.82 mmol) was dissolved in DCM (5 mL) and mCPBA (224 mg, 0.91 mmol) was added. The reaction mixture was stirred at RT for 30 min. Then 7N NH₃ in MeOH (1.2 mL) was added and the reactor was sealed. The reaction mixture was stirred at 65 °C overnight. Next the volatiles were evaporated under reduced pressure and the residue was dissolved in DCM/MeOH mixture and injected onto a SCX-2 column (10 g, conditioned with DCM). The resin was washed thoroughly with 20% MeOH /DCM. The product was eluted with 20 % 7N NH₃ MeOH in DCM yielding the title compound as an orange solid.

LCMS (Method B): R_T = 0.97 min, m/z = 332/334/336.

¹H NMR (500 MHz, DMSO-cfe) d 9.05 (s, 1 H), 8.85 (s, 1 H), 8.17-7.96 (m, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.69-7.60 (m, 1 H).

Intermediate D: 6-(2-Chloro-6-methylphenyl)-2-(methylthio)-5-oxo-5,6-dihvdropyridor4,3- dlpyrimidine-8-carbonitrile

Obtained as described in WO2018/011570 (incorporated herein by reference in its entirely and in particular page: 39, Intermediate E).

Intermediate E: 6-(2-Chloro-6-methylphenyl)-8-(3-methoxyprop-1-vn-1-yl)-2-

(methylthio)pyridor4,3-cflpyrimidin-5(6/-/)-one

Obtained similarly to Intermediate B starting from 8-bromo-6-(2-chloro-6-methyl-phenyl)-2- (methylthio)pyrido[3,4-d]pyrimidin-5(6H)-one (prepared according to the previously reported procedure contained in WO 2014/167347 [Page 54, Example 2, Step 1], replacing 2,6- dichloroaniline with 2-chloro-6-methylaniline).

General Procedure 1 :

Intermediate A or B (1 eq., typically 0.110 mmol) was dissolved in DCM (typically 2 ml_) and mCPBA (1.1 eq.) was added. The reaction mixture was stirred at RT for 30 min. and then washed with aqueous sodium thiosulfate solution. The aqueous layer was extracted with DCM (3 x 2 ml_)). The organic extracts were combined, dried (anh. MgS0₄) and evaporated under reduced pressure. The residue was suspended in 2-propanol (typically 2 ml_) and the aniline derivative (1 eq.) was added. The reaction mixture was stirred at 80 °C overnight. Next the volatiles were evaporated under reduced pressure and the residue was purified by flash chromatography (20-100 % EtOAc in cyclohexane, then 0-20 % MeOH in EtOAc if required). The product containing fractions were combined and evaporated under reduced pressure, yielding the desired compound.

General Procedure 2:

The Boc derivative was dissolved in DCM (typically 2 ml_) and TFA was added (typically 1 ml_) the reaction mixture was stirred at RT for 30 min. The volatiles were evaporated under reduced pressure and the residue was dissolved in DCM and injected onto a SCX-2 column, conditioned with DCM. The cartridge was washed with 20% MeOH in DCM and then the bound target compound was eluted with 20% 7N NH₃ in MeOH / DCM. The product containing fractions were evaporated under reduced pressure, yielding the title product.

General Procedure 3:

The Boc derivative was dissolved in 1 ,4-dioxane (typically 2 ml_) and 4 M HCI in 1 ,4- dioxane (50 equiv.) was added. The solution was allowed to stir at RT for 2-3 hours. The volatiles were next evaporated under reduced pressure and loaded onto a pre-washed (with 20% MeOH/DCM) SCX-2 cartridge and the cartridge was washed with 20%

MeOH/DCM. The product was then eluted with 20% 7N NH₃/MeOH in DCM and the product containing fractions were evaporated under reduced pressure to give the title product. General Procedure 4:

Amine (typically 0.05 -0.15 mmol) was dissolved in MeOH/ACN (1/1) solution (Typically 2-4 ml_ of MeOH and 2-4 ml_ of MeOH). 10 eq. of 37% formaldehyde in water solution were added then followed by 10 eq. of NaHB(OAc)₃. The reaction mixture was stirred at RT for 0.5-16h. The volatiles were evaporated under reduced pressure. The residue was dissolved in DCM and washed with 1 M NaOH. The organic layer was separated and the aqueous was extracted twice with equal volumes of DCM. The organic layers were combined, dried (anh. MgS0₄) and evaporated under reduce pressure to give the title product. If required - the obtained material was purified by flash chromatography.

EXAMPLES

The following non-limiting examples further illustrate the present invention.

Example 1 : 6-(2,6-Dichlorophenyl)-2-((4-(4-methylpiperidin-4-yl)phenyl)amino)-5-oxo-5,6- dihydropyridor4,3-dlpyrimidine-8-carbonitrile

Step 1: 4-Methyl-4-(4-nitrophenyl)piperidine:

4-Methyl-4-phenyl-piperidine (500 mg, 2.85 mmol) was dissolved in MTBE (5 mL) and chilled in an ice bath. Next nitric acid (0.182 mL, 2.85 mmol) was added dropwise. The reaction mixture was stirred at 0-5 °C for about 30 min. Then the volatiles were evaporated under reduced pressure. The residue was suspended in DCM (7.5 mL) and added dropwise to ice-cold sulfuric acid (5.3 mL). The reaction mixture was stirred at 0°C for 3h and then poured onto ice. The resultant mixture was basified with 4M NaOH. The product was extracted with EtOAc (4 x 200 mL). The extracts were combined, dried (anh. MgS0₄) and evaporated under reduced pressure, yielding the crude product as yellowish oil (650 mg, 100%).

LCMS (Method A): R_T = 0.60 min, m/z = 221 [M+H]⁺.

¹H NMR (500 MHz, CDCI₃) d 8.18 (d, 2H), 7.51 (d, 2H), 3.04-2.91 (m, 2H), 2.91-2.78 (m, 2H), 2.12-2.00 (m, 2H), 1.83-1.71 (m, 2H), 1.29 (s, 3H). Step 2: tert-Butyl 4-methyl-4-(4-nitrophenyl)piperidine-1-carboxylate:

4-Methyl-4-(4-nitrophenyl)piperidine (628 mg, 2.85 mmol) was dissolved in DCM (20 ml_) and di-te/f-butyldicarbonate (684 mg, 3.13 mmol) in DCM (5 ml_) was added followed by DIPEA (1.13 ml_, 6.49 mmol). The reaction mixture was stirred for 3h at RT. The volatiles were evaporated under reduced pressure and the oily residue was purified by flash chromatography (10-30% EtOAc in cyclohexane), yielding the product as a clear oil (777 mg, 85%).

LCMS (Method A): R_T = 1.86 min, m/z = 265 [M+H-56]⁺.

¹ H NMR (500 MHz, CDCI₃) d 8.19 (d, 2H), 7.50 (d, 2H), 3.54-3.39 (m, 4H), 2.13-1.96 (m, 2H), 1.86-1.66 (m, 2H), 1.45 (s, 9H), 1.30 (s, 3H).

Step 3: tert-Butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate :

tert- Butyl 4-methyl-4-(4-nitrophenyl)piperidine-1-carboxylate (770 mg, 2.40 mmol) was dissolved in EtOH (20 ml_), heated to 70°C and 10% Pd/C (102 mg) was added followed by ammonium formate (758 mg, 12.02 mmol). The reaction was stirred at 70°C until intensive gas evolution took place (15 min) and then it was cooled to RT and filtered through Celite. The Celite was washed with EtOAc. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (20-50% EtOAc in cyclohexane), yielding the product as a clear oil (562 mg, 80%).

LCMS (Method A): R_T = 1.13 min, m/z = 235 [M+H-56]⁺.

¹ H NMR (500 MHz, CDCI₃) d 7.11 (d, 2H), 6.67 (d, 2H), 3.58 (s, 2H), 3.54-3.41 (m, 2H), 3.43-3.28 (m, 2H), 2.04-1.94 (m, 2H), 1.69-1.58 (m, 2H), 1.44 (s, 9H), 1.20 (s, 3H).

Step 4: 6-(2, 6-Dichlorophenyl)-2-((4-(4-methylpiperidin-4-yl)phenyl)amino)-5-oxo-5, 6- dihydropyrido[4,3-d]pyrimidine-8-carbonitrile:

Intermediate A (40 mg, 0.1 10 mmol) was reacted with tert- butyl 4-(4-aminophenyl)-4- methylpiperidine-1-carboxylate according to General Procedure 1. The obtained material was reacted according to General Procedure 2, yielding the title compound as a yellow solid (16mg, 29%).

LCMS (Method A): R_T = 0.89 min, m/z = 505/507/509 [M+H]⁺.

¹ H NMR (500 MHz, CDCI₃) d 9.29 (s, 1 H), 7.87 (s, 1 H), 7.77 (s, 2H), 7.55 (d, 2H), 7.51-7.43 (m, 1 H), 7.44-7.30 (m, 2H), 3.04-2.90 (m, 2H), 2.91-2.78 (m, 2H), 2.15-2.04 (m, 2H), 1.81- 1.73 (m, 2H), 1.27 (s, 3H). Example 2: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(1 ,7-diazaspiror3.5lnonan-7- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl 7-(2-methoxy-4-nitrophenyl)-1, 7-diazaspiro[3.5]nonane-1-carboxylate: tert- Butyl 1 ,7-diazaspiro[3.5]nonane-1-carboxylate (commercial, 300 mg, 1.33 mmol) was dissolved in DMA (5 ml_) and 1-fluoro-2-methoxy-4-nitrobenzene (227 mg, 1.33 mmol) was added followed by potassium carbonate (916 mg, 6.63 mmol). The suspension was heated to 120°C and stirred overnight before cooling to RT and diluting with EtOAc. The organic phase was washed with 1 x water and 3 x 50% saturated brine solution and dried (anh. MgS0₄) and concentrated in vacuo to give the crude product (546 mg, 99%) as a yellow solid which was taken on as such into the next step.

LCMS (Method B): R_T = 1.55 min, m/z = 379 [M+H]⁺.

Step 2: tert-Butyl 7-(4-amino-2-methoxyphenyl)-1, 7-diazaspiro[3.5]nonane-1-carboxylate: tert- Butyl 7-(2-methoxy-4-nitrophenyl)-1 ,7-diazaspiro[3.5]nonane-1-carboxylate (546 mg, 1.32 mmol) was dissolved in EtOH (12 ml_), heated to 70°C and 10% Pd/C (14 mg, 0.13 mmol) was added followed by ammonium formate (498 mg, 7.90 mmol). The temperature was increased to 90°C and the reaction was stirred for 1 hour before it was cooled to RT and filtered through Celite. The Celite was washed with EtOAc and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (0- 80% EtOAc in cyclohexane) to give the product (387 mg, 74%) as a beige solid.

LCMS (Method B): R_T = 0.69 min, m/z = 348 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) d 6.63-6.58 (m, 1 H), 6.23-6.20 (m, 1 H), 6.08-6.04 (m,

1 H), 4.68 (s, 2NH), 3.76-3.70 (m, 1 H), 3.69 (s, 3H), 3.67-3.62 (m, 1 H), 3.09-3.00 (m, 2H), 2.47-2.38 (m, 2H), 2.35-2.26 (m, 1 H), 2.21-2.12 (m, 1 H), 2.03-1.94 (m, 2H), 1.75-1.65 (m, 2H), 1.43-1.35 (m, 9H).

Step 3: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(1, 7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile:

Intermediate A (135 mg, 0.371 mmol) was reacted with tert- butyl 7-(4-amino-2- methoxyphenyl)-1 ,7-diazaspiro[3.5]nonane-1-carboxylate according to General procedure 1. The product precipitated out of the reaction mixture and this was isolated via vacuum filtration and washed with 2-propanol to give tert- butyl 7-(4-((8-cyano-6-(2,6- dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)-2-methoxyphenyl)-1 ,7- diazaspiro[3.5]nonane-1-carboxylate as a beige solid (158 mg, 63%). This material was reacted according to General Procedure 3, followed by further purification via column chromatography (20-100% EtOAc in cyclohexane, then 0-50% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to yield the title compound (94 mg, 70%) as a yellow solid.

LCMS (Method B): R_T = 0.89 min, m/z = 562/564 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.60 (broad s, NH), 9.17 (s, 1 H), 8.95 (s, 1 H), 7.98-7.91 (broad s, 1 H), 7.79-7.75 (m, 2H), 7.64 (dd, 1 H), 7.24-7.19 (m, 1 H), 6.88-6.83 (m, 1 H), 3.87 (s, 3H), 3.33 (t, 2H), 2.98-2.92 (m, 2H), 2.79-2.72 (m, 2H), 2.00 (t, 2H), 1.84-1.77 (m, 2H), 1.75-1.68 (m, 2H).

Example 3: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(4-(methylamino)piperidin-1- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl (1-(2-methoxy-4-nitrophenyl)piperidin-4-yl)carbamate:

tert- Butyl piperidin-4-ylcarbamate (commercial, 500 mg, 3.22 mmol) was dissolved in DMA (10 ml_) and 1-fluoro-2-methoxy-4-nitrobenzene (552 mg, 3.22 mmol) was added followed by potassium carbonate (2.23 g, 16.1 mmol). The suspension was heated to 120°C and stirred overnight before cooling and diluting with EtOAc. The organic phase was washed with 1 x water and 3 x 50% saturated brine solution and subsequently dried (anh. MgS0₄) and concentrated in vacuo to give the crude product (1.1 g, 78%) as an orange solid which was taken on as such into the next step.

LCMS (Method B): R_T = 1.45 min, m/z = 352 [M+H]⁺.

Step 2: tert-Butyl (1-(2-methoxy-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate:

tert- Butyl (1-(2-methoxy-4-nitrophenyl)piperidin-4-yl)carbamate (1.13 g, 2.52 mmol) was dissolved in DMF (15 mL) and the stirred solution was cooled to 0°C before the addition of sodium hydride (252 mg, 6.29 mmol) in one portion. The mixture was allowed to stir for 15 minutes before the addition of iodomethane (0.47 ml_, 7.55 mmol). The mixture was allowed to warm to RT and stirred overnight. The mixture was poured into sat. NH₄CI solution and extracted with 3 x EtOAc. The combined organic extracts were dried (anh. MgS0₄) and concentrated in vacuo to give the crude product, which was then purified via flash chromatography (0-50% EtOAc in cyclohexane) to give the title compound (962 mg, 93%) as a yellow solid.

LCMS (Method B): R_T = 1.81 min, m/z = 366 [M+H]⁺.

Step 3: tert-Butyl (1 -(4-ami no-2-methoxy henyl) pi peridin-4-yl)(methyl)carbamate:

tert- Butyl (1-(2-methoxy-4-nitrophenyl)piperidin-4-yl)(methyl)carbamate (962 mg, 2.34 mmol) was dissolved in EtOH (20 ml_), heated to 70°C and 10% Pd/C (25 mg, 0.234 mmol) was added followed by ammonium formate (886 mg, 14.1 mmol). The temperature was increased to 90°C and the reaction was stirred for 1 hour before it was cooled to RT and filtered through Celite. The Celite was washed with EtOAc and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (0-100%

EtOAc in cyclohexane) to give the product (665 mg, 84%) as a pink solid.

LCMS (Method B): R_T = 0.71 min, m/z = 336 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 6.63 (d, 1 H), 6.23-6.21 (m, 1 H), 6.08-6.04 (m, 1 H), 4.67 (s, 2NH), 3.90-3.73 (broad s, 1 H), 3.68 (s, 3H), 3.19-3.13 (m, 2H), 2.70 (s, 3H), 2.51-2.45 (m, 2H - hidden), 1.81-1.71 (m, 2H), 1.58-1.49 (m, 2H), 1.40 (s, 9H).

Step 4: 6-(2, 6-Dichlorophenyl)-2-((3-methoxy-4-(4-(methylamino)piperidin- 1- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile:

Intermediate A (150 mg, 0.413 mmol) was reacted with tert- butyl (1-(4-amino-2- methoxyphenyl)piperidin-4-yl)(methyl)carbamate (139 mg, 0.413 mmol) according to General procedure 1. The product precipitated out of the reaction mixture and this was isolated via vacuum filtration and washed with 2-propanol to give tert- butyl (1-(4-((8-cyano- 6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)-2- methoxyphenyl)piperidin-4-yl)(methyl)carbamate (237 mg, 88%) as a yellow solid. This material was reacted according to General Procedure 3 to yield the final product (181 mg, 90%) as a yellow solid.

LCMS (Method B): R_T = 0.86 min, m/z = 550/552 [M+H]⁺.

¹ H NMR (500 MHz, CDCI₃) d 9.26 (broad s, NH), 8.05 (s, 1 H), 7.76 (s, 1 H), 7.70 (s, 1 H), 7.56-7.52 (m, 2H), 7.47-7.43 (m, 1 H), 6.97-6.94 (m, 1 H), 6.93-6.88 (m, 1 H), 4.04 (s,

3H), 3.51-3.44 (m, 2H), 2.70-2.62 (m, 2H), 2.55-2.50 (m, 1 H), 2.49 (s, 3H), 2.06-1.99 (m, 2H), 1.65-1.56 (m, 2H). Example 4: rac-6-(2,6-Dichlorophenyl)-2-((4-(morpholin-2-yl)phenyl)amino)-5-oxo-5,6- dihvdropyridor4,3-dlpyrimidine-8-carbonitrile

Step 1: rac-tert-Butyl 2-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)phenyl)morpholine-4-carboxylate:

Following general procedure 1 , Intermediate A (50 mg, 0.14 mmol) was reacted with mCPBA (37 mg, 0.15 mmol) and then with rac-te/f-butyl 2-(4-aminophenyl)morpholine-4- carboxylate (38 mg, 0.14 mmol) to afford rac-te/f-butyl 2-(4-((8-cyano-6-(2,6- dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)phenyl)morpholine-4- carboxylate (61 mg, 75%).

LCMS (Method B): R_T = 1.57 min, m/z = 537 [M+H-56]⁺.

Step 2: rac-6-(2, 6-Dichlorophenyl)-2-((4-(morpholin-2-yl)phenyl)amino)-5-oxo-5, 6- dihydropyrido[4,3-d]pyrimidine-8-carbonitrile:

To rac-te/f-butyl 2-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)phenyl)morpholine-4-carboxylate (61 mg, 0.10 mmol) in DCM (2 ml_) was added 4M HCI in 1 ,4-dioxane (0.30 ml_, 1.23 mmol). The reaction was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue was loaded onto a pre-washed SCX-2 column and washed with 20% MeOH in DCM, the product was then eluted with 20% 7N NH₃ in MeOH / DCM (1 :4). Product containing fractions were concentrated to afford the target molecule (49 mg, 97%).

LCMS (Method B): R_T = 0.82 min, m/z = 492/495 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.74 (s, 1 H), 9.23 (s, 1 H), 8.97 (s, 2H), 7.98 (s, 2H), 7.79 (d, 2H), 7.69-7.62 (m, 1 H), 7.31 (d, 2H), 4.41-4.33 (m, 1 H), 3.92-3.85 (m, 1 H), 3.65-3.55 (m, 1 H), 2.96-2.89 (m, 1 H), 2.80-2.70 (m, 2H), 2.58-2.52 (m, 1 H). Example 5: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2,6-diazaspiror3.3lheptan-2- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl 6-(2-methoxy-4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate:

A mixture of tert- butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (commercial, 520 mg, 2.62 mmol), 2-bromo-5-nitroanisole (609 mg, 2.62 mmol), and cesium carbonate (2.56 g, 7.87 mmol) in 1 ,4-dioxane (20 ml_) was de-gassed by bubbling nitrogen through the reaction mixture for 5 min. Xantphos (167 mg, 0.29 mmol) and Pd₂(dba)₃ (120 mg, 0.13 mmol) were then charged and the reaction mixture was heated at 100°C overnight. The mixture was filtered through Celite, the filter cake was washed with EtOAc and the combined filtrate was concentrated in vacuo. The residue was purified by flash chromatography (20-60% EtOAc in cyclohexane) to afford tert- butyl 6-(2-methoxy-4-nitro-phenyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (150 mg, 16%).

LCMS (Method A): R_T = 1.64 min, m/z = 350 [M+H]⁺.

Step 2: tert-Butyl 6-(4-amino-2-methoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate:

A solution of tert- butyl 6-(2-methoxy-4-nitro-phenyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (150 mg, 0.43 mmol) in MeOH (200 ml_) was hydrogenated, using the H- Cube® (10% Pd/C, 1.0 mL/min, 35°C, Full Mode, 30 bar pressure). The solvent was concentrated in vacuo to afford the crude target compound (130 mg, 95%) which was taken on as such.

LCMS (Method A): R_T = 0.75 min, m/z = 320 [M+H]⁺.

Step 3: tert-Butyl 6-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)-2-methoxyphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate:

Following general procedure 1 , Intermediate A (148 mg, 0.41 mmol) was reacted with tert- butyl 6-(4-amino-2-methoxy-phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (130 mg,

0.41 mmol) at 95°C for 4hr to afford the target compound (240 mg, 93%).

LCMS (Method B): R_T = 1.50 min, m/z = 634/636 [M+H]⁺. Step 4: 6-(2, 6-Dichlorophenyl)-2-((3-methoxy-4-(2, 6-diazaspiro[3.3]heptan-2- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile:

tert- Butyl 6-[4-[[8-cyano-6-(2,6-dichlorophenyl)-5-oxo-pyrido[4,3-c]pyrimidin-2-yl]amino]-2- methoxy-phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 0.32 mmol) was dissolved in DCM (5.0 ml_) and TFA (1.0 ml_, 12.98 mmol) was added. The reaction mixture was stirred at RT for 30 min and then the volatiles were evaporated under reduced pressure. The product was purified by flash chromatography (KP-NH, 30-100% EtOAc in cyclohexane followed by 5% MeOH in EtOAc) to afford the target compound (80 mg, 48%). LCMS (Method B): R_T = 0.83 min, m/z = 534/536 [M+H]⁺.

¹H NMR (500 MHz, CDCI₃) d 9.34-9.19 (m, 1 H), 7.99 (s, 1 H), 7.76 (s, 1 H), 7.64 (s, 1 H), 7.54 (d, J = 7.8 Hz, 2H), 7.48-7.42 (m, 1 H), 6.84 (d, J = 6.4 Hz, 1 H), 6.45 (d, J = 8.4 Hz,

1 H), 4.01 (s, 4H), 3.97 (s, 3H), 3.86-3.76 (m, 5H).

Example 6: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(6-methyl-2,6-diazaspiror3.3lheptan-2- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

A mixture of 2-[4-(2,6-diazaspiro[3.3]heptan-2-yl)-3-methoxy-anilino]-6-(2,6- dichlorophenyl)-5-oxo-pyrido[4,3-c(]pyrimidine-8-carbonitrile (40 mg, 0.07 mmol) (obtained as described in example 5), MeOH (0.5 ml_), MeCN (3 ml_) and 37% aqueous

formaldehyde solution (0.08 ml_, 0.37 mmol) was cooled in an ice bath, sodium

triacetoxyborohydride (79 mg, 0.37 mmol) was then added portionwise. After addition the reaction was stirred for 30 min at 0°C, followed by stirring for 2 hr at RT. The reaction was concentrated almost to dryness in vacuo and the residue was taken up in DCM and washed with 2M aq. Na₂C0₃ twice followed by water. The organic phase was dried using a Biotage phase separator cartridge and concentrated in vacuo. The solid residue was slurried in a mixture of DMSO and MeOH and the solid was collected by filtration, washed twice with MeOH and dried on the sintered funnel to afford the target compound (25 mg, 61%).

LCMS (Method B): R_T = 0.87 min, m/z = 548/550 [M+H]⁺. ¹ H NMR (500 MHz, CDCI₃) d 9.23 (s, 1 H), 7.99 (s, 1 H), 7.75 (s, 1 H), 7.65 (s, 1 H), 7.54 (d, 2H), 7.49-7.41 (m, 1 H), 6.84 (d, 1 H), 6.44 (d, 1 H), 4.07-3.74 (m, 7H), 3.37 (s, 4H), 2.31 (s, 3H).

Example 7: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(4-(methylamino)piperidin-1- yl)phenyl)amino)-8-(3-methoxyprop-1-vn-1-yl)pyridoi4,3-cflpyrimidin-5(6/-/)-one

Intermediate B (150 mg, 0.369 mmol) was reacted with tert- butyl (1-(4-amino-2- methoxyphenyl)piperidin-4-yl)(methyl)carbamate ( obtained as described in Example 3, Steps 1-3) (124 mg, 0.369 mmol) according to General procedure 1 to give 6-(2,6- dichlorophenyl)-2-((3-methoxy-4-(4-(methylamino)piperidin-1-yl)phenyl)amino)-8-(3- methoxyprop-1-yn-1-yl)pyrido[4,3-d]pyrimidin-5(6/-/)-one (153 mg, 58%) as a yellow solid. This material was reacted according to General Procedure 3 followed by further purification via column chromatography (20-100% EtOAc in cyclohexane, then 0-60% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to yield the final product (22 mg, 17%) as a yellow solid.

LCMS (Method B): R_T = 0.86 min, m/z = 593/595 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.33 (broad s, NH), 9.15 (s, 1 H), 8.27 (s, 1 H), 7.80-7.72 (m, 3H), 7.62-7.58 (m, 1 H), 7.52-7.46 (broad s, 1 H), 6.87 (d, 1 H), 4.37 (s, 2H), 3.80 (s, 3H), 3.34 (s, 3H), 3.28-3.25 (m, 2H), 2.60-2.53 (m, 2H), 2.39-2.32 (m, 1 H), 2.30 (s, 3H), 1.90- 1.84 (m, 2H), 1.42-1.33 (m, 2H). Example 8: 6-(2,6-Dichlorophenyl)-2-((4-(1 ,4-dimethylpiperidin-4-yl)phenyl)amino)-5-oxo-

5,6-dihvdropyridor4,3-dlpyrimidine-8-carbonitrile

6-(2,6-Dichlorophenyl)-2-((4-(4-methylpiperidin-4-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile (Obtained as described in Example 1) (30 mg, 0.059 mmol) was reacted according to General Procedure 4 yielding the title compound (20 mg, 65%) as off-white solid .

LCMS (Method B): R_T = 0.92 min, m/z = 519/521 [M+H]⁺.

¹H NMR (500 MHz, CDCI₃) d 9.30 (s, 1 H), 7.98-7.82 (m, 1 H), 7.83-7.74 (m, 2H), 7.57-7.52 (m, 2H), 7.48-7.43 (m, 1 H), 7.40 (d, 2H), 2.64 (s, 2H), 2.55-2.38 (m, 2H), 2.34 (s, 3H), 2.29- 2.17 (m, 2H), 1.96-1.85 (m, 2H), 1.26 (s, 3H).

Example 9: (S)-2-((4-(3-Aminopyrrolidin-1-yl)-3-methylphenyl)amino)-6-(2,6- dichlorophenyl)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl (S)-(1-(2-methyl-4-nitrophenyl)pyrrolidin-3-yl)carbamate

1-Fluoro-2-methyl-4-nitrobenzene (0.42 g, 2.68 mmol), tert- butyl (S)-pyrrolidin-3- ylcarbamate (0.5 g, 2.68 mmol) and potassium carbonate (1.86 g, 13.42 mmol) were suspended in DMA (2 ml_). The reaction mixture was heated at 140 °C for 20h. Next transferred to a separatory funnel and water (20 ml_) followed by EtOAc (20 ml_) were added. The organic layer was separated and then washed with water (2 x 20 ml_) and brine (20 ml_). The extract was dried (anh. MgS0₄) and evaporated under reduced pressure.

The residue was purified by flash chromatography (10-50% EtOAc in cyclohexane) yielding the title compound (712 mg, 83%) as a yellow solid. LCMS (Method B): R_T = 1.42 min, m/z = 322 [M+H]⁺.

Step 2: tert-Butyl (S)-(1-(4-amino-2-methylphenyl)pyrrolidin-3-yl)carbamate

tert- Butyl (S)-(1-(2-methyl-4-nitrophenyl)pyrrolidin-3-yl)carbamate (0.71 g, 2.21 mmol) was dissolved in EtOH, heated to 70 °C and 10% Pd/C (94 mg, 0.089 mmol) was added followed by ammonium formate (699 mg, 1 1.1 mmol). The reaction mixture was stirred at 70 °C until intensive gas evolution (15 min) then cooled to RT and filtered through Celite. The Celite was washed with EtOAc. The filtrate was evaporated under reduced pressure. The product was purified by flash chromatography (20-50% EtOAc in cyclohexane) yielding a clear oil of product (639 mg, 99%) that solidified upon storage.

LCMS (Method B): R_T = 0.70 min, m/z = 292 [M+H]⁺.

Step 3: (S)-2-((4-(3-Aminopyrrolidin- 1-yl)-3-methylphenyl)amino)-6-(2, 6-dichlorophenyl)-5- oxo-5, 6-dihydropyrido[4, 3-d]pyrimidine-8-carbonitrile

Intermediate A (100 mg, 0.725 mmol) was reacted with tert- butyl (S)-(1-(4-amino-2- methylphenyl)pyrrolidin-3-yl)carbamate according to General Procedure 1 yielding tert- butyl (S)-(1-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2- yl)amino)-2-methylphenyl)pyrrolidin-3-yl)carbamate (139 mg, 83%). The obtained material was reacted according to General Procedure 2 yielding the title compounds (95 mg, 82%) as a yellow solid.

LCMS (Method B): R_T = 0.89 min, m/z = 506/508 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.54 (s, 1 H), 9.14 (s, 1 H), 8.93 (s, 1 H), 7.98 (s, 1 H), 7.78 (d, 2H), 7.69-7.62 (m, 1 H), 7.61-7.30 (m, 1 H), 6.80 (d, 1 H), 3.47 (q, 1 H), 3.31-3.25 (m, 1 H), 3.25-3.19 (m, 1 H), 3.18-3.11 (m, 1 H), 2.83 (dd, 1 H), 2.28 (s, 3H), 2.1 1-2.02 (m, 1 H), 1.86 (s, 2H), 1.64-1.54 (m, 1 H).

Example 10: (S)-2-((4-(3-Aminopyrrolidin-1-yl)-3-methylphenyl)amino)-6-(2,6- dichlorophenyl)-8-(3-methoxyprop-1-vn-1-yl)pyridor4,3-cflpyrimidin-5(6/-/)-one

Intermediate B (100 mg, 0.725 mmol) was reacted with tert- butyl (S)-(1-(4-amino-2- methylphenyl)pyrrolidin-3-yl)carbamate (Obtained as described in Example 9, Step 2) according to General Procedure 1 tert- butyl (S)-(1-(4-((6-(2,6-dichlorophenyl)-8-(3- methoxyprop-1-yn-1-yl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)-2- methylphenyl)pyrrolidin-3-yl)carbamate (112 mg, 47%). The obtained material was reacted according to General Procedure 2 yielding the title compounds (86 mg, 91 %) as a yellow solid.

LCMS (Method B): R_T = 0.93 min, m/z = 549/551 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.31 (s, 1 H), 9.11 (s, 1 H), 8.28 (s, 1 H), 8.03-7.85 (m,

1 H), 7.73 (d, J = 8.1 Hz, 2H), 7.72-7.65 (m, 1 H), 7.62-7.57 (m, 1 H), 6.82 (d, J = 8.8 Hz,

1 H), 4.40 (s, 2H), 3.48 (p, J = 6.0 Hz, 1 H), 3.35 (s, 3H), 3.25 (dd, J = 9.2, 6.1 Hz, 1 H), 3.23- 3.17 (m, 1 H), 3.17-3.09 (m, 1 H), 2.82 (dd, J = 9.0, 5.3 Hz, 1 H), 2.26 (s, 3H), 2.12-2.03 (m,

1 H), 1.85 (s, 2H), 1.63-1.54 (m, 1 H).

Example 1 1 : (S)-6-(2,6-Dichlorophenyl)-2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-3- methylphenyl)amino)-5-oxo-5,6-dihvdropyridoi4,3-cflpyrimidine-8-carbonitrile

(S)-2-((4-(3-aminopyrrolidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile (56 mg, 0.11 mmol) (Obtained as described in Example 9: was reacted according to General Procedure 4 yielding the title compound as a yellow solid (41 mg, 69%).

LCMS (Method B): R_T = 0.95 min, m/z = 534/536 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.45 (s, 1 H), 9.07 (s, 1 H), 8.85 (s, 1 H), 7.92 (s, 1 H), 7.70 (d, 2H), 7.60-7.54 (m, 1 H), 7.54-7.22 (m, 1 H), 6.80 (d, 1 H), 3.23-3.18 (m, 1 H), 3.12-2.91 (m, 3H), 2.71 (p, 1 H), 2.20 (s, 3H), 2.11 (s, 6H), 2.03-1.91 (m, 1 H), 1.75-1.63 (m, 1 H). Example 12: (S)-6-(2,6-Dichlorophenyl)-2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-3- methylphenyl)amino)-8-(3-rnethoxyprop-1-vn-1-yl)pyridoi4,3-cflpyrimidin-5(6/-/)-one

(S)-2-((4-(3-aminopyrrolidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-8-(3- methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one (46 mg, 0.084 mmol) (Obtained as described in Example 10) was reacted according to General Procedure 4 yielding the title compound as a yellow solid (42 mg, 87%).

LCMS (Method B): R_T = 0.96 min, m/z = 577/579 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.29 (s, 1 H), 9.12 (s, 1 H), 8.26 (s, 1 H), 7.92 (s, 1 H), 7.73 (d, 3H), 7.65-7.53 (m, 1 H), 6.88 (d, 1 H), 4.40 (s, 2H), 3.35 (s, 3H), 3.29-3.22 (m, 1 H), 3.15-

2.98 (m, 3H), 2.79 (p, 1 H), 2.26 (s, 3H), 2.18 (s, 6H), 2.09-2.00 (m, 1 H), 1.79-1.70 (m, 1 H).

Example 13: 2-((4-(4-Aminopiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)- 8-(3-methoxyprop-1-vn-1-yl)pyridoi4,3-cflpyhmidin-5(6/-/)-one

Intermediate B (150 mg, 0.369 mmol) was reacted with tert- butyl (1-(4-amino-2- methoxyphenyl)piperidin-4-yl)carbamate (Obtained as described in Example 32, Steps 1-2) according to General Procedure 1 giving tert- butyl (1-(4-((6-(2,6-dichlorophenyl)-8-(3- methoxyprop-1-yn-1-yl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)-2- methoxyphenyl)piperidin-4-yl)carbamate (108 mg, 43%). The obtained material was reacted according to General Procedure 2 yielding the title compounds (82 mg, 89%) as a yellow solid.

LCMS (Method B): R_T = 0.82 min, m/z = 579/581 [M+H]⁺. ¹ H NMR (500 MHz, DMSO-cfe) d 10.36 (s, 1 H), 9.15 (s, 1 H), 8.29 (s, 1 H), 7.83-7.75 (m, 1 H), 7.74 (d, 2H), 7.63-7.57 (m, 1 H), 7.50 (s, 1 H), 6.87 (d, 1 H), 4.37 (s, 2H), 3.80 (s, 3H), 3.34 (s, 3H), 3.29-3.23 (m, 2H), 2.68-2.60 (m, 1 H), 2.59-2.51 (m, 2H), 1.87-1.59 (m, 4H), 1.44-1.34 (m, 2H).

Example 14: 6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methoxyphenyl)amino)-8-(3-methoxyprop-1-vn-1-yl)pyridoi4,3-cflpyrimidin-5(6/-/)-one

2-((4-(4-Aminopiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)-8-(3- methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one (46 mg, 0.079 mmol) (Obtained as described in Example 13) was reacted according to General Procedure 4 yielding the title compound as a yellow solid (43 mg, 89%).

LCMS (Method B): R_T = 0.89 min, m/z = 607/609 [M+H]⁺.

1 H NMR (500 MHz, DMSO-cfe) d 10.33 (s, 1 H), 9.15 (s, 1 H), 8.27 (s, 1 H), 7.83-7.75 (m,

1 H), 7.73 (d, 2H), 7.62-7.57 (m, 1 H), 7.49 (s, 1 H), 6.87 (d, 1 H), 4.37 (s, 2H), 3.81 (s, 3H), 3.40-3.35 (m, 2H), 3.29 (s, 3H), 2.52 (s, 2H), 2.20 (s, 6H), 2.19-2.12 (m, 1 H), 1.86-1.76 (m, 2H), 1.58-1.47 (m, 2H). Example 15: (S)-2-((4-(3-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2,6- dichlorophenyl)-5-oxo-5,6-dihvdropyridoi4,3-dlpyrimidine-8-carbonitrile

Step 1: tert-Butyl (S)-(1-(2-methyl-4-nitrophenyl)piperidin-3-yl)carbamate

tert- Butyl (S)-piperidin-3-ylcarbamate (175 mg, 0.874 mmol), 1-fluoro-2-methyl-4- nitrobenzene (136 mg, 0.874 mmol), K₂C0₃ (604 mg, 4.37 mmol) in DMA (1 ml_) were heated at 140 °C for 20 h. Next the reaction mixture was chilled and transferred to a separatory funnel. Water (20 ml_) and EtOAc (20ml_) were added. The aqueous layer was separated and discarded. The organic layer was washed with water (2 x 20 ml_) and brine (20 ml_), then dried (anh. MgS0₄) and evaporated under reduced pressure. The residue was purified by flash chromatography (10-50% EtOAc in cyclohexane) yielding the title compound (232 mg, 79%) as a yellow oil.

LCMS (Method B): R_T = 1.57 min, m/z = 336 [M+H]⁺.

Step 2: tert-Butyl (S)-(1-(4-amino-2-methylphenyl)piperidin-3-yl)carbamate

tert- Butyl (S)-(1-(2-methyl-4-nitrophenyl)piperidin-3-yl)carbamate (0.23 g, 0.6917mmol) was dissolved in EtOH (10 ml_), heated to 70 °C and 10% Pd/C (30 mg, 0.028 mmol) was added followed by ammonium formate (218 mg, 3.46 mmol). The reaction was stirred at 70 °C until intensive gas evolution. The reaction mixture was cooled to RT and filtered through Celite. The Celite was washed with EtOAc. The filtrate was evaporated under reduced pressure. The product was purified by flash chromatography (20-80% EtOAc in

cyclohexane) yielding a clear oil of product that solidified upon storage.

LCMS (Method B): R_T = 0.80 min, m/z = 306 [M+H]⁺.

Step 3: (S)-2-((4-(3-Aminopiperidin- 1-yl)-3-methylphenyl)amino)-6-(2, 6-dichlorophenyl)-5- oxo-5, 6-dihydropyrido[4, 3-d]pyrimidine-8-carbonitrile

Intermediate A (100 mg, 0.275 mmol) was reacted with tert- butyl (S)-(1-(4-amino-2- methylphenyl)piperidin-3-yl)carbamate according to General Procedure 1 yielding tert- butyl (S)-(1-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2- yl)amino)-2-methylphenyl)piperidin-3-yl)carbamate (157 mg, 92%). The obtained material was reacted according to General Procedure 2 yielding the title compound (101 mg, 87%) as yellow solid.

LCMS (Method B): R_T = 0.96 min, m/z = 520/522 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) d 10.62 (s, 1 H), 9.18 (s, 1 H), 8.96 (s, 1 H), 8.04 (s, 1 H), 7.79 (d, J = 8.1 Hz, 2H), 7.73-7.40 (m, 2H), 6.97 (d, J = 8.7 Hz, 1 H), 3.05-2.97 (m, 1 H), 2.94- 2.85 (m, 1 H), 2.85-2.77 (m, 1 H), 2.33-2.20 (m, 4H), 1.92-1.53 (m, 4H), 1.18-1.04 (m, 1 H). Example 16: (S)-6-(2,6-Dichlorophenyl)-2-((4-(3-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-5-oxo-5,6-dihvdropyridoi4,3-cflpyrimidine-8-carbonitrile

(S)-2-((4-(3-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-c]pyrimidine-8-carbonitrile (82 mg, 0.158 mmol) (Obtained as described in Example 15) was reacted according to the General Procedure 4 yielding the title compound as yellow solid (58 mg, 67 %).

LCMS (Method B): R_T = 1.01 min, m/z = 548/550 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.58 (s, 1 H), 9.17 (s, 1 H), 8.93 (s, 1 H), 8.03 (s, 1 H), 7.77 (d, J = 8.1 Hz, 2H), 7.73-7.45 (m, 2H), 7.01 (d, J = 8.7 Hz, 1 H), 3.20-3.10 (m, 1 H), 2.99- 2.90 (m, 1 H), 2.49-2.45 (m, 1 H), 2.44-2.37 (m, 2H), 2.25 (s, 3H), 2.22 (s, 6H), 1.97-1.88 (m, 1 H), 1.84-1.74 (m, 1 H), 1.66-1.53 (m, 1 H), 1.30-1.17 (m, 1 H).

Example 17: 2-((4-(4-(Azetidin-1-yl)piperidin-1-yl)-3-methylphenyl)amino)-6-(2,6- dichlorophenyl)-5-oxo-5,6-dihvdropyridoi4,3-cflpyrimidine-8-carbonithle

Step 1: tert-Butyl (1-(2-methyl-4-nitrophenyl)piperidin-4-yl)carbamate

1-Fluoro-2-methyl-4-nitrobenzene (1.0 g, 6.45 mmol), tert- butyl piperidin-4-ylcarbamate (1.29 g, 6.45 mmol) and potassium carbonate (4.45 g, 32.2 mmol) were suspended in DMA (4 ml_). The reaction mixture was heated at 140 °C for 40h. Next transferred to a

separatory funnel. Water (40 ml_) and EtOAc (40 ml_) were added. The organic layer was separated and washed with water (2 x 40 ml_) and brine (40 ml_), then dried (anh. MgS0₄) and evaporated under reduced pressure. The residue was purified by flash chromatography (20-50% EtOAc in cyclohexane) yielding the title compound (1570 mg, 73%) as a yellow solid.

LCMS (Method B): R_T = 1.56 min, m/z = 236 [M+H]⁺

Step 2: 1-(2-Methyl-4-nitrophenyl)piperidin-4-amine

tert- Butyl (1-(2-methyl-4-nitrophenyl)piperidin-4-yl)carbamate (500.0 mg, 1.49 mmol) was dissolved in DCM (4 ml_) and TFA (2.0 ml_) was added. The reaction mixture was stirred for 30 min at RT and then the volatiles were evaporated under reduced pressure. The oily residue was dissolved in DCM (50 ml_) and washed with 2M NaOH (50 ml_). The organic layer was separated. The aqueous layer was extracted with DCM (50 ml_). The extracts were combined, dried (anh. MgS0₄) and evaporated under reduced pressure yielding the title compound as a yellow oil that solidified upon storage (348 mg, 99%).

LCMS (Method B): R_T = 0.64 min, m/z = 236 [M+H]⁺.

Step 3: 4-(Azetidin- 1-yl)- 1-(2-methyl-4-nitrophenyl) piperidine

1-(2-Methyl-4-nitrophenyl)piperidin-4-amine (348 mg, 1.48 mmol) was dissolved in MeCN (6 mL) and K₂C0₃ (2.0 mL, 4.44 mmol) was added followed by 1 ,3-dibromopropane (0.17 mL, 1.63 mmol). The reaction mixture was stirred for 72h at 50 °C. Acetic anhydride was added then and the reaction mixture was stirred for app 1 h at RT. Then the volatiles were evaporated under reduced pressure. The residue was taken into EtOAc / water solution (30 ml /30 ml) and the organic layer was separated. The aqueous layer was extracted with EtOAc (30 mL). The extracts were combined, dried (anh. MgS0₄) and evaporated under reduced pressure. The residue was dissolved in DCM and purified by flash

chromatography (0-10 % MeOH in DCM) yielding the title compound as yellow oil (397 mg, 47%).

LCMS (Method B): R_T = 0.75 min, m/z = 276 [M+H]+

Step 4: 4-(4-(Azetidin- 1-yl)piperidin-1-yl)-3-methylaniline

To 4-(azetidin-1-yl)-1-(2-methyl-4-nitrophenyl)piperidine (254 mg, 0.92 mmol) was added MeOH (10 mL), water (2 mL), iron (515 mg, 9.22 mmol), and ammonium chloride (493 mg, 9.22 mmol). The reaction mixture was refluxed for 2h. Then chilled to RT and filtered through Celite. The Cellite was washed with EtOAc. The filtrate was evaporated under reduced pressure and purified by flash chromatography (0- 10% MeOH in DCM) yielding the title compound as a yellow oil (142 mg, 63%).

LCMS (Method B): R_T = 0.15 min, m/z = 246 [M+H]⁺. Step 5: 2-((4-(4-(Azetidin- 1-yl) i eridin- 1-yl)-3-methylphenyl)amino)-6-(2, 6-dichlorophenyl)- 5-oxo-5, 6-dihydropyrido[ 4, 3-d]pyrimidine-8-carbonitrile

Intermediate A (52 mg, 0.143 mmol) was reacted with 4-(4-(azetidin-1-yl)piperidin-1-yl)-3- methylaniline according to General Procedure 1 yielding the title compound as yellow solid (9 mg, 11 %).

LCMS (Method B): R_T = 1.02 min, m/z = 560/562/564 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.57 (s, 1 H), 9.17 (s, 1 H), 8.93 (s, 1 H), 8.03 (s, 1 H), 7.77 (d, 2H), 7.70-7.59 (m, 2H), 6.99 (d, 1 H), 3.18-3.05 (m, 4H), 3.04-2.95 (m, 2H), 2.62-2.54 (m, 2H), 2.27 (s, 3H), 2.11 (s, 1 H), 1.94 (p, 2H), 1.76-1.68 (m, 2H), 1.37-1.27 (m, 2H).

Example 18: 2-((4-(4-(Azetidin-1-yl)piperidin-1-yl)-3-methylphenyl)amino)-6-(2,6- dichlorophenyl)-8-(3-methoxyprop-1-vn-1-yl)pyridoi4,3-cflpyrimidin-5(6/-/)-one

Intermediate B (58 mg, 0.143 mmol) was reacted with 4-(4-(azetidin-1-yl)piperidin-1-yl)-3- methylaniline (obtained as described in Example 17, Steps 1-4) according to General Procedure 1 yielding the title compound as yellow solid (24 mg, 28%).

LCMS (Method B): R_T = 1.04 min, m/z = 603/605/607 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-d6) d 10.34 (s, 1 H), 9.14 (s, 1 H), 8.28 (s, 1 H), 8.02-7.86 (m,

1 H), 7.86-7.68 (m, 3H), 7.66-7.54 (m, 1 H), 7.00 (d, 1 H), 4.40 (s, 2H), 3.35 (s, 3H), 3.21- 3.06 (m, 4H), 3.04-2.95 (m, 2H), 2.61-2.53 (m, 2H), 2.24 (s, 3H), 2.20-2.1 1 (m, 1 H), 2.01- 1.91 (m, 2H), 1.78-1.69 (m, 2H), 1.37-1.27 (m, 2H).

Example 19: 2-((4-(G 1 ,3'-Biazetidinl-1 '-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)- 5-oxo-5,6-dihvdropyridoi4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl [1 ,3'-biazetidine]-1 '-carboxylate

tert- Butyl 3-oxoazetidine-1 -carboxylate (300.0 mg, 1.75 mmol) was dissolved in 1 ,2- dichloroethane (2 ml_) and azetidine (0.12 ml_, 1.75 mmol) was added followed by acetic acid (0.01 ml_, 0.088 mmol). The reaction mixture was stirred at RT overnight. Then sodium triacetoxyborohydride (743 mg, 3.50 mmol) was added and the stirring was continued for 4h. Next saturated Na₂C0₃ aq. (10 ml_) was added and the resultant mixture was extracted with DCM (3x10 ml_). The organic extracts were combined dried (anh. MgS0₄) and evaporated under reduced pressure yielding a clear oil of product that was used in the next step without further purification (367 mg, 98%).

¹ H NMR (500 MHz, CDCI₃) d 3.88 (dd, J = 9.2, 7.0 Hz, 2H), 3.71 (dd, J = 9.0, 4.5 Hz, 2H), 3.33-3.26 (m, 1 H), 3.23 (t, J = 7.1 Hz, 4H), 2.15-2.06 (m, 2H), 1.42 (s, 9H).

Step 2: 1 ,3'-Biazetidine ditrifluoroacetate tert- Butyl [1 ,3'-biazetidine]-T-carboxylate carboxylate (362 mg, 1.70 mmol) was dissolved in DCM (6 ml_) and TFA (3.0 ml_) was added. The reaction mixture was stirred for 30 min at RT and then the volatiles were evaporated under reduced pressure. The crude product was used in the next step without further purification (580 mg, 100%).

¹ H NMR (500 MHz, DMSO-d6) d 9.18-8.86 (m, 2H), 4.49 (p, J = 7.9 Hz, 1 H), 4.25-3.96 (m, 8H), 2.42-2.25 (m, 2H).

Step 3: 1 '-(2-Methoxy-4-nitrophenyl)-1 ,3'-biazetidine

1-Fluoro-2-methoxy-4-nitrobenzene (282 mg, 1.65 mmol), 1 ,3'-biazetidine ditrifluoroacetate (560 mg, 1.65 mmol) and potassium carbonate (1600 mg, 11.5 mmol) were suspended in DMA (3 ml_). The reaction mixture was heated at 80 °C for 16h. Next transferred to a separatory funnel, water (40 ml_) and EtOAc (40 ml_) were added. The aqueous layer was separated and discarded. The organic layer was washed 2x with water/brine 1/1 (40 ml_), dried (anh. MgS0₄) and evaporated under reduced pressure. The residue was purified by flash chromatography (0-20 MeOH in DCM) yielding the title compound as yellow oil (370 mg, 85%).

LCMS (Method B): R_T = 0.60min, m/z = 264 [M+H]⁺.

Step 4: 4-([1 ,3'-Biazetidin]-T-yl)-3-methoxyaniline To 1 '-(2-methoxy-4-nitrophenyl)-1 ,3'-biazetidine (430 mg, 1.63 mmol) was added MeOH (15 ml_), water (3 ml_), iron (912 mg, 16.3 mmol), and ammonium chloride (874 mg, 16.3 mmol). The reaction mixture was refluxed for 2h and then chilled to RT and filtered through Celite. The Celite was washed with EtOAc and MeOH. The filtrate was evaporated under reduced pressure. The residue was dissolved in EtOAc 1 M NaOH + brine mixture (EtOAc 40ml_ and 40 ml_ aqueous) and the organic layer was separated. The aqueous phase was extracted with EtOAc (5x 40 ml_). The extracts were combined, dried (anh. MgS0₄) and evaporated under reduced pressure yielding the title compound as a yellow /brown oil. The product was used in the next step without further purification (280 mg, 73%).

¹ H NMR (500 MHz, CDCI₃) d 6.31 (d, 1 H), 6.25-6.20 (m, 2H), 3.83 (t, 2H), 3.75 (s, 3H), 3.58-3.51 (m, 2H), 3.48-3.42 (m, 1 H), 3.26 (t, 4H), 2.12-2.04 (m, 3H).

Step 5: 2-((4-([ 1 ,3'-Biazetidin]- 1 '-yl)-3-methoxyphenyl)amino)-6-(2, 6-dichlorophenyl)-5-oxo- 5, 6-dihydropyrido[4, 3-d]pyrimidine-8-carbonitrile

Intermediate A (100 mg, 0.275 mmol) was reacted with 4-([1 ,3'-biazetidin]-T-yl)-3- methoxyaniline according to General Procedure 1 yielding the title compound as brownish solid (16 mg, 11 %).

LCMS (Method B): R_T = 0.98 min, m/z = 548/550/552 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.53 (s, 1 H), 9.14 (s, 1 H), 8.94 (s, 1 H), 7.89 (s, 1 H), 7.78 (d, 2H), 7.68-7.61 (m, 1 H), 7.16 (d, 1 H), 6.36 (d, 1 H), 3.88-3.66 (m, 5H), 3.56 (dd, 2H), 3.43-3.35 (m, 1 H), 3.18 (t, 3H), 1.98 (p, 2H).

Example 20: 2-((4-(H ,3'-Biazetidinl-T-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)-

8-(3-methoxyprop-1-vn-1-yl)pyridor4,3-cflpyhmidin-5(6/-/)-one

Intermediate B (100 mg, 0.246 mmol) was reacted with 4-([1 ,3'-biazetidin]-T-yl)-3- methoxyaniline (Obtained as described in Example 19, Steps 1-4) according to General Procedure 1 yielding the title compound as brownish solid (9 mg, 6%). LCMS (Method B): R_T = 0.99 min, m/z = 591/593/595 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.26 (s, 1 H), 9.12 (s, 1 H), 8.26 (s, 1 H), 7.74 (d, 2H), 7.72-7.64 (m, 1 H), 7.64-7.56 (m, 1 H), 7.52-7.37 (m, 1 H), 6.36 (d, 1 H), 4.37 (s, 2H), 3.83 (t, 2H), 3.74 (s, 3H), 3.55 (dd, 2H), 3.43-3.36 (m, 1 H), 3.35 (s, 3H), 3.19 (t, 4H), 1.99 (p, 2H).

Example 21 : 6-(2,6-Dichlorophenyl)-8-(3-methoxyprop-1 -vn-1 -yl)-2-((4-(4-methylpiperidin-4- yl)phenyl)amino)pyridoi4,3-dlpyrimidin-5(6/-/)-one

Intermediate B (140 mg, 0.344 mmol) was reacted with tert- butyl 4-(4-aminophenyl)-4- methylpiperidine-1 -carboxylate (obtained as described in Example 1 , Step 1 -3 according to General Procedure 1 . The obtained material was reacted according to General Procedure 2, yielding the title compound as a yellow solid (45 mg, 24%).

LCMS (Method B): R_T = 0.95 min, m/z = 548/550/552 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.53 (s, 1 H), 9.23-9.14 (m, 1 H), 8.33-8.25 (m, 1 H), 8.16- 7.92 (m, 2H), 7.74 (d, 2H), 7.60 (t, J = 8.2 Hz, 1 H), 7.40-7.22 (m, 2H), 4.43 (s, 2H), 3.38 (s, 3H), 2.96-2.84 (m, 2H), 2.78-2.66 (m, 2H), 2.07-1 .96 (m, 2H), 1 .73-1 .64 (m, 2H), 1 .24-1.15 (m, 3H).

Example 22: 6-(2,6-Dichlorophenyl)-2-((4-(1 ,4-dimethylpiperidin-4-yl)phenyl)amino)-8-(3- methoxyprop-1 -vn-1 -yl)pyridoi4,3-cflpyhmidin-5(6/-/)-one

6-(2,6-Dichlorophenyl)-8-(3-methoxyprop-1-yn-1-yl)-2-((4-(4-methylpiperidin-4- yl)phenyl)amino)pyrido[4,3-c]pyrimidin-5(6/-/)-one (53 mg, 0.097 mmol) (obtained as described in Example 21) was reacted according to General Procedure 4 yielding the title compound as yellow solid (10 mg, 18%).

LCMS (Method B): R_T = 0.96 min, m/z = 562/564/566 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.51 (s, 1 H), 9.18 (s, 1 H), 8.30 (s, 1 H), 8.14-7.94 (m, 2H), 7.74 (d, , 2H), 7.64-7.55 (m, 1 H), 7.33 (d, 2H), 4.43 (s, 2H), 3.37 (s, 3H), 2.42-2.18 (m, 4H), 2.12 (s, 3H), 2.08-1.96 (m, 2H), 1.77-1.63 (m, 2H), 1.16 (s, 3H).

Example 23: 6-(2,6-Dichlorophenyl)-2-((4-(3-methylpiperidin-3-yl)phenyl)amino)-5-oxo-5,6- dihvdropyridoi4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl 3-(4-aminophenyl)-3-methylpiperidine-1-carboxylate

A solution of 3-methyl-3-phenylpiperidine (5.7 g, 32.41 mmol) in MTBE (50 mL) was cooled to-5 °C. To this solution was added 57.5 % nitric add (2.77 ml, 34.0 mol). After the addition the mixture was agitated at this temperature for 10 min. The solid was filtered, washed with TBME and dried under vacuum. Then the salt was suspended in DCM (30 mL) and slowly added to H₂S0₄ (20 mL) at-5 °C. After the addition the mixture was agitated at this temperature for 3b at RT. The reaction mixture was poured onto 300 mL ice/water, basified with Na₂C0₃ (pH > 10) and extracted with dich!oromethane. The organic layer was separated, dried and evaporated. The crude 3-methy!-3-(4-nitrophenyl)piperidine (containing meta-isomer) was used for the next step without purification (4 g, 93 %).

To a solution of 3-methy!-3-(4-nitropheny!)piperidine (4 g, 18.16 mmol) in DCM (40 mL) di- fe/f-butyl dicarbonate (3.96 g, 18.16 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was washed with hexane and dried yielding the crude tert- butyl 3-(4-nitrophenyl)-3-methyl-piperidine-1- carboxylate (5.5 g, 94 %). This was dissolved in methanol (60 mL), degassed and treated with 10 % Pd/C (0.55 g). The suspension was shaken under 55 psi hydrogen overnight and then filtered through a bed of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography yielding the title compound as a brown solid 0.56 g (1 1 %). ¹ H NMR (400 MHz, CDCI₃) d 7.17 (d, J = 8.1 Hz, 2H), 6.68 (d, J = 8.0 Hz, 2H), 3.96-3.49 (m, 4H), 3.49-3.37 (m, 2H), 3.33-3.20 (m, 1 H), 2.08-1.91 (m, 1 H), 1.79-1.54 (m, 2H), 1.47 (s, 9H), 1.17 (s, 3H).

Step 2: tert-Butyl 3-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)phenyl)-3-methylpiperidine-1-carboxylate

Imtermediate A (125 mg, 0.344 mmol) was reacted with tert- butyl 3-(4-aminophenyl)-3- methylpiperidine-1-carboxylate according to General Procedure 1 yielding the title compounds as a yellow gum (195 mg, 94%).

LCMS (Method B): R_T = 1.73 min, m/z = 549/551/553 [M+H-56]⁺.

Step 3: 6-(2, 6-Dichlorophenyl)-2-((4-(3-methylpiperidin-3-yl)phenyl)amino)-5-oxo-5, 6- dihydropyrido[4,3-d]pyrimidine-8-carbonitrile

To tert- butyl 3-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin- 2-yl)amino)phenyl)-3-methylpiperidine-1-carboxylate (195 mg, 0.322 mmol) in DCM (20 ml_) was added 4 M HCI in 1 ,4-dioxane (0.13 ml_, 3.86 mmol). The reaction was then stirred at RT for 3 days. The precipitated solid was collected by filtration washed with DCM and dried. This was dissolved in DCM:MeOH and loaded onto a pre-washed with DCM SCX-2 cartridge, the cartridge was washed with 20% MeOH in DCM and the product eluted with 20% 7M NH₃ in DCM. Fractions containing the desired product were evaporated under vacuum yielding the title compound as yellow solid (94 mg, 56%).

LCMS (Method B): R_T = 0.92 min, m/z = 505/507/509 [M+H-56]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.77-10.49 (m, 1 H), 9.24-9.15 (m, 1 H), 9.00-8.91 (m, 1 H), 8.09-7.81 (m, 2H), 7.83-7.73 (m, 2H), 7.70-7.59 (m, 1 H), 7.45-7.32 (m, 2H), 3.10 (d, J = 12.6 Hz, 1 H), 2.92-2.78 (m, 2H), 2.74-2.65 (m, 1 H), 2.04-1.93 (m, 1 H), 1.74-1.53 (m, 2H), 1.50-1.40 (m, 1 H), 1.29-1.23 (m, 1 H), 1.22 (s, 3H).

Example 24: 6-(2,6-Dichlorophenyl)-2-((4-(1 ,3-dimethylpiperidin-3-yl)phenyl)amino)-5-oxo- 5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

A mixture of 6-(2,6-dichlorophenyl)-2-((4-(3-methylpiperidin-3-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile (60 mg, 0.119 mmol) (obtained as described in Example 23), MeOH (0.5 ml_), MeCN (3 ml_) and 37% aqueous formaldehyde solution (0.12 ml_, 0.59 mmol) was cooled in an ice bath, sodium triacetoxyborohydride (126 mg, 0.59 mmol) was then added by portion. After addition the reaction was stirred for 30 min at 0°C and 2hr at RT. The reaction was concentrated, taken up in DCM and washed with 2M aq.Na₂C0₃ twice followed by water. The organic layer was dried and evaporated under reduced pressure yielding the title compound as a yellow solid (52 mg, 84%).

LCMS (Method B): R_T = 0.92 min, m/z = 519/521/523 [M+H-56]⁺.

¹H NMR (500 MHz, DMSO-cfe) d 10.76-10.48 (m, 1 H), 9.20 (s, 1 H), 8.95 (s, 1 H), 8.06-7.81 (m, 2H), 7.78 (d, J = 8.2 Hz, 2H), 7.70-7.58 (m, 1 H), 7.38 (d, J = 8.8 Hz, 2H), 2.66-2.54 (m, 1 H), 2.35-2.20 (m, 3H), 2.18 (s, 3H), 1.89-1.78 (m, 1 H), 1.64-1.45 (m, 2H), 1.46-1.35 (m, 1 H), 1.26-1.15 (m, 4H).

Example 25: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2,7-diazaspiror3.5lnonan-7- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl 7-(2-methoxy-4-nitrophenyl)-2, 7-diazaspiro[3.5]nonane-2-carboxylate To a solution of 1-fluoro-2-methoxy-4-nitrobenzene (378 mg, 2.21 mmol) in DMA (15 ml_) was added tert- butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (500 mg, 2.21 mmol) and potassium carbonate (1.53 g, 11.05 mmol). The reaction mixture was stirred in a sealed vial overnight. The reaction mixture was allowed to cool before it was diluted with EtOAc and washed with water, the aqueous was extracted once more with EtOAc. The combined organic extracts were then washed with 50% sat. brine three times, dried (anh. MgS0₄) and concentrated in vacuo. The crude residue was then purified by column

chromatography (5-55% EtOAc in cyclohexane) to afford the title compound (668 mg, 1.56 mmol, 70%) as a yellow solid.

LCMS (Method B): R_T = 1.60 min, m/z = 378 [M+H]⁺. Step 2: tert-Butyl 7-(4-amino-2-methoxyphenyl)-2, 7-diazaspiro[3.5]nonane-2-carboxylate To tert- butyl 7-(2-methoxy-4-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.66 g, 1.75 mmol) was added EtOH (30 ml_). The reaction was heated to 55 °C and 10% Pd/C (130 mg, 0.122 mmol) was added followed by ammonium formate (0.66 g, 10.49 mmol) added by portion. The reaction mixture was heated until intensive gas evolution. After cooling the reaction was filtered through Celite and the filter cake was washed with EtOH. The filtrate was concentrated in vacuo and the residue was taken up in DCM and washed with aqueous NaHC0₃ twice followed by brine. The organic layer was dried and concentrated to dryness. The residue was purified by flash chromatography (0-10% EtOAc in cyclohexane) yielding the title compound as a pink solid (586 mg, 96%).

LCMS (Method B): R_T = 0.64 min, m/z = 348 [M+H]⁺.

Step 3: tert-Butyl 7-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)-2-methoxyphenyl)-2, 7-diazaspiro[3.5]nonane-2-carboxylate

Intermediate A (100 mg, 0.275 mmol) was reacted with tert- butyl 7-(4-amino-2- methoxyphenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate according to General Procedure 1 yielding the title compound a yellow solid (183 mg, 100%).

LCMS (Method B): R_T = 1.23 min, m/z = 662/664/666 [M+H]⁺.

Step 4: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2, 7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile

To a solution of tert- butyl 7-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-2-methoxyphenyl)-2,7-diazaspiro[3.5]nonane-2- carboxylate (180 mg, 0.272 mmol) in DCM (20 mL) was added 4 M HCI in 1 ,4-dioxane (0.11 mL, 3.26 mmol). The reaction was then stirred at RT over the weekend. The precipitated yellow solid was collected by filtration washed with DCM and dried, this afforded the desired product as the HCI salt (110mg, 63%). The free base was obtained by preparative LCMS in basic conditions.

LCMS (Method B): R_T = 0.75 min, m/z = 562/564/566 [M+H]⁺.

¹H NMR (500 MHz, CDCI₃) d 9.25 (s, 1 H), 8.04 (s, 1 H), 7.76 (s, 1 H), 7.68 (s, 1 H), 7.54 (d, 2H), 7.45 (dd, 1 H), 6.97-6.81 (m, 2H), 4.14-3.80 (m, 4H), 3.44 (s, 3H), 3.05-2.82 (m, 4H), 2.04-1.89 (m, 4H). Example 26: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2-methyl-2,7-diazaspiror3.5lnonan-7- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5- oxo-5, 6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile hydrochloride (50 mg, 0.084 mmol) (obtained as described in Example 25), MeCN (3 ml_), MeOH (0.5 ml_) and 37% aqueous formaldehyde solution (0.08 ml_, 0.42 mmol) was cooled in an ice bath. Sodium triacetoxyborohydride (88 mg, 0.42 mmol) was then added by portion. The reaction was stirred for 30 min at 0°C and 2h at RT. The reaction was concentrated and the residue taken up in DCM and washed twice with 2M aq.Na₂C0₃ followed by water. The organic layer was dried and evaporated under reduced pressure. The residue was purified by flash chromatography (20-100% EtOAc in cyclohexane) yielding the title compound as a white solid (25 mg, 52%).

LCMS (Method B): R_T = 0.79 min, m/z = 576/578/580 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) d 10.59 (s, 1 H), 9.17 (s, 1 H), 8.95 (s, 1 H), 8.00-7.86 (m, 1 H), 7.77 (d, 2H), 7.69-7.59 (m, 1 H), 7.25-7.17 (m, 1 H), 6.85 (d, 1 H), 3.87 (s, 3H), 2.93 (s, 4H), 2.88-2.75 (m, 4H), 2.23 (s, 3H), 1.84-1.70 (m, 4H).

Example 27: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(1 ,6-diazaspiror3.3lheptan-6- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl 6-(2-methoxy-4-nitrophenyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of 1-fluoro-2-methoxy-4-nitrobenzene (135 mg, 0.79 mmol) in DMA (2 ml_) was added tert- butyl 1 ,6-diazaspiro[3.3]heptane-1-carboxylate oxalate (192 mg, 0.39 mmol) and potassium carbonate (545 mg, 3.94 mmol). The reaction was stirred at 120°C overnight. The reaction mixture was allowed to cool before it was diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with 50% sat. brine three times, dried (anh. MgS0₄) and concentrated in vacuo. The crude residue was purified by column chromatography (5-42% EtOAc in cyclohexane) yielding the title compound (240 mg, 87%) as a yellow gum.

LCMS (Method B): R_T = 1.45 min, m/z = 350 [M+H]⁺.

Step 2: tert-Butyl 6-(4-amino-2-methoxyphenyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate To a solution of te/f-butyl 6-(2-methoxy-4-nitrophenyl)-1 ,6-diazaspiro[3.3]heptane-1- carboxylate (310 mg, 0.89 mmol) in MeOH (1.5 ml_) and DCM (1.5 ml_) was charged tin (II) chloride dihydrate (601 mg, 2.66 mmol). The reaction was stirred at RT for 3 days. The reaction was poured onto 10M NaOH and DCM was added. The layers were separated and the organic layer washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography (20-100% ethyl acetate in

cyclohexane) yielding the title compound (30 mg, 10%) yield) as a brown gum.

LCMS (Method B): R_T = 0.70 min, m/z = 320 [M+H]⁺.

Step 3: tert-Butyl 6-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)-2-methoxyphenyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate Intermediate A (34 mg, 0.094 mmol) was reacted with tert- butyl 6-(4-amino-2- methoxyphenyl)-1 ,6-diazaspiro[3.3]heptane-1-carboxylate according to General Procedure 1 , yielding the title compound (35 mg, 59%) as an orange gum.

LCMS (Method B): R_T = 1.51 min, m/z = 634/636/638 [M+H]⁺.

Step 4: 6-(2, 6-Dichlorophenyl)-2-((3-methoxy-4-( 1, 6-diazaspiro[3.3]heptan-6- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile

To a solution of tert- butyl 6-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)-2-methoxyphenyl)-1 ,6-diazaspiro[3.3]heptane-1- carboxylate (35 mg, 0.055 mmol) in DCM (2 mL) at RT was charged TFA (0.5 mL, 6.49 mmol). The reaction was then stirred at RT for 2.5 h. The reaction mixture was loaded onto a pre-washed (20% MeOH in DCM) SCX-2 (5g) cartridge, the cartridge was then washed with 20% MeOH in DCM (50 mL) and the product eluted with 20% 7N NH₃ in MeOH in DCM. The product containing fractions were evaporated under reduced pressure yielding the title compound (23 g, 79%) as an orange solid.

LCMS (Method B): R_T = 0.92 min, m/z = 534/536/538 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.52 (s, 1 H), 9.14 (s, 1 H), 8.93 (s, 1 H), 7.89 (s, 1 H), 7.77 (d, , 2H), 7.69-7.54 (m, 1 H), 7.21-7.12 (m, 1 H), 6.35 (d, 1 H), 3.99 (d, 2H), 3.82 (s, 3H), 3.70 (d, 2H), 3.35-3.29 (m, 2H), 2.44 (t, 2H).

Example 28: _ 2-((4-(Azetidin-3-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihvdropyridoi4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl 3-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate

Intermediate A (150 mg, 0.454 mmol) was reacted with tert- butyl 3-(4- aminophenyl)azetidine-1-carboxylate according to General Procedure 1 yielding the title compound (65 mg, 28%).

LCMS (Method B): R_T = 1.56 min, m/z = 507/509/511 [M+H]⁺.

Step 2: 2-((4-(Azetidin-3-yl)phenyl)amino)-6-(2, 6-dichlorophenyl)-5-oxo-5, 6- dihydropyrido[4,3-d]pyrimidine-8-carbonitrile

To tert- butyl 3-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin- 2-yl)amino)phenyl)azetidine-1-carboxylate (65 mg, 0.12 mmol) in DCM (10 mL) was added 4 M HCI in 1 ,4-dioxane (0.35 mL, 1.38 mmol). The reaction was then stirred at RT for 3 days. Reaction mixture was evaporated under reduced pressure and the product was purified by Prep HPLC in basic conditions yielding the title compound as a yellow solid (7 mg, 13%).

LCMS (Method B): R_T = 1.56 min, m/z = 507/509/511 [M+H]⁺. Ή NMR (500 MHz, DMSO-cfe) d 10.71 (s, 1 H), 9.22 (s, 1 H), 8.96 (s, 1 H), 8.09-7.85 (m, 2H), 7.79 (d, 2H), 7.70-7.59 (m, 1 H), 7.35 (d, 2H), 3.89-3.80 (m, 1 H), 3.77 (t, 2H), 3.62 (t, 2H).

Example 29: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(1-methyl-1 ,7-diazaspiroi3.5lnonan-7- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridoi4,3-cflpyrimidine-8-carbonitrile

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(1 ,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5- oxo-5, 6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile (as obtained in Example 2, steps 1-3) (38 mg, 0.068 mmol) was reacted according to General Procedure 4 before being further purified by flash chromatography (0-100% EtOAc in Cyclohexane, then 0-50% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to yield the title compound (32 mg, 81 %) as a yellow solid.

LCMS (Method B): R_T = 0.93 min, m/z = 576/578 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.6 (s, NH), 9.18 (s, 1 H), 8.95 (s, 1 H), 7.95 (broad s,

1 H), 7.80-7.74 (m, 2H), 7.67-7.61 (m, 1 H), 7.25-7.18 (d, 1 H), 6.89-6.84 (d, 1 H), 3.88 (s,

3H), 3.28-3.23 (m, 2H), 3.1 1-3.06 (m, 2H), 2.55-2.53 (m, 2H), 2.13 (s, 3H), 1.91-1.85 (m, 2H), 1.77-1.66 (m, 4H).

Example 30: 2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-5- oxo-5, 6-dihydropyridor4,3-dlpyrimidine-8-carbonitrile

Step 1: tert-Butyl (1-(2-methyl-4-nitrophenyl)piperidin-4-yl)carbamate: 1-Fluoro-2-methyl-4-nitrobenzene (1 g, 6.45 mmol) was dissolved in DMA (20 ml_) and tert- butyl piperidin-4-ylcarbamate (1.29 g, 6.45 mmol) was added followed by potassium carbonate (2.67 g, 19.34 mmol). The suspension was heated to 120°C and stirred for 48 hours before cooling to RT and diluting with EtOAc. The organic phase was washed with 1 x water and 3 x 50% saturated brine solution and dried (anh. MgS0₄) and concentrated in vacuo to give the crude product (2.57 g, 89%) as a yellow brown oil which was taken on as such into the next step.

LCMS (Method A): R_T = 1.72 min, m/z = 336 [M+H]⁺.

Step 2: tert-Butyl (1-(4-amino-2-methylphenyl)piperidin-4-yl)carbamate:

tert- Butyl (1-(2-methyl-4-nitrophenyl)piperidin-4-yl)carbamate (1.95 mg, 5.81 mmol) was dissolved in EtOH (50 ml_), heated to 70°C and 10% Pd/C (37 mg, 0.349 mmol) was added followed by ammonium formate (2.20 g, 34.88 mmol). The temperature was increased to 90°C and the reaction was stirred for 1 hour before it was cooled to RT and filtered through Celite. The Celite was washed with EtOAc and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (0-100% EtOAc in cyclohexane) to give the product (1.40 g, 79%) as a yellow solid.

LCMS (Method A): R_T = 0.55 min, m/z = 306 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) d 6.86 (d, 1 H), 6.56-6.53 (m, 1 H), 6.51-6.47 (m, 1 H), 4.53- 4.45 (m, 1 H), 3.64-3.49 (broad s, 1 H), 2.98-2.92 (m, 2H), 2.70-2.63 (m, 2H), 2.21 (s, 3H), 2.04-1.97 (m, 2H), 1.59-1.50 (m, 2H), 1.46 (s, 9H).

Step 3: 2-((4-(4-Aminopiperidin- 1-yl)-3-methylphenyl)amino)-6-(2, 6-dichlorophenyl)-5-oxo- 5, 6-dihydropyrido[4, 3-d]pyrimidine-8-carbonitrile:

Intermediate A (238 mg, 0.655 mmol) was reacted with tert- butyl (1-(4-amino-2- methylphenyl)piperidin-4-yl)carbamate (200 mg, 0.655 mmol) according to General procedure 1. The product precipitated out of the reaction mixture and this was isolated via vacuum filtration and washed with 2-propanol to give tert- butyl (1-(4-((8-cyano-6-(2,6- dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)-2- methylphenyl)piperidin-4-yl)carbamate as a beige solid (304 mg, 70%). This material was reacted according to General Procedure 3, followed by further purification via column chromatography (20-100% EtOAc in cyclohexane, then 0-50% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to yield the title compound (82 mg, 32%) as a yellow solid.

LCMS (Method A): R_T = 0.91 min, m/z = 520/522 [M+H]⁺. ¹ H NMR (500 MHz, DMSO-cfe) d 1 1.57-9.80 (bs, 1 H), 9.36-9.1 1 (m, 1 H), 9.04-8.78 (m, 1 H), 8.16-7.35 (m, 5H), 7.12-6.92 (m, 1 H), 3.14-2.93 (m, 2H), 2.84-2.55 (m, 3H), 2.34-2.18 (m, 3H), 2.04-1.48 (m, 4H), 1.47-1.33 (m, 2H).

Example 31 : 6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-c]pyrimidine-8-carbonitrile (as obtained in example 30, steps 1-2) (59 mg, 0.113 mmol) was reacted according to General Procedure 4 and further purified via flash chromatography (0-5% MeOH in DCM) to give the target compound (47 mg, 76%) as a yellow solid.

LCMS (Method A): R_T = 0.98 min, m/z = 547/549 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.6 (broad s, 1 H), 9.17 (s, 1 H), 8.95 (s, 1 H), 8.04 (broad s, 1 H), 7.80-7.76 (m, 2H), 7.70-7.62 (m, 2H), 7.00 (d, 1 H), 3.09-3.04 (m, 2H), 2.62-2.55 (m, 2H), 2.26 (s, 3H), 2.21 (s, 6H), 2.20-2.14 (m, 1 H), 1.87-1.80 (m, 2H), 1.58-1.49 (m, 2H).

Example 32: 2-((4-(4-Aminopiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)- 5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl (1-(2-methoxy-4-nitrophenyl)piperidin-4-yl)carbamate:

tert- Butyl piperidin-4-ylcarbamate (500 mg, 3.22 mmol) was dissolved in DMA (10 ml_) and 1-fluoro-2-methoxy-4-nitrobenzene (552 mg, 3.22 mmol) was added followed by potassium carbonate (2.23 g, 16.1 1 mmol). The suspension was heated to 120°C and stirred for 48 hours before cooling to RT and diluting with EtOAc. The organic phase was washed with 1 x water and 3 x 50% saturated brine solution and dried (anh. MgS0₄) and concentrated in vacuo to give the crude product (1.02 g, 75%) as an orange solid which was taken on as such into the next step.

LCMS (Method A): R_T = 1.60 min, m/z = 352 [M+H]⁺.

Step 2: tert-Butyl ( 1-(4-amino-2-methoxyphenyl)piperidin-4-yl)carbamate :

tert- Butyl (1-(2-methoxyl-4-nitrophenyl)piperidin-4-yl)carbamate (1.02 mg, 2.90 mmol) was dissolved in EtOH (25 ml_), heated to 70°C and 10% Pd/C (31 mg, 0.290 mmol) was added followed by ammonium formate (1.10 g, 17.42 mmol). The temperature was increased to 90 °C and the reaction was stirred for 1 hour before it was cooled to RT and filtered through Celite. The Celite was washed with EtOAc and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (0-100% EtOAc in cyclohexane) to give the product (846 mg, 80%) as a light brown solid.

LCMS (Method A): R_T = 0.53 min, m/z = 322 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 6.82-6.76 (m, NH), 6.63-6.58 (m, 1 H), 6.22-6.19 (m, 1 H), 6.08-6.03 (m, 1 H), 4.68 (s, 2NH), 3.67 (s, 3H), 3.30-3.23 (broad s, 1 H), 3.07-3.02 (m, 2H), 2.48-2.41 (m, 2H), 1.74-1.69 (m, 2H), 1.52-1.43 (m, 2H), 1.38 (s, 9H).

Step 3: 2-((4-(4-Aminopiperidin- 1-yl)-3-methoxyphenyl)amino)-6-(2, 6-dichlorophenyl)-5- oxo-5, 6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile:

Intermediate A (200 mg, 0.551 mmol) was reacted with tert- butyl (1-(4-amino-2- methoxyphenyl)piperidin-4-yl)carbamate (177 mg, 0.551 mmol) according to General procedure 1. The product precipitated out of the reaction mixture and this was isolated via vacuum filtration and washed with 2-propanol to give tert- butyl (1-(4-((8-cyano-6-(2,6- dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-2- methoxyphenyl)piperidin-4-yl)carbamate as a beige solid (245 mg, 70%). This material was reacted according to General Procedure 3, followed by further purification via column chromatography (20-100% EtOAc in cyclohexane, then 0-50% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to yield the title compound (172 mg, 82%) as a yellow solid.

LCMS (Method A): R_T = 0.76 min, m/z = 535/537 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 1 1.68-9.77 (bs, 1 H), 9.32-9.14 (m, 1 H), 9.02-8.78 (m, 1 H), 8.01-7.57 (m, 4H), 7.27-7.12 (m, 1 H), 6.96-6.83 (m, 1 H), 3.97-3.72 (m, 3H), 3.29-3.22 (m, 2H), 2.85-2.53 (m, 3H), 1.97-1.49 (m, 4H), 1.46-1.31 (m, 2H). Example 33: 2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2-chloro-6- methylphenyl)-5-oxo-5,6-dihvdropyridoi4,3-dlpyrimidine-8-carbonitrile

Intermediate D (200 mg, 0.551 mmol) was reacted with tert- butyl (1-(4-amino-2- methylphenyl)piperidin-4-yl)carbamate ( obtained as described in Example 30, Steps 1-2) (168 mg, 0.551 mmol) according to General procedure 1. The product precipitated out of the reaction mixture and this was isolated via vacuum filtration and washed with 2-propanol to give tert- butyl (1-(4-((6-(2-chloro-6-methylphenyl)-8-cyano-5-oxo-5,6-dihydropyrido[4,3- c(]pyrimidin-2-yl)amino)-2-methylphenyl)piperidin-4-yl)carbamate as a yellow solid (304 mg, 70%). This material was reacted according to General Procedure 3 to yield the title compound (188 mg, 99%) as a yellow solid.

LCMS (Method A): R_T = 0.94 min, m/z = 500/502 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) d 10.6-10.4 (broad s, NH), 9.16 (s, 1 H), 8.81 (s, 1 H), 8.07- 8.01 (broad s, Atropisomer A, 0.5H), 7.72-7.65 (broad s, Atropisomer B, 0.5H), 7.58-7.54 (m, 1 H), 7.51-7.43 (m, 3H), 7.02-6.97 (m, 1 H), 3.03-2.95 (m, 2H), 2.72-2.65 (m, 1 H), 2.63- 2.56 (m, 2H), 2.25 (s, 3H), 2.16 (s, 3H), 1.84-1.77 (m, 2H), 1.46-1.36 (m, 2H).

Example 34: 2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-8- (3-methoxyprop-1-vn-1-yl)pyridor4,3-cflpyhmidin-5(6/-/)-one

Intermediate B (200 mg, 0.492 mmol) was reacted with tert- butyl (1-(4-amino-2- methylphenyl)piperidin-4-yl)carbamate ( obtained as described in Example 30, Steps 1-2) (150 mg, 0.492 mmol) according to General procedure 1. The reaction was cooled to RT and the solvent removed in vacuo before the resulting residue was purified by flash chromatography (0-40% EtOAc in Cyclohexane) to give tert- butyl (1-(4-((6-(2,6- dichlorophenyl)-8-(3-methoxyprop-1-yn-1-yl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2- yl)amino)-2-methylphenyl)piperidin-4-yl)carbamate as a yellow solid (170 mg, 51 %). This material was reacted according to General Procedure 3 to yield the title compound (11 1 mg, 77%) as a yellow solid.

LCMS (Method A): R_T = 0.94 min, m/z = 562/564 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.45-10.30 (broad s, NH), 9.14 (s, 1 H), 8.29 (s, 1 H), 8.02-7.92 (broad s, 1 H), 7.82-7.75 (broad s, 1 H), 7.75-7.72 (m, 2H), 7.62-7.58 (m, 1 H), 7.02-6.97 (m, 1 H), 4.40 (s, 2H), 3.35 (s, 3H), 3.02-2.96 (m, 2H), 2.73-2.66 (m, 1 H), 2.62- 2.56 (m, 2H), 2.25 (s, 3H), 1.84-1.78 (m, 2H), 1.47-1.37 (m, 2H).

Example 35: 6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methoxyphenyl)amino)-5-oxo-5,6-dihvdropyridoi4,3-cflpyrimidine-8-carbonitrile

2-((4-(4-Aminopiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile (obtained as described in example 32, steps 1-3) (50 mg, 0.093 mmol) was reacted according to General Procedure 4 before being further purified by flash chromatography (0-100% EtOAc in Cyclohexane, then 0-30% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to yield the title compound (29 mg, 56%) as a yellow solid.

LCMS (Method B): R_T = 0.81 min, m/z = 564/566 [M+H]⁺.

¹ H NMR (500 MHz, CDCI₃) d 9.26 (broad s, NH), 8.06 (s, 1 H), 7.77 (s, 1 H), 7.71 (s, 1 H), 7.56-7.52 (m, 2H), 7.48-7.43 (m, 1 H), 7.00 (d, 1 H), 6.97-6.93 (m, 1 H), 6.92-6.87 (m, 1 H), 4.08-3.87 (m, 3H) 3.59-3.52 (m, 2H), 2.62-2.54 (m, 2H), 2.36-2.28 (m, 7H), 1.93-1.87 (m, 2H), 1.83-1.74 (m, 2H).

Example 36: 2-((4-(1 ,7-Diazaspiror3.5lnonan-7-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5- oxo-5, 6-dihydropyridor4,3-dlpyrimidine-8-carbonitrile:

Step 1: tert-Butyl 7-(4-nitrophenyl)-1 , 7-diazaspiro[3.5]nonane-1 -carboxylate:

tert- Butyl piperidin-4-yl carbamate (500 mg, 2.21 mmol) was dissolved in DMA (15 ml_) and 1-fluoro-4-nitrobenzene (commercial, 312 mg, 2.21 mmol) was added followed by potassium carbonate (1.53 g, 11.05 mmol). The suspension was heated to 120°C and stirred for 48 hours before cooling to RT and diluting with EtOAc. The organic phase was washed with 1 x water and 3 x 50% saturated brine solution and dried (anh. MgS0₄) and concentrated in vacuo to give the crude product (877 mg, 89%) as a yellow brown oil. The material was purified by flash chromatography (0-50% EtOAc in Cyclohexane) to give the desired compound as an orange solid (633 mg, 82%).

LCMS (Method A): R_T = 1.61 min, m/z = 348 [M+H]⁺.

Step 2: tert-Butyl 7-(4-aminophenyl)-1 , 7-diazaspiro[3.5]nonane-1 -carboxylate:

tert-Butyl 7-(4-nitrophenyl)-1, 7-diazaspiro[3.5]nonane-1 -carboxylate (633 mg, 1.82 mmol) was dissolved in EtOH (18 ml_), heated to 70°C and 10% Pd/C (19 mg, 0.182 mmol) was added followed by ammonium formate (689 mg, 10.92 mmol). The temperature was increased to 90°C and the reaction was stirred for 1 hour before it was cooled to RT and filtered through Celite. The Celite was washed with EtOAc and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (0-80% EtOAc in cyclohexane) to give the product (499 mg, 85%) as a yellow solid.

LCMS (Method A): R_T = 0.62 min, m/z = 318 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) d 6.71-6.67 (m, 2H), 6.49-6.46 (m, 2H), 3.76-3.63 (m, 2H), 3.35-3.27 (2H), 2.48-2.43 (m, 2H), 2.32-2.13 (m, 2H), 2.02-1.96 (m, 2H), 1.77-1.69 (m, 2H), 1.37 (s, 9H).

Step 3: 2-((4-(1, 7-Diazaspiro[3.5]nonan-7-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo- 5, 6-dihydropyrido[4, 3-d]pyrimidine-8-carbonitrile:

Intermediate A (100 mg, 0.275 mmol) was reacted with tert- butyl 7-(4-aminophenyl)-1 ,7- diazaspiro[3.5]nonane-1 -carboxylate (87 mg, 0.275 mmol) according to General procedure 1. The reaction mixture was allowed to cool and the solvent removed in vacuo before the residue was purified via flash chromatography (0-50% EtOAc in Cyclohexane) to give tert- butyl 7-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2- yl)amino)phenyl)-1 ,7-diazaspiro[3.5]nonane-1 -carboxylate as a yellow solid (127 mg, 73%). This material was reacted according to General Procedure 3 to yield the title compound (92 mg, 86%) as a yellow solid.

LCMS (Method A): R_T = 0.88 min, m/z = 532/534 [M+H]⁺. ¹H NMR (500 MHz, CDCI₃) d 7.79-7.75 (m, 1 H), 7.74 (s, 1 H), 7.63-7.59 (broad s, 1 H), 7.59-7.56 (m, 2H), 7.47-7.42 (m, 2H), 7.03-6.95 (m, 2H), 3.56-3.51 (m, 2H), 3.30-3.24 (m, 2H), 3.10-3.04 (m, 2H), 2.17-2.13 (m, 2H), 1.99-1.93 (m, 2H), 1.90-1.83 (m, 2H).

Example 37: 6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(4-(methylamino)piperidin-1- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridoi4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl methyl(1-(2-methyl-4-nitrophenyl)piperidin-4-yl)carbamate

tert- Butyl (1-(2-methyl-4-nitrophenyl)piperidin-4-yl)carbamate (as obtained in example 1, step 1) (1.1 g, 3.28 mmol) was dissolved in DMF (20 ml_) and cooled to 0 °C before the addition of sodium hydride (60% in mineral oil) (328 mg, 8.20 mmol). The reaction was stirred at 0 °C for 15 minutes before the addition of iodomethane (0.61 ml_, 9.84 mmol). The reaction mixture was allowed to warm to RT and stirred overnight before pouring over saturated ammonium chloride solution (50 ml_) and extracted with EtOAc (2 x 50 ml_). The organics were washed with 50% sat. brine solution (3 x 50 ml_) before being combined, dried (anh. MgS0₄) and evaporated under reduced pressure to give the crude product (1.24 g) as a yellow solid. This was taken on as such into the next step.

LCMS (Method A): R_T = 1.93 min, m/z = 350 [M+H]⁺.

Step 2: tert-Butyl (1 -(4-ami no-2-methyl phenyl) pi peridin-4-yl)(methyl)carbamate

tert- Butyl methyl(1-(2-methyl-4-nitrophenyl)piperidin-4-yl)carbamate (1.19 mg, 3.42 mmol) was dissolved in a 1 :1 solution of EtOH and THF (40 ml_) and SnCI_{2 *} 2H₂0 was added. The reaction was heated to 50°C overnight before being cooled to RT and solvent removed under reduced pressure. The residue was taken up in EtOAc (50 ml_) and washed with 10 N aqueous NaOH solution (20 ml_). The aqueous layer was extracted with EtOAc (2 x 20 ml_) and the combined organics were dried (anh. MgS0₄) and evaporated under reduced pressure before the residue was purified by flash chromatography (0-50% EtOAc in cyclohexane) to give the desired product (681 mg, 62%) as a yellow solid.

LCMS (Method A): R_T = 0.78 min, m/z = 320 [M+H]⁺. ¹ H NMR (500 MHz, DMSO-cfe) d 6.76 (d, 1 H), 6.39-6.37 (m, 1 H), 6.35-6.31 (m, 1 H), 3.95- 3.65 (broad m, 1 H), 2.92-2.87 (m, 2H), 2.71 (s, 3H), 2.60-2.53 (m, 2H), 2.11 (s, 3H), 1.83- 1.72 (m, 2H), 1.61-1.52 (m, 2H), 1.41 (s, 9H).

Step 3: 6-(2, 6-Dichlorophenyl)-2-((3-methyl-4-(4-(methylamino)piperidin- 1- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile

Intermediate A (179 mg, 0.493 mmol) was reacted with tert- butyl (1-(4-amino-2- methylphenyl)piperidin-4-yl)(methyl)carbamate (157 mg, 0.493 mmol) according to General procedure 1. The product precipitated out of the reaction mixture and this was isolated via vacuum filtration and washed with 2-propanol to give tert- butyl (1-(4-((8-cyano-6-(2,6- dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)-2- methylphenyl)piperidin-4-yl)(methyl)carbamate as a yellow solid (284 mg, 88%). This material was reacted according to General Procedure 3 to yield the title compound (202 mg, 85%) as a yellow solid.

LCMS (Method B): R_T = 0.92 min, m/z = 534/536 [M+H]⁺.

¹ H NMR (500 MHz, CDCI₃) d 10.61 (broad s, NH), 9.17 (s, 1 H), 8.95 (s, 1 H), 8.03 (broad s, 1 H), 7.80-7.76 (m, 2H), 7.71-7.62 (m, 2H), 7.00 (d, 1 H), 3.04-2.98 (m, 2H), 2.63-2.57 (m, 2H), 2.41-2.35 (m, 1 H), 2.30 (s, 3H), 2.26 (s, 3H), 1.93-1.86 (m, 2H), 1.74-1.56 (broad s, NH), 1.43-1.34 (m, 2H).

Example 38: 6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(1 ,7-diazaspiror3.5lnonan-7- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl 7-(2-methyl-4-nitrophenyl)-1, 7-diazaspiro[3.5]nonane-1-carboxylate:

tert- Butyl 1 ,7-diazaspiro[3.5]nonane-1-carboxylate (500 mg, 2.21 mmol) was dissolved in DMA (15 ml_) and 1-fluoro-2-methyl-4-nitrobenzene (commercial, 343 mg, 2.21 mmol) was added followed by potassium carbonate (1.53 g, 11.05 mmol). The suspension was heated to 120°C and stirred for 24 hours before cooling to RT and diluting with EtOAc. The organic phase was washed with 1 x water and 3 x 50% saturated brine solution and dried (anh. MgS0₄) and concentrated in vacuo. The residue was purified by flash chromatography (0- 50% EtOAc in Cyclohexane) to give the desired compound (379 g, 46%) as a yellow solid.

LCMS (Method A): R_T = 1.86 min, m/z = 362 [M+H]⁺.

Step 2: tert-Butyl 7-(4-amino-2-methylphenyl)-1 , 7-diazaspiro[3.5]nonane-1-carboxylate: tert- Butyl 7-(2-methyl-4-nitrophenyl)-1 ,7-diazaspiro[3.5]nonane-1-carboxylate (379 mg, 1.05 mmol) was dissolved in EtOH (12 ml_), heated to 70°C and 10% Pd/C (1 1 mg, 0.105 mmol) was added followed by ammonium formate (397 g, 6.29 mmol). The temperature was increased to 90°C and the reaction was stirred for 1 hour before it was cooled to RT and filtered through Celite. The Celite was washed with EtOAc and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (0- 80% EtOAc in cyclohexane) to give the product (327 mg, 83%) as a brown solid.

LCMS (Method A): R_T = 0.77 min, m/z = 332 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 6.72 (d, 1 H), 6.39-6.37 (m, 1 H), 6.34-6.30 (m, 1 H), 3.76- 3.64 (m, 2H), 2.80-2.74 (m, 2H), 2.49-2.44 (m, 2H), 2.34-2.17 (m, 2H), 2.12-2.09 (m, 3H), 2.03-1.98 (m, 2H), 1.77-1.69 (m, 2H), 1.42-1.36 (m, 9H).

Step 3: 6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(1, 7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile:

Intermediate A (100 mg, 0.275 mmol) was reacted with tert- butyl 7-(4-amino-2- methylphenyl)-1 ,7-diazaspiro[3.5]nonane-1-carboxylate (91 mg, 0.275 mmol) according to General procedure 1. The product precipitated out of the reaction mixture and this was isolated via vacuum filtration and washed with 2-propanol to give tert- butyl 7-(4-((8-cyano- 6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)-2- methylphenyl)-1 ,7-diazaspiro[3.5]nonane-1-carboxylate as a yellow solid (134 mg, 75%). This material was reacted according to General Procedure 3, followed by further purification via column chromatography (20-100% EtOAc in cyclohexane, then 0-50% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to yield the title compound (61 mg, 54%) as a yellow solid.

LCMS (Method B): R_T = 0.98 min, m/z = 546/548 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) 10.7-10.5 (broad s, NH), 9.17 (s, 1 H), 8.93 (s, 1 H), 8.06- 7.98 (broad s, 1 H), 7.79-7.75 (m, 2H), 7.70-7.62 (m, 2H), 6.98 (d, 1 H), 3.36-3.32 (m, 2H), 2.83-2.77 (m, 2H), 2.69-2.64 (m, 2H), 2.26 (s, 3H), 2.05-2.00 (m, 2H), 1.86-1.79 (m, 2H), 1.77-1.70 (m, 2H). Example 39: 2-((4-(4-Amino-4-methylpiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6- dichlorophenyl)-5-oxo-5,6-dihvdropyridor4,3-dlpyrimidine-8-carbonitrile

Step 1: tert-Butyl (1-(2-methoxy-4-nitrophenyl)-4-methylpiperidin-4-yl)carbamate

tert- Butyl (4-methylpiperidin-4-yl)carbamate (commercial, 1.5 g, 7.00 mmol) was dissolved in DMA (15 ml_) and 1-fluoro-2-methoxy-4-nitrobenzene (1.2 g, 7.00 mmol) was added followed by potassium carbonate (4.8 g, 35.0 mmol). The suspension was heated to 120 °C and stirred overnight before cooling to RT and diluting with EtOAc. The organic phase was washed with 1 x water and 3 x 50% saturated brine solution and dried (anh. MgS0₄) and concentrated in vacuo to give the crude product (2.72 g, 95%) as a yellow solid which was taken on as such into the next step.

LCMS (Method B): R_T = 1.59 min, m/z = 367 [M+H]⁺.

Step 2: tert-Butyl (1-(4-amino-2-methoxyphenyl)-4-methylpiperidin-4-yl)carbamate tert- Butyl (1-(2-methoxy-4-nitrophenyl)-4-methylpiperidin-4-yl)carbamate (2.72 g, 6.62 mmol) was dissolved in EtOH (40 ml_), heated to 70 °C and 10% Pd/C (71 mg, 0.66 mmol) was added followed by ammonium formate (2.51 g, 39.7 mmol). The temperature was increased to 90 °C and the reaction was stirred for 1 hour before it was cooled to RT and filtered through Celite. The Celite was washed with EtOAc and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (0-100% EtOAc in cyclohexane) to give the product (1.04 g, 47%) as a pink solid.

LCMS (Method B): R_T = 0.67 min, m/z = 336 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) d 6.61 (d, 1 H), 6.33-6.25 (broad s, NH), 6.22-6.20 (m, 1 H), 6.08-6.05 (m, 1 H), 4.64 (s, 2H), 3.67 (s, 3H), 2.78-2.72 (m, 2H), 2.71-2.64 (m, 2H), 2.07- 1.99 (m, 2H), 1.56-1.49 (m, 2H), 1.38 (s, 9H), 1.24 (s, 3H).

Step 3: 2-((4-(4-Amino-4-methylpiperidin- 1-yl)-3-methoxyphenyl)amino)-6-(2, 6- dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile

Intermediate A (60 mg, 0.165 mmol) was reacted with tert- butyl (1-(4-amino-2- methoxyphenyl)-4-methylpiperidin-4-yl)carbamate according to General procedure 1 to give the title compound (107 g, 100%) as a yellow solid. This material was reacted according to General Procedure 3 to yield the title compound (72 mg, 79%) as a yellow solid.

LCMS (Method B): R_T = 0.81 min, m/z = 550/552 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.59 (broad s, NH), 9.17 (s, 1 H), 8.95 (s, 1 H), 7.94 (broad s, 1 H), 7.79-7.76 (m, 2H), 7.67-7.62 (m, 1 H), 7.24-7.20 (m, 1 H), 6.90 (d, 1 H), 3.87 (s, 3H), 3.00-2.94 (m, 2H), 2.93-2.86 (m, 2H), 1.60-1.53 (m, 2H), 1.51-1.36 (m, 2H + 2NH), 1.08 (s, 3H).

Example 40: 2-((4-(4-Amino-4-methylpiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6- dichlorophenyl)-8-(3-methoxyprop-1-vn-1-yl)pyridoi4,3-cflpyrimidin-5(6/-/)-one

Intermediate B (85 mg, 0.209 mmol) was reacted with tert- butyl (1-(4-amino-2- methoxyphenyl)-4-methylpiperidin-4-yl)carbamate ( obtained as described in Example 39, Steps 1-2) (70 mg, 0.209 mmol) according to General procedure 1. The reaction was cooled to RT and the solvent removed in vacuo before the resulting residue was purified by flash chromatography (0-50% EtOAc in Cyclohexane) to give tert- butyl (1-(4-((6-(2,6- dichlorophenyl)-8-(3-methoxyprop-1-yn-1-yl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2- yl)amino)-2-methoxyphenyl)-4-methylpiperidin-4-yl)carbamate as a yellow solid (95 mg, 64%). This material was reacted according to General Procedure 3 to yield the title compound (56 mg, 82%) as a yellow solid.

LCMS (Method B): R_T = 0.85 min, m/z = 593/595 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.32 (broad s, NH), 9.15 (s, 1 H), 8.27 (s, 1 H), 7.82-7.71 (m, 3H), 7.62-7.57 (m, 1 H), 7.48 (broad s, 1 H), 6.90 (d, 1 H), 4.37 (s, 2H), 3.80 (s, 3H), 3.35 (s, 3H), 3.00-2.94 (m, 2H), 2.93-2.86 (m, 2H), 2.76-2.69 (m, 2H), 1.61-1.54 (m, 2H), 1.53- 1.41 (m, 2H + 2NH), 1.08 (s, 3H). Example 41 : 6-(2,6-Dichlorophenyl)-2-((4-(3-(dimethylamino)azetidin-1-yl)-3- methoxyphenyl)amino)-5-oxo-5,6-dihvdropyridoi4,3-dlpyrimidine-8-carbonitrile

Step 1: 1-(4-Amino-2-methoxyphenyl)-N, N-dimethylazetidin-3-amine

A 50-mL, round-bottomed flask fitted with a magnetic stir-bar was charged with Pd₂(dba)₃ (21 mg, 0.02 mmol), BINAP (29 mg, 0.05 mmol), and Cs₂C0₃ (1.13 g, 3.45 mmol). After purging with nitrogen for 5 minutes, toluene was added (10 ml_) while being stirred. Next, the 1-iodo-2-methoxy-4-nitrobenzene (0.32 g, 1.15 mmol), 3-(dimethylammono)azetidin dihydrochloride (0.2 g, 1.15 mmol), and toluene (distilled, 10 ml_) was added. The dark red mixture was refluxed overnight. After cooling to room temperature, the mixture was filtered, washed with toluene. Concentration in vacuo gave crude brown oil which was further purified using flash chromatography to give 0.2 g of the nitro product as yellow solid. This was dissolved in

EtOAc (10 ml) aand saturated solution of NH₄CI in water (10 ml_) was added followed by a zinc powder (0.26 g, 4 mmol). The resultant suspension was stirred at RT overnight. Then the reaction mixture was filtered, organic layer was separated and water was extracted with EtOAc again (2x25 ml_). The combined organic layers were dried and evaporated yielding the title compound: 0.17 g (69 % over two steps).

¹H NMR (500 MHz, CDCI₃) d 6.35 (d, J = 8.0 Hz, 1 H), 6.30-6.14 (m, 2H), 3.96 (t, J = 6.8 Hz, 2H), 3.76 (s, 3H), 3.47 (t, J = 6.9 Hz, 2H), 3.22-3.11 (m, 1 H), 3.11-2.72 (m, 2H), 2.17 (s, 6H).

Intermediate A (109 mg, 0.300 mmol) was reacted with 1-(4-amino-2-methoxyphenyl)-/\/,/\/- dimethylazetidin-3-amine (66 mg, 0.300 mmol) according to General Procedure 1 and purified by flash chromatography (20-100% EtOAc in Cyclohexane, then 0-10% of a stock solution of 20% 7N NH₃/MeOH in EtOAc), followed by further purification via HPLC prep under basic conditions to yield the title compound (75 mg, 46%) as a yellow/orange solid. LCMS (Method B): R_T = 0.93 min, m/z = 536/538 [M+H]⁺. ¹ H NMR (500 MHz, DMSO-cfe) d 10.52 (s, NH), 9.14 (s, 1 H), 8.93 (s, 1 H), 7.89 (s, 1 H), 7.79-7.75 (m, 2H), 7.67-7.62 (m, 1 H), 7.19-7.14 (m, 1 H), 6.39 (d, 1 H), 3.97-3.90 (m, 2H), 3.85-3.70 (m, 3H), 3.52-3.47 (m, 2H), 3.08-3.01 (m, 1 H), 2.08 (s, 6H).

Example 42: 2-((4-(4-Amino-4-methylpiperidin-1-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5- oxo-5, 6-dihydropyridor4,3-dlpyrimidine-8-carbonitrile

Step 1: tert-Butyl (4-methyl-1-(4-nitrophenyl)piperidin-4-yl)carbamate

tert- Butyl (4-methylpiperidin-4-yl)carbamate (commercial, 1 g, 4.67 mmol) was dissolved in DMA (12 ml_) and 1-fluoro-4-nitrobenzene (0.66 g, 4.67 mmol) was added followed by potassium carbonate (3.22 g, 23.3 mmol). The suspension was heated to 120°C and stirred overnight before cooling to RT and diluting with EtOAc. The organic phase was washed with 1 x water and 3 x 50% saturated brine solution and dried (anh. MgS0₄) and concentrated in vacuo. The material was purified via flash chromatography (0-30% EtOAc in Cyclohexane) to give tert- butyl (4-methyl-1-(4-nitrophenyl)piperidin-4-yl)carbamate (1.28 g, 73%) as a yellow solid.

LCMS (Method B): R_T = 1.49 min, m/z = 336 [M+H]⁺.

Step 2: tert-Butyl (1-(4-aminophenyl)-4-methylpiperidin-4-yl)carbamate

tert- Butyl (4-methyl-1-(4-nitrophenyl)piperidin-4-yl)carbamate (1.28 g, 3.82 mmol) was dissolved in EtOH (35 ml_), heated to 70°C and 10% Pd/C (41 mg, 0.38 mmol) was added followed by ammonium formate (1.44 g, 22.9 mmol). The temperature was increased to 90°C and the reaction was stirred for 1 hour before it was cooled to RT and filtered through Celite. The Celite was washed with EtOAc and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (0-100% EtOAc in cyclohexane) to give the product (1.02 g, 87%) as a pink solid.

LCMS (Method B): R_T = 0.68 min, m/z = 306 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 6.69-6.65 (m, 2H), 6.49-6.46 (m, 2H), 6.39-6.30 (broad s, NH), 4.48 (s, 2NH), 2.99-2.92 (m, 2H), 2.79-2.72 (m, 2H), 2.1 1-2.02 (m, 2H), 1.57-1.49 (m, 2H), 1.38 (s, 9H), 1.23 (s, 3H). Step 3: 2-((4-(4-Amino-4-methylpiperidin- 1 -yl)phenyl)amino)-6-(2, 6-dichlorophenyl)-5-oxo- 5, 6-dihydropyrido[4, 3-d]pyrimidine-8-carbonitrile

Intermediate A (150 mg, 0.413 mmol) was reacted with tert- butyl (1-(4-aminophenyl)-4- methylpiperidin-4-yl)carbamate according to General procedure 1. The product precipitated out of the reaction mixture and this was isolated via vacuum filtration and washed with 2- propanol to give tert- butyl (1-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)phenyl)-4-methylpiperidin-4-yl)carbamate (256 mg, 100%) as a yellow solid. This material was reacted according to General Procedure 3 to yield the title compound (194 mg, 88%) as a yellow solid.

LCMS (Method B): R_T = 0.90 min, m/z = 520/522 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.63-10.34 (broad s, NH), 9.14 (s, 1 H), 8.91 (s, 1 H), 7.87-7.80 (m, 1 H), 7.79-7.75 (m, 2H), 7.66-7.62 (m, 1 H), 7.55-7.42 (broad s, 1 H), 6.94-6.90 (m, 2H), 3.20-3.15 (m, 4H), 1.57-1.43 (m, 4H), 1.07 (s, 3H).

Example 43: 6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)-4-methylpiperidin-1-yl)-3- methoxyphenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

2-((4-(4-Amino-4-methylpiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)-5- oxo-5, 6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile (obtained as described in example 39) (22 mg, 0.039 mmol) was reacted according to General Procedure 4 to yield the title compound (20 mg, 90%) as a yellow solid.

LCMS (Method B): R_T = 0.92 min, m/z = 578/580 [M+H]⁺.

¹ H NMR (500 MHz, CDCI₃) d 10.59 (s, NH), 9.17 (s, 1 H), 8.95 (s, 1 H), 7.96-7.91 (broad s, 1 H), 7.79-7.75 (m, 2H), 7.67-7.62 (m, 1 H), 7.24-7.20 (m, 1 H), 6.91-6.87 (d, 1 H), 3.87 (s, 3H), 3.07-3.00 (m, 2H), 2.86-2.78 (m, 2H), 2.15 (s, 6H), 1.81-1.74 (m, 2H), 1.58-1.51 (m, 2H), 0.88 (s, 3H). Example 44: 6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)-4-methylpiperidin-1- y

l)phenyl)amino)-5-oxo-5 6-dihvdropyridoi4 3-dlpyrimidine-8-carbonitrile

2-((4-(4-Amino-4-methylpiperidin-1-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile (obtained as described in example 42) (48 g, 0.092 mmol) was reacted according to General Procedure 4 to yield the title compound (46 mg, 89%) as a yellow solid.

LCMS (Method B): R_T = 0.92 min, m/z = 548/550 [M+H]⁺.

¹H NMR (500 MHz, CDCI₃) d 10.56-10.48 (broad s, 0.8NH, rotamer A), 10.42-10.33 (broad s, 0.2NH, rotamer B), 9.14 (s, 1 H), 8.91 (s, 1 H), 7.87-7.81 (m, 1 H), 7.79-7.75 (m, 2H), 7.66- 7.61 (m, 1 H), 7.55-7.44 (broad s, 1 H), 6.94-6.89 (m, 2H), 3.20-3.07 (m, 4H), 2.14 (s, 6H), 1.83-1.76 (m, 2H), 1.56-1.49 (m, 2H), 0.87 (s, 3H).

Example 45: 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(4-methyl-4-(methylamino)piperidin-1 - yl)phenyl)amino)-5-oxo-5,6-dihvdropyridoi4,3-cflpyrimidine-8-carbonitrile

Step 1: tert-Butyl (1-(2-methoxy-4-nitrophenyl)-4-methylpiperidin-4-yl)(methyl)carbamate tert- Butyl (1-(2-methoxy-4-nitrophenyl)-4-methylpiperidin-4-yl)carbamate (as obtained in example 39, step 1) (568 mg, 1.55 mmol) was dissolved in DMF (10 ml_) and cooled to 0 °C before the addition of sodium hydride (60% in mineral oil) (155 mg, 3.88 mmol). The reaction was stirred at 0 °C for 15 minutes before the addition of iodomethane (290 pl_, 4.66 mmol). The reaction mixture was allowed to warm to RT and stirred overnight before pouring over saturated ammonium chloride solution (50 ml_) and extracted with EtOAc (2 x 50 ml_). The organics were washed with 50% sat. brine solution (3 x 50 ml_) before being combined, dried (anh. MgS0₄) and evaporated under reduced pressure. The material was purified by flash chromatography (0-50% EtOAc in Cyclohexane) to give the title compound (390 mg, 65%) as a yellow solid.

LCMS (Method B): R_T = 1.70 min, m/z = 380 [M+H]⁺.

Step 2: tert-Butyl (1-(4-amino-2-methoxyphenyl)-4-methylpiperidin-4-yl)(methyl)carbamate tert- Butyl (1-(2-methoxy-4-nitrophenyl)-4-methylpiperidin-4-yl)(methyl)carbamate (390 mg, 1.03 mmol) was dissolved in EtOH (10 ml_), heated to 70 °C and 10% Pd/C (1 1 mg, 0.103 mmol) was added followed by ammonium formate (389 mg, 6.17 mmol). The temperature was increased to 90°C and the reaction was stirred for 4 hours before it was cooled to RT and filtered through Celite. The Celite was washed with EtOAc and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography (0- 100% EtOAc in cyclohexane, then 0-20% MeOH in EtOAc) to give the product (128 mg, 34%) as a pink solid.

LCMS (Method B): R_T = 0.74 min, m/z = 350 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 6.62 (d, 1 H), 6.22 (m, 1 H), 6.08-6.05 (m, 1 H), 3.68 (s, 3H), 2.80 (s, 3H), 2.79-2.68 (m, 4H), 2.27-2.20 (m, 2H), 1.84-1.77 (m, 2H), 1.40 (s, 9H), 1.24 (s, 3H).

Step 3: 6-(2, 6-Dichlorophenyl)-2-((3-methoxy-4-(4-methyl-4-(methylamino)piperidin- 1- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbonitrile

Intermediate A (130 mg, 0.358 mmol) was reacted with tert- butyl (1-(4-amino-2- methoxyphenyl)-4-methylpiperidin-4-yl)(methyl)carbamate (125 mg, 0.358 mmol) according to General procedure 1. The product precipitated out of the reaction mixture and this was isolated via vacuum filtration and washed with 2-propanol to give tert- butyl (1-(4-((8-cyano- 6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)-2- methoxyphenyl)-4-methylpiperidin-4-yl)(methyl)carbamate as a yellow solid (148 mg, 60%). This material was reacted according to General Procedure 3 to yield the title compound (1 17 mg, 95%) as a yellow/orange solid.

LCMS (Method B): R_T = 0.90 min, m/z = 564/566 [M+H]⁺.

¹ H NMR (500 MHz, CDCI₃) d 10.59 (broad s, NH), 9.17 (s, 1 H), 8.95 (s, 1 H), 7.94 (broad s, 1 H), 7.79-7.75 (m, 2H), 7.67-7.62 (m, 1 H), 7.25-7.19 (m, 1 H), 6.91-6.87 (m, 1 H), 3.87 (broad s, 3H), 3.03-2.95 (m, 2H), 2.89-2.82 (m, 2H), 2.20 (s, 3H), 1.64-1.49 (m, 4H), 1.04 (s, 3H). Example 46: 6-(2,6-Dichlorophenyl)-2-((4-(3-methylazetidin-3-yl)phenyl)amino)-5-oxo-5,6- dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

To a solution of 3-(4-bromophenyl)-3-methylazetidine trifluoroacetate (commercial, 507 mg, 1.49 mmol) in a 2: 1 ratio of 1 ,4-dioxane and water (7.5 ml_) was added triethylamine (0.42 ml_, 2.98 mmol) and di-te/f-butyl dicarbonate (488 mg, 2.24 mmol). The reaction was stirred at RT overnight before the volatiles were removed in vacuo and the residue taken up in DCM and washed with 2 x water and 1 x brine solution. The aqueous phase was extracted with 2 x DCM and the combined organics were dried (Biotage Phase separator) and evaporated under reduced pressure. The material was purified by flash chromatography (0- 20% EtOAc in Cyclohexane) to give tert- butyl 3-(4-bromophenyl)-3-methylazetidine-1- carboxylate (452 mg, 93%) as a white solid.

LCMS (Method B): R_T = 1.64 min, m/z = 226/228 [M-100]⁺.

¹ H NMR (500 MHz, CDCI₃) d 7.54-7.51 (m, 2H), 7.25-7.23 (m, 2H), 4.05-4.00 (m, 2H), 3.88- 3.82 (m, 2H), 1.52 (s, 3H), 1.38 (s, 9H).

Step 2: tert-Butyl 3-(4-((8-cyano-6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3- d]pyrimidin-2-yl)amino)phenyl)-3-methylazetidine-1-carboxylate

To a solution of tert- butyl 3-(4-bromophenyl)-3-methylazetidine-1-carboxylate (40 mg, 0.123 mmol) in 1 ,4-dioxane (1.2 ml_) was added cesium carbonate (121 mg, 0.370 mmol) and Xantphos (8 mg, 0.014 mmol). The mixture was degassed (N₂ bubbling) before addition of palladium acetate (1.4 mg, 0.006 mmol) and the reaction was heated to 65 °C and stirred under nitrogen atmosphere for 15 minutes. Intermediate C (41 mg, 0.123 mmol) was then added and the vial was sealed and heated to 150 °C for 1 hour in the Biotage microwave. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (0-40% EtOAc in Cyclohexane) before further purification via HPLC prep under basic conditions to give tert- butyl 3-(4-((8-cyano- 6-(2,6-dichlorophenyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)phenyl)-3- methylazetidine-1-carboxylate (13 mg, 19%) as a yellow solid. This material was reacted according to General Procedure 3 to yield the title compound (10 mg, 79%) as a pale yellow solid.

LCMS (Method B): R_T = 0.91 min, m/z = 477/479 [M+H]⁺.

¹ H NMR (500 MHz, CDCI₃) d 10.77-10.60 (broad s, NH), 9.21 (s, 1 H), 8.95 (s, 1 H), 8.06- 7.89 (broad s, 2H), 7.80-7.76 (m, 2H), 7.67-7.62 (m, 1 H), 7.22-7.17 (m, 2H), 3.79-3.75 (m, 2H), 3.42-3.39 (m, 2H), 1.57 (s, 3H).

Example 47: 6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-8-(3-methoxyprop-1-vn-1-yl)pyridor4,3-cflpyrimidin-5(6/-/)-one

2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-8-(3- methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one (obtained as described in example 34) (40 mg, 0.071 mmol) was reacted according to General Procedure 4 and purified by flash chromatography (0-100% EtOAc in Cyclohexane, then 0-30% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to yield the title compound (36 mg, 80%) as a yellow solid. LCMS (Method B): R_T = 0.93 min, m/z = 591/593 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.4 (broad s, NH), 9.14 (s, 1 H), 8.30 (s, 1 H), 8.01-7.94 (broad m, 1 H), 7.80-7.76 (broad m, 1 H), 7.75-7.72 (m, 2H), 7.62-7.58 (m, 2H), 7.00 (d, 1 H), 4.40 (s, 2H), 3.35 (s, 3H), 3.08-3.04 (m, 2H), 2.61-2.54 (m, 2H), 2.26 (s, 3H), 2.21 (s, 6H), 2.20-2.14 (m, 1 H), 1.87-1.80 (m, 2H), 1.58-1.49 (m, 2H).

Example 48: 6-(2,6-Dichlorophenyl)-2-((4-(1-methyl-1 ,7-diazaspiror3.5lnonan-7- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

2-((4-(1 ,7-Diazaspiro[3.5]nonan-7-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile (as obtained in Example 36, steps 1-3) (30 mg, 0.056 mmol) was reacted according to General Procedure 4 and further purified via flash chromatography (0-100% EtOAc in Cyclohexane, then 0-30% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to give the title compound (26 mg, 84%) as a yellow solid. LCMS (Method B): R_T = 0.86 min, m/z = 546/548 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-d6): d 10.6 (s, NH), 9.14 (s, 1 H), 8.93 (s, 1 H), 7.86-7.82 (m, 1 H), 7.79-7.76 (m, 2H), 7.66-7.63 (m, 1 H), 7.53-7.46 (broad s, 1 H), 6.96-6.91 (m, 2H), 3.64-3.57 (m, 2H), 3.09 (t, 2H), 2.68-2.60 (m, 2H), 2.10 (s, 3H), 1.89 (t, 2H), 1.77-1.71 (m, 2H), 1.69-1.61 (m, 2H).

Example 49: 6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(1-methyl-1 ,7-diazaspiror3.5lnonan-7- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

6-(2,6-Dichlorophenyl)-2-((3-methyl-4-(1 ,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-oxo- 5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile (as obtained in Example 38, steps 1-3) (24.7 mg, 0.045 mmol) was reacted according to General Procedure 4 and further purified via flash chromatography (0-100% EtOAc in Cyclohexane, then 0-50% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to give the title compound (21 mg, 81 %) as a yellow solid. LCMS (Method B): R_T = 0.98 min, m/z = 560/562 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-d6): d 10.6 (s, NH), 9.17 (s, 1 H), 8.93 (s, 1 H), 8.09-7.97 (broad s, 1 H), 7.79-7.75 (m, 2H), 7.70-7.61 (m, 2H), 7.00 (d, 1 H), 3.12-3.07 (t, 2H), 2.98-2.92 (m, 2H), 2.63-2.56 (m, 2H), 2.27 (s, 3H), 2.14 (s, 3H), 1.93-1.88 (t, 2H), 1.80-1.67 (m, 4H).

Example 50: 2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2-chloro-6- methylphenyl)-8-(3-methoxyprop-1-vn-1-yl)pyridor4,3-cflpyhmidin-5(6/-/)-one

Intermediate E (200 mg, 0.518 mmol) was reacted with tert- butyl (1-(4-amino-2- methylphenyl)piperidin-4-yl)carbamate ( obtained as described in Example 30, Steps 1-2) (158 mg, 0.518 mmol) according to General procedure 1. The reaction was cooled to RT and the solvent removed in vacuo before the resulting residue was purified by flash chromatography (0-35% EtOAc in Cyclohexane) to give tert- butyl (1-(4-((6-(2-chloro-6- methylphenyl)-8-(3-methoxyprop-1-yn-1-yl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2- yl)amino)-2-methylphenyl)piperidin-4-yl)carbamate as a yellow solid (87 mg, 25%). This material was reacted according to General Procedure 3 to yield the title compound (62 mg, 85%) as a yellow solid.

LCMS (Method A): R_T = 0.93 min, m/z = 543 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.38-10.26 (broad s, NH), 9.14 (s, 1 H), 8.16 (s, 1 H), 8.02-7.93 (broad s, 1 H), 7.82-7.74 (broad s, 1 H), 7.56-7.52 (m, 1 H), 7.48-7.40 (m, 2H), 7.02-6.96 (m, 1 H), 4.40 (s, 2H), 3.35 (s, 3H), 3.01-2.95 (m, 2H), 2.70-2.64 (m, 1 H), 2.62- 2.55 (m, 2H), 2.25 (s, 3H), 2.14 (s, 3H), 1.83-1.77 (m, 2H), 1.45-1.36 (m, 2H).

Example 51 : 6-(2-Chloro-6-methylphenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-8-(3-methoxyprop-1-vn-1-yl)pyridor4,3-cflpyrimidin-5(6/-/)-one

2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2-chloro-6-methylphenyl)-8-(3- methoxyprop-1-yn-1-yl)pyrido[4,3-c(]pyrimidin-5(6/-/)-one (obtained as described in example 50) (20 mg, 0.037 mmol) was reacted according to General Procedure 4 and purified by flash chromatography (0-100% EtOAc in Cyclohexane, then 0-20% MeOH in EtOAc) to yield the title compound (7 mg, 35%) as a yellow solid.

LCMS (Method B): R_T = 0.94 min, m/z = 571/573 [M+H]⁺.

¹ H NMR (500 MHz, DMSO-cfe) d 10.3 (broad s, NH), 9.14 (s, 1 H), 8.16 (s, 1 H), 8.04-7.93 (broad s, 1 H), 7.83-7.73 (broad s, 1 H), 7.55-7.52 (m, 1 H), 7.48-7.41 (m, 2H), 7.00 (d, 1 H), 4.40 (s, 2H), 3.35 (s, 3H), 3.09-3.03 (m, 2H), 2.61-2.54 (m, 2H), 2.21 (s, 6H), 2.20-2.15 (m, 1 H), 2.14 (s, 3H), 1.87-1.81 (m, 2H), 1.58-1.49 (m, 2H). Example 52: 6-(2-Chloro-6-methylphenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

2-((4-(4-Aminopiperidin-1-yl)-3-methylphenyl)amino)-6-(2-chloro-6-methylphenyl)-5-oxo- 5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile (obtained as described in example 33) (50 mg, 0.100 mmol) was reacted according to General Procedure 4 and purified by flash chromatography (0-100% EtOAc in Cyclohexane, then 0-30% of a stock solution of 20% 7N NH₃/MeOH in EtOAc) to yield the title compound (60 mg, 89%) as a yellow solid.

LCMS (Method B): R_T = 0.91 min, m/z = 528/530 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) d 10.5 (broad s, NH), 9.16 (s, 1 H), 8.81 (s, 1 H), 8.08-8.01 (broad s, 1 H), 7.73-7.63 (broad s, 1 H), 7.58-7.54 (m, 1 H), 7.51-7.43 (m, 2H), 6.99 (d, 1 H), 3.09-3.03 (m, 2H), 2.62-2.55 (m, 2H), 2.26 (s, 3H), 2.21 (s, 6H), 2.19-2.14 (m, 4H), 1.86- 1.81 (m, 2H), 1.58-1.49 (m, 2H).

Example 53: 6-(2-Chloro-6-methylphenyl)-2-((3-methyl-4-(4-(methylamino)piperidin-1- yl)phenyl)amino)-5-oxo-5,6-dihvdropyridor4,3-cflpyrimidine-8-carbonitrile

Intermediate D (180 mg, 0.525 mmol) was reacted with tert- butyl (1-(4-amino-2- methylphenyl)piperidin-4-yl)(methyl)carbamate ( obtained as described in Example 31, Steps 1-2) (168 mg, 0.525 mmol) according to General Procedure 1. The reaction was cooled to RT and the solvent removed in vacuo before the resulting residue was purified by flash chromatography (0-50% EtOAc in Cyclohexane) to give tert- butyl (1-(4-((6-(2-chloro- 6-methylphenyl)-8-cyano-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidin-2-yl)amino)-2- methylphenyl)piperidin-4-yl)(methyl)carbamate (322mg, 100%) as a yellow solid. This material was reacted according to General Procedure 3 to yield the title compound (225 g, 83%) as a yellow solid.

LCMS (Method B): R_T = 0.90 min, m/z = 515 [M+H]⁺.

¹H NMR (500 MHz, DMSO-cfe) d 10.54 (broad s, NH), 9.16 (s, 1 H), 8.81 (s, 1 H), 8.10-7.98 (broad s, 1 H), 7.74-7.64 (broad m, 1 H), 7.58-7.54 (m, 1 H), 7.51-7.53 (m, 2H), 7.00 (d,

1 H), 3.05-2.98 (m, 2H), 2.63-2.56 (m, 2H), 2.46-2.39 (m, 1 H), 2.32 (s, 3H), 2.25 (s, 3H), 2.16 (s, 3H), 1.94-1.87 (m, 2H), 1.45-1.35 (m, 2H).

Comparison of compounds of the present invention with comparative example compounds The Examples were tested for Wee-1 kinase inhibitory effect (Wee-1 IC₅₀ value), permeability (Caco-2 value) and proliferation (HT29) EC₅₀. Comparative compounds were also tested using the same tests. The test method employed to determine Wee-1 kinase inhibitory effect was the same as that taught in WO 2015/092431 (see page 350 to 358). The test methods employed to determine permeability (Caco-2 value) and proliferation (HT29) EC₅₀ were as follows:

i. Determination of Caco-2 permeability was carried out at Cyprotex using standard protocols and SOPs.

ii. Determination of proliferation (HT29) EC₅₀ was carried out using the following

protocol: HT29 cells (ATCC # HTB-38; 5000 cells/well) were seeded in a white opaque clear bottom 96 well plate (Corning #3903) and treated after 24 h with increasing concentrations of compound (typically in a 9 dp curve ranging from 30 mM to 1.0 nM). Unless otherwise stated, compounds were stored as 10 mM DMSO stock under inert atmosphere using the MultiPod system. Compounds dilutions were prepared fresh prior to the assay. Cell viability was assessed by CellTiter-Glo^® using a Synergy 4 plate reader (BioTek) after 72 h as recommended by the manufacturer’s instructions (Promega; # G7571). Analysis and EC₅₀ values were derived using GraphPadPrism (GraphPad Software, Inc, La Jolla, CA; four- parameter logistic function).

The data is provided in Tables 1 and 2 below: Table 1 : Comparison of Wee1 IC₅₀ values with comparative example compounds

Table 2: Comparison with comparative example compounds

Compounds of the invention thus exhibit improved inhibitory potency against Wee-1 and further exhibit improved inhibition of cell proliferation measured in a cellular assay.

Claims

CLAIMS:

1. A compound of Formula (a):

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2;

n is 0, 1 or 2; and

Y is

Y is

2. The compound of claim 1 , or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein Y is

3. The compound of claim 1 , or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein Y is

4. The compound of claim 3, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein a is 1 and b is 0.

5. The compound of claim 3, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein a is 0 and b is 1.

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein: R¹ is an alkynyl group or a cyano group;

R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2; and

n is 0, 1 or 2;

with the proviso that R³ and R⁴ cannot both be a hydrogen atom.

7. The compound of claim 6, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein R³ is a cyano group, an alkyl group or a cycloalkyl group.

8. A compound of Formula (c):

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R⁹ is a hydrogen atom, a cyano group, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group; and

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group.

9. A compound of Formula (d):

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R¹⁰ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group;

m is 0, 1 or 2; and

n is 0, 1 or 2.

10. The compound of any of claims 1 to 7 and 9, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein m is 1.

11. The compound of any of claims 1 to 7 and 9, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein m is 0.

12. The compound of any of claims 1 to 7 and 9 to 11 , or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein n is 1.

13. The compound of any of claims 1 to 7 and 9 to 11 , or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein n is 0.

14. A compound of Formula (e):

or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein:

R¹ is an alkynyl group or a cyano group;

R¹¹ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁴ is a hydrogen atom, an alkyl group or a cycloalkyl group;

R⁶ is a chlorine atom or a methyl group;

X is CH₂ or O; and

p is 1 or 2.

15. The compound of claim 14, or a pharmaceutically acceptable salt or N-oxide derivative thereof, wherein p is 1.

16. The compound of claim 14 or claim 15, or a pharmaceutically acceptable salt or N- oxide derivative thereof, wherein X is O.

17. The compound of any of the preceding claims, or a pharmaceutically acceptable salt or N-oxide derivative thereof, wherein R² is an alkoxy group.

18. The compound of any of the preceding claims, or a pharmaceutically acceptable salt or N-oxide derivative thereof, wherein R¹ is a cyano group.

19. The compound of any of claims 1-17, or a pharmaceutically acceptable salt or N- oxide derivative thereof, wherein R¹ is an alkynyl group.

20. The compound of any of claims 1-17 and 19, or a pharmaceutically acceptable salt or N-oxide derivative thereof, wherein R¹ is an alkynyl group substituted by an alkoxy group.

21. The compound of any of the preceding claims, or a pharmaceutically acceptable salt or N-oxide derivative thereof, wherein R⁶ is a chlorine atom.

22. The compound of claim 1 or any of claims 3 to 21 , or a pharmaceutically acceptable salt or N-oxide derivative thereof, wherein R⁴ is a hydrogen atom or an alkyl group.

23. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or N- oxide derivative thereof, wherein the compound is:

(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile; 2-((4-(4-(Azetidin-1-yl)piperidin-1-yl)-3-methylphenyl)amino)-6-(2,6-dichlorophenyl)-

8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c(]pyrimidin-5(6/-/)-one;

2-((4-([1 ,3'-Biazetidin]-1'-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-

5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

2-((4-([1 ,3'-Biazetidin]-1'-yl)-3-methoxyphenyl)amino)-6-(2,6-dichlorophenyl)-8-(3- methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

2-((4-(4-Amino-4-methylpiperidin-1-yl)-3-methoxyphenyl)amino)-6-(2,6- dichlorophenyl)-8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((4-(3-methylazetidin-3-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c]pyrimidine-8-carbonitrile; 6-(2,6-Dichlorophenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c]pyrimidin-5(6/-/)-one;

6-(2-Chloro-6-methylphenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-8-(3-methoxyprop-1-yn-1-yl)pyrido[4,3-c(]pyrimidin-5(6/-/)-one;

6-(2-Chloro-6-methylphenyl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3- methylphenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile; or

6-(2-Chloro-6-methylphenyl)-2-((3-methyl-4-(4-(methylamino)piperidin-1- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile.

24. The compound of claim 1 , claim 3 or claim 4, or a pharmaceutically acceptable salt or N-oxide derivative thereof, wherein the compound is:

6-(2,6-dichlorophenyl)-2-((3-methoxy-4-(1 ,7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(1 ,6-diazaspiro[3.3]heptan-6- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((4-(1 -methyl-1 , 7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)- 5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile; or

25. The compound of claim 1 , claim 3 or claim 5, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein the compound is:

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2,6-diazaspiro[3.3]heptan-2- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile;

6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2,7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile; or 6-(2,6-Dichlorophenyl)-2-((3-methoxy-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7- yl)phenyl)amino)-5-oxo-5,6-dihydropyrido[4,3-c]pyrimidine-8-carbonitrile.

26. The compound of claim 6, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein the compound is:

6-(2,6-Dichlorophenyl)-2-((4-(3-methylpiperidin-3-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c(]pyrimidine-8-carbonitrile; or

27. The compound of claim 8, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein the compound is:

2-((4-(Azetidin-3-yl)phenyl)amino)-6-(2,6-dichlorophenyl)-5-oxo-5,6- dihydropyrido[4,3-c]pyrimidine-8-carbonitrile; or

28. The compound of claims 14 to 16, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, wherein the compound is:

rac-6-(2,6-Dichlorophenyl)-2-((4-(morpholin-2-yl)phenyl)amino)-5-oxo-5,6- dihydropyrido[4,3-c]pyrimidine-8-carbonitrile.

29. A pharmaceutical composition comprising the compound of any of claims 1 to 28, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, and at least one pharmaceutically acceptable excipient.

30. The pharmaceutical composition of claim 29 comprising one or more further pharmaceutically active agents.

31. The compound of any of claims 1 to 28, or a pharmaceutically acceptable salt or N- oxide derivative thereof, or the pharmaceutical composition of claim 29 or 30, for use in therapy.

32. The compound of any of claims 1 to 28, or a pharmaceutically acceptable salt or N- oxide derivative thereof, or the pharmaceutical composition of claim 29 or 30, for use as a medicament.

33. The compound of any of claims 1 to 28, or a pharmaceutically acceptable salt or N- oxide derivative thereof, or the pharmaceutical composition of claim 29 or 30, for use in treating or preventing cancer.

34. Use of the compound as defined in any of claims 1 to 28, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition of claim 29 or 30, for the manufacture of a medicament for treating or preventing cancer.

35. A method of treating or preventing cancer in a human or animal patient comprising administering to a patient in need thereof an effective amount of a compound according to any of claims 1 to 28, or a pharmaceutically acceptable salt or /V-oxide derivative thereof, or the pharmaceutical composition according to claim 29 or claim 30.