INTRODUCTION

[0001] The present invention relates to certain compounds that function as inhibitors of BCL6 (B-cell lymphoma 6) activity. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which BCL6 activity is implicated.

BACKGROUND OF THE INVENTION

[0002] BCL6 is a zinc finger transcription repressor that plays a key role in the formation and development of germinal centres, in which B cells undergo somatic hypermutation and recombination of the immunoglobulin genes, in order to generate diversity in antibodies against a variety of foreign antigens (Dent et al. , Science, 1997, 276, 589-592). BCL6 allows the proliferation of antibody producing B cells by repressing genes involved in DNA damage response, cell cycle arrest and apoptosis. BCL6 mediates this repression by recruiting the corepressor proteins SMRT, NCoR and BCoR to an extended groove motif that forms along the dimer interface of the BCL6 BTB (BR-C, Ttk and Bab) domain (Ahmad et al., Mol Cell, 2003, 12, 1551-1564; Ghetu et al. , Mol Cell, 2008, 29, 384-391). Genetic upregulation of the BCL6 gene, as seen in many lymphomas, leads to malignant B cell proliferation (Hatzi & Melnick, Trends Mol Med, 2014, 20, 343-352). Therefore, there exists a need to develop agents that inhibit the tumourigenic effects of BCL6, either by selectively binding to the BTB domain and preventing corepressor recruitment, or by binding to the BTB domain and inducing protein degradation (Kerres et al. Cell Rep., 2017, 20, 2860-2875).

SUMMARY OF THE INVENTION

[0003] According to a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0004] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0005] According to a further aspect of the present invention, there is provided a method of inhibiting BCL6 activity, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein. [0006] According to a further aspect of the present invention, there is provided a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0007] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder in which BCL6 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0008] According to a further aspect of the present invention, there is provided a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0009] According to a further aspect of the present invention, there is provided a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0010] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0011] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition.

[0012] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer.

[0013] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of BCL6 activity.

[0014] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which BCL6 activity is implicated.

[0015] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

[0016] Suitably, the proliferative disorder is cancer, suitably a human cancer (for example haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)) and multiple myeloma, and solid tumours (including glioma, breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary))).

[0017] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0018] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of BCL6 activity.

[0019] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which BCL6 activity is implicated.

[0020] According to a further aspect of the present invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0021] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.

[0022] According to a further aspect of the present invention, there are provided novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.

[0023] Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0024] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0025] It is to be appreciated that references to“treating” or“treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.“Treating” or“treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0026] A“therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0027] In this specification the term“alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as“propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as“isopropyl” are specific for the branched chain version only. For example, “(1 -6C)alkyl” includes (1- 4C)alkyl, (1-3C)alkyl, propyl, isopropyl and f-butyl.

[0028] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0029] An“alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), dimethylmethylene (-C(CH3)2-), 2-methylpropylene (- CH ₂ CH(CH ₃ )CH ₂ -), pentylene (-CH2CH2CH2CH2CH2-), and the like.

[0030] “(3-10C)cycloalkyl” means a hydrocarbon ring containing from 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl. [0031] The term “alkoxy” refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy and f-butoxy.

[0032] The term“haloalkyl” or“haloalkoxy” is used herein to refer to an alkyl or alkoxy group respectively in which one or more hydrogen atomes have been replaced by halogen (e.g. fluorine) atoms. Examples of haloalkyl groups include -CH2F, -CHF2 and -CF ₃ . Examples of haloalkoxy groups include -OCH2F, and -OCF ₃ .

[0033] The term“halo” or“halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro.

[0034] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2/-/-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 ,1 -dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 ,1 -dioxide, thiomorpholinyl, thiomorpholinyl 1 ,1 -dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1- yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0035] By“bridged ring systems” is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 ^th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.

[0036] By“spiro bicyclic ring systems” we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6- azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-6- azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7- azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0037] The term“heteroaryl” or“heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0038] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1 ,2-b][1 ,2,4]triazinyl.“Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-

1.2.3.4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro- benzo[1 ,4]dioxinyl, benzo[1 ,3]dioxolyl, 2,2-dioxo-1 ,3-dihydro-2-benzothienyl, 4, 5,6,7- tetrahydrobenzofuranyl, indolinyl, 1 ,2,3,4-tetrahydro-1 ,8-naphthyridinyl,

1.2.3.4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2/-/-pyrido[3,2-b][1 ,4]oxazinyl.

[0039] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted.

[0040] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0041] The phrase“compound of the invention” means those compounds which are disclosed herein, both generically and specifically.

Compounds of the invention

[0042] In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural formula (I), shown below:

Formula (I)

wherein:

X is selected from N or CH;

R ¹ is selected from hydrogen or a group of the formula:

-L-Y-Z

wherein:

L is absent or (1-3C)alkylene; Y is absent, O or N(R ⁴ ); and

Z is hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl, heteroaryl or heterocyclyl; wherein when Z is (1-6C)alkyl, (3-7C)cycloalkyl, heteroaryl or heterocyclyl it is optionally further substituted by one or more substituent groups independently selected from hydroxy, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy and (3-7C)cycloalkyl;

R ² is NR ⁵ R ⁶ ;

R ³ is hydrogen or methyl;

R ⁴ is hydrogen or (1-4C)alkyl;

R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl ring,

wherein in the 4- to 7-membered heterocyclyl ring:

a) the nitrogen atom is the only heteroatom in the ring;

b) the ring is monocyclic or spiro-attached to a (3-4C)cycloalkyl ring or a 5- to 6-membered heterocyclyl ring, the (3-4C)cycloalkyl and 5- to 6-membered heterocyclyl rings being optionally substituted with one or more halo substituents; and

c) the ring is optionally substituted with one or more substituent groups independently selected from hydroxy, halo, cyano, (1-4C)alkyl, (1- 4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (3-7C)cycloalkyl, C(0)0R ⁷ , C(0)NR ⁸ R ⁹ , S0 ₂ (1-4C)alkyl, (1-3C)alkylene-R ¹⁰ and 0-(1- 3C)alkylene-R ¹⁰ ;

R ⁷ , R ⁸ and R ⁹ are independently selected from hydrogen and (1-4C)alkyl; and

R ¹⁰ is selected from hydroxy, cyano, (1-4C)alkoxy, (1-4C)haloalkoxy, NHC(0)-0- (1-4C)alkyl, NHC(0)-(1-4C)alkyl, (3-7C)cycloalkyl and 0-CH ₂ -(3-7C)cycloalkyl; provided that the compound of Formula (I) is not one of the following compounds: 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H- benzo[d]imidazol-2-one;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,N-dimethylpipe ridine-4- carboxamide; 5-((5-chloro-2-(piperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hy droxy-3-methylbutyl)- 1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin -4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-methylpiperidin-1-yl)pyrimidin-4-yl)ami no)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(trifluoromethyl)piperidin-1-yl)pyrimid in-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

(S)-5-((5-chloro-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyri midin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1 -yl)pyrimidin-4-yl)amino)- 3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-(4,4-difluoro-3-(methoxymethyl)piperidin-1-yl )pyrimidin-4- yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3- hydroxy-3- ethylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl )amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)py rimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-(trifluoromethyl)piperidin-1-yl)pyrimid in-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)pyrim idin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4- yl)amino)-1 ,3-bis(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)pyrimidi n-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-1 ,3-bis(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-

2-one;

5-((5-chloro-2-(3-(methoxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl) pyrimidin-4-yl)amino)-

3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-((3R,5S)-3,5-dimethylazepan-1-yl)pyrimidin-4- yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-1-(2-(dimethylamino)ethyl)-3-(3-hydroxy-3-methylbu tyl)-1 , 3-dihydro- 2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-(2-morpholinoethyl)- 1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidy l]pyrimidin-4- yl]amino]-1-(2-hydroxyethyl)-3-(3-hydroxy-3-methyl-butyl)ben zimidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4- yl)amino)-1-(2,2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl) -1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-4-carb onitrile; 1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-3-carb onitrile; or 5-((5-chloro-2-(3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one.

[0043] Particular compounds of the invention include, for example, compounds of the Formula I, or pharmaceutically acceptable salts, hydrates and/or solvates thereof, wherein, unless otherwise stated, each of X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (32) hereinafter: -

(1) X is N;

(2) X is CH;

(3) R ¹ is hydrogen;

(4) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is absent or (1-3C)alkylene;

Y is absent, O or N(R ⁴ ); and

Z is hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl, heteroaryl or heterocyclyl; wherein when Z is (1-6C)alkyl, (3-7C)cycloalkyl, heteroaryl or heterocyclyl it is optionally further substituted by one or more substituent groups independently selected from hydroxy, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy and (3-7C)cycloalkyl;

(5) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is absent or (1-3C)alkylene;

Y is absent, O or N(R ⁴ ); and

Z is hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl or heterocyclyl; wherein when Z is (1-6C)alkyl, (3-7C)cycloalkyl or heterocyclyl it is optionally further substituted by one or more substituent groups independently selected from hydroxy, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy and (3- 7C)cycloalkyl;

(6) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is absent or (1-3C)alkylene;

Y is absent, O or N(R ⁴ ); and

Z is hydrogen, (1-4C)alkyl, (3-7C)cycloalkyl or heterocyclyl; wherein when Z is (1-6C)alkyl, (3-7C)cycloalkyl or heterocyclyl it is optionally further substituted by one or more substituent groups independently selected from hydroxy, fluoro, methyl, trifluoromethyl, methoxy and cyclopropyl;

(7) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is (1-3C)alkylene;

Y is absent, O or N(R ⁴ ); and

Z is hydrogen, (1-6C)alkyl, (3-7C)cycloalkyl, heteroaryl or heterocyclyl; wherein when Z is (1-6C)alkyl, (3-7C)cycloalkyl, heteroaryl or heterocyclyl it is optionally further substituted by one or more substituent groups independently selected from hydroxy, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy and (3-7C)cycloalkyl; (8) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is (1-3C)alkylene;

Y is absent, O or N(R ⁴ ); and

Z is (1-6C)alkyl, (3-7C)cycloalkyl or heterocyclyl; wherein Z is optionally further substituted by one or more substituent groups independently selected from hydroxy, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy and (3-7C)cycloalkyl;

(9) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is (1-3C)alkylene;

Y is O or N(R ⁴ ); and

Z is (1-6C)alkyl, (3-7C)cycloalkyl or heterocyclyl; wherein Z is optionally further substituted by one or more substituent groups independently selected from hydroxy, halo, (1-4C)alkyl, (1-4C)alkoxy and (3-7C)cycloalkyl;

(10) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is (1-3C)alkylene;

Y is O or N(R ⁴ ); and

Z is (1-3C)alkyl or (3-7C)cycloalkyl; wherein Z is optionally further substituted by one or more substituent groups independently selected from hydroxy, fluoro, methyl and cyclopropyl;

(1 1) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is (1-3C)alkylene;

Y is absent; and Z is (3-7C)cycloalkyl or heterocyclyl; wherein when Z is optionally further substituted by one or more substituent groups independently selected from hydroxy, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy and (3- 7C)cycloalkyl;

(12) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is (1-3C)alkylene;

Y is absent; and

Z is heterocyclyl; wherein when Z is optionally further substituted by one or more substituent groups independently selected from hydroxy, fluoro and methyl;

(13) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is absent;

Y is absent; and

Z is (1-6C)alkyl optionally further substituted by one or more substituent groups independently selected from hydroxy, halo, (1-4C)alkoxy and (3- 7C)cycloalkyl;

(14) R ¹ is a group of the formula:

-L-Y-Z

wherein:

L is absent;

Y is absent; and

Z is (1-4C)alkyl optionally further substituted by one or more substituent groups independently selected from hydroxy, fluoro, methoxy and cyclopropyl;

(15) R ¹ is a group of the formula:

-L-Y-Z

wherein: L is absent;

Y is absent; and

Z is (1-6C)alkyl substituted by one or two substituent groups independently selected from hydroxy, fluoro, methoxy and cyclopropyl;

(16) R ¹ is methyl;

(17) R ¹ is selected from methyl or one of the following groups:

wherein— denotes the point of attachment to the rest of the compound of formula I;

(18) R ¹ is selected from methyl or one of the following groups:

wherein— denotes the point of attachment to the rest of the compound of formula I;

(19) R ³ is methyl;

(20) R ³ is hydrogen;

(21) R ⁴ is hydrogen;

(22) R ⁴ is (1-4C)alkyl;

(23) R ⁴ is methyl;

(24) R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl ring, wherein in the 4- to 7-membered heterocyclyl ring:

a) the nitrogen atom is the only heteroatom in the ring;

b) the ring is monocyclic or spiro-attached to a cyclobutyl ring or a 5- to 6- membered heterocyclyl ring, the cyclobutyl and 5- to 6-membered heterocyclyl rings being optionally substituted with one or more halo substituents; and

c) the ring is optionally substituted with one or more substituent groups independently selected from hydroxy, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy, (3-7C)cycloalkyl, C(0)OR ⁷ , C(0)NR ⁸ R ⁹ , S0 ₂ (1- 4C)alkyl, (1-3C)alkylene-R ¹⁰ and 0-(1-3C)alkylene-R ¹⁰ ;

(25) R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl ring, wherein in the 4- to 7-membered heterocyclyl ring:

a) the nitrogen atom is the only heteroatom in the ring;

b) the ring is monocyclic or spiro-attached to a cyclobutyl ring, the cyclobutyl ring being optionally substituted with one or more fluoro substituents; and

c) the ring is optionally substituted with one or more substituent groups independently selected from hydroxy, fluoro, cyano, (1-2C)alkyl, trifluoromethyl, methoxy, trifluoromethoxy, C(0)OR ⁷ , C(0)NR ⁸ R ⁹ , SC>2Me and (1-2C)alkylene-R ¹⁰ ;

(26) R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl ring, wherein in the 4- to 7-membered heterocyclyl ring:

a) the nitrogen atom is the only heteroatom in the ring; b) the ring is monocyclic; and

c) the ring is optionally substituted with one or more substituent groups independently selected from hydroxy, fluoro, cyano, (1-2C)alkyl, trifluoromethyl, methoxy, trifluoromethoxy, C(0)0R ⁷ , C(0)NR ⁸ R ⁹ and (1-2C)alkylene-R ¹⁰ ;

(27) R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl ring, wherein in the 4- to 7-membered heterocyclyl ring:

a) the nitrogen atom is the only heteroatom in the ring;

b) the ring is monocyclic; and

c) the ring is optionally substituted with one or more substituent groups independently selected from hydroxy, fluoro, cyano, (1-2C)alkyl, trifluoromethyl, C(0)0R ⁷ , C(0)NR ⁸ R ⁹ and CH ₂ -R ¹⁰ ;

(28) R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl ring, wherein each ring may be optionally substituted with one or more substituent groups independently selected from hydroxy, fluoro, cyano, (1-2C)alkyl, trifluoromethyl, C(0)0R ⁷ , C(0)NR ⁸ R ⁹ and CH2-R ¹⁰ ;

(29) R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocyclyl ring, wherein in the 5- to 6-membered heterocyclyl ring:

a) the nitrogen atom is the only heteroatom in the ring;

b) the ring is monocyclic; and

c) the ring is substituted with one or more substituent groups independently selected from hydroxy, fluoro, cyano, (1-2C)alkyl, trifluoromethyl, C(0)0R ⁷ , C(0)NR ⁸ R ⁹ and CH2-R ¹⁰ ;

(30) R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a piperidinyl ring, wherein the piperidinyl ring is substituted with one or more substituent groups independently selected from hydroxy, fluoro, cyano, (1-2C)alkyl, trifluoromethyl, C(0)OR ⁷ , C(0)NR ⁸ R ⁹ and CH ₂ -R ¹⁰ ;

(31) R ² is selected from one of the following groups:

wherein— denotes the point of attachment to the rest of the compound of formula

(32) R ² is selected from one of the following groups:

wherein— denotes the point of attachment to the rest of the compound of formula I;

[0044] Suitably, X is as defined in any one of paragraphs (1) to (2) above. Most suitably, X is as defined in paragraph (2) above.

[0045] Suitably, R ¹ is as defined in any one of paragraphs (3) to (18) above. Most suitably, R ¹ is as defined in paragraph (18) above.

[0046] Suitably, R ³ is as defined in any one of paragraphs (19) to (20) above. Most suitably, R ³ is as defined in paragraph (19) above.

[0047] Suitably, R ⁴ is as defined in any one of paragraphs (21) to (23) above. Most suitably R ⁴ is as defined in paragraph (21) above.

[0048] Suitably, R ⁵ and R ⁶ are as defined in any one of paragraphs (24) to (30) above. Most suitably R ⁵ and R ⁶ are as defined in paragraph (30) above. [0049] Suitably, R ² is as defined in any one of paragraphs (31) to (32) above. Most suitably R ² is as defined in paragraph (32) above.

[0050] In a particular group of compounds of the invention, X is CH, i.e. the compounds have the structural formula IA (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula IA

wherein each of R ¹ , R ² and R ³ are as defined hereinabove, provided that the compound of Formula (IA) is not one of the following compounds:

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,N-dimethylpipe ridine-4-carboxamide;

5-((5-chloro-2-(piperidin-1-yl)pyrimidin-4-yl)amino)-3-(3 -hydroxy-3-methylbutyl)-1- methyl-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin -4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-methylpiperidin-1-yl)pyrimidin-4-yl)amino) -3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(trifluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

(S)-5-((5-chloro-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrimid in-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(methoxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)pyrim idin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-(trifluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)- 1 ,3-bis(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)pyrimidi n-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(methoxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-3,5-dimethylazepan-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1-(2-(dimethylamino)ethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

3-(3-hydroxy-3-methylbutyl)-1-(2-morpholinoethyl)-1 ,3-dihydro-2H-benzo[d]imidazol-

2-one;

5-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidy l]pyrimidin-4-yl]amino]-1-

(2-hydroxyethyl)-3-(3-hydroxy-3-methyl-butyl)benzimidazol -2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1-(2,2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-

2-one;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-4-carb onitrile;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-3-carb onitrile; or

5-((5-chloro-2-(3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one.

[0051] In an embodiment of the compounds of Formula IA:

R ¹ is as defined in any one of paragraphs (3) to (18) above;

R ² is as defined in any one of paragraphs (31) to (32) above; and R ³ is as defined in any one of paragraphs (19) to (20) above.

[0052] In another embodiment of the compounds of Formula IA:

R ¹ is as defined in paragraph (18) above;

R ² is as defined in paragraph (32) above; and

R ³ is as defined in paragraph (19) above.

[0053] In a particular group of compounds of the invention, R ³ is methyl, i.e. the compounds have the structural formula IB (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula IB

wherein each of X, R ¹ and R ² are as defined hereinabove, provided that the compound of Formula (IB) is not one of the following compounds:

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)- 3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,N-dimethylpipe ridine-4-carboxamide; 5-((5-chloro-2-(piperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hy droxy-3-methylbutyl)-1- methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin -4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-methylpiperidin-1-yl)pyrimidin-4-yl)amino) -3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(trifluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

(S)-5-((5-chloro-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrimid in-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(methoxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl )amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)py rimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-(trifluoromethyl)piperidin-1-yl)pyrimid in-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)pyrim idin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-

1.3-bis(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)pyrimidi n-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1.3-bis(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-(3-(methoxymethyl)piperidin-1-yl)pyrimidin -4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl) pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-3,5-dimethylazepan-1-yl)pyrimidin -4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-

1-(2-(dimethylamino)ethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

3-(3-hydroxy-3-methylbutyl)-1-(2-morpholinoethyl)-1 ,3-dihydro-2H-benzo[d]imidazol-

2-one;

5-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidy l]pyrimidin-4-yl]amino]-1-

(2-hydroxyethyl)-3-(3-hydroxy-3-methyl-butyl)benzimidazol -2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1-(2,2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-

2-one;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-4-carb onitrile;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-ox o-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-3-carb onitrile; or 5-((5-chloro-2-(3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one.

[0054] In an embodiment of the compounds of Formula IB:

X is as defined in any one of paragraphs (1) to (2) above;

R ¹ is as defined in any one of paragraphs (3) to (18) above; and

R ² is as defined in any one of paragraphs (31) to (32) above.

[0055] In another embodiment of the compounds of Formula IB:

X is as defined in paragraph (2) above;

R ¹ is as defined in paragraph (18) above; and

R ² is as defined in paragraph (32) above.

[0056] In a particular group of compounds of the invention, X is CH and R ³ is methyl, i.e. the compounds have the structural formula IC (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula IC

wherein R ¹ and R ² are as defined hereinabove, provided that the compound of Formula (IC) is not one of the following compounds:

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,N-dimethylpipe ridine-4-carboxamide;

5-((5-chloro-2-(piperidin-1-yl)pyrimidin-4-yl)amino)-3-(3 -hydroxy-3-methylbutyl)-1- methyl-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin -4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-methylpiperidin-1-yl)pyrimidin-4-yl)amino) -3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(trifluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; (S)-5-((5-chloro-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrimid in-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3-

(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(methoxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3-

(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-

3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)pyrim idin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-(trifluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-

3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1 ,3-bis(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)pyrimidi n-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(methoxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-3,5-dimethylazepan-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-

3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1-(2-(dimethylamino)ethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

3-(3-hydroxy-3-methylbutyl)-1-(2-morpholinoethyl)-1 ,3-dihydro-2H-benzo[d]imidazol-

2-one;

5-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidy l]pyrimidin-4-yl]amino]-1-

(2-hydroxyethyl)-3-(3-hydroxy-3-methyl-butyl)benzimidazol -2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1-(2,2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-

2-one; 1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-4-carb onitrile;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-3-carb onitrile; or

5-((5-chloro-2-(3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one.

[0057] In an embodiment of the compounds of Formula IC:

R ¹ is as defined in any one of paragraphs (3) to (18) above; and

R ² is as defined in any one of paragraphs (31) to (32).

[0058] In another embodiment of the compounds of Formula IC:

R ¹ is as defined in paragraph (18) above; and

R ² is as defined in paragraph (32) above.

[0059] In a particular group of compounds of the invention, X is CH and R ¹ and R ³ are both methyl, i.e. the compounds have the structural formula ID (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula ID

wherein R ² is as defined hereinabove, provided that the compound of Formula (ID) is not one of the following compounds:

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)- 3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,N-dimethylpipe ridine-4-carboxamide; 5-((5-chloro-2-(piperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hy droxy-3-methylbutyl)-1- methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin -4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-methylpiperidin-1-yl)pyrimidin-4-yl)amino) -3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-(3-(trifluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

(S)-5-((5-chloro-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrimid in-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(methoxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)pyrim idin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-(trifluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4S)-3,4-difluoropyrrolidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4S)-3,4-dimethylpyrrolidin-1-yl)pyrimidi n-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(methoxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-3,5-dimethylazepan-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-4-carb onitrile;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-3-carb onitrile; or

5-((5-chloro-2-(3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one.

[0060] In an embodiment of the compounds of Formula ID, R ² is as defined in any one of paragraphs (31) to (32) above.

[0061] In another embodiment of the compounds of Formula ID, R ² is as defined in paragraph (32) above. [0062] In a particular group of compounds of the invention, the compounds have the structural formula IE (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

wherein each of X, R ¹ and R ³ are as defined hereinabove, R ¹¹ is selected from hydroxy, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (3-7C)cycloalkyl, C(0)OR ⁷ , C(0)NR ⁸ R ⁹ , S0 ₂ (1-4C)alkyl, (1-3C)alkylene-R ¹⁰ and 0-(1-3C)alkylene-R ¹⁰ , wherein R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined hereinabove and n is 0, 1 or 2; provided that the compound of Formula (IE) is not one of the following compounds:

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)- 3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(methoxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1.3-bis(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1.3-bis(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1-(2-(dimethylamino)ethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

3-(3-hydroxy-3-methylbutyl)-1-(2-morpholinoethyl)-1 ,3-dihydro-2H-benzo[d]imidazol-

2-one; 5-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidy l]pyrimidin-4-yl]amino]-1- (2-hydroxyethyl)-3-(3-hydroxy-3-methyl-butyl)benzimidazol-2- one; or

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1-(2,2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-

2-one.

[0063] In an embodiment of the compounds of Formula IE:

X is as defined in any one of paragraphs (1) to (2) above;

R ¹ is as defined in any one of paragraphs (3) to (18) above;

R ³ is as defined in any one of paragraphs (19) to (20) above;

R ¹¹ is selected from hydroxy, halo, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (3-7C)cycloalkyl and (1-3C)alkylene-R ¹⁰ ; and

n is 0, 1 or 2.

[0064] In another embodiment of the compounds of Formula IE:

X is as defined in paragraph (2) above;

R ¹ is as defined in paragraph (18) above;

R ³ is as defined in paragraph (19) above;

R ¹¹ is selected from hydroxy, methyl, cyclopropyl and CH2OH; and

n is 0, 1 or 2

[0065] In a particular group of compounds of the invention, the compounds have the structural formula IF (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula IF

wherein each of X, R ¹ and R ³ are as defined hereinabove and each R ¹² is independently selected from hydrogen, hydroxy, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy, (3-7C)cycloalkyl, C(0)OR ⁷ , C(0)NR ⁸ R ⁹ , S0 ₂ (1-4C)alkyl, (1-3C)alkylene-R ¹⁰ and 0-(1-3C)alkylene-R ¹ °, wherein R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined hereinabove; provided that the compound of Formula (IF) is not one of the following compounds:

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(methoxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3- (3-hydroxy-3- ethylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1.3-bis(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1.3-bis(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1-(2-(dimethylamino)ethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

3-(3-hydroxy-3-methylbutyl)-1-(2-morpholinoethyl)-1 ,3-dihydro-2H-benzo[d]imidazol-

2-one;

5-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidy l]pyrimidin-4-yl]amino]-1- (2-hydroxyethyl)-3-(3-hydroxy-3-methyl-butyl)benzimidazol-2- one; or

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

1-(2,2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-

2-one.

[0066] In an embodiment of the compounds of Formula IF:

X is as defined in any one of paragraphs (1) to (2) above;

R ¹ is as defined in any one of paragraphs (3) to (18) above;

R ³ is as defined in any one of paragraphs (19) to (20) above; and

each R ¹² is independently selected from hydrogen, hydroxy, (1-2C)alkyl, (1-2C)alkoxy,

(1-2C)haloalkoxy, (3-7C)cycloalkyl and (1-3C)alkylene-R ¹⁰ .

[0067] In another embodiment of the compounds of Formula IF:

X is as defined in paragraph (2) above;

R ¹ is as defined in paragraph (18) above;

R ³ is as defined in paragraph (19) above; and

each R ¹² is independently selected from hydrogen, methyl and CH2OH. [0068] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((R)-2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((S)-2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(((R)-tetrahydrofuran-2-yl)methyl)- 1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(2-methoxyethyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((tetrahydrofuran-3-yl)methyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(2- hydroxy-2-methylpropyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)- 1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(1-hydroxypropan-2-yl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-2, 2-dimethylpropyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)-1-

(2-methoxyethyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

(S)-5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-y l)amino)-3-(3-hydroxy-3- methylbutyl)-1-((tetrahydrofuran-2-yl)methyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((R)-tetrahydrofuran-3-yl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl )amino)-1-(2-hydroxy-2-methylpropyl)-

3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((S)-tetrahydrofuran-3-yl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((1 -methyl-1 H-pyrazol-4-yl)methyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4r,5S)-4-fluoro-3,5-dimethylpiperidin-1- yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3- ethylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-(3-(fluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-3-fluoro-5-hydroxypiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-hydroxypiperidin-1-yl)pyri midin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

(S)-5-((5-chloro-2-(4,4-difluoro-2-(hydroxymethyl)pyrrolidin -1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-4-y l)amino)-3-(3-hydroxy-3-methylbutyl)- 1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrimidin -4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-2-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3,3-dimethylpiperidin-1-yl)pyri midin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(2-hydroxypropan-2-yl)piperid in-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin -4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)pyrimi din-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

(R)-5-((5-chloro-2-(4,4-difluoro-2-(hydroxymethyl)pyrrolidin -1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl) pyrimidin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-3,3-dimethylpiperidin-1-yl)pyrimid in-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin -1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-3,3,5,5-tetramethylpiperidin-1- yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-(3,3-difluoro-5-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4-hydroxy-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxypiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)-1- methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3-difluoro-4-hydroxypiperidin-1-yl)pyri idin-4-yl)a ino)-3-(3-hydroxy-3- ethylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-(2-(hydroxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(difluoromethyl)piperidin-1-yl)pyrimidin-4 -yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-4-methylpiperidin-1-yl)pyrimidin-4 -yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3-difluoro-4-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3-difluoro-4-(hydroxymethyl)pyrrolidin-1-y l)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

tert-butyl ((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo -2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)me thyl)carbamate;

5-((5-chloro-2-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrim idin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

N-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl- 2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)me thyl)acetamide;

N-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl- 2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)me thyl)isobutyramide;

N-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl- 2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)me thyl)pivalamide;

1-(2-(1 ,3-dioxolan-2-yl)ethyl)-5-((5-chloro-2-((3R,5S)-4,4-difluoro -3,5-dimethylpiperidin-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoroazepan-1-yl)pyrimidin-4-yl)amino )-3-(3-hydroxy-3-methylbutyl)-1- methyl-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(hydroxymethyl)-5-methylpiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-((3R,5R)-3-(hydroxymethyl)-5-methylpiperidin- 1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-3-(hydroxymethyl)-5-methylpiperid in-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(hydroxymethyl)-4-(trifluoromethyl)pipe ridin-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

(R)-5-((5-chloro-2-(3-fluoropyrrolidin-1-yl)pyrimidin-4-yl)a mino)-3-(3-hydroxy-3-methylbutyl)- 1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

(S)-5-((5-chloro-2-(3-fluoropyrrolidin-1-yl)pyrimidin-4-yl)a mino)-3-(3-hydroxy-3-methylbutyl)- 1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-fluoropiperidin-1-yl)pyrimidin-4-yl)amino) -3-(3-hydroxy-3-methylbutyl)-1- methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

2-(1-(5-chloro-4-((3-(3-hydroxy-3- ethylbutyl)-1- ethyl-2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)ac etonitrile;

5-((5-chloro-2-(3-(methylsulfonyl)piperidin-1-yl)pyri idin-4-yl)a ino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-(3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy-

3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyri midin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl)ami no)-3-(3-hydroxy-3-methylbutyl)-1- methyl-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)pyri midin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)p yrimidin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3-dimethylpiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)- 1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-ethylpiperidin-1-yl)pyrimidin-4-yl)amino)- 3-(3-hydroxy-3-methylbutyl)-1- methyl-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 6-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-1-(3-hydroxy-3-methylbutyl)-3- methyl-1 , 3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-1-(3-

((cyclopropylmethyl)amino)propyl)-3-(3-hydroxy-3-methylbu tyl)-1 ,3-dihydro-2H- benzo[d]i idazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-3-(3- hydroxy-3-methylbutyl)-1-(3-(methyla ino)propyl)-1 ,3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyri idin-4-yl)a ino)-1-(3-

(dimethylamino)propyl)-3-(3-hydroxy-3- ethylbutyl)-1 ,3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyri idin-4-yl)a ino)-1-(3-

((cyclopropylmethyl)(methyl)amino)propyl)-3-(3-hydroxy-3- methylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-1-(3-

(cyclopropylamino)propyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-1-(3-

((2,2-difluoroethyl)a ino)propyl)-3-(3-hydroxy-3- ethylbutyl)-1 ,3-dihydro-2H- benzo[d]i idazol-2-one;

1-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-5-((5-chloro-2 -((3R,5S)-4,4-difluoro-3,5- dimethylpiperidin-1-yl)pyrimidin-4-yl)a ino)-3-(3-hydroxy-3- ethylbutyl)-1 ,3-dihydro-2H- benzo[d]i idazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-3-(3- hydroxy-3- ethylbutyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1 ,3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyri idin-4-yl)a ino)-1-(2-

((cyclopropylmethyl)amino)ethyl)-3-(3-hydroxy-3-methylbut yl)-1 ,3-dihydro-2H- benzo[d]i idazol-2-one;

1-(2-(azetidin-1-yl)ethyl)-5-((5-chloro-2-((3R,5S)-4,4-diflu oro-3,5-di ethylpiperidin-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3- ethylbutyl)-1 ,3-dihydro-2H-benzo[d]i idazol-2-one; 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-3-(3- hydroxy-3-methylbutyl)-1-(2-(methyla ino)ethyl)-1 ,3-dihydro-2H-benzo[d]i idazol-2-one; 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-3-(3- hydroxy-3- ethylbutyl)-1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1 ,3-dihydro-2H-benzo[d]i idazol-

2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-1-(2-

((2,2-difluoroethyl)a ino)ethyl)-3-(3-hydroxy-3- ethylbutyl)-1 ,3-dihydro-2H- benzo[d]i idazol-2-one; 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(3-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(2-hydroxyethyl)piperidin- 1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(2-(hydroxymethyl)-3-methylpiperidin-1-yl) pyrimidin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(2-hydroxyethyl)piperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(trifluoromethyl)azetidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3-difluoro-4-hydroxypyrrolidin-1-yl)pyrimi din-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-hydroxy-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3,4,4-tetrafluoropiperidin-1-yl)pyrimid in-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-(fluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-(difluoromethyl)piperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-3-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(hydroxymethyl)-4-methylpiperidin-1-yl) pyrimidin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-fluoro-4-hydroxypiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-fluoro-3-(hydroxymethyl)piperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,5-dimethylpipe ridine-3-carboxamide;

(3S,5S)-1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl -2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,5-dimethylpipe ridine-3-carboxamide;

(3R,5S)-1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl -2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,5-dimethylpipe ridine-3-carboxamide;

5-((5-chloro-2-(4-methylazepan-1-yl)pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1- methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-(3-methylazepan-1-yl)pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1- methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-5-methylazepan-1-yl)pyri idin-4-yl)a ino)-3-(3-hydroxy-3- ethylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-(4-hydroxy-4-methylazepan-1-yl)pyrimidin-4 -yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)-5-methylpiper idin-1-yl)pyrimidin-4-yl)amino)-3-

(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1-(2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)-1-

(2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(2- cyclopropyl-2-hydroxyethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(3-hydroxybutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3-((2- fluoroethyl)amino)propyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

6-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-1-(3-hydroxy-3- methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

6-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-3-((R)-3- hydroxybutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-((cyclopropylmethoxy)methyl)-4,4-difluo ropiperidin-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-1-(2-cyclopropyl-2- hydroxyethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)-1- (3-hydroxybutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one; and

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-3-methylbutyl)-3-(methyl-d ₃ )-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one. [0069] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:

5-((5-chloro-2-((3R,4r,5S)-4-fluoro-3,5-dimethylpiperidin-1- yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(fluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-3-fluoro-5-hydroxypiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-hydroxypiperidin-1-yl)pyri midin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(2-hydroxypropan-2-yl)piperid in-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-(hydroxymethyl)piperidin-1-yl)pyrimidin -4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-3,3-dimethylpiperidin-1-yl)pyrimid in-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin -1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-3,3,5,5-tetramethylpiperidin-1- yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3-difluoro-5-(hydroxymethyl)piperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4-hydroxy-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxypiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)-1- methyl-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(2-(hydroxymethyl)piperidin-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(difluoromethyl)piperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-4-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3-difluoro-4-(hydroxymethyl)piperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; tert-butyl ((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo -2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)me thyl)carbamate;

5-((5-chloro-2-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrim idin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

N-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-o xo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)me thyl)acetamide;

N-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-o xo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)me thyl)isobutyramide;

N-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-o xo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)me thyl)pivalamide;

5-((5-chloro-2-(3-(hydroxymethyl)-5-methylpiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy-

3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(hydroxymethyl)-4-(trifluoromethyl)piperid in-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-fluoropiperidin-1-yl)pyrimidin-4-yl)ami no)-3-(3-hydroxy-3-methylbutyl)-1- methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

2-(1-(5-chloro-4-((3-(3-hydroxy-3- ethylbutyl)-1- ethyl-2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)ac etonitrile;

5-((5-chloro-2-(3-(methylsulfonyl)piperidin-1-yl)pyri idin-4-yl)a ino)-3-(3-hydroxy-3- ethylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-(3-(hydroxymethyl)-3-methylpiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy-

3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-3-methylpiperidin-1-yl)pyrimidin-4 -yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-1-(3-hydroxy-3-methylbutyl)-3- methyl-1 , 3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3-

((cyclopropylmethyl)amino)propyl)-3-(3-hydroxy-3-methylbu tyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(3-(methylamino)propyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-1-(3-

(dimethylamino)propyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-1-(3-

((cyclopropylmethyl)(methyl)amino)propyl)-3-(3-hydroxy-3- methylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one; 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3-

(cyclopropylamino)propyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

1-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-5-((5-chloro-2 -((3R,5S)-4,4-difluoro-3,5- dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(2-

((cyclopropylmethyl)amino)ethyl)-3-(3-hydroxy-3-methylbut yl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

1-(2-(azetidin-1-yl)ethyl)-5-((5-chloro-2-((3R,5S)-4,4-diflu oro-3,5-dimethylpiperidin-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-(4,4-difluoro-3-(2-hydroxyethyl)piperidin-1-y l)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(2-(hydroxymethyl)-3-methylpiperidin-1-yl) pyrimidin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(2-hydroxyethyl)piperidin-1-yl)pyrimidin-4 -yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-1-(3-hydroxy-3- methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-(3-hydroxy-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-3-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(hydroxymethyl)-4-methylpiperidin-1-yl) pyrimidin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-fluoro-3-(hydroxymethyl)piperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4-hydroxy-4-methylazepan-1-yl)pyrimidin-4-yl )amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

(3S,5S)-1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-met hyl-2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,5-dimethylpipe ridine-3-carboxamide;

(3R,5S)-1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-met hyl-2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,5-dimethylpipe ridine-3-carboxamide;

6-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl )pyrimidin-4-yl)amino)-1-(3- hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)-5-methylpi peridin-1-yl)pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-((3R,5R)-3-(hydroxymethyl)-5-methylpiperidin- 1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one; or

5-((5-chloro-2-((3R,5S)-3-(hydroxymethyl)-5-methylpiperid in-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one.

[0070] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((R)-2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((S)-2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(((R)-tetrahydrofuran-2-yl)methyl)- 1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(2-methoxyethyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((tetrahydrofuran-3-yl)methyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(2- hydroxy-2-methylpropyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)- 1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(1-hydroxypropan-2-yl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-2,2-dimethylpropyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)-1-

(2-methoxyethyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

(S)-5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-y l)amino)-3-(3-hydroxy-3- methylbutyl)-1-((tetrahydrofuran-2-yl)methyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((R)-tetrahydrofuran-3-yl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-1-(2-hydroxy-2-methylpropyl)- 3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((1 -methyl-1 H-pyrazol-4-yl)methyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,4r,5S)-4-fluoro-3,5-dimethylpiperidin-1- yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-(3-(fluoromethyl)piperidin-1-yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-3-fluoro-5-hydroxypiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-hydroxypiperidin-1-yl)pyri midin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

(S)-5-((5-chloro-2-(4,4-difluoro-2-(hydroxymethyl)pyrrolidin -1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-4-y l)amino)-3-(3-hydroxy-3-methylbutyl)- 1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrimidin -4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-2-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3,3-dimethylpiperidin-1-yl)pyri midin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(2-hydroxypropan-2-yl)piperid in-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

tert-butyl ((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo -2,3-dihydro-1 H- benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)me thyl)carbamate;

1-(2-(1 ,3-dioxolan-2-yl)ethyl)-5-((5-chloro-2-((3R,5S)-4,4-difluoro -3,5-dimethylpiperidin-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoroazepan-1-yl)pyrimidin-4-yl)amino )-3-(3-hydroxy-3-methylbutyl)-1- methyl-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(3-(hydroxymethyl)-5-methylpiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3-hydroxy- 3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 6-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)am ino)-1-(3-hydroxy-3-methylbutyl)-3- methyl-1 , 3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3-

((cyclopropylmethyl)amino)propyl)-3-(3-hydroxy-3-methylbu tyl)-1 ,3-dihydro-2H- benzo[d]i idazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(3-(methyla ino)propyl)-1 ,3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-1-(3-

(dimethylamino)propyl)-3-(3-hydroxy-3- ethylbutyl)-1 ,3-dihydro-2H-benzo[d]i idazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-1-(3-

((cyclopropylmethyl)(methyl)amino)propyl)-3-(3-hydroxy-3- methylbutyl)-1 ,3-dihydro-2H- benzo[d]i idazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3-

(cyclopropylamino)propyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-1-(3-

((2,2-difluoroethyl)a ino)propyl)-3-(3-hydroxy-3- ethylbutyl)-1 ,3-dihydro-2H- benzo[d]i idazol-2-one;

1-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-5-((5-chloro-2 -((3R,5S)-4,4-difluoro-3,5- dimethylpiperidin-1-yl)pyrimidin-4-yl)a ino)-3-(3-hydroxy-3- ethylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-3-(3- hydroxy-3- ethylbutyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1 ,3-dihydro-2H-benzo[d]i idazol-2-one;

1-(2-(azetidin-1-yl)ethyl)-5-((5-chloro-2-((3R,5S)-4,4-di fluoro-3,5-di ethylpiperidin-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3- ethylbutyl)-1 ,3-dihydro-2H-benzo[d]i idazol-2-one; 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-3-(3- hydroxy-3-methylbutyl)-1-(2-(methyla ino)ethyl)-1 ,3-dihydro-2H-benzo[d]i idazol-2-one; 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-3-(3- hydroxy-3- ethylbutyl)-1-(2-(3-hydroxyazetidin-1-yl)ethyl)-1 ,3-dihydro-2H-benzo[d]i idazol-

2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-1-(2- ((2,2-difluoroethyl)a ino)ethyl)-3-(3-hydroxy-3- ethylbutyl)-1 ,3-dihydro-2H- benzo[d]i idazol-2-one; or

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyri idin-4-yl)a ino)-3-(3- hydroxy-3-methylbutyl)-1-(3-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one. [0071] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((R)-2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-((S)-2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4-yl)amino)-3-((R)-3- hydroxybutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(2- hydroxy-2-methylpropyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one;

5-((5-chloro-2-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl)ami no)-3-(3-hydroxy-3-methylbutyl)-1- methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

6-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl )amino)-1-(3-hydroxy-3-methylbutyl)-3- methyl-1 , 3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(3-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidi n-4-yl)amino)-1-(3-hydroxy-3- methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

6-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;

5-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrim idin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1-(2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl )amino)-3-(3-hydroxy-3-methylbutyl)-1- (2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-(3-hydroxybutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one;

5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)-5-methylpiper idin-1-yl)pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one;

6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-1-(3- hydroxy-3-methylbutyl)-3-(methyl-d ₃ )-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; or rac-5-((5-chloro-2-((3R,5S)-3-(hydroxymethyl)-5-methylpiperi din-1-yl)pyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one. [0072] The various functional groups and substituents making up the compounds of the Formula (I), or sub-formulae IA to IF, are typically chosen such that the molecular weight of the compound of the formula (I) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600.

[0073] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric, methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0074] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture”.

[0075] The compounds of this invention may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.

[0076] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and 180; and the like. Therefore, for the avoidance of doubt, where a CH3 group is defined as a substituent herein at a given position, the present invention also encompasses the substituent CD3 at that same position.

[0077] It is also to be understood that certain compounds of the Formula (I), or sub-formulae I A to IF, may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity.

[0078] It is also to be understood that certain compounds of the Formula I, or sub-formulae IA to IF, may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.

[0079] Compounds of the Formula I, or sub-formulae IA to IF, may exist in a number of different tautomeric forms and references to compounds of the Formula I, or sub-formulae I A to IF, include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula I, or sub-formulae IA to IF. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.

H

I o \ .OH H ⁺ _N o

— c— c = C=c — c=c

I \ / \ H ⁺ / \

keto enol enolate

[0080] Compounds of the Formula I, or sub-formulae IA to IF, containing an amine function may also form N-oxides. A reference herein to a compound of the Formula I, or sub-formulae I A to IF, that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a te/fiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0081] The compounds of Formula (I), or sub-formulae IA to IF, may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I), or sub-formulae IA to IF, and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I), or sub formulae I A to IF.

[0082] Accordingly, the present invention includes those compounds of the Formula (I), or sub-formulae IA to IF, as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I, or sub-formulae I A to IF, that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I), or sub-formulae IA to IF, may be a synthetically-produced compound or a metabolically-produced compound.

[0083] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae IA to IF, is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0084] Various forms of pro-drug have been described, for example in the following documents:

a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5“Design and Application of Pro-drugs”, by H. Bundgaard p. 1 13-191 (1991);

d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

e) H. Bundgaard, et al. , Journal of Pharmaceutical Sciences, 77, 285 (1988);

f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);

g) J. Rautio, et al. Nature Reviews Drug Discovery (2018);

h) T. Higuchi and V. Stella,“Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and

i) E. Roche (editor),“Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0085] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I, or sub-formulae I A to IF, that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula I, or sub-formulae IA to IF, containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include (1-6C)alkyl esters such as methyl, ethyl and tert- butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2- oxo-1 , 3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.

[0086] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae IA to IF, that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula I, or sub-formulae I A to IF, containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1-6C) ₂ carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(1- 4C)alkylpiperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0087] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae IA to IF, that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (1- 4C)alkylamine such as methylamine, a [(1-4C)alkyl] ₂ amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0088] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I, or sub-formulae IA to IF, that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with (1-10C)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and

4-(1-4C)alkyl)piperazin-1-ylmethyl.

[0089] The in vivo effects of a compound of the Formula (I), or sub-formulae IA to IF, may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I), or sub-formulae IA to IF. As stated hereinbefore, the in vivo effects of a compound of the Formula (I), or sub-formulae IA to IF, may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0090] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

[0091] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.

Synthesis

[0092] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples. [0093] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0094] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0095] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0096] For examples of protecting groups see one of the many general texts on the subject, for example,‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0097] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0098] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a te/f-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0099] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[00100] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[00101] Resins may also be used as a protecting group.

[00102] The methodology employed to synthesise a compound of Formula (I), or sub formulae IA to IF, will vary depending on the nature of X, R ¹ , R ² , R ³ and any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.

[00103] Once a compound of Formula (I), or sub-formulae IA to IF, has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of:

(i) removing any protecting groups present;

(ii) converting the compound Formula (I) into another compound of Formula (I);

(iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or

(iv) forming a prodrug thereof.

[00104] An example of (ii) above is when a compound of Formula (I) is synthesised and then one or more of the groups of X, R ¹ , R ² , R ³ may be further reacted to change the nature of the group and provide an alternative compound of Formula (I). For example, the compound can be reacted to convert any R group into a substituent group other than hydrogen.

[00105] The resultant compounds of Formula (I), or sub-formulae IA to IF, can be isolated and purified using techniques well known in the art. [00106] The compounds of Formula (I) may be synthesised by the general synthetic routes (e.g. Schemes 1 to 5) below, specific examples of which are described in more detail in the Examples.

wherein, Y and Y ² are each a halogen such as F, Cl, Br or a suitable alternative such as OTf or SC>2Me and R ¹ , R ³ , R ⁵ , R ⁶ , X are appropriate groups chosen from those defined previously.

[00107] The reaction between amines R ⁵ R ⁶ NH and 2-halopyrimidines (II) to form compounds of formula (I) as shown in Scheme 1 may be carried out at elevated temperature (e.g. 60-200 °C), using conventional or microwave heating, in a suitable solvent or solvent mixture, such as NMP, DMA, DMF, dioxane or acetonitrile. The reaction is carried out in the presence of a base (such as triethylamine or DIPEA, cesium carbonate), a polymer supported base (such as MP-carbonate or PS-TBD) or with no base. Alternative reaction conditions include the use of transition metal catalysts.

[00108] Compounds of formula (II) may be prepared from compounds of formula (III), by heating in the presence or absence of base, or by palladium catalysis, using conditions including those described in the previous paragraph. Displacement of dihalopyrimidines such as dichloropyrimidine under these conditions normally occurs primarily at the 4-position.

[00109] A compound of formula (I) may be converted to another compound of formula (I) by methods generally known to those skilled in the art.

Scheme 2

wherein, R ¹ , R ³ , X and Y are appropriate groups chosen from those defined previously.

[00110] The reduction of nitro compounds (IV) to aromatic amines (III) may be carried out by numerous methods which are well known in the art. Hydrogenation can be carried out in the presence of a metal catalyst such as palladium, often in the form of palladium on carbon, in an appropriate solvent or mixture of solvents such as ethanol, methanol, ethyl acetate or ethanol/NMP at ambient or elevated temperature (such as 60-75 °C) using conventional or microwave heating. These reactions are carried out under a hydrogen atmosphere, or alternatively by“transfer hydrogenation” using a reagent such as ammonium formate or triethylsilane. An alternative method uses tin(ll) chloride in an appropriate solvent or solvent mixture, such as ethanol and trifluoroethanol, at elevated temperatures such as 120 °C using conventional or microwave heating. Other approaches are known in the art such as iron or zinc metal mediated reductions.

[00111] Alternatively, compounds of formula (III) may be obtained from aromatic halides or similar compounds (V), by reaction with ammonia or an equivalent of ammonia under metal catalysed conditions. Examples of this transformation are well known and include the amination of aryl bromides or iodides using copper(l) oxide, ammonium hydroxide solution at elevated temperatures in an appropriate solvent (such as 140 °C in NMP). Alternatively, particularly where Y=CI, palladium acetate and benzophenone imine may be used as described in Shen etal., Angew. Chem. Int. Ed. 2005, 44, 1371. Reactions are typically carried out using a base such as sodium tert- butoxide in an appropriate solvent or solvent mixture such as 1 ,2-dimethoxyethane at elevated temperatures. Hydrolysis of the imine intermediate thus formed can be carried out in a one-pot procedure at rt with the addition of an acid such as HCI.

Scheme 3

wherein Y ¹ is a halogen such as Cl, Br, I or a suitable alternative such as OTs, OTf or SC>2Me, and Y, R ¹ , R ³ , Xare appropriate groups chosen from those defined previously.

[00112] Compounds (IV) may be formed by alkylation of compounds (VI), using an appropriate alkylating agent such as 3-hydroxy-3-methyl-butyl 4-methylbenzenesulfonate, in an appropriate solvent such as acetonitrile or DMF, in the presence of a base such as cesium carbonate, at ambient or elevated temperature (e.g. 60 - 100 °C). [00113] Compounds (VI) may be formed by cyclisation of diamino compounds (VII). Possible conditions include the use of bis(2,5-dioxopyrrolidin-1-yl) carbonate in acetonitrile at ambient temperature, but alternative conditions for these cyclisations are well known in the art using reagents such as carbonyl diimidazole, triphosgene and urea. Compounds (VII) may be formed by reaction of compounds (VIII) with an appropriate amine R ¹ -NH2. Suitable conditions for these transformations include the use of a base (such as DIPEA) in an appropriate solvent (such as NMP) at elevated temperature (such as 150-200 °C), although many alternative conditions are known by those skilled in the art for this class of transformation, including metal- catalysed couplings. The same sequence may be used to convert compounds (Vlll-a) into compounds of formula (V)

[00114] Alternatively, the more reactive di-nitro compounds (IX) can be used to prepare (VII) by halogen displacement followed by nitro reduction as described in the literature, for example Freitag et al, Bioorg. Med. Chem. 2011 , 19, 3669. Amines R ¹ -NH2, and nitro-or halo- compounds (IX), (VIII) and (Vlll-a) may be prepared by known methods or obtained from commercial suppliers.

Scheme 4

wherein R is a small alkyl group, or both R groups together form a 5-6 membered cyclic acetal, X, R ³ , R ⁴ , R ⁵ , R ⁶ are appropriate groups chosen from those defined previously, and R ^z is an optionally substituted (1-6C)alkyl, (3-7C)cycloalkyl, heteroaryl or heterocyclyl group.

[00115] Compounds of formula (I) may be converted to other groups of formula (I) by known methods, including but not limited by the examples described here. For example, acetal (l-a) may be deprotected to form aldehyde (X) by treatment with acid (such as TFA) in the presence of water and optionally with an organic co-solvent such as THF, at ambient or elevated temperature (such as 40 - 70 °C). Methods for reductive amination with amines R ⁴ R ^Z NH to form compounds (l-b) are well known and include those described in Abdel-Magid et al, J. Org. Chem., 1996, 61, 3849. Further transformations from aldehyde (X) enable access to other substituents, such as alcohols (l-c) via reduction with a reducing agent such as sodium borohydride, in an appropriate solvent such as methanol.

Scheme 5

wherein X, Y, R ¹ and R ³ are chosen from groups previously defined.

[00116] Compounds (IV) and (V) may also be formed by alkylation of compounds (XI) and (XII). Alkylation conditions are well known in the art, and include the use of an alkyl halide, tosylate or equivalent in an appropriate solvent such as acetonitrile or DMF, in the presence of a base such as cesium carbonate, at ambient or elevated temperature (e.g. 60 - 100 °C). Compounds (XI) and (XII) may be prepared by known methods including variations on those procedures described above.

Biological Activity

[00117] The biological assays described in the Examples section herein may be used to measure the pharmacological effects of the compounds of the present invention.

[00118] Although the pharmacological properties of the compounds of Formula I vary with structural change, as expected, the compounds of the invention were found to be active in the HTRF in vitro assay described in the Examples section.

[00119] In general, as illustrated by the Example compound data in Table 1 , in the HTRF assay described in the Examples section, the compounds of the invention demonstrate a pICso of 5.0 or more, with preferred compounds of the invention demonstrating a pICso of 6.0 or more.

[00120] In the immunofluorescence assay described herein in the Examples section, certain compounds of the invention have been shown to enable degradation of BCL6. This is illustrated by the Example compound data shown in Table 2, wherein compounds of the invention demonstrate a pDCso of 5.5 or more, with preferred compounds of the invention demonstrating a pDCso of 6.5 or more, and the most preferred compounds of the invention demonstrating a pDCso of 7.0 or more.

[00121] In general, as illustrated by the Example compound data in Table 3, in the SU-DHL4 cell viability assay described herein in the Examples section, compounds of the invention may inhibit cell proliferation with a Glso of 2.0 mM or less, with preferred compounds of the invention inhibiting cell proliferation with a Glso of 1.0 pM or less.

[00122] The following data were generated for the Examples:

Table 1 - HTRF in vitro Assay

Table 2 - SU-DHL4 Degradation Assay

Table 3 - SU-DHL4 Cell Viability Assay

Table 4 - OCI-LY1 MSD degradation assay

Pharmaceutical Compositions

[00123] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. [00124] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[00125] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

[00126] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.

[00127] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[00128] The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[00129] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention. Therapeutic Uses and Applications

[00130] The present invention provides compounds that function as inhibitors of BCL6 activity.

[00131] The present invention therefore provides a method of inhibiting BCL6 activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[00132] The present invention also provides a method of treating a disease or disorder in which BCL6 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[00133] The present invention provides a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[00134] The present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[00135] The present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[00136] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.

[00137] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.

[00138] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer.

[00139] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of BCL6 activity (i.e. in the inhibition of BCL6 transcriptional repression and/or co-repressor binding).

[00140] Certain compounds of the present invention have been found to bind to BCL6 and initiated the degradation of BCL6. Thus, the present invention also provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the degradation of BCL6.

[00141] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which BCL6 activity is implicated.

[00142] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

[00143] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for use in the treatment of human cancers.

[00144] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of BCL6 activity (i.e. in the inhibition of BCL6 transcriptional repression and/or co-repressor binding).

[00145] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the degradation of BCL6.

[00146] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which BCL6 activity is implicated.

[00147] The term "proliferative disorder" and "proliferative condition" are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro ox in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers (including breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary), leukaemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), lymphomas (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lymphatic, blood, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.

[00148] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).

[00149] The compound of Formula (I), or a pharmaceutically acceptable salt thereof, being an inhibitor of BCL6, has potential therapeutic uses in a variety of BCL6-mediated disease states. BCL6 expression has been linked to a variety of lymphomas (Wagner et al. , British J Haematology, 2010, 152, 3-12). BCL6 is involved in chromosomal translocations in diffuse large B-cell lymphoma (DLBCL) and inhibitors of BCL6 have been reported to kill DLBCL cells (Cerchietti et al., Cancer Cell, 2010, 17, 400-41 1), primary low grade follicular lymphoma cells (Cardenas et al., Clin Cancer Res, 2017, 23(4), 885-893) and Burkitt lymphoma cells (Polo et al., Nat Med, 2004, 10, 1329-1335). BCL6 is required for the formation of follicular helper T cells (Hatzi et al., J Exp Med, 2015, 212(4), 539-553), which raises the possibility that BCL6 inhibitors may be used to treat angioimmunoblastic T-cell lymphoma (AITL), in which BCL6 is strongly expressed (Cortes & Palomero, Curr Opin Hematol, 2016, 23, 434-443).

[00150] BCL6 has also been implicated in leukaemia cells which have acquired resistance to tyrosine kinase inhibitors (TKIs). TKIs typically fail to eradicate leukaemia- initiating cells, which may often cause recurrence of leukaemia after initial treatment. BCL6 has been identified as an important component of the TKI drug-resistance pathway in both Ph+ acute lymphoblastic leukaemia (ALL) (Duy et al., Nature, 201 1 , 473, 384-388) and Ph+ chronic myeloid leukaemia (CML) (Hurtz et al., J Exp Med, 201 1 , 208(11), 2163-2174). Inhibitors of BCL6 may therefore be used to treat ALL and CML in combination with a TKI.

[00151] Further non-haematological, solid tumours may be treated with an inhibitor of BCL6. BCL6 is amplified in approximately 50% of breast tumours and is expressed in many breast cancer cell lines, including triple negative breast cancer cell lines (Walker et al., Oncogene, 2015, 34, 1073-1082). BCL6 is also important for the survival and proliferation of non-small cell lung cancer (NSCLC) cells, primarily due to repression of genes involved in DNA damage repair (Marullo et al., Proc 107 ^th Annual Meeting AACR, 2016, Abstract nr 1271 and Deb et al., Cancer Res., 2017, Apr. 4 _^ doi: 10.1 158/0008-5472.CAN-15-3052). BCL6 amplification may also be prevalent in squamous cell carcinomas (SCC) (including SCC of the head & neck, oesophagus, lung and ovary). Furthermore, inhibition of BCL6 has recently been reported to be a suitable therapeutic target for glioma and glioblastoma (Xu et al. , Proc. Natl. Acad. Sci. U.S.A, 2017, 1 14(15), 3981-3986).

[00152] According to a further aspect of the specification there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the treatment of haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)) and multiple myeloma, and of solid tumours (including glioma, breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary)).

[00153] According to a further feature of this aspect of the specification there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the treatment of lymphomas, including DLBCL, FL, BL and AITL.

[00154] According to a further feature of this aspect of the specification there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the treatment of DLBCL and FL.

[00155] According to a further feature of this aspect of the specification there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the treatment of leukaemias, including ALL and CML.

[00156] According to a further feature of this aspect of the specification there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the treatment of solid tumours, including glioma, breast cancer, NSCLC and SCC.

[00157] According to a further feature of this aspect of the specification there is provided a method for treating haematological cancers such as lymphomas (including DLBCL, FL, BL and AITL), leukaemias (including ALL and CML) and multiple myeloma, and of solid tumours (including glioma, breast cancer, NSCLC and SCC (including SCC of the head and neck, oesophagus, lung and ovary)) in a warm-blooded animal such as man that is in need of such treatment, which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[00158] According to a further feature of this aspect of the specification there is provided a method for treating lymphomas, including DLBCL, FL, BL and AITL, in a warm-blooded animal such as man that is in need of such treatment, which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[00159] According to a further feature of this aspect of the specification there is provided a method for treating DLBCL and FL, in a warm-blooded animal such as man that is in need of such treatment, which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[00160] According to a further feature of this aspect of the specification there is provided a method for treating leukaemias, including ALL and CML, in a warm-blooded animal such as man that is in need of such treatment, which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[00161] According to a further feature of this aspect of the specification there is provided a method for treating solid tumours (including glioma, breast cancer, NSCLC and SCC (including SCC of the head and neck, oesophagus, lung and ovary)), in a warm-blooded animal such as man that is in need of such treatment, which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[00162] According to a further feature of this aspect of the specification there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of haematological cancers such as lymphomas (including DLBCL, FL, BL and AITL), leukaemias (including ALL and CML) and multiple myeloma, and of solid tumours (including glioma, breast cancer, NSCLC and SCC (including SCC of the head and neck, oesophagus, lung and ovary)).

[00163] According to a further feature of this aspect of the specification there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of lymphomas, including DLBCL, FL, BL and AITL.

[00164] According to a further feature of this aspect of the specification there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of DLBCL and FL.

[00165] According to a further feature of this aspect of the specification there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of leukaemias, including ALL and CML. [00166] According to a further feature of this aspect of the specification there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of solid tumours (including glioma, breast cancer, NSCLC and SCC (including SCC of the head and neck, oesophagus, lung and ovary)).

[00167] It will be appreciated that the provisos recited in respect of the compounds of Formula I , as defined hereinabove, exclude certain compounds perse, but the use of these compounds in any of the therapeutic applications, methods and/or combination therapies defined herein is still encompassed by the present invention.

Routes of Administration

[00168] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e. , at the site of desired action).

[00169] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g. , by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

Combination Therapies

[00170] The antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:-

(i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), steroid hormones, including progestogens (for example megestrol acetate) and corticosteroids (for example dexamethasone, prednisone and prednisolone), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;

(iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]- 5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), A/-(2-chloro-6- methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-meth ylpyrimidin-4-ylamino}thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase];

(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as A/-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4- amine (gefitinib, ZD1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-/\/-(3-chloro-4-fluorophenyl)-7-(3-morpholinoprop oxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN 107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin -1- ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin anb3 function and angiostatin)];

(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan;

(viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

(ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and

(x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

[00171] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.

[00172] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more chemotherapeutic agents selected from a BCL-2 family inhibitor (e.g. Venetoclax and/or navitoclax), a BTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Tirabrutinib (ONO/GS-4059), BGB- 3111 or Spebrutinib (CC-292) or a TNF inhibitor (e.g. Lenalidomide).

[00173] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[00174] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.

[00175] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition, such as cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed herein above.

[00176] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a tyrosine kinase inhibitor.

[00177] According to this aspect of the invention there is provided a combination for use in the treatment of leukaemia (such as ALL or CML) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a tyrosine kinase inhibitor.

[00178] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.

[00179] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of cancer in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.

[00180] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of leukaemia (such as ALL or CML) in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.

[00181] Herein, where the term“combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[00182] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.

EXAMPLES

Abbreviations

APCI Atmospheric pressure chemical ionization

aq. Aqueous

br broad (in NMR spectrum)

CV column volumes (in column chromatography)

d doublet (in NMR spectrum)

DCM dichloromethane

DIPEA diisopropylethylamine

DMA N,N-dimethylacetamide

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

ESI electrospray ionisation

EtOAc ethyl acetate

FID free induction decay

h hour(s)

HPLC High Performance Liquid Chromatography

HRMS high resolution mass spectrometry

KP-Sil Biotage™ KP-Sil (50uM irregular silica)

LCMS liquid chromatography and mass spectrometry MeOH methanol

MeCN acetonitrile

MS mass spectrometry

Ms mesyl (methanesulfonyl)

m multiplet (in NMR spectrum)

MHz megahertz

min minute(s)

mins minutes

MP macroporous polystyrene (solid support for polymer-bound reagents, such as

Biotage MP-carbonate)

m/z mass to charge ratio

NMP N-methylpyrrolidinone

NMR nuclear magnetic resonance

NOESY nuclear Overhauser effect spectroscopy

Pd/C palladium on activated charcoal

PS-TBD a polymer-supported bicyclic guanidine moiety (1 ,5,7-triazabicyclo[4.4.0]dec-5-ene) used as a base

ppm parts per million

q quartet (in NMR spectrum)

QToF Quadrupole Time-of-flight

quin. quintet (in NMR spectrum)

Rt retention time (in LCMS)

rt room temperature

s singlet (in NMR spectrum)

sat. saturated

SCX-2 strong cation exchange (e.g. Isolute® SCX-2 columns)

t triplet (in NMR spectrum)

Tf triflate (trifluoromethane sulfonate)

TFA trifluoroacetic acid

THF tetrahydrofuran

Ts tosyl (4-toluenesulfonyl)

uL microlitres

Analytical methods: LCMS

Method T2

[00183] LC/MS and HRMS analysis was performed on an Agilent 1200 series HPLC and diode array detector coupled to a 6210 time of flight mass spectrometer with dual multimode APCI/ESI source. Analytical separation was carried out at 40°C on a Merck Chromolith Flash column (RP-18e, 25 x 2 m ) using a flow rate of 1.5 mL/min in a 2 minute gradient elution with detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing formic acid at 0.1 %. Gradient elution was as follows: 5:95 (A/B) to 100:0 (A/B) over 1.25 min, 100:0 (A/B) for 0.5 min, and then reversion back to 5:95 (A/B) over 0.05 min, finally 5:95 (A/B) for 0.2 min.

Method T4

[00184] As for method T2 except at 30°C, using a flow rate of 0.75 mL/min in a 4 minute gradient elution as follows: 5:95 (A/B) to 100:0 (A/B) over 2.5 min, 100:0 (A/B) for 1 min, and then reversion back to 5:95 (A/B) over 0.1 min, finally 5:95 (A/B) for 0.4 min.

Method X2

[00185] LC/MS and HRMS analysis was performed on a Waters Acquity UPLC and diode array detector coupled to a Waters G2 QToF mass spectrometer fitted with a multimode ESI/APCI source. Analytical separation was carried out at 30°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6u, 100A) using a flow rate of 0.5 mL/min in a 2 minute gradient elution with detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing formic acid at 0.1 %. Gradient elution was as follows: 10:90 (A/B) to 90: 10 (A/B) over 1.25 min, 90: 10 (A/B) for 0.5 min, and then reversion back to 10:90 (A/B) over 0.15 min, finally 10:90 (A/B) for 0.1 min.

Method X4

[00186] As for method X2, except using a flow rate of 0.3 mL/min in a 4 minute gradient elution as follows: 10:90 (A/B) to 90: 10 (A/B) over 3 min, 90: 10 (A/B) for 0.5 min, and then reversion back to 10:90 (A/B) over 0.3 min, finally 10:90 (A/B) for 0.2 min.

Analytical methods: NMR

[00187] NMR data was collected on a Bruker Avance 500 spectrometer equipped with a 5 mm BBO/QNP probe or on a Bruker Avance Neo 600 spectrometer equipped with a 5 mm TCI Cryo-Probe. The ¹ H and ¹³ C spectra were referenced to the internal deuterated solvent. All NMR data were acquired at the temperature of 298 K. All data were acquired and processed using Bruker Topspin 2.1 or Bruker Topspin 4.

[00188] The ¹ H-NMR spectrum was acquired using a Bruker standard 1 D zg30 pulse sequence with 16 scans. The sweep width was 20.5 ppm, and the FID contained 64k time- domain data points.

[00189] As is well known in the art, in certain cases exchangeable (OH, NH) protons are not observed in the NMR spectrum due to exchange with deuterium (for example in methanol-d4) or are very broad and not clearly observed due to rapid exchange (for example with residual water in chloroform-d). In certain solvents, such as acetone-d _¾ slower exchange may occur, resulting in reduced integrals for these protons.

Purification methods

[00190] Unless otherwise described in the text, HPLC purification was carried out on an Agilent 6120 MS-Prep LC using an ACE 5 C18-PFP 250 x 21.2 mm column using a 15 min gradient of water: methanol (both modified with 0.1 % formic acid) - for example 10-100 %, 40- 100 %, 60-100 % or 55-80 %, at a flow rate of 20ml_ per minute. Alternative column sizes and flow rates were used dependent on the scale of the purification, chosen from ACE 5 C18-PFP 250 x 10 mm (flow rate 5ml_ per minute) or ACE 5 C18-PFP 250 x 30mm (flow rate 40ml_ per minute).

[00191] Flash column chromatography was carried out using prepacked Biotage™ SNAP KP- Sil columns. Reverse phase chromatography was carried out using a Biotage™ SNAP Ultra C18 12g or 30g column, or a KP-C18 30g column, using a gradient of water: methanol (both modified with 0.1 % formic acid).

Example compounds

Example 1a: 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -((R)-2-hydroxypropyl)-1 ,3-dihydro-2H-benzo-

[d]imidazol-2-one

[00192] A mixture of DIPEA (0.05 ml_, 0.27 mmol), (3S,5 )-4,4-difluoro-3, 5-dimethyl- piperidine hydrochloride (19 mg, 0.10 mmol) and ( )-5-((2,5-dichloropyrimidin-4-yl)amino)-3- (3-hydroxy-3-methylbutyl)-1-(2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[c(]imidazol-2-one

(Intermediate A1 a, 15 mg, 0.034 mmol) in NMP (0.6 ml_) was heated to 80 °C for 2 days, then diluted with DMSO and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-50-80-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (6 mg). LCMS (method X4) Rt 3.27min; m/z 553.2499 expected 553.2505 for CaeHseCIFaNeOs [M+H] ⁺ . ¹ H NMR (600 MHz, Chloroform-d) d 8.01 (s, 1 H), 7.39 (d, J = 2.0 Hz, 1 H), 7.24 (dd, J = 8.4, 2.0 Hz, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 7.02 (s, 1 H), 4.66 - 4.58 (m, 2H), 4.30 - 4.19 (m, 1 H), 4.08 (t, J = 7.3 Hz, 2H), 3.97 (dd, J = 14.6, 3.3 Hz, 1 H), 3.88 (dd, J = 14.6, 7.4 Hz, 1 H), 2.76 (dd, J = 13.4, 1 1.9 Hz, 2H), 2.05 - 1.90 (m, 2H), overlapping with 1.92 (t, J = 7.3 Hz, 2H), 1.32 (m, 9H), 1.08 (d, J = 6.7 Hz, 6H). OH signals not observed.

[00193] The following tabulated compounds, examples 1 b to 1 e, were prepared by a method analogous to that used in the preparation of example 1 a, starting from the appropriate intermediate as shown in the table below.

Example 2a: 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-1 -(2-hydroxy-2-methylpropyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one

[00194] A mixture of DIPEA (0.03 ml_, 0.17 mmol), (3S,5R)-4,4-difluoro-3, 5-dimethyl- piperidine hydrochloride (12 mg, 0.0646 mmol) and 5-((2,5-dichloropyrimidin-4-yl)amino)-1- (2-hydroxy-2-methylpropyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one (Intermediate A2a, 10 mg, 0.022 mmol) in NMP (0.6 ml_) was heated at 140 °C under microwave irradiation for 1 h. After cooling the mixture was diluted with DMSO and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-50-90-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (9 mg). LCMS (Method X4) Rt 3.31 min; m/z 567.2639 expected 567.2662 for CayHssCIFaNeOs [M+H] ⁺ . ¹ H NMR (600 MHz, Chloroform-d) d 8.01 (s, 1 H), 7.39 (d, J = 2.0 Hz, 1 H), 7.24 (dd, J = 8.5, 2.0 Hz, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 7.03 (s, 1 H), 4.61 (br d, J = 13.2 Hz, 2H), 4.09 (t, J = 7.3 Hz, 2H), 3.91 (s, 2H), 3.08 (1 H, s), 2.76 (dd, J = 13.4, 1 1.9 Hz, 2H), 2.16 (1 H, s), 2.06 - 1.88 (m, 2H), overlapping with 1.93 (t, J = 7.3 Hz, 2H), 1.34 (s, 6H), 1.32 (s, 6H), 1.07 (d, J = 6.7 Hz, 6H).

[00195] The following tabulated compounds, examples 2b to 2j, were prepared by a method analogous to that used in the preparation of example 2a, starting from the appropriate intermediate as shown in the table and the appropriate amine. For example 2j, the reaction was carried out by heating in the microwave at 180 °C for 1 hour.

Example 3a: 5-((5-chloro-2-((3R,4r,5S)-4-fluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1, 3-dihydro-2H-benzo[d]imidazol-2- one

[00196] A mixture of DIPEA (0.01 ml_, 0.076 mmol), (3R,4r,5S)-4-fluoro-3,5- dimethylpiperidine hydrochloride (Intermediate C1 a, 5.1 mg, 0.03 mmol), 5-((2,5- dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]- imidazol-2-one (Intermediate A3a, 12 mg, 0.03 mmol) in NMP (0.6 ml_) was heated at 140 °C under microwave irradiation for 1.5 h. After cooling the mixture was purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 30-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (9.2 mg). LCMS (Method T4) Rt 2.90 min; m/z 491.2342 expected 491.2332 for C ₂₄ H ₃₃ CIFN ₆ O ₂ [M+H] ⁺ . ¹ H NMR (600 MHz, methanol-d4) d 7.92 (s, 1 H), 7.41 - 7.40 (m, 1 H), 7.39 (dd, J = 8.3, 1.9 Hz, 1 H), 7.13 (dd, J = 8.4, 1.2 Hz, 1 H), 4.56 - 4.50 (m, 2H), 4.07 - 4.01 (m, 2H), 3.83 (dt, J = 49.9, 9.9 Hz, 1 H), 3.45 (s, 3H), 2.52 (t, J = 12.5 Hz, 2H), 1.90 - 1.84 (m, 2H), 1.74 - 1.63 (m, 2H), 1.30 (s, 6H), 1.02 (d, J = 6.5 Hz, 6H).

[00197] The following examples 3b to 3i were prepared by a method analogous to that used in the preparation of example 3a, using 5-((2,5-dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one (Intermediate A3a) and the appropriate amine. Higher reaction temperatures were used in the preparation of examples 3g, 3i (160 °C) and 3h (180 °C). Amines used are available commercially, except for 2-(4,4- difluoropiperidin-3-yl)propan-2-ol, which was prepared by hydrogenation of 2-(1 -benzyl-4, 4- difluoro-3-piperidyl)propan-2-ol (Intermediate C2b) using Pd(OH) ₂ .

[00198] The following tabulated examples 4a to 4u were prepared by a method analogous to that used in the preparation of example 3a, using Intermediate A3a and the appropriate amine. Higher temperatures of 160 °C were used for the preparation of examples 4k and 4I.

Amines used can be obtained from commercial suppliers, except for the following:

• (5,5-difluoropiperidin-3-yl)methanol used in the preparation of example 4h, (3,3- difluoropiperidin-4-yl)methanol used in the preparation of example 4o, and (4,4- difluoropyrrolidin-3-yl)methanol used in the preparation of example 4p, which were each prepared by treatment of the corresponding, commercially available, Boc-protected amines with TFA in DCM at room temperature, followed by purification using an SCX-2 column.

• 3,3-difluoropiperidin-4-ol, used in the preparation of example 4k, which was prepared by reduction of commercially available 3,3-difluoropiperidin-4-one hydrochloride with sodium borohydride.

• 3,3,5,5-tetramethylpiperidin-4-ol (Intermediate C2a) used in the preparation of example 4g, was prepared as described below.

• (3R,5S)-3,5-dimethylpiperidin-4-ol (Intermediate C1 b), used in the preparation of example 4i, was prepared as described below.

• 3-((cyclopropylmethoxy)methyl)-4,4-difluoropiperidine used in the preparation of example 4v was prepared by alkylation of commercially available tert-butyl 4,4-difluoro-3- (hydroxymethyl)piperidine-l-carboxylate with bromomethyl cyclopropane, followed by treatment with TFA in DCM at room temperature then purification using an SCX-2 column.

Example 5a: 1 -(2-(1,3-dioxolan-2-yl)ethyl)-5-((5-chloro-2-((3R,5S)-4,4-di fluoro-3,5- dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-

2H-benzo[d]imidazol-2-one

[00199] A mixture of DIPEA (1 ml_, 5.8 mmol), (3S,5R)-4,4-difluoro-3, 5-dimethyl-piperidine hydrochloride (400 mg, 2.15 mmol) and 1-(2-(1 ,3-dioxolan-2-yl)ethyl)-5-((2,5- dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol- 2-one (Intermediate A4a, 350 mg, 0.73 mmol) in NMP (0.6 ml_) was heated to 80 °C for 2 days. It was diluted with DMSO and purified using reverse phase flash chromatography (Biotage 30g KP-C18, 10-50-100-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (400 mg) as a brown gum. LCMS (Method X4) Rt 3.44min; m/z 595.2625 expected 595.261 1 for CasHssCIFaNeCU [M+H] ⁺ . ¹ H NMR (600 MHz, chloroform-d) d 8.01 (s, 1 H), 7.36 (d, J = 1.9 Hz, 1 H), 7.22 (dd, J = 8.4, 2.0 Hz, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 7.03 (s, 1 H), 4.97 (t, J = 4.5 Hz, 1 H), 4.61 (dt, J = 13.2, 3.9 Hz, 2H), 4.06 (m, 4H), 4.03 - 3.97 (m, 2H), 3.91 - 3.86 (m, 2H), 2.76 (dd, J = 13.4, 1 1.9 Hz, 2H), 2.15 (td, J = 7.1 , 4.5 Hz, 2H), 2.12 - 1.94 (m, 2H), 1.91 (t, J = 7.3 Hz, 2H), 1.31 (s, 6H), 1.07 (d, J = 6.7 Hz, 6H). OH signal not observed in NMR.

Example 5b: 6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-1 -(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one

[00200] DIPEA (43 uL, 0.2492 mmol), (3S,5R)-4,4-difluoro-3, 5-dimethyl-piperidine hydrochloride (17 mg, 0.09 mmol) and tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1 H-benzo[d]imidazole-1-carboxylate

(Intermediate A5a, 15 mg, 0.031 mmol) in NMP (0.6 mL) was heated to 80 °C for 2 days. 2M aq. HCI (1 mL) was added and the mixture heated to 50 °C for 1 hour. It was evaporated under reduced pressure, then the resulting NMP solution was diluted with DMSO and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-50-90-100% methanol in water, 0.1 % formic acid modifier) to give the title compound as an off-white solid (9.8 mg). LCMS (Method X4) Rt 3.22min; m/z 495.2090 expected 495.2087 for C23H30CIF2N6O2 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d6) d 10.77 (s, 1 H); 8.78 (s, 1 H), 8.04 (s, 1 H), 7.30 (d, J = 1.9 Hz, 1 H), 7.19 (dd, J = 8.3, 2.0 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 4.59 - 4.39 (m, 3H), 3.92 - 3.77 (m, 2H), 2.63 (dd, J = 13.4, 1 1.9 Hz, 2H), 2.08 - 1.92 (m, 2H), 1.76 - 1.67 (m, 2H), 1.17 (s, 6H), 0.94 (d, J = 6.7 Hz, 6H).

Example 6a: 5-((5-chloro-2-(4,4-difluoroazepan-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one

[00201] A mixture of 4,4-difluoroazepane hydrochloride (8 mg, 0.047 mmol), 5-((2,5- dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]- imidazol-2-one (Intermediate A3a, 20 mg, 0.051 mmol) and MP-carbonate (Biotage, 80 mg, 0.25 mmol) in acetonitrile (1 mL) was heated to 80 °C overnight. The reaction mixture was diluted with methanol (2 mL) and loaded onto an Isolute 1 g SCX-2 column which had been primed with methanol. Further methanol (2 mL) was used to ensure all the material was transferred. The column was washed with 3: 1 DCM/methanol (10 mL), then eluted with 20% (1.4M methanolic ammonia) in DCM. Ammonia fractions were evaporated to give the title compound as a yellow gum (12mg). LCMS (Method X4) Rt 2.66min, m/z 495.2080 expected 495.2087 for C23H30CIF2N6O2 [M+H] ⁺ .

[00202] The following tabulated compounds 6b and 7a to 7o were prepared by a method analogous to that used for the synthesis of example 6a. Compounds were submitted following SCX-2 purification as described above, and show >90% purity by LCMS. Examples 6b, 7a, 7h contain a mixture of cis and trans diastereoisomers. Example 7b shows 89% purity by LCMS. Example 7f was further purified by reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-100% methanol in water, 0.1% formic acid modifier) to give compound as the formic acid salt. Example 7I was additionally heated to 110 °C for 6h in a sealed tube.

Example 8a: 6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-1 -(3-hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-

2-one

[00203] 2,4,5-trichloropyrimidine (22 mg, 0.12 mmol) and DIPEA (35 uL, 0.2 mmol) were added to a solution of 6-amino-1-(3-hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (Intermediate B2a, 20 mg, 0.08 mmol) in NMP (0.8 mL). The resulting mixture was heated for 1 h at 140°C in the microwave. (3R,5S)-4,4-difluoro-3,5- dimethyl-piperidine hydrochloride (32.6 mg, 0.18 mmol) was then added to the reaction mixture and heating in the microwave continued for 1 h at 140°C. A further addition of (3R,5S)- 4, 4-difluoro-3, 5-dimethyl-piperidine hydrochloride (16.3 mg, 0.09 mmol) was made and heating in the microwave continued for 1 h at 140 °C. The sample was purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 10-100% methanol in water, 0.1 % formic acid modifier) affording the title compound (39 mg) as a pale brown solid. LCMS (Method T4) Rt 3.12min; m/z 510.2179 expected 510.2190 for C23H31CIF2N7O2 [M+H] ⁺ . ¹ H NMR (600 MHz, Chloroform-d) d 8.14 (d, J = 2.1 Hz, 1 H), 7.99 (s, 1 H), 7.58 (d, J = 2.1 Hz, 1 H), 6.96 (s, 1 H), 4.55 (br. d, J = 12.9 Hz, 2H), 4.06 - 4.02 (m, 2H), 3.50 (s, 3H), 2.71 (t, J = 12.7 Hz, 2H), 1.99 - 1.85 (m, 4H), 1.30 (s, 6H), 1.03 (d, J = 6.8 Hz, 6H). OH not observed.

Example 8b: 6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-1 -(3-hydroxy-3-methylbutyl)-3-(methyl-c/ ₃ )-1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one

[00204] Prepared by a method analogous to that used in the synthesis of example 8a, using intermediate B2b. ¹ H NMR (500 MHz, Methanol-d4) d 8.26 (d, J = 2.0 Hz, 1 H), 7.98 (s, 1 H), 7.73 (d, J = 2.0 Hz, 1 H), 4.54 - 4.49 (m, 2H), 4.10 - 3.97 (m, 2H), 2.70 (t, J = 12.7 Hz, 2H), 2.01 - 1.90 (m, 2H), 1.91 - 1.80 (m, 2H), 1.29 (s, 6H), 1.00 (d, J = 6.8 Hz, 6H). HRMS (Method T4) m/z 513.2376, expected 513.2379 for C ₂₃ H ₂₈ D ₃ CIF ₂ N ₇ 0 ₂ ⁺ [M+H] ⁺ .

Example 9a: 6-((5-chloro-2-(4,4-difluoropiperidin-1 -yl)pyrimidin-4-yl)amino)-1 -(3- hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[00205] To 6-((2,5-dichloropyrimidin-4-yl)amino)-1-(3-hydroxy-3-methylb utyl)-3-methyl-1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (Intermediate A6a, 30 mg, 0.076 mmol) was added 4,4-difluoropiperidine hydrochloride (18 mg, 0.11 mmol), NMP (0.76 ml_ and DIPEA (39 uL, 0.23 mmol). The vial was sealed then heated in the microwave for 1 h at 140°C. The sample was purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 10- 100% methanol in water, 0.1 % formic acid modifier) affording the title compound (34 mg) as a pale yellow solid. LCMS (Method X4) Rt 3.01 min; m/z 482.1885 expected 482.1883 for C21 H27CIF2N7O2 [M+H] ⁺ . ¹ H NMR (600 MHz, Chloroform-d) d 8.12 (d, J = 2.1 Hz, 1 H), 7.99 (s, 1 H), 7.61 (d, J = 2.1 Hz, 1 H), 6.97 (s, 1 H), 4.03 (dd, J = 8.4, 6.8 Hz, 2H), 3.85 (t, J = 5.9 Hz, 4H), 3.49 (s, 3H), 2.14 (br. s, 1 H), 1.96 (tt, J = 13.3, 5.9 Hz, 4H), 1.90 - 1.84 (m, 2H), 1.30 (s, 6H). Example 10a: 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin- 4-yl)amino)-1 -(3-((cyclopropylmethyl)amino)propyl)-3-(3-hydroxy-3-methylb utyl)-1 ,3- dihydro-2H-benzo[d]imidazol-2-one:formic acid (1 :1 )

[00206] To a solution of 3-(5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2 ,3-dihydro-1 H-benzo[d]imidazol- 1-yl)propanal (Intermediate A7a, 50 g, 0.09 mmol) in THF (1 ml_) was added sequentially cyclopropanemethylamine (0.04 ml_, 0.47 mmol) and sodium triacetoxyborohydride (30 mg, 0.14 mmol). The resulting mixture was stirred for 4 days at room temperature. Added further sodium triacetoxyborohydride (30 mg, 0.14 mmol) and heated to 60 °C for 1 h. Added water 1 ml_ and stirred for 1 0 minutes, then evaporated under reduced pressure, then redissolved in DMSO and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-50-80-100% methanol in water, 0.1 % formic acid modifier) to give 18 mg of yellow gum, which was triturated with diethyl ether to give the title compound (1 1 mg) as a white solid. LCMS (Method X4) Rt 2.88 min; m/z 606.3132 expected 606.3135 for C30H43CIF2N7O2 [M+H]+; ¹ H NMR (500 MHz, Chloroform-d) d 8.53 (s, 1 H), 8.01 (s, 1 H), 7.44 (d, J = 2.0 Hz, 1 H), 7.27 (dd, J = 8.4, 2.0 Hz, 1 H), 7.07 (s, 1 H), 7.01 (d, J = 8.5 Hz, 1 H), 5.33 (s, 1 H), 4.62 (d, J = 13.1 Hz, 2H), 4.08 (m, 4H), 2.96 (t, J = 6.4 Hz, 2H), 2.85 - 2.67 (m, 4H), 2.22 (t, J = 6.3 Hz, 2H), 2.10 - 1.84 (m, 4H), 1.32 (s, 6H), 1.18 (m, 1 H), 1.08 (d, J = 6.7 Hz, 6H), 0.73 - 0.58 (m, 2H), 0.39 (t, J = 5.1 Hz, 2H).

Example 10b: 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin- 4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -(3-(methylamino)propyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one:formic acid (1 :2)

[00207] To a solution of 3-(5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2 ,3-dihydro-1 H-benzo[d]imidazol- 1-yl)propanal (Intermediate A7a, 40 mg, 0.073 mmol) in THF (1 ml_) was added sequentially methylamine 2M in THF (0.25 ml_, 0.5 mmol) and sodium triacetoxyborohydride (24 mg, 0.1 1 mmol). The resulting mixture was stirred for 2 days. A couple of drops of water were added, and the mixture evaporated under reduced pressure, then redissolved in DMSO and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-50- 80-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (1 0 mg). LCMS (Method X4) Rt 2.81 min; m/z 566.2830 expected 566.2822 for C27H39CIF2N7O2 [M+H] ⁺ ; ¹ H NMR (500 MHz, Chloroform-d) d 8.32 (s, 2H), 8.02 (s, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 7.31 - 7.23 (m, 1 H, overlapping with chloroform peak), 7.1 1 (s, 1 H), 7.01 (d, J = 8.5 Hz, 1 H), 4.61 (d, J = 12.9 Hz, 2H), 4.17 - 4.01 (m, 4H), 3.04 (t, J = 6.4 Hz, 2H), 2.80-2.70 (m, 5H), 2.66 (s, 1 H), 2.24 (t, J = 6.3 Hz, 2H), 2.06 - 1.86 (m, 4H), 1.33 (s, 6H), 1.08 (d, J = 6.7 Hz, 6H).

Example 10c: 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin- 4-yl)amino)-1 -(3-(dimethylamino)propyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one:formic acid (1 :2)

[00208] To a solution of 3-(5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2 ,3-dihydro-1 H-benzo[d]imidazol- 1-yl)propanal (Intermediate A7a, 20 mg, 0.036 mmol) in THF (1 ml_) was added dimethylamine solution in THF (0.05 ml_, 0.1 mmol). Sodium triacetoxyborohydride (12 mg, 0.057 mmol) was added and the reaction mixture was stirred at rt for 48 h. Added further sodium triacetoxyborohydride (12 mg, 0.057 mmol) and dimethylamine solution in THF (0.05 ml_, 0.1 mmol) and heated to 60 °C in a sealed tube for 5 hours. After cooling to rt, a couple of drops of water were added and the resulting mixture concentrated under reduced pressure. The residue was then taken up in DMSO (1 ml_) and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-45-80-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (12 mg). LCMS (Method T4) Rt 2.63min; m/z 580.2971 expected 580.2973 for C28H41CIF2N7O2 [M+H] ⁺ . ¹ H NMR (600 MHz, Chloroform-d) d 8.29 (s, 2H), 8.01 (s, 1 H), 7.41 (d, J = 1.9 Hz, 1 H), 7.25 (dd, J = 8.5, 1.9 Hz, 1 H), 7.07 (s, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 4.62 (dt, J = 13, 4 Hz, 2H), 4.07 (t, J = 7.1 Hz, 2H), 4.01 (t, J = 6.7 Hz, 2H), 3.1 1 - 2.97 (m, 2H), 2.76 (t, J = 12.7 Hz, 2H), 2.69 (s, 6H), 2.65 (s, 1 H), 2.22 (m, 2H), 2.10 - 1.94 (m, 1 H), 1.91 (t, J = 7.1 Hz, 2H), 1.31 (s, 6H), 1.08 (d, J = 6.7 Hz, 6H).

Example 10d : 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin- 4-yl)amino)-1 -(3-((cyclopropylmethyl)(methyl)amino)propyl)-3-(3-hydroxy-3 - methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one:formic acid (1 :1)

[00209] (Cyclopropylmethyl)methylamine hydrochloride salt (20 mg, 0.23 mmol) was dissolved in THF (0.5 ml_) and 3 eq. of MP-carbonate resin was added. The resulting mixture was stirred for 30 mins, and resin removed by filtration. The resulting solution was added to a solution of 3-(5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-1-yl)propanal (Intermediate A7a, 20 mg, 0.036 mmol) in THF (1 ml_), followed by sodium triacetoxyborohydride ( 12 mg, 0.057 mmol). The resulting mixture was stirred for 4 days. Further sodium triacetoxyborohydride (12 mg, 0.057 mmol) was added and the resulting mixture was heated to 60 °C for 1 h. After cooling to rt, a couple of drops of water were added and the resulting mixture concentrated under reduced pressure. The residue was then taken up in DMSO (1 ml_) and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-50-80-100% methanol in water, 0.1 % formic acid modifier). Fractions containing product were combined and evaporated to the title compound (8 mg). LCMS (Method X4) Rt 2.88min; m/z 620.3289 expected 620.3291 for C ₃₁ H ₄₅ CIF ₂ N ₇ O ₂ [M+H] ⁺ ; ¹ H NMR (600 MHz, Chloroform-d) d 8.36 (s, 1 H), 8.01 (s, 1 H), 7.40 (d, J = 1.9 Hz, 1 H), 7.24 (dd, J = 8.4, 2.0 Hz, 1 H), 7.07 - 6.95 (m, 2H), 4.63 (dt, J = 13.4, 3.8 Hz, 2H), 4.07 (t, J = 7.0 Hz, 2H), 3.99 (t, J = 6.8 Hz, 2H), 3.09 - 2.96 (m, 2H), 2.79 - 2.72 (m, 4H), 2.66 (s, 3H, NMe), 2.20 (p, J = 6.9 Hz, 2H), 2.07 - 1.95 (br m, 2H), 1.91 (t, J = 7.0 Hz, 2H), 1.31 (s, 6H), 1.08 (d, J = 6.7 Hz, 6H), 1.06 - 0.97 (m, 1 H), 0.74 - 0.59 (m, 2H), 0.40 - 0.29 (m, 2H). OH, NH+ not observed. Example 10e: 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin- 4-yl)amino)-1 -(3-(cyclopropylamino)propyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro- 2H-benzo[d]imidazol-2-one:formic acid (1 :1 )

[00210] To a solution of 3-(5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2 ,3-dihydro-1 H-benzo[d]imidazol- 1-yl)propanal (Intermediate A7a, 20 g, 0.036 mmol) in THF (1 ml_) was added sequentially cyclopropylamine ( 15 uL, 0.22 mmol) and sodium triacetoxyborohydride (12 mg, 0.057 mmol). After 2 days stirring at rt, further sodium triacetoxyborohydride (12 mg, 0.057 mmol) was added and the mixture heated to 60 °C for 1 hour. A couple of drops of water were added, and the mixture evaporated under reduced pressure, then redissolved in DMSO and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20- 100% methanol in water, 0.1 % formic acid modifier) to give the title compound (9 mg). LCMS (Method X4) Rt 2.86min; m/z 592.2998 expected 592.2978 for C29H41CIF2N7O2 [M+H] ⁺ . ¹ H NMR (600 MHz, Chloroform-d) d 8.31 (s, 1 H), 8.01 (s, 1 H), 7.42 (d, J = 1.9 Hz, 1 H), 7.26 (dd, J = 8.5, 2.0 Hz, 2H), 7.05 (s, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 4.65 - 4.57 (m, 2H), 4.09 (t, J = 7.0 Hz, 2H), 4.07 - 4.00 (m, 2H), 2.99 (t, J = 6.4 Hz, 2H), 2.76 (t, J = 12.7 Hz, 2H), 2.65 (s, 1 H), 2.42 (m, 1 H), 2.16 (p, J = 6.4 Hz, 2H), 2.06 - 1.94 (m, 2H), 1.91 (t, J = 7.0 Hz, 2H), 1.33 (s, 6H), 1.08 (d, J = 6.7 Hz, 6H), 0.93 - 0.84 (m, 2H), 0.77 - 0.66 (m, 2H).

Example 10f: 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin- 4-yl)amino)-1 -(3-((2,2-difluoroethyl)amino)propyl)-3-(3-hydroxy-3-methylb utyl)-1 ,3- dihydro-2H-benzo[d]imidazol-2-one:formic acid (1 :2)

[00211] To a solution of 3-(5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2 ,3-dihydro-1 H-benzo[d]imidazol- 1-yl)propanal (Intermediate A7a, 20 mg, 0.036 mmol) in THF (1 ml_) was added 2,2- difluoroethylamine (5 uL, 0.07 mmol) then sodium triacetoxyborohydride (12 mg, 0.057 mmol), and the resulting mixture stirred at rt for 48h. A couple of drops of water were added to the reaction mixture before concentrating under reduced pressure. The residue was then taken up in DMSO (1 ml_) and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-50-90-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (15 mg). LCMS (Method T4) Rt 2.65min; m/z 616.2782 expected 616.2784 for C28H39CIF4N7O2 [M+H] ⁺ . ¹ H NMR (600 MHz, Chloroform-d) d 8.1 1 (s, 2H), 8.03 (s, 1 H), 7.41 (d, J = 1.9 Hz, 1 H), 7.27 (dd, J = 8.4 and 2.0 Hz, 1 H, partly obscured by solvent peak), 7.06 (s, 1 H), 7.02 (d, J = 8.4 Hz, 1 H), 6.05 (tt, J = 56.2, 4.1 Hz, 1 H), 4.61 (br d, J = 12.8, 2H), 4.09 (t, J = 7.1 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 3.16 (td, J = 14.7, 4.2 Hz, 2H), 2.89 (t, J = 6.5 Hz, 2H), 2.77 (t, J = 12.7 Hz, 2H), 2.08 (app p, J = 6.5 Hz, 2H), 2.04 - 1.94 (m, 2H), 1.92 (t, J = 7.1 Hz, 2H), 1.33 (s, 6H), 1.08 (d, J = 6.7 Hz, 6H). OH, NH ₂ ⁺ not observed.

[00212] Examples 10g to 10m were prepared from Intermediate A7b: 2-(5-((5-chloro-2- ((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4 -yl)amino)-3-(3-hydroxy-3-methyl- butyl)-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-1-yl)acetaldehyde using conditions analogous to those used in the preparation of compound 10f. For examples 10i, 10j, 10k, and 10m, acetic acid was added to the reaction mixture. The formation of example 10k employed overnight heating at 60 °C.

Example 10n: 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-

4-yl)amino)-1 -(3-((2-fluoroethyl)amino)propyl)-3-(3-hydroxy-3-methylbutyl )-1 ,3- dihydro-2H-benzo[d]imidazol-2-one

[00213] Example 10n may be prepared by analogous methods to Example 10f.

Example 11 : 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -(3-hydroxypropyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one

[00214] To a solution of 3-(5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1- yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2 ,3-dihydro-1 H-benzo[d]imidazol- 1-yl)propanal (Intermediate A7a, 20 mg, 0.036 mmol) in THF (1 ml_) and methanol (0.5ml_) was added sodium borohydride (3 mg, 0.08 mmol) and the resulting mixture stirred at rt for 2 days, then quenched by addition of a few drops of water. Evaporated under reduced pressure, diluted with DMSO and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-50-90-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (9 mg). LCMS (Method T4) Rt 3.00min; m/z 553.2488 expected 553.2500 for CaeHseCIFaNeOs [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d6) d 8.81 (s, 1 H), 8.05 (s, 1 H), 7.38 (d, J = 1.9 Hz, 1 H), 7.29 (dd, J = 8.4, 1.9 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 4.57 (br t, J = 5.5 Hz, 1 H), 4.49 (br d, J = 12.8 Hz, 2H), 4.46 (s, 1 H), 3.88 (t, J = 7.5 Hz, 4H), 3.43 (t, J = 7.2 Hz, 2H), 2.64 (app t, 2H), 2.14 - 1.90 (m, 2H), 1.79 (p, J = 6.6 Hz, 2H), 1.73 - 1.65 (m, 2H), 1.16 (s, 6H), 0.94 (d, J = 6.7 Hz, 6H).

[00215] The following tabulated examples 12a to 12d were prepared by a method analogous to that used in the preparation of example 3a, using Intermediate A3a and the appropriate amine. For example 12b, the reaction was heated for 16h. For the preparation of example 12c, the reaction was stirred at 110 °C for 7 days. For the preparation of example 12e, MP- carbonate resin was used in place of DIPEA. Amines used were obtained from commercial suppliers, except for 2-(4,4-difluoropiperidin-3-yl)ethan-1-ol, used in the preparation of example 12a, which was prepared from commercially available 2-(1-(tert-butoxycarbonyl)-4,4- difluoropiperidin-3-yl)acetic acid by borane reduction, followed by deprotection of the Boc group using TFA.

[00216] The following tabulated compounds, examples 13a to 13c, were prepared by a method analogous to that used in the preparation of example 2a, starting from the appropriate intermediate as shown in the table and the appropriate amine.

[00217] The following tabulated compounds, examples 14a to 14m, were prepared by a method analogous to that used for the synthesis of example 6a, using the appropriate amine and Intermediate A3a. Compounds were analysed following SCX-2 purification, and show >90% purity by LCMS. Example 14g was further purified by preparative HPLC (C18 column, 15 minute gradient elution from 60:40 to 30:70 water: methanol (both modified with 0.1 % formic acid) at a flow rate of 20ml_/min).

Example 14m: rac-(3S,5S)-1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-me thyl-2-oxo-

2,3-dihydro-1 H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,5-dimethylpi peridine-3- carboxamide

Example 14n: rac-(3R,5S)-1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-me thyl-2-oxo-

2,3-dihydro-1 H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N,5-dimethylpi peridine-3- carboxamide

[00218] Example 14m and Example 14n were prepared as a 3:1 mixture of transxis diastereoisomers by a method analogous to that used for the synthesis of example 6a, using N,5-dimethylpiperidine-3-carboxamide and Intermediate A3a. The crude product was purified by chromatography (SCX-2). LCMS (Method X4) Rt 2.13min; m/z 516.2526 and Rt 2.26min; m/z 516.2525 expected 516.2484 for CaHssCINyCV [M+H] ⁺ .

[00219] The product was separated into its constituent diastereoisomers by preparative HPLC (C18, 15 minute gradient elution from 60:40 to 30:70 water: methanol (0.1 % formic acid modifier) at a flow rate of 20 mL/min. The earlier running isomer was assigned as the trans isomer (Example 14m), and the later running, minor, isomer was assigned as the cis isomer (Example 14n) on the basis of the ¹ H NMR signal at 1.39 ppm (the 4-piperidinyl axial proton) being a quartet with a large coupling constant caused by a geminal and two trans- diaxial proton couplings, which is indicative of both the amide and the methyl group being equatorial.

Example 14m: LCMS (Method T4) Rt 2.37min; m/z 516.2481 expected 516.2484 for CasHssCINyCV [M+H] ⁺ ; ¹ H NMR (500 MHz, CD ₃ OD) d 7.95 (s, 1 H), 7.46 (d, J = 1.9 Hz, 1 H),

7.36 (dd, J = 8.4, 1.9 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 4.07 - 4.00 (m, 2H), 3.91 (dd, J = 13.7, 6.3 Hz, 1 H), 3.86 - 3.75 (m, 2H), 3.45 (s, 3H), 3.40 - 3.33 (m, 1 H), 2.65 - 2.58 (m, 1 H) overlapping with 2.60 (s, 3H), 2.07 (m, 1 H), 1.94 - 1.84 (m, 3H), 1.56 (m, 1 H), 1.30 (s, 3H),

1.30 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H, pip Me).

Example 14n: LCMS (Method T4) Rt 2.45min; m/z 516.2487 expected 516.2484 for CasHssCINyCV [M+H] ⁺ ; ¹ H NMR (500 MHz, CD ₃ OD) d 7.93 (s, 1 H,), 7.48 (d, J = 1.9 Hz, 1 H),

7.37 (dd, J = 8.4, 1.9 Hz, 1 H), 7.12 (d, J = 8.4 Hz, 1 H), 4.69 (br d, J = 12.5 Hz, 1 H), 4.55 (br d, J = 13.4 Hz, 1 H), 4.10 - 3.96 (m, 2H), 3.45 (s, 3H), 2.84 (dd, J = 13.0, 1 1.5 Hz, 1 H), 2.72 (s, 3H), 2.44 - 2.32 (m, 2H), 1.95 - 1.84 (m, 3H), 1.60 (br m, 1 H), 1.39 (q, J = 12.3 Hz, 1 H),

1.31 (d, J = 2.7 Hz, 6H), 0.94 (d, J = 6.6 Hz, 3H).

Example 15: (S)-6-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin- 1 -yl)pyrimidin- 4-yl)amino)-1 -(3-hydro xy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4, 5- b]pyridin-2-one; or

(R)-6-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)piperidin- 1 -yl)pyrimidin-4-yl)amino)- 1 -(3-hydro xy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

Step 1: ( 1-(5-chloro-4-(methylthio)pyrimidin-2-yl)-4,4-difluoropiperi din-3-yl)methanol f single enantiomer of unknown stereochemistry /

[00220] A mixture of (1 -benzyl-4, 4-difluoropiperidin-3-yl) ethanol (400 g, 1.66 mmol) and palladium hydroxide (10 mg, 0.083 mmol) in EtOH (3.3 ml_) was stirred at rt under a balloon of H2 gas for 16h. Filtered and solvent removed under vacuum to afford 287 mg of a mixture of -1.9:1 (4,4-difluoropiperidin-3-yl)methanol : (1-benzyl-4,4-difluoropiperidin-3-yl)methanol. This was combined with 2,5-dichloro-4-(methylthio)pyrimidine (217 mg, 1.11 mmol) and DIPEA (0.58 ml_, 3.34 mmol) in IPA (3.4 ml_), and heated in a sealed vessel to 120°C for 4 h. The solvent was removed under vacuum and the crude product was redissolved, loaded onto silica, and purified by flash column chromatography (0 - 50% EtOAc in cyclohexane) to afford racemic title compound (316 mg) as a clear oil which slowly crystallised on standing. LCMS (Method T2) Rt 1.54 min; m/z 310.0594 expected 310.0587 for C ₁₁ H ₁₅ CIF ₂ N ₃ OS ⁺ [M+H] ⁺ . The product (280 mg) was dissolved to 25 mg/ml_ in 1 :1 IPA:DCM and was then purified by SFC (Lux C4, 10:90 IPA:C0 ₂ ). The earlier running fraction was collected and evaporated, then dried under vacuum to give a colourless gum (101 mg). Chiral purity was analysed by SFC [Lux C4 (4.6mm x 250mm, 5um), 40 °C, 4 mL/min, 15:85 IPA:C0 ₂ (0.2% v/v NH3) Rt 2.17min, >98% ee over minor isomer at Rt 2.52min.

Step 2: ( 1-(5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)-4, 4-difluoropiperidin-3-yl)methanol,

[00221] (1-(5-chloro-4-(methylthio)pyrimidin-2-yl)-4,4-difluoropiper idin-3-yl)methanol (single enantiomer of unknown stereochemistry from step 1 , 50 mg, 0.16 mmol) was dissolved in DCM (0.85 mL) and MeCN (0.85 mL) and stirred at 0 °C. 3-Chloroperoxybenzoic acid (73 mg, 0.33 mmol) was added portionwise and the reaction mixture was warmed to room temperature and stirred for 16 h. DCM (20 mL) was added and the reaction mixture was washed with sat. sodium thiosulfate and sat. sodium bicarbonate (20 mL). The organic layer was separated, dried and the solvent removed, then product purified by flash column chromatography (12 g, KP-Sil, 0-5% methanol in DCM) to give the title compound (40 mg) as a colourless oil. LCMS (Method T2) Rt 1.20 min; m/z 342 [M+H] ⁺ . Step 3: 6-((5-chioro-2-(4,4-difiuoro-3-(hvdroxymethvi)piperidin-1-vi )pyrimidin-4-vi)amino)-1- (3-hydroxy-3-methylbutyl)-3-methyl- 1 ,3-dihydro-2H-imidazof4, 5-b]pyridin-2-one f single

[00222] To a mixture of 6-amino-1-(3-hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (Intermediate B2a, 7.3 mg, 0.029 mmol), and (1-(5-chloro-4- (methylsulfonyl)pyrimidin-2-yl)-4,4-difluoropiperidin-3-yl)m ethanol (from step 2, 10 mg, 0.029 mmol) in TFE (0.6 ml_) was added trifluoroacetic acid (2 pl_, 0.029 mmol) and the reaction was heated at 80 °C for 19 h. Crude product was purified by reverse-phase chromatography (Biotage SNAP-Ultra C18, 12 g, 30-100% methanol in water (0.1 % formic acid modifier)) to give the title compound (4.5 mg) as a brown oil. LCMS (Method T4) Rt 2.68 min; m/z 512.1940, expected 512.1983 for C22H29CIF2N7O3 [M+H] ⁺ . ¹ H NMR (600 MHz, Methanol- d ₄ ) d 8.22 (d, J = 1.9 Hz, 1 H), 8.01 - 7.97 (m, 1 H), 7.83 (d, J = 2.0 Hz, 1 H), 4.44 (d, J = 13.6 Hz, 1 H), 4.27 - 4.20 (m, 1 H), 4.10 - 4.01 (m, 2H), 3.87 (dd, J = 1 1.2, 4.1 Hz, 1 H), 3.51 - 3.44 (m, 5H), 3.38 (s, 1 H), 2.17 - 2.08 (m, 1 H), 2.06 - 1.97 (m, 1 H), 1.96 - 1.84 (m, 3H), 1.30 (s, 6H).

[00223] The following compounds, examples 16a to 16d, were prepared by a method analogous to that used in the preparation of example 1 a, starting from the appropriate intermediate and amine as described below.

Example 16a: 5-((5-chloro-2-(4,4-difluoro-3-methylpiperidin-1 -yl)pyrimidin-4-yl)amino)-

3-(3-hydroxy-3-methylbutyl)-1 -(2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2- one

[00224] This compound was prepared as a 1 : 1 mixture of two diastereoisomers, 5-((5-chloro- 2-((S)-4,4-difluoro-3-methylpiperidin-1-yl)pyrimidin-4-yl)am ino)-3-(3-hydroxy-3-methylbutyl)- 1-((R)-2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one and 5-((5-chloro-2-((R)-4,4- difluoro-3-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-h ydroxy-3-methylbutyl)-1-((R)-2- hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one, by reaction of (R)- 5-((2,5- dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1- (2-hydroxypropyl)-1 , 3-dihydro- 2H-benzo[c(]imidazol-2-one (Intermediate A1 a) with racemic 4,4-difluoro-3-methylpiperidine hydrochloride. LCMS (Method T4) Rt 2.89min; m/z 539.2347 expected 539.2343 for C25H34CIF2N6O3 [M+H] ⁺ .

Example 16b: 5-((5-chloro-2-(4,4-difluoropiperidin-1 -yl)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -(2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one

[00225] This compound was prepared as a single enantiomer: (R)-5-((5-chloro-2-(4,4- difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1-(2-hydroxypropyl)- 1 ,3-dihydro-2H-benzo[d]imidazol-2-one by reaction of Intermediate A1 a with 4,4- difluoropiperidine hydrochloride. LCMS (Method T4) Rt 2.77min; m/z 525.2180 expected 525.2187 for C ₂₄ H ₃₂ CIF ₂ N ₆ 0 ₃ [M+H] ⁺ . ¹ H NMR (500 MHz, CDCI ₃ ) d 8.02 (s, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.16 (dd, J = 8.5, 2.0 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 7.05 (s, 1 H, NH), 4.25 (m, 1 H), 4.06 (t, J = 7.3 Hz, 2H), 3.96 (dd, J = 14.5, 3.3 Hz, 1 H), 3.93 - 3.86 (m, 5H), 2.00 (tt, J = 13.7, 5.9 Hz, 4H), 1.91 (t, J = 7.2 Hz, 2H), 1.35 - 1.26 (m, 9H) [OH not observed].

Example 16c: 5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin- 4-yl)amino)-1 -(2-cyclopropyl-2-hydroxyethyl)-3-(3-hydroxy-3-methylbutyl)- 1 , 3-dihydro- 2H-benzo[d]imidazol-2-one

[00226] This compound was prepared as a racemate by reaction of Intermediate A1 i with (3S,5R)-4,4-difluoro-3,5-dimethylpiperidine hydrochloride. LCMS (Method T4) Rt 3.14min; m/z 579.2660 expected 579.2656 for C ₂₈ H ₃₈ CIF ₂ N ₆ O ₃ [M+H] ⁺ . ¹ H NMR (500 MHz, CDCI ₃ ) d 8.00 (s, 1 H), 7.37 (d, J = 2.0 Hz, 1 H), 7.22 (dd, J = 8.5, 2.0 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 7.01 (s, 1 H), 4.61 (br d, J = 12.8 Hz, 2H), 4.15 (dd, J = 14.6, 3.5 Hz, 1 H), 4.10 - 3.99 (m, 3H), 3.34 (td, J = 7.7, 3.5 Hz, 1 H), 2.75 (t, J = 12.8 Hz, 2H), 2.10 - 1.77 (m, 4H), 1.31 (s, 6H), 1.06 (d, J = 6.7 Hz, 6H), 1.06 - 0.92 (m, 1 H), 0.62 - 0.51 (m, 2H), 0.41 (m, 1 H), 0.36 - 0.26 (m, 1 H) [OH not observed]. Example 16d: 5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-

4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -(3-hydroxybutyl)-1 ,3-dihydro-2H- benzo[d]imidazol-2-one

[00227] This compound was prepared as a racemate by reaction of Intermediate A1 h with (3S,5R)-4,4-difluoro-3,5-dimethylpiperidine hydrochloride. LCMS (Method T4) Rt 3.08 min; m/z 567.2650 expected 567.2656 for CayHssCIFaNeOs [M+H] ⁺ . ¹ H NMR (500 MHz, CDCh) d 8.00 (s, 1 H), 7.40 (d, J = 1.9 Hz, 1 H), 7.25 (dd, J = 8.4, 2.0 Hz, 1 H), 7.05 - 6.99 (m, 2H), 4.61 (br d, J = 13 Hz, 2H), 4.27 (m, 1 H), 4.07 (m, 2H), 3.88 (m, 1 H), 3.70 (m, 1 H), 2.75 (t, J = 13 Hz, 2H), 2.02 - 1.84 (m, 5H), 1.71 (m, 1 H), 1.32 (s, 3H, N3 chain Me), 1.32 (s, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 6.7 Hz, 6H) [OH not observed].

Example 17: 5-((5-chloro-2-(4,4-difluoro-3-(hydroxymethyl)-5-methylpiper idin-1 - yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H- benzo[d]imidazol-2-one (racemic, cis diastereoisomer)

Step 1: 1-benzyl-3-((benzyloxy)methyl)-5-methylpiperidin-4-one

[00228] A solution of 1-benzyl-3-methylpiperidin-4-one (500 mg, 2.46 mmol) and lithium diisopropylamide (2M solution in THF/heptane/ethylbenzene (Sigma-Aldrich), 1.84 ml_, 3.68 mmol) in THF (10 ml_) was stirred at rt for 15 mins. Benzyl chloromethyl ether (0.68 ml_, 4.92 mmol) was then added in one portion and the reaction mixture was stirred for 1 h, then quenched by addition of MeOH/NH4CI and stirred for 2 h. The resulting mixture was left to stand for 5 days, then partitioned between DCM (50 ml_) and water (50 ml_). Aq extracted twice with DCM (50 ml_) and the organics were combined, washed with brine (50 ml_), sat. NaHCC>3 (50 ml_), dried over magnesium sulfate and the solvent removed under vacuum to afford an orange oil. This was purified by reverse-phase chromatography (25 - 80% MeOH in water, 0.1 % formic acid) to afford the title compound (135 mg, mixture of diastereoisomers) as a yellow glass. LCMS (Method T2) rt 1.27 min, m/z 324.18 [M+H] ⁺ .

Step 2: 1-benzyl-3-((benzyloxy)methyl)-4,4-difluoro-5-methylpiperidi ne

[00229] 1-benzyl-3-((benzyloxy)methyl)-5-methylpiperidin-4-one (from step 1 , 133 mg, 0.41 mmol) was dissolved in DCM (2 ml_). (Diethylamino)sulfur trifluoride (163 pl_, 1.23 mmol) was added in one portion and the reaction mixture was stirred at 45 °C for 24 h, then quenched by addition of MeOH followed by slow dropwise addition of sat aq NaHCC>3 with vigorous stirring. The mixture was diluted with DCM (15 ml_) and water (15 ml_) and partitioned. Aqueous layer was extracted twice with DCM (15 ml_) and the organics were combined, washed with sat aq NhUCI (25 ml_), brine (25 ml_) and dried by passing through a hydrophobic frit to afford crude product. This was purified by reverse phase chromatography (10 - 75% MeOH in water, 0.1 % formic acid to afford the title compound (54 mg) as an orange oil. LCMS (Method T2) rt 1.34 mins, m/z 346.20 [M+H]+.

Step 3: (4,4-difluoro-5-methylpiperidin-3-yl)methanol

[00230] To a solution of 1-benzyl-3-((benzyloxy)methyl)-4,4-difluoro-5-methylpiperidi ne (from step 2, 54 mg, 0.156 mmol) in THF (2 mL) and EtOH (2 mL) was added palladium hydroxide (22 mg, 0.156 mmol) and the suspension was placed under at atmosphere of H2 gas at 5 bar pressure. The reaction mixture was then allowed to stir at rt for 24 h and was then stood at room temperature for 5 days. Cone. HCI (26 pL, 0.313 mmol) was added, and the reaction mixture stirred under a hydrogen atmosphere at between rt and 60 °C for 2 d. Further cone. HCI (125 pL) was added followed by palladium hydroxide (22 mg, 0.156 mmol) and the reaction mixture was heated to 60 °C for 24 h under a hydrogen atmosphere. Further cone. HCI (125 pL) and palladium hydroxide (22 mg, 0.156 mmol) was added and the reaction mixture was heated to 60 °C for 24 h under a hydrogen atmosphere. The reaction mixture was filtered through celite, dried, and purified by SCX-2 cartridge (loading in MeOH acidified by addition of formic acid and eluting with 2M NH3 in MeOH). Dried to afford 32 mg of an orange oil. Crude product was redissolved in EtOH/EtOAc and palladium hydroxide (22 mg, 0.156 mmol) was added followed by cone. HCI (125 pL) and the reaction mixture was heated to 60 °C under an atmosphere of hydrogen for 40 h. The reaction mixture was filtered through celite, dried, and purified by SCX2 cartridge (loading in MeOH acidified by addition of formic acid and eluting with 2M NH3 in MeOH) to afford the title compound (17 mg, mixture of diastereoisomers) as a brown oil. LCMS (Method T4) rt 0.21 min, m/z 166.107, expected 166.1038 for C ₇ H ₁₄ F ₂ NO ⁺ [M+H] ⁺ . Step 4: 5-((5-chloro-2-(4,4-difluoro-3-(hvdroxymethyl)-5-methylpiper idin-1-yl)pyrimidin-4- yl)amino)-3-(3-hvdroxy-3-methylbutyl)-1 -methyl-1, 3-dihydro-2H-benzo[dlimidazol-2-one (racemic, cis diastereoisomer)

[00231] (4,4-difluoro-5-methylpiperidin-3-yl)methanol (from step 3, 12 g, 0.076 mmol) was dissolved in MeCN (1 ml_) and added to 5-((2,5-dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one (intermediate A3a, 15 mg, 0.038 mmol) . To this solution was added DIPEA (27 pl_, 0.152 mmol) and the reaction mixture was heated to 140 °C for 1 h, then to 160 °C for 13 h. DIPEA (27 mI_, 0.152 mmol) was added and the resulting mixture heated to 160 °C for 90 mins. NMP (0.5 ml_) was added and the reaction mixture was heated to 160 °C for 90 mins, then to 165 °C for 8 h. The resulting mixture was purified by reverse-phase chromatography (40 - 100% MeOH in water, 0.1 % formic acid). Product fractions were further purified by SCX-2, and by flash column chromatography (0 - 10% MeOH in DCM) to give the title compound (3 mg). ¹ H NMR (600 MHz, Methanol-d _? ) d 7.97 (s, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.40 (s, 1 H), 7.14 (d, J = 8.8 Hz, 1 H), 4.99 (d, J = 13.7 Hz, 1 H), 4.58 (d, J = 13.5 Hz, 1 H), 4.09 - 4.02 (m, 2H), 4.00 - 3.96 (m, 1 H), 3.55 - 3.51 (m, 1 H), 3.45 (s, 3H), 2.80 (t, J = 12.7 Hz, 1 H), 2.72 (t, J = 12.7 Hz, 1 H), 2.16 - 1.93 (m, 2H), 1.94 - 1.81 (m, 2H), 1.30 (s, 6H), 1.01 (d, J = 6.6 Hz, 3H). LCMS (Method T4), rt 2.80 mins, m/z 525.2188, expected 525.2187 for C ₂₄ H ₃₂ CIF ₂ N ₆ O ₃ [M+H] ⁺ .

Example 18a: rac-5-((5-chloro-2-((3R,5R)-3-(hydroxymethyl)-5-methylpiperi din-1 - yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H- benzo[d]imidazol-2-one:formic acid (1 :1 )

Example 18b: rac-5-((5-chloro-2-((3R,5S)-3-(hydroxymethyl)-5-methylpiperi din-1 - yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H- benzo[d]imidazol-2-one:formic acid (1 :1 )

[00232] 5-((5-chloro-2-(3-(hydroxymethyl)-5-methylpiperidin-1-yl)pyr imidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one (Example 6b, 20mg) was separated into its diastereoisomers by preparative HPLC (ACE 5 C18-PFP column (5m, 250x21.2mm), 15 minute gradient elution from 55:45 to 35:65 water: methanol (both modified with 0.1 % formic acid) at a flow rate of 20ml_/min). Minor product (Example 18a, 1.2 mg) eluted first, followed by some mixed fractions which were discarded, then pure fractions of major product (Example 18b, 2.4 mg).

Example 18a: ¹ H NMR (600 MHz, CD ₃ OD) d 8.23 (s, 1 H, formic acid), 7.90 (s, 1 H), 7.48 (d,

J = 1.9 Hz, 1 H), 7.39 (dd, J = 8.4, 1.9 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 4.08 - 4.03 (m, 2H), 4.01 (dd, J = 13.0, 3.9 Hz, 1 H), 3.90 (dd, J = 13.3, 5.2 Hz, 1 H), 3.55 (dd, J = 13.3, 3.6 Hz,

1 H), 3.45 (s, 3H), 3.44 - 3.35 (m, 2H), 3.09 (dd, J = 13.0, 8.4 Hz, 1 H), 1.96 - 1.87 (m, 1 H), 1.90 - 1.85 (m, 2H), 1.86 - 1.78 (m, 1 H), 1.70 (dt, J = 13.3, 5.0 Hz, 1 H), 1.42 (m, 1 H), 1.30 (d, J = 1.8 Hz, 6H), 0.91 (d, J = 6.7 Hz, 3H). LCMS (Method T4) Rt 2.44min; m/z 489.2372 expected 489.2375 for C ₂₄ H ₃₄ CIN ₆ O ₃ [M+H] ⁺ .

Example 18b: ¹ H NMR (600 MHz, CD ₃ OD) d 8.13 (s, 1 H, formic acid), 7.91 (s, 1 H), 7.44 (m, 2H), 7.15 - 7.10 (m, 1 H), 4.74 (m, 1 H), 4.53 (m, 1 H), 4.08 - 4.02 (m, 2H), 3.47 (dd, J = 10.9, 5.4 Hz, 1 H), 3.44 (s, 3H), 3.39 (dd, J = 10.9, 7.0 Hz, 1 H), 2.44 (dd, J = 13.0, 1 1.5 Hz, 1 H), 2.34 (dd, J = 13.0, 11.4 Hz, 1 H), 1.91 - 1.81 (m, 3H), 1.70 (m, 1 H), 1.60 (m, 1 H), 1.30 (s,

6H), 0.93 (d, J = 6.6 Hz, 3H), 0.87 (q, J = 12.2 Hz, 1 H) [Assigned as cis product due to 4- piperidinyl axial proton at 0.87ppm being a quartet with a large coupling constant, consistent with one geminal and two trans- diaxial couplings] LCMS (Method T4) Rt 2.46min; m/z 489.2381 expected 489.2375 for C ₂₄ H ₃₄ CIN ₆ O ₃ [M+H] ⁺ .

Intermediate compounds

Intermediate A1 a: (R)-5-((2,5-dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3-met hyl- butyl)-1 -(2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one

Step 1: (R)- 1 -(2-hydroxypropyl) -5-nitro- 1, 3-dihydro-2H-benzo[ d]imidazol-2-one

[00233] A mixture of 2-fluoro-5-nitroaniline (0.65 g, 4.16 mmol), DIPEA (2 mL, 11.5 mmol) and (2R)-1-aminopropan-2-ol ( 0.50 mL, 6.42 mmol) in NMP (5 mL) was heated to 150 °C for 4 days, then allowed to cool to rt and diluted with acetonitrile (5mL). Bis(2,5-dioxopyrrolidin- 1-yl) carbonate (2.50 g, 9.8 mmol) was added and the resulting mixture stirred for 2h at rt. Added water and acidified to pH4 by addition of 10% aq. citric acid solution; layers were separated, and the organic phase washed with water, brine, then dried over sodium sulfate and purified using reverse phase flash chromatography (Biotage 30g KP-C18-HS, 2-15-60- 100% methanol in water, 0.1 % formic acid modifier) to give (R)-1-(2-hydroxypropyl)-5-nitro- 1 ,3-dihydro-2H-benzo[d]imidazol-2-one (205mg) which was taken forward to the next step without further purification. LCMS (Method X2) Rt 0.91 min; m/z 220.0712 expected 220.0717 for C10H 10N3O3+ [M-water+H] ⁺ .

Step 2: (R)-3-(3-hydroxy-3-methylbutyl)- 1 -(2-hydroxy ropyl) -5-nitro- 1, 3-dihydro-2H-benzo[d]- imidazol-2-one

[00234] A mixture of (R)-1-(2-hydroxypropyl)-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (from step 1 , 205 mg), (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (Intermediate D1 , 350 mg, 1.35 mmol) and dicesium carbonate (600 mg, 1.84 mmol) in DMF (8 ml_) was heated to 120 °C for 1 hour. The resulting mixture was cooled to rt and partitioned between DCM and water. The pH was adjusted to 5 using 10% aq. citric acid solution and layers separated, and aqueous phase extracted with further DCM. Combined organics were dried over sodium sulfate, filtered and evaporated under reduced pressure, then purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-60% methanol in water, 0.1 % formic acid modifier) to give (R)-3-(3-hydroxy-3-methylbutyl)-1-(2-hydroxypropyl)- 5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (100 mg). LCMS (Method X2) Rt 1.10min; m/z 346.15 [M+Na] ⁺

Step 3: (R)-5-amino-3-(3-hydroxy-3-methylbutyl)- 1-(2-hydroxypropyl)- 1, 3-dihydro-2H- benzof d]imidazol-2-one

[00235] To 10% palladium on carbon (16 mg) in ethanol (6 mL) under argon was added (R)- 3-(3-hydroxy-3-methylbutyl)-1-(2-hydroxypropyl)-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2- one (from Step 2, 100 mg). The vessel was evacuated and refilled with hydrogen, then stirred at rt for 1 day. Evacuated and refilled with nitrogen, added further 10% palladium on carbon (16 mg, 0.015 mmol), evacuated and refilled with hydrogen, stirred at rt for 3h, then evacuated and refilled with nitrogen, filtered through Celite washing with ethanol, and evaporated to give the title compound as a brown sticky gum, used without further purification in subsequent step assuming complete conversion. LCMS (Method X2) Rt 0.60min, m/z 294.18 [M+H] ⁺ .

Step 4: (R)-5-((2, 5-dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)- 1-(2- hydroxypropyl)- 1, 3-dihydro-2H-benzo[d]imidazol-2-one [00236] A mixture of 2,4,5-trichloropyrimidine (0.04 ml_, 0.35 mmol), (R)-5-amino-3-(3- hydroxy-3-methylbutyl)-1-(2-hydroxypropyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (from step 3, 90 mg, 0.31 mmol) and DIPEA (0.065 ml_, 0.37 mmol) in NMP (1 ml_) was heated to 1 10 °C for 1 h, then purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (65 mg). LCMS (Method X2) Rt 1.23min; m/z 440.14 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform- d) d 8.21 (s, 1 H), 7.68 (d, J = 1.6 Hz, 1 H), 7.31 (s, 1 H), 7.12 - 7.04 (m, 2H), 4.24 (br m, 1 H), 4.14 - 4.07 (m, 2H), 3.96 (dd, J = 14.5, 3.3 Hz, 1 H), 3.87 (dd, J = 14.6, 7.4 Hz, 1 H), 2.88 (d, J = 4.4 Hz, 1 H), 2.06 (s, 1 H), 2.00 - 1.93 (m, 2H), 1.34 (s, 6H), 1.30 (d, J = 6.3 Hz, 3H).

[00237] The following tabulated compounds A1 b to A1 g were prepared by a multi-step procedure analogous to that used in the synthesis of Intermediate A1 a.

Intermediate A2a: 5-((2,5-dichloropyrimidin-4-yl)amino)-1 -(2-hydroxy-2-methylpropyl)- 3-(3-hydroxy-3-methylbutyl)-1,3-dihydro-2H-benzo[d]imidazol- 2-one

Step 1: 1-(2-hydroxy-2-methylpropyl)-5-nitro-1,3-dihydro-2H-benzo[d] imidazol-2-one

[00238] A mixture of 2-fluoro-5-nitroaniline (1.0 g, 6.4 mmol), DIPEA (2.25 ml_, 12.9 mmol) and 1-amino-2-methylpropan-2-ol (0.9 g, 10.1 mmol) in NMP (5 ml_) was heated at 180 °C for 72 h in a sealed tube. The mixture was allowed to cool to rt and was partitioned between DCM and water. The mixture was acidified to pH 5 by addition of 10% aq. citric acid solution, the layers were separated, and the organic layer washed with further dilute citric acid at pH 5. Combined organic phases were dried over sodium sulfate, filtered and evaporated to give a black solution in NMP. This was diluted with acetonitrile (25 ml_) and bis(2,5-dioxopyrrolidin- 1-yl) carbonate (2.5 g, 9.8 mmol) was added portion-wise. After stirring at rt for 1 hour, water and DCM were added and the mixture adjusted to -pH 5 using 10% aq. citric acid solution. Layers were separated, and the aqueous phase was extracted with further DCM. Combined organic phases were dried over sodium sulfate, filtered and evaporated to give the product as a dark orange solution in NMP. It was further dried under high vacuum to give 1- (2-hydroxy-2-methylpropyl)-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (283mg) as a sticky brown solid which was taken on to step 2 without further purification. LCMS (Method X2) Rt 0.97min; m/z 234.09 [M-water+H] ⁺ .

Step 2: 1-(2-hydroxy-2-methylpropyl)-3-(3-hydroxy-3-methylbutyl)-5-n itro- 1, 3-dihydro-2H- benzof d]imidazol-2-one

[00239] To a mixture of 1-(2-hydroxy-2-methylpropyl)-5-nitro-1 ,3-dihydro-2H-benzo[d]- imidazol-2-one (from step 1 , 283 mg) and cesium carbonate (0.8 g, 2.46 mmol) in acetonitrile (10 mL) was added (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (Intermediate D1 , 0.40 g, 1.55 mmol) and the resulting mixture heated to 60 °C for 3 h. After cooling, water and DCM were added, the mixture neutralised by addition of 10% aqueous citric acid and separated. The aqueous layer was extracted with further DCM, and combined organics washed with brine, dried over sodium sulfate, evaporated and purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-55% methanol in water, 0.1 % formic acid modifier) to give 1-(2-hydroxy-2-methylpropyl)-3-(3-hydroxy-3-methylbutyl)-5-n itro-1 ,3- dihydro-2H-benzo[d]-imidazol-2-one (280 mg). LCMS (method X2) Rt 1.14min; m/z 320.16 [M-water+H] ⁺ .

Step 3: 5-amino-1-(2-hydroxy-2-methylpropyl)-3-(3-hydroxy-3-methylbu tyl)- 1, 3-dihydro-2H- benzof d]imidazol-2-one

[00240] To 10% palladium on carbon (50 mg) in ethanol (10 mL) under argon was added 1- (2-hydroxy-2-methylpropyl)-3-(3-hydroxy-3-methylbutyl)-5-nit ro-1 ,3-dihydro-2H-benzo[d]- imidazol-2-one (from Step 2, 280 mg, 0.83 mmol). The vessel was evacuated and refilled with hydrogen and stirred at rt overnight. Pd catalyst was removed by filtration under argon, washing with ethanol, and the resulting solution was evaporated to yield 5-amino-1-(2- hydroxy-2-methylpropyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (270 mg). LCMS (Method X2) Rt 0.68min; m/z 330.17 [M+Na] ⁺ . Step 4: 5-((2, 5-dichloropyrimidin-4-yl)amino)- 1-(2-hydroxy-2-methylpropyl)-3-(3-hydroxy-3- methyl butyl)- 1, 3-dihydro-2H-benzo[d]imidazol-2-one

[00241] A mixture of 2,4,5-trichloropyrimidine (0.11 ml_, 0.96 mmol), 5-amino-1-(2-hydroxy- 2-methylpropyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (from Step 3, 270 mg, 0.88 mmol) and DIPEA (190 uL, 1.1 mmol) in NMP (1 mL) was heated to 80 °C overnight. The resulting mixture was purified using reverse phase flash chromatography (Biotage 12g SNAP Ultra C18, 20-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (263 mg). LCMS (Method X2) Rt 1.27min m/z 454.1412 expected 454.1412 for C20H26CI2N5O3 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform-d) d 8.21 (s, 1 H), 7.69 (d, J = 2.0 Hz, 1 H), 7.32 (s, 1 H), 7.13 (d, J = 8.4 Hz, 1 H), 7.07 (dd, J = 8.4, 2.0 Hz, 1 H), 4.15 - 4.08 (m, 2H), 3.90 (s, 2H), 2.01 - 1.94 (m, 2H), 1.34 (s, 6H), 1.32 (s, 6H). OHs not observed.

[00242] The following tabulated compounds A2b to A2e were prepared by a multi-step procedure analogous to that used in the synthesis of Intermediate A1 a.

Intermediate A3a: 5-((2,5-dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylb utyl)-1 - methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one

[00243] A solution of 5-amino-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H- benzo[d]imidazol-2-one (Intermediate B1 a, 5.63 g, 22.6 mmol), 2,4,5-trichloropyrimidine (4.56 g, 24.85 mmol) and DIPEA (9.8 ml_, 56.5 mmol) in NMP (45 ml_) was heated for 2 hours at 140 °C. Once cooled to rt the mixture was poured into ice-water (250 ml_) then extracted with DCM (2 x 250 ml_). The combined organic extracts were washed with water (2 x 500 ml_) and brine (100 ml_) then dried over MgS0 ₄ , filtered and concentrated affording a dark brown residue. This residue was taken up in ethanol (80 ml_) and warmed to 60°C for 2 mins, then cooled by placing the flask into ice-water. The mixture was then filtered, and the solid collected and washed with -200 ml_ of cold ethanol, then dried on the filter to give the title compound as a pale yellow powdery solid (6.27 g). LCMS (Method T2) Rt 1.40min m/z 396.10 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d6) d 9.57 (s, 1 H), 8.34 (s, 1 H), 7.36 (d, J = 1.9 Hz, 1 H), 7.20 (dd, J = 8.4, 1.9 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 4.45 (s, 1 H), 3.92 - 3.85 (m, 2H), 3.33 (s, 3H), 1.76 - 1.69 (m, 2H), 1.17 (s, 6H).

Intermediate A4a: 1 -(2-(1 ,3-dioxolan-2-yl)ethyl)-5-((2,5-dichloropyrimidin-4-yl)amino )-3- (3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one

Step 1: 1 -(2-(1 ,3-dioxolan-2-yl)ethyl)-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one

[00244] A mixture of 2-fluoro-5-nitroaniline (1.5 g, 9.6 mmol), DIPEA (3.39 ml_, 19.4 mmol) and 2-(2-aminoethyl)-1 ,3-dioxolane (1.3 ml_, 11.9 mmol) in NMP (6 ml_) was heated to 200 °C overnight. Allowed to cool to rt and diluted with acetonitrile (5 ml_), then added disuccinimidyl carbonate (2.96 g, 1 1.6 mmol. Added further disuccinimidyl carbonate at 20 min intervals until no further change was observed by LCMS analysis. The resulting mixture was partitioned between DCM and water, acidified to pH 6 by addition of 10% citric acid, separated and extracted aqueous layer with further DCM. Combined organics were dried, evaporated and crude material purified using reverse phase flash chromatography in two portions (Biotage 30g SNAP Ultra C18, 5-10-60-100% methanol in water, 0.1 % formic acid modifier). Isolated product from two runs was combined and evaporated. Although mass ion consistent with product was not observed, product was assumed to be 1-(2-(1 ,3-dioxolan-2-yl)ethyl)-5-nitro- 1 ,3-dihydro-2H-benzo[d]imidazol-2-one (1 g) and was continued to the next step on that basis. LCMS (Method X2) Rt 1.05min.

Step 2: 1 -(2-(1 ,3-dioxolan-2-yl)ethyl)-3-(3-hydroxy-3-methylbutyl)-5-nitro- 1 ,3-dihydro-2H- benzof d]imidazol-2-one

[00245] To material from step 1 (1 g) was added cesium carbonate (1.5 g, 4.6 mmol), (3- hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (1.03 g, 4 mmol) and acetonitrile (30mL) and the resulting mixture was heated to 1 10 °C for 1 hour. Added further cesium carbonate (1.5 g, 4.6 mmol), (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (1.03 g, 4 mmol), and heated to 1 10 °C for 1 hour. The resulting mixture was partitioned between DCM and water, acidified to pH 6 by addition of 10% citric acid, separated and extracted aqueous layer with further DCM. Combined organics were dried, evaporated and crude material purified using reverse phase flash chromatography (Biotage 30g SNAP C18, 5-20-60-100% methanol in water, 0.1 % formic acid modifier) to give 1-(2-(1 ,3-dioxolan-2-yl)ethyl)-3-(3-hydroxy-3- methylbutyl)-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (700 mg). LCMS (Method X2) Rt 1.20min; m/z 388.1484 expected 388.1485 for C^HasNsOeNa [M+Na] ⁺ .

Step 3: 1 -(2-(1 ,3-dioxolan-2-yl)ethyl)-5-amino-3-(3-hydroxy-3-methylbutyl)- 1 ,3-dihydro-2H- benzof d]imidazol-2-one

[00246] To 1-(2-(1 ,3-dioxolan-2-yl)ethyl)-3-(3-hydroxy-3-methylbutyl)-5-nitro- 1 ,3-dihydro-2H- benzo[d]imidazol-2-one (from Step 2, 350 mg, 0.96 mmol) in ethanol (5 mL) under nitrogen was added 10% palladium on carbon (50 mg). Evacuated and refilled with hydrogen, stirred at rt for 18h. Evacuated and refilled with nitrogen, filtered through Celite , washing with ethanol, and evaporated to give 1-(2-(1 ,3-dioxolan-2-yl)ethyl)-5-amino-3-(3-hydroxy-3- methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one as a yellow gum (320 g) which was directly used in the next step. LCMS (Method X2) Rt 0.70min; m/z 336.20 [M+H] ⁺ .

Step 4: 1-(2-(1 ,3-dioxolan-2-yl)ethyl)-5-((2, 5-dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3- methyl butyl)- 1, 3-dihydro-2H-benzo[d]imidazol-2-one

[00247] A mixture of 2,4,5-trichloropyrimidine (125 uL, 1.09 mmol), 1-(2-(1 ,3-dioxolan-2- yl)ethyl)-5-amino-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (from step 3, 320 mg) and DIPEA (0.2 ml_, 1.15 mmol) in NMP(1 ml_) was heated to 1 10 °C for 45 mins, then purified using reverse phase flash chromatography (Biotage 30g KP-C18, 20-100% methanol in water, 0.1 % formic acid modifier) to give the title compound (390 mg). LCMS (Method X2) Rt 1.32min; m/z 482.1409 expected 482.1362 for C ₂₁ H ₂₆ CI ₂ N ₅ O ₄ [M+H] ⁺ . ¹ H NMR (500 MHz, chloroform-d) d 8.21 (s, 1 H), 7.63 (s, 1 H), 7.31 (s, 1 H), 7.07 (m, 2H), 4.95 (t, J = 4.5 Hz, 1 H), 4.12 - 4.07 (m, 2H), 4.05 (t, J = 7.1 Hz, 2H), 4.03 - 3.97 (m, 2H), 3.89 - 3.86 (m, 2H), 2.14 (m, 2H), 1.99 - 1.92 (m, 2H), 1.33 (s, 6H).

Intermediate A5a: tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-2-oxo-2,3-dihydro-1 H-benzo[d]imidazole-1 -carboxylate

Step 1: tert-butyl 5-nitro-2-oxo-2,3-dihydro-1 H-benzo[d]imidazole-1 -carboxylate

[00248] 5-nitro-2-benzimidazolinone (3.3 g, 17.9 mmol) was suspended in THF (20mL) and added to sodium hydride (60% in mineral oil, 0.74 g, 18.5 mmol) under nitrogen. After 30 minutes, a solution of di-tert-butyl dicarbonate (3.92 g, 18 mmol) was added dropwise. The resulting mixture was stirred overnight at room temperature, then sat. aq. ammonium chloride solution was added and resulting mixture evaporated under reduced pressure to remove THF. Some of the water was also removed, resulting in lots of solid precipitate. Added ethyl acetate (100 mL), DCM (200 mL) and water (200 mL), filtered and separated, organic phase dried over sodium sulfate and evaporated to give 2g of crude yellow solid, which was then purified by flash column chromatography (100g KP-SIL, 30-80% ethyl acetate in cyclohexane). Two broad peaks were eluted. The earlier, minor, peak was collected and identified as tert-butyl 5-nitro-2-oxo-2,3-dihydro-1 H-benzo[d]imidazole-1 -carboxylate (170 mg). ¹ H NMR (600 MHz, DMSO-d6) d 1 1.74 (s, 1 H, NH), 8.04 (dd, J = 8.9, 2.4 Hz, 1 H, 6-benzimidazolone), 7.84 (d, J = 8.9 Hz, 1 H, 7-benzimidazolone), 7.73 (d, J = 2.3 Hz, 1 H, 4-benzimidazolone), 1.61 (s, 9H, tBu group). Regiochemistry determined by NOESY which showed an NOE between peaks at 1.61 (tBu group) and 7.84 (7-benzimidazolone).

Step 2: tert-butyl 3-(3-hydroxy-3-methylbutyl)-5-nitro-2-oxo-2,3-dihydro-1H- benzof d] imidazole- 1 -carboxylate

[00249] A mixture of tert-butyl 5-nitro-2-oxo-3H-benzimidazole-1 -carboxylate (from step 1 , 170 mg, 0.61 mmol), (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (Intermediate D1 , 315 mg, 1.22 mmol) and cesium carbonate (600 mg, 1.84 mmol) in DMF (3 ml_) was heated to 80 °C for 1.5h, then allowed to cool and stood at rt overnight. The resulting mixture was partitioned between DCM and water and neutralised by addition of 10% citric acid solution. Organic phase was separated and dried by passing through a phase separator, then evaporated under reduced pressure to give tert-butyl 3-(3-hydroxy-3-methylbutyl)-5-nitro-2- oxo-2, 3-dihydro-1 H-benzo[d]imidazole-1 -carboxylate (100 mg). LCMS (Method X2) Rt 1.44min m/z 388.15 [M+Na] ⁺ .

Step 3: tert-butyl 5-((2, 5-dichloropyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)- 2-oxo- 2, 3-d I hydro- 1 H-benzo[d]imidazole-1 -carboxylate

[00250] To 10% palladium on carbon (7 mg, 0.0066 mmol) in ethanol (3 ml_) under argon was added tert-butyl 3-(3-hydroxy-3-methyl-butyl)-5-nitro-2-oxo-benzimidazole-1 -carboxylate (from Step 2, 50 mg, 0.14 mmol). Evacuated and refilled with hydrogen, stirred at rt for 3 days. Evacuated and refilled with nitrogen, filtered through Celite washing with ethanol, and evaporated to give a grey sticky gum. This was combined with 2,4,5-trichloropyrimidine (18 uL, 0.16 mmol), and DIPEA (30 uL, 0.17 mmol) in NMP (0.5 ml_) and was heated to 110 °C overnight. The resulting mixture was purified using reverse phase flash chromatography (Biotage 12g KP-C18, 20-100% methanol in water, 0.1 % formic acid modifier). Collected the later running of three peaks which was identified as the title compound (15 mg). LCMS (Method X2) Rt 1 52min; m/z 504.1190 expected 504.1181 for C21 HhsChNsCLNa [M+Na] ⁺ . ¹ H NMR (500 MHz, Chloroform-d) d 8.24 (s, 1 H), 7.84 (d, J = 8.6 Hz, 1 H), 7.81 (d, J = 2.1 Hz, 1 H), 7.35 (s, 1 H), 7.03 (dd, J = 8.6, 2.2 Hz, 1 H), 4.11 - 4.03 (m, 2H), 2.00 - 1.92 (m, 2H), 1.69 (s, 9H), 1.36 (s, 6H).

Intermediate A6a: 6-((2,5-dichloropyrimidin-4-yl)amino)-1 -(3-hydroxy-3-methylbutyl)-3- methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[00251] A sealed vial containing 6-amino-1-(3-hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one (Intermediate B2a, 280 g, 1.12 mmol), 2,4,5- trichloropyrimidine (354 mg, 1.93 mmol) and DIPEA (0.49 ml_, 2.8 mmol) in NMP (2.24 ml_) was heated in a microwave for 2 h at 140°C. Once cooled, the sample was purified using reverse phase flash chromatography (Biotage 30g KP-C18, 10-100% methanol in water, 0.1 % formic acid modifier) affording 6-((2,5-dichloropyrimidin-4-yl)amino)-1-(3-hydroxy-3- methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (413 mg) as a dark yellow solid. LCMS (Method T2) Rt 1.35min m/z 397.10 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform-d) d 8.23 (s, 1 H), 8.03 (d, J = 2.1 Hz, 1 H), 7.89 (d, J = 2.1 Hz, 1 H), 7.28 (br. s, 1 H), 4.12 - 4.05 (m, 2H), 3.50 (s, 3H), 1.97 - 1.90 (m, 2H), 1.33 (s, 6H).

Intermediate A7a: 3-(5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidi n-1 - yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2 ,3-dihydro-1 H-benzo[d]- imidazol-1 -yl)propanal

[00252] TFA (1.5 ml_) was added dropwise to a solution of 1-(2-(1 ,3-dioxolan-2-yl)ethyl)-5- ((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-y l)pyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (Example 5a, 225 mg, 0.34 mmol) in THF (2 ml_) and water (1 ml_). The solution was heated to 70 °C and stirred for 2h. The mixture was concentrated under reduced pressure to remove the excess TFA and THF. The residue was then taken up in water and DCM, then washed with sat. aq. sodium bicarbonate solution to remove residual TFA. Organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (180 mg). LCMS (Method X2) Rt 1.53 min, m/z 583.2618 expected 583.261 1 for C27H38CIF2N6O4 [M+H+methanol] ⁺ (methanol adduct from LCMS solvent). Weaker signal also observed for m/z 551.2357 expected 551.2349 for C26H34CIF2N6O3 [M+H] ⁺ .

Intermediate A7b: 2-(5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidi n-1 - yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2 ,3-dihydro-1 H- benzo[d]imidazol-1 -yl)acetaldehyde

Step 1: 1-(2, 2-dimethoxyethyl)-5-nitro- 1, 3-dihydro-2H-benzo[d]imidazol-2-one

[00253] A mixture of 2-fluoro-5-nitroaniline (10 g, 64.1 mmol), aminoacetaldehyde dimethyl acetal (10.4 ml_, 96 mmol) and DIPEA (22.3 ml_, 128 mmol) in NMP (64.1 ml_) was heated at 180 °C overnight. The mixture was allowed to cool to rt then poured into ice-water. The mixture was extracted with EtOAc, then the combined organic extracts were thoroughly washed with water and brine then dried over MgS0 ₄ , filtered and concentrated affording L/ ¹ - (2, 2-dimethoxyethyl)-4-nitrobenzene-1 , 2-diamine (14.1 g). This was dissolved in acetonitrile (320 ml_) and disuccinimidyl carbonate (24.6 g, 96 mmol) was added, followed by triethylamine (26.8 ml_, 192 mmol). The mixture was stirred at rt overnight, then concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgS0 ₄ , filtered and concentrated. The crude residue was purified in 2 batches by flash column chromatography (Biotage KP-Sil 50g eluting 20-100% EtOAc in cyclohexane) affording 1-(2,2-dimethoxyethyl)-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (6.5 g) as a deep orange solid. LCMS (Method X2) Rt 1.07min m/z 236.07 [M-MeOH+H] ⁺ .

Step 2: 1-(2, 2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl)-5-nitro- 1, 3-dihydro-2H-benzo[d]- imidazol-2-one

[00254] A mixture of 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (Intermediate D1 , 9.42 g, 36.5 mmol), cesium carbonate (15.9 g, 49 mmol), 1-(2,2-dimethoxyethyl)-5-nitro-1 ,3- dihydro-2H-benzo[d]imidazol-2-one (from Step 1 , 6.5 g, 24.3 mmol) and acetonitrile (243 ml_) was heated to reflux for 1 hour, then the mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic extracts were dried over MgSCU, filtered and concentrated. The residue was then purified by flash column chromatography (Biotage KP-Sil 100g eluting 40-100% EtOAc in cyclohexane) affording 1 -(2,2- dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl)-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (4.7 g) as a yellow sticky oil which solidified under vacuum. LCMS (Method T2) Rt 1.34min m/z 354.16 [M+H] ⁺ .

Step 3: 5-((2, 5-dichloropyrimidin-4-yl)amino)-1-(2,2-dimethoxyethyl)-3-(3- hydroxy-3- methylbutyl)- 1, 3-dihydro-2H-benzo[d]imidazol-2-one

[00255] Pd/C (10 wt%, 100 mg) was added to a solution of 1-(2,2-dimethoxyethyl)-3-(3- hydroxy-3-methylbutyl)-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (from Step 2, 2.2 g, 6.23 mmol) in ethyl acetate (31 ml_) then placed under an atmosphere of hydrogen and stirred at 60 °C overnight. Once cooled, the mixture was filtered through a pad of Celite and washed through with EtOAc then concentrated in vacuo to give a dark brown oil. To this material (5- amino-1-(2,2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol- 2-one) was added 2,4,5-trichloropyrimidine (1.71 g, 9.3 mmol), NMP (12.4 ml_) and DIPEA (2.16 ml_, 12.4 mmol) and the resulting mixture was heated in a microwave for 4 h at 140°C. The sample was purified, in 2 batches, using reverse phase flash chromatography (Biotage 30g SNAP Ultra C18, 10-100% methanol in water, 0.1 % formic acid modifier) affording 5-((2,5- dichloropyrimidin-4-yl)amino)-1-(2,2-dimethoxyethyl)-3-(3-hy droxy-3-methylbutyl)-1 ,3- dihydro-2H-benzo[d]imidazol-2-one (2.38 g) as an orange solid. LCMS (Method T2) Rt 1.45min m/z 470.15 [M+H] ⁺ .

Step 4: 5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4-yl)amino)- 1-(2,2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one

[00256] (3R,5S)-4,4-difluoro-3, 5-dimethyl-piperidine hydrochloride (237 mg, 1.28 mmol) and DIPEA (463 uL, 2.66 mmol) were added to a solution of 5-((2,5-dichloropyrimidin-4-yl)amino)- 1-(2,2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (from Step 3, 500 mg, 1.06 mmol) in NMP (5.3 ml_). The mixture was heated in a microwave for 4 h at 140 °C. The sample was purified directly, in 2 batches, using reverse phase flash chromatography (Biotage 30g SNAP Ultra C18, 10-100% methanol in water, 0.1 % formic acid modifier) affording 5-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1 -yl)pyrimidin-4- yl)amino)-1-(2,2-dimethoxyethyl)-3-(3-hydroxy-3-methylbutyl) -1 ,3-dihydro-2H-benzo[d]- imidazol-2-one (530 mg) as a yellow solid. LCMS (Method T2) Rt 1.64min m/z 583.26 [M+H] ⁺ .

Step 5: 2-(5-(( 5-chloro-2-(( 3S,5R) -4, 4-difluoro-3, 5-dimethylpiperidin- 1 -yl) pyrimidin-4- yl)amino)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-b enzo[d]imidazol-1- yl) acetaldehyde

[00257] TFA (3 mL, 0.91 mmol) was added dropwise to a solution of 5-((5-chloro-2-((3S,5R)- 4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino )-1-(2,2-dimethoxyethyl)-3-(3- hydroxy-3-methylbutyl)-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (from Step 4, 530 mg, 0.91 mmol) in a mixture of THF (5 mL) and water (2.5 mL). The solution was heated to 70°C and stirred for 2.5 hours. The mixture was concentrated in vacuo and the residue then taken up in water and DCM and washed with sat. aq. NaHCC>3. The aqueous fraction was further extracted with DCM then the combined organic extracts washed with brine and dried over MgSCL, filtered and concentrated affording the title compound (480 mg) as a pale yellow solid. LCMS (Method T2) Rt 1.59min m/z 537.22 [M+H] ⁺ . Intermediate A8a: (R)-5-((2,5-dichloropyrimidin-4-yl)amino)-3-(3-hydroxybutyl) -1 - methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one

Step 1: (R)-3-hydroxybutyl 4-methylbenzenesulfonate

[00258] A solution of (3R)-butane-1 ,3-diol (1.0 ml_, 11.1 mmol) in dry DCM (10 ml_) under a nitrogen atmosphere was cooled in a salt-ice bath (bath temp -12 °C). Triethylamine (2.25 ml_, 16.1 mmol) was added followed by a solution of 4-methylbenzenesulfonyl chloride (2.2 g, 1 1.5 mmol) in dry DCM (6ml_) over 10 minutes. The resulting mixture was allowed to warm slowly to room temperature and stirred for 20 h, then diluted with DCM, washed with 10% citric acid (x2), sat. sodium bicarbonate solution (x2), brine (x1), dried over sodium sulfate, filtered and evaporated under reduced pressure to give a pale yellow oil. This was purified by flash column chromatography (50g KP-Sil, 10-30% ethyl acetate in cyclohexane) to give (R)-3- hydroxybutyl 4-methylbenzenesulfonate (1.33 g) as a clear oil. LCMS (Method X2) Rt 1 15min; m/z 267.0680 expected 267.0667 for CnH ₁₆ 04SNa [M+Na] ⁺ .

Step 2: (R)-3-(3-hydroxybutyl)- 1 -methyl-5-nitro- 1, 3-dihydro-2H-benzo[d]imidazol-2-one

[00259] To a mixture of 3-methyl-6-nitro-1 H-benzimidazol-2-one (350mg, 1.8 mmol) and cesium carbonate (980mg, 3 mmol) in acetonitrile (4 ml_) was added a solution of (R)-3- hydroxybutyl 4-methylbenzenesulfonate (from Step 1 , 525mg, 2.15 mmol) in acetonitrile (1 ml_) and the resulting mixture was stirred at room temperature overnight. Added further cesium carbonate (0.5g) and heated to 60 °C for 5h. The resulting mixture was partitioned between DCM and water, acidified to pH4 using 10% citric acid and separated and dried using a phase separator column. The resulting yellow solution was evaporated under reduced pressure then triturated with diethyl ether to give (R)-3-(3-hydroxybutyl)-1-methyl-5-nitro-1 ,3- dihydro-2H-benzo[d]imidazol-2-one (382 mg) as a pale yellow solid. ¹ H NMR (500 MHz, DMSO-d6) d 8.09 (d, J = 2.2 Hz, 1 H), 8.06 (dd, J = 8.6, 2.2 Hz, 1 H), 7.36 (d, J = 8.6 Hz, 1 H), 4.63 (d, J = 4.9 Hz, 1 H), 4.05 - 3.91 (m, 2H), 3.68 - 3.57 (m, 1 H), 3.40 (s, 3H), 1.79 - 1.59 (m, 2H), 1.09 (d, J = 6.2 Hz, 3H).

Step 3: (R)-5-amino-3-(3-hydroxybuty/)- 1 -methyl· 1, 3-dihydro-2H-benzo[d]imidazol-2-one

[00260] To a mixture of Pd/C (10 wt%) (20 mg, 0.019 mmol) and ammonium formate (200 mg, 3.17 mmol) in a dry vessel under argon was added (R)-3-(3-hydroxybutyl)-1-methyl-5- nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (from Step 2, 82 mg, 0.31 mmol) in ethanol (3ml_), and the resulting mixture was evacuated and refilled with argon three times, then heated at 60 °C for 1 hour. A further batch was prepared in the same manner, but with heating at 100 °C under microwave irradiation for 1 hour. Both methods showed complete conversion to product, and mixture were combined and filtered through Celite under argon, washing with ethanol (20ml_), and the filtrates concentrated under reduced pressure to give (R)-5-amino-3- (3-hydroxybutyl)-1-methyl-1 ,3-dihydro-2H-benzo[d]imidazol-2-one containing 1 equivalent of residual ethanol (165mg). ¹ H NMR (500 MHz, Chloroform-d) d 6.81 (d, J = 8.2 Hz, 1 H), 6.50 (dd, J = 8.2, 2.1 Hz, 1 H), 6.45 (d, J = 2.0 Hz, 1 H), 4.24 (m, 1 H), 3.81 - 3.70 (m, 1 H, overlapping with 2H q from residual ethanol), 3.66 (m, 1 H), 3.39 (s, 3H), 1.86 (m, 1 H), 1.65 (m, 1 H), 1.26 (t, J = 7.0 Hz, 3H from residual ethanol), 1.19 (d, J = 6.3 Hz, 3H).

Step 4: (R)-5-((2,5-dichloropyrimidin-4-yl)amino)-3-(3-hydroxybutyl) -1 -methyl-1, 3-dihydro- 2H-benzo[ d]imidazol-2-one

[00261] A mixture of 2,4,5-trichloropyrimidine (15mg, 0.08mmol), (R)-5-amino-3-(3- hydroxybutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one:ethanol (1 : 1 , from Step 3, 18.3 mg) and DIPEA (15uL, 0.09mmol) in NMP (0.5 ml_) was heated in the microwave to 140 °C for 30 min. The resulting mixture was diluted with DCM and water, aqueous layer adjusted to pH 5 using 10% citric acid solution and extracted with further DCM. Combined organics were filtered and dried using a phase separator column and evaporated under reduced pressure. The resulting solution in NMP was diluted with 0.8ml_ DMSO:acetonitrile (2: 1 v/v) and purified by preparative HPLC (ACE 5 C18-PFP column (5m, 250x30mm), 15 minute gradient elution from 60:40 to 0: 100 water: methanol (both modified with 0.1 % formic acid) at a flow rate of 40ml_/min). 1 : 1 ethyl acetate: diethyl ether (2ml_) was added, the mixture was capped, sonicated then left to stand overnight to give the title compound (8.7 mg). LCMS (4 min) Rt 2.44min; m/z 382.0848 expected 382.0838 [M+H] ⁺ for C^H^ChNsOa; ¹ H NMR (500 MHz, Chloroform-d) d 8.22 (s, 1 H), 7.60 (d, J = 2.0 Hz, 1 H), 7.33 (s, 1 H), 7.14 (dd, J = 8.3, 2.1 Hz, 1 H), 7.02 (d, J = 8.3 Hz, 1 H), 4.28 (m, 1 H), 3.92 (m, 1 H), 3.73 (m, 1 H), 3.48 (s, 3H), 1.96 (m, 1 H), 1.74 (m, 1 H), 1.23 (d, J = 6.2 Hz, 3H).

Intermediate B1a: 5-amino-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H- benzo[d]imidazol-2-one

Step 1: 1-methyl-5-nitro- 1, 3-dihydro-2H-benzo[d]imidazol-2-one

[00262] To a mixture of A^-methyl^-nitrobenzene-l , 2-diamine (10.5 g, 62.8 mmol) in acetonitrile (150 ml_) cooled to 0 °C was added portionwise disuccinimidyl carbonate (21.7 g, 84.7 mmol) over 20 minutes. The mixture was stirred at rt for 18h then poured into ice-water, forming a precipitate. The solid was collected by suction filtration and washed sequentially with water, DCM and diethyl ether affording 1-methyl-5-nitro-1 ,3-dihydro-2H- benzo[d]imidazol-2-one (11.12 g) as an orange-red solid. LCMS (Method X2) Rt 0.94min m/z 194.06 [M+H] ⁺ .

Step 2: 3-(3-hydroxy-3-methylbutyl)- 1-methyl-5-nitro- 1, 3-dihydro-2H-benzo[d]imidazol-2-one

[00263] A mixture of 1-methyl-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (from Step 1 , 9.05 g, 46.9 mmol), cesium carbonate (30.5 g, 93.7 mmol), 3-hydroxy-3-methylbutyl 4- methylbenzenesulfonate (Intermediate D1, 16.4 g, 63.5 mmol) and acetonitrile (234 ml_) was heated to reflux for 4 hours. The mixture was concentrated in vacuo. The residue was then diluted with water (500 ml_) and stirred for 30 mins, forming a precipitate, which was filtered and washed thoroughly with water. The collected solid was dried under vacuum affording 3- (3-hydroxy-3-methylbutyl)-1-methyl-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (12.03 g) as a red-brown solid. LCMS (Method T2) Rt 1.25min m/z 262.13 [M-water+H] ⁺ .

Step 3: 5-amino-3-(3-hydroxy-3-methy/buty/)- 1 -methyl· 1, 3-dihydro-2H-benzo[d]imidazol-2- one

[00264] Pd/C (10 wt%, 240 mg) was added to a solution of 3-(3-hydroxy-3-methylbutyl)-1- methyl-5-nitro-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (6.3 g, 22.6 mmol) in ethanol (113 mL), which was then placed under an atmosphere of hydrogen and stirred at 60°C for 3 hours. The mixture was filtered through a pad of Celite and washed through with ethanol. The resulting solution was then concentrated in vacuo to give the title compound (5.85 g) as a pale pink solid. LCMS (Method T2) Rt 0.23min m/z 232.15 [M-water+H] ⁺ .

Intermediate B2a: 6-amino-1 -(3-hydro xy-3-methylbutyl)-3-methyl-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one

Step 1: 6-bromo-3-methyl- 1, 3-dihydro-2H-imidazo[4, 5-b]pyridin-2-one

[00265] To a mixture of 5-bromo-/\/ ² -methylpyridine-2, 3-diamine (1.0 g, 4.95 mmol) in acetonitrile (49.5 mL) cooled to 0 °C was added portionwise disuccinimidyl carbonate (1.90 g, 7.4 mmol) over 20 minutes. The mixture was stirred at rt for 18h then poured into ice water, forming a precipitate. The solid was collected by suction filtration and washed with water, affording 6-bromo-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (748 mg) as a green/grey solid. LCMS (Method T2) Rt 1.06min m/z 227.98 [M+H] ⁺ .

Step 2: 6-bromo-1-(3-hydroxy-3-methylbutyl)-3-methyl- 1, 3-dihydro-2H-imidazo[4, 5-b]pyridin-

2-one

[00266] A mixture of 6-bromo-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (from Step 1 , 720 mg, 3.16 mmol), cesium carbonate (2.06 g, 6.31 mmol), (3-hydroxy-3-methyl- butyl) 4-methylbenzenesulfonate (Intermediate D1 , 1.22 g, 4.74 mmol) and acetonitrile (14.4 ml_) was refluxed for 2 hours. The mixture was concentrated in vacuo. The residue was then diluted with water and extracted with EtOAc. The organic extracts were dried over MgSCU, filtered and concentrated. The residue was then purified by flash column chromatography (Biotage KP-Sil 25g eluting 20-80% EtOAc in cyclohexane) affording 6-bromo-1-(3-hydroxy-

3-methylbutyl)-3-methyl-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (914 mg) as a green/grey solid. LCMS (Method T2) Rt 1.32min m/z 314.06 [M+H] ⁺ .

Step 3: 6-amino-1-(3-hydroxy-3-methylbutyl)-3-methyl- 1, 3-dihydro-2H-imidazo[4, 5-b]pyridin- 2-one

[00267] A sealed vial containing 6-bromo-1-(3-hydroxy-3-methylbutyl)-3-methyl-1 ,3-dihydro- 2H-imidazo[4,5-b]pyridin-2-one (from Step 2, 700 mg, 2.23 mmol), copper(l) oxide (63.8 mg, 0.446 mmol), ammonium hydroxide solution (28-30% NH3, 10 mL) and NMP (0.8 mL) was degassed for 5 mins with argon then heated in the microwave at 140°C for 4 h. The mixture was concentrated then purified using an SCX-2 cartridge, washing with methanol then methanolic ammonia. All collected fractions were combined and concentrated then purified by flash column chromatography (Biotage KP-Sil 50g eluting 0-10% MeOH in DCM) affording the title compound (360 mg) as a grey/green solid. LCMS (Method T2) Rt 0.42min m/z 251.16 [M+H] ⁺ .

Intermediate B2b: 6-amino-1 -(3-hydro xy-3-methylbutyl)-3-(methyl-c/ ₃ )-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one

Step 1 : 5-bromo-N-(methyl-d ₃ )-3-nitropyridin-2-amine

[00268] 5-Bromo-2-chloro-3-nitropyridine (1 g, 4.2 mmol) was dissolved in THF (8.4 mL) and cooled to 0 °C. DIPEA (1.83 mL, 10.5 mmol) was added and trideuteriomethanamine hydrochloride (327 mg, 4.63 mmol) was added portionwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. DMF (2 ml_) was added and the mixture stirred at room temperature for 4 days. Further trideuteriomethanamine hydrochloride (60 mg) and DIPEA (0.5 ml_) was added and the mixture stirred at room temperature for 24h, then evaporated. Water was added and the resulting orange solid collected by filtration (872 mg). LCMS (method T2) rt 1.35 mins; m/z 234.9910 expected 234.9904 for C ₆ H ₄ D ₃ BrN ₃ 0 ₂ + [M+H] ⁺ .

Step 2: 6-bromo-3-(methyl-d ₃ )-1 ,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

[00269] 5-bromo-N-(methyl-d ₃ )-3-nitropyridin-2-amine (from step 1 , 810 mg, 3.45 mmol) and tin(ll) chloride (1.31 g, 6.9 mmol) were dissolved in ethanol : TFE (16 ml_, 3:1 v/v) and the reaction mixture was heated to 80 °C for 2 h. Further tin(ll) chloride (1.31 g, 6.9 mmol) was added and the reaction mixture was heated to 85 °C for 3 h, then stood at room temperature overnight. The resulting mixture was purified by SCX-2 cartridge, washing with water and methanol and eluting with 2M methanolic ammonia to give the title compound as a brown oil (1 g). This was dissolved in DMF:pyridine (15ml_, 1 :1 v/v) and cooled to 0 °C, then disuccinimidyl carbonate (2.65 g, 10.3 mmol) was added portionwise. The resulting mixture was stirred at 90 °C for 18 h, then concentrated. Water was added and the reaction mixture was extracted with EtOAc seven times. The organics were combined, washed with 2M aq sodium carbonate, brine, dried over magnesium sulfate, and concentrated. Residue was purified by flash column chromatography (0 - 15% MeOH in DCM) to afford 264 mg of a brown solid. LCMS (Method T2) rt 1.07 min, m/z 230.9953 expected 230.9955 for CyFUDsBrlW [M+H] ⁺ .

Step 3: 6-bromo-1-(3-hydroxy-3-methylbutyl)-3-(methyl-d3)-1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one

[00270] A solution of (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (Intermediate D1 , 354 mg, 1.37 mmol) in acetonitrile (6.6 mL) was added to 6-bromo-3-(methyl-cf ₃ )-1 ,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (from step 2, 264 mg, 1.14 mmol) and cesium carbonate (745 mg, 2.29 mmol). The resulting mixture was heated to 90 °C for 1 h, then partitioned between DCM and water. The aqueous layer was extracted with DCM (x2) and combined organics washed with saturated sodium bicarbonate solution then concentrated to an orange oil. This was purified by flash column chromatography (20 - 80% EtOAc in cyclohexane) to give the title compound as a pink solid (241 mg). LCMS (Method T2) rt 1.33 min, m/z 317.0681 expected 317.0687 for C ₁₂ H ₁₄ D ₃ BrN ₃ 0 ₂ ⁺ [M+H] ⁺ .

Step 4: 6-amino-1-(3-hydroxy-3-methylbutyl)-3-(methyl-d ₃ )-1 ,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one

[00271] To a solution of 6-bromo-1-(3-hydroxy-3-methylbutyl)-3-(methyl-cf ₃ )-1 ,3-dihydro-2H- imidazo[4,5-b]pyridin-2-one (250 mg, 0.79 mmol) in NMP (0.5 mL) was added copper(l) oxide (1 1.3 mg, 0.079 mmol) and ammonium hydroxide (2.5 ml_, 62.8 mmol). The reaction mixture was then heated to 140 °C for 1.5 h using a microwave, then concentrated under vacuum and purified by flash column chromatography (0 - 30% MeOH in DCM) to afford the title compound (65 mg) as a black solid. LCMS (Method T2) rt 0.48 min, m/z 254.1689 expected 254.1691 for C ₁₂ H ₁₆ D3N402 ⁺ [M+H] ⁺ .

Intermediate C1a: (3R,4r,5S)-4-fluoro-3,5-dimethylpiperidine hydrochloride

Step 1: (3R,5S)-1-benzyl-4-fluoro-3, 5-dimethyl-piperidine

[00272] To a solution of (3R,5S)-1 -benzyl-3, 5-dimethyl-piperidin-4-ol (Intermediate C1 c, 50 mg, 0.23 mmol) in DCM (2 ml_) at -50 °C was added diethylaminosulfur trifluoride (74 mg, 0.46 mmol). The reaction was allowed to warm to rt and stirred for 16 h before sat. aq. NaHCC>3 was added, and the layers separated. The aqueous layer was extracted with DCM. The combined organic layers were separated, dried over MgSCL and concentrated under reduced pressure to give (3R,5S)-1-benzyl-4-fluoro-3, 5-dimethyl-piperidine (47 mg) as a yellow oil. LCMS (Method T2) Rt 0.43min; m/z 222 [M+H] ⁺ .

Step 2: (3R,4r,5S)-4-fluoro-3, 5-dimethyl-piperidine hydrochloride

[00273] To (3R,5S)-1-benzyl-4-fluoro-3, 5-dimethyl-piperidine (from step 1 , 47 mg, 0.21 mmol) in ethanol (4 mL) under argon was added 10% Pd/C (22 mg). The flask was evacuated and back-filled with hydrogen twice before being stirred at rt under a hydrogen balloon for 5h. A further portion of 10% Pd/C (22 mg, 0.022 mmol) was added and the flask was evacuated and back-filled with hydrogen twice before being stirred at rt under a hydrogen balloon for 16h. The reaction was filtered through Celite (eluent methanol) and the filtrate was concentrated under reduced pressure to half of its initial volume. To this was added 4 M HCI in 1 ,4-dioxane (0.6 mL), and the resulting suspension was stirred at rt for 10 min, before being concentrated under reduced pressure to give the title compound (Intermediate C1a, single diastereoisomer, 31 mg) as a white solid. LCMS (Method T4) Rt 0.16 min; m/z 132 [M+H] ⁺ . ¹ H NMR (500 MHz, Methanol-d4) d 3.98 (dtd, J = 48.8, 10.0, 1.6 Hz, 1 H, CHF), 3.42 - 3.30 (m, 2H), 2.81 (t, J = 12.8 Hz, 2H), 2.14 - 2.02 (m, 2H), 1.1 1 (d, J = 6.6 Hz, 6H). NMR suggests a single diastereoisomer is obtained, assigned as the trans (3R,4r,5S) isomer.

Intermediate C1 b: (3R,4s,5S)-3,5-dimethylpiperidin-4-ol: (3R,4r,5S)-3,5- dimethylpiperidin-4-ol (1 :1)

[00274] To (3R,5S)-1 -benzyl-3, 5-dimethyl-piperidin-4-ol (Intermediate C1 c, 44 mg, 0.20 mmol) in ethanol (2 ml_) under argon was added 10% Pd/C (22 mg). The flask was evacuated and back-filled with hydrogen twice before being stirred at rt under a hydrogen balloon for 5 h.

The reaction was filtered through Celite (eluent methanol) and the filtrate was concentrated under reduced pressure to give (3R,5S)-3,5-dimethylpiperidin-4-ol (Intermediate C1 b, 1 : 1 mixture of diastereoisomers, 26 mg) as yellow needles. LCMS (Method T4) Rt 0.16 min; m/z 132 [M+H] ⁺ . ¹ H NMR (500 MHz, Methanol-d4) d 3.57 (t, J = 2.3 Hz, A, 1 H, CHOH), 2.96 (ddd, J = 12.5, 4.1 , 1.4 Hz, B, 2H), 2.71 - 2.67 (m, B, 1 H), 2.67 - 2.58 (m, A, 4H), 2.25 (dd, J = 12.9, 11.5 Hz, B, 2H), 1.79 - 1.68 (m, A, 2H), 1.54 - 1.43 (m, B, 2H), 0.97 (d, J = 6.6 Hz, B, 6H), 0.94 (d, J = 6.9 Hz, A, 6H). Component A is tentatively assigned as the cis (3R,4s,5S) isomer based on the small couplings from the signal at 3.57ppm.

Intermediate C1c: (3R,4s,5S)-1 -benzyl-3,5-dimethylpiperidin-4-ol: (3R,4R,5S)-1 -benzyl- 3, 5-dimethylpiperidin-

[00275] To a solution of (3R,5S)-1 -benzyl-3, 5-dimethyl-piperidin-4-one (100 mg, 0.460 mmol) in methanol (1 ml_) at 5 °C was added sodium borohydride (21 mg, 0.55 mmol) in two portions. The reaction was allowed to warm to room temperature and stirred for 16 h. The mixture was concentrated under reduced pressure, and the resulting residue was partitioned between water and EtOAc. The organic layer was separated, dried and concentrated under reduced pressure to give the title compound (Intermediate C1 c, 1 :1 mixture of diastereoisomers, 98 mg, 97%) as a colourless oil. 1 H NMR (500 MHz, Chloroform-d) d 7.36 - 7.31 (m, 8H), 7.30 - 7.25 (m, 2H), 3.60 - 3.56 (m, 1 H), 3.52 (s, 2H), 3.49 (s, 2H), 2.87 - 2.79 (m, 2H), 2.72 - 2.66 (m, 1 H), 2.56 - 2.49 (m, 2H), 1.98 (t, J = 11.4 Hz, 2H), 1.94 - 1.83 (m, 2H), 1.75 - 1.65 (m, 4H), 0.97 (d, J = 6.1 Hz, 6H), 0.94 (d, J = 6.8 Hz, 6H).

Intermediate C2a: 3,3,5,5-tetramethylpiperidin-4-ol

Step 1: tert-butyl 4-hydroxy-3,3,5,5-tetramethylpiperidine-1-carboxylate [00276] To a solution of tert- butyl 3,3,5,5-tetramethyl-4-oxo-piperidine-1-carboxylate (523 mg, 2.05 mmol) in methanol (8 ml_) was added sodium borohydride (465 mg, 12.3 mmol) at rt. The resulting solution was stirred for 12h. After cooling the solution in an ice-bath, water (10 ml_) was added to quench the excess NaBhU. Solvents were then concentrated by reduced pressure. Solid formed was collected by filtration and washed with water and dried affording tert- butyl 4-hydroxy-3,3,5,5-tetramethylpiperidine-1-carboxylate (477 mg) as a white solid. ¹ H NMR (600 MHz, Methanol-d4) d 3.77 (m, 2H), 3.02 (s, 1 H), 2.62 (d, J = 13.4 Hz, 1 H), 2.51 (d, J = 13.4 Hz, 1 H), 1.48 (s, 9H), 0.95 (s, 12H).

Step 2: 3,3,5,5-tetramethylpiperidin-4-ol

[00277] A mixture of tert- butyl 4-hydroxy-3,3,5,5-tetramethylpiperidine-1-carboxylate (from step 1 , 94 mg, 0.37 mmol) and trifluoroacetic acid (0.50 ml_) in DCM (4.00 ml_) was stirred at 25°C for 12h. After removal of the solvent, the crude was purified by SCX-2 (5G) column to give the title compound (34 mg) as a white solid. ¹ H NMR (600 MHz, Methanol-d4) d 3.22 (s, 1 H), 3.12 (d, J = 12.9 Hz, 2H), 2.88 (d, J = 12.9 Hz, 2H), 1.11 (s, 6H), 1.08 (s, 6H).

Intermediate C2b: 2-(1 -benzyl-4, 4-difluoro-3-piperidyl)propan-2-ol

[00278] To a solution of ethyl 1 -benzyl-4, 4-difluoro-piperidine-3-carboxylate (209 mg, 0.74 mmol) in THF (8 ml_) was added methylmagnesium bromide (0.99 ml_, 2.96 mmol, 3M in ether) under nitrogen at 25 °C. The solution was stirred at this temp for 12h. Further methylmagnesium bromide (0.99 ml_, 2.96 mmol, 3M in ether) was added and the mixture was stirred for an additional 3 hours. Methanol (6 ml_) was added to quenched the excess methylmagnesium bromide. After all volatiles were removed, EtOAc was added to the crude material, which was then stirred for 15 min and solid removed by filtration. The filtrate was washed with water and the organic layer was dried with Na2SC>4. After filtration and removal of EtOAc, the title compound (56 mg) was obtained as a colourless oil, used without further purification. LCMS (Method T2) m/z 270.2 [M+H] ⁺ , Rt 0.75 min.

Intermediate C2c: 3,3-dimethylpiperidin-4-ol

[00279] To a solution of tert- butyl 3,3-dimethyl-4-oxo-piperidine-1-carboxylate (160 mg, 0.70 mmol) in methanol (8 ml_) was added portionwise sodium borohydride (80 mg, 2.11 mmol). The solution was stirred at 25 °C for 12h. Water (1 ml_) was added to quench the excess sodium borohydride. After all volatiles were removed, the crude was dried under high vacuum for 3h. DCM (10 ml_) was then added to the crude, followed by trifluoroacetic acid (0.7 ml_). The resulting solution was stirred at rt for 12h. Crude product was purified using an SCX-2 (2G) column to give the title compound (38 mg) as a colourless oil, which was used without further purification. ¹ H NMR (500 MHz, methanol-d4) d 3.34 (dd, J = 10.2, 4.4 Hz, 1 H), 3.33 - 3.31 (m, 1 H), 3.01 (dtd, J = 13.1 , 4.2, 1.6 Hz, 1 H), 2.62 (dd, J = 13.1 , 1.6 Hz, 1 H), 2.60 - 2.52 (m, 1 H), 1.67 (dq, J = 13.1 , 4.2 Hz, 1 H), 1.55 (dddd, J = 13.1 , 11.0, 10.1 , 4.4 Hz, 1 H), 0.94 (s, 3H), 0.93 (s, 3H).

Intermediate D1 : 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate

[00280] To a solution of 3-methylbutane-1 ,3-diol (27 g, 0.26 mol) and triethylamine (40 ml_, 0.29 mol) in DCM (250 ml_) at 0 °C was added dropwise 4-methylbenzenesulfonyl chloride (50 g, 84 mmol) in 200 ml_ of DCM over 1 h. Stirred at 0 °C for 4 h, added water (200 ml_) and stirred for 45 minutes. Adjusted to pH 10 by addition of 2M NaOH and separated. Organic phase was washed sequentially with 200m L of half-saturated sodium bicarbonate solution (x2), water, 1 M HCI, brine, then dried over magnesium sulfate, filtered and concentrated to give a yellow oil. This was dissolved in DCM/cyclohexane and purified by flash column chromatography (340g KP-SIL, 3CV cyclohexane, 4CV 0-40% ethyl acetate in cyclohexane, 3CV 40% ethyl acetate in cyclohexane) to give the title compound (39.9 g) as a colourless oil. ¹ H NMR (500 MHz, Chloroform-d) d 7.85 - 7.78 (m, 2H), 7.40 - 7.34 (m, 2H), 4.23 (t, J = 6.8 Hz, 2H), 2.47 (s, 3H), 1.88 (t, J = 6.8 Hz, 2H), 1.23 (s, 6H).

Biological Assays

HTRF assay

[00281] Each 15 pL HTRF reaction in a 384-well black Proxiplate (Perkin Elmer) contained 1 nM Trx-6xHis-BCL6 (in house-produced, human BCL6 BTB domain covering amino-acid sequence 5-129), 300 nM BCOR-AF633 peptide (RSEIISTAPSSWWPGP-Cys- AlexaFluor 633-amide, Cambridge Research Biochemical) and 0.5nM anti-6xHis-Terbium cryptate (CisBio Bioassays, France), in assay buffer (25 mM Hepes pH8, 100 mM NaCI, 0.05% Tween20, 0.5 mM TCEP, 0.05% bovine serum albumin). Test compounds in DMSO or DMSO alone were added to the wells using an ECHO550 acoustic dispenser (Labcyte Inc) to give the appropriate test concentration in 0.7% v/v DMSO final. After 2 hours incubation at room temperature the plate was read on an Envision plate reader (Perkin Elmer) with 337 nm laser excitation, a first emission filter APC 665 nm and a second emission filter Europium 615 nm. The % inhibition at each concentration was calculated by normalising FRET ratio to the appropriate high (DMSO with all reagents) and low (DMSO without BCL6) controls. The compound IC50 values were determined using GraphPad Prism 6.0 or Dotmatics (Bishops Stortford, UK) software by fitting the normalised data to a sigmoidal four-parameter logistic fit equation.

[00282] The results of this assay are shown in Table 1 above as the pICso values.

Immunofluorescence-based BCL6 degradation assay

[00283] DC50 values (compound concentration at which 50% of endogenous BCL6 protein is degraded) were determined in SUDHL-4 cells (American Type Culture Collection) in an immunofluorescence-based assay using an lnCell2200 high content imaging system (GE Healthcare). Briefly, 40 pl_ of lymphoma suspension cells cultured in RPMI 1640-10% FBS (Sigma-Aldrich or PAN Biotech UK Ltd) were platted on fibronectin (Sigma catalogue F1141) -coated 384 well Cell Carrier Ultra plate (Perkin Elmer catalogue 6057300) at 1.2 104 cells/well. After 20 hours cell culture at 37°C/C02 incubator, compounds were dispensed in the cell culture plate using ECHO550 acoustic dispenser (Labcyte, Inc.), as 8 point- concentration response (ranging from 5 nM to 10 mM) in 0.67% final DMSO concentration. Cells were incubated with compound for 2 hours at 37°C/C02 incubator followed by fixation in 4.5% formaldehyde (37% formaldehyde solution, Sigma catalogue F8775) at room temperature for 15 min. After fixing, cells were washed in 1xTBS (Tris Buffer Saline) using a Power Washer 384 (Tecan Group Ltd). Blocking and cell permeabilisation were performed by incubating the fixed cells for 1 hour at room temperature in 1xTBS, 5% BSA, 1 % Triton X100, followed by three washes on PW384 plate washer. Primary and secondary antibodies were prepared in 1xTBS, 1 % BSA, 0.2% Triton X100. BCL6 expression was detected by incubating the cells for 1 h30 with BCL6 rabbit polyclonal antibody (Sigma Catalogue HPA004899) at 1 :250, 0.8pg/ml, followed by 1 hour in chicken anti-Rabbit Alexa 488 conjugated antibody (Life Technology) at 1 :500. After incubation in each antibody, cells were washes four times in 1xTBS-0.05% tween on PW384 plate washer. Cells were finally incubated for 60 min with nuclear staining RedDot2 dye (Biotium) at 0.5x the stock concentration in 1xTBS. BCL6 expression in the absence or presence of compound was detected on lnCell2200 with 20x objective and quantified on InCell Analyser 3.7.2 workstation (GE Healthcare). The % response at each concentration was calculated by normalising BCL6 expression in the presence of compound to the appropriate high (DMSO) and low (DMSO with 7 mM of a control compound (5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin- 1-yl)pyrimidin-4- yl)amino)-3-(3-hydroxy-3-methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one)) controls. The compound DC50 values were determined using GraphPad Prism 6.0 or Dotmatics (Bishops Stortford, UK) software by fitting the normalised data to a sigmoidal four- parameter logistic fit equation. [00284] The results of this assay are shown in Table 2 above as the pDCso values.

14-day cell proliferation assay

[00285] SU-DHL-4 cells were seeded in 96-well culture plates at a density of 2000 cells/well in RPMI-1640 medium (Sigma-Aldrich) supplemented with 10% FBS (Gibco). Compounds were initially dispensed into 96-well U-bottom plates using an Echo 550 acoustic dispenser (Labcyte Inc.), then diluted in RPMI-1640 medium and transferred onto the cells. Cells were treated with 8 compound concentrations in duplicate, ranging from 1 nM to 10 mM, in a final DMSO concentration of 0.1 % and final volume of 100 pi. Cells were incubated with compound for 14 days, with medium changes at days 3, 7 and 10 carried out as follows: fresh 96-well cell culture plates were prepared containing 100 pi medium plus compound at the assay concentrations (white plates were used on day 10 to optimise luminescence measurement). Assay plates containing cells were vortexed to mix and cell density in one control well was counted using a Coulter Z2 cell counter (Beckman Coulter). The volume of medium containing 2000 cells in the control well was calculated and this volume of cells was transferred from every well of the assay plates to the corresponding well of the fresh plates containing compound. After 14 days, CellTiter Glo reagent (Promega) was added to the medium in each well of the assay plate at a ratio of 1 :2, mixed on a plate shaker, then incubated at room temperature for 10 minutes. Luminescence was measured using an Envision plate reader (Perkin Elmer) and the relative luminescence at each compound concentration, compared to DMSO alone, was calculated. GI50 values were determined using a 4-parameter curve fit in Dotmatics (Bishops Stortford, UK).

[00286] The results of this assay are shown in Table 3 above.

Mesoscale Discovery (MSD) Degradation Assay

[00287] An MSD assay was developed for screening of compounds to determine the degradation of endogenous BCL6 in OCI-Ly1 cells. Briefly, test compounds in DMSO or DMSO alone to a total of 1332.5 nL/well were dispensed to a 96-well Nunc™ Edge 2 plate (ThermoFisher Scientific, 267544) using an Echo® 550 acoustic dispenser (Labcyte Inc) to give the appropriate test concentration in 0.67% v/v DMSO final. OCI-Ly1 passaged in Iscove’s Modified Dulbecco’s Medium (IMDM, ThermoFisher Scientific, 12440053) supplemented with 10% heat-inactivated fetal bovine serum (Sera Plus, PAN Biotech, P30- 3702 ) were added to the compound/DMSO at a density of 2.5 x 105 cells/mL in 200 pL media/ well. After 2 hours incubation at 37 °C + 5% CO2 the plate was centrifuged at 300 x g for 5 minutes. Using a BioTek 405TS plate washer for all wash and aspiration steps, media was removed and cells were rinsed with PBS, centrifuged as before and PBS removed. Cells were lysed in 50 pL ice-cold lysis buffer at pH 7.4 containing 50 mM Tris-HCI, 150 mM NaCI, 1 % Triton X-100 (v/v), 1 mM PMSF, 1 mM activated sodium vanadate, 1 mM EDTA, phosphatase inhibitors 2 and 3 (1 :50 dilution) and protease inhibitor cocktail (1 : 100 dilution). The plate was shaken briefly and incubated on ice for 5-10 minutes before being frozen overnight at -20 °C or continuing the assay. A 96-well MSD standard bind plate (MSD, L15XA-3) which was coated overnight with 1 pg/mL anti-human BCL6 goat antibody in PBS (R&D Systems, AF5046) was blocked in 3% BSA in TBS + 0.1 % Tween-2 0 for 1 hour with shaking. Wells were emptied thoroughly before 40 pL/well of lysate was transferred from the cell plate. The MSD plate was incubated at RT for 1 hour with shaking then washed three times with TBS + 0.1 % Tween-20. Antibodies were prepared in TBS + 0.1 % Tween-20 + 1 % BSA. Anti-human BCL6 rabbit antibody (Cell Signalling Technology, 14895S) was added at 1 : 100 dilution at 25 pL/well. The plate was incubated and washed as before. MSD Sulfo-tag anti-rabbit detection antibody (MSD, R32AB-1) at 1 : 1000 dilution at 25 pL/well was added. The plate was incubated and washed as before and MSD Gold read buffer (MSD R92TG) at 1 : 1 dilution with water at 150 pL/well was added. The plate was read within 10 minutes on the MSD Quickplex reader. The % inhibition at each concentration was calculated by normalising the electrochemiluminescent signal to the appropriate high (DMSO) and low ((5-((5-chloro-2- ((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4 -yl)amino)-3-(3-hydroxy-3- methylbutyl)-1 -methyl-1 , 3-dihydro-2H-benzo[d]imidazol-2-one) at 2 pM) controls. DC50 values (compound concentration at which 50% of endogenous BCL6 protein is degraded) were determined using GraphPad Prism 6.0 or Dotmatics (Bishops Stortford, UK) software by fitting the normalised data to a sigmoidal four-parameter logistic fit equation.

[00288] The results obtained using this assay are shown in Table 4.

[00289] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.