N-(4-(5-CHLOROPYRIDINE-3-YL)PHENYL)-2-(2-(CYCLOPROPANESULFONAMIDO)PYRIMIDINE-4-YL)BUTANAMIDE DERIVATIVES AND SIMILAR COMPOUNDS AS HUMAN CTPS1 HIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISEASES

Description

Field of the invention

[0001] The invention relates to novel compounds, processes for the manufacture of such compounds, related intermediates, compositions comprising such compounds and the use of such compounds as cytidine triphosphate synthase 1 inhibitors, particularly in the treatment or prophylaxis of disorders associated with cell proliferation.Background of the invention

[0002] Nucleotides are a key building block for cellular metabolic processes such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. There are two classes of nucleotides, that contain either purine or pyrimidine bases, both of which are important for metabolic processes. Based on this, many therapies have been developed to target different aspects of nucleotide synthesis, with some inhibiting generation of purine nucleotides and some pyrimidine nucleotides or both.

[0003] The pyrimidine nucleotide cytidine 5' triphosphate (CTP) is a precursor required not just for the anabolism of DNA and RNA but also phospholipids and sialyation of proteins. CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases (or synthetases) 1 and 2 (CTPS1 and CTPS2) (Evans and Guy 2004; Higgins, et al. 2007; Ostrander, et al. 1998).

[0004] CTPS1 and CTPS2 catalyse the conversion of uridine triphosphate (UTP) and glutamine into cytidine triphosphate (CTP) and L-glutamate:

[0005] Both enzymes have two domains, an N-terminal synthetase domain and a C-terminal glutaminase domain (Kursula, et al. 2006). The synthetase domain transfers a phosphate from adenosine triphosphate (ATP) to the 4-position of UTP to create an activated intermediate, 4-phospho-UTP. The glutaminase domain generates ammonia from glutamine, via a covalent thioester intermediate with a conserved active site cysteine, generating glutamate. This ammonium is transferred from the glutaminase domain to the synthetase domain via a tunnel or can be derived from external ammonium. This ammonium is then used by the synthetase domain to generate CTP from the 4-phospho-UTP (Lieberman, 1956).

[0006] Although CTPS exists as two isozymes in humans and other eukaryotic organisms, CTPS1 and CTPS2, functional differences between the two isozymes are not yet fully elucidated (van Kuilenburg, et al. 2000).

[0007] The immune system provides protection from infections and has therefore evolved to rapidly respond to the wide variety of pathogens that the individual may be exposed to. This response can take many forms, but the expansion and differentiation of immune populations is a critical element and is hence closely linked to rapid cell proliferation. Within this, CTP synthase activity appears to play an important role in DNA synthesis and the rapid expansion of lymphocytes following activation (Fairbanks, et al. 1995; van den Berg, et al. 1995).

[0008] Strong clinical validation that CTPS1 is the critical enzyme in human lymphocyte proliferation came with the identification of a loss-of-function homozygous mutation (rs145092287) in this enzyme that causes a distinct and life-threatening immunodeficiency, characterized by an impaired capacity of activated T- and B-cells to proliferate in response to antigen receptor-mediated activation. Activated CTPS1-deficient cells were shown to have decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of cytidine. CTPS1 expression was found to be low in resting lymphocytes, but rapidly upregulated following activation of these cells. Expression of CTPS1 in other tissues was generally low. CTPS2 seems to be ubiquitously expressed in a range of cells and tissues but at low levels, and the failure of CTPS2, which is still intact in the patients, to compensate for the mutated CTPS1, supports CTPS1 being the critical enzyme for the immune populations affected in the patients (Martin, et al. 2014).

[0009] Overall, these findings suggest that CTPS1 is a critical enzyme necessary to meet the demands for the supply of CTP required by several important immune cell populations.

[0010] Normally the immune response is tightly regulated to ensure protection from infection, whilst controlling any response targeting host tissues. In certain situations, the control of this process is not effective, leading to immune-mediated pathology. A wide range of human diseases are thought to be due to such inappropriate responses mediated by different elements of the immune system.

[0011] Given the role that cell populations, such as T and B lymphocytes, are thought to play in a wide range of autoimmune and other diseases, CTPS1 represents a target for a new class of immunosuppressive agents. Inhibition of CTPS1 therefore provides a novel approach to the inhibition of activated lymphocytes and selected other immune cell populations such as Natural Killer cells, Mucosal-Associated Invariant T (MAIT) and Invariant Natural Killer T cells, highlighted by the phenotype of the human mutation patients (Martin, et al. 2014).

[0012] Cancer can affect multiple cell types and tissues but the underlying cause is a breakdown in the control of cell division. This process is highly complex, requiring careful coordination of multiple pathways, many of which remain to be fully characterised. Cell division requires the effective replication of the cell's DNA and other constituents. Interfering with a cell's ability to replicate by targeting nucleic acid synthesis has been a core approach in cancer therapy for many years. Examples of therapies acting in this way are 6-thioguanine, 6-mecaptopurine, 5-fluorouracil, cytarabine, gemcitabine and pemetrexed.

[0013] As indicated above, pathways involved in providing the key building blocks for nucleic acid replication are the purine and pyrimidine synthesis pathways, and pyrimidine biosynthesis has been observed to be up-regulated in tumors and neoplastic cells.

[0014] CTPS activity is upregulated in a range of tumour types of both haematological and non-haematological origin, although heterogeneity is observed among patients. Linkages have also been made between high enzyme levels and resistance to chemotherapeutic agents.

[0015] Currently, the precise role that CTPS1 and CTPS2 may play in cancer is not completely clear. Several non-selective CTPS inhibitors have been developed for oncology indications up to phase I / II clinical trials, but were stopped due to toxicity and efficacy issues.

[0016] Most of the developed inhibitors are nucleoside-analogue prodrugs (3-deazauridine, CPEC, carbodine), which are converted to the active triphosphorylated metabolite by the kinases involved in pyrimidine biosynthesis: uridine / cytidine kinase, nucleoside monophosphate-kinase (NMP-kinase) and nucleoside diphosphatekinase (NDP-kinase). The remaining inhibitors (acivicin, DON) are reactive analogues of glutamine, which irreversibly inhibit the glutaminase domain of CTPS. Gemcitibine is also reported to have some inhibitory activity against CTPS (McClusky et al., 2016).

[0017] CTPS therefore appears to be an important target in the cancer field. The nature of all of the above compounds is such that effects on other pathways are likely to contribute to the efficacy they show in inhibiting tumours.

[0018] Selective CTPS inhibitors therefore offer an attractive alternative approach for the treatment of tumours. Compounds with different potencies against CTPS1 and CTPS2 may offer important opportunities to target different tumours depending upon their relative dependence on these enzymes.

[0019] CTPS1 has also been suggested to play a role in vascular smooth muscle cell proliferation following vascular injury or surgery (Tang, et al. 2013).

[0020] As far as is known to date, no selective CTPS1 inhibitors have been developed. Recently, the CTPS1 selective inhibitory peptide CTpep-3 has been identified. The inhibitory effects of CTpep-3 however, were seen in cell free assays but not in the cellular context. This was not unexpected though, since the peptide is unlikely to enter the cell and hence is not easily developable as a therapeutic (Sakamoto, et al. 2017).

[0021] In summary, the available information and data strongly suggest that inhibitors of CTPS1 will reduce the proliferation of a number of immune and cancer cell populations, with the potential for an effect on other selected cell types such as vascular smooth muscle cells as well. Inhibitors of CTPS1 may therefore be expected to have utility for treatment or prophylaxis in a wide range of indications where the pathology is driven by these populations.

[0022] CTPS1 inhibitors represent a novel approach for inhibiting selected components of the immune system in various tissues, and the related pathologies or pathological conditions such as, in general terms, rejection of transplanted cells and tissues, Graft-related diseases or disorders, allergies and autoimmune diseases. In addition, CTPS1 inhibitors offer therapeutic potential in a range of cancer indications and in enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis.

[0023] International patent applications WO2019 / 106156, WO2019 / 106146, WO2019 / 179652 and WO2019 / 180244 and WO2020 / 083975 disclose CTPS1 inhibitors. Patent applications EP3543232, EP3492454 and EP3578551 disclose CTPS1 inhibitors. International patent application WO2014 / 170435 discloses methods and pharmaceutical composition for inhibiting lymphocyte proliferation. International patent application WO02 / 24665 discloses aryl-alkane sulfonamides and their use as endothelin receptor antagonists. International patent application WO02 / 16318 discloses thiourea derivatives as vanilloid receptor modulators. US2003 / 158218 discloses thrombin inhibitors. Sandosham et al. "Heterocycles, vol. 37, mo. 1, 1994, pages 501-514" discloses the synthesis of pyrmidinyl triflates and palladium catalyzed coupling with organotin and organozinc reagents. CN104262071 discloses a photocatalysis synthesis method of biphenyl compounds. GB1575803 discloses 3,7-disubstituted-3-cephem-4-carboxylic acid compounds which have antimicrobial activity. GB155007 discloses intermediates used in the preparation of substituted cephem carboxylic acid derivatives.Summary of the Invention

[0024] The invention provides a compound of formula (I): wherein ring B is selected from the group consisting of: wherein X, Y and Z are as defined below; and wherein R 3b3c is R 3b or R 3c as defined below; wherein when B is (B-a) the compound of formula (I) is a compound of formula (I-a): wherein: A a is A aa or A ba ; wherein: A aa is an amine linker having the following structure: -NH-, -CH 2 NH- or -NHCH 2 -; A ba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR 2a ; Z is N or CR 3a ; with the proviso that when at least one of X or Z is N, Y cannot be N; R 2a is H, halo, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl; and R 3a is H, halo, CH 3 , OCH 3 , CF 3 or OCF 3 ; wherein at least one of R 2a and R 3a is H; R 1a is R 1aa or R 1ba ; wherein: R 1aa is NR 32a R 33a ; R 1ba is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 ; R 4a and R 5a are R 4aa and R 5aa , or R 4ba and R 5ba ; wherein: R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21a R 22a ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heterocycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29a ; or R 4ba and R 5ba are each independently H, C 1-6 alkyl, C 1-6 alkylOH, C 1-6 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, or R 4ba and R 5ba together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and when A a is -NHC(=O)- or -NHCH 2 -: R 4ba and R 5ba may additionally be selected from halo, OC 1-6 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl and NR 21a R 22a ; Ar1a is a 6-membered aryl or heteroaryl; Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A a ; R 10a is H, halo, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN; R 11a is H, F, Cl, C 1-2 alkyl, CF 3 , OCH 3 or CN; R 12a is attached to Ar2 in the ortho or meta position relative to Ar1a and R 12a is H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 3-5 cycloalkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, hydroxy, C 1-4 alkylOH, SO 2 C 1-2 alkyl, C(O)N(C 1-2 alkyl) 2 , NHC(O)C 1-3 alkyl or NR 23a R 24a ; and when A a is -NHC(=O)-, -NH- or -NHCH 2 -: R 12a may additionally be selected from CN, OCH 2 CH 2 N(CH 3 ) 2 and a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R 12a together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 13a is H or halo; R 21a is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl, C 1-3 alkylOC 1-2 alkyl, C 1-4 haloalkyl, or C 4-6 heterocycloalkyl; R 22a is H or CH 3 ; R 23a is H or C 1-2 alkyl; and R 24a is H or C 1-2 alkyl R 29a is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , CF 3 , N(C 1-3 alkyl) 2 , or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; R 32a is C 1-3 alkyl and R 33a is C 1-3 alkyl; or R 32a and R 33a together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; wherein: R 1a is R 1aa ; and / or R 4a and R 5a are R 4aa and R 5aa ; and / or A a is A aa ; and wherein when B is (B-bc) and R 3b3c is R 3b , the compound of formula (I) is a compound of formula (I-b): A b is A ab or A bb ; wherein: A ab is -NR 6b CH 2 - or -NR 6b -; A bb is -NR 6b C(=O)-; R 1b is R 1ab or R 1bb ; wherein: R 1ab is NR 32b R 33b ; R 1bb is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R 3b is H, halo, CH 3 , OC 1-2 alkyl or CF 3 ; or R 3b together with R 5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R 4b and R 5b are either R 4ab and R 5ab or R 4bb and R 5bb ; wherein: R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21b R 22b ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heteroycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29b ; or R 4bb and R 5bb are each independently H, halo, C 1-6 alkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-6 alkylOH, C 1-6 haloalkyl, OC 1-6 haloalkyl or NR 21b R 22b , or R 4bb is H and R 5bb together with R 3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, or R 4bb and R 5bb together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, or R 4bb is H and R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring; or R 4bb is O and R 5bb is absent; R 6b is H or C 1-3 alkyl, or R 6b together with R 11b when in the ortho-position to group A b are a C 2 alkylene chain forming a 5-membered ring, or R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring and R 4bb is H; Ar1b is 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A b ; R 10b is H, halo, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN; R 11b is H, F, Cl, CH 3 , ethyl, OCH 3 , CF 3 , OCF 3 or CN, or R 11b , when in the ortho-position to group A b , together with R 6b are a C 2 alkylene chain forming a 5-membered ring; R 12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R 12b is H, halo, C 1-4 alkyl, C 2-4 alkynyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 3-5 cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , OH, C 1-4 alkylOH, CN, C 1-3 alkyleneOC 1-3 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, C(=O)C 1-2 alkyl, NR 23b R 24b , SO 2 C 1-4 alkyl, SOC 1-4 alkyl, SC 1-4 alkyl, SH, C(O)N(CH 3 ) 2 , NHC(O)C 1-3 alkyl, C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R 12b together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 13b is H, halo, CH 3 or OCH 3 ; R 21b is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl, C 1-3 alkylOC 1-2 alkyl, C 1-4 haloalkyl, or C 4-6 heterocycloalkyl; R 22b is H or CH 3 ; R 23b is H or C 1-2 alkyl; R 24b is H or C 1-2 alkyl; R 29b is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , CF 3 , N(C 1-3 alkyl) 2 , or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and R 32b is C 1-3 alkyl and R 33b is C 1-3 alkyl; or R 32b and R 33b together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; wherein: R 1b is R 1ab ; and / or R 4b and R 5b are R 4ab and R 5ab ; and / or A b is A ab ; or wherein when B is (B-bc) and R 3b3c is R 3c , the compound of formula (I) is a compound of formula (I-c): wherein: A c is A ac or A bc ; wherein: A ac is -CH 2 NR 6c -; A bc is -C(=O)NR 6c -; R 1c is R 1ac or R 1bc ; wherein: R 1ac is NR 32c R 33c ; R 1bc is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R 3c is H, CH 3 , halo, OC 1-2 alkyl or CF 3 ; R 4c and R 5c are either R 4ac and R 5aa or R 4bc and R 5bc ; wherein: R 4ac and R 5aa together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21c R 22c ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ac and R 5aa together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heteroycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ac and R 5aa together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29c ; or R 4bc and R 5bc are each independently H, C 1-6 alkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-6 alkylOH or C 1-6 haloalkyl, or R 4bc and R 5bc together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl ring; R 6c is H or C 1-3 alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A c ; R 10c is H, halo, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN; R 11c is H, F, Cl, CH 3 , ethyl, OCH 3 , CF 3 , OCF 3 or CN; R 12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R 12c is H, halo, C 1-4 alkyl, C 2-4 alkynyl, C(=O)C 1-2 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, CN, OC 0-2 alkyleneC 3-5 cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , OH, C 1-4 alkylOH, NR 23c R 24c , SO 2 CH 3 , C(O)N(CH 3 ) 2 , NHC(O)C 1-3 alkyl, or a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R 12c together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 21c is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl, C 1-3 alkylOC 1-2 alkyl, C 1-4 haloalkyl, or C 4-6 heterocycloalkyl; R 22c is H or CH 3 ; R 23c is H or C 1-2 alkyl; R 24c is H or C 1-2 alkyl; R 29c is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , CF 3 , N(C 1-3 alkyl) 2 , or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and R 32c is C 1-3 alkyl and R 33c is C 1-3 alkyl; or R 32c and R 33c together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; wherein: R 1c is R 1ac ; and / or R 4c and R 5c are R 4ac and R 5ac ; and / or A c is A ac .

[0025] In one embodiment, the compound formula (I) is a compound of formula (I-a).

[0026] In another embodiment, the compound formula (I) is a compound of formula (I-b).

[0027] In another embodiment, the compound formula (I) is a compound of formula (I-c).

[0028] A compound of formula (I) may be provided in the form of a salt and / or solvate thereof.. In particular, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or solvate, such as a pharmaceutically acceptable salt.

[0029] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament, in particular for use in the inhibition of CTPS1 in a subject or the prophylaxis or treatment of associated diseases or disorders, such as those in which a reduction in T-cell and / or B-cell proliferation would be beneficial.

[0030] Suitably the disease or disorder is selected from: inflammatory skin diseases such as psoriasis or lichen planus; acute and / or chronic GVHD such as steroid resistant acute GVHD; acute lymphoproliferative syndrome (ALPS); systemic lupus erythematosus, lupus nephritis or cutaneous lupus; and transplantation. In addition, the disease or disorder may be selected from myasthenia gravis, multiple sclerosis, and scleroderma / systemic sclerosis.

[0031] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of cancer.

[0032] Also provided is a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject.

[0033] Also provided are pharmaceutical compositions containing a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier or excipient.Detailed description of the Invention

[0034] In one embodiment there is provided a compound of formula (I) as described above, or a salt such as a pharmaceutically acceptable salt and / or solvate thereof.

[0035] Suitably, the invention provides a compound of formula (I): wherein ring B is selected from the group consisting of: wherein X, Y and Z are as defined below; and wherein R 3b3c is R 3b or R 3c as defined below; wherein when B is (B-a) the compound of formula (I) is a compound of formula (I-a): wherein: A a is A aa or A ba ; wherein: A aa is an amine linker having the following structure: -NH-, -CH 2 NH- or -NHCH 2 -; A ba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR 2a ; Z is N or CR 3a ; with the proviso that when at least one of X or Z is N, Y cannot be N; R 2a is H, halo, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl; and R 3a is H, halo, CH 3 , OCH 3 , CF 3 or OCF 3 ; wherein at least one of R 2a and R 3a is H; R 1a is R 1aa or R 1ba ; wherein: R 1aa is NR 32a R 33a ; R 1ba is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 ; R 4a and R 5a are R 4aa and R 5aa , or R 4ba and R 5ba ; wherein: R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21a R 22a ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heterocycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29a ; or R 4ba and R 5ba are each independently H, C 1-6 alkyl, C 1-6 alkylOH, C 1-6 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, or R 4ba and R 5ba together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and when A a is -NHC(=O)- or -NHCH 2 -: R 4ba and R 5ba may additionally be selected from halo, OC 1-6 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl and NR 21a R 22a ; Ar1a is a 6-membered aryl or heteroaryl; Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A a ; R 10a is H, halo, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN; R 11a is H, F, Cl, C 1-2 alkyl, CF 3 , OCH 3 or CN; R 12a is attached to Ar2 in the ortho or meta position relative to Ar1a and R 12a is H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 3-5 cycloalkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, hydroxy, C 1-4 alkylOH, SO 2 C 1-2 alkyl, C(O)N(C 1-2 alkyl) 2 , NHC(O)C 1-3 alkyl or NR 23a R 24a ; and when A a is -NHC(=O)-, -NH- or -NHCH 2 -: R 12a may additionally be selected from CN, OCH 2 CH 2 N(CH 3 ) 2 and a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R 12a together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 13a is H or halo; R 21a is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl; R 22a is H or CH 3 ; R 23a is H or C 1-2 alkyl; and R 24a is H or C 1-2 alkyl R 29a is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 ; R 32a is C 1-3 alkyl and R 33a is C 1-3 alkyl; or R 32a and R 33a together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; wherein R 1a is R 1aa ; and / or R 4a and R 5a are R 4aa and R 5aa ; and / or A a is A aa ; and wherein when B is (B-bc) and R 3b3c is R 3b , the compound of formula (I) is a compound of formula (I-b): wherein: A b is A ab or A bb ; wherein: A ab is -NR 6b CH 2 - or -NR 6b -; A bb is -NR 6b C(=O)-; R 1b is R 1ab or R 1bb ; wherein: R 1ab is NR 32b R 33b ; R 1bb is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R 3b is H, halo, CH 3 , OC 1-2 alkyl or CF 3 ; or R 3b together with R 5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R 4b and R 5b are either R 4ab and R 5ab or R 4bb and R 5bb ; wherein: R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21b R 22b ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heteroycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29b ; or R 4bb and R 5bb are each independently H, halo, C 1-6 alkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-6 alkylOH, C 1-6 haloalkyl, OC 1-6 haloalkyl or NR 21b R 22b , or R 4bb is H and R 5bb together with R 3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, or R 4bb and R 5bb together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, or R 4bb is H and R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring; or R 4bb is O and R 5bb is absent; R 6b is H or C 1-3 alkyl, or R 6b together with R 11b when in the ortho-position to group A b are a C 2 alkylene chain forming a 5-membered ring, or R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring and R 4bb is H; Ar1b is 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A b ; R 10b is H, halo, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN; R 11b is H, F, Cl, CH 3 , ethyl, OCH 3 , CF 3 , OCF 3 or CN, or R 11b , when in the ortho-position to group A b , together with R 6b are a C 2 alkylene chain forming a 5-membered ring; R 12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R 12b is H, halo, C 1-4 alkyl, C 2-4 alkynyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 3-5 cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , OH, C 1-4 alkylOH, CN, C 1-3 alkyleneOC 1-3 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, C(=O)C 1-2 alkyl, NR 23b R 24b , SO 2 C 1-4 alkyl, SOC 1-4 alkyl, SC 1-4 alkyl, SH, C(O)N(CH 3 ) 2 , NHC(O)C 1-3 alkyl, C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R 12b together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 13b is H, halo, CH 3 or OCH 3 ; R 21b is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl; R 22b is H or CH 3 ; R 23b is H or C 1-2 alkyl; R 24b is H or C 1-2 alkyl; R 29b is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 ; and R 32b is C 1-3 alkyl and R 33b is C 1-3 alkyl; or R 32b and R 33b together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; wherein: R 1b is R 1ab ; and / or R 4b and R 5b are R 4ab and R 5ab ; and / or A b is A ab ; or wherein when B is (B-bc) and R 3b3c is R 3c , the compound of formula (I) is a compound of formula (I-c): wherein: A c is A ac or A bc ; A ac is -CH 2 NR 6c -; A bc is -C(=O)NR 6c -; R 1c is R 1ac or R 1bc ; wherein: R 1ac is NR 32c R 33c ; R 1bc is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R 3c is H, CH 3 , halo, OC 1-2 alkyl or CF 3 ; R 4c and R 5c are either R 4ac and R 5aa or R 4bc and R 5bc ; wherein: R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21c R 22c ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heteroycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29c ; or R 4bc and R 5bc are each independently H, C 1-6 alkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-6 alkylOH or C 1-6 haloalkyl, or R 4bc and R 5bc together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl ring; R 6c is H or C 1-3 alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A c ; R 10c is H, halo, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN; R 11c is H, F, Cl, CH 3 , ethyl, OCH 3 , CF 3 , OCF 3 or CN; R 12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R 12c is H, halo, C 1-4 alkyl, C 2-4 alkynyl, C(=O)C 1-2 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, CN, OC 0-2 alkyleneC 3-5 cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , OH, C 1-4 alkylOH, NR 23c R 24c , SO 2 CH 3 , C(O)N(CH 3 ) 2 , NHC(O)C 1-3 alkyl, or a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R 12c together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 21c is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl; R 22c is H or CH 3 ; R 23c is H or C 1-2 alkyl; R 24c is H or C 1-2 alkyl; R 29c is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 ; and R 32c is C 1-3 alkyl and R 33c is C 1-3 alkyl; or R 32c and R 33c together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; wherein: R 1c is R 1ac ; and / or R 4c and R 5c are R 4ac and R 5ac ; and / or A c is A ac .

[0036] More suitably, there is provided a compound of formula (I-a).

[0037] Alternatively, there is provided a compound of formula (I-b).

[0038] Alternatively, there is provided a compound of formula (I-c).Compounds of formula (I-a)

[0039] The invention provides a compound of formula (I-a): wherein: A a is A aa or A ba ; wherein: A aa is an amine linker having the following structure: -NH-, -CH 2 NH- or -NHCH 2 -; A ba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR 2a ; Z is N or CR 3a ; with the proviso that when at least one of X or Z is N, Y cannot be N; R 1a is R 1aa or R 1ba ; wherein: R 1aa is NR 32a R 33a ; R 1ba is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 ; R 2a is H, halo, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl; R 3a is H, halo, CH 3 , OCH 3 , CF 3 or OCF 3 ; wherein at least one of R 2a and R 3a is H; R 4a and R 5a are R 4aa and R 5aa , or R 4ba and R 5ba ; wherein: R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21a R 22a ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heterocycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29a ; or R 4ba and R 5ba are each independently H, C 1-6 alkyl, C 1-6 alkylOH, C 1-6 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, or R 4ba and R 5ba together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and when A a is -NHC(=O)- or -NHCH 2 -: R 4ba and R 5ba may additionally be selected from halo, OC 1-6 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl and NR 21a R 22a ; Ar1a is a 6-membered aryl or heteroaryl; Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A a ; R 10a is H, halo, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN; R 11a is H, F, Cl, C 1-2 alkyl, CF 3 , OCH 3 or CN; R 12a is attached to Ar2a in the ortho or meta position relative to Ar1a and R 12a is H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 3-5 cycloalkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, hydroxy, C 1-4 alkylOH, SO 2 C 1-2 alkyl, C(O)N(C 1-2 alkyl) 2 , NHC(O)C 1-3 alkyl or NR 23a R 24a ; and when A a is -NHC(=O)-, -NH- or -NHCH 2 -: R 12a may additionally be selected from CN, OCH 2 CH 2 N(CH 3 ) 2 and a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R 12a together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 13a is H or halo; R 21a is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl, C 1-3 alkylOC 1-2 alkyl, C 1-4 haloalkyl, or C 4-6 heterocycloalkyl; R 22a is H or CH 3 ; R 23a is H or C 1-2 alkyl; and R 24a is H or C 1-2 alkyl; R 29a is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , CF 3 , N(C 1-3 alkyl) 2 , or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; R 32a is C 1-3 alkyl and R 33a is C 1-3 alkyl; or R 32a and R 33a together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; or a salt and / or solvate thereof.

[0040] Suitably, R 1c is R 1ac ; and / or R 4c and R 5c are R 4ac and R 5ac ; and / or A c is A ac .

[0041] The invention also provides a compound of formula (I-a): wherein: A a is A aa or A ba ; wherein: A aa is an amine linker having the following structure: -NH-, -CH 2 NH- or -NHCH 2 -; A ba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR 2a ; Z is N or CR 3a ; with the proviso that when at least one of X or Z is N, Y cannot be N; R 1a is R 1aa or R 1ba ; wherein: R 1aa is NR 32a R 33a ; R 1ba is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 ; R 2a is H, halo, C 1-2 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl or OC 1-2 haloalkyl; R 3a is H, halo, CH 3 , OCH 3 , CF 3 or OCF 3 ; wherein at least one of R 2a and R 3a is H; R 4a and R 5a are R 4aa and R 5aa , or R 4ba and R 5ba ; wherein: R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21a R 22a ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heterocycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29a ; or R 4ba and R 5ba are each independently H, C 1-6 alkyl, C 1-6 alkylOH, C 1-6 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, or R 4ba and R 5ba together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and when A a is -NHC(=O)- or -NHCH 2 -: R 4ba and R 5ba may additionally be selected from halo, OC 1-6 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl and NR 21a R 22a ; Ar1a is a 6-membered aryl or heteroaryl; Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A a ; R 10a is H, halo, C 1-3 alkyl, C 1-2 haloalkyl, OC 1-2 alkyl, OC 1-2 haloalkyl or CN; R 11a is H, F, Cl, C 1-2 alkyl, CF 3 , OCH 3 or CN; R 12a is attached to Ar2a in the ortho or meta position relative to Ar1a and R 12a is H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 3-5 cycloalkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, hydroxy, C 1-4 alkylOH, SO 2 C 1-2 alkyl, C(O)N(C 1-2 alkyl) 2 , NHC(O)C 1-3 alkyl or NR 23a R 24a ; and when A a is -NHC(=O)-, -NH- or -NHCH 2 -: R 12a may additionally be selected from CN, OCH 2 CH 2 N(CH 3 ) 2 and a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R 12a together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 13a is H or halo; R 21a is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl; R 22a is H or CH 3 ; R 23a is H or C 1-2 alkyl; and R 24a is H or C 1-2 alkyl; R 29a is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 ; R 32a is C 1-3 alkyl and R 33a is C 1-3 alkyl; or R 32a and R 33a together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; or a salt and / or solvate thereof .

[0042] Suitably, R 1c is R 1ac ; and / or R 4c and R 5c are R 4ac and R 5ac ; and / or A c is A ac .

[0043] The phrase 'A ba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-' means the following structures form:

[0044] Reference to R 4 and R 5 above includes variables R 4a , R 5a , R 4aa , R 5aa , R 4ba and R 5ba , and reference to Ar1 and Ar2 includes variables Ar1a and Ar2a.

[0045] The phrase 'A aa is an amine linker having the following structure: -CH 2 NH- or -NHCH 2 -' means the following structures form:

[0046] Reference to R 4 and R 5 above includes variables R 4a , R 5a , R 4aa , R 5aa , R 4ba and R 5ba , and reference to Ar1 and Ar2 includes variables Ar1a and Ar2a.

[0047] In one embodiment, A ba is -C(=O)NH-. In another embodiment, A ba is -NHC(=O)-. In an additional embodiment, A aa is -NH-. In a further embodiment, A aa is -CH 2 NH-. In another embodiment, A aa is -NHCH 2 -.

[0048] In one embodiment X is N. In another embodiment, X is CH.

[0049] In one embodiment, Y is N. In another embodiment, Y is CR 2a .

[0050] In one embodiment, Z is N. In another embodiment, Z is CR 3a .

[0051] Suitably, X is N, Y is CR 2a and Z is CR 3a . Alternatively, X is CH, Y is N and Z is CR 3a . Alternatively, X is CH, Y is CR 2a and Z is CR 3a . Alternatively, X is CH, Y is CR 22 and Z is N. Alternatively, X is N, Y is CR 2a and Z is N.

[0052] In one embodiment of the invention, R 1a is R 1aa , i.e. is NR 32a R 33a . In an embodiment R 32a is C 1-3 alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R 33a is C 1-3 alkyl, such as methyl or ethyl, e.g. methyl. Suitably, R 32a and R 33a are both methyl. Suitably, R 32a and R 33a are both ethyl. Suitably, R 32a is methyl and R 33a is ethyl.

[0053] In another embodiment, R 32a and R 33a together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl. Suitably, the C 3-5 heterocycloalkyl is aziridinyl, azetidinyl or pyrrolidinyl.

[0054] Suitably, R 1a is R 1ba .

[0055] In one embodiment of the invention R 1ba is C 1-5 alkyl. When R 1ba is C 1-5 alkyl, R 1ba may be methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or tert-butyl) or pentyl (e.g. n-pentyl, sec-pentyl or 3-pentyl).

[0056] In a second embodiment of the invention R 1ba is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 . In some embodiments, R 1ba is C 0-2 alkyleneC 3-5 cycloalkyl. In other embodiments, R 1ba is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is substituted by CH 3 . R 1ba may be C 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1ba may be C 1 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1ba may be C 2 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1ba may be C 0-2 alkyleneC 3 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1ba may be C 0-2 alkyleneC 4 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1ba may be C 0-2 alkyleneC 5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . Suitably, where C 0-2 alkyleneC 3-5 cycloalkyl is optionally substituted by CH 3 , the CH 3 is at the point of attachment of the C 3-5 cycloalkyl to the C 0-2 alkylene.

[0057] In a third embodiment, R 1ba is CF 3 .

[0058] Suitably R 1ba is cyclopropyl, cyclopropyl substituted by CH 3 at the point of attachment, cyclobutyl, CH 3 or CH 2 CH 3 . In particular R 1ba is cyclopropyl, cyclobutyl, CH 3 or CH 2 CH 3 , especially cyclopropyl.

[0059] In one embodiment, R 2a is H. In a second embodiment, R 2a is halo such as F, Cl or Br, e.g. Cl or Br. In a third embodiment, R 2a is C 1-2 alkyl. When R 2a is C 1-2 alkyl, R 2a may be methyl or ethyl, such as methyl. In a fourth embodiment, R 2a is OC 1-2 alkyl. When R 2a is OC 1-2 alkyl, may be OCH 3 or OEt, such as OCH 3 . In a fifth embodiment, R 2a is C 1-2 haloalkyl. When R 2a is C 1-2 haloalkyl, R 2a may be CF 3 or CH 2 CF 3 , such as CF 3 . In a sixth embodiment, R 2a is OC 1-2 haloalkyl. When R 2a is OC 1-2 haloalkyl, R 2a may be OCF 3 or OCH 2 CF 3 , such as OCF 3 .

[0060] Suitably, R 2a is H, CH 3 or CF 3 , such as H or CH 3 , in particular H.

[0061] In one embodiment R 3a is H. In a second embodiment R 3a is halo, in particular chloro or fluoro, especially fluoro. In a third embodiment, R 3a is CH 3 . In a fourth embodiment, R 3a is OCH 3 . In a fifth embodiment, R 3a is CF 3 . In a sixth embodiment, R 3a is OCF 3 .

[0062] Suitably, R 3a is H, halo in particular chloro or fluoro, especially fluoro, CH 3 or CF 3 . More suitably, R 3a is H or F, such as H.

[0063] Suitably, at least one of R 2a and R 3a is H.

[0064] In one embodiment, R 4a and R 5a are R 4aa and R 5aa .

[0065] Suitably, R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21a R 22a .

[0066] In one embodiment, the C 3-6 cycloalkyl is cyclopropyl. In another embodiment, the C 3-6 cycloalkyl is cyclobutyl. In another embodiment, the C 3-6 cycloalkyl is cyclopentyl. In another embodiment, the C 3-6 cycloalkyl is cyclohexyl.

[0067] In one embodiment the C 3-6 cycloalkyl is substituted by one substituent. In a second embodiment the C 3-6 cycloalkyl is substituted by two substituents.

[0068] In one embodiment, the substituent is C 1-3 alkyl. Suitably, the substituent is methyl. Suitably, the substituent is ethyl. Suitably, the substituent is n-propyl. Suitably, the substituent is iso-propyl.

[0069] In a second embodiment, the substituent is C 1-3 alkylOH. Suitably, the substituent is CH 2 OH. Suitably, the substituent is CH 2 CH 2 OH. Suitably, the substituent is CH 2 CH 2 CH 2 OH.

[0070] In a third embodiment, the substituent is C 1-3 haloalkyl. Suitably the C 1-3 alkyl group is substituted by one, two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is C 1 haloalkyl such as CF 3 . Suitably, the substituent is C 2 haloalkyl such as CH 2 CF 3 .

[0071] In a fourth embodiment, the substituent is C 0-2 alkyleneC 3-6 cycloalkyl, in particular C 0-2 alkyleneC 3-5 cycloalkyl, such as C 3-5 cycloalkyl, C 1 alkyleneC 3-5 cycloalkyl or C 2 alkyleneC 3-5 cycloalkyl.

[0072] In a fifth embodiment, the substituent is C 0-2 alkyleneC 3-6 heterocycloalkyl such as C 0-2 alkyleneC 3 heterocycloalkyl, C 0-2 alkyleneC 4 heterocycloalkyl, C 0-2 alkyleneC 5 heterocycloalkyl, C 0-2 alkyleneC 6 heterocycloalkyl, C 0 alkyleneC 3-6 heterocycloalkyl, C 1 alkyleneC 3-6 heterocycloalkyl and C 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0073] In a sixth embodiment, the substituent is C 1-3 alkyleneOC 1-3 alkyl, in particular C 1-2 alkyleneOC 1-2 alkyl such as C 1 alkyleneOC 1 alkyl, C 2 alkyleneOC 1 alkyl, C 1 alkyleneOC 2 alkyl or C 2 alkyleneOC 2 alkyl.

[0074] In a seventh embodiment, the substituent is halo, in particular fluoro or chloro such as chloro.

[0075] In an eighth embodiment, the substituent is OC 1-3 haloalkyl. Suitably the OC 1-3 alkyl group is substituted by one two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is OC 1 haloalkyl such as OCF 3 . Suitably, the substituent is OC 2 haloalkyl such as OCH 2 CF 3 .

[0076] In a ninth embodiment, the substituent is OC 0-2 alkyleneC 3-6 cycloalkyl, such as OC 3-6 cycloalkyl, OC 1 alkyleneC 3-6 cycloalkyl or OC 2 alkyleneC 3-6 cycloalkyl.

[0077] In a tenth embodiment, the substituent is OC 0-2 alkyleneC 3-6 heterocycloalkyl such as OC 0-2 alkyleneC 3 heterocycloalkyl, OC 0-2 alkyleneC 4 heterocycloalkyl, OC 0-2 alkyleneC 5 heterocycloalkyl, OC 0-2 alkyleneC 6 heterocycloalkyl, OC 0 alkyleneC 3-6 heterocycloalkyl, OC 1 alkyleneC 3-6 heterocycloalkyl and OC 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0078] In an eleventh embodiment, the substituent is OC 1-3 alkyl, such as OCH 3 or OCH 2 CH 3 .

[0079] In a twelfth embodiment, the substituent is NR 21a R 22a wherein R 21a and R 22a are defined elsewhere herein.

[0080] In an embodiment the substituent is oxo.

[0081] In another embodiment the substituent is OH.

[0082] Suitably, the one or two substituents, in particular one substituent, are independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, halo, OC 1-3 haloalkyl, OC 1-3 alkyl and NR 21a R 22a .

[0083] More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OC 1-3 alkyl and NR 21a R 22a .

[0084] Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro and NR 21a R 22a .

[0085] When the substituent is NR 21a R 22a , in one embodiment R 21a is H. In a second embodiment R 21a is C 1-5 alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R 21a is C(O)C 1-5 alkyl, such as C(O)CH 3 . In a fourth embodiment R 21a is C(O)OC 1-5 alkyl, such as C(O)OCH 3 or C(O)Otert-butyl. In a fifth embodiment R 21a is C 1-3 alkylOC 1-2 alkyl such as C 1 alkylOC 1 alkyl, C 2 alkylOC 1 alkyl or C 3 alkylOC 1 alkyl e.g. C 2 alkylOC 1 alkyl. In a sixth embodiment, R 21a is C 1-4 haloalkyl, such as CF 3 , CH 2 CF 3 or CH 2 CHF 2 e.g. CH 2 CHF 2 . In a seventh embodiment R 21a is C 4-6 heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

[0086] When the substituent is NR 21a R 22a , in one embodiment R 22a is H. In a second embodiment R 22a is methyl.

[0087] Suitably, R 21a is C(O)OCH 3 and R 22a is H. Suitably, R 21a is C(O)CH 3 and R 22a is H. Suitably, R 21a and R 22a are both CH 3 . Suitably, R 21a and R 22a are both H.

[0088] Alternatively, R 4aa and R 5aa suitably together with the carbon atom to which they are attached form a C 3-6 cycloalkyl and one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl.

[0089] In one embodiment the C 3-6 cycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C 3-6 cycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent being independently selected from the group consisting of C 1-2 alkyl or OCH 3 .

[0090] Suitably one of the carbons of the C 3-6 cycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached is a C 4-6 cycloalkyl. Suitably the further C 3-6 heterocycloalkyl is an oxygen containing C 3-6 heterocycloalkyl.

[0091] Alternatively, R 4aa and R 5aa suitably together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heterocycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl.

[0092] In one embodiment the C 3-6 heterocycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C 3-6 heterocycloalkyl formed by R 4aa and R 5aa together with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent being independently selected from the group consisting of C 1-2 alkyl or OCH 3 .

[0093] In an embodiment, R 4aa and R 5aa together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29a .

[0094] Suitably, the C 3-6 heterocycloalkyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.

[0095] Suitably, when the C 3-6 heterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:

[0096] The C 3-6 heterocycloalkyl may be other groups as defined elsewhere herein.

[0097] In an embodiment, R 29a is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 . In one embodiment, R 29a is C 1-3 alkyl such as methyl. In another embodiment, R 29a is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 . In some embodiments, R 29a is C 0-2 alkyleneC 3-5 cycloalkyl. In other embodiments, R 29a is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is substituted by CH 3 . R 29a may be C 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29a may be C 1 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29a may be C 2 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29a may be C 0-2 alkyleneC 3 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29a may be C 0-2 alkyleneC 4 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29a may be C 0-2 alkyleneC 5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . Suitably, where C 0-2 alkyleneC 3-5 cycloalkyl is optionally substituted by CH 3 , the CH 3 is at the point of attachment of the C 3-5 cycloalkyl to the C 0-2 alkylene. In another embodiment, R 29a is CF 3 . In another embodiment, R 29a is N(C 1-3 alkyl) 2 such as N(CH 3 ) 2 . In another embodiment, R 29a is a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is not substituted by methyl. In one embodiment, R 29a is a 5-membered heteroaryl such as pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, such as pyrazolyl. Suitably the pyrazolyl is substituted by methyl. In another embodiment, R 29a is a 6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0098] In another embodiment, R 4a and R 5a are R 4ba and R 5ba .

[0099] In one embodiment, R 4ba and R 5ba together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl in particular cyclopropyl or cyclopentyl. In a second embodiment, R 4ba and R 5ba together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl, such as a heterocyclohexyl, in particular a tetrahydropyranyl. Any nitrogen atom such as one nitrogen atom in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted. In a third embodiment, R 4ba is C 1-6 alkyl, in particular C 1-4 alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment, R 4ba is C 1-3 alkyleneOC 1-3 alkyl, in particular C 1-2 alkyleneOC 1-2 alkyl such as C 1 alkyleneOC 1 alkyl, C 2 alkyleneOC 1 alkyl, C 1 alkyleneOC 2 alkyl or C 2 alkyleneOC 2 alkyl. In a fifth embodiment, R 4ba is H. In a sixth embodiment, R 4ba is halo, such as chloro or fluoro, especially fluoro. In a seventh embodiment, R 4ba is C 1-6 haloalkyl, such as CF 3 or CH 2 CF 3 . In an eighth embodiment, R 4ba is C 0-2 alkyleneC 3-6 cycloalkyl such as C 3-6 cycloalkyl, C 1 alkyleneC 3-6 cycloalkyl, C 2 alkyleneC 3-6 cycloal kyl, C 0-2 alkyleneC 3 cycloalkyl, C 0-2 alkyleneC 4 cycloalkyl, C 0-2 alkyleneC 5 cycloalkyl or C 0-2 alkyleneC 6 cycloalkyl. In a ninth embodiment, R 4ba is C 0-2 alkyleneC 3-6 heterocycloalkyl such as C 3-6 heterocycloalkyl, C 1 alkyleneC 3-6 heterocycloalkyl, C 2 alkyleneC 3-6 heterocycloalkyl, C 0-2 alkyleneC 3 heterocycloalkyl, C 0-2 alkyleneC 4 hetero-cycloalkyl, C 0-2 alkyleneC 5 heterocycloalkyl or C 0-2 alkyleneC 6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted. In a tenth embodiment, R 4ba is C 1-6 alkylOH, such as CH 2 OH or CH 2 CH 2 OH. In an eleventh embodiment, R 4ba is OC 1-6 haloalkyl, such as OC 1-4 haloalkyl, such as OCF 3 or OCHF 2 . In a twelfth embodiment, R 4ba is OC 0-2 alkyleneC 3-6 cycloalkyl such as OC 3-6 cycloalkyl, OC 1 alkyleneC 3-6 cycloalkyl, OC 2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3 cycloalkyl, OC 0-2 alkyleneC 4 cycloalkyl, OC 0-2 alkyleneC 5 cycloalkyl or OC 0-2 alkyleneC 6 cycloalkyl. In a thirteenth embodiment, R 4ba is OC 1-6 alkyl, in particular OC 1-4 alkyl such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a fourteenth embodiment, R 4ba is OC 0-2 alkyleneC 3-6 heterocycloalkyl such as OC 3-6 heterocycloalkyl, OC 1 alkyleneC 3-6 heterocycloalkyl, OC 2 alkyleneC 3-6 heterocycloalkyl, OC 0-2 alkyleneC 3 heterocycloalkyl, OC 0-2 alkyleneC 4 hetero-cycloalkyl, OC 0-2 alkyleneC 5 heterocycloalkyl or OC 0-2 alkyleneC 6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted. In a fifteenth embodiment, R 4ba is NR 21a R 22a .

[0100] When A a is -NHC(=O)- or -C(=O)NH-, suitably, R 4ba is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyIOH, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, or R 4ba and R 5ba together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl. When A a is -NHC(=O)-, suitably R 4ba may additionally be selected from halo, OC 1-6 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl or NR 21a R 22a .

[0101] When A a is -NH-, -CH 2 NH- or -NHCH 2 -, suitably, R 4ba is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylOH, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, or R 4ba and R 5ba together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl. When A a is -NHCH 2 -, suitably R 4ba may additionally be selected from halo, OC 1-6 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl or NR 21a R 22a .

[0102] Suitably R 4ba is H, fluoro, CH 3 , ethyl, OCH 3 or CH 2 CH 2 OCH 3 , such as fluoro, ethyl, OCH 3 or CH 2 CH 2 OCH 3 .

[0103] Suitably R 4ba is H, CH 3 , ethyl or CH 2 CH 2 OCH 3 , in particular CH 3 or ethyl.

[0104] Suitably R 4ba and R 5ba together with the carbon atom to which they are attached form a cyclopropyl or cyclopentyl, in particular a cyclopentyl.

[0105] Suitably R 4ba and R 5ba together with the carbon atom to which they are attached form a heterocyclohexyl, such as tetrahydropyranyl or piperidinyl, especially tetrahydropyranyl. Any nitrogen atom such as one nitrogen atom in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0106] Suitably R 4ba and R 5ba together with the carbon atom to which they are attached form a heterocyclobutyl, such as azetidinyl. Any nitrogen atom such as one nitrogen atom in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0107] When R 4ba is NR 21a R 22a , in one embodiment R 21a is H. In a second embodiment R 21a is C 1-5 alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R 21a is C(O)C 1-5 alkyl, such as C(O)CH 3 . In a fourth embodiment R 21a is C(O)OC 1-5 alkyl, such as C(O)OCH 3 or C(O)Otert-butyl. In a fifth embodiment R 21a is C 1-3 alkylOC 1-2 alkyl such as C 1 alkylOC 1 alkyl, C 2 alkylOC 1 alkyl or C 3 alkylOC 1 alkyl e.g. C 2 alkylOC 1 alkyl. In a sixth embodiment, R 21a is C 1-4 haloalkyl, such as CF 3 , CH 2 CF 3 or CH 2 CHF 2 e.g. CH 2 CHF 2 . In a seventh embodiment R 21a is C 4-6 heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

[0108] When R 4ba is NR 21a R 22a , in one embodiment R 22a is H. In a second embodiment R 22a is methyl.

[0109] For example, R 4ba is NH 2 , N(CH 3 ) 2 , NHC(O)CH 3 , NHC(O)OCH 3 , NHC(O)Otert-butyl and CH 2 CH 2 OH, especially, N(CH 3 ) 2 , NHC(O)CH 3 , NHC(O)OCH 3 .

[0110] Suitably, R 21a is C(O)OCH 3 and R 22a is H. Suitably, R 21a is C(O)CH 3 and R 22a is H. Suitably, R 21a and R 22a are both CH 3 . Suitably, R 21a and R 22a are both H.

[0111] In one embodiment R 5ba is C 1-6 alkyl, in particular C 1-4 alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a second embodiment R 5b , is C 1-3 alkyleneOC 1-3 alkyl, in particular C 1-2 alkyleneOC 1-2 alkyl such as C 1 alkyleneOC 1 alkyl, C 2 alkyleneOC 1 alkyl, C 1 alkyleneOC 2 alkyl or C 2 alkyleneOC 2 alkyl. In a third embodiment R 5ba is H. In a fourth embodiment, R 5ba is halo, such as chloro or fluoro, especially fluoro. In a fifth embodiment, R 5ba is C 1-6 haloalkyl, such as CF 3 or CH 2 CF 3 . In a sixth embodiment, R 5ba is C 0-2 alkyleneC 3-6 cycloalkyl such as C 3-6 cycloalkyl, C 1 alkyleneC 3-6 cycloalkyl, C 2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3 cycloalkyl, C 0-2 alkyleneC 4 cycloalkyl, C 0-2 alkyleneC 5 cycloalkyl or C 0-2 alkyleneC 6 cycloalkyl. In a seventh embodiment, R 5ba is C 0-2 alkyleneC 3-6 heterocycloalkyl such as C 3-6 heterocycloalkyl, C 1 alkyleneC 3-6 heterocycloalkyl, C 2 alkyleneC 3-6 heterocycloalkyl, C 0-2 alkyleneC 3 heterocycloalkyl, C 0-2 alkyleneC 4 hetero-cycloalkyl, C 0-2 alkyleneC 5 heterocycloalkyl or C 0-2 alkyleneC 6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted. In an eighth embodiment, R 5ba is C 1-6 alkylOH, such as CH 2 OH or CH 2 CH 2 OH. In a ninth embodiment, R 5ba is OC 1-6 haloalkyl, such as OC 1-4 haloalkyl, such as OCF 3 or OCHF 2 . In a tenth embodiment, R 5ba is OC 0-2 alkyleneC 3-6 cycloalkyl such as OC 3-6 cycloalkyl, OC 1 alkyleneC 3-6 cycloalkyl, OC 2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3 cycloalkyl, OC 0-2 alkyleneC 4 cycloalkyl, OC 0-2 alkyleneC 5 cycloalkyl or OC 0-2 alkyleneC 6 cycloalkyl. In an eleventh embodiment, R 5ba is OC 1-6 alkyl, in particular OC 1-4 alkyl such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a twelfth embodiment, R 5ba is OC 0-2 alkyleneC 3-6 heterocycloalkyl such as OC 3-6 heterocycloalkyl, OC 1 alkyleneC 3-6 heterocycloalkyl, OC 2 alkyleneC 3-6 heterocycloalkyl, OC 0-2 alkyleneC 3 heterocycloalkyl, OC 0-2 alkyleneC 4 hetero-cycloalkyl, OC 0-2 alkyleneC 5 heterocycloalkyl or OC 0-2 alkyleneC 6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted. In a thirteenth embodiment, R 5ba is NR 21a R 22a .

[0112] When A a is -NHC(=O)- or -C(=O)NH-, suitably, R 5ba is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylOH, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, or R 4ba and R 5ba together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl. When A a is -NHC(=O)-, suitably R 5ba may additionally be selected from halo, OC 1-6 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl or NR 21a R 22a .

[0113] When A a is -NH-, -CH 2 NH- or -NHCH 2 -, suitably, R 5ba is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylOH, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, or R 4ba and R 5ba together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl. When A a is -NHCH 2 -, suitably R 5ba may additionally be selected from halo, OC 1-6 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl or NR 21a R 22a .

[0114] When R 5ba is NR 21a R 22a , in one embodiment R 21a is H. In a second embodiment R 21a is C 1-5 alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R 21a is C(O)C 1-5 alkyl, such as C(O)CH 3 . In a fourth embodiment R 21a is C(O)OC 1-5 alkyl, such as C(O)OCH 3 or C(O)Otert-butyl. In a fifth embodiment R 21a is C 1-3 alkylOC 1-2 alkyl such as C 1 alkylOC 1 alkyl, C 2 alkylOC 1 alkyl or C 3 alkylOC 1 alkyl e.g. C 2 alkylOC 1 alkyl. In a sixth embodiment, R 21a is C 1-4 haloalkyl, such as CF 3 , CH 2 CF 3 or CH 2 CHF 2 e.g. CH 2 CHF 2 . In a seventh embodiment R 21a is C 4-6 heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

[0115] When R 5ba is NR 21a R 22a , in one embodiment R 22a is H. In a second embodiment R 22a is methyl.

[0116] For example, R 5ba is NH 2 , N(CH 3 ) 2 , NHC(O)CH 3 , NHC(O)OCH 3 , NHC(O)Otert-butyl and CH 2 CH 2 OH, especially, N(CH 3 ) 2 , NHC(O)CH 3 , NHC(O)OCH 3 .

[0117] Suitably, R 21a is C(O)OCH 3 and R 22a is H. Suitably, R 21a is C(O)CH 3 and R 22a is H. Suitably, R 21a and R 22a are both CH 3 . Suitably, R 21a and R 22a are both H.

[0118] Suitably R 5ba is H, F, CH 3 or ethyl such as H, CH 3 or ethyl.

[0119] Suitably R 4ba is H, CH 3 , ethyl or CH 2 CH 2 OCH 3 and R 5ba is H, CH 3 or ethyl, in particular R 4ba is CH 3 , or ethyl and R 5ba is H, methyl or ethyl. For example, R 4ba and R 5ba are H, R 4ba and R 5ba are methyl, R 4ba and R 5ba are ethyl or R 4ba is CH 2 CH 2 OCH 3 and R 5ba is H.

[0120] Suitably, R 4ba is F and R 5ba is ethyl.

[0121] Suitably, R 4ba is F and R 5ba is F.

[0122] Suitably, R 4ba is ethyl and R 5ba is H.

[0123] Suitably R 4ba and R 5ba are arranged in the following configuration: wherein R 4 and R 5 include variables R 4a , R 5a , R 4aa , R 5aa , R 4ba and R 5ba .

[0124] In one embodiment Ar1a is a 6-membered aryl, i.e. phenyl. In a second embodimentAr1a is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).

[0125] In particular Ar1a is phenyl, 2-pyridyl or 3-pyridyl, such as phenyl or 2-pyridyl.

[0126] In one embodiment R 10a is H. In a second embodiment R 10a is halo, for example fluoro or chloro. In a third embodiment R 10a is C 1-3 alkyl such as C 1-2 alkyl, such as CH 3 or ethyl. In a fourth embodiment R 10a is OC 1-2 alkyl, such as OCH 3 or ethoxy. In a fifth embodiment R 10a is OC 1-2 haloalkyl, such as OCF 3 . In a sixth embodiment R 10a is CN. In a seventh embodiment, R 10a is C 1-2 haloalkyl such as CF 3 .

[0127] Suitably R 10a is H, fluoro, chloro, CH 3 , CF 3 , OCH 3 , OCF 3 or CN, such as H, fluoro, chloro, CH 3 , OCH 3 , OCF 3 or CN, in particular H, fluoro, chloro, OCH 3 , OCF 3 or CN especially H or fluoro.

[0128] Suitably, R 10a is H, F or CH 3 .

[0129] In one embodiment R 11a is H. In a second embodiment R 11a is F. In a third embodiment, R 11a is C 1-2 alkyl such as CH 3 or Et, such as CH 3 . In a fourth embodiment R 11a is OCH 3 . In a fifth embodiment, R 11a is Cl. In a sixth embodiment, R 11a is Et. In a seventh embodiment, R 11a is CF 3 . In an eighth embodiment, R 11a is CN.

[0130] Suitably, R 11a is H, F, CH 3 or OCH 3 , such as H, For CH 3 , such as H or F, such as H.

[0131] In one embodiment, R 10a is in the ortho position with respect to group Aa. In another embodiment, R 10a is in the meta position with respect to group Aa. Suitably R 10a is in the ortho position with respect to group Aa.

[0132] In one embodiment, R 11a is in the ortho position with respect to group Aa. In another embodiment, R 11a is in the meta position with respect to group Aa. Suitably R 11a is in the ortho position with respect to group Aa.

[0133] In one embodiment Ar2a is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar2a is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).

[0134] In particular Ar2a is 3-pyridyl or 2,5-pyrazinyl, especially 2,5-pyrazinyl.

[0135] In one embodiment R 12a is H. In a second embodiment R 12a is halo, for example fluoro or chloro. In a third embodiment R 12a is C 1-4 alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment R 12a is OC 1-4 alkyl, such as OCH 3 , ethoxy, isopropoxy or n-propoxy. In a fifth embodiment R 12a is OC 0-2 alkyleneC 3-5 cycloalkyl, such as OC 3-5 cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC 1 alkyleneC 3-5 cycloalkyl or OC 2 alkyleneC 3-5 cycloalkyl. In a sixth embodiment R 12a is CN. In a seventh embodiment R 12a is C 1-4 haloalkyl, such as CF 3 . In an eighth embodiment R 12a is OC 1-4 haloalkyl, such as OCF 3 , OCHF 2 or OCH 2 CF 3 . In a ninth embodiment, R 12a is C 2-4 alkenyl such as C(=CH 2 )CH 3 . In a tenth embodiment, R 12a is C 0-2 alkyleneC 3-5 cycloalkyl such as C 3-5 cycloalkyl, C 1 alkyleneC 3-5 cycloalkyl, C 2 alkyleneC 3-5 cycloalkyl, C 0-2 alkyleneC 3 cycloalkyl, C 0-2 alkyleneC 4 cycloalkyl or C 0-2 alkyleneC 5 cycloalkyl. In an eleventh embodiment, R 12a is hydroxy. In a twelfth embodiment, R 12a is C 1-4 alkylOH such as CH 2 OH. In a thirteenth embodiment, R 12a is SO 2 C 1-2 alkyl such as SO 2 CH 3 . In a fourteenth embodiment, R 12a is C(O)N(C 1-2 alkyl) 2 such as C(O)N(CH 3 ) 2 . In a fifteenth embodiment, R 12a is NHC(O)C 1-3 alkyl. In a sixteenth embodiment, R 12a is NR 23a R 24a . In a seventeenth embodiment, R 12a is OCH 2 CH 2 N(CH 3 ) 2 . In an eighteenth embodiment, R 12a is a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is pyrrolidinyl. Suitably, the heterocyclohexyl ring is piperidinyl or piperazinyl. Any nitrogen atom such as one nitrogen atom in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted. In a nineteenth embodiment, R 12a together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ).

[0136] When Aa is -NHC(=O)- or -C(=O)NH-, suitably, R 12a is attached to Ar2a in the ortho or meta position relative to Ar1a and R 12a is H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 3-5 cycloalkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, hydroxy, C 1-4 alkylOH, SO 2 C 1-2 alkyl, C(O)N(C 1-2 alkyl) 2 , NHC(O)C 1-3 alkyl or NR 23a R 24a .

[0137] When Aa is -NHC(=O)-, suitably R 12a may additionally be selected from CN, OCH 2 CH 2 N(CH 3 ) 2 and a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R 12a together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ).

[0138] When Aa is -NH-, -CH 2 NH- or -NHCH 2 -, suitably, R 12a is attached to Ar2a in the ortho or meta position relative to Ar1a and R 12a is H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 3-5 cycloalkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, hydroxy, C 1-4 alkylOH, SO 2 C 1-2 alkyl, C(O)N(C 1-2 alkyl) 2 , NHC(O)C 1-3 alkyl or NR 23a R 24a .

[0139] When Aa is -NH- or -NHCH 2 -, suitably R 12a may additionally be selected from CN, OCH 2 CH 2 N(CH 3 ) 2 and a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R 12a together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ).

[0140] R 12a is suitably H, F, Cl, CH 3 , OCH 3 , OEt, OiPr, OCyclopropyl, CN, CF 3 , OCHF 2 or OCH 2 CF 3 . In particular, R 12a is Cl, CN, CF 3 , OCHF 2 , OCH 2 CF 3 , OCH 3 , OEt, OiPr, OCyclopropyl, such as CF 3 , OCHF 2 , OCH 2 CF 3 , OCH 3 , OEt, OiPr, OCyclopropyl, e.g. OEt.

[0141] R 12a is suitably H, F, Cl, CH 3 , iPr, OCH 3 , OEt, OiPr, OCyclopropyl, CN, CF 3 , OCHF 2 , OCH 2 CF 3 , C 3 cycloalkyl or C(=CH 2 )CH 3 . In particular, R 12a is Cl, iPr, OCH 3 , OEt, OiPr, OCyclopropyl, CN, CF 3 , OCHF 2 , OCH 2 CF 3 , C 3 cycloalkyl or C(=CH 2 )CH 3 , such as Cl, OCH 3 , OEt, OiPr, OCyclopropyl, CF 3 , OCHF 2 , OCH 2 CF 3 or C 3 cycloalkyl, e.g. OEt.

[0142] When Aa is -C(=O)NH-, suitably R 12a is CF 3 , OEt or OiPr, such as OEt or OiPr.

[0143] Suitably R 12a is in the meta position of Ar2a. Alternatively, R 12a is in the ortho position of Ar2a.

[0144] In one embodiment, R 13a is H. In another embodiment, R 13a is halo such as F or Cl, suitably F.

[0145] In one embodiment, R 13a is in the ortho position with respect to Ar1a. In another embodiment, R 13a is in the para position with respect to Ar1a. In another embodiment, R 13a is in the meta position with respect to Ar1a.

[0146] In one embodiment, R 23a is H. In another embodiment, R 23a is C 1-2 alkyl such as methyl.

[0147] In one embodiment, R 24a is H. In another embodiment R 24a is C 1-2 alkyl such as methyl.

[0148] Suitably, R 23a is H and R 24a is ethyl. Suitably, R 23a is CH 3 and R 24a is CH 3 .

[0149] Desirably, a compound of formula (I) does not include 2-(6-(methylsulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetamide.

[0150] In one embodiment, at least one of R 10a , R 11a , R 12a and R 13a is other than H.

[0151] Suitably, at least one of R 4a , R 5a , R 10a , R 11a , R 12a and R 13a is other than H.

[0152] More suitably, when R 1a is methyl, at least one of R 4a , R 5a , R 10a , R 11a , R 12a and R 13a is other than H.

[0153] The present invention provides the compounds described in any one of Examples P226, P227, P228, P229, P230, P235, P242, P244, P248, P251, P254, P255, P256, P258, P260 and P261.

[0154] The present invention also provides the compounds described in any one of Examples P288, P289, P290, P291, P292, P293, P294, P295, P296, P297, P298, P299, P300, P301, P302, P303, P304, P305, P306, P307, P308, P309, P310, P311, P312, P313, P314, P315, P316, P317 and P318.

[0155] The present invention provides the following compounds: 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-oxocyclohexanecarboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 2); N-(4-(1-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4,4-difluorocyclohexane-1-carboxamide; 8-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide; 4-(2-((N,N-dimethylsulfamoyl)amino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; N-(4-(1-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide; N-(4-(1-((4-(6-ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide; N-(4-(4-(((4-(6-ethoxypyrazin-2-yl)phenyl)amino)methyl)tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl)cyclopropanesulfonamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-5,8-dioxaspiro[3.4]octane-2-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide; and N-(4-(1-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamidearboxamide.

[0156] The present invention also provides the following compounds: 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(N,N-dimethylsulfamoyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-((trifluoromethyl)sulfonyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide; 1-(cyanomethyl)-4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; ethyl 2-(4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)piperidin-1-yl)acetate; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; 1-(Cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide; 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide (diastereomer 1); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide (diastereomer 2); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 2); 4-amino-1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(methyl(oxetan-3-yl)amino)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((2,2-difluoroethyl)(methyl)amino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide (diastereomer 2); 4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; and 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide. Compounds of formula (I-b)

[0157] The invention provides a compound of formula (I-b): wherein A b is A ab or A bb ; A ab is -NR 6b CH 2 - or -NR 6b -; A bb is -NR 6b C(=O)-; R 1b is R 1ab or R 1bb , wherein: R 1ab is NR 32b R 33b ; R 1bb is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R 3b is H, halo, CH 3 , OC 1-2 alkyl or CF 3 ; or R 3b together with R 5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R 4b and R 5b are either R 4ab and R 5ab or R 4bb and R 5bb ; wherein: R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21b R 22b ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heteroycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29b ; or R 4bb and R 5bb are each independently H, halo, C 1-6 alkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-6 alkylOH, C 1-6 haloalkyl, OC 1-6 haloalkyl or NR 21b R 22b , or R 4bb is H and R 5bb together with R 3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, or R 4bb and R 5bb together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, or R 4bb is H and R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring; or R 4bb is O and R 5bb is absent; R 6b is H or C 1-3 alkyl, or R 6b together with R 11b when in the ortho-position to group A b are a C 2 alkylene chain forming a 5-membered ring, or R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring and R 4bb is H; Ar1b is 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A b ; R 10b is H, halo, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN; R 11b is H, F, Cl, CH 3 , ethyl, OCH 3 , CF 3 , OCF 3 or CN, or R 11b , when in the ortho-position to group A b , together with R 6b are a C 2 alkylene chain forming a 5-membered ring; R 12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R 12b is H, halo, C 1-4 alkyl, C 2-4 alkynyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 3-5 cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , OH, C 1-4 alkylOH, CN, C 1-3 alkyleneOC 1-3 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, C(=O)C 1-2 alkyl, NR 23b R 24b , SO 2 C 1-4 alkyl, SOC 1-4 alkyl, SC 1-4 alkyl, SH, C(O)N(CH 3 ) 2 , NHC(O)C 1-3 alkyl, C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R 12b together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 13b is H, halo, CH 3 or OCH 3 ; R 21b is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl, C 1-3 alkylOC 1-2 alkyl, C 1-4 haloalkyl, or C 4-6 heterocycloalkyl; R 22b is H or CH 3 ; R 23b is H or C 1-2 alkyl; R 24b is H or C 1-2 alkyl; R 29b is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , CF 3 , N(C 1-3 alkyl) 2 , or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and R 32b is C 1-3 alkyl and R 33b is C 1-3 alkyl; or R 32b and R 33b together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; or a salt and / or solvate thereof.

[0158] Suitably, R 1b is R 1ab ; and / or R 4b and R 5b are R 4ab and R 5ab ; and / or A is A ab .

[0159] The invention also provides a compound of formula (I-b): wherein A b is A ab or A bb ; A ab is -NR 6b CH 2 - or -NR 6b -; A bb is -NR 6b C(=O)-; R 1b is R 1ab or R 1bb , wherein: R 1ab is NR 32b R 33b ; R 1bb is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R 3b is H, halo, CH 3 , OC 1-2 alkyl or CF 3 ; or R 3b together with R 5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R 4b and R 5b are either R 4ab and R 5ab or R 4bb and R 5bb ; wherein: R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21b R 22b ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heteroycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29b ; or R 4bb and R 5bb are each independently H, halo, C 1-6 alkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-6 alkylOH, C 1-6 haloalkyl, OC 1-6 haloalkyl or NR 21b R 22b , or R 4bb is H and R 5bb together with R 3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, or R 4bb and R 5bb together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, or R 4bb is H and R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring; or R 4bb is O and R 5bb is absent; R 6b is H or C 1-3 alkyl, or R 6b together with R 11b when in the ortho-position to group A b are a C 2 alkylene chain forming a 5-membered ring, or R 5pp and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring and R 4bb is H; Ar1b is 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A b ; R 10b is H, halo, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN; R 11b is H, F, Cl, CH 3 , ethyl, OCH 3 , CF 3 , OCF 3 or CN, or R 11b , when in the ortho-position to group A b , together with R 6b are a C 2 alkylene chain forming a 5-membered ring; R 12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R 12b is H, halo, C 1-4 alkyl, C 2-4 alkynyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 3-5 cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , OH, C 1-4 alkylOH, CN, C 1-3 alkyleneOC 1-3 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, C(=O)C 1-2 alkyl, NR 23b R 24b , SO 2 C 1-4 alkyl, SOC 1-4 alkyl, SC 1-4 alkyl, SH, C(O)N(CH 3 ) 2 , NHC(O)C 1-3 alkyl, C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R 12b together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 13b is H, halo, CH 3 or OCH 3 ; R 21b is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl; R 22b is H or CH 3 ; R 23b is H or C 1-2 alkyl; R 24b is H or C 1-2 alkyl; R 29b is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 ; and R 32b is C 1-3 alkyl and R 33b is C 1-3 alkyl; or R 32b and R 33b together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; or a salt and / or solvate thereof.

[0160] Suitably, R 1b is R 1ab ; and / or R 4b and R 5b are R 4ab and R 5ab ; and / or A is A ab .

[0161] In one embodiment of the invention, R 1b is R 1ab , i.e. is NR 32b R 33b . In an embodiment, R 32b is C 1-3 alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R 33b is C 1-3 alkyl, such as methyl or ethyl, e.g. methyl. Suitably, R 32b and R 33b are both methyl. Suitably, R 32b and R 33b are both ethyl. Suitably, R 32b is methyl and R 33b is ethyl.

[0162] In another embodiment, R 32b and R 33b together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl. Suitably, the C 3-5 heterocycloalkyl is aziridinyl, azetidinyl or pyrrolidinyl.

[0163] Suitably, R 1b is R 1bb .

[0164] In one embodiment of the invention R 1bb is C 1-5 alkyl. When R 1bb is C 1-5 alkyl, R 1bb may be methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or tert-butyl) or pentyl (e.g. n-pentyl, sec-pentyl or 3-pentyl). Suitably, when R 1bb is C 1-5 alkyl, R 1bb may be methyl, ethyl, propyl (e.g. isopropyl) or butyl (e.g. sec-butyl or tert-butyl), especially methyl, ethyl or isopropyl and in particular methyl.

[0165] In a second embodiment of the invention R 1bb is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 . In some embodiments, R 1bb is C 0-2 alkyleneC 3-5 cycloalkyl. In other embodiments, R 1bb is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is substituted by CH 3 . R 1bb may be C 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bb may be C 1 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bb may be C 2 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bb may be C 0-2 alkyleneC 3 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bb may be C 0-2 alkyleneC 4 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bb may be C 0-2 alkyleneC 5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . Suitably, where C 0-2 alkyleneC 3-5 cycloalkyl is optionally substituted by CH 3 , the CH 3 is at the point of attachment of the C 3-5 cycloalkyl to the C 0-2 alkylene.

[0166] In a third embodiment of the invention R 1bb is CF 3 .

[0167] In a fourth embodiment of the invention R 1bb is C 1-3 alkyleneOC 1-2 alkyl such as C 1-2 alkyleneOC 1-2 alkyl. When R 1bb is C 1-3 alkyleneOC 1-2 alkyl, R 1bb may be methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl or propoxyethyl. When R 1bb is C 1-2 alkyleneOC 1-2 alkyl, R 1bb may be methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl.

[0168] Suitably R 1bb is cyclopropyl, cyclopropyl substituted by CH 3 at the point of attachment, cyclobutyl, CH 3 , isopropyl, sec-butyl, tert-butyl or CF 3 . In particular R 1bb is cyclopropyl, cyclopropyl substituted by CH 3 at the point of attachment, cyclobutyl, CH 3 , isopropyl, sec-butyl or tert-butyl, especially cyclopropyl, cyclopropyl substituted by CH 3 at the point of attachment, cyclobutyl or isopropyl, such as cyclopropyl or cyclopropyl substituted by CH 3 at the point of attachment.

[0169] Additionally of interest is when R 1bb is cyclopentyl, methyl, ethyl, cyclopropylmethylene and methoxyethyl, in particular cyclopentyl, methyl, ethyl and cyclopropylmethylene, especially ethyl and methyl, such as methyl.

[0170] Consequently, suitably R 1bb is cyclopropyl, cyclopropyl substituted by CH 3 at the point of attachment, cyclopropylmethylene, cyclobutyl, cyclopentyl, CH 3 , ethyl, isopropyl, sec-butyl, tert-butyl, methoxyethyl or CF 3 . In particular R 1bb is cyclopropyl, cyclopropyl substituted by CH 3 at the point of attachment, cyclopropylmethylene, cyclobutyl, cyclopentyl, CH 3 , ethyl, isopropyl, sec-butyl or tert-butyl, especially cyclopropyl, cyclopropyl substituted by CH 3 at the point of attachment, cyclobutyl, CH 3 , ethyl or isopropyl, such as cyclopropyl, cyclopropyl substituted by CH 3 at the point of attachment, ethyl or methyl such as cyclopropyl, cyclopropyl substituted by CH 3 at the point of attachment or methyl.

[0171] In one embodiment R 3b is H. In a second embodiment R 3b is halo, in particular chloro or fluoro, especially chloro. In a third embodiment R 3b is CH 3 . In a fourth embodiment R 3b is CF 3 . In a fifth embodiment R 3b together with R 5bb forms a 5- or 6-membered cycloalkyl, in particular a 5-membered cycloalkyl. In a sixth embodiment R 3b is OC 1-2 alkyl such as OCH 3 . In a seventh embodiment R 3b together with R 5bb forms a 5- or 6-membered oxygen-containing heterocycloalkyl, in particular a 5-membered heterocycloalkyl.

[0172] The phrase 'R 3b together with R 5bb forms a 5- or 6-membered cycloalkyl' means that compounds with the following exemplary substructure are formed:

[0173] The phrase 'R 3b together with R 5bb forms a 5- or 6-membered oxygen containing heterocycloalkyl' means that compounds with the following substructure are formed:

[0174] In particular R 3b is H, CH 3 or R 3b together with R 5bb forms a 5- or 6-membered cycloalkyl, especially H, CH 3 or R 3b together with R 5bb forms a 5-membered cycloalkyl, such as R 3b is H or CH 3 , e.g. H.

[0175] In one embodiment, R 4b and R 5b are R 4ab and R 5ab .

[0176] Suitably, R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21b R 22b .

[0177] In one embodiment, the C 3-6 cycloalkyl is cyclopropyl. In another embodiment, the C 3-6 cycloalkyl is cyclobutyl. In another embodiment, the C 3-6 cycloalkyl is cyclopentyl. In another embodiment, the C 3-6 cycloalkyl is cyclohexyl.

[0178] In one embodiment the C 3-6 cycloalkyl is substituted by one substituent. In a second embodiment the C 3-6 cycloalkyl is substituted by two substituents.

[0179] In one embodiment, the substituent is C 1-3 alkyl. Suitably, the substituent is methyl. Suitably, the substituent is ethyl. Suitably, the substituent is n-propyl. Suitably, the substituent is iso-propyl.

[0180] In a second embodiment, the substituent is C 1-3 alkylOH. Suitably, the substituent is CH 2 OH. Suitably, the substituent is CH 2 CH 2 OH. Suitably, the substituent is CH 2 CH 2 CH 2 OH.

[0181] In a third embodiment, the substituent is C 1-3 haloalkyl. Suitably the C 1-3 alkyl group is substituted by one two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is C 1 haloalkyl such as CF 3 . Suitably, the substituent is C 2 haloalkyl such as CH 2 CF 3 .

[0182] In a fourth embodiment, the substituent is C 0-2 alkyleneC 3-6 cycloalkyl, in particular C 0-2 alkyleneC 3-5 cycloalkyl, such as C 3-5 cycloalkyl, C 1 alkyleneC 3-5 cycloalkyl or C 2 alkyleneC 3-5 cycloalkyl.

[0183] In a fifth embodiment, the substituent is C 0-2 alkyleneC 3-6 heterocycloalkyl such as C 0-2 alkyleneC 3 heterocycloalkyl, C 0-2 alkyleneC 4 heterocycloalkyl, C 0-2 alkyleneC 5 heterocycloalkyl, C 0-2 alkyleneC 6 heterocycloalkyl, C 0 alkyleneC 3-6 heterocycloalkyl, C 1 alkyleneC 3-6 heterocycloalkyl and C 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0184] In a sixth embodiment, the substituent is C 1-3 alkyleneOC 1-3 alkyl, in particular C 1-2 alkyleneOC 1-2 alkyl such as C 1 alkyleneOC 1 alkyl, C 2 alkyleneOC 1 alkyl, C 1 alkyleneOC 2 alkyl or C 2 alkyleneOC 2 alkyl.

[0185] In a seventh embodiment, the substituent is halo, in particular fluoro or chloro such as chloro.

[0186] In an eighth embodiment, the substituent is OC 1-3 haloalkyl. Suitably the OC 1-3 alkyl group is substituted by one two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is OC 1 haloalkyl such as OCF 3 . Suitably, the substituent is OC 2 haloalkyl such as OCH 2 CF 3 .

[0187] In a ninth embodiment, the substituent is OC 0-2 alkyleneC 3-6 cycloalkyl, such as OC 3-6 cycloalkyl, OC 1 alkyleneC 3-6 cycloalkyl or OC 2 alkyleneC 3-6 cycloalkyl.

[0188] In a tenth embodiment, the substituent is OC 0-2 alkyleneC 3-6 heterocycloalkyl such as OC 0-2 alkyleneC 3 heterocycloalkyl, OC 0-2 alkyleneC 4 heterocycloalkyl, OC 0-2 alkyleneC 5 heterocycloalkyl, OC 0-2 alkyleneC 6 heterocycloalkyl, OC 0 alkyleneC 3-6 heterocycloalkyl, OC 1 alkyleneC 3-6 heterocycloalkyl and OC 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0189] In an eleventh embodiment, the substituent is OC 1-3 alkyl, such as OCH 3 or OCH 2 CH 3 .

[0190] In a twelfth embodiment, the substituent is NR 21b R 22b .

[0191] In one embodiment R 21b is H. In a second embodiment R 21b is C 1-5 alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R 21b is C(O)C 1-5 alkyl, such as C(O)CH 3 . In a fourth embodiment R 21b is C(O)OC 1-5 alkyl, such as C(O)OCH 3 or C(O)Otert-butyl. In a fifth embodiment R 21b is C 1-3 alkylOC 1-2 alkyl such as C 1 alkylOC 1 alkyl, C 2 alkylOC 1 alkyl or C 3 alkylOC 1 alkyl e.g. C 2 alkylOC 1 alkyl. In a sixth embodiment, R 21b is C 1-4 haloalkyl, such as CF 3 , CH 2 CF 3 or CH 2 CHF 2 e.g. CH 2 CHF 2 . In a seventh embodiment R 21b is C 4-6 heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

[0192] When the substituent is NR 21b R 22b , in one embodiment R 22b is H. In a second embodiment R 22b is methyl.

[0193] Suitably, R 21b is C(O)OCH 3 and R 22b is H. Suitably, R 21b is C(O)CH 3 and R 22b is H. Suitably, R 21b and R 22b are both CH 3 . Suitably, R 21b and R 22b are both H.

[0194] In a thirteenth embodiment, the substituent is oxo.

[0195] In a fourteenth embodiment, the substituent is OH.

[0196] Suitably, the one or two substituents, in particular one substituent, are independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, halo, OC 1-3 haloalkyl, OC 1-3 alkyl and NR 21b R 22b .

[0197] More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OC 1-3 alkyl and NR 21b R 22b .

[0198] Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro, NR 21b R 22b .

[0199] Alternatively, R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 cycloalkyl and one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl.

[0200] In one embodiment the C 3-6 cycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C 3-6 cycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent is independently selected from the group consisting of C 1-2 alkyl or OCH 3 .

[0201] Suitably one of the carbons of the C 3-6 cycloalkyl which is formed by R 4ab and R 5ab is a spiro centre such that a spirocyclic ring system is formed, wherein the C 3-6 cycloalkyl which is formed by R 4ab and R 5ab is a C 4-6 cycloalkyl. Suitably the C 3-6 heterocycloalkyl is an oxygen containing C 3-6 heterocycloalkyl. Suitably, the C 3-6 heterocycloalkyl is an oxygen comprising, such as containing, C 3-6 heterocycloalkyl ring, such as a C 5 cycloalkyl ring.

[0202] In an embodiment, R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heteroycloalkyl formed by R 4ab and R 5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl. Suitably, each substituent is independently selected from the group consisting of C 1-2 alkyl or OCH 3 .

[0203] Suitably one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed containing further ring C, wherein C is a C 4-6 heterocycloalkyl. Suitably the C 4-6 heterocycloalkyl is an oxygen containing C 4-6 heterocycloalkyl such as tetrahydropyranyl or 1,3-dioxolanyl.

[0204] In an embodiment, R 4ab and R 5ab together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29b .

[0205] Suitably, the C 3-6 heterocycloalkyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.

[0206] Suitably, when the C 3-6 heterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:

[0207] The C 3-6 heterocycloalkyl may be other groups as defined elsewhere herein.

[0208] In an embodiment, R 29b is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 . In one embodiment, R 29b is C 1-3 alkyl such as methyl. In another embodiment, R 29b is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 . In some embodiments, R 29b is C 0-2 alkyleneC 3-5 cycloalkyl. In other embodiments, R 29b is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is substituted by CH 3 . R 29b may be C 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29b may be C 1 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29b may be C 2 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29b may be C 0-2 alkyleneC 3 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29b may be C 0-2 alkyleneC 4 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29b may be C 0-2 alkyleneC 5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . Suitably, where C 0-2 alkyleneC 3-5 cycloalkyl is optionally substituted by CH 3 , the CH 3 is at the point of attachment of the C 3-5 cycloalkyl to the C 0-2 alkylene. In another embodiment, R 29b is CF 3 . In another embodiment, R 29b is N(C 1-3 alkyl) 2 such as N(CH 3 ) 2 . In another embodiment, R 29b is a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is not substituted by methyl. In one embodiment, R 29b is a 5-membered heteroaryl such as pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, such as pyrazolyl. Suitably the pyrazolyl is substituted by methyl. In another embodiment, R 29b is a 6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0209] In another embodiment, R 4b and R 5b are R 4bb and R 5bb .

[0210] In one embodiment R 4bb is O and R 5bb is absent. The person skilled in the art will appreciate that in this embodiment, the following moiety forms, in order to retain the correct carbon valency of 4:

[0211] In a second embodiment, R 4bb and R 5bb together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl. In a third embodiment R 4bb is C 1-6 alkyl, in particular C 1-4 alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment R 4bb is C 0-2 alkyleneC 3-6 cycloalkyl, in particular C 0-2 alkyleneC 3-5 cycloalkyl, such as C 3-5 cycloalkyl, C 1 alkyleneC 3-5 cycloalkyl or C 2 alkyleneC 3-5 cycloalkyl. In a fifth embodiment R 4bb is OC 1-6 alkyl, in particular OC 1-4 alkyl, such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a sixth embodiment R 4bb is OC 0-2 alkyleneC 3-6 cycloalkyl, such as OC 3-6 cycloalkyl, OC 1 alkyleneC 3-6 cycloalkyl or OC 2 alkyleneC 3-6 cycloalkyl. In a seventh embodiment R 4bb is C 1-3 alkyleneOC 1-3 alkyl, in particular C 1-2 alkyleneOC 1-2 alkyl such as C 1 alkyleneOC 1 alkyl, C 2 alkyleneOC 1 alkyl, C 1 alkyleneOC 2 alkyl or C 2 alkyleneOC 2 alkyl. In an eighth embodiment R 4bb is C 1-6 haloalkyl, in particular C 1-4 haloalkyl. In a ninth embodiment R 4bb is OC 1-6 haloalkyl, in particular OC 1-4 haloalkyl. In a tenth embodiment R 4bb is H. In an eleventh embodiment R 4bb is halo such as fluoro. In a twelfth embodiment R 4bb is C 1-6 alkylOH, such as CH 2 OH or CH 2 CH 2 OH, in particular CH 2 CH 2 OH. In a thirteenth embodiment R 4bb is NR 21b R 22b . In a fourteenth embodiment, R 4bb is C 0-2 alkyleneC 3-6 heterocycloalkyl such as C 0-2 alkyleneC 3 heterocycloalkyl, C 0-2 alkyleneC 4 heterocycloalkyl, C 0-2 alkyleneC 5 heterocycloalkyl, C 0-2 alkyleneC 6 heterocycloalkyl, C 0 alkyleneC 3-6 heterocycloalkyl, C 1 alkyleneC 3-6 heterocycloalkyl and C 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted. In a fifteenth embodiment, R 4bb and R 5bb together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl, such as tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, such as tetrahydrofuranyl or piperidinyl. If the C 3-6 heterocycloalkyl group comprises (e.g. contains) a nitrogen atom, independently the nitrogen atom(s) may be unsubstituted (NH) or the nitrogen atom(s) may be substituted, for example substituted by a group selected from the following: C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . In a fifteenth embodiment, R 4bb is H and R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring. In a sixteenth embodiment, R 4bb is OC 0-2 alkyleneC 3-6 heterocycloalkyl such as OC 0-2 alkyleneC 3 heterocycloalkyl, OC 0-2 alkyleneC 4 heterocycloalkyl, OC 0-2 alkyleneC 5 heterocycloalkyl, OC 0-2 alkyleneC 6 heterocycloalkyl, OC 0 alkyleneC 3-6 heterocycloalkyl, OC 1 alkyleneC 3-6 heterocycloalkyl and OC 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0212] When R 4bb is H and R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring, suitably a 5-membered ring, compounds comprising one of the following moieties are formed:

[0213] When R 4bb is NR 21b R 22b , in one embodiment R 21b is H. In a second embodiment R 21b is C 1-5 alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R 21b is C(O)C 1-5 alkyl, such as C(O)CH 3 . In a fourth embodiment R 21b is C(O)OC 1-5 alkyl, such as C(O)OCH 3 or C(O)Otert-butyl. In a fifth embodiment R 21b is C 1-3 alkylOC 1-2 alkyl such as C 1 alkylOC 1 alkyl, C 2 alkylOC 1 alkyl or C 3 alkylOC 1 alkyl e.g. C 2 alkylOC 1 alkyl. In a sixth embodiment, R 21b is C 1-4 haloalkyl, such as CF 3 , CH 2 CF 3 or CH 2 CHF 2 e.g. CH 2 CHF 2 . In a seventh embodiment R 21b is C 4-6 heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

[0214] When R 4bb is NR 21b R 22b , in one embodiment R 22b is H. In a second embodiment R 22b is methyl.

[0215] Suitably R 4bb is H, CH 3 , ethyl, isopropyl, fluoro, OCH 3 , isopropoxy or CH 2 CH 2 OCH 3 , in particular H, CH 3 , ethyl, fluoro, OCH 3 , isopropoxy or CH 2 CH 2 OCH 3 , especially H, CH 3 , ethyl, OCH 3 or CH 2 CH 2 OCH 3 .

[0216] Additionally of interest is when R 4bb is NH 2 , N(CH 3 ) 2 , NHC(O)CH 3 , NHC(O)OCH 3 , NHC(O)Otert-butyl and CH 2 CH 2 OH, especially, N(CH 3 ) 2 , NHC(O)CH 3 , NHC(O)OCH 3 .

[0217] Suitably, R 21b is C(O)OCH 3 and R 22b is H. Suitably, R 21b is C(O)CH 3 and R 22b is H. Suitably, R 21b and R 22b are both CH 3 . Suitably, R 21b and R 22b are both H.

[0218] Consequently, suitably R 4bb is H, CH 3 , ethyl, isopropyl, fluoro, OCH 3 , isopropoxy, CH 2 CH 2 OCH 3 , NH 2 , N(CH 3 ) 2 , NHC(O)CH 3 , NHC(O)OCH 3 , NHC(O)Otert-butyl or CH 2 CH 2 OH, in particular H, CH 3 , ethyl, fluoro, OCH 3 , isopropoxy, CH 2 CH 2 OCH 3 , NH 2 , N(CH 3 ) 2 , NHC(O)CH 3 , NHC(O)OCH 3 , NHC(O)Otert-butyl or CH 2 CH 2 OH, especially H, CH 3 , ethyl, OCH 3 , CH 2 CH 2 OCH 3 , N(CH 3 ) 2 , NHC(O)CH 3 or NHC(O)OCH 3 .

[0219] Suitably R 4bb may be C=O and R 5bb is absent.

[0220] Suitably R 4bb and R 5bb together with the carbon atom to which they are attached form a cyclopropyl or cyclopentyl, in particular a cyclopentyl.

[0221] Suitably R 4bb is H and R 3b together with R 5bb forms a 5- or 6-membered cycloalkyl, in particular a 5-membered cycloalkyl, especially R 4bb is H and R 3b together with R 5bb forms a 5- or 6-membered cycloalkyl, such as a 5-membered cycloalkyl.

[0222] In one embodiment R 5bb is C 1-6 alkyl, in particular C 1-4 alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a second embodiment R 5bb is C 0-2 alkyleneC 3-6 cycloalkyl, in particular C 0-2 alkyleneC 3-5 cycloalkyl, such as C 3-5 cycloalkyl, C 1 alkyleneC 3-5 cycloalkyl or C 2 alkyleneC 3-5 cycloalkyl. In a third embodiment R 5bb is OC 1-6 alkyl, in particular OC 1-4 alkyl, such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a fourth embodiment R 5bb is OC 0-2 alkyleneC 3-6 cycloalkyl, such as OC 3-6 cycloalkyl, OC 1 alkyleneC 3-6 cycloalkyl or OC 2 alkyleneC 3-6 cycloalkyl. In a fifth embodiment R 5bb is C 1-3 alkyleneOC 1-3 alkyl, in particular C 1-2 alkyleneOC 1-2 alkyl such as C 1 alkyleneOC 1 alkyl, C 2 alkyleneOC 1 alkyl, C 1 alkyleneOC 2 alkyl or C 2 alkyleneOC 2 alkyl. In a sixth embodiment R 5bb is C 1-6 haloalkyl, in particular C 1-4 haloalkyl. In a seventh embodiment R 5bb is OC 1-6 haloalkyl, in particular OC 1-4 haloalkyl. In an eighth embodiment R 5bb is H. In a ninth embodiment R 5bb is halo such as fluoro. In a tenth embodiment R 5bb is C 1-6 alkylOH, such as CH 2 OH or CH 2 CH 2 OH, in particular CH 2 CH 2 OH. In an eleventh embodiment R 5bb is NR 21b R 22b . In a twelfth embodiment, R 5bb is C 0-2 alkyleneC 3-6 heterocycloalkyl such as C 0-2 alkyleneC 3 heterocycloalkyl, C 0-2 alkyleneC 4 heterocycloalkyl, C 0-2 alkyleneC 5 heterocycloalkyl, C 0-2 alkyleneC 6 heterocycloalkyl, C 0 alkyleneC 3-6 heterocycloalkyl, C 1 alkyleneC 3-6 heterocycloalkyl and C 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted. In a thirteenth embodiment, R 5bb is OC 0-2 alkyleneC 3-6 heterocycloalkyl such as OC 0-2 alkyleneC 3 heterocycloalkyl, OC 0-2 alkyleneC 4 heterocycloalkyl, OC 0-2 alkyleneC 5 heterocycloalkyl, OC 0-2 alkyleneC 6 heterocycloalkyl, OC 0 alkyleneC 3-6 heterocycloalkyl, OC 1 alkyleneC 3-6 heterocycloalkyl and OC 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0223] Suitably R 5bb is H, CH 3 , ethyl, isopropyl or fluoro, in particular R 5bb is H, methyl or ethyl.

[0224] Suitably R 4bb is H, CH 3 , ethyl, fluoro, OCH 3 , propoxy or CH 2 CH 2 OCH 3 and R 5bb is H, CH 3 , ethyl or fluoro, in particular R 4bb is H, CH 3 , ethyl or OCH 3 and R 5bb is H, methyl or ethyl. For example, R 4bb and R 5bb are H, R 4bb and R 5bb are methyl, R 4bb and R 5bb are ethyl, R 4bb is CH 2 CH 2 OCH 3 and R 5bb is H or R 4bb and R 5bb are fluoro.

[0225] Suitably, when R 4bb is other than H, methyl, ethyl or fluoro, then R 5bb is H.

[0226] In one embodiment, A b is A ab . Suitably, A ab is -NR 6b CH 2 -. Alternatively, A ab is -NR 6b -.

[0227] In another embodiment, A b is A bb i.e. -NR 6b C(=O)-.

[0228] In one embodiment R 6b is H. In a second embodiment R 6b is C 1-3 alkyl, in particular methyl. In a third embodiment R 6b together with R 11b in the ortho-position to group A b are a C 2 alkylene chain forming a 5-membered ring. In a fourth embodiment, R 4bb is H and R 5bb and R 6b are a C 2-3 alkylene chain forming a 5- or 6-membered ring in particular a 5-membered ring.

[0229] Suitably R 6b is H, methyl or R 6b together with R 11b when in the ortho-position to group A b are a C 2 alkylene chain forming a 5-membered ring. In particular R 6b is H or R 6b together with R 11b in the ortho-position to group A b are a C 2 alkylene chain forming a 5-membered ring, especially R 6b is H.

[0230] The term 'R 6b together with R 11b in the ortho-position to group A b are a C 2 alkylene chain forming a 5-membered ring' as used herein means that compounds with the following exemplary substructure are formed: wherein W may be N or CR 10b .

[0231] In one embodiment Ar1b is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar1b is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).

[0232] In particular Ar1b is phenyl, 2-pyridyl, 3-pyridyl or 2,6-pyrimidinyl, especially phenyl, 2-pyridyl or 3-pyridyl, such as phenyl or 2-pyridyl.

[0233] In one embodiment R 10b is H. In a second embodiment R 10b is halo, for example fluoro or chloro. In a third embodiment R 10b is C 1-3 alkyl, such as CH 3 , ethyl or isopropyl, in particular C 1-2 alkyl, such as CH 3 or ethyl. In a fourth embodiment R 10b is OC 1-2 alkyl, such as OCH 3 or ethoxy. In a fifth embodiment R 10b is C 1-2 haloalkyl, such as CF 3 . In a sixth embodiment R 10b is OC 1-2 haloalkyl, such as OCF 3 . In a seventh embodiment R 10b is CN.

[0234] Suitably R 10b is H, fluoro, chloro, CH 3 , OCH 3 , ethoxy, OCF 3 or CN, in particular H, fluoro, chloro, CH 3 , OCH 3 , ethoxy or OCF 3 , especially or H, fluoro, chloro, CH 3 , OCH 3 or OCF 3 , such as H, fluoro or CH 3 .

[0235] Additionally of interest are compounds wherein R 10b is ethyl, isopropyl and CF 3 , in particular isopropyl and CF 3 . Additionally of interest are compounds when R 10b is CN.

[0236] Consequently, suitably R 10b is H, fluoro, chloro, CH 3 , ethyl, isopropyl, OCH 3 , ethoxy, OCF 3 , CF 3 or CN, in particular H, fluoro, chloro, CH 3 , isopropyl, OCH 3 , ethoxy, OCF 3 or CF 3 , especially or H, fluoro, chloro, CH 3 , isopropyl, OCH 3 , OCF 3 or CF 3 , such as H, fluoro or CH 3 .

[0237] In one embodiment R 11b is H. In a second embodiment R 11b is F. In a third embodiment, R 11b is CH 3 . In a fourth embodiment R 6b together with R 11b in the ortho-position to group A b are a C 2 alkylene chain forming a 5-membered ring. In a fifth embodiment R 11b is ethyl. In a sixth embodiment R 11b is Cl. In a seventh embodiment R 11b is OCH 3 . In an eighth embodiment, R 11b is CF 3 . In a ninth embodiment, R 11b is OCF 3 . In a tenth embodiment, R 11b is CN. In an eleventh embodiment R 6b together with R 11b in the ortho-position to group A b are a C 2 alkylene chain forming a 5-membered ring.

[0238] Suitably, R 10b and R 11b are both CH 3 . Suitably, R 10b and R 11b are both H. Suitably, R 10b and R 11b are both fluoro.

[0239] In one embodiment, R 10b is in the ortho position with respect to group A b . In another embodiment, R 10b is in the meta position with respect to group A b . Suitably R 10b is in the ortho position with respect to group A b .

[0240] In one embodiment, R 11b is in the ortho position with respect to group A b . In another embodiment, R 11b is in the meta position with respect to group A b . Suitably R 11b is in the ortho position with respect to group A b .

[0241] In one embodiment Ar2b is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar2b is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).

[0242] In particular Ar2b is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyridazinyl, 3,4-pyridazinyl, 3,5-pyrimidinyl or 2,5-pyrazinyl, especially 3-pyridyl, 3,5-pyrimidinyl or 2,5-pyrazinyl, such as 3-pyridyl or 2,5-pyrazinyl.

[0243] In one embodiment R 12b is H. In a second embodiment R 12b is halo, for example fluoro or chloro. In a third embodiment R 12b is C 1-4 alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment R 12b is C 2-4 alkynyl, such as C≡CH. In a fifth embodiment R 12b is C 0-2 alkyleneC 3-5 cycloalkyl, such as C 3-5 cycloalkyl (e.g. cyclopropyl), C 1 alkyleneC 3-5 cycloalkyl or C 2 alkyleneC 3-5 cycloalkyl. In a sixth embodiment R 12b is OC 1-4 alkyl, such as OCH 3 , ethoxy, isopropoxy or n-propoxy. In a seventh embodiment R 12b is OC 0-2 alkyleneC 3-5 cycloalkyl, such as OC 3-5 cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC 1 alkyleneC 3-5 cycloalkyl or OC 2 alkyleneC 3-5 cycloalkyl. In an eighth embodiment R 12b is OCH 2 CH 2 N(CH 3 ) 2 . In a ninth embodiment R 12b is C 1-4 alkylOH, such as CH 2 OH or C(CH 3 ) 2 OH. In a tenth embodiment R 12b is CN. In an eleventh embodiment R 12b is C 1-3 alkyleneOC 1-3 alkyl. In a twelfth embodiment R 12b is C 1-4 haloalkyl, such as CF 3 . In a thirteenth embodiment R 12b is OC 1-4 haloalkyl, such as OCF 3 , OCHF 2 or OCH 2 CF 3 . In a fourteenth embodiment R 12b is NR 23b R 24b such as N(CH 3 ) 2 . In a fifteenth embodiment R 12b is S(O) 2 C 1-4 alkyl such as SO 2 CH 3 . In a sixteenth embodiment R 12b is C(O)N(CH 3 ) 2 . In a seventeenth embodiment R 12b is NHC(O)C 1-3 alkyl such as NHC(O)CH 3 . In an eighteenth embodiment R 12b is a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, such as a C 5 heterocycloalkyl, in particular pyrrolidinyl, or a C 6 heterocycloalkyl such as morpholinyl. In a nineteenth embodiment R 12b is OH. In a twentieth embodiment R 12b is C(=O)C 1-2 alkyl. In a twentyfirst embodiment R 12b is S(O)C 1-4 alkyl. In a twentysecond embodiment R 12b is SC 1-4 alkyl. In a twentythird embodiment R 12b is SH. In a twentyfourth embodiment, R 12b together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ).

[0244] R 12b is suitably H, fluoro, chloro, CH 3 , cyclopropyl, C≡CH, OCH 3 , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF 3 , OCF 3 , OCHF 2 , OCH 2 CF 3 , CH 2 OH, N(CH 3 ) 2 , NHC(O)CH 3 , SO 2 CH 3 , C(O)N(CH 3 ) 2 or pyrrolidinyl, in particular H, fluoro, chloro, CH 3 , cyclopropyl, C≡CH, OCH 3 , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF 3 , OCF 3 , OCHF 2 , OCH 2 CF 3 , CH 2 OH, C(O)N(CH 3 ) 2 or pyrrolidinyl, especially H, fluoro, chloro, CH 3 , cyclopropyl, C≡CH, OCH 3 , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF 3 , OCHF 2 , OCH 2 CF 3 or pyrrolidinyl, such as H, fluoro, chloro, CH 3 , C≡CH, OCH 3 , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF 3 , OCHF 2 or OCH 2 CF 3 .

[0245] Additionally of interest are ethyl, 2-methoxyisopropyl and OH, especially ethyl.

[0246] In one embodiment, R 23b is H. In another embodiment, R 23b is C 1-2 alkyl such as methyl.

[0247] In one embodiment, R 24b is H. In another embodiment R 24b is C 1-2 alkyl such as methyl.

[0248] Suitably, R 23b is H and R 24b is ethyl. Suitably, R 23b is CH 3 and R 24b is CH 3 .

[0249] Consequently, suitably R 12b is H, fluoro, chloro, CH 3 , ethyl, cyclopropyl, C≡CH, OCH 3 , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF 3 , OCF 3 , OCHF 2 , OCH 2 CF 3 , OH, CH 2 OH, N(CH 3 ) 2 , NHC(O)CH 3 , SO 2 CH 3 , C(O)N(CH 3 ) 2 or pyrrolidinyl, in particular H, fluoro, chloro, CH 3 , ethyl, cyclopropyl, C≡CH, OCH 3 , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF 3 , OCF 3 , OCHF 2 , OCH 2 CF 3 , CH 2 OH, C(O)N(CH 3 ) 2 or pyrrolidinyl, especially H, fluoro, chloro, CH 3 , ethyl, cyclopropyl, C≡CH, OCH 3 , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF 3 , OCHF 2 , OCH 2 CF 3 or pyrrolidinyl, such as H, fluoro, chloro, CH 3 , C≡CH, OCH 3 , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF 3 , OCHF 2 or OCH 2 CF 3 .

[0250] Suitably R 12b is suitably in the meta position of Ar2b. Alternatively, R 12b is in the ortho position of Ar2b.

[0251] In one embodiment R 13b is methyl. In a second embodiment R 13b is H. In a third embodiment R 13b is methoxy. In a fourth embodiment R 13b is halo such as fluoro.

[0252] In one embodiment, R 13b is in the ortho position with respect to Ar1b. In another embodiment, R 13b is in the para position with respect to Ar1b.

[0253] The present invention provides compound T466.

[0254] The present invention provides the following compound: N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)-2-methylpropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide.Compounds of formula (I-c)

[0255] The invention provides a compound of formula (I-c): wherein A c is A ac or A bc ; A ac is -CH 2 NR 6c -; A bc is -C(=O)NR 6c -; R 1c is R 1ac or R 1bc ; wherein: R 1ac is NR 32c R 33c ; R 1bc is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R 3c is H, CH 3 , halo, OC 1-2 alkyl or CF 3 ; R 4c and R 5c are either R 4ac and R 5ac or R 4bc and R 5bc ; wherein: R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21c R 22c ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heteroycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29c ; or R 4bc and R 5bc are each independently H, C 1-6 alkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-6 alkylOH or C 1-6 haloalkyl, or R 4bc and R 5bc together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl ring; R 6c is H or C 1-3 alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A c ; R 10c is H, halo, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN; R 11c is H, F, Cl, CH 3 , ethyl, OCH 3 , CF 3 , OCF 3 or CN; R 12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R 12c is H, halo, C 1-4 alkyl, C 2-4 alkynyl, C(=O)C 1-2 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, CN, OC 0-2 alkyleneC 3-5 cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , OH, C 1-4 alkylOH, NR 23c R 24c , SO 2 CH 3 , C(O)N(CH 3 ) 2 , NHC(O)C 1-3 alkyl, or a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R 12c together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 21c is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(O)OC 1-5 alkyl, C 1-3 alkylOC 1-2 alkyl, C 1-4 haloalkyl, or C 4-6 heterocycloalkyl; R 22c is H or CH 3 ; R 23c is H or C 1-2 alkyl; R 24c is H or C 1-2 alkyl; R 29c is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , CF 3 , N(C 1-3 alkyl) 2 , or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and R 32c is C 1-3 alkyl and R 33c is C 1-3 alkyl; or R 32c and R 33c together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; or a salt and / or solvate thereof.

[0256] Suitably, R 1c is R 1ac ; and / or R 4c and R 5c are R 4ac and R 5ac ; and / or A c is A ac .

[0257] The invention also provides a compound of formula (I-c): wherein A c is A ac or A bc ; A ac is -CH 2 NR 6c -; A bc is -C(=O)NR 6c -; R 1c is R 1ac or R 1bc ; wherein: R 1ac is NR 32c R 33c ; R 1bc is C 1-5 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , C 1-3 alkyleneOC 1-2 alkyl, or CF 3 ; R 3c is H, CH 3 , halo, OC 1-2 alkyl or CF 3 ; R 4c and R 5c are either R 4ac and R 5ac or R 4bc and R 5bc ; wherein: R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21c R 22c ; or one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heteroycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl; or R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29c ; or R 4bc and R 5bc are each independently H, C 1-6 alkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-6 alkylOH or C 1-6 haloalkyl, or R 4bc and R 5bc together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl ring; R 6c is H or C 1-3 alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A c ; R 10c is H, halo, C 1-3 alkyl, OC 1-2 alkyl, C 1-2 haloalkyl, OC 1-2 haloalkyl or CN; R 11c is H, F, Cl, CH 3 , ethyl, OCH 3 , CF 3 , OCF 3 or CN; R 12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R 12c is H, halo, C 1-4 alkyl, C 2-4 alkynyl, C(=O)C 1-2 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-4 haloalkyl, OC 1-4 haloalkyl, CN, OC 0-2 alkyleneC 3-5 cycloalkyl, OCH 2 CH 2 N(CH 3 ) 2 , OH, C 1-4 alkylOH, NR 23c R 24c , SO 2 CH 3 , C(O)N(CH 3 ) 2 , NHC(O)C 1-3 alkyl, or a C 3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R 12c together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ); R 21c is H, C 1-5 alkyl, C(O)C 1-5 alkyl, C(0)OC 1-5 alkyl; R 22c is H or CH 3 ; R 23c is H or C 1-2 alkyl; R 24c is H or C 1-2 alkyl; R 29c is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 ; and R 32c is C 1-3 alkyl and R 33c is C 1-3 alkyl; or R 32c and R 33c together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl; or a salt and / or solvate thereof.

[0258] Suitably, R 1c is R 1ac ; and / or R 4c and R 5c are R 4ac and R 5ac ; and / or A c is A ac .

[0259] When R 4bc and / or R 5bc is C 0 alkyleneC 3-6 heterocycloalkyl, any heteroatom in the heterocycloalkyl may not be directly connected to the carbon to which R 4bc and R 5bc are connected.

[0260] In one embodiment of the invention, R 1c is R 1ac , i.e. is NR 32c R 33c . In an embodiment, R 32c is C 1-3 alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R 33c is C 1-3 alkyl, such as methyl or ethyl, e.g. methyl. Suitably, R 32c and R 33c are both methyl. Suitably, R 32c and R 33c are both ethyl. Suitably, R 32c is methyl and R 33c is ethyl.

[0261] In another embodiment, R 32c and R 33c together with the nitrogen atom to which they are attached form a C 3-5 heterocycloalkyl. Suitably, the C 3-5 heterocycloalkyl is aziridinyl, azetidinyl or pyrrolidinyl.

[0262] Suitably, R 1c is R 1bc .

[0263] In one embodiment of the invention R 1bc is C 1-5 alkyl such as C 1-4 alkyl. When R 1bc is C 1-5 alkyl, R 1bc is methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or tert-butyl) or pentyl (e.g. n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl or active pentyl). When R 1bc is C 1-4 alkyl, R 1bc is methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl).

[0264] In a second embodiment of the invention R 1bc is C 1-3 alkyleneOC 1-2 alkyl such as C 1-2 alkyleneOC 1-2 alkyl. R 1bc may be C 1 alkyleneOC 1 alkyl. R 1bc may be C 1 alkyleneOC 2 alkyl. R 1bc may be C 2 alkyleneOC 1 alkyl. R 1bc may be C 2 alkyleneOC 2 alkyl. R 1bc may be C 3 alkyleneOC 1 alkyl. R 1bc may be C 3 alkyleneOC 2 alkyl.

[0265] In a third embodiment of the invention R 1bc is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 such as C 0-1 alkyleneC 3-4 cycloalkyl which cycloalkyl is optionally substituted by CH 3 . In some embodiments, R 1bc is C 0-2 alkyleneC 3-5 cycloalkyl such as C 0-1 alkyleneC 3-4 cycloalkyl. In other embodiments, R 1bc is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is substituted by CH 3 such as C 0-1 alkyleneC 3-4 cycloalkyl which cycloalkyl is substituted by CH 3 . R 1bc may be C 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 such as C 3-4 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bc may be C 1 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bc may be C 1 alkyleneC 3-4 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bc may be C 2 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bc may be C 2 alkyleneC 3-4 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bc may be C 0-2 alkyleneC 3 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bc may be C 0-1 alkyleneC 3 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bc may be C 0-2 alkyleneC 4 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bc may be C 0-1 alkyleneC 4 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bc may be C 0-2 alkyleneC 5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 1bc may be C 0-1 alkyleneC 5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . Suitably, where C 0-2 alkyleneC 3-5 cycloalkyl such as C 0-1 alkyleneC 3-4 cycloalkyl is optionally substituted by CH 3 , the CH 3 is at the point of attachment of the C 3-5 cycloalkyl to the C 0-2 alkylene such as at the point of attachment of the C 3-4 cycloalkyl to the C 0-1 alkylene.

[0266] Suitably R 1bc is cyclopropyl.

[0267] In a fourth embodiment of the invention, R 1bc is CF 3 .

[0268] In one embodiment R 3c is H. In a second embodiment R 3c is CH 3 . In a third embodiment, R 3c is halo. In an example, R 3c is F. In a second example, R 3c is Cl. In a fourth embodiment, R 3c is OC 1-2 alkyl. Suitably R 3c is OCH 3 . Suitably, R 3c is OCH 2 CH 3 . In a fifth embodiment, R 3c is CF 3 .

[0269] Suitably, R 3c is H.

[0270] In one embodiment, R 4c and R 5c are R 4ac and R 5ac .

[0271] Suitably, R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 1-3 alkyl, halo, OC 1-3 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-3 alkyl and NR 21c R 22c .

[0272] In one embodiment, the C 3-6 cycloalkyl is cyclopropyl. In another embodiment, the C 3-6 cycloalkyl is cyclobutyl. In another embodiment, the C 3-6 cycloalkyl is cyclopentyl. In another embodiment, the C 3-6 cycloalkyl is cyclohexyl.

[0273] In one embodiment the C 3-6 cycloalkyl is substituted by one substituent. In a second embodiment the C 3-6 cycloalkyl is substituted by two substituents.

[0274] In one embodiment, the substituent is C 1-3 alkyl. Suitably, the substituent is methyl. Suitably, the substituent is ethyl. Suitably, the substituent is n-propyl. Suitably, the substituent is iso-propyl.

[0275] In a second embodiment, the substituent is C 1-3 alkylOH. Suitably, the substituent is CH 2 OH. Suitably, the substituent is CH 2 CH 2 OH. Suitably, the substituent is CH 2 CH 2 CH 2 OH.

[0276] In a third embodiment, the substituent is C 1-3 haloalkyl. Suitably the C 1-3 alkyl group is substituted by one two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is C 1 haloalkyl such as CF 3 . Suitably, the substituent is C 2 haloalkyl such as CH 2 CF 3 .

[0277] In a fourth embodiment, the substituent is C 0-2 alkyleneC 3-6 cycloalkyl, in particular C 0-2 alkyleneC 3-5 cycloalkyl, such as C 3-5 cycloalkyl, C 1 alkyleneC 3-5 cycloalkyl or C 2 alkyleneC 3-5 cycloalkyl.

[0278] In a fifth embodiment, the substituent is C 0-2 alkyleneC 3-6 heterocycloalkyl such as C 0-2 alkyleneC 3 heterocycloalkyl, C 0-2 alkyleneC 4 heterocycloalkyl, C 0-2 alkyleneC 5 heterocycloalkyl, C 0-2 alkyleneC 6 heterocycloalkyl, C 0 alkyleneC 3-6 heterocycloalkyl, C 1 alkyleneC 3-6 heterocycloalkyl and C 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0279] In a sixth embodiment, the substituent is C 1-3 alkyleneOC 1-3 alkyl, in particular C 1-2 alkyleneOC 1-2 alkyl such as C 1 alkyleneOC 1 alkyl, C 2 alkyleneOC 1 alkyl, C 1 alkyleneOC 2 alkyl or C 2 alkyleneOC 2 alkyl.

[0280] In a seventh embodiment, the substituent is halo, in particular fluoro or chloro such as chloro.

[0281] In an eighth embodiment, the substituent is OC 1-3 haloalkyl. Suitably the OC 1-3 alkyl group is substituted by one two or three, such as one, halogen atom. Suitably, the halogen atom is fluoro or chloro such as fluoro. Suitably, the substituent is OC 1 haloalkyl such as OCF 3 . Suitably, the substituent is OC 2 haloalkyl such as OCH 2 CF 3 .

[0282] In a ninth embodiment, the substituent is OC 0-2 alkyleneC 3-6 cycloalkyl, such as OC 3-6 cycloalkyl, OC 1 alkyleneC 3-6 cycloalkyl or OC 2 alkyleneC 3-6 cycloalkyl.

[0283] In a tenth embodiment, the substituent is OC 0-2 alkyleneC 3-6 heterocycloalkyl such as OC 0-2 alkyleneC 3 heterocycloalkyl, OC 0-2 alkyleneC 4 heterocycloalkyl, OC 0-2 alkyleneC 5 heterocycloalkyl, OC 0-2 alkyleneC 6 heterocycloalkyl, OC 0 alkyleneC 3-6 heterocycloalkyl, OC 1 alkyleneC 3-6 heterocycloalkyl and OC 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom(s) (such as one nitrogen atom) in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0284] In an eleventh embodiment, the substituent is OC 1-3 alkyl, such as OCH 3 or OCH 2 CH 3 .

[0285] In a twelfth embodiment, the substituent is NR 21c R 22c . In one embodiment R 21c is H. In a second embodiment R 21c is C 1-5 alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R 21c is C(O)C 1-5 alkyl, such as C(O)CH 3 . In a fourth embodiment R 21c is C(O)OC 1-5 alkyl, such as C(O)OCH 3 or C(O)Otert-butyl. In a fifth embodiment R 21c is C 1-3 alkylOC 1-2 alkyl such as C 1 alkylOC 1 alkyl, C 2 alkylOC 1 alkyl or C 3 alkylOC 1 alkyl e.g. C 2 alkylOC 1 alkyl. In a sixth embodiment, R 21c is C 1-4 haloalkyl, such as CF 3 , CH 2 CF 3 or CH 2 CHF 2 e.g. CH 2 CHF 2 . In a seventh embodiment R 21c is C 4-6 heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

[0286] When the substituent is NR 21c R 22c , in one embodiment R 22c is H. In a second embodiment R 22c is methyl.

[0287] Suitably, R 21c is C(O)OCH 3 and R 22c is H. Suitably, R 21c is C(O)CH 3 and R 22c is H. Suitably, R 21c and R 22c are both CH 3 . Suitably, R 21c and R 22c are both H.

[0288] In a thirteenth embodiment, the substituent is oxo.

[0289] In a fourteenth embodiment, the substituent is OH.

[0290] Suitably, the one or two substituents, in particular one substituent, are independently selected from the group consisting of C 1-3 alkyl, oxo, OH, C 1-3 alkylOH, C 1-3 haloalkyl, halo, OC 1-3 haloalkyl, OC 1-3 alkyl and NR 21c R 22c .

[0291] More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OC 1-3 alkyl and NR 21c R 22c .

[0292] Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro, NR 21c R 22c .

[0293] Alternatively, R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 cycloalkyl and one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 cycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl.

[0294] In one embodiment the C 3-6 cycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C 3-6 cycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent is independently selected from the group consisting of C 1-2 alkyl or OCH 3 .

[0295] Suitably one of the carbons of the C 3-6 cycloalkyl which is formed by R 4ac and R 5ac is a spiro centre such that a spirocyclic ring system is formed, wherein the C 3-6 cycloalkyl which is formed by R 4ac and R 5ac is a C 4-6 cycloalkyl. Suitably the C 3-6 heterocycloalkyl is an oxygen containing C 3-6 heterocycloalkyl. Suitably, the C 3-6 heterocycloalkyl is an oxygen comprising, such as containing, C 3-6 heterocycloalkyl ring, such as a C 5 cycloalkyl ring.

[0296] In an embodiment, R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, and wherein the C 3-6 heteroycloalkyl formed by R 4ac and R 5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C 1-3 alkyl or OC 1-3 alkyl. Suitably, each substituent is independently selected from the group consisting of C 1-2 alkyl or OCH 3 .

[0297] Suitably one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed containing further ring C, wherein C is a C 4-6 heterocycloalkyl. Suitably the C 4-6 heterocycloalkyl is an oxygen containing C 4-6 heterocycloalkyl such as tetrahydropyranyl or 1,3-dioxolanyl.

[0298] As stated above, when a heterocycloalkyl is formed from R 4c and R 5c together with the carbon atom to which they are attached, suitably any heteroatom is not directly connected to the carbon to which R 4c and R 5c are attached.

[0299] In an embodiment, R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O) 2 R 29c .

[0300] Suitably, the C 3-6 heterocycloalkyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.

[0301] Suitably, when the C 3-6 heterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:

[0302] The C 3-6 heterocycloalkyl may be other groups as defined elsewhere herein.

[0303] In an embodiment, R 29c is C 1-3 alkyl, C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 , or CF 3 . In one embodiment, R 29c is C 1-3 alkyl such as methyl. In another embodiment, R 29c is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is optionally substituted by CH 3 . In some embodiments, R 29c is C 0-2 alkyleneC 3-5 cycloalkyl. In other embodiments, R 29c is C 0-2 alkyleneC 3-5 cycloalkyl which cycloalkyl is substituted by CH 3 . R 29c may be C 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29c may be C 1 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29c may be C 2 alkyleneC 3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29c may be C 0-2 alkyleneC 3 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29c may be C 0-2 alkyleneC 4 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . R 29c may be C 0-2 alkyleneC 5 cycloalkyl, which cycloalkyl is optionally substituted by CH 3 . Suitably, where C 0-2 alkyleneC 3-5 cycloalkyl is optionally substituted by CH 3 , the CH 3 is at the point of attachment of the C 3-5 cycloalkyl to the C 0-2 alkylene. In another embodiment, R 29c is CF 3 . In another embodiment, R 29c is N(C 1-3 alkyl) 2 such as N(CH 3 ) 2 . In another embodiment, R 29c is a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is substituted by methyl. In one embodiment, the 5 or 6 membered heteroaryl is not substituted by methyl. In one embodiment, R 29c is a 5-membered heteroaryl such as pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, such as pyrazolyl. Suitably the pyrazolyl is substituted by methyl. In another embodiment, R 29c is a 6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0304] In another embodiment, R 4c and R 5c are R 4bc and R 5bc .

[0305] In one embodiment, R 4bc is H. In a second embodiment R 4bc is C 1-6 alkyl such as C 1-4 alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R 4bc may also be pentyl (e.g. n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl or active pentyl) or hexyl (e.g. n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl). In a third embodiment, R 4bc is C 0-2 alkyleneC 3-6 cycloalkyl such as C 0-2 alkyleneC 3-5 cycloalkyl, such as C 0-2 alkyleneC 3 cycloalkyl, C 0-2 alkyleneC 4 cycloalkyl, C 0-2 alkyleneC 5 cycloalkyl, C 0 alkyleneC 3-5 cycloalkyl, C 1 alkyleneC 3-5 cycloalkyl and C 2 alkyleneC 3-5 cycloalkyl. R 4bc may also be C 0-2 alkyleneC 6 cycloalkyl, C 0 alkyleneC 3-6 cycloalkyl, C 1 alkyleneC 3-6 cycloalkyl and C 2 alkyleneC 3-6 cycloalkyl. In a fourth embodiment R 4bc is C 1-3 alkyleneOC 1-3 alkyl, in particular C 1-2 alkyleneOC 1-2 alkyl such as C 1 alkyleneOC 1 alkyl, C 2 alkyleneOC 1 alkyl, C 1 alkyleneOC 2 alkyl or C 2 alkyleneOC 2 alkyl. In a fifth embodiment R 4bc is C 1-6 alkylOH such as C 1-4 alkylOH such as C 1 alkylOH, C 2 alkylOH, C 3 alkylOH or C 4 alkylOH wherein C 1-4 alkyl is methyl, ethyl, propyl (n-propyl or isopropyl) and butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R 4bc may also be C 5 alkylOH or C 6 alkylOH. In a sixth embodiment, R 4bc is C 1-6 haloalkyl such as C 1-4 haloalkyl such as C 1 haloalkyl (e.g. CF 3 ), C 2 haloalkyl (e.g. CH 2 CF 3 ), C 3 haloalkyl (e.g. CH 2 CH 2 CF 3 ) or C 4 haloalkyl (e.g. CH 2 CH 2 CH 2 CF 3 ). R 4bc may also be C 5 haloalkyl (e.g. CH 2 CH 2 CH 2 CH 2 CF 3 ) or C 6 haloalkyl (e.g. CH 2 CH 2 CH 2 CH 2 CH 2 CF 3 ). In a seventh embodiment, R 4bc is C 0-2 alkyleneC 3-6 heterocycloalkyl such as C 0-2 alkyleneC 3 heterocycloalkyl, C 0-2 alkyleneC 4 heterocycloalkyl, C 0-2 alkyleneC 5 heterocycloalkyl, C 0-2 alkyleneC 6 heterocycloalkyl, C 0 alkyleneC 3-6 heterocycloalkyl, C 1 alkyleneC 3-6 heterocycloalkyl and C 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl of a C 0-2 alkyleneC 3-6 heterocycloalkyl group is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted. In an eighth embodiment, R 4bc and R 5b , together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl ring. Suitably R 4bc and R 5b , together with the carbon atom to which they are attached form a C 3-6 cycloalkyl ring, such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. Suitably R 4bc and R 5b , together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl ring, such as a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen atom in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0306] Suitably R 4bc is H, CH 3 or ethyl, in particular CH 3 or ethyl. Suitably, R 4bc and R 5b , together with the carbon atom to which they are attached form a C 3-6 cycloalkyl ring, such as a cyclopropyl ring.

[0307] In one embodiment, R 5b , is H. In a second embodiment R 5bc is C 1-6 alkyl such as C 1-4 alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R 5b , may also be pentyl (e.g. n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl and active pentyl) or hexyl (e.g. n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl). In a third embodiment, R 5b , is C 0-2 alkyleneC 3-6 cycloalkyl such as C 0-2 alkyleneC 3-5 cycloalkyl, such as C 0-2 alkyleneC 3 cycloalkyl, C 0-2 alkyleneC 4 cycloalkyl, C 0-2 alkyleneC 5 cycloalkyl, C 0 alkyleneC 3-5 cycloalkyl, C 1 alkyleneC 3-5 cycloalkyl and C 2 alkyleneC 3-5 cycloalkyl. R 5b , may also be C 0-2 alkyleneC 6 cycloalkyl, C 0 alkyleneC 3-6 cycloalkyl, C 1 alkyleneC 3-6 cycloalkyl and C 2 alkyleneC 3-6 cycloalkyl. In a fourth embodiment R 5bc is C 1-3 alkyleneOC 1-3 alkyl, in particular C 1-2 alkyleneOC 1-2 alkyl such as C 1 alkyleneOC 1 alkyl, C 2 alkyleneOC 1 alkyl, C 1 alkyleneOC 2 alkyl or C 2 alkyleneOC 2 alkyl. In a fifth embodiment R 5b , is C 1-6 alkylOH such as C 1-4 alkylOH such as C 1 alkylOH, C 2 alkylOH, C 3 alkylOH or C 4 alkylOH wherein C 1-4 alkyl is methyl, ethyl, propyl (n-propyl or isopropyl) and butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R 5bc may also be C 5 alkylOH or C 6 alkylOH. In a sixth embodiment, R 5bc is C 1-6 haloalkyl such as C 1-4 haloalkyl such as C 1 haloalkyl (e.g. CF 3 ), C 2 haloalkyl (e.g. CH 2 CF 3 ), C 3 haloalkyl (e.g. CH 2 CH 2 CF 3 ), C 4 haloalkyl (e.g. CH 2 CH 2 CH 2 CF 3 ). R 5bc may also be C 5 haloalkyl (e.g. CH 2 CH 2 CH 2 CH 2 CF 3 ) or C 6 haloalkyl (e.g. CH 2 CH 2 CH 2 CH 2 CH 2 CF 3 ). In a seventh embodiment, R 5b , is C 0-2 alkyleneC 3-6 heterocycloalkyl such as C 0-2 alkyleneC 3 heterocycloalkyl, C 0-2 alkyleneC 4 heterocycloalkyl, C 0-2 alkyleneC 5 heterocycloalkyl, C 0-2 alkyleneC 6 heterocycloalkyl, C 0 alkyleneC 3-6 heterocycloalkyl, C 1 alkyleneC 3-6 heterocycloalkyl and C 2 alkyleneC 3-6 heterocycloalkyl. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Suitably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as one nitrogen in the C 3-6 heterocycloalkyl ring may be substituted, for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Suitably, any nitrogen atom in the C 3-6 heterocycloalkyl ring is not substituted.

[0308] Suitably R 5bc is H, CH 3 or ethyl, in particular CH 3 or ethyl. Suitably, R 4bc and R 5b , together with the carbon atom to which they are attached form a C 3-6 cycloalkyl ring, such as a cyclopropyl ring.

[0309] Suitably R 4bc is H, CH 3 or ethyl and R 5b , is H, CH 3 or ethyl, in particular R 4bc is CH 3 or ethyl and R 5b , is CH 3 or ethyl. For example, R 4bc and R 5b , are H, R 4bc and R 5bc are methyl or R 4bc and R 5bc are ethyl.

[0310] Suitably, R 4bc is CH 2 CH 2 OCH 3 and R 5bc is H.

[0311] In one embodiment, A c is A ac i.e. -CH 2 NR 6c -.

[0312] In another embodiment, A c is A bc i.e. -C(=O)NR 6c -.

[0313] In one embodiment, R 6c is H. In another embodiment, R 6c is C 1-3 alkyl, in particular CH 3 .

[0314] In one embodiment Ar1c is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar1c is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).

[0315] In particular Ar1c is phenyl or 2-pyridyl, such as phenyl.

[0316] In one embodiment R 10c is H. In a second embodiment R 10c is halo, for example fluoro or chloro. In a third embodiment R 10c is C 1-3 alkyl, i.e. CH 3 , ethyl or propyl (e.g. n-propyl or iso-propyl). In a fourth embodiment R 10c is OC 1-2 alkyl, such as OCH 3 or ethoxy. In a fifth embodiment, R 10c is C 1-2 haloalkyl, such as CF 3 or CH 2 CF 3 . In a sixth embodiment R 10c is OC 1-2 haloalkyl, such as OCF 3 . In a seventh embodiment R 10c is CN.

[0317] Suitably R 10c is H, fluoro, OCH 3 , CH 3 or CF 3 , in particular H or fluoro, especially H.

[0318] Suitably R 10c is attached at the ortho position of Ar1c relative to group A c (i.e. proximal to group A c ).

[0319] In one embodiment R 11c is H. In a second embodiment R 11c is F. In a third embodiment, R 11c is Cl. In a fourth embodiment R 11c is CH 3 . In a fifth embodiment R 11c is CH 2 CH 3 . In a sixth embodiment R 11c is OCH 3 . In a seventh embodiment R 11c is CF 3 . In an eighth embodiment R 11c is OCF 3 . In a ninth embodiment R 11c is CN.

[0320] In one embodiment, R 11c is in the ortho position relative to group A c . In another embodiment, R 11c is in the meta position relative to group A c .

[0321] In one embodiment Ar2c is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar2c is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl).

[0322] In particular Ar2c is 3-pyridyl or 2,5-pyrazinyl, especially 2,5-pyrazinyl.

[0323] In one embodiment R 12c is H. In a second embodiment R 12c is halo, for example fluoro or chloro. In a third embodiment R 12c is C 1-4 alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment, R 12c is C 2-4 alkynyl such as C 2 alkynyl (i.e. C≡CH). In a fifth embodiment, R 12c is C(=O)C 1-2 alkyl, such as C(=O)C 1 alkyl or C(=O)C 2 alkyl. In a sixth embodiment R 12c is OC 0-2 alkyleneC 3-5 cycloalkyl, such as OC 3-5 cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC 1 alkyleneC 3-5 cycloalkyl or OC 2 alkyleneC 3-5 cycloalkyl. In a seventh embodiment R 12c is OC 1-4 alkyl, such as OCH 3 , ethoxy, iso-propoxy or n-propoxy. In an eighth embodiment, R 12c is C 1-3 alkyleneOC 1-3 alkyl in particular C 1-2 alkyleneOC 1-2 alkyl such as C 1 alkyleneOC 1 alkyl, C 2 alkyleneOC 1 alkyl, C 1 alkyleneOC 2 alkyl or C 2 alkyleneOC 2 alkyl. In a ninth embodiment R 12c is C 1-4 haloalkyl, such as CF 3 . In a tenth embodiment R 12c is OC 1-4 haloalkyl, such as OCF 3 , OCHF 2 or OCH 2 CF 3 . In an eleventh embodiment R 12c is CN. In an eleventh embodiment R 12c is OC 0-2 alkyleneC 3-5 cycloalkyl, such as OC 3-5 cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC 1 alkyleneC 3-5 cycloalkyl or OC 2 alkyleneC 3-5 cycloalkyl. In a twelfth embodiment R 12c is OCH 2 CH 2 N(CH 3 ) 2 . In a thirteenth embodiment R 12c is OH. In a fourteenth embodiment R 12c is C 1-4 alkylOH, such as CH 2 OH or C(CH 3 ) 2 OH. In a fifteenth embodiment R 12c is NR 23c R 24c . In a sixteenth embodiment R 12c is SO 2 CH 3 . In a seventeenth embodiment R 12c is C(O)N(CH 3 ) 2 . In an eighteenth embodiment R 12c is NHC(O)C 1-3 alkyl such as NHC(O)CH 3 . In a nineteenth embodiment R 12c is a C 3-6 heterocycloalkyl comprising (such as containing) one nitrogen located at the point of attachment to Ar2c, such as a C 5 heterocycloalkyl, in particular pyrrolidinyl, or a C 6 heterocycloalkyl such as morpholinyl. In a twentieth embodiment, R 12c together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ).

[0324] In one embodiment, R 23c is H. In another embodiment, R 23c is C 1-2 alkyl i.e. CH 3 or CH 2 CH 3 .

[0325] In one embodiment, R 24c is H. In another embodiment, R 24c is C 1-2 alkyl i.e. CH 3 or CH 2 CH 3 .

[0326] R 12c is suitably H, fluoro, chloro, CH 3 , Et, OCH 3 , OEt, OiPr, CF 3 or OCH 2 CF 3 . In particular, R 12c is fluoro, chloro, CH 3 , OCH 3 , OEt, OiPr or CF 3 , for example chloro, OEt, OiPr or CF 3 such as chloro, OEt or CF 3 .

[0327] R 12c is suitably attached at the meta position of Ar2c. Alternatively, R 12c is attached at the ortho position of Ar2c.

[0328] The present invention provides compounds R94 and R95.

[0329] The present invention provides the following compounds: N-(4-(2-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide; and N-(4-(2-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide. General Terms and Definitions

[0330] In this section reference to variables and compounds of formula (I) are taken to generically cover variables wherein the suffix "a", "b" or "c" has been added. For example, reference to R 4 is taken to include reference to R 4a , R 4b and R 4c as well as sub-groups within these variables. The same applies for all other variables discussed in this section. Similarly, reference to compounds of formula (I) is taken to include compounds of formula (I-a), (I-b) and / or (I-c).

[0331] The term 'alkyl' as used herein, such as in C 1-3 alkyl, C 1-4 alkyl, C 1-5 alkyl or C 1-6 alkyl e.g. C 1-3 alkyl, C 1-4 alkyl or C 1-5 alkyl, or such as in C 1-2 alkyl, C 1-3 alkyl or C 1-4 alkyl whether alone or forming part of a larger group such as an Oalkyl group (e.g. OC 1-3 alkyl, OC 1-4 alkyl and OC 1-5 alkyl or OC 1-2 alkyl, OC 1-3 alkyl or OC 1-4 alkyl), is a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of alkyl groups include the C 1-5 alkyl groups methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and n-pentyl, sec-pentyl and 3-pentyl, in particular the C 1-3 alkyl groups methyl, ethyl, n-propyl and iso-propyl. Examples of alkyl groups also include the C 1-4 alkyl groups methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl, in particular the C 1-3 alkyl groups methyl, ethyl, n-propyl and iso-propyl such as C 1-2 alkyl groups methyl and ethyl. Reference to "propyl" includes n-propyl and iso-propyl, and reference to "butyl" includes n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of Oalkyl groups include the OC 1-4 alkyl groups methoxy, ethoxy, propoxy (which includes n-propoxy and iso-propoxy) and butoxy (which includes n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy). C 5 alkyl groups as used herein, whether alone or forming part of a larger group such as an OC 5 alkyl group is a straight or a branched fully saturated hydrocarbon chain containing five carbon atoms. Examples of C 5 alkyl groups include n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl and active pentyl. C 6 alkyl groups as used herein, whether alone or forming part of a larger group such as an OC 6 alkyl group is a straight or a branched fully saturated hydrocarbon chain containing six carbon atoms. Examples of C 6 alkyl groups include n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.

[0332] The term 'alkylene' as used herein, such as in C 0-2 alkyleneC 3-5 cycloalkyl, C 1-3 alkyleneOC 1-2 alkyl C 1-2 alkyleneOC 1-2 alkyl or OC 0-2 alkyleneC 3-5 cycloalkyl is a bifunctional straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of C 0-2 alkylene groups are where the group is absent (i.e. C 0 ), methylene (C 1 ) and ethylene (C 2 ). Examples of C 1-3 alkylene groups are where the group is methylene (C 1 ), ethylene (C 2 ) and propylene (C 3 ). Examples of C 1-2 alkylene groups are where the group is methylene (C 1 ) and ethylene (C 2 ). Examples of C 0-1 alkylene groups are where the group is absent (C 0 ) and methylene (C 1 ).

[0333] The term 'alkenyl' as used herein, such as in C 2-4 alkenyl, is a straight or branched hydrocarbon chain containing the specified number of carbon atoms and a carbon-carbon double bond.

[0334] The term 'alkynyl' as used herein, such as in C 2-4 alkynyl such as in C 2 alkynyl is an unbranched hydrocarbon chain containing the specified number of carbons (e.g. 2, 3 or 4 carbons, such as two carbons), two of which carbon atoms are linked by a carbon-carbon triple bond.

[0335] The term 'cycloalkyl' as used herein, such as in C 3-4 cycloalkyl, C 3-5 cycloalkyl or C 3-6 cycloalkyl, whether alone or forming part of a larger group such as OC 3-5 cycloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-5 cycloalkyl or C 0-1 alkyleneC 3-4 cycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms. Examples of cycloalkyl groups include the C 3-6 cycloalkyl groups cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in particular the C 3-5 cycloalkyl groups cyclopropyl, cyclobutyl and cyclopentyl:

[0336] When B is B-a, the term 'heterocycloalkyl' as used herein, such as in C 3-6 heterocycloalkyl or C 0-2 alkyleneC 3-6 heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms, wherein at least one of the carbon atoms in the ring is replaced by a heteroatom such as N, S or O. When B is B-bc, the term 'heterocycloalkyl' as used herein, such as in C 3-6 heterocycloalkyl or C 0-2 alkyleneC 3-6 heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of ring atoms and includes the ring atom through which the heterocycloalkyl group is attached, wherein at least one of the atoms in the ring is a heteroatom such as O, N or S.

[0337] As required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively the nitrogen atom(s) may be substituted (such as one nitrogen atom is substituted), for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . Wherein a ring heteroatom is S, the term 'heterocycloalkyl' includes wherein the S atom(s) is substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e. S(O) or S(O) 2 ). Alternatively, any sulphur atom(s) in the C 3-6 heterocycloalkyl ring is not substituted.

[0338] Examples of C 3-6 heterocycloalkyl groups include those comprising one heteroatom such as containing one heteroatom (e.g. oxygen) or containing two heteroatoms (e.g. two oxygen atoms or one oxygen atom and one nitrogen atom). Other examples of C 3-6 heterocycloalkyl include those comprising one heteratom atom such as containing one heteroatom (e.g. one oxygen atom or one nitrogen atom) or containing two heteroatoms (e.g. two nitrogen atoms or one nitrogen atom and one oxygen atom). Particular examples of C 3-6 heterocycloalkyl comprising one nitrogen atom include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, especially piperidinyl, pyrrolidinyl and morpholinyl. Particular examples of C 3-6 heterocycloalkyl comprising one oxygen atom include oxiranyl, oxetanyl, 3-dioxolanyl, morpholinyl, 1,4-oxathianyl, tetrahydropyranyl, 1,4-thioxanyl and 1,3,5-trioxanyl. Examples of C 3-6 heterocycloalkyl include those comprising one oxygen atom such as containing one oxygen atom, or containing two oxygen atoms. Particular examples of C 3-6 heterocycloalkyl comprising one oxygen atom include oxiranyl, oxetanyl, 3-dioxolanyl, morpholinyl, 1,4-oxathianyl, tetrahydropyranyl, 1,4-thioxanyl and 1,3,5-trioxanyl. Particular examples of C 3-6 heterocycloalkyl comprising one nitrogen atom include piperidinyl. Other examples of C 3-6 heterocycloalkyl comprising one nitrogen atom include pyrrolidinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, such as piperidinyl.

[0339] In one embodiment and when B is B-a, the term 'heterocycloalkyl' as used herein, such as in C 3-6 heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms, wherein at least one of the carbon atoms in the ring is replaced by a heteroatom such as N, S or O. Examples of C 3-6 heterocycloalkyl groups include those comprising one heteroatom such as containing one heteroatom (e.g. oxygen) or containing two heteroatoms (e.g. two oxygen atoms or one oxygen atom and one nitrogen atom).

[0340] When B is B-bc and the compound is a compound of formula (I-b), the term 'heterocycloalkyl' as used herein, such as in C 3-6 heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of ring atoms and includes the ring atom through which the heterocycloalkyl group is attached, wherein at least one of the atoms in the ring is a heteroatom such as O, N or S. Examples of C 3-6 heterocycloalkyl include those comprising one nitrogen atom such as containing one heteroatom (i.e. nitrogen) or containing two heteroatoms (e.g. two nitrogen atoms or one nitrogen atom and one oxygen atom).

[0341] The term '5- or 6-membered oxygen-containing heterocycloalkyl' as used herein, is a fully saturated hydrocarbon ring containing the specified number of ring atoms (i.e. 5 or 6), wherein at least one ring atom is an oxygen atom and the ring does not contain heteroatoms other than oxygen. Examples of oxygen-containing heterocycloalkyl groups are oxiranyl, oxetanyl, tetrahydrofuranyl, 3-dioxolanyl, tetrahydropyranyl, and 1,3,5-trioxanyl, such as tetrahydrofuranyl and tetrahydropyranyl. An example of a nitrogen-containing heterocycloalkyl group is piperidinyl.

[0342] The heterocycloalkyl groups may have any one of the following structures: wherein each Q is independently selected from O, N or S, such as O or N. When Q is N, as required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively the nitrogen atom(s) may be substituted (such as one nitrogen atom is substituted), for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . When any Q is S, the S atoms can be substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e. S(O) or S(O) 2 ). When R 4 and R 5 are R 4a and R 5a , Q is N substituted by S(O) 2 R 29 . Alternatively, any sulphur atom(s) in the C 3-6 heterocycloalkyl ring is not substituted.

[0343] When A a is -C(=O)NH-, -NH- or -CH 2 NH- and R 4a and / or R 5a is C 0 alkyleneC 3-6 heterocycloalkyl, or when R 4a and R 5a together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl, any heteroatom in the heterocycloalkyl may not be directly connected to the carbon to which R 4a and R 5a are connected.

[0344] When B is B-a, suitably, heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms wherein at least one of the carbon atoms is replaced by a heteroatom such as N, S or O wherein as required by valency, any nitrogen atom is connected to a hydrogen atom, and wherein the S atom is not present as an oxide.

[0345] When B is B-bc and the compound is a compound of formula (I-b), suitably, heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of ring atoms and includes the ring atom through which the heterocycloalkyl group is attached, wherein at least one of the atoms in the ring is a heteroatom such as O, N or S. Suitably, as required by valency, any nitrogen atom is connected to a hydrogen atom. Suitably any S atom is not present as an oxide. In particular, any nitrogen atom is connected to a hydrogen atom and any S atom is not present as an oxide.

[0346] When B is B-bc and the compound is a compound of formula (I-c), and when the heterocycloalkyl is formed from R 4 and R 5 together with the carbon atom to which they are attached, suitably any heteroatom is not directly connected to the carbon to which R 4 and R 5 are attached. Thus suitably, when the heterocycloalkyl is formed from R 4 and R 5 together with the carbon atom to which they are attached, the heterocycloalkyl may be: wherein each Q is independently O, N or S such as O or N. When Q is N, as required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively the nitrogen atom (s) may be substituted (such as one nitrogen atom is substituted), for example by C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C 3-6 heterocycloalkyl ring include C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 . When any Q is S, the S atom(s) can be substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e. S(O) or S(O) 2 ). When R 4 and R 5 are R 4a and R 5a , Q is N substituted by - S(O) 2 R 29 . Alternatively, any sulphur atom(s) in the C 3-6 heterocycloalkyl ring is not substituted.

[0347] The term 'halo' or 'halogen' as used herein, refers to fluorine, chlorine, bromine or iodine. Particular examples of halo are fluorine and chlorine, especially fluorine.

[0348] The term 'haloalkyl' as used herein, such as in C 1-6 haloalkyl, such as in C 1-4 haloalkyl or C 1-2 haloalkyl, whether alone or forming part of a larger group such as an Ohaloalkyl group, such as in OC 1-6 haloalkyl,such as in OC 1-4 haloalkyl or OC 1-2 haloalkyl, is a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms and at least one halogen atom, such as fluoro or chloro, especially fluoro. An example of haloalkyl is CF 3 . Further examples of haloalkyl are CHF 2 and CH 2 CF 3 . Another example of haloalkyl is CH 2 CHF 2 . Examples of Ohaloalkyl include OCF 3 , OCHF 2 and OCH 2 CF 3 .

[0349] The term '6-membered aryl' as used herein refers to a phenyl ring.

[0350] The term '6-membered heteroaryl' as used herein refers to 6-membered aromatic rings containing at least one heteroatom (e.g. nitrogen). Exemplary 6-membered heteroaryls include one nitrogen atom (pyridinyl), two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl) and three nitrogen atoms (triazinyl).

[0351] The phrase 'in the para position relative to group A' as used herein, such as in relation to the position of Ar2, means that compounds with the following substructure are formed: wherein when B is B-a, W 1 may be N, CH, CR 10a or CR 11a , and W 2 may be N, CH or CR 12a as allowed by the definitions provided for compounds of formula (I). W 2 may also be CR 13a as allowed by the definitions provided for compounds of formula (I-a); and when B is B-bc and the compound is a compound of formula (I-b), compounds with the following substructure are formed: wherein W may be N, CH, CR 10b or CR 11b , and Y may be N, CH, CR 12b or CR 13b as allowed by the definitions provided for compounds of formula (I-b); and when B is B-bc and the compound is a compound of formula (I-c), compounds with the following substructure are formed: wherein W may be N, CH or CR 10c , and Y may be N, CH or CR 12c as required by the definitions provided for compounds of formula (I-c). W may also be CR 11c as allowed by the definitions provided for compounds of formula (I-c).

[0352] The terms 'ortho' and 'meta' as used herein, such as when used in respect of defining the position of R 12 on Ar2 is with respect to Ar1, means that the following structures may form: when B is B-a: when B is B-bc and the compound is a compound of formula (I-b): wherein X represents a substituent e.g. R 12b ; and when B is B-bc and the compound is a compound of formula (I-c): wherein all variables listed above are as defined elsewhere herein.

[0353] When a spirocyclic ring system is said to form, e.g. when R 4aa and R 5aa , R 4ab and R 5ab , or R 4ac and R 5ac , suitably together with the carbon atom to which they are attached form a C 3-6 cycloalkyl and one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, the following spirocyclic groups are encompassed (which may optionally be substituted as mentioned above): wherein C is a C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, as defined elsewhere herein. In one embodiment C is a C 3-6 cycloalkyl ring. In a second embodiment C is a C 3-6 heterocycloalkyl ring.

[0354] For example, one of the carbons is quaternary and is attached to a 5-membered dioxalane ring to form the following structure: wherein m is 1 or 2 and n is 0, 1 or 2. Suitably m is 2 and n is 2.

[0355] Alternatively, when a spirocyclic ring system is said to form, e.g. when R 4aa and R 5aa , R 4ab and R 5ab , or R 4ac and R 5ac together with the carbon atom to which they are attached form a C 3-6 heteroycloalkyl wherein one of the carbons of the C 3-6 heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 heterocycloalkyl ring and a further C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, the following spirocyclic groups are encompassed (which may optionally be substituted as mentioned above): wherein C is a C 3-6 cycloalkyl ring or a C 3-6 heterocycloalkyl ring, as defined elsewhere herein, and HC is a C 3-6 heterocycloalkyl ring formed by R 4a and R 5a (i.e. R 4aa and R 5aa , R 4ab and R 5ab , or R 4ac and R 5ac ) as defined elsewhere herein. In one embodiment C is a C 3-6 cycloalkyl ring. In a second embodiment C is a C 3-6 heterocycloalkyl ring.

[0356] Throughout the specification Ar1 and Ar2 may be depicted as follows:

[0357] All depictions with respect to Ar1 are equivalent and all depictions with respect to Ar2 are equivalent, unless the context requires otherwise, depictions of Ar1 and Ar2 should not be taken to exclude the presence of heteroatoms or substitutions. Ar1 encompasses the variables Ar1a, Ar1b and Ar1c. Ar2 encompasses the variables Ar2a, Ar2b and Ar2c.

[0358] The present invention provides N-oxides of the compound of formula (I). Suitably, when R 12 together with a nitrogen atom to which it is attached forms an N-oxide (N +< -O -< ), the example following structures are formed:

[0359] The position numbering for Ar1 is in respect of group A, with the carbon at the point of attachment designated position 1 and other numbers providing the relative location of the nitrogen atoms, for example:

[0360] The position numbering for Ar2 is in respect of the point of attachment to Ar1, for example:

[0361] Reference to compounds of formula (I) throughout the application is intended to encompass reference to compounds of formulae (I-a), (I-b) and (I-c).

[0362] The compounds of the invention may be provided in the form of a pharmaceutically acceptable salt and / or solvate thereof. In particular, a pharmaceutically acceptable salt.

[0363] Compounds of the invention of particular interest are those demonstrating an IC 50 of 1 uM or lower, especially 100nM or lower, in respect of CTPS1 enzyme, using the methods of the examples (or comparable methods).

[0364] Compounds of the invention of particular interest are those demonstrating a selectivity for CTPS1 over CTPS2 of 2-30 fold, suitably >30-60 fold or more suitably >60 fold, using the methods of the examples (or comparable methods). Desirably the selectivity is for human CTPS1 over human CTPS2.

[0365] It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of the compounds of formula (I) may be of use in other contexts such as during preparation of the compounds of formula (I). Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge et al. (1977). Such pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid additional salts may be formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.

[0366] Certain of the compounds of formula (I) may form acid or base addition salts with one or more equivalents of the acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0367] The compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water).

[0368] It is to be understood that the present invention encompasses all isomers of formula (I) including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0369] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the "natural isotopic form") or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an "unnatural variant isotopic form"). It is understood that an atom may naturally exist as a mixture of mass numbers. The term "unnatural variant isotopic form" also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an "uncommon isotope") has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or >99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term "unnatural variant isotopic form" also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0370] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium ( 2< H or D), carbon-11 ( 11< C), carbon-13 ( 13< C), carbon-14 ( 14< C) , nitrogen-13 ( 13< N), nitrogen-15 ( 15< N), oxygen-15 ( 15< O), oxygen-17 ( 17< O), oxygen-18 ( 18< O), phosphorus-32 ( 32< P), sulphur-35 ( 35< S), chlorine-36 ( 36< Cl), chlorine-37 ( 31< Cl), fluorine-18 ( 18< F) iodine-123 ( 123< I), iodine-125 ( 125< I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0371] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3< H, and carbon-14, i.e. 14< C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e. 2< H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as 11< C, 18< F, 15< O and 13< N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0372] In one embodiment, the compounds of the invention are provided in a natural isotopic form.

[0373] In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. 2< H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0374] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0375] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

[0376] In general, the compounds of formula (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth below, those in the Examples, and modifications thereof.General Routes:

[0377] In this section reference to variables and compounds of formula (I) are taken to generically cover variables wherein the suffix "a", "b" or "c" has been added. For example, reference to R 4 is taken to include reference to R 4a , R 4b and R 4c as well as sub-groups within these variables. The same applies for all other variables discussed in this section. Reference to compounds of formula (I) is taken to include compounds of formula (I-a), (I-b) and / or (I-c).

[0378] Generic and specific routes by which compounds disclosed herein and compound examples of the invention may be conveniently prepared are disclosed in WO2019 / 106156, WO2019 / 106146, WO2019 / 179652, WO2019 / 180244 and WO2020 / 083975, as well as those routes summarised below, and adaptations thereof.Compounds of formula (I-a)

[0379] Compounds of formula (I-a) may be synthesised according to general and specific methods disclosed in WO2019 / 179652, WO2019 / 180244 and WO2020 / 083975. For the avoidance of doubt, reference to variables in each of the schemes in this section encompasses variables specific to compounds of formula (I-a). For example, R 1 includes R 1a . Furthermore, reference to intermediates in each of the schemes in this section encompasses corresponding intermediates for compounds of formula (I-a). For example, reference to compounds of formula (II) encompasses compounds of formula (II-a).

[0380] Suitably, R 2 is H, (IX) is converted to (X) using a base and alkyl halide or X-CH 2 -(CH 2 )n-X wherein n = 1,2,3 and the compounds of general formula (I) are obtained by a five step process.

[0381] In general and as illustrated in Schemes 1a and 1b, compounds of general formula (I) may be obtained by a five or six step process from a 2,4-dichloropyrimidine derivative of general formula (VIII) . Firstly, the derivative (VIII) can be reacted with an unsymmetrical malonate ester as shown in Schemes 1a, 1b of WO2019 / 179652, or 1a or 1b herein. For example, the unsymmetrical malonate ester can be treated with a base such as Cs 2 CO 3 in the presence of di-chloropyrimidine (VIII) in a solvent such as DMF and heated to an elevated temperature such as 80 °C, followed by an aqueous work-up to obtain compounds of formula (VII) . This intermediate compound can then be deprotected at this stage via a decarboxylation, initiated by the use of a strong acid such as TFA to yield intermediate derivative (IX) . Certain intermediates such as (IX) where R 3 = H, are commercially available. Reaction of a methyl 2-(2-chloropyrimidin-4-yl)acetate derivative of general formula (IX) with an inorganic base such as potassium carbonate, in the presence of an alkylating agent leads to alkylation alpha to the ester. It will be understood by persons skilled in the art that both mono- and dialkylation may be achieved with careful control of the reaction conditions, but for a more reliable synthesis of the monoalkylated product, an alternative procedure should be considered (as in Scheme 1a of WO2019179652). R 4 and R 5 can be connected to form a C 3-6 cycloalkyl ring as defined above ((IX) to (X) ). Such compounds may be prepared by double alkylation with a dihaloalkane, such as 1,2-dibromoethane or 1,3-dibromobutane in the presence of an inorganic base such as sodium hydroxide. For compounds of general formula (I) wherein R 4 and R 5 together with the carbon to which they are attached form a C 3-6 heterocycloalkyl, double alkylation of intermediates (IX) using a di-haloheteroalkane (such as BrCH 2 CH 2 OCH 2 CH 2 Br) in the presence of a base such as Cs 2 CO 3 in a solvent such as MeCN at an elevated temperature such as 60 °C followed by direct column chromatography can be used to provide compounds of formula (X) .

[0382] Palladium catalysed sulfamination of intermediate (X) may be achieved using a catalyst such as [t-BuXPhosPd(allyl)]OTf or t-BuXPhos-Pd-G3 and substituted sulfonamide nucleophile (VI) , in the presence of an inorganic base, for example potassium carbonate to form intermediate derivative (II) . Alternatively, sulfamination of intermediate (X) may be achieved using a substituted sulfonamide nucleophile (VI) , in the presence of an inorganic base, for example Cs 2 CO 3 and a solvent such as N-methyl pyrrolidinone to form intermediates (II) which may be obtained by precipitation following dilution in aqueous 4M HCl.

[0383] Final transformation to compounds of general formula (I) can be prepared by conversion of intermediate (II) by activation of the ester moiety using trimethylaluminium (usually a 2.0 M solution in toluene or heptane) and addition of amine (III) (commercially available or prepared as in Schemes 6a, 6b, 7a or 7b of WO2019179652). Alternatively, compounds of formula (I) may be obtained by a strong base-mediated amide formation between compounds (II) and (III) at room temperature using bases such as iPrMgCl, LiHMDS or KOtBu.

[0384] Compounds of the general formula (VII) where R 2 is O-alkyl may be accessed in two steps from commercial 2,4,6-trichloropyrimidine derivatives such as (VIII) where R 2 is Cl. Reaction of an unsymmetrical malonate ester can yield compounds such as (VII) which can then be treated with an alkoxide base such as sodium methoxide to displace the more reactive chloride to give compounds of general formula (VII) where R 2 = O-alkyl. Such compounds can then be progressed to final compounds of formula (I) following the steps previously described in Schemes 1a or 1b.

[0385] Compounds of general formula (I) where R 1 , Ar1 and Ar2 are defined above and R 4 and R 5 together with the carbon to which they are attached form a C 3-6 heterocycloalkyl, may be prepared in five steps starting from intermediate of general formula (VIII) . Firstly, alkyl esters of general formula (XXVII) can be treated with a strong base such as LiHMDS then reacted with 2,4-dichloropyrimidines such as derivative (VIII) . Such compounds can then be converted to final compounds using the methods described in Scheme 1b. If any protecting groups remain after amide coupling, treatment with a strong acid such as TFA may yield final compounds of formula (I) .

[0386] Following deprotection compounds of general formula (I) where R 1 , Ar1 and Ar2 are defined above and R 4 and R 5 together with the carbon to which they are attached form a C 3-6 aminocycloalkyl, may be further elaborated by treatment with a suitable electrophile such as an acid chloride or an isocyanate, to yield the corresponding amide or urea. Such compounds may also undergo reductive amination in the presence of a suitable aldehyde or ketone followed by treatment with sodium triacetoxyborohydride.

[0387] Intermediates of formula (III) wherein Ar1, R 10 , R 11 , R 12 and R 13 are defined above and Ar2 is an unsubstituted or substituted 3-pyridyl ring, may be synthesised by coupling under Suzuki conditions of a boronate of general formula (XII) , wherein R 12 and R 13 are defined above and Z represents a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group, to a substituted pyridine of formula (XI) where X denotes a halide. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.

[0388] Intermediates of formula (III) wherein Ar1, R 10 , R 11 , R 12 and R 13 are defined above and Ar2 is an unsubstituted or substituted 2,5-pyrazinyl ring, may be synthesised by coupling under Suzuki conditions of an aromatic halide of general formula (XII) and Z represents a halide, to a boronate of general formula (XI) where X denotes a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II) and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.Benzamide pyrimidines

[0389]

[0390] Compounds of general formula (I) may be obtained by a four step process, as shown in Scheme 4. 2-Chloropyrimidine-4-carbonitrile (XXXIX) can be converted to the corresponding sulfonamide (XXXX) using palladium catalysed sulfamination conditions previously reported in Scheme 1a and 1b of WO2019179652. Reduction of the nitrile group using sodium borohydride in the presence of nickel (II) chloride and di-tert-butyl dicarbonate may yield the protected benzylamine derivative of general formula (XXXXI). Deprotection can be carried out by acid hydrolysis using HCl in dioxane to yield benzylamine derivative of general formula (XXXXII). Amide coupling conditions may then be employed to convert the benzylamine derivative (XXXXII) to amides of general formula (I) by employing a coupling reagent together with a biaryl carboxylic acid (XXXXIII) (commercially available or prepared as in Scheme 19 of WO2019179652 or Scheme 6 herein).

[0391] Compounds of general formula (I) where A is an amine linker such as -CH 2 NH-, where R 1 , Ar 1 and Ar 2 are defined above, R 4 is C 1-6 alkyl and R 5 is H or C 1-6 alkyl or R 4 and R 5 together with the carbon to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl may be accessed in one step from benzyl amines such as (XXXXII). Reaction of (XXXXII) with aromatic aldehydes (LXXII) in the presence of a hydride source such as sodium triacetoxyborohydride may yield amines of formula (I).

[0392] Compounds of general formula (I) where R 1 , Ar 1 and Ar 2 are defined above, R 4 is C 1-6 alkyl and R 5 is H or C 1-6 alkyl or R 4 and R 5 together with the carbon to which they are attached form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl may be obtained by a six step process, as shown in Scheme 5. Firstly, the carboxylic acid (LVXII) can be obtained by hydrolysis of methyl ester (XXXIII) using an alkali metal base such as lithium hydroxide. Curtius rearrangement can be carried out, for example, using diphenylphosphoryl azide in the presence of propylphosphonic anhydride, triethylamine and tert-butanol to yield carbamates such as (LVXIII). Deprotection can be carried out by acid hydrolysis using HCl in dioxane to yield benzylamine derivative of general formula (LVXIX). Amide coupling conditions may then be employed to convert the benzylamine derivative (LVXIX) to amides of general formula (LXX) by employing a coupling reagent together with a biaryl carboxylic acid (XXXXIII) (commercially available or prepared as in Scheme 19 of WO2019179652). Compound of formula (LXX) can then be progressed to compounds of formula (I) following the oxidation, displacement sequence described in Scheme 9a.

[0393] Intermediates of formula (LXXII) where Ar 2 is an unsubstituted or substituted 2-pyrazine ring or 3-pyridyl ring, may be synthesised as shown in Scheme 6, in a one-pot, two step procedure starting with borylation of (XI) , where X denotes a halogen such as Br or Cl. followed by coupling under Suzuki conditions with an aromatic halide of general formula (XII) , of which R 12 and R 13 are defined above and Z represents Br or Cl. Initially compounds such as (XI) , can be converted to the corresponding boronate using a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH 2 Cl 2 adduct and an inorganic base such as potassium acetate in a solvent such as dioxane. Aromatic halide (XII) may then be added to the reaction mixture along with an aqueous solution of an inorganic base such as caesium carbonate to yield alcohols of formula (LXXI) . The aldehydes of general formula (LXXII) are obtained by treatment with an oxidant such as manganese dioxide.

[0394] In general compounds of formula (I) where R 4 and R 5 together with the carbon to which they are attached form a 1,4-dioxaspiro[4.5]decane (i.e. m and n are 2) may be treated with a strong acid, such as HCl, to yield cyclic ketones of formula (I) . Such ketones may then be treated with a hydride source, such as sodium borohydride, to yield the corresponding exocyclic alcohol or reacted with an amine, such as dimethylamine, followed by sodium triacetoxyborohydride to yield exocyclic amines of formula (I) .

[0395] Compounds of formula (I) wherein A is -NR 6 CH 2 - can be obtained from compounds of formula (I) wherein A is -NR 6 C(=O)-, by the reduction of the amide to the amine using a reducing agent such as LiAlH 4 in a solvent such as THF.

[0396] In general and as illustrated in Scheme 9a, compounds of formula (I) wherein R 1 , Ar1 and Ar2 are as defined above, alkyl is C 1-4 alkyl such as methyl or ethyl, e.g. methyl, and for example, R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl ring may be prepared starting from a general intermediate of formula (XXXIII). Intermediates such as (LXXIV) may be obtained by subjecting compounds such as (XXXIII) to amide coupling conditions such as those described in Scheme 9 of WO2019179652 using iPrMgCl. Thioethers of the general formula (LXXIII) may be transformed to sulfoxides or sulfones (LXXIV) in the presence of an oxidising agent such as mCPBA. Displacement of the sulfone group with a primary sulphonamide (VI) in the presence of a base such as Cs 2 CO 3 and a solvent such as N-methyl pyrrolidone gives compounds of formula (I).

[0397] Compounds of formula (I) may also be accessed by oxidation of (XXXIII) to form sulphone (LXXXIII), which can be coupled with (VI), and then (III) using standard conditions disclosed elsewhere herein to give compounds of formula (I).

[0398] In general and as illustrated in Scheme 9b, compounds of formula (I) wherein R 1 , Ar1 and Ar2 are as defined above, alkyl is C 1-4 alkyl such as methyl or ethyl, e.g. methyl, and for example, R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl ring may be prepared starting from a general intermediate of formula (LXXX) . Intermediates such as (LXXXI) may be obtained by subjecting compounds such as (LXXX) and (III) to reductive amination conditions such as those described in Scheme 7. Thioethers of the general formula (LXXXI) may be transformed to sulfoxides or sulfones (LXXXII) in the presence of an oxidising agent such as mCPBA. Displacement of the sulfone group with a primary sulphonamide (VI) in the presence of a base such as Cs 2 CO 3 and a solvent such as N-methyl pyrrolidone gives compounds of formula (I). wherein R is H, C 1-4 alkyl (e.g. methyl and ethyl) or benzyl. In general and as illustrated in Scheme 9c, compounds of formula (I) wherein R 1 , X, Y, Z, Ar1 and Ar2 are as defined above and K is C 1-4 alkyl, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)OC 1-4 alkylaryl such as C(O)OBz, C(O)NHC 1-4 alkyl, C(O)NHC 1-4 alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C 1-4 haloalkyl, C(O)OC 1-4 haloalkyl or C(O)NHC 1-4 haloalkyl such as C(O)OtBu, C 1-4 alkylCN such as CH 2 CN, C(O)C 1-3 alkylOC 1-2 alkyl such as C(O)CH 2 OCH 3 , and C 1-2 alkylC(O)OC 1-4 alkyl such as CH 2 C(O)OCH 2 CH 3 , may be prepared in five steps from compounds of formula (LVX). An intermediate of formula (XXXVII) may be coupled to a compound of formula (LVX) in the presence of a base such as LiHMDS to give a compound of formula (XXXIII). Thioethers of the general formula (XXXIII) may be transformed to a sulfoxide of formula (XXXIV) or a sulfone of formula (LXXXIII) in the presence of an oxidising agent such as mCPBA. The skilled person will appreciate that formation of the sulfoxide or sulfone can be controlled by varying the number of equivalents of oxidising agent used, the length of reaction and / or the temperature of the reaction. Displacement of the sulfoxide group or the sulfone group with a primary sulfonamide (VI ) in the presence of a base such as Cs 2 CO 3 and a solvent such as N-methyl pyrrolidone gives compounds of formula (II) . Compounds of formula (I) may be obtained by a strong base-mediated amide formation between compounds (II) and (III) at room temperature using bases such as iPrMgCl, LiHMDS or KOtBu, to give compounds of formula (I-P), followed by removal of the Boc group using a strong acid such as TFA, and introduction of the N-substituent K. Introduction of K may be performed by reaction of the free NH group with K-LG wherein LG is a leaving group such as halo e.g. chloro or bromo, under standard conditions known to the skilled person, or by any other N-substituent forming conditions known to the skilled person (such as Mitsunobu conditions, reductive amination or N-acylation), to give a compound of formula (I).

[0399] In general and as illustrated in Scheme 10, compounds of formula (I) wherein R 1 , Ar1 and Ar2 are as defined above, alkyl is C 1-4 alkyl such as methyl or ethyl, e.g. methyl, and for example, R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl ring may be prepared starting from chloro-pyrimidine (LXXV) . Intermediates (XXXVII) are coupled to chloro-pyrimidine (LXXV) in the presence of a base such as LiHMDS to give intermediates (LXXVI). Thioethers of the general formula (LXXVI) may then be transformed to compounds of formula (I) following the route described in Scheme 9a of WO2019179652.

[0400] In general and as illustrated in Scheme 11, compounds of formula (I) wherein R 1 , Ar1 and Ar2 are as defined above, R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 heterocycloalkyl ring may be prepared starting from alcohols (LXXI), which as oxidised to aldehydes (LXXII) in the presence of MnO 2 in a non-protic solvent such as DCM. Reductive coupling of amine (LXXIX) and aldehyde (LXXII) in the presence of a hydride source such as sodium triacetoxyborohydride in an aprotic solvent such as DCM in the presence of a proton source such as acetic acid affords compounds of formula (I) following the route described in Scheme 11.

[0401] Compounds of formula (I) wherein A is -NH- and R 4 or R 5 is H may be prepared by reductive coupling of the appropriate amine and aldehyde in the presence of a hydride source such as sodium triacetoxyborohydride.Compounds of formula (I-b)

[0402] Compounds of formula (I-b) may be synthesised by general and specific methods disclosed in WO2019 / 106156 and those disclosed below. For the avoidance of doubt, reference to variables in each of the schemes in this section encompasses variables specific to compounds of formula (I-b). For example, R 1 includes R 1b . Furthermore, reference to intermediates in each of the schemes in this section encompasses corresponding intermediates for compounds of formula (I-b). For example, reference to compounds of formula (II) encompasses compounds of formula (II-b).

[0403] Compounds of formula (I) may be obtained by a general process whereby a carboxylic acid precursor (II) , or a suitably protected derivative thereof, is reacted with an activating agent, to generate a reactive, electrophilic carboxylic acid derivative, followed by subsequent reaction with an amine of formula (IX) . Intermediates of formula (X) are then converted to a compound of the invention of general formula (I) by coupling under Suzuki conditions with an aromatic halide or boronate of general formula (XI) , of which X is defined above and represents usually a bromide, a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as bis(diphenylphosphino)ferrocene]dichloropalladium(ll) and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water. It will be understood by persons skilled in the art that many catalysts and conditions can be employed for such couplings.

[0404] Intermediates of formula (III) where Ar2 is an unsubstituted or substituted 3-pyridyl ring, may be synthesised by coupling under Suzuki conditions of a boronate of general formula (XI) , of which R 12< and R 13< are defined above and Z represents a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group, to a substituted pyridine of formula (IX) of which R 10< and R 11< are defined above and where X denotes a halide. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and an inorganic base such as potassium carbonate in a solvent mixture of 1,4-dioxane and water.

[0405] Intermediates of formula (III) where Ar2 is an unsubstituted or substituted 2-pyrazine ring, may be synthesised by coupling under Suzuki conditions of an aromatic halide of general formula (XI) , of which R 12< and R 13< are defined above and Z represents a halide, to a boronate of general formula (IX) of which R 10< and R 11< are defined above and where X denotes a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(ll) and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.

[0406] Compound of general formula (XVII) may be prepared by conversion of a suitable 2-(2-aminothiazol-4-yl)acetate derivative, such as a methyl or ethyl derivative, by a Sandmeyer type reaction using an organic nitrite, such as n-butylnitrite, in the presence of a halide source, such as Cu(I)Br in acetonitrile. Such reactions can be undertaken at temperatures of RT to 60 °C. Introduction of R 4 / R 5 can be undertaken by two alternative methods at this stage. Firstly, alkylation of compounds of general formula (XVII) can be undertaken by addition of a suitable base, for example, LiHMDS, together with an alkylating agent, such as iodomethane which results in dialkylation alpha to the ester moiety to yield compounds of formula (XVIII), where R 4b = R 5b = Me. Secondly, diazotisation of compounds of general formula (XVII) with the use of an diazo transfer reagent, such as 4-acetamidobenzenesulfonyl azide, under basic conditions, followed by treatment with rhodium and subsequent insertion of the corresponding nucleophile, such as isopropyl alcohol, gives intermediates of general formula (XVIII) where R 4b = Oisopropoxy and R 5b = H.

[0407] Introduction of the sulfonamide group in the preparation of compounds of formula (IV) may be achieved by an Ullmann coupling reaction i.e. Cu mediated coupling conditions using amines of formula (XXIV) and a copper catalyst, such as Cu(I)I, in the presence of an inorganic base, potassium carbonate, and a diamine ligand in dioxane. Such reactions are typically carried out at elevated temperatures such as 80 °C. Alternatively, conversion of compounds of formula (XVIII) to (IV) can be achieved via a palladium mediated coupling, for example using a catalyst such as [t-BuXPhos Pd(allyl)]OTf and substituted sulfonamide nucleophile (XXIV), in the presence of an inorganic base, for example potassium carbonate to form compounds of formula (IV) . Palladium mediatiated coupling conditions are particularly useful when R 4 and R 5 together with the carbon atom to which they are attached form a 5- or 6-membered heterocycloalkyl, such as a tetrahydropyranyl. The alkyl esters of formula (IV) may be conveniently converted to compounds of formula (I) according to synthetic steps reported in Scheme 13. wherein halo is, for example, bromo. Compounds of formula (XXVII), for example, when R 4b is H and R 5b and R 6 are a C 2-3 alkylene chain forming a 5- or 6-membered ring, can be accessed in three steps from compounds of formula (XXV) . Acylation of compounds of formula (XXV) in the presence of a strong base such as LDA followed by a quench with an -< OAc source such as EtOAc provides compounds of formula (XXVI). Compounds of formula (XXVII) can be made from (XXVI) following addition of bromine and quench with a suitable thiourea, before a coupling with sulfonyl chlorides of formula (VI) to give compounds of formula (XXVIII). Compounds of formula (I) may be accessed using conditions set out in Scheme 14.

[0408] In general compounds of formula (I) where R 4 and R 5 together with the carbon to which they are attached form a 1,4-dioxaspiro[4.5]decane (i.e. m is 2 and n is 2) may be treated with a strong acid such as HCl to yield cyclic ketones of formula (I) . Such ketones may then be treated with a hydride source such as sodium borohydride to yield the corresponding exocyclic alcohol or reacted with an amine such as dimethylamine followed by sodium triacetoxyborohydride to yield exocyclic amines of formula (I).

[0409] Compounds of formula (I) wherein A is -NR 6 CH 2 - can be obtained from compounds of formula (I) wherein A is -NR 6 C(=O)-, by the reduction of the amide to the amine using a reducing agent such as LiAlH 4 in a solvent such as THF.

[0410] Compounds of formula (I) wherein A is -NR 6 - and R 5 or R 4 are H can be obtained in a single step by a reductive amination between ketones of formula (XXIX) and amines of formula (III) in the presence of a hydride source such as sodium triacetoxyborohydride.Compounds of formula (I-c)

[0411] Compounds of formula (I-c) may be synthesised by general and specific methods disclosed in WO2019 / 106146 and those disclosed below. For the avoidance of doubt, reference to variables in each of the schemes in this section encompasses variables specific to compounds of formula (I-c). For example, R 1 includes R 1c . Furthermore, reference to intermediates in each of the schemes in this section encompasses corresponding intermediates for compounds of formula (I-c). For example, reference to compounds of formula (II) encompasses compounds of formula (II-c).

[0412] Compounds of formula (XIII) may be obtained by a general process as shown in Scheme 21 whereby a carboxylic acid precursor (XIV) is reacted with an activating agent such as HATU, T3P or Ghosez's reagent, to generate a reactive, electrophilic carboxylic acid derivative, followed by subsequent reaction with an amine of formula (II) . Intermediates of formula (XIII) are then converted to a compound of general formula (I) by coupling under Suzuki conditions with an aromatic halide of general formula (XII), of which X is defined in Scheme 21 and represents a dihydroxyboryl or dialkyloxyboryl group, such as a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH 2 Cl 2 adduct and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water under an inert atmosphere such as a nitrogen atmosphere. It will be understood by persons skilled in the art that many catalysts and conditions can be employed for such couplings.

[0413] Intermediates of formula (III) where Ar 2 is an unsubstituted or substituted 2-pyrazine ring or 3-pyridyl ring, may be synthesised as shown in Scheme 22 by coupling under Suzuki conditions of an aromatic halide of general formula (XII) , of which R 10 and R 12 are defined above and Z represents a halide such as Br or Cl, to a boronate of general formula (XVI) where X denotes a dihydroxyboryl or dialkyloxyboryl group, such as a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH 2 Cl 2 adduct and an inorganic base such as cesium carbonate in a solvent mixture of dioxane and water under an inert atmosphere such as a nitrogen atmosphere. The carboxylic acids of general formula (III) are obtained by either deprotection of the t-butyl ester using a strong acid, such as TFA in a solvent of CH 2 Cl 2 , hydrolysis of the methyl ester using an alkali metal hydroxide such as NaOH in a solvent mixture such as THF / MeOH or hydrolysis of the nitrile using a strong acid such as concentrated HCl. Compounds of formula (III-A) may also be made using this method.

[0414] Compounds of formula (I) wherein A a is -CH 2 NR 6 - can be accessed in two steps from compounds of formula (XXII) . Oxidation of the alcohol (XXII) under standard oxidation conditions such as MnO 2 gives aldehyde (XXIII) . A reductive amination using a hydride source such as sodium triacetoxyborohydride between aldehyde (XXIII) and amine (II) gives compounds of formula (I).

[0415] In general compounds of formula (I) where R 4a and R 5a together with the carbon to which they are attached form a C 3-6 cycloalkyl wherein one of the carbons of the C 3-6 cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C 3-6 cycloalkyl ring and a C 3-6 heterocycloalkyl ring, such as a 1,4-dioxaspiro[4.5]decane moiety (m is 2 and n is 2), may be treated with a strong acid such as HCl to yield cyclic ketones of formula (I) . Such ketones may then be treated with a hydride source such as sodium borohydride to yield the corresponding exocyclic alcohol or reacted with an amine such as dimethylamine followed by sodium triacetoxyborohydride to yield exocyclic amines of formula (I) .Intermediates of the Invention Compounds of formula (I-a)

[0416] The present invention provides intermediates of the following general formulae, wherein unless otherwise stated, the variable groups and associated preferences are as defined previously for compounds of formula (I-a): a compound of formula (II-a): wherein X, Y and Z are as defined herein, R is H, C 1-6 alkyl (e.g. methyl and ethyl) or benzyl, R 1 is R 1aa and / or R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (XX-a): wherein X, Y, Z, R 10 , R 11 , R 12 , R 13 , Ar 1 and Ar 2 are as defined herein, P is a nitrogen protecting group such as para-methoxybenzyl, R 1 is R 1aa and / or R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (XXIV-a): wherein X, Y, Z, R 10 , R 11 , R 12 , R 13 , A, Ar 1 and Ar 2 are as defined herein, P is a nitrogen protecting group such as para-methoxybenzyl, R 1 is R 1aa and / or R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (XXXI-a): wherein X, Y, Z, R 10 , R 11 , R 12 , R 13 , Ar 1 and A 2 are as defined herein, A is A a and / or R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (XXXXII-a): wherein X, Y and Z are as defined herein, R 1 is R 1aa and / or R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (LI-a): wherein X, Y, Z, Ar 1 and Ar 2 are as defined herein, X 1 is Cl or Br, A is A aa and / or R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (LVIII-a): wherein X, Y, Z, and Ar 1 are as defined herein, A is A a and / or R 1 is R 1aa and / or R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (XXXIII-a): wherein X, Y and Z are as defined herein, alkyl is C 1-4 alkyl such as methyl or ethyl, e.g. methyl and R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (LXXIII-a): wherein X, Y, Z, A 1 , Ar 2 are as defined herein and R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (LXXIV-a): wherein X, Y, Z, Ar 1 and Ar 2 are as defined herein, and R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (LXXXIII-a): wherein X, Y and Z are as defined herein, alkyl is C 1-4 alkyl such as methyl or ethyl, e.g. methyl and R 4 and R 5 are R 4aa and R 5aa ; a compound of formula (XXXIV-a): wherein X, Y and Z are as defined herein, and alkyl is C 1-4 alkyl such as methyl or ethyl, e.g. methyl;

[0417] Compounds of formula (I) may be considered intermediates for further compounds of formula (I), as described in the Examples below.

[0418] Included as an aspect of the invention are all novel intermediates described in the examples, including: Intermediates INTC186 to INTC218; and Intermediates INTC232 to INTC247.

[0419] Included as an aspect of the invention are salts such as pharmaceutically acceptable salts of any one of the intermediates claimed herein.Compounds of formula (I-b)

[0420] The present invention also provides intermediates of the following general formulae, wherein unless otherwise stated, the variable groups and associated preferences are as defined previously for compounds of formula (I-b): Compounds of formula (II-b) wherein R 3 , is as defined herein R 1 is R 1ab and / or R 4 and R 5 are R 4ab and R 5ab ; Compounds of formula (IV-b) wherein R 3 is as defined herein, R is C 1-6 alkyl (e.g. methyl, ethyl) or benzyl, R 1 is R 1ab and / or R 4 and R 5 are R 4ab and R 5ab .

[0421] Included as an aspect of the invention are salts such as pharmaceutically acceptable salts of any one of the intermediates claimed herein.Compounds of formula (I-c)

[0422] The present invention also provides intermediates of the following general formulae, wherein unless otherwise stated, the variable groups and associated preferences are as defined previously for compounds of formula (I-c): a compound of formula (II-c): wherein R 3 is as defined herein, R 1 is R 1ac and / or R 4 and R 5 are R 4ac and R 5ac ; a compound of formula (VIII-c) : wherein R 3 and R 4 are as defined herein and R 1 is R 1ac .

[0423] Included as an aspect of the invention are salts such as pharmaceutically acceptable salts of any one of the intermediates claimed herein.Therapeutic Methods

[0424] In the following section, reference to compounds of formula (I) encompasses compounds of formula (I-a), (I-b) and (I-c).

[0425] Compounds of formula (I) of the present invention have utility as inhibitors of CTPS1.

[0426] Therefore, the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g. salt), for use as a medicament, in particular in the treatment or prophylaxis of a disease or disorder wherein an inhibitor of CTPS1 is beneficial, for example those diseases and disorders mentioned herein below.

[0427] More suitably, the disease or disorder wherein an inhibitor of CTPS1 is beneficial is a disease or disorder wherein a reduction in T-cell and / or B-cell proliferation would be beneficial.

[0428] The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g. salt) thereof, for use in the inhibition of CTPS1 in a subject.

[0429] The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g. salt) thereof, for use in the reduction of T-cell and / or B-cell proliferation in a subject.

[0430] More suitably, the disease or disorder wherein an inhibitor of CTPS1 is beneficial is a disease or disorder wherein a reduction in T-cell and / or B-cell proliferation would be beneficial.

[0431] The term 'treatment' or 'treating' as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms.

[0432] The term 'prophylaxis' or 'preventing' is used herein to mean preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction.

[0433] Suitably, the disease or disorder is selected from rejection of transplanted cells and tissues, Graft-related diseases or disorders, allergies and autoimmune diseases.

[0434] In one embodiment the disease or disorder is the rejection of transplanted cells and tissues. The subject may have been transplanted with a graft selected from the group consisting of heart, kidney, lung, liver, pancreas, pancreatic islets, brain tissue, stomach, large intestine, small intestine, cornea, skin, trachea, bone, bone marrow (or any other source of hematopoietic precursor cells and stem cells including hematopoietic cells mobilized from bone marrow into peripheral blood or umbilical cord blood cells), muscle, or bladder. The compounds of the invention may be of use in preventing or suppressing an immune response associated with rejection of a donor tissue, cell, graft or organ transplant in a subject.

[0435] In a further embodiment the disease or disorder is a Graft-related disease or disorder. Graft-related diseases or disorders include graft versus host disease (GVHD), such as GVHD associated with bone marrow transplantation, and immune disorders resulting from or associated with rejection of organ, tissue, or cell graft transplantation (e.g., tissue or cell allografts or xenografts), including, e.g., grafts of skin, muscle, neurons, islets, organs, parenchymal cells of the liver, etc, and Host-Versus-Graft-Disease (HVGD). The compounds of the invention may be of use in preventing or suppressing acute rejection of such transplant in the recipient and / or for long-term maintenance therapy to prevent rejection of such transplant in the recipient (e.g., inhibiting rejection of insulin-producing islet cell transplant from a donor in the subject recipient suffering from diabetes). Thus the compounds of the invention have utility in preventing Host-Versus-Graft-Disease (HVGD) and Graft-Versus-Host-Disease (GVHD).

[0436] A CTPS1 inhibitor may be administered to the subject before, after transplantation and / or during transplantation. In some embodiments, the CTPS1 inhibitor may be administered to the subject on a periodic basis before and / or after transplantation.

[0437] In another embodiment, the disease or disorder is an allergy.

[0438] In additional embodiments the immune related disease or disorder is an autoimmune disease. As used herein, an "autoimmune disease" is a disease or disorder directed at a subject's own tissues. Examples of autoimmune diseases include, but are not limited to Addison's Disease, Adult-onset Still's disease, Alopecia Areata, Alzheimer's disease, Anti-neutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis, Ankylosing Spondylitis, Anti-phospholipid Syndrome (Hughes' Syndrome), Aplastic Anemia, Arthritis, Asthma, Atherosclerosis, Atherosclerotic plaque, Atopic Dermatitis, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Autoimmune Hypophysitis (Lymphocytic Hypophysitis), Autoimmune Inner Ear Disease, Autoimmune Lymphoproliferative Syndrome, Autoimmune Myocarditis, Autoimmune Neutropenia, Autoimmune Oophoritis, Autoimmune Orchitis, Auto-Inflammatory Diseases requiring an immunosuppressive treatment, Azoospermia, Bechet's Disease, Berger's Disease, Bullous Pemphigoid, Cardiomyopathy, Cardiovascular disease, Celiac disease including Refractory Celiac Disease (type I and type II), Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic Idiopathic Polyneuritis, Chronic Inflammatory Demyelinating Polyneuropathy (CIPD), Chronic Relapsing Polyneuropathy (Guillain-Barré syndrome), Churg-Strauss Syndrome (CSS), Cicatricial Pemphigoid, Cold Agglutinin Disease (CAD), chronic obstructive pulmonary disease (COPD), CREST Syndrome, Cryoglobulin Syndromes, Cutaneous Lupus, Dermatitis Herpetiformis, Dermatomyositis, Eczema, Epidermolysis Bullosa Acquisita, Essential Mixed Cryoglobulinemia, Evan's Syndrome, Exophthalmos, Fibromyalgia, Goodpasture's Syndrome, Grave's disease, Hemophagocytic Lymphohistiocytosis (HLH) (including Type 1 Hemophagocytic Lymphohistiocytosis), Histiocytosis / Histiocytic Disorders, Hashimoto's Thyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura (ITP), IgA Nephropathy, Immunoproliferative Diseases or Disorders, Inflammatory Bowel Disease (IBD), Interstitial Lung Disease, Juvenile Arthritis, Juvenile Idiopathic Arthritis (JIA), Kawasaki's Disease, Lambert-Eaton Myasthenic Syndrome, Lichen Planus, Localized Scleroderma, Lupus Nephritis, Ménière's Disease, Microangiopathic Hemoytic Anemia, Microscopic Polyangitis, Miller Fischer Syndrome / Acute Disseminated Encephalomyeloradiculopathy, Mixed Connective Tissue Disease, Multiple Sclerosis (MS), Muscular Rheumatism, Myalgic Encephalomyelitis (ME), Myasthenia Gravis, Ocular Inflammation, Pemphigus Foliaceus, Pemphigus Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes (Whitaker's syndrome), Polymyalgia Rheumatica, Polymyositis, Primary Agammaglobulinemia, Primary Biliary Cirrhosis / Autoimmune Cholangiopathy, Primary Glomerulonephritis, Primary Sclerosing Cholangitis, Psoriasis, Psoriatic Arthritis, Pure Red Cell Anemia, Raynaud's Phenomenon, Reiter's Syndrome / Reactive Arthritis, Relapsing Polychondritis, Restenosis, Rheumatic Fever, Rheumatic Disease, Rheumatoid Arthritis, Sarcoidosis, Schmidt's Syndrome, Scleroderma / Systemic Sclerosis, Sjörgen's Syndrome, Stiff-Man Syndrome, The Sweet Syndrome (Febrile Neutrophilic Dermatosis), Systemic Lupus Erythematosus (SLE), Systemic Scleroderma, Takayasu Arteritis, Temporal Arteritis / Giant Cell Arteritis, Thyroiditis, Type 1 diabetes, Type 2 diabetes, Uveitis, Vasculitis, Vitiligo, Wegener's Granulomatosis, and X-linked lymphoproliferative disease.

[0439] Of particular interest are diseases and disorders which are mainly driven by T-cell activation and proliferation, including: diseases and disorders which are not linked to alloreactivity including: ▪ Alopecia areata, atopic dermatitis, eczema, psoriasis, lichen planus, psoriatic arthritis, vitiligo; ▪ Uveitis; ▪ Ankylosing spondylitis, Reiter's syndrome / reactive arthritis; ▪ Aplastic anemia, autoimmune lymphoproliferative syndrome / disorders, hemophagocytic lymphohistiocytosis; ▪ Type 1 diabetes; and ▪ Refractory celiac disease; Acute rejection of grafted tissues and transplanted organs; acute graft versus host disease (GVHD) after transplantation of bone marrow cells or any other source of allogenic cells including hematopoietic precursors cells and / or stem cells.

[0440] Also of interest are diseases and disorders which are driven by both T- and B-cell activation and proliferation, with an important involvement of B-cells, including: diseases and disorders for which the involvement of pathogenic auto-antibodies is well characterized, including: Allergy; Cicatricial pemphigoid, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus foliaceus, pemphigus vulgaris, dermatitis herpetiformis; ANCA-associated vasculitis and microscopic polyangitis, vasculitis, Wegener's granulomatosis; Churg-Strauss syndrome (CSS), polyarteritis nodosa, cryoglobulin syndromes and essential mixed cryglobulinemia; Systemic lupus erythematosus (SLE), antiphospholipid syndrome (Hughes' syndrome), cutaneous lupus, lupus nephritis, mixed connective tissue disease; Thyroiditis, Hashimoto thyroiditis, Grave's disease, exophthalmos; Autoimmune hemolytic anemia, autoimmune neutropenia, ITP, pernicious anaemia, pure red cell anaemia, micro-angiopathic hemolytic anemia; Primary glomerulonephritis, Berger's disease, Goodpasture's syndrome, IgA nephropathy; and Chronic idiopathic polyneuritis, chronic inflammatory demyelinating polyneuropathy (CIPD), chronic relapsing polyneuropathy (Guillain-Barré syndrome), Miller Fischer syndrome, Stiff man syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis. diseases and disorders for which the involvement of B-cells is less clearly characterized (although sometimes illustrated by the efficacy of anti-CD20 monoclonal antibodies or intravenous immunoglobulin infusions) and may not correspond or be limited to the production of pathogenic antibodies (nevertheless, non-pathogenic antibodies are sometimes described or even often present and used as a diagnosis biomarker), including: Addison's disease, autoimmune oophoritis and azoospermia, polyglandular syndromes (Whitaker's syndrome), Schmidt's syndrome; Autoimmune myocarditis, cardiomyopathy, Kawasaki's disease; Rheumatoid arthritis, Sjögren's syndrome, mixed connective tissue disease, polymyositis and dermatomyositis; polychondritis; Primary glomerulonephritis; Multiple sclerosis; Autoimmune hepatitis, primary biliary cirrhosis / autoimmune cholangiopathy, ▪ Hyper acute rejection of transplanted organs; ▪ Chronic rejection of graft or transplants; ▪ Chronic Graft versus Host reaction / disease after transplantation of bone marrow cells or hematopoietic precursor cells.

[0441] Additionally of interest are diseases and disorders for which the mechanism is shared between activation / proliferation of T-cells and activation / proliferation of innate immune cells and other inflammatory cellular subpopulations (including myeloid cells such as macrophages or granulocytes) and resident cells (such as fibroblasts and endothelial cells), including: ▪ COPD, idiopathic pulmonary fibrosis, interstitial lung disease, sarcoidosis; ▪ Adult onset Still's disease, juvenile idiopathic arthritis, Systemic sclerosis, CREST syndrome where B cells and pathogen antibodies may also play a role; the Sweet syndrome; Takayasu arteritis, temporal arteritis / giant cell arteritis; ▪ Ulcerative cholangitis, inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis, primary sclerosing cholangitis.

[0442] Also of interest are diseases and disorders for which the mechanism remains poorly characterized but involves the activation and proliferation of T-cells, including: ▪ Alzheimer's disease, cardiovascular syndrome, type 2 diabetes, restenosis, chronic fatigue immune dysfunction syndrome (CFIDS). Autoimmune Lymphoproliferative disorders, including: ▪ Autoimmune Lymphoproliferative Syndrome and X-linked lymphoproliferative disease.

[0443] Suitably the disease or disorder is selected from: inflammatory skin diseases such as psoriasis or lichen planus; acute and / or chronic GVHD such as steroid resistant acute GVHD; acute lymphoproliferative syndrome; systemic lupus erythematosus, lupus nephritis or cutaneous lupus; or transplantation. In addition, the disease or disorder may be selected from myasthenia gravis, multiple sclerosis, and scleroderma / systemic sclerosis.

[0444] The compounds of formula (I) may be used in the treatment of cancer.

[0445] Thus, in one embodiment there is provided a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of cancer.

[0446] Suitably the cancer is a haematological cancer, such as Acute myeloid leukemia, Angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet Syndrome, T-cell Non-Hodgkins lymphoma (including natural killer / T-cell lymphoma, adult T-cell leukaemia / lymphoma, enteropathy type T-cell lymphoma, hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell Non-Hodgkins lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, Follicular lymphoma, Mantle cell lymphoma, Marginal Zone lymphoma), Hairy Cell Leukemia, Hodgkin lymphoma, Lymphoblastic lymphoma, Lymphoplasmacytic lymphoma, Mucosa-associated lymphoid tissue lymphoma, Multiple myeloma, Myelodysplastic syndrome, Plasma cell myeloma, Primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorders (such as chronic myeloid leukemia, primary myelofibrosis, essential thrombocytemia, polycytemia vera) or chronic lymphocytic leukemia.

[0447] Alternatively, the cancer is a non-haematological cancer, such as selected from the group consisting of bladder cancer, breast, melanoma, neuroblastoma, malignant pleural mesothelioma, and sarcoma.

[0448] In addition, compounds of formula (I) may be used in enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject. For example, the compounds of formula (I) may be used in preventing, reducing, or inhibiting neointima formation. A medical device may be treated prior to insertion or implantation with an effective amount of a composition comprising a compound of formula (I) in order to prevent, reduce, or inhibit neointima formation following insertion or implantation of the device or graft into the subject. The device can be a device that is inserted into the subject transiently, or a device that is implanted permanently. In some embodiments, the device is a surgical device. Examples of medical devices include, but are not limited to, needles, cannulas, catheters, shunts, balloons, and implants such as stents and valves.

[0449] Suitably the subject is a mammal, in particular the subject is a human.Pharmaceutical Compositions

[0450] In the following section, reference to compounds of formula (I) encompasses compounds of formula (I-a), (I-b) and (I-c).

[0451] For use in therapy the compounds of the invention are usually administered as a pharmaceutical composition. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g. salt) thereof, and a pharmaceutically acceptable carrier or excipient.

[0452] In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g. salt) thereof, for use in the treatment or prophylaxis of a disease or disorder as described herein.

[0453] The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates thereof may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration, and the pharmaceutical compositions adapted accordingly.

[0454] The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates thereof may be administered topically, for example to the eye, gut or skin. Thus, in an embodiment there is provided a pharmaceutical composition comprising a compound of the invention optionally in combination with one or more topically acceptable diluents or carriers.

[0455] A pharmaceutical composition of the invention may be delivered topically to the skin. Compositions suitable for transdermal administration include ointments, gels and patches. Such a pharmaceutical composition may also suitably be in the form of a cream, lotion, foam, powder, paste or tincture.

[0456] The pharmaceutical composition may suitably include vitamin D3 analogues (e.g. calcipotriol and maxacalcitol), steroids (e.g. fluticasone propionate, betamethasone valerate and clobetasol propionate), retinoids (e.g. tazarotene), coal tar and dithranol. Topical medicaments are often used in combination with each other (e.g. a vitamin D3 and a steroid) or with further agents such as salicylic acid.

[0457] A pharmaceutical composition of the invention may be delivered topically to the eye. Such a pharmaceutical composition may suitably be in the form of eye drops or an ointment.

[0458] A pharmaceutical composition of the invention may be delivered topically to the gut. Such a pharmaceutical composition may suitably be delivered orally, such as in the form of a tablet or a capsule, or rectally, such as in the form of a suppository.

[0459] Suitably, delayed release formulations are in the form of a capsule.

[0460] The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates thereof which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.

[0461] A liquid formulation will generally consist of a suspension or solution of the active ingredient (such as a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g. salt) thereof) in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and / or colouring agent.

[0462] A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.

[0463] A composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient (such as a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g. salt) thereof) can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

[0464] Typical parenteral compositions consist of a solution or suspension of the active ingredient (such as a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g. salt) thereof) in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

[0465] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluoro-chloro-hydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.

[0466] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0467] Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0468] Suitably, the composition is in unit dose form such as a tablet, capsule or ampoule.

[0469] The composition may for example contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration. The composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain from 0.05 mg to 2000 mg, for example from 1.0 mg to 500 mg, of the active material, depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from 100 mg to 400 mg of the carrier, depending on the method of administration. The dose of the compound used in the treatment or prophylaxis of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.

[0470] The invention provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof together with a further pharmaceutically acceptable active ingredient or ingredients.

[0471] The invention provides a compound of formula (I), for use in combination with a further pharmaceutically acceptable active ingredient or ingredients.

[0472] When the compounds are used in combination with other therapeutic agents, the compounds may be administered separately, sequentially or simultaneously by any convenient route.

[0473] Optimal combinations may depend on the disease or disorder. Possible combinations include those with one or more active agents selected from the list consisting of: 5-aminosalicylic acid, or a prodrug thereof (such as sulfasalazine, olsalazine or bisalazide); corticosteroids (e.g. prednisolone, methylprednisolone, or budesonide); immunosuppressants (e.g. cyclosporin, tacrolimus, sirolimus, methotrexate, azathioprine mycophenolate mofetil, leflunomide, cyclophosphamide, 6-mercaptopurine or anti-lymphocyte (or thymocyte) globulins); anti-TNF-alpha antibodies (e.g., infliximab, adalimumab, certolizumab pegol or golimumab); anti-IL12 / IL23 antibodies (e.g., ustekinumab); anti-IL6 or anti-IL6R antibodies, anti-IL17 antibodies or small molecule IL12 / IL23 inhibitors (e.g., apilimod); Anti-alpha-4-beta-7 antibodies (e.g., vedolizumab); MAdCAM-1 blockers (e.g., PF-00547659); antibodies against the cell adhesion molecule alpha-4-integrin (e.g., natalizumab); antibodies against the IL2 receptor alpha subunit (e.g., daclizumab or basiliximab); JAK inhibitors including JAK1 and JAK3 inhibitors (e.g., tofacitinib, baricitinib, R348); Syk inhibitors and prodrugs thereof (e.g., fostamatinib and R-406); Phosphodiesterase-4 inhibitors (e.g., tetomilast); HMPL-004; probiotics; Dersalazine; semapimod / CPSI-2364; and protein kinase C inhibitors (e.g. AEB-071).

[0474] For cancer, the further pharmaceutically acceptable active ingredient may be selected from anti-mitotic agents such as vinblastine, paclitaxel and docetaxel; alkylating agents, for example cisplatin, carboplatin, dacarbazine and cyclophosphamide; antimetabolites, for example 5-fluorouracil, cytosine arabinoside and hydroxyurea; intercalating agents for example adriamycin and bleomycin; topoisomerase inhibitors for example etoposide, topotecan and irinotecan; thymidylate synthase inhibitors for example raltitrexed; PI3 kinase inhibitors for example idelalisib; mTor inhibitors for example everolimus and temsirolimus; proteasome inhibitors for example bortezomib; histone deacetylase inhibitors for example panobinostat or vorinostat; and hedgehog pathway blockers such as vismodegib.

[0475] The further pharmaceutically acceptable active ingredient may be selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib.

[0476] Anticancer antibodies may be included in a combination therapy and may be selected from the group consisting of olaratumab, daratumumab, necitumumab, dinutuximab, traztuzumab emtansine, pertuzumab, obinutuzumab, brentuximab, ofatumumab, panitumumab, catumaxomab, bevacizumab, cetuximab, tositumomab, traztuzumab, gentuzumab ozogamycin and rituximab.

[0477] Compounds or pharmaceutical compositions of the invention may also be used in combination with radiotherapy.

[0478] Some of the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. The individual components of combinations may also be administered separately, through the same or different routes.

[0479] When a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.Medical Devices

[0480] In the following section, reference to compounds of formula (I) encompasses compounds of formula (I-a), (I-b) and (I-c).

[0481] In an embodiment, compounds of the invention or pharmaceutical compositions comprising said compounds may be formulated to permit incorporation into the medical device, thus providing application of the compound or composition directly to the site to prevent or treat conditions disclosed herein.

[0482] In an embodiment, the compounds of the invention or pharmaceutical composition thereof is formulated by including it within a coating onto the medical device. There are various coatings that can be utilized such as, for example, polymer coatings that can release the compound over a prescribed time period. The compound, or a pharmaceutical composition thereof, can be embedded directly within the medical device. In some embodiments, the compound is coated onto or within the device in a delivery vehicle such as a microparticle or liposome that facilitates its release and delivery. In some embodiments, the compound or pharmaceutical composition is miscible in the coating.

[0483] In some embodiments, the medical device is a vascular implant such as a stent. Stents are utilized in medicine to prevent or eliminate vascular restrictions. The implants may be inserted into a restricted vessel whereby the restricted vessel is widened. Excessive growth of the adjacent cells following vascular implantation results in a restriction of the vessel particularly at the ends of the implants which results in reduced effectiveness of the implants. If a vascular implant is inserted into a human artery for the elimination of for example an arteriosclerotic stenosis, intima hyperplasia can occur within a year at the ends of the vascular implant and results in renewed stenosis ("restenosis").

[0484] Accordingly, in some embodiments, the stents are coated or loaded with a composition including a compound of the invention or pharmaceutical composition thereof and optionally a targeting signal, a delivery vehicle, or a combination thereof. Many stents are commercially available or otherwise know in the art.

[0485] In some embodiments, the stent is a drug-eluting stent. Various drug eluting stents that simultaneously deliver a therapeutic substance to the treatment site while providing artificial radial support to the wall tissue are known in the art. Endoluminal devices including stents are sometimes coated on their outer surfaces with a substance such as a drug releasing agent, growth factor, or the like. Stents have also been developed having a hollow tubular structure with holes or ports cut through the sidewall to allow drug elution from a central lumen. Although the hollow nature of the stent allows the central lumen to be loaded with a drug solution that is delivered via the ports or holes in the sidewall of the stent, the hollow tubular structure may not have suitable mechanical strength to provide adequate scaffolding in the vessel.

[0486] In some embodiments, the devices are also coated or impregnated with a compound of the invention, or pharmaceutical composition thereof and one or more additional therapeutic agents, including, but not limited to, antiplatelet agents, anticoagulant agents, anti-inflammatory agents, antimicrobial agents, antimetabolic agents, additional anti-neointima agents, additional antiproliferative agents, immunomodulators, antiproliferative agents, agents that affect migration and extracellular matrix production, agents that affect platelet deposition or formation of thrombis, and agents that promote vascular healing and re-endothelialization, such as those and others described in Sousa et al. (2003) and Salu et al. (2004).

[0487] Examples of antithrombin agents include, but are not limited to, Heparin (including low molecular heparin), R-Hirudin, Hirulog, Argatroban, Efegatran, Tick anticoagulant peptide, and Ppack.

[0488] Examples of antiproliferative agents include, but are not limited to, Paclitaxel (Taxol), QP-2 Vincristin, Methotrexat, Angiopeptin, Mitomycin, BCP 678, Antisense c-myc, ABT 578, Actinomycin-D, RestenASE, 1 -Chlor- deoxyadenosin, PCNA Ribozym, and Celecoxib.

[0489] Examples of anti-restenosis agents include, but are not limited to, immunomodulators such as Sirolimus (Rapamycin), Tacrolimus, Biorest, Mizoribin, Cyclosporin, Interferon-γ lb, Leflunomid, Tranilast, Corticosteroide, Mycophenolic acid and Biphosphonate.

[0490] Examples of anti-migratory agents and extracellular matrix modulators include, but are not limited to Halofuginone, Propyl-hydroxylase-Inhibitors, C- Proteinase-Inhibitors, MMP-Inhibitors, Batimastat, Probucol.

[0491] Examples of antiplatelet agents include, but are not limited to, heparin.

[0492] Examples of wound healing agents and endothelialization promoters include vascular epithelial growth factor ("VEGF"), 17 -Estradiol, Tkase- Inhibitors, BCP 671, Statins, nitric oxide ("NO")-Donors, and endothelial progenitor cell ("EPC")-antibodies.

[0493] Besides coronary applications, drugs and active agents may be incorporated into the stent or stent coating for other indications. For example, in urological applications, antibiotic agents may be incorporated into the stent or stent coating for the prevention of infection. In gastroenterological and urological applications, active agents may be incorporated into the stent or stent coating for the local treatment of carcinoma. It may also be advantageous to incorporate in or on the stent a contrast agent, radiopaque markers, or other additives to allow the stent to be imaged in vivo for tracking, positioning, and other purposes. Such additives could be added to the absorbable composition used to make the stent or stent coating, or absorbed into, melted onto, or sprayed onto the surface of part or all of the stent. Preferred additives for this purpose include silver, iodine and iodine labelled compounds, barium sulfate, gadolinium oxide, bismuth derivatives, zirconium dioxide, cadmium, tungsten, gold tantalum, bismuth, platinum, iridium, and rhodium. These additives may be, but are not limited to, micro- or nano-sized particles or nano particles. Radio-opacity may be determined by fluoroscopy or by x-ray analysis.

[0494] A compound of the invention and one or more additional agents, or pharmaceutical composition thereof, can be incorporated into the stent, either by loading the compound and one or more additional agents, or pharmaceutical composition thereof into the absorbable material prior to processing, and / or coating the surface of the stent with the agent(s). The rate of release of agent may be controlled by a number of methods including varying the following: the ratio of the absorbable material to the compound and one or more additional agents, or pharmaceutical composition, the molecular weight of the absorbable material, the composition of the compound and one or more additional agents, or pharmaceutical composition, the composition of the absorbable polymer, the coating thickness, the number of coating layers and their relative thicknesses, and / or the compound and one or more additional agents, or pharmaceutical composition concentration. Top coats of polymers and other materials, including absorbable polymers, may also be applied to active agent coatings to control the rate of release. For example, P4HB can be applied as a top coat on a metallic stent coated with P4HB including an active agent to retard the release of the active agent.

[0495] The invention is further exemplified by the following non-limiting examples.EXAMPLES

[0496] Abbreviations used herein are defined below. Any abbreviations not defined are intended to convey their generally accepted meaning.Abbreviations

[0497] Acacetyl (C(O)CH 3 ) AcOHglacial acetic acid AlMe 3 trimethylaluminium aqaqueous ArAromatic ring BEHethylene bridged hybrid BispinBis(pinacolato)diboron; 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane Bzbenzyl (CH 2 -phenyl) Boctert-butyloxycarbonyl protecting group Cs 2 CO 3 Cesium carbonate CSHcharged surface hybrid ddoublet DABAL-Me 3 adduct of trimethylaluminum and 1,4-diazabicyclo[2.2.2]octane DCMdichloromethane DIPEAN,N-diisopropylethylamine dioxane1,4-dioxane DMAP4-dimethylaminopyridine DMEdimethoxyethane DMFN,N-dimethylformamide DMSOdimethyl sulfoxide DMPDess-Martin Periodinane DPPAdiphenylphosphoryl azide dppf1,1'-bis(diphenylphosphino)ferrocene (ES +< )electrospray ionisation, positive mode (ES -< )electrospray ionisation, negative mode ESIelectrospray ionisation Etethyl EtlEthyl iodide EtOAcethyl acetate EtOHethanol ggrams Halhalogen HATU1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HPLChigh performance liquid chromatography hr(s)hour(s) IC 50 50% inhibitory concentration iPriso-propyl iPrMgCliso-propyl magnesium chloride K 2 CO 3 potassium carbonate LCMSliquid chromatography-mass spectrometry LiHMDSlithium hexamethyldisilazide LiOHlithium hydroxide (M+H) +< protonated molecular ion (M-H) -< unprotonated molecular ion Mmolar concentration mCPBAMeta-chloroperoxybenzoic acid mLmillilitre mmmillimiter mmolmillimole Memethyl MeCNacetonitrile Meliodomethane MeOHmethanol MesClmethanesulfonyl chloride MHzmegahertz min(s)minute(s) MSDmass selective detector m / zmass-to-charge ratio N 2 nitrogen gas NH 3 ammonia NH 4 Clammonium chloride NaHsodium hydride NaHCO 3 sodium bicarbonate NaBH(OAc) 3 Sodium triacetoxyborohydride nmnanometre NMRnuclear magnetic resonance (spectroscopy) NSFIN-fluorobenzenesulfonimide P4HBpoly-4-hydroxybutyrate PDAphotodiode array Pd 170chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropybiphenyl)palladium(ll) or XPhos Pd(crotyl)Cl Pd 174allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(ll) triflate or [tBuXPhosPd(allyl)]OTf [Pd(allyl)Cl 2 ] 2 bis(allyl)dichlorodipalladium PdCl 2 (dppf)[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium(0) PMB4-methoxybenzyl prep HPLCpreparative high performance liquid chromatography Phphenyl pos / negpositive / negative qquartet RF / MSRapidFire Mass Spectrometry RTroom temperature Rtretention time RPreverse phase ssinglet S N Arnucleophilic aromatic substitution satsaturated SCXsolid supported cation exchange (resin) SelectfluorN-chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate) ttriplet tButert-butyl T3P2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide TBMEtert-butyl methyl ether TFATrifluoroacetic acid [t-BuXPhosallyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'- Pd(allyl)]OTfbiphenyl)palladium(ll) triflate THFtetrahydrofuran TMP2,2,6,6-tetramethylpiperidinyl TMSOKpotassium trimethylsilanolate TTIPtitanium tetraisopropoxide UPLCultra performance liquid chromatography UVultraviolet v / vvolume / volume VWDvariable wave detector wtweight ummicrometre uLmicrolitre °Cdegrees Celsius General Procedures

[0498] All starting materials and solvents were obtained either from commercial sources or prepared according to the literature. Unless otherwise stated all reactions were stirred. Organic solutions were routinely dried over anhydrous magnesium sulfate. Hydrogenations were performed on a Thales H-cube flow reactor under the conditions stated.

[0499] Column chromatography was performed on pre-packed silica (230-400 mesh, 40-63 um) cartridges using the amount indicated. SCX was purchased from Supelco and treated with 1M hydrochloric acid prior to use. Unless stated otherwise the reaction mixture to be purified was first diluted with MeOH and made acidic with a few drops of AcOH. This solution was loaded directly onto the SCX and washed with MeOH. The desired material was then eluted by washing with 0.7 M NH 3 in MeOH.Preparative Reverse Phase High Performance Liquid ChromatographyPrep HPLC Acidic prep

[0500] Waters X-Select CSH column C18, 5 um (19 x 50 mm), flow rate 28 mL min -1< eluting with a H 2 O-MeCN gradient containing 0.1 % v / v formic acid over 6.5 min using UV detection at 254 nm.Basic prep

[0501] Waters X-Bridge Prep column C18, 5 um (19 x 50 mm), flow rate 28 mL min -1< eluting with a 10 mM NH 4 HCO 3 -MeCN gradient over 6.5 min using UV detection at 254 nm.Analytical Methods Reverse Phase HPLC Conditions for the LCMS Analytical MethodsHPLC acidic: Acidic LCMS 4 minute (5-95%)

[0502] Analytical LCMS was carried out using a Waters X-Select CSH C18, 2.5 um, 4.6x30 mm column eluting with a gradient of 0.1 % Formic acid in MeCN in 0.1 % Formic acid in water. The gradient from 5-95 % 0.1 % Formic acid in MeCN occurs between 0.00-3.00 minutes at 2.5 mL / min with a flush from 3.01-3.5 minutes at 4.5 mL / min. A column re-equilibration to 5% MeCN is from 3.60-4.00 minutes at 2.5 mL / min. UV spectra of the eluted peaks were measured using an Agilent 1260 Infinity VWD at 254 nm. Mass spectra were measured using an Agilent 6120 MSD running with positive / negative switching.HPLC basic: Basic LCMS 4 minute (5-95%)

[0503] Analytical LCMS was carried out using a Waters X-Select BEH C18, 2.5 um, 4.6x30 mm column eluting with a gradient of MeCN in aqueous 10mM ammonium bicarbonate. The gradient from 5-95% MeCN occurs between 0.00-3.00 minutes at 2.5mL / min with a flush from 3.01-3.5 minutes at 4.5 mL / min. A column re-equilibration to 5% MeCN is from 3.60-4.00 minutes at 2.5mL / min. UV spectra of the eluted peaks were measured using an Agilent 1260 Infinity VWD at 254nm. Mass spectra were measured using an Agilent 6120 MSD running with positive / negative switching.Reverse Phase HPLC Conditions for the UPLC Analytical MethodsUPLC acidic: Acidic UPLC 3 minute

[0504] Analytical UPLC / MS was carried out using a Waters Acquity CSH C18, 1.7 um, 2.1x30 mm column eluting with a gradient of 0.1% Formic acid in MeCN in 0.1% Formic acid in water. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.11 minutes. The gradient from 5-95% occurs between 0.11-2.15 minutes with a flush from 2.15-2.56 minutes. A column re-equilibration to 5% MeCN is from 2.56-2.83 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos / neg switching.Acidic UPLC 2 Acidic UPLC 1 minute

[0505] Analytical UPLC / MS was carried out using a Waters Acquity CSH C18, 1.7 um, 2.1x30 mm column eluting with a gradient of 0.1% Formic acid in MeCN in 0.1% Formic acid in water. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.08 minutes. The gradient from 5-95% occurs between 0.08-0.70 minutes with a flush from 0.7-0.8 minutes. A column re-equilibration to 5% MeCN is from 0.8-0.9 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos / neg switching.UPLC basic: Basic UPLC 3 minute

[0506] Analytical UPLC / MS was carried out using a Waters Acquity BEH C18, 1.7 um, 2.1x30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.11 minutes. The gradient from 5-95% occurs between 0.11-2.15 minutes with a flush from 2.15-2.56 minutes. A column re-equilibration to 5% MeCN is from 2.56-2.83 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos / neg switching.Basic UPLC 2 Basic UPLC 1 minute

[0507] Analytical UPLC / MS was carried out using a Waters Acquity BEH C18, 1.7 um, 2.1x30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.08 minutes. The gradient from 5-95% occurs between 0.08-0.70 minutes with a flush from 0.7-0.8 minutes. A column re-equilibration to 5% MeCN is from 0.8-0.9 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos / neg switching.

[0508] Column temperature is 40 °C in all runs. Injection volume is 3 uL and the flow rate is 0.77 mL / min. PDA scan from 210-400 nm on all runs.Normal Phase HPLC Conditions for the Chiral Analytical Methods

[0509] Chiral IC3 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6x250 mm, 1.0 mL / min, 25-70% EtOH (0.2% TFA) in iso-hexane (0.2% TFA) Chiral IC4 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6x250 mm, 1.0 mL / min, 40% EtOH (0.2% TFA) in 4:1 heptane / chloroform (0.2 % TFA). Chiral IC5 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6x250 mm, 1.0 mL / min, 20% EtOH (0.2% TFA) in iso-hexane (0.2% TFA). Reverse Phase HPLC Conditions for the Chiral Analytical Methods

[0510] Chiral IC6 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6x250 mm, 1.0 mL / min, 50% MeCN (0.1 % formic acid) in water (0.1 % formic acid). Chiral IC7 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6x250 mm, 1.0 mL / min, 5-95% MeCN (0.1 % formic acid) in water (0.1 % formic acid). 1< H NMR Spectroscopy

[0511] 1< H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz or Bruker Avance III HD spectrometer at 500 MHz using residual undeuterated solvent as reference and unless specified otherwise were run in DMSO-d6.Preparation of Intermediates

[0512] Known synthetic intermediates were procured from commercial sources or were obtained using published literature procedures. Additional intermediates were prepared by the representative synthetic processes described herein.Compounds of formula (I-a) - Intermediates

[0513] Any one of Methods 1-1q (referred to later herein) or A-N and Q-R may be used in the synthesis of the compounds of formula (I). For example, a scheme which is shown using a compound wherein X = N, Y = CR 2 and Z = CR 3 may also be used in the synthesis of compounds wherein X, Y and Z are as defined in the claims.

[0514] The synthesis of INTC1 to INTC179 and INTD1 to INTD86 is disclosed in at least one of WO2019 / 179652, WO2019 / 180244 and WO2020 / 083975.Method A: Decarboxylation of chloro-heterocycles such as chloro-pyrimidines

[0515]

[0516] TFA (10 eq) was added dropwise to an ice-cooled, stirred solution of malonate derivative (1 eq) in DCM (15 volumes). The reaction vessel was stirred at RT for 18 hrs and then concentrated. The crude product was purified by normal phase chromatography.Method B: Alkylation

[0517]

[0518] Base (2.5 - 5 eq) was added to an ice-cooled, stirred mixture of methyl 2-(2-chloropyrimidin-4-yl)acetate (1 eq) in appropriate polar aprotic solvent such as DMF or acetone (10 volumes). After 20 min, alkyl halide (1-5 eq) was added. The reaction vessel was stirred at 0 °C for 30 mins then at RT for 2 hrs. The reaction was quenched with NH 4 Cl (aq) or 1M HCl (aq), stirred for 20 mins then extracted with EtOAc. The organic phases were dried (phase separator) and concentrated. The crude product was purified by normal phase chromatography.Method C: Formation of sulfonamides from aromatic halides

[0519]

[0520] 2-Chloropyrimidine intermediate (1 eq), sulfonamide (1.2 eq) and base (2 eq) were dissolved in dioxane (40 volumes). The mixture was degassed (N 2 , 5 mins) then catalyst (5 mol%) was added. The resulting mixture was heated under nitrogen at 90 °C for 2 hrs. The mixture was filtered, washing with EtOAc or DCM and the resulting filtrate was concentrated. The crude product was purified by normal phase chromatography or trituration using a suitable solvent.Method D: Decarboxylation of pyrimidines bearing sulfonamides

[0521]

[0522] TFA (10 eq) was added dropwise to an ice-cooled, stirred solution of malonate derivative (1 eq) in DCM (15 volumes). The reaction vessel was stirred at RT for 18 hrs and then concentrated. The crude product was purified by normal phase chromatography.Method H: Benzylic fluorination of hetero-aromatic esters

[0523]

[0524] A solution of hetero-aromatic ester (1 eq) in THF (10 volumes) was cooled to -78 °C to which was added LiHMDS (1.25 eq 1M in THF). The reaction mixture was then warmed to RT for 1 hr. The solution was cooled to -78 °C and a solution (in THF) of, or solid, NSFI (1.25 eq) was added dropwise then warmed to RT for 2 hrs. The solution was diluted with sat. NaHCO 3 (aq) and the product was extracted into EtOAc. The crude product was purified by normal phase chromatography.Method I: Buchwald coupling - sulfonylation

[0525]

[0526] 2-Bromopyridine intermediate (1 eq), sulfonamide (1.2 eq) and base (2 eq) were dissolved in dioxane (40 volumes). The mixture was degassed (N 2 , 5 mins) then catalyst (5 mol%) was added. The resulting mixture was heated under nitrogen at 90 °C for 2 hrs. The mixture was filtered, washing with EtOAc or DCM and the resulting filtrate was concentrated. The crude product was purified by normal phase chromatography.Method J: Hydrolysis

[0527]

[0528] 2M LiOH (aq, 2 eq) was added into a solution of ester (1 eq) in MeOH (3 volumes) and THF (3 volumes) and the resulting reaction mixture was stirred at 50 °C for 2 hrs. The solvent was removed under reduced pressure and then was acidified with 1M HCl (aq) until pH 3. The solution was extracted with EtOAc, the organic phase was passed through a phase separator and the solvent was removed. The compound was used crude or purified by reverse phase chromatography.Amine intermediate preparation Method E: Suzuki coupling of halo anilines with heteroaromatic boronates

[0529]

[0530] A solution of Ar1-X (1 eq) and Ar2-Z (1 eq) in solvent (3 volumes) and base (2.5 eq) was degassed (N 2 , 5 min) and heated to 40 °C whereupon Pd catalyst (3 mol%) was added and the reaction mixture further degassed (N 2 , 5 min) before being heated to 90 °C for 90 mins. The reaction mixture was allowed to cool to RT. In general, the desired compound was purified by column chromatography.Method F: Suzuki coupling of heteroaromatic halides with aniline boronates

[0531]

[0532] Pd catalyst (5 mol%) was added to a degassed (N 2 , 5 mins) solution of Ar1-X (1 eq), Ar2-Z (1 eq) and base (3 eq, 6.85 mmol) in solvent (3 volumes). The solution was then degassed further (N 2 , 5 mins) and then heated to 90 °C for 2 hrs then allowed to cool to RT. In general, the desired compound was purified by column chromatography.Method G: Telescoped boronate formation and Suzuki coupling

[0533]

[0534] Bispin (1.1 eq) and KOAc (4 eq) were added to Ar1-Hal (1 eq) in dioxane (5 volumes). The reaction was heated to 60 °C and degassed (N 2 , 5 mins). PdCl 2 (dppf) (5 mol%) was added to the reaction mixture and the temperature was increased to 90 °C for 1 hr. The reaction mixture was then cooled to RT and a solution of Ar2-Hal (1 eq) in dioxane (3 volumes) was added, followed by a solution of K 2 CO 3 (4 eq) in water (2 volumes). The temperature was then increased to 90 °C for 18 hrs. The reaction was cooled to RT, an aqueous work up was performed and the crude compound was purified by normal phase chromatography.Anilines Method K: Suzuki coupling

[0535]

[0536] A solution of boronic acid (1 eq), aryl halide (1.05 eq.) and Cs 2 CO 3 (3 eq.) in a mixture of dioxane (40 volumes) and water (6 volumes) was degassed (N 2 , 5 mins). PdCl 2 (dppf).CH 2 Cl 2 (5 mol%) was added and the reaction was further degassed (N 2 ) before being heated to 90 °C for 18 hrs. The reaction mixture was filtered through celite before an aqueous workup was undertaken, followed by purification by normal phase chromatography.Method L: Ester deprotection with TFA

[0537]

[0538] A solution of the ester (1 eq) in DCM (20 volumes) was treated with TFA (10 eq.) and stirred at RT for 3 hrs. The reaction mixture was then concentrated and azeotroped with MeOH and MeCN. No further purification was undertaken.Method M: Ester deprotection with base

[0539]

[0540] A solution of the ester (1 eq) in a mixture of THF / MeOH (4 / 1 volumes) was treated with LiOH (2.2-6 eq.) and stirred between RT and 50 °C for between 3 hrs and 18 hrs. The organic solvents were removed in vacuo then acidified with 1 M HCl and extracted with EtOAc. The organic phases were combined, dried (Na 2 SO 4 ), filtered and concentrated. The products were used directly in the next step with no further purification undertaken.Method N: Potassium salt formation

[0541]

[0542] A solution of the ester (1 eq.) in THF (4 volumes) was treated with TMSOK (1 eq.) and stirred at RT for 2 hrs before the reaction mixtures were filtered and washed with iso-hexanes. The products were used directly in the next step with no further purification und...

Claims

1. A compound of formula (I): wherein ring B is selected from the group consisting of: wherein X, Y and Z are as defined below; and wherein R3b3c is R3b or R3c as defined below; wherein when B is (B-a) the compound of formula (I) is a compound of formula (I-a): wherein: Aa is Aaa or Aba; wherein: Aaa is an amine linker having the following structure: -NH-, -CH2NH- or -NHCH2-; Aba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR2a; Z is N or CR3a; with the proviso that when at least one of X or Z is N, Y cannot be N; R2a is H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; and R3a is H, halo, CH3, OCH3, CF3 or OCF3; wherein at least one of R2a and R3a is H; R1a is R1aa or R1ba; wherein: R1aa is NR32aR33a; R1ba is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; R4a and R5a are R4aa and R5aa, or R4ba and R5ba; wherein: R4aa and R5aa together with the carbon atom to which they are attached form a C3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21aR22a; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4aa and R5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4aa and R5aa together with the carbon atom to which they are attached form a C3-6heterocycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heterocycloalkyl formed by R4aa and R5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4aa and R5aa together with the carbon atom to which they are attached form a C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29a; or R4ba and R5ba are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4ba and R5ba together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl; and when Aa is -NHC(=O)- or -NHCH2-: R4ba and R5ba may additionally be selected from halo, OC1-6haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl and NR21aR22a; Ar1a is a 6-membered aryl or heteroaryl; Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group Aa; R10a is H, halo, C1-3alkyl, C1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl or CN; R11a is H, F, Cl, C1-2alkyl, CF3, OCH3 or CN; R12a is attached to Ar2 in the ortho or meta position relative to Ar1a and R12a is H, halo, C1-4alkyl, C2-4alkenyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, C1-4haloalkyl, OC1-4haloalkyl, hydroxy, C1-4alkylOH, SO2C1-2alkyl, C(O)N(C1-2alkyl)2, NHC(O)C1-3alkyl or NR23aR24a; and when Aa is -NHC(=O)-, -NH- or -NHCH2-: R12a may additionally be selected from CN, OCH2CH2N(CH3)2 and a C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R12a together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R13a is H or halo; R21a is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl, C1-3alkylOC1-2alkyl, C1-4haloalkyl, or C4-6heterocycloalkyl; R22a is H or CH3; R23a is H or C1-2alkyl; and R24a is H or C1-2alkyl R29a is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, CF3, N(C1-3alkyl)2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; R32a is C1-3alkyl and R33a is C1-3alkyl; or R32a and R33a together with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; wherein R1a is R1aa; and / or R4a and R5a are R4aa and R6aa; and / or Aa is Aaa; and wherein when B is (B-bc) and R3b3c is R3b, the compound of formula (I) is a compound of formula (I-b): wherein: Ab is Aab or Abb; wherein: Aab is -NR6bCH2- or -NR6b-; Abb is -NR6bC(=O)-; R1b is R1ab or R1bb; wherein: R1ab is NR32bR33b; R1bb is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3b is H, halo, CH3, OC1-2alkyl or CF3; or R3b together with R5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R4b and R5b are either R4ab and R5ab or R4bb and R5bb; wherein: R4ab and R5ab together with the carbon atom to which they are attached form a C3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21bR22b; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4ab and R5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ab and R5ab together with the carbon atom to which they are attached form a C3-6heteroycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heteroycloalkyl formed by R4ab and R5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ab and R5ab together with the carbon atom to which they are attached form a C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29b; or R4bb and R5bb are each independently H, halo, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl, OC0-2alkyleneC3-6cycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH, C1-6haloalkyl, OC1-6haloalkyl or NR21bR22b, or R4bb is H and R5bb together with R3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, or R4bb and R5bb together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl, or R4bb is H and R5bb and R6b are a C2-3alkylene chain forming a 5- or 6-membered ring; or R4bb is O and R5bb is absent; R6b is H or C1-3alkyl, or R6b together with R11b when in the ortho-position to group Ab are a C2alkylene chain forming a 5-membered ring, or R5bb and R6b are a C2-3alkylene chain forming a 5- or 6-membered ring and R4bb is H; Ar1b is 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group Ab; R10b is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11b is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN, or R11b, when in the ortho-position to group Ab, together with R6b are a C2alkylene chain forming a 5-membered ring; R12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R12b is H, halo, C1-4alkyl, C2-4alkynyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, OCH2CH2N(CH3)2, OH, C1-4alkylOH, CN, C1-3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, C(=O)C1-2alkyl, NR23bR24b, SO2C1-4alkyl, SOC1-4alkyl, SC1-4alkyl, SH, C(O)N(CH3)2, NHC(O)C1-3alkyl, C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R12b together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R13b is H, halo, CH3 or OCH3; R21b is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl, C1-3alkylOC1-2alkyl, C1-4haloalkyl, or C4-6heterocycloalkyl; R22b is H or CH3; R23b is H or C1-2alkyl; R24b is H or C1-2alkyl; R29b is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, CF3, N(C1-3alkyl)2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and R32b is C1-3alkyl and R33b is C1-3alkyl; or R32b and R33b together with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; wherein: R1b is R1ab; and / or R4b and R5b are R4ab and R5ab; and / or Ab is Aab; or wherein when B is (B-bc) and R3b3c is R3c, the compound of formula (I) is a compound of formula (I-c): wherein: Ac is Aac or Abc; wherein: Aac is -CH2NR6c-; Abc is -C(=O)NR6c-; R1c is R1ac or R1bc; wherein: R1ac is NR32cR33c; R1bc is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3c is H, CH3, halo, OC1-2alkyl or CF3; R4c and R5c are either R4ac and R5ac or R4bc and R5bc; wherein: R4ac and R5ac together with the carbon atom to which they are attached form a C3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21cR22c; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4ac and R5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ac and R5ac together with the carbon atom to which they are attached form a C3-6heteroycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heteroycloalkyl formed by R4ac and R5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ac and R5ac together with the carbon atom to which they are attached form a C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29c; or R4bc and R5bc are each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1-6haloalkyl, or R4bc and R5bc together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl ring; R6c is H or C1-3alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group Ac; R10c is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11c is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN; R12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R12c is H, halo, C1-4alkyl, C2-4alkynyl, C(=O)C1-2alkyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, C1-3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, CN, OC0-2alkyleneC3-5cycloalkyl, OCH2CH2N(CH3)2, OH, C1-4alkylOH, NR23cR24c, SO2CH3, C(O)N(CH3)2, NHC(O)C1-3alkyl, or a C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R12c together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R21c is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl, C1-3alkylOC1-2alkyl, C1-4haloalkyl, or C4-6heterocycloalkyl; R22c is H or CH3; R23c is H or C1-2alkyl; R24c is H or C1-2alkyl; R29c is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, CF3, N(C1-3alkyl)2, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and R32c is C1-3alkyl and R33c is C1-3alkyl; or R32c and R33c together with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; wherein: R1c is R1ac; and / or R4c and R5c are R4ac and R5ac; and / or Ac is Aac; or a salt and / or solvate thereof.

2. The compound, salt and / or solvate thereof according to claim 1 which is a compound of formula (I): wherein ring B is selected from the group consisting of: wherein X, Y and Z are as defined below; and: wherein R3b3c is R3b or R3c as defined below; wherein when B is (B-a) the compound of formula (I) is a compound of formula (I-a): wherein: Aa is Aaa or Aba; wherein: Aaa is an amine linker having the following structure: -NH-, -CH2NH- or -NHCH2-; Aba is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR2a; Z is N or CR3a; with the proviso that when at least one of X or Z is N, Y cannot be N; R2a is H, halo, C1-2alkyl, OC1-2alkyl, C1-2haloalkyl or OC1-2haloalkyl; and R3a is H, halo, CH3, OCH3, CF3 or OCF3; wherein at least one of R2a and R3a is H; R1a is R1aa or R1ba; wherein: R1aa is NR32aR33a; R1ba is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; R4a and R5a are R4aa and R5aa, or R4ba and R5ba; wherein: R4aa and R5aa together with the carbon atom to which they are attached form a C3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21aR22a; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4aa and R5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4aa and R5aa together with the carbon atom to which they are attached form a C3-6heterocycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heterocycloalkyl formed by R4aa and R5aa together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4aa and R5aa together with the carbon atom to which they are attached form a C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29a; or R4ba and R5ba are each independently H, C1-6alkyl, C1-6alkylOH, C1-6haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, or R4ba and R5ba together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl; and when Aa is -NHC(=O)- or -NHCH2-: R4ba and R5ba may additionally be selected from halo, OC1-6haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl and NR21aR22a; Ar1a is a 6-membered aryl or heteroaryl; Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group Aa; R10a is H, halo, C1-3alkyl, C1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl or CN; R11a is H, F, Cl, C1-2alkyl, CF3, OCH3 or CN; R12a is attached to Ar2 in the ortho or meta position relative to Ar1a and R12a is H, halo, C1-4alkyl, C2-4alkenyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, C1-4haloalkyl, OC1-4haloalkyl, hydroxy, C1-4alkylOH, SO2C1-2alkyl, C(O)N(C1-2alkyl)2, NHC(O)C1-3alkyl or NR23aR24a; and when Aa is -NHC(=O)-, -NH- or -NHCH2-: R12a may additionally be selected from CN, OCH2CH2N(CH3)2 and a C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R12a together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R13a is H or halo; R21a is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; R22a is H or CH3; R23a is H or C1-2alkyl; and R24a is H or C1-2alkyl R29a is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; R32a is C1-3alkyl and R33 is C1-3alkyl; or R32a and R33a together with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; wherein R1a is R1aa; and / or R4a and R5a are R4aa and R5aa; and / or Aa is Aaa; and wherein when B is (B-bc) and R3b3c is R3b, the compound of formula (I) is a compound of formula (I-b): wherein: Ab is Aab or Abb; wherein: Aab is -NR6bCH2- or -NR6b-; Abb is -NR6bC(=O)-; R1b is R1ab or R1bb; wherein: R1ab is NR32bR33b; R1bb is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3b is H, halo, CH3, OC1-2alkyl or CF3; or R3b together with R5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl; R4b and R5b are either R4ab and R5ab or R4bb and R5bb; wherein: R4ab and R5ab together with the carbon atom to which they are attached form a C3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21bR22b; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4ab and R5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ab and R5ab together with the carbon atom to which they are attached form a C3-6heteroycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heteroycloalkyl formed by R4ab and R5ab together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ab and R5ab together with the carbon atom to which they are attached form a C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29b; or R4bb and R5bb are each independently H, halo, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, OC1-6alkyl, OC0-2alkyleneC3-6cycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH, C1-6haloalkyl, OC1-6haloalkyl or NR21bR22b, or R4bb is H and R5bb together with R3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, or R4bb and R5bb together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl, or R4bb is H and R5bb and R6b are a C2-3alkylene chain forming a 5- or 6-membered ring; or R4bb is O and R5bb is absent; R6b is H or C1-3alkyl, or R6b together with R11b when in the ortho-position to group Ab are a C2alkylene chain forming a 5-membered ring, or R5bb and R6b are a C2-3alkylene chain forming a 5- or 6-membered ring and R4bb is H; Ar1b is 6-membered aryl or heteroaryl; Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group Ab; R10b is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11b is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN, or R11b, when in the ortho-position to group Ab, together with R6b are a C2alkylene chain forming a 5-membered ring; R12b is attached to Ar2b in the ortho or meta position relative to Ar1b and R12b is H, halo, C1-4alkyl, C2-4alkynyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, OC0-2alkyleneC3-5cycloalkyl, OCH2CH2N(CH3)2, OH, C1-4alkylOH, CN, C1-3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, C(=O)C1-2alkyl, NR23bR24b, SO2C1-4alkyl, SOC1-4alkyl, SC1-4alkyl, SH, C(O)N(CH3)2, NHC(O)C1-3alkyl, C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R12b together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R13b is H, halo, CH3 or OCH3; R21b is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; R22b is H or CH3; R23b is H or C1-2alkyl; R24b is H or C1-2alkyl; R29b is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; and R32b is C1-3alkyl and R33b is C1-3alkyl; or R32b and R33b together with the nitrogen atom to which they are attached form a C3-6heterocycloalkyl; wherein: R1b is R1ab; and / or R4b and R5b are R4ab and R5ab; and / or Ab is Aab; or wherein when B is (B-bc) and R3b3c is R3c, the compound of formula (I) is a compound of formula (I-c): wherein: Ac is Aac or Abc; Aac is -CH2NR6c-; Abc is -C(=O)NR6c-; R1c is R1ac or R1bc; wherein: R1ac is NR32cR33c; R1bc is C1-5alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, C1-3alkyleneOC1-2alkyl, or CF3; R3c is H, CH3, halo, OC1-2alkyl or CF3; R4c and R5c are either R4ac and R5ac or R4bc and R5bc; wherein: R4ac and R5ac together with the carbon atom to which they are attached form a C3-6cycloalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl, oxo, OH, C1-3alkylOH, C1-3haloalkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, halo, OC1-3haloalkyl, OC0-2alkyleneC3-6cycloalkyl, OC0-2alkyleneC3-6heterocycloalkyl, OC1-3alkyl and NR21cR22c; or one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6cycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6cycloalkyl formed by R4ac and R5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ac and R5ac together with the carbon atom to which they are attached form a C3-6heteroycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6heterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heteroycloalkyl formed by R4ac and R5ac together with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C1-3alkyl or OC1-3alkyl; or R4ac and R5ac together with the carbon atom to which they are attached form a C3-6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(O)2R29c; or R4bc and R5bc are each independently H, C1-6alkyl, C0-2alkyleneC3-6cycloalkyl, C0-2alkyleneC3-6heterocycloalkyl, C1-3alkyleneOC1-3alkyl, C1-6alkylOH or C1-6haloalkyl, or R4bc and R5bc together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl ring; R6c is H or C1-3alkyl; Ar1c is a 6-membered aryl or heteroaryl; Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group Ac; R10c is H, halo, C1-3alkyl, OC1-2alkyl, C1-2haloalkyl, OC1-2haloalkyl or CN; R11c is H, F, Cl, CH3, ethyl, OCH3, CF3, OCF3 or CN; R12c is attached to Ar2c in the meta or ortho position relative to Ar1c and R12c is H, halo, C1-4alkyl, C2-4alkynyl, C(=O)C1-2alkyl, C0-2alkyleneC3-5cycloalkyl, OC1-4alkyl, C1-3alkyleneOC1-3alkyl, C1-4haloalkyl, OC1-4haloalkyl, CN, OC0-2alkyleneC3-5cycloalkyl, OCH2CH2N(CH3)2, OH, C1-4alkylOH, NR23cR24c, SO2CH3, C(O)N(CH3)2, NHC(O)C1-3alkyl, or a C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R12c together with a nitrogen atom to which it is attached forms an N-oxide (N+-O-); R21c is H, C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl; R22c is H or CH3; R23c is H or C1-2alkyl; R24c is H or C1-2alkyl; R29c is C1-3alkyl, C0-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; and R32c is C1-3alkyl and R33c is C1-3alkyl; or R32c and R33c together with the nitrogen atom to which they are attached form a C3-5heterocycloalkyl; wherein: R1c is R1ac; and / or R4c and R5c are R4ac and R5ac; and / or Ac is Aac; or a salt and / or solvate thereof.

3. The compound, salt and / or solvate thereof according to claim 1 or 2, which is the compound or a pharmaceutically acceptable salt and / or solvate thereof.

4. The pharmaceutically acceptable salt and solvate of a compound of formula (I) according to claim 3.

5. The pharmaceutically acceptable salt of a compound of formula (I) according to claim 3.

6. The pharmaceutically acceptable solvate of a compound of formula (I) according to claim 3.

7. The compound of formula (I) according to claim 1 or 2.

8. The compound, salt and / or solvate thereof according to any one of claims 1 to 7 wherein the compound of formula (I) is a compound of formula (I-a).

9. The compound, salt and / or solvate thereof according to any one of claims 1 to 7 wherein the compound of formula (I) is a compound of formula (I-b).

10. The compound, salt and / or solvate thereof according to any one of claims 1 to 7 wherein the compound of formula (I) is a compound of formula (I-c).

11. The compound, salt and / or solvate thereof according to any one of claims 8 to 10 wherein R1a is R1aa, R1b is R1ab or R1c is R1ac.

12. The compound, salt and / or solvate thereof according to any one of claims 8 to 11 wherein R4a and R5a are R4aa and R5aa, R4b and R5b are R4ab and R5ab or R4c and R5c are R4ac and R5ac.

13. The compound, salt and / or solvate thereof according to any one of claims 8 to 12 wherein Aa is Aaa, Ab is Aab or Ac is Aac.

14. The compound, salt and / or solvate thereof according to claim 1 which is selected from the group consisting of: 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-oxocyclohexanecarboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 2); N-(4-(1-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4,4-difluorocyclohexane-1-carboxamide; 8-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide; 4-(2-((N,N-dimethylsulfamoyl)amino)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; N-(4-(1-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide; N-(4-(1-((4-(6-ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide; N-(4-(4-(((4-(6-ethoxypyrazin-2-yl)phenyl)amino)methyl)tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl)cyclopropanesulfonamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-5,8-dioxaspiro[3.4]octane-2-carboxamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide; N-(4-(1-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamidearboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(N,N-dimethylsulfamoyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-((trifluoromethyl)sulfonyl)piperidine-4-carboxamide; 4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide; 1-(cyanomethyl)-4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; ethyl 2-(4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)piperidin-1-yl)acetate; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; 1-(Cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide; 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide (diastereomer 1); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-4-methoxycyclohexane-1-carboxamide (diastereomer 2); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 2); 4-amino-1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(methyl(oxetan-3-yl)amino)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-((2-methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 2); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((2,2-difluoroethyl)(methyl)amino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)cyclohexane-1-carboxamide (diastereomer 2); 4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; 4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide; N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)-2-methylpropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide; N-(4-(2-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide; N-(4-(2-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide; and pharmaceutically acceptable salts and / or solvates of any one thereof.

15. A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 3 to 14.

16. The compound, pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 3 to 14 or a pharmaceutical composition according to claim 15 for use as a medicament.

17. The compound pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 3 to 14 or a pharmaceutical composition according to claim 15, for use in the treatment of a haematological cancer.

18. The compound pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 3 to 14 or a pharmaceutical composition according to claim 15, for use in the treatment of a non-haematological cancer.

19. A compound which is selected from the group consisting of: - a compound of formula (II-a): wherein X, Y and Z are as defined in claim 1, R is H, C1-6alkyl (e.g. methyl and ethyl) or benzyl, R1 is R1aa and / or R4 and R5 are R4aa and R5aa; and R1aa, R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (XX-a): wherein X, Y, Z, R10, R11, R12, R13, Ar1 and Ar2 are as defined in claim 1, P is a nitrogen protecting group such as para-methoxybenzyl, R1 is R1aa and / or R4 and R5 are R4aa and R5aa; and R1aa, R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (XXIV-a): wherein X, Y, Z, R10, R11, R12, R13, A, Ar1 and Ar2 are as defined in claim 1, P is a nitrogen protecting group such as para-methoxybenzyl, R1 is R1aa and / or R4 and R5 are R4aa and R5aa; and R1aa, R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (XXXI-a): wherein X, Y, Z, R10, R11, R12, R13, Ar1 and A2 are as defined in claim 1, A is Aa and / or R4 and R5 are R4aa and R5aa; and R4aa and R5aa are as defined in claim 1; and R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (XXXXII-a): wherein X, Y and Z are as defined in claim 1, R1 is R1aa and / or R4 and R5 are R4aa and R5aa; and R1aa, R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (LI-a): wherein X, Y, Z, Ar1 and Ar2 are as defined in claim 1, X1 is Cl or Br, A is Aaa and / or R4 and R5 are R4aa and R5aa. and Aaa, R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (LXXIII-a): wherein X, Y, Z, A1, Ar2 are as defined in claim 1, and R4 and R5 are R4aa and R5aa; and R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (LXXIV-a): wherein X, Y, Z, Ar1 and Ar2 are as defined in claim 1, and R4 and R5 are R4aa and R5aa; and R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (LXXXIII-a): wherein X, Y and Z are as defined in claim 1, alkyl is C1-4alkyl such as methyl or ethyl, e.g. methyl and R4 and R5 are R4aa and R5aa; and R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (XXXIV-a): wherein X, Y and Z are as defined in claim 1, and alkyl is C1-4alkyl such as methyl or ethyl, e.g. methyl; and salts thereof; - a compound of formula (LVIII-a): wherein X, Y, Z, and Ar1 are as defined in claim 1, A is Aa and / or R1 is R1aa and / or R4 and R5 are R4aa and R5aa; and R1aa, R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (XXXIII-a): wherein X, Y and Z are as defined in claim 1, alkyl is C1-4alkyl such as methyl or ethyl, e.g. methyl and R4 and R5 are R4aa and R5aa; and R4aa and R5aa are as defined in claim 1; and salts thereof; - a compound of formula (II-b) wherein R3 is as defined in claim 1, R1 is R1ab and / or R4 and R5 are R4ab and R5ab; and R1ab, R4ab and R5ab are as defined in claim 1; and salts thereof; - a compound of formula (IV-b) wherein R3 is as defined in claim 1, R is C1-6alkyl (e.g. methyl, ethyl) or benzyl, R1 is R1ab and / or R4 and R5 are R4ab and R6ab; and R1ab, R4ab and R5ab are as defined in claim 1; and salts thereof; - a compound of formula (II-c): wherein R3 is as defined in claim 1, R1 is R1ac and / or R4 and R5 are R4ac and R5ac; and R1ac, R4ac and R5ac are as defined in claim 1; and salts thereof; - a compound of formula (VIII-c): wherein R3 and R4 are as defined in claim 1 and R1 is R1ac; and R1ac are as defined in claim 1; and salts thereof.