N-(4-(5-CHLOROPYRIDIN-3-YL)PHENYL)-2-(2-(CYCLOPROPANESULFONA MIDO)PYRIMIDIN-4-YL) BUTANAMIDE DERIVATIVES AND RELATED COMPOUNDS AS HUMAN CTPS1 INHIBITORS FOR THE

TREATMENT OF PROLIFERATIVE DISEASES

Field of the invention

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

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.

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).

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

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). 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).

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).

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).

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.

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.

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 at 2014). 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.

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.

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.

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/ll clinical trials, but were stopped due to toxicity and efficacy issues.

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).

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.

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.

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

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 ai 2017).

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.

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.

International patent applications W02019/106156, W02019/106146, WO2019/179652 and WO2019/180244 and W02020/083975 disclose CTPS1 inhibitors.

Summary of the Invention

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

-bc); wherein R _{3 3c} 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 (l-a): wherein:

A _a is Aaa or A _ba ;

wherein: A _aa is an amine linker having the following structure: -NH-, -CH2NH- or -IMHCH2-;

A _ba is an amide linker having the following structure: -C(=0)NH- or -NHC(=0)-;

X is N or CH;

Y is N or CR _2a ;

Z is N or CR3 _a,

with the proviso that when at least one of X or Z is N, Y cannot be N;

R _2a is H, halo, Ci-2alkyl, OCi-2alkyl, Ci-2haloalkyl or OCi-2haloalkyl; 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;

Rl a IS Riaa OG Ri ba!

wherein:

Riaa is N R ₃ 2aR ₃₃ ai

Ri _ba is Ci-salkyl, Co-2alkyleneC ₃ -5cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , or CF ₃ ;

R _4a and R _5a are R _4aa and R _5aa , or R _{4 a} and R _5ba ;

wherein:

R _4aa and R _5aa together with the carbon atom to which they are attached form a C _3. ecycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci. 3alkylOH, Ci- ₃ haloalkyl, Co-2alkyleneC ₃ -6cycloalkyl, Co-2alkyleneC _{3. 6} heterocycloalkyl, Ci- ₃ alkyleneOCi. ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- ₂ alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and N R ₂ 1aR22a; OG

one of the carbons of the C ₃ -ecycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -ecycloalkyl ring and a further C _3. ecycloalkyl ring or a C ₃ -eheterocycloalkyl ring, and wherein the C _{3. 6} cycloalkyl formed by R _aa 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 Ci- 3alkyl or OCi- ₃ alkyl; or

R _4aa and Rs _aa 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 _aa 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 Ci- ₃ alkyl or OCi- 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(0) ₂ R _29a ; or

R _{4 a} and Rs _ba are each independently H, Ci- ₆ alkyl, Ci-salkylOH, Ci- ₆ haloalkyl, Co- 2alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC _3-6 heterocycloalkyl, Ci- ₃ alkyleneOCi- 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(=0)- or -NHCH ₂ -:

R _4ba and Rs _ba may additionally be selected from halo, OCi- ₆ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₆ alkyl and NR _2ia R _22a ;

Ari a is a 6-membered aryl or heteroaryl;

Ar2a is a 6-membered aryl or heteroaryl and is attached to Ari a in the para position relative to group A _a ;

Ri _0a is H, halo, Ci- ₃ alkyl, Ci- ₂ haloalkyl, OCi- ₂ alkyl, OCi- ₂ haloalkyl or CN;

Rua is H, F, Cl, Ci. ₂ alkyl, CF ₃ , OCH ₃ or CN; Ri _2a is attached to Ar2 in the ortho or meta position relative to Aria and Ri _2a is H, halo, leneC _3-5 cycloalkyl, OCi- ₄ alkyl, OCo- ₂ alkyleneC _3-5 cycloalkyl, hydroxy, Ci- ₄ alkylOH, S0 ₂ Ci- ₂ alkyl, C(0)N(Ci- ₂ alkyl) ₂ , and

when A _a is -NHC(=0)-, -NH- or -NHCH ₂ -:

Ri _2a may additionally be selected from CN, OCH ₂ CH ₂ N(CH ₃ ) ₂ and a C ₃ - 6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or Ri _2a together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0-);

R _13a is H or halo;

R _2ia is H, Ci salkyl, C(0)Ci-salkyl, C(0)0Ci- ₅ alkyl, Ci- ₃ alkylOCi- ₂ alkyl, Ci- ₄ haloalkyl, or C ₄ - 6heterocycloalkyl;

R _22a is H or CH ₃ ;

R _23a is H or Ci- ₂ alkyl; and

R _24a is H or Ci. ₂ alkyl

R _29a is Ci- ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , CF ₃ , N(Ci- 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 Ci- ₃ alkyl and R ₃₃ is Ci- 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:

Ria is Ri _aa ; and/or

R _a 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 (l-b): A _b is Aab or Abb;

wherein:

Aab is -NR _6b CH ₂ - or -NRsb-;

A _bb is -NRe _b C(=0)-;

Ri b is Rlab OG Ri bb,

wherein:

Rlab is N R32bR33b;

Ri _bb is Ci-salkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , Ci- ₃ alkyleneOCi- ₂ alkyl, or CF ₃ ;

R _3b is H, halo, CH ₃ , OCi- ₂ alkyl or CF ₃ ;

or R ₃ together with Rsbb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen- containing heterocycloalkyl;

R _b and Rsb are either R _4a b and Rsab or R ₄ bb and Rsbb;

wherein:

R _4ab and Rs _ab together with the carbon atom to which they are attached form a C ₃ - 6 _C ydoalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci- 3alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC ₃ -

₆ heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC ₃ -ecycloalkyl, OCo- ₂ alkyleneC ₃ -eheterocycloalkyl, OCi- ₃ alkyl and NR _21b R _22b ; or

one of the carbons of the C _3-6 cydoalkyl 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 - 6cycloalkyl formed by R _4a b and Rsab 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 Ci- 3alkyl or OCi- ₃ alkyl; or

R _4ab and R _5ab together with the carbon atom to which they are attached form a C _3. eheteroycloalkyl wherein one of the carbons of the C ₃ -eheterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -echeterocycloalkyl 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 Ci- ₃ alkyl or OCi- ₃ alkyl; or

R _4ab and Rs _ab 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(0) ₂ R _29b ; or

R _4bb and R _5b are each independently H, halo, Ci-ealkyl, Co-2alkyleneC ₃ -ecycloalkyl, Co-2alkyleneC ₃ -6heterocycloalkyl, OCi- ₆ alkyl, OCo-2alkyleneC ₃ -6cycloalkyl, Ci- 3alkyleneOCi- ₃ alkyl, Ci- ₆ alkylOH, Ci- ₆ haloalkyl, OCi- ₆ haloalkyl or NR _2i R22 _b ,

or R _4bb is H and Rsbb together with R ₃ form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl,

or R _{4 b} and R _{5 b} together with the carbon atom to which they are attached form a C _3-6 cydoalkyl or C _3-6 heterocycloalkyl, or R _4bb is H and Rs _bb and R _6b are a C2- ₃ alkylene chain forming a 5- or 6- membered ring; or R _4bb is O and R _5b is absent;

Re is H or Ci. ₃ alkyl,

or R ₆ together with Ru _b when in the ortho-position to group A _b are a C2alkylene chain forming a 5-membered ring, or R _{5 b} and R _6b are a C _2.3 alkylene chain forming a 5- or 6-membered ring and R _{4 b} is H;

Ar1 b is 6-membered aryl or heteroaryl;

Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1 b in the para position relative to group A _b ;

R _10b is H, halo, Ci- ₃ alkyl, OCi. ₂ alkyl, Ci- ₂ haloalkyl, OCi- ₂ haloalkyl or CN; Rub is H, F, Cl, CHs, ethyl, OCH ₃ , CF ₃ , OCF ₃ or CN,

or Ru _b , when in the ortho-position to group A , together with Re _b are a C2alkylene chain forming a 5-membered ring;

Ri2 _b is attached to Ar2b in the ortho or meta position relative to Ar1 b and Ri2 _b is H, halo, Ci-4alkyl, C^alkynyl, Co-2alkyleneC ₃ -5cycloalkyl, OCi-4alkyl, OCo-2alkyleneC ₃ -5cycloalkyl,

0CH ₂ CH ₂ N(CH ₃ ) ₂ , OH, Ci. ₄ alkylOH, CN, Ci. ₃ alkyleneOCi_ ₃ alkyl, Ci. ₄ haloalkyl, OCi. 4haloalkyl, C(=0)Ci- ₂ alkyl, NR _23b R _24b , S0 ₂ Ci- ₄ alkyl, SOCi-4alkyl, SCi-4alkyl, SH, C(0)N(CH ₃ ) ₂ , NHC(0)Ci- ₃ alkyl, C _3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or Ri2 together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0);

Ris _b is H, halo, CH ₃ or OCH ₃ ;

R _2ib is H, Ci salkyl, C(0)Ci-salkyl, C(0)0Ci- ₅ alkyl, Ci- ₃ alkylOCi-2alkyl, Ci-4haloalkyl, or C4- 6heterocycloalkyl;

R _{2 b} is H or CH ₃ ;

R _23b is H or Ci-2alkyl;

R ₂ 4 _b is H or Ci-2alkyl;

R _29b is Ci- ₃ alkyl, Co-2alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , CF ₃ , N(Ci- 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 Ci- ₃ alkyl and R ₃₃ is Ci- ₃ alkyl; or

R ₃ 2 _b and R _33b together with the nitrogen atom to which they are attached form a C _3. 5heterocycloalkyl;

wherein:

Ri b is Ri _ab ; and/or

R _b and R _5b are R _4ab and R _5ab ; and/or

A is A _a ; or

wherein when B is (B-bc) and R3 _b 3 _c is R3 _c , the compound of formula (I) is a compound of formula (l-c): wherein:

Ao is Aao or A _c ;

wherein:

Aac is -CH2NR6 _C -;

Abc is -C(-0)NR6 _C -;

Rl c IS Riac Or Ribci

wherein:

Riac is N R32cR33c

Ri _b c is Ci- ₅ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by

CH ₃ , Ci- ₃ alkyleneOCi- ₂ alkyl, or CF ₃ ;

R _3O is H, CH ₃ , halo, OCi- ₂ alkyl or CF ₃ ;

R4C and Rec are either R4ac and Rs _ac or R4 _bc and Rsbc;

wherein:

R4 _ac and Rs _ac together with the carbon atom to which they are attached form a C3-

_6C ydoalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci- 3alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC ₃ - 6heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo-

₂ alkyleneC ₃ -ecycloalkyl, OCo- ₂ alkyleneC ₃ -eheterocycloalkyl, OCi- ₃ alkyl and NR ₂ ICR22 _C ; or

one of the carbons of the Cs ecycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C _3-6 cycloalkyl ring and a further C ₃ - 6cycloalkyl ring or a C _3-6 heterocycloalkyl ring, and wherein the C _{3. 6} cycloalkyl formed by R _ac 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 Ci- 3alkyl or OCi- ₃ alkyl; or

R _4ac and R _5ac together with the carbon atom to which they are attached form a C _3. eheteroycloalkyl wherein one of the carbons of the C ₃ -eheterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -echeterocycloalkyl 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 _ac 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 Ci- ₃ alkyl or OCi- ₃ alkyl; or

R _4ac and Rs _ac 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(0) ₂ R _29C ; or

R _4bc and R _5bc are each independently H, Ci-ealkyl, Co- ₂ alkyleneC ₃ -ecycloalkyl, Co- 2alkyleneC _3-6 heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, Ci-6alkylOH or Ci-6haloalkyl, or R _4bc and Rs _bc together with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C ₃ -6heterocycloalkyl ring;

Rs _c is H or Ci- ₃ alkyl;

Ar1 c is a 6-membered aryl or heteroaryl;

Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1 c in the para position relative to group A _c ;

R _10c is H, halo, Ci- ₃ alkyl, OCi- ₂ alkyl, Ci- ₂ haloalkyl, OCi- ₂ haloalkyl or CN;

Rue is H, F, Cl, CHs, ethyl, OCH ₃ , CF ₃ , OCF ₃ or CN;

Ri _2c is attached to Ar2c in the meta or ortho position relative to Ar1 c and RI _2C is H, halo, Ci- ₄ alkyl, C _2-4 alkynyl, C(=0)Ci- ₂ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl, OCi- ₄ alkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, Ci- ₄ haloalkyl, OCi- ₄ haloalkyl, CN, OCo- ₂ alkyleneC _3-5 cycloalkyl, OCH ₂ CH ₂ N(CH ₃ ) ₂ , OH, Ci. ₄ alkylOH, NR _23c R _24c , S0 ₂ CH ₃ , C(0)N(CH ₃ ) ₂ , NHC(0)Ci_ ₃ alkyl, or a C _3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or RI _2C together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ^_ );

R _2ic is H, Ci-ealkyl, C(0)Ci- ₅ alkyl, C(0)0Ci- ₅ alkyl, Ci-3alkylOCi-2alkyl, Ci-4haloalkyl, or C ₄ - ₆ heterocydoalkyl;

R ₂ 2 _C is H or CH ₃ ; R _23C is H or Ci- ₂ alkyl;

R _24C is H or Ci- ₂ alkyl;

R _29C is Ci_ ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cydoalkyl is optionally substituted by CH ₃ , CF ₃ , N(Ci- 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 Ci- ₃ alkyl and R _33c is Ci- 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:

Ric is R _1ac ; and/or

R _4C and R _5C are R _4ac and R _5ac ; and/or

Ac IS Aac-

In one embodiment, the compound formula (I) is a compound of formula (l-a).

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

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

A compound of formula (I) may be provided in the form of a salt and/or solvate thereof and/or derivative thereof. Suitably, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and/or solvate thereof and/or derivative 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.

Also provided is a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative 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.

Further, there is provided a method for 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, by administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.

Additionally provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, in the manufacture of a medicament for 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.

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.

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

Further, there is provided a method for treating cancer in a subject, by administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.

Additionally provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

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

Further, there is provided a method for enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject, by administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.

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

Also provided are pharmaceutical compositions containing a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, and a pharmaceutically acceptable carrier or excipient.

Also provided are processes for preparing compounds of formula (I) and novel intermediates of use in the preparation of compounds of formula (I). Detailed description of the Invention

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

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

-bc); wherein R _3b3c is or R _C as defined below;

wherein when B is (B-a) the compound of formula (I) is a compound of formula (l-a):

wherein:

A _a is Aaa OG Abal

wherein:

A _aa is an amine linker having the following structure: -NH-, -CH ₂ NH- or -NHCH ₂ -; A _a is an amide linker having the following structure: -C(=0)NH- or -NHC(=0)-;

X is N or CH;

Y is N or CR _2a ;

Z is N or CR _a;

with the proviso that when at least one of X or Z is N, Y cannot be N; R _2a is H, halo, Ci- ₂ alkyl, OCi- ₂ alkyl, Ci- ₂ haloalkyl or OCi- 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 FI;

Rla IS Riaa OG Riba,

wherein:

Riaa is NR _32a R _33a ;

Ri _ta is Ci- ₅ alkyl, Co- 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 _a and R _5ba ;

wherein:

R _4aa and R _5aa together with the carbon atom to which they are attached form a C _3. ecycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci- 3alkylOH, Ci. ₃ haloalkyl, Co- ₂ alkyleneC _3.6 cycloalkyl, Co- ₂ alkyleneC _3. 6heterocycloalkyl, Ci. ₃ alkyleneOCi. ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and N R21aR22a OG

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. ecycloalkyl 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 Ci. 3alkyl or OCi- ₃ alkyl; or

R _4aa and Rs _aa together with the carbon atom to which they are attached form a C _3. 6heterocycloalkyl wherein one of the carbons of the C _3. 6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -6heterocycloalkyl ring and a further C ₃ -6cycloalkyl ring or a C ₃ -6heterocycloalkyl ring, and wherein the C _3. 6heterocycloalkyl formed by R _4aa and Rs _aa 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 Ci- ₃ alkyl or OCi. ₃ alkyl; or R _4aa and Rs _aa together with the carbon atom to which they are attached form a C ₃ - 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(0) ₂ R _29a ; or

R _4ba and R _5ba are each independently H, Ci-ealkyl, Ci-salkylOH, Ci-ehaloalkyl, Co- 2alkyleneC ₃ -ecycloalkyl, Co- ₂ alkyleneC ₃ -sheterocycloalkyl, Ci- ₃ alkyleneOCi- 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(=0)- or -NHCH ₂ -:

R _ba and R _{5 a} may additionally be selected from halo, OCi- ₆ haloalkyl, OC ₀ - 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₆ alkyl and NR _21a R22a;

Ari a is a 6-membered aryl or heteroaryl;

Ar2a is a 6-membered aryl or heteroaryl and is attached to Ari a in the para position relative to group A _a ;

Rio _a is H, halo, Ci- ₃ alkyl, Ci- ₂ haloalkyl, OCi- ₂ alkyl, OCi- ₂ haloalkyl or CN;

Rua is H, F, Cl, Ci. ₂ alkyl, CF ₃ , OCH ₃ or CN;

Ri _2a is attached to Ar2 in the ortho or meta position relative to Aria and Ri _2a is H, halo, Ci. ₄ alkyl, C _2-4 alkenyl, Co- ₂ alkyleneC _3-5 cycloalkyl, OCi- ₄ alkyl, OCo- ₂ alkyleneC _3-5 cycloalkyl, Ci. ₄ haloalkyl, OCi- ₄ haloalkyl _, hydroxy, Ci- alkylOH, S0 ₂ Ci- ₂ alkyl, C(0)N(Ci- ₂ alkyl) ₂ , NHC(0)Ci- ₃ alkyl or NR _23a R _24a ; and

when A _a is -NHC(=0)-, -NH- or -NHCH ₂ -:

Ri _2a may additionally be selected from CN, OCH ₂ CH ₂ N(CH3) ₂ and a C3- 6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or Ri _2a together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0-);

Ri _3a is H or halo;

R _2ia is H, Ci-ealkyl, C(0)Ci-salkyl, C(0)OCi- ₅ alkyl;

R _22a is H or CH ₃ ;

R _23a is H or Ci. ₂ alkyl; and R _24a is H or Ci- ₂ alkyl R29a is Ci- ₃ alkyl, Co-2alkyleneC ₃ -5cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , or CF ₃ ;

R _32a is Ci- ₃ alkyl and R ₃₃ is Ci- ₃ alkyl; or

R _32a and R _33a together with the nitrogen atom to which they are attached form a C ₃ . 5heterocydoalkyl; wherein

Ria is Ri _aa ; and/or

R _4a and Rs _a are R _4aa and Rs _aa ; and/or

A _a is A _aa ; and wherein when B is (B-bc) and R _3b 3c is R3 _b , the compound of formula (I) is a compound of formula (l-b):

wherein:

A _b is Aab or Abb;

wherein:

Aa is -NRebCH ₂ - or -NR _8b -;

A _bb is -NR _6b C(-0)-;

Rib IS Rlab Or Ribbi

wherein: Rlab is N R _32b R33b!

Ri _bb is Ci-salkyl, Co-2alkyleneC ₃ -5cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , Ci- ₃ alkyleneOCi-2alkyl, or CF ₃ ;

R _3b is H, halo, CH ₃ , OCi-2alkyl or CF ₃ ; or R ₃ together with R _5bb forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen- containing heterocycloalkyl;

R _4b and R ₅ are either R _4ab and R _5ab or R _{4 b} and R ₅ i wherein:

R _4ab and R _5ab together with the carbon atom to which they are attached form a C ₃ - ecycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci. 3alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co-2alkyleneC3- 6heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and N R21 bR22b 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 -ecycloalkyl ring and a further C ₃ - ecycloalkyl ring or a C ₃ -eheterocycloalkyl ring, and wherein the C ₃ - ecycloalkyl formed by R _4a b and R _5a b 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 Ci- 3alkyl or OCi- ₃ alkyl; or

R _4a b and Rsab together with the carbon atom to which they are attached form a C ₃ - 6heteroycloalkyl 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 cheterocycloalkyl 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 _4a b and Rsab 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 Ci. ₃ alkyl or OCi. ₃ alkyl; or

R _4a b and R _5a b together with the carbon atom to which they are attached form a C ₃ - 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(0) ₂ R _29b ; or

R _4bb and Rs _bb are each independently H , halo, Ci-6alkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC ₃ -sheterocycloalkyl, OCi-salkyl, OCo- ₂ alkyleneC _3-6 cycloalkyl, Ci- 3alkyleneOCi- ₃ alkyl, Ci-6alkylOH, Ci-6haloalkyl, OCi-6haloalkyl or NR _2ib R _22b ,

or R ₄ b is H and R ₅ bb together with R ₃ form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl, or R _4bb and Rs _bb together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl, or R _4bb is H and Rsbb and Reb are a C _2.3 alkylene chain forming a 5- or 6- membered ring; or R _4b is O and R _5b is absent;

R _6b is H or Ci-3alkyl,

or R _6b together with Rn when in the ortho-position to group A _b are a C ₂ alkylene chain forming a 5-membered ring,

or R ₅ bb and R ₆ b are a C ₂ -3alkylene chain forming a 5- or 6-membered ring and R b is H;

Ar1 b is 6-membered aryl or heteroaryl;

Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1 b in the para position relative to group A _b ;

Rio _b is H, halo, Ci-3alkyl, OCi- ₂ alkyl, Ci_ ₂ haloalkyl, OCi_ ₂ haloalkyl or CN;

Rut is H, F, Cl, CHs, ethyl, OCH ₃ , CF ₃ , OCF ₃ or CN,

or Rii _b , when in the ortho-position to group A _b , together with R _eb are a C ₂ alkylene chain forming a 5-membered ring;

Ri _2b is attached to Ar2b in the ortho or meta position relative to Ar1 b and Ri _2b is H, halo, Ci. ₄ alkyl, C _2.4 alkynyl, Co- ₂ alkyleneC ₃ -5cycloalkyl, OCi- ₄ alkyl, OCo- ₂ alkyleneC3-5Cycloalkyl, OCH ₂ CH ₂ N(CH ₃ )2, OH, Ci. ₄ alkylOH, CN, Ci. ₃ alkyleneOCi. ₃ alkyl, Ci. ₄ haloalkyl, OCi. ₄ haloalkyl, C(=0)Ci- ₂ alkyl, NR _23b R _24b , S0 ₂ Ci- ₄ alkyl, SOCi- ₄ alkyl, SCi- ₄ alkyl, SH, C(0)N(CH ₃ ) ₂ , NHC(0)Ci- ₃ alkyl, C _3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or Ri _2b together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ^_ );

Ri _3b is H, halo, CH ₃ or OCH ₃ ;

R _2ib is H, Ci-5alkyl, C(0)Ci-salkyl, C(0)OCi- ₅ alkyl;

R ₂₂ is H or CH ₃ ;

R _23b is H or Ci- ₂ alkyl;

R _24b is H or Ci. ₂ alkyl;

R _å 9 _b is Ci-3alkyl, Co-2alkyleneC ₃ -5cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , or CF ₃ ; and

F?32 _b is Ci-3alkyl and R ₃ 3 _b is Ci-3alkyl; or R _32b and R _33b together with the nitrogen atom to which they are attached form a C ₃ - sheterocycloalkyl;

wherein:

Ri b is Ri _ab ; and/or

R _4b and R _5b are R _4ab and R _5ab ; and/or

A is Aabi or

wherein when B is (B-bc) and R _3b3c is R _3c , the compound of formula (I) is a compound of formula (l-c):

wherein:

Ac is Aac or Ab _C ;

Aac is -CH2NR6C-;

Abe is -C(-0)NR6 _C -;

Rl c IS Riac Or Ribci

wherein:

Riac is N R32cR33c;

Ri _bc is Ci- ₅ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , Ci- ₃ alkyleneOCi- ₂ alkyl, or CF ₃ ;

R _3C is H, CH ₃ , halo, OCi- ₂ alkyl or CF ₃ ; R _4C and Rec are either R _4ac and Rsac or R _4bc and Rsb _C ;

wherein:

R _4ac and R _5ac together with the carbon atom to which they are attached form a C _{3. 6} cydoalkyl which is: substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci-

₃ alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC ₃ - ₆ heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and

NR _2ic R _22c ; or

one of the carbons of the C ₃ -ecycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -ecycloalkyl ring and a further C ₃ - 6cycloalkyl ring or a C _3-6 heterocycloalkyl ring, and wherein the C ₃ - 6cycloalkyl formed by R _ac 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 Ci- 3alkyl or OCi- ₃ alkyl; or

R _4ac and Rs _ac together with the carbon atom to which they are attached form a C ₃ - 6heteroycloalkyl 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 Cheterocycloalkyl 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 Ci- ₃ alkyl or OCi. ₃ alkyl; or

R _4ac and R _5ac together with the carbon atom to which they are attached form a C ₃ - 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(0) ₂ R _29C ; or

R _4bc and R _5bc are each independently H, Ci-6alkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- 2alkyleneC ₃ -6heterocycloalkyl, Ci- ₃ alkyleneOCi. ₃ alkyl, Ci- _S alkylOH or Ci. _B haloalkyl, or R _{4 G} 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;

R6 _C is H or Ci-3alkyl;

Ar1 c is a 6-membered aryl or heteroaryl;

Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1 c in the para position relative to group A ₀ ;

Rio _c is H, halo, Ci- ₃ alkyl, OCi- ₂ alkyl, Ci- ₂ haloalkyl, OCi- ₂ haloalkyl or CN;

Rue is H, F, Cl, CH ₃ , ethyl, OCH ₃ , CF ₃ , OCF ₃ or CN;

Ri _2c is attached to Ar2c in the meta or ortho position relative to Ar1 c and Ri _2c is H, halo, Ci- ₄ alkyl, C _2.4 alkynyl, C(=0)Ci- ₂ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl, OCi- ₄ alkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, Ci- ₄ haloalkyl, OCi- ₄ haloalkyl, CN, OCo- ₂ alkyleneC ₃ -scydoalkyl, OCH ₂ CH ₂ N(CH ₃ ) ₂ , OH, Ci- ₄ alkylOH, NR _23c R24c, S0 ₂ CH ₃ , C(0)N(CH ₃ ) ₂ , NHC(0)Ci. 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 ⁺ -0 ^_

);

R21 _C is H, Ci- ₅ alkyl, C(0)Ci- ₅ alkyl, C(0)OCi- ₅ alkyl;

R22C is H or CH3;

R _23c is H or Ci. ₂ alkyl;

R _24C is H or Ci- ₂ alkyl;

R ₂ 9 _C is Ci- ₃ alkyl, Co- ₂ alkyleneC ₃ -scycloalkyl which cycloalkyl is optionally substituted by CH3, or CF3; and

R _32C is Ci- ₃ alkyl and R _33c is Ci- ₃ alkyl; or

R _32C and R _33C together with the nitrogen atom to which they are attached form a C ₃ - 5heterocydoalkyl;

wherein:

Rio is Ria _C ; and/or

R _4C and R5 _C are R _4ac and Rsa _C ; and/or

AQ IS Aac-

More suitably, there is provided a compound of formula (l-a).

Alternatively, there is provided a compound of formula (l-b).

Alternatively, there is provided a compound of formula (l-c).

Compounds of formula (l-a)

The invention provides a compound of formula (l-a):

wherein:

Aa is Aaa OG A _ba ;

wherein: A _aa is an amine linker having the following structure: -NH-, -CH ₂ NH- or -NHChh-; A _ba is an amide linker having the following structure: -C(=0)NH- or -NHC(=0)-;

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 _la IS Riaa OG Riba,

wherein:

Riaa is NR _32a R _33a ;

Ri _ta is Ci- ₅ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH3, or CF ₃ ;

R _2a is H, halo, Ci- ₂ alkyl, OCi- ₂ alkyl, Ci- ₂ haloalkyl or OCi- 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 FI;

R _4a and R _5a are R _4aa and R _5aa , or R _{4 a} 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 Ci- ₃ alkyl, oxo, OH, Ci- 3alkylOH, Ci. ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC _{3. 6} heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and NR _21a R _22a ; OG

one of the carbons of the C ₃ -ecycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -ecycloalkyl ring and a further C ₃ - 6cycloalkyl 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 Ci- 3alkyl or OCi- ₃ alkyl; or R _4aa and Rs _aa together with the carbon atom to which they are attached form a C ₃ - 6heterocycloalkyl 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 - 6heterocycloalkyl formed by R _4aa and R _aa 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 Ci- ₃ alkyl or OCi- ₃ alkyl; or

R _4aa and R _5aa together with the carbon atom to which they are attached form a C ₃ - 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(0) ₂ R _29a ; or

R _4ba and R _5ba are each independently H, Ci- ₆ alkyl, Ci-salkylOH, Ci- ₆ haloalkyl, Co- 2alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC ₃ -sheterocycloalkyl, Ci- ₃ alkyleneOCi- 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(=0)- or -NHCH ₂ -:

R _4ba and Rs _ba may additionally be selected from halo, OCi- ₆ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₆ alkyl and

NR _2la R22a;

Ari a is a 6-membered aryl or heteroaryl;

Ar2a is a 6-membered aryl or heteroaryl and is attached to Aria in the para position relative to group A _a ;

Rio _a is H, halo, Ci- ₃ alkyl, Ci- ₂ haloalkyl, OCi- ₂ alkyl, OCi- ₂ haloalkyl or CN;

Ru _a is H, F, Cl, Ci. ₂ alkyl, CF ₃ , OCH ₃ or CN;

Ri _2a is attached to Ar2a in the ortho or meta position relative to Ari a and Ri _2a is H, halo, Ci. ₄ alkyl, C _2.4 alkenyl, Co- ₂ alkyleneC _3-5 cycloalkyl, OCi- ₄ alkyl, OCo- ₂ alkyleneC _3-5 cycloalkyl, Ci. ₄ haloalkyl, OCi. ₄ haloalkyl _, hydroxy, Ci- ₄ alkylOH, S0 ₂ Ci- ₂ alkyl, C(0)N(Ci. ₂ alkyl) ₂ , NHC(0)Ci- ₃ alkyl or NR _23a R _24a ; and

when A _a is -NHC(=0)-, -NH- or -NHCH ₂ -:

Ri ₂₃ may additionally be selected from CN, OCH ₂ CH ₂ N(CH ₃ ) ₂ and a C ₃ - 6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or Ri _2a together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ); Ri3a is H or halo;

R _2ia is H, Ci-salkyl, C(0)Ci-salkyl, C(0)0Ci- ₅ alkyl, Ci- ₃ alkylOCi-2alkyl, Ci-4haloalkyl, or C4- eheterocycloalkyl;

R ₂ 2 _a is H or CH ₃ ; R _23a is H or Ci. ₂ alkyl; and

R _{2 a} is H or Ci- ₂ alkyl;

R ₂ 9 _a is Ci- ₃ alkyl, Co- ₂ alkyleneC _3. 5cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , CF ₃ , N(Ci. 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 Ci. ₃ alkyl and R _33a is Ci- ₃ alkyl; or

R _32a and R _33a together with the nitrogen atom to which they are attached form a C _3. 5heterocycloalkyl; or a salt and/or solvate thereof and/or derivative thereof.

Suitably, Ri _c is Ri _ac ; and/or R _4c and R _5c are R _4ac and R _5ac ; and/or A _c is A _ac .

The invention also provides a compound of formula (l-a):

wherein:

Aa is A _aa or Aba;

wherein:

A _aa is an amine linker having the following structure: -NH-, -CH ₂ NH- or -NHCH ₂ -; A _a is an amide linker having the following structure: -C(=0)NH- or -NHC(=0)-;

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;

Rl a IS Rlaa OG Rl baJ wherein:

Rlaa IS NR _32a R _33a ;

Ri _ba is Ci_5alkyl, Co- ₂ alkyleneC ₃ -5cycloalkyl which cydoalkyl is optionally substituted by CH ₃ , or CF ₃ ;

R _a is H, halo, Ci- ₂ alkyl, OCi- ₂ alkyl, Ci- ₂ haloalkyl or OCi- 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 _{4 a} and R _5ba ;

wherein:

R _4aa and Rs _aa together with the carbon atom to which they are attached form a C ₃ - 6cycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci. 3alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, C _0-2 alkyleneC _3. eheterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and NR _2ia 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 - 6cycloalkyl ring or a C _3-6 heterocycloalkyl ring, and wherein the C ₃ - 6cycloalkyl formed by R _4aa and Rs _aa 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 Ci- 3alkyl or OCi- 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 Ci- ₃ alkyl or OCi- ₃ alkyl; or R _4aa and Rs _aa together with the carbon atom to which they are attached form a C ₃ - 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(0) ₂ R _29a ; or

R _4ba and R _5ba are each independently H, Ci-ealkyl, Ci-salkylOH, Ci-ehaloalkyl, Co- 2alkyleneC ₃ -ecycloalkyl, Co- ₂ alkyleneC ₃ -sheterocycloalkyl, Ci- ₃ alkyleneOCi- 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(=0)- or -NHCH ₂ -:

R _ba and R _{5 a} may additionally be selected from halo, OCi- ₆ haloalkyl, OC ₀ - 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₆ alkyl and NR _21a R22a;

Ari a is a 6-membered aryl or heteroaryl;

Ar2a is a 6-membered aryl or heteroaryl and is attached to Ari a in the para position relative to group A _a ;

Rio _a is H, halo, Ci- ₃ alkyl, Ci- ₂ haloalkyl, OCi- ₂ alkyl, OCi- ₂ haloalkyl or CN;

Rua is H, F, Cl, Ci. ₂ alkyl, CF ₃ , OCH ₃ or CN;

Ri _2a is attached to Ar2a in the ortho or meta position relative to Ari a and Ri _2a is H, halo, Ci. ₄ alkyl, C _2-4 alkenyl, Co- ₂ alkyleneC _3-5 cycloalkyl, OCi- ₄ alkyl, OCo- ₂ alkyleneC _3-5 cycloalkyl, Ci. ₄ haloalkyl, OCi- ₄ haloalkyl _, hydroxy, Ci- alkylOH, S0 ₂ Ci- ₂ alkyl, C(0)N(Ci- ₂ alkyl) ₂ , NHC(0)Ci- ₃ alkyl or NR _23a R _24a ; and

when A _a is -NHC(=0)-, -NH- or -NHCH ₂ -:

Ri _2a may additionally be selected from CN, OCH ₂ CH ₂ N(CH3) ₂ and a C3- 6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or Ri _2a together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0-);

Ri _3a is H or halo;

R _2ia is H, Ci-ealkyl, C(0)Ci-salkyl, C(0)OCi- ₅ alkyl;

R _22a is H or CH ₃ ;

R _23a is H or Ci. ₂ alkyl; and R _24a is H or Ci- ₂ alkyl; R29 _a is Ci- ₃ alkyl, Co-2alkyleneC _3. 5cycloalkyl which cycloalkyl is optionally substituted by CHs, or CF ₃ ;

R32 _a is Ci-3alkyl and R _33a is Ci-3alkyl; or

R32 _a and R3 _3a together with the nitrogen atom to which they are attached form a C _3. 5heterocycloalkyl; or a salt and/or solvate thereof and/or derivative thereof.

Suitably, Ri _c is Ri _ac ; and/or R _c and R _5c are R _4ac and R _5ac ; and/or A ₀ is A _ao .

The phrase‘A _ba is an amide linker having the following structure: -C(=0)NH- or -NHC(=0)-’ means the following structures form:

Reference to R ₄ and R ₅ above includes variables R _4a , R _5a , R _4aa , Rs _aa , R _4ba and R _5ba , and reference to Ar1 and Ar2 includes variables Aria and Ar2a.

The phrase‘A _aa is an amine linker having the following structure: -CH ₂ NH- or -NHCH ₂ -’ means the following structures form:

-NHCH ₂ - -CH ₂ NH-

Reference to R ₄ and R5 above includes variables R _4a , Rs _a , R _4aa , Rs _aa , R _4ba and Rs _ba , and reference to Ar1 and Ar2 includes variables Aria and Ar2a.

In one embodiment, A _ba is -C(=0)NH-. In another embodiment, A _ba is -NHC(=0)-. 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 -.

In one embodiment X is N. In another embodiment, X is CH.

In one embodiment, Y is N. In another embodiment, Y is CR2 _a .

In one embodiment, Z is N. In another embodiment, Z is CR3 _a . 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 _2a and Z is N. Alternatively, X is N, Y is CR _2a and Z is N.

In one embodiment of the invention, Ri _a is Ri _aa , i.e. is NR _32a R _33a . In an embodiment R _32a is Ci- ₃ alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R _33a is Ci- 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.

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 pyrrol id iny I.

Suitably, Ri _a is Ri _a .

In one embodiment of the invention Ri _ba is Ci-salkyl. When Ri _ba is Ci-salkyl, Ri _ba may be methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or ferf-butyl) or pentyl (e.g. n-pentyl, sec-pentyl or 3-pentyl).

In a second embodiment of the invention Ri _ba is Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ . In some embodiments, Ri _ba is Co- ₂ alkyleneC _3-5 cycloalkyl. In other embodiments, Ri _ba is Co- ₂ alkyleneC _3.5 cycloalkyl which cycloalkyl is substituted by CH ₃ . Ri _ba may be C _3.5 cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Ri _a may be CialkyleneC _{3. 5} cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Ri _a may be C ₂ alkyleneC _{3. 5} cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R _{1 a} may be C ₀ - ₂ alkyleneC ₃ cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Ri _ba may be Co- ₂ alkyleneC ₄ cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Ri _ba may be Co- ₂ alkyleneC ₅ cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Suitably, where Co- 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 a third embodiment, Ri _ba is CF ₃ .

Suitably Ri _a is cyclopropyl, cyclopropyl substituted by CH ₃ at the point of attachment, cyclobutyl, CH ₃ or CH ₂ CH ₃ . In particular Ri _ba is cyclopropyl, cyclobutyl, CH ₃ or CH ₂ CH ₃ , especially cyclopropyl.

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 Ci- ₂ alkyl. When R _2a is Ci- ₂ alkyl, R _2a may be methyl or ethyl, such as methyl. In a fourth embodiment, R _2a is OCi- ₂ alkyl. When R _2a is OCi- ₂ alkyl, may be OCH ₃ or OEt, such as OCH _3. In a fifth embodiment, R _2a is Ci- ₂ haloalkyl. When R _2a is Ci. ₂ haloalkyl, R _2a may be CF ₃ or CH ₂ CF ₃ , such as CF _3. In a sixth embodiment, R _2a is OCi- ₂ haloalkyl. When R _2a is OCi. ₂ haloalkyl, R _2a may be OCF ₃ or OCH ₂ CF ₃ , such as OCF ₃ . Suitably, R _åa is H, CH3 or CF3, such as H or CH3, in particular H.

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 .

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.

Suitably, at least one of R _2a and R _3a is H.

In one embodiment, R _a and R _5a are R _4aa and R _5aa .

Suitably, R _4aa and Rs _aa together with the carbon atom to which they are attached form a C ₃ - 6cycloalkyl which is substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci. ₃ alkyl, oxo, OH, Ci. ₃ alkylOH, Ci. ₃ haloalkyl, Co- ₂ alkyleneC ₃ -6cycloalkyl, Co- ₂ alkyleneC _3-6 heterocycloalkyl, Ci. ₃ alkyleneOCi. ₃ alkyl, halo, OC ₁ - ₃ haloalkyl, OCo- ₂ alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and NR _2ia R _22a .

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

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

In one embodiment, the substituent is Ci- ₃ alkyl. Suitably, the substituent is methyl. Suitably, the substituent is ethyl. Suitably, the substituent is n-propyl. Suitably, the substituent is iso-propyl.

In a second embodiment, the substituent is Ci- 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.

In a third embodiment, the substituent is Ci- ₃ haloalkyl. Suitably the Ci- 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 Cihaloalkyl such as CF ₃ . Suitably, the substituent is C ₂ haloalkyl such as CH ₂ CF ₃ .

In a fourth embodiment, the substituent is Co- ₂ alkyleneC _3-6 cycloalkyl, in particular Co- ₂ alkyleneC _{3. 5} cycloalkyl, such as C _3-5 cycloalkyl, CialkyleneC _3-5 cycloalkyl or C ₂ alkyleneC _3-5 cycloalkyl.

In a fifth embodiment, the substituent is Co- ₂ alkyleneC _3-6 heterocycloalkyl such as Co- ₂ alkyleneC ₃ heterocycloalkyl, Co- ₂ alkyleneC ₄ heterocycloalkyl, Co^alkyleneCsheterocycloalkyl, Co- ₂ alkyleneC ₆ heterocycloalkyl, CoalkyleneC ₃ -6heterocycloalkyl, CialkyleneC ₃ -6heterocycloalkyl and C ₂ alkyleneC ₃ -6heterocycloalkyl. 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 Ci- ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C3-6heterocycloalkyl ring include Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkylOCi- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C3-6heterocycloalkyl ring is not substituted.

In a sixth embodiment, the substituent is Ci- ₃ alkyleneOCi- ₃ alkyl, in particular Ci- ₂ alkyleneOCi- ₂ alkyl such as CialkyleneOCialkyl, C ₂ alkyleneOCialkyl, CialkyleneOC ₂ alkyl or C ₂ alkyleneOC ₂ alkyl.

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

In an eighth embodiment, the substituent is OCi-3haloalkyl. Suitably the OCi-3alkyl 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 OCihaloalkyl such as OCF ₃ . Suitably, the substituent is OC ₂ haloalkyl such as OCH ₂ CF ₃ .

In a ninth embodiment, the substituent is OCo-2alkyleneC _3. 6cycloalkyl, such as OC _3-6 cycloalkyl, OCialkyleneC _3-6 cycloalkyl or OC ₂ alkyleneC ₃ -scycloalkyl.

In a tenth embodiment, the substituent is OCo- ₂ alkyleneC ₃ -eheterocycloalkyl such as OCo- ₂ alkyleneC ₃ heterocycloalkyl, OCo- ₂ alkyleneC ₄ heterocycloalkyl, OCo^alkyleneCsheterocycloalkyl, OCo- ₂ alkyleneCeheterocycloalkyl, OCoalkyleneC ₃ -eheterocycloalkyl, OCialkyleneC ₃ - eheterocycloalkyl and OC ₂ alkyleneC _3.8 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 Ci- ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C _3-6 heterocycloalkyl ring include Ci_ ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkylOCi- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci. ₄ alkyl such as CH ₂ C(0)0CH ₂ CH _3. Suitably, any nitrogen atom in the C _3.6 heterocycloalkyl ring is not substituted.

In an eleventh embodiment, the substituent is OCi-3alkyl, such as OCH ₃ or OCH2CH3. In a twelfth embodiment, the substituent is NR _{2i a} R _22a wherein R _2ia and R _22a are defined elsewhere herein.

In an embodiment the substituent is oxo.

In another embodiment the substituent is OH.

Suitably, the one or two substituents, in particular one substituent, are independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci- ₃ alkylOH, Ci- ₃ haloalkyl, halo, OCi- ₃ haloalkyl, OCi- ₃ alkyl and NR _2ia R _22a .

More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OCi- ₃ alkyl and NR _2ia R _22a .

Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro and NR _{?i a} R _a.

When the substituent is NR _{2i a} R _22a , in one embodiment R _{2i a} is H. In a second embodiment R _2ia is Ci- ₅ alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R _2ia is C(0)Ci- ₅ alkyl, such as C(0)CH ₃ . In a fourth embodiment R _2ia is C(0)OCi-salkyl, such as C(0)OCH ₃ or C(0)Otert-butyl. In a fifth embodiment R _2ia is Ci- ₃ alkylOCi- ₂ alkyl such as CialkylOCialkyl, C ₂ alkylOCialkyl or CsalkylOCialkyl e.g. C ₂ alkylOCi alkyl. In a sixth embodiment, R _2ia is Ci- 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 _2ia is C _4-6 heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When the substituent is NR _{2i a} R _22a , in one embodiment R _22a is H. In a second embodiment R _22a is methyl.

Suitably, R _2ia is C(0)OCH ₃ and R _22a is H. Suitably, R _21a is C(0)CH ₃ and R _22a is H . Suitably, R _2ia and R _22a are both CH ₃ . Suitably, R _2ia and R _22a are both H.

Alternatively, R _4aa and Rs _aa 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 -scycloalkyl 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 Rs _aa 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 Ci- ₃ alkyl or OCi- ₃ alkyl.

In one embodiment the C ₃ -ecycloalkyl formed by R _4aa and R _aa together with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C ₃ -ecycloalkyl 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 Ci- ₂ alkyl or OCH ₃ . Suitably one of the carbons of the C _3-6 cycloalkyl formed by R _4aa and Rs _aa 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.

Alternatively, R _4aa and R _5aa suitably together with the carbon atom to which they are attached form a C ₃ -sheterocycloalkyl wherein one of the carbons of the C ₃ -eheterocycloalkyl 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 -sheterocycloalkyl formed by R _aa 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 Ci- ₃ alkyl or OCi- ₃ alkyl.

In one embodiment the C _3-6 heterocycloalkyl formed by R _4aa and Rs _aa together with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C ₃ - ₆ heterocycloalkyl formed by R _aa 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 Ci- alkyl or OCH ₃ .

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(0) ₂ R29a·

Suitably, the C _3-6 heterocycloalkyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.

Suitably, when the C ₃ -eheterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:

The C ₃ -eheterocycloalkyl may be other groups as defined elsewhere herein.

In an embodiment, R _2ga is Ci- ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , or CF _3. In one embodiment, R _2ga is Ci- ₃ alkyl such as methyl. In another embodiment, R _2ga is Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ . In some embodiments, R _2ga is Co- ₂ alkyleneC _3-5 cycloalkyl. In other embodiments, R _29a is Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is substituted by CH ₃ . R _29a may be C ₃ -scycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R _2ga may be CialkyleneC ₃ -scycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R _2ga may be C ₂ alkyleneC _3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R29 _a may be Co-2alkyleneC3cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R29 _a may be Co-2alkyleneC4cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R29 _a may be Co^alkyleneCscycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Suitably, where C ₀ -2alkyleneC ₃ -5cycloalkyl is optionally substituted by CH ₃ , the CH ₃ is at the point of attachment of the C ₃ -5cycloalkyl to the Co-2alkylene. In another embodiment, R ₂ 9 _a is CF ₃ . In another embodiment, R _2ga is N(Ci- ₃ alkyl) ₂ such as N(CH ₃ ) ₂ . In another embodiment, R _2ga 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.

In another embodiment, R4 _a and Rs _a are R4 _ba and Rs _ba.

In one embodiment, R _4ba and R _ba 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 Ci- ₄ alkyl, C(0)H, C(0)Ci- alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C ₃ -eheterocycloalkyl ring include Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)OCi- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C _3.6 heterocycloalkyl ring is not substituted. In a third embodiment, R _ba is Ci- ₆ alkyl, in particular Ci-4alkyl 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 Ci- ₃ alkyleneOCi- ₃ alkyl, in particular Ci- ₂ alkyleneOCi- ₂ alkyl such as CialkyleneOCialkyl, C ₂ alkyleneOCialkyl, CialkyleneOC ₂ alkyl or C ₂ alkyleneOC ₂ alkyl. In a fifth embodiment, R4 _ba is H. In a sixth embodiment, R4 _ba is halo, such as chloro or fluoro, especially fluoro. In a seventh embodiment, R4 _ba is Ci- ₆ haloalkyl, such as CF ₃ or CH ₂ CF _3. In an eighth embodiment, R4 _ba is Co- ₂ alkyleneC _3-6 cycloalkyl such as C _3-6 cycloalkyl, CialkyleneC _3-6 cycloalkyl, C ₂ alkyleneC _3-6 cycloalkyl, Co-2alkyleneC ₃ cycloalkyl, Co-2alkyleneC4cycloalkyl, Co- ₂ alkyleneC5cycloalkyl or Co-2alkyleneC6cycloalkyl. In a ninth embodiment, R4 _ba is Co-2alkyleneC _{3. 6} heterocycloalkyl such as C _3.6 heterocycloalkyl, CialkyleneC _3.6 heterocycloalkyl, C ₂ alkyleneC _{3. 6} heterocycloalkyl, Co-2alkyleneC ₃ heterocycloalkyl, Co-2alkyleneC4hetero-cycloalkyl, Co- ₂ alkyleneC5heterocycloalkyl or Co-2alkyleneC6heterocycloalkyl. 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 Ci. ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi_ ₄ alkyl, C(0)OCi_ ₄ alkylaryl such as C(0)0Bz, C(0)NHCi_ ₄ alkyl, C(0)N HCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C3-sheterocycloalkyl ring include Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C _3-6 heterocycloalkyl ring is not substituted. In a tenth embodiment, R _4ba is Ci. ealkylOH, such as CH ₂ OH or CH ₂ CH ₂ OH. In an eleventh embodiment, R _4ba is OCi-ehaloalkyl, such as OCi- ₄ haloalkyl, such as OCF ₃ or OCHF ₂ . In a twelfth embodiment, R _4ba is OCo-2alkyleneC _3. ecycloalkyl such as OC ₃ -scycloalkyl, OCialkyleneC ₃ -ecycloalkyl, OC ₂ alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC ₃ cycloalkyl, OCo-2alkyleneC ₄ cycloalkyl, OCo^alkyleneCscycloalkyl or OCo- ₂ alkyleneC ₆ cycloalkyl. In a thirteenth embodiment, R _ba is OCi- ₆ alkyl, in particular OCi- 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 _a is OCo-2alkyleneC ₃ -6heterocycloalkyl such as OC _3-6 heterocycloalkyl, OCialkyleneC _3-6 heterocycloalkyl, OC2alkyleneC ₃ -6heterocycloalkyl, OCo-2alkyleneC ₃ heterocycloalkyl, OCo-2alkyleneC ₄ hetero-cycloalkyl, OCo-

₂ alkyleneC5heterocycloalkyl or OCo-2alkyleneC6heterocycloalkyl. 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 Ci. ₄ alkyl, C(0)H, C(0)Ci. ₄ alkyl, C(0)OCi_ ₄ alkyl, C(0)OCi_ ₄ alkylaryl such as C(0)0Bz, C(0)NHCi. ₄ alkyl, C(0)N HCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi. ₄ haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C ₃ -sheterocycloalkyl ring include Ci- ₄ alkylCN such as CH2CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH 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 _2ia R _22a -

When A _a is -NHC(=0)- or -C(=0)NH-, suitably, R _4ba is H, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkylOH, Co- ₂ alkyleneC ₃ -ecycloalkyl, Co-2alkyleneC ₃ -eheterocycloalkyl, Ci- ₃ alkyleneOCi- 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(=0)-, suitably R _{4 a} may additionally be selected from halo, OCi- ₆ haloalkyl, OCo-2alkyleneC ₃ -6cycloalkyl, OCo-2alkyleneC ₃ -6heterocycloalkyl, OCi- ₆ alkyl or NR21aR22a. When A _a is -NH-, -CH ₂ NH- or -N HCH ₂ -, suitably, R _4ba is H, Ci- _S alkyl, Ci-ehaloalkyl, Ci- ₆ alkylOH, Co- ₂ alkyleneC3-scycloalkyl, Co- ₂ alkyleneC3-6heterocycloalkyl, Ci-3alkyleneOCi-3alkyl, or R _4ba and R _5ba together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3- ₆ heterocycloalkyl. When A _a is -NHCH ₂ -, suitably R _{4 a} may additionally be selected from halo, OC1- ₆ haloalkyl, OC _0-2 alkyleneC3-6cycloalkyl, OC _0-2 alkyleneC3-6heterocycloalkyl, OCi- ₆ alkyl or NR _2i aR ₂₂ a-

Suitably R _4ba is H, fluoro, CH ₃ , ethyl, OCH ₃ or CH ₂ CH ₂ OCH3, such as fluoro, ethyl, OCH ₃ or CH ₂ CH ₂ OCH ₃ .

Suitably R _4ba is H, CH3, ethyl or CH ₂ CH ₂ OCH3, in particular CH3 or ethyl.

Suitably R _{4 a} and R _5ba together with the carbon atom to which they are attached form a cyclopropyl or cyclopentyl, in particular a cyclopentyl.

Suitably R _4ba and Rs _ba 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 C3-6heterocycloalkyl ring may be substituted, for example by Ci- ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)N HCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi. ₄ haloalkyl or C(0)N HCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C3-6heterocycloalkyl ring include Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- 3alkylOCi- ₂ alkyl such as C(0)CH ₂ 0CH3, and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH3. Suitably, any nitrogen atom in the C3-6heterocycloalkyl ring is not substituted.

Suitably R _ba 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 C3- eheterocycloalkyl ring may be substituted, for example by Ci- ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi. ₄ alkyl, C(0)OCi_ ₄ alkylaryl such as C(0)OBz, C(0)NHCi_ ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- haloalkyl, C(0)OCi- haloalkyl or C(0)NHCi- haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C3- ₆ heterocycloalkyl ring include Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C3-6heterocycloalkyl ring is not substituted.

When R _4ba is NR _2ia R _22a , in one embodiment R _2ia is H. In a second embodiment R _2ia is Ci-salkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R _2ia is C(0)Ci-salkyl, such as C(0)CH ₃ . In a fourth embodiment R _2ia is C(0)OCi- ₅ alkyl, such as C(0)OCH ₃ or C(0)Ofert-butyl. In a fifth embodiment R _{2i a} is Ci-3alkylOCi- ₂ alkyl such as CialkylOCialkyl, C ₂ alkylOCialkyl or C3alkylOCialkyl e.g. C ₂ alkylOCialkyl. In a sixth embodiment, R _2ia is Ci- 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 _{2i a} is C ₄ . ₆ eterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When R _4ba is NR _ia R22 _a , in one embodiment R ₂ 2 _a is H. In a second embodiment R _22a is methyl.

For example, R _{4 a} is NH ₂ , N(CH ₃ ) ₂ , NHC(0)CH ₃ , NHC(0)OCH ₃ , NHC(0)Oferf-butyl and CH ₂ CH ₂ OH, especially, N(CH ₃ ) ₂ , NHC(0)CH ₃ , NHC(0)OCH _3.

Suitably, R _2ia is C(0)OCH ₃ and R _22a is H. Suitably, R _2ia is C(0)CH ₃ and R _22a is H . Suitably, R _2ia and R _22a are both CH ₃ . Suitably, R _2ia and R _22a are both H.

In one embodiment R _5ba is Ci- ₆ alkyl, in particular Ci- ₄ alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or ferf-butyl). In a second embodiment R _5ba is Ci- ₃ alkyleneOCi- ₃ alkyl, in particular Ci- ₂ alkyleneOCi- ₂ alkyl such as CialkyleneOCialkyl, C ₂ alkyleneOCialkyl, CialkyleneOC ₂ alkyl or C ₂ alkyleneOC ₂ alkyl. In a third embodiment Rs _ba is H . In a fourth embodiment, Rs _ba is halo, such as chloro or fluoro, especially fluoro. In a fifth embodiment, Rs _ba is Ci- ₆ haloalkyl, such as CF ₃ or CH ₂ CF _3. In a sixth embodiment, Rs _ba is Co-

2alkyleneC ₃ heterocycloalkyl, Co-2alkyleneC ₄ hetero-cycloalkyl, Co^alkyleneCsheterocycloalkyl or Co-2alkyleneC6heterocycloalkyl. 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 Ci- alkyl, C(0)H, C(0)Ci. ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)N HCi- alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)N HCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C ₃ -sheterocycloalkyl ring include Ci- alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C _3.6 heterocycloalkyl ring is not substituted. In an eighth embodiment, R _5ba is Ci. _e alkylOH, such as CH ₂ OH or CH ₂ CH ₂ OH. In a ninth embodiment, R _5ba is OCi-ehaloalkyl, such as OCi- ₄ haloalkyl, such as OCF ₃ or OCHF ₂ . In a tenth embodiment, R _5ba is OC _0-2 alkyleneC _3. ecycloalkyl such as OC _3-8 cycloalkyl, OCialkyleneC ₃ -ecycloalkyl, OC ₂ alkyleneC ₃ -ecycloalkyl, OCo- ₂ alkyleneC ₃ cycloalkyl, OC _0-2 alkyleneC ₄ cycloalkyl, OCo- ₂ alkyleneC ₅ cycloalkyl or OC ₀ - ₂ alkyleneC ₆ cycloalkyl. In an eleventh embodiment, R _5ba is OCi- ₆ alkyl, in particular OCi- 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 OCo-2alkyleneC ₃ -6heterocycloalkyl such as OC3-6heterocycloalkyl, OCialkyleneC3-6heterocycloalkyl, OC ₂ alkyleneC3-6heterocycloalkyl, OCo- ₂ alkyleneC3heterocycloalkyl, OCo. ₂ alkyleneC4hetero-cycloalkyl, OCo- ₂ alkyleneC5heterocycloalkyl or OCo- 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 C3-6heterocycloalkyl ring may be substituted, for example by Ci-4alkyl, C(0)H, C(0)Ci. ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C3-eheterocycloalkyl ring include Ci-4alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C ₃ -eheterocycloalkyl ring is not substituted. In a thirteenth embodiment, R _5ba is

NR _2la R _22a .

When A _a is -NHC(=0)- or -C(=0)NH-, suitably, Rs _ba is H, Ci- ₆ alkyl, Ci- ₆ haloalkyl, Ci- ₆ alkylOH, Co- ₂ alkyleneC _3-6 cycloalkyl, Co-2alkyleneC ₃ -6heterocycloalkyl, Ci- ₃ alkyleneOCi. ₃ alkyl, or R4 _ba and Rs _ba 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(=0)-, suitably Rs _ba may additionally be selected from halo, OCi- ₆ haloalkyl, OCo- ₂ alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₆ alkyl or NR _2la R _22a .

When A _a is -NH-, -CH ₂ NH- or -NHCH ₂ -, suitably, R _5ba is H, Ci- ₈ alkyl, Ci- ₆ haloalkyl, Ci- _e alkylOH, Co-2alkyleneC ₃ -8cycloalkyl, Co- ₂ alkyleneC ₃ -eheterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, or R _ba and R _5ba together with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3. eheterocycloalkyl. When A _a is -NHCH ₂ -, suitably R _5ba may additionally be selected from halo, OCi- ₆ haloalkyl, OC ₀ -2alkyleneC ₃ -6cycloalkyl, OC ₀ -2alkyleneC _3. 6heterocycloalkyl, OCi- ₆ alkyl or NR _2la R _22a .

When Rsba is NR _2ia R _22a , in one embodiment R _2ia is H. In a second embodiment R _2ia is Ci-salkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R _2ia is C(0)Ci-salkyl, such as C(0)CH ₃ . In a fourth embodiment R _2ia is C(0)OCi-salkyl, such as C(0)OCH ₃ or butyl. In a fifth embodiment R _2ia is Ci-3alkylOCi- ₂ alkyl such as CialkylOCialkyl, ialkyl or C ₃ alkylOCialkyl e.g. C ₂ alkylOCialkyl. In a sixth embodiment, R _2ia is Ci- such as CF ₃ , CFI ₂ CF ₃ or CFI ₂ CFIF ₂ e.g. CFI ₂ CFIF ₂ . In a seventh embodiment R _2ia is C4- loalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When R _5ba is NR _2ia R22 _a , in one embodiment R _22a is H. In a second embodiment R _22a is methyl. For example, R _Sba is NH ₂ , N(CH ₃ ) ₂ , NHC(0)CH ₃ , NHC(0)0CH ₃ , NHC(0)Oferf-butyl and CH2CH2OH, especially, N(CH ₃ ) ₂ , NHC(0)CH ₃ , NHC(0)0CH ₃ .

Suitably, R _2ia is C(0)0CH ₃ and R _22a is H. Suitably, R _2ia is C(0)CH ₃ and R _22a is H . Suitably, R _2ia and R _22a are both CH ₃ . Suitably, R _2ia and R _22a are both H.

Suitably Rs _ba is H, F, CH ₃ or ethyl such as H, CH ₃ or ethyl.

Suitably R _4b a is H, CH ₃ , ethyl or CH ₂ CH ₂ OCH ₃ and R ₅ a is H, CH ₃ or ethyl, in particular R _4b a is CH ₃ , or ethyl and R _5b a is H, methyl or ethyl. For example, R _{4 a} and R _5b a are H, R _4ba and R _5ba are methyl, R _4ba and R _5ba are ethyl or R _{4 a} is CH ₂ CH ₂ OCH ₃ and R _5b a is H.

Suitably, R _ba is F and R _5ba is ethyl.

Suitably, R _4ba is F and Rsba is F.

Suitably, R _ba is ethyl and R _5ba is H.

Suitably R _4ba and Rs _ba are arranged in the following configuration:

wherein R ₄ and R ₅ include variables R _4a , Rsa, R _4aa, Rs _aa , R _4ba and R _5ba .

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

In particular Ari a is phenyl, 2-pyridyl or 3-pyridyl, such as phenyl or 2-pyridyl.

In one embodiment Ri _0a is H. In a second embodiment Ri _0a is halo, for example fluoro or chloro. In a third embodiment Ri _0a is Ci- ₃ alkyl such as Ci- ₂ alkyl, such as CH ₃ or ethyl. In a fourth embodiment Ri _0a is OCi- ₂ alkyl, such as OCH ₃ or ethoxy. In a fifth embodiment Ri _0a is OC1- ₂ haloalkyl, such as OCF ₃ . In a sixth embodiment Ri _0a is CN. In a seventh embodiment, Ri _0a is Ci- ₂ haloalkyl such as CF ₃ .

Suitably Rio _a 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.

Suitably, Ri _0a is H, F or CH ₃ .

In one embodiment Rn _a is H. In a second embodiment Rn _a is F. In a third embodiment, Rn _a is Ci_ ₂ alkyl such as CH ₃ or Et, such as CH ₃ . In a fourth embodiment Rn _a is OCH ₃ . In a fifth embodiment, Rn _a is Cl. In a sixth embodiment, Rn _a is Et. In a seventh embodiment, Rn _a is CF ₃ . In an eighth embodiment, Rn _a is CN. Suitably, Rn _a is H, F, Ch or OCH3, such as H, F or CH3, such as H or F, such as H.

In one embodiment, Ri _0a is in the ortho position with respect to group Aa. In another embodiment, Rioa is in the meta position with respect to group Aa. Suitably Ri _0a is in the ortho position with respect to group Aa.

In one embodiment, Rn _a is in the ortho position with respect to group Aa. In another embodiment, Rua is in the meta position with respect to group Aa. Suitably Rn _a is in the ortho position with respect to group Aa.

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).

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

In one embodiment Ri _2a is H. In a second embodiment Ri _2a is halo, for example fluoro or chloro. In a third embodiment Ri _2a is Ci-4alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or ferf-butyl). In a fourth embodiment Ri _2a is OCi- alkyl, such as OCH3, ethoxy, isopropoxy or n-propoxy. In a fifth embodiment Ri _2a is OCo-2alkyleneC3-5cycloalkyl, such as OC3-5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OCialkyleneCs-scycloalkyl or OC ₂ alkyleneC3-5cycloalkyl. In a sixth embodiment Ri _2a is CN. In a seventh embodiment Ri _2a is Ci- ₄ haloalkyl, such as CF _3. In an eighth embodiment Ri _2a is OCi- haloalkyl, such as OCF ₃ , OCHF ₂ or OCH ₂ CF ₃ . In a ninth embodiment, Ri _2a is C _2.4 alkenyl such as C(=CH ₂ )CH ₃ . In a tenth embodiment, R _12a is Co- ₂ alkyleneC ₃ -5cycloalkyl such

C ₂ alkyleneC3-5cycloalkyl, Co-2alkyleneC3cycloalky

2alkyleneC5cycloalkyl. In an eleventh embodiment, Ri _2a is hydroxy. In a twelfth embodiment, Ri _2a is Ci- ₄ alkylOH such as CH ₂ OH. In a thirteenth embodiment, Ri _2a is S0 ₂ Ci- ₂ alkyl such as S0 ₂ CH ₃ . In a fourteenth embodiment, Ri _2a is C(0)N(Ci- ₂ alkyl) ₂ such as C(0)N(CH ₃ ) ₂ . In a fifteenth embodiment, Ri _2a is NHC(0)Ci- ₃ alkyl. In a sixteenth embodiment, Ri _2a is NR _23a R _24a . In a seventeenth embodiment, Ri _2a is OCH ₂ CH ₂ N(CH ₃ )2. In an eighteenth embodiment, Ri _2a is a C3- 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 Cs eheterocycloalkyl ring may be substituted, for example by Ci_ ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci. ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C3-6heterocycloalkyl ring include Ci- ₄ alkylCISI such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci. ₂ alkyl such as C(0)CH ₂ 0CH3, and Ci. ₂ alkylC(0)0Ci. ₄ alkyl such as CH ₂ C(0)0CH ₂ CH3. Suitably, any nitrogen atom in the C _3-6 heterocycloalkyl ring is not substituted. In a nineteenth embodiment, Ri _2a together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ).

When Aa is -NHC(=0)- or -C(=0)NH-, suitably, Ri _a is attached to Ar2a in the ortho or meta position relative to Aria and Ri _2a is H, halo, Ci- ₄ alkyl, C^alkenyl, Co- ₂ alkyleneC _3-5 cycloalkyl, OCi- ₄ alkyl, OCo- ₂ alkyleneC _3-5 cycloalkyl, Ci- ₄ haloalkyl, OCi- ₄ haloalkyl _, hydroxy, Ci- ₄ alkylOH, S0 ₂ Ci- ₂ alkyl, C(O) N (C 1 - ₂ al ky l) ₂ , NHC(0)Ci- ₃ alkyl or NR _23a R _24a .

When Aa is -NHC(=0)-, suitably Ri _2a may additionally be selected from CN, OCH ₂ CH ₂ N(CH3) ₂ and a C _3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or Ri _2a together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ).

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 Aria and Ri _2a is H, halo, Ci- ₄ alkyl, C _2-4 alkenyl, Co- ₂ alkyleneC _3-5 cycloalkyl, OCi- ₄ alkyl, OCo- ₂ alkyleneC _3-5 cycloalkyl, Ci- ₄ haloalkyl, OCi- ₄ haloalkyl _, hydroxy, Ci- ₄ alkylOH, S0 ₂ Ci- ₂ alkyl, C(0)N(Ci- ₂ alkyl) ₂ , NHC(0)Ci- ₃ alkyl or NR _23a R _24a .

When Aa is -NH- or -NHCH ₂ -, suitably Ri _2a 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 Ri _2a together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0-).

Ri _2a is suitably H, F, Cl, CH ₃ , OCH ₃ , OEt, O/Pr, OCyclopropyl, CN, CF ₃ , OCHF ₂ or OCH ₂ CF ₃ . In particular, Ri _2a is Cl, CN, CF ₃ , OCFIF ₂ , OCFI ₂ CF ₃ , OCFI ₃ , OEt, O/Pr, OCyclopropyl, such as CF ₃ , OCFIF ₂ , OCFI ₂ CF ₃ , OCFI ₃ , OEt, O/Pr, OCyclopropyl, e.g. OEt.

R _i2a is suitably H, F, Cl, CH ₃ , iPr, OCH ₃ , OEt, O/Pr, OCyclopropyl, CN, CF ₃ , OCHF ₂ , OCH ₂ CF ₃ , Cscycloalkyl or C(=CH ₂ )CH _3. In particular, Ri _2a is Cl, iPr, OCH ₃ , OEt, O/Pr, OCyclopropyl, CN, CF ₃ , OCHF ₂ , OCFI ₂ CF ₃ , Cscycloalkyl or C(=CH ₂ )CFl ₃ , such as Cl, OCH ₃ , OEt, O/Pr, OCyclopropyl, CF ₃ , OCHF ₂ , OCH ₂ CF ₃ or Cscycloalkyl, e.g. OEt.

When Aa is -C(=0)NFI-, suitably Ri _2a is CF ₃ , OEt or OiPr, such as OEt or OiPr.

Suitably Ri _2a is in the meta position of Ar2a. Alternatively, Ri _2a is in the ortho position of Ar2a.

In one embodiment, Ri _3a is H. In another embodiment, Ri _3a is halo such as F or Cl, suitably F.

In one embodiment, Ri _3a is in the ortho position with respect to Aria. In another embodiment, Ri _3a is in the para position with respect to Aria. In another embodiment, Ri _3a is in the meta position with respect to Ar1 a.

In one embodiment, R _23a is H. In another embodiment, R _23a is Ci_ ₂ alkyl such as methyl.

In one embodiment, R _24a is H. In another embodiment R _24a is Ci- ₂ alkyl such as methyl.

Suitably, R _23a is FI and R _24a is ethyl. Suitably, R _23a is CFI ₃ and R _24a is CFI ₃ . Desirably, a compound of formula (I) does not include 2-(6-(methylsulfonamido)pyrazin-2-yl)-N- (4-(pyridin-3-yl)phenyl)acetamide.

In one embodiment, at least one of Ri _0a , Rn _a , Ri2 _a and Ri _3a is other than H.

Suitably, at least one of R4a, Rsa, Rio _a , Rna, Ri2a and R a is other than H.

More suitably, when R _1a is methyl, at least one of R _4a , R _5a , Rioa, Rna, Ri2a and Ri _3a is other than H.

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.

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.

The present invention provides the following compounds:

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-4- oxocyclohexanecarboxamide;

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide;

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide (diastereomer 1);

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide (diastereomer 2);

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylami no)-A/-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)cyclohexane-1-carboxamide;

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylami no)-A/-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1);

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylami no)-A/-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 2);

A/-(4-(1-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)pro pyl)pyrimidin-2- yl)cyclopropanesulfonamide;

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-et hoxypyrazin-2-yl)pyridin-2-yl)-4,4- difluorocyclohexane-1-carboxamide; 8-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-1 ,4- dioxaspiro[4.5]decane-8-carboxamide;

4-(2-((A/,A/-dimethylsulfamoyl)amino)pyrimidin-4-yl)-A/-(5-( 6-ethoxypyrazin-2-yl)pyridin-2- yl)tetrahydro-2/-/-pyran-4-carboxamide;

4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethox ypyrazin-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)cycl opropyl)pyrimidin-2- yl)cyclopropanesulfonamide;

N-(4-(4-(((4-(6-ethoxypyrazin-2-yl)phenyl)amino)methyl)tetra hydro-2H-pyran-4-yl)pyrimidin-2- yl)cyclopropanesulfonamide;

2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-5,8- dioxaspiro[3.4]octane-2-carboxamide;

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-4- methoxycyclohexane-1 -carboxamide; and

/V-(4-(1-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)propyl)pyrim idin-2- yl)cyclopropanesulfonamidearboxamide.

The present invention also provides the following compounds:

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-/V-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-1-(2- methoxyacetyl)piperidine-4-carboxamide;

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-/V-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-1-

(ethylsulfonyl)piperidine-4-carboxamide;

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(cyclopropyl sulfonyl)-A/-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)piperidine-4-carboxamide;

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(/V,A/-dimet hylsulfamoyl)-A/-(5-(6- ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4- carboxamide;

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-/V-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-1-

((trifluoromethyl)sulfonyl)piperidine-4-carboxamide;

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-/V-(5-(6-et hoxypyrazin-2-yl)pyridin-2-yl)-1-((1- methyl-1 /-/-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-et hoxypyrazin-2-yl)pyridin-2- yl)carbamoyl)piperidin-1-yl)acetate;

A/-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfona mido)pyrimidin-4-yl)-1-(2- methoxyacetyl)piperidine-4-carboxamide;

/V-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfona mido)pyrimidin-4-yl)-1-

(methylsulfonyl)piperidine-4-carboxamide;

A/-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfona mido)pyrimidin-4-yl)-1-

(ethylsulfonyl)piperidine-4-carboxamide;

1-(Cyclopropylsulfonyl)-A/-(5-(6-ethoxypyrazin-2-yl)pyridin- 2-yl)-4-(2-

(ethylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide ;

/V-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfona mido)pyrimidin-4-yl)-1-((1 -methyl-1 /-/- pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide;

1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclop ropylpyrazin-2-yl)pyridin-2-yl)-4- methoxycyclohexane-1 -carboxamide (diastereomer 1);

1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclop ropylpyrazin-2-yl)pyridin-2-yl)-4- methoxycyclohexane-1-carboxamide (diastereomer 2);

1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-/V-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-4- (pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 1);

1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-/V-(5-(6-ethox ypyrazin-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-ethoxy pyrazin-2-yl)pyridin-2-yl)-4- morpholinocyclohexane-1-carboxamide (diastereomer 1);

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxy pyrazin-2-yl)pyridin-2-yl)-4- morpholinocyclohexane-1-carboxamide (diastereomer 2);

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxy pyrazin-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-ethoxy pyrazin-2-yl)pyridin-2-yl)-4-((2- methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 1); 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxy pyrazin-2-yl)pyridin-2-yl)-4-((2- methoxyethyl)(methyl)amino)cyclohexane-1-carboxamide (diastereomer 2);

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((2,2-dif luoroethyl)(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-eth oxypyrazin-2-yl)pyridin-2-yl)-4-(4- methylpiperazin-1-yl)cyclohexane-1 -carboxamide (diastereomer 1);

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-eth oxypyrazin-2-yl)pyridin-2-yl)-4-(4- methylpiperazin-1-yl)cyclohexane-1 -carboxamide (diastereomer 2);

4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-1- (methylsulfonyl)piperidine-4-carboxamide;

4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyc lopropylpyrazin-2-yl)pyridin-2-yl)-1-

(methylsulfonyl)piperidine-4-carboxamide;

4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-eth oxypyrazin-2-yl)pyridin-2-yl)-1-

(methylsulfonyl)piperidine-4-carboxamide;

4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyc lopropylpyrazin-2-yl)pyridin-2-yl)-1- (ethylsulfonyl)piperidine-4-carboxamide; and

4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-eth oxypyrazin-2-yl)pyridin-2-yl)-1-

(ethylsulfonyl)piperidine-4-carboxamide.

Compounds of formula fl-b ^' ) The invention provides a compound of formula (l-b):

wherein

A _b is Aab or Abbi

Aab is -NRebCH ₂ - or -NReb-;

Abb is -NR6bC(-0)-;

Ri b IS Riab Or Ri bb,

wherein: Rlab IS N R32bR33b

Ri _bb is Ci- ₅ alkyl, Co^alkyleneCs-scycloalkyl which cycloalkyl is optionally substituted by CH ₃ , Ci- ₃ alkyleneOCi- ₂ alkyl, or CF ₃ ;

R _3b is H, halo, CH ₃ , OCi- ₂ alkyl or CF ₃ ;

or R _3b together with R _5bt forms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl;

R ₄ b and R ₅ b are either R _4a b and R _5a b or R ₄ b and R ₅ bbi

wherein:

R _ab and R _5a together with the carbon atom to which they are attached form a C ₃ - 6cycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci- 3alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC ₃ - 6heterocydoalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and NR21bR22b; 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 - 6cycloalkyl ring or a C _3-6 heterocycloalkyl ring, and wherein the C ₃ - 6cycloalkyl 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 Ci. 3alkyl or OCi- ₃ alkyl; or

R _4ab and Rs _ab together with the carbon atom to which they are attached form a C ₃ - 6heteroycloalkyl 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 cheterocycloalkyl 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 Rs _ab 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 Ci- ₃ alkyl or OCi. ₃ alkyl; or

R _4ab and R _5ab together with the carbon atom to which they are attached form a C _3. eheterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(0) ₂ R _29b ; or R _4bb and Rs _bb are each independently H, halo, Ci- ₆ alkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC ₃ -sheterocycloalkyl, OCi- ₆ alkyl, OCo- ₂ alkyleneC _3-6 cycloalkyl, OCo- 2alkyleneC _3-6 heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, Ci- ₆ alkylOH, C-i-ehaloalkyl, OCi- ₆ haloalkyl or NR _2ib R _22b ,

or R _4b is H and R _5b together with R _3b form a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl,

or R _4bb and Rs _bb together with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl,

or R _{4 b} is H and R _bb and R _S are a C _2-3 alkylene chain forming a 5- or 6- membered ring; or R _4bb is O and Rsbb is absent;

R _6b is H or Ci- ₃ alkyl,

or Re together with Rn _b when in the ortho-position to group A are a C ₂ alkylene chain forming a 5-membered ring,

or Rs _bb and R _6b are a C _2.3 alkylene chain forming a 5- or 6-membered ring and R _4bb is H;

Ar1 b is 6-membered aryl or heteroaryl;

Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1 b in the para position relative to group A _b ;

Rio _b is H, halo, Ci- ₃ alkyl, OCi- ₂ alkyl, Ci- ₂ haloalkyl, OCi- ₂ haloalkyl or CN;

Ru _b is H, F, Cl, CH ₃ , ethyl, OCH ₃ , CF ₃ , OCF ₃ or CN,

or Ru _b , when in the ortho-position to group A _b , together with R _6b are a C ₂ alkylene chain forming a 5-membered ring;

Ri _2b is attached to Ar2b in the ortho or meta position relative to Ar1 b and Ri _2b is FI, halo, Ci- ₄ alkyl, C _2.4 alkynyl, Co- ₂ alkyleneC _3-5 cycloalkyl, OCi- ₄ alkyl, OCo- ₂ alkyleneC _3-5 cycloalkyl, OCH ₂ CH ₂ N(CH ₃ ) ₂ , OH, Ci- ₄ alkylOH, CN, Ci- ₃ alkyleneOCi- ₃ alkyl, Ci- ₄ haloalkyl, OCi- ₄ haloalkyl, C(=0)Ci- ₂ alkyl, NR _23b R _24b , S0 ₂ Ci- ₄ alkyl, SOCi- ₄ alkyl, SCi- ₄ alkyl, SH, C(0)N(CH ₃ ) ₂ , NHC(0)Ci- ₃ alkyl, C _3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or Ri _2b together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 );

Ris _b is H, halo, CH ₃ or OCH ₃ ; R _{2i b} is H, Ci-ealkyl, C(0)Ci-salkyl, C(0)OCi-salkyl, Ci- ₃ alkylOCi- ₂ alkyl, Ci- ₄ haloalkyl, or C ₄ . ₆ heterocycloalkyl;

R _2b is H or CH ₃ ;

R _23b is H or Ci. ₂ alkyl;

R _24b is H or Ci. ₂ alkyl;

R _29b is Ci- ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , CF ₃ , N(Ci- 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 Ci- ₃ alkyl and R _33b is Ci- ₃ alkyl; or

R ₃ 2 _b and R ₃ 3 _b together with the nitrogen atom to which they are attached form a C ₃ .

₅ heterocycloalkyl; or a salt and/or solvate thereof and/or derivative thereof.

Suitably, Ri is Ri _a ; and/or R _b and R _5b are R _4ab and R _5ab ; and/or A is A _a .

The invention also provides a compound of formula (l-b):

wherein

A _b is Aab or Abb;

A _ab is -NR6bCH2- or -NR6b-;

Ab is -NR6bC(-0)-;

Rib is Ria or Ri _bb ;

wherein:

Riab IS NR _32b R33b;

Ri _b is Ci_ ₅ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , Ci- ₃ alkyleneOCi- ₂ alkyl, or CF ₃ ;

R _3b is H, halo, CH ₃ , OCi. ₂ alkyl or CF ₃ ; or R _3b together with Rs _bb 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 _{4 b} and R _5bbi

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 Ci- ₃ alkyl, oxo, OH, Ci- 3alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC _{3. 6} heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi_ ₃ alkyl and NR2ibR22bi 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 _ab 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 Ci. 3alkyl or OCi- ₃ alkyl; or

R _4a 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 cheterocycloalkyl 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 Rsa _b 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 Ci- ₃ alkyl or OCi. ₃ alkyl; or

R _ab 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(0) ₂ R _29b ; or

R _4bb and Rs _bb are each independently H, halo, Ci- ₆ alkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₆ alkyl, OCo- ₂ alkyleneC _3-6 cycloalkyl, OCo- 2alkyleneC _3-6 heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, Ci- ₆ alkylOH, Ci-shaloalkyl, OCi- ₆ haloalkyl or NR _2ib R _22b , or R _4bb is H and Rsbb together with R3b 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 -ecycloalkyl or C ₃ -eheterocycloalkyl,

or R _4bb is H and Rs _bb and R _6b are a C _2-3 alkylene chain forming a 5- or 6- membered ring; or R ₄ is O and R _5b is absent;

Rs _b is H or Ci- ₃ alkyl,

or R _6b together with Ru _b 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 _{4 b} is H;

Ar1 b is 6-membered aryl or heteroaryl;

Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1 b in the para position relative to group A _b ;

Rio _b is H, halo, Ci- ₃ alkyl, OCi- ₂ alkyl, Ci- ₂ haloalkyl, OCi- ₂ haloalkyl or CN;

Rub is H, F, Cl, CH ₃ , ethyl, OCH ₃ , CF ₃ , OCF ₃ or CN,

or Ru _b , when in the ortho-position to group A , together with R _6b are a C ₂ alkylene chain forming a 5-membered ring;

Ri _2b is attached to Ar2b in the ortho or meta position relative to Ar1 b and Ri _b is H, halo, Ci- ₄ alkyl, C _2-4 alkynyl, Co- ₂ alkyleneC _3-5 cycloalkyl, OCi- ₄ alkyl, OCo- ₂ alkyleneC _3-5 cycloalkyl, OCH ₂ CH ₂ N(CH ₃ ) ₂ , OH, Ci- ₄ alkylOH, CN, Ci- ₃ alkyleneOCi- ₃ alkyl, Ci- ₄ haloalkyl, OCi- ₄ haloalkyl, C(=0)Ci- ₂ alkyl, NR _23b R _24b , S0 ₂ Ci- ₄ alkyl, SOCi- ₄ alkyl, SCi- ₄ alkyl, SH, C(0)N(CH ₃ ) ₂ , NHC(0)Ci- ₃ alkyl, C _3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or Ri _2b together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ^_ );

Ris _b is H, halo, CH ₃ or OCH ₃ ;

R _2ib is H, Ci. ₅ alkyl, C(0)Ci- ₅ alkyl, C(0)OCi. ₅ alkyl;

R22b is H or CH3;

R _23b is H or Ci- ₂ alkyl;

R _24b is H or Ci- ₂ alkyl; R _29b is Ci- ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , or CF ₃ ; and

R _32b is Ci- ₃ alkyl and R _33b is Ci- ₃ alkyl; or

R _32b and R _33b together with the nitrogen atom to which they are attached form a C _3.

5heterocycloalkyl; or a salt and/or solvate thereof and/or derivative thereof.

Suitably, Ri _b is Ri _ab ; and/or R _b and R _5b are R _4ab and R _5ab ; and/or A is A _ab .

In one embodiment of the invention, Ri _b is Riab, i.e. is NR3 ₂ R33 . In an embodiment, R _32b is Ci. ₃ alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R _33b is Ci- ₃ alkyl, such as methyl or ethyl, e.g. methyl. Suitably, R _32b and R _33b are both methyl. Suitably, R ₃₂ and R _33b are both ethyl. Suitably, R _32b is methyl and R _33b is ethyl.

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 pyrrol id iny I.

Suitably, Ri _b is Ri _bb.

In one embodiment of the invention Ri _bb is Ci-salkyl. When Ri _bb is Ci-salkyl, Ri _bb 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 Ri _bb is Ci- ₅ alkyl, Ri 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.

In a second embodiment of the invention Ri _bb is Co- ₂ alkyleneC ₃ -scycloalkyl which cycloalkyl is optionally substituted by CH ₃ . In some embodiments, Ri _bb is Co- ₂ alkyleneC ₃ -scycloalkyl. In other embodiments, Ri _bb is Co- ₂ alkyleneC ₃ -scycloalkyl which cycloalkyl is substituted by CH _3. Ri _bb may be C _3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH _3. Ri _bb may be CialkyleneC _{3. 5} cycloalkyl, which cycloalkyl is optionally substituted by CH _3. Ri _bb may be C ₂ alkyleneC _{3. 5} cycloalkyl, which cycloalkyl is optionally substituted by CH _3. Ri _b may be Co- ₂ alkyleneC ₃ cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Ri _bb may be Co- ₂ alkyleneC ₄ cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Ri _b may be Co- ₂ alkyleneC ₅ cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Suitably, where Co- 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 Co- ₂ alkylene.

In a third embodiment of the invention Ri _b is CF ₃ . In a fourth embodiment of the invention Ri _bb is Ci-3alkyleneOCi-2alkyl such as Ci-2alkyleneOCi- ₂ alkyl. When Ri _b is Ci-3alkyleneOCi-2alkyl, Ri _b may be methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl or propoxyethyl. When Ri _bb is Ci-2alkyleneOCi-2alkyl, Ri _b may be methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl.

Suitably Ri _bb 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 Ri _b 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.

Additionally of interest is when Ri _bb is cyclopentyl, methyl, ethyl, cyclopropylmethylene and methoxyethyl, in particular cyclopentyl, methyl, ethyl and cyclopropylmethylene, especially ethyl and methyl, such as methyl.

Consequently, suitably Ri _bb 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 Ri _b 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.

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 OCi- 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.

The phrase‘R ₃ together with R _5bb forms a 5- or 6-membered cycloalkyl’ means that compounds with the following exemplary substructure are formed:

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: In particular R _3b is H, CH ₃ or R ₃ together with R _5bb forms a 5- or 6-membered cycloalkyl, especially H, CH ₃ or R _3b together with Rs _bb forms a 5-membered cycloalkyl, such as R _3b is H or CH ₃ , e.g. H.

In one embodiment, R4b and Rsb are R4ab and Rsab.

Suitably, R _4ab and R _5ab together with the carbon atom to which they are attached form a C _3. ecycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci. ₃ alkylOH, Ci. ₃ haloalkyl, Co- ₂ alkyleneC _{3. 6} cycloalkyl, Co- ₂ alkyleneC _3.6 heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- ₂ alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi. ₃ alkyl and NR _ib R _22b .

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 -ecycloalkyl is cyclohexyl.

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.

In one embodiment, the substituent is Ci- ₃ alkyl. Suitably, the substituent is methyl. Suitably, the substituent is ethyl. Suitably, the substituent is n-propyl. Suitably, the substituent is iso-propyl.

In a second embodiment, the substituent is Ci- 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.

In a third embodiment, the substituent is Ci. ₃ haloalkyl. Suitably the Ci. 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 Cihaloalkyl such as CF ₃ . Suitably, the substituent is C ₂ haloalkyl such as CH ₂ CF ₃ .

In a fourth embodiment, the substituent is Co- ₂ alkyleneC ₃ -ecycloalkyl, in particular Co- ₂ alkyleneC _{3. 5} cycloalkyl, such as C _3-5 cycloalkyl, CialkyleneC _3-5 cycloalkyl or C ₂ alkyleneC _3-5 cycloalkyl.

In a fifth embodiment, the substituent is Co- ₂ alkyleneC _3.6 heterocycloalkyl such as Co- ₂ alkyleneC ₃ heterocycloalkyl, Co- ₂ alkyleneC ₄ heterocycloalkyl, Co^alkyleneCsheterocycloalkyl, Co- ₂ alkyleneC ₆ heterocycloalkyl, CoalkyleneC _3-6 heterocycloalkyl, CialkyleneC _3-6 heterocycloalkyl and C2alkyleneC3-6heterocycloalkyl. 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 Ci-4alkyl, C(0)H, C(O) C _h alky I, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C3-6heterocycloalkyl ring include Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkylOCi- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C ₃ -eheterocycloalkyl ring is not substituted.

In a sixth embodiment, the substituent is Ci-3alkyleneOCi- ₃ alkyl, in particular Ci- ₂ alkyleneOCi- ₂ alkyl such as CialkyleneOCialkyl, C ₂ alkyleneOCialkyl, CialkyleneOC ₂ alkyl or C ₂ alkyleneOC ₂ alkyl.

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

In an eighth embodiment, the substituent is OCi- ₃ haloalkyl. Suitably the OCi- 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 OCihaloalkyl such as OCF ₃ . Suitably, the substituent is OC ₂ haloalkyl such as OCH ₂ CF ₃ .

In a ninth embodiment, the substituent is OCo-2alkyleneC ₃ -6cycloalkyl, such as OC _3-6 cycloalkyl, OCialkyleneC3-6cycloalkyl or OC2alkyleneC ₃ -scycloalkyl.

In a tenth embodiment, the substituent is OCo-2alkyleneC ₃ -eheterocycloalkyl such as OCo- ₂ alkyleneC ₃ heterocycloalkyl, OCo-2alkyleneC4heterocycloalkyl, OCo^alkyleneCsheterocycloalkyl, OCo-2alkyleneC ₆ heterocycloalkyl, OC ₀ alkyleneC _3. eheterocycloalkyl, OCialkyleneC _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 Ci- ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi. 4alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- 4haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C _3-6 heterocycloalkyl ring include Ci-4alkylCN such as CH ₂ CN, C(0)Ci. ₃ alkylOCi-2alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH _3. Suitably, any nitrogen atom in the C _3-6 heterocycloalkyl ring is not substituted. In an eleventh embodiment, the substituent is OCi- ₃ alkyl, such as OCH ₃ or OCH ₂ CH ₃ .

In a twelfth embodiment, the substituent is NR _2ib R _22b .

In one embodiment R ₂ -i _b is H. In a second embodiment R _{2i b} is Ci-salkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R _2ib is C(0)Ci- ₅ alkyl, such as C(0)CH _3. In a fourth embodiment R _2ib is C(0)OCi- ₅ alkyl, such as C(0)OCH ₃ or C(0)Otert-butyl. In a fifth embodiment R _2ib is Ci- ₃ alkylOCi. ₂ alkyl such as CialkylOCialkyl, C ₂ alkylOCialkyl or C ₃ alkylOCialkyl e.g. C ₂ alkylOCialkyl. In a sixth embodiment, R _2ib is Ci- 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 _2ib is C _4-6 heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When the substituent is NR _2i R _22b , in one embodiment R _22b is H. In a second embodiment R _22b is methyl.

Suitably, R _2ib is C(0)OCH ₃ and R _22b is H. Suitably, R _2ib is C(0)CH ₃ and R _22b is H . Suitably, R _2ib and R _22b are both CH3. Suitably, R _2ib and R _22b are both H.

In a thirteenth embodiment, the substituent is oxo.

In a fourteenth embodiment, the substituent is OH.

Suitably, the one or two substituents, in particular one substituent, are independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci- ₃ alkylOH, Ci- ₃ haloalkyl, halo, OCi- ₃ haloalkyl, OCi- ₃ alkyl and NR _2ib R _22b .

More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OCi- ₃ alkyl and NR _2ib R _22b ·

Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro, NR _2ib R _22b .

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 Ci- ₃ alkyl or OCi- ₃ alkyl.

In one embodiment the C _3-6 cycloalkyl formed by R _ab 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 Rs _ab 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 Ci_ ₂ alkyl or OCH3. Suitably one of the carbons of the C _3-6 cycloalkyl which is formed by R _4ab and Rs _ab is a spiro centre such that a spirocyclic ring system is formed, wherein the C _3-6 cycloalkyl which is formed by R _a b and R _5ab is a C ₄ -scycloalkyl. 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.

In an embodiment, R _4a b and R _5a b 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 _ab 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 Ci- ₃ alkyl or OCi- ₃ alkyl. Suitably, each substituent is independently selected from the group consisting of Ci_ ₂ alkyl or OCH _3.

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^heterocycloalkyl such as tetrahydropyranyl or 1,3-dioxolanyl.

In an embodiment, R _4a b and R _5a b together with the carbon atom to which they are attached form a C ₃ -sheterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(0)2R29b-

Suitably, the C _3-6 heterocycloalkyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.

Suitably, when the C ₃ -eheterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:

The C _3-6 heterocycloalkyl may be other groups as defined elsewhere herein.

In an embodiment, R _9b is Ci- ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , or CF ₃ . In one embodiment, R _9b is Ci- ₃ alkyl such as methyl. In another embodiment, R _29b is Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ . In some embodiments, R _29b is Co- ₂ alkyleneC _3-5 cycloalkyl. In other embodiments, R _9b is Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is substituted by CH ₃ . R _29b may be C ₃ -scycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R _29b may be CialkyleneC ₃ -scycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R _å9b may be C ₂ alkyleneC ₃ -scycloalkyl, 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 Co^alkyleneCscycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Suitably, where Co- 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 Co- ₂ alkylene. In another embodiment, R ₂₉ is CF ₃ . In another embodiment, R _29b is N(Ci- ₃ alkyl) ₂ such as N(CH ₃ ) ₂ · In another embodiment, R _2gb 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.

In another embodiment, R _4b and Rsb are R _4bb and Rsbb.

In one embodiment R _{4 t} is O and R _5tb 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:

R _bb - O

R _5bb = absent

In a second embodiment, R _4bb and R _5bb together with the carbon atom to which they are attached form a C ₃ -ecycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl. In a third embodiment R _4bb is Ci- ₆ alkyl, in particular Ci- 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 _b is Co- ₂ alkyleneC _3-6 cycloalkyl, in particular Co- ₂ alkyleneC ₃ -scycloalkyl, such as C ₃ -scycloalkyl, CialkyleneC ₃ -scycloalkyl or C ₂ alkyleneC _3-5 cycloalkyl. In a fifth embodiment R _{4 b} is OCi. ₆ alkyl, in particular OCi- 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 _{4 b} is OCo- ₂ alkyleneC _3.6 cycloalkyl, such as OC ₃ - ₆ cycloalkyl, OCialkyleneC _3-6 cycloalkyl or OC ₂ alkyleneC _3-6 cycloalkyl. In a seventh embodiment R _{4 b} is Ci- ₃ alkyleneOCi- ₃ alkyl, in particular Ci- ₂ alkyleneOCi- ₂ alkyl such as CialkyleneOCialkyl, C ₂ alkyleneOCialkyl, CialkyleneOC ₂ alkyl or C ₂ alkyleneOC ₂ alkyl. In an eighth embodiment R _{4 b} is Ci_ ₆ haloalkyl, in particular Ci_ ₄ haloalkyl. In a ninth embodiment R _{4 b} is OCi_ ₆ haloalkyl, in particular OCi_ ₄ haloalkyl. In a tenth embodiment R _{4 b} is H. In an eleventh embodiment R _4bb is halo such as fluoro. In a twelfth embodiment R4 _bb is Ci- ₆ alkylOH, such as CH2OH or CH2CH2OH, in particular CH2CH2OH. In a thirteenth embodiment R _4bb is NR _{2i b} R22 _b . In a fourteenth embodiment, R ₄ is Co-2alkyleneC3-sheterocycloalkyl such as Co-2alkyleneC3heterocycloalkyl, Co- ₂ alkyleneC ₄ heterocycloalkyl, Co-2alkyleneC ₅ heterocycloalkyl, Co-2alkyleneC ₆ heterocycloalkyl, CoalkyleneC _3-6 heterocycloalkyl, CialkyleneC _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 Ci. ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- alkyl, C(0)OCi- alkylaryl such as C(0)0Bz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C _3. eheterocycloalkyl ring include Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C ₃ -sheterocycloalkyl ring is not substituted. In a fifteenth embodiment, R ₄ b and R ₅ bb 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: Ci_ ₄ alkyl, C(0)H , C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)0Bz, C(0)NHCi- ₄ alkyl, C(0)N HCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C3-6heterocycloalkyl ring include Ci- ₄ alkylCISI such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CFl ₂ 0CFl3, and Ci- ₂ alkylC(0)0Ci- ₄ aikyl such as CFI ₂ C(0)0CFl ₂ CFl3. In a fifteenth embodiment, R ₄ is FI and Rs _b and R _6b are a C _2.3 alkylene chain forming a 5- or 6-membered ring. In a sixteenth embodiment, R _{4 b} is OCo- ₂ alkyleneC _3-6 heterocycloalkyl such as OCo- ₂ alkyleneC ₃ heterocycloalkyl, OCo- ₂ alkyleneC ₄ heterocycloalkyl, OCo^alkyleneCsheterocycloalkyl, OCo- ₂ alkyleneC ₆ heterocycloalkyl, OCoalkyleneC _3-6 heterocycloalkyl, OCialkyleneC _{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 Ci- ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)0Bz, C(0)NHCi- ₄ alkyl, C(0)NFICi- ₄ alkylaryl such as C(0)NFIBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)0Ci- ₄ haloalkyl or C(0)NFICi- ₄ haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C3-6heterocycloalkyl ring include Ci-4alkylCN such as CH2CN, C(0)Ci- ₃ alkylOCi-2alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C3-6heterocycloalkyl ring is not substituted.

When R _4bb is H and R _5bb and Re _b are a C2-3alkylene chain forming a 5- or 6-membered ring, suitably a 5-membered ring, compounds comprising one of the following moieties are formed:

When R _{4 b} is NR _i R22 _b , in one embodiment R _2ib is H. In a second embodiment R _{2i b} is Ci-salkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R _i is C(0)Ci- ₅ alkyl, such as C(0)CH ₃ . In a fourth embodiment R _{2i b} is C(0)OCi- ₅ alkyl, such as C(0)0CH ₃ or C(0)Otert-butyl. In a fifth embodiment R _{2i b} is Ci- ₃ alkylOCi-2alkyl such as CialkylOCialkyl, C2alkylOCialkyl or C ₃ alkylOCialkyl e.g. C2alkylOCialkyl. In a sixth embodiment, R _{i b} is Ci- ₄ haloalkyl, such as CF ₃ , CH2CF3 or CFI2CFIF2 e.g. CFI2CFIF2. In a seventh embodiment R _{2i b} is C ₄ - eheterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When R _4bb is NR _2ib R _22b , in one embodiment R _2b is H. In a second embodiment R _22b is methyl.

Suitably R _4bb is FI, CFI ₃ , ethyl, isopropyl, fluoro, OCFI ₃ , isopropoxy or CFI ₂ CFI ₂ OCFI ₃ , in particular FI, CFI ₃ , ethyl, fluoro, OCFI ₃ , isopropoxy or CFI ₂ CFI ₂ OCFI ₃ , especially FI, CFH ₃ , ethyl, OCFI ₃ or CH2CH2OCH3.

Additionally of interest is when R _{4 b} is NH ₂ , N(CH ₃ ) , NHC(0)CH ₃ , NHC(0)OCH ₃ , NHC(0)Otert- butyl and CH ₂ CH ₂ OH, especially, N(CH ₃ ) ₂ , NHC(0)CH ₃ , NHC(0)OCH ₃ .

Suitably, R _2ib is C(0)OCFl3 and R _22b is FI. Suitably, R _åib is C(0)CFl3 and R _22b is FI. Suitably, R _åib and R _22b are both CFH ₃ . Suitably, R _åib and R ₂₂ are both FI.

Consequently, suitably R _4bb is FI, CFH ₃ , ethyl, isopropyl, fluoro, OCFI ₃ , isopropoxy, CFhCFhOCF , NH ₂ , N(CH ₃ ) ₂ , NHC(0)CH ₃ , NHC(0)OCH ₃ , NHC(0)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(0)CH ₃ , NHC(0)OCH ₃ , NHC(0)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(0)CH ₃ or NHC(0)OCH ₃ .

Suitably R _bb may be C=0 and R _5bb is absent.

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. Suitably R4 _bb is H and f¾, together with Rs _bb forms a 5- or 6-membered cycloalkyl, in particular a 5-membered cycloalkyl, especially R _bb is H and R _3b together with R _5bb forms a 5- or 6-membered cycloalkyl, such as a 5-membered cycloalkyl.

In one embodiment R _5bb is Ci-salkyl, in particular Ci- 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 Co-2alkyleneC3-6cycloalkyl, in particular Co-2alkyleneC3-5cycloalkyl, such as C3-scycloalkyl, CialkyleneC ₃ -5cycloalkyl or C ₂ alkyleneC ₃ -5cycloalkyl. In a third embodiment R _5bb is OCi- ₆ alkyl, in particular OCi- 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 OCo-2alkyleneC _{3. 6} cycloalkyl, such as OC _3-6 cycloalkyl, OCialkyleneC3-scycloalkyl or OC2alkyleneC ₃ -6cycloalkyl. In a fifth embodiment Rs _b is Ci- ₃ alkyleneOCi- ₃ alkyl, in particular Ci-2alkyleneOCi-2alkyl such as CialkyleneOCialkyl, C2alkyleneOCialkyl, CialkyleneOC2alkyl or C2alkyleneOC2alkyl. In a sixth embodiment Rs _bb is Ci_ ₆ haloalkyl, in particular Ci- ₄ haloalkyl. In a seventh embodiment Rs _bb is OCi- ₆ haloalkyl, in particular OCi- ₄ haloalkyl. In an eighth embodiment Rs _bb is H. In a ninth embodiment Rs _bb is halo such as fluoro. In a tenth embodiment Rs _b is Ci- ₆ alkylOH, such as CH ₂ OH or CH2CH2OH, in particular CH2CH2OH. In an eleventh embodiment Rsbb is NR2i R22 . In a twelfth embodiment, Rs _bb is Co-2alkyleneC3-sheterocycloalkyl such as Co-2alkyleneC ₃ heterocycloalkyl, Co- 2alkyleneC ₄ heterocycloalkyl, Co^alkyleneCsheterocycloalkyl, Co-2alkyleneC6heterocycloalkyl, CoalkyleneC _3-6 heterocycloalkyl, CialkyleneC ₃ -sheterocycloalkyl 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 Ci- ₄ alkyl, C(0)H, C(0)Ci. ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)N HCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)N HCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C _3-6 heterocycloalkyl ring include Ci. ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C ₃ -eheterocycloalkyl ring is not substituted. In a thirteenth embodiment, R _5bb is OC ₀ - ₂ alkyleneC ₃ -eheterocycloalkyl such as OCo-2alkyleneC ₃ heterocycloalkyl, OC ₀ - ₂ alkyleneC ₄ heterocycloalkyl, OCo^alkyleneCsheterocycloalkyl, OCo-2alkyleneCeheterocycloalkyl, OCoalkyleneC _3-6 heterocycloalkyl, OCialkyleneC ₃ -eheterocycloalkyl 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 Ci- ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)0Bz, C(0)NHCi- ₄ alkyl, C(0)NHCi- alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi. ₄ haloalkyl or C(0)NHCi. haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C _{3. 6} heterocycloalkyl ring include Ci- alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C _3-6 heterocycloalkyl ring is not substituted.

Suitably R _5bb is H, CH ₃ , ethyl, isopropyl or fluoro, in particular R _5bb is H , methyl or ethyl.

Suitably R _4b is H, CH ₃ , ethyl, fluoro, OCH ₃ , propoxy or CH ₂ CH ₂ OCH ₃ and Rs _b is H, CH ₃ , ethyl or fluoro, in particular R _4bb is H, CH ₃ , ethyl or OCH ₃ and Rs _bb is H, methyl or ethyl. For example, R _4bb and Rsbb are H, R _4bb and Rs _bb are methyl, R _{4 b} and Rs _bb are ethyl, R _4bb is CH ₂ CH ₂ OCH ₃ and Rs _bb is H or R _4bb and Rs _bb are fluoro.

Suitably, when R _bb is other than H, methyl, ethyl or fluoro, then R _5b is H.

In one embodiment, A _b is A _ab. Suitably, A _ab is -NR _6b CH ₂ -. Alternatively, A _ab is -NR _6b -.

In another embodiment, A is A _bb i.e. -NR _6b C(=0)-.

In one embodiment R ₃ is H. In a second embodiment R _eb is Ci- ₃ alkyl, in particular methyl. In a third embodiment R ₃ together with Rn in the ortho-position to group A _b are a C ₂ alkylene chain forming a 5-membered ring. In a fourth embodiment, R _b is H and R _5bb and R _8b are a C _2.3 alkylene chain forming a 5- or 6-membered ring in particular a 5-membered ring.

Suitably R _6b is H, methyl or R _6b together with Ru _b 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 Ru _b in the ortho-position to group A _b are a C ₂ alkylene chain forming a 5-membered ring, especially R _6b is H.

The term 'R _8b together with Rn _b 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 CRio _b .

In one embodiment Ar1 b is a 6-membered aryl, i.e. phenyl. In a second embodiment Ar1 b is a 6- membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl). 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.

In one embodiment Ri _0b is H. In a second embodiment Ri _0b is halo, for example fluoro or chloro. In a third embodiment Ri _0b is Ci-3alkyl, such as CH ₃ , ethyl or isopropyl, in particular Ci-2alkyl, such as CH ₃ or ethyl. In a fourth embodiment Ri _0b is OCi-2alkyl, such as OCH ₃ or ethoxy. In a fifth embodiment Ri _0b is Ci-2haloalkyl, such as CF ₃ . In a sixth embodiment Ri _0b is OCi-2haloalkyl, such as OCF ₃ . In a seventh embodiment Ri _0b is CN.

Suitably Rio _b 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 .

Additionally of interest are compounds wherein Rio _b is ethyl, isopropyl and CF ₃ , in particular isopropyl and CF ₃ . Additionally of interest are compounds when Rio _b is CN.

Consequently, suitably Rio _b 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.

In one embodiment R _b is H. In a second embodiment Rn _b is F. In a third embodiment, Rn _b is CH ₃ . In a fourth embodiment R _6b together with Rn in the ortho-position to group A _b are a C ₂ alkylene chain forming a 5-membered ring. In a fifth embodiment Rn _b is ethyl. In a sixth embodiment Rn is Cl. In a seventh embodiment Rn _b is OCH ₃ . In an eighth embodiment, Rn _b is CF ₃ . In a ninth embodiment, Rn _b is OCF ₃ . In a tenth embodiment, Rn is CN. In an eleventh embodiment R _eb together with Rn _b in the ortho-position to group A _b are a C2alkylene chain forming a 5-membered ring.

Suitably, Rio _b and Ru _b are both CH _3. Suitably, Rio _b and Rn _b are both H. Suitably, Rio _b and Rn _b are both fluoro.

In one embodiment, Ri _0b is in the ortho position with respect to group A _b . In another embodiment, Rio _b is in the meta position with respect to group A _b . Suitably Ri _0b is in the ortho position with respect to group A .

In one embodiment, Rn _b is in the ortho position with respect to group A _b . In another embodiment, Ru _b is in the meta position with respect to group A _b . Suitably Rn is in the ortho position with respect to group A .

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). 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.

In one embodiment Ri _2b is H. In a second embodiment Ri _2b is halo, for example fluoro or chloro. In a third embodiment Ri _2b is Ci- 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 Ri ₂ is C _2-4 alkynyl, such as CºCH. In a fifth embodiment Ri _2b is Co- ₂ alkyleneC ₃ -scycloalkyl, such as C ₃ -scycloalkyl (e.g. cyclopropyl), CialkyleneCs-scycloalkyl or C ₂ alkyleneC _3-5 cycloalkyl. In a sixth embodiment Ri ₂ is OCi- ₄ alkyl, such as OCH ₃ , ethoxy, isopropoxy or n-propoxy. In a seventh embodiment Ri ₂ is OCo- ₂ alkyleneC _3-5 cycloalkyl, such as OC _3-5 cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OCialkyleneC _3-5 cycloalkyl or OC ₂ alkyleneC _3-5 cycloalkyl. In an eighth embodiment Ri _2b is OCH ₂ CH ₂ N(CH ₃ ) _2. In a ninth embodiment Ri _2b is Ci- ₄ alkylOH, such as CH ₂ OH or C(CH ₃ ) ₂ 0H. In a tenth embodiment Ri _2b is CN. In an eleventh embodiment Ri _2b is Ci- ₃ alkyleneOCi- ₃ alkyl. In a twelfth embodiment Ri _2b is Ci- ₄ haloalkyl, such as CF _3. In a thirteenth embodiment Ri _2b is OC ₁ - ₄ haloalkyl, such as OCF ₃ , OCHF ₂ or OCH ₂ CF _3. In a fourteenth embodiment Ri _2b is NR _23b R _24b such as N(CH3) ₂ . In a fifteenth embodiment Ri _2b is S(0) ₂ Ci- ₄ alkyl such as SO ₂ CH3. In a sixteenth embodiment Ri _2b is C(0)N(CH3) ₂ . In a seventeenth embodiment Ri _2b is NHC(0)Ci-3alkyl such as NHC(0)CH3. In an eighteenth embodiment Ri _2b is a C3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, such as a Csheterocycloalkyl, in particular pyrrolidinyl, or a Csheterocycloalkyl such as morpholinyl. In a nineteenth embodiment Ri _2b is OH. In a twentieth embodiment Ri _2b is C(=0)Ci- ₂ alkyl. In a twentyfirst embodiment Ri _2b is S(0)Ci- ₄ alkyl. In a twentysecond embodiment Ri _2b is SCi- ₄ alkyl. In a twentythird embodiment Ri _2b is SH. In a twentyfourth embodiment, R _12b together with a nitrogen atom to which it is attached forms an N- oxide (N ⁺ -0 ).

Ri ₂ is suitably H, fluoro, chloro, CH ₃ , cyclopropyl, CºCH, 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(0)CH ₃ , S0 ₂ CH ₃ , C(0)N(CH ₃ ) ₂ or pyrrolidinyl, in particular H, fluoro, chloro, CH ₃ , cyclopropyl, CºCH, OCH ₃ , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF ₃ , OCF ₃ , OCHF ₂ , OCH ₂ CF ₃ , CH ₂ OH, C(0)N(CH ₃ ) ₂ or pyrrolidinyl, especially H, fluoro, chloro, CH ₃ , cyclopropyl, CºCH, 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 , CºCH, OCH ₃ , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF ₃ , OCHF ₂ or OCH ₂ CF _3.

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

In one embodiment, R _23b is H. In another embodiment, R _23b is Ci- ₂ alkyl such as methyl.

In one embodiment, R _24b is H. In another embodiment R _24b is Ci- ₂ alkyl such as methyl. Suitably, R _å3b is H and F¾ _4b is ethyl. Suitably, R _23b is CFh and R _24b is CH3.

Consequently, suitably Ri ₂ is H, fluoro, chloro, CH ₃ , ethyl, cyclopropyl, CºCH, OCH ₃ , ethoxy, n- propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF ₃ , OCF ₃ , OCFIF ₂ , OCFl ₂ CF ₃ , OH, CFI ₂ OFI, N(CH ₃ ) ₂ , NHC(0)CH ₃ , SO ₂ CH3, C(0)N(CH ₃ ) ₂ or pyrrolidinyl, in particular FI, fluoro, chloro, CH ₃ , ethyl, cyclopropyl, CºCFI, OCFI ₃ , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CFs, OCF ₃ , OCHF ₂ , OCH ₂ CF ₃ , CH ₂ OH, C(0)N(CH ₃ ) ₂ or pyrrolidinyl, especially H, fluoro, chloro, CH ₃ , ethyl, cyclopropyl, CºCFI, OCFI ₃ , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF ₃ , OCFIF ₂ , OCFI ₂ CF ₃ or pyrrolidinyl, such as FI, fluoro, chloro, CH ₃ , CºCFI, OCFI ₃ , ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF ₃ , OCFIF ₂ or OCFI ₂ CF ₃ .

Suitably Ri2 is suitably in the meta position of Ar2b. Alternatively, Ri2 is in the ortho position of Ar2b.

In one embodiment Ri _3b is methyl. In a second embodiment Ri _3b is FI. In a third embodiment Ri _3b is methoxy. In a fourth embodiment Ri _3b is halo such as fluoro.

In one embodiment, Ri3 _b is in the ortho position with respect to Ar1 b. In another embodiment, Ri3 _b is in the para position with respect to Ar1 b.

The present invention provides compound T466.

The present invention provides the following compound:

N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)-2-methyl propan-2-yl)thiazol-2- yl)cyclopropanesulfonamide.

Compounds of formula (l-c)

The invention provides a compound of formula (l-c):

wherein

Ao is Aao or A _c ;

Aac IS -CH2NR6 _C -;

A c is -C(-0)NR6 _C -;

Rl c is Rlac OG Rlbc,

wherein: Rlac IS N R32cR33c

Ri _bc is Ci-salkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , Ci- ₃ alkyleneOCi- ₂ alkyl, or CF ₃ ;

R _3C is H, CH ₃ , halo, OCi- ₂ alkyl or CF ₃ ;

R _4C and R _5C are either R _4ac and R _5ac or R _{4 c} and R _5bC ;

wherein:

R _4ac and Rs _ac together with the carbon atom to which they are attached form a C ₃ - 6cycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci. 3alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC _3. eheterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC ₃ -ecycloalkyl, OCo- ₂ alkyleneC ₃ -eheterocycloalkyl, OCi- ₃ alkyl and NR2icR22c; or

one of the carbons of the C _3. 6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -6cycloalkyl ring and a further C ₃ - 6cycloalkyl ring or a C ₃ -6heterocycloalkyl ring, and wherein the C ₃ - 6cycloalkyl formed by R _4ac and Rs _ac 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 Ci- salkyl or OCi- ₃ alkyl; or

R _ac and R _5ac together with the carbon atom to which they are attached form a C _3. eheteroycloalkyl wherein one of the carbons of the C _3-e heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -eCheterocycloalkyl ring and a further C _3-6 cycloalkyl ring or a C _3-6 heterocycloalkyl ring, and wherein the C ₃ -6heteroycloalkyl formed by R _ac 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 Ci- ₃ alkyl or OCi- ₃ alkyl; or

R _4ac and Rs _ac together with the carbon atom to which they are attached form a C ₃ - 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(0) ₂ R _29C ; or

R _4bc and R _5bc are each independently FI, Ci. _e alkyl, C _0-2 alkyleneC _3. ecycloalkyl, C ₀ - 2alkyleneC ₃ -eheterocycloalkyl, Ci. ₃ alkyleneOCi. ₃ alkyl, Ci- _S alkylOFI or Ci- _S haloalkyl, or R _4bc and Rs _bc together with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl ring;

Rs _c is H or Ci- ₃ alkyl;

Ar1 c is a 6-membered aryl or heteroaryl;

Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1 c in the para position relative to group A _c ;

Rioc is H, halo, Ci- ₃ alkyl, OCi- ₂ alkyl, Ci- ₂ haloalkyl, OCi- ₂ haloalkyl or CN;

Rue is H, F, Cl, CH ₃ , ethyl, OCH ₃ , CF ₃ , OCF ₃ or CN;

Ri _2c is attached to Ar2c in the meta or ortho position relative to Ar1 c and RI _2C is FI, halo,

or a C ₃ -eheterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or RI _2C together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 );

R _21C is H, Ci-salkyl, C(0)Ci-salkyl, C(0)OCi-salkyl, Ci- ₃ alkylOCi- ₂ alkyl, Ci- ₄ haloalkyl, or C ₄ - ₆ eterocycloalkyl;

R _22C is H or CH ₃ ;

R ₂ 3 _C is H or Ci- ₂ alkyl;

R _24C is H or Ci- ₂ alkyl;

R _29C is Ci- ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , CF ₃ , N(Ci- 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 Ci- ₃ alkyl and R _33c is Ci_ 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 and/or derivative thereof.

Suitably, Ri _c is Ri _ac ; and/or R4c and Rs _c are R4ac and Rsa _C ; and/or A _c is A _ac .

The invention also provides a compound of formula (l-c): wherein

A _c is A _ac or A _bc ;

Aac IS -CH2N R6C·!

Abe is -C(=0)N Rec-;

Rlc is Rlac OG Rlbcl

wherein:

Rlac is NR32CR33C;

Ri _bc is Ci- ₅ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH3, Ci-3alkyleneOCi- ₂ alkyl, or CF3;

R _3C is H, CH3, halo, OCi- ₂ alkyl or CF ₃ ;

R _4O 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 - ecycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci. 3alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co-2alkyleneC ₃ - 6heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and

NR2icR22c or

one of the carbons of the C ₃ -ecycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -ecycloalkyl ring and a further C ₃ - ecycloalkyl ring or a C ₃ -eheterocycloalkyl ring, and wherein the C ₃ - 6cycloalkyl formed by R _ac 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 Ci- 3alkyl or OCi- ₃ alkyl; or R _4ac and Rs _ac together with the carbon atom to which they are attached form a C ₃ - 6heteroycloalkyl wherein one of the carbons of the C3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3-6Cheterocycloalkyl 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 Ci- ₃ alkyl or OCi- 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(0) ₂ R _29C ; or

R _bc and R _5bc are each independently H, Ci- ₆ alkyl, Co- ₂ alkyleneC3-6cycloalkyl, Co- 2alkyleneC3-6heterocycloalkyl, Ci-3alkyleneOCi-3alkyl, Ci-ealkylOH or C-i-ehaloalkyl, or R _4bG 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 Ci. ₃ alkyl;

Ar1 c is a 6-membered aryl or heteroaryl;

Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1 c in the para position relative to group A ₀ ;

Rio _c is H, halo, Ci- ₃ alkyl, OCi- ₂ alkyl, Ci-2haloalkyl, OCi- ₂ haloalkyl or CN;

Rue is H, F, Cl, CH ₃ , ethyl, OCH ₃ , CF ₃ , OCF ₃ or CN;

Ri2 _c is attached to Ar2c in the meta or ortho position relative to Ar1 c and Ri2 _c is H, halo, Ci- ₄ alkyl, C2- ₄ alkynyl, C(=0)Ci- ₂ alkyl, Co- ₂ alkyleneC ₃ -5cycloalkyl, OCi- ₄ alkyl, Ci- ₃ alkyleneOCi. ₃ alkyl, Ci- ₄ haloalkyl, OCi- ₄ haloalkyl, CN, OCo-2alkyleneC ₃ -5cycloalkyl, OCH ₂ CH ₂ N(CH ₃ ) ₂ , OH, Ci- ₄ alkylOH, NR _23c R24 _c , S0 ₂ CH ₃ , C(0)N(CH ₃ ) ₂ , NHC(0)Ci. ₃ alkyl, or a C _3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or Ri _2c together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ^_ );

R ₂ I _C is H, Ci. ₅ alkyl, C(0)Ci- ₅ alkyl, C(0)OCi- ₅ alkyl; R ₂ 2 _C is H or CH ₃ ;

R _23C is H or Ci- ₂ alkyl;

R _24C is H or Ci. ₂ alkyl; R _29C is Ci- ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , or CF ₃ ; and

R _32C is Ci- ₃ alkyl and R _33c is Ci- 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 and/or derivative thereof.

Suitably, Ri _c is Ri _ac ; and/or R _c and R _5c are R _4ac and R _5ac ; and/or A ₀ is A _ao .

When R _4bc and/or Rs _bc is CoalkyleneC _3-6 heterocycloalkyl, any heteroatom in the heterocycloalkyl may not be directly connected to the carbon to which R _4bc and Rs _bc are connected.

In one embodiment of the invention, R _1c is Ri _ac , i.e. is NR _32c R _33c · In an embodiment, R _32c is Ci. ₃ alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R _33c is Ci- 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.

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 pyrrol id iny I.

Suitably, Ri _c is Ri _bc .

In one embodiment of the invention Ri _c is Ci-salkyl such as Ci- ₄ alkyl. When Ri _c is Ci-salkyl, Ri _c 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 Ri _bc is Ci- ₄ alkyl, Ri _bc is methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert- butyl).

In a second embodiment of the invention Ri _bc is Ci- ₃ alkyleneOCi- ₂ alkyl such as Ci- ₂ alkyleneOCi- ₂ alkyl. Ri _bc may be CialkyleneOCialkyl. Ri _bc may be CialkyleneOC ₂ alkyl. Ri _bc may be C ₂ alkyleneOCialkyl. Ri _bc may be C ₂ alkyleneOC ₂ alkyl. Ri _bc may be CsalkyleneOCialkyl. Ri _bc may be C ₃ alkyleneOC ₂ alkyl.

In a third embodiment of the invention Ri _bc is Co- ₂ alkyleneC ₃ -scycloalkyl which cycloalkyl is optionally substituted by CH ₃ such as Co-ialkyleneC _3-4 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ . In some embodiments, Ri _bc is Co- ₂ alkyleneC _3-5 cycloalkyl such as Co- ialkyleneC _3-4 cycloalkyl. In other embodiments, Ri _bc is Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is substituted by CH ₃ such as Co-ialkyleneC _3.4 cycloalkyl which cycloalkyl is substituted by CH ₃ . Ri _bc may be C _3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ such as C _3.4 cycloalkyl, which cydoalkyl is optionally substituted by CH _3. Ri _bc may be CialkyleneC _3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Ri _bc may be CialkyleneC _3-4 cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Ri bc may be C ₂ alkyleneC _3-5 cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . Ri _bc may be C ₂ alkyleneC _3-4 cycloalkyl, which cycloalkyl is optionally

substituted by CH ₃ . Suitably, where Co- ₂ alkyleneC _3-5 cycloalkyl such as C ₀ -ialkyleneC _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 Co- ₂ alkylene such as at the point of attachment of the C _3-4 cycloalkyl to the Co-ialkylene.

Suitably Ri _bc is cyclopropyl.

In a fourth embodiment of the invention, R _{1 c} is CF ₃ .

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 .

Suitably, R _3c is H.

In one embodiment, R _4c and R _5c are R _4ac and R _5ac .

Suitably, R _4aG 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 Ci- ₃ alkyl, oxo, OH, Ci- ₃ alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _{3. 6} cycloalkyl, Co- ₂ alkyleneC _3-6 heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- ₂ alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and NR ₂ I _C R _22C .

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.

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.

In one embodiment, the substituent is Ci- ₃ alkyl. Suitably, the substituent is methyl. Suitably, the substituent is ethyl. Suitably, the substituent is n-propyl. Suitably, the substituent is iso-propyl. In a second embodiment, the substituent is Ci- 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.

In a third embodiment, the substituent is Ci- ₃ haloalkyl. Suitably the Ci- 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 Cihaloalkyl such as CF ₃ . Suitably, the substituent is C ₂ haloalkyl such as CH ₂ CF ₃ .

In a fourth embodiment, the substituent is Co- ₂ alkyleneC _3-6 cycloalkyl, in particular Co- ₂ alkyleneC ₃ - ₅ cycloalkyl, such as C ₃ -scycloalkyl, CialkyleneC _3-5 cycloalkyl or C ₂ alkyleneC _3-5 cycloalkyl.

In a fifth embodiment, the substituent is C _0-2 alkyleneC _3-6 heterocycloalkyl such as C ₀ - ₂ alkyleneC ₃ heterocycloalkyl, Co- ₂ alkyleneC ₄ heterocycloalkyl, Co^alkyleneCsheterocycloalkyl, C ₀ - ₂ alkyleneCeheterocycloalkyl, CoalkyleneC ₃ -eheterocycloalkyl, CialkyleneC ₃ -eheterocycloalkyl and C ₂ alkyleneC ₃ -eheterocycloalkyl. 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 Ci- ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)0Ci- ₄ alkyl, C(0)0Ci- ₄ alkylaryl such as C(0)0Bz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C _3-6 heterocycloalkyl ring include Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkylOCi_ ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CFkCiOJOCFkCF . Suitably, any nitrogen atom in the Cs eheterocycloalkyl ring is not substituted.

In a sixth embodiment, the substituent is Ci- ₃ alkyleneOCi. ₃ alkyl, in particular Ci- ₂ alkyleneOCi. ₂ alkyl such as CialkyleneOCialkyl, C ₂ alkyleneOCialkyl, CialkyleneOC ₂ alkyl or C ₂ alkyleneOC ₂ alkyl.

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

In an eighth embodiment, the substituent is OCi- ₃ haloalkyl. Suitably the OCi- 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 OCihaloalkyl such as OCF ₃ . Suitably, the substituent is Cihaloalkyl such as OCH ₂ CF ₃ .

In a ninth embodiment, the substituent is OCo- ₂ alkyleneC ₃ -ecycloalkyl, such as Ci-ecycloalkyl, OCialkyleneC ₃ -ecycloalkyl or OC alkyleneC _3-8 cycloalkyl.

In a tenth embodiment, the substituent is OCo- ₂ alkyleneC _3-6 heterocycloalkyl such as OCo- ₂ alkyleneC ₃ heterocycloalkyl, OCo- ₂ alkyleneC ₄ heterocycloalkyl, OCo^alkyleneCsheterocycloalkyl, OCo- ₂ alkyleneC ₆ heterocycloalkyl, OCoalkyleneC _3-6 heterocycloalkyl, OCialkyleneC ₃ - ₆ eterocycloalkyl and OC2alkyleneC3-sheterocycloalkyl. 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 Ci. _¨ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi. ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C _3-6 heterocycloalkyl ring include Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkylOCi- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C ₃ -eheterocycloalkyl ring is not substituted.

In an eleventh embodiment, the substituent is OCi- ₃ alkyl, such as OCH ₃ or OCH ₂ CH _3.

In a twelfth embodiment, the substituent is NR _2ic R ₂ 2 _c . In one embodiment R ₂ I _C is H. In a second embodiment R ₂ I _C is Ci- ₅ alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R ₂ I _C is C(0)Ci- ₅ alkyl, such as C(0)CH ₃ . In a fourth embodiment R ₂ I _C is C(0)OCi. ₅ alkyl, such as C(0)OCH ₃ or C(0)Otert-butyl. In a fifth embodiment R ₂ I _C is Ci- ₃ alkylOCi- ₂ alkyl such as CialkylOCialkyl, C ₂ alkylOCialkyl or C ₃ alkylOCialkyl e.g. C ₂ alkylOCialkyl. In a sixth embodiment, R ₂ I _C is Ci- 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.

When the substituent is NR ₂ I _C R _22C , in one embodiment R _22c is H. In a second embodiment R _22c is methyl.

Suitably, R _2IC is C(0)OCH ₃ and R _22c is H. Suitably, R _{2I C} is C(0)CH ₃ and R _22c is H. Suitably, R _{2I C} and R _22C are both CH ₃ . Suitably, R ₂ I _C and R _22c are both H.

In a thirteenth embodiment, the substituent is oxo.

In a fourteenth embodiment, the substituent is OH.

Suitably, the one or two substituents, in particular one substituent, are independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci- ₃ alkylOH, Ci- ₃ haloalkyl, halo, OCi. ₃ haloalkyl, OCi- ₃ alkyl and NR _21c R _22c .

More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OCi- ₃ alkyl and NR ₂ I _C R _22c .

Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro, NR _2ic R _22c . Alternatively, R _4ac and Rs _ac 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 -6cycloalkyl 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 Ci- ₃ alkyl or OCi- ₃ alkyl.

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 Ci- ₂ alkyl or OCH3.

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 -6cycloalkyl. Suitably the C ₃ -6heterocycloalkyl is an oxygen containing C ₃ - ₆ heterocycloalkyl. Suitably, the C ₃ -6heterocycloalkyl is an oxygen comprising, such as containing, C _3-6 heterocycloalkyl ring, such as a Cscycloalkyl ring.

In an embodiment, R _ao 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 -sheteroycloalkyl 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 Ci- ₃ alkyl or OCi- ₃ alkyl. Suitably, each substituent is independently selected from the group consisting of Ci- ₂ alkyl or OCH _3.

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.

As stated above, when a heterocycloalkyl is formed from R _4G 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 Rs _c are attached.

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(0)2R29 _C - Suitably, the C _3-6 heterocycloalkyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.

Suitably, when the C ₃ -eheterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:

The C _3-6 heterocycloalkyl may be other groups as defined elsewhere herein.

In an embodiment, R _29c is Ci- ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , or CF ₃ . In one embodiment, R _29C is Ci- ₃ alkyl such as methyl. In another embodiment, R _29c is Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ . In some embodiments, R _29c is Co- ₂ alkyleneC ₃ -scycloalkyl. In other embodiments, R _29c is Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is substituted by CH ₃ . R _29C may be C ₃ -scycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R29 _C may be CialkyleneC ₃ -scycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R _29C may be C ₂ alkyleneC ₃ -scycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R _29c may be Co- ₂ alkyleneC ₃ cycloalkyl, which cycloalkyl is optionally substituted by CH ₃ . R _29C may be Co- ₂ alkyleneC ₄ cycloalkyl, which cycloalkyl is optionally substituted by CH _3. R _29C may be Co- ₂ alkyleneC ₅ cycloalkyl, which cycloalkyl is optionally substituted by CH _3. Suitably, where Co- ₂ alkyleneC _3-5 cycloalkyl is optionally substituted by CH ₃ , the CH ₃ is at the point of attachment of the Cs-scycloalkyl to the Co- ₂ alkylene. In another embodiment, R _2gc is CF _3. In another embodiment, R _2gc is N(Ci_ 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 _2gc is a 6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.

In another embodiment, R _4c and R _5c are R _4bc and R _5bc .

In one embodiment, R _{4 C} is H. In a second embodiment R _4bC is Ci- ₆ alkyl such as Ci. 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 Co-2alkyleneC3-6cycloalkyl such as Co-2alkyleneC3-5cycloalkyl, such as Co- ₂ alkyleneC3cycloalkyl, Co-2alkyleneC4cycloalkyl, Co^alkyleneCscycloalkyl, CoalkyleneC _{3. 5} cycloalkyl, CialkyleneCs-scycloalkyl and C2alkyleneC3-5cycloalkyl. R _bc may also be Co- ₂ alkyleneC ₆ cycloalkyl, C ₀ alkyleneC3-6cycloalkyl, CialkyleneC _3-6 cycloalkyl and C ₂ alkyleneC _{3. 6} cycloalkyl. In a fourth embodiment R _4bc is Ci- ₃ alkyleneOCi- ₃ alkyl, in particular Ci. ₂ alkyleneOCi. ₂ alkyl such as CialkyleneOCialkyl, C ₂ alkyleneOCialkyl, CialkyleneOC ₂ alkyl or C ₂ alkyleneOC ₂ alkyl. In a fifth embodiment R _4bc is Ci- ₆ alkylOH such as Ci-4alkylOH such as CialkylOH, C ₂ alkylOH, C ₃ alkylOH or C4alkylOH wherein Ci-4alkyl 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 Ci. ₆ haloalkyl such as Ci. ₄ haloalkyl such as Cihaloalkyl (e.g. CF ₃ ), C ₂ haloalkyl (e.g. CH ₂ CF ₃ ), C ₃ haloalky F ₃ ) or C4haloalkyl (e.g. CFI ₂ CFI ₂ CFI ₂ CF ₃ ). R _{4 c} may also be Cshaloalkyl (e.g CF ₃ ) or Cehaloalkyl (e.g. CFI ₂ CFI ₂ CFI ₂ CFl2CFl2CF ₃ ). In a seventh embodiment, C ₃ -eheterocycloalkyl such as Co-2alkyleneC ₃ heterocycloalkyl, rocycloalkyl, Co-

₂ alkyleneC5heterocycloalkyl, Co-2alkyleneC6hetero leneC _3-6 heterocycloalkyl, CialkyleneC _3-6 heterocycloalkyl and C2alkyleneC ₃ -6heterocycloalkyl. Suitably the heterocycloalkyl of a Co-2alkyleneC ₃ -6heterocycloalkyl 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 Ci-4alkyl, C(0)FI, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)0Bz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NFICi- 4haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C _{3. 6} heterocycloalkyl ring include Ci-4alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CFl ₂ 0CFI ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CFl ₂ C(0)0CFl ₂ CFI ₃ . Suitably, any nitrogen atom in the C _3-6 heterocycloalkyl ring is not substituted. In an eighth embodiment, R4 _bc and Rs _bc together with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _{3. 6} heterocycloalkyl ring. Suitably R4 _bc and Rs _bc 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 _5bc 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 Ci-4alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- alkylaryl such as C(0)0Bz, C(0)NHCi- ₄ alkyl, C(0)NFICi- ₄ alkylaryl such as C(0)NFIBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NFICi- ₄ haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C3-sheterocycloalkyl ring include Ci-4alkylCN such as CH2CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ . Suitably, any nitrogen atom in the C3-6heterocycloalkyl ring is not substituted.

Suitably R _4bc is H, CH ₃ or ethyl, in particular CH ₃ or ethyl. Suitably, R _4bc and R _5bc together with the carbon atom to which they are attached form a C3-6cycloalkyl ring, such as a cyclopropyl ring.

In one embodiment, Rs _c is H. In a second embodiment Rs _bc is Ci- ₆ alkyl such as Ci-4alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). Rs _bc 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, Rs _bc is Co-2alkyleneC3-6cycloalkyl such such as Co- ₂ alkyleneC3cycloalkyl, Co-2alkyleneC4cycloalkyl, oalkyleneC ₃ - ₅ cycloalkyl, CialkyleneCs-scycloalkyl and C2alkyleneC3-5cycloalkyl. R _{5 c} may also be Co- ₂ alkyleneC ₆ cycloalkyl, CoalkyleneC _3-6 cycloalkyl, CialkyleneC _3-6 cycloalkyl and C ₂ alkyleneC _{3. 6} cycloalkyl. In a fourth embodiment R _5b c is Ci-3alkyleneOCi- ₃ alkyl, in particular Ci. ₂ alkyleneOCi. ₂ alkyl such as CialkyleneOCialkyl, C ₂ alkyleneOCialkyl, CialkyleneOC ₂ alkyl or C ₂ alkyleneOC ₂ alkyl. In a fifth embodiment R _5b c is Ci- ₆ alkylOH such as Ci- ₄ alkylOH such as CialkylOH, C ₂ alkylOH, C ₃ alkylOH or C4alkylOH wherein Ci. ₄ alkyl is methyl, ethyl, propyl (n-propyl or isopropyl) and butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R _b c may also be C ₅ alkylOH or CealkylOH. In a sixth embodiment, R _{5 c} is Ci. _e haloalkyl such as Ci- haloalkyl such as Cihaloalkyl (e.g. CF3), C ₂ haloalkyl (e.g. CH ₂ CF ₃ ), C ₃ haloalkyl (e.g. CFI ₂ CFI ₂ CF ₃ ), C4haloalkyl (e.g. CFI ₂ CFI ₂ CFI ₂ CF ₃ ). R _{5 c} may also be Cshaloalkyl (e.g. CFI ₂ CFI ₂ CFI ₂ CFI ₂ CF ₃ ) or Cehaloalkyl (e.g. CFI ₂ CFI ₂ CFI ₂ CFI ₂ CFI ₂ CF ₃ ). In a seventh embodiment, R _5bc is Co-2alkyleneC ₃ -eheterocycloalkyl such as Co-2alkyleneC ₃ heterocycloalkyl, Co-2alkyleneC4heterocycloalkyl, Co-

₂ alkyleneC ₅ heterocycloalkyl, Co- ₂ alkyleneC ₆ heterocycloalkyl, CoalkyleneC _3-6 heterocycloalkyl, CialkyleneC _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 Ci-4alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)N HCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci_ ₄ haloalkyl, C(0)OCi_ ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)OtBu. Additional substituent groups on any nitrogen atom(s) in the C ₃ -sheterocycloalkyl ring include Ci-4alkylCN such as CH ₂ CN, C(0)Ci. ₃ alkyl0Ci. ₂ alkyl such as C(0)CFI ₂ 0CFl3, and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CFl ₂ C(0)0CFl ₂ CFI ₃ . Suitably, any nitrogen atom in the C _3-6 heterocycloalkyl ring is not substituted. Suitably Rs _bc is H, CH ₃ or ethyl, in particular CH ₃ or ethyl. Suitably, R4 _bc and Rs _bc together with the carbon atom to which they are attached form a C3-6cycloalkyl ring, such as a cyclopropyl ring.

Suitably R _4bc is H, CH ₃ or ethyl and R _5bc is H, CH ₃ or ethyl, in particular R _4bc is CH ₃ or ethyl and Rs _bc is CH ₃ or ethyl. For example, R _4bc and R _5bc are H, R _4bc and R _5bc are methyl or R _{4 c} and R _5bc are ethyl.

Suitably, R _4bc is CH ₂ CH ₂ OCH3 and Rs c is H.

In one embodiment, A _c is A _ac i.e. -CH ₂ NR _6c -.

In another embodiment, A _c is A _c i.e. -C(=0)NR _6c -.

In one embodiment, R _6c is H. In another embodiment, R _6c is Ci- ₃ alkyl, in particular CH ₃ .

In one embodiment Ar1 c 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).

In particular Ar1 c is phenyl or 2-pyridyl, such as phenyl.

In one embodiment Ri _0c is H. In a second embodiment Ri _0c is halo, for example fluoro or chloro. In a third embodiment Ri _0c is Ci- ₃ alkyl, i.e. CH ₃ , ethyl or propyl (e.g. n-propyl or /so-propyl). In a fourth embodiment Ri _0c is OCi. ₂ alkyl, such as OCH ₃ or ethoxy. In a fifth embodiment, Ri _0c is Ci. ₂ haloalkyl, such as CF ₃ or CH ₂ CF ₃ . In a sixth embodiment Ri _0c is OCi. ₂ haloalkyl, such as OCF ₃ . In a seventh embodiment Ri _0c is CN.

Suitably Ri _0c is H, fluoro, OCH ₃ , CH ₃ or CF ₃ , in particular H or fluoro, especially H.

Suitably Rio _c is attached at the ortho position of Ar1 c relative to group A _c (i.e. proximal to group Ac).

In one embodiment Rn _c is H. In a second embodiment Rn _c is F. In a third embodiment, Rn _c is Cl. In a fourth embodiment Rn _c is CH ₃ . In a fifth embodiment Rn _c is CH ₂ CH ₃ . In a sixth embodiment Rn _c is OCH ₃ . In a seventh embodiment Rn _c is CF ₃ . In an eighth embodiment Rn _c is OCF ₃ . In a ninth embodiment Rn _c is CN.

In one embodiment, Rn _c is in the ortho position relative to group A _c . In another embodiment, Rn _c is in the meta position relative to group A _c .

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).

In particular Ar2c is 3-pyridyl or 2,5-pyrazinyl, especially 2,5-pyrazinyl. In one embodiment Ri2 _c is H. In a second embodiment Ri2 _c is halo, for example fluoro or chloro. In a third embodiment RI _C is Ci-4alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n- butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment, RI _C is C2-4alkynyl such as C ₂ alkynyl (i.e. CºCH). In a fifth embodiment, RI _2C is C(=0)Ci- ₂ alkyl, such as C(=0)Cialkyl or C(=0)C ₂ alkyl. In a sixth embodiment RI _2C is OCo-2alkyleneC _3-5 cycloalkyl, such as OC ₃ -5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OCialkyleneC ₃ -5cycloalkyl or OC ₂ alkyleneC ₃ -5cycloalkyl. In a seventh embodiment RI _2C is OCi-4alkyl, such as OCH ₃ , ethoxy, iso- propoxy or n-propoxy. In an eighth embodiment, RI _2C is Ci- ₃ alkyleneOCi- ₃ alkyl in particular Ci- ₂ alkyleneOCi- ₂ alkyl such as CialkyleneOCialkyl, C ₂ alkyleneOCialkyl, CialkyleneOC ₂ alkyl or C ₂ alkyleneOC ₂ alkyl. In a ninth embodiment RI _2C is Ci- ₄ haloalkyl, such as CF _3. In a tenth embodiment R _12c is OCi- ₄ haloalkyl, such as OCF ₃ , OCFIF ₂ or OCFI ₂ CF ₃ . In an eleventh embodiment RI _2C is CN. In an eleventh embodiment RI _2C is OCo-2alkyleneC ₃ -5cycloalkyl, such as OC ₃ -5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OCialkyleneC ₃ -5cycloalkyl or OC ₂ alkyleneC ₃ -5cycloalkyl. In a twelfth embodiment RI _2C is OCFl2CFl2N(CFl3)2. In a thirteenth embodiment RI _2C is OFI. In a fourteenth embodiment RI _2C is Ci- ₄ alkylOH, such as CFI2OFI or C(CFI ₃ ) ₂ 0FI. In a fifteenth embodiment RI _2C is NR _23c R24 _c . In a sixteenth embodiment Ri _2c is S0 ₂ CFI ₃ . In a seventeenth embodiment RI _2C is C(0)N(CFI ₃ ) ₂ . In an eighteenth embodiment RI _2C is NFIC(0)Ci- ₃ alkyl such as NFIC(0)CFI ₃ . In a nineteenth embodiment Ri _2c is a C _3-6 heterocycloalkyl comprising (such as containing) one nitrogen located at the point of attachment to Ar2c, such as a Csheterocycloalkyl, in particular pyrrolidinyl, or a Ceheterocycloalkyl such as morpholinyl. In a twentieth embodiment, RI _2C together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ).

In one embodiment, R _23c is FI. In another embodiment, R _23c is Ci-2alkyl i.e. CFH ₃ or CFH ₂ CFH ₃ .

In one embodiment, R _24c is FI. In another embodiment, R ₂ 4 _c is Ci-2alkyl i.e. CFH ₃ or CFI ₂ CFI ₃ .

Ri2 _c is suitably H, fluoro, chloro, CH ₃ , Et, OCFI ₃ , OEt, OiPr, CF ₃ or OCH ₂ CF _3. In particular, RI _2C is fluoro, chloro, CH ₃ , OCH ₃ , OEt, OiPr or CF ₃ , for example chloro, OEt, O/Pr or CF ₃ such as chloro, OEt or CF ₃ .

RI _2C is suitably attached at the meta position of Ar2c. Alternatively, RI _2C is attached at the ortho position of Ar2c.

The present invention provides compounds R94 and R95.

The present invention provides the following compounds:

/V-(4-(2-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)pro pan-2-yl)thiazol-2- yl)cyclopropanesulfonamide; and

A/-(4-(2-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amin o)propan-2-yl)thiazol-2- yl)cyclopropanesulfonamide. General Terms and Definitions

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 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 (l-a), (l-b) and/or (l-c).

The term‘alkyl’ as used herein, such as in Ci- ₃ alkyl, Ci. ₄ alkyl, Ci-salkyl or Ci- ₆ alkyl e.g. Ci- ₃ alkyl, Ci- ₄ alkyl or Ci-salkyl, or such as in Ci- ₂ alkyl, Ci- ₃ alkyl or Ci- ₄ alkyl whether alone or forming part of a larger group such as an Oalkyl group (e.g. OCi- ₃ alkyl, OCi- ₄ alkyl and OCi-salkyl or OCi- ₂ alkyl, OCi- ₃ alkyl or OCi- 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 Ci-salkyl groups methyl, ethyl, n-propyl, /so- propyl, n-butyl, /so- butyl, sec-butyl, tert-butyl and n-pentyl, sec-pentyl and 3-pentyl, in particular the Ci- ₃ alkyl groups methyl, ethyl, n-propyl and /so-propyl. Examples of alkyl groups also include the Ci- alkyl groups methyl, ethyl, n-propyl, /so-propyl, n-butyl, /so- butyl, sec-butyl and terf-butyl, in particular the Ci- ₃ alkyl groups methyl, ethyl, n-propyl and / ^' so-propyl such as Ci- ₂ alkyl groups methyl and ethyl. Reference to“propyl” includes n-propyl and /so-propyl, and reference to“butyl” includes n-butyl, isobutyl, sec-butyl and fert-butyl. Examples of Oalkyl groups include the OCi. ₄ alkyl groups methoxy, ethoxy, propoxy (which includes n-propoxy and /so-propoxy) and butoxy (which includes n-butoxy, /so- 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 OCsalkyl group is a straight or a branched fully saturated hydrocarbon chain containing five carbon atoms. Examples of Csalkyl groups include n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl and active pentyl. Cealkyl groups as used herein, whether alone or forming part of a larger group such as an OCealkyl 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.

The term‘alkylene’ as used herein, such as in Co- ₂ alkyleneC _3-5 cycloalkyl, Ci- ₃ alkyleneOCi- ₂ alkyl Ci- ₂ alkyleneOCi- ₂ alkyl or OCo- ₂ alkyleneC ₃ -scycloalkyl is a bifunctional straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of Co- ₂ alkylene groups are where the group is absent (i.e. Co), methylene (Ci) and ethylene (C ₂ ). Examples of Ci- ₃ alkylene groups are where the group is methylene (Ci), ethylene (C ₂ ) and propylene (C ₃ ). Examples of Ci- ₂ alkylene groups are where the group is methylene (Ci) and ethylene (C ₂ ). Examples of Co-ialkylene groups are where the group is absent (Co) and methylene (Ci).

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. The term‘alkynyl’ as used herein, such as in C2-4alkynyl 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.

The term‘cycloalkyl’ as used herein, such as in C^cycloalkyl, C3-5cycloalkyl or C3-ecycloalkyl, whether alone or forming part of a larger group such as OC3-5cycloalkyl, Co- ₂ alkyleneC3- ₆ cycloalkyl, Co- ₂ alkyleneC3-5cycloalkyl or Co-ialkyleneC3-4cycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms. Examples of cycloalkyl groups include the C3-6cycloalkyl groups cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in particular the C3-5cycloalkyl groups cyclopropyl, cyclobutyl and cyclopentyl:

C ₃ cycloalkyl C ₄ cycloalkyl C ₅ cycloalkyl C ₆ cycloalkyl

When B is B-a, the term‘heterocycloalkyl’ as used herein, such as in C3-6heterocycloalkyl or Co- 2alkyleneC3-6heterocycloalkyl 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 C3-6heterocycloalkyl or Co-2alkyleneC3-6heterocycloalkyl 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.

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 Ci-4alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)0Ci- ₄ alkyl, C(0)0Ci- ₄ alkylaryl such as C(0)0Bz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C3.sheterocycloalkyl ring include Ci^alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH3. 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(0) ₂ ). Alternatively, any sulphur atom(s) in the C3-sheterocycloalkyl ring is not substituted. Examples of C3-6heterocycloalkyl 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 C3-6heterocycloalkyl 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 C3-6heterocycloalkyl comprising one nitrogen atom include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, especially piperidinyl, pyrrolidinyl and morpholinyl. Particular examples of C3-6heterocycloalkyl 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 _3-8 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 -eheterocycloalkyl 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.

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).

When B is B-bc and the compound is a compound of formula (l-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).

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. 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 Ci-4alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)0Ci- ₄ alkyl, C(0)0Ci- ₄ alkylaryl such as C(0)0Bz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C3-6heterocycloalkyl ring include Ci-4alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH 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(0) ₂ ). When R ₄ and R ₅ are R _4a and R _5a , Q is N substituted by S(0) ₂ R ₂₉ . Alternatively, any sulphur atom(s) in the C3- eheterocycloalkyl ring is not substituted.

When A _a is -C(=0)NH-, -NH- or -CH ₂ NH- and R _4a and/or R _5a is CoalkyleneC3-6heterocycloalkyl, or when R4 _a and Rs _a together with the carbon atom to which they are attached form a C3- ₆ heterocycloalkyl, any heteroatom in the heterocycloalkyl may not be directly connected to the carbon to which R _a and R _5a are connected.

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.

When B is B-bc and the compound is a compound of formula (l-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. When B is B-bc and the compound is a compound of formula (l-c), and when the heterocycloalkyl is formed from R 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 Ci- ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)0Bz, C(0)N HCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)N HCi- haloalkyl such as C(0)0tBu. Additional substituent groups on any nitrogen atom(s) in the C3-6heterocycloalkyl ring include Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkylOCi-2alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH 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(0) ₂ ). When R ₄ and R ₅ are R _4a and R _5a , Q is N substituted by - S(0) ₂ R _29. Alternatively, any sulphur atom(s) in the C ₃ -sheterocycloalkyl ring is not substituted.

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.

The term ‘haloalkyl’ as used herein, such as in Ci-shaloalkyl, such as in Ci- ₄ haloalkyl or Ci- ₂ haloalkyl, whether alone or forming part of a larger group such as an Ohaloalkyl group, such as in OCi- ₆ haloalkyl,such as in OCi- ₄ haloalkyl or OCi- 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.

The term‘6-membered aryl’ as used herein refers to a phenyl ring.

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).

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, Wi may be N, CH, CRioa or CRn _a , and W ₂ may be N, CH or CRi _2a as allowed by the definitions provided for compounds of formula (I). W ₂ may also be CRi _3a as allowed by the definitions provided for compounds of formula (l-a); and

when B is B-bc and the compound is a compound of formula (l-b), compounds with the following substructure are formed:

wherein W may be N, CH, CRio _b or CRn _t> , and Y may be N, CH, CRi _2b or CRi _3b as allowed by the definitions provided for compounds of formula (l-b);

and when B is B-bc and the compound is a compound of formula (l-c), compounds with the following substructure are formed:

wherein W may be N, CH or CRio _c , and Y may be N, CH or CRi _2c as required by the definitions provided for compounds of formula (l-c). W may also be CRn _c as allowed by the definitions provided for compounds of formula (l-c).

The terms‘ortho’ and‘meta’ as used herein, such as when used in respect of defining the position of R12 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 (l-b):

wherein X represents a substituent e.g. Ri _b ; and

when B is B-bc and the compound is a compound of formula (l-c):

wherein all variables listed above are as defined elsewhere herein.

When a spirocyclic ring system is said to form, e.g. when R4 _aa and Rs _aa , R4 _ab and Rs _ab , or R4 _ac and R5 _ac , suitably together with the carbon atom to which they are attached form a C3-6cycloalkyl and 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, the following spirocyclic groups are encompassed (which may optionally be substituted as mentioned above):

wherein C is a C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, as defined elsewhere herein. In one embodiment C is a C3-6cycloalkyl ring. In a second embodiment C is a C3-6heterocycloalkyl ring.

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.

Alternatively, when a spirocyclic ring system is said to form, e.g. when R _4aa and R _5aa , R _4a 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.

Throughout the specification Ar1 and Ar2 may be depicted as follows: 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 Ari a, Ar1 b and Ar1c. Ar2 encompasses the variables Ar2a, Ar2b and Ar2c.

The present invention provides N-oxides of the compound of formula (I). Suitably, when R12 together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ^_ ), the example following structures are formed: 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:

2-pyridyl 3-pyridyl 2,6-pyrimidinyl

2-pyridyl 3-pyridyl

2-pyridyl

The position numbering for Ar2 is in respect of the point of attachment to Ar1 , for example: 2-pyridyl 3-pyridyl 4-pyridyl 2,5-pyrazinyl

3,5-pyrimidinyl 2,6-pyrimidinyl 2,3-pyridazinyl 3,4-pyridazinyl _e g 3-pyridyl 2,5-pyrazinyl

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

The compounds of the invention may be provided in the form of a pharmaceutically acceptable salt and/or solvate thereof and/or derivative 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.

Compounds of the invention of particular interest are those demonstrating an IC ₅ o of 1 uM or lower, especially 100nM or lower, in respect of CTPS1 enzyme, using the methods of the examples (or comparable methods).

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.

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.

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. 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).

It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention.

As used herein "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable prodrug such as an ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

It is to be understood that the present invention encompasses all isomers of formula (I) and their pharmaceutically acceptable derivatives, 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.

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.

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 0), oxygen-17 ( ¹⁷ 0), oxygen-18 ( ¹⁸ 0), phosphorus-32 ( ³² P), sulphur-35 ( ³⁵ S), chlorine-36 ( ³⁶ CI), chlorine-37 ( ³⁷ CI), fluorine-18 ( ¹⁸ F) iodine-123 ( ¹²³ l), iodine-125 ( ¹²⁵ l) 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.

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 0 and ¹³ N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

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

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.

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.

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. 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:

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 (l-a), (l-b) and/or (l-c).

Generic and specific routes by which compounds disclosed herein and compound examples of the invention may be conveniently prepared are disclosed in W02019/106156, WO2019/106146, WO2019/179652, WO2019/180244 and W02020/083975, each of which is herein incorporated in its entirety by reference, as well as those routes summarised below, and adaptations thereof.

Compounds of formula (l-al

Compounds of formula (l-a) may be synthesised according to general and specific methods disclosed in WO2019/179652, WO2019/180244 and W02020/083975. For the avoidance of doubt, reference to variables in each of the schemes in this section encompasses variables specific to compounds of formula (l-a). For example, Ri includes Ri _a . Furthermore, reference to intermediates in each of the schemes in this section encompasses corresponding intermediates for compounds of formula (l-a). For example, reference to compounds of formula (II) encompasses compounds of formula (I l-a).

Scheme 1a

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. In general and as illustrated in Schemes 1a and 1 b, 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, 1 b of WO2019/179652, or 1a or 1 b herein. For example, the unsymmetrical malonate ester can be treated with a base such as Cs ₂ C0 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 -scycloalkyl 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 BrChhCFhOChhCFhBr) in the presence of a base such as Cs ₂ C0 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).

Palladium catalysed sulfamination of intermediate (X) may be achieved using a catalyst such as [f-BuXPhosPd(allyl)]OTf or f-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 C0 ₃ and a solvent such as N-methyl pyrrolidinone to form intermediates (II) which may be obtained by precipitation following dilution in aqueous 4M HCI.

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 iPrMgCI, LiHMDS or KOtBu. Compounds of the general formula (VII) where R2 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 1 b.

Compounds of general formula (I) where Ri, Ar1 and Ar2 are defined above and R ₄ and R ₅ together with the carbon to which they are attached form a C3-6heterocycloalkyl, 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 1 b. If any protecting groups remain after amide coupling, treatment with a strong acid such as TFA may yield final compounds of formula

(I)

Following deprotection compounds of general formula (I) where Ri , Ar1 and Ar2 are defined above and R ₄ and R ₅ together with the carbon to which they are attached form a C3-6 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.

Scheme 2

Z = B(OH) ₂ , B(pin)

X = Br, Cl

Intermediates of formula (III) wherein Ar1 , R10, Rn , Ri2 and R^ 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 R12 and R13 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 , T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.

Scheme 3

Z = Br, Cl

X = B(OH) _2I B(pin) Intermediates of formula (III) wherein Ar1 , Rio, Rn, R12 and R13 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 ,T-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.

Benzamide pyrimidines

Scheme 4

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 1 a and 1 b of WO2019179652. Reduction of the nitrile group using sodium borohydride in the presence of nickel (II) chloride and di-fert-butyl dicarbonate may yield the protected benzylamine derivative of general formula (XXXXI). Deprotection can be carried out by acid hydrolysis using HCI 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).

Compounds of general formula (I) where A is an amine linker such as -CH2NH-, where Ri , An and Ar ₂ are defined above, R ₄ is Ci- _e alkyl and R ₅ is H or Ci. _e alkyl or R ₄ and R ₅ together with the carbon to which they are attached form a C3-6cycloalkyl or C3-sheterocycloalkyl 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). Scheme 5

Ar ₂ ^ .i-

(LXX) Ar·, OH (LVXIX)

(XXXXIII)

Compounds of general formula (I) where Ri , An and Ar ₂ are defined above, R ₄ is Ci- ₆ alkyl and R ₅ is H or Ci-salkyl or R ₄ and R5 together with the carbon to which they are attached form a C3- ₆ cycloalkyl or C3-6heterocycloalkyl 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 HCI 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. Scheme 6

X a nd Z = Br, Cl (XI) Y = CH ₂ OH

Intermediates of formula (LXXII) where Ar 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 _I2 and R _I3 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(ll).CH ₂ CI 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.

Scheme 7

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 HCI, 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). Scheme 8

Compounds of formula (I) wherein A is -NR ₆ CH ₂ - can be obtained from compounds of formula (I) wherein A is -NR _e C(=0)-, by the reduction of the amide to the amine using a reducing agent such as UAIH4 in a solvent such as THF.

Scheme 9a

In general and as illustrated in Scheme 9a, compounds of formula (I) wherein Ri, Ar1 and Ar2 are as defined above, alkyl is Ci- 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 -eheterocycloalkyl 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 iPrMgCI. 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 CS2CO3 and a solvent such as /V-methyl pyrrolidone gives compounds of formula (I).

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). Scheme 9b

^ ²

In general and as illustrated in Scheme 9b, compounds of formula (I) wherein Ri, Ar1 and Ar2 are as defined above, alkyl is Ci. 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 CS2CO3 and a solvent such as A/-methyl pyrrolidone gives compounds of formula (I).

Scheme 9c

wherein R is H, Ci-4alkyl (e g. methyl and ethyl) or benzyl. In general and as illustrated in Scheme 9c, compounds of formula (I) wherein Ri , X, Y, Z, Ar1 and Ar2 are as defined above and K is Ci. ₄ alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi. ₄ alkyl, C(0)OCi_ ₄ alkylaryl such as

₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci.

4haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)0tBu, Ci- ₄ alkylCN such

3alkylOCi-2alkyl such as C(0)CH ₂ 0CH3, and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such a

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 C0 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 iPrMgCI, LiHMDS or KOtBu, to give compounds of formula (l-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).

Scheme 10

O .

(XXVII) In general and as illustrated in Scheme 10, compounds of formula (I) wherein Ri, Ar1 and Ar2 are as defined above, alkyl is Ci. 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 C3-6heterocycloalkyl 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.

Scheme 11

(LXXI) (LXXI I) O)

In general and as illustrated in Scheme 11 , compounds of formula (I) wherein Ri, Ar1 and Ar2 are as defined above, R ₄ and Rs together with the carbon atom to which they are attached form a C3- ₆ heterocycloalkyl ring may be prepared starting from alcohols (LXXI), which as oxidised to aldehydes (LXXII) in the presence of MnC>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.

Scheme 12 Compounds of formula (I) wherein A is -NH- and R4 or R5 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 d-b ^' )

Compounds of formula (l-b) may be synthesised by general and specific methods disclosed in W02019/106156 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 (l-b). For example, Ri includes Ri _b . 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).

Scheme 13

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. Scheme 14

Z = B(0H) ₂ , B(pin)

X = Br, Cl

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 ,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane and an inorganic base such as potassium carbonate in a solvent mixture of 1 ,4-dioxane and water.

Scheme 15

Z = Br, Cl

X = B(OH) _2I Bpin

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 ,T-bis(diphenylphosphino) ferrocene]dichloropalladium(ll) and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water. Scheme 16

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(l)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 = Rs _b = 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 Rs _b - H.

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(l)l, 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 [i-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 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.

Scheme 17

wherein halo is, for example, bromo. Compounds of formula (XXVII), for example, when R _4b is H and Re _b and R ₆ are a C^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.

Scheme 18

In general compounds of formula (I) where R ₄ and Rs 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 HCI 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).

Scheme 19

Compounds of formula (I) wherein A is -NR6CH2- can be obtained from compounds of formula (I) wherein A is -NR ₆ C(=0)-, by the reduction of the amide to the amine using a reducing agent such as UAIH ₄ in a solvent such as THF.

Scheme 20

Compounds of formula (I) wherein A is -NR6- and R5 or R4 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 (l-c)

Compounds of formula (l-c) may be synthesised by general and specific methods disclosed in W02019/106146 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 (l-c). For example, Ri includes Ri _c . 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) . Scheme 21

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(ll).CH ₂ Cl2 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.

Scheme 22

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 RI ₂ 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(ll).CH ₂ CI 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 CI 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 HCI. Compounds of formula (lll-A) may also be made using this method.

Scheme 23

Compounds of formula (I) wherein A _a is -CH2NR6- can be accessed in two steps from compounds of formula (XXII). Oxidation of the alcohol (XXII) under standard oxidation conditions such as Mn0 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). Scheme 24

In general compounds of formula (I) where R _a and R _5a together with the carbon to which they are attached form a C3-6cycloalkyl wherein one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C _3-6 cycloalkyl ring and a C3-6heterocycloalkyl 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 HCI 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 (l-a)

The present invention also relates to novel intermediates in the synthesis of compounds of formula (l-a) such as compounds of formula (ll-a) to (LVIX-a) such as compounds of formula (II- a) to (XXV-a), such as compounds of formula (ll-a)-(XX-a). Particular intermediates of interest are those of the following general formulae, wherein the variable groups and associated preferences are as defined previously for compounds of formula (l-a):

a compound of formula (ll-a):

wherein R is H, Ci-salkyl (e.g. methyl and ethyl) or benzyl;

a compound of formula (XX-a):

wherein P is a nitrogen protecting group such as para-methoxybenzyl; a compound of formula (XXIV-a):

wherein P is a nitrogen protecting group such as para-methoxybenzyl; a compound of formula (XXXI-a):

a compound of formula (XXXXII-a): a compound of formula (Ll-a):

wherein Xi is Cl or Br.

- a compound of formula (LVIII-a):

a compound of formula (XXXIII-a):

wherein alkyl is Ci-4alkyl such as methyl or ethyl, e.g. methyl;

- a compound of formula (LXXIII-a):

a compound of formula (LXXIV-a):

n = 2 sulfone a compound of formula (LXXXIII-a): R ₄ R5 O Q

alkyl' Y Ύ Y

o z. .x

(LXXXIII-a) a compound of formula (XXXIV-a):

(XXXIV-a) a compound of formula (LXXI-a):

a compound of formula (LXXII-a):

Suitably, at least one of R ₁₀ , Rn and R ₁₂ is other than H.

There is also provided protected derivatives of a compound of formula (I). There is also provided protected derivatives of any one of the above intermediates, such as (ll-a), (XX-a), (XXIV-a), (XXXI -a), (XXXXII-a), (Ll-a), (LVIII-a), (XXXIII-a), (LXXIII-a), (LXXIV-a) and (LXXXIII-a). For example, if the compound of formula (I) comprises a heterocyclyl group comprising a nitrogen atom, for example, when R _4ba and R _{5 a} join to form a piperidinyl ring, the nitrogen atom may be protected with a suitable nitrogen protecting group such as Boc. Also provided are compounds of formula (I) or any one of the above mentioned intermediates in which the protecting group, such as the Boc group has been removed.

Compounds of formula (I) may be considered intermediates for further compounds of formula (I), as described in the Examples below. 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. Included as an aspect of the invention are salts such as pharmaceutically acceptable salts of any one of the intermediates disclosed herein, such as any one of compounds of formulae (II- a)-(LXXVII-a).

Compounds of formula (Ί-b)

The present invention also relates to novel intermediates in the synthesis of compounds of formula (l-b) such as compounds of formula (ll-b), (IV-b), (V-b), (Vl-b), (Vll-b), (X-b), (Xll-b), (XVIII-b), (CIC-b), (XX-b), (XXI-b), (XXII-b) and (XXIII-b). Particular intermediates of interest are those of the following general formulae, wherein the variable groups and associated preferences are as defined previously for compounds of formula (l-b):

Compounds of formula (ll-b)

wherein Ri, R3, R4 and Rs are as defined herein;

Compounds of formula (IV-b)

wherein R is Ci. ₆ alkyl (e.g. methyl, ethyl) or benzyl.

Suitably, the intermediate is not:

Suitably, when the compound is a compound of formula (IV-b), R _4b and R _5b cannot both be H when Rib is CH ₃ .

Included as an aspect of the invention are salts such as pharmaceutically acceptable salts of any one of the intermediates disclosed herein, such as any one of compounds of formulae (II- b), (IV-b), (V-b), (Vl-b), (Vll-b), (X-b), (Xll-b), (XVIII-b), (CIC-b), (XX-b), (XXI-b), (XXII-b) and (XXIII-b).

Other intermediates of interest include those disclosed in W02019/106156 such as INTA92, INTA93, INTA94, INTA95, INTA96, INTA97, INTA98, INTA103, INTA104, INTA105, INTA107, INTA3, INTA47, INTA48, INTA72, INTA106, INTB37, INTB38, INTB43.

Compounds of formula (l-c)

The present invention also relates to novel intermediates in the synthesis of compounds of formula (l-c) such as compounds of formula (ll-c), (IV-c), (V-c), (Vl-c), (Vlll-c), (IX-c), (X-c), (XI- c), (Xlll-c), (XVIII-c), (XIX-c), (XX-c) and (XXI-c). Particular intermediates of interest are those of the following general formulae, wherein the variable groups and associated preferences are as defined previously for compounds of formula (l-c):

a compound of formula (ll-c):

a compound of formula (Vlll-c):

(¾

(Vlll-c)

Included as an aspect of the invention are salts such as pharmaceutically acceptable salts of any one of the intermediates disclosed herein, such as any one of compounds of formulae (ll-c), (IV-c), (V-c), (Vl-c), (Vlll-c), (IX-c), (X-c), (Xl-c), (Xlll-c), (XVIII-c), (XIX-c), (XX-c) and (XXI-c).

Therapeutic Methods

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

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

Therefore, the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof, 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.

The invention provides a method for 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, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof.

The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) and/or derivative, in the manufacture of a medicament for 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.

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.

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

The invention provides a method for the inhibition of CTPS1 in a subject, which comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof.

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

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

The invention provides a method for the reduction of T-cell and/or B-cell proliferation in a subject, which comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof.

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

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. The term‘treatment’ or‘treating’ as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms.

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.

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

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.

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).

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.

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

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 Lymphoprol iterative 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 (Cl PD), Chronic Relapsing Polyneuropathy (Guillain-Barre 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, Meniere'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, Sjorgen'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.

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.

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-Barre 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, Sjogren’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.

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.

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 Lymphoprol iterative disorders, including:

Autoimmune Lymphoproliferative Syndrome and X-linked lymphoproliferative disease.

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.

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

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

Further, there is provided a method for treating cancer in a subject, by administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof.

Additionally provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof and/or derivative thereof, in the manufacture of a medicament for the treatment of cancer in a subject.

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.

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. 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.

Suitably the subject is a mammal, in particular the subject is a human.

Pharmaceutical Compositions

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

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) and/or derivative thereof, and a pharmaceutically acceptable carrier or excipient.

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) and/or derivative thereof, for use in the treatment or prophylaxis of a disease or disorder as described herein.

In a further embodiment, there is provided a method for the prophylaxis or treatment of a disease or disorder as described herein, which comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof.

The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) and/or derivative thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder as described herein.

The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives 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. The compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives 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.

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.

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.

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.

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.

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

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

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) and/or derivative 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.

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.

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) and/or derivative 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.

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) and/or derivative 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.

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.

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.

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

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

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.

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

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

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

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-l L12/I L23 antibodies (e.g., ustekinumab); anti-IL6 or anti-IL6R antibodies, anti-l L17 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).

For cancer, the further pharmaceutically acceptable active ingredient may be selected from antimitotic 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. 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.

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.

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

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.

When a compound of formula (I) or a pharmaceutically acceptable derivative 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

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

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.

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.

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”).

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.

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.

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).

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. 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.

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

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

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

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.

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.

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.

The invention is further exemplified by the following non-limiting examples.

EXAMPLES

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

Abbreviations

Ac acetyl (C(0)CH ₃ )

AcOH glacial acetic acid

AIMe ₃ trimethylaluminium

aq aqueous

Ar Aromatic ring

BEH ethylene bridged hybrid

Bis(pinacolato)diboron; 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1 ,3,2-

Bispin

dioxaborolane

Bz benzyl (CFb-phenyl)

Boc ferf-butyloxycarbonyl protecting group

CS2CO3 Cesium carbonate

CSH charged surface hybrid

d doublet

DABAL-Me ₃ adduct of trimethylaluminum and 1 ,4-diazabicyclo[2.2.2]octane

DCM dichloromethane

DIPEA N,N-diisopropylethylamine

dioxane 1 ,4-dioxane

DMAP 4-dimethylaminopyridine

DME dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DMP Dess-Martin Periodinane

DPPA diphenylphosphoryl azide

dppf 1 , 1 '-bis(diphenylphosphino)ferrocene

(ES ⁺ ) electrospray ionisation, positive mode

(ES-) electrospray ionisation, negative mode ESI electrospray ionisation

Et ethyl

Etl Ethyl iodide

EtOAc ethyl acetate

EtOH ethanol

g grams

Hal halogen

1-[bis(dimethylamino)methylene]-1 /-/-1 ,2,3-triazolo[4,5-fc>]pyridinium 3-

HATU

oxid hexafluorophosphate

HPLC high performance liquid chromatography

hr(s) hour(s)

IC50 50% inhibitory concentration

iPr /sopropyl

iPrMgCI /so-propyl magnesium chloride

K2CO3 potassium carbonate

LCMS liquid chromatography-mass spectrometry

□HMDS lithium hexamethyldisilazide

LiOH lithium hydroxide

(M+H) ⁺ protonated molecular ion

(M-H)- unprotonated molecular ion

M molar concentration

mCPBA Meta-chloroperoxybenzoic acid

mL millilitre

mm millimiter

mmol millimole

Me methyl

MeCN acetonitrile

Mel iodomethane

MeOH methanol

MesCI methanesulfonyl chloride

MHz megahertz

min(s) minute(s)

MSD mass selective detector

m/z mass-to-charge ratio

N ₂ nitrogen gas

N H ₃ ammonia

N H4CI ammonium chloride

NaH sodium hydride NaHCOs sodium bicarbonate

NaBH(OAc) ₃ Sodium triacetoxyborohydride

nm nanometre

NMR nuclear magnetic resonance (spectroscopy)

NSFI A/-fluorobenzenesulfonimide

P4HB poly-4-hydroxybutyrate

PDA photodiode array

chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-

Pd 170

triisopropybiphenyl)palladium(ll) or XPhos Pd(crotyl)CI

allyl(2-di-ierf-butylphosphino-2',4',6'-triisopropyl-1,1'-

Pd 174

biphenyl)palladium(ll) triflate or [fBuXPhosPd(allyl)]OTf

[Pd(allyl)CI ₂ ]2 bis(allyl)dichlorodipalladium

PdCI ₂ (dppf) [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)

Pd(PPh ₃ ) ₄ tetrakis(triphenylphosphine)palladium(0)

PMB 4-methoxybenzyl

prep HPLC preparative high performance liquid chromatography

Ph phenyl

pos/neg positive/negative

q quartet

RF/MS RapidFire Mass Spectrometry

RT room temperature

Rt retention time

RP reverse phase

s singlet

S _N AT nucleophilic aromatic substitution

sat saturated

SCX solid supported cation exchange (resin)

Selectfluor A/-chloromethyl-/V-fluorotriethylenediammonium bis(tetrafluoroborate) t triplet

tBu fert-butyl

T3P 2.4.6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-tri oxide

TBME ferf-butyl methyl ether

TFA Trifluoroacetic acid

[f-BuXPhos allyl(2-di-fert-butylphosphino-2',4',6'-triisopropyl-1 , -

Pd(allyl)]OTf biphenyl)palladium(ll) triflate

THF tetrahydrofuran

TMP 2.2.6.6-tetramethylpiperidinyl

TMSOK potassium trimethylsilanolate TTIP titanium tetraisopropoxide

UPLC ultra performance liquid chromatography

UV ultraviolet

v/v volume/volume

VWD variable wave detector

wt weight

urn micrometre

uL microlitre

°C degrees Celsius

General Procedures

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.

Column chromatography was performed on pre-packed silica (230-400 mesh, 40-63 urn) 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 Chromatography

Prep HPLC

Acidic prep

Waters X-Select CSH column C18, 5 urn (19 x 50 mm), flow rate 28 ml_ min ^-1 eluting with a H2O- MeCN gradient containing 0.1 % v/v formic acid over 6.5 min using UV detection at 254 nm.

Basic prep

Waters X-Bridge Prep column C18, 5 urn (19 x 50 mm), flow rate 28 ml. min ¹ eluting with a 10 mM NH ₄ HC03-MeCN gradient over 6.5 min using UV detection at 254 nm.

Analytical Methods

Reverse Phase HPLC Conditions for the LCMS Analytical Methods

HPLC acidic: Acidic LCMS 4 minute (5-95%)

Analytical LCMS was carried out using a Waters X-Select CSH C18, 2.5 urn, 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%)

Analytical LCMS was carried out using a Waters X-Select BEH C18, 2.5 urn, 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 Methods

UPLC acidic: Acidic UPLC 3 minute

Analytical UPLC/MS was carried out using a Waters Acquity CSH C18, 1.7 urn, 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

Analytical UPLC/MS was carried out using a Waters Acquity CSH C18, 1.7 urn, 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

Analytical UPLC/MS was carried out using a Waters Acquity BEH C18, 1.7 urn, 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 0.1 1-2.15 minutes with a flush from 2.15-2.56 minutes. A column reequilibration 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

Analytical UPLC/MS was carried out using a Waters Acquity BEH C18, 1.7 urn, 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 reequilibration 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.

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

Chiral IC3 method: Chiral HPLC (Diacel Chiralpak IC, 5 urn, 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 urn, 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 urn, 4.6x250 mm, 1.0 mL/min, 20% EtOH (0.2% TFA) in /so-hexane (0.2% TFA).

Reverse Phase HPLC Conditions for the Chiral Analytical Methods

Chiral IC6 method: Chiral HPLC (Diacel Chiralpak IC, 5 urn, 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 urn, 4.6x250 mm, 1.0 mL/min, 5-95% MeCN (0.1 % formic acid) in water (0.1 % formic acid).

¹ H NMR Spectroscopy

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

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 (l-a) - Intermediates

Any one of Methods 1-1 q (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.

The synthesis of INTC1 to INTC179 and INTD1 to INTD86 is disclosed in at least one of WO2019/179652, WO2019/180244 and W02020/083975, each of which is herein incorporated in its entirety by reference.

Method A: Decarboxylation of chloro-heterocycles such as chloro-pyrimidines

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

n = 1 ,2,3 n = 1 ,2,3

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 NhUCI (aq) or 1 M HCI (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

2-Chloropyrimidine intermediate (1 eq), sulfonamide (1.2 eq) and base (2 eq) were dissolved in dioxane (40 volumes). The mixture was degassed (N , 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

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

X = CH, N

Y = CR ₂ , N

Z = CR _3I N

W = Hal, N(PMB)S0 ₂ Alkyl

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 1 M in THF). The reaction mixture was then warmed to RT for 1 hr. The solution was cooled to -78 °C and a solution (in TH F) of, or solid, NSFI (1.25 eq) was added dropwise then warmed to RT for 2 hrs. The solution was diluted with sat. NaHCC>3 (aq) and the product was extracted into EtOAc. The crude product was purified by normal phase chromatography.

Method I: Buchwald coupling - sulfonylation

2-Bromopyridine intermediate (1 eq), sulfonamide (1.2 eq) and base (2 eq) were dissolved in dioxane (40 volumes). The mixture was degassed (N2, 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

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 1 M HCI (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

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

Z = Br, Cl

X = B(OH) _2I B(pin)

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

Bispin (1.1 eq) and KOAc (4 eq) were added to Arl-Hal (1 eq) in dioxane (5 volumes). The reaction was heated to 60 °C and degassed (N ₂ , 5 mins). PdCl2(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 K2CO3 (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

Z = Br, Cl

X = B(OH) ₂ , Bpin Y = C0 ₂ t-Bu, C0 ₂ Me, CN

A solution of boronic acid (1 eq), aryl halide (1.05 eq.) and CS2CO3 (3 eq.) in a mixture of dioxane (40 volumes) and water (6 volumes) was degassed (ISI2, 5 mins). PdCl2(dppf).CH2Cl2 (5 mol%) was added and the reaction was further degassed (N2) 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

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

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 HCI and extracted with EtOAc. The organic phases were combined, dried (Na ₂ SC>4), filtered and concentrated. The products were used directly in the next step with no further purification undertaken.

Method N: Potassium salt formation

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 undertaken. Method P: SNAR using 4-chloro-2-(methylthio)-heterocycles

A solution of hetero-aromatic chloride (1 eq) and ester (1 eq) in THF (5-20 volumes) was warmed to 30 °C to which was added LiHMDS (1.25 eq 1-1.5M in THF). The reaction mixture was stirred at this temperature for up to 3 hrs, then was poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (MgS0 ₄ ), filtered and the solvent removed in vacuo to afford the desired compound. If required, the crude product was purified by normal phase chromatography.

Table 1 : The following intermediates were made according to Method P.

Ethyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-4-carboxylate INTC191

To a solution of 1-ferf-butyl 4-ethyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-1 ,4-dicarboxylate (4 g, 9.44 mmol) INTC187 in DCM (30 mL) at RT was added TFA (5 ml_). The reaction mixture was stirred at RT for 1 hr. Additional TFA (5 mL) added and the reaction was stirred at RT for a further 1 hr. The reaction mixture was quenched by addition of NaHC0 ₃ (aq, 100mL), gas evolved, and was diluted with DCM (50 mL). The organics were isolated and dried (MgS0 ₄ ), filtered and solvent removed in vacuo to afford ethyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-4-carboxylate (2.6 g, 9.15 mmol, 97% yield) as a brown oil. Rt 0.97 min (HPLC, acidic); m/z 282 (M+H) ⁺ (ES+); No NMR data collected.

Ethyl 1-(methylsulfonyl)-4-(2-(methylthio)pyrimidin-4-yl)piperidin e-4-carboxylate INTC192

To a stirred solution of ethyl 4-(2-(methylthio)pyrimidin-4-yl)piperidine-4-carboxylate (1.3 g, 4.62 mmol) INTC191 in DCM (15 mL) at RT was added TEA (1.42 mL, 10.16 mmol) and then MesCI (0.37 mL, 5.08 mmol). After 1 hr, 1 M HCI ( aq , 50 mL) and DCM (30 mL) were added. The organic layer was isolated by passage through a phase separation cartridge and then concentrated in vacuo to afford ethyl 1-(methylsulfonyl)-4-(2-(methylthio)pyrimidin-4-yl)piperidin e-4-carboxylate (1.21 g, 3.37 mmol, 73% yield) as a brown oil. Rt 1.93 min (HPLC, acidic); m/z 360 (M+H) ⁺ (ES+); No NMR data collected.

Amide formation

(4-(2-(Methylthio)pyrimidin-4-yl)tetrahydro-2/-/-pyran-4-yl) methanol INTC197

LiCI (0.95 g, 22.4 mmol) followed by NaBH ₄ (0.85 g, 22.4 mmol) and EtOH (15 mL) was added into a stirring solution of methyl 4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2/-/-pyran-4- carboxylate INTC178 (3 g, 11.2 mmol) in THF (15 mL).The resulting reaction mixture was stirred at RT for 18 hrs. The reaction mixture was acidified with 1 M HCI (aq, 20 mL) and the volatiles were removed in vacuo. The residue was extracted with DCM (3 x 150 mL). The organic extract was dried (MgSCL), filtered and solvent removed in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EA//so-hexanes) to afford (4-(2- (methylthio)pyrimidin-4-yl)tetrahydro-2/-/-pyran-4-yl)methan ol (2.3g, 9.09 mmol, 81 % yield) as a colourless gum. Rt 0.80 min (UPLC acidic); m/z 241 (M+H) ⁺ (ES ⁺ ). ¹ H NMR (500 MHz, DMSO- d6) d 8.54 (d, J = 5.3 Hz, 1 H), 7.23 (d, J = 5.3 Hz, 1 H), 4.73 (t, J = 5.6 Hz, 1 H), 3.74-3.67 (m, 2H), 3.49 (d, J = 5.7 Hz, 2H), 3.35 - 3.27 (m, 2H), 2.50 (s, 3H), 2.19 - 2.10 (m, 2H), 1.77-1.67 (m, 2H).

4-(2-(Methylthio)pyrimidin-4-yl)tetrahydro-2/-/-pyran-4-carb aldehyde INTC198

DMP (1.77 g, 4.16 mmol) was added portionwise into a stirring solution of (4-(2- (methylthio)pyrimidin-4-yl)tetrahydro-2/-/-pyran-4-yl)methan ol INTC197 (1 g, 4.16 mmol) in DCM (25 ml). The resulting reaction mixture was stirred at RT for 1 hr. The reaction mixture was poured into sat. NaHCCh ( aq , 100 ml_) and extracted with DCM (3 x 100 ml_). The organic extract was sequentially washed with saturated sat. NaHCC>3 (aq, 100 ml_), and brine (100 ml_). The organic extract was dried (MgSC ), filtered and solvent in vacuo to afford 4-(2-(methylthio)pyrimidin-4- yl)tetrahydro-2/-/-pyran-4-carbaldehyde (900 mg, 3.40 mmol, 82% yield) as a colorless oil. Rt 1.61 min (HPLC acidic); m/z 239 (M+H) ⁺ (ES ⁺ ). ¹ H NMR (500 MHz, DMSO-d6) d 9.63 (s, 1 H), 8.65 (d, J = 5.2 Hz, 1 H), 7.30 (d, J = 5.2 Hz, 1 H), 3.68-3.59 (m, 2H), 3.56-3.48 (m, 2H), 2.51 (s, 3H), 2.28 - 2.20 (m, 2H), 2.16-2.09 (m, 2H).

4-(6-Ethoxypyrazin-2-yl)-/V-((4-(2-(methylthio)pyrimidin-4-y l)tetrahydro-2/-/-pyran-4- yl)methyl)aniline INTC199

NaBH(OAc) ₃ (1.07 g, 5.04 mmol) was added into a suspension of 4-(2-(methylthio)pyrimidin-4- yl)tetrahydro-2/-/-pyran-4-carbaldehyde INTC198 (400 mg, 1.68 mmol) and 4-(6-ethoxypyrazin-2- yl)aniline INTD18 (542 mg, 2.52 mmol) in DCM (10 ml) and the resulting reaction mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was diluted with DCM (100 ml.) and sequentially washed with sat. NaHC0 ₃ (aq, 2 x 100 ml_) and brine (100 ml_), dried (MgSC ), filtered and solvent removed in vacuo. The crude product was purified by chromatography on silica gel (25 g cartridge, 0-100% EtOAc/ so-hexanes) to afford 4-(6-ethoxypyrazin-2-yl)-A/-((4-(2- (methylthio)pyrimidin-4-yl)tetrahydro-2/-/-pyran-4-yl)methyl )aniline (312 mg, 0.706 mmol, 42% yield) as a yellow gum. Rt 2.49 min (HPLC acidic); m/z 438 (M+H) ⁺ (ES ⁺ ). ¹ H NMR (500 MHz, DMSO-d6) d 8.57 (s, 1 H), 8.52 (d, J = 5.2 Hz, 1 H), 7.99 (s, 1 H), 7.81 - 7.74 (m, 2H), 7.29 (d, J = 5.3 Hz, 1 H), 6.66 - 6.57 (m, 2H), 6.00 (t, J = 6.6 Hz, 1 H), 4.42 (q, J = 7.0 Hz, 2H), 3.80 - 3.70 (m, 2H), 3.38 (d, J = 6.6 Hz, 2H), 3.32 - 3.26 (m, 2H), 2.52 (s, 3H), 2.32 - 2.26 (m, 2H), 1.89-1.80 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H). Method Q: Oxidation of thioethers to sulfones or sulfoxides

X = CH, N

Y = CR ₂ , N w = so, so ₂

Z = CR ₃ , N

L = C(0)0Alkyl, C(0)NHAr, CH ₂ NHAr mCPBA (2.2 eq) was portionwise to a stirred solution of thiother (1 eq) in DCM (20-50 volumes) maintaining the internal temperature at RT. The resulting mixture was stirred at RT for a further 3 hrs. The reaction mixture was poured into sat. aq. Na SC>3 and extracted with DCM. The organic extract was sequentially washed with sat. aq. NaHCC>3 and brine, dried (MgSC ), filtered and solvent removed in vacuo to afford the desire compound.

Table 2: The following intermediates were made according to Method Q.

Method R: Formation of sulfonamides from aromatic sulfones

To a solution of sulfone (1.0 eq) and primary sulfonamide (1.1 - 2.0 eq) in polar aprotic solvent such as NMP (5-100 volumes) was added an inorganic base (3 eq) such as cesium carbonate and heated to 40-90 °C for 1-3 hrs. The reaction mixture was cooled to RT and diluted with water (50-100 volumes) and the mixture was washed with MTBE (100 volumes) and the aqueous was slowly acidified to pH 5 or lower using an appropriate acid such as HCI. The resulting precipitate was filtered to afford desired sulfonamide product. Table 3: The following intermediates were made according to Method R.

A/-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulf onamido)pyrimidin-4-yl)piperidine-4- carboxamide hydrochloride INTC235

This compound was prepared by Boc-deprotection with HCI of INTC234, [HPLC acidic], 513, (2.72).

4-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-/V-(5-(6-etho xypyrazin-2-yl)pyridin-2-yl)piperidine-

4-carboxamide hydrochloride INTC240

This compound was prepared by Boc-deprotection with HCI of INTC239, [UPLC Acidic], 525, (0.83); ¹ H NMR (DMSO-d6) 11.18 (s, 1 H), 10.39 (s, 1 H), 9.02 (d, J = 2.4 Hz, 1 H), 8.94 - 8.73 (m, 3H), 8.52 (dd, J = 8.8, 2.4 Hz, 1 H), 8.41 (s, 1 H), 8.26 (s, 1 H), 8.23 (s, 1 H), 8.19 (d, J = 8.8 Hz, 1 H), 4.47 (q, J = 7.0 Hz, 2H), 3.37 - 3.22 (m, 2H), 3.15 - 3.11 (m, 3H), 2.74 - 2.68 (m, 2H), 2.43 - 2.40 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.09 - 1.03 (m, 2H), 0.91 - 0.82 (m, 2H).

4-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-/V-(5-(6-cy clopropylpyrazin-2-yl)pyridin-2- yl)piperidine-4-carboxamide hydrochloride INTC245

This compound was prepared by Boc-deprotection with HCI of INTC244, [HPLC Acidic], 521 , (1.30); ¹ H NMR (DMSO-d6) 11.42 (s, 1 H), 10.23 (s, 1 H), 9.03 - 8.96 (m, 2H), 8.89 - 8.70 (m, 2H), 8.63 - 8.57 (m, 2H), 8.52 - 8.46 (m, 1 H), 8.21 (d, J = 8.8 Hz, 1 H), 6.89 (d, J = 5.7 Hz, 1 H), 3.29 - 3.07 (m, 5H), 2.53 (s, 2H), 2.29 - 2.22 (m, 1 H), 1.13 - 1.06 (m, 6H), 0.95 - 0.89 (m, 2H). 2H not observed potentially obscured broad H2O peak.

4-(4-(Cyclopropanesulfonamido)pyrimidin-2-yl)-/V-(5-(6-et hoxypyrazin-2-yl)pyridin-2- yl)piperidine-4-carboxamide hydrochloride INTC247

This compound was prepared by Boc-deprotection with HCI of INTC246, [HPLC Acidic], 521 , (1.30).

Method 13: t-BuOK mediated amide coupling from ester

A stirred solution of ester (1.0 eq) and amine (1.1 eq) in THF (10-50 volumes) and DMSO (5 volumes) was cooled to 0 °C under an inert atmosphere. To the reaction mixture was added a solution of f-BuOK (3.3 eq) as a solution THF (10-50 volumes) over 15-60 mins. After addition was complete the reaction was warmed to RT for 1 hr. Reaction was quenched by the addition of aqueous acid either acetic acid or dilute HCI (1 M) until acidic pH was achieved. The reaction was diluted with water and extracted with EtOAc. The organics were combined, dried (phase separator) and concentrated in vacuo. The crude product was purified by reverse or normal phase chromatography or a combination of both.

(4-(6-Ethoxypyrazin-2-yl)-2-fluorophenyl)methanol INTD87

Prepared as for INTD84 using (4-bromo-2-fluorophenyl)methanol (205 mg, 1.00 mmol) and 2- ethoxy-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazine (250 mg, 1.00 mmol) to afford (4- (6-ethoxypyrazin-2-yl)-2-fluorophenyl)methanol (260 mg, 0.995 mmol, quantitative yield) was isolated as a yellow gum. Rt 1.25 min (UPLC, acidic); m/z 249 (M+H) ⁺ (ES ⁺ ); ¹ H NM R (500 MHz, DMSO-d6) d 8.85 (s, 1 H), 8.26 (s, 1 H), 7.99 (dd, J = 8.0, 1.7 Hz, 1 H), 7.91 (dd, J = 1 1 .6, 1.7 Hz, 1 H), 7.66 - 7.57 (m, 1 H), 5.37 (t, J = 5.8 Hz, 1 H), 4.62 (d, J = 5.8 Hz, 2H), 4.49 (q, J = 7.0 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H).

4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzaldehyde INTD88

Prepared as for INTD85 using (4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)methanol INTD87 (1.00 g, 4.03 mmol) to afford 4-(6-ethoxypyrazin-2-yl)-2-fluorobenzaldehyde (448 mg, 1.78 mmol, 44% yield) as a colourless solid. Rt 0.67 min (UPLC 2, acidic); m/z 247 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (500 MHz, DMSO-d6) d 10.28 (s, 1 H), 8.98 (s, 1 H), 8.37 (s, 1 H), 8.22 - 8.13 (m, 2H), 7.99 (dd, J = 8.3, 7.3 Hz, 1 H), 4.52 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H).

Compounds of formula (l-a) - Examples

The synthesis of a number of known CTPS1 inhibitors is disclosed in WO2019/179652, WO2019/180244 and W02020/083975 (see compounds P1 to P225). Such compounds are made using general methods disclosed herein and represent further examples of compounds which are CTPS1 inhibitors. The full synthetic methods and characterising data for compounds P1 to P225 are provided in WO2019/179652, WO2019/180244 and W02020/083975, each of which is herein incorporated in its entirety by reference.

Amide formation

Method 1 : Amide coupling using HATU

To a stirred suspension of the acid or the potassium salt (1 eq, X= H or K) and DI PEA (6 eq) in DMF (15 vol) the aniline (1 eq) and HATU (1.5 eq) were added. The reaction was stirred at RT for 18 hrs then concentrated in vacuo. MeOH and 2M NaOH (aq) were added. The mixture was stirred for 30 min then concentrated in vacuo. The aqueous phase acidified to pH 6 with 1 M HCI (aq) and the product extracted into DCM. The organics were combined, dried (phase separator) and concentrated in vacuo.

The crude product was purified by reverse or normal phase chromatography or a combination of both.

A/-(4-(5-Chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfon amido)pyrimidin-4-yl)butanamide P1

Method 2: AIMe ₃ mediated amide coupling from ester

To an ice cooled solution of aniline (2 eq) in toluene (40 volumes) was added AIMe ₃ (2.0 M in heptane, 2 eq). The mixture was stirred at this temperature for 5 mins then at RT for 10 mins. To this solution was added ester (1 eq) in one portion and the resultant mixture heated and stirred at 80 °C for 2 hrs. The reaction mixture was cooled in an ice bath and carefully quenched with MeOH (10 volumes). After stirring for 20 mins the mixture was diluted in a mixture of DCM/MeOH (10 volumes), filtered through celite and the filtrate concentrated. The crude product was purified by reverse or normal phase chromatography.

1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(4-(6-ethox ypyrazin-2- yl)phenyl)cyclopentanecarboxamide P2

2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(4-(6-metho xypyrazin-2-yl)phenyl)-2- methylpropanamide P3

2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-/V-(4 -(5-(trifluoromethyl)pyridin-3- yl)phenyl)propanamide P4

2-Methyl-N-(2-methyl-4-(6-methylpyrazin-2-yl)phenyl)-2-(2-(m ethylsulfonamido)pyrimidin-4- yl)propanamide P5

Method 2b: DABALMe ₃ mediated amide coupling from ester

X = CH, N

Y = CR ₂ , N

z = CR ₂ , N

To a solution of ester (1 eq) and aniline (1.5 eq) in toluene (30 volumes) was added DABAL-Me ₃ (1.5 eq) and the resulting mixture was heated at 100 °C for 4 h. The reaction mixture was cooled to 0 °C and quenched by careful addition of 1 M HCI (aq, 20 volumes). The aqueous phase was extracted with EtOAc (3 x 20 volumes). The combined organics were washed with 1 M HCI (aq, 2 x 10 volumes), dried over Na ₂ SC>4, filtered and concentrated in vacuo. The crude product was purified by reverse or normal phase chromatography.

Method 3: Amide coupling from potassium salt using T3P

Pyridine (10 eq) followed by T3P (50 wt% in DMF, 2 eq) was added to a stirring solution of amine (1.1 eq) and potassium 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanoate (1 eq) in DMF (16 volumes). The resulting reaction was stirred at RT for 24 hrs. The crude reaction mixture was concentrated in vacuo then diluted with NH CI (sat. aq) and extracted with DCM. The combined organic extracts were dried (phase separator) and the solvent removed. The crude product was purified by reverse or normal phase chromatography. 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(2-fluoro-4 -(pyrazin-2-yl)phenyl)butanamide

P6

2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(trifl uoromethyl)pyridin-3- yl)phenyl)butanamide P7

2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(trifl uoromethyl)pyrazin-2- yl)phenyl)acetamide P8

Method 4: Amide coupling from lithium salt using T3P

/V-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(A/- (4- methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl)butanam ide INTC51

Method 5: NH-Amide formation via amide deprotection and/or decarboxylation

To a solution of the protected amide in DCM a mixture of TFA (88 eq) and triflic acid (1-6 eq) was added and the mixture left stirring at RT for 18-36 hrs and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel or by RP chromatography.

Method 6: Deprotection of Sulfonamide

Method 7: Sulfonylation from aromatic chloride

X = CH, N

Y = CR ₂ , N

Z = CR ₃ , N

2-Chloro-heteroaromatic intermediate (1 eq), sulfonamide (1 .2 eq) and base (2 eq) were dissolved in dioxane (40 volumes). The mixture was degassed (evacuated and backfilled with N ₂ x 3) then catalyst (10 mol%) was added. The resulting mixture was heated under nitrogen at 90 °C for 2 hrs. The mixture was cooled to RT, diluted with sat. NH4CI (aq, 80 volumes) and DCM (80 volumes). The phases were separated and the aqueous was extracted with further DCM (2 x 80 volumes). The combined organics were dried (MgSC ), filtered and concentrated in vacuo. The crude product was purified by normal phase chromatography or trituration using a suitable solvent.

Method 8: Amide coupling using 1-chloro-A/,/V,2-trimethylprop-1-en-1 -amine

1-Chloro-A/,/V,2-trimethylprop-1-en-1-amine (2 eq) was added to a solution of carboxylic acid (1 eq) in DCM (20 volumes). The reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated in vacuo and the residue redissolved in DCM (20 volumes) before addition of pyridine (2 ml.) followed by addition of the appropriate amine (1.1 eq). The reaction mixture was stirred at RT for 2 hrs. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 9: Suzuki ArBr

To a suspension of Ar1-Br (1 eq) in dioxane (10 volumes) was added arylboronic acid or ester (1 eq) and a solution of K ₂ CO ₃ (2 eq) in water (5 volumes). The resulting suspension was degassed (N2, 5 mins). PdCl2(dppf)-CH2Cl2 adduct or other appropriate catalyst (10 mol%) was added and the reaction mixture was stirred at 80 °C for 2 hrs. The reaction mixture was then cooled to RT. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 10: T3P with free acid

Pyridine (10 eq) followed by T3P (50 wt% in DMF, 2 eq) was added to a stirring solution of amine (1.1 eq) and carboxylic acid (1 eq) in DMF (16 volumes). The resulting reaction was stirred at RT for 24 hrs. The crude reaction mixture was concentrated in vacuo then diluted with NH ₄ CI (sat. aq) and extracted with DCM. The combined organic extracts were dried (phase separator) and the solvent removed. The crude product was purified by reverse or normal phase chromatography. Table 4: Compounds P9-P115, P117-P225

2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-is opropylpyrazin-2-yl)pyridin-2-yl)-2- methylpropanamide P116

A solution of 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-/V-(5 -(6-(prop-1-en-2- yl)pyrazin-2-yl)pyridin-2-yl)propanamide P122 (77 mg, 0.161 mmol) in MeOH/DCM (4: 1 , 10 mL) was hydrogenated using the H-Cube flow hydrogenation apparatus (10% Pd/C, 30x4 mm, Full hydrogen, 25 °C, 1 mL/min). The crude product was purified by chromatography on silica gel (12 g column, 50-100% EtOAc//so-hexane) to afford 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)- /V-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropana mide (21 mg, 0.043 mmol, 27% yield) as a white solid. Rt 2.22 mins (HPLC acidic); m/z 482 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (500 MHz, DMSO- d6) 5 11.23 (s, 1 H), 10.15 (s, 1 H), 9.10 (s, 1 H), 9.03 (dd, J = 2.4, 0.8 Hz, 1 H), 8.59 (d, J = 5.3 Hz, 1 H), 8.56 (s, 1 H), 8.52 (dd, J = 8.8, 2.5 Hz, 1 H), 8.21 (dd, J = 8.8, 0.8 Hz, 1 H), 7.19 (d, J = 5.3 Hz, 1 H), 3.23 - 3.10 (m, 2H), 1.61 (s, 6H), 1.32 (d, J = 6.9 Hz, 6H), 1.04 - 0.97 (m, 2H), 0.80 - 0.72 (m, 2H).

The following compounds were prepared using the methods described herein and below. Numbering of certain intermediates refers either to intermediates disclosed herein, or intermediates disclosed in WO2019/179652, WO2019/180244 and/or W02020/083975. 1 -(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethoxy pyrazin-2-yl)pyridin-2-yl)-4- oxocyclohexanecarboxamide P226

A solution of HCI (1 N in water) (17.19 ml_, 17.19 mmol) was added into a stirring solution of 8-(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethoxypyra zin-2-yl)pyridin-2-yl)-1 ,4- dioxaspiro[4.5]decane-8-carboxamide P244 (1.0 g, 1.72 mmol) in THF (30 ml_). The resulting reaction mixture was stirred at 30 °C for 14 days. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 ml.) and brine (100 ml_). The organic extract was dried (MgSCU), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc//so-hexanes) to afford 1-(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethoxypyra zin-2-yl)pyridin-2-yl)-4- oxocyclohexanecarboxamide (414 mg, 0.762 mmol, 44% yield) as a white solid. Rt 2.03 min (HPLC acidic); m/z 538 (M+H) ⁺ (ES ⁺ ). Ή NMR (500 MHz, DMSO-d6) d 1 1.32 (s, 1 H), 10.33 (s, 1 H), 9.03 (d, J = 2.5 Hz, 1 H), 8.85 (s, 1 H), 8.64 (d, J = 5.3 Hz, 1 H), 8.51 (dd, J = 8.8, 2.5 Hz, 1 H), 8.31 - 8.20 (m, 2H), 7.30 (d, J = 5.3 Hz, 1 H), 4.48 (q, J = 7.0 Hz, 2H), 3.28-3.21 (m, 1 H), 2.78-

2.68 (m, 2H), 2.60-2.41 (m, 4H (obscured by DMSO)), 2.39 - 2.32 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H), 110-1 .02 (m, 2H), 0.92-0.82 (m, 2H).

1 -(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethoxy pyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexane-1-carboxamide

NaBH ₄ (10.6 mg, 0.28 mmol) was added into a stirring suspension of 1 -(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethoxypyra zin-2-yl)pyridin-2-yl)-4- oxocyclohexanecarboxamide P226 (100 mg, 0.186 mmol) in EtOH (20 ml.) and stirred at RT for 3 hrs. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on RP Flash C18 (24 g column, 0-100% MeCN/Water O.1 % formic acid) to afford two diastereoisomers of the title compound. P227 - First eluting peak from column

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethox ypyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide (26 mg, 0.048 mmol, 26% yield) as a white solid. Rt 1 .85 min (HPLC, acidic); m/z 540 (M+H) ⁺ (ES ⁺ ); Ή NMR (500 MHz, DMSO-d6) d 11.24 (s, 1 H), 10.05 (s, 1 H), 9.06 - 8.98 (m, 1 H), 8.85 (s, 1 H), 8.57 (d, J = 5.3 Hz, 1 H), 8.51 (dd, J = 8.8, 2.5 Hz, 1 H), 8.26

(s, 1 H), 8.23 - 8.20 (m, 1 H), 7.19 (d, J = 5.3 Hz, 1 H), 4.58 (d, J = 4.7 Hz, 1 H), 4.48 (q, J = 7.0 Hz, 2H), 3.56-3.45 (m, 1 H), 3.29-3.22 (m, 1 H), 2.60 (d, J = 13.6 Hz, 2H), 1.91 - 1.77 (m, 4H), 1 .52 - 1.37 (m, 5H), 1.07-0.99 (m, 2H), 0.88-0.78 (m, 2H).

P228 - Second eluting peak from Column

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-et hoxypyrazin-2-yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide (23 mg, 0.042 mmol, 22% yield) as a white solid. Rt 1 .95 min (HPLC, acidic); m/z 540 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (500 MHz, DMSO-d6) d 11.31 (s, 1 H), 9.75 (s, 1 H), 9.02 (d, J = 2.4 Hz, 1 H), 8.83 (s, 1 H), 8.62 (s, 1 H), 8.48 (dd, J = 8.8, 2.5 Hz, 1 H), 8.25 (s, 1 H), 8.13 (d, J = 8.8 Hz, 1 H), 7.29 (s, 1 H), 4.51 - 4.44 (m, 3H), 3.70-3.62 (m, 1 H), 3.29-3.20 (m, 1 H), 2.22-2.11 (m, 2H), 1.80-1.68 (m, 2H), 1.41-1.29 (m, 7H), 1.11-1.05 (m, 2H), 0.96-0.88 (m,

2H).

1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethyl amino)-/V-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)cyclohexane-1-carboxamide

NaH(BOAc) ₃ (1 18 mg, 0.558 mmol) was added into a suspension of 1 -(2- (cyclopropanesulfonamido)pyrimidin-4-yl)-A/-(5-(6-ethoxypyra zin-2-yl)pyridin-2-yl)-4- oxocyclohexanecarboxamide (100 mg, 0.186 mmol) P226 and dimethylamine (2M in THF) (0.93 mL, 1.86 mmol) in DCM (10 mL) and the resulting reaction mixture was stirred at RT for 18 hrs. The reaction mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (Acidic prep method (5-95% MeCN in water) to afford two diastereoisomers of the title compound.

P229 - First eluting peak from Prep HPLC

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylami no)-A/-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)cyclohexane-1-carboxamide (22 mg, 0.037 mmol, 20% yield) as a white solid. Rt 1.40 min (HPLC, acidic); m/z 567 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (500 MHz, DMSO-d6) d 10.17 (s, 1 H), 9.02 (d, J = 2.4 Hz, 1 H), 8.84 (s, 1 H), 8.60 - 8.44 (m, 2H), 8.25 (s, 1 H), 8.22 - 8.20 (m, 2H), 7.09 (d, J = 5.3 Hz, 1 H), 4.48 (q, J = 7.0 Hz, 2H), 3.28-3.20 (m, 1 H), 2.72 (d, J = 13.4 Hz, 2H), 2.32 (s, 6H), 2.25 (s, 1 H), 1.91 (d, J = 12.3 Hz, 2H), 1.79 (t, J = 12.6 Hz, 2H), 1.51 (q, J = 12.2 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H), 1.03-0.98 (m, 2H), 0.87 - 0.73 (m, 2H). P230 - Second eluting peak from Prep HPLC

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylami no)-A/-(5-(6-ethoxypyrazin-2- yl)pyridin-2-yl)cyclohexane-1-carboxamide (26 mg, 0.045 mmol, 24% yield) as a white solid. Rt 1.48 min (HPLC, acidic); m/z 567 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (500 MHz, DMSO-d6) d 9.65 (s, 1 H), 9.02 (d, J = 2.4 Hz, 1 H), 8.83 (s, 1 H), 8.55 (d, J = 5.2 Hz, 1 H), 8.48 (dd, J = 8.8, 2.4 Hz, 1 H), 8.25 (s, 1 H), 8.20 (s, 1 H), 8.10 (d, J = 8.8 Hz, 1 H), 7.19 (d, J = 5.3 Hz, 1 H), 4.47 (q, J = 7.0 Hz, 2H),

3.25-3.18 (m, 1 H), 2.78-2.67 (m, 2H), 2.48-2.39 (m, 1 H), 2.26 (s, 6H), 2.02 (t, J = 12.4 Hz, 2H), 1.87-1.77 (m, 2H), 1.42 - 1.29 (m, 5H), 1.07-1.00 (m, 2H), 0.97 - 0.85 (m, 2H).

Method 11 : /-PrMgCI mediated amide coupling from ester

To an ice cooled solution of aniline (1.1 eq) in THF (10-50 volumes) was added /-PrMgCI (2.0 M in THF, 2.0 eq) dropwise over 5-15 mins to maintain an internal temperature of less than 10 °C. The reaction mixture was warmed to RT over 45 mins, then a solution of ester (1 .0 eq) in THF (5- 20 volumes) was added dropwise over 5 - 15 min. The reaction mixture was stirred at ambient temperature for 5-15 mins then further /-PrMgCI (2.0 M in THF, 2.0 eq) was added dropwise over 5-20 min. The reaction mixture was stirred at RT for 30 mins and then the solution was slowly poured into 1 M HCI (aq) and extracted with EtOAc. The organics were combined, dried (phase separator) and concentrated in vacuo. The crude product was purified by reverse or normal phase chromatography or a combination of both.

Reductive amination General method:

Method 12: Reductive amination

To a suspension of aldehyde (1.5 eq) and amine (HCI salt can be used, 1.0 eq) in an organic solvent such as DCM (2-10 volumes) was added AcOH (1.0 eq) at RT and stirred for up to 1 hr. NaBH(OAc) ₃ (1-2 eq) was then added and stirring continued for up to 24 hrs and monitored by LCMS. On completion 1 % NH ₃ in MeOH (10 volumes) was added and the volatiles removed in vacuo. The crude product was purified by reverse or normal phase chromatography or a combination of both.

/V-(4-(1-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)pro pyl)pyrimidin-2- yl)cyclopropanesulfonamide P235

A suspension of 4-(6-ethoxypyrazin-2-yl)-2-fluorobenzaldehyde INTD88 (259 mg, 1.05 mmol) and /V-(4-(1-aminopropyl)pyrimidin-2-yl)cyclopropanesulfonamide INTC162 (300 mg, 1.05 mmol) in DCM (2 mL) was treated with AcOH (0.065 ml_, 1.14 mmol) and stirred for 15 mins then NaBH(OAc) ₃ (223 mg, 1.06 mmol) was added and the reaction mixture was stirred at RT for 3 hrs. To the reaction mixture was added 1 % NH ₃ in MeOH (2 mL) and the volatiles were removed in vacuo. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 15-70% MeCN/10 mM ammonium bicarbonate). The crude material was purified by capture and release on SCX (1 g) eluting with MeOH (20 mL) then removing product with 1 % NH ₃ in MeOH (30 mL). The crude material was finally purified a second time by chromatography on RP Flash C18 (12 g cartridge, 10-50% MeCN/10 mM Ammonium Bicarbonate) to afford A/-(4-(1-((4-(6- ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propyl)pyrimidin-2- yl)cyclopropanesulfonamide (20 mg, 0.031 mmol, 3% yield) as a yellow gum. Rt 2.02 min (HPLC, basic); m/z 487 (M+H) ⁺ (ES ⁺ ); ¹ H NMR (500 MHz, DMSO-d6) d 8.85 (s, 1 H), 8.27 - 8.26 (m, 2H), 7.96 (d, J = 7.8 Hz, 1 H), 7.87 (d, J = 11.4 Hz, 1 H), 7.67 - 7.58 (m, 1 H), 7.23 (d, J = 5.1 Hz, 1 H), 5.38 (t, J = 5.7 Hz, 1 H), 4.62 (d, J = 5.8 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 3.52 - 3.50 (m, 1 H), 1.71 - 1.67 (m, 2H), 1.41 (t, J =

7.0 Hz, 3H), 1.13 - 1.09 (m, 2H), 1.04 - 1.01 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). Two exchangeable protons not observed.

Table 5: Preparation methods and characterisation data of certain intermediates and examples

P242 onwards

Compounds of formula (l-b) - Intermediates

The synthesis of intermediates INTA1 to INTA117 and INTB1 to INTB120 is disclosed in W02019/106156, which is herein incorporated in its entirety by reference, and uses the general methods shown below.

Method A: Formation of thiazole amines from ketoesters

To a solution of ketoester (1 eq) in an alcoholic solvent such as MeOH or EtOH (1 volume) at 0 °C was added bromine (1.5 eq) dropwise over 10 mins. The reaction was stirred at 0 °C for 10 mins. The reaction mixture was then heated at 30 °C for 2 hrs. After cooling to RT the reaction mixture was diluted with water. The product was extracted using an appropriate solvent such as EtOAc. The combined organics were dried (Na ₂ SC>4) and concentrated in vacuo. The resulting compound was dissolved in alcoholic solvent such as MeOH or EtOH (1 volume) and thiourea (1 eq) was added. The reaction mixture was heated at 40 °C for 1 hr, then stirred at RT for 18 hrs. The reaction mixture was concentrated in vacuo and purified by normal phase chromatography or via trituration with an appropriate solvent.

Method B: Formation of sulfonamides from sulfonyl chlorides

A solution of amine (1.0 eq) and appropriate sulfonyl chloride (1.1 eq) in pyridine (3M volumes) was warmed to 40 °C and stirred for 18 hrs. The reaction mixture was purified by normal or reverse phase chromatography or via trituration with an appropriate solvent.

Method C: Formation of sulfonamides from heterocyclic halides

A suspension of (l /^fi /VI .AC-dimethylcyclohexane-l , 2-diamine (0.2 eq), bromothiazole intermediate (1 eq), alkylsulfonamide (1 eq), and K2CO3 (1.1 eq) in dioxane (10 volumes) at 40 °C was degassed (N ₂ , 5 mins) then copper(l) iodide (0.1 equiv.) was added. The solution was again degassed (N ₂ , 5 mins) before being warmed to 80 °C. The reaction was progressed for 2 hrs before being allowed to cool to RT. 1M HCI (aq) was added and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried (Na ₂ SC>4), filtered and concentrated. The crude material was purified by normal phase chromatography.

Method D: Formation of acids from esters

To a solution of ester (1.0 eq.) in THF/MeOH (2:1) was added a solution of appropriate base (2.0 eq. of LiOH or NaOH aq solutions at 1-2M). The reaction was stirred at RT or with heating up to 50 °C. The reaction was concentrated in vacuo to half volume and was acidified with 1 M HCI. The product was extracted using an appropriate organic solvent (EtOAc). The combined organics were dried (Na ₂ S04) and concentrated in vacuo to give the desired compound.

Aniline intermediate preparation

Method E: Suzuki coupling of halo anilines with heteroaromatic boronates

2 = B(UM) ₂ , tspin

X = Br, Cl

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 is purified by column chromatography. Method F: Suzuki coupling of heteroaromatic halides with aniline boronates

Z = Br, Cl

X = B(OH) _2I Bpin

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 is purified by column chromatography.

Method G: Telescoped boronate formation and Suzuki coupling

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 (ISI ₂ , 5 mins). PdCI ₂ (dppf)-DCM adduct (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 C0 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.

Method H: Suzuki coupling of halo pyrimidines with heteroaromatic boronates

Z = B(OH) ₂ , Bpin

A solution of 5-bromo-2-chloropyrimidine (1.2 eq) and Ar2-Z (1 eq) in solvent (3 volumes) and base (4 eq) was degassed (N ₂ , 5 min) and heated to 40 °C whereupon Pd catalyst (5 mol%) was added and the reaction mixture further degassed (N2, 5 min) before being heated to 90 °C for up to 24 hrs. The reaction mixture was allowed to cool to RT and an aqueous work-up was performed. In general, the desired compound is purified by column chromatography.

Compounds of formula (l-b) - Examples

The synthesis of a number of known CTPS1 inhibitors is disclosed in W02019/106156 (see compounds T1 to T465). Such compounds are made using general methods disclosed herein and represent further examples of compounds which are CTPS1 inhibitors. The full synthetic methods and characterising data for compounds T1 to T465 are provided in W02019/106156.

Amide couplings

1 - Activating

Method 1 : HATU (1.2 eq) was added to a solution of appropriate acid (1 eq), amine (1 eq) and DIPEA (3 eq) in DCM (10 volumes) at RT. The reaction was stirred at RT for 18 hrs. The solvent was removed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 1b: 1-chloro-N,N,2-trimethylprop-1-en-1-amine (2 eq) was added to a solution of 2- (2- (cydopropanesulfonamido)thiazol-4-yl)-2-methylpropanoic acid (1 eq) in DCM (20 volumes). The reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated in vacuo and the residue redissolved in pyridine (2 mL) before addition of the appropriate amine (1.1 eq). The reaction mixture was stirred at RT for 2 hrs. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 1c: T3P (50% in EtOAc, 2.5 eq) was added to a solution of appropriate acid (1 eq), amine (1 eq) and pyridine (3 eq) in a mixture of EtOAc (20 volumes) and DMF (10 volumes). The reaction was stirred for 1 hr at RT. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 1e: Thionyl chloride (2 eq) was added to a solution of an appropriate acid (1 eq) in toluene (20 volumes) at 70 °C. The reaction mixture was stirred at 70 °C for 1 hr. The reaction mixture was cooled to RT and concentrated to dryness. The resulting intermediate was redissolved in EtOAc (10 volumes) and a solution of amine (1.1 eq) in EtOAc (20 volumes) was added followed by triethylamine (2 eq). The reaction mixture was stirred at 40 °C for 16 hrs. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Suzuki couplings

Method 2: Suzuki coupling of Ar1 -Bromide with heteroaromatic boronates

To a suspension of Ar1-Br (1 eq) in dioxane (10 volumes) was added arylboronic acid or ester (1 eq) and 2M K ₂ PO ₄ (2 eq). The resulting suspension was heated to 60 °C and degassed (N ₂ , 5 mins). Pd 170 or other appropriate catalyst (5 mol %) was added and the reaction mixtures were stirred at 60 °C for 16 hrs. The reaction mixture was then cooled to RT. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 2b: Suzuki coupling of Ar1 -B(OR) ₂ with heteroaromatic halides

PdCl2(dppf)-CH ₂ Cl2 (10 mol %) or other appropriate catalyst was added to a degassed (ISI ₂ , 5 mins) solution of Ar1-B(OR) ₂ (1 eq), Ar2-halide (1.2 eq) and K2CO3 (5 eq) in dioxane (10 volumes) and water (15 volumes). The solution was then degassed further (N ₂ , 5 mins) and then heated to 90 °C for 1-2 hrs. The reaction mixture was allowed to cool to RT. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 3: Coupling of primary amides with 2-chloropyrimidines

To a solution of amide (1 eq) and 2-chloropyrimidine (1 eq) in dioxane (30 volumes) was added CS2CO3 (1.5 eq). The reaction mixture was heated to 60 °C and degassed (N ₂ , 5 mins). Pd 177 (10 mol %) was added to the reaction mixture and the temperature was increased to 90 °C. After 2 hrs, the reaction was stirred for 16 hrs at 60 °C. The reaction mixture was cooled to RT and an aqueous work up was performed. The crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

N-([1 , T-biphenyl]-4-yl)-2-(2-(methylsulfonamido)thiazol-4-yl)aceta mide T1

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(5-(py razin-2-yl)pyridin-2-yl)butanamide

T3

Prepared as Method 1 b from INTB41 and 5-(pyrazin-2-yl)pyridin-2-amine (Cheng et al., 2016). 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(p yrimidin-2-yl)phenyl)propanamide

T4

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3- yl)phenyl)butanamide T5

The racemate T5 (180 mg) was separated by chiral preparative HPLC (Gilson, iso-hexane + 0.2% TFA: DCM, 4: 1 with EtOH 30%). A salt exchange (TFA to HCI) was undertaken by adding 1.25M HCI (EtOFI, 2 mL x 5) and removing solvent to afford:

Peak A: Stereochemistry of product was not assigned

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin -3-yl)phenyl)butanamide.FICI T6.

Peak B: Stereochemistry of product was not assigned

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3- yl)phenyl)butanamide.HCI T7.

N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfona mido)thiazol-4-yl)butanamide T8

Prepared as Method 1 from INTB38.

The racemate T8 was separated by chiral preparative HPLC (30% EtOH vs 4:1 isoehexanes +0.2%TFA: DCM IA column). A salt exchange (TFA to HCI) was undertaken by adding 1.25M HCI (EtOH, 2 mL x 5) and removing solvent to afford:

Peak A: Stereochemistry of product was not assigned

N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulf onamido)thiazol-4-yl)butanamide.HCI.

Peak B: Stereochemistry of product was not assigned

N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfona mido)thiazol-4-yl)butanamide.HCI T10.

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(p yrimidin-5-yl)phenyl)butanamide

T11 Prepared as Method 1 from INTB40.

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(p yridin-3-yl)phenyl)butanamide T12

Prepared as Method 1 from INTB40 and 4-(pyridin-3-yl)aniline (Xing-Li et al, 2009)

The racemate T12 was separated by chiral preparative HPLC (Gilson, iso-hexane + 0.2% TFA: DCM, 4: 1 with EtOH 30%). A salt exchange (TFA to HCI) was undertaken by adding 1.25M HCI (EtOH, 2 mL x 5) and removing solvent to afford:

Peak A: Stereochemistry of product was not assigned

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4 -(pyridin-3-yl)phenyl)butanamide.HCI

T13.

Peak B: Stereochemistry of product was not assigned

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4 -(pyridin-3-yl)phenyl)butanamide.HCI

T14.

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-methoxyp yridin-3-yl)phenyl)-2- methylpropanamide T15

N-(2-chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfon amido)thiazol-4-yl)acetamide T16 2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2-methy l-N-(4-(6-(trifluoromethyl)pyrazin-

2-yl)phenyl)propanamide T17

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4 -(pyrimidin-5-yl)phenyl)propanamide

T18

6-(4-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpr opanamido)phenyl)-N,N- dimethylpyrazine-2-carboxamide T19

N-(5-(5-cyanopyridin-3-yl)pyrimidin-2-yl)-2-(2-(cyclopropane sulfonamido)thiazol-4-yl)-2- methylpropanamide T20

N-([1 , 1 '-biphenyl]-4-yl)-2-(5-chloro-2-(cyclopropanesulfonamido)thi azol-4-yl)acetamide T21 2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethynylp yrazin-2-yl)phenyl)butanamide T22

Table 6: Compounds T23-T322, T422-T443 and T445-T465.

Method 2c: Telescoped boronate formation and Suzuki coupling on sulfonamide scaffold

A suspension of Ar1-Br (1 eq), bispin (1.1 eq) and KOAc (2 eq) in dioxane (50 volumes) was degassed (N ₂ , 5 mins, x 3) then charged with PdCl2(dppf)-DCM adduct (5 mol %) and again degassed (N2, 5 mins, x 3). The reaction mixture was heated to 90 °C for 1 hr and then the reaction was allowed to cool to RT. Ar2-Z (1 eq) and 2M K ₂ CO ₃ (aq, 2 eq) were added and the reaction was then heated to 90 °C for 18 hrs. The reaction was allowed to cool to RT, an aqueous work up was performed and the crude compound was purified by normal phase chromatography.

2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6- ethoxypyrazin-2- yl)phenyl)acetamide T325

2-acetamido-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4 -(6-ethoxypyrazin-2- yl)phenyl)acetamide T326

methyl (1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-((4-(6-ethoxy pyrazin-2-yl)phenyl)amino)-

2-oxoethyl)carbamate T327

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino )-N-(4-(6-ethoxypyrazin-2- yl)phenyl)acetamide T328

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypy razin-2-yl)phenyl)-4- hydroxybutanamide T329

The racemate T410 was separated by chiral preparative HPLC [Chiralpak® IB (Daicel Ltd.) column (4.6 mm x 25 mm), flow rate 0.5 mL min ¹ eluting with a mixture of (30% of ethanol) ethanol in heptane + 0.2% Et ₂ NH, UV detection at 254 nm followed by SCX (300 mg) purification (elution with MeOH) to afford:

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypy razin-2-yl)phenyl)-2- methoxyacetamide T410

The racemate T410 was prepared using Method 1 b was separated by chiral preparative HPLC using a Diacel Chiralpak IB column (30% EtOH (0.1 % DEA) in iso-hexane (0.2% DEA) to afford:

Peak 1 : Stereochemistry of product was unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethox ypyrazin-2-yl)phenyl)-2- methoxyacetamide T330.

Peak 2: Stereochemistry of product was unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypy razin-2-yl)phenyl)-2- methoxyacetamide T331. Table 7: Compounds T332-T416

2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-A/-(4-(6-(eth ylamino)pyrazin-2- yl)phenyl)butanamide T444

2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-/V-(5-(6 -(trifluoromethyl)pyrazin-2- yl)pyridin-2-yl)acetamide hydrochloride T417

2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-/V-(4-(6 -ethoxypyrazin-2-yl)-2- fluorophenyl)acetamide hydrochloride T419

2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-A/-(2-fl uoro-4-(6-(trifluoromethyl)pyrazin-2- yl)phenyl)acetamide T418 2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino )-A/-(2-fluoro-4-(6- (trifluoromethyl)pyrazin-2-yl)phenyl)acetamide T420

2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino )-/V-(4-(6-ethoxypyrazin-2-yl)-2- fluorophenyl)acetamide T421

N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)-2-methylpro pan-2-yl)thiazol-2- yl)cyclopropanesulfonamide T466

LiAlhU (0.870 mL, 1.74 mmol) was added into a solution of 2-(2- (cyclopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyridi n-3-yl)phenyl)-2-methylpropanamide T42 (200 mg, 0.434 mmol) in THF (20 mL, 0.434 mmol) and the resulting solution was stirred at RT for 16 hrs. The reaction mixture was quenched with sat. NH CI ( aq , 50 mL) and extracted with EtOAc (3 x 50 mL). The organic extract was dried (MgSCL), filtered and solvent removed in vacuo. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 5-100% MeCN/10 mM ammonium bicarbonate) to afford N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)- 2-methylpropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide (23 mg, 0.050 mmol, 12 % yield) as a white solid. Rt 1.83 min (HPLC basic); m/z 447 (M+H) ⁺ (ES ⁺ ). ¹ H NMR (500 MHz, DMSO-d6) d 12.57 (s, 1 H), 8.82 (d, J = 2.4 Hz, 1 H), 8.47-8.43 (m,1 H), 8.00-7.95 (m, 1 H), 7.46 (dd, J = 13.4,

2.2 Hz, 1 H), 7.39 (dd, J = 8.0, 4.7 Hz, 1 H), 7.35-7.31 (m, 1 H), 6.92 (t, J = 8.9 Hz, 1 H), 6.40 (s, 1 H), 5.50 (t, J = 4.4 Hz, 1 H), 3.36-3.28 (m, 2H (obscured by water peak)), 2.56 - 2.51 (m, 1 H, (obscured by DMSO peak)), 1.27 (s, 6H), 0.90-0.79 (m, 4H).

Compounds of formula (l-c) - Intermediates

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.

The synthesis of INTE1 to INTE39 and INTF1 to INTF53 is disclosed in W02019/106146 and uses the general methods disclosed below.

Method A: Reductive amination

A solution of aldehyde/ketone (1 eq.) in THF was treated with AcOH (1 eq ), amine (1 eq.) and a reducing agent such as STAB (1.2 eq.) and stirred at RT for 1 hr. The reaction mixture was quenched by addition of MeOH then loaded directly on to SCX (1 g/mmol of substrate), washed with MeOH and the product was eluted with 1 M NH ₃ in MeOH. The crude product was then concentrated onto silica and purified by normal phase chromatography.

Method B: Benzylamine deprotection (TFA)

Benzylamine derivative (1 eq.) was dissolved in TFA (50 eq.) and heated to 70 °C for 1 - 24 hrs. The reaction was allowed to cool to RT, then was loaded on to SCX (1 g/mmol of substrate) and washed with MeOH. The required compound was eluted with 1 % NH3 in MeOH. Method D: Ester deprotection with TFA

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 E: Ester deprotection with base

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 18hrs. The organic solvents were removed in vacuo then acidified with 1 M HCI and extracted with EtOAc. The organic phases were combined, dried (Na ₂ S0 ), filtered and concentrated. The products were used directly in the next step with no further purification undertaken.

Method F: Potassium salt formation

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 undertaken.

Compounds of formula (l-c) - Examples The synthesis of a number of known CTPS1 inhibitors is disclosed in WO2019/106146 (see compounds R1 to R93). Such compounds are made using general methods disclosed herein and represent further examples of compounds which are CTPS1 inhibitors. The full synthetic methods and characterising data for compounds R1 to R93 are provided in W02019/106146, which is herein incorporated in its entirety by reference.

Method 1 : Amide coupling

Method 1 a: HATU (1.2 eq.) was added to a solution of appropriate acid (1 eq.), amine (1 eq.) and DIPEA (3 eq.) in DMF (10 volumes) at RT. The reaction was stirred at RT for 18 hrs. The solvent was removed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 1 b: 1-chloro-/V,/\/,2-trimethylprop-1-en-1-amine (2 eq.) was added to a solution of appropriate acid (1 eq.) in DCM (20 volumes). The reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated in vacuo and the residue dissolved in DCM (20 volumes) before addition of DIPEA (3 eq.) and the appropriate amine (1 eq). The reaction mixture was stirred at RT for 2 hrs. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 1c: T3P (50wt% in EtOAc, 2.5 eq.) was added to a solution of appropriate acid (1 eq.), amine (1 eq.) and pyridine (3 eq.) in a mixture of EtOAc (20 volumes) and DMF (10 volumes). The reaction was stirred for 1 hr at RT. An aqueous work up was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 2a: Suzuki [ArB(OR)2 core]

PdCl2(dppf)-CH2Cl2 (10 mol %) or other appropriate catalyst was added to a degassed (N2, 5 mins) solution of Ar1-B(OR) ₂ (1 eq.), Ar2-halide (1 eq.) and K ₂ CO ₃ (3 eq.) in dioxane (10 volumes) and water (1 volumes). The solution was then degassed further (N ₂ , 5 mins) and heated to 90 °C for 1-2 hrs. The reaction mixture was allowed to cool to RT. An aqueous workup was performed and the crude product was purified by normal phase chromatography, reverse phase chromatography or trituration from an appropriate solvent.

Method 2b: Telescoped Miyaura Borylation/Suzuki Protocol

Z = Br, Cl

A suspension of Ar1-Br (1 eq ), Bispin (1.1 eq.) and KOAc (2 eq.) in dioxane (50 volumes) was degassed (N2) then charged with PdCl2(dppf).CH2Cl2 (5 mol %) and again degassed (N2). The reaction mixture was heated to 90 °C for 1-24 hrs, recharging the Pd-catalyst if required. On formation of the boronate ester the reaction was allowed to cool to RT. Ar2-Z (1 eq.) and 2 M K2CO3 (aq, 2 eq.) were added, degassed (N2) and the reaction was then heated to 90 °C for 18 hrs. The reaction was allowed to cool to RT, an aqueous work up was performed and the crude compound was purified by normal phase chromatography.

Representative for Method 1 a

A/-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(pyri din-3-yl)benzamide R1

Representative for Method 1 b

N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-( trifluoromethyl)pyridin-3- yl)benzamide R2 The racemic mixture R2 was separated by chiral preparative HPLC using chiral method A. A salt exchange (TFA to HCI) was undertaken by adding 1.25 M HCI (EtOH, 2 mL x 5) and removing solvent to afford:

Peak 1 : Stereochemistry of product was not defined R3

A/-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5- (trifluoromethyl)pyridin-3- yl)benzamide. HCI R3.

Peak 2: Stereochemistry of product was not defined R4

/V-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5- (trifluoromethyl)pyridin-3- yl)benzamide. HCI R4.

Representative for Method 1 c

A/-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6- (trifluoromethyl)pyrazin-2- yl)benzamide R5

Representative for Method 2a

A/-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)- 4-(6-ethoxypyrazin-2-yl)-2- fluorobenzamide R6

Representative for Method 2b

/V-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)- 4-(6-ethoxypyrazin-2-yl)-2- methoxybenzamide R7 Table 8: Compounds R8 to R93

A/-(4-(2-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino) propan-2-yl)thiazol-2- yl)cyclopropanesulfonamide R94

A solution of 4-(6-ethoxypyrazin-2-yl)-2-fluorobenzaldehyde (75 mg, 0.305 mmol) INTF57 and N- (4-(2-aminopropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide INTE14 (80 mg, 0.305 mmol) in DCM (2 mL) was treated with AcOH (0.02 ml_, 0.35 mmol) and stirred for 1 hr whereupon sodium triacetoxyborohydride (70 mg, 0.33 mmol) was added and the reaction mixture was stirred at RT for 4 hrs. The reaction mixture was treated with 1 % NH ₃ in MeOH (2 mL) and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 15- 70% MeCN/10 mM Ammonium Bicarbonate) to /V-(4-(2-((4-(6-ethoxypyrazin-2-yl)-2- fluorobenzyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulf onamide (30 mg, 0.056 mmol, 18% yield) was isolated as a colourless solid. Rt 0.95 min (UPLC acidic); m/z 492 (M+H) ⁺ (ES ⁺ ). ¹ H NMR (500 MHz, DMSO-d6) d 8.86 - 8.81 (m, 1 H), 8.28 - 8.18 (m, 1 H), 7.96 - 7.93 (m, 1 H), 7.91 - 7.82 (m, 1 H), 7.67 - 7.50 (m, 1 H), 6.49-6.14 (v. br. m., 3H), 4.49 (q, J = 7.1 Hz, 2H), 3.59 - 3.48 (m, 2H), 2.50 - 2.39 (m, 1 H), 1.48 - 1.14 (m, 9H), 0.91 - 0.59 (m, 4H).

A/-(4-(2-(((5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amin o)propan-2-yl)thiazol-2- yl)cyclopropanesulfonamide R95

Prepared as for R94 using 5-(6-ethoxypyrazin-2-yl)picolinaldehyde (70 mg, 0.305 mmol) INTF55 and /V-(4-(2-aminopropan-2-yl)thiazol-2-yl)cyclopropanesulfonami de INTE14 (80 mg, 0.305 mmol) to afford A/-(4-(2-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amin o)propan-2-yl)thiazol- 2-yl)cyclopropanesulfonamide (36 mg, 0.073 mmol, 24% yield) as a red solid. Rt 0.81 min (UPLC acidic); m/z 475 (M+H) ⁺ (ES ⁺ ). ¹ H NMR (500 MHz, DMSO-d6) d 9.21 (d, J = 2.3 Hz, 1 H), 8.88 (s, 1 H), 8.44 (dd, J = 8.2, 2.4 Hz, 1 H), 8.30 (s, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 6.50 (s, 1 H), 4.49 (q, J = 7.0 Hz, 2H), 3.68 (s, 2H), 2.59 - 2.53 (m, 1 H), 1.45 - 1.37 (m, 9H), 0.92 - 0.82 (m, 4H), 2 x N-H not observed.

Biological Examples Biological Example 1 - Human CTPS1 Enzyme Inhibition

The enzyme inhibitory activities of compounds invented against the target of interest were determined using the ADP-Glo™ Max assay (Promega, UK). Assays for human CTPS1 were performed in 1x assay buffer containing 50mM Tris, 10mM MgCh, 0.01 % Tween-20, pH to 8.0 accordingly. Finally, immediately before use, L-cysteine was added to the 1x assay buffer to a final concentration of 2mM. All reagents are from Sigma-Aldrich unless specified otherwise. Human full length active C-terminal FLAG-HiSs-tag CTPS1 (UniProtKB - P17812, CTPS1 [1-591]- GGDYKDDDDKGGHHHHHHHH (CTPS1[1-591]-SEQ ID NO: 1)) was obtained from Proteros biostructures GmbH.

Assay Procedure

3x human CTPS1 protein was prepared in 1x assay buffer to the final working protein concentration required for the reaction. A 2uL volume per well of 3x human CTPS1 protein was mixed with 2uL per well of 3x test compound (compound prepared in 1x assay buffer to an appropriate final 3x compound concentration respective to the concentration response curve designed for the compounds under test) for 10 minutes at 25°C. The enzymatic reaction was then initiated by addition of a 2uL per well volume of a pre-mixed substrate mix (UltraPure ATP from ADP-Glo™ Max kit (0.31 mM), GTP (0.034mM), UTP (0.48mM) and L-glutamine (0.186mM)) and the mixture was incubated for an appropriate amount of time within the determined linear phase of the reaction at 25°C under sealed plate conditions with constant agitation at 500 revolutions per minute (rpm). ADP-Glo™ Max reagent was added for 60 minutes (6pL per well) and subsequently ADP-Glo™ Max development reagent was added for 60 minutes (12uL per well) prior to signal detection in a microplate reader (EnVision® Multilabel Reader, Perkin Elmer). Following each reagent addition over the course of the assay, assay plates were pulse centrifuged for 30 seconds at 500rpm.

In all cases, the enzyme converts ATP to ADP and the ADP-Glo™ Max reagent subsequently depletes any remaining endogenous ATP in the reaction system. The ADP-Glo™ Max detection reagent converts the ADP that has been enzymatically produced back into ATP and using ATP as a substrate together with luciferin for the enzyme luciferase, light is generated which produces a detectable luminescence. The luminescent signal measured is directly proportional to the amount of ADP produced by the enzyme reaction and a reduction in this signal upon compound treatment demonstrates enzyme inhibition. The percentage inhibition produced by each concentration of compound was calculated using the equation shown below:

( Mean _mn - Mean _Inh )

% Inhibition— 1— x 100

( Mean _mn - Mean _Max)

Percentage inhibition was then plotted against compound concentration, and the 50% inhibitory concentration (IC50) was determined from the resultant concentration-response curve.

The data for compounds of formula (I) tested are presented below.

Table 9: Human CTPS1 Enzyme Inhibition data grouped by potency range (± indicates I C50 in the range of >10 to 20 micromolar, + indicates IC50 in the range >1 to 10 micromolar, ++ indicates I C50 in the range >0.1 to 1 micromolar, +++ indicates I C50 of <0.1 micromolar)

Table 10: Human CTPS1 Enzyme Inhibition data grouped by potency range (± indicates IC50 in the range of >10 to 20 micromolar, + indicates IC50 in the range >1 to 10 micromolar, ++ indicates IC50 in the range >0.1 to 1 micromolar, +++ indicates IC50 of <0.1 micromolar)

Table 11 : Human CTPS1 Enzyme Inhibition data grouped by potency range (± indicates IC50 in the range of >10 to 21 micromolar, + indicates IC50 in the range >1 to 10 micromolar, ++ indicates IC50 in the range >0.1 to 1 micromolar, +++ indicates IC50 of <0.1 micromolar)

All compounds disclosed in Tables 9 to 1 1 were found to demonstrate inhibition of CTPS1 enzyme in this assay. Consequently, these compounds may be expected to have utility in the inhibition of CTPS1. The compounds of the invention are also expected to have utility as research tools, for example, for use in CTPS assays.

The data for all compounds of formula (I) (including (l-a), (l-b) and (l-c) tested wherein Ri is Ri _a ; and/or R ₄ and R ₅ are R _4a and Rs _a ; and/or A is A _a are presented below.

Table 12: Human CTPS1 Enzyme Inhibition data grouped by potency range (± indicates IC ₅₀ in the range of >10 to 20 micromolar, + indicates IC ₅₀ in the range >1 to 10 micromolar, ++ indicates IC ₅₀ in the range >0.1 to 1 micromolar, +++ indicates IC ₅₀ of <0.1 micromolar)

Table 13: Human CTPS1 Enzyme Inhibition data grouped by potency range (+++ indicates IC50 of <0.1 micromolar)

Table 14: Human CTPS1 Enzyme Inhibition data grouped by potency range (+++ indicates IC50 of <0.1 micromolar)

All compounds of the invention which have been tested were found to demonstrate inhibition of CTPS1 enzyme in this assay (see Tables 12 to 14). Consequently, these compounds may be expected to have utility in the inhibition of CTPS1. In particular, activity is retained following reduction of the amide (group A) to the amine derivative (see Examples R94 and T466).

Biological Example 2 - RapidFire/MS-based Enzyme Selectivity Assays.

Human CTPS1 versus CTPS2 Selectivity Assessment by RapidFire/MS Analysis.

The enzyme inhibitory activities against each target isoform of interest may be determined for the compounds of the invention using an optimised RapidFire high-throughput mass spectrometry (RF/MS) assay format. RF/MS assays for both human CTPS1 and CTPS2 may be performed in assay buffer consisting of 50mM HEPES (Merck), 20mM MgCh, 5mM KCI, 1 mM DTT, 0.01 % Tween-20, pH to 8.0 accordingly. Human full-length active C-terminal FLAG-His- tag CTPS1 (UniProtKB - P17812, CTPS1 [1-591 ]-GGDYKDDDDKGGHHHHHHHH (CTPS1 [1 - 591]-SEQ ID NO: 1 )) may be obtained from Proteros biostructures GmbH. Human full length active C-terminal FLAG-His-Avi tagged CTPS2 (UniProtKB - Q9N RF8, CTPS2 [1- 586]- DYKDDDDKHHHHHHGLNDIFEAQKI EWHE (CTPS2 [1-586]-SEQ ID NO: 2)) may be obtained from Harker Bio.

Assay Procedure

Human CTPS (1 or 2) protein may be prepared in 1x assay buffer to the final working protein concentration required for the reaction. A 2uL volume per well of 2x CTPS (1 or 2) protein may be mixed with 40nl_ of compound using acoustic (ECHO) delivery and incubated for 10 minutes at 25°C. Each isoform enzymatic reaction may be subsequently initiated by addition of 2uL per well of a 2x substrate mix in assay buffer. For hCTPSI : ATP (0.3mM), UTP (0.2mM), GTP (0.07mM) and L-glutamine (0.1 mM). For hCTPS2: ATP (0.1 mM), UTP (0.04mM), GTP (0.03mM) and L-glutamine (0.1 mM). Each mixture may be incubated for an appropriate amount of time per isoform within the determined linear phase of the reaction at 25°C. A 60uL volume of stop solution (1 % formic acid with 0.5uM ¹³ Cg- ¹⁵ N ₃ -CTP in H ₂ O) may be added and the plate immediately heat-sealed and centrifuged for 10 minutes at 4,000rpm. Following centrifugation, plates may be loaded onto the Agilent RapidFire microfluidic solid phase extraction system coupled to an API4000 triple quadrupole mass spectrometer (RF/MS) for analysis.

In all cases, the enzyme converts UTP to CTP. Highly specific and sensitive multiple reaction monitoring (MRM) MS methods may be optimised for the detection of the enzymatic reaction product, CTP, and the stable isotope labelled product standard ¹³ C ₉ - ¹⁵ N ₃ -CTP. Readout for data analysis may be calculated as the ratio between the peak area of the product CTP and the internal standard ¹³ Cg- ¹⁵ N ₃ -CTP. For data reporting, the following equation may be used:

R= P_

IS

(R = ratio/readout, P = product signal area, IS = internal standard signal area)

For each screening plate, the means of the negative (DMSO) and positive control values were used for the calculation of the respective assay window (S/B) and Z’ values. The median of the respective control values was used for calculation of percent inhibition according to the following equation:

I Rnea - RsamDle %

[Rneg ^— Rpos]

(I = Inhibition, R _neg = median of negative control readout values, R _pos = median of positive control readout values, R _SamPie = sample readout value)

Percentage inhibition was then plotted against compound concentration, and the 50% inhibitory concentration (IC ₅₀ ) was determined from the resultant concentration-response curve.

Fold selectivity between CTPS1 and CTPS2 was subsequently calculated according to the following equation:

Fold selectivity = CTPS2 ICsn

CTPS1 ICso

The data for all compounds disclosed herein that were tested in Biological Example 2 are presented below. Table 15: Selectivity data split into grouping of 2-30 fold (+), >30-60 fold (++) or >60 fold (+++)

Table 16: Selectivity data split into grouping of 2-30 fold (+), >30-60 fold (++) or >60 fold (+++)

The data for all compounds of formula (I) tested wherein Ri is Ri _a ; and/or R ₄ and R ₅ are R _4a and R _5a ; and/or A is A _a are presented in Table 17.

Table 17: Selectivity data split into grouping of 2-30 fold (+), >30-60 fold (++) or >60 fold (+++)

All compounds tested in the assay described in Biological Assay 2 were found to have at least 2 fold selectivity for CTPS1 over CTPS2, with many compounds having a selectivity for CTPS1 of over 60 fold. In particular, these compounds may be expected to have utility in the treatment of diseases whereby a selective CTPS1 compound is beneficial.

The compounds of the invention are also expected to have utility as research tools, for example, for use in CTPS assays.

Throughout the specification and the claims and clauses which follow, unless the context requires otherwise, the word‘comprise’, and variations such as‘comprises’ and‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the claims which follow. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. Clauses of the invention:

Clause 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

-bc);

wherein R _3b 3 _c is R ₃ or R _3c as defined below;

wherein when B is (B-a) the compound of formula (I) is a compound of formula (l-a):

wherein:

A _a IS A _aa OG 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(=0)NH- or -NHC(=0)-;

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, Ci- ₂ alkyl, OCi- ₂ alkyl, Ci- ₂ haloalkyl or OCi- 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;

Rla iS Rlaa OG Riba,

wherein:

Rlaa is N R _32a R ₃ 3a;

Ri _ba is Ci- ₅ alkyl, Co- 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 _{4 a} 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 Ci- ₃ alkyl, oxo, OH, Ci- ₃ alkylOH, Ci. ₃ haloalkyl, Co- ₂ alkyleneC _3.6 cycloalkyl, Co- ₂ alkyleneC _{3. 6} heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OC ₀ - 2alkyleneC ₃ -6cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and N R _21a R22al or

one of the carbons of the C ₃ -6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -6cycloalkyl ring and a further C ₃ -6cycloalkyl ring or a C ₃ -6heterocycloalkyl ring, and wherein the C _3. scycloalkyl 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 Ci_ 3al kyl or OCi- 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 -6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -6heterocycloalkyl ring and a further C _3-6 cycloalkyl ring or a C _3.s 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 Ci- ₃ alkyl or OCi- ₃ alkyl; or

R _4aa and Rs _aa together with the carbon atom to which they are attached form a C ₃ - 6heterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(0) ₂ R _29a ; or

R _4ba and R _5ba are each independently H, C-i-salkyl, Ci-ealkylOH, Ci-ehaloalkyl, Co- 2alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC _3-6 heterocycloalkyl, Ci- ₃ alkyleneOCi- 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(=0)- or -NHCH ₂ -:

R _4ba and R _5ba may additionally be selected from halo, OCi- ₆ haloalkyl, OCo- 2alkyleneC ₃ -ecycloalkyl, OCo- ₂ alkyleneC ₃ -eheterocycloalkyl, OCi-ealkyl and

NR21aR22a;

Aria is a 6-membered aryl or heteroaryl;

Ar2a is a 6-membered aryl or heteroaryl and is attached to Aria in the para position relative to group A _a ;

Rio _a is H, halo, Ci- ₃ alkyl, Ci- ₂ haloalkyl, OCi- ₂ alkyl, OCi- ₂ haloalkyl or CN;

Rii _a is H, F, Cl, Ci. ₂ alkyl, CF ₃ , OCH ₃ or CN;

Ri _2a is attached to Ar2 in the ortho or meta position relative to Aria and Ri _2a is H, halo, leneC _3-5 cycloalkyl, OCi- ₄ alkyl, OCo- ₂ alkyleneC _3-5 cycloalkyl, hydroxy, Ci- ₄ alkylOH, S0 ₂ Ci- ₂ alkyl, C(0)N(Ci- ₂ alkyl) ₂ , ; and

when A _a is -NHC(=0)-, -NH- or -NHCH2-:

Ri _2a may additionally be selected from CN, OCH ₂ CH ₂ N(CH ₃ ) ₂ and a C ₃ - 6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or Ri _2a together with a nitrogen atom to which it is attached forms an N- oxide (N ⁺ -0 );

Ri _3a is H or halo;

R2i _a is H, Ci-5alkyl, C(0)Ci-salkyl, C(0)OCi-salkyl, Ci-3alkylOCi-2alkyl, Ci-4haloalkyl, or C4-sheterocycloalkyl; R ₂₂ a is H or CH ₃ ;

R ₂₃ a is H or Ci. ₂ alkyl; and R _24a is H or Ci- ₂ alkyl

R ₂₉ a is Ci- ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , CF ₃ , N(Ci_ 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 Ci. ₃ alkyl and R ₃₃ is Ci. ₃ alkyl; or

R ₃₂ a and R _33a together with the nitrogen atom to which they are attached form a C ₃ - 5heterocycloalkyl; wherein:

Ria is Ri _aa ; and/or

R _a and R _5a are R _4aa and R _5a a; and/or

A _a is A _aa ; and wherein when B is (B-bc) and R _3b 3 _c is R _3b , the compound of formula (I) is a compound of formula (l-b):

Ab is Aab or Abb;

wherein:

A _ab is -NR _6b CH ₂ - or -NR _6b -;

Ab is -NR6bC(-0)-;

Rib is Riab or Ri _b ;

wherein:

Riab is NR _32b R33b;

Ri _bb is Ci- ₅ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , Ci- ₃ alkyleneOCi- ₂ alkyl, or CF ₃ ; R _3b is H, halo, CH ₃ , OCi- 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 Rs _ab together with the carbon atom to which they are attached form a C ₃ - ecycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci- ₃ alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC _3. sheterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC ₃ -6cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and NR2i _b R22 _b ; or

one of the carbons of the C ₃ -6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C _3. 6cycloalkyl ring and a further C ₃ -6cycloalkyl ring or a C _3. 6heterocycloalkyl 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 Ci- 3al kyl or OCi- 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 -6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -6Cheterocycloalkyl ring and a further C ₃ -6cycloalkyl ring or a C ₃ -sheterocycloalkyl ring, and wherein the C ₃ -6heteroycloalkyl formed by R _4ab and Rs _ab 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 Ci- ₃ alkyl or OCi. ₃ alkyl; or

R _4a 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(0) R _29b ; or

R _4bb and R _5bb are each independently H, halo, Ci-6alkyl, Co- ₂ alkyleneC _{3. 6} cycloalkyl, Co- ₂ alkyleneC ₃ -sheterocycloalkyl, OCi-6alkyl, OCo- ₂ alkyleneC ₃ . ₆ cycloalkyl, Ci-3alkyleneOCi-3alkyl, Ci- ₆ alkylOH, Ci-shaloalkyl, OCi-shaloalkyl or

NR21bR22b,

or R _bb 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 _4b and R _5b together with the carbon atom to which they are attached form a C3-ecycloalkyl or C3-eheterocycloalkyl,

or R _4bb is H and Rs _bb and R ₆ are a C2-3alkylene chain forming a 5- or 6- membered ring; or R _b is O and R _5bb is absent;

Re _b is H or Ci-3alkyl,

or R _6b together with Rn when in the ortho-position to group A are a C alkylene chain forming a 5-membered ring, or R _5b and R _6b are a C2-3alkylene chain forming a 5- or 6-membered ring and R _4bb is H;

Ar1 b is 6-membered aryl or heteroaryl;

Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1 b in the para position relative to group A ;

Rio _b is H, halo, Ci-3alkyl, OCi-2alkyl, Ci-2haloalkyl, OCi-2haloalkyl or CN;

Ru _b is H, F, Cl, CHs, ethyl, OCH ₃ , CF ₃ , OCF ₃ or CN,

or Ru _b , when in the ortho-position to group A , together with R ₆ are a C ₂ alkylene chain forming a 5-membered ring;

Ri2 _b is attached to Ar2b in the ortho or meta position relative to Ar1 b and Ri _2b is H, halo,

the point of attachment to Ar2b, or Ri2 _b together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 );

Ris is H, halo, CH ₃ or OCH ₃ ;

R _2ib is H, Ci-5alkyl, C(0)Ci-salkyl, C(0)OCi-salkyl, Ci-3alkylOCi-2alkyl, Ci- ₄ haloalkyl, or C _4-6 heterocycloalkyl; R ₂ 2b is H or CH ₃ ;

R ₂₃ b is H or Ci. ₂ alkyl;

R ₂₄ b is H or Ci- ₂ alkyl;

R ₂ 9 _b is Ci-3alkyl, Co-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH3, CF3, N(Ci_3alkyl) ₂ , or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and

R ₃ 2b is Ci. ₃ alkyl and R ₃₃ b is Ci. ₃ alkyl; or

R _32b and R ₃₃ b together with the nitrogen atom to which they are attached form a C ₃ - 5heterocycloalkyl; wherein:

Ri b is Riab; and/or

R b and R ₅ b are R _4a b and R _5a b; and/or

A is A _ab ; or wherein when B is (B-bc) and R _3b 3c is R _3c , the compound of formula (I) is a compound of formula (l-c):

wherein:

Ac is A _ac or A _c ;

wherein:

Aac is -CH ₂ NR _6c -;

Abc is -C(-0)NR _6c -;

Rlc IS Rlac OG Rl bc

wherein:

Rlac IS N R ₃₂ CR ₃ 3C; Ri _bc is Ci-salkyl, Co- ₂ alkyleneC ₃ -scycloalkyl which cycloalkyl is optionally substituted by CH ₃ , Ci- ₃ alkyleneOCi- ₂ alkyl, or CF ₃ ;

R _3C is H, CH ₃ , halo, OCi- ₂ alkyl or CF ₃ ;

R _4c and Rsc are either R _4ac and R _5ac or R _4bc and R _5bc ;

wherein:

R _4ac and Rs _ac together with the carbon atom to which they are attached form a C ₃ - ecycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci- ₃ alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC ₃ - sheterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC ₃ -6cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and NR210R220; or

one of the carbons of the C ₃ -6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C _3. 6cycloalkyl ring and a further C ₃ -6cycloalkyl ring or a C _3. 6heterocycloalkyl 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 Ci- 3al kyl or OCi- 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 -6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C ₃ -6Cheterocycloalkyl ring and a further C ₃ -6cycloalkyl ring or a C ₃ -sheterocycloalkyl ring, and wherein the C ₃ -6heteroycloalkyl formed by R _4ac and Rs _ac 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 Ci- ₃ alkyl or OCi. 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(0) ₂ R _29c ; or

R _4bc and R _5bc are each independently H, Ci- ₃ alkyl, Co- ₂ alkyleneC _3-6 cycloalkyl, Co- 2alkyleneC ₃ -6heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, Ci-6alkylOH or Ci- 6haloalkyl, or R _b c and R _5b c together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heterocycloalkyl ring;

R _6C is H or Ci- 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 ;

Rio _c is H, halo, Ci. ₃ alkyl, OCi- ₂ alkyl, Ci. ₂ haloalkyl, OCi- ₂ haloalkyl or CN;

Rue is H, F, Cl, CHs, ethyl, OCH ₃ , CF ₃ , OCF ₃ or CN;

Ri _2c is attached to Ar2c in the meta or ortho position relative to Ar1c and Ri _2c is H, halo, Ci- ₄ alkyl, C _2-4 alkynyl, C(=0)Ci. ₂ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl, OCi- ₄ alkyl, Ci- 3alkyleneOCi- ₃ alkyl, Ci. ₄ haloalkyl, OCi. haloalkyl, CN, OC _0.2 alkyleneC _3-5 cycloalkyl, OCH ₂ CH ₂ N(CH ₃ ) ₂ , OH, Ci- ₄ alkylOH, NR _23c R _24c , S0 ₂ CH ₃ , C(0)N(CH ₃ ) ₂ , NHC(0)Ci. ₃ alkyl, or a C _3-6 heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or RI _2C together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ - 0-);

R _2ic is H, Ci- ₅ alkyl, C(0)Ci-salkyl, C(0)OCi-salkyl, Ci- ₃ alkylOCi- ₂ alkyl, Ci- ₄ haloalkyl, or C ₄ -eheterocycloalkyl;

R _22C is H or CH ₃ ;

R _23C is H or Ci- ₂ alkyl;

R _{2 C} is H or Ci- ₂ alkyl;

R _29C is Ci- ₃ alkyl, Co- ₂ alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by CH ₃ , CF3, N(Ci- 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 Ci- ₃ alkyl and R _33c is Ci- ₃ alkyl; or

R3 _2C and R33 _C together with the nitrogen atom to which they are attached form a C3- 5heterocycloalkyl;

wherein:

Ric is Ria _C ; and/or

R _4c and R5 _C are R _4ac and Rsa _C ; and/or

A _c IS A _ac , or a salt and/or solvate thereof and/or derivative thereof.

Clause 2. A compound of formula (I) according to clause 1 wherein the compound of formula (I) is a compound of formula (l-a).

Clause 3. A compound of formula (I) according to clause 1 or clause 2 wherein the compound of formula (I) is a compound of formula (l-a):

wherein

A _a is Aaa OG Abai

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(=0)NH- or -NHC(=0)-;

X is N or CH;

Y is N or CR _2a ;

Z is N or CR3 _a;

with the proviso that when at least one of X or Z is N, Y cannot be N;

Rla IS Rlaa OG Riba,

wherein

Rlaa is N R3 _2a R33a;

Ri ba is Ci-5alkyl, Co-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by Ch , or CF3;

R _2a is H, halo, Ci- ₂ alkyl, OCi- ₂ alkyl, Ci- ₂ haloalkyl or OCi- 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 _{4 a} and R _5ba ;

wherein R _4aa and R _5aa together with the carbon atom to which they are attached form a C ₃ - 6cycloalkyl which is:

substituted by one or two substituents, each substituent being independently selected from the group consisting of Ci- ₃ alkyl, oxo, OH, Ci-3alkylOH, Ci-3haloalkyl, Co- ₂ alkyleneC3-6cycloalkyl, Co-2alkyleneC3- eheterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₃ alkyl and NR ₂ - _a R _22a ; OG

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 - 6cycloalkyl 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 Ci_ 3al kyl or OCi- ₃ alkyl; or

R _aa and R _5aa together with the carbon atom to which they are attached form a C ₃ - 6heterocycloalkyl 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 heterocydoalkyl 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 Ci- ₃ alkyl or OC _1.3 a I kyl; or

R _4aa and Rs _aa 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(0) ₂ R _29a ; or

R _{4 a} and R _5ba are each independently H, Ci- ₆ alkyl, Ci- ₆ alkylOH, Ci- _B haloalkyl, C ₀ - ₂ alkyleneC _3-6 cycloalkyl, Co- ₂ alkyleneC _3-6 heterocycloalkyl, Ci- ₃ alkyleneOCi. ₃ alkyl, or R _4a and R _5a 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(=0)- or -IMHCH ₂ -:

R _4ba and Rs _ba may additionally be selected from halo, OCi- ₆ haloalkyl, OCo- 2alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC _3-6 heterocycloalkyl, OCi- ₆ alkyl and

NR _2ia R _22a ; Aria is a 6-membered aryl or heteroaryl;

Ar2a is a 6-membered aryl or heteroaryl and is attached to Aria in the para position relative to group A _a ;

Rio _a is H, halo, Ci-3alkyl, Ci-2haloalkyl, OCi-2alkyl, OCi-2haloalkyl or CN; Rue is H, F, Cl, Ci- ₂ alkyl, CF ₃ , OCH ₃ or CN;

Ri2 _a is attached to Ar2a in the ortho or meta position relative to Aria and Ri2 _a is H, halo, Ci. alkyl, C _2-4 alkenyl, Co- ₂ alkyleneC ₃ -5cycloalkyl, OCi- alkyl, OCo-2alkyleneC ₃ -5cycloalkyl, Ci- haloalkyl, OCi- ₄ haloalkyl _, hydroxy, Ci- ₄ alkylOH, S0 ₂ Ci- ₂ alkyl, C(0)N(Ci- ₂ alkyl) ₂ , NHC(0)Ci- ₃ alkyl or NR _23a R2 _4a ; and

when A _a is -NHC(=0)-, -NH- or -NHCH ₂ -:

Ri2 _a 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 Ri _2a together with a nitrogen atom to which it is attached forms an N- oxide (N ⁺ -0 );

Ri _3a is H or halo;

R _2ia is H, Ci- ₅ alkyl, C(0)Ci. _s alkyl, C(0)OCi- ₅ alkyl;

R _22a is H or CH ₃ ;

R _23a is H or Ci-2alkyl; and

R _24a is H or Ci-2alkyl;

R ₂ sa is Ci- ₃ alkyl, Co-2alkyleneC _3-5 cycloalkyl which cycloalkyl is optionally substituted by

CH ₃ , or CF ₃ ;

R ₃ 2 _a is Ci- ₃ alkyl and R _33a is Ci- ₃ alkyl; or

R ₃ 2 _a and R _33a together with the nitrogen atom to which they are attached form a C _3. 5heterocycloalkyl;

wherein

Ri _a is Ri _aa ; and/or

R _4a and R _5a are R _4aa and R _5aa ; and/or

A is A _a ;

or a salt and/or solvate thereof and/or derivative thereof. Clause 4. The compound according to any one of clauses 1 to 3 wherein A _a is -C(=0)NH-.

Clause 5. The compound according to any one of clauses 1 to 3 wherein A _a is -NHC(=0)-.

Clause 6. The compound according to any one of clauses 1 to 3 wherein A _a is -NH-.

Clause 7. The compound according to any one of clauses 1 to 3 wherein A _a is -CH ₂ NH-. Clause 8. The compound according to any one of clauses 1 to 3 wherein A _a is -NHCH2-.

Clause 9. The compound according to any one of clauses 1 to 8 wherein X is N.

Clause 10. The compound according to any one of clauses 1 to 8 wherein X is CH.

Clause 1 1. The compound according to any one of clauses 1 to 8 or 10 wherein Y is N.

Clause 12. The compound according to any one of clauses 1 to 10 wherein Y is CR2 _a .

Clause 13. The compound according to any one of clauses 1 to 10 or 12 wherein Z is N.

Clause 14. The compound according to any one of clauses 1 to 12 wherein Z is CR3 _a .

Clause 15. The compound according to any one of clauses 1 to 8 wherein X is N, Y is CR _2a and Z is N.

Clause 16. The compound according to any one of clauses 1 to 8 wherein X is N, Y is CR _2a and Z is CR3 _a .

Clause 17. The compound according to any one of clauses 1 to 8 wherein X is CH, Y is N and Z is CR3 _a .

Clause 18. The compound according to any one of clauses 1 to 8 wherein X is CH, Y is CR _2a and Z is CR3 _a.

Clause 19. The compound according to any one of clauses 1 to 8 wherein X is CH, Y is CR _2a and Z is N.

Clause 20. The compound according to any one of clauses 1 to 19 wherein Ri _a is Ri _aa .

Clause 21. The compound according to clause 20 wherein Ri _aa is NR3 _2a R33a, R3 _2a is Ci-3alkyl and R33a is Ci-3alkyl.

Clause 22. The compound according to clause 21 wherein R ₃ 2 _a is methyl or ethyl, such as methyl.

Clause 23. The compound according to either clause 21 or 22 wherein R33 _a is methyl or ethyl, such as methyl.

Clause 24. The compound according to clause 21 wherein R ₃ 2 _a is methyl and R ₃ 3 _a is methyl. Clause 25. The compound according to clause 20 wherein Ri _aa is NR ₃ 2 _a R33 _a and wherein R ₃ 2 _a and R _33a together with the nitrogen atom to which they are attached form a C ₃ -5heterocycloalkyl.

Clause 26. The compound according to clause 25 wherein the C ₃ -5heterocycloalkyl is selected from the group consisting of aziridine, azetidine and pyrrolidine.

Clause 27. The compound according to any one of clauses 1 to 19 wherein Ri _a is Ri _ba .

Clause 28. The compound according to any one of clauses 1 to 19 wherein Ri _a is Ci-salkyl.

Clause 29. The compound according to any one of clauses 1 to 19 wherein Ri _a is C ₀ -

₂ alkyleneC ₃ -5cycloalkyl which cycloalkyl is optionally substituted by CH ₃ .

Clause 30. The compound according to clause 29 wherein Ri _a is Co-2alkyleneC ₃ -5cycloalkyl. Clause 31. The compound according to clause 29 wherein Ri _a is Co-2alkyleneC ₃ -5cycloalkyl which cycloalkyl is substituted by CH ₃ .

Clause 32. The compound according to any one of clauses 29 to 31 wherein Ri _a is C _3. scycloalkyl optionally substituted by CH ₃ .

Clause 33. The compound according to any one of clauses 29 to 31 wherein Ri _a is CialkyleneC ₃ -5cycloalkyl optionally substituted by CH ₃ .

Clause 34. The compound according to any one of clauses 29 to 31 wherein Ri _a is C2alkyleneC ₃ -5cycloalkyl optionally substituted by CH ₃ .

Clause 35. The compound according to any one of clauses 1 to 19 wherein Ri _a is cyclopropyl, cyclopropyl substituted by CH ₃ at the point of attachment, cyclobutyl, methyl or ethyl.

Clause 36. The compound according to clause 35 wherein Ri _a is cyclopropyl, methyl or ethyl.

Clause 37. The compound according to clause 36 wherein R _1a is cyclopropyl.

Clause 38. The compound according to any one of clauses 1 to 19 wherein Ri _a is CF ₃ . Clause 39. The compound according to any one of clauses 1 to 38 wherein R2 _a is H.

Clause 40. The compound according to any one of clauses 1 to 38 wherein R _2a is halo, such as F, Cl or Br e.g. Cl or Br.

Clause 41. The compound according to any one of clauses 1 to 38 wherein R2 _a is Ci-2alkyl such as CH ₃ . Clause 42. The compound according to any one of clauses 1 to 38 wherein R _2a is OCi- ₂ alkyl such as OCH3.

Clause 43. The compound according to any one of clauses 1 to 38 wherein R _2a is Ci.

2haloalkyl such as CF ₃ .

Clause 44. The compound according to any one of clauses 1 to 38 wherein R _2a is OCi- ₂ haloalkyl such as OCF ₃ .

Clause 45. The compound according to any one of clauses 1 to 44 wherein R3 _a is H.

Clause 46. The compound according to any one of clauses 1 to 44 wherein R _3a is halo.

Clause 47. The compound according to clause 46 wherein R _3a is fluoro.

Clause 48. The compound according to any one of clauses 1 to 44 wherein R _3a is CH ₃ .

Clause 49. The compound according to any one of clauses 1 to 44 wherein R _3a is OCH ₃ .

Clause 50. The compound according to any one of clauses 1 to 44 wherein R _3a is CF ₃ .

Clause 51. The compound according to any one of clauses 1 to 44 wherein R _3a is OCF ₃ .

Clause 52. The compound according to any one of clauses 1 to 51 wherein at least one of

R _2a and R _3a is H.

Clause 53. The compound according to any one of clauses 1 to 52 wherein R4 _a and Rs _a are

R4aa and R 5.Ί _!

Clause 54. The compound according to clause 53 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 Ci. ₃ alkyl, oxo, OH, Ci- ₃ alkylOH, Ci- ₃ haloalkyl, Co- ₂ alkyleneC _3-S cycloalkyl, C _0-2 alkyleneC ₃ - ₆ heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, halo, OCi- ₃ haloalkyl, OCo- ₂ alkyleneC _3-6 cycloalkyl, OCo- ₂ alkyleneC3-6heterocycloalkyl, OCi. ₃ alkyl and NR _21a R _22a .

Clause 55. The compound according to clause 54 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 substituent.

Clause 56. The compound according to either clause 54or 55 wherein each substituent is independently selected from the group consisting of Ci-3alkyl, oxo, OH, Ci-3alkylOH, Ci- ₃ haloalkyl, halo, OCi-3haloalkyl, OCi-3alkyl and NR _2ia R22 _a .

Clause 57. The compound according to clause 56 wherein each substituent is

independently selected from the group consisting of oxo, OH, halo, OCi-3alkyl and NR _2ia R22 _a . Clause 58. The compound according to clause 57 wherein each substituent is

independently selected from the group consisting of oxo, OH, fluoro and NR _2ia R22 _a .

Clause 59. The compound according to clause 53 wherein R _4aa and R _5aa together with the carbon atom to which they are attached form a C3-6cycloalkyl wherein one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C _3.

6cycloalkyl 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 Ci- ₃ alkyl or OCi- ₃ alkyl.

Clause 60. The compound according to clause 53 wherein 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 -sheterocycloalkyl formed by R _4aa and Rs _aa 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 Ci- ₃ alkyl or OCi- ₃ alkyl.

Clause 61. The compound according to either clause 59 or 60 wherein R _4aa and R _5aa together with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3.

6heterocycloalkyl which is substituted by one substituent.

Clause 62. The compound according to either clause 59 or 60 wherein R _4aa and R _5aa together with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3.

6heterocycloalkyl which is unsubstituted.

Clause 63. The compound according to any one of clauses 59, 60 or 61 wherein each substituent is independently selected from the group consisting of Ci-2alkyl or OCH ₃ .

Clause 64. The compound according to any one of clauses 59 to 63 wherein a spirocyclic ring system is formed by the C ₃ -ecycloalkyl or C ₃ -eheterocycloalkyl ring and a further C ₃ - ₆ cycloalkyl ring.

Clause 65. The compound according to any one of clauses 59 to 63 wherein a spirocyclic ring system is formed by the C _3-6 cycloalkyl or C _3-6 heterocycloalkyl ring and a further C _3.

6heterocycloalkyl ring.

Clause 66. The compound according to any one of clauses 59 or 61 to 65 wherein the C ₃ - ₆ cycloalkyl formed by R _4aa and R _5aa together with the carbon atom to which they are attached is cyclopropyl. Clause 67. The compound according to any one of clauses 59 or 61 to 65 wherein the C3- ₆ cycloalkyl formed by R _4aa and R _5aa together with the carbon atom to which they are attached is cyclobutyl.

Clause 68. The compound according to any one of clauses 59 or 61 to 65 wherein the C3- ₆ cycloalkyl formed by R _4aa and Rs _aa together with the carbon atom to which they are attached is cyclopentyl.

Clause 69. The compound according to any one of clauses 59 or 61 to 65 wherein the C3- ₆ cycloalkyl formed by R _4aa and R _5aa together with the carbon atom to which they are attached is cyclohexyl.

Clause 70. The compound according to any one of clauses 60 to 65 wherein the C3- ₆ heterocycloalkyl formed by R _aa and R _5aa together with the carbon atom to which they are attached is heterocyclopropyl.

Clause 71. The compound according to any one of clauses 60 to 65 wherein the C3- eheterocycloalkyl formed by R _4aa and R _5aa together with the carbon atom to which they are attached is heterocyclobutyl.

Clause 72. The compound according to any one of clauses 60 to 65 wherein the C3- ₆ heterocycloalkyl formed by R _4aa and Rs _aa together with the carbon atom to which they are attached is heterocyclopentyl.

Clause 73. The compound according to any one of clauses 60 to 65 wherein the C ₃ - ₆ heterocycloalkyl formed by R _4aa and R _5aa together with the carbon atom to which they are attached is heterocyclohexyl.

Clause 74. The compound according to any one of clauses 59 or 61 to 69 wherein 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.

Clause 75. The compound according to any one of clauses 54 to 58 wherein R2i _a is H.

Clause 76. The compound according to any one of clauses 54 to 58 wherein R _2ia is Ci- ₅ alkyl, such as methyl, ethyl or propyl. Clause 77. The compound according to any one of clauses 54 to 58 wherein R _2ia is C(0)Ci- 5alkyl, such as C(0)CH ₃ .

Clause 78. The compound according to any one of clauses 54 to 58 wherein R _2ia is C(0)0Ci- ₅ alkyl, such as C(0)0CH ₃ or C(0)Otert-butyl.

Clause 79. The compound according to any one of clauses 54 to 58 wherein R _2ia is Ci- ₃ alkylOCi- ₂ alkyl such as CH ₂ CH ₂ OCH ₃ .

Clause 80. The compound according to any one of clauses 54 to 58 wherein R _2ia is Ci- 4haloalkyl such as CH ₂ CHF _2.

Clause 81. The compound according to any one of clauses 54 to 58 wherein R _2ia is C4- ₆ heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.

Clause 82. The compound according to any one of clauses 54 to 58 or 75 to 81 wherein R _22a is H.

Clause 83. The compound according to any one of clauses 54 to 58 or 75 to 81 wherein R ₂ 2a is CH ₃ .

Clause 84. The compound according to clause 53 wherein R _aa and R _5aa together with the carbon atom to which they are attached form a C ₃ -eheterocycloalkyl comprising one nitrogen atom, wherein said nitrogen atom is substituted by -S(0) ₂ R _29a .

Clause 85. The compound according to clause 84 wherein the C _3-6 heterocycloalkyl is piperidinyl and the nitrogen atom is in the 4-position relative to the quaternary carbon:

Clause 86. The compound according to either clause 84 or 85 wherein R _29a is Ci- ₃ alkyl.

Clause 87. The compound according to clause 86 wherein R _29a is methyl.

Clause 88. The compound according to either clause 84 or 85 wherein R _29a is N(Ci- ₃ alkyl) ₂ e.g. N(CH ₃ ) ₂ .

Clause 89. The compound according to either clause 84 or 85 wherein R _29a is 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl such as pyrazolyl substituted by methyl. Clause 90. The compound according to any one of clauses 1 to 52 wherein R _a and R _5a are R _4ba and R5 _ba .

Clause 91. The compound according to any one of clauses 1 to 52 or 90 wherein R _a is H.

Clause 92. The compound according to any one of clauses 1 to 52 or 90 wherein R _4ba is Ci- ealkyl.

Clause 93. The compound according to clause 92 wherein R _4ba is methyl or ethyl.

Clause 94. The compound according to any one of clauses 1 to 52 or 90 wherein R _4ba is Ci. ealkylOH.

Clause 95. The compound according to any one of clauses 1 to 52 or 90 wherein R _{4 a} is Ci- ₆ haloalkyl such as CF ₃ .

Clause 96. The compound according to any one of clauses 1 to 52 or 90 wherein R _a is C _{0. 2} alkyleneC3-6cycloalkyl.

Clause 97. The compound according to any one of clauses 1 to 52 or 90 wherein R _4ba is Co- ₂ alkyleneC3-6heterocycloalkyl.

Clause 98. The compound according to any one of clauses 1 to 52 or 90 wherein R _4ba is Ci_ 3alkyleneOCi-3alkyl.

Clause 99. The compound according to clause 98 wherein R _ba is C ₂ alkyleneOCi. ₃ alkyl.

Clause 100. The compound according to clause 99 wherein R _4ba is CH ₂ CH ₂ OCH ₃ .

Clause 101. The compound according to any one of clauses 1 to 52 or 90 wherein R _4ba is halo.

Clause 102. The compound according to clause 101 wherein R _4ba is fluoro.

Clause 103. The compound according to any one of clauses 1 to 52 or 90 wherein R _a is OCi- ₆ haloalkyl, such as OCi- ₄ haloalkyl.

Clause 104. The compound according to any one of clauses 1 to 52 or 90 wherein R _4ba is OCo-2alkyleneC ₃ -6cycloalkyl.

Clause 105. The compound according to any one of clauses 1 to 52 or 90 wherein R _4ba is OCo-2alkyleneC ₃ -eheterocycloalkyl.

Clause 106. The compound according to any one of clauses 1 to 52 or 90 wherein R _4ba is OCi- ₆ alkyl, in particular OCi- ₄ alkyl. Clause 107. The compound according to any one of clauses 1 to 52 or 90 wherein R _ba is

NR _2ia R _22a .

Clause 108. The compound according to clause 107 wherein R _{2i a} is H, CH ₃ , C(0)CH ₃ , C(0)OCH ₃ or C(0)Otert-butyl.

Clause 109. The compound according to clause 107 wherein R _{2i a} is Ci- ₃ alkylOCi- ₂ alkyl such as CH ₂ CH ₂ OCH ₃ .

Clause 1 10. The compound according to clause 107 wherein R _{2i a} is Ci-4haloalkyl such as CH ₂ CHF _2.

Clause 1 1 1. The compound according to clause 107 wherein R _{2i a} is C^heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.

Clause 1 12. The compound according to any one of clauses 107 or 1 1 1 wherein R _22a is H or CH ₃ such as H.

Clause 1 13. The compound according to any one of clauses 107 to 112 wherein R _2ia is C(0)OCH ₃ and R _22a is H, R _2ia is C(0)CH ₃ and R _22a is H, R _2ia and R _22a are both CH ₃ , or R _2ia and R _22a are both H.

Clause 1 14. The compound according to any one of clauses 1 to 52 or 90 wherein R _4ba is H, Ci-ealkyl, Ci-salkylOH, Ci-ehaloalkyl, Co-2alkyleneC ₃ -ecycloalkyl, Co-2alkyleneC _3.

6heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, or R _{4 a} and R _5ba together with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl.

Clause 1 15. The compound according to any one of clauses 1 to 52 or 90 wherein R _4ba is halo, OCi. ₆ haloalkyl, OC _0-2 alkyleneC _3.6 cycloalkyl, OC _0.2 alkyleneC _3.6 heterocycloalkyl, OCi. ₆ alkyl or NR _2ia R _22a .

Clause 1 16. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein Rsba IS H.

Clause 1 17. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein Rs _ba is Ci-ealkyl.

Clause 1 18. The compound according to clause 1 17 wherein R _5b a is methyl or ethyl.

Clause 1 19. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein Rs _ba is Ci-ealkylOH.

Clause 120. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein Rs _a is Ci- ₆ haloalkyl such as CF ₃ . Clause 121. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein F?5 _ba is Co-2alkyleneC3-6cycloalkyl.

Clause 122. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein Re _ba is Co-2alkyleneC3-6heterocycloalkyl.

Clause 123. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein s _ba is Ci-3alkyleneOCi-3alkyl, such as C2alkyleneOCi-3alkyl e.g. CH2CH2OCH3.

Clause 124. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R _5ba is halo.

Clause 125. The compound according to clause 124 wherein R _5ba is fluoro.

Clause 126. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R _5ba is OCi- ₆ haloalkyl, such as OCi-4haloalkyl.

Clause 127. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R _5ba is OCo-2alkyleneC3-6cycloalkyl.

Clause 128. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R _5ba is OCo-2alkyleneC3-eheterocycloalkyl.

Clause 129. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein Rs _ba is OCi- ₆ alkyl, in particular OCi-4alkyl.

Clause 130. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein

R5ba IS N R2laR22a- Clause 131. The compound according to clause 130 wherein R _2ia is H, CH ₃ , C(0)CH ₃ , C(0)OCH ₃ or C(0)Otert-butyl.

Clause 132. The compound according to clause 130 wherein R2i _a is Ci-3alkylOCi-2alkyl such as CH2CH2OCH3.

Clause 133. The compound according to clause 130 wherein R _2ia is Ci-4haloalkyl such as CH2CHF2.

Clause 134. The compound according to clause 130 wherein R2i _a is C4-6heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.

Clause 135. The compound according to any one of clauses 130 to 134 wherein R 2 _a is H or CH ₃ such as H. Clause 136. The compound according to any one of clauses 130 to 134 wherein R _ia is C(0)OCH ₃ and R _22a is H, R _2ia is C(0)CH ₃ and R _22a is H, R _2ia and R _22a are both CH ₃ , or R _2ia and R _22a are both H.

Clause 137. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein Re _ba is H, Ci- ₆ alkyl, Ci-salkylOH, Ci-shaloalkyl, Co-2alkyleneC ₃ -6cycloalkyl, Co-2alkyleneC _3.

6heterocycloalkyl, Ci- ₃ alkyleneOCi- ₃ alkyl, or R4 and Rs together with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl.

Clause 138. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R _5ba is halo, OCi- ₆ haloalkyl, OCo-2alkyleneC ₃ -6cycloalkyl, OCo-2alkyleneC ₃ -6heterocycloalkyl, OCi-ealkyl or NR _2ia R _22a .

Clause 139. The compound according to any one of clauses 1 to 52 or 90 to 116 wherein R _4ba and R _5ba are both H.

Clause 140. The compound according to any one of clauses 1 to 52 , 93 or 118 wherein R _4ba and R _5ba are both methyl.

Clause 141. The compound according to any one of clauses 1 to 52, 93 or 118 wherein R _4ba and R5 _ba are both ethyl.

Clause 142. The compound according to any one of clauses 1 to 52, 102 or 125 wherein R _{4 a} and R _5ba are both fluoro.

Clause 143. The compound according to any one of clauses 1 to 52, 102 or 116 wherein R _{4 a} is ethyl and R _5ba is H.

Clause 144. The compound according to any one of clauses 1 to 52, 102 or 118 wherein R _4ba is fluoro and Rsba is ethyl.

Clause 145. The compound according to any one of clauses 1 to 52, 100 or 116 wherein R _{4 a} is CH ₂ CH ₂ OCH ₃ and R _5ba is H.

Clause 146. The compound according to any one of clauses 143 to 145 wherein R _4ba and Rs _ba are arranged in an S configuration.

Clause 147. The compound according to any one of clauses 1 to 52 or 90 wherein R _{4 a} and R _5ba together with the carbon atom to which they are attached form a C _3-6 cycloalkyl.

Clause 148. The compound according to clause 147 wherein R _{4 a} and R _5ba together with the carbon atom to which they are attached form a cyclopropyl ring or a cyclopentyl ring, such as a cyclopentyl ring. Clause 149. The compound according to any one of clauses 1 to 52 or 90 wherein R _ba and R _5ba together with the carbon atom to which they are attached form a C3-6heterocycloalkyl, such as heterocyclohexyl, such as tetrahydropyranal.

Clause 150. The compound according to any one of clauses 1 to 149 wherein Aria is phenyl.

Clause 151. The compound according to any one of clauses 1 to 149 wherein Aria is 2- pyridyl.

Clause 152. The compound according to any one of clauses 1 to 149 wherein Aria is 3- pyridyl. Clause 153. The compound according to any one of clauses 1 to 152 wherein Ar2a is 3- pyridyl.

Clause 154. The compound according to any one of clauses 1 to 152 wherein Ar2a is 2,5- pyrazinyl.

Clause 155. The compound according to any one of clauses 1 to 154 wherein Rio _a is H. Clause 156. The compound according to any one of clauses 1 to 154 wherein Ri _0a is halo such as fluoro or chloro.

Clause 157. The compound according to any one of clauses 1 to 154 wherein Rio _a is Ci- ₃ alkyl.

Clause 158. The compound according to clause 157 wherein Ri _0a is Ci- ₂ alkyl such as CH ₃ . Clause 159. The compound according to any one of clauses 1 to 154 wherein Ri _0a is Ci- ₂ haloalkyl such as CF ₃ .

Clause 160. The compound according to any one of clauses 1 to 154 wherein Rio _a is OCi- ₂ alkyl such as OCH ₃ .

Clause 161. The compound according to any one of clauses 1 to 154 wherein Ri _0a is OCi- ₂ haloalkyl such as OCF ₃ .

Clause 162. The compound according to any one of clauses 1 to 154 wherein Rio _a is CN.

Clause 163. The compound according to any one of clauses 1 to 162 wherein Rn _a is H.

Clause 164. The compound according to any one of clauses 1 to 162 wherein Rn _a is F.

Clause 165. The compound according to any one of clauses 1 to 162 wherein Rn _a is Cl. Clause 166. The compound according to any one of clauses 1 to 162 wherein Rn _a is Ci- ₂ alkyl.

Clause 167. The compound according to clause 166 wherein Rn _a is CH ₃ .

Clause 168. The compound according to any one of clauses 1 to 162 wherein Rn _a is CF ₃ .

Clause 169. The compound according to any one of clauses 1 to 162 wherein Rn _a is OCH ₃ .

Clause 170. The compound according to any one of clauses 1 to 162 wherein Rn _a is CN.

Clause 171. The compound according to any one of clauses 1 to 170 wherein Ri _2a is H.

Clause 172. The compound according to any one of clauses 1 to 170 wherein Ri _2a is halo such as fluoro or chloro.

Clause 173. The compound according to any one of clauses 1 to 170 wherein Ri _2a is Ci- ₄ alkyl such as CH ₃ .

Clause 174. The compound according to any one of clauses 1 to 170 wherein Ri _2a is C _{2. 4} alkenyl.

Clause 175. The compound according to any one of clauses 1 to 170 wherein Ri _2a is Co- ₂ alkyleneC ₃ -5cycloalkyl such as CoalkyleneC ₃ cycloalkyl.

Clause 176. The compound according to any one of clauses 1 to 170 wherein Ri _2a is OCi- alkyl such as methoxy, ethoxy or isopropoxy.

Clause 177. The compound according to any one of clauses 1 to 170 wherein Ri _2a is OCo- ₂ alkyleneC ₃ -5cycloalkyl such as OCoalkyleneC ₃ cycloalkyl.

Clause 178. The compound according to any one of clauses 1 to 170 wherein Ri _2a is Ci- ₄ haloalkyl such as CF ₃ .

Clause 179. The compound according to any one of clauses 1 to 170 wherein Ri _2a is OCi- haloalkyl such as OCFI ₂ CF ₃ or OCFIF ₂ .

Clause 180. The compound according to any one of clauses 1 to 170 wherein Ri _2a is OFI.

Clause 181. The compound according to any one of clauses 1 to 170 wherein Ri _2a is Ci- ₄ alkylOH.

Clause 182. The compound according to any one of clauses 1 to 170 wherein Ri _2a is S0 ₂ Ci- ₂ alkyl.

Clause 183. The compound according to any one of clauses 1 to 170 wherein Ri _2a is NHC(0)Ci- ₃ alkyl. Clause 184. The compound according to any one of clauses 1 to 170 wherein Ri _2a is

N R _23a R ₂ 4 _a .

Clause 185. The compound according to clause 184 wherein R _23a is H or Ci- ₂ alkyl such as H or CH ₃ .

Clause 186. The compound according to clause 184 or 185 wherein R _{2 a} is H or Ci- ₂ alkyl such as CH ₃ or ethyl.

Clause 187. The compound according to any one of clauses 184 to 186 wherein R _23a is H and R _24a is ethyl; or R _23a is CH ₃ and R _24a is CH _3.

Clause 188. The compound according to any one of clauses 1 to 170 wherein Ri _2a is CN.

Clause 189. The compound according to any one of clauses 1 to 170 wherein Ri _2a is

OCH ₂ CH ₂ N(CH ₃ ) ₂ .

Clause 190. The compound according to any one of clauses 1 to 170 wherein Ri _2a is a C _{3. 6} heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a.

Clause 191. The compound according to any one of clauses 1 to 170 wherein Ri _2a together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ).

Clause 192. The compound according to any one of clauses 1 to 170 wherein Ri _2a is C(0)N(Ci- ₂ alkyl) _2.

Clause 193. The compound according to any one of clauses 1 to 192 wherein Ri _3a is H.

Clause 194. The compound according to any one of clauses 1 to 192 wherein Ri _3a is halo such as fluoro or chloro e.g. fluoro.

Clause 195. The compound according to any one of clauses 1 to 194 when Ri _ba is methyl, at least one of R ₄ ba, Rsba, Rioba, Ruba, Ri2 a and Ri ₃ a is other than H.

Clause 196. The compound according to any one of clauses 1 to 195 wherein at least one, such as only one, nitrogen atom in any of the C _3-6 heterocycloalkyl rings, such as only one of the C ₃ -eheterocycloalkyl rings is substituted, for example by Ci-4alkyl, C(0)H, C(0)Ci- ₄ alkyl, C(0)OCi- ₄ alkyl, C(0)OCi- ₄ alkylaryl such as C(0)OBz, C(0)NHCi- ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl, C(0)NHCi- ₄ haloalkyl such as C(0)OtBu, Ci-4alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , or Ci- ₂ alkylC(0)0Ci. ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ .

Clause 197. The compound according to any one of clauses 1 to 195 wherein all nitrogen atoms in all C _3-6 heterocycloalkyl rings are not substituted. Clause 198. The compound according to any one of clauses 1 to 197 wherein at least one, such as only one, sulphur atom in any of the C3-6heterocycloalkyl rings, such as only one of the C3-6heterocycloalkyl rings is substituted, for example by one oxygen atom to form S=0 or by two oxygen atoms to form S(0) ₂ . Clause 199. The compound according to any one of clauses 1 to 197 wherein all sulphur atoms in all C3-6heterocycloalkyl rings are not substituted.

Clause 200. The compound according to any one of clauses 1 to 199 wherein Ri _a is Ri _aa and R _4a and R _5a are R _4aa and R _5aa .

Clause 201. The compound according to any one of clauses 1 to 199 wherein Ri _a is Ri _aa and A _a is -NH-, -CH ₂ NH- or -NHCH ₂ -.

Clause 202. The compound according to any one of clauses 1 to 199 wherein R _4a and R _5a are R _4aa and R _5aa and A _a is -NH-, -CH ₂ NH- or -NHCH ₂ -.

Clause 203. The compound according to any one of clauses 1 to 199 wherein Ri _a is Ri _aa , R _4a and R _5a are R _4aa and Rs _aa and A _a is -NH-, -CH ₂ NH- or -NHCH ₂ -. Clause 204. A compound of the examples P226, P227, P228, P229, P230, P235, P242, P244, P248, P251 , P254, P255, P256, P258, P260, P261 , 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.

Clause 205. A compound of formula (ll-a):

wherein Ri , X, Y, Z, R ₄ and R ₅ are as defined in any preceding clause and R is H, Ci-ealkyl (e.g. methyl and ethyl) or benzyl, or a salt, such as a pharmaceutically acceptable salt, thereof.

Clause 206. A compound of formula (XX-a):

wherein Ar1 , Ar2, Ri , X, Y, Z, R , Rs, R1 ₀ , R11 , R12 and R1 ₃ are as defined in any preceding clause and P is a nitrogen protecting group such as para-methoxybenzyl, or a salt, such as a pharmaceutically acceptable salt, thereof.

Clause 207. A compound of formula (XXIV-a):

wherein Ar1 , Ar2, A, Ri , X, Y, Z, R4, R5, R1 ₀ , R11 , R12 and R1 ₃ are as defined in any preceding clause and P is a nitrogen protecting group such as para-methoxybenzyl, or a salt such as a pharmaceutically acceptable salt, thereof.

Clause 208. A compound of formula (XXXI-a):

wherein Ar1 , Ar2, A, X, Y, Z, R4, Rs, R10, R11 , R12 and R13 are as defined in any preceding clause, or a salt, such as a pharmaceutically acceptable salt, thereof.

Clause 209. A compound of formula (XXXXII-a):

wherein Ri, X, Y, Z, R ₄ and R ₅ are as defined in any preceding clause, or a salt, such as a pharmaceutically acceptable salt, thereof.

Clause 210. A compound of formula (Ll-a):

wherein Ar1 , Ar2, A, R4 and R5 are as defined in any preceding clause and Xi is Cl or Br, or a salt, such as a pharmaceutically acceptable salt, thereof. Clause 211. A compound of formula (LVIII-a):

wherein Ri, Ar1 , A, X, Y, Z, R ₄ and R ₅ are as defined in any preceding clause, or a salt, such as a pharmaceutically acceptable salt, thereof.

Clause 212. A compound of formula (XXXIII-a):

wherein X, Y, Z, R ₄ and Rs are as defined in any preceding clause and alkyl is Ci_ ₄ alkyl such as methyl or ethyl, e.g. methyl, or a salt, such as a pharmaceutically acceptable salt, thereof.

Clause 213. A compound of formula (LXXXIII-a):

(LXXXIII-a) wherein X, Y, Z, R ₄ and R ₅ are as defined in any preceding clause and alkyl is Ci- ₄ alkyl such as methyl or ethyl, e.g. methyl, or a salt, such as pharmaceutically acceptable salt, thereof.

Clause 214. A compound selected from the group consisting of:

a compound of formula (XXXIV-a):

Boc

wherein and alkyl is Ci_ ₄ alkyl such as methyl or ethyl, e.g. methyl;

a compound of formula (LXXIII-a): a compound of formula (LXXIV-a):

n = 2 sulfone . wherein X, Y, Z, R ₄ , Rs, Ar1 and Ar2 are as defined in any preceding clause;

and salts such as pharmaceutically acceptable salts, thereof.

Clause 215. A compound of formula (LXXI-a):

wherein Ar1 , Ar2, Rio, Rn, R12 and Ri ₃ are as defined in any preceding clause, or a salt such as a pharmaceutically acceptable salt, thereof. Clause 216. A compound of formula (LXXII-a):

wherein Ar1 , Ar2, R10, R1 1, R12 and R13 are as defined in any preceding clause, or a salt such as a pharmaceutically acceptable salt, thereof.

Clause 217. A compound of INTC186 to INTC218 and INTC232 to INTC247, or salt such as pharmaceutically acceptable salt thereof.

Clause 218. The compound of formula (I) according to clause 1 wherein the compound of formula (I) is a compound of formula (l-b). Clause 219. The compound according to clause 218 wherein Ri is Ri _ab .

Clause 220. The compound according to clause 219 wherein Ri _ab is NR _32b R _33b and wherein R32 _b is Ci-3alkyl and R _33b is Ci- ₃ alkyl.

Clause 221. The compound according to clause 220 wherein R _32b is methyl or ethyl.

Clause 222. The compound according to clause 221 wherein R ₃ 2 _b is methyl.

Clause 223. The compound according to any one of clauses 220 or 222 wherein R _33b is methyl or ethyl such as methyl.

Clause 224. The compound according to any one of clauses 220 to 223 wherein R _32b is methyl and R ₃₃ is methyl.

Clause 225. The compound according to clause 219 wherein Ri _a is NR ₃ 2 _b R33 and R ₃ 2 _b and R33 _b together with the nitrogen atom to which they are attached form a C _3.5 heterocycloalkyl.

Clause 226. The compound according to clause 225 wherein the C ₃ -5heterocycloalkyl is selected from the group consisting of aziridine, azetidine and pyrrolidine.

Clause 227. The compound according to clause 218 wherein Ri is Ri .

Clause 228. The compound according to clause 227 wherein Ri _bb is Ci-salkyl such as CH ₃ or ethyl.

Clause 229. The compound according to clause 228 wherein Ri _bb is CH ₃ .

Clause 230. The compound according to any one of clauses 227 wherein Ri _bb is Co- 2alkyleneC ₃ -5cycloalkyl which cycloalkyl is optionally substituted by CH _3.

Clause 231. The compound according to clause 230, wherein Ri _bb is C ₀ -2alkyleneC _3.

5cycloalkyl.

Clause 232. The compound according to clause 230, wherein Ri is Co-2alkyleneC _3.

scycloalkyl which cycloalkyl is substituted by CH ₃ .

Clause 233. The compound according to any one of clauses 230 to 232, wherein Ri _bb is C _3. 5cycloalkyl, optionally substituted by CH ₃ .

Clause 234. The compound according to any one of clauses 230 to 232, wherein Ri _bb is CialkyleneC ₃ -5cycloalkyl which cycloalkyl is optionally substituted by CH ₃ .

Clause 235. The compound according to any one of clauses 230 to 232, wherein Ri _bb is C2alkyleneC ₃ -5cycloalkyl which cycloalkyl is optionally substituted by CH ₃ . Clause 236. The compound according to any one of clauses 230 to 235, wherein Ri _b is Co- ₂ alkyleneC ₃ cycloalkyl which cycloalkyl is optionally substituted by CH ₃ .

Clause 237. The compound according to any one of clauses 230 to 235 wherein Ri is Co- ₂ alkyleneC4cycloalkyl which cycloalkyl is optionally substituted by CH ₃ .

Clause 238. The compound according to any one of clauses 230 to 235 wherein Ri _bb is Co- ₂ alkyleneC5cycloalkyl which cycloalkyl is optionally substituted by CH ₃ .

Clause 239. The compound according to any one of clauses 230 to 238 wherein Ri _bb 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.

Clause 240. The compound according to any one of clauses 239 wherein Ri _bb is cyclopropyl, cyclopropyl substituted by CH ₃ at the point of attachment, cyclobutyl, CH ₃ , isopropyl, sec-butyl or tert-butyl.

Clause 241. The compound according to any clause 240 wherein Ri _bb is cyclopropyl, cyclopropyl substituted by CH ₃ at the point of attachment, cyclobutyl or isopropyl.

Clause 242. The compound according to any one of clauses 218 to 241 wherein R _3b is H.

Clause 243. The compound according to any one of clauses 218 to 241 wherein R _3b is chloro or fluoro.

Clause 244. The compound according to any one of clauses 218 to 241 wherein R _3b is CH _3.

Clause 245. The compound according to any one of clauses 218 to 241 wherein R _3b is

OCH ₃ .

Clause 246. The compound according to any one of clauses 218 to 241 wherein R _3b is CF ₃ .

Clause 247. The compound according to any one of clauses 218 to 241 wherein R _3b together with R _5bb forms a 5- or 6-membered cycloalkyl.

Clause 248. The compound according to clause 247 wherein R _3b together with R _5bb forms a 5-membered cycloalkyl.

Clause 249. The compound according to any one of clauses 218 to 248 wherein R4 _b and Rs _b are R _4ab and R _5ab.

Clause 250. The compound according to clause 249 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 Ci-3alkyl, oxo, OH, Ci-3alkylOH, Ci-3haloalkyl, Co-2alkyleneC3-6cycloalkyl, Co-2alkyleneC _3.

6heterocycloalkyl, Ci-3alkyleneOCi-3alkyl, halo, OCi-3haloalkyl, OCo-2alkyleneC3-6cycloalkyl, OCo-2alkyleneC3-6heterocycloalkyl, OCi-3alkyl and NR _2ib R22 _b .

Clause 251. The compound according to clause 250 wherein R _a b and R _5ab together with the carbon atom to which they are attached form a C3-6cycloalkyl which is substituted by one substituent.

Clause 252. The compound according to clause 250 or 251 wherein each substituent is independently selected from the group consisting of Ci-3alkyl, oxo, OH, Ci-3alkylOH, Ci- ₃ haloalkyl, halo, OCi-3haloalkyl, OCi-3alkyl and NR _2ib R22 _b .

Clause 253. The compound according to clause 252 wherein each substituent is

independently selected from the group consisting of oxo, OH, halo, OCi-3alkyl and NR _2ib R22 _b , such as oxo, OH, fluoro and NR _2i R22 _b .

Clause 254. The compound according to any one of clauses 250 to 253 wherein R _2ib is H.

Clause 255. The compound according to any one of clauses 250 to 253 wherein R _2ib is Ci_ salkyl, such as methyl, ethyl or propyl.

Clause 256. The compound according to any one of clauses 250 to 253 wherein R _2i is C(0)Ci- ₅ alkyl, such as C(0)CH ₃ .

Clause 257. The compound according to any one of clauses 250 to 253 wherein R _2ib is C(0)OCi- ₅ alkyl, such as C(0)OCH ₃ or C(0)Otert-butyl.

Clause 258. The compound according to any one of clauses 250 to 253 wherein R _2ib is Ci. ₃ alkylOCi. ₂ alkyl such as CH ₂ CH ₂ OCH ₃ .

Clause 259. The compound according to any one of clauses 250 to 253 wherein R _2i is Ci- ₄ haloalkyl such as CH ₂ CHF ₂ .

Clause 260. The compound according to any one of clauses 250 to 253 wherein R _2ib is C _{4. 6} heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.

Clause 261. The compound according to any one of clauses 250 to 260 wherein R ₂₂ is H.

Clause 262. The compound according to any one of clauses 250 to 260 wherein R _22b is CH ₃ .

Clause 263. The compound according to clause 249 wherein R _4ab and Rs _ab together with the carbon atom to which they are attached form a C3-6cycloalkyl wherein one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C _3.

6cycloalkyl ring and a further C3-6cycloalkyl ring or a C _3-6 heterocycloalkyl ring, and wherein the C _3-6 cycloalkyl formed by R _4ab and Rs _ab 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 Ci-3alkyl or OCi-3alkyl.

Clause 264. The compound according to clause 249 wherein R _ab and R _5ab 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 C3-6cheterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C3-6heteroycloalkyl 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 Ci-3alkyl or OCi-3alkyl.

Clause 265. The compound according to either clause 263 or 264 wherein R _a and R _5ab together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3- ₆ heteroycloalkyl which is substituted by one substituent.

Clause 266. The compound according to clause 263 or 264 wherein R _ab and R _5ab together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heteroycloalkyl which is unsubstituted.

Clause 267. The compound according to any one of clauses 263 to 266 wherein each substituent is independently selected from the group consisting of Ci-2alkyl or OCH ₃ .

Clause 268. The compound according to any one of clauses 263 to 267 wherein a spirocyclic ring system is formed by the C3-6cycloalkyl or C3-6heteroycloalkyl ring and a further C3- ₆ cycloalkyl ring.

Clause 269. The compound according to any one of clauses 263 to 267 wherein a spirocyclic ring system is formed by the C3-6cycloalkyl or C3-6heteroycloalkyl ring and a further C3-6heterocycloalkyl ring.

Clause 270. The compound according to any one of clauses 263 or 265 to 269 wherein the C3-6cycloalkyl formed by R _4ab and Rs _ab together with the carbon atom to which they are attached is cyclopropyl.

Clause 271. The compound according to any one of clauses 263 or 265 to 269 wherein the C _3-6 cycloalkyl formed by R _4ab and R _5ab together with the carbon atom to which they are attached is cyclobutyl.

Clause 272. The compound according to any one of clauses 263 or 265 to 269 wherein the C3-6cycloalkyl formed by R _4a and R _5ab together with the carbon atom to which they are attached is cyclopentyl. Clause 273. The compound according to any one of clauses 263 or 265 to 269 wherein the C3-6cycloalkyl formed by R _4a b and R _5a b together with the carbon atom to which they are attached is cyclohexyl.

Clause 274. The compound according to any one of clauses 264 to 269 wherein the C3- ₆ heterocycloalkyl formed by R _4ab and Rs _ab together with the carbon atom to which they are attached is heterocyclopropyl.

Clause 275. The compound according to any one of clauses 264 to 269 wherein the C3- ₆ heterocycloalkyl formed by R _a b and R _5a b together with the carbon atom to which they are attached is heterocyclobutyl. Clause 276. The compound according to any one of clauses 264 to 269 wherein the C3- ₆ heterocycloalkyl formed by R _a b and R _5a b together with the carbon atom to which they are attached is heterocyclopentyl.

Clause 277. The compound according to any one of clauses 264 to 269 wherein the C3- eheterocycloalkyl formed by R _4ab and R _5a together with the carbon atom to which they are attached is heterocyclohexyl.

Clause 278. The compound according to any one of clauses 263 or 265 to 273 wherein 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.

Clause 279. The compound according to clause 249 wherein R _4a and R _5ab 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(0)2R29 _b .

Clause 280. The compound according to clause 279 wherein the C _3-6 heterocycloalkyl is piperidinyl and the nitrogen atom is in the 4-position relative to the quaternary carbon: Clause 281. The compound according to clause 279 or 280 wherein R ₂ 9 _b is Ci-3alkyl.

Clause 282. The compound according to clause 281 wherein R _29b is methyl.

Clause 283. The compound according to either clause 279 or 280 wherein R ₂ 9 _b is N(Ci- ₃ alkyl) ₂ e.g. N(CH ₃ ) ₂ .

Clause 284. The compound according to either clause 279 or 280 wherein R ₂ 9 _b is 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl such as pyrazolyl substituted by methyl.

Clause 285. The compound according to any one of clauses 218 to 248 wherein R _4b and R ₅ are R _{4 b} and R _5b .

Clause 286. The compound according to any one of clauses 218 to 246 and 285 wherein R _4bb is H and R ₃ together with R _5bb form a 5- or 6-membered oxygen-containing

heterocycloalkyl such as tetrahydrofuranyl or tetrahydropyranyl.

Clause 287. The compound according to any one of clauses 218 to 246 and 285 wherein R _4bb together with R _5bb form a C _3-6 cycloalkyl.

Clause 288. The compound according to clause 287 wherein R _4bb together with R _5bb form cyclopropyl or cyclopentyl.

Clause 289. The compound according to any one of clauses 218 to 246 and 285 wherein R _4bb together with Rs _bb form a C _3-6 heterocycloalkyl.

Clause 290. The compound according to clause 289 wherein R _4bb together with R _5bb form heterocyclopentyl or heterocyclohexyl, such as tetrahydrofuranyl, pyrrolidinyl,

tetrahydropyranyl or piperidinyl such as tetrahydropyranyl or piperidinyl.

Clause 291. The compound according to any one of clauses 218 to 248 and 285, wherein

R _b is Ci. ₆ alkyl, in particular Ci. alkyl such as methyl, ethyl or propyl (n-propyl or isopropyl). Clause 292. The compound according to any one of clauses 218 to 248 and 285, wherein such as C _3-6 cycloalkyl, CialkyleneC _3-6 cycloalkyl or Clause 293. The compound according to any one of clauses 218 to 248 and 285, wherein R _4bb is OCi- ₆ alkyl, in particular OCi-4alkyl, such as methoxy or isopropoxy.

Clause 294. The compound according to any one of clauses 218 to 248 and 285, wherein R _4bb is OCo-2alkyleneC3-6cycloalkyl such as OC3-scycloalkyl, OCialkyleneC3-6cycloalkyl or OC2alkyleneC3-6cycloalkyl.

Clause 295. The compound according to any one of clauses 218 to 248 and 285, wherein R _4bb is Ci-3alkyleneOCi-3alkyl, in particular Ci-2alkyleneOCi-2alkyl, such as CH2CH2OCH3.

Clause 296. The compound according to any one of clauses 218 to 248 and 285, wherein R4 _bb is Ci- ₆ haloalkyl, in particular Ci-4haloalkyl.

Clause 297. The compound according to any one of clauses 218 to 248 and 285, wherein R _4bb is OCi- ₆ haloalkyl, in particular OCi-4haloalkyl.

Clause 298. The compound according to clause 218 to 248 and 285 wherein R _4bb is H.

Clause 299. The compound according to clause 218 to 248 and 285 wherein R _bb is halo such as F.

Clause 300. The compound according to clause 218 to 248 and 285 wherein R _bb is Ci- ealkylOH, such as CH ₂ CH ₂ OH.

Clause 301. The compound according to clause 218 to 248 and 285 wherein R4 _b is

NR21bR22b-

Clause 302. The compound according to clause 301 wherein R _{2i b} is H.

Clause 303. The compound according to clause 301 wherein R _{2i b} is Ci-salkyl, such as methyl, ethyl or propyl.

Clause 304. The compound according to clause 301 wherein R2i _b is C(0)Ci-salkyl, such as C(0)CH ₃ .

Clause 305. The compound according to clause 301 wherein R _{2i b} is C(0)OCi- ₅ alkyl, such as C(0)OCH ₃ or C(0)Otert-butyl.

Clause 306. The compound according to clause 301 wherein R2i _b is Ci- ₃ alkylOCi-2alkyl such as CH ₂ CH ₂ OCH _3.

Clause 307. The compound according to clause 301 wherein R _{2i b} is Ci-4haloalkyl such as CH2CHF2.

Clause 308. The compound according to clause 301 wherein R _{2i b} is C^heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane. Clause 309. The compound according to clause 301 to 308 wherein R ₂ 2 _b is H.

Clause 310. The compound according to clause 301 to 308 wherein R _22b is CH ₃ .

Clause 311. The compound according to any one of clauses 218 to 248 and 285 wherein R _bb is Co-2alkyleneC3-eheterocycloalkyl.

Clause 312. The compound according to any one of clauses 218 to 31 1 wherein any nitrogen atom in the C3-6heterocycloalkyl ring is substituted, for example by Ci-4alkyl, C(0)H, C(0)Ci_ ₄ alkyl, C(0)OCi_ ₄ alkyl, C(0)OCi_ ₄ alkylaryl such as C(0)OBz, C(0)NHCi_ ₄ alkyl, C(0)NHCi_ ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi. ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)OtBu, Ci- ₄ alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH3, and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH3.

Clause 313. The compound according to any one of clauses 218 to 31 1 wherein any nitrogen atom in the C _3-6 heterocycloalkyl ring is not substituted.

Clause 314. The compound according to any one of clauses 218 to 313 wherein any sulphur atom in the C _3-6 heterocycloalkyl ring is substituted, for example by one oxygen atom to form S=0 or by two oxygen atoms to form S(0) ₂ .

Clause 315. The compound according to any one of clauses 218 to 313 wherein any sulphur atom in the C _3-6 heterocycloalkyl ring is not substituted.

Clause 316. The compound according to any one of clauses 218 to 246 and 285 to 315, wherein R _5bb is H, methyl, ethyl or fluoro e.g. H, methyl or ethyl.

Clause 317. The compound according to clause 316, wherein Rs _bb is H.

Clause 318. The compound according to any one of clauses 218 to 246 and 285 to 316 wherein R _{4 t} and R _5bb are methyl.

Clause 319. The compound according to any one of clauses 218 to 246 and 285 to 316 wherein R _4bb and Rs _bb are ethyl.

Clause 320. The compound according to any one of clauses 218 to 246 and 285 wherein R _bb is H and R _5bb and R _6b are a C2-3alkylene chain forming a 5- or 6-membered ring, such as a 5-membered ring.

Clause 321. The compound according to any one of clauses 218 to 246 and 285 wherein R _4bb is O and R _5bb is absent.

Clause 322. The compound according to any one of clauses 218 to 246 and 285 wherein R _4bb is ethyl and Rs _bb is H and the groups are arranged in the S configuration. Clause 323. The compound according to any one of clauses 218 to 322 wherein A is A _ab . Clause 324. The compound according to clause 323 wherein A _a is -NR _6b CH ₂ -.

Clause 325. The compound according to clause 323 wherein A _ab is -NR _6b -.

Clause 326. The compound according to any one of clauses 218 to 322 wherein A is A _b . Clause 327. The compound according to clause 324 or 325 wherein R _6b is H.

Clause 328. The compound according to clause 324 or 325 wherein R _eb is Ci-3alkyl such as

CH ₃ .

Clause 329. The compound according to clause 324 or 325 wherein R _6b together with Rn _b in the ortho-position to group A _b are a C ₂ alkylene chain forming a 5-membered ring.

Clause 330. The compound according to any one of clauses 218 to 329 wherein Ar1 b is phenyl.

Clause 331. The compound according to any one of clauses 218 to 329 wherein Ar1 b is pyridyl.

Clause 332. The compound according to clause 331 wherein Ar1b is 2-pyridyl.

Clause 333. The compound according to any one of clauses 218 to 329 wherein Ar1 b is pyridazinyl.

Clause 334. The compound according to any one of clauses 218 to 329 wherein Ar1 b is pyrimidinyl.

Clause 335. The compound according to any one of clauses 218 to 329 wherein Ar1 b is pyrazinyl.

Clause 336. The compound according to any one of clauses 218 to 335 wherein Ri _0b is H.

Clause 337. The compound according to any one of clauses 218 to 335 wherein Rio _b is chloro or fluoro, such as fluoro.

Clause 338. The compound according to any one of clauses 218 to 335 wherein Ri _0b is methoxy or ethoxy such as methoxy.

Clause 339. The compound according to any one of clauses 218 to 335 wherein Rio _b is Ci_ ₃ alkyl.

Clause 340. The compound according to clause 339 wherein Ri _0b is methyl.

Clause 341. The compound according to any one of clauses 218 to 335 wherein Ri _0b is OCF ₃ . Clause 342. The compound according to any one of clauses 218 to 335 wherein Ri _0b is CF ₃ .

Clause 343. The compound according to any one of clauses 218 to 335 wherein Ri _0b is CN.

Clause 344. The compound according to any one of clauses 337 to 343 wherein Ri _0b is in the ortho or meta position with respect to group A _b , such as the ortho position with respect to group A _b .

Clause 345. The compound according to any one of clauses 218 to 334 wherein Rn is H.

Clause 346. The compound according to any one of clauses 218 to 334 wherein Rn _b is fluoro.

Clause 347. The compound according to any one of clauses 218 to 334 wherein Rn is methyl.

Clause 348. The compound according to clause 346 or 347 wherein Rn is in the ortho or meta position with respect to group A , such as the ortho position with respect to group A .

Clause 349. The compound according to any one of clauses 218 to 348 wherein Ar2b is phenyl.

Clause 350. The compound according to any one of clauses 218 to 348 wherein Ar2b is pyridyl.

Clause 351. The compound according to clause 350 wherein Ar2b is 3-pyridyl.

Clause 352. The compound according to any one of clauses 218 to 348 wherein Ar2b is pyridazinyl.

Clause 353. The compound according to any one of clauses 218 to 348 wherein Ar2b is pyrimidinyl.

Clause 354. The compound according to any one of clauses 218 to 348 wherein Ar2b is pyrazinyl.

Clause 355. The compound according to any one of clauses 218 to 354 wherein Ri _2b is H. Clause 356. The compound according to any one of clauses 218 to 354 wherein Ri _åb is halo, such as F or Cl.

Clause 357. The compound according to any one of clauses 218 to 354 wherein Ri _2b is Ci- ₄ alkyl, such as ethyl or methyl, especially methyl.

Clause 358. The compound according to any one of clauses 218 to 354 wherein Ri _2b is C _{2. 4} alkynyl, such as CºCH. Clause 359. The compound according to any one of clauses 218 to 354 wherein Ri _2b is Co- ₂ alkyleneC3-5cycloalkyl, such as cyclopropyl.

Clause 360. The compound according to any one of clauses 218 to 354 wherein Ri ₂ is OCi- ₄ alkyl such as methoxy, ethoxy, isopropoxy or n-propoxy.

Clause 361. The compound according to any one of clauses 218 to 354 wherein Ri _2b is OCo- ₂ alkyleneC3-5cycloalkyl, such as cyclopropoxyl or cyclobutoxy.

Clause 362. The compound according to any one of clauses 218 to 354 wherein Ri _2b is OCH ₂ CH ₂ N(CH ₃ )2

Clause 363. The compound according to any one of clauses 218 to 354 wherein Ri _2b is Ci- ₄ alkylOH, such as CH ₂ OH or C(CH ₃ ) OH.

Clause 364. The compound according to any one of clauses 218 to 354 wherein Ri ₂ is CN.

Clause 365. The compound according to any one of clauses 218 to 354 wherein Ri ₂ is Ci- ₃ alkyleneOCi-3alkyl.

Clause 366. The compound according to any one of clauses 218 to 354 wherein Ri _2b is Ci- ₄ haloalkyl, such as CF ₃ .

Clause 367. The compound according to any one of clauses 218 to 354 wherein Ri _2b is OCi- ₄ haloalkyl, such as OCF3, OCHF ₂ or OCH ₂ CF3.

Clause 368. The compound according to any one of clauses 218 to 354 wherein Ri ₂ is C(=0)Ci- ₂ alkyl, such as C(=0)Chl ₃ .

Clause 369. The compound according to any one of clauses 218 to 354 wherein Ri ₂ is NR _23b R _24b .

Clause 370. The compound according to clause 369 wherein Ri _2b is N(CH3)2.

Clause 371. The compound according to clause 369 wherein R _12b is N(FI)Et.

Clause 372. The compound according to any one of clauses 218 to 354 wherein Ri ₂ is SC>2Ci- ₄ alkyl.

Clause 373. The compound according to clause 372 wherein Ri _2b is SO2CFI3.

Clause 374. The compound according to any one of clauses 218 to 354 wherein Ri ₂ is C(0)N(CH ₃ ) ₂ .

Clause 375. The compound according to any one of clauses 218 to 354 wherein Ri _2b is NHC(0)Ci- ₃ alkyl such as NHC(0)CH ₃ . Clause 376. The compound according to any one of clauses 218 to 354 wherein Ri _2b is OH.

Clause 377. The compound according to any one of clauses 218 to 354 wherein Ri _2b is C _{3. 6} heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b such as a Csheterocycloalkyl or Ceheterocycloalkyl, and in particular pyrrolidinyl.

Clause 378. The compound according to any one of clauses 218 to 354 wherein Ri _2b together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ).

Clause 379. The compound according to any one of clauses 218 to 378 wherein Ri _2b is in the meta position of Ar2b.

Clause 380. The compound according to any one of clauses 218 to 378 wherein Ri _2b is in the ortho position of Ar2b.

Clause 381. The compound according to any one of clauses 218 to 380 wherein Ri _3b is H.

Clause 382. The compound according to any one of clauses 218 to 380 wherein Ri _3b is methyl.

Clause 383. The compound according to clause 382 wherein Ri _3b is in the ortho position with respect to Ar1 b.

Clause 384. The compound according to clause 382 wherein Ri _3b is in the para position with respect to Ar1 b.

Clause 385. The compound according to any one of clauses 218 to 384 wherein Ri _b is Ri _ab and R _4b and R _5b are R _4ab and R _5ab .

Clause 386. The compound according to any one of clauses 218 to 384 wherein Ri is Ri _a and A is A _a .

Clause 387. The compound according to any one of clauses 218 to 384 wherein R _4b and Rs _b are R _4ab and Rs _ab and A _b is A _ab .

Clause 388. The compound according to any one of clauses 218 to 384 wherein Ri _b is Ri _ab , R _b and R _5b are R _4ab and R _5ab and A _b is A _ab .

Clause 389. A compound of the example T466.

Clause 390. A compound of formula (ll-b):

wherein Ri, R ₃ , R ₄ and R ₅ are as defined in any one of clauses 218 to 389 and R is H, Ci-salkyl (e.g. methyl and ethyl) or benzyl.

Clause 391. A compound of formula (X-b):

X = Cl, Br, B(OH) ₂ , Bpin (X-b)

wherein Ar1 , Ri, R ₃ , R ₄ , Rs and R ₆ are as defined in any one of clauses 218 to 389.

Clause 392. A compound of formula (Xll-b):

wherein Ri, R ₃ , R ₄ and R ₅ are as defined in any one of clauses 218 to 389.

Clause 393. The compound of formula (I) according to clause 1 wherein the compound of formula (I) is a compound of formula (l-c).

Clause 394. The compound according to clause 393 wherein Ri _c is Ri _ac .

Clause 395. The compound according to clause 394 wherein Ri _ac is NR ₃ 2 _C R33 _c and wherein R _32C is Ci. ₃ alkyl and R _33c is Ci. ₃ alkyl.

Clause 396. The compound according to clause 395 wherein R _32c is methyl or ethyl.

Clause 397. The compound according to clause 396 wherein R _32c is methyl.

Clause 398. The compound according to any one of clauses 395 to 397 wherein R _33c is methyl or ethyl.

Clause 399. The compound according to clause 398 wherein R _33c is methyl.

Clause 400. The compound according to any one of clauses 397 to 399 wherein R _32c is methyl and R _33C is methyl.

Clause 401. The compound according to clause 394 wherein Ri _ac is NR ₃ 2 _c R33 _c and R _32c and R _33C together with the nitrogen atom to which they are attached form a C ₃ -5heterocycloalkyl. Clause 402. The compound according to clause 401 wherein the C3-sheterocycloalkyl is selected from the group consisting of aziridine, azetidine and pyrrolidine.

Clause 403. The compound according to clause 393 wherein Ri _c is Ri _bc .

Clause 404. The compound according to clause 403 wherein Ri _bc is Ci-salkyl.

Clause 405. The compound according to clause 403 wherein Ri _b0 is Ci-3alkyleneOCi-2alkyl.

Clause 406. The compound according to clause 405 wherein Ri _bc is Ci-2alkyleneOCi-2alkyl.

Clause 407. The compound according to clause 403 wherein Ri _bc is Co-2alkyleneC3-5cycloalkyl which cycloalkyl is optionally substituted by CH ₃ .

Clause 408. The compound according to clause 407 wherein Ri _bc is Co-ialkyleneC3-4cycloalkyl which cycloalkyl is optionally substituted by Ch .

Clause 409. The compound according to clause 408 wherein Ri _bc is Co-ialkyleneC3- ₄ cycloalkyl.

Clause 410. The compound according to any one of clauses 407 or 409 wherein Ri _bc is C3- ₄ cycloalkyl.

Clause 41 1. The compound according to clause 410 wherein Ri _bc is cyclopropyl. Clause 412. The compound according to clause 408 wherein Ri _bc is Co-ialkyleneC3-4cycloalkyl which cycloalkyl is substituted by CH ₃ .

Clause 413. The compound according to any one of clauses 393 to 412 wherein R3 _C is H.

Clause 414. The compound according to any one of clauses 393 to 412 wherein R _3c is Me.

Clause 415. The compound according to any one of clauses 393 to 412 wherein R _3c is halo. Clause 416. The compound according to clause 415 wherein R3 _C is F.

Clause 417. The compound according to clause 415 wherein R _3c is Cl.

Clause 418. The compound according to any one of clauses 393 to 412 wherein R _3c is OC1- ₂ alkyl.

Clause 419. The compound according to any one of clauses 393 to 412 wherein R3 _c is OCF3. Clause 420. The compound according to any one of clauses 393 to 412 wherein R _3c is CF ₃ .

Clause 421. The compound according to any one of clauses 393 to 420 wherein R4 _c and R50 are R _4ac and R _5ac.

Clause 422. The compound according to clause 421 wherein R _4a c and R _5ac 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 Ci-3alkyl, oxo, OH, Ci-3alkylOH, Ci-3haloalkyl, Co-2alkyleneC3-6cycloalkyl, Co- ₂ alkyleneC ₃ - ₆ heterocycloalkyl, Ci-3alkyleneOCi-3alkyl, halo, OCi-3haloalkyl, OCo-2alkyleneC3-6cycloalkyl, OCo- ₂ alkyleneC3-6heterocycloalkyl, OCi-3alkyl and NR210R22 _G .

Clause 423. The compound according to clause 422 wherein R4 _ac and Rs _ac together with the carbon atom to which they are attached form a C3-6cycloalkyl which is substituted by one substituent.

Clause 424. The compound according to clause 422 or 423 wherein each substituent is independently selected from the group consisting of Ci-3alkyl, oxo, OH, Ci-3alkylOH, Ci- ₃ haloalkyl, halo, OCi-3haloalkyl, OCi-3alkyl and NR ₂ I _C R _22o .

Clause 425. The compound according to clause 424 wherein each substituent is

independently selected from the group consisting of oxo, OH, halo, OCi-3alkyl and NR ₂ I _C R22 _C , such as oxo, OH, fluoro and NR ₂ I _C R22 _C .

Clause 426. The compound according to any one of clauses 422 to 425 wherein R ₂ I _C is H.

Clause 427. The compound according to any one of clauses 422 to 425 wherein R ₂ I _C is Ci_ 5alkyl, such as methyl, ethyl or propyl.

Clause 428. The compound according to any one of clauses 422 to 425 wherein R ₂ I _C is C(0)Ci- ₅ alkyl, such as C(0)CH ₃ .

Clause 429. The compound according to any one of clauses 422 to 425 wherein R ₂ I _C is C(0)0Ci- ₅ alkyl, such as C(0)0CH ₃ or C(0)Otert-butyl.

Clause 430. The compound according to any one of clauses 422 to 425 wherein R ₂ I _C is Ci_ 3alkylOCi- ₂ alkyl such as CH ₂ CH ₂ OCH3.

Clause 431. The compound according to any one of clauses 422 to 425 wherein R _21c is Ci- ₄ haloalkyl such as CH ₂ CHF ₂ .

Clause 432. The compound according to any one of clauses 422 to 425 wherein R ₂ I _C is C _{4. 6} heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.

Clause 433. The compound according to any one of clauses 422 to 432 wherein R _22c is H.

Clause 434. The compound according to any one of clauses 422 to 432 wherein R _22c is CH ₃ .

Clause 435. The compound according to clause 421 wherein R _4ac and Rs _ac together with the carbon atom to which they are attached form a C3-6cycloalkyl wherein one of the carbons of the C3-6cycloalkyl is a spiro centre such that a spirocyclic ring system is formed by the C3- ₆ cycloalkyl ring and a further C3-6cycloalkyl ring or a C ₃ -sheterocycloalkyl ring, and wherein the C3-6cycloalkyl 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 Ci-3alkyl or OCi-3alkyl.

Clause 436. The compound according to clause 421 wherein R _4ac and R _5ac 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 C3-6Cheterocycloalkyl ring and a further C3-6cycloalkyl ring or a C3-6heterocycloalkyl ring, and wherein the C _3-6 heteroydoalkyl 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 Ci-3alkyl or OCi-3alkyl.

Clause 437. The compound according to either clause 435 or 436 wherein R _ac and R _5ac together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3- ₆ heteroydoalkyl which is substituted by one substituent.

Clause 438. The compound according to clause 435 or 436 wherein R _ac and R _5ac together with the carbon atom to which they are attached form a C3-6cycloalkyl or C3-6heteroycloalkyl which is unsubstituted.

Clause 439. The compound according to any one of clauses 435 to 438 wherein each substituent is independently selected from the group consisting of Ci-2alkyl or OCH ₃ .

Clause 440. The compound according to any one of clauses 435 to 439 wherein a spirocyclic ring system is formed by the C3-6cycloalkyl or C3-6heteroycloalkyl ring and a further C3- ₆ cycloalkyl ring.

Clause 441. The compound according to any one of clauses 435 to 439 wherein a spirocyclic ring system is formed by the C _3-6 cycloalkyl or C3-6heteroycloalkyl ring and a further C ₃ - eheterocycloalkyl ring.

Clause 442. The compound according to any one of clauses 435 or 437 to 441 wherein the C3-6cycloalkyl formed by R _4ac and Rs _ao together with the carbon atom to which they are attached is cyclopropyl.

Clause 443. The compound according to any one of clauses 435 or 437 to 441 wherein the C _3-6 cycloalkyl formed by R _4ac and R _5ac together with the carbon atom to which they are attached is cyclobutyl.

Clause 444. The compound according to any one of clauses 435 or 437 to 441 wherein the C3-6cycloalkyl formed by R _4ac and R _5ao together with the carbon atom to which they are attached is cyclopentyl. Clause 445. The compound according to any one of clauses 435 or 437 to 441 wherein the C3-6cycloalkyl formed by R _4ac and R _5ac together with the carbon atom to which they are attached is cyclohexyl.

Clause 446. The compound according to any one of clauses 436 to 441 wherein the C3- ₆ heterocycloalkyl formed by R _4ac and Rs _ac together with the carbon atom to which they are attached is heterocyclopropyl.

Clause 447. The compound according to any one of clauses 436 to 441 wherein the C3- ₆ heterocycloalkyl formed by R _ac and R _5ac together with the carbon atom to which they are attached is heterocyclobutyl. Clause 448. The compound according to any one of clauses 436 to 441 wherein the C3- ₆ heterocycloalkyl formed by R _ac and R _5ac together with the carbon atom to which they are attached is heterocyclopentyl.

Clause 449. The compound according to any one of clauses 436 to 441 wherein the C3- eheterocycloalkyl formed by R _4ac and R _ac together with the carbon atom to which they are attached is heterocyclohexyl.

Clause 450. The compound according to any one of clauses 435 or 437 to 445 wherein one of the carbons is quaternary and is attached to a 5-membered dioxolane ring to form the following structure:

wherein m is 1 or 2 and n is 0, 1 or 2.

Clause 451. The compound according to clause 421 wherein R _4ac and R _5ac 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(0)2R29c.

Clause 452. The compound according to clause 451 wherein the C _3-6 heterocycloalkyl is piperidinyl and the nitrogen atom is in the 4-position relative to the quaternary carbon: Clause 453. The compound according to clause 451 or 452 wherein R29 _C is Ci-3alkyl.

Clause 454. The compound according to clause 453 wherein R ₂ 9 _C is methyl.

Clause 455. The compound according to either clause 451 or 452 wherein R ₂ 9 _C is N(Ci- ₃ alkyl) ₂ e.g. N(CH ₃ ) ₂ .

Clause 456. The compound according to either clause 451 or 452 wherein R _2gc is 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl such as pyrazolyl substituted by methyl.

Clause 457. The compound according to any one of clauses 393 to 420 wherein R _4c and R _5c are R _4bc and R _5bc .

Clause 458. The compound according to any one of clauses 393 to 420 and 457 wherein R _{4 c} is H.

Clause 459. The compound according to any one of clauses 393 to 420 and 457 wherein R _4bc is Ci- ₆ alkyl.

Clause 460. The compound according to clause 459 wherein R _4b0 is Ci- ₄ alkyl.

Clause 461. The compound according to clause 460 wherein R _4bc is methyl or ethyl.

Clause 462. The compound according to any one of clauses 393 to 420 and 457 wherein R _4bc is Co-2alkyleneC3-ecycloalkyl.

Clause 463. The compound according to clause 462 wherein R _4bG is Co- ₂ alkyleneC3-5cycloalkyl. Clause 464. The compound according to any one of clauses 393 to 420 and 457 wherein R _4bc is Ci-3alkyleneOCi-3alkyl such as CH2CH2OCH3.

Clause 465. The compound according to any one of clauses 393 to 420 and 457 wherein R _c is Co-2alkyleneC3-6heterocycloalkyl.

Clause 466. The compound according to any one of clauses 393 to 420 and 457 wherein R _4bc is Ci- ₆ alkylOH.

Clause 467. The compound according to clause 466 wherein R _4bc is Ci- ₄ alkylOH. Clause 468. The compound according to clause 393 to 420 and 457 wherein R _bc is Ci- ₆ haloalkyl.

Clause 469. The compound according to clause 468 wherein R _4bc is Ci- ₄ haloalkyl.

Clause 470. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R _bc is H.

Clause 471. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein Rs _bc is Ci-salkyl.

Clause 472. The compound according to clause 471 wherein R _{5 c} is Ci- ₄ alkyl.

Clause 473. The compound according to clause 472 wherein R _5bc is methyl or ethyl.

Clause 474. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R _5bc is Co-2alkyleneC ₃ -6cycloalkyl.

Clause 475. The compound according to clause 474 wherein R _{5 c} is Co-2alkyleneC3-5cycloalkyl.

Clause 476. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R _5bc is Co-2alkyleneC3-6heterocycloalkyl.

Clause 477. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R _5bc is Ci- ₃ alkyleneOCi-3alkyl such as CH2CH2OCH3.

Clause 478. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R _5bc is Ci-salkylOH.

Clause 479. The compound according to clause 478 wherein Rs _bc is Ci- ₄ alkylOH.

Clause 480. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R _5bc is Ci- ₆ haloalkyl.

Clause 481. The compound according to clause 480 wherein R _5bc is Ci- ₄ haloalkyl.

Clause 482. The compound according to any one of clauses 393 to 420 wherein R _4bc and Rs _bc together with the carbon atom to which they are attached form a C3-6cycloalkyl such as cyclopropyl.

Clause 483. The compound according to any one of clauses 393 to 420 wherein R _4bc and R _5bc together with the carbon atom to which they are attached form a C ₃ -eheterocycloalkyl such as tetrahydropyranyl or piperidinyl.

Clause 484. The compound according to any one of clauses 393 to 483 wherein at least one, such as one, nitrogen atom of a C3-6heterocycloalkyl ring is substituted, for example by Ci- ₄ alkyl, C(0)H, C(0)Ci. ₄ alkyl, C(0)OCi. ₄ alkyl, C(0)OCi. ₄ alkylaryl such as C(0)OBz, C(0)NHCi. ₄ alkyl, C(0)NHCi- ₄ alkylaryl such as C(0)NHBz, an Fmoc group, C(0)Ci- ₄ haloalkyl, C(0)OCi- ₄ haloalkyl or C(0)NHCi- ₄ haloalkyl such as C(0)OtBu, Ci-4alkylCN such as CH ₂ CN, C(0)Ci- ₃ alkyl0Ci- ₂ alkyl such as C(0)CH ₂ 0CH ₃ , and Ci- ₂ alkylC(0)0Ci- ₄ alkyl such as CH ₂ C(0)0CH ₂ CH ₃ ..

Clause 485. The compound according to any one of clauses 393 to 483 wherein any nitrogen atom in the C3-6heterocycloalkyl ring is not substituted.

Clause 486. The compound according to any one of clauses 393 to 485 wherein at least one, such as one, sulphur atom of a C3-eheterocycloalkyl ring is substituted, for example by one oxygen atom to form S=0 or by two oxygen atoms to form S(0) ₂ .

Clause 487. The compound according to any one of clauses 393 to 485 wherein any sulphur atom in the C3-6heterocycloalkyl ring is not substituted.

Clause 488. The compound according to any one of clauses 393 to 470 wherein R _4bc and R _{5 c} are both H .

Clause 489. The compound according to any one of clauses 393 to 473 wherein R _4bc and Rs _bc are both methyl.

Clause 490. The compound according to any one of clauses 393 to 473 wherein R _bc and R _5bc are both ethyl.

Clause 491. The compound according to any one of clauses 393 to 470 wherein R _4bc is ethyl and R _5bc is H.

Clause 492. The compound according to clause 491 wherein F?4 _bc and Rs _bc are arranged in an S configuration.

Clause 493. The compound according to any one of clauses 393 to 492 wherein A _c is - CH ₂ NR _6c -.

Clause 494. The compound according to any one of clauses 393 to 492 wherein A _c is A _bc .

Clause 495. The compound according to clause 493 wherein R _6c is H.

Clause 496. The compound according to clause 493 wherein R _ec is Ci-3alkyl.

Clause 497. The compound according to clause 496 wherein R _6C is methyl.

Clause 498. The compound according to clause 496 wherein R _6c is ethyl.

Clause 499. The compound according to any one of clauses 393 to 498 wherein Ar1c is phenyl.

Clause 500. The compound according to any one of clauses 393 to 498 wherein Ar1c is 2- pyridyl. Clause 501. The compound according to any one of clauses 393 to 500 wherein Ar2c is 3- pyridyl.

Clause 502. The compound according to any one of clauses 393 to 500 wherein Ar2c is 2,5- pyrazinyl.

Clause 503. The compound according to any one of clauses 393 to 502 wherein Ri _0c is H.

Clause 504. The compound according to any one of clauses 393 to 502 wherein Ri _0c is halo such as F.

Clause 505. The compound according to any one of clauses 393 to 502 wherein Ri _0c is Ci- ₃ alkyl such as methyl.

Clause 506. The compound according to any one of clauses 393 to 502 wherein Ri _0c is OCi- ₂ alkyl such as OCH ₃ .

Clause 507. The compound according to any one of clauses 393 to 502 wherein Ri _0c is Ci- ₂ haloalkyl such as CF ₃ .

Clause 508. The compound according to any one of clauses 393 to 502 wherein Ri _0c is OCi- ₂ haloalkyl.

Clause 509. The compound according to any one of clauses 393 to 502 wherein Rio _c is CN.

Clause 510. The compound according to any one of clauses 504 to 509 wherein Ri _0c is ortho to group A _c .

Clause 511. The compound according to any one of clauses 393 to 510 wherein Rn _c is H. Clause 512. The compound according to any one of clauses 393 to 510 wherein Rn _c is F.

Clause 513. The compound according to any one of clauses 393 to 510 wherein Rn _c is Cl.

Clause 514. The compound according to any one of clauses 393 to 510 wherein Rn _c is CH ₃ .

Clause 515. The compound according to any one of clauses 393 to 510 wherein Rn _c is ethyl.

Clause 516. The compound according to any one of clauses 393 to 510 wherein Rn _c is OCH ₃ .

Clause 517. The compound according to any one of clauses 393 to 510 wherein Rn _c is CF ₃ .

Clause 518. The compound according to any one of clauses 393 to 510 wherein Rn _c is

OCF ₃ .

Clause 519. The compound according to any one of clauses 393 to 510 wherein Rn _c is CN. Clause 520. The compound according to any one of clauses 393 to 519 wherein RI _2C is H.

Clause 521. The compound according to any one of clauses 393 to 519 wherein RI _2C is halo such as fluoro or chloro.

Clause 522. The compound according to any one of clauses 393 to 519 wherein RI _2C is Ci- ₄ alkyl such as CH ₃ or ethyl.

Clause 523. The compound according to any one of clauses 393 to 519 wherein RI _2C is C _2. 4alkynyl.

Clause 524. The compound according to clause 523 wherein RI _2C is C ₂ alkynyl.

Clause 525. The compound according to any one of clauses 393 to 519 wherein RI _2C is C(=0)Ci- ₂ alkyl such as C(=0)CH ₃ .

Clause 526. The compound according to any one of clauses 393 to 519 wherein RI _2C is C _{0. 2} alkyleneC ₃ .5 cycloalkyl.

Clause 527. The compound according to any one of clauses 393 to 519 wherein RI _2C is OCi- ₄ alkyl such as OCH ₃ , OEt or OiPr.

Clause 528. The compound according to any one of clauses 393 to 519 wherein RI _2C is Ci_ ₃ alkyleneOCi- ₃ alkyl.

Clause 529. The compound according to any one of clauses 393 to 519 wherein RI _2C is Ci- ₄ haloalkyl such as CF ₃ .

Clause 530. The compound according to any one of clauses 393 to 519 wherein RI _2C is OCi- haloalkyl such as OCH ₂ CF ₃ .

Clause 531. The compound according to any one of clauses 393 to 519 wherein RI _2C is CN.

Clause 532. The compound according to any one of clauses 393 to 519 wherein RI _2C is OC ₀ -

₂ alkyleneC _3-5 cycloalkyl.

Clause 533. The compound according to any one of clauses 393 to 519 wherein RI _2C is OCH ₂ CH ₂ N(CH ₃ ) _2.

Clause 534. The compound according to any one of clauses 393 to 519 wherein RI _2C is OH.

Clause 535. The compound according to any one of clauses 393 to 519 wherein RI _2C is Ci-

₄ alkylOH.

Clause 536. The compound according to any one of clauses 393 to 519 wherein RI _2C is NR _23c R _24c . Clause 537. The compound according to clause 536 wherein R ₂ 3 _c is H.

Clause 538 The compound according to clause 536 wherein R ₂ 3 _c is Ci- ₂ alkyl such as CH ₃ .

Clause 539. The compound according to any one of clauses 536 to 538 wherein R _24c is H.

Clause 540. The compound according to any one of clauses 536 to 538 wherein R _24c is Ci- ₂ alkyl such as CH3.

Clause 541. The compound according to any one of clauses 393 to 519 wherein Ri _2c is S0 ₂ CH ₃ .

Clause 542. The compound according to any one of clauses 393 to 519 wherein R _I2C is C(0)N(CH ₃ ) ₂ .

Clause 543. The compound according to any one of clauses 393 to 519 wherein R _I2C is NHC(0)Ci. ₃ alkyl.

Clause 544. The compound according to any one of clauses 393 to 519 wherein R _I2C is a C3- ₆ heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c.

Clause 545. The compound according to any one of clauses 393 to 519 wherein R _I2C together with a nitrogen atom to which it is attached forms an N-oxide (N ⁺ -0 ).

Clause 546. The compound according to any one of clauses 521 to 545 wherein R _I2C is attached at the meta position of Ar2c.

Clause 547. The compound according to any one of clauses 521 to 545 wherein R _I2C is attached at the ortho position of Ar2c.

Clause 548. The compound according to any one of clauses 393 to 547 wherein Ri _c is Ri _ac and R _4C and Rs _c are R _4ac and Rsac.

Clause 549. The compound according to any one of clauses 393 to 547 wherein Ri _c is Ri _ac and A _c is A _ac .

Clause 550. The compound according to any one of clauses 393 to 547 wherein R _4c and R _5o are R _4ac and Rs _ac and A _c is A _ac .

Clause 551. The compound according to any one of clauses 393 to 547 wherein Ri _c is Ri _ac , R _4C and R _5C are R _4ac and R _5ac and A _c is A _ac .

Clause 552. A compound which is R94 or R95.

Clause 553. A compound of formula (ll-c): wherein Ri, R ₃ , R ₄ and R ₅ are as defined in clause 393.

Clause 554. A compound of formula (Vlll-c):

wherein Ri, R ₃ and R ₄ are as defined in clause 393.

Clause 555. A compound according to any one of clauses 1 to 554 which is in the form of a salt.

Clause 556. A compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552, for use as a medicament.

Clause 557. The compound according to clause 556, for use in the inhibition of CTPS1 in a subject.

Clause 558. The compound according to clause 556, for use in the reduction of T-cell and/or B-cell proliferation in a subject.

Clause 559. The compound according to clause 556, for use in the treatment or prophylaxis of: 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; or transplantation.

Clause 560. The compound according to clause 556, for use in the treatment or prophylaxis of myasthenia gravis, multiple sclerosis or scleroderma/systemic sclerosis.

Clause 561. A compound according to clause 556, for use in the treatment of cancer.

Clause 562. A method for treating cancer in a subject, by administering to a subject in need thereof a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552.

Clause 563. Use of a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552, in the manufacture of a medicament for the treatment of cancer in a subject. Clause 564. The compound according to clause 561 , the method according to clause 562 or the use according to clause 563 wherein the cancer is a haematological cancer.

Clause 565. The compound, method or use according to clause 564 wherein the haematological cancer is selected from the group consisting of 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) and chronic lymphocytic leukemia.

Clause 566. The compound according to clause 561 , the method according to clause 562 or the use according to clause 563 wherein the cancer is a non-haematological cancer such as bladder cancer, breast cancer, melanoma, neuroblastoma, malignant pleural mesothelioma and sarcoma, such as breast cancer and melanoma.

Clause 567. The compound according to clause 556, for use in enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject.

Clause 568. A method for enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject, by administering to a subject in need thereof a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552.

Clause 569. Use of a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552, in the manufacture of a medicament for enhancing recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject.

Clause 570. A method for the inhibition of CTPS1 in a subject, which comprises administering to the subject an effective amount of a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552. Clause 571. Use of a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552, in the manufacture of a medicament for the inhibition of CTPS1 in a subject.

Clause 572. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 204, 218 to 389 or 393 to 552.

Clause 573. The compound, method, use or composition according to any one of clauses 556 to 572, for administration to a human subject.

Clause 574. The compound, method, use or composition according to any one of clauses 556 to 573, for administration in conjunction with a further pharmaceutically acceptable active ingredient or ingredients. Clause 575. The compound, method, use or composition according to any one of clauses 556 to 574, for topical administration to the skin, eye or gut.

Clause 576. The compound according to any one of clauses 1 to 555, which is in natural isotopic form.

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