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:

[Image Omitted]

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 al. 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/II 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 al. 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 VNO2019/106156, WO2019/106146, WO02019/179652 and WO2019/180244 and WO2020/083975 disclose CTPS1 inhibitors.

SUMMARY OF THE INVENTION

The invention provides a compound of formula (I):

[Image Omitted]

wherein ring B is selected from the group consisting of:

[Image Omitted]

- wherein X, Y and Z are as defined below; and

[Image Omitted]

- wherein R_3b3cis R_3bor R_3cas defined below;

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

[Image Omitted]

- wherein:
- A_ais A_aaor A_ba;
  - wherein:
  - A_aais an amine linker having the following structure: —NH—, —CH₂NH— or —NHCH₂—;
  - A_bais an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—;
- X is N or CH;
- Y is N or CR_2a;
- Z is N or CR_3a,
  - with the proviso that when at least one of X or Z is N, Y cannot be N;
- R_2ais H, halo, C_1-2alkyl, OC_1-2alkyl, C_1-2haloalkyl or OC_1-2haloalkyl; and
- R_3ais H, halo, CH₃, OCH₃, CF₃or OCF₃;
  - wherein at least one of R_2aand R_3ais H;
- R_1ais R_1aaor R_1ba;
  - wherein:
  - R_1aais NR_32aR_33a;
  - R_1bais C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃;
- R_4aand R_5aare R_4aaand R_5aa, or R_4baand R_5ba;
  - wherein:
  - R_4aaand R_5aatogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21aR_22a; 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aaand R_5aatogether 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aaand R_5aatogether 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(O)₂R_29a; or
  - R_4baand R_5baare each independently H, C_1-6alkyl, C_1-6alkylOH, C_1-6haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl; and
  - when A_ais —NHC(═O)— or —NHCH₂—:
  - R_4baand R_5bamay additionally be selected from halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl and NR_21aR_22a;
- Ar1a is a 6-membered aryl or heteroaryl;
- Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A_a;
- R_10ais H, halo, C_1-3alkyl, C_1-2haloalkyl, OC_1-2alkyl, OC_1-2haloalkyl or CN;
- R_11ais H, F, Cl, C_1-2alkyl, CF₃, OCH₃or CN;
- R_12ais attached to Ar2 in the ortho or meta position relative to Ar1a and R_12ais H, halo, C_1-4alkyl, C_2-4alkenyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, C_1-4haloalkyl, OC_1-4haloalkyl, hydroxy, C_1-4alkylOH, SO₂C_1-2alkyl, C(O)N(C_1-2alky)₂, NHC(O)C_1-3alkyl or NR_23aR_24a; and
  - when A_ais —NHC(═O)—, —NH— or —NHCH₂—:
  - R_12amay additionally be selected from CN, OCH₂CH₂N(CH₃)₂and a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_13ais H or halo;
- R_21ais H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl, C_1-3alkylOC_1-2alkyl, C_1-4haloalkyl, or C_4-6heterocycloalkyl;
- R_22ais H or CH₃;
- R_23ais H or C_1-2alkyl; and
- R_24ais H or C_1-2alkyl
- R_29ais C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, CF₃, N(C_1-3alkyl)₂, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl;
- R_32ais C_1-3alkyl and R₃₃is C_1-3alkyl; or
- R_32aand R_33atogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl;
- wherein:
- R_1ais R_1aa; and/or
- R_4aand R_5aare R_4aaand R_5aa; and/or
- A_ais A_aa; and

wherein when B is (B-bc) and R_3b3cis R_3b, the compound of formula (I) is a compound of formula (I-b):

[Image Omitted]

- A_bis A_abor A_bb;
- wherein:
  - A_abis —NR_6bCH₂— or —NR_6b—;
  - A_bbis —NR_6bC(═O)—;
- R_1bis R_1abor R_1bb;
- wherein:
  - R_1abis NR_32bR_33b;
  - R_1bbis C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, C_1-3alkyleneOC_1-2alkyl, or CF₃;
- R_3bis H, halo, CH₃, OC_1-2alkyl or CF₃;
- or R_3btogether with R_5bbforms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl;
- R_4band R_5bare either R_4aband R_5abor R_4bband R_5bb;
- wherein:
  - R_4aband R_5abtogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21bR_22b; 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_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aband R_5abtogether 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(O)₂R_29b; or
  - R_4bband R_5bbare each independently H, halo, C_1-6alkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl, OC_0-2alkyleneC_3-6cycloalkyl, C_1-3alkyleneOC_1-3alkyl, C_1-6alkylOH, C_1-6haloalkyl, OC_1-6haloalkyl or NR_21bR_22b,
    - or R_4bbis H and R_5bbtogether with R_3bform a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl,
    - or R_4bband R_5bbtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl,
    - or R_4bbis H and R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring;
    - or R_4bbis O and R_5bbis absent;
- R_6bis H or C_1-3alkyl,
  - or R_6btogether with R_11bwhen in the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring,
  - or R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring and R_4bbis H;
- Ar1b is 6-membered aryl or heteroaryl;
- Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A_b;
- R_10bis H, halo, C_1-3alkyl, OC_1-2alkyl, C_1-2haloalkyl, OC_1-2haloalkyl or CN;
- R_11bis H, F, Cl, CH₃, ethyl, OCH₃, CF₃, OCF₃or CN,
  - or R_11b, when in the ortho-position to group A_b, together with R_6bare a C₂alkylene chain forming a 5-membered ring;
- R_12bis attached to Ar2b in the ortho or meta position relative to Ar1b and R_12bis H, halo, C_1-4alkyl, C_2-4alkynyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, OCH₂CH₂N(CH₃)₂, OH, C_1-4alkylOH, CN, C_1-3alkyleneOC_1-2alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, C(═O)C_1-2alkyl, NR_23bR_24b, SO₂C_1-4alkyl, SOC_1-4alkyl, SC_1-4alkyl, SH, C(O)N(CH₃)₂, NHC(O)C_1-3alkyl, C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R_12btogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_13bis H, halo, CH₃or OCH₃;
- R_21bis H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl, C_1-3alkylOC_1-2alkyl, C_1-4haloalkyl, or C_4-6heterocycloalkyl;
- R_22bis H or CH₃;
- R_23bis H or C_1-2alkyl;
- R_24bis H or C_1-2alkyl;
- R_29bis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, CF₃, N(C_1-3alkyl)₂, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and
- R_32bis C_1-3alkyl and R_33bis C_1-3alkyl; or
- R_32band R_33btogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl;
- wherein:
- R_1bis R_1ab; and/or
- R_4band R_5bare R_4aband R_5ab; and/or
- A is A_b; or

wherein when B is (B-bc) and R_3b3cis R_3c, the compound of formula (I) is a compound of formula (I-c):

[Image Omitted]

wherein:

- A_cis A_acor A_bc;
  - wherein:
  - A_acis —CH₂NR_6c—;
  - A_bcis —C(═O)NR_6c—;
- R_1cis R_1acor R_1bc;
- wherein:
  - R_1acis NR_32cR_33c;
- R_1bcis C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, C_1-3alkyleneOC_1-2alkyl, or CF₃;
- R_3cis H, CH₃, halo, OC_1-2alkyl or CF₃;
- R_4cand R_5care either R_4acand R_5acor R_4bcand R_5bc;
- wherein:
  - R_4acand R_5actogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21cR_22c; 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_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4acand R_5actogether 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(O)₂R_29c; or
  - R_4bcand R_5acare each independently H, C_1-3alkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, C_1-3alkylOH or C_1-6haloalkyl,
  - or R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl ring;
- R_6cis H or C_1-3alkyl;
- Ar1c is a 6-membered aryl or heteroaryl;
- Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A_c;
- R_10cis H, halo, C_1-3alkyl, OC_1-2alkyl, C_1-2haloalkyl, OC_1-2haloalkyl or CN;
- R_11cis H, F, Cl, CH₃, ethyl, OCH₃, CF₃, OCF₃or CN;
- R_12cis attached to Ar2c in the meta or ortho position relative to Ar1c and R_12cis H, halo, C_1-4alkyl, C_2-4alkynyl, C(═O)C_1-2alkyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, C_1-3alkyleneOC_1-3alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, CN, OC_0-2alkyleneC_3-5cycloalkyl, OCH₂CH₂N(CH₃)₂, OH, C_1-4alkylOH, NR_23cR_24c, SO₂CH₃, C(O)N(CH₃)₂, NHC(O)C_1-3alkyl, or a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R_12ctogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_21cis H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl, C_1-3alkylOC_1-2alkyl, C_1-4haloalkyl, or C_4-6heterocycloalkyl;
- R_22cis H or CH₃;
- R_23cis H or C_1-2alkyl;
- R_24cis H or C_1-2alkyl;
- R_29cis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, CF₃, N(C_1-3alkyl)₂, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and
- R_32cis C_1-3alkyl and R_33cis C_1-3alkyl; or
- R_32cand R_33ctogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl;
  
  wherein:
- R_1cis R_1ac; and/or
- R_4cand R_5care R_4acand R_5ac; and/or
- A_cis A_ac.

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

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

In another embodiment, the compound formula (I) is a compound of formula (I-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):

[Image Omitted]

wherein ring B is selected from the group consisting of:

[Image Omitted]

- wherein X, Y and Z are as defined below; and

[Image Omitted]

- wherein R_3b3cis R_3bor R_3cas defined below;

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

[Image Omitted]

- wherein:
- A_ais A_aaor A_ba;
  - wherein:
  - A_aais an amine linker having the following structure: —NH—, —CH₂NH— or —NHCH₂—;
  - A_bais an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—;
- X is N or CH;
- Y is N or CR_2a;
- Z is N or CR_3a;
  - with the proviso that when at least one of X or Z is N, Y cannot be N;
- R_2ais H, halo, C_1-2alkyl, OC_1-2alkyl, C_1-2haloalkyl or OC_1-2haloalkyl; and
- R_3ais H, halo, CH₃, OCH₃, CF₃or OCF₃;
  - wherein at least one of R_2aand R_3ais H;
- R_1ais R_1aaor R_1ba;
  - wherein:
  - R_1aais NR_32aR_33a;
  - R_1bais C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃;
- R_4aand R_5aare R_4aaand R_5aaor R_4baand R_5ba;
  - wherein:
  - R_4aand R_5atogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21aR_22a; 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aaand R_5aatogether 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aaand R_5aatogether 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(O)₂R_29a; or
  - R_4baand R_5baare each independently H, C_1-6alkyl, C_1-6alkylOH, C_1-6haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl; and
  - when A_ais —NHC(═O)— or —NHCH₂—:
  - R_4baand R_5bamay additionally be selected from halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl and NR_21aR_22a;
- Ar1a is a 6-membered aryl or heteroaryl;
- Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A_a;
- R_10ais H, halo, C_1-3alkyl, C_1-2haloalkyl, OC_1-2alkyl, OC_1-2haloalkyl or CN;
- R_11ais H, F, Cl, C_1-2alkyl, CF₃, OCH₃or CN;
- R_12ais attached to Ar2 in the ortho or meta position relative to Ar1a and R_12ais H, halo, C_1-4alkyl, C_2-4alkenyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, C_1-4haloalkyl, OC_1-4haloalkyl, hydroxy, C_1-4alkylOH, SO₂C_1-2alkyl, C(O)N(C_1-2alkyl)₂, NHC(O)C_1-3alkyl or NR_23aR_24a; and
  - when A_ais —NHC(═O)—, —NH— or —NHCH₂—:
  - R_12amay additionally be selected from CN, OCH₂CH₂N(CH₃)₂and a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_13ais H or halo;
- R_21ais H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl;
- R_22ais H or CH₃;
- R_23ais H or C_1-2alkyl; and
- R_24ais H or C_1-2alkyl
- R_29ais C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃;
- R_32ais C_1-3alkyl and R₃₃is C_1-3alkyl; or
- R_32aand R_33atogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl;

wherein

- R_1ais R_1aa; and/or
- R_4aand R_5aare R_4aaand R_5aa; and/or
- A_ais A_aa; and
  
  wherein when B is (B-bc) and R_3b3cis R_3b, the compound of formula (I) is a compound of formula (I-b):

[Image Omitted]

- wherein:
- A_bis A_abor A_bb;
  - wherein:
    - A_abis —NR_6bCH₂— or —NR_6b—;
    - A_bbis —NR_6bC(═O)—;
- R_1bis R_1abor R_1bb;
- wherein:
  - R_1abis NR_32bR_33b;
  - R_1bbis C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, C_1-3alkyleneOC_1-2alkyl, or CF₃;
- R_3bis H, halo, CH₃, OC_1-2alkyl or CF₃;
- or R_3btogether with R_5bforms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl;
- R_4band R_5bare either R_4aband R_5abor R_4bband R_5bb;
- wherein:
  - R_4aband R_5abtogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21bR_22b; 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_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aband R_5abtogether 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(O)₂R_29b; or
  - R_4bband R_5bbare each independently H, halo, C_1-6alkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl, OC_0-2alkyleneC_3-4cycloalkyl, C_1-3alkyleneOC_1-3alkyl, C_1-6alkylOH, C_1-6haloalkyl, OC_1-6haloalkyl or NR_21bR_22b,
    - or R_4bbis H and R_5bbtogether with R_3bform a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl,
    - or R_4bband R_5bbtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl,
    - or R_4bbis H and R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring;
    - or R_4bbis O and R_5bbis absent;
- R_6bis H or C_1-3alkyl,
  - or R_6btogether with R_11bwhen in the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring,
  - or R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring and R_4bbis H;
- Ar1b is 6-membered aryl or heteroaryl;
- Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A_b;
- R_10bis H, halo, C_1-3alkyl, OC_1-2alkyl, C_1-2haloalkyl, OC_1-2haloalkyl or CN;
- R_11bis H, F, Cl, CH₃, ethyl, OCH₃, CF₃, OCF₃or CN,
  - or R_11bwhen in the ortho-position to group A_b, together with R_6bare a C₂alkylene chain forming a 5-membered ring;
- R_12bis attached to Ar2b in the ortho or meta position relative to Ar1b and R_12bis H, halo, C_1-4alkyl, C_2-4alkynyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, OCH₂CH₂N(CH₃)₂, OH, C_1-4alkylOH, CN, C_1-3alkyleneOC_1-3alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, C(═O)C_1-2alkyl, NR_23bR_24b, SO₂C_1-4alkyl, SOC_1-4alkyl, SC_1-4alkyl, SH, C(O)N(CH₃)₂, NHC(O)C_1-3alkyl, C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R_12btogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_13bis H, halo, CH₃or OCH₃;
- R_21bis H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl;
- R_22bis H or CH₃;
- R_23bis H or C_1-2alkyl;
- R_24bis H or C_1-2alkyl;
- R_29bis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃; and
- R_32ais C_1-3alkyl and R_33bis C_1-3alky; or
- R_32band R_33btogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl;

wherein:

- R_1bis R_1ab; and/or
- R_4band R_5bare R_4aband R_5ab; and/or
- A is A_ab; or

wherein when B is (B-bc) and R_3b3cis R_3c, the compound of formula (I) is a compound of formula (I-c):

[Image Omitted]

wherein:

- A_cis A_acor A_bc;
  - A_acis —CH₂NR_6c—;
  - A_bcis —C(═O)NR_6c—;
  - R_1cis R_1acor R_1bc;
- wherein:
  - R_1acis NR_32cR_33c;
- R_1bcis C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, C_1-3alkyleneOC_1-2alkyl, or CF₃;
- R_3cis H, CH₃, halo, OC_1-2alkyl or CF₃;
- R_4cand R_5care either R_4acand R_5acor R_4bcand R_5bc;
- wherein:
  - R_4acand R_5actogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-4heterocycloalkyl, OC_1-3alkyl and NR_21cR_22c; 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_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4acand R_5actogether 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(O)₂R_29c; or
  - R_4bcand R_5bcare each independently H, C_1-6alkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, C_1-6alkylOH or C_1-6haloalkyl,
  - or R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl ring;
- R_6cis H or C_1-3alkyl;
- Ar1c is a 6-membered aryl or heteroaryl;
- Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the pare position relative to group A_c;
- R_10cis H, halo, C_1-3alkyl, OC_1-2alkyl, C_1-2haloalkyl, OC_1-2haloalkyl or CN;
- R_11cis H, F, Cl, CH₃, ethyl, OCH₃, CF₃, OCF₃or CN;
- R_12cis attached to Ar2c in the meta or ortho position relative to Ar1c and R_12cis H, halo, C_1-4alkyl, C_2-4alkynyl, C(═O)C_1-2alkyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, C_1-3alkyleneOC_1-3alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, CN, OC_0-2alkyleneC_3-5cycloalkyl, OCH₂CH₂N(CH₃)₂, OH, C_1-4alkylOH, NR_23cR_24c, SO₂CH₃, C(O)N(CH₃)₂, NHC(O)C_1-3alkyl, or a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R_12ctogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_21cis H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl;
- R_22cis H or CH₃;
- R_23cis H or C_1-2alkyl;
- R_24cis H or C_1-2alkyl;
- R_29cis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃; and
- R_32cis C_1-3alkyl and R_33cis C_1-3alkyl; or
- R_32cand R_33ctogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl;
  
  wherein:
- R_1cis R_1ac; and/or
- R_4cand R_5care R_4acand R_5ac; and/or
- A_cis A_ac.

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

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

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

Compounds of Formula (I-a)

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

[Image Omitted]

wherein:

- A_ais A_aaor A_ba;
- wherein:
  - A_aais an amine linker having the following structure: —NH—, —CH₂NH— or —NHCH₂—;
  - A_bais an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—;
- X is N or CH;
- Y is N or CR_2a;
- Z is N or CR_3a;
  - with the proviso that when at least one of X or Z is N, Y cannot be N;
- R_1ais R_1aaor R_1ba;
  - wherein:
  - R_1aais NR_32aR_33a;
  - R_1bais C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃;
- R_2ais H, halo, C_1-2alkyl, OC_1-2alkyl, C_1-2haloalkyl or OC_1-2haloalkyl;
- R_3ais H, halo, CH₃, OCH₃, CF₃or OCF₃;
  - wherein at least one of R_2aand R_3ais H;
- R_4aand R_5aare R_4aaand R_5aa, or R_4baand R_5ba;
  - wherein:
  - R_4aaand R_5aatogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-4cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-4heterocycloalkyl, OC_1-3alkyl and NR_21aR_22a; 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
    - R_4aaand R_5aatogether 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
    - R_4aaand R_5aatogether 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(O)₂R_29a; or
    - R_4baand R_5baare each independently H, C_1-6alkyl, C_1-6alkylOH, C_1-6haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl; and
    - when A_ais —NHC(═O)— or —NHCH₂—:
    - R_4baand R_5bamay additionally be selected from halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-4heterocycloalkyl, OC_1-6alkyl and NR_21aR_22a;
- Ar1a is a 6-membered aryl or heteroaryl;
- Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A_a;
- R_10ais H, halo, C_1-3alkyl, C_1-2haloalkyl, OC_1-2alkyl, OC_1-2haloalkyl or CN;
- R_11ais H, F, Cl, C_1-2alkyl, CF₃, OCH₃or CN;
- R_12ais attached to Ar2a in the ortho or meta position relative to Ar1a and R_12ais H, halo, C_1-4alkyl, C_2-4alkenyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, C_1-4haloalkyl, OC_1-4haloalkyl, hydroxy, C_1-4alkylOH, SO₂C_1-2alkyl, C(O)N(C_1-2alkyl)₂, NHC(O)C_1-3alkyl or NR_23aR_24a; and
  - when A_ais —NHC(═O)—, —NH— or —NHCH₂—:
  - R_12amay additionally be selected from CN, OCH₂CH₂N(CH₃)₂and a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_13ais H or halo;
- R_21ais H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl, C_1-5alkylOC_1-2alkyl, C_1-4haloalkyl, or C_4-6heterocycloalkyl;
- R_22ais H or CH₃;
- R_23ais H or C_1-2alkyl; and
- R_24ais H or C_1-2alkyl;
- R_29ais C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, CF₃, N(C_1-3alkyl)₂, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl;
- R_32ais C_1-3alkyl and R_33ais C_1-3alkyl; or
- R_32aand R_33atogether 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, R_1cis R_1ac; and/or R_4cand R_5care R_4acand R_5ac; and/or A_cis A_ac.

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

[Image Omitted]

wherein:

- A_ais A_aaor A_ba;
- wherein:
  - A_aais an amine linker having the following structure: —NH—, —CH₂NH— or —NHCH₂—;
  - A_bais an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—;
- X is N or CH;
- Y is N or CR_2a;
- Z is N or CR_3a;
  - with the proviso that when at least one of X or Z is N, Y cannot be N;
- R_1ais R_1aaor R_1ba;
  - wherein:
  - R_1aais NR_32aR_33a;
  - R_1bais C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃;
- R_2ais H, halo, C_1-2alkyl, OC_1-2alkyl, C_1-2haloalkyl or OC_1-2haloalkyl;
- R_3ais H, halo, CH₃, OCH₃, CF₃or OCF₃;
  - wherein at least one of R_2aand R_3ais H;
- R_4aand R_5aare R_4aaand R_5aa, or R_4baand R_5ba;
  - wherein:
  - R_4aaand R_5aatogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21aR_22a; 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
- R_4aaand R_5aatogether 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aaand R_5aatogether 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(O)₂R_29a; or
  - R_4baand R_5ba, are each independently H, C_1-6alkyl, C_1-6alkylOH, C_1-6haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl; and
  - when A_ais —NHC(═O)— or —NHCH₂—:
  - R_4baand R_5bamay additionally be selected from halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl and NR_21aR_22a;
- Ar1a is a 6-membered aryl or heteroaryl;
- Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A_a;
- R_10ais H, halo, C_1-3alkyl, C_1-2haloalkyl, OC_1-2alkyl, OC_1-2haloalkyl or CN; R_11ais H, F, Cl, C_1-2alkyl, CF₃, OCH₃or CN; R_12ais attached to Ar2a in the ortho or meta position relative to Ar1a and R_12ais H, halo, C_1-4alkyl, C_2-4alkenyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, C_1-4haloalkyl, OC_1-4haloalkyl, hydroxy, C_1-4alkylOH, SO₂C_1-2alkyl, C(O)N(C_1-2alkyl)₂, NHC(O)C_1-3alkyl or NR_23aR_24a; and
  - when A_ais —NHC(═O)—, —NH— or —NHCH₂—:
  - R_12amay additionally be selected from CN, OCH₂CH₂N(CH₃)₂and a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_13ais H or halo;
- R_21ais H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl;
- R_21ais H or CH₃;
- R_23ais H or C_1-2alkyl; and
- R_24ais H or C_1-2alky;
- R_29ais C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃;
- R_32ais C_1-3alkyl and R_33ais C_1-3alkyl; or
- R_32aand R_33atogether 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, R_1cis R_1ac; and/or R_4cand R_5care R_4acand R_5ac; and/or A_cis A_ac.

The phrase ‘A_bais an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—’ means the following structures form:

[Image Omitted]

Reference to R₄and R₅above includes variables R_4a, R_5a, R_4aa, R_5aa, R_4baand R_5ba, and reference to Ar1 and Ar2 includes variables Ar1a and Ar2a.

The phrase ‘A_aais an amine linker having the following structure: —CH₂NH— or —NHCH₂—’ means the following structures form:

[Image Omitted]

Reference to R₄and R₅above includes variables R_4a, R_5a, R_4aa, R_5aa, R_4baand R_5ba, and reference to Ar1 and Ar2 includes variables Ar1a and Ar2a.

In one embodiment, A_bais —C(═O)NH—. In another embodiment, A_bais —NHC(═O)—. In an additional embodiment, A_aais —NH—. In a further embodiment, A_aais —CH₂NH—. In another embodiment, A_aais —NHCH₂—.

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

In one embodiment, Y is N. In another embodiment, Y is CR_2a.

In one embodiment. Z is N. In another embodiment, Z is CR_3a.

Suitably, X is N, Y is CR_2aand Z is CR_3a. Alternatively, X is CH, Y is N and Z is CR_3a. Alternatively, X is CH, Y is CR_2aand Z is CR_3a. Alternatively, X is CH, Y is CR_2aand Z is N. Alternatively, X is N, Y is CR_2aand Z is N.

In one embodiment of the invention, R_1ais R_1aa, i.e. is NR_32aR_33a. In an embodiment R₃₂, is C_1-3alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R_33ais C_1-3alkyl, such as methyl or ethyl, e.g. methyl. Suitably, R_32aand R_33aare both methyl. Suitably, R_32aand R_33aare both ethyl. Suitably, R_32ais methyl and R_33ais ethyl.

In another embodiment, R_32aand R_33atogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl. Suitably, the C_3-5heterocycloalkyl is aziridinyl, azetidinyl or pyrrolidinyl.

Suitably, R_1ais R_1ba.

In one embodiment of the invention R_1bais C_1-5alkyl. When R_1bais C_1-5alkyl, R_1bamay 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).

In a second embodiment of the invention R_1bais C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃. In some embodiments, R_1bais C_0-2alkyleneC_3-5cycloalkyl. In other embodiments, R_1bais C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is substituted by CH₃. R_1bamay be C_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bamay be C₁alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bamay be C₂alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bamay be C_0-2alkyleneC₃cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bamay be C_0-2alkyleneC₄cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bamay be C_0-2alkyleneC₅cycloalkyl, which cycloalkyl is optionally substituted by CH₃. Suitably, where C_0-2alkyleneC_3-5cycloalkyl is optionally substituted by CH₃, the CH₃is at the point of attachment of the C_3-5cycloalkyl to the C_0-2alkylene.

In a third embodiment, R_1bais CF₃.

Suitably R_1bais cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclobutyl, CH₃or CH₂CH₃. In particular R_1bais cyclopropyl, cyclobutyl, CH₃or CH₂CH₃, especially cyclopropyl.

In one embodiment, R_2ais H. In a second embodiment, R_2ais halo such as F, Cl or Br, e.g. Cl or Br. In a third embodiment, R_2ais C_1-2alkyl. When R_2ais C_1-2alkyl, R_2amay be methyl or ethyl, such as methyl. In a fourth embodiment, R_2ais OC_1-2alkyl. When R_2ais OC_1-2alkyl, may be OCH₃or OEt, such as OCH₃. In a fifth embodiment, R_2ais C_1-2haloalkyl. When R₂is C_1-2haloalkyl, R_2amay be CF₃or CH₂CF₃, such as CF₃. In a sixth embodiment, R_2ais OC_1-2haloalkyl. When R₂is OC_1-2haloalkyl, R_2amay be OCF₃or OCH₂CF₃, such as OCF₃.

Suitably, R2 is H, CH₃or CF₃, such as H or CH₃, in particular H.

In one embodiment R_3ais H. In a second embodiment R_3ais halo, in particular chloro or fluoro, especially fluoro. In a third embodiment, R_3ais CH₃. In a fourth embodiment, R_3ais OCH₃. In a fifth embodiment, R_3ais CF₃. In a sixth embodiment, R_3ais OCF₃.

Suitably, R_3ais H, halo in particular chloro or fluoro, especially fluoro, CH₃or CF₃. More suitably, R_3ais H or F, such as H.

Suitably, at least one of R_2aand R_3ais H.

In one embodiment, R_4aand R_5aare R_4aaand R_5aa.

Suitably, R_4aaand R_5aatogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21aR_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 C_1-3alkyl. 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 C_1-3alkylOH. Suitably, the substituent is CH₂OH.

Suitably, the substituent is CH₂CH₂OH. Suitably, the substituent is CH₂CH₂CH₂OH.

In a third embodiment, the substituent is C_1-3haloalkyl. Suitably the C_1-3alkyl 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 C₁haloalkyl such as CF₃. Suitably, the substituent is C₂haloalkyl such as CH₂CF₃.

In a fourth embodiment, the substituent is C_0-2alkyleneC_3-6cycloalkyl, in particular C_0-2alkyleneC_3-5cycloalkyl, such as C_3-5cycloalkyl, C₁alkyleneC_3-5cycloalkyl or C_0-2alkyleneC_3-5cycloalkyl.

In a fifth embodiment, the substituent is C_0-2alkyleneC_3-6heterocycloalkyl such as C_0-2alkyleneC₃heterocycloalkyl, C_0-2alkyleneC₄heterocycloalkyl, C_0-2alkyleneC₅heterocycloalkyl, C_0-2alkyleneC₆heterocycloalkyl, C₀alkyleneC_3-6heterocycloalkyl, C₁alkyleneC_3-6heterocycloalkyl and C₂alkyleneC_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_3-6heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_1-3heterocycloalkyl ring is not substituted.

In a sixth embodiment, the substituent is C_1-3alkyleneOC_1-3alkyl, in particular C_1-2alkyleneOC_1-2alkyl such as C₁alkyleneOC₁alkyl, C₂alkyleneOC₁alkyl, C₁alkyleneOC₂alkyl or C₂alkyleneOC₂alkyl.

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

In an eighth embodiment, the substituent is OC_1-3haloalkyl. Suitably the OC_1-3alkyl 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 OC₁haloalkyl such as OCF₃. Suitably, the substituent is OC₂haloalkyl such as OCH₂CF₃.

In a ninth embodiment, the substituent is OC_0-2alkyleneC_3-6cycloalkyl, such as OC_3-6cycloalkyl, OC₁alkyleneC_3-6cycloalkyl or OC₂alkyleneC_3-6cycloalkyl.

In a tenth embodiment, the substituent is OC_0-2alkyleneC_3-6heterocycloalkyl such as OC_0-2alkyleneC₃heterocycloalkyl, C_0-2alkyleneC₄heterocycloalkyl, OC_0-2alkyleneC₅heterocycloalkyl, OC_0-2alkyleneC₆heterocycloalkyl, OC₀alkyleneC_3-6heterocycloalkyl, OC₁alkyleneC_3-6heterocycloalkyl and OC₂alkyleneC_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) (such as one nitrogen atom) in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

In an eleventh embodiment, the substituent is OC_1-3alkyl, such as OCH₃or OCH₂CH₃.

In a twelfth embodiment, the substituent is NR_21aR_22awherein R_21aand R_22aare 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, halo, OC_1-3haloalkyl, OC_1-3alkyl and NR_21aR_22a.

More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OC_1-3alkyl and NR_21aR_22a.

Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro and NR_21aR_22a.

When the substituent is NR_21aR_22a, in one embodiment R_21ais H. In a second embodiment R_21ais C_1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R_21ais C(O)C_1-5alkyl, such as C(O)CH₃. In a fourth embodiment R_21ais C(O)OC_1-2alkyl, such as C(O)OCH₃or C(O)Otert-butyl. In a fifth embodiment R_21ais C_1-3alkylOC_1-2alkyl such as C₁alkylOC₁alkyl, C₂alkylOC₁alkyl or C₃alkylOC₁alkyl e.g. C₂alkylOC₁alkyl. In a sixth embodiment, R_21ais C_1-4haloalkyl, such as CF₃, CH₂CF₃or CH₂CHF₂e.g. CH₂CHF₂. In a seventh embodiment R_21ais C_4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When the substituent is NR_21aR_22a, in one embodiment R_22ais H. In a second embodiment R_22ais methyl.

Suitably, R_21ais C(O)OCH₃and R_22ais H. Suitably, R_21ais C(O)CH₃and R_22ais H. Suitably, R_21aand R_22aare both CH₃. Suitably, R_21aand R_22aare both H.

Alternatively, R_4aaand R_5aasuitably together with the carbon atom to which they are attached form a C_3-6cycloalkyl and 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl.

In one embodiment the C_3-6cycloalkyl formed by R_4aaand R_5aatogether with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C_3-6cycloalkyl formed by R_4aaand R_5aatogether with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent being independently selected from the group consisting of C_1-2alkyl or OCH₃.

Suitably one of the carbons of the C_3-6cycloalkyl formed by R_4aaand R_5aatogether with the carbon atom to which they are attached is a C_4-6cycloalkyl. Suitably the further C_3-6heterocycloalkyl is an oxygen containing C_3-6heterocycloalkyl.

Alternatively, R_4aaand R_5aasuitably 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl.

In one embodiment the C_3-6heterocycloalkyl formed by R_4aaand R_5aatogether with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C_3-6heterocycloalkyl formed by R_4aaand R_5aatogether with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent being independently selected from the group consisting of C_1-2alkyl or OCH₃.

In an embodiment, R_4aaand R_5aatogether 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(O)₂R_29a.

Suitably, the C_3-6heterocycloalkyl is selected from the group consisting of azirdinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.

Suitably, when the C_3-6heterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:

[Image Omitted]

The C_3-6heterocycloalkyl may be other groups as defined elsewhere herein.

In an embodiment, R_29ais C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃. In one embodiment, R_29ais C_1-3alkyl such as methyl. In another embodiment, R_29ais C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃. In some embodiments, R_29ais C_0-2alkyleneC_3-5cycloalkyl. In other embodiments, R_29ais C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is substituted by CH₃. R_29amay be C_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29amay be C₁alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29amay be C₂alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29amay be C_0-2alkyleneC₃cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29amay be C_0-2alkyleneC₄cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29amay be C_0-2alkyleneC₅cycloalkyl, which cycloalkyl is optionally substituted by CH₃. Suitably, where C_0-2alkyleneC_3-5cycloalkyl is optionally substituted by CH₃, the CH₃is at the point of attachment of the C_3-5cycloalkyl to the C_0-2alkylene. In another embodiment, R_29ais CF₃. In another embodiment, R_29ais N(C_1-3alkyl)₂such as N(CH₃)₂. In another embodiment, R_29ais 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_29ais 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_29ais a 6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.

In another embodiment, R_4aand R_5aare R_4baand R_5ba.

In one embodiment, R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl in particular cyclopropyl or cyclopentyl. In a second embodiment, R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6heterocycloalkyl, such as a heterocyclohexyl, in particular a tetrahydropyranyl. Any nitrogen atom such as one nitrogen atom in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted. In a third embodiment, R_4bais C_1-6alkyl, in particular C_1-4alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-buty). In a fourth embodiment, R_4bais C_1-3alkyleneOC_1-3alkyl, in particular C_1-2alkyleneOC_1-2alkyl such as C₁alkyleneOC₁alkyl, C₂alkyleneOC₁alkyl, C₁alkyleneOC₂alkyl or C₂alkyleneOC₂alkyl. In a fifth embodiment, R_4bais H. In a sixth embodiment, R_4bais halo, such as chloro or fluoro, especially fluoro. In a seventh embodiment, R_4bais C_1-6haloalkyl, such as CF₃or CH₂CF₃. In an eighth embodiment, R_4bais C_0-2alkyleneC_3-6cycloalkyl such as C_3-6cycloalkyl, C₁alkyleneC_3-6cycloalkyl, C₂alkyleneC_3-6cycloalkyl, C_0-2alkyleneC₃cycloalkyl, C_0-2alkyleneC₄cycloalkyl, C_0-2alkyleneC₅cycloalkyl or C_0-2alkyleneC₆cycloalkyl. In a ninth embodiment, R_4bais C_0-2alkyleneC_3-6heterocycloalkyl such as C_3-6heterocycloalkyl, C₁alkyleneC_3-6heterocycloalkyl, C₂alkyleneC_3-6heterocycloalkyl, C_0-2alkyleneC₃heterocycloalkyl, C_0-2alkyleneC₄hetero-cycloalkyl, C_0-2alkyleneC₅heterocycloalkyl or C_0-2alkyleneC₆heterocycloalkyl. 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_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted. In a tenth embodiment, R_4bais C_1-6alkylOH, such as CH₂OH or CH₂CH₂OH. In an eleventh embodiment, R_4bais OC_1-6haloalkyl, such as OC_1-4haloalkyl, such as OCF₃or OCHF₂. In a twelfth embodiment, R_4bais OC_0-2alkyleneC_3-6cycloalkyl such as OC_3-6cycloalkyl, OC₁alkyleneC_3-6cycloalkyl, OC₂alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC₃cycloalkyl, OC_0-2alkyleneC₄cycloalkyl, OC_0-2alkyleneC₅cycloalkyl or OC_0-2alkyleneC₆cycloalkyl. In a thirteenth embodiment, R_4bais OC_1-6alkyl, in particular OC_1-4alkyl such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a fourteenth embodiment, R_4bais OC_0-2alkyleneC_3-6heterocycloalkyl such as OC_3-6heterocycloalkyl, OC₁alkyleneC_3-6heterocycloalkyl, OC₂alkyleneC_3-6heterocycloalkyl, OC_0-2alkyleneC₃heterocycloalkyl, OC_0-2alkyleneC₄hetero-cycloalkyl, OC_0-2alkyleneC₅heterocycloalkyl or OC_0-2alkyleneC₆heterocycloalkyl. 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_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted. In a fifteenth embodiment, R_4bais NR_21aR_22a.

When A_ais —NHC(═O)— or —C(═O)NH—, suitably, R_4bais H, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkylOH, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl. When A_ais —NHC(═O)—, suitably R_4bamay additionally be selected from halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl or NR_21aR_22a.

When A_ais —NH—, —CH₂NH— or —NHCH₂—, suitably, R_4bais H, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkylOH, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl. When A_ais —NHCH₂—, suitably R_4bamay additionally be selected from halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl or NR_21aR_22a.

Suitably R_4bais H, fluoro, CH₃, ethyl, OCH₃or CH₂CH₂OCH₃, such as fluoro, ethyl, OCH₃or CH₂CH₂OCH₃.

Suitably R_4bais H, CH₃, ethyl or CH₂CH₂OCH₃, in particular CH₃or ethyl.

Suitably R_4baand R_5batogether with the carbon atom to which they are attached form a cyclopropyl or cyclopentyl, in particular a cyclopentyl.

Suitably R_4baand R_5batogether with the carbon atom to which they are attached form a heterocyclohexyl, such as tetrahydropyranyl or piperidinyl, especially tetrahydropyranyl. Any nitrogen atom such as one nitrogen atom in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-2alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

Suitably R_4baand R_5batogether with the carbon atom to which they are attached form a heterocyclobutyl, such as azetidinyl. Any nitrogen atom such as one nitrogen atom in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

When R_4bais NR_21aR_22a, in one embodiment R_21ais H. In a second embodiment R_21ais C_1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R_21ais C(O)C_1-5alkyl, such as C(O)CH₃. In a fourth embodiment R_21ais C(O)OC_1-5alkyl, such as C(O)OCH₃or C(O)Otert-butyl. In a fifth embodiment R_21ais C_1-3alkylOC_1-2alkyl such as C₁alkylOC₁alkyl, C₂alkylOC₁alkyl or C₃alkylOC₁alkyl e.g. C₂alkylOC₁alkyl. In a sixth embodiment, R_21ais C_1-4haloalkyl, such as CF₃, CH₂CF₃or CH₂CHF₂e.g. CH₂CHF₂. In a seventh embodiment R_21ais C_4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When R_4bais NR_21aR_22a, in one embodiment R_22ais H. In a second embodiment R_22ais methyl.

For example, R_4bais NH₂, N(CH₃)₂, NHC(O)CH₃, NHC(O)OCH₃, NHC(O)Otert-butyl and CH₂CH₂OH, especially, N(CH₃)₂, NHC(O)CH₃, NHC(O)OCH₃.

Suitably, R_21ais C(O)OCH₃and R_22ais H. Suitably, R_21ais C(O)CH₃and R_22ais H. Suitably, R_21aand R_22aare both CH₃. Suitably, R_21aand R_22aare both H.

In one embodiment R_5bais C_1-6alkyl, in particular C_1-4alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a second embodiment R_5bais C_1-3alkyleneOC_1-3alkyl, in particular C_1-2alkyleneOC_1-2alkyl such as C₁alkyleneOC₁alkyl, C₂alkyleneOC₁alkyl, C₁alkyleneOC₂alkyl or C₂alkyleneOC₂alkyl. In a third embodiment R_5bais H. In a fourth embodiment, R_5bais halo, such as chloro or fluoro, especially fluoro. In a fifth embodiment, R_5bais C_1-6haloalkyl, such as CF₃or CH₂CF₃. In a sixth embodiment, R_5bais C_0-2alkyleneC_3-6cycloalkyl such as C_3-6cycloalkyl, C₁alkyleneC_3-6cycloalkyl, C₂alkyleneC_3-6cycloalkyl, C_0-2alkyleneC₃cycloalkyl, C_0-2alkyleneC₄cycloalkyl, C_0-2alkyeneC₅cycloalkyl or C_0-2alkyleneC₆cycloalkyl. In a seventh embodiment, R_5bais C_0-2alkyleneC_3-4heterocycloalkyl such as C_3-6heterocycloalkyl, C₁alkyleneC_3-6heterocycloalkyl, C₂alkyleneC_3-6heterocycloalkyl, C_0-2alkyleneC₆heterocycloalkyl, C_0-2alkyleneC₄hetero-cycloalkyl, C_0-2alkyleneC₅heterocycloalkyl or C_0-2alkyleneC₆heterocycloalkyl. 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_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted. In an eighth embodiment, R_5bais C_1-6alkylOH, such as CH₂OH or CH₂CH₂OH. In a ninth embodiment, R_5bais OC_1-6haloalkyl, such as OC_1-4haloalkyl, such as OCF₃or OCHF₂. In a tenth embodiment, R_5bais OC_0-2alkyleneC_3-6cycloalkyl such as OC_3-6cycloalkyl, OC₁alkyleneC_3-6cycloalkyl, OC₂alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC₃cycloalkyl, OC_0-2alkyleneC₄cycloalkyl, OC_0-2alkyleneC₅cycloalkyl or OC_0-2alkyleneC₆cycloalkyl. In an eleventh embodiment, R_5bais OC_1-6alkyl, in particular OC_1-4alkyl such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a twelfth embodiment, R_5bais OC_0-2alkyleneC_3-6heterocycloalkyl such as OC_3-6heterocycloalkyl, OC₁alkyleneC_3-6heterocycloalkyl, OC₂alkyleneC_3-6heterocycloalkyl, OC_0-2alkyleneC₃heterocycloalkyl, C_0-2alkyleneC₄hetero-cycloalkyl, OC_0-2alkyleneC₅heterocycloalkyl or OC_0-2alkyleneC₆heterocycloalkyl. 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_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC₄haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted. In a thirteenth embodiment, R_5bais NR_21aR_22a.

When A_ais —NHC(═O)— or —C(═O)NH—, suitably, R_5bais H, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkylOH, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl. When A_ais —NHC(═O)—, suitably R_5bamay additionally be selected from halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl or NR_21aR_22a.

When A_ais —NH—, —CH₂NH— or —NHCH₂—, suitably, R_5bais H, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkylOH, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl. When A_ais —NHCH₂—, suitably R_5bamay additionally be selected from halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl or NR_21aR_22a.

When R_5bais NR_21aR_22a, in one embodiment R_21ais H. In a second embodiment R_21ais C_1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R_21ais C(O)C_1-5alkyl, such as C(O)CH₃. In a fourth embodiment R_21ais C(C)OC_1-5alkyl, such as C(O)OCH₃or C(O)Otert-butyl. In a fifth embodiment R_21ais C_1-3alkylOC_1-2alkyl such as C₁alkylOC₁alkyl, C₂alkylOC₁alkyl or C₃alkylOC₁alkyl e.g. C₂alkylOC₁alkyl. In a sixth embodiment, R_21ais C_1-4haloalkyl, such as CF₃, CH₂CF₃or CH₂CHF₂e.g. CH₂CHF₂. In a seventh embodiment R_21ais C_4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When R_5bais NR_21aR_22a, in one embodiment R_22ais H. In a second embodiment R_22ais methyl.

For example, R_5bais NH₂, N(CH₃)₂, NHC(O)CH₃, NHC(O)OCH₃, NHC(O)Otert-butyl and CH₂CH₂OH, especially, N(CH₃)₂, NHC(O)CH₃, NHC(O)OCH₃.

Suitably, R_21ais C(O)OCH₃and R_22ais H. Suitably, R_21ais C(O)CH₃and R_22ais H. Suitably, R_21aand R_22aare both CH₃. Suitably, R_21aand R_22aare both H.

Suitably R_5bais H, F, CH₃or ethyl such as H, CH₃or ethyl.

Suitably R_4bais H, CH₃, ethyl or CH₂CH₂OCH₃and R_5bais H, CH₃or ethyl, in particular R_4bais CH₃, or ethyl and R_5bais H, methyl or ethyl. For example, R_4baand R_5baare H, R_4baand R_5baare methyl, R_4baand R_5baare ethyl or R_4bais CH₂CH₂OCH₃and R_5bais H.

Suitably, R_4bais F and R_5bais ethyl.

Suitably, R_4bais F and R_5bais F.

Suitably, R_4bais ethyl and R_5bais H.

Suitably R_4baand R_5baare arranged in the following configuration:

[Image Omitted]

wherein R₄and R₅include variables R_4a, R_5a, R_4aa, R_5aa, R_4baand R_5ba.

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

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

In one embodiment R_10ais H. In a second embodiment R_10ais halo, for example fluoro or chloro. In a third embodiment R_10ais C_1-3alkyl such as C_1-2alkyl, such as CH₃or ethyl. In a fourth embodiment R_10ais OC_1-2alkyl, such as OCH₃or ethoxy. In a fifth embodiment R_10ais OC_1-2haloalkyl, such as OCF₃. In a sixth embodiment R_10ais CN. In a seventh embodiment, R_10ais C_1-2haloalkyl such as CF₃.

Suitably R_10ais H, fluoro, chloro, CH₃, CF₃, OCH₃, OCF₃or CN, such as H, fluoro, chloro, CH₃, OCH₃, OCF₃or CN, in particular H, fluoro, chloro, OCH₃, OCF₃or CN especially H or fluoro.

Suitably, R_10ais H, F or CH₃.

In one embodiment R_11ais H. In a second embodiment R_11ais F. In a third embodiment, R_11ais C_1-2alkyl such as CH₃or Et, such as CH₃. In a fourth embodiment R_11ais OCH₃. In a fifth embodiment, R_11ais Cl. In a sixth embodiment, R_11ais Et. In a seventh embodiment, R_11ais CF₃. In an eighth embodiment, R_11ais CN.

Suitably, R_11ais H, F, CH₃or OCH₃, such as H, F or CH₃, such as H or F, such as H.

In one embodiment, R_10ais in the ortho position with respect to group Aa. In another embodiment, R_10ais in the meta position with respect to group Aa. Suitably R_10ais in the ortho position with respect to group Aa.

In one embodiment, R_11ais in the ortho position with respect to group Aa. In another embodiment, R_11ais in the meta position with respect to group Aa. Suitably R_11ais 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 R_12ais H. In a second embodiment R_12ais halo, for example fluoro or chloro. In a third embodiment R_12ais C_1-4alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment R_12ais OC_1-4alkyl, such as OCH₃, ethoxy, isopropoxy or n-propoxy. In a fifth embodiment R_12ais OC_0-2alkyleneC_3-5cycloalkyl, such as OC_3-5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC₁alkyleneC_3-5cycloalkyl or OC₂alkyleneC_3-5cycloalkyl. In a sixth embodiment R_12ais CN. In a seventh embodiment R_12ais C_1-4haloalkyl, such as CF₃. In an eighth embodiment R_12ais OC_1-4haloalkyl, such as OCF₃, OCHF₂or OCH₂CF₃. In a ninth embodiment, R_12ais C_2-4alkenyl such as C(═CH₂)CH₃. In a tenth embodiment, R_12ais C_0-2alkyleneC_3-5cycloalkyl such as C_3-5cycloalkyl, C₁alkyleneC_3-5cycloalkyl, C₂alkyleneC_3-5cycloalkyl, C_0-2alkyleneC₃cycloalkyl, C_0-2alkyleneC₄cycloalkyl or C_0-2alkyleneC₅cycloalkyl. In an eleventh embodiment, R_12ais hydroxy. In a twelfth embodiment, R_12ais C_1-4alkylOH such as CH₂OH. In a thirteenth embodiment, R_12ais SO₂C_1-2alkyl such as SO₂CH₃. In a fourteenth embodiment, R_12ais C(O)N(C_1-2alkyl)₂such as C(O)N(CH₃)₂. In a fifteenth embodiment, R_12ais NHC(O)C_1-3alkyl. In a sixteenth embodiment, R_12ais NR_23aR_24a. In a seventeenth embodiment, R_12ais OCH₂CH₂N(CH₃)₂. In an eighteenth embodiment, R_12ais a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a. Suitably the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Suitably, the heterocyclopentyl ring is pyrrolidinyl. Suitably, the heterocyclohexyl ring is piperidinyl or piperazinyl. Any nitrogen atom such as one nitrogen atom in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted. In a nineteenth embodiment, R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻).

When Aa is —NHC(═O)— or —C(═O)NH—, suitably, R_12ais attached to Ar2a in the ortho or meta position relative to Ar1a and R_12ais H, halo, C_1-4alkyl, C_2-4alkenyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, C_1-4haloalkyl, OC_1-4haloalkyl, hydroxy, C_1-4alkylOH, SO₂C_1-2alkyl, C(O)N(C_1-2alkyl)₂, NHC(O)C_1-3alkyl or NR_23aR_24a.

When Aa is —NHC(═O)—, suitably R_12amay additionally be selected from CN, OCH₂CH₂N(CH₃)₂and a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻).

When Aa is —NH—, —CH₂NH— or —NHCH₂—, suitably, R_12ais attached to Ar2a in the ortho or meta position relative to Ar1a and R_12ais H, halo, C_1-4alkyl, C_2-4alkenyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, C_1-4haloalkyl, OC_1-4haloalkyl, hydroxy, C_1-4alkylOH, SO₂C_1-2alkyl, C(O)N(C_1-2alkyl)₂, NHC(O)C_1-3alkyl or NR_23aR_24a.

When Aa is —NH— or —NHCH₂—, suitably R_12amay additionally be selected from CN, OCH₂CH₂N(CH₃)₂and a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻).

R_12ais suitably H, F, Cl, CH₃, OCH₃, OEt, OiPr, OCyclopropyl, CN, CF₃, OCHF₂or OCH₂CF₃. In particular, R_12ais Cl, CN, CF₃, OCHF₂, OCH₂CF₃, OCH₃, OEt, OiPr, OCyclopropyl, such as CF₃, OCHF₂, OCH₂CF₃, OCH₃, OEt, OiPr, OCyclopropyl, e.g. OEt.

R_12ais suitably H, F, Cl, CH₃, iPr, OCH₃, OEt, OiPr, OCyclopropyl, CN, CF₃, OCHF₂, OCH₂CF₃, C₃cycloalkyl or C(═CH₂)CH₃. In particular, R_12ais Cl, iPr, OCH₃, OEt, OiPr, OCyclopropyl, CN, CF₃, OCHF₂, OCH₂CF₃, C₃cycloalkyl or C(═CH₂)CH₃, such as Cl, OCH₃, OEt, OiPr, OCyclopropyl, CF₃, OCHF₂, OCH₂CF₃or C₃cycloalkyl, e.g. OEt.

When Aa is —C(═O)NH—, suitably R_12ais CF₃, OEt or OiPr, such as OEt or OiPr.

Suitably R_12ais in the meta position of Ar2a. Alternatively, R_12ais in the ortho position of Ar2a.

In one embodiment, R_13ais H. In another embodiment, R_13ais halo such as F or Cl, suitably F.

In one embodiment, R_13ais in the ortho position with respect to Ar1a. In another embodiment, R_13ais in the para position with respect to Ar1a. In another embodiment, R_13ais in the meta position with respect to Ar1a.

In one embodiment, R_23ais H. In another embodiment, R_23ais C_1-2alkyl such as methyl.

In one embodiment, R_24ais H. In another embodiment R_24ais C_1-2alkyl such as methyl.

Suitably, R_23ais H and R_24ais ethyl. Suitably, R_23ais CH₃and R_24ais CH₃.

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 R_10a, R_11a, R_12aand R_13ais other than H.

Suitably, at least one of R_4a, R_5a, R_10a, R_11a, R_12aand R_13ais other than H.

More suitably, when R_1ais methyl, at least one of R_4a, R_5a, R_10a, R_11a, R_12aand R_13ais 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)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4-oxocyclohexanecarboxamide;

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4-hydroxycyclohexanecarboxamide;

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 1);

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4-hydroxycyclohexanecarboxamide (diastereomer 2);

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)cyclohexane-1-carboxamide;

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyidin-2-yl)cyclohexane-1-carboxamide (diastereomer 1);

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyidin-2-yl)cyclohexane-1-carboxamide (diastereomer 2);

N-(4-(1-((4-(6-Ethoxypyrazin-2-yq)-2-fluorobenzyl)amino)propy)pyrimidin-2-yl)cyclopropanesulfonamide;

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4,4-difluorocyclohexane-1-carboxamide;

8-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide;

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

4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;

N-(4-(1-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide;

N-(4-(1-((4-(6-ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)cyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide;

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

2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-5,8-dioxaspiro[3.4]octane-2-carboxamide;

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-4-methoxycyclohexane-1-carboxamide; and

N-(4-(1-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamidearboxamide.

The present invention also provides the following compounds:

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide;

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide;

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide;

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-1-(N,N-dimethylsulfamoyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide;

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1-((trifluoromethyl)sulfonyl)piperidine-4-carboxamide;

4-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyrdin-2-yl)-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide;

1-(cyanomethyl)-4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyidin-2-yl)piperidine-4-carboxamide;

ethyl 2-(4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)piperidin-1-yl)acetate;

N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(2-methoxyacetyl)piperidine-4-carboxamide;

N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;

N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide;

1-(Cyclopropylsulfonyl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide;

N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidine-4-carboxamide;

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

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

1-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 1);

1-(2-(Cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(pyrrolidin-1-yl)cyclohexane-1-carboxamide (diastereomer 2);

4-amino-1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1);

1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-morpholinocyclohexane-1-carboxamide (diastereomer 1);

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

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(methyl(oxetan-3-yl)amino)cyclohexane-1-carboxamide (diastereomer 1);

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

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

1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((2,2-difluoroethyl)(methyl)amino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide (diastereomer 1);

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

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

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

4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;

4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(methylsulfonyl)piperidine-4-carboxamide;

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

4-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-1-(ethylsulfonyl)piperidine-4-carboxamide.

Compounds of Formula (I-b)

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

[Image Omitted]

wherein

- A_bis A_abor A_bb;
  - A_abis —NR_6bCH₂— or —NR_6b—;
  - A_bbis —NR_6bC(═O)—;
- R_1bis R_1abor R_1bb;
- wherein:
  - R_1abis NR_32aR_33b;
- R_1bbis C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, C_1-3alkyleneOC_1-2alkyl, or CF₃;
- R_3bis H, halo, CH₃, OC_1-2alkyl or CF₃;
  - or R_3btogether with R_5bbforms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl;
- R_4band R_5bare either R_4aband R_5abor R_4bband R_5bb;
- wherein:
  - R_4aband R_5abtogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21bR_22b; 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_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aband R_5abtogether 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(O)₂R_29b; or
  - R_4bband R_5bbare each independently H, halo, C_1-6alkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, C_1-6alkylOH, C_1-6haloalkyl, OC_1-6haloalkyl or NR_21bR_22b,
    - or R_4bbis H and R_5bbtogether with R_3bform a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl,
    - or R_4bband R_5bbtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl,
    - or R_4bbis H and R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring;
    - or R_4bbis O and R_5bbis absent;
- R_6bis H or C_1-3alkyl,
  - or R_6btogether with R_11bwhen in the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring,
  - or R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring and R_4bbis H;
- Ar1b is 6-membered aryl or heteroaryl;
- Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the para position relative to group A_b;
- R_10bis H, halo, C_1-3alkyl, OC_1-2alkyl, C_1-2haloalkyl, OC_1-2haloalkyl or CN;
- R_11bis H, F, Cl, CH₃, ethyl, OCH₃, CF₃, OCF₃or CN,
  - or R_11b, when in the ortho-position to group A_b, together with R_6bare a C₂alkylene chain forming a 5-membered ring;
- R_12bis attached to Ar2b in the ortho or meta position relative to Ar1b and R_12bis H, halo, C_1-4alkyl, C_2-4alkynyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, OCH₂CH₂N(CH₃)₂, OH, C_1-4alkylOH, CN, C_1-3alkyleneOC_1-3alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, C(═O)C_1-2alkyl, NR_23bR_24b, SO₂C_1-4alkyl, SOC_1-4alkyl, SC_1-4alkyl, SH, C(O)N(CH₃)₂, NHC(O)C_1-3alkyl, C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R_12btogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_13bis H, halo, CH₃or OCH₃;
- R_21bis H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl, C_1-5alkylOC_1-2alkyl, C_1-4haloalkyl, or C_4-6heterocycloalkyl;
- R_22bis H or CH₃;
- R_23bis H or C_1-2alkyl;
- R_24bis H or C_1-2alkyl;
- R_29bis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, CF₃, N(C_1-3alkyl)₂, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and
- R_32bis C_1-3alkyl and R_33bis C_1-3alkyl; or
- R_32band R_33btogether 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, R_1bis R_1a; and/or R_4band R_5bare R_4aband R_5ab; and/or A is A_ab.

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

[Image Omitted]

wherein

- A_bis A_abor A_bb;
  - A_abis —NR_6bCH₂— or —NR_6b—;
  - A_bbis —NR_6bC(═O)—;
- R_1bis R_1abor R_1bb;
- wherein:
  - R_1abis NR_32aR_33b;
- R_1bbis C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, C_1-3alkyleneOC_1-2alkyl, or CF₃;
- R_3bis H, halo, CH₃, OC_1-2alkyl or CF₃;
  - or R_3btogether with R_5bbforms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl;
- R_4band R_5bare either R_4aband R_5abor R_4bband R_5bb;
- wherein:
  - R_4aband R_5abtogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21bR_22b; 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_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aband R_5abtogether 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(O)₂R_29b; or
  - R_4bband R_5bbare each independently H, halo, C_1-6alkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, C_1-6alkylOH, C_1-6haloalkyl, OC_1-6haloalkyl or NR_21bR_22b,
    - or R_4bbis H and R_5bbtogether with R_3bform a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl,
    - or R_4bband R_5bbtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl,
    - or R_4bbis H and R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring;
    - or R_4bbis O and R_5bbis absent;
- R_6bis H or C_1-3alkyl,
  - or R_6btogether with R_11bwhen in the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring,
  - or R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring and R_4bbis H;
- Ar1b is 6-membered aryl or heteroaryl;
- Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the pare position relative to group A_b;
- R_10bis H, halo, C_1-3alkyl, OC_1-2alkyl, C_1-2haloalkyl, OC_1-2haloalkyl or CN;
- R_11bis H, F, Cl, CH₃, ethyl, OCH₃, CF₃, OCF₃or CN,
  - or R_11b, when in the ortho-position to group A_b, together with R_6bare a C₂alkylene chain forming a 5-membered ring;
- R_12ais attached to Ar2b in the ortho or meta position relative to Ar1b and R_12ais H, halo, C_1-4alkyl, C_2-4alkynyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, OCH₂CH₂N(CH₃)₂, OH, C_1-4alkylOH, CN, C_1-3alkyleneOC_1-3alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, C(═O)C_1-2alkyl, NR_23bR_24b, SO₂C_1-4alkyl, SOC_1-4alkyl, SC_1-4alkyl, SH, C(O)N(CH₃)₂, NHC(O)C_1-3alkyl, C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_13bis H, halo, CH₃or OCH₃;
- R_21bis H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl;
- R_22bis H or CH₃;
- R_23bis H or C_1-2alkyl;
- R_24bis H or C_1-2alky;
- R_29bis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃; and
- R_32ais C_1-3alkyl and R_33bis C_1-3alkyl; or
- R_32band R_33btogether 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, R_1bis R_1ab; and/or R_4band R_5bare R_4aband R_5ab; and/or A is A_ab.

In one embodiment of the invention, R_1bis R_1ab, i.e. is NR_32bR_33b. In an embodiment, R_32bis C_1-3alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R_33bis C_1-3alkyl, such as methyl or ethyl, e.g. methyl. Suitably, R_32band R_33bare both methyl. Suitably, R_32aand R_33bare both ethyl. Suitably, R_32bis methyl and R_33bis ethyl.

In another embodiment, R_32band R_33btogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl. Suitably, the C_3-5heterocycloalkyl is aziridinyl, azetidinyl or pyrrolidinyl.

Suitably, R_1bis R_1bb.

In one embodiment of the invention R_1bbis C_1-5alkyl. When R_1bbis C_1-5alkyl, R_1bbmay be methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or tert-butyl) or pentyl (e.g. n-pentyl, sec-pentyl or 3-pentyl). Suitably, when R_1bbis C_1-5alkyl, R_1bbmay 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 R_1bbis C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃. In some embodiments, R_1bbis C_0-2alkyleneC_3-5cycloalkyl. In other embodiments, R_1bbis C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is substituted by CH₃. R_1bbmay be C_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bbmay be C₁alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bbmay be C₂alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bbmay be C_0-2alkyleneC₃cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bbmay be C_0-2alkyleneC₄cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bbmay be C_0-2alkyleneC₅cycloalkyl, which cycloalkyl is optionally substituted by CH₃. Suitably, where C_0-2alkyleneC_3-5cycloalkyl is optionally substituted by CH₃, the CH₃is at the point of attachment of the C_3-5cycloalkyl to the C_0-2alkylene.

In a third embodiment of the invention R_1bbis CF₃.

In a fourth embodiment of the invention R_1bbis C_1-3alkyleneOC_1-2alkyl such as C_1-2alkyleneOC_1-2alkyl. When R_1bbis C_1-3alkyleneOC_1-2alkyl, R_1bbmay be methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl or propoxyethyl. When R_1bbis C_1-2alkyleneOC_1-2alkyl, R_1bbmay be methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl.

Suitably R_1bbis cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclobutyl, CH₃, isopropyl, sec-butyl, tert-butyl or CF₃. In particular R_1bbis cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclobutyl, CH₃, isopropyl, sec-butyl or tert-butyl, especially cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclobutyl or isopropyl, such as cyclopropyl or cyclopropyl substituted by CH₃at the point of attachment.

Additionally of interest is when R_1bbis cyclopentyl, methyl, ethyl, cyclopropylmethylene and methoxyethyl, in particular cyclopentyl, methyl, ethyl and cyclopropylmethylene, especially ethyl and methyl, such as methyl.

Consequently, suitably R_1bbis cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclopropylmethylene, cyclobutyl, cyclopentyl, CH₃, ethyl, isopropyl, sec-butyl, tert-butyl, methoxyethyl or CF₃. In particular R_1bbis cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclopropylmethylene, cyclobutyl, cyclopentyl, CH₃, ethyl, isopropyl, sec-butyl or tert-butyl, especially cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclobutyl, CH₃, ethyl or isopropyl, such as cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, ethyl or methyl such as cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment or methyl.

In one embodiment R_3bis H. In a second embodiment R_3bis halo, in particular chloro or fluoro, especially chloro. In a third embodiment R_3bis CH₃. In a fourth embodiment R_3bis CF₃. In a fifth embodiment R_3btogether with R_5bbforms a 5- or 6-membered cycloalkyl, in particular a 5-membered cycloalkyl. In a sixth embodiment R_3bis OC_1-2alkyl such as OCH₃. In a seventh embodiment R_3btogether with R_5bbforms a 5- or 6-membered oxygen-containing heterocycloalkyl, in particular a 5-membered heterocycloalkyl.

The phrase ‘R_3btogether with R_5bbforms a 5- or 6-membered cycloalkyl’ means that compounds with the following exemplary substructure are formed:

[Image Omitted]

The phrase ‘R_3btogether with R_5bbforms a 5- or 6-membered oxygen containing heterocycloalkyl’ means that compounds with the following substructure are formed:

[Image Omitted]

In particular R_3bis H, CH₃or R_3btogether with R_5bbforms a 5- or 6-membered cycloalkyl, especially H, CH₃or R_3btogether with R_5bbforms a 5-membered cycloalkyl, such as R_3bis H or CH₃, e.g. H.

In one embodiment, R_4band R_5bare R_4aband R_5ab.

Suitably, R_4aband R_5abtogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21bR_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 C_1-3alkyl. 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 C_1-2alkylOH. Suitably, the substituent is CH₂OH. Suitably, the substituent is CH₂CH₂OH. Suitably, the substituent is CH₂CH₂CH₂OH.

In a third embodiment, the substituent is C_1-3haloalkyl. Suitably the C_1-3alkyl 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 C₁haloalkyl such as CF₃. Suitably, the substituent is C₂haloalkyl such as CH₂CF₃.

In a fourth embodiment, the substituent is C_0-2alkyleneC_3-6cycloalkyl, in particular C_0-2alkyleneC_3-5cycloalkyl, such as C_3-5cycloalkyl, C₁alkyleneC_3-5cycloalkyl or C₂alkyleneC_3-5cycloalkyl.

In a fifth embodiment, the substituent is C_0-2alkyleneC_3-6heterocycloalkyl such as C_0-2alkyleneC₃heterocycloalkyl, C_0-2alkyleneC₄heterocycloalkyl, C_0-2alkyleneC₅heterocycloalkyl, C_0-2alkyleneC₆heterocycloalkyl, C₀alkyleneC_3-6heterocycloalkyl, C₁alkyleneC_3-6heterocycloalkyl and C₂alkyleneC_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_3-6heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

In a sixth embodiment, the substituent is C_1-3alkyleneOC_1-3alkyl, in particular C_1-2alkyleneOC_1-2alkyl such as C₁alkyleneOC₁alkyl, C₂alkyleneOC₁alkyl, C₁alkyleneOC₂alkyl or C₂alkyleneOC₂alkyl.

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

In an eighth embodiment, the substituent is OC_1-3haloalkyl. Suitably the OC_1-3alkyl 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 OC₁haloalkyl such as OCF₃. Suitably, the substituent is OC₂haloalkyl such as OCH₂CF₃.

In a ninth embodiment, the substituent is OC_0-2alkyleneC_3-6cycloalkyl, such as OC_3-6cycloalkyl, OC₁alkyleneC_3-6cycloalkyl or OC₂alkyleneC_3-6cycloalkyl.

In a tenth embodiment, the substituent is OC_0-2alkyleneC_3-6heterocycloalkyl such as OC_0-2alkyleneC₃heterocycloalkyl, OC_0-2alkyleneC₄heterocycloalkyl, OC_0-2alkyleneC₅heterocycloalkyl, OC_0-2alkyleneC₆heterocycloalkyl, OC₀alkyleneC_3-6heterocycloalkyl, OC₁alkyleneC_3-6heterocycloalkyl and OC₂alkyleneC_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) (such as one nitrogen atom) in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC₄alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

In an eleventh embodiment, the substituent is OC_1-3alkyl, such as OCH₃or OCH₂CH₃.

In a twelfth embodiment, the substituent is NR_21bR_22b.

In one embodiment R_21bis H. In a second embodiment R_21bis C_1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R_21bis C(O)C_1-5alkyl, such as C(O)CH₃. In a fourth embodiment R_21bis C(O)OC_1-5alkyl, such as C(O)OCH₃or C(O)Otert-butyl. In a fifth embodiment R_21bis C_1-3alkylOC_1-2alkyl such as C₁alkylOC₁alkyl, C₂alkylOC₁alkyl or C₃alkylOC₁alkyl e.g. C₂alkylOC₁alkyl. In a sixth embodiment, R_21bis C_1-4haloalkyl, such as CF₃, CH₂CF₃or CH₂CHF₂e.g. CH₂CHF₂. In a seventh embodiment R_21bis C_4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When the substituent is NR_21bR_22b, in one embodiment R_22bis H. In a second embodiment R_22bis methyl.

Suitably, R_21bis C(O)OCH₃and R_22bis H. Suitably, R_21bis C(O)CH₃and R_22bis H. Suitably, R_21band R_22bare both CH₃. Suitably, R_21band R_22bare 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, halo, OC_1-3haloalkyl, OC_1-3alkyl and NR_21bR_22b.

More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OC_1-3alkyl and NR_21bR_22b.

Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro, NR_21bR_22b.

Alternatively, R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl and 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_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl.

In one embodiment the C_3-6cycloalkyl formed by R_4aband R_5abtogether with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C_3-6cycloalkyl formed by R_4aband R_5abtogether with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent is independently selected from the group consisting of C_1-2alkyl or OCH₃.

Suitably one of the carbons of the C_3-6cycloalkyl which is formed by R_4aband R_5abis a spiro centre such that a spirocyclic ring system is formed, wherein the C_3-6cycloalkyl which is formed by R_4aband R_5abis a C_4-6cycloalkyl. Suitably the C_3-5heterocycloalkyl is an oxygen containing C_3-6heterocycloalkyl. Suitably, the C_3-6heterocycloalkyl is an oxygen comprising, such as containing, C_3-6heterocycloalkyl ring, such as a C₅cycloalkyl ring.

In an embodiment, R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl. Suitably, each substituent is independently selected from the group consisting of C_1-2alkyl or OCH₃.

Suitably one of the carbons of the C_3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed containing further ring C, wherein C is a C_4-6heterocycloalkyl. Suitably the C_4-6heterocycloalkyl is an oxygen containing C_4-6heterocycloalkyl such as tetrahydropyranyl or 1,3-dioxolanyl.

In an embodiment, R_4aband R_5abtogether 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(O)₂R_29b.

Suitably, the C_3-6heterocycloalkyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.

Suitably, when the C_3-6heterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:

[Image Omitted]

The C_3-6heterocycloalkyl may be other groups as defined elsewhere herein.

In an embodiment, R_29bis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃. In one embodiment, R_29bis C_1-3alkyl such as methyl. In another embodiment, R_29bis C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃. In some embodiments, R₂is C_0-2alkyleneC_3-5cycloalkyl. In other embodiments, R_29ais C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is substituted by CH₃. R_29bmay be C_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29bmay be C₁alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29bmay be C₂alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29bmay be C_0-2alkyleneC₃cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29bmay be C_0-2alkyleneC₄cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29bmay be C_0-2alkyleneC₅cycloalkyl, which cycloalkyl is optionally substituted by CH₃. Suitably, where C_0-2alkyleneC_3-5cycloalkyl is optionally substituted by CH₃, the CH₃is at the point of attachment of the C_3-5cycloalkyl to the C_0-2alkylene. In another embodiment, R_29bis CF₃. In another embodiment, R_29bis N(C_1-3alkyl)₂such as N(CH₃)₂. In another embodiment, R_29bis 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_29bis 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_29bis a 6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.

In another embodiment, R_4band R_5bare R_4bband R_5bb.

In one embodiment R_4bbis O and R_5bbis 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:

[Image Omitted]

In a second embodiment, R_4bband R_5bbtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl. In a third embodiment R_4bbis C_1-6alkyl, in particular C_1-4alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment R_4bbis C_0-2alkyleneC_3-6cycloalkyl, in particular C_0-2alkyleneC_3-5cycloalkyl, such as C_3-5cycloalkyl, C₁alkyleneC_3-5cycloalkyl or C₂alkyleneC_3-5cycloalkyl. In a fifth embodiment R_4bbis OC_1-6alkyl, in particular OC_1-4alkyl, such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a sixth embodiment R_4bbis OC_0-2alkyleneC_3-6cycloalkyl, such as OC_3-6cycloalkyl, OC₁alkyleneC_3-6cycloalkyl or OC₂alkyleneC_3-6cycloalkyl. In a seventh embodiment R_4bbis C_1-3alkyleneOC_1-3alkyl, in particular C_1-2alkyleneOC_1-2alkyl such as C₁alkyleneOC₁alkyl, C₂alkyleneOC₁alkyl, C₁alkyleneOC₂alkyl or C₂alkyleneOC₂alkyl. In an eighth embodiment R_4bbis C_1-6haloalkyl, in particular C_1-44haloalkyl. In a ninth embodiment R_4bbis OC_1-6haloalkyl, in particular OC_1-4haloalkyl. In a tenth embodiment R_4bbis H. In an eleventh embodiment R_4bbis halo such as fluoro. In a twelfth embodiment R_4bbis C_1-6alkylOH, such as CH₂OH or CH₂CH₂OH, in particular CH₂CH₂OH. In a thirteenth embodiment R_4bbis NR_21bR_22b. In a fourteenth embodiment, R_4bbis C_0-2alkyleneC_3-6heterocycloalkyl such as C_0-2alkyleneC₃heterocycloalkyl, C_0-2alkyleneC₄heterocycloalkyl, C_0-2alkyleneC₅heterocycloalkyl, C_0-2alkyleneC₆heterocycloalkyl, C₀alkyleneC_3-6heterocycloalkyl, C₁alkyleneC_3-6heterocycloalkyl and C₂alkyleneC_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) (such as one nitrogen atom) in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted. In a fifteenth embodiment, R_4bband R_5bbtogether with the carbon atom to which they are attached form a C_3-6heterocycloalkyl, such as tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, such as tetrahydrofuranyl or piperidinyl. If the C_3-6heterocycloalkyl group comprises (e.g. contains) a nitrogen atom, independently the nitrogen atom(s) may be unsubstituted (NH) or the nitrogen atom(s) may be substituted, for example substituted by a group selected from the following: C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. In a fifteenth embodiment, R_4bbis H and R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring. In a sixteenth embodiment, R_4bbis OC_0-2alkyleneC_3-6heterocycloalkyl such as OC_0-2alkyleneC₃heterocycloalkyl, OC_0-2alkyleneC₄heterocycloalkyl, OC_0-2alkyleneC₅heterocycloalkyl, C_0-2alkyleneC₆heterocycloalkyl, OC₀alkyleneC_3-6heterocycloalkyl, OC₁alkyleneC_3-6heterocycloalkyl and OC₂alkyleneC_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) (such as one nitrogen atom) in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

When R_4bbis H and R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring, suitably a 5-membered ring, compounds comprising one of the following moieties are formed:

[Image Omitted]

When R_4bbis NR_21bR_22b, in one embodiment R_21bis H. In a second embodiment R_21bis C_1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R_21bis C(O)C_1-5alkyl, such as C(O)CH₃. In a fourth embodiment R_21bis C(O)OC_1-5alkyl, such as C(O)OCH₃or C(O)Otert-butyl. In a fifth embodiment R_21bis C_1-3alkylOC_1-2alkyl such as C₁alkylOC₁alkyl, C₂alkylOC₁alkyl or C₃alkylOC₁alkyl e.g. C₂alkylOC₁alkyl. In a sixth embodiment, R_21bis C_1-4haloalkyl, such as CF₃, CH₂CF₃or CH₂CHF₂e.g. CH₂CHF₂. In a seventh embodiment R_21bis C_4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When R_4bbis NR_21bR_22b, in one embodiment R_22bis H. In a second embodiment R_22bis methyl.

Suitably R_4bbis H, CH₃, ethyl, isopropyl, fluoro, OCH₃, isopropoxy or CH₂CH₂OCH₃, in particular H, CH₃, ethyl, fluoro, OCH₃, isopropoxy or CH₂CH₂OCH₃, especially H, CH₃, ethyl, OCH₃or CH₂CH₂OCH₃.

Additionally of interest is when R_4bbis NH₂, N(CH₃)₂, NHC(O)CH₃, NHC(O)OCH₃, NHC(O)Otert-butyl and CH₂CH₂OH, especially, N(CH₃)₂, NHC(O)CH₃, NHC(O)OCH₃.

Suitably, R_21bis C(O)OCH₃and R_22bis H. Suitably, R_21bis C(O)CH₃and R_22bis H. Suitably, R_21band R_22bare both CH₃. Suitably, R_21band R_22bare both H.

Consequently, suitably R_4bbis H, CH₃, ethyl, isopropyl, fluoro, OCH₃, isopropoxy, CH₂CH₂OCH₃, NH₂, N(CH₃)₂, NHC(O)CH₃, NHC(O)OCH₃, NHC(O)Otert-butyl or CH₂CH₂OH, in particular H, CH₃, ethyl, fluoro, OCH₃, isopropoxy, CH₂CH₂OCH₃, NH₂, N(CH₃)₂, NHC(O)CH₃, NHC(O)OCH₃, NHC(O)Otert-butyl or CH₂CH₂OH, especially H, CH₃, ethyl, OCH₃, CH₂CH₂OCH₃, N(CH₃)₂, NHC(O)CH₃or NHC(O)OCH₃.

Suitably R_4bbmay be C═O and R_5bbis absent.

Suitably R_4bband R_5bbtogether with the carbon atom to which they are attached form a cyclopropyl or cyclopentyl, in particular a cyclopentyl.

Suitably R_4bbis H and R_3btogether with R_5bbforms a 5- or 6-membered cycloalkyl, in particular a 5-membered cycloalkyl, especially R_4bbis H and R_3btogether with R_5bbforms a 5- or 6-membered cycloalkyl, such as a 5-membered cycloalkyl.

In one embodiment R_5bbis C_1-6alkyl, in particular C_1-4alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a second embodiment R_5bbis C_0-2alkyleneC_3-6cycloalkyl, in particular C_0-2alkyleneC_3-5cycloalkyl, such as C_3-5cycloalkyl, C₁alkyleneC_3-5cycloalkyl or C₂alkyleneC_3-5cycloalkyl. In a third embodiment R_5bbis OC_1-6alkyl, in particular OC_1-4alkyl, such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a fourth embodiment R_5bbis OC_0-2alkyleneC_3-6cycloalkyl, such as OC_3-6cycloalkyl, OC₁alkyleneC_3-6cycloalkyl or OC₂alkyleneC_3-6cycloalkyl. In a fifth embodiment R_5bbis C_1-3alkyleneOC_1-3alkyl, in particular C_1-2alkyleneOC_1-2alkyl such as C₁alkyleneOC₁alkyl, C₂alkyleneOC₁alkyl, C₁alkyleneOC₂alkyl or C₂alkyleneOC₂alkyl. In a sixth embodiment R_5bbis C_1-6haloalkyl, in particular C_1-4haloalkyl. In a seventh embodiment R_5bbis OC_1-6haloalkyl, in particular OC_1-4haloalkyl. In an eighth embodiment R_5bbis H. In a ninth embodiment R_5bbis halo such as fluoro. In a tenth embodiment R_5bbis C_1-6alkylOH, such as CH₂OH or CH₂CH₂OH, in particular CH₂CH₂OH. In an eleventh embodiment R_5bbis NR_21bR_22b. In a twelfth embodiment, R_5bbis C_0-2alkyleneC_3-6heterocycloalkyl such as C_0-2alkyleneC_3-6heterocycloalkyl, C_0-2alkyleneC₄heterocycloalkyl, C_0-2alkyleneC₅heterocycloalkyl, C_0-2alkyleneC₆heterocycloalkyl, C₀alkyleneC_3-6heterocycloalkyl, C₁alkyleneC_3-6heterocycloalkyl and C₂alkyleneC_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_3-6heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted. In a thirteenth embodiment, R_5bbis OC_0-2alkyleneC_3-6heterocycloalkyl such as OC_0-2alkyleneC₃heterocycloalkyl, OC_0-2alkyleneC₄heterocycloalkyl, OC_0-2alkyleneC₅heterocycloalkyl, OC_0-2alkyleneC₆heterocycloalkyl, OC₀alkyleneC_3-6heterocycloalkyl, OC₁alkyleneC_3-6heterocycloalkyl and OC₂alkyleneC_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) (such as one nitrogen atom) in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-4heterocycloalkyl ring is not substituted.

Suitably R_5bbis H, CH₃, ethyl, isopropyl or fluoro, in particular R_5bbis H, methyl or ethyl.

Suitably R_4bbis H, CH₃, ethyl, fluoro, OCH₃, propoxy or CH₂CH₂OCH₃and R_5bbis H, CH₃, ethyl or fluoro, in particular R_4bbis H, CH₃, ethyl or OCH₃and R_5bbis H, methyl or ethyl. For example, R_4bband R_5bbare H, R_4bband R_5bbare methyl, R_4bband R_5bbare ethyl, R_4bbis CH₂CH₂OCH₃and R_5bbis H or R_4bband R_5bbare fluoro.

Suitably, when R_4bbis other than H, methyl, ethyl or fluoro, then R_5bbis H.

In one embodiment, A_bis A_ab. Suitably, A_abis —NR_6bCH₂—. Alternatively, A_abis —NR_6b—.

In another embodiment, A_bis A_bbi.e. —NR_6bC(═O)—.

In one embodiment R_6bis H. In a second embodiment R_6bis C_1-3alkyl, in particular methyl. In a third embodiment R_6btogether with R_11bin the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring. In a fourth embodiment, R_4bbis H and R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring in particular a 5-membered ring.

Suitably R_6bis H, methyl or R_6btogether with R_11bwhen in the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring. In particular R_6bis H or R_6btogether with R_11bin the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring, especially R_6bis H.

The term ‘R_6btogether with R_11bin the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring’ as used herein means that compounds with the following exemplary substructure are formed:

[Image Omitted]

wherein W may be N or CR_10a.

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

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 R_10bis H. In a second embodiment R_10bis halo, for example fluoro or chloro. In a third embodiment R_10bis C_1-3alkyl, such as CH₃, ethyl or isopropyl, in particular C_1-2alkyl, such as CH₃or ethyl. In a fourth embodiment R_10bis OC_1-2alkyl, such as OCH₃or ethoxy. In a fifth embodiment R_10bis C_1-2haloalkyl, such as CF₃. In a sixth embodiment R_10bis OC_1-2haloalkyl, such as OCF₃. In a seventh embodiment R_10bis CN.

Suitably R_10bis H, fluoro, chloro, CH₃, OCH₃, ethoxy, OCF₃or CN, in particular H, fluoro, chloro, CH₃, OCH₃, ethoxy or OCF₃, especially or H, fluoro, chloro, CH₃, OCH₃or OCF₃, such as H, fluoro or CH₃.

Additionally of interest are compounds wherein R_10bis ethyl, isopropyl and CF₃, in particular isopropyl and CF₃. Additionally of interest are compounds when R_10bis CN.

Consequently, suitably R_10bis H, fluoro, chloro, CH₃, ethyl, isopropyl, OCH₃, ethoxy, OCF₃, CF₃or CN, in particular H, fluoro, chloro, CH₃, isopropyl, OCH₃, ethoxy, OCF₃or CF₃, especially or H, fluoro, chloro, CH₃, isopropyl, OCH₃, OCF₃or CF₃, such as H, fluoro or CH₃.

In one embodiment R_11bis H. In a second embodiment R_11bis F. In a third embodiment, R_11bis CH₃. In a fourth embodiment R_6btogether with R_11bin the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring. In a fifth embodiment R_11bis ethyl. In a sixth embodiment R_11bis Cl. In a seventh embodiment R_11bis OCH₃. In an eighth embodiment, R₁₁, is CF₃. In a ninth embodiment, R_11bis OCF₃. In a tenth embodiment, R_11bis CN. In an eleventh embodiment R_6btogether with R_11bin the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring.

Suitably, R_10band R_11bare both CH₃. Suitably, R_10band R_11bare both H. Suitably, R_10band R_11bare both fluoro.

In one embodiment, R_10bis in the ortho position with respect to group A_b. In another embodiment, R_10bis in the meta position with respect to group A_b. Suitably R_10bis in the ortho position with respect to group A_b.

In one embodiment, R_11bis in the ortho position with respect to group A_b. In another embodiment, R_11bis in the meta position with respect to group A_b. Suitably R_11bis in the ortho position with respect to group A_b.

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 R_12bis H. In a second embodiment R_12bis halo, for example fluoro or chloro. In a third embodiment R_12bis C_1-4alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment R_12bis C_2-4alkynyl, such as C≡CH. In a fifth embodiment R_12bis C_0-2alkyleneC_3-5cycloalkyl, such as C_3-5cycloalkyl (e.g. cyclopropyl), C₁alkyleneC_3-5cycloalkyl or C₂alkyleneC_3-5cycloalkyl. In a sixth embodiment R_12bis OC_1-4alkyl, such as OCH₃, ethoxy, isopropoxy or n-propoxy. In a seventh embodiment R_12bis OC_0-2alkyleneC_3-5cycloalkyl, such as OC_3-5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC₁alkyleneC_3-5cycloalkyl or OC₂alkyleneC_3-5cycloalkyl. In an eighth embodiment R_12bis OCH₂CH₂N(CH₃)₂. In a ninth embodiment R_12bis C_1-4alkylOH, such as CH₂OH or C(CH₃)₂OH. In a tenth embodiment R_12bis CN. In an eleventh embodiment R_12bis C_1-3alkyleneOC_1-3alkyl. In a twelfth embodiment R_12bis C_1-4haloalkyl, such as CF₃. In a thirteenth embodiment R_12bis OC_1-4haloalkyl, such as OCF₃, OCHF₂or OCH₂CF₃. In a fourteenth embodiment R_12bis NR_23bR_24bsuch as N(CH₃)₂. In a fifteenth embodiment R_12bis S(O)₂C_1-4alkyl such as SO₂CH₃. In a sixteenth embodiment R_12bis C(O)N(CH₃)₂. In a seventeenth embodiment R_12bis NHC(O)C_1-3alkyl such as NHC(O)CH₃. In an eighteenth embodiment R_12bis a C_3-6heterocyloalkyl comprising one nitrogen located at the point of attachment to Ar2b, such as a C₅heterocycloalkyl, in particular pyrrolidinyl, or a C₆heterocycloalkyl such as morpholinyl. In a nineteenth embodiment R_12bis OH. In a twentieth embodiment R_12bis C(═O)C_1-2alkyl. In a twenty first embodiment R_12bis S(O)C_1-4alkyl. In a twenty second embodiment R_12bis SC_1-4alkyl. In a twenty third embodiment R_12bis SH. In a twenty fourth embodiment, R_12btogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻).

R_12bis suitably H, fluoro, chloro, CH₃, cyclopropyl, C≡CH, OCH₃, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF₃, OCF₃, OCHF₂, OCH₂CF₃, CH₂OH, N(CH₃)₂, NHC(O)CH₃, SO₂CH₃, C(O)N(CH₃)₂or pyrrolidinyl, in particular H, fluoro, chloro, CH₃, cyclopropyl, C≡CH, OCH₃, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF₃, OCF₃, OCHF₂, OCH₂CF₃, CH₂OH, C(O)N(CH₃)₂or pyrrolidinyl, especially H, fluoro, chloro, CH₃, cyclopropyl, C≡CH, OCH₃, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF₃, OCHF₂, OCH₂CF₃or pyrrolidinyl, such as H, fluoro, chloro, CH₃, C≡CH, OCH₃, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF₃, OCHF₂or OCH₂CF₃.

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

In one embodiment, R_23bis H. In another embodiment, R_23bis C_1-2alkyl such as methyl.

In one embodiment, R_24bis H. In another embodiment R_24bis C_1-2alkyl such as methyl.

Suitably, R_23bis H and R_24bis ethyl. Suitably, R_23bis CH₃and R_24bis CH₃.

Consequently, suitably R_12bis H, fluoro, chloro, CH₃, ethyl, cyclopropyl, C≡CH, OCH₃, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF₃, OCF₃, OCHF₂, OCH₂CF₃, OH, CH₂OH, N(CH₃)₂, NHC(O)CH₃, SO₂CH₃, C(O)N(CH₃)₂or pyrrolidinyl, in particular H, fluoro, chloro, CH₃, ethyl, cyclopropyl, C≡CH, OCH₃, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, CN, CF₃, OCF₃, OCHF₂, OCH₂CF₃, CH₂OH, C(O)N(CH₃)₂or pyrrolidinyl, especially H, fluoro, chloro, CH₃, ethyl, cyclopropyl, C≡CH, OCH₃, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF₃, OCHF₂, OCH₂CF₃or pyrrolidinyl, such as H, fluoro, chloro, CH₃, C≡CH, OCH₃, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, CN, CF₃, OCHF₂or OCH₂CF₃.

Suitably R_12bis suitably in the meta position of Ar2b. Alternatively, R_12bis in the ortho position of Ar2b.

In one embodiment R_13bis methyl. In a second embodiment R_13bis H. In a third embodiment R_13bis methoxy. In a fourth embodiment R_13bis halo such as fluoro.

In one embodiment, R_13bis in the ortho position with respect to Ar1b. In another embodiment, R_13bis in the para position with respect to Ar1b.

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-methylpropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide
Compounds of Formula (I-c)

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

[Image Omitted]

wherein

- A_cis A_acor A_bc;
  - A_acis —CH₂NR_6c—;
  - A_bcis —C(═O)NR_6c—;
- R_1cis R_1acor R_1bc;
- wherein:
  - R_1acis NR_32cR_33c;
- R_1bcis C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, C_1-3alkyleneOC_1-2alkyl, or CF₃;
- R_3cis H, CH₃, halo, OC_1-2alkyl or CF₃;
- R_4cand R_5care either R_4acand R_5acor R_4bcand R_5bc;
- wherein:
  - R_4acand R_5actogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21cR_22c; 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_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4acand R_5actogether 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(O)₂R_29c; or
  - R_4baand R_5bcare each independently H, C_1-6alkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, C_1-6alkylOH or C_1-6haloalkyl, or R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl ring;
- R_6cis H or C_1-3alkyl;
- Ar1c is a 6-membered aryl or heteroaryl;
- Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A_c;
- R_10cis H, halo, C_1-3alkyl, OC_1-2alkyl, C_1-2haloalkyl, OC_1-2haloalkyl or CN;
- R_11cis H, F, Cl, CH₃, ethyl, OCH₃, CF₃, OCF₃or CN;
- R_12cis attached to Ar2c in the meta or ortho position relative to Ar1c and R_12cis H, halo, C_1-4alkyl, C_2-4alkynyl, C(═O)C_1-2alkyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, C_1-3alkyleneOC_1-3alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, CN, OC_0-2alkyleneC_3-5cycloalkyl, OCH₂CH₂N(CH₃)₂, OH, C_1-4alkylOH, NR_23cR_24c, SO₂CH₃, C(O)N(CH₃)₂, NHC(O)C_1-3alkyl, or a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R_12ctogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_21cis H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl, C_1-3alkylOC_1-2alkyl, C_1-4haloalkyl, or C_4-6heterocycloalkyl;
- R_22cis H or CH₃;
- R_23cis H or C_1-2alkyl;
- R_24cis H or C_1-2alkyl;
- R_29cis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, CF₃, N(C_1-3alkyl)₂, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and
- R_32cis C_1-3alkyl and R_33cis C_1-3alkyl; or
- R_32cand R_33ctogether with the nitrogen atom to which they are attached form a C_3-6heterocycloalkyl;

or a salt and/or solvate thereof and/or derivative thereof.

Suitably, R_1cis R_1ac; and/or R_4cand R_5care R_4acand R_5ac; and/or A_cis A_ac.

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

[Image Omitted]

wherein

- A_cis A_acor A_bc;
  - A_acis —CH₂NR_6c—;
  - A_bcis —C(═O)NR_6c—;
- R_1cis R_1acor R_1bc;
- wherein:
  - R_1acis NR_32cR_33c;
- R_1bcis C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, C_1-3alkyleneOC_1-2alkyl, or CF₃;
- R_3cis H, CH₃, halo, OC_1-2alkyl or CF₃;
- R_4cand R_5care either R_4acand R_5acor R_4bcand R_5bc;
- wherein:
  - R_4acand R_5actogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21cR_22c; 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_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4acand R_5actogether 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(O)₂R_29c; or
  - R_4bcand R_5bcare each independently H, C_1-6alkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, C_1-6alkylOH or C_1-6haloalkyl,
  - or R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl ring;
- R_6cis H or C_1-3alkyl;
- Ar1c is a 6-membered aryl or heteroaryl;
- Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A_c;
- R_10cis H, halo, C_1-3alkyl, OC_1-2alkyl, C_1-2haloalkyl, OC_1-2haloalkyl or CN;
- R_11cis H, F, Cl, CH₃, ethyl, OCH₃, CF₃, OCF₃or CN;
- R_12cis attached to Ar2c in the meta or ortho position relative to Ar1c and R_12cis H, halo, C_1-4alkyl, C_2-4alkynyl, C(═O)C_1-2alkyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, C_1-3alkyleneOC_1-3alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, CN, OC_0-2alkyleneC_3-5cycloalkyl, OCH₂CH₂N(CH₃)₂, OH, C_1-4alkylOH, NR_23cR_24c, SO₂CH₃, C(O)N(CH₃)₂, NHC(O)C_1-3alkyl, or a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R_12ctogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_21cis H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl;
- R_22cis H or CH₃;
- R_23cis H or C_1-2alkyl;
- R_24cis H or C_1-2alkyl;
- R_29cis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃; and
- R_32cis C_1-3alkyl and R_33cis C_1-3alkyl; or
- R_32cand R₃₃together 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, R_1cis R_1ac; and/or R_4cand R_5care R_4acand R_5ac; and/or A_cis A_ac.

When R_4bcand/or R_5bcis C₀alkyleneC_3-6heterocycloalkyl, any heteroatom in the heterocycloalkyl may not be directly connected to the carbon to which R_4bcand R_5bcare connected.

In one embodiment of the invention, R_1cis R_1ac, i.e. is NR_32cR_33c. In an embodiment, R_32cis C_1-3alkyl, such as methyl or ethyl, e.g. methyl. In an embodiment, R_33cis C_1-3alkyl, such as methyl or ethyl, e.g. methyl. Suitably, R_32cand R_33care both methyl. Suitably, R_32cand R_33care both ethyl. Suitably, R_32cis methyl and R_33cis ethyl.

In another embodiment, R_32cand R_33ctogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl. Suitably, the C_3-5heterocycloalkyl is aziridinyl, azetidinyl or pyrrolidinyl.

Suitably, R_1cis R_1bc.

In one embodiment of the invention R_1bcis C_1-5alkyl such as C_1-4alkyl. When R_1bcis C_1-5alkyl, R_1bcis methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or tert-butyl) or pentyl (e.g. n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl or active pentyl). When R_1bcis C_1-4alkyl, R_1bcis methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl).

In a second embodiment of the invention R_1bcis C_1-3alkyleneOC_1-2alkyl such as C_1-2alkyleneOC_1-2alkyl. R_1bcmay be C₁alkyleneOC₁alkyl. R_1bcmay be C₁alkyleneOC₂alkyl. R_1bcmay be C₂alkyleneOC₁alkyl. R_1bcmay be C₂alkyleneOC₂alkyl. R_1bcmay be C₃alkyleneOC₁alkyl. R_1bcmay be C₃alkyleneOC₂alkyl.

In a third embodiment of the invention R_1bcis C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃such as C_0-1alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃. In some embodiments, R_1bcis C_0-2alkyleneC_3-5cycloalkyl such as C_0-1alkyleneC_3-4cycloalkyl. In other embodiments, R_1bcis C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is substituted by CH₃such as C_0-1alkyleneC_3-4cycloalkyl which cycloalkyl is substituted by CH₃. R_1bcmay be C_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃such as C_3-4cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bcmay be C₁alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bcmay be C₁alkyleneC_3-4cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bcmay be C₂alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bcmay be C₂alkyleneC_3-4cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bcmay be C_0-2alkyleneC₃cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bcmay be C_0-1alkyleneC₃cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bcmay be C_0-2alkyleneC₄cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bcmay be C_0-1alkyleneC₄cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bcmay be C_0-2alkyleneC₅cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_1bcmay be C_0-1alkyleneC₅cycloalkyl, which cycloalkyl is optionally substituted by CH₃. Suitably, where C_0-2alkyleneC_3-5cycloalkyl such as C_0-1alkyleneC_3-4cycloalkyl is optionally substituted by CH₃, the CH₃is at the point of attachment of the C_3-5cycloalkyl to the C_0-2alkylene such as at the point of attachment of the C_3-4cycloalkyl to the C_0-1alkylene.

Suitably R_1bcis cyclopropyl.

In a fourth embodiment of the invention, R_1bcis CF₃.

In one embodiment R_3cis H. In a second embodiment R_3cis CH₃. In a third embodiment, R_3cis halo. In an example, R_3cis F. In a second example, R_3cis Cl. In a fourth embodiment, R_3cis OC_1-2alkyl. Suitably R_3cis OCH₃. Suitably, R_3cis OCH₂CH₃. In a fifth embodiment, R_3cis CF₃.

Suitably, R_3cis H.

In one embodiment, R_4cand R_5care R_4acand R_5ac.

Suitably, R_4acand R_5actogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21cR_22c.

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 C_1-3alkyl. 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 C_1-3alkylOH. Suitably, the substituent is CH₂OH. Suitably, the substituent is CH₂CH₂OH. Suitably, the substituent is CH₂CH₂CH₂OH.

In a third embodiment, the substituent is C_1-3haloalkyl. Suitably the C_1-3alkyl 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 C₁haloalkyl such as CF₃. Suitably, the substituent is C₂haloalkyl such as CH₂CF₃.

In a fourth embodiment, the substituent is C_0-2alkyleneC_3-6cycloalkyl, in particular C_0-2alkyleneC_3-5cycloalkyl, such as C_3-5cycloalkyl, C₁alkyleneC_3-5cycloalkyl or C₂alkyleneC_3-5cycloalkyl.

In a fifth embodiment, the substituent is C_0-2alkyleneC_3-6heterocycloalkyl such as C_0-2alkyleneC₃heterocycloalkyl, C_0-2alkyleneC₄heterocycloalkyl, C_0-2alkyleneC₅heterocycloalkyl, C_0-2alkyleneC₆heterocycloalkyl, C₀alkyleneC_3-6heterocycloalkyl, C₁alkyleneC_3-6heterocycloalkyl and C₂alkyleneC_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_3-6heterocycloalkyl ring may be substituted (such as one nitrogen atom is substituted), for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

In a sixth embodiment, the substituent is C_1-3alkyleneOC_1-3alkyl, in particular C_1-2alkyleneOC_1-2alkyl such as C₁alkyleneOC₁alkyl, C₂alkyleneOC₁alkyl, C₁alkyleneOC₂alkyl or C₂alkyleneOC₂alkyl.

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

In an eighth embodiment, the substituent is OC_1-3haloalkyl. Suitably the OC_1-3alkyl 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 OC₁haloalkyl such as OCF₃. Suitably, the substituent is OC₂haloalkyl such as OCH₂CF₃.

In a ninth embodiment, the substituent is OC_0-2alkyleneC_3-6cycloalkyl, such as OC_3-6cycloalkyl, OC₁alkyleneC_3-6cycloalkyl or OC₂alkyleneC_3-6cycloalkyl.

In a tenth embodiment, the substituent is OC_0-2alkyleneC_3-6heterocycloalkyl such as OC_0-2alkyleneC₃heterocycloalkyl, OC_0-2alkyleneC₄heterocycloalkyl, OC_0-2alkyleneC₅heterocycloalkyl, OC_0-2alkyleneC₆heterocycloalkyl, OC₀alkyleneC_3-6heterocycloalkyl, OC₁alkyleneC_3-6heterocycloalkyl and OC₂alkyleneC_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) (such as one nitrogen atom) in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

In an eleventh embodiment, the substituent is OC_1-3alkyl, such as OCH₃or OCH₂CH₃.

In a twelfth embodiment, the substituent is NR_21cR_22c. In one embodiment R_21cis H. In a second embodiment R_21cis C_1-5alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment R_21cis C(O)C_1-5alkyl, such as C(O)CH₃. In a fourth embodiment R_21cis C(O)OC_1-5alkyl, such as C(O)OCH₃or C(O)Otert-butyl. In a fifth embodiment R_21cis C_1-3alkylOC_1-2alkyl such as C₁alkylOC₁alkyl, C₂alkylOC₁alkyl or C₃alkylOC₁alkyl e.g. C₂alkylOC₁alkyl. In a sixth embodiment, R_21cis C_1-4haloalkyl, such as CF₃, CH₂CF₃or CH₂CHF₂e.g. CH₂CHF₂. In a seventh embodiment R_21cis C_4-6heterocycloalkyl, such as oxetanyl, tetrahydrofuranyl or tetrahydropyranyl e.g. oxetanyl, in particular 3-oxetanyl.

When the substituent is NR_21cR_22c, in one embodiment R_22cis H. In a second embodiment R_22cis methyl.

Suitably, R_21cis C(O)OCH₃and R_22cis H. Suitably, R_21cis C(O)CH₃and R_22cis H. Suitably, R_21cand R_22care both CH₃. Suitably, R_21cand R_22care 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, halo, OC_1-3haloalkyl, OC_1-3alkyl and NR_21cR_22c.

More suitably, the substituent is independently selected from the group consisting of oxo, OH, halo, OC_1-3alkyl and NR_21cR_22c.

Most suitably, the substituent is independently selected from the group consisting of oxo, OH, fluoro, NR_21cR_22c.

Alternatively, R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6cycloalkyl and 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_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl.

In one embodiment the C_3-6cycloalkyl formed by R_4acand R_5actogether with the carbon atom to which they are attached is unsubstituted. In a second embodiment the C_3-6cycloalkyl formed by R_4acand R_5actogether with the carbon atom to which they are attached is substituted by one or two substituents, in particular one substituent. Suitably, each substituent is independently selected from the group consisting of C_1-2alkyl or OCH₃.

Suitably one of the carbons of the C_3-6cycloalkyl which is formed by R_4acand R_5acis a spiro centre such that a spirocyclic ring system is formed, wherein the C_3-6cycloalkyl which is formed by R_4acand R_5acis a C_4-6cycloalkyl. Suitably the C_3-6heterocycloalkyl is an oxygen containing C_3-6heterocycloalkyl. Suitably, the C_3-6heterocycloalkyl is an oxygen comprising, such as containing, C_3-6heterocycloalkyl ring, such as a C₅cycloalkyl ring.

In an embodiment, R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl. Suitably, each substituent is independently selected from the group consisting of C_1-2alkyl or OCH₃.

Suitably one of the carbons of the C_3-6heterocycloalkyl is a spiro centre such that a spirocyclic ring system is formed containing further ring C, wherein C is a C_4-6heterocycloalkyl. Suitably the C_4-6heterocycloalkyl is an oxygen containing C_4-6heterocycloalkyl such as tetrahydropyranyl or 1,3-dioxolanyl.

As stated above, when a heterocycloalkyl is formed from R_4cand R_5ctogether with the carbon atom to which they are attached, suitably any heteroatom is not directly connected to the carbon to which R_4cand R_5care attached.

In an embodiment, R_4acand R_5actogether 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(O)₂R_29c.

Suitably, the C_3-6heterocycloalkyl is selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl such as piperidinyl.

Suitably, when the C_3-6heterocycloalkyl is piperidinyl, the nitrogen atom is in the 4-position relative to the quaternary carbon:

[Image Omitted]

The C_3-6heterocycloalkyl may be other groups as defined elsewhere herein.

In an embodiment, R_29cis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃. In one embodiment, R_29cis C_1-3alkyl such as methyl. In another embodiment, R_29cis C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃. In some embodiments, R_29cis C_0-2alkyleneC_3-5cycloalkyl. In other embodiments, R_29cis C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is substituted by CH₃. R_29cmay be C_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29cmay be C₁alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29cmay be C₂alkyleneC_3-5cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29cmay be C_0-2alkyleneC₃cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29cmay be C_0-2alkyleneC₄cycloalkyl, which cycloalkyl is optionally substituted by CH₃. R_29cmay be C_0-2alkyleneC₅cycloalkyl, which cycloalkyl is optionally substituted by CH₃. Suitably, where C_0-2alkyleneC_3-5cycloalkyl is optionally substituted by CH₃, the CH₃is at the point of attachment of the C_3-5cycloalkyl to the C_0-2alkylene. In another embodiment, R_29cis CF₃. In another embodiment, R_29cis N(C_1-3alkyl)₂such as N(CH₃)₂. In another embodiment, R_29cis 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_29cis 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_29cis a 6-membered heteroaryl such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl.

In another embodiment, R_4cand R_5care R_4bcand R_5bc.

In one embodiment, R_4bcis H. In a second embodiment R_4bcis C_1-6alkyl such as C_1-4alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R_4bcmay 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_4bcis C_0-2alkyleneC_3-6cycloalkyl such as C_0-2alkyleneC_3-5cycloalkyl, such as C_0-2alkyleneC₃cycloalkyl, C_0-2alkyleneC₄cycloalkyl, C_0-2alkyleneC₅cycloalkyl, C₀alkyleneC_3-5cycloalkyl, C₁alkyleneC_3-5cycloalkyl and C₂alkyleneC_3-5cycloalkyl. R_4bcmay also be C_0-2alkyleneC₆cycloalkyl, C₀alkyleneC_3-6cycloalkyl, C₁alkyleneC_3-6cycloalkyl and C₂alkyleneC_3-6cycloalkyl. In a fourth embodiment R_4bcis C_1-3alkyleneOC_1-3alkyl, in particular C_1-2alkyleneOC_1-2alkyl such as C₁alkyleneOC₁alkyl, C₂alkyleneOC₁alkyl, C₁alkyleneOC₂alkyl or C₂alkyleneOC₂alkyl. In a fifth embodiment R_4bcis C_1-6alkylOH such as C_1-4alkylOH such as C₁alkylOH, C₂alkylOH, C₃alkylOH or C₄alkylOH wherein C_1-4alkyl is methyl, ethyl, propyl (n-propyl or isopropyl) and butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R_4bcmay also be C₅alkylOH or C₆alkylOH. In a sixth embodiment, R_4bcis C_1-6haloalkyl such as C_1-4haloalkyl such as C₁haloalkyl (e.g. CF₃), C₂haloalkyl (e.g. CH₂CF₃), C₃haloalkyl (e.g. CH₂CH₂CF₃) or C₄haloalkyl (e.g. CH₂CH₂CH₂CF₃). R_4bcmay also be C₅haloalkyl (e.g. CH₂CH₂CH₂CH₂CF₃) or C₆haloalkyl (e.g. CH₂CH₂CH₂CH₂CH₂CF₃). In a seventh embodiment, R_4bcis C_0-2alkyleneC_3-6heterocycloalkyl such as C_0-2alkyleneC₃heterocycloalkyl, C_0-2alkyleneC₄heterocycloalkyl, C_0-2alkyleneC₅heterocycloalkyl, C_0-2alkyleneC₆heterocycloalkyl, C₀alkyleneC_3-6heterocycloalkyl, C₁alkyleneC_3-6heterocycloalkyl and C₂alkyleneC_3-6heterocycloalkyl. Suitably the heterocycloalkyl of a C_0-2alkyleneC_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_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted. In an eighth embodiment, R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl ring. Suitably R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6cycloalkyl ring, such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring. Suitably R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6heterocycloalkyl 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_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

Suitably R_4bcis H, CH₃or ethyl, in particular CH₃or ethyl. Suitably, R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6cycloalkyl ring, such as a cyclopropyl ring.

In one embodiment, R_5bcis H. In a second embodiment R_5bcis C_1-6alkyl such as C_1-4alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R_5bcmay also be pentyl (e.g. n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl and active pentyl) or hexyl (e.g. n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl). In a third embodiment, R_5bcis C_0-2alkyleneC_3-6cycloalkyl such as C_0-2alkyleneC_3-5cycloalkyl, such as C_0-2alkyleneC₃cycloalkyl, C_0-2alkyleneC₄cycloalkyl, C_0-2alkyleneC₅cycloalkyl, C₀alkyleneC_3-5cycloalkyl, C₁alkyleneC_3-5cycloalkyl and C₂alkyleneC_3-5cycloalkyl. R_5bcmay also be C_0-2alkyleneC₆cycloalkyl, C₀alkyleneC_3-6cycloalkyl, C₁alkyleneC_3-6cycloalkyl and C₂alkyleneC_3-6cycloalkyl. In a fourth embodiment R_5bcis C_1-3alkyleneOC_1-3alkyl, in particular C_1-2alkyleneOC_1-2alkyl such as C₁alkyleneOC₁alkyl, C₂alkyleneOC₁alkyl, C₁alkyleneOC₂alkyl or C₂alkyleneOC₂alkyl. In a fifth embodiment R_5bcis C_1-6alkylOH such as C_1-4alkylOH such as C₁alkylOH, C₂alkylOH, C₃alkylOH or C₄alkylOH wherein C_1-4alkyl is methyl, ethyl, propyl (n-propyl or isopropyl) and butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). R_5bcmay also be C₅alkylOH or C₆alkylOH. In a sixth embodiment, R_5bcis C_1-6haloalkyl such as C_1-4haloalkyl such as C₁haloalkyl (e.g. CF₃), C₂haloalkyl (e.g. CH₂CF₃), C₃haloalkyl (e.g. CH₂CH₂CF₃), C₄haloalkyl (e.g. CH₂CH₂CH₂CF₃). R_5bcmay also be C₅haloalkyl (e.g. CH₂CH₂CH₂CH₂CF₃) or C₆haloalkyl (e.g. CH₂CH₂CH₂CH₂CH₂CF₃). In a seventh embodiment, R_5bcis C_0-2alkyleneC_3-6heterocycloalkyl such as C_0-2alkyleneC₃heterocycloalkyl, C_0-2alkyleneC₄heterocycloalkyl, C_0-2alkyleneC₅heterocycloalkyl, C_0-2alkyleneC₆heterocycloalkyl, C₀alkyleneC_3-6heterocycloalkyl, C₁alkyleneC_3-6heterocycloalkyl and C₂alkyleneC_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 such as one nitrogen in the C_3-6heterocycloalkyl ring may be substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC₄alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Suitably, any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

Suitably R_5bcis H, CH₃or ethyl, in particular CH₃or ethyl. Suitably, R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6cycloalkyl ring, such as a cyclopropyl ring.

Suitably R_4bcis H, CH₃or ethyl and R_5bcis H, CH₃or ethyl, in particular R_4bcis CH₃or ethyl and R_5bcis CH₃or ethyl. For example, R_4bcand R_5bcare H, R_4bcand R_5bcare methyl or R_4bcand R_5bcare ethyl.

Suitably, R_4bcis CH₂CH₂OCH₃and R_5bcis H.

In one embodiment, A_cis A_aci.e. —CH₂NR_6c—.

In another embodiment, A_cis A_bci.e. —C(═O)NR_6c—.

In one embodiment, R_6cis H. In another embodiment, R_6cis C_1-3alkyl, in particular CH₃.

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

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

In one embodiment R_10cis H. In a second embodiment R_10cis halo, for example fluoro or chloro. In a third embodiment R_10cis C_1-3alkyl, i.e. CH₃, ethyl or propyl (e.g. n-propyl or iso-propyl). In a fourth embodiment R_10cis OC_1-2alkyl, such as OCH₃or ethoxy. In a fifth embodiment, R_10cis C_1-2haloalkyl, such as CF₃or CH₂CF₃. In a sixth embodiment R_10cis OC_1-2haloalkyl, such as OCF₃. In a seventh embodiment R_10cis CN.

Suitably R_10cis H, fluoro, OCH₃, CH₃or CF₃, in particular H or fluoro, especially H.

Suitably R_10cis attached at the ortho position of Ar1c relative to group A_c(i.e. proximal to group A_c).

In one embodiment R_11cis H. In a second embodiment R_11cis F. In a third embodiment, R_11cis Cl. In a fourth embodiment R_11cis CH₃. In a fifth embodiment R_11cis CH₂CH₃. In a sixth embodiment R_11cis OCH₃. In a seventh embodiment R_11cis CF₃. In an eighth embodiment R_11cis OCF₃. In a ninth embodiment R_11cis CN.

In one embodiment, R_11cis in the ortho position relative to group A_c. In another embodiment R_11cis 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 R_12cis H. In a second embodiment R_12cis halo, for example fluoro or chloro. In a third embodiment R_12cis C_1-4alkyl, i.e. methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment, R_12cis C_2-4alkynyl such as C₂alkynyl (i.e. C≡CH). In a fifth embodiment, R_12cis C(═O)C_1-2alkyl, such as C(═O)C₁alkyl or C(═O)C₂alkyl. In a sixth embodiment R_12cis OC_1-2alkyleneC_3-5cycloalkyl, such as OC_3-5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC₁alkyleneC_3-5cycloalkyl or OC₂alkyleneC_3-5cycloalkyl. In a seventh embodiment R_12cis OC_1-4alkyl, such as OCH_3-5ethoxy, iso-propoxy or n-propoxy. In an eighth embodiment, R_12cis C_1-3alkyleneOC_1-3alkyl in particular C_1-2alkyleneOC_1-2alkyl such as C₁alkyleneOC₁alkyl, C₂alkyleneOC₁alkyl, C₁alkyleneOC₂alkyl or C₂alkyleneOC₂alkyl. In a ninth embodiment R_12cis C_1-4haloalkyl, such as CF₃. In a tenth embodiment R_12cis OC_1-4haloalkyl, such as OCF₃, OCHF₂or OCH₂CF₃. In an eleventh embodiment R_12cis CN. In an eleventh embodiment R_12cis OC_0-2alkyleneC_3-5cycloalkyl, such as OC_3-5cycloalkyl (e.g. cyclopropoxy or cyclobutoxy), OC₁alkyleneC_3-5cycloalkyl or OC₂alkyleneC_3-5cycloalkyl. In a twelfth embodiment R_12cis OCH₂CH₂N(CH₃)₂. In a thirteenth embodiment R_12cis OH. In a fourteenth embodiment R_12cis C_1-4alkylOH, such as CH₂OH or C(CH₃)₂OH. In a fifteenth embodiment R_12cis NR_23cR_24c. In a sixteenth embodiment R_12cis SO₂CH₃. In a seventeenth embodiment R_12cis C(O)N(CH₃)₂. In an eighteenth embodiment R_12cis NHC(O)C_1-3alkyl such as NHC(O)CH₃. In a nineteenth embodiment R_12cis a C_3-6heterocycloalkyl comprising (such as containing) one nitrogen located at the point of attachment to Ar2c, such as a C₅heterocycloalkyl, in particular pyrrolidinyl, or a C₆heterocycloalkyl such as morpholinyl. In a twentieth embodiment, R_12ctogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻).

In one embodiment, R_23cis H. In another embodiment, R_23cis C_1-2alkyl i.e. CH₃or CH₂CH₃.

In one embodiment, R_24cis H. In another embodiment, R_24cis C_1-2alkyl i.e. CH₃or CH₂CH₃.

R_12cis suitably H, fluoro, chloro, CH₃, Et, OCH₃, OEt, OiPr, CF₃or OCH₂CF₃. In particular, R_12cis fluoro, chloro, CH₃, OCH₃, OEt, OiPr or CF₃, for example chloro, OEt, OiPr or CF₃such as chloro, OEt or CF₃.

R_12cis suitably attached at the meta position of Ar2c. Alternatively, R_12cis attached at the ortho position of Ar2c.

The present invention provides compounds R94 and R95.

The present invention provides the following compounds:

N-(4-(2-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide; and

N-(4-(2-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide.

General Terms and Definitions

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 R₄is taken to include reference to R_4a, R_4band R_4cas well as sub-groups within these variables. The same applies for all other variables discussed in this section. Similarly, reference to compounds of formula (I) is taken to include compounds of formula (I-a), (I-b) and/or (I-c).

The term ‘alkyl’ as used herein, such as in C_1-3alkyl, C_1-4alkyl, C_1-5alkyl or C_1-6alkyl e.g. C_1-3alkyl, C_1-4alkyl or C_1-5alkyl, or such as in C_1-2alkyl, C_1-3alkyl or C_1-4alkyl whether alone or forming part of a larger group such as an Oalkyl group (e.g. OC_1-3alkyl, OC_1-4alkyl and OC_1-5alkyl or OC_1-2alkyl, OC_1-3alkyl or OC_1-4alkyl), is a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of alkyl groups include the C_1-5alkyl groups methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and n-pentyl, sec-pentyl and 3-pentyl, in particular the C_1-3alkyl groups methyl, ethyl, n-propyl and iso-propyl. Examples of alkyl groups also include the C_1-4alkyl groups methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl, in particular the C_1-3alkyl groups methyl, ethyl, n-propyl and iso-propyl such as C_1-2alkyl groups methyl and ethyl. Reference to “propyl” includes n-propyl and iso-propyl, and reference to “butyl” includes n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of Oalkyl groups include the OC_1-4alkyl groups methoxy, ethoxy, propoxy (which includes n-propoxy and iso-propoxy) and butoxy (which includes n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy). C₅alkyl groups as used herein, whether alone or forming part of a larger group such as an OC₅alkyl group is a straight or a branched fully saturated hydrocarbon chain containing five carbon atoms. Examples of C₅alkyl groups include n-pentyl, sec-pentyl, 3-pentyl, sec-isopentyl and active pentyl. C₅alkyl groups as used herein, whether alone or forming part of a larger group such as an OC₆alkyl group is a straight or a branched fully saturated hydrocarbon chain containing six carbon atoms. Examples of C₆alkyl groups include n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.

The term ‘alkylene’ as used herein, such as in C_0-2alkyleneC_3-5cycloalkyl, C_1-3alkyleneOC_1-2alkyl C_1-2alkyleneOC_1-2alkyl or OC_0-2alkyleneC_3-5cycloalkyl is a bifunctional straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of C_0-2alkylene groups are where the group is absent (i.e. C₀), methylene (C₁) and ethylene (C₂). Examples of C_1-3alkylene groups are where the group is methylene (C₁), ethylene (C₂) and propylene (C₃). Examples of C_1-2alkylene groups are where the group is methylene (C₁) and ethylene (C₂). Examples of C_0-1alkylene groups are where the group is absent (C₀) and methylene (C₁).

The term ‘alkenyl’ as used herein, such as in C_2-4alkenyl, 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 C_2-4alkynyl such as in C₂alkynyl 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_3-4cycloalkyl, C_3-5cycloalkyl or C_3-6cycloalkyl, whether alone or forming part of a larger group such as OC_3-5cycloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-5cycloalkyl or C_0-1alkyleneC_3-4cycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms. Examples of cycloalkyl groups include the C_3-6cycloalkyl groups cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in particular the C_3-5cycloalkyl groups cyclopropyl, cyclobutyl and cyclopentyl:

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When B is B-a, the term ‘heterocycloalkyl’ as used herein, such as in C_3-6heterocycloalkyl or C_0-2alkyleneC_3-6heterocycloalkyl 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 C_3-6heterocycloalkyl or C_0-2alkyleneC_3-6heterocycloalkyl 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 C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. Wherein a ring heteroatom is S, the term ‘heterocycloalkyl’ includes wherein the S atom(s) is substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e. S(O) or S(O)₂). Alternatively, any sulphur atom(s) in the C_3-6heterocycloalkyl ring is not substituted.

Examples of C_3-6heterocycloalkyl 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 C_3-6heterocycloalkyl include those comprising one heteroatom atom such as containing one heteroatom (e.g. one oxygen atom or one nitrogen atom) or containing two heteroatoms (e.g. two nitrogen atoms or one nitrogen atom and one oxygen atom). Particular examples of C_3-6heterocycloalkyl comprising one nitrogen atom include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, especially piperidinyl, pyrrolidinyl and morpholinyl. Particular examples of C_3-6heterocycloalkyl 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_3-6heterocycloalkyl include those comprising one oxygen atom such as containing one oxygen atom, or containing two oxygen atoms. Particular examples of C_3-6heterocycloalkyl 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_3-6heterocycloalkyl comprising one nitrogen atom include piperidinyl. Other examples of C_3-6heterocycloalkyl 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_3-6heterocycloalkyl 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. Examples of C_3-6heterocycloalkyl 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).

When B is B-bc and the compound is a compound of formula (I-b), the term ‘heterocycloalkyl’ as used herein, such as in C_3-6heterocycloalkyl 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. Examples of C_3-6heterocycloalkyl 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:

[Image Omitted]

wherein each Q is independently selected from O, N or S, such as O or N. When Q is N, as required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively the nitrogen atom(s) may be substituted (such as one nitrogen atom is substituted), for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. When any Q is S, the S atoms can be substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e. S(O) or S(O)₂). When R₄and R₅are R_4aand R_5a, Q is N substituted by S(O)₂R₂₉. Alternatively, any sulphur atom(s) in the C_3-6heterocycloalkyl ring is not substituted.

When A_ais —C(═O)NH—, —NH— or —CH₂NH— and R_4aand/or R_5ais C₀alkyleneC_3-6heterocycloalkyl, or when R_4aand R_5atogether with the carbon atom to which they are attached form a C_3-6heterocycloalkyl, any heteroatom in the heterocycloalkyl may not be directly connected to the carbon to which R_4aand R_5aare 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 (I-b), suitably, heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of ring atoms and includes the ring atom through which the heterocycloalkyl group is attached, wherein at least one of the atoms in the ring is a heteroatom such as O, N or S. Suitably, as required by valency, any nitrogen atom is connected to a hydrogen atom. Suitably any S atom is not present as an oxide. In particular, any nitrogen atom is connected to a hydrogen atom and any S atom is not present as an oxide.

When B is B-bc and the compound is a compound of formula (I-c), and when the heterocycloalkyl is formed from R₄and R₅together with the carbon atom to which they are attached, suitably any heteroatom is not directly connected to the carbon to which R₄and R₅are attached. Thus suitably, when the heterocycloalkyl is formed from R₄and R₅together with the carbon atom to which they are attached, the heterocycloalkyl may be:

[Image Omitted]

wherein each Q is independently O, N or S such as O or N. When Q is N, as required by valency, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively the nitrogen atom (s) may be substituted (such as one nitrogen atom is substituted), for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu. Additional substituent groups on any nitrogen atom(s) in the C_3-6heterocycloalkyl ring include C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃. When any Q is S, the S atom(s) can be substituted (such as one S atom is substituted) by one or two oxygen atoms (i.e. S(O) or S(O)₂). When R₄and R₅are R_4aand R_5a, Q is N substituted by —S(O)₂R₂₉. Alternatively, any sulphur atom(s) in the C_3-6heterocycloalkyl 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 C_1-6haloalkyl, such as in C_1-4haloalkyl or C_1-2haloalkyl, whether alone or forming part of a larger group such as an Ohaloalkyl group, such as in OC_1-6haloalkyl, such as in OC_1-4haloalkyl or OC_1-2haloalkyl, 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 CF₃. Further examples of haloalkyl are CHF₂and CH₂CF₃. Another example of haloalkyl is CH₂CHF₂. Examples of Ohaloalkyl include OCF₃, OCHF₂and OCH₂CF₃.

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:

[Image Omitted]

wherein when B is B-a, W₁may be N, CH, CR_10aor CR_11a, and W₂may be N, CH or CR_12aas allowed by the definitions provided for compounds of formula (I). W₂may also be CR_13aas allowed by the definitions provided for compounds of formula (I-a); and

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

[Image Omitted]

wherein W may be N, CH, CR_10bor CR_11b, and Y may be N, CH, CR_12bor CR_13bas allowed by the definitions provided for compounds of formula (I-b);

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

[Image Omitted]

wherein W may be N, CH or CR_10c, and Y may be N, CH or CR_12cas required by the definitions provided for compounds of formula (I-c). W may also be CR_11cas allowed by the definitions provided for compounds of formula (I-c).

The terms ‘ortho’ and ‘meta’ as used herein, such as when used in respect of defining the position of R₁₂on Ar2 is with respect to Ar1, means that the following structures may form:

when B is B-a:

[Image Omitted]

when B is B-bc and the compound is a compound of formula (I-b):

[Image Omitted]

wherein X represents a substituent e.g. R_12b; and

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

[Image Omitted]

wherein all variables listed above are as defined elsewhere herein.

When a spirocyclic ring system is said to form, e.g. when R_4aaand R_5aa, R_4aband R_5ab, or R_4acand R_5ac, suitably together with the carbon atom to which they are attached form a C_3-6cycloalkyl and 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, the following spirocyclic groups are encompassed (which may optionally be substituted as mentioned above):

[Image Omitted]

wherein C is a C_3-6cycloalkyl ring or a C_3-6heterocycloalkyl ring, as defined elsewhere herein. In one embodiment C is a C_3-6cycloalkyl ring. In a second embodiment C is a C_3-6heterocycloalkyl ring.

For example, one of the carbons is quaternary and is attached to a 5-membered dioxalane ring to form the following structure:

[Image Omitted]

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_4aaand R_5aa, R_4aband R_5ab, or R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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, the following spirocyclic groups are encompassed (which may optionally be substituted as mentioned above):

[Image Omitted]

wherein C is a C_3-6cycloalkyl ring or a C_3-6heterocycloalkyl ring, as defined elsewhere herein, and HC is a C_3-6heterocycloalkyl ring formed by R_4aand R_5a(i.e. R_4aaand R_5aa, R_4aband R_ab, or R_4acand R_5ac) as defined elsewhere herein. In one embodiment C is a C_3-6cycloalkyl ring. In a second embodiment C is a C_3-6heterocycloalkyl ring.

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

[Image Omitted]

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 Ar1 a, Ar1b and Ar1c. Ar2 encompasses the variables Ar2a, Ar2b and Ar2c.

The present invention provides N-oxides of the compound of formula (I). Suitably, when R₁₂together with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻), the example following structures are formed:

[Image Omitted]

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:

[Image Omitted]

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

[Image Omitted]

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

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 IC₅₀of 1 uM or lower, especially 100 nM 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 (²H or D), carbon-11 (¹¹C), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-15 (¹⁵N), oxygen-15 (¹⁵O), oxygen-17 (¹⁷O), oxygen-18 (¹⁹O), phosphorus-32 (³²P), sulphur-35 (³⁵S), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl), fluorine-18 (¹⁸F) iodine-123 (¹²³I), iodine-125 (¹²⁵I) 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. ³H, and carbon-14, i.e. ¹⁴C, 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. ²H 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 ¹¹C, ¹⁸F, ¹⁵O and ¹³N, 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. ²H 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 R₄is taken to include reference to R_4a, R_4band R_4cas well as sub-groups within these variables. The same applies for all other variables discussed in this section. Reference to compounds of formula (I) is taken to include compounds of formula (I-a), (I-b) and/or (I-c).

Generic and specific routes by which compounds disclosed herein and compound examples of the invention may be conveniently prepared are disclosed in WO2019/106156, WO2019/106146, WO2019/179652, WO02019/180244 and WO2020/083975, each of which is herein incorporated in its entirety by reference, as well as those routes summarised below, and adaptations thereof.

Compounds of Formula (I-a)

Compounds of formula (I-a) may be synthesised according to general and specific methods disclosed in WO2019/179652, WO2019/180244 and WO02020/083975. For the avoidance of doubt, reference to variables in each of the schemes in this section encompasses variables specific to compounds of formula (I-a). For example, R₁includes R_1a. Furthermore, reference to intermediates in each of the schemes in this section encompasses corresponding intermediates for compounds of formula (I-a). For example, reference to compounds of formula (II) encompasses compounds of formula (II-a).

[Image Omitted]

[Image Omitted]

Suitably, R₂is H, (IX) is converted to (X) using a base and alkyl halide or X—CH₂—(CH₂)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 1b, compounds of general formula (I) may be obtained by a five or six step process from a 2,4-dichloropyrimidine derivative of general formula (VIII). Firstly, the derivative (VIII) can be reacted with an unsymmetrical malonate ester as shown in Schemes 1a, 1b of WO2019/179652, or 1a or 1b herein. For example, the unsymmetrical malonate ester can be treated with a base such as Cs₂CO_Min 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 R₃=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). R₄and R₅can be connected to form a C_3-6cycloalkyl 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 R₄and R₅together with the carbon to which they are attached form a C_3-6heterocycloalkyl, double alkylation of intermediates (IX) using a di-haloheteroalkane (such as BrCH₂CH₂OCH₂CH₂Br) in the presence of a base such as Cs₂CO₃in 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 [t-BuXPhosPd(allyl)]OTf or t-BuXPhos-Pd-G3 and substituted sulfonamide nucleophile (VI), in the presence of an inorganic base, for example potassium carbonate to form intermediate derivative (II). Alternatively, sulfamination of intermediate (X) may be achieved using a substituted sulfonamide nucleophile (VI), in the presence of an inorganic base, for example Cs₂CO₃and a solvent such as N-methyl pyrrolidinone to form intermediates (II) which may be obtained by precipitation following dilution in aqueous 4M HCl.

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 (ill) (commercially available or prepared as in Schemes 6a, 6b, 7a or 7b of WO2019179652). Alternatively, compounds of formula (I) may be obtained by a strong base-mediated amide formation between compounds (II) and (III) at room temperature using bases such as iPrMgCl, UHMDS or KOtBu.

Compounds of the general formula (VII) where R₂is O-alkyl may be accessed in two steps from commercial 2,4,6-trichloropyrimidine derivatives such as (VIII) where R₂is 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 R₂=O-alkyl. Such compounds can then be progressed to final compounds of formula (I) following the steps previously described in Schemes 1a or 1b.

Compounds of general formula (I) where R1, Ar1 and Ar2 are defined above and R₄and R₅together with the carbon to which they are attached form a C_3-6heterocycloalkyl, 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 1b. 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 R₁, Ar1 and Ar2 are defined above and R₄and R₅together with the carbon to which they are attached form a C_3-6aminocycloalkyl, 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.

[Image Omitted]

Intermediates of formula (III) wherein Ar1, R₁₀, R₁₁, R₁₂and R₁₃are 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 R₁₂and R₁₃are defined above and Z represents a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group, to a substituted pyridine of formula (XI) where X denotes a halide. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.

[Image Omitted]

Intermediates of formula (III) wherein Ar1, R₁₀, R₁₁, R₁₂and R₁₃are defined above and Ar2 is an unsubstituted or substituted 2,5-pyrazinyl ring, may be synthesised by coupling under Suzuki conditions of an aromatic halide of general formula (XII) and Z represents a halide, to a boronate of general formula (XI) where X denotes a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium or [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.

Benzamide Pyrimidines

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

Compounds of general formula (I) where A is an amine linker such as —CH₂NH—, where R₁, Ar₁and Ar₂are defined above, R₄is C_1-6alkyl and R₅is H or C_1-6alkyl or R₄and R₅together with the carbon to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl 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).

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Compounds of general formula (I) where R₁, Ar₁and Ar₂are defined above, R₄is C_1-6alkyl and R₅is H or C_1-6alkyl or R₄and R₅together with the carbon to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl 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 HCl in dioxane to yield benzylamine derivative of general formula (LVXIX). Amide coupling conditions may then be employed to convert the benzylamine derivative (LVXIX) to amides of general formula (LXX) by employing a coupling reagent together with a biaryl carboxylic acid (XXXXIII) (commercially available or prepared as in Scheme 19 of WO02019179652). Compound of formula (LXX) can then be progressed to compounds of formula (I) following the oxidation, displacement sequence described in Scheme 9a.

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Intermediates of formula (LXXII) where Ar₂is 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 R₁₂and R₁₃are defined above and Z represents Br or Cl. Initially compounds such as (XI), can be converted to the corresponding boronate using a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂adduct 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.

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In general compounds of formula (I) where R₄and R₅together with the carbon to which they are attached form a 1,4-dioxaspiro[4.5]decane (i.e. m and n are 2) may be treated with a strong acid, such as HCl, to yield cyclic ketones of formula (I). Such ketones may then be treated with a hydride source, such as sodium borohydride, to yield the corresponding exocyclic alcohol or reacted with an amine, such as dimethylamine, followed by sodium triacetoxyborohydride to yield exocydic amines of formula (I).

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Compounds of formula (I) wherein A is —NR₆CH₂— can be obtained from compounds of formula (I) wherein A is —NR₆C(═O)—, by the reduction of the amide to the amine using a reducing agent such as LiAlH₄in a solvent such as THF.

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In general and as illustrated in Scheme 9a, compounds of formula (I) wherein R₁, Ar1 and Ar2 are as defined above, alkyl is C_1-4alkyl such as methyl or ethyl, e.g. methyl, and for example, R₄and R₅together with the carbon atom to which they are attached form a C_3-6heterocycloalkyl ring may be prepared starting from a general intermediate of formula (XXXIII). Intermediates such as (LXXIV) may be obtained by subjecting compounds such as (XXXIII) to amide coupling conditions such as those described in Scheme 9 of WO2019179652 using iPrMgCl. Thioethers of the general formula (LXXIII) may be transformed to sulfoxides or sulfones (LXXIV) in the presence of an oxidising agent such as mCPBA. Displacement of the sulfone group with a primary sulphonamide (VI) in the presence of a base such as Cs₂CO₃and a solvent such as N-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).

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In general and as illustrated in Scheme 9b, compounds of formula (I) wherein R₁, Ar1 and Ar2 are as defined above, alkyl is C_1-4alkyl such as methyl or ethyl, e.g. methyl, and for example, R₄and R₅together with the carbon atom to which they are attached form a C_3-6heterocycloalkyl 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 Cs₂CO₃and a solvent such as N-methyl pyrrolidone gives compounds of formula (I).

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wherein R is H, C_1-4alkyl (e.g. methyl and ethyl) or benzyl. In general and as illustrated in Scheme 9c, compounds of formula (I) wherein R₁, X, Y, Z, Ar1 and Ar2 are as defined above and K is C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu, C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃, may be prepared in five steps from compounds of formula (LVX). An intermediate of formula (XXXVI) 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 Cs₂CO₃and a solvent such as N-methyl pyrrolidone gives compounds of formula (II). Compounds of formula (I) may be obtained by a strong base-mediated amide formation between compounds (II) and (III) at room temperature using bases such as iPrMgCl, UHMDS or KOtBu, to give compounds of formula (I-P), followed by removal of the Boc group using a strong acid such as TFA, and introduction of the N-substituent K. Introduction of K may be performed by reaction of the free NH group with K-LG wherein LG is a leaving group such as halo e.g. chloro or bromo, under standard conditions known to the skilled person, or by any other N-substituent forming conditions known to the skilled person (such as Mitsunobu conditions, reductive amination or N-acylation), to give a compound of formula (I).

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In general and as illustrated in Scheme 10, compounds of formula (I) wherein R₁, Ar1 and Ar2 are as defined above, alkyl is C_1-4alkyl such as methyl or ethyl, e.g. methyl, and for example, R₄and R₅together with the carbon atom to which they are attached form a C_3-6heterocycloalkyl 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.

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In general and as illustrated in Scheme 11, compounds of formula (I) wherein R1, Ar1 and Ar2 are as defined above, R₄and R₅together with the carbon atom to which they are attached form a C_3-6heterocycloalkyl ring may be prepared starting from alcohols (LXXI), which as oxidised to aldehydes (LXXII) in the presence of MnO₂in 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.

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Compounds of formula (I) wherein A is —NH— and R₄or R₅is H may be prepared by reductive coupling of the appropriate amine and aldehyde in the presence of a hydride source such as sodium triacetoxyborohydride.

Compounds of Formula (I-b)

Compounds of formula (I-b) may be synthesised by general and specific methods disclosed in WO2019/106156 and those disclosed below. For the avoidance of doubt, reference to variables in each of the schemes in this section encompasses variables specific to compounds of formula (I-b). For example, R₁includes R_1b. Furthermore, reference to intermediates in each of the schemes in this section encompasses corresponding intermediates for compounds of formula (I-b). For example, reference to compounds of formula (II) encompasses compounds of formula (II-b).

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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(II) 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.

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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 R¹²and R¹³are 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 R¹⁰and R¹¹are defined above and where X denotes a halide. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and an inorganic base such as potassium carbonate in a solvent mixture of 1,4-dioxane and water.

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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 R¹²and R¹³are defined above and Z represents a halide, to a boronate of general formula (IX) of which R¹⁰and R¹¹are defined above and where X denotes a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium or [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) and an inorganic base such as potassium carbonate in a solvent mixture of dioxane and water.

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Compound of general formula (XVII) may be prepared by conversion of a suitable 2-(2-aminothiazol-4-yl)acetate derivative, such as a methyl or ethyl derivative, by a Sandmeyer type reaction using an organic nitrite, such as n-butylnitrite, in the presence of a halide source, such as Cu(I)Br in acetonitrille. Such reactions can be undertaken at temperatures of RT to 60° C.

Introduction of R₄/R₅can be undertaken by two alternative methods at this stage. Firstly, alkylation of compounds of general formula (XVII) can be undertaken by addition of a suitable base, for example, LiHMDS, together with an alkylating agent, such as iodomethane which results in dialkylation alpha to the ester moiety to yield compounds of formula (XVIII), where R_4b=R_5b=Me. Secondly, diazotisation of compounds of general formula (XVII) with the use of an diazo transfer reagent, such as 4-acetamidobenzenesulfonyl azide, under basic conditions, followed by treatment with rhodium and subsequent insertion of the corresponding nucleophile, such as isopropyl alcohol, gives intermediates of general formula (XVIII) where R_4b=Oisopropoxy and R_5b=H.

Introduction of the sulfonamide group in the preparation of compounds of formula (IV) may be achieved by an Ullmann coupling reaction i.e. Cu mediated coupling conditions using amines of formula (XXIV) and a copper catalyst, such as Cu(I)I, in the presence of an inorganic base, potassium carbonate, and a diamine ligand in dioxane. Such reactions are typically carried out at elevated temperatures such as 80° C. Alternatively, conversion of compounds of formula (XVIII) to (IV) can be achieved via a palladium mediated coupling, for example using a catalyst such as [t-BuXPhos Pd(allyl)]OTf and substituted sulfonamide nucleophile (XXIV), in the presence of an inorganic base, for example potassium carbonate to form compounds of formula (IV). Palladium meditated coupling conditions are particularly useful when R₄and R₅together 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.

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wherein halo is, for example, bromo. Compounds of formula (XXVII), for example, when R_4bis H and R_5band R₆are a C_2-3alkylene 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.

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In general compounds of formula (I) where R₄and R₅together with the carbon to which they are attached form a 1,4-dioxaspiro[4.5]decane (i.e. m is 2 and n is 2) may be treated with a strong acid such as HCl to yield cyclic ketones of formula (I). Such ketones may then be treated with a hydride source such as sodium borohydride to yield the corresponding exocyclic alcohol or reacted with an amine such as dimethylamine followed by sodium triacetoxyborohydride to yield exocyclic amines of formula (I).

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Compounds of formula (I) wherein A is —NR₆CH₂— can be obtained from compounds of formula (I) wherein A is —NR₆C(═O)—, by the reduction of the amide to the amine using a reducing agent such as LiAlH₄in a solvent such as THF.

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Compounds of formula (I) wherein A is —NR₆— and R₅or R₄are H can be obtained in a single step by a reductive amination between ketones of formula (XXIX) and amines of formula (III) in the presence of a hydride source such as sodium triacetoxyborohydride.

Compounds of Formula (I-c)

Compounds of formula (I-c) may be synthesised by general and specific methods disclosed in WO02019/106148 and those disclosed below. For the avoidance of doubt, reference to variables in each of the schemes in this section encompasses variables specific to compounds of formula (I-c). For example, R₁includes R_1c. Furthermore, reference to intermediates in each of the schemes in this section encompasses corresponding intermediates for compounds of formula (I-c). For example, reference to compounds of formula (II) encompasses compounds of formula (II-c).

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Compounds of formula (XIII) may be obtained by a general process as shown in Scheme 21 whereby a carboxylic acid precursor (XIV) is reacted with an activating agent such as HATU, T3P or Ghosez's reagent, to generate a reactive, electrophilic carboxylic acid derivative, followed by subsequent reaction with an amine of formula (II). Intermediates of formula (XIII) are then converted to a compound of general formula (I) by coupling under Suzuki conditions with an aromatic halide of general formula (XII), of which X is defined in Scheme 21 and represents a dihydroxyboryl or dialkyloxyboryl group, such as a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂adduct 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.

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Intermediates of formula (III) where Ar₂is 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 R₁₀and R₁₂are defined above and Z represents a halide such as Br or Cl, to a boronate of general formula (XVI) where X denotes a dihydroxyboryl or dialkyloxyboryl group, such as a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂adduct 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 CH₂Cl₂, hydrolysis of the methyl ester using an alkali metal hydroxide such as NaOH in a solvent mixture such as THF/MeOH or hydrolysis of the nitrile using a strong acid such as concentrated HCl. Compounds of formula (III-A) may also be made using this method.

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Compounds of formula (I) wherein A_ais —CH₂NR₆— can be accessed in two steps from compounds of formula (XXII). Oxidation of the alcohol (XXII) under standard oxidation conditions such as MnO₂gives aldehyde (XXIII). A reductive amination using a hydride source such as sodium tiacetoxyborohydride between aldehyde (XXIII) and amine (II) gives compounds of formula (I).

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In general compounds of the formula (I) where R_4aand R_5atogether with the carbon to the which they are attached form a C_3-6cycloalkyl wherein one of the carbons of the C_3-6cycloalkyl is a spiro centre such that spirocyclic ring system is formed by the C_3-6cycloalkyl ring and a C_3-6heterocycloalkyl 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 HCl to yield cyclic ketones of formula (I). Such ketones may then be treated with a hydride source such as sodium borohydride to yield the corresponding exocyclic alcohol or reacted with an amine such as dimethylamine followed by sodium triacetoxyborohydride to yield exocyclic amines of formula (I).

Intermediates of the Invention

Compounds of Formula (I-a)

The present invention also relates to novel intermediates in the synthesis of compounds of formula (I-a) such as compounds of formula (II-a) to (LVIX-a) such as compounds of formula (II-a) to (XXV-a), such as compounds of formula (II-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 (I-a):

- a compound of formula (II-a):

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wherein R is H, C_1-6alkyl (e.g. methyl and ethyl) or benzyl;

- a compound of formula (XX-a):

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wherein P is a nitrogen protecting group such as para-methoxybenzyl;

- a compound of formula (XXIV-a):

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wherein P is a nitrogen protecting group such as para-methoxybenzyl;

- a compound of formula (XXXI-a):

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- a compound of formula (XXXXII-a):

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- a compound of formula (LI-a):

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wherein X₁is Cl or Br.

- a compound of formula (LVIII-a):

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- a compound of formula (LXXIII-a):

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wherein alkyl is C_1-4alkyl such as methyl or ethyl, e.g. methyl;

- a compound of formula (LXXIII-a)

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- a compound of formula (LXXIV-a):

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- a compound of formula (LXXXIII-a):

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- a compound of formula (XXXIV-a):

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- a compound of formula (LXXI-a):

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- a compound of formula (LXXII-a):

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Suitably, at least one of R₁₀, R₁₁and R₁₂is 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 (II-a), (XX-a), (XXIV-a), (XXXI-a), (XXXXII-a), (LI-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_4baand R_5bajoin 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 (I-b)

The present invention also relates to novel intermediates in the synthesis of compounds of formula (I-b) such as compounds of formula (II-b), (IV-b), (V-b), (VI-b), (VII-b), (X-b), (XII-b), (XVIII-b), (XIX-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 (I-b):

- Compounds of formula (II-b)

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wherein R₁, R₃, R₄and R₅are as defined herein;

- Compounds of formula (IV-b)

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wherein R is C_1-6alkyl (e.g. methyl, ethyl) or benzyl.

Suitably, the intermediate is not:

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Suitably, when the compound is a compound of formula (IV-b), R_4band R_5bcannot both be H when R_1bis CH₃.

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), (VI-b), (VII-b), (X-b), (XII-b), (XVIII-b), (XIX-b), (XX-b), (XXI-b), (XXII-b) and (XXIII-b).

Other intermediates of interest include those disclosed in WO2019/106156 such as INTA92, INTA93, INTA94, INTA95, INTA96, INTA97, INTA98, INTA103, INTA104, INTA105, INTA107, INTA3, INTA47, INTA48, INTA72, INTA106, INTB37, INTB38, INTB43.

Compounds of Formula (I-c)

The present invention also relates to novel intermediates in the synthesis of compounds of formula (I-c) such as compounds of formula (II-c), (IV-c), (V-c), (VI-c), (VIII-c), (IX-c), (X-c), (XI-c), (XIII-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 (I-c):

- a compound of formula (II-c):

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- a compound of formula (VIII-c):

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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-c), (IV-c), (V-c), (VI-c), (VIII-c), (IX-c), (X-c), (XI-c), (XIII-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 (I-a), (I-b) and (I-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), A plastic Anemia, Arthritis, Asthma, Atherosclerosis, Atherosclerotic plaque, Atopic Dermatitis, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Autoimmune Hypophysitis (Lymphocytic Hypophysitis), Autoimmune Inner Ear Disease, Autoimmune Lymphoproliferative Syndrome, Autoimmune Myocarditis, Autoimmune Neutropenia, Autoimmune Oophoritis, Autoimmune Orchitis, Auto-Inflammatory Diseases requiring an immunosuppressive treatment, Azoospermia, Bechet's Disease, Berger's Disease, Bullous Pemphigoid, Cardiomyopathy, Cardiovascular disease, Celiac disease including Refractory Celiac Disease (type I and type II), Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic Idiopathic Polyneuritis, Chronic Inflammatory Demyelinating Polyneuropathy (CIPD), Chronic Relapsing Polyneuropathy (Guillain-Barré syndrome), Churg-Strauss Syndrome (CSS), Cicatricial Pemphigoid, Cold Agglutinin Disease (CAD), chronic obstructive pulmonary disease (COPD), CREST Syndrome, Cryoglobulin Syndromes, Cutaneous Lupus, Dermatitis Herpetiformis, Dermatomyositis, Eczema, Epidermolysis Bullosa Acquisita, Essential Mixed Cryoglobulinemia, Evan's Syndrome, Exophthalmos, Fibromyalgia, Goodpasture's Syndrome, Grave's disease, Hemophagocytic Lymphohistiocytosis (HLH) (including Type 1 Hemophagocytic Lymphohistiocytosis), Histiocytosis/Histiocytic Disorders, Hashimoto's Thyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura (ITP), IgA Nephropathy, Immunoproliferative Diseases or Disorders, Inflammatory Bowel Disease (IBD), Interstitial Lung Disease, Juvenile Arthritis, Juvenile Idiopathic Arthritis (JIA), Kawasaki's Disease, Lambert-Eaton Myasthenic Syndrome, Lichen Planus, Localized Scleroderma, Lupus Nephritis, Méniére's Disease, Microangiopathic Hemoytic Anemia, Microscopic Polyangitis, Miller Fischer Syndrome/Acute Disseminated Encephalomyeloradiculopathy, Mixed Connective Tissue Disease, Multiple Sclerosis (MS), Muscular Rheumatism, Myalgic Encephalomyelitis (ME), Myasthenia Gravis, Ocular Inflammation, Pemphigus Foliaceus, Pemphigus Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes (Whitaker's syndrome), Polymyalgia Rheumatica, Polymyositis, Primary Agammaglobulinemia, Primary Biliary Cirrhosis/Autoimmune Cholangiopathy, Primary Glomerulonephritis, Primary Sclerosing Cholangitis, Psoriasis, Psoriatic Arthritis, Pure Red Cell Anemia, Raynaud's Phenomenon, Reiter's Syndrome/Reactive Arthritis, Relapsing Polychondritis, Restenosis, Rheumatic Fever, Rheumatic Disease, Rheumatoid Arthritis, Sarcoidosis, Schmidt's Syndrome, Scleroderma/Systemic Sclerosis, Sjörgen's Syndrome, Stiff-Man Syndrome, The Sweet Syndrome (Febrile Neutrophilic Dermatosis), Systemic Lupus Erythematosus (SLE), Systemic Scleroderma, Takayasu Arteritis, Temporal Arteritis/Giant Cell Arteritis, Thyroiditis, Type 1 diabetes, Type 2 diabetes, Uveitis, Vasculitis, Vitiligo, Wegener's Granulomatosis, and X-linked lymphoproliferative disease.

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:
  - a 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; a Thyroiditis, Hashimoto thyroiditis, Grave's disease, exophthalmos;
  - Autoimmune hemolytic anemia, autoimmune neutropenia, ITP, pernicious anaemia, pure red cell anaemia, micro-angiopathic hemolytic anemia;
  - Primary glomerulonephritis, Berger's disease, Goodpasture's syndrome, IgA nephropathy; and
  - Chronic idiopathic polyneuritis, chronic inflammatory demyelinating polyneuropathy (CIPD), chronic relapsing polyneuropathy (Guillain-Barré syndrome), Miller Fischer syndrome, Stiff man syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis.
- diseases and disorders for which the involvement of B-cells is less clearly characterized (although sometimes illustrated by the efficacy of anti-CD20 monoclonal antibodies or intravenous immunoglobulin infusions) and may not correspond or be limited to the production of pathogenic antibodies (nevertheless, non-pathogenic antibodies are sometimes described or even often present and used as a diagnosis biomarker), including:
  - Addison's disease, autoimmune oophoritis and azoospermia, polyglandular syndromes (Whitaker's syndrome), Schmidt's syndrome;
  - Autoimmune myocarditis, cardiomyopathy, Kawasaki's disease;
  - Rheumatoid arthritis, Sjögren's syndrome, mixed connective tissue disease, polymyositis and dermatomyositis; polychondritis;
  - Primary glomerulonephritis;
  - Multiple sclerosis;
  - Autoimmune hepatitis, primary biliary cirrhosis/autoimmune cholangiopathy,
  - Hyper acute rejection of transplanted organs;
  - Chronic rejection of graft or transplants;
  - Chronic Graft versus Host reaction/disease after transplantation of bone marrow cells or hematopoietic precursor cells.

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 Lymphoproliferative 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 (I-a), (I-b) and (I-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-IL12/IL23 antibodies (e.g., ustekinumab); anti-IL6 or anti-IL6R antibodies, anti-IL17 antibodies or small molecule IL12/IL23 inhibitors (e.g., apilimod); Anti-alpha-4-beta-7 antibodies (e.g., vedolizumab); MAdCAM-1 blockers (e.g., PF-00547659); antibodies against the cell adhesion molecule alpha-4-integrin (e.g., natalizumab); antibodies against the IL2 receptor alpha subunit (e.g., daclizumab or basiliximab); JAK inhibitors including JAK1 and JAK3 inhibitors (e.g., tofacitinib, baricitinib, R348); Syk inhibitors and prodrugs thereof (e.g., fostamatinib and R-406); Phosphodiesterase-4 inhibitors (e.g., tetomilast); HMPL-004; probiotics; Dersalazine; semapimod/CPSI-2364; and protein kinase C inhibitors (e.g. AEB-071).

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

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 (I-a), (I-b) and (I-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 parts 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-γ Ib, 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-Inhibitors, C-Proteinase-Inhibitors, MMP-Inhibitors, 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(O)CH₃)
- AcOH glacial acetic acid
- AlMe₃trimethylaluminium
- aq aqueous
- Ar Aromatic ring
- BEH ethylene bridged hybrid
- Bispin Bis(pinacolato)diboron; 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane
- Bz benzyl (CH₂-phenyl)
- Boc tert-butyloxycarbonyl protecting group
- Cs₂CO₃Cesium carbonate
- CSH charged surface hybrid
- d doublet
- DABAL-Me₃adduct 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
- EtI Ethyl iodide
- EtOAc ethyl acetate
- EtOH ethanol
- g grams
- Hal halogen
- HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
- HPLC high performance liquid chromatography
- hr(s) hour(s)
- IC₅₀50% inhibitory concentration
- iPr iso-propyl
- iPrMgCl iso-propyl magnesium chloride
- K₂CO₃potassium carbonate
- LCMS liquid chromatography-mass spectrometry
- LiHMDS 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
- MeI iodomethane
- MeOH methanol
- MesCl methanesulfonyl chloride
- MHz megahertz
- min(s) minute(s)
- MSD mass selective detector
- m/z mass-to-charge ratio
- N₂nitrogen gas
- NH₃ammonia
- NH₄Cl ammonium chloride
- NaH sodium hydride
- NaHCO₃sodium bicarbonate
- NaBH(OAc)₃Sodium triacetoxyborohydride
- nm nanometre
- NMR nuclear magnetic resonance (spectroscopy)
- NSFI N-fluorobenzenesulfonimide
- P4HB poly-4-hydroxybutyrate
- PDA photodiode array
- Pd 170 chloro(crotyl)(2-dicyclohexylphosphino-2′,4′,6′-triisopropybiphenyl)palladium(II) or XPhos Pd(crotyl)Cl
- Pd 174 allyl(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II) triflate or [tBuXPhosPd(allyl)]OTf
- [Pd(allyl)Cl₂]₂bis(allyl)dichlorodipalladium
- PdCl₂(dppf) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
- Pd(PPh₃)₄tetrakis(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_NAr nucleophilic aromatic substitution
- sat saturated
- SCX solid supported cation exchange (resin)
- Selectfluor N-chloromethyl-N′-fluorotriethylenediammonium bis(tetrafluoroborate)
- t triplet
- tBu tert-butyl
- T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
- TBME tert-butyl methyl ether
- TFA Trifluoroacetic acid
- [t-BuXPhos Pd(allyl)]OTf allyl(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)palladium(II) 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
- um 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 um) cartridges using the amount indicated. SCX was purchased from Supelco and treated with 1M hydrochloric acid prior to use. Unless stated otherwise the reaction mixture to be purified was first diluted with MeOH and made acidic with a few drops of AcOH. This solution was loaded directly onto the SCX and washed with MeOH. The desired material was then eluted by washing with 0.7 M NH₃in MeOH.

Preparative Reverse Phase High Performance Liquid Chromatography

Prep HPLC

Acidic Prep

Waters X-Select CSH column C18, 5 um (19×50 mm), flow rate 28 mL min⁻¹eluting with a H₂O-MeCN gradient containing 0.1% v/v formic acid over 8.5 min using UV detection at 254 nm.

Basic Prep

Waters X-Bridge Prep column C18, 5 um (19×50 mm), flow rate 28 mL min⁻¹eluting with a 10 mM NH₄HCO₃-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 um, 4.6×30 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 um, 4.6×30 mm column eluting with a gradient of MeCN in aqueous 10 mM ammonium bicarbonate. The gradient from 5-95% 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.

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 um, 2.1×30 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 um, 2.1×30 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 um, 2.1×30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.11 minutes. The gradient from 5-95% occurs between 0.11-2.15 minutes with a flush from 2.15-2.56 minutes. A column re-equilibration to 5% MeCN is from 2.56-2.83 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos/neg switching.

Basic UPLC 2 Basic UPLC 1 minute Analytical UPLC/MS was carried out using a Waters Acquity BEH C18, 1.7 um, 2.1×30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.08 minutes. The gradient from 5-95% occurs between 0.08-0.70 minutes with a flush from 0.7-0.8 minutes. A column re-equilibration to 5% MeCN is from 0.8-0.9 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos/neg switching.

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 um, 4.6×250 mm, 1.0 mL/min, 25-70% EtOH (0.2% TFA) in iso-hexane (0.2% TFA)

Chiral IC4 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6×250 mm, 1.0 mL/min, 40% EtOH (0.2% TFA) in 4:1 heptane/chloroform (0.2% TFA).

Chiral IC5 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6×250 mm, 1.0 mL/min, 20% EtOH (0.2% TFA) in iso-hexane (0.2% TFA).

Reverse Phase HPLC Conditions for the Chiral Analytical Methods

Chiral IC6 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6×250 mm, 1.0 mL/min, 50% MeCN (0.1% formic acid) in water (0.1% formic acid).

Chiral IC7 method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6×250 mm, 1.0 mL/min, 5-95% MeCN (0.1% formic acid) in water (0.1% formic acid).

¹H NMR Spectroscopy

¹H 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 (I-a)—Intermediates

Any one of Methods 1-1q (referred to later herein) or A-N and Q-R may be used in the synthesis of the compounds of formula (I). For example, a scheme which is shown using a compound wherein X=N, Y=CR₂and Z=CR₃may 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 WO02019/179852, VNO2019/180244 and VNO2020/083975, each of which is herein incorporated in its entirety by reference.

Method A: Decarboxylation of Chloro-Heterocycles Such as Chloro-Pyrimidines

[Image Omitted]

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

[Image Omitted]

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 NH₄Cl (aq) or 1M HCl (aq), stirred for 20 mins then extracted with EtOAc. The organic phases were died (phase separator) and concentrated. The crude product was purified by normal phase chromatography.

Method C: Formation of Sulfonamides from Aromatic Halides

[Image Omitted]

2-Chloropyrimidine 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 or trituration using a suitable solvent.

Method D: Decarboxylation of Pyrimidines Bearing Sulfonamides

[Image Omitted]

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

[Image Omitted]

A solution of hetero-aromatic ester (1 eq) in THF (10 volumes) was cooled to −78° C. to which was added LiHMDS (1.25 eq 1M in THF). The reaction mixture was then warmed to RT for 1 hr. The solution was cooled to −78° C. and a solution (in THF) of, or solid, NSFI (1.25 eq) was added dropwise then warmed to RT for 2 hrs. The solution was diluted with sat NaHCO₃(aq) and the product was extracted into EtOAc. The crude product was purified by normal phase chromatography.

Method I: Buchwald Coupling—Sulfonylation

[Image Omitted]

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

[Image Omitted]

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

Amine Intermediate Preparation

Method E: Suzuki Coupling of Halo Anilines with Heteroaromatic Boronates

[Image Omitted]

A solution of Ar1-X (1 eq) and Ar2-Z (1 eq) in solvent (3 volumes) and base (2.5 eq) was degassed (N₂, 5 min) and heated to 40° C. whereupon Pd catalyst (3 mol %) was added and the reaction mixture further degassed (N₂, 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

[Image Omitted]

Pd catalyst (5 mol %) was added to a degassed (N₂, 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 (N₂, 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

[Image Omitted]

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 (N₂, 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

[Image Omitted]

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 (N₂, 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

[Image Omitted]

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

[Image Omitted]

A solution of the ester (1 eq) in a mixture of THF/MeOH (4/1 volumes) was treated with LiOH (2.2-6 eq.) and stirred between RT and 50° C. for between 3 hrs and 18 hrs. The organic solvents were removed in vacuo then acidified with 1 M HCl and extracted with EtOAc. The organic phases were combined, dried (Na₂SO₄), filtered and concentrated. The products were used directly in the next step with no further purification undertaken.

Method N: Potassium Salt Formation

[Image Omitted]

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

[Image Omitted]

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 UHMDS (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 (MgSO₄), 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.

Name/Structure
Synthesis

(All examples containing
Method, [LCMS

chiral centres are
Method], m/z
¹H NMR Chemical Shift Data

INTC
racemates unless stated)
(M + H)⁺, (Rt/min)
(DMSO-d6 unless stated)

INTC186

[Image Omitted]

Method P, [HPCL acidic], 325 (1.99).
8.60 (d, J = 5.3 Hz, 1H), 7.24 (d, J = 5.3 Hz, 1H), 3.88-3.86 (m, 4H), 3.65 (s, 3H), 2.49 (s, 3H), 2.30-2.24 (m, 2H), 2.16-2.07 (m, 2H), 1.65-1.56 (m, 4H).

INTC187

[Image Omitted]

Method P, [HPLC acidic], 382 (2.54).
8.61 (d, J = 5.3 Hz, 1H), 7.25 (d, J = 5.3 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.73-3.65 (m, 2H), 3.32 (s, 1H), 2.49 (s, 3H), 2.26- 2.20 (m, 1H), 2.02-1.93 (m, 2H), 1.40 (s, 9H), 1.14 (t, J = 7.1 Hz, 3H), 1H obscured by DMSO and 1H by obscured by water

INTC188

[Image Omitted]

Method P, [HPLC acidic], 297 (1.76).
No data collected

INTC190

[Image Omitted]

Method P, [HPLC acidic], 297 (2.00).
8.63-8.56 (m, 1H), 7.22 (d, J = 5.2 Hz, 1H), 3.65 (s, 3H), 3.24 (s, 3H), 3.23-3.20 (m, 1H), 2.48 (s, 3H), 2.40-2.28 (m, 2H), 1.93-1.80 (m, 4H), 1.36-1.24 (m, 2H).

INTC236

[Image Omitted]

Method P, [HPLC acidic], (M − Boc) + H 268, (1.58)
8.53 (s, 1H), 8.40 (s, 1H), 3.72- 3.59 (m, 2H), 3.66 (s, 3H), 3.24- 3.00 (m, 2H), 2.52 (s, 3H), 2.25-2.30 (m, 2H), 2.00-2.10 (m, 2H), 1.40 (s, 9H).

INTC241

[Image Omitted]

Method P, [HPLC Acidic], (M − tBu) + H 312, (1.57)
8.45 (d, J = 5.5 Hz, 1H), 7.35 (d, J = 5.5 Hz, 1H), 3.64 (s, 3H), 3.62-3.55 (m, 2H), 2.53-2.47 (m, 2H), 2.21-2.09 (m, 4H), 1.40 (s, 9H). 3H not observed, obscured by DMSO peak.

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

[Image Omitted]

To a solution of 1-tert-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 NaHCO₃(aq, 100 mL), gas evolved, and was diluted with DCM (50 mL). The organics were isolated and dried (MgSO₄), 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)piperidine-4-carboxylate INTC192

[Image Omitted]

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 MesCl (0.37 mL, 5.08 mmol). After 1 hr, 1 M HCl (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)piperidine-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-2H-pyran-4-yl)methanol INTC197

[Image Omitted]

LiCl (0.95 g, 22.4 mmol) followed by NaBH₄(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-2H-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 1M HCl (aq, 20 mL) and the volatiles were removed in vacuo. The residue was extracted with DCM (3×150 mL). The organic extract was dried (MgSO₄), filtered and solvent removed in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EA/iso-hexanes) to afford (4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)methanol (2.3 g, 9.09 mmol, 81% yield) as a colourless gum. Rt 0.80 min (UPLC acidic); m/z 241 (M+H)⁺ (ES+). ¹H NMR (500 MHz, DMSO-d6) δ 8.54 (d, J=5.3 Hz, 1H), 7.23 (d, J=5.3 Hz, 1H), 4.73 (t, J=5.6 Hz, 1H), 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-2H-pyran-4-carbaldehyde INTC198

[Image Omitted]

DMP (1.77 g, 4.16 mmol) was added portionwise into a stirring solution of (4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)methanol 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. NaHCO₃(aq, 100 mL) and extracted with DCM (3×100 mL). The organic extract was sequentially washed with saturated sat. NaHCO₃(aq, 100 mL), and brine (100 mL). The organic extract was dried (MgSO₄), filtered and solvent in vacuo to afford 4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-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⁺). ¹H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.65 (d, J=5.2 Hz, 1H), 7.30 (d, J=5.2 Hz, 1H), 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)-N-((4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-yl)methyl)aniline INTC199

[Image Omitted]

NaBH(OAc)₃(1.07 g, 5.04 mmol) was added into a suspension of 4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-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. NaHCO₃(aq, 2×100 mL) and brine (100 mL), dried (MgSO₄), filtered and solvent removed in vacuo. The crude product was purified by chromatography on silica gel (25 g cartridge, 0-100% EtOAc/iso-hexanes) to afford 4-(6-ethoxypyrazin-2-yl)-N-((4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-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⁺). ¹H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 7.99 (s, 1H), 7.81-7.74 (m, 2H), 7.29 (d, J=5.3 Hz, 1H), 6.66-6.57 (m, 2H), 6.00 (t, J=6.6 Hz, 1H), 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

[Image Omitted]

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. Na₂SO₃and extracted with DCM. The organic extract was sequentially washed with sat aq. NaHCO₃and brine, dried (MgSO₄), filtered and solvent removed in vacuo to afford the desire compound.

TABLE 2

The following intermediates were made according to Method Q.

Synthesis

Method,

Name/Structure
[LCMS

(All examples containing chiral
Method], m/z

centres are racemates unless
(M + H)⁺,
¹H NMR Chemical Shift Data

INTC
stated)
(Rt/min)
(DMSO-d6 unless stated)

INTC203

[Image Omitted]

Method Q using INTC186, [HPLC acidic], 357 (1.49).
9.06 (d, J = 5.3 Hz, 1H), 7.93 (d, J = 5.3 Hz, 1H), 3.91-3.83 (m, 4H), 3.66 (s, 3H), 3.41 (s, 3H), 2.37-2.29 (m, 2H), 2.29- 2.18 (m, 2H), 1.68-1.56 (m, 4H).

INTC207

[Image Omitted]

Method Q using INTC199, [HPLC, acidic], 454 (1.89).
8.87 (d, J = 5.3 Hz, 1H), 8.56 (s, 1H), 7.99 (s, 1H), 7.77- 7.71 (m, 3H), 6.57-6.47 (m, 2H), 6.07 (t, J = 6.7 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 3.80- 3.74 (m, 2H), 3.47-3.42 (m, 2H), 3.31-3.24 (m, 2H), 2.83 (s, 3H), 2.36 (d, J = 13.4 Hz, 2H), 1.95-1.84 (m, 2H), 1.37 (t, J = 7.0 Hz, 3H).

INTC208

[Image Omitted]

Method Q using INTC188, [HPLC, acidic], 329 (1.27).
No data collected

INTC210

[Image Omitted]

Method Q using INTC190, [HPLC acidic], 329 (1.46).
No data collected

INTC233

[Image Omitted]

Method Q using INTC232, [HPLC Acidic], 568, (2.23)
No NMR recorded

INTC237

[Image Omitted]

Method Q using INTC236, [HPLC acidic], (M − Boc) + H 300, (1.32)
9.19 (s, 1H), 9.17 (s, 1H), 3.67 (s, 3H), 3.59-3.46 (m, 2H), 3.35 (s, 3H), 3.30-3.20 (m, 2H), 2.36-2.28 (m, 2H), 2.28- 2.19 (m, 2H), 1.40 (d, J = 5.3 Hz, 9H).

INTC242

[Image Omitted]

Method Q using INTC241, [UPLC Acidic], (M − Boc) + H 284, (0.57)
No NMR recorded

Method R: Formation of Sulfonamides from Aromatic Sulfones

[Image Omitted]

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 HCl. The resulting precipitate was filtered to afford desired sulfonamide product.

TABLE 3

The following intermediates were made according to Method R.

Synthesis

Method,

[LCMS

Method],
¹H NMR Chemical Shift

Name/Structure
m/z
Data

(All examples containing chiral
(M + H)⁺,
(DMSO-d6 unless
Base,

INTC
centres are racemates unless stated)
(Rt/min)
stated)
Solvent

INTC214

[Image Omitted]

Method R using INTC203, [HPLC acidic], 398 (1.63).
11.28 (s, 1H), 8.63-8.54 (m, 1H), 7.21-7.11 (m, 1H), 3.87 (s, 3H), 3.65 (s, 4H), 3.24-3.15 (m, 1H), 2.31-2.23 (m, 2H), 2.18- 2.02 (m, 2H), 1.70-1.52 (m, 4H), 1.19-0.99 (m, 4H).
Cs₂CO₃, NMP

INTC215

[Image Omitted]

Method R using INTC205, [HPLC acidic], 433 (1.63).
No data collected
Cs₂CO₃, NMP

INTC216

[Image Omitted]

Method R using INTC208, [UPLC acidic], 370 (0.48).
11.32 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 7.20 (d, J = 5.2 Hz, 1H), 3.87-3.82 (m, 2H), 3.82-3.78 (m, 2H), 3.66 (s, 3H), 3.27- 3.18 (m, 1H), 3.05-2.97 (m, 2H), 2.98-2.84 (m, 2H), 1.17-1.08 (m, 2H), 1.07-0.99 (m, 2H).
Cs₂CO₃, NMP

INTC218

[Image Omitted]

Method R using INTC210, [HPLC acidic], 370 (1.62).
11.25 (s, 1H), 8.57 (d, J = 5.3 Hz, 1H), 7.23-7.11 (m, 1H), 3.65 (s, 3H), 3.24 (s, 3H), 3.23-3.20 (m, 1H), 2.48-2.54 (m 1H, obscured by DMSO peak) 2.37-2.29 (m, 2H), 1.97-1.80 (m, 4H), 1.36- 1.24 (m, 2H), 1.16- 1.01 (m, 4H).
Cs₂CO₃, NMP

INTC234

[Image Omitted]

Method R using INTC233 and ethane sulfonamide, [HPLC Acidic], 613, (2.48)
11.23 (s, 1H), 10.18 (s, 1H), 9.04 (dd, J = 2.5, 0.8 Hz, 1H), 8.85 (s, 1H), 8.61 (d, J = 5.3 Hz, 1H), 8.51 (dd, J = 8.8, 2.5 Hz, 1H), 8.26 (s, 1H), 8.23- 8.17 (m, 1H), 7.23 (d, J = 5.3 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.68-3.62 (m, 2H), 3.56-3.48 (m, 2H), 2.44 (d, J = 14.1 Hz, 2H), 2.13-2.04 (m, 2H), 1.41 (d, J = 4.6 Hz, 11H), 1.13 (t, J = 7.3 Hz, 3H), 0.89-0.79 (m, 3H).
Cs₂CO₃, NMP

INTC238

[Image Omitted]

Method R using INTC237 and cyclopropyl sulfonamide, [UPLC Basic], (M − Boc) + H 341, (1.12)
No NMR recorded
Cs₂CO₃, NMP

INTC243

[Image Omitted]

Method R using INTC242 and cyclopropyl sulfonamide, [HPLC Acidic], (M − Boc) + H 341, (2.03)
11.31 (s, 1H), 8.51 (d, J = 5.7 Hz, 1H), 6.82 (d, J = 5.7 Hz, 1H), 3.66-3.59 (m, 4H), 3.15-3.06 (m, 4H), 2.18-2.05 (m, 4H), 1.40 (s, 10H), 1.15-1.05 (m, 4H).
Cs2CO₃, NMP

N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide hydrochloride INTC235

[Image Omitted]

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

4-(6-(Cydopropanesulfonamido) pyrazin-2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride INTC240

[Image Omitted]

This compound was prepared by Boc-deprotection with HCl of INTC239, [UPLC Acidic], 525, (0.83); ¹H NMR (DMSO-d6) 11.18 (s, 1H), 10.39 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.94-8.73 (m, 3H), 8.52 (dd, J=8.8, 2.4 Hz, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.23 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 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)-N-(5-(6-cyclopropylpyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride INTC245

[Image Omitted]

This compound was prepared by Boc-deprotection with HCl of INTC244, [HPLC Acidic], 521, (1.30); ¹H NMR (DMSO-d6) 11.42 (s, 1H), 10.23 (s, 1H), 9.03-8.96 (m, 2H), 8.89-8.70 (m, 2H), 8.63-8.57 (m, 2H), 8.52-8.48 (m, 1H), 8.21 (d, J=8.8 Hz, 1H), 6.89 (d, J=5.7 Hz, 1H), 3.29-3.07 (m, 5H), 2.53 (s, 2H), 2.29-2.22 (m, 1H), 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)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide hydrochloride INTC247

[Image Omitted]

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

Method 13: t-BuOK Mediated Amide Coupling from Ester

[Image Omitted]

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 15-80 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 HCl (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.

Synthesis
¹H NMR Chemical Shift

Name/Structure
Method, [LCMS
Data

(All examples containing chiral centres
Method], m/z
(DMSO-d6 unless

INTC
are racemates unless stated)
(M + H)⁺, (RT/Min)
stated)

INTC232

[Image Omitted]

Method 13 using INTC187 and INTD33, [HPLC Acidic], 552, (2.78)
No NMR recorded

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

[Image Omitted]

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⁺); ¹H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.26 (s, 1H), 7.99 (dd, J=8.0, 1.7 Hz, 1H), 7.91 (dd, J=11.6, 1.7 Hz, 1H), 7.66-7.57 (m, 1H), 5.37 (t, J=5.8 Hz, 1H), 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

[Image Omitted]

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⁺); ¹H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.98 (s, 1H), 8.37 (s, 1H), 8.22-8.13 (m, 2H), 7.99 (dd, J=8.3, 7.3 Hz, 1H), 4.52 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H).

Compounds of Formula (I-a)—Examples

The synthesis of a number of known CTPS1 inhibitors is disclosed in WO2019/179652, WO2019/180244 and WO2020/083975 (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 WO2020/083975, each of which is herein incorporated in its entirety by reference.

Amide Formation

Method 1: Amide Coupling Using HATU

[Image Omitted]

To a stirred suspension of the acid or the potassium salt (1 eq, X=H or K) and DIPEA (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 1M HCl (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.

N-(4-(5-Chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide P1

[Image Omitted]

Method 2: AlMe₃Mediated Amide Coupling from Ester

[Image Omitted]

To an ice cooled solution of aniline (2 eq) in toluene (40 volumes) was added AlMe₃(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)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)cyclopentanecarboxamide P2

[Image Omitted]

2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2-methylpropanamide P3

[Image Omitted]

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

[Image Omitted]

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

[Image Omitted]

Method 2b: DABALMe₃Mediated Amide Coupling from Ester

[Image Omitted]

To a solution of ester (1 eq) and aniline (1.5 eq) in toluene (30 volumes) was added DABAL-Me₃(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 HCl (aq, 20 volumes). The aqueous phase was extracted with EtOAc (3×20 volumes). The combined organics were washed with 1 M HCl (aq, 2×10 volumes), dried over Na₂SO₄, 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

[Image Omitted]

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 NH₄Cl (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)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)butanamide P6

[Image Omitted]

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

[Image Omitted]

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

[Image Omitted]

Method 4: Amide Coupling from Lithium Salt Using T3P

N-(5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl)butanamide INTC51

[Image Omitted]

Method 5: NH-Amide Formation Via Amide Deprotection and/or Decarboxylation

[Image Omitted]

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

[Image Omitted]

Method 7: Sulfonylation from Aromatic Chloride

[Image Omitted]

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 N₂×3) 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. NH₄Cl (aq, 80 volumes) and DCM (80 volumes). The phases were separated and the aqueous was extracted with further DCM (2×80 volumes). The combined organics were dried (MgSO₄), 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-N,N,2-trimethylprop-1-en-1-amine

[Image Omitted]

1-Chloro-N,N,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

[Image Omitted]

To a suspension of Ar1-Br (1 eq) in dioxane (10 volumes) was added arylboronic acid or ester (1 eq) and a solution of K₂CO₃(2 eq) in water (5 volumes). The resulting suspension was degassed (N₂, 5 mins). PdCl₂(dppf)-CH₂Cl₂adduct 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

[Image Omitted]

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 NH₄Cl (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

Name/Structure

(All examples containing chiral

centres are racemates unless

P
stated)

P9
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-isopropoxypyrazin-2-

yl)pyridin-2-yl)-2-methylpropanamide

[Image Omitted]

P10
2-(2- (cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)-2-ethylbutanamide

[Image Omitted]

P11
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

P12
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(6-

isopropoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

P13
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(5-(trifluoromethyl)pyridin-

3-yl)phenyl)acetamide

[Image Omitted]

P14
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(5-(2,2,2-

trifluoroethoxy)pyridin-3-

yl)phenyl)acetamide

[Image Omitted]

P15
2-(2-(cyclopropanesulfonamido)-5-

fluoropyrimidin-4-yl)-N-(4-(pyriidn-3-

yl)phenyl)acetamide

[Image Omitted]

P16
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(pyridin-3-

yl)phenyl)acetamide

[Image Omitted]

P17
N-([1,1′-biphenyl]-4-yl)-2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)acetamide

[Image Omitted]

P18
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

P19
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-methoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

P20
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-(2,2,2-

trifluoroethoxy)pyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

P21
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-isopropoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

P22
2-(2-

(cyclobutanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-

yl)pyridin-2-yl)-2-methylpropanamide

[Image Omitted]

P23
2-(2-

(cyclobutanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(6-

isopropoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P24
2-(2-

(cyclobutanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

methylphenyl)-2-methylpropanamide

[Image Omitted]

P25
2-(2-

(cyclobutanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-methoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P26
2-(2-

(cyclobutanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P27
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

fluoropyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

P28
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5′-ethoxy-[3,3′-bipyridin]-6-

yl)-2-methylpropanamide

[Image Omitted]

P29
N-([3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methylpropanamide

[Image Omitted]

P30
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methyl-N-(5-(6-

(trifluoromethyl)pyrazin-2-yl)pyridin-

2-yl)propanamide

[Image Omitted]

P31
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-

yl)pyridin-2-yl)-2-methylpropanamide

[Image Omitted]

P32
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-cyclopropoxypyrazin-2-

yl)pyridin-2-yl)-2-methylpropanamide

[Image Omitted]

P33
N-(2-chloro-4-(6-ethoxypyrazin-2-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methylpropanamide

[Image Omitted]

P34
N-(2-cyano-4-(6-ethoxypyrazin-2-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methylpropanamide

[Image Omitted]

P35
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(5-

isopropoxypyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P36
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(pyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P37
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(6-

(trifluoromethyl)pyrazin-2-yl)phenyl)-

2-methylpropanamide

[Image Omitted]

P38
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)-2-methylpropanamide

[Image Omitted]

P39
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-96-

isopropoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P40
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluoro-5-methylphenyl)-2-

methylpropanamide

[Image Omitted]

P41
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,6-

difluorophenyl)-2-

methylpropanamide

[Image Omitted]

P42
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(pyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P43
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methyl-N-(2-methyl-4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

P44
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,3-

dimethylphenyl)-2-

methylpropanamide

[Image Omitted]

P45
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-5-

fluoro-2-methylphenyl)-2-

methylpropanamide

[Image Omitted]

P46
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,5-

dimethylphenyl)-2-

methylpropanamide

[Image Omitted]

P47
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

(trifluoromethoxy)phenyl)-2-

methylpropanamide

[Image Omitted]

P48
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-5-

fluoro-2-methoxyphenyl)-2-

methylpropanamide

[Image Omitted]

P49
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

methoxyphenyl)-2-

methylpropanamide

[Image Omitted]

P50
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methyl-N-(4-(pyrimidin-5-

yl)phenyl)propanamide

[Image Omitted]

P51
N-(4-(-chloropyridin-3-yl)phenyl)-2-

(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methylpropanamide

[Image Omitted]

P52
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-

(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methylpropanamide

[Image Omitted]

P53
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(5-fluoropyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P54
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methyl-N-(4-(5-methylpyridin-

3-yl)phenyl)propanamide

[Image Omitted]

P55
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-94-95-

(difluoroethoxy)pyridin-3-yl)phenyl)-

2-methylpropanamide

[Image Omitted]

P56
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(5-methoxypyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P57
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(5-ethoxypyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P58
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(5-isopropoxypyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P59
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methyl-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

P60
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methyl-N-(3′-(trifluoromethyl)-

[1,1′-biphenyl]-4-yl)propanamide

[Image Omitted]

P61
N-(3′-chloro-[1,1′-biphenyl]-4-yl)-2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methylpropanamide

[Image Omitted]

P62
N-(3′-cyano-[1,1′-biphenyl]-4-yl)-2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methylpropanamide

[Image Omitted]

P63
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(3′-ethoxy-[1,1′-biphenyl]-4-

yl)-2-methylpropanamide

[Image Omitted]

P64
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methyl-N-(4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

P65
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P66
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-cyclopropoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P67
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-isopropoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P68
2-(2-(cyclopropanesulfonamido)-5-

fluropyrimidin-4-yl)-N-(4-(9-

ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P69
N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methyl-2-(2-((1-methylcyclopropane)-

1-sulfonamido)pyrimidin-4-

yl)propanamide

[Image Omitted]

P70
2-(2-(cyclopropanesulfonamido)-5-

methylpyrimidin-4-yl)-N-(4-(6-

ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P71
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methyl-N-(4-(pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

P72
N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)-2-(2-

(ethylsulfonamido)pyrimidin-4-yl)-2-

methylpropanamide

[Image Omitted]

P73
2-(2-(ethylsulfonamido)pyrimidin-4-

yl)-2-methyl-N-(4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

P74
N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

(2-(ethylsulfonamido)pyrimidin-4-yl)-

2-methylpropanamide

[Image Omitted]

P75
N-(5-(6-ethoxypyrazin-2-yl)-3-

fluoropyridin-2-yl)-2-methyl-2-(2-

(methylsulfonamido)pyrimidin-4-

yl)propanamide

[Image Omitted]

P76
N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-methyl-2-(2-

(methylsulfonamido)pyrimidin-4-

yl)propanamide

[Image Omitted]

P77
N-(2-fluoro-4-(5-isopropoxypyridin-3-

yl)phenyl)-2-methyl-2-(2-

(methylsulfonamido)pyrimidin-4-

yl)propanamide

[Image Omitted]

P78
N-(2-fluoro-4-(6-isopropoxypyrazin-2-

yl)phenyl)-2-methyl-2-(2-

(methylsulfonamido)pyrimidin-4-

yl)propanamide

[Image Omitted]

P79
2-methyl-N-(2-methyl-4-(6-

(trifluoromethyl)pyrazin-2-yl)phenyl)-

2-(2-(methylsulfonamido)pyrimidin-4-

yl)propanamide

[Image Omitted]

P80
2-methyl-2-(2-

(methylsulfonamido)pyrimidin-4-yl)-

N-(4-(6-(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

P81
N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methyl-2-(2-

(methylsulfonamido)pyrimidin-4-

yl)propanamide

[Image Omitted]

P82
2-(2-((1,1-

dimethylethyl)sulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P83
1-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)cyclopropanecarboxamide

[Image Omitted]

P84
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5′-(trifluoromethyl)-[3,3′-

bipyridin]-6-yl)butanamide

[Image Omitted]

P85
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5′-(2,2,2-trifluoroethoxy)-

[3,3′-bipyridin]-6-yl)butanamide

[Image Omitted]

P86
N-([3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)butanamide

[Image Omitted]

P87
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-

2-yl)pyridin-2-yl)butanamide

[Image Omitted]

P88
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

P89
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-isopropoxypyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

P90
N-(4-(5-chloropyridin-3-yl)-2-

fluorophenyl)-2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)butanamide

[Image Omitted]

P91
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(5-(2,2,2-

trifluoroethoxy)pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

P92
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(5-

isopropoxypyridin-3-

yl)phenyl)butanamide

[Image Omitted]

P93
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

P94
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P95
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(6-

methoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P96
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)butanamide

[Image Omitted]

P97
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(6-

isopropoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P98
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(2-fluoro-4-(6-(2,2,2-

trifluoroethoxy)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P99
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-

(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)butanamide

[Image Omitted]

P100
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(5-(2,2,2-

trifluoroethoxy)pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

P101
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(5-isopropoxypyridin-3-

yl)phenyl)butanamide

[Image Omitted]

P102
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

P103
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-(trifluoromethyl)pyrazin-

2-yl)phenyl)butanamide

[Image Omitted]

P104
N-(4-(6-chloropyrazin-2-yl)phenyl)-2-

(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)butanamide

[Image Omitted]

P105
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P106
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-methoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P107
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-isopropoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P108
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(9-(2,2,2-

trifluoroethoxy)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P109
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P110
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(9-ethoxypyrazin-2-

yl)phenyl)-4-methoxypbutanamide

[Image Omitted]

P111
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

P112
2-(2-

(Cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-

yl)pyridin-2-yl)-2-fluorobutanamide

[Image Omitted]

P113
Single enantiomer - stereochemistry

not assigned 2-(2-

(Cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-

yl)pyridin-2-yl)-2-fluorobutanamide

[Image Omitted]

P114
Single enantiomer - stereochemistry

not assigned 2-(2-

(Cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-

yl)pyridin-2-yl)-2-fluorobutanamide

[Image Omitted]

P115
4-(2-

(Cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-

yl)pyridin-2-yl)tetrahydro-2H-pyran-4-

carboxamide

[Image Omitted]

P117
2-(2-

(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)-2,2-difluoroacetamide

[Image Omitted]

P118
N-((2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)methyl)-4-(6-ethoxypyrazin-2-

yl)benzamide

[Image Omitted]

P122
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methyl-N-(5-(6-(prop-1-en-2-

yl)pyrazin-2-yl)pyridin-2-yl)propanamide

[Image Omitted]

P123
2-(2-(cyclopropanesulfonamido)-6-

methylpyrimidin-4-yl)-N-(5-(6-

ethoxypyrazin-2-yl)pyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

P124
2-(2-(cyclopropanesulfonamido)-6-

(trifluoromethyl)pyrimidin-4-yl)-N-(5-(6-

ethoxypyrazin-2-yl)pyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

P125
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-cyclopropylpyrazin-2-

yl)pyridin-2-yl)-2-methylpropanamide

[Image Omitted]

P126
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(6-(6-ethoxypyrazin-2-yl)pyridin-3-

yl)-2-methylpropanamide

[Image Omitted]

P128
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(9-cyclopropylpyrazin-2-yl)-2-

fluorophenyl)-2-methylpropanamide

[Image Omitted]

P129
2-(2-(cyclopropanesulfonamido)-6-

methylpyrimidin-4-yl)-N-(4-(6-

ethoxypyrazin-2-yl)-2-fluorophenyl)-2-

methylpropanamide

[Image Omitted]

P130
2-(2-(cyclopropanesulfonamido)-6-

(trifluoromethyl)pyrimidin-4-yl)-N-(4-(6-

ethoxypyrazin-2-yl)-2-fluorophenyl)-2-

methylpropanamide

[Image Omitted]

P131
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-2-methyl-N-(4-(6-(prop-1-en-1-

yl)pyrazin-2-yl)phenyl)propanamide

[Image Omitted]

P132
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-isopropylpyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P133
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-(dimethylamino)pyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

P134
2-(2-(cyclopropanesulfonamido)-6-

methylpyrimidin-4-yl)-N-(4-(6-

ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P135
2-(2-(cyclopropanesulfonamido)-6-

(trifluoromethyl)pyrimidin-4-yl)-N-(4-(6-

ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P127
2-(2-(Cyclopropanesulfonamido)-6-

methoxypyrimidin-4-yl)-2-methyl-N-(4-

(pyridin-3-yl)phenyl)propanamide

[Image Omitted]

P136
1-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)cyclopentane-1-carboxamide

[Image Omitted]

P137
4-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)tetrahydro-2H-pyran-4-

carboxamide

[Image Omitted]

P138
N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-

(2-(methylsulfonamido)pyrimidin-4-

yl)piperidine-4-carboxamide

[Image Omitted]

P139
tert-butyl 4-(2-

(cyclopropanesulfonamido)pyrimidin-4-yl)-

4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)carbamoyl)piperidine-1-carboxylate

[Image Omitted]

P140
4-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)piperidine-4-carboxamide

[Image Omitted]

P141
tert-butyl 3-(2-

(cyclopropanesulfonamido)pyrimidin-4-yl)-

3-((5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)carbamoyl)azetidine-1-carboxylate

[Image Omitted]

P142
tert-butyl 4-((5-(6-ethoxypyrazin-2-

yl)pyridin-2-yl)carbamoyl)-4-(2-

(methylsulfonamido)pyrimidin-4-

yl)piperidine-1-carboxylate

[Image Omitted]

P143
4-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)tetrahydro-2H-pyran-4-

carboxamide

[Image Omitted]

P144
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

fluoropyridin-2-yl)-4-methoxybutanamide

[Image Omitted]

P145
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-4-methoxybutanamide

[Image Omitted]

P146
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)-4-methoxybutanamide

[Image Omitted]

P147
N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-

methoxy-2-methyl-2-(2-

(methylsulfonamido)pyrimidin-4-

yl)butanamide

[Image Omitted]

P148
N-(5′-chloro-[3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)butanamide

[Image Omitted]

P149
N-(5′-chloro-[3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)pyrimidin-4-yl)-

2-fluorobutanamide

[Image Omitted]

P150
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-cyclopropylpyrazin-2-

yl)pyridin-2-yl)-2-fluorobutanamide

[Image Omitted]

P151
N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-

fluoro-2-(2-(methylsulfonamido)pyrimidin-

4-yl)butanamide

[Image Omitted]

P155
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

methylpyridin-2-yl)butanamide

[Image Omitted]

P156
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-cyclopropylpyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

P157
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-(2,2,2-

trifluoroethoxy)pyrazin-2-yl)pyridin-2-

yl)butanamide

[Image Omitted]

P158
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(3-fluoro-5-(6-methoxypyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

P159
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-methoxypyrazin-2-yl)pyridin-

2-yl)butanamide

[Image Omitted]

P160
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-cyclopropylpyrazin-2-yl)-2-

fluorophenyl)butanamide

[Image Omitted]

P161
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(9-ethoxypyrazin-2-yl)-2-

methylphenyl)butanamide

[Image Omitted]

P162
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

fluoropyridin-2-yl)butanamide

[Image Omitted]

P163
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-methylbutanamide

[Image Omitted]

P152
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-fluoro-3-methylbutanamide

[Image Omitted]

P153
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)-3-methylbutanamide

[Image Omitted]

P154
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-3-methylbutanamide

[Image Omitted]

P164
2-(2-(cyclopropanesulfonamido)pyrimidin-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-

2-methoxyacetamide

[Image Omitted]

P165
Single enantiomer - stereochemistry

unassigned

N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-

fluoro-2-(2-(methylsulfonamido)pyrimidin-

4-yl)butanamide

[Image Omitted]

P166
Single enantiomer - stereochemistry

unassigned

N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-

fluoro-2-(2-(methylsulfonamido)pyrimidin-

4-yl)butanamide

[Image Omitted]

P167
N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6-

(cyclopropanesulfonamido)pyridin-2-

yl)acetamide

[Image Omitted]

P168
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(6-

(cyclopropanesulfonamido)pyridin-2-

yl)acetamide

[Image Omitted]

P169
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(5-fluoropyridin-3-

yl)phenyl)acetamide

[Image Omitted]

P170
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(6-methoxypyridin-3-

yl)phenyl)acetamide

[Image Omitted]

P171
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(pyridin-3-yl)phenyl)acetamide

[Image Omitted]

P172
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

P173
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(6-methoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

P174
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(pyrazin-2-yl)phenyl)acetamide

[Image Omitted]

P175
N-([3,3′-bipyridin]-6-yl)-2-(6-

(cyclopropanesulfonamido)pyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

P176
N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6-

(cyclopropanesulfonamido)pyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

P177
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P178
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P179
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-2-methyl-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

P180
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P181
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-2-methyl-N-(4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

P182
N-(4-(6-chloropyrazin-2-yl)phenyl)-2-(6-

(cyclopropanesulfonamido)pyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

P183
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P184
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P185
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-2-methyl-N-(4-(pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

P186
4-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)tetrahydro-2H-pyran-4-carboxamide

[Image Omitted]

P187
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

P188
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)butanamide

[Image Omitted]

P189
N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6-

(cyclopropanesulfonamido)pyridin-2-

yl)butanamide

[Image Omitted]

P190
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)butanamide

[Image Omitted]

P191
2-(6-(cyclopropanesulfonamido)pyridin-2-

yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P192
2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(4-(pyridin-3-yl)phenyl)acetamide

[Image Omitted]

P193
2-(6-(ethylsulfonamido)pyrazin-2-yl)-N-(4-

(pyridin-3-yl)phenyl)acetamide

[Image Omitted]

P194
2-(6-(methylsulfonamido)pyrazin-2-yl)-N-

(4-(pyridin-3-yl)phenyl)acetamide

[Image Omitted]

P195
2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-methylpropanamide

[Image Omitted]

P196
2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

P197
4-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)tetrahydro-2H-pyran-4-carboxmaide

[Image Omitted]

P198
2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-4-methoxy-2-methylbutanamide

[Image Omitted]

P199
N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-

methoxy-2-methyl-2-(6-

(methylsulfonamido)pyrazin-2-

yl)butanamide

[Image Omitted]

P200
2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-fluorobutanamide

[Image Omitted]

P201
2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)butanamide

[Image Omitted]

P202
2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

P203
2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-methoxyacetamide

[Image Omitted]

P204
2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methoxyacetamide

[Image Omitted]

P205
2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-methoxypropanamide

[Image Omitted]

P205a
Single enantiomer - stereochemistry

unassigned

2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-methoxypropanamide

[Image Omitted]

P205b
Single enantiomer - stereochemistry

unassigned

2-(6-(cyclopropanesulfonamido)pyrazin-2-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-methoxypropanamide

[Image Omitted]

P206
Single enantiomer - stereochemistry

unassigned

2-(6-(2-cyclopropanesulfonamido)pyrazin-

2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-fluorobutanamide

[Image Omitted]

P207
Single enantiomer - stereochemistry

unassigned

2-(6-(cyclopropanesulfonamido)pyrazin-

2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-fluorobutanamide

[Image Omitted]

P208
2-(4-(cyclopropanesulfonamido)pyrimidin-

2-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)butanamide

[Image Omitted]

P209
N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)cyclopropyl)-4-(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

P210
N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)propyl)-5-(6-ethoxypyrazin-2-

yl)picolinamide

[Image Omitted]

P211
N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)propyl)-2-fluoro-4-(5-

(trifluoromethyl)pyridin-3-yl)benzamide

[Image Omitted]

P212
4-(5-chloropyridin-3-yl)-N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)propyl)-2-fluorobenzamide

[Image Omitted]

P213
N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-

yl)benzamide

[Image Omitted]

P214
4-(5-chloropyridin-3-yl)-N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)propyl)benzamide

[Image Omitted]

P215
N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-

(trifluoromethyl)benzamide

[Image Omitted]

P216
N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

P217
N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)propyl)-4-(6-(trifluoromethyl)pyrazin-2-

yl)benzamide

[Image Omitted]

P218
N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)propyl)-4-(6-isopropoxypyrazin-2-

yl)benzamide

[Image Omitted]

P219
N-(1-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)propyl)-4-(6-ethoxypyrazin-2-

yl)benzamide

[Image Omitted]

P220
N-(2-(2-

(cyclopropanesulfonamido)pyrimidin-4-

yl)butan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

P221
N-(2-(6-

(cyclopropanesulfonamido)pyrazin-2-

yl)propan-2-yl)-2-fluoro-4-(6-

isopropoxypyrazin-2-yl)benzamide

[Image Omitted]

P222
N-(2-(6-

(cyclopropanesulfonamido)pyrazin-2-

yl)propan-2-yl)-4-(6-

(trifluoromethyl)pyrazin-2-yl)benzamide

[Image Omitted]

P223
N-(1-(6-

(cyclopropanesulfonamido)pyrazin-2-

yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

P224
Single enantiomer - stereochemistry

unassigned

N-(1-(6-

(cyclopropanesulfonamido)pyrazin-2-

yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

P225
Single enantiomer - stereochemistry

unassigned

N-(1-(6-

(cyclopropanesulfonamido)pyrazin-2-

yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

2-(2-(Cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide P116

[Image Omitted]

A solution of 2-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(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, 30×4 mm, Full hydrogen, 25° C., 1 mL/min). The crude product was purified by chromatography on silica gel (12 g column, 50-100% EtOAc/iso-hexane) to afford 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide (21 mg, 0.043 mmol, 27% yield) as a white solid. Rt 2.22 mins (HPLC acidic); m/z 482 (M+H)⁺ (ES⁺); ¹H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 10.15 (s, 1H), 9.10 (s, 1H), 9.03 (dd, J=2.4, 0.8 Hz, 1H), 8.59 (d, J=5.3 Hz, 1H), 8.56 (s, 1H), 8.52 (dd, J=8.8, 2.5 Hz, 1H), 8.21 (dd, J=8.8, 0.8 Hz, 1H), 7.19 (d, J=5.3 Hz, 1H), 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 WO02019/179852, WO2019/180244 and/or WO2020/083975.

1-(2-(Cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-oxocyclohexanecarboxamide P226

[Image Omitted]

A solution of HCl (1N in water) (17.19 mL, 17.19 mmol) was added into a stirring solution of 8-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-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 (MgSO₄), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/iso-hexanes) to afford 1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-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⁺). ¹H NMR (500 MHz, DMSO-d6) δ 11.32 (s, 1H), 10.33 (s, 1H), 9.03 (d, J=2.5 Hz, 1H), 8.85 (s, 1H), 8.64 (d, J=5.3 Hz, 1H), 8.51 (dd, J=8.8, 2.5 Hz, 1H), 8.31-8.20 (m, 2H), 7.30 (d, J=5.3 Hz, 1H), 4.48 (q, J=7.0 Hz, 2H), 3.28-3.21 (m, 1H), 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)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-hydroxycyclohexane-1-carboxamide

[Image Omitted]

NaBH₄(10.6 mg, 0.28 mmol) was added into a stirring suspension of 1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-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 0.1% formic acid) to afford two diastereoisomers of the title compound.

P227—First Eluting Peak from Column

1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-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⁺); ¹H NMR (500 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.05 (s, 1H), 9.06-8.98 (m, 1H), 8.85 (s, 1H), 8.57 (d, J=5.3 Hz, 1H), 8.51 (dd, J=8.8, 2.5 Hz, 1H), 8.26 (s, 1H), 8.23-8.20 (m, 1H), 7.19 (d, J=5.3 Hz, 1H), 4.58 (d, J=4.7 Hz, 1H), 4.48 (q, J=7.0 Hz, 2H), 3.56-3.45 (m, 1H), 3.29-3.22 (m, 1H), 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)-N-(5-(6-ethoxypyrazin-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⁺); ¹H NMR (500 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.75 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.83 (s, 1H), 8.62 (s, 1H), 8.48 (dd, J=8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.29 (s, 1H), 4.51-4.44 (m, 3H), 3.70-3.62 (m, 1H), 3.29-3.20 (m, 1H), 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-(Cydopropanesulfonamido)pyrimidin-4-yl)-4-(dimethylamino)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)cyclohexane-1-carboxamide

[Image Omitted]

NaH(BOAc)₃(118 mg, 0.558 mmol) was added into a suspension of 1-(2-(cydopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-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-(dimethylamino)-N-(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⁺); ¹H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.84 (s, 1H), 8.60-8.44 (m, 2H), 8.25 (s, 1H), 8.22-8.20 (m, 2H), 7.09 (d, J=5.3 Hz, 1H), 4.48 (q, J=7.0 Hz, 2H), 3.28-3.20 (m, 1H), 2.72 (d, J=13.4 Hz, 2H), 2.32 (s, 6H), 2.25 (s, 1H), 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-(dimethylamino)-N-(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⁺); ¹H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.83 (s, 1H), 8.55 (d, J=5.2 Hz, 1H), 8.48 (dd, J=8.8, 2.4 Hz, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.19 (d, J=5.3 Hz, 1H), 4.47 (q, J=7.0 Hz, 2H), 3.25-3.18 (m, 1H), 2.78-2.67 (m, 2H), 2.48-2.39 (m, 1H), 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: i-PrMgCl mediated amide coupling from ester

[Image Omitted]

To an ice cooled solution of aniline (1.1 eq) in THF (10-50 volumes) was added i-PrMgCl (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 i-PrMgCl (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 1M HCl (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

[Image Omitted]

To a suspension of aldehyde (1.5 eq) and amine (HCl 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% NH₃in 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.

N-(4-(1-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propyl)pyrimidin-2-yl)cyclopropanesulfonamide P235

[Image Omitted]

A suspension of 4-(6-ethoxypyrazin-2-yl)-2-fluorobenzaldehyde INTD88 (259 mg, 1.05 mmol) and N-(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% NH₃in 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% NH₃in 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 N-(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⁺); ¹H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.27-8.26 (m, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.87 (d, J=11.4 Hz, 1H), 7.67-7.58 (m, 1H), 7.23 (d, J=5.1 Hz, 1H), 5.38 (t, J=5.7 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 4.49 (q, J=7.1 Hz, 2H), 3.52-3.50 (m, 1H), 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

Synthesis Method,

[LCMS Method],
¹H NMR Chemical Shift

INTC#

m/z (M + H)⁺,
Data (DMSO-d6 unless

or P#
Name/Structure (All examples containing chiral centres are racemates unless stated)
(Rt/Min)
stated)

INTC 246

[Image Omitted]

Method 11 using INTC243 and INTD33, [UPLC Acidic], 625, (1.66)
11.32 (s, 1H), 9.99 (s, 1H), 9.01 (d, J = 2.4 Hz, 1H), 8.84 (s, 1H), 8.58-8.55 (m, 1H), 8.53-8.47 (m, 1H), 8.25 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 5.8 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.51-3.48 (m, 2H), 3.38-3.32 (m, 2H), 3.16- 3.12 (m, 1H), 2.32-2.29 (m, 4H), 1.41 (s, 9H), 1.40 (t, J = 7.10 Hz, 3H), 1.08 (s, 2H), 0.96-0.91 (m, 2H).

INTC 239

[Image Omitted]

Method 11 using INTC238 and INTD33, [UPLC Acidic], 625, (1.63)
11.06 (s, 1H), 10.17 (s, 1H), 9.01 (s, 1H), 8.83 (s, 1H), 8.52-8.46 (m, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 8.21-8.15 (m, 2H), 4.47 (q, J = 7.0 Hz, 2H), 3.71-3.65 (m, 2H), 3.28-3.16 (m, 2H), 3.13-3.03 (m, 1H), 2.18-2.05 (m, 2H), 1.43-1.36 (m, 12H), 1.05-1.02 (m, 2H), 0.86-0.81 (m, 2H). 2H not observed, obscured by DMSO peak.

INTC 244

[Image Omitted]

Method 11 using INTC243 and INTD54, [HPLC Acidic], 621, (2.57)
11.32 (s, 1H), 9.97 (s, 1H), 9.02-8.95 (m, 2H), 8.58 (s, 1H), 8.56 (s, 1H), 8.46 (dd, J = 8.8, 2.4 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 5.8 Hz, 1H), 3.50-3.47 (m, 2H), 3.42-3.26 (m, 2H), 3.16-3.12 (m, 1H), 2.32-2.22 (m, 5H), 1.41 (s, 9H), 1.17-1.06 (m, 6H), 0.96-0.91 (m, 2H).

P242

[Image Omitted]

Method 11: using INTC212 and INTD33, [HPLC Acidic], 560, (2.42)
11.33 (s, 1H), 10.28 (s, 1H), 9.03 (dd, J = 2.5, 0.8 Hz, 1H), 8.85 (s, 1H), 8.63 (d, J = 5.3 Hz, 1H), 8.51 (dd, J = 8.8, 2.5 Hz, 1H), 8.26 (s, 1H), 8.19 (dd, J = 8.8, 0.8 Hz, 1H), 7.26 (d, J = 5.4 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.27-3.18 (m, 1H), 2.65-2.53 (m, 2H), 2.29-2.18 (m, 2H), 2.13-2.01 (m, 4H), 1.40 (t, J = 7.0 Hz, 3H), 1.11-1.02 (m, 2H), 0.92-0.83 (m, 2H).

P244

[Image Omitted]

Method 11: using INTC214 and INTD33, [HPLC Acidic], 582, (2.20)
11.29 (s, 1H), 10.05 (s, 1H), 9.02 (dd, J = 2.5, 0.8 Hz, 1H), 8.84 (s, 1H), 8.60 (d, J = 5.3 Hz, 1H), 8.50 (dd, J = 8.8, 2.5 Hz, 1H), 8.26 (s, 1H), 8.22-8.11 (m, 1H), 7.23 (s, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.88 (s, 4H), 3.28-3.18 (m, 1H), 2.55-2.47 (m, 2H obscured by water peak), 2.27-2.13 (m, 2H), 1.79-1.62 (m, 4H), 1.40 (t, J = 7.0 Hz, 3H), 1.09-1.00 (m, 2H), 0.94-0.80 (m, 2H).

P248

[Image Omitted]

Method R: using INTC204, [HPLC Acidic], 529, (2.10)
11.04 (s, 1H), 10.02 (s, 1H), 9.04 (d, J = 2.5 Hz, 1H), 8.85 (s, 1H), 8.60 (d, J = 5.3 Hz, 1H), 8.51 (dd, J = 8.8, 2.5 Hz, 1H), 8.26 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 5.3 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.73-3.57 (m, 4H), 2.84 (s, 6H), 2.47-2.37 (m, 2H), 2.28-2.17 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H).

P251

[Image Omitted]

Method 11: using INTC215 and INTD33, [HPLC Acidic], 603, (2.05)
11.33 (s, 1H), 10.27 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.85 (s, 1H), 8.63 (d, J = 5.3 Hz, 1H), 8.54-8.48 (m, 1H), 8.26 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 5.3 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.47-3.40 (m, 2H), 3.29-3.21 (m, 1H), 3.10 (t, J = 10.7 Hz, 2H), 2.87 (s, 2H), 2.64-2.57 (m, 2H), 2.33-2.21 (m, 2H), 1.43-1.37 (m, 3H), 1.32-1.09 (m, 1H), 1.09-1.04 (m, 2H), 0.92-0.80 (m, 2H).

P254

[Image Omitted]

Method 12 using INTC156 and INTD85, [UPLC Basic], 468, (1.07)
11.08 (s, 1H), 9.22 (d, J = 2.3 Hz, 1H), 8.88 (s, 1H), 8.50-8.42 (m, 2H), 8.29 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 5.2 Hz, 1H), 4.50 (q, J = 7.0 Hz, 2H), 3.94 (s, 2H), 3.16-3.13 (m, 1H), 1.41 (t, J = 7.0 Hz, 3H), 1.38-1.33 (m, 2H), 1.26-1.21 (m, 2H), 1.09-0.99 (m, 4H). One exchangeable proton not observed

P255

[Image Omitted]

Method 12 using INTC156 and INTD88, [UPLC Basic], 485, (1.36)
11.06 (s, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.48 (s, 1H), 8.27 (d, J = 2.5 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 11.5 Hz, 1H), 7.70-7.63 (m, 1H), 7.43 (s, 1H), 4.53-4.45 (m, 2H), 3.84 (s, 2H), 3.16-3.12 (m, 1H), 1.44-1.39 (m, 3H), 1.38-1.32 (m, 2H), 1.27-1.21 (m, 2H), 1.09-1.01 (m, 4H). One exchangeable proton not observed

P256

[Image Omitted]

Method R using INTC207, [HPLC Acidic], 511, (2.19)
11.23 (s, 1H), 8.57 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.00 (s, 1H), 7.83-7.74 (m, 2H), 7.22 (d, J = 5.1 Hz, 1H), 6.67-6.59 (m, 2H), 6.02 (d, J = 6.5 Hz, 1H), 4.42 (q, J = 7.0 Hz, 2H), 3.80-3.69 (m, 2H), 3.42-3.27 (m, 4H), 3.25-3.17 (m, 1H), 2.34-2.25 (m, 2H), 1.89-1.80 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H), 1.14-1.06 (m, 2H), 1.07-0.98 (m, 2H

P258

[Image Omitted]

Method 11: using INTC216 and INTD33, [UPLC acidic], 554, (1.32)
11.31 (s, 1H), 10.56 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.84 (s, 1H), 8.60 (d, J = 5.3 Hz, 1H), 8.51 (dd, J = 8.8, 2.5 Hz, 1H), 8.26-8.20 (m, 2H), 7.30 (d, J = 5.3 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.89-3.78 (m, 4H), 3.32-3.25 (m, 1H), 3.18-3.11 (m, 2H), 2.99-2.92 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.10-1.01 (m, 2H), 0.94-0.87 (m, 2H).

P260

[Image Omitted]

Method 11: using INTC218 and INTD33, [HPLC Acidic], 554, (2.17 and 2.27)
11.26 (s, 1H), 10.04 (s, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.84 (d, J = 1.9 Hz, 1H), 8.60 (d, J = 5.6 Hz, 1H), 8.55-8.46 (m, 1H), 8.25 (s, 1H), 8.22-8.14 (m, 1H), 7.22 (d, J = 5.4 Hz, 1H), 4.48 (qd, J = 7.0, 2.3 Hz, 2H), 3.30-3.18 (m, 4H), 2.59 (d, J = 13.3 Hz, 2H), 2.40-2.19 (m, 1H), 1.97-1.84 (m, 2H), 1.83-1.50 (m, 2H), 1.48-1.36 (m, 4H), 1.11-0.98 (m, 2H), 0.94-0.71 (m, 3H).

P261

[Image Omitted]

Method 12 using INTC155 and INTD18, [UPLC Acidic], 455, (1.48)
Methanol-d4, 8.45-8.39 (m, 2H), 7.90 (s, 1H), 7.86-7.81 (m, 2H), 7.70-7.62 (m, 1H), 7.61-7.54 (m, 1H), 7.12 (d, J = 5.2 Hz, 1H), 6.69-6.64 (m, 2H), 4.49 (q, J = 7.1 Hz, 2H), 4.45-4.39 (m, 1H), 3.24-3.15 (m, 1H), 2.06-1.85 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.34-1.25 (m, 1H), 1.24-1.15 (m, 1H), 1.09 (t, J = 7.4 Hz, 3H), 1.07-1.00 (m, 1H), 0.96-0.86 (m, 1H).

P288

[Image Omitted]

Prepared by reacting P140 (in WO2019/179652) with 2- methoxyacetyl chloride, TEA, in DCM at RT for 24 h, [UPLC Acidic], 597, (1.21)
11.38 (s, 1H), 10.21 (s, 1H), 9.02 (dd, J = 2.5, 0.8 Hz, 1H), 8.83 (s, 1H), 8.61 (d, J = 5.4 Hz, 1H), 8.49 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.21-8.13 (m, 1H), 7.25-7.20 (m, 1H), 4.47 (q, J = 7.0 Hz, 2H), 4.10 (m, 2H), 3.90 (d, J = 13.5 Hz, 1H), 3.60 (d, J = 13.6 Hz, 1H), 3.28 (s, 3H), 3.26-3.21 (dt, m, 1H), 2.47 (s, 3H), 2.20-2.05 (m, 3H), 1.39 (t, J = 7.0 Hz, 3H), 1.05-1.03 (m, 2H), 0.91-0.85 (m, 2H).

P289

[Image Omitted]

Prepared by reacting P140 (in WO2019/179652) with ethanesulfonyl chloride, TEA, in DCM at RT for 24 h, [UPLC Acidic], 617, (1.38)
11.32 (s, 1H), 10.25 (s, 1H), 9.02 (d, J = 2.5 Hz, 1H), 8.84 (s, 1H), 8.62 (d, J = 5.4 Hz, 1H), 8.50 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.26-7.22 (m, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.51-3.45 (m, 2H), 3.21-3.13 (m, 2H), 3.05 (q, J = 7.4 Hz, 2H), 2.61-2.54 (m, 2H), 2.26-2.18 (m, 1H), 1.39 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.3 Hz, 3H), 1.08-1.02 (m, 2H), 0.91-0.80 (m, 4H).

P290

[Image Omitted]

Prepared by reacting P140 (in WO2019/179652) with cyclopropane sulfonyl chloride, TEA, in DCM at RT for 24 h, [UPLC Acidic], 629, (1.38)
11.32 (s, 1H), 10.29 (s, 1H), 9.03 (dd, J = 2.4, 0.8 Hz, 1H), 8.85 (s, 1H), 8.63 (d, J = 5.3 Hz, 1H), 8.51 (dd, J = 8.8, 2.5 Hz, 1H), 8.26 (s, 1H), 8.21 (dd, J = 8.8, 0.8 Hz, 1H), 7.26 (d, J = 5.4 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.55-3.49 (m, 2H), 3.29-3.11 (m, 3H), 2.69-2.52 (m, 4H), 2.29-2.17 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H), 1.10-1.01 (m, 2H), 1.01-0.79 (m, 5H).

P291

[Image Omitted]

Prepared by reacting P140 (in WO2019/179652) with dimethylsulfamoyl chloride, TEA, in DCM at RT for 24 h, [UPLC Acidic], 632, (1.45)
11.32 (s, 1H), 10.24 (s, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.84 (s, 1H), 8.62 (d, J = 5.3 Hz, 1H), 8.50 (dd, J = 8.8, 2.4 Hz, 1H), 8.25 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 5.4 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.45-3.39 (m, 2H), 3.26-3.21 (m, 1H), 3.20-3.12 (m, 2H), 2.74 (s, 6H), 2.59-2.53 (m, 2H), 2.26-2.18 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.07-1.04 (m, 2H), 0.86-0.82 (m, 2H).

P292

[Image Omitted]

Prepared by reacting P140 (in WO2019/179652) with trifluoromethane- sulfonic anhydride, TEA, in DCM at RT for 24 h, [UPLC Acidic], 657, (1.62)
11.35 (s, 1H), 10.36 (s, 1H), 9.03 (d, J = 2.4 Hz, 1H), 8.84 (s, 1H), 8.62 (d, J = 5.3 Hz, 1H), 8.51 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 5.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.78-3.74 (m, 2H), 3.53-3.49 (m, 2H), 3.26-3.18 (m, 1H), 2.69-2.55 (m, 2H), 2.29 (s, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.08-1.03 (m, 2H), 0.92-0.77 (m, 2H).

P293

[Image Omitted]

Prepared by reacting P140 (in WO2019/179652) with methyl-1H- pyrazole-3- sulfonyl chloride, TEA, in DCM at RT for 24 h, [UPLC Acidic], 669, (1.34)
11.30 (s, 1H), 10.23 (s, 1H), 9.01 (d, J = 2.5 Hz, 1H), 8.83 (s, 1H), 8.61 (d, J = 5.3 Hz, 1H), 8.47 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 5.3 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.58-3.38 (m, 2H), 3.25-3.16 (m, 1H), 2.92-2.85 (m, 2H), 2.62-2.56 (m, 2H), 2.25-2.16 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.07-1.00 (m, 2H), 0.91-0.79 (m, 2H).

P294

[Image Omitted]

Alkylation capping using INTC247 and 2- bromoacetonitrile, [UPLC Acidic], 564, (1.23)
11.34 (s, 1H), 9.92 (s, 1H), 9.04-9.00 (m, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 8.51 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.21 (d, J = 8.7 Hz, 1H), 6.84 (s, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.70 (s, 2H), 3.18-3.14 (m, 1H), 2.42 (s, 6H), 1.40 (t, J = 7.0 Hz, 3H), 1.09-1.05 (m, 2H), 0.96-0.91 (m, 2H). 2H obscured in DMSO peak

P295

[Image Omitted]

Prepared by reacting INTC247 and ethyl 2- oxoacetate, [UPLC Acidic], 611, (0.95)
11.32 (s, 1H), 9.83 (s, 1H), 9.01 (d, J = 2.5 Hz, 1H), 8.84 (s, 1H), 8.50 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 6.81 (s, 1H), 4.48 (q, J = 7.0 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 3.20-3.17 (m, 2H), 3.15-3.12 (m, 1H), 2.60-2.57 (m, 3H), 2.40-2.36 (m, 4H), 1.93-1.90 (m, 1H), 1.40 (t, J = 7.0 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H), 1.07-1.04 (m, 2H), 0.92 (d, J = 6.4 Hz, 2H). 1H obscured in DMSO.

P296

[Image Omitted]

Prepared as for P288 using INTC235 and 2- methoxyacetyl chloride, [UPLC Acidic], 585, (1.18)
11.24 (s, 1H), 10.23 (s, 1H), 9.04 (d, J = 2.5 Hz, 1H), 8.85 (s, 1H), 8.62 (s, 1H), 8.51 (dd, J = 8.7, 2.5 Hz, 1H), 8.26 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.24 (s, 1H), 4.48 (q, J = 7.0 Hz, 2H), 4.20-4.02 (m, 2H), 3.89 (s, 1H), 3.59 (s, 1H), 3.51 (s, 2H), 3.41-3.33 (m, 1H), 3.29 (s, 3H), 3.22 (s, 1H), 2.24-1.95 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H), 1.12 (t, J = 7.4 Hz, 3H), 0.89-0.80 (m, 2H).

P297

[Image Omitted]

Prepared as for P288 using INTC235 and methanesulfonyl chloride, [UPLC Acidic], 591, (1.26)
11.25 (s, 1H), 10.27 (s, 1H), 9.03 (d, J = 2.5 Hz, 1H), 8.84 (s, 1H), 8.62 (d, J = 5.3 Hz, 1H), 8.51 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 5.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.53 (q, J = 7.3 Hz, 2H), 3.42 (d, J = 12.9 Hz, 2H), 3.09 (t, J = 10.7 Hz, 2H), 2.86 (s, 3H), 2.59-2.54 (m, 2H), 2.28-2.19 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.13 (t, J = 7.3 Hz, 3H).

P298

[Image Omitted]

Prepared as for P288 using INTC235 and ethanesulfonyl chloride, [UPLC Acidic], 605, (1.34)
11.24 (s, 1H), 10.25 (s, 1H), 9.03 (d, J = 2.5 Hz, 1H), 8.84 (s, 1H), 8.61 (d, J = 5.3 Hz, 1H), 8.50 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 5.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.56-3.43 (m, 4H), 3.20-3.12 (m, 2H), 3.04 (q, J = 7.4 Hz, 2H), 2.58-2.50 (m, 2H), 2.25-2.14 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.4 Hz, 3H), 1.12 (t, J = 7.3 Hz, 3H).

P299

[Image Omitted]

Prepared as for P288 using INTC235 and cyclopropane sulfonyl chloride, [UPLC Acidic], 617, (1.35)
11.27 (s, 1H), 10.28 (s, 1H), 9.04 (d, J = 2.4 Hz, 1H), 8.84 (s, 1H), 8.61 (d, J = 5.3 Hz, 1H), 8.51 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.23-7.20 (m, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.53-3.47 (m, 4H), 3.19 (t, J = 11.0 Hz, 2H), 2.67-2.51 (m, 4H), 2.27-2.18 (m, 1H), 1.40 (t, J = 7.0 Hz, 3H), 1.12 (t, J = 7.4 Hz, 3H), 0.99-0.88 (m, 4H)

P300

[Image Omitted]

Prepared as for P288 using INTC235 and 1- methyl-1H- pyrazole-3- sulfony chloride, [UPLC Acidic], 657, (1.30)
11.22 (s, 1H), 10.24 (s, 1H), 9.01 (dd, J = 2.4, 0.8 Hz, 1H), 8.83 (s, 1H), 8.60 (d, J = 5.3 Hz, 1H), 8.48 (dd, J = 8.7, 2.5 Hz, 1H), 8.25 (s, 1H), 8.10-8.05 (m, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 5.3 Hz, 1H), 6.65 (d, J = 2.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.53-3.39 (m, 4H), 2.93-2.84 (m, 2H), 2.60-2.53 (m, 2H), 2.24-2.15 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.09 (t, J = 7.3 Hz, 3H).

P301

[Image Omitted]

Method 11, using INTC218 and INTD54, [UPLC Acidic], 549, (1.37)
11.28 (s, 1H), 10.01 (s, 1H), 9.01 (s, 1H), 8.98 (d, J = 2.4 Hz, 1H), 8.58 (s, 1H), 8.51-8.31 (m, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H), 3.24 (s, 3H), 2.78-2.53 (m, 2H), 2.33-2.15 (m, 1H), 2.03-1.77 (m, 4H), 1.55-1.33 (m, 2H), 1.22-0.98 (m, 6H), 0.91-0.75 (m, 2H). 1H not observed, 2H obscured under DMSO peak

P302

[Image Omitted]

Prepared as for P229 using P226 and pyrrolidine, [UPLC Acidic], 593, (0.91)
9.56 (s, 1H), 9.01 (d, J = 2.4 Hz, 1H), 8.82 (s, 1H), 8.47 (dd, J = 8.8, 2.6 Hz, 2H), 8.24 (s, 1H), 8.18 (s, 2H), 8.09 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 4.46 (q, J = 7.0 Hz, 2H), 3.15-3.11 (m, 1H), 2.87-2.83 (m, 3H), 2.71-2.68 (m, 2H), 2.02-1.99 (m, 3H), 1.96-1.92 (m, 2H), 1.78-1.75 (m, 5H), 1.45-1.41 (m, 2H), 1.38 (t, J = 7.0 Hz, 3H), 1.01-0.97 (m, 2H), 0.90-0.85 (m, 2H). Isolated as formate salt

P303

[Image Omitted]

Prepared as for P229 using P226 and pyrrolidine, [UPLC Acidic], 593, (0.85)
10.19 (s, 1H), 9.04-9.00 (m, 1H), 8.84 (s, 1H), 8.52 (d, J = 5.3 Hz, 1H), 8.49 (dd, J = 8.8, 2.5 Hz, 1H), 8.26-8.23 (m, 3H), 8.23-8.17 (m, 1H), 7.06 (d, J = 5.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.28-3.19 (m, 1H), 2.73-2.57 (m, 5H), 2.05-1.99 (m, 3H), 1.85-1.73 (m, 7H), 1.65-1.48 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.03-0.96 (m, 2H), 0.85-0.76 (m, 2H). Isolated as formate salt

P304

[Image Omitted]

Prepared as for P229 using P226 and ammonium acetate, [UPLC Acidic], 539, (0.78)
10.22 (s, 1H), 9.05 (d, J = 2.5 Hz, 1H), 8.85 (s, 1H), 8.52 (dd, J = 8.8, 2.5 Hz, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 6.70 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 3.19-3.08 (m, 2H), 2.71-2.65 (m, 2H), 2.02-1.96 (m, 2H), 1.92-1.82 (m, 2H), 1.68-1.54 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H), 0.91-0.86 (m, 2H), 0.71-0.65 (m, 2H), 2H not observed Isolated as partial formate salt

P305

[Image Omitted]

Prepared as for P229 using P226 and morpholine, [UPLC Basic], 609, (1.12)
9.64 (s, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.83 (s, 1H), 8.62 (d, J = 5.3 Hz, 1H), 8.47 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.16 (s, 1H formate), 8.10 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 5.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.53 (t, J = 4.6 Hz, 4H), 3.30-3.21 (m, 1H), 2.71 (d, J = 13.3 Hz, 2H), 2.42-2.36 (m, 4H), 2.28-2.24 (m, 1H), 2.08-1.99 (m, 2H), 1.81-1.75 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.34-1.24 (m, 2H), 1.10 (dt, J = 6.5, 3.3 Hz, 2H), 1.04-0.94 (m, 2H). 1H not observed. Isolated as formate salt.

P306

[Image Omitted]

Prepared as for P229 using P226 and morpholine, [UPLC Basic], 609, (1.07)
10.13, (s, 1H), 9.03-8.99 (m, 1H), 8.83 (s, 1H), 8.57 (d, J = 5.3 Hz, 1H), 8.49 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.23-8.19 (m, 1H), 8.15 (s, 1H) formate, 7.16 (d, J = 5.3 Hz, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.57-3.51 (m, 4H), 3.30-3.21 (m, 1H), 2.72-2.66 (m, 2H), 2.45 (d, J = 5.0 Hz, 4H), 2.30-2.22 (m, 1H), 1.80-1.84 (m, 2H), 1.82-1.73 (m, 2H), 1.51-1.42 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.04-0.97 (m, 2H), 0.86-0.78 (m, 2H). 1H not observed. Isolated as formate salt

P307

[Image Omitted]

Prepared as for P229 using P226 and N- methyloxetan-3- amine, [UPLC Basic], 609, (1.01)
10.16 (s, 1H), 9.01 (d, J = 2.5 Hz, 1H), 8.83 (s, 1H), 8.55 (d, J = 5.3 Hz, 1H), 8.50 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.15 (s, 0.4H, partial formate salt), 7.13 (d, J = 5.4 Hz, 1H), 4.51-4.42 (m, 6H), 3.91-3.82 (m, 1H), 3.29-3.19 (m, 1H), 2.71-2.65 (m, 2H), 2.43-2.30 (m, 1H), 2.06 (s, 3H), 1.77-1.68 (m, 2H), 1.68-1.62 (m, 2H), 1.52-1.47 (m, 1H), 1.47-1.38 (m, 3H), 1.40-1.36 (m, 1H), 1.04-0.97 (m, 2H), 0.83-0.76 (m, 2H). 1H not observed. Isolated as partial formate salt

P308

[Image Omitted]

Prepared as for P229 using P226 and 2-methoxy-N- methylethan-1- amine, [UPLC Basic], 611, (0.98)
10.14 (s, 1H), 9.06-9.00 (m, 1H), 8.84 (s, 1H), 8.55 (d, J = 5.4 Hz, 1H), 8.50 (dd, J = 8.7, 2.5 Hz, 1H), 8.30-8.24 (m, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H, formate), 7.13 (d, J = 5.4 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.37 (t, J = 6.1 Hz, 2H), 3.29-3.22 (m, 1H), 3.22 (s, 3H), 2.77-2.64 (m, 2H), 2.61-2.53 (m, 1H), 2.21 (s, 3H), 1.88-1.66 (m, 4H), 1.55-1.43 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H), 1.05-0.95 (m, 2H), 0.85-0.77 (m, 2H). 1H not observed. Isolated as formate salt. 2H obscured by DMSO peak.

P309

[Image Omitted]

Prepared as for P229 using P226 and 2-methoxy-N- methylethan-1- amine, [UPLC Basic], 611, (1.02)
9.60 (s, 1H), 9.02 (d, J = 2.5 Hz, 1H), 8.83 (s, 1H), 8.55 (s, 1H), 8.47 (dd, J = 9.0, 2.5 Hz, 1H), 8.25 (s, 1H), 8.18 (s, 1H formate), 8.08 (d, J = 8.8 Hz, 1H), 7.20-7.10 (m, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.26 (s, 1H), 3.21 (s, 3H), 2.78-2.72 (m, 2H), 2.13 (s, 3H), 2.02-1.92 (m, 2H), 1.73-1.67 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.28-1.22 (m, 2H), 1.06-0.97 (m, 2H), 0.96-0.78 (m, 2H). 1H not observed. Isolated as formate salt. 5H obscured by DMSO and H₂O peaks

P310

[Image Omitted]

Prepared as for P229 using P226 and 2,2-difluoro- N-methylethan-1- amine, HCl, [UPLC Basic], 617, (1.33)
10.16 (s, 1H), 9.02 (d, J = 2.5 Hz, 1H), 8.84 (s, 1H), 8.58-8.53 (m, 1H), 8.53-8.45 (m, 1H), 8.27-8.20 (m, 2H), 7.13 (d, J = 5.4 Hz, 1H), 6.14-5.86 (m, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.69-3.60 (m, 1H), 3.30-3.21 (m, 1H), 2.79-2.66 (m, 4H), 2.27 (s, 3H), 1.81-1.72 (m, 4H), 1.53-1.45 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H), 1.05-0.99 (m, 2H), 0.85-0.77 (m, 2H). 1H not observed. Isolated as partial formate salt.

P311

[Image Omitted]

Prepared as for P229 using P226 and 1- methylpiperazine, [UPLC Basic], 622, (0.97)
9.60 (s, 1H), 9.02 (d, J = 2.5 Hz, 1H), 8.83 (s, 1H), 8.55 (s, 1H), 8.47 (dd, J = 9.0, 2.5 Hz, 1H), 8.25 (s, 1H), 8.18 (s, 1H formate), 8.08 (d, J = 8.8 Hz, 1H), 7.20-7.10 (m, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.26 (s, 1H), 3.21 (s, 3H), 2.78-2.72 (m, 2H), 2.13 (s, 3H), 2.02-1.92 (m, 2H), 1.73-1.67 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.28-1.22 (m, 2H), 1.06-0.97 (m, 2H), 0.96-0.78 (m, 2H). 1H not observed. Isolated as formate salt. 5H obscured by DMSO and H₂O peaks

P312

[Image Omitted]

Prepared as for P229 using P226 and 1- methylpiperazine, [UPLC Basic], 622, (0.91)
10.12 (s, 1H), 9.04-9.00 (m, 1H), 8.84 (s, 1H), 8.57-8.53 (m, 1H), 8.53-8.47 (m, 1H), 8.28-8.23 (m, 1H), 8.23-8.16 (m, 1.5H) (formate), 7.13 (d, J = 5.4 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.28-3.21 (m, 1H), 2.72-2.66 (m, 2H), 2.42-2.25 (m, 8H), 2.16 (s, 3H), 1.84 (d, J = 12.5 Hz, 2H), 1.81-1.72 (m, 2H), 1.51-1.43 (m, 2H), 1.43-1.37 (m, 3H), 1.05-0.98 (m, 2H), 0.85-0.78 (m, 2H), 1H not observed. Isolated as partial formate salt. 1H obscured by DMSO

P313

[Image Omitted]

Method 11, using INTC218 and INTD54, [UPLC Acidic], 550, (1.42)
11.29 (s, 1H), 9.88 (s, 1H), 9.00-8.98 (m, 2H), 8.60-8.58 (m, 2H), 8.45 (dd, J = 8.8, 2.5 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 7.20 (s, 1H) 3.22 (s, 3H), 2.38-2.34 (m, 2H), 2.32-2.18 (m, 3H), 1.82-1.75 (m, 2H), 1.58-1.50 (m, 2H), 1.29-1.24 (m, 2H), 1.10-1.05 (m, 5H), 0.92-0.85 (m, 3H)

P314

[Image Omitted]

Prepared as for P288 using INTC240 and methanesulfonyl chloride, [HPLC Acidic], 603, (2.02)
11.08 (s, 1H), 10.26 (s, 1H), 9.01 (d, J = 2.4 Hz, 1H), 8.83 (s, 1H), 8.49 (dd, J = 8.8, 2.4 Hz, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 8.23-8.17 (m, 2H), 4.47 (q, J = 7.0 Hz, 2H), 3.47-3.41 (m, 2H), 3.15-3.04 (m, 3H), 2.86 (s, 3H), 2.69-2.63 (m, 2H), 2.32-2.23 (m, 2H), 1.42-1.36 (m, 3H), 1.07-1.00 (m, 2H), 0.88-0.77 (m, 2H).

P315

[Image Omitted]

Prepared as for P288 using INTC245 and methanesulfonyl chloride, [HPLC Acidic], 599, (2.06)
11.35 (s, 1H), 10.06 (s, 1H), 9.03-8.96 (m, 2H), 8.59 (d, J = 5.7 Hz, 2H), 8.47 (dd, J = 8.8, 2.4 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 5.7 Hz, 1H), 3.37-3.32 (m, 1H), 3.22-3.13 (m, 4H), 2.85 (s, 3H), 2.49-2.38 (m, 4H), 2.30-2.22 (m, 1H), 1.21-1.02 (m, 6H), 0.99-0.91 (m, 2H).

P316

[Image Omitted]

Prepared as for P288 using INTC247 and methanesulfonyl chloride, [UPLC Acidic], 603, (1.33)
11.35 (s, 1H), 10.08 (s, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.84 (s, 1H), 8.59 (d, J = 5.7 Hz, 1H), 8.53-8.47 (m, 1H), 8.27-8.20 (m, 2H), 6.88 (d, J = 5.7 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.34-3.30 (m, 2H), 3.22-3.14 (m, 3H), 2.85 (s, 3H), 2.50-2.38 (m, 4H), 1.40 (t, J = 7.0 Hz, 3H), 1.17-1.05 (m, 2H), 0.99-0.91 (m, 2H).

P317

[Image Omitted]

Prepared as for P288 using INTC245 and ethanesulfonyl chloride, [HPLC Acidic], 613, (2.15)
11.35 (s, 1H), 10.06 (s, 1H), 9.00 (s, 1H), 8.98 (d, J = 2.4 Hz, 1H), 8.61-8.56 (m, 2H), 8.47 (dd, J = 8.8, 2.4 Hz, 1H), 8.21 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 5.7 Hz, 1H), 3.41-3.34 (m, 2H), 3.29-3.21 (m, 2H), 3.21-3.12 (m, 1H), 3.04 (q, J = 7.3 Hz, 2H), 2.48-2.34 (m, 4H), 2.30-2.22 (m, 1H), 1.19 (t, J = 7.3 Hz, 3H), 1.16-1.06 (m, 6H), 0.98-0.90 (m, 2H).

P318

[Image Omitted]

Prepared as for P288 using INTC247 and ethanesulfonyl chloride, [HPLC Acidic], 617, (2.16)
11.35 (s, 1H), 10.07 (s, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.84 (s, 1H), 8.59-8.55 (m, 1H), 8.50 (dd, J = 8.7, 2.4 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 5.9 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.43-3.21 (m, 4H), 3.20-3.12 (m, 1H), 3.04 (q, J = 7.3 Hz, 2H), 2.47-2.37 (m, 4H), 1.40 (t, J = 7.0 Hz, 3H), 1.19 (t, J = 7.3 Hz, 3H), 1.09-1.05 (m, 2H), 0.96-0.91 (m, 2H).

Compounds of Formula (I-b)—Intermediates

The synthesis of intermediates INTA1 to INTA117 and INTB1 to INTB120 is disclosed in WO2019/106156, which is herein incorporated in its entirety by reference, and uses the general methods shown below.

Method A: Formation of Thiazole Amines from Ketoesters

[Image Omitted]

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 (Na₂SO₄) 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

[Image Omitted]

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

[Image Omitted]

A suspension of (1R,2R)—N1,N2-dimethylcyclohexane-1,2-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 (N₂, 5 mins) then copper(I) iodide (0.1 equiv.) was added. The solution was again degassed (N₂, 5 mins) before being warmed to 80° C. The reaction was progressed for 2 hrs before being allowed to cool to RT. 1M HCl (aq) was added and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried (Na₂SO₄), filtered and concentrated. The crude material was purified by normal phase chromatography.

Method D: Formation of Acids from Esters

[Image Omitted]

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 1M HCl. The product was extracted using an appropriate organic solvent (EtOAc). The combined organics were dried (Na₂SO₄) and concentrated in vacuo to give the desired compound.

Aniline Intermediate Preparation

Method E: Suzuki Coupling of Halo Anilines with Heteroaromatic Boronates

[Image Omitted]

A solution of Ar1-X (1 eq) and Ar2-Z (1 eq) in solvent (3 volumes) and base (2.5 eq) was degassed (N₂, 5 min) and heated to 40° C. whereupon Pd catalyst (3 mol %) was added and the reaction mixture further degassed (N₂, 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

[Image Omitted]

Pd catalyst (5 mol %) was added to a degassed (N₂, 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 (N₂, 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

[Image Omitted]

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 (N₂, 5 mins). PdCl₂(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 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.

Method H: Suzuki Coupling of Halo Pyrimidines with Heteroaromatic Boronates

[Image Omitted]

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 (N₂, 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 (I-b)—Examples

The synthesis of a number of known CTPS1 inhibitors is disclosed in WO2019/106156 (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 WO2019/106156.

Amide Couplings

[Image Omitted]

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

[Image Omitted]

To a suspension of Ar1-Br (1 eq) in dioxane (10 volumes) was added arylboronic acid or ester (1 eq) and 2M K₂PO₄(2 eq). The resulting suspension was heated to 60° C. and degassed (N₂, 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)₂with Heteroaromatic Halides

[Image Omitted]

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 (1.2 eq) and K₂CO₃(5 eq) in dioxane (10 volumes) and water (15 volumes). The solution was then degassed further (N₂, 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

[Image Omitted]

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 (N₂, 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-([1,1′-biphenyl]-4-yl)-2-(2-(methylsulfonamido)thiazol-4-yl)acetamide T1

[Image Omitted]

N-([1,1′-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide T2

[Image Omitted]

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-ethyl-N-(5-(pyrazin-2-yl)pyridin-2-yl)butanamide T3

[Image Omitted]

Prepared as Method 1b from INTB41 and 5-(pyrazin-2-yl)pyridin-2-amine (Cheng et al., 2016).

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrimidin-2-yl)phenyl)propanamide T4

[Image Omitted]

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

[Image Omitted]

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 HCl) was undertaken by adding 1.25M HCl (EtOH, 2 mL×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.HCl T6.

Peak B: Stereochemistry of Product was not Assigned

2-(2-(cydopropanesulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-yl)phenyl)butanamide.HCl T7.

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

[Image Omitted]

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 HCl) was undertaken by adding 1.25M HCl (EtOH, 2 mL×5) and removing solvent to afford:

Peak A: Stereochemistry of Product was not Assigned

N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide.HCl.

Peak B: Stereochemistry of Product was not Assigned

N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)butanamide.HCl T10.

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyrimidin-5-yl)phenyl)butanamide T11

[Image Omitted]

Prepared as Method 1 from INTB40.

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyridin-3-yl)phenyl)butanamide T12

[Image Omitted]

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 HCl) was undertaken by adding 1.25M HCl (EtOH, 2 mL×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.HCl T13.

Peak B: Stereochemistry of Product was not Assigned

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-3-methyl-N-(4-(pyridin-3-yl)phenyl)butanamide.HCl T14.

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(5-methoxypyridin-3-yl)phenyl)-2-methylpropanamide T15

[Image Omitted]

N-(2-chloro-4-(pyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)acetamide T16

[Image Omitted]

2-(2-(cyclopropanesulfonamido)-5-methylthiazol-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide T17

[Image Omitted]

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methyl-N-(4-(pyrimidin-5-yl)phenyl)propanamide T18

[Image Omitted]

6-(4-(2-(2-(cydopropanesulfonamido)thiazol-4-yl)-2-methylpropanamido)phenyl)-N,N-dimethylpyrazine-2-carboxamide T19

[Image Omitted]

N-(5-(5-cyanopyridin-3-yl)pyrimidin-2-yl)-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-methylpropanamide T20

[Image Omitted]

N-([1,1′-biphenyl]4-yl)-2-(5-chloro-2-(cydopropanesulfonamido)thiazol-4-yl)acetamide T21

[Image Omitted]

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethynylpyrazin-2-yl)phenyl)butanamide T22

[Image Omitted]

TABLE 6

Compounds T23-T322, T422-T443 and T445-T465.

Name/Structure

(All examples containing chiral

centres are racemates unless

T#
stated)

T23
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(6-(pyrimidin-5-yl)pyridin-3-

yl)acetamide

[Image Omitted]

T24
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-phenylpyridin-2-yl)acetamide

[Image Omitted]

T25
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4′-fluoro-[1,1′-biphenyl]-4-

yl)acetamide

[Image Omitted]

T26
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-methyl-N-(4-(pyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T27
2-([2,3′-bipyridin]-5-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T28
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(3′-methoxy-[1,1′-biphenyl]-4-

yl)-2-methylpropanamide

[Image Omitted]

T29
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T30
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(5-methylpyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T31
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(pyridazin-4-

yl)phenyl)propanamide

[Image Omitted]

T32
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T33
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-methoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T34
N-(3-cyano-4-(pyrazin-2-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-methylpropanamide

[Image Omitted]

T35
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(6-

(trifluoromethyl)pyrazin-2-yl)pyridin-2-

yl)propanamide

[Image Omitted]

T36
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2,3-difluoro-4-(pyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T37
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(pyridin-3-

yl)pyrimidin-2-yl)propanamide

[Image Omitted]

T38
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(6-propoxypyrazin-

2-yl)pyridin-2-yl)propanamide

[Image Omitted]

T39
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(3-fluoro-4-(pyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T40
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(pyridin-3-yl)-2-

(trifluoromethoxy)phenyl)propanamide

[Image Omitted]

T41
N-(2-chloro-4-(pyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-methylpropanamide

[Image Omitted]

T42
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)-

2-methylpropanamide

[Image Omitted]

T43
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(3-methoxy-4-(pyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T44
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(2-methoxypyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T45
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-(hydroxymethyl)pyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T46
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-methoxypyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T47
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-methylpropanamide

[Image Omitted]

T48
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(5-

(trifluoromethyl)pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T49
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(5-

(methylsulfonyl)pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T50
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-methoxy-4-(5-

methoxypyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T51
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(6-(trifluoromethyl)-

[2,3′-bipyridin]-6′-yl)propanamide

[Image Omitted]

T52
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T53
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(6-

morpholinopyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T54
N-(4-(6-cyclobutoxypyrazin-2-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T55
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(6-propoxypyrazin-

2-yl)phenyl)propanamide

[Image Omitted]

T56
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-methoxypyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T57
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methoxy-N-(4-(6-

methoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

T58
N-(4-(5-chloropyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-isopropoxyacetamide

[Image Omitted]

T59
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-4-methoxy-N-(5-(6-

(trifluoromethyl)pyrazin-2-yl)pyridin-2-

yl)butanamide

[Image Omitted]

T60
N-([1,1′-biphenyl]-4-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2,2-difluoroacetamide

[Image Omitted]

T61
2-(2-(cyclobutanesulfonamido)thiazol-

4-yl)-N-(4-(6-methoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

T62
N-([3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T63
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-phenylpyridin-2-

yl)propanamide

[Image Omitted]

T64
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(pyrimidin-5-yl)pyridin-2-

yl)acetamide

[Image Omitted]

T65
N-([3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)acetamide

[Image Omitted]

T66
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(6-phenylpyridin-3-yl)acetamide

[Image Omitted]

T67
N-([2,3′-bipyridin]-5-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)acetamide

[Image Omitted]

T68
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(pyridazin-3-

yl)phenyl)propanamide

[Image Omitted]

T69
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(pyridazin-4-

yl)phenyl)butanamide

[Image Omitted]

T70
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T71
N-(4-(5-chloropyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-4-methoxybutanamide

[Image Omitted]

T72
Single enantiomer—

stereochemistry unassigned 2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-fluoropyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T73
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T74
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-3-methyl-N-(4-(pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T75
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-propoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T76
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-isopropoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T77
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-cyclopropoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T78
N-(4-(6-chloropyrazin-2-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)butanamide

[Image Omitted]

T79
N-(4-(6-cyanopyrazin-2-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)butanamide

[Image Omitted]

T80
Single enantiomer—

stereochemistry unassigned

2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T81
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-methoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

T82
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(pyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

T83
N-([1,1′-biphenyl]-4-yl)-2-

(cyclopropanesulfonamido)-4,5,6,7-

tetrahydrobenzo[d]thiazole-4-

carboxamide

[Image Omitted]

T84
2-(cyclopropanesulfonamido)-N-(4-

(pyridin-3-yl)phenyl)-4,5,6,7-

tetrahydrobenzo[d]thiazole-4-

carboxamide

[Image Omitted]

T85
N-([1,1′-biphenyl]-4-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T86
N-([1,1′-biphenyl]-4-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-3-methylbutanamide

[Image Omitted]

T87
N-(3′-chloro-[1,1′-biphenyl]-4-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T88
N-(3′-cyano-[1,1′-biphenyl]-4-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T89
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2,2-difluoro-N-(4-(pyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T90
N-(4-(5-fluoropyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)butanamide

[Image Omitted]

T91
Single enantiomer—

stereochemistry unassigned

N-(4-(5-fluoropyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)butanamide. HCl

[Image Omitted]

T92
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-ethyl-N-(4-(pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T93
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-ethylbutanamide

[Image Omitted]

T94
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-ethoxypyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T95
N-(4-(5-chloropyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)propanamide

[Image Omitted]

T96
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-ethoxypyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T97
N-([1,1′-biphenyl]-4-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T98
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(4-methylpyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T99
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-methylpyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T100
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(2-methylpyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T101
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-methylpyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T102
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T103
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(2-methylpyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T104
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-oxo-N-(4-(pyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T105
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(6-methylpyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T106
Single enantiomer—

stereochemistry unassigned

2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T107
Single enantiomer—

stereochemistry unassigned

2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methoxy-N-(4-(6-

methoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

T108
Single enantiomer—

stereochemistry unassigned

2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methoxy-N-(4-(6-

methoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

T109
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(6-(2,2,2-

trifluoroethoxy)pyrazin-2-yl)pyridin-2-

yl)propanamide

[Image Omitted]

T110
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(3-fluoro-5-(pyrazin-2-yl)pyridin-

2-yl)-2-methylpropanamide

[Image Omitted]

T111
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

fluoropyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

T112
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(3-fluoro-5-(6-

(trifluoromethyl)pyrazin-2-yl)pyridin-2-

yl)-2-methylpropanamide

[Image Omitted]

T113
N-(5-(6-cyanopyrazin-2-yl)-3-

fluoropyridin-2-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T114
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5′-(2,2,2-

trifluoroethoxy)-[3,3′-bipyridin]-6-

yl)propanamide

[Image Omitted]

T115
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5′-(difluoromethoxy)-[3,3′-

bipyridin]-6-yl)-2-methylpropanamide

[Image Omitted]

T116
N-([2,3′-bipyridin]-5-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T117
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(6-(pyrimidin-5-

yl)pyridin-3-yl)propanamide

[Image Omitted]

T118
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-(difluoromethoxy)pyridin-

3-yl)phenyl)-2-methylpropanamide

[Image Omitted]

T119
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-ethyl-N-(4-(6-methoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T120
N-(4-(5-chloropyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-ethylbutanamide

[Image Omitted]

T121
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-ethyl-N-(2-fluoro-4-(pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T122
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-ethyl-N-(4-(pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T123
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-ethyl-N-(4-(6-propoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T124
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-

(trifluoromethyl)pyrazin-2-yl)phenyl)-

2-methylpropanamide

[Image Omitted]

T125
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-ethoxypyridin-3-yl)-2-

fluorophenyl)-2-methylpropanamide

[Image Omitted]

T126
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-fluoropyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T127
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(6-(2,2,2-

trifluoroethoxy)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T128
N-(4-(5-chloropyridin-3-yl)-2-

fluorophenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T129
N-(4-(5-cyanopyridin-3-yl)-2-

fluorophenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T130
1-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-methoxypyrazin-2-

yl)phenyl)cyclopentane-1-

carboxamide

[Image Omitted]

T131
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-(2,2,2-

trifluoroethoxy)pyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T132
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-(2,2,2-

trifluoroethoxy)pyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T133
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-

(trifluoromethyl)pyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T134
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)-2-methylpropanamide

[Image Omitted]

T135
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(5-(2,2,2-

trifluoroethoxy)pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T136
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethynylpyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T137
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

methylphenyl)-2-methylpropanamide

[Image Omitted]

T138
N-(4-(6-chloropyrazin-2-yl)-2-

methylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T139
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-(difluoromethoxy)pyridin-

3-yl)-2-fluorophenyl)-2-

methylpropanamide

[Image Omitted]

T140
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(pyrazin-2-

yl)pyridin-2-yl)propanamide

[Image Omitted]

T141
N-(5-(6-cyclobutoxypyrazin-2-

yl)pyridin-2-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T142
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-cyclopropoxypyrazin-2-

yl)pyridin-2-yl)-2-methylpropanamide

[Image Omitted]

T143
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-isopropoxypyrazin-2-

yl)pyridin-2-yl)-2-methylpropanamide

[Image Omitted]

T144
N-([3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-ethylbutanamide

[Image Omitted]

T145
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5′-ethoxy-[3,3′-bipyridin]-6-yl)-

2-ethylbutanamide

[Image Omitted]

T146
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5′-propoxy-[3,3′-

bipyridin]-6-yl)propanamide

[Image Omitted]

T147
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-ethyl-N-(5-(6-

(trifluoromethyl)pyrazin-2-yl)pyridin-2-

yl)butanamide

[Image Omitted]

T148
N-([3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methylpropanamide

[Image Omitted]

T149
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-methoxy-4-(pyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T150
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(3-methoxy-4-(pyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T151
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(3-fluoro-4-(pyridin-3-yl)phenyl)-

2-methylpropanamide

[Image Omitted]

T152
N-(3-cyano-4-(pyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-methylpropanamide

[Image Omitted]

T153
N-(3-chloro-4-(pyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-methylpropanamide

[Image Omitted]

T154
N-(4-(6-cyanopyrazin-2-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-methylpropanamide

[Image Omitted]

T155
N-(4-(6-chloropyrazin-2-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-methylpropanamide

[Image Omitted]

T156
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-ethyl-N-(4-(5-fluoropyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T157
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(5-propoxypyridin-

3-yl)phenyl)propanamide

[Image Omitted]

T158
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-isopropoxypyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T159
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-isopropoxypyridin-

3-yl)phenyl)-2-methylpropanamide

[Image Omitted]

T160
N-(4-(6-chloropyrazin-2-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-ethylbutanamide

[Image Omitted]

T161
N-(4-(6-cyanopyrazin-2-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-ethylbutanamide

[Image Omitted]

T163
2-methyl-2-(2-

(methylsulfonamido)thiazol-4-yl)-N-

(4-(pyridin-3-yl)phenyl)propanamide

[Image Omitted]

T164
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N,2-dimethyl-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T169
2-(cyclopropanesulfonamido)-N-(5-(6-

(trifluoromethyl)pyrazin-2-yl)pyridin-2-

yl)-5,6-dihydro-4H-

cyclopenta[d]thiazole-4-carboxamide

[Image Omitted]

T170
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-4-methoxy-N-(5-(pyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

T171
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-4-methoxy-N-(5′-methoxy-[3,3′-

bipyridin]-6-yl)butanamide

[Image Omitted]

T172
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-2-isopropoxy-N-(5-(6-

(trifluoromethyl)pyrazin-2-yl)pyridin-2-

yl)acetamide

[Image Omitted]

T173
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-propoxypyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

T174
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-isopropoxypyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

T175
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

T176
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-methoxypyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

T177
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-

2-yl)butanamide

[Image Omitted]

T178
N-(5-(6-cyanopyrazin-2-yl)pyridin-2-

yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T179
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5′-fluoro-[3,3′-bipyridin]-6-

yl)butanamide

[Image Omitted]

T180
N-(5′-cyano-[3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T181
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-phenylpyridin-2-

yl)butanamide

[Image Omitted]

T182
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-(2,2,2-

trifluoroethoxy)pyrazin-2-yl)pyridin-2-

yl)butanamide

[Image Omitted]

T183
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

fluoropyridin-2-yl)butanamide

[Image Omitted]

T184
N-(5-(6-cyanopyrazin-2-yl)-3-

fluoropyridin-2-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T185
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5′-(2,2,2-trifluoroethoxy)-[3,3′-

bipyridin]-6-yl)butanamide

[Image Omitted]

T186
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5′-(difluoromethoxy)-[3,3′-

bipyridin]-6-yl)butanamide

[Image Omitted]

T187
N-(5-(6-chloropyrazin-2-yl)pyridin-2-

yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T188
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2,3-difluoro-4-(pyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T189
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T190
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-4-methoxy-N-(4-(6-

methoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T191
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-

4-methoxybutanamide

[Image Omitted]

T192
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T193
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-(trifluoromethyl)pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T194
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-

4-yl)butanamide

[Image Omitted]

T195
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(2,2,2-

trifluoroethoxy)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T196
2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T197
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T198
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)butanamide

[Image Omitted]

T199
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-ethoxypyridin-3-yl)-2-

fluorophenyl)butanamide

[Image Omitted]

T200
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-fluoropyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T201
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T202
N-(4-(5-cyanopyridin-3-yl)-2-fluorophenyl)-

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T203
N-(4-(5-chloropyridin-3-yl)-2-fluorophenyl)-

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T204
Single enantiomer—stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T205
Single enantiomer—stereochemistry

unassigned 2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-N-

(4-(6-ethoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T206
N-(4-(1-(5-(6-ethoxypyrazin-2-yl)indolin-1-

yl)-1-oxobutan-2-yl)thiazol-2-

yl)cyclopropanesulfonamide

[Image Omitted]

T207
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-(2,2,2-

trifluoroethoxy)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T208
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-methoxypyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T209
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-(difluoromethoxy)pyridin-3-yl)-

2-fluorophenyl)butanamide

[Image Omitted]

T210
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-(difluoromethoxy)pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T211
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-(2,2,2-trifluoroethoxy)pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T212
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-(2,2,2-

trifluoroethoxy)pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T213
2-(cyclopropanesulfonamido)-N-(4-

(pyridin-3-yl)phenyl)-5,6-dihydro-4H-

cyclopenta[d]thiazole-4-carboxamide

[Image Omitted]

T214
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methoxy-N-(5-(6-

(trifluoromethyl)pyrazin-2-yl)pyridin-2-

yl)acetamide

[Image Omitted]

T215
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-methoxy-4-(pyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T216
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(pyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T217
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-

(cyclopropanesulfonamido)-5,6-dihydro-

4H-cyclopenta[d]thiazole-4-carboxamide

[Image Omitted]

T218
2-(cyclopropanesulfonamido)-N-(4-(5-

fluoropyridin-3-yl)phenyl)-5,6-dihydro-4H-

cyclopenta[d]thiazole-4-carboxamide

[Image Omitted]

T219
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methoxy-N-(4-(pyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T220
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(pyridin-3-yl)phenyl)-2-

methoxyacetamide

[Image Omitted]

T221
N-(2-chloro-4-(pyridin-3-yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T222
Single enantiomer—stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T223
Single enantiomer—stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T224
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5′-methoxy-[3,3′-bipyridin]-6-yl)-2-

methylpropanamide

[Image Omitted]

T225
N-(5′-chloro-[3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T226
N-(5′-cyano-[3,3′-bipyridin]-6-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T227
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-fluoro-[3,3′-bipyridin]-6-yl)-2-

methylpropanamide

[Image Omitted]

T228
N-(5′-cyano-5-fluoro-[3,3′-bipyridin]-6-yl)-2-

(2-(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T229
N-(5′-chloro-5-fluoro-[3,3′-bipyridin]-6-yl)-2-

(2-(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T230
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5,5′-difluoro-[3,3′-bipyridin]-6-yl)-2-

methylpropanamide

[Image Omitted]

T231
N-(5-(3-chloro-5-methylphenyl)pyridin-2-

yl)-2-(2-(cyclopropanesulfonamido)thiazol-

4-yl)-2-methylpropanamide

[Image Omitted]

T232
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(3-methoxyphenyl)pyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

T233
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(3-fluoro-5-methoxyphenyl)pyridin-

2-yl)-2-methylpropanamide

[Image Omitted]

T234
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(3,5-dimethoxyphenyl)pyridin-2-

yl)-2-methylpropanamide

[Image Omitted]

T235
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(3-

(trifluoromethyl)phenyl)pyridin-2-

yl)propanamide

[Image Omitted]

T236
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(3-

(trifluoromethoxy)phenyl)pyridin-2-

yl)propanamide

[Image Omitted]

T237
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(3-(2-hydroxypropan-2-

yl)phenyl)pyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

T238
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(3-

morpholinophenyl)pyridin-2-

yl)propanamide

[Image Omitted]

T239
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(6-phenylpyridin-3-

yl)propanamide

[Image Omitted]

T240
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(2-fluoropyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T241
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-(hydroxymethyl)pyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T242
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(2-methoxypyrimidin-5-

yl)phenyl)acetamide

[Image Omitted]

T243
N-(4′-(tert-butyl)-[1,1′-biphenyl]-4-yl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)acetamide

[Image Omitted]

T244
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(pyridin-3-yl)phenyl)acetamide

[Image Omitted]

T245
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(pyridin-4-yl)phenyl)acetamide

[Image Omitted]

T246
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2′-methoxy-[1,1′-biphenyl]-4-

yl)acetamide

[Image Omitted]

T247
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(pyrimidin-5-yl)phenyl)acetamide

[Image Omitted]

T248
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(2-

(trifluoromethyl)pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T249
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5′-methyl-[3,3′-bipyridin]-6-

yl)propanamide

[Image Omitted]

T250
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(2-methoxy-4-methylpyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T251
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-methoxy-5-methylpyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T252
N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T253
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-fluoropyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T254
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(4-methylpyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T255
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(4-

(trifluoromethyl)pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T256
N-(4-(5-chloropyridin-3-yl)-2-

methoxyphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T257
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-(dimethylamino)pyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T258
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-methoxy-4-(5-methylpyridin-3-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T259
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-methoxy-4-(5-

(trifluoromethyl)pyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T260
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-methoxypyridin-3-

yl)phenyl)acetamide

[Image Omitted]

T261
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5′-fluoro-[3,3′-bipyridin]-6-yl)-2-

methylpropanamide

[Image Omitted]

T262
N-(5-(6-chloropyrazin-2-yl)pyridin-2-yl)-2-

(2-(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T263
N-(5-(6-cyanopyrazin-2-yl)pyridin-2-yl)-2-

(2-(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T264
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(pyrimidin-5-yl)pyridin-2-

yl)propanamide

[Image Omitted]

T265
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-methoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T266
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(6-methylpyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T267
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T268
N-(4-(6-chloropyridin-2-yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T269
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-methoxypyridin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T270
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(6-

(trifluoromethyl)pyridin-2-

yl)phenyl)propanamide

[Image Omitted]

T271
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(4-methoxypyridin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T272
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-

2-methylpropanamide

[Image Omitted]

T273
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-cyclopropoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T274
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(pyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T275
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-methoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T276
N-(4-(6-chloro-3-methylpyrazin-2-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T277
N-(4-(6-chloro-5-methylpyrazin-2-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T278
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(6-(pyrrolidin-1-

yl)pyrazin-2-yl)phenyl)propanamide

[Image Omitted]

T279
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(2-

(dimethylamino)ethoxy)pyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T280
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(3-methylpyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T281
N-(4-(6-acetamidopyrazin-2-yl)phenyl)-2-

(2-(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T282
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5,6-dimethylpyrazin-2-yl)phenyl)-

2-methylpropanamide

[Image Omitted]

T283
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(hydroxymethyl)pyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T284
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(3,6-dimethylpyrazin-2-yl)phenyl)-

2-methylpropanamide

[Image Omitted]

T285
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-methoxypyridin-3-yl)-2-

methylphenyl)-2-methylpropanamide

[Image Omitted]

T286
N-(4-(5-cyanopyridin-3-yl)-2-

methylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T287
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-fluoropyridin-3-yl)-2-

methylphenyl)-2-methylpropanamide

[Image Omitted]

T288
N-(4-(5-chloropyridin-3-yl)-3-

methylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T289
N-(4-(5-cyanopyridin-3-yl)-3-

ethoxyphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T290
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-ethoxypyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T291
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-cyclopropylpyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T292
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(5-methoxypyridin-3-yl)pyrimidin-

2-yl)-2-methylpropanamide

[Image Omitted]

T293
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(5-fluoropyridin-3-yl)pyrimidin-2-

yl)-2-methylpropanamide

[Image Omitted]

T294
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(5-

(trifluoromethyl)pyridin-3-yl)pyrimidin-2-

yl)propanamide

[Image Omitted]

T295
N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-

methyl-2-(2-((2-

methylpropyl)sulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T296
N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methyl-2-(2-

((trifluoromethyl)sulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T297
2-methyl-2-(2-((1-

methylethyl)sulfonamido)thiazol-4-yl)-N-(4-

(pyridin-3-yl)phenyl)propanamide

[Image Omitted]

T298
N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methyl-2-(2-((1-

methylethyl)sulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T299
2-methyl-2-(2-((1-methylcyclopropane)-1-

sulfonamido)thiazol-4-yl)-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T300
N-(4-(5-chloropyridin-3-yl)phenyl)-2-

methyl-2-(2-((1-methylcyclopropane)-1-

sulfonamido)thiazol-4-yl)propanamide

[Image Omitted]

T301
N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methyl-2-(2-((1-methylcyclopropane)-1-

sulfonamido)thiazol-4-yl)propanamide

[Image Omitted]

T302
2-methyl-2-(2-((1-methylcyclopropane)-1-

sulfonamido)thiazol-4-yl)-N-(4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T303
2-(2-((1,1-

dimethylethyl)sulfonamido)thiazol-4-yl)-2-

methyl-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T304
2-(2-((1,1-

dimethylethyl)sulfonamido)thiazol-4-yl)-N-

(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T305
2-(2-((1,1-

dimethylethyl)sulfonamido)thiazol-4-yl)-2-

methyl-N-(4-(6-(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T306
2-(2-(cyclobutanesulfonamido)thiazol-4-yl)-

2-methyl-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T307
2-(2-(cyclobutanesulfonamido)thiazol-4-yl)-

N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T308
2-(2-(cyclobutanesulfonamido)thiazol-4-yl)-

2-methyl-N-(4-(6-(trifluoromethyl)pyrazin-

2-yl)phenyl)propanamide

[Image Omitted]

T309
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-

N,2-dimethylpropanamide

[Image Omitted]

T310
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N,2-dimethyl-N-(4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T311
2-methyl-2-(2-((2-

methylpropyl)sulfonamido)thiazol-4-yl)-N-

(4-(pyridin-3-yl)phenyl)propanamide

[Image Omitted]

T312
N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methyl-2-(2-((2-

methylpropyl)sulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T313
2-methyl-2-(2-((2-

methylpropyl)sulfonamido)thiazol-4-yl)-N-

(4-(6-(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T314
N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-

(cyclopropanesulfonamido)-5-

methylthiazol-4-yl)-2-methylpropanamide

[Image Omitted]

T315
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-methyl-N-(4-(pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T316
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-N-

methylbutanamide

[Image Omitted]

T317
2-(2-(cyclopropanesulfonamido)-5-

methylthiazol-4-yl)-N-(4-(6-ethoxypyrazin-

2-yl)phenyl)-2-methylpropanamide

[Image Omitted]

T318
N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-

N,2-dimethylpropanamide

[Image Omitted]

T319
2-(2-(cyclopropanesulfonamido)-5-

methylthiazol-4-yl)-2-methyl-N-(4-(pyridin-

3-yl)phenyl)propanamide

[Image Omitted]

T320
N-(4-(5-cyanopyridin-3-yl)-2,6-

dimethylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T321
N-(4-(5-chloropyridin-3-yl)-2,6-

dimethylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T322
N-(4-(5-cyanopyridin-3-yl)-3-

methylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T422
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-

2,2-difluoroacetamide

[Image Omitted]

T423
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)acetamide

[Image Omitted]

T424
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)acetamide

[Image Omitted]

T425
2-methyl-2-(2-(methylsulfonamido)thiazol-

4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-

yl)pyridin-2-yl)propanamide

[Image Omitted]

T426
N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-3-

yl)phenyl)-2-methyl-2-(2-

(methylsulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T427
2-(2-

((cyclopropylmethyl)sulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-

3-yl)phenyl)-2-methylpropanamide

[Image Omitted]

T428
N-(4-(5-chloro-4-methylpyridin-3-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T429
N-(4-(6-ethoxypyrazin-2-yl)-2-

(trifluoromethyl)phenyl)-2-methyl-2-(2-

(methylsulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T430
2-(2-

((cyclopropylmethyl)sulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-

(trifluoromethyl)pyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T431
N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)-2-methyl-2-(2-

(methylsulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T432
N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)-2-(2-((2-

methoxyethyl)sulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T433
2-(2-

((cyclopropylmethyl)sulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)-2-methylpropanamide

[Image Omitted]

T434
N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methyl-2-(2-(methylsulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T435
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

fluoropyridin-2-yl)-4-methoxybutanamide

[Image Omitted]

T436
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-

4-methoxybutanamide

[Image Omitted]

T437
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-4-methoxy-N-(4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)butanamide

[Image Omitted]

T438
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

methylpyridin-2-yl)butanamide

[Image Omitted]

T439
N-(2-chloro-4-(6-ethoxypyrazin-2-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T440
N-(2-cyano-4-(6-ethoxypyrazin-2-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T441
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

methylphenyl)butanamide

[Image Omitted]

T442
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

(trifluoromethoxy)phenyl)butanamide

[Image Omitted]

T443
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

methoxyphenyl)butanamide

[Image Omitted]

T445
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

fluoropyridin-2-yl)-2-methoxyacetamide

[Image Omitted]

T446
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-

2-methoxyacetamide

[Image Omitted]

T447
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-fluoropyridin-3-yl)-2-

(trifluoromethyl)phenyl)-2-

methoxyacetamide

[Image Omitted]

T448
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-(trifluoromethyl)pyridin-

3-yl)phenyl)-2-methoxyacetamide

[Image Omitted]

T449
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

(trifluoromethyl)phenyl)-2-

methoxyacetamide

[Image Omitted]

T450
N-(2-chloro-4-(6-ethoxypyrazin-2-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methoxyacetamide

[Image Omitted]

T451
N-(2-cyano-4-(6-ethoxypyrazin-2-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methoxyacetamide

[Image Omitted]

T452
N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-

yl)phenyl)-2-methoxy-2-(2-

(methylsulfonamido)thiazol-4-yl)acetamide

[Image Omitted]

T453
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2,6-

difluorophenyl)-2-methoxyacetamide

[Image Omitted]

T454
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

(trifluoromethoxy)phenyl)-2-

methoxyacetamide

[Image Omitted]

T455
N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methoxy-2-(2-(methylsulfonamido)thiazol-

4-yl)acetamide

[Image Omitted]

T456
Single enantiomer—stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

fluoropyridin-2-yl)butanamide

[Image Omitted]

T457
Single enantiomer—stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)-3-

fluoropyridin-2-yl)butanamide

[Image Omitted]

T458
Single enantiomer—stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-

(trifluoromethyl)pyrazin-2-yl)phenyl)-2-

methoxyacetamide

[Image Omitted]

T459
Single enantiomer—stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-

(trifluoromethyl)pyrazin-2-yl)phenyl)-2-

methoxyacetamide

[Image Omitted]

T460
4-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)tetrahydro-2H-pyran-4-

carboxamide

[Image Omitted]

T461
4-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-

yl)pyridin-2-yl)tetrahydro-2H-pyran-4-

carboxamide

[Image Omitted]

T462
4-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)tetrahydro-2H-pyran-4-carboxamide

[Image Omitted]

T463
N-(4-(1-(4-(5-methoxypyridin-3-yl)phenyl)-

2-oxopyrrolidin-3-yl)thiazol-2-

yl)cyclopropanesulfonamide

[Image Omitted]

T464
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(5-(6-methylpyrazin-2-

yl)pyridin-2-yl)propanamide

[Image Omitted]

T465
N-(4-(6-cyanopyrazin-2-yl)-2-

methylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

Method 2c: Telescoped Boronate Formation and Suzuki Coupling on Sulfonamide Scaffold

[Image Omitted]

A suspension of Ar1-Br (1 eq), bispin (1.1 eq.) and KOAc (2 eq) in dioxane (50 volumes) was degassed (N₂, 5 mins, ×3) then charged with PdCl₂(dppo)-DCM adduct (5 mol %) and again degassed (N₂, 5 mins, ×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 K₂CO₃(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

[Image Omitted]

2-acetamido-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide T326

[Image Omitted]

methyl (1-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-((4-(6-ethoxypyrazin-2-yl)phenyl)amino)-2-oxoethyl)carbamate T327

[Image Omitted]

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)acetamide T328

[Image Omitted]

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-hydroxybutanamide T329

[Image Omitted]

The racemate T410 was separated by chiral preparative HPLC [Chiralpak® IB (Daicel Ltd.) column (4.6 mm×25 mm), flow rate 0.5 mL min⁻¹eluting with a mixture of (30% of ethanol) ethanol in heptane+0.2% Et₂NH, 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-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide T410

[Image Omitted]

The racemate T410 was prepared using Method 1b 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-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide T330.

Peak 2: Stereochemistry of Product was Unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide T331.

TABLE 7

Compounds T332-T416

Name/Structure

(All examples containing chiral

T#
centres are racemates unless stated)

T332
2-(2-((2-

methoxyethyl)sulfonamido)thiazol-4-yl)-2-

methyl-N-(5-(6-(trifluoronnethyl)pyrazin-2-

yl)pyridin-2-yl)propanamide

[Image Omitted]

T333
2-(2-(cyclopentanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T334
2-(2-(cyclopentanesulfonamido)thiazol-4-

yl)-2-methyl-N-(4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T335
2-(2-(cyclopentanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T336
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-

2-yl)-2-methylpropanamide

[Image Omitted]

T337
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5′-ethoxy-[3,3′-bipyridin]-6-yl)-2-

methylpropanamide

[Image Omitted]

T338
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-(2-hydroxypropan-2-

yl)pyrazin-2-yl)pyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

T339
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-(2-methoxypropan-2-

yl)pyrazin-2-yl)pyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

T340
2-(2-(cyclopropanesulfonamido)-5-

methylthiazol-4-yl)-2-methyl-N-(5-(6-

(trifluoromethyl)pyrazin-2-yl)pyridin-2-

yl)propanamide

[Image Omitted]

T341
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-

yl)-2-methylpropanamide

[Image Omitted]

T342
2-(2-(cyclopropanesulfonamido)-5-

methylthiazol-4-yl)-N-(5-(6-

ethoxypyrazin-2-yl)pyridin-2-yl)-2-

methylpropanamide

[Image Omitted]

T343
N-(4-(5-chloropyridin-3-yl)-2-

(trifluoromethyl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T344
N-(4-(5-cyanopyridin-3-yl)-2-

(trifluoromethyl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T345
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(5-fluoropyridin-3-yl)-2-

(trifluoromethyl)phenyl)-2-

methylpropanamide

[Image Omitted]

T346
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(2-(trifluoromethyl)-4-(6-

(trifluoromethyl)pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T347
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

(trifluoromethyl)phenyl)-2-

methylpropanamide

[Image Omitted]

T348
N-(4-(5-chloropyridin-3-yl)-2,6-

diethylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T349
N-(4-(5-cyanopyridin-3-yl)-2,6-

diethylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T350
2-(2-(cyclopropanesulfonamido)-5-

methylthiazol-4-yl)-N-(2-fluoro-4-(5-

(trifluoromethyl)pyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T351
N-(4-(5-chloropyridin-3-yl)-2,6-

difluorophenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T352
N-(4-(5-chloropyridin-3-yl)-2-fluoro-5-

methylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T353
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-(2-methoxypropan-2-

yl)pyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T354
2-(2-(cyclopropanesulfonamido)-5-

methylthiazol-4-yl)-N-(2-fluoro-4-(6-

(trifluoromethyl)pyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T355
N-(4-(6-cyanopyrazin-2-yl)-2-

fluorophenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T356
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethylpyrazin-2-yl)-2-

fluorophenyl)-2-methylpropanamide

[Image Omitted]

T357
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T358
2-(2-(cyclopropanesulfonamido)-5-

methylthiazol-4-yl)-N-(4-(6-

ethoxypyrazin-2-yl)-2-fluorophenyl)-2-

methylpropanamide

[Image Omitted]

T359
N-(4-(5-chloropyridin-3-yl)-2-

isopropylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T360
N-(4-(5-cyanopyridin-3-yl)-2-

isopropylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T361
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-isopropyl-4-(6-

(trifluoromethyl)pyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T362
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

isopropylphenyl)-2-methylpropanamide

[Image Omitted]

T363
N-(4-(5-chloropyridin-3-yl)-3-fluoro-2-

methylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T364
N-(4-(5-chloropyridin-3-yl)-5-fluoro-2-

methylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T365
N-(4-(5-chloropyridin-3-yl)-2,3-

dimethylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T366
N-(4-(5-chloropyridin-3-yl)-2,5-

dimethylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T367
N-(4-(5-cyanopyridin-3-yl)-3-fluoro-2-

methylphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T368
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-2-methyl-N-(2-methyl-4-(6-

(trifluoromethyl) pyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T369
N-(4-(5-chloropyridin-3-yl)-5-fluoro-2-

methoxyphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T370
N-(4-(5-chloropyridin-3-yl)-3-

(trifluoromethyl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T371
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-3-

methylphenyl)-2-methylpropanamide

[Image Omitted]

T372
N-(4-(5-chloropyridin-3-yl)-3-

ethoxyphenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T373
N-(4-(5-chloropyridin-3-yl)phenyl)-1-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)cyclopropane-1-carboxamide

[Image Omitted]

T374
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-

(cyclopropanesulfonamido)-5-

methylthiazol-4-yl)-2-methylpropanamide

[Image Omitted]

T375
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(2-methoxypropan-2-

yl)pyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T376
2-(5-chloro-2-

(cyclopropanesulfonamido)thiazol-4-yl)-

N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T377
2-(2-(cyclopropanesulfonamido)-5-

methoxythiazol-4-yl)-N-(4-(6-

ethoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T378
N-(4-(6-(cyclopentylmethoxy)pyrazin-2-

yl)phenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-

2-methylpropanamide

[Image Omitted]

T379
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-hydroxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T380
2-(2-(ethylsulfonamido)thiazol-4-yl)-2-

methyl-N-(5′-(trifluoromethyl)-[3,3′-

bipyridin]-6-yl)propanamide

[Image Omitted]

T381
2-(2-(ethylsulfonamido)thiazol-4-yl)-2-

methyl-N-(5-(6-(trifluoromethyl)pyrazin-2-

yl)pyridin-2-yl)propanamide

[Image Omitted]

T382
N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-

(2-(ethylsulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T383
2-(2-(ethylsulfonamido)thiazol-4-yl)-N-(2-

fluoro-4-(6-isopropoxypyrazin-2-

yl)phenyl)-2-methylpropanamide

[Image Omitted]

T384
N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-

(ethylsulfonamido)thiazol-4-yl)-2-

methylpropanamide

[Image Omitted]

T385
2-(2-(ethylsulfonamido)thiazol-4-yl)-N-(4-

(5-fluoropyridin-3-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T386
2-(2-(ethylsulfonamido)thiazol-4-yl)-2-

methyl-N-(4-(pyridin-3-

yl)phenyl)propanamide

[Image Omitted]

T387
2-(2-(ethylsulfonamido)thiazol-4-yl)-2-

methyl-N-(4-(6-(trifluoromethyppyrazin-2-

yl)phenyl)propanamide

[Image Omitted]

T388
2-(2-(ethylsulfonamido)thiazol-4-yl)-N-(4-

(6-isopropoxypyrazin-2-yl)phenyl)-2-

methylpropanamide

[Image Omitted]

T389
2-methyl-2-(2-

(methylsulfonamido)thiazol-4-yl)-N-(5′-

(trifluoromethyl)-[3,3′-bipyridin]-6-

yl)propanamide

[Image Omitted]

T390
N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-y0-2-

methyl-2-(2-(methylsulfonamido)thiazol-

4-yl)propanamide

[Image Omitted]

T391
N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-

2-yl)phenyl)-2-methyl-2-(2-

(methylsulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T392
N-(2-fluoro-4-(6-isopropoxypyrazin-2-

yl)phenyl)-2-methyl-2-(2-

(methylsulfonamido)thiazol-4-

yl)propanamide

[Image Omitted]

T393
N-(4-(5-chloropyridin-3-yl)phenyl)-2-

methyl-2-(2-(methylsulfonamido)thiazol-

4-yl)propanamide

[Image Omitted]

T394
2-methyl-2-(2-

(methylsulfonamido)thiazol-4-yl)-N-(4-(6-

(trifluoromethyl)pyrazin-2-yl)phenyl)

propanamide

[Image Omitted]

T395
N-(4-(6-isopropoxypyrazin-2-yl)phenyl)-2-

methyl-2-(2-(methylsulfonamido)thiazol-

4-yl)propanamide

[Image Omitted]

T396
2-(2-

((cyclopropylmethyl)sulfonamido)thiazol-

4-yl)-2-methyl-N-(5-(6-

(trifluoromethyl)pyrazin-2-yl)pyridin-2-

yl)propanamide

[Image Omitted]

T397
1-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(trifluoromethyl)pyrazin-2-

yl)phenyl)cyclopropane-1-carboxamide

[Image Omitted]

T398
1-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-

yl)phenyl)cyclopropane-1-carboxamide

[Image Omitted]

T399
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-

(trifluoromethyppyrazin-2-yl)phenyl)-4-

methylpropanamide

[Image Omitted]

T400
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-isopropoxypyrazin-2-

yl)phenyl)-4-methoxybutanamide

[Image Omitted]

T401
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridin-

2-yl)butanamide

[Image Omitted]

T402
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(5-(6-(2-methoxypropan-2-

yl)pyrazin-2-yl)pyridin-2-yl)butanamide

[Image Omitted]

T403
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-(2-methoxypropan-2-

yl)pyrazin-2-yl)phenyl)butanamide

[Image Omitted]

T404
N-(4-(6-cyanopyrazin-2-yl)-2-

fluorophenyl)-2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)butanamide

[Image Omitted]

T405
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethylpyrazin-2-yl)-2-

fluorophenyl)butanamide

[Image Omitted]

T406
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-(2-methoxypropan-2-

yl)pyrazin-2-yl)phenyl)butanamide

[Image Omitted]

T407
tert-butyl (1-(2-

(cyclopropanesulfonamido)thiazol-4-yl)-2-

((4-(6-ethoxypyrazin-2-yl)phenyl)amino)-

2-oxoethyl)carbamate

[Image Omitted]

T408
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(6-

(trifluoromethyl)pyrazin-2-yl)phenyl)-2-

methoxyacetamide

[Image Omitted]

T409
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)-2-methoxyacetamide

[Image Omitted]

T410
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-

methoxyacetamide

[Image Omitted]

T411
2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-isopropoxypyrazin-2-

yl)phenyl)-2-methoxyacetamide

[Image Omitted]

T412
Single enantiomer - stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)butanamide

[Image Omitted]

T413
Single enantiomer - stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-

4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-

fluorophenyl)butanamide

[Image Omitted]

T414
Single enantiomer - stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-

4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-

yl)pyridin-2-yl)butanamide

[Image Omitted]

T415
Single enantiomer - stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-

(trifluoromethyl)pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

T416
Single enantiomer - stereochemistry

unassigned

2-(2-(cyclopropanesulfonamido)thiazol-4-

yl)-N-(2-fluoro-4-(5-

(trifluoromethyl)pyridin-3-

yl)phenyl)butanamide

[Image Omitted]

2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-(ethylamino)pyrazin-2-yl)phenyl)butanamide T444

[Image Omitted]

2-Amino-2-(2-(cyclopropanesulfonamido)thiazolyl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)acetamide hydrochloride T417

[Image Omitted]

2-Amino-2-(2-(cyclopropanesulfonamido)thiazol-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)acetamide hydrochloride T419

[Image Omitted]

2-Amino-2-(2-(cyclopropanesulifonamido)thiazol-4-yl)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide T418

[Image Omitted]

2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(2-fluoro-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide T420

[Image Omitted]

2-(2-(Cyclopropanesulfonamido)thiazol-4-yl)-2-(dimethylamino)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)acetamide T421

[Image Omitted]

N-(4-(1-((2-fluoro-4-(pyridin-3-yl)phenyl)amino)-2-methylpropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide T466

[Image Omitted]

LiAlH₄(0.870 mL, 1.74 mmol) was added into a solution of 2-(2-(cydopropanesulfonamido)thiazol-4-yl)-N-(2-fluoro-4-(pyridin-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. NH₄Cl (aq, 50 mL) and extracted with EtOAc (3×50 mL). The organic extract was dried (MgSO₄), 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⁺). ¹H NMR (500 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.47-8.43 (m, 1H), 8.00-7.95 (m, 1H), 7.46 (dd, J=13.4, 2.2 Hz, 1H), 7.39 (dd, J=8.0, 4.7 Hz, 1H), 7.35-7.31 (m, 1H), 6.92 (t, J=8.9 Hz, 1H), 6.40 (s, 1H), 5.50 (t, J=4.4 Hz, 1H), 3.36-3.28 (m, 2H (obscured by water peak)), 2.56-2.51 (m, 1H, (obscured by DMSO peak)), 1.27 (s, 6H), 0.90-0.79 (m, 4H).

Compounds of Formula (I-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 WO2019/106146 and uses the general methods disclosed below.

Method A: Reductive Amination

[Image Omitted]

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 NH₃in MeOH. The crude product was then concentrated onto silica and purified by normal phase chromatography.

Method B: Benzylamine Deprotection (TFA)

[Image Omitted]

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% NH₃in MeOH.

Method D: Ester Deprotection with TFA

[Image Omitted]

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

[Image Omitted]

A solution of the ester (1 eq) in a mixture of THF/MeOH (4/1 volumes) was treated with LiOH (2.2-6 eq.) and stirred between RT and 50° C. for between 3 hrs and 18 hrs. The organic solvents were removed in vacuo then acidified with 1 M HCl and extracted with EtOAc. The organic phases were combined, dried (Na₂SO₄), filtered and concentrated. The products were used directly in the next step with no further purification undertaken.

Method F: Potassium Salt Formation

[Image Omitted]

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 (I-c)—Examples

The synthesis of a number of known CTPS1 inhibitors is disclosed in VNO2019/106146 (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 WO2019/106146, which is herein incorporated in its entirety by reference.

Method 1: Amide Coupling

[Image Omitted]

Method 1a: 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 1b: 1-chloro-N,N,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 (50 wt % 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)₂Core]

[Image Omitted]

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 K₂CO₃(3 eq.) in dioxane (10 volumes) and water (1 volumes). The solution was then degassed further (N₂, 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

[Image Omitted]

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(eq, 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 1a

N-((2-(cyclopropanesulfonamido)thiazol-4-yl)methyl)-4-(pyridin-3-yl)benzamide R1

[Image Omitted]

Representative for Method 1b

N-(1-(2-(cydopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide R2

[Image Omitted]

The racemic mixture R2 was separated by chiral preparative HPLC using chiral method A. A salt exchange (TFA to HCl) was undertaken by adding 1.25 M HCl (EtOH, 2 mL×5) and removing solvent to afford:

Peak 1: Stereochemistry of Product was not Defined R3

N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide. HCl R3.

Peak 2: Stereochemistry of Product was not Defined R4

N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide. HCl R4.

Representative for Method 1c

N-(1-(2-(cyclopropanesulfonamido)thiazol-4-yl)propyl)-4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide R5

[Image Omitted]

Representative for Method 2a

N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide R6

[Image Omitted]

Representative for Method 2b

N-(2-(2-(cyclopropanesulfonamido)thiazol-4-yl)propan-2-yl)-4-(6-ethoxypyrazin-2-yl)-2-methoxybenzamide R7

[Image Omitted]

TABLE 8

Compounds R8 to R93

Name/Structure

(All examples containing chiral

R
centres are racemic unless stated)

R8
N-((2-(cyclopropanesulfon-

amido)thiazol-4-yl)methyl)-5-

phenylpicolinamide

[Image Omitted]

R9
N-((2-(cyclopropanesulfon-

amido)thiazol-4-ypmethyl)-[1,1′-

biphenyl]-4-carboxamide

[Image Omitted]

R10
N-((2-(cyclopropanesulfon-

amido)thiazol-4-yl)methyl)-2-fluoro-4-

(6-(trifluoromethyl)-pyrazin-2-

yl)benzamide

[Image Omitted]

R11
N-((2-(cyclopropanesulfon-

amido)thiazol-4-yl)methyl)-4-(6-

ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

R12
N-((2-(cyclopropanesulfon-

amido)thiazol-4-yl)methyl)-4-(6-

(trifluoromethyl)pyrazin-2-

yl)benzamide

[Image Omitted]

R13
N-((2-(cyclopropanesulfon-

amido)thiazol-4-yl)methyl)-4-(6-

isopropoxypyrazin-2-yl)benzamide

[Image Omitted]

R14
N-((2-(cyclopropanesulfon-

amido)thiazol-4-yl)methyl)-4-(6-

ethoxypyrazin-2-yl)benzamide

[Image Omitted]

R15
N-(3-(2-(cyclopropanesulfon-

amido)thiazol-4-yppentan-3-yl)-4-(5-

(trifluoromethyl) pyridin-3-

yl)benzamide

[Image Omitted]

R16
N-(3-(2-(cyclopropanesulfon-

amido)thiazol-4-yppentan-3-yl)-4-(5-

fluoropyridin-3-yl)benzamide

[Image Omitted]

R17
N-(3-(2-(cyclopropanesulfon-

amido)thiazol-4-yppentan-3-yl)-4-(5-

methylpyridin-3-yl)benzamide

[Image Omitted]

R18
N-(3-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)pentan-3-yl)-4-

(pyridin-3-yl)benzamide

[Image Omitted]

R19
N-(3-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)pentan-3-yl)-4-(6-

(trifluoromethyl) pyrazin-2-

yl)benzamide

[Image Omitted]

R20
4-(6-chloropyrazin-2-yl)-N-(3-(2-

(cyclopropanesulfonamido)

thiazol-4-yl)pentan-3-yl)benzamide

[Image Omitted]

R21
N-(3-(2-(cyclopropanesulfon-

amido)thiazol-4-yppentan-3-yl)-4-(6-

methylpyrazin-2-yl)benzamide

[Image Omitted]

R22
N-(3-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)pentan-3-yl)-4-

(pyrazin-2-yl)benzamide

[Image Omitted]

R23
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-5-(6-

ethoxypyrazin-2-yl)-3-

fluoropicolinamide

[Image Omitted]

R24
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-y0propan-2-yl)-5-(6-

(trifluoromethyl)pyrazin-2-

yl)picolinamide

[Image Omitted]

R25
5-(6-chloropyrazin-2-yl)-N-(2-(2-

(cyclopropanesulfonamido)

thiazol-4-yl)propan-2-yl)picolinamide

[Image Omitted]

R26
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-5-(6-

ethoxypyrazin-2-yl)picolinamide

[Image Omitted]

R27
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-[2,2′-

bipyridine]-5-carboxamide

[Image Omitted]

R28
4-(5-chloropyridin-3-yl)-N-(2-(2-

(cyclopropanesulfon-amido)thiazol-4-

yl)propan-2-yl)benzamide

[Image Omitted]

R29
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-2-

fluoro-4-(5-(trifluoromethyl)pyridin-3-

yl)benzamide

[Image Omitted]

R30
4-(5-chloropyridin-3-yl)-N-(2-(2-

(cyclopropanesulfon-amido)thiazol-4-

yl)propan-2-yl)-2-fluorobenzamide

[Image Omitted]

R31
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-2-

fluoro-4-(5-fluoropyridin-3-

yl)benzamide

[Image Omitted]

R32
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-2-

methoxy-4-(5-(trifluoromethyl)pyridin-

3-yl)benzamide

[Image Omitted]

R33
N-(2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propan-2-yl)-4-(2-methylpyridin-3-

yl)benzamide

[Image Omitted]

R34
4-(5-acetylpyridin-3-yl)-N-(2-(2-

(cyclopropanesulfon-amido)thiazol-4-

yl)propan-2-yl)benzamide

[Image Omitted]

R35
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-(5-

(trifluoromethyl)pyridin-3-

yl)benzamide

[Image Omitted]

R36
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yppropan-2-yl)-4-(5-

fluoropyridin-3-yl)benzamide

[Image Omitted]

R37
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-(5-

methylpyridin-3-yl)benzamide

[Image Omitted]

R38
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yppropan-2-yl)-4-(5-

methoxypyridin-3-yl)benzamide

[Image Omitted]

R39
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-

(pyridin-3-yl)benzamide

[Image Omitted]

R40
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-3′-

(trifluoromethyl)-[1,1′-biphenyl]-4-

carboxamide

[Image Omitted]

R41
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-(6-

ethylpyrazin-2-yl)-2-fluorobenzamide

[Image Omitted]

R42
N-(2-(2-(cyclopropane

sulfonamido)thiazol-4-yl)propan-2-yl)-

2-fluoro-4-(6-(trifluoromethyl)pyrazin-

2-yl)benzamide

[Image Omitted]

R43
N-(2-(2-(cyclopropane

sulfonamido)thiazol-4-yl)propan-2-yl)-

2-fluoro-4-(6-isopropoxypyrazin-2-

yl)benzamide

[Image Omitted]

R44
N-(2-(2-(cyclopropanesulfon

amido)thiazol-4-yl)propan-2-yl)-2-

fluoro-4-(6-(2,2,2-

trifluoroethoxy)pyrazin-2-

yl)benzamide

[Image Omitted]

R45
N-(2-(2-(cyclopropane

sulfonamido)thiazol-4-yl)propan-2-yl)-

2-methyl-4-(6-

(trifluoromethyl)pyrazin-2-

yl)benzamide

[Image Omitted]

R46
N-(2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propan-2-yl)-4-(6-ethoxypyrazin-2-

yl)-2-methyl benzamide

[Image Omitted]

R47
N-(2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propan-2-yl)-4-(6-ethoxypyrazin-2-

yl)-2-(trifluoromethyl)benzamide

[Image Omitted]

R48
N-(2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propan-2-yl)-2-methoxy-4-(6-

(trifluoromethyl)pyrazin-2-

yl)benzamide

[Image Omitted]

R49
4-(6-chloropyrazin-2-yl)-N-(2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propan-2-yl)-2-methoxybenzamide

[Image Omitted]

R50
4-(6-cyanopyrazin-2-yl)-N-(2-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propan-2-yl)-2-methoxybenzamide

[Image Omitted]

R51
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-(6-

(trifluoromethyl) pyrazin-2-yl)benzamide

[Image Omitted]

R52
4-(6-chloropyrazin-2-yl)-N-(2-(2-

(cyclopropanesulfon-amido)thiazol-4-

yl)propan-2-yl)benzamide

[Image Omitted]

R53
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-(6-

methylpyrazin-2-yl)benzamide

[Image Omitted]

R54
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-(6-

methoxypyrazin-2-yl)benzamide

[Image Omitted]

R55
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-(6-

ethoxypyrazin-2-yl)benzamide

[Image Omitted]

R56
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-(6-

isopropoxypyrazin-2-yl)benzamide

[Image Omitted]

R57
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-(6-

(2,2,2-trifluoroethoxy)pyrazin-2-

yl)benzamide

[Image Omitted]

R58
N-(2-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)propan-2-yl)-4-

(pyrazin-2-yl)benzamide

[Image Omitted]

R59
RACEMIC, N-(1-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propyl)-4-(5-fluoropyridin-3-

yl)benzamide

[Image Omitted]

R60
RACEMIC, N-(1-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propyl)-4-(5-methylpyridin-3-

yl)benzamide

[Image Omitted]

R61
RACEMIC, N-(1-(2-

(cyclopropanesulfonamido)thiazol-4-

Apropyl)-4-(pyridin-3-yl)benzamide

[Image Omitted]

R62
RACEMIC, N-(1-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

R63
RACEMIC, N-(1-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-

fluoro-N-methylbenzamide

[Image Omitted]

R64
RACEMIC, N-(1-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propyl)-2-fluoro-4-(6-

isopropoxypyrazin-2-yl)benzamide

[Image Omitted]

R65
RACEMIC, 4-(6-chloropyrazin-2-yl)-N-

(1-(2-(cyclopropanesulfonamido)thiazol-

4-yl)propyl)benzamide

[Image Omitted]

R66
RACEMIC, N-(1-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propyl)-4-(6-methylpyrazin-2-

yl)benzamide

[Image Omitted]

R67
RACEMIC, N-(1-(2-

(cyclopropanesulfonamido)thiazol-4-

yl)propyl)-4-(pyrazin-2-yl)benzamide

[Image Omitted]

R68
SINGLE ENANTIOMER -

stereochemistry unassigned, N-(1-(2-

(cyclopropanesulfon-amido)thiazol-4-

yl)propyl)-4-(5-fluoropyridin-3-

yl)benzamide

[Image Omitted]

R69
SINGLE ENANTIOMER -

stereochemistry unassigned, N-(1-(2-

(cyclopropanesulfon-amido)thiazol-4-

yl)propyl)-4-(5-fluoropyridin-3-

yl)benzamide

[Image Omitted]

R70
SINGLE ENANTIOMER -

stereochemistry unassigned, N-(1-(2-

(cyclopropanesulfon-amido)thiazol-4-

yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

R71
SINGLE ENANTIOMER -

stereochemistry unassigned, N-(1-(2-

(cyclopropanesulfon-amido)thiazol-4-

yl)propyl)-4-(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

R72
N-(2-(2-(cyclopropanesulfon-amido)-5-

methylthiazol-4-yl)propan-2-yl)-5-(6-

ethoxypyrazin-2-yl)picolinamide

[Image Omitted]

R73
N-(2-(5-chloro-2-(cycloprop-

anesulfonamido)thiazol-4-Apropan-2-

yl)-5-(6-ethoxypyrazin-2-yl)picolinamide

[Image Omitted]

R74
N-(2-(2-(cyclopropanesulfon-amido)-5-

methylthiazol-4-yl)propan-2-yl)-4-(6-

ethoxypyrazin-2-yl)-2-fluorobenzamide

[Image Omitted]

R75
N-(2-(5-chloro-2-(cycloprop-

anesulfonamido)thiazol-4-yl)propan-2-

yl)-4-(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

R76
N-(2-(2-(cyclopropanesulfon-amido)-5-

methylthiazol-4-yl)propan-2-yl)-2-

methyl-4-(6-(trifluoromethyl)pyrazin-2-

yl)benzamide

[Image Omitted]

R77
N-(2-(5-chloro-2-(cycloprop-

anesulfonamido)thiazol-4-Apropan-2-

yl)-2-methyl-4-(6-

(trifluoromethyl)pyrazin-2-yl)benzamide

[Image Omitted]

R78
N-(2-(2-(cyclopropanesulfon-amido)-5-

methylthiazol-4-yl)propan-2-yl)-4-(6-

(trifluoromethyl)pyrazin-2-yl)benzamide

[Image Omitted]

R79
N-(2-(5-chloro-2-(cycloprop-

anesulfonamido)thiazol-4-yl)propan-2-

yl)-4-(6-(trifluoromethyl)pyrazin-2-

yl)benzamide

[Image Omitted]

R80
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)cyclo-propyl)-5-(6-

ethoxypyrazin-2-yl)picolinamide

[Image Omitted]

R81
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)cyclo-propyl)-4-

(pyridin-3-yl)benzamide

[Image Omitted]

R82
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)cyclo-propyl)-4-(6-

ethoxypyrazin-2-yl)-2-fluorobenzamide

[Image Omitted]

R83
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)cyclopropyl)-2-

methyl-4-(6-(trifluoromethyl)pyrazin-2-

yl)benzamide

[Image Omitted]

R84
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)cyclopropyl)-4-(6-

(trifluoromethyl)pyrazin-2-yl)benzamide

[Image Omitted]

R85
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)-3-methoxypropyl)-4-

(5-fluoropyridin-3-yl)benzamide

[Image Omitted]

R86
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)-3-methoxypropyl)-4-

(6-ethyl-pyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

R87
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)-3-methoxypropyl)-2-

fluoro-4-(6-(trifluoromethyl)pyrazin-2-

yl)benzamide

[Image Omitted]

R88
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)-3-methoxypropyl)-4-

(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

R89
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)-3-methoxypropyl)-2-

fluoro-4-(6-isopropoxypyrazin-2-

yl)benzamide

[Image Omitted]

R90
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)-3-methoxypropyl)-4-

(6-ethoxy-pyrazin-2-yl)benzamide

[Image Omitted]

R91
N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)ethyl)-4-(6-

ethoxypyrazin-2-yl)-2-fluorobenzamide

[Image Omitted]

R92
SINGLE ENANTIOMER -

stereochemistry unassigned

N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)-3-methoxypropyl)-4-

(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

R93
SINGLE ENANTIOMER -

stereochemistry unassigned

N-(1-(2-(cyclopropanesulfon-

amido)thiazol-4-yl)-3-methoxypropyl)-4-

(6-ethoxypyrazin-2-yl)-2-

fluorobenzamide

[Image Omitted]

N-(4-(2-((4-(6-Ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide R94

[Image Omitted]

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 tiacetoxyborohydride (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% NH₃in 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 N-(4-(2-((4-(6-ethoxypyrazin-2-yl)-2-fluorobenzyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide (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⁺). ¹H NMR (500 MHz, DMSO-d6) δ 8.86-8.81 (m, 1H), 8.28-8.18 (m, 1H), 7.96-7.93 (m, 1H), 7.91-7.82 (m, 1H), 7.67-7.50 (m, 1H), 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, 1H), 1.48-1.14 (m, 9H), 0.91-0.59 (m, 4H).

N-(4-(2-(((5-(6-Ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)propan-2-yl)thiazol-2-yl)cyclopropanesulfonamide R95

[Image Omitted]

Prepared as for R94 using 5-(6-ethoxypyrazin-2-yl)picolinaldehyde (70 mg, 0.305 mmol) INTF55 and N-(4-(2-aminopropan-2-yl)thiazol-2-yl)cyclopropanesulfonamide INTE14 (80 mg, 0.305 mmol) to afford N-(4-(2-(((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methyl)amino)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⁺). ¹H NMR (500 MHz, DMSO-d6) δ 9.21 (d, J=2.3 Hz, 1H), 8.88 (s, 1H), 8.44 (dd, J=8.2, 2.4 Hz, 1H), 8.30 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 6.50 (s, 1H), 4.49 (q, J=7.0 Hz, 2H), 3.68 (s, 2H), 2.59-2.53 (m, 1H), 1.45-1.37 (m, 9H), 0.92-0.82 (m, 4H), 2×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 1× assay buffer containing 50 mM Tris, 10 mM MgCl₂, 0.01% Tween-20, pH to 8.0 accordingly. Finally, immediately before use, L-cysteine was added to the 1× assay buffer to a final concentration of 2 mM. All reagents are from Sigma-Aldrich unless specified otherwise. Human full length active C-terminal FLAG-His₈-tag CTPS1 (UniProtKB—P17812, CTPS1[1-591]-GGDYKDDDDKGGHHHHHHHH (CTPS1[1-591]—SEQ ID NO: 1)) was obtained from Proteros biostructures GmbH.

Assay Procedure

3× human CTPS1 protein was prepared in 1× assay buffer to the final working protein concentration required for the reaction. A 2 uL volume per well of 3× human CTPS1 protein was mixed with 2 uL per well of 3× test compound (compound prepared in 1× assay buffer to an appropriate final 3× 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 2 uL per well volume of a pre-mixed substrate mix (UltraPure ATP from ADP-Glo™ Max kit (0.31 mM), GTP (0.034 mM), UTP (0.48 mM) and L-glutamine (0.186 mM)) 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 (6 μL per well) and subsequently ADP-Glo™ Max development reagent was added for 60 minutes (12 uL 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 500 rpm.

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:

%
⁢

Inhibition

=

1
-

(

Mean
Min

-

Mean
Inh

)

(

Mean
Min

-

Mean
Max

)

×
100

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 IC₅₀in the range of >10 to 20 micromolar, + indicates IC₅₀

in the range >1 to 10 micromolar, ++ indicates IC₅₀in the

range >0.1 to 1 micromolar, +++ indicates IC₅₀of ≤0.1 micromolar)

P
CTPS1

P1
++

P2
+++

P3
+++

P4
++

P5
+

P6
++

P7
++

P8
+++

P9
+++

P10
+++

P11
+++

P12
+++

P13
++

P14
++

P15
+

P16
++

P17
+

P18
+++

P19
+++

P20
+++

P21
+++

P22
++

P23
++

P24
++

P25
++

P26
++

P27
+++

P28
++

P29
+

P30
+++

P31
+++

P32
+++

P33
+++

P34
+++

P35
++

P36
+

P37
+++

P38
+++

P39
+++

P40
++

P41
+++

P42
+

P43
++

P44
++

P45
++

P46
++

P47
+++

P48
++

P49
+++

P50
+

P51
++

P52
++

P53
++

P54
++

P55
+++

P56
++

P57
++

P58
++

P59
+

P60
+

P61
+

P62
+

P63
±

P64
+++

P65
+++

P66
++

P67
+++

P68
++

P69
++

P70
+

P71
+

P72
++

P73
++

P74
++

P75
++

P76
++

P77
+

P78
++

P79
++

P80
++

P81
+++

P82
+

P83
+++

P84
++

P85
++

P86
+

P87
+++

P88
+++

P89
+++

P90
++

P91
++

P92
++

P93
+

P94
+++

P95
+++

P96
+++

P97
+++

P98
+++

P99
++

P100
++

P101
++

P102
++

P103
++

P104
++

P105
+++

P106
+++

P107
+++

P108
+++

P109
++

P110
+++

P111
++

P112
+++

P113
+++

P114
+++

P115
+++

P116
++

P117
+++

P118
+++

P122
++

P123
++

P124
++

P125
++

P126
+++

P128
++

P129
++

P130
++

P131
++

P132
++

P133
+

P134
++

P135
++

P136
+++

P137
+++

P138
++

P139
++

n = 4

+++

n = 6

P140
++

P141
++

P142
++

P143
+++

P144
+++

P145
+++

P146
+++

P147
++

P148
+++

P149
+++

P150
+++

P151
+++

P152
+++

P153
+++

P154
+++

P155
+++

P156
+++

P157
+++

P158
++

P159
+++

P160
+++

P161
+++

P162
+++

P163
+++

P164
+++

P165
+++

P166
+++

P167
++

P168
++

P169
++

P170
++

P171
+

P172
++

P173
+++

P174
+

P175
+

P176
+

P177
+

P178
+

P179
+

P180
+

P181
+

P182
++

P183
++

P184
++

P185
+

P186
+++

P187
++

P188
+++

P189
+

P190
++

P191
++

P192
+

P193
+

P194
58.6 uM

P195
+++

P196
+++

P197
+++

P198
+++

P199
++

P200
+++

P201
+++

P202
+++

P203
+++

P204
+++

P205
+++

P206
+++

P207
+++

P208
+++

P209
++

P210
++

P211
++

P212
++

P213
++

P214
++

P215
++

P216
+++

P217
++

P218
+++

P219
++

P220
++

P221
++

P222
++

P223
++

P224
++

P225
+++

TABLE 10

Human CTPS1 Enzyme Inhibition data grouped by potency range (±

indicates IC₅₀in the range of >10 to 20 micromolar, + indicates IC₅₀

in the range >1 to 10 micromolar, ++ indicates IC₅₀in the

range >0.1 to 1 micromolar, +++ indicates IC₅₀of ≤0.1 micromolar)

T #
CTPS1

T1
+

T2
++

T3
++

T4
+

T5
+++

T6
++

T7
+++

T8
+++

T9
+++

T10
+++

T11
++

T12
++

T13
++

T14
++

T15
++

T16
++

T17
++

T18
+++

T19
++

T20
++

T21
+

T22
+++

T23
++

T24
++

T25
+

T26
++

T27
++

T28
++

T29
+++

T30
+++

T31
+

T32
+++

T33
+++

T34
++

T35
+++

T36
++

T37
++

T38
+++

T39
++

T40
+++

T41
++

T42
+++

T43
++

T44
++

T45
++

T46
+

T47
+++

T48
+++

T49
++

T50
+++

T51
+++

T52
+++

T53
+

T54
++

T55
+++

T56
+++

T57
+++

T58
+++

T59
+++

T60
++

T61
+++

T62
++

T63
++

T64
++

T65
++

T66
++

T67
++

T68
++

T69
+

T70
++

T71
+++

T72
+++

T73
+++

T74
++

T75
+++

T76
+++

T77
+++

T78
+++

T79
++

T80
+++

T81
+++

T82
+++

T83
+

T84
++

T85
++

T86
+

T87
++

T88
++

T89
+++

T90
+++

T91
+++

T92
+++

T93
+++

T94
+++

T95
+++

T96
+++

T97
++

T98
++

T99
+++

T100
++

T101
+

T102
+++

T103
++

T104
++

T105
+

T106
+++

T107
+++

T108
+++

T109
+++

T110
++

T111
+++

T112
+++

T113
+

T114
++

T115
+++

T116
++

T117
++

T118
+++

T119
+++

T120
+++

T121
+++

T122
+++

T123
+++

T124
+++

T125
+++

T126
+++

T127
+++

T128
+++

T129
+++

T130
+++

T131
+++

T132
++

T133
+++

T134
+++

T135
++

T136
+++

T137
+++

T138
+++

T139
+++

T140
++

T141
++

T142
+++

T143
+++

T144
++

T145
+++

T146
++

T147
+++

T148
++

T149
+++

T150
++

T151
++

T152
++

T153
++

T154
++

T155
+++

T156
+++

T157
+++

T158
+++

T159
+++

T160
+++

T161
++

(n = 2)

+

(n = 6)

T163
++

T164
+

T169
++

T170
++

T171
+++

T172
+++

T173
+++

T174
+++

T175
+++

T176
+++

T177
+++

T178
+

T179
+++

T180
+++

T181
++

T182
+++

T183
+++

T184
+

T185
+++

(n = 1)

++

(n = 2)

T186
+++

T187
+++

T188
++

T189
+++

T190
+++

T191
+++

T192
+++

T193
+++

T194
+++

T195
+++

T196
+++

T197
+++

T198
+++

T199
+++

T200
+++

T201
+++

T202
+++

T203
+++

T204
+++

T205
+++

T206
+++

T207
+++

T208
+++

T209
+++

T210
+++

T211
+++

(n = 1)

++

(n = 2)

T212
+++

T213
++

T214
+++

T215
+++

T216
++

T217
+++

T218
++

T219
+++

T220
+++

T221
+++

T222
++

T223
+++

T224
+++

T225
+++

T226
+++

T227
++

T228
+++

T229
+++

T230
+++

T231
+

T232
++

T233
+

T234
+

T235
++

T236
++

T237
+

T238
+

T239
++

T240
++

T241
++

T242
+

T243
+

T244
++

T245
+

T246
++

T247
++

T248
+

T249
+++

T250
+

T251
+

T252
+++

T253
+++

T254
++

T255
+

T256
+++

T257
++

T258
++

T259
+++

T260
+

T261
+++

T262
+++

T263
+

T264
++

T265
+++

T266
+++

T267
+++

T268
++

T269
++

T270
++

T271
+

T272
+++

T273
+++

T274
+++

T275
+++

T276
++

T277
++

T278
+++

T279
+

T280
+

T281
++

T282
++

T283
++

T284
+

T285
+++

T286
+++

T287
+++

T288
++

T289
++

T290
+++

T291
+++

T292
++

T293
++

T294
++

T295
++

T296
++

T297
+

T298
+++

T299
++

T300
++

T301
+++

T302
++

T303
+

T304
++

T305
++

T306
++

T307
+++

T308
++

T309
+

T310
+

T311
+

T312
++

T313
++

T314
++

T315
++

T316
++

T317
++

T318
+

T319
+

T320
++

T321
+++

T322
++

T325
+++

T326
+++

T327
+++

T328
+++

T329
+++

T330
+++

T331
+++

T332
++

T333
+

T334
++

T335
++

T336
++

T337
+++

T338
+

T339
+

T340
++

T341
+++

T342
+++

T343
+++

T344
+++

T345
+++

T346
++

T347
+++

T348
++

T349
++

T350
++

T351
++

(n = 1)

+++

(n = 2)

T352
++

T353
++

T354
++

T355
+

T356
+++

T357
+++

T358
+++

T359
+++

T360
++

T361
++

T362
+++

T363
+++

T364
++

T365
+++

T366
++

T367
+++

T368
+++

T369
++

T370
+

T371
+++

T372
++

T373
+++

T374
+

T375
++

T376
++

T377
++

T378
+

T379
+

T380
+++

T381
+++

T382
+++

T383
+++

T384
++

T385
+++

T386
++

T387
+++

T388
+++

T389
++

T390
+++

T391
+++

T392
+++

T393
++

T394
+++

T395
+++

T396
++

T397
++

T398
+++

T399
+++

T400
+++

T401
++

T402
+

T403
++

T404
++

T405
+++

T406
++

T407
+++

T408
+++

T409
+++

T410
+++

T411
+++

T412
+++

T413
+++

T414
+++

T415
++

T416
+++

T417
++

T418
++

T419
+++

T420
+++

T421
+++

T422
++

T423
+++

T424
+++

T425
+++

T426
++

T427
++

T428
++

T429
+++

T430
++

T431
+++

T432
++

T433
+++

T434
+++

T435
+++

T436
+++

T437
+++

T438
+++

T439
+++

T440
+++

T441
+++

T442
+++

T443
+++

T444
+++

T445
+++

T446
+++

T447
+++

T448
+++

T449
+++

T450
+++

T451
+++

T452
+++

T453
+++

T454
+++

T455
+++

T456
+++

T457
+++

T458
+++

T459
+++

T463
++

T464
+++

T465
+

TABLE 11

Human CTPS1 Enzyme Inhibition data grouped by potency range (±

indicates IC₅₀in the range of >10 to 21 micromolar, + indicates IC₅₀

in the range >1 to 10 micromolar, ++ indicates IC₅₀in the

range >0.1 to 1 micromolar, +++ indicates IC₅₀of ≤0.1 micromolar)

R
CTPS1

R1
++

R2
++

R3
++

R4
+++

R5
+++

R6
+++

R7
++

R8
+

R9
+

R10
+++

R11
+++

R12
+++

R13
+++

R14
+++

R15
+++

R16
++

R17
++

R18
++

R19
+++

R20
+++

R21
+++

R22
++

R23
++

R24
++

R25
++

R26
++

R27
±

R28
+++

R29
+++

R30
++

R31
++

R32
++

R33
+

R34
+

R35
+++

R36
++

R37
+++

R38
++

R39
++

R40
++

R41
++

R42
+++

R43
+++

R44
++

R45
++

R46
++

R47
++

R48
++

R49
++

R50
+

R51
+++

R52
+++

R53
++

R54
+++

R55
+++

R56
+++

R57
++

R58
++

R59
++

R60
++

R61
++

R62
++

R63
++

R64
++

R65
+++

R66
++

R67
++

R68
+

R69
+++

R70
++

R71
+++

R72
+

R73
+

R74
++

R75
++

R76
++

R77
+

R78
++

R79
++

R80
+++

R81
++

R82
+++

R83
+++

R84
+++

R85
++

R86
++

R87
++

R88
++

R89
+++

R90
+++

R91
+++

R92
+++

R93
+++

All compounds disclosed in Tables 9 to 11 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 (I-a), (I-b) and (I-c) tested wherein R₁is R_1a; and/or R₄and R₅are R_4aand R_5a; and/or A is A_aare presented below.

TABLE 12

Human CTPS1 Enzyme Inhibition data grouped by potency range (±

indicates IC₅₀in the range of >10 to 20 micromolar, + indicates IC₅₀

in the range >1 to 10 micromolar, ++ indicates IC₅₀in the

range >0.1 to 1 micromolar, +++ indicates IC₅₀of ≤0.1 micromolar)

P
CTPS1

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
+++

P318
+++

TABLE 13

Human CTPS1 Enzyme Inhibition data grouped by potency range (+++

indicates IC₅₀of ≤0.1 micromolar)

R
CTPS1

T466
±

TABLE 14

Human CTPS1 Enzyme Inhibition data grouped by potency range (+++

indicates IC₅₀of ≤0.1 micromolar)

R
CTPS1

R94
+++

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 50 mM HEPES (Merck), 20 mM MgCl₂, 5 mM KCl, 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—Q9NRF8, CTPS2 [1-586]-DYKDDDDKHHHHHHGLNDIFEAQKIEWHE (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 1× assay buffer to the final working protein concentration required for the reaction. A 2 uL volume per well of 2×CTPS (1 or 2) protein may be mixed with 40 nL 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 2 uL per well of a 2× substrate mix in assay buffer. For hCTPS1: ATP (0.3 mM), UTP (0.2 mM), GTP (0.07 mM) and L-glutamine (0.1 mM). For hCTPS2: ATP (0.1 mM), UTP (0.04 mM), GTP (0.03 mM) 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 80 uL volume of stop solution (1% formic acid with 0.5 uM ¹³C₉-¹⁵N₃-CTP in H₂O) may be added and the plate immediately heat-sealed and centrifuged for 10 minutes at 4,000 rpm. 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 ¹³C₉-¹⁵N₃-CTP. Readout for data analysis may be calculated as the ratio between the peak area of the product CTP and the internal standard ¹³C₉-¹⁵N₃-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
=

R
neg

-

R

sample
⁢

%

[

R
neg

-

R
pos

]

(I=Inhibition, R_neq=median of negative control readout values, R_pos=median of positive control readout values, R_sample=sample readout value)

Percentage inhibition was then plotted against compound concentration, and the 50% inhibitory concentration (IC₅₀) was determined from the resultant concentration-response curve.

Fold selectivity between CTPS1 and CTPS2 was subsequently calculated according to the following equation:

Fold
⁢

selectivity

=

CTPS
⁢
2

❘

C
50

CTPS
⁢
1

❘

C
50

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 (+++)

P
Selectivity

P1
+

P2
+++

P9
+++

P12
++

P16
++

P18
++

P21
++

P31
+++

P34
+

P38
+

P39
+

P59
+

P65
++

P68
++

P70
+

P74
++

P76
++

P83
+++

P87
++

P88
+++

P89
+++

P95
+

P96
+

P98
+++

P103
+

P105
++

P108
+++

P110
++

P112
++

P113
+

P114
+++

P115
+++

P118
+++

P125
++

P128
+

P132
++

P136
+++

P143
+++

P145
+++

P146
+++

P151
+++

P155
+

P158
+

P159
+++

P161
+

P162
++

P163
+++

P164
+

P188
++

P191
++

P195
+++

P196
+++

P197
+++

P198
+++

P200
++

P201
+++

P202
+++

P205a
+++

P205b
++

P206
+++

P207
+

P216
+++

P221
+

P222
+

TABLE 16

Selectivity data split into grouping of 2-30 fold (+), >30-60

fold (++) or >60 fold (+++)

R
Selectivity

R5
+

R6
++

R7
++

R11
++

R19
++

R23
++

R25
++

R26
+++

R41
++

R42
++

R43
++

R45
++

R46
+

R47
+

R48
++

R51
++

R52
+++

R54
+

R55
+++

R56
+++

R62
+++

R63
+

R64
++

R68
++

R69
+++

R70
+++

R71
+++

R73
+

R74
++

R75
+++

R76
+

R78
++

R79
+

R80
+++

R82
+++

R83
+++

R84
+++

R86
+++

R87
++

R88
+++

R89
+++

R90
++

R91
+++

R92
+++

R93
+++

The data for all compounds of formula (I) tested wherein R₁is R_1a; and/or R₄and R₅are R_4aand R_5a; and/or A is A_aare presented in Table 17.

TABLE 17

Selectivity data split into grouping of 2-30 fold (+), >30-60

fold (++) or >60 fold (+++)

P
Selectivity

P226
+++

P227
+++

P228
+++

P229
+++

P230
+

P242
+++

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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):

[Image Omitted]

wherein ring B is selected from the group consisting of:

[Image Omitted]

- wherein X, Y and Z are as defined below; and

[Image Omitted]

- wherein R_3b3cis R_3bor R_3cas defined below;

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

[Image Omitted]

- wherein:
- A_ais A_aaor A_ba;
  - wherein:
  - A_aais an amine linker having the following structure: —NH—, —CH₂NH— or —NHCH₂—;
  - A_bais an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—;
- X is N or CH;
- Y is N or CR_2a;
- Z is N or CR_3a;
  - with the proviso that when at least one of X or Z is N, Y cannot be N;
- R_2ais H, halo, C_1-2alkyl, OC_1-2alkyl, C_1-2haloalkyl or OC_1-2haloalkyl; and
- R_3ais H, halo, CH₃, OCH₃, CF₃or OCF₃;
  - wherein at least one of R_2aand R_3ais H;
- R_1ais R_1aaor R_1ba;
  - wherein:
  - R_1aais NR_32aR_33a;
  - R_1bais C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃;
- R_4aand R_5aare R_4aaand R_5aa, or R_4baand R_5ba;
  - wherein:
  - R_4aaand R_5aatogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkykeneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21aR_22a; 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aaand R_5aatogether 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or R_4aaand R_5aatogether 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(O)₂R_29a; or
  - R_4baand R_5baare each independently H, C_1-6alkyl, C_1-6alkylOH, C_1-6haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl; and
  - when A_ais —NHC(═O)— or —NHCH₂—:
  - R_4baand R_5bamay additionally be selected from halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl and NR_21aR_22a;
- Ar1a is a 6-membered aryl or heteroaryl;
- Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A_a;
- R_10ais H, halo, C_1-3alkyl, C_1-2haloalkyl, OC_1-2alkyl, OC_1-2haloalkyl or CN;
- R_11ais H, F, Cl, C_1-2alkyl, CF₃, OCH₃or CN;
- R_12ais attached to Ar2 in the ortho or meta position relative to Ar1a and R_12ais H, halo, C_1-4alkyl, C_2-4alkenyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, C_1-4haloalkyl, OC_1-4haloalkyl, hydroxy, C_1-4alkylOH, SO₂C_1-2alkyl, C(O)N(C_1-2alkyl)₂, NHC(O)C_1-3alkyl or NR_23aR_24a; and
  - when A_ais —NHC(═O)—, —NH— or —NHCH₂—:
  - R_12amay additionally be selected from CN, OCH₂CH₂N(CH₃)₂and a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O—);
- R_13ais H or halo;
- R_21ais H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl, C_1-3alkylOC_1-2alkyl, C_1-4haloalkyl, or C_4-6heterocycloalkyl;
- R_22ais H or CH₃;
- R_23ais H or C_1-2alkyl; and
- R_24ais H or C_1-2alkyl
- R_29ais C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, CF₃, N(C_1-3alkyl)₂, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl;
- R_32ais C_1-3alkyl and R₃₃is C_1-3alkyl; or
- R_32aand R_33atogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl;
- wherein:
- R_1ais R_1aa; and/or
- R_4aand R_5aare R_4aaand R_5aa; and/or
- A_ais A_aa; and

wherein when B is (B-bc) and R_3a3cis R_3b, the compound of formula (I) is a compound of formula (I-b):

[Image Omitted]

- A_bis A_abor A_bb;
- wherein:
  - A_abis —NR_6bCH₂— or —NR_6b—;
  - A_bbis —NR_6bC(═O)—;
- R_1bis R_1abor R_1bb;
- wherein:
  - R_1abis NR_32bR_33b;
  - R_1bbis C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, C_1-3alkyleneOC_1-2alkyl, or CF₃;
- R_3bis H, halo, CH₃, OC_1-2alkyl or CF₃;
- or R_3btogether with R_5bbforms a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl;
- R_4band R_5bare either R_4aband R_5abor R_4bband R_5bb;
- wherein:
  - R_4aband R_5abtogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21bR_22a; 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_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aband R_5abtogether 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(O)₂R_29b; or
  - R_4bband R_5bbare each independently H, halo, C_1-6alkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl, OC_0-2alkyleneC_3-6cycloalkyl, C_1-3alkyleneOC_1-3alkyl, C_1-6alkylOH, C_1-6haloalkyl, OC_1-6haloalkyl or NR_21bR_22b,
    - or R_4bbis H and R_5bbtogether with R_3bform a 5- or 6-membered cycloalkyl or 5 or 6 membered oxygen-containing heterocycloalkyl,
    - or R_4bband R_5bbtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl,
    - or R_4bbis H and R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring;
    - or R_4bbis O and R_5bbis absent;
- R_6bis H or C_1-3alkyl,
  - or R_6btogether with R_11bwhen in the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring,
  - or R_5bband R_6bare a C_2-3alkylene chain forming a 5- or 6-membered ring and R_4bbis H;
- Ar1b is 6-membered aryl or heteroaryl;
- Ar2b is a 6-membered aryl or heteroaryl and is attached to Ar1b in the pare position relative to group A_b;
- R_10bis H, halo, C_1-3alkyl, OC_1-2alkyl, C_1-2haloalkyl, OC_1-2haloalkyl or CN;
- R_11bis H, F, Cl, CH₃, ethyl, OCH₃, CF₃, OCF₃or CN,
  - or R_11b, when in the ortho-position to group A_b, together with R_6bare a C₂alkylene chain forming a 5-membered ring;
- R_12bis attached to Ar2b in the ortho or meta position relative to Ar1b and R_12bis H, halo, C_1-4alkyl, C_2-4alkynyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, OCH₂CH₂N(CH₃)₂, OH, C_1-4alkylOH, CN, C_1-3alkyleneOC_1-3alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, C(═O)C_1-2alkyl, NR_23bR_24b, SO₂C_1-4alkyl, SOC_1-4alkyl, SC_1-4alkyl, SH, C(O)N(CH₃)₂, NHC(O)C_1-3alkyl, C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b, or R_12btogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_13bis H, halo, CH₃or OCH₃;
- R_21bis H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl, C_1-3alkylOC_1-2alkyl, C_1-4haloalkyl, or C_4-6heterocycloalkyl;
- R_22ais H or CH₃;
- R_22bis H or C_1-2alkyl;
- R_24bis H or C_1-2alkyl;
- R_29bis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, CF₃, N(C_1-3alkyl)₂, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and
- R_32bis C_1-3alkyl and R_33bis C_1-3alkyl; or
- R_32band R_33btogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl;
- wherein:
- R_1bis R_1ab; and/or
- R_4band R_5bare R_4aband R_5ab; and/or
- A is A_ab; or

wherein when B is (B-bc) and R_3b3cis R_3c, the compound of formula (I) is a compound of formula (I-c):

[Image Omitted]

wherein:

- A_cis A_acor A_bc;
  - wherein:
  - A_acis —CH₂NR_6c—;
  - A_bcis —C(═O)NR_6c—;
- R_1cis R_1acor R_1bc;
- wherein:
  - R_1acis NR_32cR_33c;
- R_1bcis C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, C_1-3alkyleneOC_1-2alkyl, or CF₃;
- R_3cis H, CH₃, halo, OC_1-2alkyl or CF₃;
- R_4cand R_5care either R_4acand R_5bcor R_4bcand R_5bc;
- wherein:
  - R_4acand R_5actogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21cR_22c; 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_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4acand R_5actogether 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(O)₂R_29c; or
  - R_4bcand R_5bcare each independently H, C_1-6alkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, C_1-6alkylOH or C_1-6haloalkyl,
  - or R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl ring;
- R_6cis H or C_1-3alkyl;
- Ar1c is a 6-membered aryl or heteroaryl;
- Ar2c is a 6-membered aryl or heteroaryl and is attached to Ar1c in the para position relative to group A_c;
- R_10cis H, halo, C_1-3alkyl, OC_1-2alkyl, C_1-2haloalkyl, OC_1-2haloalkyl or CN;
- R_11cis H, F, Cl, CH₃, ethyl, OCH₃, CF₃, OCF₃or CN;
- R_12cis attached to Ar2c in the meta or ortho position relative to Ar1c and R_12cis H, halo, C_1-4alkyl, C_2-4alkynyl, C(═O)C_1-2alkyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, C_1-3alkyleneOC_1-3alkyl, C_1-4haloalkyl, OC_1-4haloalkyl, CN, OC_0-2alkyleneC_3-5cycloalkyl, OCH₂CH₂N(CH₃)₂, OH, C_1-4alkylOH, NR_23cR_24c, SO₂CH₃, C(O)N(CH₃)₂, NHC(O)C_1-3alkyl, or a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2c, or R_12ctogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_21cis H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl, C_1-3alkylOC_1-2alkyl, C_1-4haloalkyl, or C_4-6heterocycloalkyl;
- R_22cis H or CH₃;
- R_23cis H or C_1-2alkyl;
- R_24cis H or C_1-2alkyl;
- R_29cis C_1-3alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, CF₃, N(C_1-3alkyl)₂, or a 5 or 6 membered heteroaryl wherein the 5 or 6 membered heteroaryl is optionally substituted by methyl; and
- R_32cis C_1-3alkyl and R_33cis C_1-3alkyl; or
- R_32cand R_33ctogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl;

wherein:

- R_1cis R_1ac; and/or
- R_4cand R_5care R_4acand R_5ac; and/or
- A_cis 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 (I-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 (I-a):

[Image Omitted]

wherein

- A_ais A_aaor A_ba;
- wherein
  - A_aais an amine linker having the following structure: —NH—, —CH₂NH— or —NHCH₂—;
  - A_bais an amide linker having the following structure: —C(═O)NH— or —NHC(═O)—;
- X is N or CH;
- Y is N or CR_2a;
- Z is N or CR_3a;
  - with the proviso that when at least one of X or Z is N, Y cannot be N;
- R_1ais R_1aaor R_1ba;
  - wherein
  - R_1aais NR_32aR_33a;
  - R_1bais C_1-5alkyl, C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃;
- R_2ais H, halo, C_1-2alkyl, OC_1-2alkyl, C_1-2haloalkyl or OC_1-2haloalkyl;
- R_3ais H, halo, CH₃, OCH₃, CF₃or OCF₃;
  - wherein at least one of R_2aand R_3ais H;
- R_4aand R_5aare R_4aaand R_5aa, or R_4baand R_5ba;
  - wherein
  - R_4aaand R_5aatogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21aR_22a; 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aaand R_5aatogether 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl; or
  - R_4aaand R_5aatogether 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(O)₂R_29a; or
- R_4baand R_5baare each independently H, C_1-6alkyl, C_1-6alkylOH, C_1-6haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4aand R_5atogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl; and
  - when A_ais —NHC(═O)— or —NHCH₂—:
  - R_4baand R_5bamay additionally be selected from halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl and NR_21aR_22a;
- Ar1a is a 6-membered aryl or heteroaryl;
- Ar2a is a 6-membered aryl or heteroaryl and is attached to Ar1a in the para position relative to group A_a;
- R_10ais H, halo, C_1-3alkyl, C_1-2haloalkyl, OC_1-2alkyl, OC_1-2haloalkyl or CN;
- R_11ais H, F, Cl, C_1-2alkyl, CF₃, OCH₃or CN;
- R_12ais attached to Ar2a in the ortho or meta position relative to Ar1a and R_12ais H, halo, C_1-4alkyl, C_2-4alkenyl, C_0-2alkyleneC_3-5cycloalkyl, OC_1-4alkyl, OC_0-2alkyleneC_3-5cycloalkyl, C_1-4haloalkyl, OC_1-4haloalkyl, hydroxy, C_1-4alkylOH, SO₂C_1-2alkyl, C(O)N(C_1-2alkyl)₂, NHC(O)C_1-3alkyl or NR_23aR_24a; and
  - when A_ais —NHC(═O)—, —NH— or —NHCH₂—:
  - R_12amay additionally be selected from CN, OCH₂CH₂N(CH₃)₂and a C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2a, or R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻);
- R_13ais H or halo;
- R_21ais H, C_1-5alkyl, C(O)C_1-5alkyl, C(O)OC_1-5alkyl;
- R_22ais H or CH₃;
- R_23ais H or C_1-2alkyl; and
- R_24ais H or C_1-2alkyl;
- R_29ais C_1-3alkyl, C_0-2alkyleneC_3-5-cycloalkyl which cycloalkyl is optionally substituted by CH₃, or CF₃;
- R_32ais C_1-3alkyl and R_33ais C_1-3alkyl; or
- R_32aand R_33atogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl;

wherein

- R_1ais R_1aa; and/or
- R_4aand R_5aare R_4aaand 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_ais —C(═O)NH—.

Clause 5. The compound according to any one of clauses 1 to 3 wherein A_ais —NHC(═O)—.

Clause 6. The compound according to any one of clauses 1 to 3 wherein A_ais —NH—.

Clause 7. The compound according to any one of clauses 1 to 3 wherein A_ais —CH₂NH—.

Clause 8. The compound according to any one of clauses 1 to 3 wherein A_ais —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 11. 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 CR_2a.

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 CR_3a.

Clause 15. The compound according to any one of clauses 1 to 8 wherein X is N, Y is CR_2aand Z is N.

Clause 16. The compound according to any one of clauses 1 to 8 wherein X is N, Y is CR_2aand Z is CR_3a.

Clause 17. The compound according to any one of clauses 1 to 8 wherein X is CH, Y is N and Z is CR_3a.

Clause 18. The compound according to any one of clauses 1 to 8 wherein X is CH, Y is CR_2aand Z is CR_3a.

Clause 19. The compound according to any one of clauses 1 to 8 wherein X is CH, Y is CR_2aand Z is N.

Clause 20. The compound according to any one of clauses 1 to 19 wherein R_1ais R_1aa.

Clause 21. The compound according to clause 20 wherein R_1aais NR_32aR_33a, R_32ais C_1-3alkyl and R_33ais C_1-3alkyl.

Clause 22. The compound according to clause 21 wherein R_32ais methyl or ethyl, such as methyl.

Clause 23. The compound according to either clause 21 or 22 wherein R_33ais methyl or ethyl, such as methyl.

Clause 24. The compound according to clause 21 wherein R_32ais methyl and R_33ais methyl.

Clause 25. The compound according to clause 20 wherein R_1aais NR_32aR_33aand wherein R_32aand R_33atogether 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 azirdine, azetidine and pyrrolidine.

Clause 27. The compound according to any one of clauses 1 to 19 wherein R_1ais R_1ba.

Clause 28. The compound according to any one of clauses 1 to 19 wherein R_1ais C_1-5alkyl.

Clause 29. The compound according to any one of clauses 1 to 19 wherein R_1ais C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃.

Clause 30. The compound according to clause 29 wherein R_1ais C_0-2alkyleneC_3-5cycloalkyl.

Clause 31. The compound according to clause 29 wherein R_1ais C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is substituted by CH₃.

Clause 32. The compound according to any one of clauses 29 to 31 wherein R_1ais C_3-5cycloalkyl optionally substituted by CH₃.

Clause 33. The compound according to any one of clauses 29 to 31 wherein R_1ais C₁alkyleneC_3-5cycloalkyl optionally substituted by CH₃.

Clause 34. The compound according to any one of clauses 29 to 31 wherein R_1ais C₂alkyleneC_3-5cycloalkyl optionally substituted by CH₃.

Clause 35. The compound according to any one of clauses 1 to 19 wherein R_1ais cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclobutyl, methyl or ethyl.

Clause 36. The compound according to clause 35 wherein R_1ais cyclopropyl, methyl or ethyl.

Clause 37. The compound according to clause 36 wherein R_1ais cyclopropyl.

Clause 38. The compound according to any one of clauses 1 to 19 wherein R_1ais CF₃.

Clause 39. The compound according to any one of clauses 1 to 38 wherein R_2ais H.

Clause 40. The compound according to any one of clauses 1 to 38 wherein R_2ais 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 R_2ais C_1-2alkyl such as CH₃.

Clause 42. The compound according to any one of clauses 1 to 38 wherein R_2ais OC_1-2alkyl such as OCH₃.

Clause 43. The compound according to any one of clauses 1 to 38 wherein R_2ais C_1-2haloalkyl such as CF₃.

Clause 44. The compound according to any one of clauses 1 to 38 wherein R_2ais OC_1-2haloalkyl such as OCF₃.

Clause 45. The compound according to any one of clauses 1 to 44 wherein R_3ais H.

Clause 46. The compound according to any one of clauses 1 to 44 wherein R_3ais halo.

Clause 47. The compound according to clause 46 wherein R_3ais fluoro.

Clause 48. The compound according to any one of clauses 1 to 44 wherein R_3ais CH₃.

Clause 49. The compound according to any one of clauses 1 to 44 wherein R_3ais OCH₃.

Clause 50. The compound according to any one of clauses 1 to 44 wherein R_3ais CF₃.

Clause 51. The compound according to any one of clauses 1 to 44 wherein R_3ais OCF₃.

Clause 52. The compound according to any one of clauses 1 to 51 wherein at least one of R_2aand R_5ais H.

Clause 53. The compound according to any one of clauses 1 to 52 wherein R_4aand R_5aare R_4aaand R_5aa.

Clause 54. The compound according to clause 53 wherein R_4aaand R_5aatogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21aR_22a.

Clause 55. The compound according to clause 54 wherein R_4aaand R_5aatogether with the carbon atom to which they are attached form a C_3-6cycloalkyl which is substituted by one substituent.

Clause 56. The compound according to either clause 54 or 55 wherein each substituent is independently selected from the group consisting of C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, halo, OC_1-3haloalkyl, OC_1-3alkyl and NR_21aR_22a.

Clause 57. The compound according to clause 56 wherein each substituent is independently selected from the group consisting of oxo, OH, halo, OC_1-3alkyl and NR_21aR_22a.

Clause 58. The compound according to clause 57 wherein each substituent is independently selected from the group consisting of oxo, OH, fluoro and NR_21aR_22a.

Clause 59. The compound according to clause 53 wherein R_4aaand R_5aatogether with the carbon atom to which they are attached form a C_3-6cycloalkyl wherein 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl.

Clause 60. The compound according to clause 53 wherein R_4aaand R_5aatogether 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_4aaand R_5aatogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl.

Clause 61. The compound according to either clause 59 or 60 wherein R_4aaand R_5aatogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl which is substituted by one substituent.

Clause 62. The compound according to either clause 59 or 60 wherein R_4aaand R_5aatogether with the carbon atom to which they are attached form a C_3-6cycloalkyl 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 C_1-2alkyl or OCH₃.

Clause 64. The compound according to any one of clauses 59 to 63 wherein a spirocyclic ring system is formed by the C_3-6cycloalkyl or C_3-6heterocycloalkyl ring and a further C_3-6cycloalkyl ring.

Clause 65. The compound according to any one of clauses 59 to 63 wherein a spirocyclic ring system is formed by the C_3-6cycloalkyl or C_3-6heterocycloalkyl 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_3-6cycloalkyl formed by R_4aaand R_5aatogether 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 C_3-6cycloalkyl formed by R_4aaand R_5aatogether 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 C_3-6cycloalkyl formed by R_4aaand R_5aatogether 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 C_3-6cycloalkyl formed by R_4aaand R_5aatogether 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 C_3-6heterocycloalkyl formed by R_4aaand R_5aatogether 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 C_3-6heterocycloalkyl formed by R_4aaand R_5aatogether 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 C_3-6heterocycloalkyl formed by R_4aaand R_5aatogether 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_3-6heterocycloalkyl formed by R_4aaand R_5aatogether 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:

[Image Omitted]

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 R_21ais H.

Clause 76. The compound according to any one of clauses 54 to 58 wherein R_21ais C_1-5alkyl, such as methyl, ethyl or propyl.

Clause 77. The compound according to any one of clauses 54 to 58 wherein R_21ais C(O)C_1-5alkyl, such as C(O)CH₃.

Clause 78. The compound according to any one of clauses 54 to 58 wherein R_21ais C(O)OC_1-5alkyl, such as C(O)OCH₃or C(O)Otert-butyl.

Clause 79. The compound according to any one of clauses 54 to 58 wherein R_21ais C_1-3alkylOC_1-2alkyl such as CH₂CH₂OCH₃.

Clause 80. The compound according to any one of clauses 54 to 58 wherein R_21ais C_1-4haloalkyl such as CH₂CHF₂.

Clause 81. The compound according to any one of clauses 54 to 58 wherein R_21ais C_4-6heterocycloalkyl 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_22ais H.

Clause 83. The compound according to any one of clauses 54 to 58 or 75 to 81 wherein R_22ais CH₃.

Clause 84. The compound according to clause 53 wherein R_4aaand R_5aatogether 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(O)₂R_29a.

Clause 85. The compound according to clause 84 wherein the C_3-6heterocycloalkyl is piperidinyl and the nitrogen atom is in the 4-position relative to the quaternary carbon:

[Image Omitted]

Clause 86. The compound according to either clause 84 or 85 wherein R_29ais C_1-3alkyl.

Clause 87. The compound according to clause 86 wherein R_29ais methyl.

Clause 88. The compound according to either clause 84 or 85 wherein R_29ais N(C_1-3alkyl)₂e.g. N(CH₃)₂.

Clause 89. The compound according to either clause 84 or 85 wherein R_29ais 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_4aand R_5aare R_4baand R_5ba.

Clause 91. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais H.

Clause 92. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais C_1-6alkyl.

Clause 93. The compound according to clause 92 wherein R_4bais methyl or ethyl.

Clause 94. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais C_1-6alkylOH.

Clause 95. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais C_1-6haloalkyl such as CF₃.

Clause 96. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais C_0-2alkyleneC_3-6cycloalkyl.

Clause 97. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais C_0-2alkyleneC_3-6heterocycloalkyl.

Clause 98. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais C_1-3alkyleneOC_1-3alkyl.

Clause 99. The compound according to clause 98 wherein R_4bais C₂alkyleneOC_1-3alkyl.

Clause 100. The compound according to clause 99 wherein R_4bais CH₂CH₂OCH₃.

Clause 101. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais halo.

Clause 102. The compound according to clause 101 wherein R_4bais fluoro.

Clause 103. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais OC_1-6haloalkyl, such as OC_1-4haloalkyl.

Clause 104. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais OC_0-2alkyleneC_3-6cycloalkyl.

Clause 105. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais OC_0-2alkyleneC_3-6heterocycloalkyl.

Clause 108. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais OC_1-6alkyl, in particular OC_1-4alkyl.

Clause 107. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais NR_21aR_22a.

Clause 108. The compound according to clause 107 wherein R_21ais H, CH₃, C(O)CH₃, C(O)OCH₃or C(O)Otert-butyl.

Clause 109. The compound according to clause 107 wherein R_21ais C_1-3alkylOC_1-2alkyl such as CH₂CH₂OCH₃.

Clause 110. The compound according to clause 107 wherein R_21ais C_1-4haloalkyl such as CH₂CHF₂.

Clause 111. The compound according to clause 107 wherein R_21ais C_4-8heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.

Clause 112. The compound according to any one of clauses 107 or 111 wherein R_22ais H or CH₃such as H.

Clause 113. The compound according to any one of clauses 107 to 112 wherein R_21ais C(O)OCH₃and R_22ais H, R_21ais C(O)CH₃and R_22ais H, R_21aand R_22aare both CH₃, or R_21aand R_22aare both H.

Clause 114. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais H, C_1-6alkyl, C_1-6alkylOH, C_1-6haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl.

Clause 115. The compound according to any one of clauses 1 to 52 or 90 wherein R_4bais halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl or NR_21aR_22a.

Clause 116. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais H.

Clause 117. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais C_1-6alkyl.

Clause 118. The compound according to clause 117 wherein R_5bais methyl or ethyl.

Clause 119. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais C_1-6alkylOH.

Clause 120. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais C_1-6haloalkyl such as CF₃.

Clause 121. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais C_0-2alkyleneC_3-6cycloalkyl.

Clause 122. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais C_0-2alkyleneC_3-6heterocycloalkyl.

Clause 123. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais C_1-3alkyleneOC_1-3alkyl, such as C₂alkyleneOC_1-3alkyl e.g. CH₂CH₂OCH₃.

Clause 124. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais halo.

Clause 125. The compound according to clause 124 wherein R_5bais fluoro.

Clause 126. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais OC_1-6haloalkyl, such as OC_1-4haloalkyl.

Clause 127. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais OC_0-2alkyleneC_3-6cycloalkyl.

Clause 128. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais OC_0-2alkyleneC_3-6heterocycloalkyl.

Clause 129. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais OC_1-6alkyl, in particular OC_1-4alkyl.

Clause 130. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais NR_21aR_22a.

Clause 131. The compound according to clause 130 wherein R_21ais H, CH₃, C(O)CH₃, C(O)OCH, or C(O)Otert-butyl.

Clause 132. The compound according to clause 130 wherein R_21ais C_1-3alkylOC_1-2alkyl such as CH₂CH₂OCH₃.

Clause 133. The compound according to clause 130 wherein R_21ais C_1-4haloalkyl such as CH₂CHF₂.

Clause 134. The compound according to clause 130 wherein R₂₁, is C_4-6heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.

Clause 135. The compound according to any one of clauses 130 to 134 wherein R_22ais H or CH₃such as H.

Clause 136. The compound according to any one of clauses 130 to 134 wherein R_21ais C(O)OCH₃and R_22ais H, R_21ais C(O)CH₃and R_22ais H, R_21aand R_22aare both CH₃, or R_21aand R_22aare both H.

Clause 137. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais H, C_1-6alkyl, C_1-6alkylOH, C_1-6haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, or R₄and R₅together with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heterocycloalkyl.

Clause 138. The compound according to any one of clauses 1 to 52 or 90 to 115 wherein R_5bais halo, OC_1-6haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-6alkyl or NR_21aR_22a.

Clause 139. The compound according to any one of clauses 1 to 52 or 90 to 116 wherein R_4baand R_5baare both H.

Clause 140. The compound according to any one of clauses 1 to 52, 93 or 118 wherein R_4baand R_5baare both methyl.

Clause 141. The compound according to any one of clauses 1 to 52, 93 or 118 wherein R_4baand R_5baare both ethyl.

Clause 142. The compound according to any one of clauses 1 to 52, 102 or 125 wherein R_4baand R_5ba, are both fluoro.

Clause 143. The compound according to any one of clauses 1 to 52,102 or 116 wherein R_4bais ethyl and R_5bais H.

Clause 144. The compound according to any one of clauses 1 to 52, 102 or 118 wherein R_4bais fluoro and R_5bais ethyl.

Clause 145. The compound according to any one of clauses 1 to 52, 100 or 116 wherein R_4bais CH₂CH₂OCH₃and R_5bais H.

Clause 148. The compound according to any one of clauses 143 to 145 wherein R_4baand R_5baare arranged in an S configuration.

Clause 147. The compound according to any one of clauses 1 to 52 or 90 wherein R_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6cycloalkyl.

Clause 148. The compound according to clause 147 wherein R_4baand R_5batogether 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_4baand R_5batogether with the carbon atom to which they are attached form a C_3-6heterocycloalkyl, such as heterocyclohexyl, such as tetrahydropyranal.

Clause 150. The compound according to any one of clauses 1 to 149 wherein Ar1a is phenyl.

Clause 151. The compound according to anyone of clauses 1 to 149 wherein Ar1a is 2-pyridyl.

Clause 152. The compound according to any one of clauses 1 to 149 wherein Ar1a 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 R_10ais H.

Clause 156. The compound according to any one of clauses 1 to 154 wherein R_10ais halo such as fluoro or chloro.

Clause 157. The compound according to any one of clauses 1 to 154 wherein R_10ais C_1-3alkyl.

Clause 158. The compound according to clause 157 wherein R_10ais C_1-2alkyl such as CH₃.

Clause 159. The compound according to any one of clauses 1 to 154 wherein R_10ais C_1-2haloalkyl such as CF₃.

Clause 160. The compound according to any one of clauses 1 to 154 wherein R_10ais OC_1-2alkyl such as OCH₃.

Clause 161. The compound according to any one of clauses 1 to 154 wherein R_10ais OC_1-2haloalkyl such as OCF₃.

Clause 162. The compound according to any one of clauses 1 to 154 wherein R_10ais CN.

Clause 163. The compound according to any one of clauses 1 to 162 wherein R_11ais H.

Clause 164. The compound according to any one of clauses 1 to 162 wherein R_11ais F.

Clause 165. The compound according to any one of clauses 1 to 162 wherein R_11ais Cl.

Clause 166. The compound according to any one of clauses 1 to 162 wherein R_11ais C_1-2alkyl.

Clause 167. The compound according to clause 166 wherein R_11ais CH₃.

Clause 168. The compound according to any one of clauses 1 to 162 wherein R_11ais CF₃.

Clause 169. The compound according to any one of clauses 1 to 162 wherein R_11ais OCH₃.

Clause 170. The compound according to any one of clauses 1 to 162 wherein R_11ais CN.

Clause 171. The compound according to any one of clauses 1 to 170 wherein R_12ais H.

Clause 172. The compound according to any one of clauses 1 to 170 wherein R_12ais halo such as fluoro or chloro.

Clause 173. The compound according to any one of clauses 1 to 170 wherein R_12ais C_1-4alkyl such as CH₃.

Clause 174. The compound according to any one of clauses 1 to 170 wherein R_12ais C_2-4alkenyl.

Clause 175. The compound according to any one of clauses 1 to 170 wherein R_12ais C_0-2alkyleneC_3-5cycloalkyl such as C₀alkyleneC₃cycloalkyl.

Clause 176. The compound according to any one of clauses 1 to 170 wherein R_12ais OC_1-4alkyl such as methoxy, ethoxy or isopropoxy.

Clause 177. The compound according to any one of clauses 1 to 170 wherein R_12ais OC_0-2alkyleneC_3-5cycloalkyl such as OC₀alkyleneC₃cycloalkyl.

Clause 178. The compound according to any one of clauses 1 to 170 wherein R_12ais C_1-4haloalkyl such as CF₃.

Clause 179. The compound according to any one of clauses 1 to 170 wherein R_12ais OC_1-4haloalkyl such as OCH₂CF₃or OCHF₂.

Clause 180. The compound according to any one of clauses 1 to 170 wherein R_12ais OH.

Clause 181. The compound according to any one of clauses 1 to 170 wherein R_12ais C_1-4alkylOH.

Clause 182. The compound according to any one of clauses 1 to 170 wherein R_12ais SO₂C_1-2alkyl.

Clause 183. The compound according to any one of clauses 1 to 170 wherein R_12ais NHC(O)C_1-3alkyl.

Clause 184. The compound according to any one of clauses 1 to 170 wherein R_12ais NR_23aR_24a.

Clause 185. The compound according to clause 184 wherein R_24ais H or C_1-2alkyl such as H or CH₃.

Clause 186. The compound according to clause 184 or 185 wherein R_24ais H or C_1-2alkyl such as CH₃or ethyl.

Clause 187. The compound according to any one of clauses 184 to 186 wherein R_23ais H and R_24ais ethyl; or R_23ais CH₃and R₂₄is CH₃.

Clause 188. The compound according to any one of clauses 1 to 170 wherein R_12ais CN.

Clause 189. The compound according to any one of clauses 1 to 170 wherein R_12ais OCH₂CH₂N(CH₃)₂.

Clause 190. The compound according to any one of clauses 1 to 170 wherein R_12ais a C_3-6heterocycloalkyl 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 R_12atogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻).

Clause 192. The compound according to any one of clauses 1 to 170 wherein R_12ais C(O)N(C_1-2alkyl)₂.

Clause 193. The compound according to any one of clauses 1 to 192 wherein R_13ais H.

Clause 194. The compound according to any one of clauses 1 to 192 wherein R_13ais halo such as fluoro or chloro e.g. fluoro.

Clause 195. The compound according to any one of clauses 1 to 194 when R_1bais methyl, at least one of R_4ba, R_5ba, R_10ba, R_11ba, R_12baand R_13bais 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_3-6heterocycloalkyl rings, such as only one of the C_3-6heterocycloalkyl rings is substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl, C(O)NHC_1-4haloalkyl such as C(O)OtBu, C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, or C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃.

Clause 197. The compound according to any one of clauses 1 to 195 wherein all nitrogen atoms in all C_3-6heterocycloalkyl 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 C_3-6heterocycloalkyl rings, such as only one of the C_3-6heterocycloalkyl rings is substituted, for example by one oxygen atom to form S═O or by two oxygen atoms to form S(O)₂.

Clause 199. The compound according to any one of clauses 1 to 197 wherein all sulphur atoms in all C_3-6heterocycloalkyl rings are not substituted.

Clause 200. The compound according to any one of clauses 1 to 199 wherein R_1ais R_1aaand R_4aand R_5aare R_4aaand R_5aa.

Clause 201. The compound according to any one of clauses 1 to 199 wherein R_1ais R_1aaand A_ais —NH—, —CH₂NH— or —NHCH₂—.

Clause 202. The compound according to any one of clauses 1 to 199 wherein R_4aand R_5aare R_4aaand R_5aaand A_ais —NH—, —CH₂NH— or —NHCH₂—.

Clause 203. The compound according to any one of clauses 1 to 199 wherein R_1ais R_1aa, R_4aand R_5aare R_4aaand R_5aaand A_ais —NH—, —CH₂NH— or —NHCH₂—.

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 (II-a):

[Image Omitted]

wherein R₁, X, Y, Z, R₄and R₅are as defined in any preceding clause and R is H, C_1-6alkyl (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):

[Image Omitted]

wherein Ar1, Ar2, R₁, X, Y, Z, R₄, R₅, R₁₀, R₁₁, R₁₂and R₁₃are 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):

[Image Omitted]

wherein Ar1, Ar2, A, R₁, X, Y, Z, R₄, R₅, R₁₀, R₁₁, R₁₂and R₁₃are 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):

[Image Omitted]

wherein Ar1, Ar2, A, X, Y, Z, R₄, R₅, R₁₀, R₁₁, R₁₂and R₁₃are as defined in any preceding clause, or a salt, such as a pharmaceutically acceptable salt, thereof.

Clause 209. A compound of formula (XXXXII-a):

[Image Omitted]

wherein R₁, X, Y, Z, R₄and R₅are as defined in any preceding clause, or a salt, such as a pharmaceutically acceptable salt, thereof.

Clause 210. A compound of formula (LI-a):

[Image Omitted]

wherein Ar1, Ar2, A, R₄and R₅are as defined in any preceding clause and X₁is Cl or Br, or a salt, such as a pharmaceutically acceptable salt, thereof.

Clause 211. A compound of formula (LVIII-a):

[Image Omitted]

wherein R₁, Ar1, A, X, Y, Z, R₄and R₅are as defined in any preceding clause, or a salt, such as a pharmaceutically acceptable salt, thereof.

Clause 212. A compound of formula (XXXIII-a):

[Image Omitted]

wherein X, Y, Z, R₄and R₅are as defined in any preceding clause and alkyl is C_1-4alkyl 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):

[Image Omitted]

wherein X, Y, Z, R₄and R₅are as defined in any preceding clause and alkyl is C_1-4alkyl 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):

[Image Omitted]

wherein and alkyl is C_1-4alkyl such as methyl or ethyl, e.g. methyl;

- a compound of formula (LXXIII-a):

[Image Omitted]

and

- a compound of formula (LXXIV-a):

[Image Omitted]

wherein X, Y, Z, R₄, R₅, 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):

[Image Omitted]

wherein Ar1, Ar2, R₁₀, R₁₁, R₁₂and R₁₃are as defined in any preceding clause, or a salt such as a pharmaceutically acceptable salt, thereof.

Clause 216. A compound of formula (LXXII-a):

[Image Omitted]

wherein Ar1, Ar2, R₁₀, R₁₁, R₁₂and R₁₃are 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 (I-b).

Clause 219. The compound according to clause 218 wherein R_1bis R_1ab.

Clause 220. The compound according to clause 219 wherein R_1abis NR_32bR_33band wherein R_32bis C_1-3alkyl and R_33bis C_1-3alkyl.

Clause 221. The compound according to clause 220 wherein R_32bis methyl or ethyl.

Clause 222. The compound according to clause 221 wherein R_32bis methyl.

Clause 223. The compound according to any one of clauses 220 or 222 wherein R_33bis methyl or ethyl such as methyl.

Clause 224. The compound according to any one of clauses 220 to 223 wherein R_32bis methyl and R_33bis methyl.

Clause 225. The compound according to clause 219 wherein R_1abis NR_32aR_33band R_32band R_33btogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl.

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 R_1bis R_1bb.

Clause 228. The compound according to clause 227 wherein R_1bbis C_1-5alkyl such as CH₃or ethyl.

Clause 229. The compound according to clause 228 wherein R_1bbis CH₃.

Clause 230. The compound according to any one of clauses 227 wherein R_1bbis C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃.

Clause 231. The compound according to clause 230, wherein R_1bbis C_0-2alkyleneC_3-5cycloalkyl.

Clause 232. The compound according to clause 230, wherein R_1bbis C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is substituted by CH₃.

Clause 233. The compound according to any one of clauses 230 to 232, wherein R_1bbis C_3-5cycloalkyl, optionally substituted by CH₃.

Clause 234. The compound according to any one of clauses 230 to 232, wherein R_1bbis C₁alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃.

Clause 235. The compound according to any one of clauses 230 to 232, wherein R_1bbis C₂alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃.

Clause 236. The compound according to any one of clauses 230 to 235, wherein R_1bbis C_0-2alkyleneC₃cycloalkyl which cycloalkyl is optionally substituted by CH₃.

Clause 237. The compound according to any one of clauses 230 to 235 wherein R_1bbis C_0-2alkyleneC₄cycloalkyl which cycloalkyl is optionally substituted by CH₃.

Clause 238. The compound according to any one of clauses 230 to 235 wherein R_1bbis C_0-2alkyleneC₃cycloalkyl which cycloalkyl is optionally substituted by CH₃.

Clause 239. The compound according to any one of clauses 230 to 238 wherein R_1bbis cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclopropylmethylene, cyclobutyl, cyclopentyl, CH₃, ethyl, isopropyl, sec-butyl or tert-butyl, especially cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclobutyl, CH₃, ethyl or isopropyl.

Clause 240. The compound according to any one of clauses 239 wherein R_1bbis cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclobutyl, CH₃, isopropyl, sec-butyl or tert-butyl.

Clause 241. The compound according to any clause 240 wherein R_1bbis cyclopropyl, cyclopropyl substituted by CH₃at the point of attachment, cyclobutyl or isopropyl.

Clause 242. The compound according to any one of clauses 218 to 241 wherein R_3bis H.

Clause 243. The compound according to any one of clauses 218 to 241 wherein R_3bis chloro or fluoro.

Clause 244. The compound according to any one of clauses 218 to 241 wherein R_3bis CH₃.

Clause 245. The compound according to any one of clauses 218 to 241 wherein R_3bis OCH₃.

Clause 246. The compound according to any one of clauses 218 to 241 wherein R_3bis CF₃.

Clause 247. The compound according to any one of clauses 218 to 241 wherein R_3btogether with R_5bbforms a 5- or 6-membered cycloalkyl.

Clause 248. The compound according to clause 247 wherein R_btogether with Ru forms a 5-membered cycloalkyl.

Clause 249. The compound according to any one of clauses 218 to 248 wherein R_4band R_5bare R_4aband R_5ab.

Clause 250. The compound according to clause 249 wherein R_4aband R_5abtogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21bR_22b.

Clause 251. The compound according to clause 250 wherein R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, halo, OC_1-3haloalkyl, OC_1-3alkyl and NR_21bR_22b.

Clause 253. The compound according to clause 252 wherein each substituent is independently selected from the group consisting of oxo, OH, halo, OC_1-3alkyl and NR_21bR_22b, such as oxo, OH, fluoro and NR_21bR_22b.

Clause 254. The compound according to any one of clauses 250 to 253 wherein R_21bis H.

Clause 255. The compound according to any one of clauses 250 to 253 wherein R_21bis C_1-5alkyl, such as methyl, ethyl or propyl.

Clause 256. The compound according to any one of clauses 250 to 253 wherein R_21bis C(O)C_1-5alkyl, such as C(O)CH₃.

Clause 257. The compound according to any one of clauses 250 to 253 wherein R_21bis C(O)OC_1-5alkyl, such as C(O)OCH₃or C(O)Otert-butyl.

Clause 258. The compound according to any one of clauses 250 to 253 wherein R_21bis C_1-3alkylOC_1-2alkyl such as CH₂CH₂OCH₃.

Clause 259. The compound according to any one of clauses 250 to 253 wherein R_21bis C_1-4haloalkyl such as CH₂CHF₂.

Clause 260. The compound according to any one of clauses 250 to 253 wherein R_21bis C_4-6heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.

Clause 261. The compound according to any one of clauses 250 to 260 wherein R_22bis H.

Clause 262. The compound according to any one of clauses 250 to 260 wherein R_22bis CH₃.

Clause 263. The compound according to clause 249 wherein R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl wherein 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_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl.

Clause 264. The compound according to clause 249 wherein R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4aband R_5abtogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl.

Clause 265. The compound according to either clause 263 or 264 wherein R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heteroycloalkyl which is substituted by one substituent.

Clause 266. The compound according to clause 263 or 264 wherein R_4aband R_5abtogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heteroycloalkyl 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 C_1-2alkyl or OCH₃.

Clause 268. The compound according to any one of clauses 263 to 267 wherein a spirocyclic ring system is formed by the C_3-6cycloalkyl or C_3-6heteroycloalkyl ring and a further C_3-6cycloalkyl ring.

Clause 269. The compound according to any one of clauses 263 to 267 wherein a spirocyclic ring system is formed by the C_3-6cycloalkyl or C_3-6heteroycloalkyl ring and a further C_3-6heterocycloalkyl ring.

Clause 270. The compound according to any one of clauses 263 or 265 to 269 wherein the C_3-6cycloalkyl formed by R_4aband R_5abtogether 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_3-6cycloalkyl formed by R_4aband R_5abtogether 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 C_3-6cycloalkyl formed by R_4aband R_5abtogether 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 C_3-6cycloalkyl formed by R_4aband R_5abtogether 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 C_3-6heterocycloalkyl formed by R_4aband R_5abtogether 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 C_3-6heterocycloalkyl formed by R_4aband R_5abtogether 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 C_3-6heterocycloalkyl formed by R_4aband R_5abtogether 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 C_3-6heterocycloalkyl formed by R_4aband R_5abtogether 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:

[Image Omitted]

wherein m is 1 or 2 and n is 0, 1 or 2.

Clause 279. The compound according to clause 249 wherein R_4aband R_5abtogether 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(O)₂R_29b.

Clause 280. The compound according to clause 279 wherein the C_3-6heterocycloalkyl is piperidinyl and the nitrogen atom is in the 4-position relative to the quaternary carbon:

[Image Omitted]

Clause 281. The compound according to clause 279 or 280wherein R_29bis C_1-3alkyl.

Clause 282. The compound according to clause 281 wherein R_29bis methyl.

Clause 283. The compound according to either clause 279 or 280wherein R is N(C_1-3alkyl)₂e.g. N(CH₃)₂.

Clause 284. The compound according to either clause 279 or 280 wherein R_29bis 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_4band R_5bare R_4bband R_5bb.

Clause 286. The compound according to any one of clauses 218 to 248 and 285 wherein R_4bbis H and R_3btogether with R_5bbform 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_4bbtogether with R_5bbform a C_3-6cycloalkyl.

Clause 288. The compound according to clause 287 wherein R_4bbtogether with R_5bbform cyclopropyl or cyclopentyl.

Clause 289. The compound according to any one of clauses 218 to 246 and 285 wherein R_4bbtogether with R_5bbform a C_3-6heterocycloalkyl.

Clause 290. The compound according to clause 289 wherein R_4bbtogether with R_5bbform 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_4bbis C_1-6alkyl, in particular C_1-4alkyl 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 R_4bbis C_0-2alkyleneC_3-6cycloalkyl, such as C_3-6cycloalkyl, C₁alkyleneC_3-6cycloalkyl or C₂alkyleneC_3-6cycloalkyl.

Clause 293. The compound according to any one of clauses 218 to 248 and 285, wherein R_4bbis OC_1-6alkyl, in particular OC_1-4alkyl, such as methoxy or isopropoxy.

Clause 294. The compound according to any one of clauses 218 to 248 and 285, wherein R_4bbis OC_0-2alkyleneC_3-6cycloalkyl such as OC_3-6cycloalkyl, OC₁alkyleneC_3-6cycloalkyl or OC₂alkyleneC_3-6cycloalkyl.

Clause 295. The compound according to any one of clauses 218 to 248 and 285, wherein R_4bbis C_1-3alkyleneOC_1-3alkyl, in particular C_1-2alkyleneOC_1-2alkyl, such as CH₂CH₂OCH₃.

Clause 298. The compound according to any one of clauses 218 to 248 and 285, wherein R_4bbis C_1-6haloalkyl, in particular C_1-4haloalkyl.

Clause 297. The compound according to any one of clauses 218 to 248 and 285, wherein R_4bbis OC_1-6haloalkyl, in particular OC_1-4haloalkyl.

Clause 298. The compound according to clause 218 to 248 and 285 wherein R_4bbis H.

Clause 299. The compound according to clause 218 to 248 and 285 wherein R_4bbis halo such as F.

Clause 300. The compound according to clause 218 to 248 and 285 wherein R_4bbis C_1-6alkylOH, such as CH₂CH₂OH.

Clause 301. The compound according to clause 218 to 248 and 285 wherein R_4bis NR_21bR_22b.

Clause 302. The compound according to clause 301 wherein R_21bis H.

Clause 303. The compound according to clause 301 wherein R_21bis C_1-5alkyl, such as methyl, ethyl or propyl.

Clause 304. The compound according to clause 301 wherein R_21bis C(O)C_1-5alkyl, such as C(O)CH₃.

Clause 305. The compound according to clause 301 wherein R_21bis C(O)OC_1-5alkyl, such as C(O)OCH₃or C(O)Otert-butyl.

Clause 308. The compound according to clause 301 wherein R_21bis C_1-3alkylOC_1-2alkyl such as CH₂CH₂OCH₃.

Clause 307. The compound according to clause 301 wherein R_21bis C_1-4haloalkyl such as CH₂CHF₂.

Clause 308. The compound according to clause 301 wherein R_21bis C_4-6heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.

Clause 309. The compound according to clause 301 to 308 wherein R_22bis H.

Clause 310. The compound according to clause 301 to 308 wherein R_22bis CH₃.

Clause 311. The compound according to any one of clauses 218 to 248 and 285 wherein R_4bbis C_0-2alkyleneC_3-6heterocycloalkyl.

Clause 312. The compound according to any one of clauses 218 to 311 wherein any nitrogen atom in the C_3-6heterocycloalkyl ring is substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu, C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃.

Clause 313. The compound according to any one of clauses 218 to 311 wherein any nitrogen atom in the C_3-6heterocycloalkyl ring is not substituted.

Clause 314. The compound according to any one of clauses 218 to 313 wherein any sulphur atom in the C_3-6heterocycloalkyl ring is substituted, for example by one oxygen atom to form S═O or by two oxygen atoms to form S(O)₂.

Clause 315. The compound according to any one of clauses 218 to 313 wherein any sulphur atom in the C_3-6heterocycloalkyl ring is not substituted.

Clause 316. The compound according to any one of clauses 218 to 246 and 285 to 315, wherein R_5bbis H, methyl, ethyl or fluoro e.g. H, methyl or ethyl.

Clause 317. The compound according to clause 316, wherein R_5bbis H.

Clause 318. The compound according to any one of clauses 218 to 246 and 285 to 316 wherein R_4bband R_5bbare methyl.

Clause 319. The compound according to any one of clauses 218 to 246 and 285 to 316 wherein R_4bband R_5bbare ethyl.

Clause 320. The compound according to any one of clauses 218 to 246 and 285 wherein R_4bbis H and R_5bband R_6bare a C_2-3alkylene 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_4bbis O and R_5bbis absent.

Clause 322. The compound according to any one of clauses 218 to 246 and 285 wherein R_4bbis ethyl and R_5bbis 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_bis A_ab.

Clause 324. The compound according to clause 323 wherein A_abis —NR_6bCH₂—.

Clause 325. The compound according to clause 323 wherein A_abis —NR_6b—.

Clause 326. The compound according to any one of clauses 218 to 322 wherein A_bis A_bb.

Clause 327. The compound according to clause 324 or 325 wherein R_6bis H.

Clause 328. The compound according to clause 324 or 325 wherein R_6bis C_1-3alkyl such as CH₃.

Clause 329. The compound according to clause 324 or 325 wherein R_6btogether with R_11bin the ortho-position to group A_bare a C₂alkylene chain forming a 5-membered ring.

Clause 330. The compound according to any one of clauses 218 to 329 wherein Ar1b is phenyl.

Clause 331. The compound according to any one of clauses 218 to 329 wherein Ar1b 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 Ar1b is pyridazinyl.

Clause 334. The compound according to any one of clauses 218 to 329 wherein Ar1b is pyrimidinyl.

Clause 335. The compound according to any one of clauses 218 to 329 wherein Ar1b is pyrazinyl.

Clause 336. The compound according to any one of clauses 218 to 335 wherein R_10bis H.

Clause 337. The compound according to any one of clauses 218 to 335 wherein R_10bis chloro or fluoro, such as fluoro.

Clause 338. The compound according to any one of clauses 218 to 335 wherein R_10bis methoxy or ethoxy such as methoxy.

Clause 339. The compound according to any one of clauses 218 to 335 wherein R_10bis C_1-3alkyl.

Clause 340. The compound according to clause 339 wherein R_10bis methyl.

Clause 341. The compound according to any one of clauses 218 to 335 wherein R_10bis OCF₃.

Clause 342. The compound according to any one of clauses 218 to 335 wherein R_10bis CF₃.

Clause 343. The compound according to any one of clauses 218 to 335 wherein R_10bis CN.

Clause 344. The compound according to any one of clauses 337 to 343 wherein R_10bis 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 R_11bis H.

Clause 346. The compound according to any one of clauses 218 to 334 wherein R_11bis fluoro.

Clause 347. The compound according to any one of clauses 218 to 334 wherein R_11bis methyl.

Clause 348. The compound according to clause 348 or 347 wherein R_11bis in the ortho or meta position with respect to group A_b, such as the ortho position with respect to group A_b.

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 R_12ais H.

Clause 356. The compound according to any one of clauses 218 to 354 wherein R_12ais halo, such as F or Cl.

Clause 357. The compound according to any one of clauses 218 to 354 wherein R_12ais C_1-4alkyl, such as ethyl or methyl, especially methyl.

Clause 358. The compound according to any one of clauses 218 to 354 wherein R_12ais C_2-4alkynyl, such as C≡CH.

Clause 359. The compound according to any one of clauses 218 to 354 wherein R_12bis C_0-2alkyleneC_3-5cycloalkyl, such as cyclopropyl.

Clause 360. The compound according to any one of clauses 218 to 354 wherein R_12ais OC_1-4alkyl such as methoxy, ethoxy, isopropoxy or n-propoxy.

Clause 361. The compound according to any one of clauses 218 to 354 wherein R_12bis OC_0-2alkyleneC_3-5cycloalkyl, such as cyclopropoxyl or cyclobutoxy.

Clause 362. The compound according to any one of clauses 218 to 354 wherein R_12ais OCH₂CH₂N(CH₃)₂

Clause 363. The compound according to any one of clauses 218 to 354 wherein R_12bis C_1-4alkylOH, such as CH₂OH or C(CH₃)₂OH.

Clause 364. The compound according to any one of clauses 218 to 354 wherein R_12bis CN.

Clause 365. The compound according to any one of clauses 218 to 354 wherein R_12bis C_1-3alkyleneOC_1-3alkyl.

Clause 366. The compound according to any one of clauses 218 to 354 wherein R_12bis C_1-4haloalkyl, such as CF₃.

Clause 387. The compound according to any one of clauses 218 to 354 wherein R_12bis OC_1-4haloalkyl, such as OCF₃, OCHF₂or OCH₂CF₃.

Clause 368. The compound according to any one of clauses 218 to 354 wherein R_12bis C(═O)C_1-2alkyl, such as C(═O)CH₃.

Clause 369. The compound according to any one of clauses 218 to 354 wherein R_12bis NR_23bR_24b.

Clause 370. The compound according to clause 369 wherein R_12bis N(CH₃)₂.

Clause 371. The compound according to clause 369 wherein R_12bis N(H)Et.

Clause 372. The compound according to any one of clauses 218 to 354 wherein R_12bis SO₂C_1-4alkyl.

Clause 373. The compound according to clause 372 wherein R_12bis SO₂CH₃.

Clause 374. The compound according to any one of clauses 218 to 354 wherein R_12bis C(O)N(CH₃)₂.

Clause 375. The compound according to any one of clauses 218 to 354 wherein R_12bis NHC(O)C_1-3alkyl such as NHC(O)CH₃.

Clause 376. The compound according to any one of clauses 218 to 354 wherein R_12bis OH.

Clause 377. The compound according to any one of clauses 218 to 354 wherein R_12bis C_3-6heterocycloalkyl comprising one nitrogen located at the point of attachment to Ar2b such as a C₅heterocycloalkyl or C₆heterocycloalkyl, and in particular pyrrolidinyl.

Clause 378. The compound according to any one of clauses 218 to 354 wherein R_12btogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻).

Clause 379. The compound according to any one of clauses 218 to 378 wherein R_12bis in the meta position of Ar2b.

Clause 380. The compound according to any one of clauses 218 to 378 wherein R_12bis in the ortho position of Ar2b.

Clause 381. The compound according to any one of clauses 218 to 380 wherein R_13bis H.

Clause 382. The compound according to any one of clauses 218 to 380 wherein R_13bis methyl.

Clause 383. The compound according to clause 382 wherein R_13bis in the ortho position with respect to Ar1b.

Clause 384. The compound according to clause 382 wherein R_13bis in the para position with respect to Ar1b.

Clause 385. The compound according to any one of clauses 218 to 384 wherein R_1bis R_1aband R_4band R_5bare R_4aband R_5ab.

Clause 386. The compound according to any one of clauses 218 to 384 wherein R_1bis R_1aband A_bis A_ab.

Clause 387. The compound according to any one of clauses 218 to 384 wherein R_1band R_1abare R_4aband R_5aband A_bis A_ab.

Clause 388. The compound according to any one of clauses 218 to 384 wherein R_1bis R_1ab, R_4band R_5bare R_4aband R_5aband A_bis A_ab.

Clause 389. A compound of the example T486.

Clause 390. A compound of formula (II-b):

[Image Omitted]

wherein R₁, R₃, R₄and R₅are as defined in any one of clauses 218 to 389 and R is H, C_1-6alkyl (e.g. methyl and ethyl) or benzyl.

Clause 391. A compound of formula (X-b):

[Image Omitted]

wherein Ar1, R₁, R₃, R₄, R₅and R_aare as defined in any one of clauses 218 to 389.

Clause 392. A compound of formula (XII-b):

[Image Omitted]

wherein R₁, R₃, R₄and R₅are 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 (I-c).

Clause 394. The compound according to clause 393 wherein R_1cis R_1ac.

Clause 395. The compound according to clause 394 wherein R_1acis NR_32cR_33cand wherein R_32cis C_1-3alkyl and R_33cis C_1-3alkyl.

Clause 396. The compound according to clause 395 wherein R_32cis methyl or ethyl.

Clause 397. The compound according to clause 396 wherein R_32cis methyl.

Clause 398. The compound according to any one of clauses 395 to 397 wherein R_32cis methyl or ethyl.

Clause 399. The compound according to clause 398 wherein R_32cis methyl.

Clause 400. The compound according to any one of clauses 397 to 399 wherein R_32cis methyl and R_33cis methyl.

Clause 401. The compound according to clause 394 wherein R_1acis NR_32cR_33cand R_32cand R_33ctogether with the nitrogen atom to which they are attached form a C_3-5heterocycloalkyl.

Clause 402. The compound according to clause 401 wherein the C_3-5heterocycloalkyl is selected from the group consisting of aziridine, azetidine and pyrrolidine.

Clause 403. The compound according to clause 393 wherein R_1cis R_1bc.

Clause 404. The compound according to clause 403 wherein R_1bcis C_1-5alkyl.

Clause 405. The compound according to clause 403 wherein R_1bcis C_1-3alkyleneOC_1-2alkyl.

Clause 406. The compound according to clause 405 wherein R_1bcis C_1-2alkyleneOC_1-2alkyl.

Clause 407. The compound according to clause 403 wherein R_1bcis C_0-2alkyleneC_3-5cycloalkyl which cycloalkyl is optionally substituted by CH₃.

Clause 408. The compound according to clause 407 wherein R_1bcis C_0-1alkyleneC_3-4cycloalkyl which cycloalkyl is optionally substituted by CH₃.

Clause 409. The compound according to clause 408 wherein R_1bcis C_0-1alkyleneC_3-4cycloalkyl.

Clause 410. The compound according to any one of clauses 407 or 409 wherein R_1bcis C_3-4cycloalkyl.

Clause 411. The compound according to clause 410 wherein R_1bcis cyclopropyl.

Clause 412. The compound according to clause 408 wherein R_1bcis C_0-1alkyleneC_3-4cycloalkyl which cycloalkyl is substituted by CH₃.

Clause 413. The compound according to any one of clauses 393 to 412 wherein R_3cis H.

Clause 414. The compound according to any one of clauses 393 to 412 wherein R_3cis Me.

Clause 415. The compound according to any one of clauses 393 to 412 wherein R_3cis halo.

Clause 416. The compound according to clause 415 wherein R_3cis F.

Clause 417. The compound according to clause 415 wherein R_3cis Cl.

Clause 418. The compound according to any one of clauses 393 to 412 wherein R_3cis OC_1-2alkyl.

Clause 419. The compound according to any one of clauses 393 to 412 wherein R_3cis OCF₃.

Clause 420. The compound according to any one of clauses 393 to 412 wherein R_3cis CF₃.

Clause 421. The compound according to any one of clauses 393 to 420 wherein R_4cand R_5care R_4acand R_5ac.

Clause 422. The compound according to clause 421 wherein R_4acand R_5actogether 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, C_0-2alkyleneC_3-6cycloalkyl, C_0-2alkyleneC_3-6heterocycloalkyl, C_1-3alkyleneOC_1-3alkyl, halo, OC_1-3haloalkyl, OC_0-2alkyleneC_3-6cycloalkyl, OC_0-2alkyleneC_3-6heterocycloalkyl, OC_1-3alkyl and NR_21cR_22c.

Clause 423. The compound according to clause 422 wherein R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6cycloalkyl 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 C_1-3alkyl, oxo, OH, C_1-3alkylOH, C_1-3haloalkyl, halo, OC_1-3haloalkyl, OC_1-3alkyl and NR_21cR_22c.

Clause 425. The compound according to clause 424 wherein each substituent is independently selected from the group consisting of oxo, OH, halo, OC_1-3alkyl and NR_21cR_22c, such as oxo, OH, fluoro and NR_21cR_22c.

Clause 426. The compound according to any one of clauses 422 to 425 wherein R_21cis H.

Clause 427. The compound according to any one of clauses 422 to 425 wherein R_21cis C_1-5alkyl, such as methyl, ethyl or propyl.

Clause 428. The compound according to any one of clauses 422 to 425 wherein R_21cis C(O)C_1-5alkyl, such as C(O)CH₃.

Clause 429. The compound according to any one of clauses 422 to 425 wherein R_21cis C(O)OC_1-5alkyl, such as C(O)OCH₃or C(O)Otert-butyl.

Clause 430. The compound according to any one of clauses 422 to 425 wherein R_21cis C_1-3alkylOC_1-2alkyl such as CH₂CH₂OCH₃.

Clause 431. The compound according to any one of clauses 422 to 425 wherein R_21cis C_1-4haloalkyl such as CH₂CHF₂.

Clause 432. The compound according to any one of clauses 422 to 425 wherein R_21cis C_4-6heterocycloalkyl such as oxetane, tetrahydrofuran or tetrahydropyran e.g. oxetane.

Clause 433. The compound according to any one of clauses 422 to 432 wherein R_22cis H.

Clause 434. The compound according to any one of clauses 422 to 432 wherein R_22cis CH₃.

Clause 435. The compound according to clause 421 wherein R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6cycloalkyl wherein 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_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl.

Clause 436. The compound according to clause 421 wherein R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6heteroycloalkyl 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_3-6heteroycloalkyl formed by R_4acand R_5actogether with the carbon atom to which they are attached may be substituted by one or two substituents, each substituent being independently selected from the group consisting of C_1-3alkyl or OC_1-3alkyl.

Clause 437. The compound according to either clause 435 or 436 wherein R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heteroycloalkyl which is substituted by one substituent.

Clause 438. The compound according to clause 435 or 436 wherein R_4acand R_5actogether with the carbon atom to which they are attached form a C_3-6cycloalkyl or C_3-6heteroycloalkyl 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 C_1-2alkyl or OCH₃.

Clause 440. The compound according to any one of clauses 435 to 439 wherein a spirocyclic ring system is formed by the C_3-6cycloalkyl or C_3-6heteroycloalkyl ring and a further C_3-6cycloalkyl ring.

Clause 441. The compound according to any one of clauses 435 to 439 wherein a spirocyclic ring system is formed by the C_3-6cycloalkyl or C_3-6heteroycloalkyl ring and a further C_3-6heterocycloalkyl ring.

Clause 442. The compound according to any one of clauses 435 or 437 to 441 wherein the C_3-6cycloalkyl formed by R_4acand R_5actogether 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_3-6cycloalkyl formed by R_4acand R_5actogether 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 C_3-6cycloalkyl formed by R_4acand R_5actogether 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 C_3-6cycloalkyl formed by R_4acand R_5actogether 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 C_3-6heterocycloalkyl formed by R_4acand R_5actogether 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 C_3-6heterocycloalkyl formed by R_4acand R_5actogether 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 C_3-6heterocycloalkyl formed by R_4acand R_5actogether 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 C_3-6heterocycloalkyl formed by R_4acand R_5actogether 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:

[Image Omitted]

wherein m is 1 or 2 and n is 0, 1 or 2.

Clause 451. The compound according to clause 421 wherein R_4acand R_5actogether 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(O)₂R_29c.

Clause 452. The compound according to clause 451 wherein the C_3-6heterocycloalkyl is piperidinyl and the nitrogen atom is in the 4-position relative to the quaternary carbon:

[Image Omitted]

Clause 453. The compound according to clause 451 or 452 wherein R_29cis C_1-3alkyl.

Clause 454. The compound according to clause 453 wherein R_29cis methyl.

Clause 455. The compound according to either clause 451 or 452 wherein R₂is N(C_1-3alkyl)₂e.g. N(CH₃)₂.

Clause 456. The compound according to either clause 451 or 452 wherein R_29cis 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_4cand R_5care R_4bcand R_5bc.

Clause 458. The compound according to any one of clauses 393 to 420 and 457 wherein R_4bcis H.

Clause 459. The compound according to any one of clauses 393 to 420 and 457 wherein R_4bcis C_1-4alkyl.

Clause 460. The compound according to clause 459 wherein R_4bcis C_1-4alkyl.

Clause 461. The compound according to clause 460 wherein R_4bcis methyl or ethyl.

Clause 462. The compound according to any one of clauses 393 to 420 and 457 wherein R_4bcis C_0-2alkyleneC_3-6cycloalkyl.

Clause 463. The compound according to clause 482 wherein R_4bcis C_0-2alkyleneC_3-5cycloalkyl.

Clause 464. The compound according to any one of clauses 393 to 420 and 457 wherein R_4bcis C_1-6alkyleneOC_1-3alkyl such as CH₂CH₂OCH₃.

Clause 465. The compound according to any one of clauses 393 to 420 and 457 wherein R_4bcis C_0-2alkyleneC_3-6heterocycloalkyl.

Clause 466. The compound according to any one of clauses 393 to 420 and 457 wherein R_4bcis C_1-6alkylOH.

Clause 467. The compound according to clause 466 wherein R_4bcis C_1-4alkylOH.

Clause 468. The compound according to clause 393 to 420 and 457 wherein R_4bcis C_1-6haloalkyl.

Clause 469. The compound according to clause 468 wherein R_4bcis C_1-4haloalkyl.

Clause 470. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R_5bcis H.

Clause 471. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R_5bcis C_1-6alkyl.

Clause 472. The compound according to clause 471 wherein R_5bcis C_1-4alkyl.

Clause 473. The compound according to clause 472 wherein R_5bcis methyl or ethyl.

Clause 474. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R_5bcis C_0-2alkyleneC_3-6cycloalkyl.

Clause 475. The compound according to clause 474 wherein R_5bcis C_0-2alkyleneC_3-5cycloalkyl.

Clause 476. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R_5bcis C_0-2akyleneC_3-6heterocycloalkyl.

Clause 477. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R_5bcis C_1-3alkyleneOC_1-3alkyl such as CH₂CH₂OCH₃.

Clause 478. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R_5bcis C_1-6alkylOH.

Clause 479. The compound according to clause 478 wherein R_5bcis C_1-4alkylOH.

Clause 480. The compound according to any one of clauses 393 to 420 and 457 to 469 wherein R_5bcis C_1-6haloalkyl.

Clause 481. The compound according to clause 480 wherein R_5bcis C_1-4haloalkyl.

Clause 482. The compound according to any one of clauses 393 to 420 wherein R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6cycloalkyl such as cyclopropyl.

Clause 483. The compound according to any one of clauses 393 to 420 wherein R_4bcand R_5bctogether with the carbon atom to which they are attached form a C_3-6heterocycloalkyl 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 C_3-6heterocycloalkyl ring is substituted, for example by C_1-4alkyl, C(O)H, C(O)C_1-4alkyl, C(O)OC_1-4alkyl, C(O)OC_1-4alkylaryl such as C(O)OBz, C(O)NHC_1-4alkyl, C(O)NHC_1-4alkylaryl such as C(O)NHBz, an Fmoc group, C(O)C_1-4haloalkyl, C(O)OC_1-4haloalkyl or C(O)NHC_1-4haloalkyl such as C(O)OtBu, C_1-4alkylCN such as CH₂CN, C(O)C_1-3alkylOC_1-2alkyl such as C(O)CH₂OCH₃, and C_1-2alkylC(O)OC_1-4alkyl such as CH₂C(O)OCH₂CH₃.

Clause 485. The compound according to any one of clauses 393 to 483 wherein any nitrogen atom in the C_3-6heterocycloalkyl 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 C_3-6heterocycloalkyl ring is substituted, for example by one oxygen atom to form S═O or by two oxygen atoms to form S(O)₂.

Clause 487. The compound according to any one of clauses 393 to 485 wherein any sulphur atom in the C_3-6heterocycloalkyl ring is not substituted.

Clause 488. The compound according to any one of clauses 393 to 470 wherein R_4bcand R_5bcare both H.

Clause 489. The compound according to any one of clauses 393 to 473 wherein R_4bcand R_5bcare both methyl.

Clause 490. The compound according to any one of clauses 393 to 473 wherein R_4bcand R_5bcare both ethyl.

Clause 491. The compound according to any one of clauses 393 to 470 wherein R_4bcis ethyl and R_5bcis H.

Clause 492. The compound according to clause 491 wherein R_4bcand R_5bcare arranged in an S configuration.

Clause 493. The compound according to any one of clauses 393 to 492 wherein A_cis —CH₂NR_6c—.

Clause 494. The compound according to any one of clauses 393 to 492 wherein A_cis A_bc.

Clause 495. The compound according to clause 493 wherein R_6cis H.

Clause 496. The compound according to clause 493 wherein R_6cis C_1-3alkyl.

Clause 497. The compound according to clause 496 wherein R_6cis methyl.

Clause 498. The compound according to clause 496 wherein R_6cis 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 R_10cis H.

Clause 504. The compound according to any one of clauses 393 to 502 wherein R_10cis halo such as F.

Clause 505. The compound according to any one of clauses 393 to 502 wherein R₁₀is C_1-3alkyl such as methyl.

Clause 506. The compound according to any one of clauses 393 to 502 wherein R_10cis OC_1-2alkyl such as OCH₃.

Clause 507. The compound according to any one of clauses 393 to 502 wherein R_10cis C_1-2haloalkyl such as CF₃.

Clause 508. The compound according to any one of clauses 393 to 502 wherein R_10cis OC_1-2haloalkyl.

Clause 509. The compound according to any one of clauses 393 to 502 wherein R_10cis CN.

Clause 510. The compound according to any one of clauses 504 to 509 wherein R_10cis ortho to group A_c.

Clause 511. The compound according to any one of clauses 393 to 510 wherein R_11cis H.

Clause 512. The compound according to any one of clauses 393 to 510 wherein R_11cis F.

Clause 513. The compound according to any one of clauses 393 to 510 wherein R_11cis Cl.

Clause 514. The compound according to any one of clauses 393 to 510 wherein R_11cis CH₃.

Clause 515. The compound according to any one of clauses 393 to 510 wherein R_11cis ethyl.

Clause 516. The compound according to any one of clauses 393 to 510 wherein R_11cis OCH₃.

Clause 517. The compound according to any one of clauses 393 to 510 wherein R_11cis CF₃.

Clause 518. The compound according to any one of clauses 393 to 510 wherein R_11cis OCF₃.

Clause 519. The compound according to any one of clauses 393 to 510 wherein R_11cis CN.

Clause 520. The compound according to any one of clauses 393 to 519 wherein R_12cis H.

Clause 521. The compound according to any one of clauses 393 to 519 wherein R_12cis halo such as fluoro or chloro.

Clause 522. The compound according to any one of clauses 393 to 519 wherein R_12cis C_1-4alkyl such as CH₃or ethyl.

Clause 523. The compound according to any one of clauses 393 to 519 wherein R_12cis C_2-4alkynyl.

Clause 524. The compound according to clause 523 wherein R_12cis C₂alkynyl.

Clause 525. The compound according to any one of clauses 393 to 519 wherein R_12cis C(═O)C_1-2alkyl such as C(═O)CH₃.

Clause 526. The compound according to any one of clauses 393 to 519 wherein R_12Cis C_0-2alkyleneC_3-5cycloalkyl.

Clause 527. The compound according to any one of clauses 393 to 519 wherein R_12cis OC_1-4alkyl such as OCH₃, OEt or OiPr.

Clause 528. The compound according to any one of clauses 393 to 519 wherein R_12cis C_1-3alkyleneOC_1-3alkyl.

Clause 529. The compound according to any one of clauses 393 to 519 wherein R_12cis C_1-4haloalkyl such as CF₃.

Clause 530. The compound according to any one of clauses 393 to 519 wherein R_12cis OC_1-4haloalkyl such as OCH₂CF₃.

Clause 531. The compound according to any one of clauses 393 to 519 wherein R_12cis CN.

Clause 532. The compound according to any one of clauses 393 to 519 wherein R_12cis OC_0-2alkyleneC_3-5cycloalkyl.

Clause 533. The compound according to any one of clauses 393 to 519 wherein R_12cis OCH₂CH₂N(CH₃)₂.

Clause 534. The compound according to any one of clauses 393 to 519 wherein R_12cis OH.

Clause 535. The compound according to any one of clauses 393 to 519 wherein R_12cis C_1-4alkylOH.

Clause 536. The compound according to any one of clauses 393 to 519 wherein R_12cis NR_23cR_24c.

Clause 537. The compound according to clause 538 wherein R_23cis H.

Clause 538 The compound according to clause 536 wherein R_23cis C_1-2alkyl such as CH₃.

Clause 539. The compound according to any one of clauses 536 to 538 wherein R_24cis H.

Clause 540. The compound according to any one of clauses 536 to 538 wherein R_24cis C_1-2alkyl such as CH₃.

Clause 541. The compound according to any one of clauses 393 to 519 wherein R_12cis SO₂CH₃.

Clause 542. The compound according to any one of clauses 393 to 519 wherein R_12cis C(O)N(CH₃)₂.

Clause 543. The compound according to any one of clauses 393 to 519 wherein R_12cis NHC(O)C_1-3alkyl.

Clause 544. The compound according to any one of clauses 393 to 519 wherein R_12cis a C_3-6heterocycloalkyl 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_12ctogether with a nitrogen atom to which it is attached forms an N-oxide (N⁺—O⁻).

Clause 546. The compound according to any one of clauses 521 to 545 wherein R_12cis attached at the meta position of Ar2c.

Clause 547. The compound according to any one of clauses 521 to 545 wherein R_12cis attached at the ortho position of Ar2c.

Clause 548. The compound according to any one of clauses 393 to 547 wherein R_1cis R_1acand R_4cand R_5care R_4acand R_5ac.

Clause 549. The compound according to any one of clauses 393 to 547 wherein R_1cis R_1acand A_cis A_ac.

Clause 550. The compound according to any one of clauses 393 to 547 wherein R_4cand R_5care R_4acand R_5acand A_cis A_ac.

Clause 551. The compound according to any one of clauses 393 to 547 wherein R_1cis R_1ac, R_4cand R_5care R_4acand R_5acand A_cis A_ac.

Clause 552. A compound which is R94 or R95.

Clause 553. A compound of formula (II-c):

[Image Omitted]

wherein R₁, R₃, R₄and R₆are as defined in clause 393.

Clause 554. A compound of formula (VIII-c):

[Image Omitted]

wherein R₁, R₃and R₄are 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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