INTRODUCTION

[0001] The present invention relates to certain compounds that are pharmacologically active compounds which modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase (SGK) proteins, in particular: serum and glucocorticoid regulated kinase isoform 1 (SGK1); serum and glucocorticoid regulated kinase isoform 2 (SGK2); and serum and glucocorticoid regulated kinase isoform 3 (SGK3). The compounds of the present invention may be used to treat disease or conditions mediated, at least in part, by inappropriate SGK activity, for example hyperproliferative diseases, including cancer, and regulation of electrolyte balance in renal and cardiovascular disease. The invention furthermore relates to processes for the preparation of these compounds, their use as pharmaceuticals, and pharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

[0002] The serum and glucocorticoid kinase (SGK) family are a subfamily of serine/threonine kinases which consist of three isoforms: SGK1 (Serum/Glucocorticoid Regulated Kinase 1 , SGK, Serum/Glucocorticoid-Regulated Kinase 1 , Serum/Glucocorticoid Regulated Kinase, Serine/Threonine-Protein Kinase Sgk1 , Serine/Threonine Protein Kinase SGK, Sgk1 Variant I3, EC 2.7.11.1 , Uniprot ID 000141); SGK2 (Serine/Threonine Kinase 2, Serum/Glucocorticoid Regulated Kinase 2, Serum/Glucocorticoid-Regulated Kinase 2, Serine/Threonine-Protein Kinase Sgk2, EC 2.7.11.1 , DJ138B7.2, H-SGK2, Uniprot ID Q9HBY8); and SKG3 (Serum/Glucocorticoid Regulated Kinase Family Member 3, Cytokine-Independent Survival Kinase, SGKL, CISK, Serum/Glucocorticoid Regulated Kinase Family, Member 3, Serum/Glucocorticoid-Regulated Kinase-Like, Serum/Glucocorticoid Regulated Kinase-Like, Serum/Glucocorticoid-Regulated Kinase 3, Serine/Threonine-Protein Kinase Sgk3, EC 2.7.11.1 , Uniprot ID Q96BR1) which are members of the larger AGC kinase family [Lang 2001] They are highly homologous proteins that share over 80% amino acid sequence identity across their catalytic domains. The SGKs are post-translationally modified and activated by phosphorylation in response to signals that stimulate PI3K, this is mediated in part by PDK1 [Lang 2001 , Kobayashi 2003, Tessier 2006] The activation of SGK1 through the PI3K signalling pathway is known to be in response to insulin, IGF and growth factors. SGK3 is distinguished by an N-terminal PX (phox) domain and in contrast to regulation of SGK1 gene transcription, the gene encoding SGK3 is not induced by serum or glucocorticoids [Kobayashi 2003, Tessier 2006] Whereas a distinguishing feature of SGK1 is stimulus- dependent regulation of transcription, cellular localisation and enzymatic activation [Firestone 2003] For SGK3 the PX domain preferentially binds to Ptdlns(3)P, thereby localizing a pool of the kinase to endosomal membranes rather than to the plasma membrane and this has been shown to be essential for activation [Kobayashi 2003, Virbasius 2001]

[0003] Peptide library screening has shown that the SGK family kinases prefer to phosphorylate a similar R-XR-X-X-S/T motif. However, in contrast to the related PKB kinase isoforms, there is a degree of flexibility in the preference for the amino acids surrounding the phosphorylation site motif [Murray 2004] There is evidence to suggest SGK3 can phosphorylate histone H2B and caspase in vitro and it has been shown to inhibit FOX03a- dependent transcriptional activity in a genetic screen to identify factors that mediate interleukin-3 dependent survival of hematopoietic cells [Liu 2000, Tessier & Woodgett 2006] SGK1 has been reported to phosphorylate NDRG1 at three C-terminal residues (Thr328, Ser330 and Thr346) [Murray 2004] Furthermore, SGK3 has been reported to phosphorylate glycogen syntheses kinase 3 beta (GSK-Ob) through direct interaction at serine-9 [Dai 2002] SGKs are also regulators of FOXO activity. FOXOs are involved in a number of pathologic and physiologic processes that include proliferation, apoptosis, autophagy, metabolism, inflammation, cytokine expression, immunity, differentiation, and resistance to oxidative stress. The activity of FOXOs is tightly regulated by posttranslational modification, including phosphorylation, acetylation, and ubiquitylation. AKT and SGK1 can phosphorylate FOX01 and FOX03 at well-defined sites, however as AKT is able to phosphorylate FOXO at the same sites as SGK1 , it may be able to compensate for SGK1 function [Wang and Liu. 2017] There is much less known about the function of SGK2 compared to the other two isoforms. Like the other SGK family members, in vitro experiments have shown that is able to modulate a range of ion channels [Lang 2006]

[0004] Protein kinases control and modulate a wide variety of biological processes through the catalytic transfer of a phosphate group from adenosine triphosphate (ATP) to their protein substrates [Manning, 2002] Since the ATP binding site is similar in different kinases and the majority of small-molecule inhibitors of kinases target the ATP binding site, a challenge in kinase inhibitor discovery is the optimization of selectivity [Huang 2009] Full length sequence alignment of the three human SGK isoforms reveals high sequence identity (> 60%). The sequence identity is even higher in the protein kinase domain (>75%) and very high for those residues defining the putative ATP binding site. The amino acid residue sequence identity in the ATP binding sites between SGK3 and the other SGK family members is 93% and 90% for SGK1 and SGK2 respectively. This striking degree of amino acid sequence similarity for the SGK isoforms in their ATP binding sites suggests an inhibitor with an ATP- competitive mechanism of inhibition would not be expected to exhibit significant SGK isoform selectivity. Therefore, given the high degree of amino acid sequence similarity for the SGK isoforms in their ATP binding sites, the development of an SGK-isoform selective ATP binding site inhibitor would represent a formidable challenge.

[0005] SGK1 mRNA is ubiquitously expressed in almost all human tissues, with highest levels in the pancreas, followed by placenta, kidney and lung [Raikwar 2008] In addition, SGK1 mRNA is found in several embryonic tissues and is detectable during organogenesis [Lee 2001] On a protein level SGK1 expression was concentrated in the intestine, brain, eyes, kidney, ovaries, breast, rectum, adrenal cortical cells, nasopharynx, neuronal cells and bone marrow poietic cells, gastric superficial mucosa, gallbladder and alveolar macrophages. SGK1 can be found throughout the cell (cytoplasm, nucleus, mitochondria, endoplasmic reticulum and cell membranes). The subcellular localization is controlled by the cell cycle, exposure to specific hormones, and environmental stress stimuli [Lang 2006] In proliferating cells, SGK1 shuttles between the nucleus and cytoplasm in synchrony with the cell cycle, and in serum/growth factor-stimulated cells it resides in the nucleus. SGK2 mRNA is highly expressed in liver, kidney and pancreas, and at lower levels in brain [Kobayashi 1999] The protein was found localized to the cytoplasm and nucleus of cells (uniprot.org). SGK3 mRNA is expressed in most tissues with highest levels in pancreas, kidney liver, heart and brain and lower levels in lung, placenta and skeletal muscle [Kobayashi 1999] SGK3 protein is expressed in most tissues and is particularly high in the heart, breast, testis, intestinal glands, gall bladder, exocrine pancreas, placenta and immune cells. Intracellularly SGK3 is localized to cytoplasmic vesicles and the nucleus.

[0006] The expression of SGKs are significantly increased in several types of cancer including gastric, colorectal, liver, breast and lung cancer making it a possible oncology target [Gasser 2014; Yao 2016; Liang 2017; Liu 2017; Tang 2018] A study has shown that approximately 50% of samples tested from patients with nodular lymphocyte predominant Hodgkin lymphoma had SGK1 mutations [Hartmann 2016] However, the functional significance of these alterations remains to be defined. The SGK1 gene has been amplified and overexpression has been observed in breast cancer a proportion of patients [Di Cristofano 2017] SGK3 expression has been linked to the oestrogen receptor both in breast cancer cell lines and in primary tumour samples [Xu 2012] A study of hepatocellular carcinoma specimens has found an amplification and overexpression of SGK3 and SGK2 were frequently detected and that their genomic activation was significantly associated with poor outcome in patients [Liu 2012; Liu 2017]

[0007] The most notable role of the SGK family is their regulation of ion channel activity, transport, and transcription. They can regulate ion channels and carrier proteins directly by phosphorylating the serine or threonine residues on the target protein, modulating their activity [Lang 2006] The SGK kinases participate in the regulation of a wide variety of ion channels and membrane transporters, for example Na+/K+-ATPase activity [Henke 2002]; K ⁺ channel activation [Gamper 2002]; regulation of cardiac Na ⁺ channels [Boehmer 2003]; regulation of the epithelial Ca2+ channel TRPV5 (ECaC1) [Embark 2004], regulation of Na ⁺ -dependent neutral amino acid transporter type 2 (hASCT2/SLC1A5) [Palmada 2005], regulation of the excitatory amino acid transporter EAAT5 [Boehmer 2005] , regulation of the epithelial calcium channel TRPV6 [Boehmer 2007], the neutral amino acid transporter SLC6A19 [Boehmer [2010], and the regulation of ENaC activity by insulin involves SGK1 catalytic activity [Pearce 2007] The most well characterised role of SGKs (mainly SGK1) is the role they play in modulating the activity of the epithelial Na+ channel (ENaC). ENaC is the channel that controls Na+ reabsorption across epithelial tissues including the colon, sweat glands, salivary ducts, airway and the distal kidney nephron. Sodium reabsorption is a major determinant of extracellular fluid volume and consequently is involved in the regulation of blood pressure. ENaC transports Na+ into cells driving the retention of water via osmosis [Butterworth 2010] All SGK isoforms can enhance ENaC activity in vitro which suggests that all three kinases are likely to participate in the regulation of epithelial Na+ transport [Friedrich 2003] Overactivity of ENaC results in excessive Na+ reabsorption in the kidney distal nephron resulting in hypokalemia, metabolic alkalosis, volume expansion and associated arterial hypertension [Butterworth 2010] Therefore, SGK expression must be controlled to maintain Na+ homeostasis [Zhou 2005]

[0008] SKG1 -knockout (sgk1 -/-) mice are viable and seemingly normal when fed a standard diet but demonstrate a defect in sodium homeostasis in which dietary salt deficiency leads to marked decrease of glomerular filtration rate and blood pressure [Wulff 2002] Enhanced SGK1 expression has been observed in the salt-sensitive Dahl rat [Farjah 2003], and moderately enhanced blood pressure is observed in individuals carrying a gain of function variant of the SGK1 gene, affecting as many as 5% of unselected Caucasians [Busjahn 2002] One study highlighted that individuals who are carrying a polymorphism of the SGK1 gene had hypertension. They also showed that the same SGK1 polymorphism was significantly more frequent in type 2 diabetic patients, indicating that SGK1 may participate in the pathogenesis of metabolic syndrome [Schwab 2008] SGK3 knockout ( sgk3 -/-) mice are viable, fertile, healthy and of normal size and weight but they display distinctly abnormal whiskers and hair coats [Alonso 2005, Ciprian 2005] In addition to the follicle phenotype, the SGK3 null mice also show a decrease in intestinal glucose transport mediated through the sodium-dependent glucose transporter SGLT1 [Dieter 2004, Sandu 2005] SGK1/SGK3 double knockout mice ( sg^-/-/sgk3-/~ ) are viable and display a phenotype reflecting properties of sgk1-l- and sgk3-/~ mice.

[0009] SGK1 plays a critical role in the induction of pathogenic Th17 cells and interacts with environmental factors such as a high salt diet to trigger Th17 development and promote tissue inflammation. Th17 cells are potent proinflam matory cells critical for clearing extracellular pathogens and for induction of multiple autoimmune diseases. IL-23 plays a critical role in stabilizing and reinforcing the Th17 phenotype by increasing expression of IL-23 receptor [Wu 2013] SGK1 is not thought not to play a role in Th17 cell differentiation, however it does promote TH2 differentiation upon activation by mTORC2, but it is not essential for TH 1 differentiation. Mice with a selective deletion of SGK1 in T cells were also resistant to experimentally induced asthma, generated robust amounts of IFN-g in response to viral infections and more readily rejected tumours. Together this shows the importance of SGK1 on driving TH2 cell differentiation and identifies SGK1 as a potential target for the treatment of TH2-mediated autoimmune and allergic diseases [Heikamp 2014] Conversely, SGK1 has been shown to be a potent negative regulator of toll-like receptor (TLR) induced inflammation. Suppression of SGK1 by siRNA in vitro, enhanced proinflammatory cytokine production in tolllike receptor engaged monocytes. In vivo, using a murine endotoxin model, SGK1 inhibition was shown to aggravate the severity of multiple organ damage and enhance the inflammatory response by heightening both proinflammatory cytokine levels and neutrophil infiltration [Zhou e2015]. This supports that SGK1 activity is key in down regulating TLR-medicated inflammation and protects against endotoxin driven failure.

[0010] The phosphatidylinositol 3-kinase (PI3K) signalling pathway controls a range of fundamental cellular processes [Engelman 2009] Classl phosphoinositide3-kinase (PI3K) generates phosphatidylinositol3,4,5-trisphosphate (Ptdlns(3,4,5)P3) at the plasma membrane in response to growth factors, activating a signalling cascade that regulates many cellular functions. The PI3K pathway is commonly dysregulated in human cancer and drives tumorigenesis by promoting aberrant cell growth and transformation. Ptdlns(3,4,5)P3 signalling is degraded and terminated by phosphoinositide phosphatases such as phosphatase and tensin homologue (PTEN), proline-rich inositol polyphosphate 5- phosphatase (PIPP) (INPP5J) and inositol polyphosphate 4-phosphatase type ll(INPP4B).

[0011] The serum and glucocorticoid inducible protein kinase (SGK) family signals downstream of the PI3K pathway as members of the AGC kinase family, the SGK sub-family proteins phosphorylate a variety of proteins, including core components of signal pathways that play important roles in multiple cellular processes, such as cell growth, proliferation, survival and apoptosis [Basnet 2008, Bruhn 2010]

[0012] SGK1 has been reported to be essential for several cancers: prostate, human melanoma and kidney cancer cells [Basnet 2008] SGK1 was highly expressed in colonic tumour samples from CRC patients, and it was shown to be essential for CRC development via the promotion of tumour cell proliferation, migration and survival [Liang 2017] SGK1 plays a critical role in promoting epithelial cell survival under conditions of cellular stress such as serum-deprivation and chemotherapy treatment [Mitkosz 2001] SGK1 is able to directly phosphorylate F0X01 at residues T32 and S315 [Brunet 2001] and has been correlated with resistance to AKT inhibition as AKT-inhibitor-resistant breast cancer possess elevated levels of SGK1 and are dependent on SGK1 for proliferation [Sommer 2013] SGK1 has been identified as a substrate of mTOR kinase activity and in breast cancer cells the dependence of SGK1 Ser422 phosphorylation on mTORCI activity associates with ER-alpha expression [Hall2012] Furthermore, the PDK1-SGK1 axis can sustain mTORCI activity upon PI3K/AKT suppression and SGK1 directly phosphorylates TSC2, resulting in mTORCI activation. Targeting SGK1 prevents mTORCI activation, restoring the antitumoral effects of PI3Ka inhibition in resistant cells [Castel 2016] SGK1 interferes with the signaling of membrane androgen receptors, to trigger down regulation on the PI3K pathway to induce apoptosis of prostate tumour cells and protect against tumour growth [Papadopoulou 2008] and promoted cell growth of prostate cancer cell lines [Sherk 2008] Unlike SGK1 , the expression of SGK3 is not regulated by glucocorticoids. Instead, ER signalling has been shown to induce SGK3 mRNA transcription [Wang 2011] and this link is found in both breast cancer cell lines and in primary tumour samples [Xu 2012] Interestingly these studies found a positive correlation between SGK3 protein expression and tumour prognosis [Xu 2012] SGK3 also promotes estrogen-mediated cell survival of ER-positive breast cancer cells and activated SGK3 can promote estrogen/ER-dependent transcription and cell survival [Xu 2012], supporting a model in which SGK3 and ER form a feedback loop [Wang 2006] SGK3 was highly expressed in breast invasive ductal carcinoma tissues, and positively correlated with the pathological grade of tumour and the ER expression [Xu 2012] SGK3 has been shown to enhance ERa transactivation activity through phosphorylation of coactivator Flightless-I [Xu 2009] SGK3 expression is higher in ER-positive breast tumors than ER-negative breast tumours [Wang 2011] Furthermore, SGK3 has been found to sustain ERa signaling and drive acquired aromatase inhibitor resistance by protecting against endoplasmic reticulum (EnR) stress- induced ERa downregulation and cell death through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function [Wang 2016] Similarly, SGK3 has also been shown to be an AR transcriptional target, that can promote prostate cancer cell proliferation. This study found that androgen/AR-dependent SGK3 expression required the estrogen receptor [Wang 2014] SGK3 expression can promote breast cancer through an AKT-independent mechanism. In this study activation of SGK3 downstream of PIK3CA and INPP4B was shown to be required for 3D proliferation, invasive migration, and tumorigenesis in vitro [Gasser 2014] In PIK3CA mutant cancer cells SGK3 undergoes PI3K- and PDK1-dependent activation, to act as an oncogenic effector independent of AKT [Vasudevan 2009] In colon cancer cells, INPP4B-mediated degradation of PTEN promoted tumour growth, proliferation and co-operatively enhanced AKT and SGK3 activation downstream of PI3K [Guo 2016] High INPP4B protein expression in fresh melanoma isolates and melanoma cell lines was associated with high pSGK3T320 levels. INPP4B shRNA knockdown attenuated melanoma cell proliferation and xenograft tumour growth, whereas INPP4B overexpression enhanced cell proliferation and promoted melanocyte anchorage-independent cell growth, driven by INPP4B-mediated activation of SGK3 in an AKT-independent manner [Chi 2015]

[0013] In view of the relevance of the SGK family proteins for various physiological processes outlined above, inhibitors of the SGK family proteins such as the compounds of the present invention can be used in the treatment of various disease states in which SGK activity plays a role or which are associated with inappropriate SGK activity, or in which inhibition, regulation or modulation of signal transduction by SGK family proteins is desired. Taken together these studies suggest selective inhibition of the SGK isoforms to be a promising therapeutic approach, particularly for the treatment of hyperproliferative diseases, including cancer, and for the regulation of electrolyte balance in renal and cardiovascular disease.

[0014] The present invention has been devised with the foregoing in mind.

[0015] 3-amino-N-(1-benzyl-1 H-pyrazol-4-yl) pyrazine-2-carboxamide and 2-amino-N-(1- benzyl-1 H-pyrazol-4-yl)nicotinamide (CAS 1311914-47-2 and 1851812-22-0) are known compounds but no pharmacological activity, and in particular no SGK inhibitory activity, has been previously disclosed for these two compounds.

SUMMARY OF THE INVENTION

[0016] According to a first aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0017] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0018] According to a further aspect of the present invention, there is provided a method of inhibiting SGK activity, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.

[0019] According to a further aspect of the present invention, there is provided a method of inhibiting cell proliferation or regulating electrolyte balance in renal and/or cardiovascular disease, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein. [0020] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder in which SGK activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0021] According to a further aspect of the present invention, there is provided a method of treating a proliferative disorder or regulating electrolyte balance in renal and/or cardiovascular disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0022] According to a further aspect of the present invention, there is provided a method of treating cancer or regulating electrolyte balance in renal and/or cardiovascular disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0023] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0024] According to a further aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition or in regulating electrolyte balance in renal and/or cardiovascular disease.

[0025] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer, in particular oestrogen positive cancers, such as breast cancer, or androgen receptor positive cancers, such as prostate cancer.

[0026] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of SGK activity.

[0027] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which SGK activity is implicated. [0028] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition or in regulating electrolyte balance in renal and/or cardiovascular disease.

[0029] Suitably, the proliferative disorder is cancer, suitably a human cancer (for example haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)) and multiple myeloma, and solid tumours (including glioma, breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary)).

[0030] According to a further aspect of the present invention, there is provided the use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.

[0031] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of SGK activity.

[0032] According to a further aspect of the present invention, there is provided a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which SGK activity is implicated.

[0033] According to a further aspect of the present invention, there is provided a process for preparing a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0034] According to a further aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.

[0035] According to a further aspect of the present invention, there are provided novel intermediates as defined herein which are suitable for use in any one of the synthetic methods set out herein.

[0036] Features, including optional, suitable, and preferred features in relation to one aspect of the invention may also be features, including optional, suitable and preferred features in relation to any other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0037] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0038] It is to be appreciated that references to“treating” or“treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.“Treating” or“treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0039] A“therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0040] In this specification the term“alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as“propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as“isopropyl” are specific for the branched chain version only. For example, “(1-6C)alkyl” includes (1- 4C)alkyl, (1-3C)alkyl, propyl, isopropyl and f-butyl.

[0041] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0042] An“alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH ₂ -), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), 2-methylpropylene (-CH ₂ CH(CH ₃ )CH ₂ -), pentylene (- CH2CH2CH2CH2CH2-), and the like.

[0043] The term“alkyenyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present within the group. Examples of alkenyl groups include ethenyl, propenyl and but-2,3-enyl and includes all possible geometric (E/Z) isomers.

[0044] The term“alkynyl” refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present within the group. Examples of alkynyl groups include acetylenyl and propynyl.

[0045] “(3-10C)cycloalkyl” means a hydrocarbon ring containing from 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl.

[0046] The term “alkoxy” refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy and f-butoxy.

[0047] The term“haloalkyl” is used herein to refer to an alkyl group in which one or more hydrogen atoms have been replaced by halogen (e.g. fluorine) atoms. Examples of haloalkyl groups include -CH ₂ F, -CHF ₂ and -CF3.

[0048] The term“halo” or“halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.

[0049] The term“carbocyclyl”,“carbocyclic” or“carbocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon-containing ring system(s). Monocyclic carbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms. Bicyclic carbocycles contain from 6 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic carbocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and spiro[3.3]heptanyl.

[0050] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2/-/-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 , 1-dioxide and thiomorpholinyl 1 , 1-dioxide. Heterocycles may comprise 1 or 2 oxo (=0) or thioxo ( =S ) substituents. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo ( =S ) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 , 1-dioxide, thiomorpholinyl, thiomorpholinyl 1 , 1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1- yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0051] By“bridged ring systems” is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 ^th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.

[0052] By“spiro bi-cyclic ring systems” we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-

6-azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-

7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0053] The term“heteroaryl” or“heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0054] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2, 1-b]thiazolyl, imidazo[1 ,2-b][1 ,2,4]triazinyl.“Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-

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

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

[0055] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0056] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0057] A bicyclic heteroaryl group may be, for example, a group selected from:

a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;

a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

a pyrrole ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;

a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms; and

a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms.

[0058] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.

[0059] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0060] The term“aryl” means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.

[0061] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example (3-6C)cycloalkyl(m-nC)alkyl comprises (m-nC)alkyl substituted by (3- 6C)cycloalkyl.

[0062] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term“wherein a/any CH, Chb, CH ₃ group or heteroatom (i.e. NH) within a R ¹ group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R ¹ group is substituted by a relevant stipulated group.

[0063] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0064] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.

Compounds of the invention

[0065] In one aspect, the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (I), shown below:

Formula (I)

wherein:

Xi is N or CH;

X ₂ is N or C-Ri ;

with the proviso that X2 is only N when Xi is CH;

Ri is selected from hydrogen, halo, cyano, amino, hydroxy, (1-2C)alkyl or (1-2C)alkoxy; either:

Yi and Y2 are N and Y3 is C-RY3 and Y4 is C-RY ₄ ; or

Yi is C, Y2 and Y3 are both N and Y4 is O;

and RY3 and R _Y are each independently selected from hydrogen, halo or methyl; R ₂ is selected from hydrogen, halo, cyano or a group of the formula:

- ^| _ ₂ -M ₂ Q ₂

wherein

l_2 is absent or a (1-3C)alkylene; M is absent, N(R _e ) or C(0)N(R _e ), wherein R _e is selected from hydrogen or (1-4C)alkyl; and

Q ₂ is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, heterocyclyl or heteroaryl;

and wherein Q ₂ is optionally substituted by one or more substituents selected from (1-4C)alkyl, (3-6C) cycloalkyl, halo, trifluorom ethyl, trifluoromethoxy, cyano, NR _g R _h , OR _g , C(0)R _g , C(0)0R _g , 0C(0)R _g , C(0)N(R _g )R _h , N(R _g )C(0)R _h , S(0) _y R _g (where y is 0, 1 or 2), S0 ₂ N(R _g )R _h , N(R _g )S0 ₂ R _h or (CH ₂ ) _z NR _g R _h (where z is 1 , 2 or 3), wherein R _g and R _h are each independently selected from hydrogen or (1-4C)alkyl, (1-4C)haloalkyl or aryl(1-2C)alkyl;

R ₃ is selected from hydrogen, (1-4C)alkyl, (1-6C)alkoxy(1-2C)alkyl or hydroxy(1-2C)alkyl; or R ₂ and R ₃ may be linked such that, together with the carbon atom to which they are attached, they form a (3-7C)cycloalkyl or a 3 to 7-membered heterocyclic ring comprising one, two or three heteroatoms selected from N, O or S, wherein the (3-7C)cycloalkyl or the 3 to 7- membered heterocyclic ring is optionally substituted by one or more substituents selected from halo, cyano, (1-4C)alkyl, NRMR2B, OR2A, C(0)R2A, C(0)0R2A, 0C(0)R2A, C(0)N(R ₂ A)R2B, N(R ₂ A)C(0)R ₂ B, S(0)yR2A (where y is 0, 1 or 2), S0 ₂ N(R ₂ A)R2B, N(R _2A )S02R2B or (CH ₂ )ZNR ₂ AR2B (where z is 1 , 2 or 3), wherein R _åA and R _YB are each independently selected from hydrogen, (1-4C)alkyl or (1-4C)haloalkyl;

Y is absent or -CR _j R _k -, wherein Rj and Rk are each independently selected from hydrogen or (1-4C)alkyl;

Z is a group of the formula:

wherein:

Zi is N or CRzi;

Z ₂ is N or CR _z2 ;

Z ₃ is N or CR _z3 ;

Z ₄ is N or CR _Z4 ;

Z ₅ is N or CR _Z5 ; å6 is N, O, S or CRzs;

å7 is N, O, S or CR _Z 7;

å8 is N, O, S or CRzs;

å9 is N, O, S or CR _zg ;

with the proviso that only 1 , 2 or 3 of åi, å2, å3, å4 or ås can be N and only one of åe, å7, å ₈ or åg can be O or S;

and wherein R _zi , R _Z 3, R _z 4, R _z s, R _z6 , R _z e and R _Z 9 are each independently selected from hydrogen, halo, methyl, methoxy, -CF ₃ , -OCF ₃ , -NH ₂ , -NHMe, -NMe ₂ , cyano, and

-C(0)NH ₂ ; and

R _z2 and R _Z 7 are selected from hydrogen, halo, cyano or a group of the formula:

-L3-M3-Q3

wherein

l_3 is absent or a (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl, halo, hydroxy or oxo;

M3 is absent or selected from O, S, SO, S0 ₂ , N(R _k ), C(O), C(0)0, OC(O), C(0)N(R _k ), N(R _k )C(0), N(R _k )C(0)N(Ri), S(0) ₂ N(R _k ), or N(R _k )S0 ₂ , wherein R _k and Ri are each independently selected from hydrogen or (1-4C)alkyl; and

Q ₃ is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, (2-6C)alkynyl, aryl, heterocyclyl or heteroaryl;

and wherein Q ₃ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR _m Rn, OR _m , C(0)R _m , C(0)0R _m , 0C(0)R _m , C(0)N(R _m )Rn, N(R _m )C(0)Rn, S(0) _y R _m (where y is 0, 1 or 2), S0 ₂ N(R _m )R _n , N(R _m )S0 ₂ R _n , (CH ₂ ) _z NR _m R _n (where z is 1 , 2 or 3), aryl, heterocyclyl or heteroaryl,

wherein R _m and R _n are each independently selected from hydrogen or (1- 4C)alkyl or

when R _m and R _n are both attached to a N atom, R _m and R _n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring which is optionally substituted by (1-4C). alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR ₀ R _P , OR ₀ , wherein R ₀ and R _p are hydrogen or (1- 2C)alkyl,

with the proviso that the compounds 3-amino-N-(1-benzyl-1 H-pyrazol-4-yl) pyrazine-2- carboxamide and 2-amino-N-(1-benzyl-1 H-pyrazol-4-yl)nicotinamide are excluded.

[0066] Particular compounds of the invention include, for example, compounds of the Formula (I), or pharmaceutically acceptable salts, hydrates and/or solvates thereof, wherein, unless otherwise stated, each of Xi, X ₂ , Yi , Y ₂ , Y ₃ , Y ₄ , R ₂ , R ₃ , Y and Z and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (34) hereinafter:

(1) Xi is CH;

(2) Xi is N;

(3) X ₂ is N;

(4) X ₂ is CH;

(5) Xi is N and X ₂ is CH;

(6) Xi is N and X ₂ is C-Ri;

(7) Xi is CH and X ₂ is N;

(8) Xi is CH and X ₂ is CH;

(9) Ri is selected from hydrogen, halo, or (1-2C)alkyl;

(10) Ri is selected from hydrogen or halo;

(11) Yi and Y are N and Y ₃ and Y are C-H;

(12) Yi is C, Y2 and Y ₃ are both N and Y ₄ is O;

(13) R is selected from hydrogen or a group of the formula:

-L2-M2-Q2

wherein

l_2 is absent;

M2 is absent or C(0)N(R _e ), wherein R _e is independently selected from hydrogen or (1- 4C)alkyl; and

Q2 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, heterocyclyl or heteroaryl;

and wherein Q2 is optionally substituted by one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, halo, trifluoromethyl, trifluoromethoxy, cyano, NR _g R _h , ORg, C(0)Rg, C(0)ORg, OC(0)R _g , C(0)N(Rg)R _h , N(Rg)C(0)R _h , S(0) _y Rg (where y is 0,

1 or 2), SC>2N(R _g )R _h , N(R _g )S0 ₂ R _{h O} r (CH2) _z NR _g R _h (where z is 1 , 2 or 3), wherein R _g and R _h are each independently selected from hydrogen or (1-4C)alkyl, (1- 4C)haloalkyl, or aryl(1-2C)alkyl; (14) R is selected from hydrogen or a group of the formula:

-L2-M2-Q2

wherein

l_2 is absent;

M2 is absent or C(0)N(R _e ), wherein R _e is independently selected from hydrogen or (1- 4C)alkyl; and

Q2 is hydrogen, (1-6C)alkyl or heterocyclyl;

and wherein Q2 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, NR _g R _h and OR _g , wherein R _g and R _h are each independently selected from hydrogen, (1-4C)alkyl or aryl(1-2C)alkyl;

(15) R ₂ is hydrogen;

(16) R ₂ is a group of the formula:

-L2-M2-Q2

wherein

l_2 is absent;

M2 is absent; and

Q2 is (1-6C)alkyl or heterocyclyl;

and wherein Q ₂ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, NR _g R _h and OR _g , wherein R _g and R _h are each independently selected from hydrogen, (1-4C)alkyl or benzyl;

(17) R ₂ is a group of the formula:

-L2-M2-Q2

wherein

l_2 is absent;

M2 is absent; and

Q ₂ is (1-6C)alkyl;

and wherein Q ₂ is substituted by one or more substituents selected from halo, NR _g R _h and OR _g , wherein R _g and R _h are each independently selected from hydrogen, (1- 4C)alkyl or benzyl;

(18) R ₂ is a group of the formula:

-|_2 ^_ M ₂ ^_ Q2

wherein

l_2 is absent;

M2 is absent; and

Q ₂ is (1-6C)alkyl; and wherein Q is substituted by NR _g R _h , wherein R _g and R _h are each independently selected from hydrogen or (1-4C)alkyl;

(19) R ₂ is a group of the formula:

-L ₂ -M ₂ -Q ₂

wherein

L ₂ is absent;

M ₂ is absent; and

Q ₂ is heterocyclyl;

and wherein Q ₂ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo and OR _g , wherein R _g is hydrogen, (1-4C)alkyl or benzyl;

(20) R ₂ is a group of the formula:

-l_ ₂ -M ₂ -Q ₂

wherein

L ₂ is absent;

M ₂ is absent; and

Q ₂ is heterocyclyl;

and wherein Q ₂ is optionally substituted by one or more substituents selected from methyl and fluoro;

(21) R ₂ is a group of the formula:

-|_2-M ₂ ^_ Q2

wherein

l_2 is absent;

M ₂ is absent; and

Q ₂ is selected from one of the following heterocyclyl groups:

wherein represents the point of attachment of the heterocyclyl group to the rest of the compound of formula I and wherein Q ₂ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo and OR _g , wherein R _g is hydrogen, (1-4C)alkyl or benzyl; (22) R is a group of the formula:

-L2-M2-Q2

wherein

l_2 is absent;

M2 is absent; and

Q2 is selected from one of the following heterocyclyl groups:

wherein LLL^ represents the point of attachment of the heterocyclyl group to the rest of the compound of formula I and wherein Q ₂ is optionally substituted by one or more substituents selected from (1-4C)alkyl, fluoro and OR _a , wherein R _g is hydrogen, (1-2C)alkyl or benzyl;

(23) R ₃ is hydrogen, methyl or hydroxymethyl;

(24) R3 is hydrogen;

(25) Y is absent;

(26) Y is -CR _j Rk-, wherein

R _j is hydrogen; and

R _k is hydrogen;

(27) Z is a phenyl ring;

(28) Z is a group of the formula: wherein vrv/w* represents the point of attachment to the rest of the compound of formula I and wherein:

Zi is N or CR _zi ;

Z2 is N or CRz2i

Z ₃ is N or CR _z3 ;

Z4 is N or CR _z ;

Z5 is N or CR _Z5 ;

with the proviso that only 0 or 1 of Zi , Z2, Z ₃ , Z 4 or Zs is N;

and wherein R _zi , R _Z 3, R _å 4 and R _z s are each independently selected from hydrogen, halo, methyl, methoxy, -CF ₃ , -OCF3, -INH2, -NHMe, -NMe2, cyano, and

-C(0)NH ₂ ; and

R _Z 2 is selected from hydrogen, halo, cyano or a group of the formula:

-L ₃ -M ₃ -Q ₃

wherein

l_3 is absent or a (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl, halo, hydroxy or oxo;

M3 is absent or selected from O, S, SO, S0 ₂ , N(R _k ), C(O), C(0)0, OC(O), C(0)N(R _k ), N(R _k )C(0), N(R _K )C(0)N(R _I ), S(0) ₂ N(R _k ), or N(R _k )S0 ₂ , wherein R _k and Ri are each independently selected from hydrogen or (1-4C)alkyl; and Q3 is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, (2-6C)alkynyl, aryl, heterocyclyl or heteroaryl;

and wherein Q ₃ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, cyano, NR _m R _n , OR _m , C(0)R _m , C(0)0R _m , 0C(0)R _m , C(0)N(R _m )R„, N(R _m )C(0)R„, S(0) _y R _m (where y is 0, 1 or 2), S0 ₂ N(R _m )R _n , N(R _m )S0 ₂ R _n , (CH ₂ ) _z NR _m R _n (where z is 1 , 2 or 3), aryl, heterocyclyl or heteroaryl,

wherein R _m and R _n are each independently selected from hydrogen or (1- 4C)alkyl or

when R _m and R _n are both attached to a N atom, R _m and R _n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring which is optionally substituted by (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR ₀ R _P , OR ₀ , wherein R ₀ and R _p are hydrogen or (1-2C)alkyl;

(29) Z is a group of the formula:

wherein ΆLL represents the point of attachment to the rest of the compound of formula I and wherein:

Zi is CRzi;

Z ₂ is CR _z2 ;

Z ₃ is CR _z3 ;

Z4 is CR _z ,

Z5 is CR _z5 ;

wherein R _zi , R _z3 , R _å4 and R _z5 are each independently selected from hydrogen, halo, methyl, methoxy, -CF ₃ , cyano, and -C(0)NH ₂ ; and

R _z2 is selected from hydrogen, halo or a group of the formula:

-L ₃ -M ₃ -Q ₃

wherein

l_ ₃ is absent or (1-3C)alkylene;

M ₃ is absent or selected from O, S0 ₂ , N(R _k ), C(0)0, C(0)N(R _k ), N(R _k )C(0) or N(R _k )S0 ₂ , wherein R _k is selected from hydrogen or (1-4C)alkyl; and

Q ₃ is hydrogen, (1-6C)alkyl, (3-6C) cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, heterocyclyl;

and wherein Q ₃ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, cyano, NR _m R _n , OR _m , C(0)N(R _m )R _n , aryl or heterocyclyl, wherein R _m and R _n are each independently selected from hydrogen or (1-4C)alkyl or

when R _m and R _n are both attached to a N atom, R _m and R _n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring;

(30) Z is a group of the formula: wherein ww ^« represents the point of attachment to the rest of the compound of formula I and wherein:

Zi is CRzi;

Z ₂ is CR _z2 ;

Z ₃ is CR _z3 ;

Z ₄ is CR _Z4

Z ₅ is CR _z5 ;

wherein R _zi , R _Z3 , R _z4 and R _z5 are each independently selected from hydrogen, fluoro, chloro, and methoxy; and

R _Z2 is selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, cyano,

NR _m Rn, OR _m , C(0)Rm, C(0)0R _m , 0C(0)R _m , C(0)N(R _m )R _n , N(R _m )C(0)R _n , S(0) _y R _m (where y is 0, 1 or 2), S0 ₂ N(R _m )Rn, N(R _m )S0 ₂ R _n , (CH ₂ ) _z NR _m Rn (where z is 1 , 2 or 3), aryl, heterocyclyl or heteroaryl and wherein R _m and R _n are each independently selected from hydrogen or (1-4C)alkyl;

(31) Z is a group of the formula:

wherein ww represents the point of attachment to the rest of the compound of formula I and wherein:

R _z2 is selected from hydrogen, halo or a group of the formula:

-L3-M3-Q3

wherein

l_ ₃ is absent or (1-3C)alkylene;

M ₃ is absent or selected from O, S0 ₂ , N(R _k ), C(0)0, C(0)N(R _k ), N(R _k )C(0) or N(R _k )S0 ₂ , wherein R _k is selected from hydrogen or (1-4C)alkyl; and

Q ₃ is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, heterocyclyl;

and wherein Q ₃ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, cyano, NR _m Rn, OR _m , C(0)N(R _m )Rn, aryl or heterocyclyl, wherein R _m and R _n are each independently selected from hydrogen or (1-4C)alkyl or

when R _m and R _n are both attached to a N atom, R _m and R _n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring;

R _z is fluoro, chloro or methyl; and

m is 0 or 1 ;

(32) Z is a group of the formula:

wherein -wv' represents the point of attachment to the rest of the compound of formula I and wherein:

R _Z 2 is selected from hydrogen, halo or a group of the formula:

-L3-M3-Q3

wherein

l_3 is absent or (1-3C)alkylene;

Ms is absent or selected from O, S0 ₂ , N(R _k ), C(0)0, C(0)N(R _k ), N(R _k )C(0) or N(R _k )S0 ₂ , wherein R _k is selected from hydrogen or (1-4C)alkyl; and

Q ₃ is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, heterocyclyl;

and wherein Q ₃ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, cyano, NR _m R _n , OR _m , C(0)N(R _m )R _n , aryl or heterocyclyl, wherein R _m and R _n are each independently selected from hydrogen or (1-4C)alkyl or

when R _m and R _n are both attached to a N atom, R _m and R _n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring; and

R _Z 4 is hydrogen, fluoro, chloro or methyl;

(33) Z is a group of the formula: wherein «ww represents the point of attachment to the rest of the compound of formula I and wherein:

R _Z 2 is selected from hydrogen, halo or a group of the formula:

-L3-M3-Q3

wherein

l_ ₃ is absent or (1-3C)alkylene;

Ms is absent or selected from O, S0 ₂ , N(R _k ), C(0)0, C(0)N(R _k ), N(R _k )C(0) or N(R _k )SC>2, wherein R _k is selected from hydrogen or (1-4C)alkyl; and

Q ₃ is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, heterocyclyl;

and wherein Q ₃ is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, cyano, NR _m Rn, OR _m , C(0)N(R _m )Rn, aryl or heterocyclyl, wherein R _m and R _n are each independently selected from hydrogen or (1-4C)alkyl or

when Rm and R _n are both attached to a N atom, R _m and R _n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring;

(34) Z is a group of the formula:

wherein ww represents the point of attachment to the rest of the compound of formula I and wherein:

R _Z 2 is selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, cyano, NR _m Rn, ORm, C(O) Rm, C(0)0Rm, 0C(0)Rm, C(0)N(Rm)Rn, N(Rm)C(0)R„, S(0)yRm (where y is 0, 1 or 2), S0 ₂ N(Rm)Rn, N(R _m )S0 ₂ Rn, (CH2)zNR _m Rn (where z is 1 , 2 or 3), aryl, heterocyclyl or heteroaryl and wherein R _m and R _n are each independently selected from hydrogen or (1-4C)alkyl.

[0067] Suitably, Xi is as defined in any one of paragraphs (1) to (2) above. Most suitably, Xi is as defined in paragraph (2) above.

[0068] Suitably, X2 is as defined in any one of paragraphs (3) to (4) above. Most suitably, X2 is as defined in paragraph (4) above.

[0069] Suitably, Xi and X ₂ are as defined in any one of paragraphs (5) to (8) above. Most suitably, Xi and X ₂ are as defined in paragraph (5) above.

[0070] Suitably, Ri is as defined in any one of paragraphs (9) to (10) above. Most suitably, Ri is as defined in paragraph (10) above.

[0071] Suitably, Yi to Y ₄ are as defined in any one of paragraphs (11) to (12) above. Most suitably, Yi to Y ₄ are as defined in paragraph (11) above.

[0072] Suitably, R ₂ is as defined in any one of paragraphs (13) to (22) above. Most suitably, R ₂ is as defined in paragraph (16) above.

[0073] Suitably, R ₃ is as defined in paragraph (23) or (24) above. Most suitably, R ₃ is as defined in paragraph (24) above

[0074] Suitably, Y is as defined in any one of paragraphs (25) to (26) above. Most suitably, Y is as defined in paragraph (25) above.

[0075] Suitably, Z is as defined in any one of paragraphs (27) to (34) above. Most suitably, Z is as defined in paragraph (27), paragraph (32) or paragraph (34) above.

[0076] Suitably an aryl group is phenyl.

[0077] In a particular group of compounds of the invention, Xi is N and X2 is CH, i.e. the compounds have the structural formula la (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula la

wherein each of Yi , Y ₂ , Y ₃ , Y ₄ , R ₂ , R ₃ , Y and Z are as defined hereinabove.

[0078] In an embodiment of the compounds of Formula la:

Yi to Y are as defined in any one of paragraphs (11) to (12) above;

R ₂ is as defined in any one of paragraphs (13) to (22) above;

R ₃ is as defined in paragraphs (23) to (24) above;

Y is as defined in any one of paragraphs (25) to (26) above; and Z is as defined in any one of paragraphs (27) to (34) above.

[0079] In another embodiment of the compounds of Formula la:

Yi to Y are as defined in paragraph (11) above;

R ₂ is as defined in paragraph (16) above;

R ₃ is as defined in paragraph (24) above;

Y is as defined in paragraph (25) above; and

Z is as defined in paragraph (27) or paragraph (34) above.

[0080] In a particular group of compounds of the invention, the compounds have the structural formula lb (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula lb

wherein each of R ₂ , R ₃ , Y and Z are as defined hereinabove.

[0081] In an embodiment of the compounds of Formula lb:

R ₂ is as defined in any one of paragraphs (13) to (22) above;

R ₃ is as defined in paragraph (23) to (24) above;

Y is as defined in any one of paragraphs (25) to (26) above; and

Z is as defined in any one of paragraphs (26) to (33) above.

[0082] In another embodiment of the compounds of Formula lb:

R ₂ is as defined in paragraph (16) above;

R ₃ is as defined in paragraph (24) above;

Y is as defined in paragraph (25) above; and

Z is as defined in paragraph (27) or paragraph (34) above.

[0083] In a particular group of compounds of the invention, R ₃ is hydrogen and Y is absent, i.e. the compounds have the structural formula lc (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Formula lc

wherein each of Xi , X , Yi , Y2, Y3, Y4, R2 and Z are as defined hereinabove.

[0084] In an embodiment of the compounds of Formula lc:

Xi and X ₂ are as defined in any one of paragraphs (5) to (8) above;

Yi to Y are as defined in any one of paragraphs (11) to (12) above;

R ₂ is as defined in any one of paragraphs (13) to (22) above; and

Z is as defined in any one of paragraphs (27) to (34) above.

[0085] In another embodiment of the compounds of Formula lc:

Xi and X ₂ are as defined in paragraph (5) above;

Yi to Y4 are as defined in paragraph (11) above;

R ₂ is as defined in paragraph (16) above; and

Z is as defined in paragraph (27) or paragraph (34) above.

[0086] In a particular group of compounds of the invention, the compounds have the structural formula Id (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

wherein each of Xi , X ₂ , Yi , Y ₂ , Y ₃ , Y ₄ , R ₂ , Zi, Z ₂ , Z ₃ , Z ₄ and Z ₅ are as defined hereinabove.

[0087] In an embodiment of the compounds of Formula Id:

Xi and X ₂ are as defined in any one of paragraphs (5) to (8) above;

Yi to Y are as defined in any one of paragraphs (11) to (12) above;

R ₂ is as defined in any one of paragraphs (13) to (22) above; and Zi to Z ₅ are as defined in any one of paragraphs (28) to (30) above.

[0088] In another embodiment of the compounds of Formula Id:

Xi and X ₂ are as defined in paragraph (5) above;

Yi to Y are as defined in paragraph (11) above;

R ₂ is as defined in paragraph (16) above; and

Zi to Z ₅ are as defined in paragraph (30) above.

[0089] In a particular group of compounds of the invention, the compounds have the structural formula le (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula le

wherein each of Xi , X ₂ , Yi , Y ₂ , Y3, Y ₄ , R2 and R _z2 are as defined hereinabove.

[0090] In an embodiment of the compounds of Formula le:

Xi and X ₂ are as defined in any one of paragraphs (5) to (8) above;

Yi to Y are as defined in any one of paragraphs (11) to (12) above;

R ₂ is as defined in any one of paragraphs (13) to (22) above; and

R _z2 is as defined in any one of paragraphs (31) to (34) above.

[0091] In another embodiment of the compounds of Formula le:

Xi and X ₂ are as defined in paragraph (5) above;

Yi to Y are as defined in paragraph (11) above;

R ₂ is as defined in paragraph (16) above; and

R _z2 is as defined in paragraph (34) above.

[0092] In a particular group of compounds of the invention, the compounds have the structural formula If (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Formula If

wherein each of Xi , X ₂ , Yi , Y ₂ , Y3, Y ₄ , R ₂ , R _z , m and R _z2 are as defined hereinabove.

[0093] In an embodiment of the compounds of Formula If:

Xi and X ₂ are as defined in any one of paragraphs (5) to (8) above;

Yi to Y are as defined in any one of paragraphs (11) to (12) above;

R ₂ is as defined in any one of paragraphs (13) to (22) above;

Rz and m are as defined in any one of paragraphs (31) or (32); and

R _z2 is as defined in any one of paragraphs (31) to (34) above.

[0094] In another embodiment of the compounds of Formula If:

Xi and X ₂ are as defined in paragraph (5) above;

Yi to Y ₄ are as defined in paragraph (11) above;

R ₂ is as defined in paragraph (16) above;

Rz and m are as defined in any one of paragraphs (31) or (32); and

R _z2 is as defined in paragraph (34) above.

[0095] In a particular group of compounds of the invention, the compounds have the structural formula Ig (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula Ig

wherein each of Xi , X ₂ , R ₂ , and R _z4 are as defined hereinabove. [0096] In an embodiment of the compounds of Formula Ig:

Xi and X ₂ are as defined in any one of paragraphs (5) to (8) above;

R ₂ is as defined in any one of paragraphs (13) to (22) above; and

R _Z4 is as defined in any one of paragraphs (28) to (30) or (32) above.

[0097] In another embodiment of the compounds of Formula Ig:

Xi and X ₂ are as defined in paragraph (5) above;

R ₂ is as defined in paragraph (16) above; and

R _Z4 is as defined in paragraph (32) above.

[0098] The compounds of formulae lc, Id, le, If or Ig will exist as chiral compounds when R ₂ is not hydrogen. Although the formulae above are depicted as racemic, it is to be understood that the scope of the invention also covers the individual {R/S) stereoisomers. In a preferred embodiment, when R ₂ and R ₃ are different substituents, then there is provided the (S) stereoisomer of the compounds of the present invention. In a preferred embodiment, when R ₃ is hydrogen and R ₂ is not hydrogen, then there is provided the (S) stereoisomer of the compounds of the present invention.

[0099] In a particular group of compounds of the invention, the compounds have the structural formulae Ih, li, Ij or Ik (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula Ij Formula Ik

wherein each of Xi, X ₂ , Yi, Y ₂ , Y ₃ , Y ₄ , Z and R _z2 are as defined hereinabove, R _z is fluoro, chloro or methyl; m is 0 or 1 ; R ₄ is hydrogen, fluoro, methyl or hydroxy, R ₅ is hydrogen or (1- 4C)alkyl, R _g and R _h are each independently selected from hydrogen or (1-4C)alkyl and q is 1 to 3.

[0100] In an embodiment of the compounds of formulae Ih, li, Ij or Ik:

Xi and X ₂ are as defined in any one of paragraphs (5) to (8) above;

Yi to Y are as defined in any one of paragraphs (11) to (12) above;

Z is as defined in any one of paragraphs (27) to (34) above;

R _Z 2 is as defined in any one of paragraphs (31) to (34) above;

R _z is fluoro, chloro or methyl;

m is 0 or 1 ;

R ₄ is hydrogen, hydroxy or fluoro;

Re is hydrogen or methyl;

R _g and R _h are independently selected from hydrogen or methyl; and

q is 1 or 2.

[0101] In another embodiment of the compounds of formulae Ih, li, Ij or Ik:

Xi and X ₂ are as defined in paragraph (5) above;

Yi to Y are as defined in paragraph (11) above;

Z is as defined in paragraph (28) or paragraph (34) above;

R _z2 is as defined in defined in paragraph (34) above;

R _z is fluoro, chloro or methyl;

m is 0 or 1 ;

R is hydrogen or fluoro;

R ₅ is hydrogen or methyl;

R _g and R _h are independently selected from hydrogen or methyl; and

q is 1.

[0102] In a particular group of compounds of the invention, the compounds have the structural formulae Im or In (a sub-definition of Formula (I)) shown below (preferably formulae Im), or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:

Formula Im Formula In

wherein R ₂ and Z are as defined hereinabove.

[0103] In an embodiment of the compounds of formulae Im or In (preferably formulae Im): R is as defined in any one of paragraphs (13) to (22) above; and Z is as defined in any one of paragraphs (27) to (32) above.

[0104] In another embodiment of the compounds of formulae Im or In (preferably formulae I m):

R ₂ is as defined in paragraph (16) above; and

Z is as defined in paragraph (27) or paragraph (32) above.

[0105] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:

3-amino-N-(1-benzyl-1 H-pyrazol-4-yl) pyrazine-2-carboxamide;

4-amino-N-(1-benzyl-1 H-pyrazol-4-yl)pyrimidine-5-carboxamide;

2-amino-N-(1-benzyl-1 H-pyrazol-4-yl)nicotinamide;

3-amino-N-(5- benzyl-1, 3, 4-oxadiazol-2-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(pyridin-2-ylmethyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-benzyl-1 H-pyrazol-4-yl)-6-bromopyrazine-2-carboxamide;

3-amino-N-(1-(4-cyanobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(aminomethyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(4-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2,5-difluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(4-methylbenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-cyanobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-fluoro-4-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-chloro-4-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2,4-difluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-chloro-5-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-phenethyl-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-chlorobenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(4-chlorobenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(3-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-chloro-4-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(trifluoromethyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3,5-difluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-chloro-4-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(3-chlorobenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(4-carbamoylbenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2,3-difluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1 -(4- fluoro-3-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1 -(3- fluoro-5-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(2-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3,4-difluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(5-fluoro-2-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(2-fluoro-5-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(2-fluoro-6-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(3-fluoro-2-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-((5-methoxypyridin-3-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(3-carbamoylbenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

Methyl 3-((4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1-yl)methyl )benzoate;

N-(1-(3-acetamidobenzyl)-1 H-pyrazol-4-yl)-3-aminopyrazine-2-carboxamide;

3-amino-N-(1-(3-bromobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(methylsulfonyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(methoxymethyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3,4-dichlorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(azetidin-3-ylmethoxy)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-ethoxybenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(2-(pyrrolidin-1-yl)ethoxy)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(cyclopropylmethoxy)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(piperidin-4-yl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(methylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-((2-hydroxyethyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-((2-morpholinoethyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-((2,2-difluoroethyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-(cyclopropylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)benz yl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide; 3-amino-N-(1-(3-methoxy-5-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-carbamoyl-5-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(3-methoxy-5-((2-(pyrrolidin-1-yl)ethyl)carbamo yl)benzyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-((3-fluoropropyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-((2-methoxyethyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(4-fluoro-3-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-fluoro-3-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(cyclopropylcarbamoyl)-2-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-((2,2-difluoroethyl)carbamoyl)-2-fluorobenzy l)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-(hydroxymethyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-amino-4-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-aminobenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-((6-aminopyridin-2-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-amino-2-chlorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-((cyanomethyl)amino)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(4-fluoro-3-isobutyramidobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(vinylsulfonamido)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-butyramido-4-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(2-chloroacetamido)-4-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

N-(1-(3-acrylamidobenzyl)-1 H-pyrazol-4-yl)-3-aminopyrazine-2-carboxamide;

3-amino-N-(1-(3-(2-chloroacetamido)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-propionamidobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(3-phenylpropanamido)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(3,3,3-trifluoropropanamido)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

(E)-3-amino-N-(1-(3-(4-(dimethylamino)but-2-enamido)benzyl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

N-(1-((6-acrylamidopyridin-2-yl)methyl)-1 H-pyrazol-4-yl)-3-aminopyrazine-2-carboxamide;

3-amino-N-(1-(3-isobutyramidobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-butyramidobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; N-(1-(3-acrylamido-4-fluorobenzyl)-1 H-pyrazol-4-yl)-3-aminopyrazine-2-carboxamide;

3-amino-N-(1-(2-chloro-3-(2-chloroacetamido)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-methacrylamidobenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(azetidin-3-yl(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(azetidin-3-yl(3-methoxyphenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-fluoroazetidin-3-yl)(3-methoxyphenyl)methyl )-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(1-(azetidin-3-yl)-2-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-((3-fluoroazetidin-3-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-fluoro-1-methylazetidin-3-yl)(phenyl)methyl )-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

2-amino-N-(1-(azetidin-3-yl(phenyl)methyl)-1 H-pyrazol-4-yl)nicotinamide;

3-amino-N-(1-(phenyl(piperidin-4-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-(dimethylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(2-(methylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(2-hydroxy-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-hydroxy-1-phenylpropyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-(methylamino)-2-oxo-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-2-oxo-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-fluoro-5-methoxyphenyl)ethyl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-methylbenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(N-propylsulfamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(pyridin-3-ylmethyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(2-cyano-1-(3-(propylcarbamoyl)phenyl)ethyl) -1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-chloro-5-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-hydroxybenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-fluoro-5-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(3-fluoro-5-(isopropylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1 -(3-chloro-5-(isopropyl carbamoyl) benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-chloro-5-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-(((6-oxopiperidin-3-yl)methyl)carbamoyl)benz yl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-(benzylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-((2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamoy l)benzyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-((tetrahydrofuran-3-yl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-((2-cyclohexylethyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-(((1-hydroxycyclopropyl)methyl)carbamoyl)ben zyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-((1-isopropylpiperidin-4-yl)carbamoyl)benzyl )-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

rac-3-amino-N-(1-(3-(((1R,3R)-3-methoxycyclopentyl)carbam oyl)benzyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

rac-3-amino-N-(1-(3-(((3R,4R)-3-methoxytetrahydro-2H-pyra n-4-yl)carbamoyl)benzyl)-1 H- pyrazol-4-yl)pyrazine-2-carboxamide;

rac-3-amino-N-(1-(3-(((1R,3S)-3-hydroxycyclopentyl)carbam oyl)benzyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

N-(1-(3-(((1 RS,5SR,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)-3- aminopyrazine-2-carboxamide;

3-amino-N-(1-(3-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ben zyl)-1 H-pyrazol-4-yl)pyrazine-

2-carboxamide;

3-amino-N-(1-(3-((1 , 1-dioxidotetrahydro-2H-thiopyran-3-yl)carbamoyl)benzyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-((3-hydroxypropyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-((4-aminobutyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(1-(3-(propylcarbamoyl)phenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(1-(3-(isopropylcarbamoyl)phenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide; 3-amino-N-(1-(3-(isopropylcarbamoyl)-5-methylbenzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-methyl-5-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-(5-ethyl-1 H-1 ,2,4-triazol-3-yl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-(3-ethylureido)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

N-(1-((1 ,4-oxazepan-2-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)-3-aminopyrazine-2-carboxamide;

3-amino-N-(1-((3-methoxyphenyl)((R)-morpholin-2-yl)methyl )-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(((R)-azetidin-2-yl)(3-methoxyphenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(((S)-azetidin-2-yl)(3-methoxyphenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(((R)-azetidin-2-yl)(3-chloro-5-methoxyphenyl)m ethyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

2-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4-yl)nicotinamide;

3-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4-yl)-6-bromopyrazine-2-carboxamide; 3-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4-yl)-6-methylpyrazine-2-carboxamide; 3-amino-N-(1-(2-amino-1-(3-fluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(((R)-morpholin-2-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(((S)-morpholin-2-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(1-(methylamino)-3-phenylpropan-2-yl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(phenyl(pyrrolidin-3-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

4-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrimidine-5- carboxamide;

3-amino-N-(1-(1-(methylamino)-3-phenylpropan-2-yl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-((methyl-d3)amino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(2-((2-fluoroethyl)amino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

2-amino-N-(1-(2-(methylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)nicotinamide;

3-amino-N-(1-(2-((cyclopropylmethyl)amino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-(ethylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(2-(methylsulfonamido)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-(oxetan-3-ylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1 -(3-amino- 3-oxo-1-phenylpropyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(2-amino-1-phenylpropyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-(dimethylamino)-1-(3-methoxyphenyl)ethyl) -1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-fluoro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3,4-difluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-chloro-4-fluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3,5-difluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(4-fluoro-3-methoxyphenyl)ethyl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-chlorophenyl)ethyl)-1H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino- N-( 1 -(2-am ino- 1 -(m-tolyl)ethyl)- 1 H-pyrazol-4-yl) pyrazi ne-2-carboxam ide;

3-amino-N-(1-(2-amino-1-(4-fluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

4-amino-N-(1-(2-amino-1-(3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrimidine-5- carboxamide;

3-amino-N-(1-(2-amino-1-(3-bromo-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-methoxy-5-methylphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-iodo-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-methoxyphenyl)propyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-(propylcarbamoyl)phenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1 -(2-am ino- 1 -(3-ethynyl-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1 -(2-am ino- 1 -(3-cyclopropyl-5-methoxyphenyl)ethyl)- 1 H-pyrazol-4-yl) pyrazine-2- carboxamide; 3-amino-N-(1-((3-hydroxyazetidin-3-yl)(3-methoxyphenyl)methy l)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-chloro-5-methoxyphenyl)((R)-piperidin-2-yl) methyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-((3-chloro-5-methoxyphenyl)((S)-piperidin-2-yl) methyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-((3-methoxyphenyl)((R)-piperidin-2-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(4-(propylcarbamoyl)phenethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-(2-oxo-2-(propylamino)ethyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

4-amino-N-(1-(3-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrimidine- 5- carboxamide;

3-amino-6-bromo-N-(1-(3-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

4-amino-N-(1-(((R)-azetidin-2-yl)(3-chloro-5-methoxyphenyl)m ethyl)-1 H-pyrazol-4- yl)pyrimidine- 5-carboxamide;

4-amino-N-(1-((3-chloro-5-methoxyphenyl)(piperidin-4-yl)meth yl)-1 H-pyrazol-4-yl)pyrimidine-

5-carboxamide;

3-amino-N-(1-((3-chloro-5-methoxyphenyl)(piperidin-4-yl)meth yl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-methoxyphenyl)((R)-piperidin-2-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-chloro-5-methoxyphenyl)(piperidin-4-yl)meth yl)-1 H-pyrazol-4-yl)-6- methy I pyrazi ne-2-carboxam ide ;

2-amino-N-(1-((3-chloro-5-methoxyphenyl)(piperidin-4-yl)meth yl)-1 H-pyrazol-4-yl)-5- fluoronicotinamide;

3-amino-6-chloro-N-(1-((3-chloro-5-methoxyphenyl)(piperidin- 4-yl)methyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-((3-chloro-5-methoxyphenyl)((R)-pyrrolidin-2-yl )methyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

4-amino-N-(1 -(2-amino- 1-(3-chloro- 5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrimidine- 5- carboxamide;

4-amino-N-(1 -(1 -amino- 3-(3-chloro- 5-methoxyphenyl)propan-2-yl)-1 H-pyrazol-4- yl)pyrimidine- 5-carboxamide;

2-amino-N-(1 -(2-amino- 1-(3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5- fluoronicotinamide;

2-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)- 1 H-pyrazol-4-yl)-5- fluoronicotinamide; 3-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-6- chloropyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-6- methy I pyrazi ne-2-carboxam ide ;

2-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5- chloronicotinamide;

2-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5- bromonicotinamide;

3-amino-N-(1-((3-aminobicyclo[1.1.1]pentan-1-yl)(3-methoxyph enyl)methyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

2-amino-N-(1-(2-amino-1-(3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5-chloronicotinamide;

4-amino-N-(1-((3-aminobicyclo[1.1.1]pentan-1-yl)(3-methox yphenyl)methyl)-1 H-pyrazol-4- yl)pyrimidine- 5-carboxamide;

3-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-6- bromopyrazine-2-carboxamide;

2-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5- methylnicotinamide;

2-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5- fluoronicotinamide;

3-amino-N-(1-(2-amino-1-(3-methoxy-5-methylphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-methoxyazetidin-3-yl)(3-methoxyphenyl)methy l)-1 H-pyrazol-4-yl)pyrazine-

2-carboxamide;

3-amino-N-(1-((3-isobutoxyazetidin-3-yl)(3-methoxyphenyl)met hyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

4-amino-N-(1-((3-methoxyazetidin-3-yl)(3-methoxyphenyl)methy l)-1 H-pyrazol-4- yl)pyrimidine- 5-carboxamide; and

2-amino-5-fluoro-N-(1-((3-methoxyazetidin-3-yl)(3-methoxyphe nyl)methyl)-1 H-pyrazol-4- yl)nicotinamide.

[0106] Further compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following compounds:

3-amino-N-(1-(3-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(4-fluoro-3-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(3-fluoro-5-methoxybenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(3-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(3-((2-hydroxyethyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-((2-morpholinoethyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-((2,2-difluoroethyl)carbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-(cyclopropylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)benz yl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-carbamoyl-5-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-Amino- N-(1-(3-(isopropyl-carbamoyl)benzyl)-1H-pyrazol-4-yl)pyrazin e-2-carboxamide;

3-amino-N-(1-(3-(2-chloroacetamido)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(azetidin-3-yl(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(azetidin-3-yl(3-methoxyphenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-fluoroazetidin-3-yl)(3-methoxyphenyl)methyl )-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-fluoroazetidin-3-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-fluoro-1-methylazetidin-3-yl)(phenyl)methyl )-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

2-amino-N-(1-(azetidin-3-yl(phenyl)methyl)-1 H-pyrazol-4-yl)nicotinamide;

3-amino-N-(1-(phenyl(piperidin-4-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-(methylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(2-amino-1-(3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(2-amino-1-(3-fluoro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-fluoro-5-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(3-fluoro-5-(isopropylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-chloro-5-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(1-(3-(propylcarbamoyl)phenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(1-(3-(isopropylcarbamoyl)phenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide; 3-amino-N-(1-((3-methoxyphenyl)((R)-morpholin-2-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(((R)-azetidin-2-yl)(3-methoxyphenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(((S)-azetidin-2-yl)(3-methoxyphenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1 -(2-amino- 1-(3-fluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(((R)-morpholin-2-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-((methyl-d3)amino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(2-amino-1-phenylpropyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-fluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-fluoro-5-methoxyphenyl)ethyl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3,4-difluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-chloro-4-fluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3,5-difluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(4-fluoro-3-methoxyphenyl)ethyl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-chlorophenyl)ethyl)-1H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

4-amino-N-(1-(2-amino-1-(3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrimidine-5- carboxamide;

3-amino-N-(1-(2-amino-1-(3-methoxyphenyl)propyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-(propylcarbamoyl)phenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

or

3-amino-N-(1-((3-hydroxyazetidin-3-yl)(3-methoxyphenyl)methy l)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide.

[0107] Further compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following compounds:

3-amino-N-(1-(azetidin-3-yl(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-((3-fluoroazetidin-3-yl)(3-methoxyphenyl)methyl )-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-fluoroazetidin-3-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-(methylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(2-amino-1-(3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1 -(2-amino- 1 -(3- fluoro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(3-fluoro-5-(propylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1-(2-amino-1-(3-fluoro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide; or

3-amino-N-(1-((3-hydroxyazetidin-3-yl)(3-methoxyphenyl)methy l)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide.

[0108] Further compounds of the present invention include any of the chiral compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, the (S)-enantiomers of the following compounds:

3-amino-N-(1-(2-amino-1-(3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

2-amino-5-fluoro-N-(1-((3-methoxyazetidin-3-yl)(3-methoxy phenyl)methyl)-1 H-pyrazol-4- yl)nicotinamide;

2-amino-N-(1-((3-chloro-5-methoxyphenyl)(piperidin-4-yl)meth yl)-1 H-pyrazol-4-yl)-5- fluoronicotinamide;

2-amino-N-(1-(2-(methylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)nicotinamide;

2-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5- bromonicotinamide;

2-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5- chloronicotinamide;

2-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5- fluoronicotinamide;

2-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5- methylnicotinamide;

2-amino-N-(1-(2-amino-1-(3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-5- fluoronicotinamide; 2-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4-yl)nicotinamide;

2-amino-N-(1-(azetidin-3-yl(phenyl)methyl)-1 H-pyrazol-4-yl)nicotinamide;

3-amino-6-chloro-N-(1-((3-chloro-5-methoxyphenyl)(piperidin- 4-yl)methyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide; 3-amino-N-(1-(((R)-azetidin-2-yl)(3-chloro-5-methoxyphenyl)m ethyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-(((R)-azetidin-2-yl)(3-methoxyphenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(((R)-morpholin-2-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(((S)-azetidin-2-yl)(3-methoxyphenyl)methyl) -1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(((S)-morpholin-2-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-((3-aminobicyclo[1.1.1]pentan-1-yl)(3-methox yphenyl)methyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-((3-chloro-5-methoxyphenyl)((R)-piperidin-2-yl) methyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-((3-chloro-5-methoxyphenyl)((S)-piperidin-2-yl) methyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-((3-chloro-5-methoxyphenyl)(piperidin-4-yl)meth yl)-1 H-pyrazol-4-yl)-6- methy I pyrazi ne-2-carboxam ide ;

3-amino-N-(1-((3-chloro-5-methoxyphenyl)(piperidin-4-yl)meth yl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-fluoro-1-methylazetidin-3-yl)(phenyl)methyl )-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-fluoroazetidin-3-yl)(3-methoxyphenyl)methyl )-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-fluoroazetidin-3-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-hydroxyazetidin-3-yl)(3-methoxyphenyl)methy l)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-isobutoxyazetidin-3-yl)(3-methoxyphenyl)met hyl)-1 H-pyrazol-4-yl)pyrazine-

2-carboxamide hydrochloride;

3-amino-N-(1-((3-methoxyazetidin-3-yl)(3-methoxyphenyl)methy l)-1 H-pyrazol-4-yl)pyrazine-

2-carboxamide;

3-amino-N-(1-((3-methoxyphenyl)((R)-morpholin-2-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-((3-methoxyphenyl)((R)-piperidin-2-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(1-(azetidin-3-yl)-2-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(1-(methylamino)-3-phenylpropan-2-yl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide; 3-amino-N-(1-(2-((2-fluoroethyl)amino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-((cyclopropylmethyl)amino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-((methyl-d3)amino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

3-amino-N-(1-(2-(dimethylamino)-1-(3-methoxyphenyl)ethyl) -1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-(dimethylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-(ethylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-(methylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide

3-amino-N-(1-(2-(methylsulfonamido)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-(oxetan-3-ylamino)-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-(propylcarbamoyl)phenyl)ethyl) -1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3,4-difluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3,5-difluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-bromo-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-chloro-4-fluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-6- bromopyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)-6- methy I pyrazi ne-2-carboxam ide ;

3-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-chlorophenyl)ethyl)-1H-pyrazol-4- yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-(3-cyclopropyl-5-methoxyphenyl)et hyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1 -(2-amino- 1 -(3-ethynyl-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1 -(2-amino- 1 -(3- fluoro- 5-methoxyphenyl)ethyl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1 -(2-amino- 1-(3-fluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide; 3-amino-N-(1 -(2-amino- 1-(3-iodo-5-methoxyphenyl) ethyl)-1 H-pyrazol-4-yl) pyrazine-2- carboxamide; 3-amino-N-(1-(2-amino-1-(3-methoxy-5-methylphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(2-amino-1-(3-methoxyphenyl)propyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1 -(2-amino- 1 -(4- fluoro-3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1 -(2-amino- 1-(4-fluorophenyl)ethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino- N-( 1 -(2-am ino- 1 -(m-tolyl)ethyl)- 1 H-pyrazol-4-yl) pyrazi ne-2-carboxam ide;

3-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4-yl)-6-bromopyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(2-amino-1-phenylpropyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(azetidin-3-yl(3-methoxyphenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide;

3-amino-N-(1-(azetidin-3-yl(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide;

3-amino-N-(1-(phenyl(pyrrolidin-3-yl)methyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide;

4-amino-N-(1-(((R)-azetidin-2-yl)(3-chloro-5-methoxyphenyl)m ethyl)-1 H-pyrazol-4- yl)pyrimidine- 5-carboxamide;

4-amino-N-(1-((3-aminobicyclo[1.1.1]pentan-1-yl)(3-methoxyph enyl)methyl)-1 H-pyrazol-4- yl)pyrimidine- 5-carboxamide;

4-amino-N-(1-((3-chloro-5-methoxyphenyl)(piperidin-4-yl)meth yl)-1 H-pyrazol-4-yl)pyrimidine-

5-carboxamide;

4-amino-N-(1-((3-methoxyazetidin-3-yl)(3-methoxyphenyl)methy l)-1 H-pyrazol-4- yl)pyrimidine-5-carboxamide;

4-amino-N-(1-(1-amino-3-(3-chloro-5-methoxyphenyl)propan-2-y l)-1 H-pyrazol-4- yl)pyrimidine-5-carboxamide;

4-amino-N-(1-(2-amino-1-(3-chloro-5-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrimidine-5- carboxamide;

4-amino-N-(1-(2-amino-1-(3-methoxyphenyl)ethyl)-1 H-pyrazol-4-yl)pyrimidine-5- carboxamide; or

N-(1-((1 ,4-oxazepan-2-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)-3-aminopyrazine-2-carboxamide.

[0109] The various functional groups and substituents making up the compounds of the Formula (I), or sub-formulae la to In, are typically chosen such that the molecular weight of the compound of the formula (I) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less. [0110] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0111] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture”.

[0112] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual ( R )- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers).

[0113] It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity and/or activity in regulating electrolyte balance in renal and/or cardiovascular disease. [0114] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and180; and the like.

[0115] It is also to be understood that certain compounds of the Formula (I), or sub-formulae la to In, may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity and/or activity in regulating electrolyte balance in renal and/or cardiovascular disease.

[0116] It is also to be understood that certain compounds of the Formula (I), or sub-formulae la to In, may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity and/or activity in regulating electrolyte balance in renal and/or cardiovascular disease.

[0117] Compounds of the Formula (I), or sub-formulae la to In, may exist in a number of different tautomeric forms and references to compounds of the Formula (I), or sub-formulae la to In, include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I), or sub-formulae la to In. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.

keto enol enolate

[0118] Compounds of the Formula (I), or sub-formulae la to Im, containing an amine function may also form N-oxides. A reference herein to a compound of the Formula (I), or sub-formulae la to In, that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0119] The compounds of Formula (I), or sub-formulae la to In, may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a propertymodifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I), or sub-formulae la to In, and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I), or subformulae la to Im.

[0120] Accordingly, the present invention includes those compounds of the Formula (I), or sub-formulae la to In, as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I), or sub-formulae la to In, that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I), or sub-formulae la to In, may be a synthetically-produced compound or a metabolically-produced compound.

[0121] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to In, is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0122] Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5“Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);

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

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

f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella,“Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and

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

[0123] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to In, that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula I, or sub-formulae la to In, containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include (1-6C)alkyl esters such as methyl, ethyl and tert- butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2- oxo-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.

[0124] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to In, that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula (I), or sub-formulae la to In, containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1-6C) ₂ carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(1- 4C)alkylpiperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0125] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to In, that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (1- 4C)alkylamine such as methylamine, a [(1-4C)alkyl] ₂ amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0126] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to In, that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with (1-10C)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, pi perazin-1-yl methyl and

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

[0127] The in vivo effects of a compound of the Formula (I), or sub-formulae la to In, may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I), or sub-formulae la to In. As stated hereinbefore, the in vivo effects of a compound of the Formula (I), or sub-formulae la to In, may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0128] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

[0129] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.

Synthesis

[0130] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0131] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0132] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised. [0133] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0134] For examples of protecting groups see one of the many general texts on the subject, for example,‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0135] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0136] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a ferf-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0137] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0138] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0139] Resins may also be used as a protecting group.

[0140] The methodology employed to synthesise a compound of Formula (I), or subformulae la to In, will vary depending on the nature of Xi, X ₂ , Yi , Y ₂ , Y ₃ , Y ₄ , R _å , R ₃ , Y and Z and any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.

[0141] Once a compound of Formula (I), or sub-formulae la to In, has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of:

(i) removing any protecting groups present;

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

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

(iv) forming a prodrug thereof.

[0142] An example of (ii) above is when a compound of Formula (I) is synthesised and then one or more of the groups Xi, X ₂ , Yi , Y ₂ , Y3, Y4, R2, R3, Y and Z may be further reacted to change the nature of the group and provide an alternative compound of Formula (I).

[0143] The resultant compounds of Formula (I), or sub-formulae la to In, can be isolated and purified using techniques well known in the art.

[0144] The compounds of Formula (I) may be synthesised by the general synthetic routes shown in Schemes 1 to 12 in the Examples section below, specific examples of which are described in more detail in the Examples.

Biological Activity

[0145] The biological assays described in the Examples section herein may be used to measure the pharmacological effects of the compounds of the present invention.

[0146] Although the pharmacological properties of the compounds of Formula (I) vary with structural change, as expected, the compounds of the invention were found to be active in the SGK3 in vitro assay and in some cases also in the SGK1 in vitro assay described in the Examples section.

[0147] In general, as illustrated by the Example compound data in Table 1 , the compounds of the invention demonstrate an ICso of 10 mM or less in the SGK3 TR-FRET assay described in the Examples section. Preferred compounds of the invention demonstrate an IC ₅₀ of 1 mM or less, or an IC ₅₀ of 100 nM or less. The most preferred compounds of the invention demonstrate an IC ₅₀ of 10 nM or less in the SGK3 TR-FRET assay.

[0148] In general, as illustrated by the Example compound data in Table 1 , the compounds of the invention demonstrate an IC ₅₀ of 10 mM or less in the SGK1 TR-FRET assay described in the Examples section. Preferred compounds of the invention demonstrate an IC ₅₀ of 5 mM or less. The most preferred compounds of the invention demonstrate an IC ₅₀ of 1 mM or less in the SGK1 TR-FRET assay.

[0149] The following TR-FRET assay data were generated for the Examples:

Table 1

[0150] As illustrated by the Example compound data in Table 2, preferred compounds of the invention demonstrate an IC50 of 10 mM or less in the SGK3 Radiometric assay described in the Examples section. The most preferred compounds of the invention demonstrate an IC50 of 100 nM or less in the SGK3 Radiometric assay.

[0151] In general, as illustrated by the Example compound data in Table 2, the compounds of the invention demonstrate an IC5 ₀ of 10 mM or less in the SGK2 Radiometric assay described in the Examples section. Preferred compounds of the invention demonstrate an IC5 ₀ of 1 mM or less. The most preferred compounds of the invention demonstrate an IC5 ₀ of 100 nM or less in the SGK2 Radiometric assay.

[0152] As illustrated by the Example compound data in Table 2, preferred compounds of the invention demonstrate an IC50 of 10 pM or less in the SGK1 Radiometric assay described in the Examples section. The most preferred compounds of the invention demonstrate an IC50 of 1 pM or less in the SGK1 Radiometric assay.

[0153] In an embodiment, preferred compounds of the invention demonstrate an IC5 ₀ of 100 nM or less in the SGK2 Radiometric assay and 1 pM or less in the SGK1 and SGK3 Radiometric assays.

[0154] The following Radiometric assay data were generated for the Examples:

Table 2

E

1

1

1

1

1 1 1

1

1

1

1

1 1 1 1 1 1 1 1

1

1 1 1 1

Pharmaceutical Compositions

[0155] In this section relating to pharmaceutical compositions, the compounds of the invention as defined hereinbefore also includes the compounds 3-amino-N-(1 -benzyl-1 H- pyrazol-4-yl)pyrazine-2-carboxamide and 2-amino-N-(1-benzyl-1 H-pyrazol-4-yl)nicotinamide.

[0156] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0157] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0158] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

[0159] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.

[0160] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0161] The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0162] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.

Therapeutic Uses and Applications

[0163] In this section relating to therapeutic uses and applications, the compounds of the invention as defined hereinbefore also includes the compounds 3-amino-N-(1 -benzyl-1 H- pyrazol-4-yl) pyrazine-2-carboxamide and 2-amino-N-(1-benzyl-1 H-pyrazol-4-yl)nicotinamide.

[0164] The present invention provides compounds that function as inhibitors of SGK activity.

[0165] The present invention therefore provides a method of inhibiting SGK activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0166] The present invention also provides a method of treating a disease or disorder in which SGK activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0167] The present invention provides a method of inhibiting cell proliferation or for regulating electrolyte balance in renal and/or cardiovascular disease, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.

[0168] The present invention provides a method of treating a proliferative disorder or for regulating electrolyte balance in renal and/or cardiovascular disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0169] The present invention provides a method of treating cancer or for regulating electrolyte balance in renal and/or cardiovascular disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0170] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0171] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition or for regulating electrolyte balance in renal and/or cardiovascular disease.

[0172] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer or for regulating electrolyte balance in renal and/or cardiovascular disease. In a particular embodiment, the cancer is human cancer, in particular oestrogen positive cancers, such as breast cancer, or androgen receptor positive cancers, such as prostate cancer.

[0173] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the inhibition of SGK activity. In particular, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the inhibition of SGK1 , SGK2 and/or SGK3 activity. Preferably, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the inhibition of SGK1 and/or SGK3 activity; most preferably, for use in the inhibition of SGK3 activity.

[0174] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which SGK activity is implicated. Preferably, the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which SGK3 activity is implicated.

[0175] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition or for regulating electrolyte balance in renal and/or cardiovascular disease.

[0176] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer or for regulating electrolyte balance in renal and/or cardiovascular disease. Suitably, the medicament is for use in the treatment of human cancers, in particular oestrogen positive cancers, such as breast cancer, or androgen receptor positive cancers, such as prostate cancer.

[0177] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of SGK (such as SGK3) activity.

[0178] The present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which SGK (such as SGK3) activity is implicated.

[0179] The term "proliferative disorder" and “proliferative condition” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro ox in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers (including breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary), leukemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), lymphomas (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), psoriasis, bone diseases, fibroprol iterative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lymphatic, blood, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.

[0180] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).

[0181] Examples of conditions for regulating electrolyte balance in renal and/or cardiovascular disease include, but are not limited to, high blood pressure or hypertension.

[0182] The compound of Formula (I), or a pharmaceutically acceptable salt thereof, being an inhibitor of SGK (in particular SGK3), has potential therapeutic uses in a variety of SGK- mediated disease states.

[0183] According to a further aspect of the specification there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the treatment of cancers such as breast cancer and prostate cancer.

[0184] According to a further feature of this aspect of the specification there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of oestrogen receptor-positive (ER+) breast cancer or androgen receptor-positive (AR+) prostate cancer.

[0185] According to a further feature of this aspect of the specification there is provided a method for treating cancers such as breast cancer and prostate cancer in a warm-blooded animal, such as man, that is in need of such treatment, which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[0186] According to a further feature of this aspect of the specification there is provided a method for treating oestrogen receptor-positive (ER+) breast cancer or androgen receptor positive (AR+) prostate cancer in a warm-blooded animal, such as man, that is in need of such treatment, which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[0187] According to a further feature of this aspect of the specification there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of cancers such as breast cancer and prostate cancer.

[0188] According to a further feature of this aspect of the specification there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of oestrogen receptor-positive (ER+) breast cancer or androgen receptor-positive (AR+) prostate cancer.

Routes of Administration

[0189] In this section relating to routes of administration, the compounds of the invention as defined hereinbefore also includes the compounds 3-amino-N-(1 -benzyl-1 H-pyrazol-4- yl)pyrazine-2-carboxamide and 2-amino-N-(1-benzyl-1 H-pyrazol-4-yl)nicotinamide.

[0190] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e., at the site of desired action).

[0191] Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g. , by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

Combination Therapies

[0192] In this section relating to combination therapies, the compounds of the invention as defined hereinbefore also includes the compounds 3-amino-N-(1 -benzyl-1 H-pyrazol-4- yl)pyrazine-2-carboxamide and 2-amino-N-(1-benzyl-1 H-pyrazol-4-yl)nicotinamide.

[0193] The antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:-

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

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

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

(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as /V-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4- amine (gefitinib, ZD1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-/V-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropo xy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU 11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin -1- ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin anb3 function and angiostatin)];

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

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

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

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

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

[0194] It is noted that approximately 70% of all breast cancers (BC) express the estrogen receptor (ER), progesterone receptor (PgR), or both, and such tumours are considered hormone receptor-positive. Estrogen binds to the ER with high affinity and specificity and functions through two main types of pathways, the classical (or nuclear) pathway and the alternative (nonnuclear) pathway. Successful targeting of genes within these nuclear and nonnuclear pathways has led to a number of agents for patients with early, advanced, or metastatic BC. It is therefore expected that serum and glucocorticoid regulated kinase (SGK) inhibitors will, in particular, also have application in combination with agents such as: Selective estrogen receptor modulators (SERMs), such as Tamoxifen and Toremifene; Aromatase inhibitors (Als), such as nonsteroidal aromatase inhibitors: Anastrozole, Fadrozole and Letrozole; and Steroidal aromatase inhibitor such as Exemestane; Selective estrogen receptor degrader (SERDs), such as Fulvestrant, Elacestrant and GDC-0810; Inhibitors of the phosphatidylinositol 3 kinase (PI3K), such as Buparlisib, Apitolisib, AZD8186, Omipalisib, Duvelisib, Gedatolisib, Copanlisib, Pictilisib, Alpelisib, Idelalisib, Acalisib, Serabelisib, Pilaralisib and Taselisib; agents that target AKT murine thymoma viral oncogene (AKT) such as MK2206, AZD5363, Afuresertib, AT13148, Miransertib and Ipatasertib; agents that target mammalian target of rapamycin inhibitor (mTOR) signaling pathway such as Everolimus, Sirolimus, Temsirolimus, Vistusertib, Sapanisertib and Ridaforolimus; agents that target the cyclin-dependent kinase 4/6 (CDK4/6) pathway such as Palbociclib, Ribociclib and Abemaciclib and Induced estrogen receptor protein degradation such as proteolysis- targeting chimaeras (PROTACs) [Brufsky, The oncologist (2018): theoncologist-2017; Lai, Nature Reviews Drug Discovery 16.2 (2017): 1012017]

[0195] Further, numerous studies indicate that prostate cancer is driven by the androgen receptor (AR), a ligand-dependent transcription factor belonging to the nuclear receptor family. The AR axis is an essential player in prostate cancer. Blocking AR function directly or indirectly or through targeting of genes within the nuclear and non-nuclear pathways and targeting growth-promoting and survival pathways that interact with AR signaling has led to a number of agents for patients with early, advanced, or metastatic prostate cancer. It is therefore expected that serum and glucocorticoid regulated kinase (SGK) inhibitors will, in particular, also have application in combination with agents such as: direct AR antagonists such as Bicalutamide, Enzalutamide, Apalutamide, Darolutamide; non-competitive AR antagonists such as ralaniten acetate (EPI-506); Indirect AR blockers such as steroid synthesis inhibitors such as Abiraterone acetate; selective androgen receptor degrader or downregulator (SARDs) and Induced androgen receptor protein degradation such as proteolysis- targeting chimaeras (PROTACs); Signaling Pathway Inhibitors such as Inhibitors of the phosphatidylinositol 3 kinase (PI3K), such as Buparlisib, Apitolisib, AZD8186, Omipalisib, Duvelisib, Gedatolisib, Copanlisib, Pictilisib, Alpelisib, Idelalisib, Acalisib, Serabelisib, Pilaralisib and Taselisib; agents that target AKT murine thymoma viral oncogene (AKT) such as MK2206, AZD5363, Afuresertib, AT13148, Miransertib and Ipatasertib; agents that target mammalian target of rapamycin inhibitor (mTOR) signaling pathway such as Everolimus, Sirolimus, Temsirolimus, Vistusertib, Sapanisertib and Ridaforolimus; agents that target the Fibroblast growth factor (FGF) signalling such as AZD4547 and Dovitinib; Agents that target the DNA Damage Repair Pathway such as inhibitors of the poly ADP ribose polymerase (PARP) family such as Olaparib, Veliparib, Rucaparib, Niraparib or agents that target inhibition of ataxia telangiectasia and Rad3-related kinase (ATR) such as BAY 1895344, AZD7762 [Nevedomskaya, International journal of molecular sciences 19.5 (2018): 1359; Lai, Nature Reviews Drug Discovery 16.2 (2017): 1012017]

[0196] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti-tumour agents selected from cyclophosphamide, epirubicin, fluorouracil, methotrexate, mitomycin C, doxorubicin, gemcitabine, docetaxel, carbazitaxel and radium-223 dichloride.

[0197] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti- hormonal agents selected from a selective estrogen receptor modulator (SERM) (e.g. tamoxifen or toremifene), a aromatase inhibitor (Al) (e.g. anastrozole, fadrozole, letrozole or exemestane), a selective estrogen receptor degrader (SERD) (e.g. fulvestrant, elacestrant or GDC-0810), a luteinising hormone (LH) blocker (e.g. goserelin), direct androgen receptor (AR) antagonist (e.g. bicalutamide, enzalutamide, apalutamide, darolutamide, cyproterone acetate or flutamide), a non-competitive AR antagonist (e.g. ralaniten acetate), a androgen steroid synthesis inhibitor (e.g. abiraterone acetate), a gonadotropin-releasing hormone (GNRH) modulator (e.g. leuprorelin, goserelin, buserelin, triptorelin, degarelix).

[0198] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or cell-cycle agents selected from a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor (e.g. palbociclib, ribociclib or abemaciclib).

[0199] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or DNA damage response agents agents selected from a poly ADP ribose polymerase (PARP) inhibitor (e.g. olaparib, veliparib, rucaparib or niraparib).

[0200] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or cell signalling agent selected from a phosphatidylinositol 3 kinase (PI3K) inhibitor , (e.g. buparlisib, apitolisib, azd8186, omipalisib, duvelisib, gedatolisib, copanlisib, pictilisib, alpelisib, idelalisib, acalisib, serabelisib, pilaralisib or taselisib), an AKT inhibitor (e.g. MK2206, AZD5363, afuresertib, AT13148, miransertib or ipatasertib); a (mTOR) signaling pathway inhibitor (e.g. everolimus, sirolimus, temsirolimus, vistusertib, sapanisertib or ridaforolimus), an Fibroblast growth factor (FGF) signalling inhibitor (e.g. AZD4547 or dovitinib).

[0201] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.

[0202] In another particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more chemotherapeutic agents selected from a BCL-2 family inhibitor (e.g. Venetoclax and/or navitoclax), a BTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Tirabrutinib (ONO/GS-4059), BGB- 31 11 or Spebrutinib (CC-292) or a TNF inhibitor (e.g. Lenalidomide).

[0203] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutical ly-active agent within its approved dosage range.

[0204] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.

[0205] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition, such as cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed herein above.

[0206] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a tyrosine kinase inhibitor.

[0207] According to this aspect of the invention there is provided a combination for use in the treatment of leukaemia (such as ALL or CML) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a tyrosine kinase inhibitor.

[0208] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.

[0209] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of cancer in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.

[0210] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of leukaemia (such as ALL or CML) in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.

[0211] Herein, where the term“combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0212] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.

EXAMPLES

[0213] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

Abbreviations

Boc for tert-butyloxycarbonyl

CDI for 1 , T-Carbonyldiimidazole

DAST for diethylaminosulfur trifluoride

DBU for 1 ,8-diazabicyclo(5.4.0)undec-7-ene DCC for dicyclohexylcarbodiimide

DOE for 1 , 1-dichloroethane

DCM for dichloromethane

DEA for diethanolamine

DEAD for diethyl azodicarboxylate

DIAD for diisopropyl azodicarboxylate

DIBAL for Diisobutylaluminium hydride

DIPEA for N,N-diisopropylethylamine, HQnig’s base

DMA for N,N-dimethylacetamide

DMAP for 4-(dimethylamino) pyridine

DMF for N,N-dimethylformamide

DMSO for dimethylsulfoxide.

EDC for 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

EtOAc for ethyl acetate

h for hours

HATU for N-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide

HBTU for (1 H-benzotriazol-1-yloxy)(dimethylamino)-N, N-dimethylmethaniminium hexafluorophosphate

HOBT for N-hydroxybenzotriazole

HPLC for High Pressure Liquid Chromatography.

LAH for lithium aluminium hydride

I PA for isopropyl alcohol

LCMS for Liquid Chromatography-Mass Spectrometry

LDA for Lithium diisopropylamide

□HMDS for Lithium bis(trimethylsilyl)amide

mCPBA for meta-chloroperoxybenzoic acid

Ml for Molecular Ion

Min for minutes

MW for microwave

NBS for N-bromosuccinamide

NCS for N-chlorosuccinamide

NFOBS for N-fluoro-o-benzenedisulfonimide

NFSI for N-fluorobenzenesulfonimide

NHS for N-hydroxysuccinimide

NIS for N-iodosuccinamide

NMM for N-methylmorpholine NMP for 1-methyl-2-pyrrolidinone

NMR for Nuclear Magnetic Resonance.

PdCl2(PPh3)2 for Bis(triphenylphosphine)palladium chloride

Pd(dppf)2Ch for [1 , 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)

Pd(dppf)2Ch.DCM for [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with DCM

(Pd(dba)2) for bis(dibenzylideneacetone)palladium

Rbf for round bottomed flask

RT for Retention Time.

SCX-2 for a silica-based sorbent with a chemically bonded propylsulfonic acid functional group

SFC for supercritical fluid chromatography

TBAF for tetra-n-butylammonium fluoride

TBDMS for tert-butyldimethylsilyl

TFAA for trifluoroacetic anhydride

TFA for trifluoroacetic acid

THF for tetrahydrofuran

TPP for tripotassium phosphate

XPhos-Pd-G1 for 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1’-biphenyl)[2-(2- aminoethyl)phenyl)]palladium(ll) chloride

XPhos-Pd-G2 for Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '-biphenyl)[2-(2'- amino-1 ,T-biphenyl)]palladium(ll)

Analytical Methods

Liquid Chromatography-Mass Spectrometry

LC-Method 1

[0214] UPLC-MS was performed on a Waters DAD + Waters SQD2, single quadrapole UPLC-MS spectrometer using an Acquity UPLC HSS Shield RP18 1.7um 100 x 2.1mm (Plus guard cartridge), maintained at temp column being initially held at 5% Acetonitrile (Far UV grade) with 0.1 % (V/V) formic acid / Water (High purity via PureLab Option unit) with 0.1 % formic acid for 0.4 minutes, followed by a linear gradient of 5-95% within 6.4 minutes and then held at 95% for 1.2 minutes (F = 0.4 mL/min).

LC-Method 2

[0215] UPLC-MS was performed on a Waters DAD + Waters SQD2, single quadrapole UPLC-MS spectrometer using an Acquity UPLC BEH Shield RP18 1.7um 100 x 2.1mm (Plus guard cartridge), maintained at temp column being initially held at 5% acetonitrile/water (with 10 mM ammonium bicarbonate) for 0.4 minutes, followed by a linear gradient of 5-95% within 6.4 minutes and then held at 95% for 1.2 minutes (F = 0.4 mL/min).

NMR

[0216] ¹ H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker instrument operating at 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (d) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad.

Purification methods

Preparative reverse-phase HPLC conditions

[0217] Preparative HPLC purification was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996/2998 UV/VIS detector, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution UV directed system. The Waters 2767 liquid handler acted as both auto-sampler and fraction collector. The columns used for the preparative purification of the compounds were a Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl or Waters Xbridge Phenyl at 10 pm 19 ^c 150 mm or Waters CSH Phenyl Hexyl, 19 ^c 150, 5 pm column. Appropriate focused gradients were selected based on acetonitrile and methanol solvent systems under either acidic or basic conditions. The modifiers used under acidic/basic conditions were formic acid or trifluoroacetic acid (0.1 % V/V) and ammonium bicarbonate (10 mM) respectively. The purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm, and triggered a threshold collection value at 260 nm and, when using the Fractionlynx, the presence of target molecular ion as observed under API conditions. Collected fractions were analysed by LCMS (Waters Acquity systems with Waters SQD).

[0218] Below is a list of methods and conditions used for preparative reverse phase HPLC purifications

Chiral Supercritical Fluid Chromatography (SFC) separation protocol

[0219] The enantiomeric separation of compounds was achieved by Supercritical Fluid Chromatography (SFC) using a Waters Thar Prepl OO preparative SFC system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid handler with Stacked Injection Module). The Waters 2767 liquid handler acted as both auto-sampler and fraction collector. Appropriate isocratic methods were selected based on methanol, ethanol or isopropanol solvent systems under un-modified or basic conditions. The standard SFC method used was modifier, CO2, 100 mL/min, 120 Bar backpressure, 40 °C column temperature. The modifier used under basic conditions was diethylamine (0.1 % V/V). The modifier used under acidic conditions was either formic acid (0.1 % V/V) or trifluoroacetic acid (0.1% V/V). The SFC purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm and triggered at a threshold collection value, typically 260 nm. Collected fractions were analysed by SFC (Waters/Thar SFC systems with Waters SQD). The fractions that contained the desired product were concentrated by vacuum centrifugation.

[0220] Below is a list of SFC methods and conditions used to resolve enantiomers or to determine enantiomeric purity

Synthesis

[0221] Several methods for the chemical synthesis of heterocyclic carboxamide compounds of the present application are described herein. These and/or other well-known methods may be modified and/or adapted in various ways in order to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood as being within the spirit and scope of this application and claims. Accordingly, it should be understood that the methods set forth in the following descriptions, schemes and examples are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure. [0222] In one approach (Scheme 1), compounds of formula [I] were prepared by the reaction of a substituted amino aromatic heterocycle of formula [II] with a carboxylic acid of general formula [III] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as EtsN, DIPEA or NMM. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the N-acylated-heterocyclic compound of general formula [F1-3]

Scheme 1

Example 1 : 3-amino-N-(1-benzyl-1H-pyrazol-4-vn pyrazine-2-carboxamide

[0223] To a stirred solution of 3-ami nopyrazine-2-carboxylic acid (8 mg, 0.058 mmol), 1- benzyl-1 H-pyrazol-4-amine (CAS: 28466-62-8), 10 mg, 0.058 mmol) and HATU (24 mg, 0.0635 mmol) in DMF (0.5 ml) was added DIPEA (0.01 ml, 0.104 mmol). The reaction mixture was stirred at room temperature for 4 hours then crude reaction mixture purified directly using preparative reverse phase HPLC (prep-LC-1) to afford the title compound as a yellow solid (7.5 mg, 45%). Ή NMR (400 MHz, DMSO): d 10.88 (s, 1 H), 8.30 (d, J = 2.3 Hz, 1 H), 8.21 (s, 1 H), 7.93 (d, J = 2.3 Hz, 1 H), 7.80 (s, 1 H), 7.62 (s, 2 H), 7.44-7.32 (m, 3 H), 7.29 (d, J = 7.1 Hz, 2 H), 5.36 (s, 2 H). LCMS (method 1): Rt = 3.76 min, m/z 295 [M ⁺ H]

[0224] The following Examples were prepared according to Scheme 1 above using the appropriate heteroaryl amine of formula [II] and the appropriate carboxylic acid [III] as described. The reactions were worked up and purified as above or according to one of the methods below: Method 1.A: Reaction mixture diluted with water and precipitate collected then re-crystallized from hot ethanol and cold water then dried in vacuum oven;

Method 1.B: Reaction mixture diluted with water and precipitate collected by filtration and oven dried.

[0225] In another approach (Scheme 2 - in which R represents an optional substituent on the phenyl ring as defined herein) compounds of formula [IV] were prepared by the reaction of carboxylic acid of general formula [III] with a 3-amino-azole with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as EtsN, DIPEA or NMM. After reaction work up, typically by a liquid- liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the N- acylated-heterocyclic compound of general formula [IV] Compounds of general formula [VI] were prepared by reacting azole-derivatives of general formula [IV] with an activated a-halo- methyl derivative of formula [V] in a polar aprotic solvent such as DMF or DMA with a suitable base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at ambient temperature or at high temperature by heating thermally. After reaction work up, typically by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. In some examples compounds of general formula [VI I] are prepared from a compounds of general formula [VI] by general N-deprotection step such as an N-Boc deprotection with TFA or HCI in a polar solvent such as DCM or Et 0. After reaction work-up typically by ion exchange purification or liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation.

Scheme 2

[VII] [VI] Example 7: 3-amino-N-(1-(4-cvanobenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide

[0226] To a stirred suspension of (1-bromomethyl) benzonitrile (36 mg, 0.196 mmol) and potassium carbonate (30 mg, 0.215 mmol) in THF (1ml) was added a solution of 3-amino-N- (1 H-pyrazol-4-yl) pyrazine-2-carboxamide (CAS:1933674-659-1), 40 mg, 0.196 mmol) in DMF (0.2 ml). The reaction mixture was stirred at room temperature for 1 hour then at 80°C overnight. The reaction was diluted with ethyl acetate and washed with water, organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and isohexane (30-70% gradient) to afford to afford the title compound. ¹ FI NMR (400 MFIz, DMSO): d 10.88 (s, 1 FI), 8.26 (d, J = 2.8 Hz, 2 H), 7.90 (d, J = 2.4 Hz, 1 H), 7.80-7.78 (m, 2 H), 7.70 (s, 1 H), 7.61-7.57 (m, 4 H), 5.41 (s, 2 H). LCMS (LC-Method 1) Rt = 3.52 min, m/z [M+H] 320.

Example 8: 3-amino-N-(1-i3-(aminomethyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide

[0227] To a stirred suspension of 3-amino-N-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide (CAS: 1933674-659-1), 100 mg, 0.490 mmol) and potassium carbonate (88 mg, 0.637 mmol) in DMF (12 ml) was added terf-butyl (3-(bromomethyl)benzyl)carbamate (147 mg, 0.490 mmol). The reaction mixture was heated to 120°C overnight. The reaction was diluted with ethyl acetate and washed with water, organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and isohexane (0-10% gradient) to afford tert-butyl (3-((4- (3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)benzyl)carbamate (50 mg, 0.155 mmol) which was dissolved in in dioxane and treated with 4M HCI in dioxane (0.24 ml, 0.979 mmol). The reaction was stirred for 2 hours then passed through a SCX-2 cartridge eluting with 7M Ammonia in methanol to obtain crude product which was purified by preparative reverse phase HPLC (prep-LC-6) to afford the title compound. Ή NMR (400 MHz, DMSO): d 10.84 (s, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 8.15 (s, 1 H), 7.89 (d, J = 2.3 Hz, 1 H), 7.76 (s, 1 H), 7.58 (s, 2 H), 7.29-7.28 (m, 2 H), 7.26-7.24 (m, 1 H), 7.21-7.17 (m, 1 H), 7.10-7.07 (m, 1 H), 5.29 (s, 2 H), 3.70 (s, 1 H), 3.28 (s, 2 H); LCMS (LC-Method 1) Rt = 2.2 min, m/z 324 [M+H]

[0228] The following Examples were prepared according to Scheme 2 using 3-amino-N- (1 H-pyrazol-4-yl) pyrazine-2-carboxamide (CAS:1933674-659-1) and the appropriate substituted benzyl halide or bromoethyl benzene or bromoalkene of general formula [V] as described at 80-100°C, benzyl chlorides heated at 110°C. The reactions were purified using one of the methods below:

Method 2.A: preparative reverse phase HPLC using one of the prep methods described.

Method 2.B: Biotage silica gel column chromatography eluting with mixtures of isohexane and ethyl acetate.

[0229] In another approach (Scheme 2a - in which R represents an optional substituent on the phenyl ring as defined herein) compounds of formula [IV] were prepared by the reaction of carboxylic acid of general formula [III] with a 3-amino-azole with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DM F in the presence of a tertiary amine base such as Et ₃ N, DI PEA or NMM. After reaction work up, typically by a liquid- liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the N- acylated-heterocyclic compound of general formula [IV]. Compounds of general formula [2a.2] were prepared by reacting azole-derivatives of general formula [IV] with an activated a-halo- methyl derivative of formula [2a.1] in a polar aprotic solvent such as DMF or DMA with a suitable base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at ambient temperature or at high temperature by heating thermally. After reaction work up, typically by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. In some examples compounds of general formula [2a.3] are prepared from a compounds of general formula [2a.2] by general N-deprotection step such as an N-Boc deprotection with TFA or HCI in a polar solvent such as DCM or Et ₂ 0. After reaction work-up typically by ion exchange purification or liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation.

Scheme 2a

Example 134: 3-amino-N-(1-(3-(N-propylsulfamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide [0230] To a stirred suspension of 3-amino-N-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide (CAS: 1933674-659-1), 62 mg, 0.304 mmol) and potassium carbonate (63 mg, 0.456 mmol) in DMF (1 ml) was added 3-(N-(tert-butoxycarbonyl)-N-propylsulfamoyl)benzyl methanesulfonate (Intermediate 2.1) (124 mg, 0.304 mmol). The reaction mixture was heated to 90°C overnight. The reaction was diluted with ethyl acetate and washed with water, organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and isohexane (20-80% gradient) to afford tert-butyl ((3-((4-(3-aminopyrazine-2-carboxamido)-1 H- pyrazol-1-yl)methyl)phenyl)sulfonyl)(propyl)carbamate (40 mg, 0.078 mmol) which was dissolved in DCM (1 ml) and treated with TFA (0.048 ml, 0.621 mmol). The reaction was stirred for 2 hours then diluted with EtOAc and washed with saturated sodium bicarbonate solution before drying with MgS04 and concentrating in vacuo to obtain crude product which was purified by preparative reverse phase HPLC (prep-LC-4) to afford the title compound (5.7 mg, 18%). Ή NMR (400 MHz, CDCh): d 9.64 (s, 1 H), 8.19 (d, J = 2.4 Hz, 1 H), 8.09 (s, 1 H), 7.84 (d, J = 2.3 Hz, 1 H), 7.82-7.78 (m, 1 H), 7.75-7.73 (m, 1 H), 7.64-7.63 (m, 1 H), 7.52- 7.47 (m, 1 H), 7.43-7.39 (m, 1 H), 5.37 (s, 2 H), 4.49 (t, J = 6.1 Hz, 1 H), 2.91 (dt, J = 6.8, 6.7 Hz, 2 H), 1.63 (s, 2 H), 1.51-1.44 (m, 2 H), 0.86 (t, J = 7.4 Hz, 3 H). LCMS (LC-Method 2) Rt = 3.64 min, m/z 416 [M+H]

Examples 262/263: 3-amino-N-(1-((3-methoxyphenylH(R)-piperidin-2-yl)methyl)-1 H- pyrazol-4-yl)pyrazine-2-carboxamide

[0231] Step 1 - ((R)-1-allylpiperidin-2-yl)(3-methoxyphenyl)methanol (Intermediate 1.2) (200 mg, 0.765 mmol) was dissolved in DCM (6 ml.) and cooled to 0 °C. Triethylamine (0.210 ml_, 1.53 mmol) was added, followed by methanesulfonyl chloride (0.071 ml_, 0.918 mmol), dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 hours, then heated to 40 °C for additional 2 hours. The reaction was allowed to cool down to room temperature, quenched with saturated ammonium chloride solution and extracted with DCM. The organic phase was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to afford ((R)-1-allylpiperidin-2-yl)(3-methoxyphenyl)methyl methanesulfonate as a yellow oil (250 mg 80% pure, 70% yield) which was used crude for the next step. LCMS m/z 276 ES+.

[0232] Step 2 - ((R)-1-allylpiperidin-2-yl)(3-methoxyphenyl)methyl methanesulfonate (250 mg, 0.736 mmol), 3-amino-N-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide (CAS 1933674-69-1 , 180 mg, 0.884 mmol) and potassium carbonate (204 mg, 1.47 mmol) were combined in DMF (5 mL) and heated to 50°C for 5 hours. The reaction mixture was then cooled to room temperature and filtered. The solid was washed with DCM and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (10-40% gradient) in cyclohexane to afford N-(1-(((R)-1 -allylpiperidin-2- yl)(3-methoxyphenyl)methyl)-1 H-pyrazol-4-yl)-3-aminopyrazine-2-carboxamide (75 mg, 23%). Ή NMR (400 MHz, CDCI ₃ ) d 9.59 (s, 1 H), 8.17 (d, J=2.4 Hz, 1 H), 8.13 (s, 1 H), 7.81 (d, J=2.4 Hz, 1 H), 7.60 (s, 1 H), 7.23 (t, J=8.0 Hz, 1H), 7.05 - 7.01 (m, 2H), 6.81 - 6.78 (m, 1 H), 5.64 - 5.54 (m, 2H), 5.09 - 5.01 (m, 2H), 3.79 (s, 3H), 3.69 - 3.62 (m, 1 H), 3.28 - 3.14 (m, 2H), 3.01 - 2.92 (m, 1 H), 2.60 - 2.52 (m, 1 H), 1.78 - 1.68 (m, 1 H), 1.62 - 1.44 (m, 4H), 1.23 - 1.13 (m, 1 H), NH ₂ not observed.

[0233] Step 3 - N-(1-(((R)-1-allylpiperidin-2-yl)(3-methoxyphenyl)methyl)-1 H-pyrazol-4-yl)-3- aminopyrazine-2-carboxamide (70 mg, 0.156 mmol) and 1 ,3-dimethylbarbituric acid (122 mg, 0.782 mmol) were combined in DCM (1 mL) under nitrogen, then tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.0156 mmol) was added and the mixture was heated to 50 °C for 3 hours. The reaction mixture was then cooled to room temperature, filtered through Celite™ and purified by preparative HPLC (prep-LC-2) to afford 3-amino-N-(1- ((3-methoxyphenyl)((R)-piperidin-2-yl)methyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide (Example 262) as a formate salt (30.6 mg, 48%)

[0234] The following Examples were prepared analogously to Example 262/263,. The compounds were purified by preparative reverse phase HPLC.

[0235] In another approach (Scheme 3 - in which R is a generic substituent) compounds of formula [IX] were prepared by a transition metal -catalysed hydroxylation reaction of a bromo- derivative of general formula [VIII] (prepared according to Scheme 2) with a borylation reagent such as bis(pinacolato)diboron with a palladium catalyst such as Pd(dppf)Cl2 or PdCl2(PPh3)2 in a polar solvent such as THF or dioxane at high temperature by thermal or microwave heating followed by reaction with a base such as NaOH or KOH in a hydrogen peroxide solution. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the hydroxy-heterocyclic compound of general formula [IX] Compounds of general formula [XI] were prepared by reacting derivatives of general formula [IX] with an activated a-alkyl derivative of formula [X] in a polar aprotic solvent such as DMF or DMA with a suitable base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at ambient temperature or at high temperature by heating thermally. After reaction work up, typically by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. Compounds of general formula [XII] are prepared by reaction of compounds of general formula [IX] with (tert-butyl-3-(bromomethyl)azetidine-1-carboxylate, in a polar aprotic solvent such as DMF or DMA with a suitable base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at ambient temperature or at high temperature by heating thermally. After reaction work up, typically by a liquid-liquid extraction the reaction product was used crude in the next step, followed by general N-Boc deprotection using a strong acid such as TFA or HCI in a polar solvent such as DCM or Et ₂ 0. After reaction work-up typically by ion exchange purification or liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. Compounds of general formula [XIII] are prepared by a transition metal-catalysed reaction of a bromo- derivative of general formula [VIII] with a palladium catalyst such as XPhos-Pd-G2 or XPhos- Pd-G1 , with N-Boc-1 ,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester in a polar solvent such as THF, dioxane or H2O with a ionic salt such as TPP. The reaction is suitably conducted at high temperature by heating thermally or under microwave heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product is used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC, or re crystallisation. Compounds of general formula [XIV] were prepared by hydrogenation with hh gas under high pressure in a Parr reactor or an H-Cube reactor, in a polar solvent such as MeOH or EtOH with a palladium catalyst such as palladium on activated charcoal or alumina. After reaction work up, typically filtration followed by a liquid-liquid extraction, the reaction product is used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation followed by a general N-Boc deprotection using a strong acid such as TFA or HCI in a polar solvent such as DCM or EΪSO. After reaction work up typically by ion exchange purification or liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re crystallisation.

Scheme 3

Example 139: 3-amino-/V-M -(3-hvdroxybenzvn-1H-pyrazol-4-vnpyrazine-2-carboxamide [0236] A solution of 3-amino-/V-(1-(3-bromobenzyl)-1/-/-pyrazol-4-yl)pyrazine-2- carboxamide (Example 45, 200 mg, 0.536 mmol), bis(pinacolato)diboron (136 mg, 0.536 mmol) and potassium acetate (53 mg, 0.536 mmol) in dioxane (20 ml) was degassed with nitrogen for 20 minutes then Pd(dppf)Cl2 (39 mg, 0.054 mmol) was added. The reaction vessel was sealed and heated to 100°C for 2 hours under nitrogen. The reaction was cooled to room temperature then diluted with EtOAc (50 ml) and filtered through celite. The filtrate was concentrated in vacuo and the residue dissolved in THF (3 ml). To the ice-cold stirred solution was added sodium hydroxide (2M, 2 ml, 4 mmol) and hydrogen peroxide solution (1 ml). The reaction was stirred at room temperature for 15 hours then diluted with EtOAc (25 ml) and washed with saturated aq. sodium bicarbonate solution (25 ml). The organic extract was washed with brine solution, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and /so-hexane (10-100% gradient) to afford the title compound. Ή NMR (400 MHz, DMSO): d 10.86 (s, 1 H), 9.45 (s, 1 H), 8.26 (d, J = 2.3 Hz, 1 H), 8.14-8.14 (m, 1 H), 7.90 (d, J = 2.4 Hz, 1 H), 7.76 (d, J = 0.6 Hz, 1 H), 7.59 (s, 2 H), 7.14 (t, J = 7.8 Hz, 1 H), 6.70-6.66 (m, 2 H), 6.60 (t, J = 1.9 Hz, 1 H), 5.23 (s, 2 H). LCMS (LC-Method 1) Rt = 3.22 min, m/z 31 1 [M+H]

Example 49: 3-amino-N-(1-(3-(azetidin-3-ylmethoxy)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide

[0237] To a stirred suspension of (tert-butyl-3-(bromomethyl)azetidine-1-carboxylate (64 mg, 0.255 mmol) and cesium carbonate (124 mg, 0.382 mmol) in DMF (1 ml) was added 3- amino-N-(1-(3-hydroxybenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide (Example 139, 100 mg, 0.255 mmol). The reaction mixture was stirred at 50°C overnight. The reaction was diluted with ethyl acetate and washed with water, organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude residue (95 mg) was treated with HCI (4M in dioxane, 1 ml, 3.96 mmol), stirring at room temperature for 90 minutes. The reaction mixture was concentrated in vacuo and the crude residue was purified by preparative reverse phase HPLC (prep-LC-6) to afford the title compound. Ή NMR (400 MHz, DMSO): d 10.86 (1 H, s), 8.26 (1 H, d, J=2.4 Hz), 8.17 (1 H, s), 7.90 (1 H, d, J=2.3 Hz), 7.77 (1 H, s), 7.60 - 7.59 (2H, m), 7.27 (1 H, dd, J=8.0, 8.0 Hz), 6.89 (1 H, d, J=8.9 Hz), 6.82 (2H, d, J=7.4 Hz), 5.28 (2H, s), 4.09 (2H, d, J=6.8 Hz), 3.90 (1 H, m), 3.58 (2H, s), 3.90 (2H, m), 3.01 - 2.94 (1 H, m); LCMS (LC-Method 1) Rt = 2.49 min, m/z 380 [M+H]

Example 51 : 3-amino-N-(1-(3-ethoxybenzyl)-1H-pyrazol-4-vnpyrazine-2-carb oxamide

[0238] To a stirred suspension of bromoethane (0.019ml, 0.258 mmol) and cesium carbonate (84 mg, 0.258 mmol) in DMF (1ml) was added 3-amino-N-(1-(3-hydroxybenzyl)-1 H- pyrazol-4-yl)pyrazine-2-carboxamide (Example 139, 40 mg, 0.129 mmol). The reaction mixture was stirred at 50°C overnight. The reaction was diluted with ethyl acetate and washed with water, organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-4) to afford the title compound. ¹ H NMR (400 MHz, DMSO): d 10.85 (s, 1 H), 8.26 (d, J = 2.3 Hz, 1 H), 8.16 (s, 1 H), 7.90 (d, J = 2.4 Hz, 1 H), 7.77 (s, 1 H), 7.59-7.59 (m, 2 H), 7.26 (dd, J = 7.9, 7.9 Hz, 1 H), 6.87-6.84 (m, 1 H), 6.82-6.78 (m, 2 H), 5.28 (s, 2 H), 4.00 (q, J = 6.9 Hz, 2 H), 1.32 (t, J = 7.0 Hz, 3 H); LCMS (LC-Method 1) Rt = 4.19 min, m/z 339 [M+H]

[0239] The following Examples were prepared according to the method used for Example 51 above, using 3-amino-N-(1-(3-hydroxybenzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide (Example 139) and the appropriate haloalkane as described in the table below. The compounds were purified by preparative reverse phase HPLC.

Example 54: 3-amino-N-(1-(3-(piperidin-4-yl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide

[0240] A solution of tert-butyl 4-(3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1- yl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (340 mg, 0.715 mmol) in methanol (30 ml) passed through H-Cube Pd/C cartridge (full hydrogen) at 50°C for 10 cycles. The reaction mixture was concentrated invacuo. The crude residue (250 mg) was dissolved in DCM (2 ml) and treated with TFA (0.33 ml, 4.35 mmol), stirring at room temperature for 90 minutes. The reaction mixture was diluted with EtOAc and washed with 2M aq. NaOH. The organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-6) to afford the title compound. Ή NMR (400 MHz, DMSO): d 10.85 (s, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 8.16 (s, 1 H), 7.90 (d, J = 2.3 Hz, 1 H), 7.77 (s, 1 H), 7.59 (s, 2 H), 7.28 (dd, J = 7.6, 7.6 Hz, 1 H), 7.18- 7.12 (m, 2 H), 7.05 (d, J = 7.7 Hz, 1 H), 5.30 (s, 2 H), 3.06-2.99 (m, 2 H), 2.61-2.57 (m, 4 H), 1.68-1.65 (m, 2 H), 1.55-1.43 (m, 2 H); LCMS (LC-Method 1) Rt = 2.52 min, m/z 378 [M+H]

[0241] In another approach (Scheme 4 - in which R represents a generic substituent) compounds of formula [XXII I] were prepared by a nucleophilic substitution reaction of an azole compound of general formula [IV] with an obromo-methyl derivative of general formula [XXII] in a polar solvent such as DMF or DMA with a base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at high temperature by heating thermally. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Compounds of general formula [XXIV] are prepared by hydrolysis of compounds of general formula [XXIII] with a base such a lithium hydroxide or sodium hydroxide in a polar solvent such as THF or EtOH and H ₂ 0. The reaction is suitably conducted at ambient or high temperature by heating thermally. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Compounds of formula [XXV] were prepared by the reaction of an amine of general formula [XXVI] with a carboxylic acid of general formula [XXIV] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as EtsN, DIPEA or NMM. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the N-acylated-heterocyclic compound a-methyl-hydroxyl compounds of general formula [XXVI I] were prepared by reduction of an ester derivative of general formula [XXIII] with a reducing agent such as DIBAL or LAH in a polar aprotic solvent such as THF of EΪSO. The reaction is suitably conducted at ambient or low temperature such as 0°C. After reaction work up, typically filtration followed by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation.

Scheme 4

Example 63: 3-((4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1 -yl)methvnbenzoic acid

[0242] Lithium hydroxide (82 mg, 3.41 mmol) was added to a stirred solution of methyl 3- ((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)benzoate [Example 43] (200 mg, 0.568 mmol) in methanol (5 ml) and water (3 ml). The reaction was stirred for 2 hours then concentrated in vacuo. The residue was dissolved in 2M HCI aq. and extracted with EtOAc (x3). Combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated invacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-6) to afford the title compound (34.6 mg, 9%). ¹ H NMR (400 MHz, DMSO): d 10.87 (s, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 8.23 (s, 1 H), 7.90-7.87 (m, 2 H), 7.83 (s, 1 H), 7.79 (s, 1 H), 7.58 (s, 2 H), 7.50-7.48 (m, 2 H), 5.41 (s, 2 H), 2.56 (s, 1 H); LCMS (LC-Method 2) Rt = 2.44 min, m/z 339 [M+H]

Example 64: 3-amino-N-(1-(3-(methylcarbamoyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide

[0243] To a stirred solution of 3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1- yl)methyl)benzoic acid [Example 63] (40 mg, 0.1 18 mmol), methylamine hydrochloride (8 mg, 0.118 mmol) and HATU (24 mg, 0.130 mmol) in DMF (1.0 ml) was added DIPEA (0.06 ml, 0.355 mmol). The reaction mixture was stirred at room temperature overnight then partitioned between EtOAc and 2M aq. HCI. The organic layer was washed with brine and concentrated invacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-1) to afford the title compound 7.4 mg, 18%). ¹ H NMR (400 MHz, DMSO): d 10.86 (s, 1 H), 8.48- 8.43 (m, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 8.20 (s, 1 H), 7.90 (d, J = 2.4 Hz, 1 H), 7.78-7.74 (m, 3 H), 7.59 (s, 2 H), 7.47-7.42 (m, 1 H), 7.40-7.37 (m, 1 H), 5.37 (s, 2 H), 2.78 (d, J = 4.6 Hz, 3 H); LCMS (LC-Method 2) Rt = 3.15 min, m/z 352 [M+H]

Example 265: 3-amino-N-M-(3-(2-oxo-2-(propylamino)ethvhbenzvh-1 H-pyrazol-4-vn pyrazine-2-carboxamide [0244] 2-(3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)phenyl)acetic acid (Intermediate 5.11) (50 mg, 0.142 mmol), HATU (81 mg, 0.213 mmol) and DIPEA (0.037 ml_, 0.213 mmol) were combined in DMF (1.5 ml_), then propylamine (0.014 ml_, 0.170 mmol) was added and the mixture was stirred at room temperature for 1 hour. The crude mixture was concentrated under reduced pressure and purified by silica gel flash chromatography eluting with ethyl acetate (10-80% gradient) in cyclohexane to afford 3-amino-N-(1-(3-(2-oxo-2- (propylamino)ethyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide as a yellow solid (28 mg, 50% yield), Ή NMR (400 MHz, DMSO) d 10.85 (s, 1 H), 8.26 - 8.25 (m, 1 H), 8.16 (s, 1 H), 8.05 - 8.00 (m, 1 H), 7.90 - 7.89 (m, 1 H), 7.76 - 7.76 (m, 1 H), 7.28 (t, J=7.6 Hz, 1 H), 7.21 - 7.08 (m, 3H), 5.29 (s, 2H), 3.02 - 2.98 (m, 2H), 1.42 - 1.36 (m, 2H), 0.84 - 0.80 (m, 3H) [formate salt, NH ₂ and NH not observed, 2H obscured by water peak]; LCMS (LC-Method 1) Rt = 3.38 min, m/z 394 [M+H]

[0245] The following Examples were prepared according to Example 1 or 64 above using the appropriate amine and carboxylic acid as described in Scheme 1 and 4. The reactions were purified using preparative reverse phase HPLC using one of the described prep methods.

Example 81 : 3-amino-N-(1-(3-(hvdroxymethyl)benzyl)-1H-pyrazol-4-yl)pyraz ine-2- carboxamide

[0246] To a stirred solution of methyl 3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1- yl)methyl)benzoate [Example 43] (200 mg, 0.568 mmol) in anhydrous DCM (2 ml) in an oven dried Rbf at 0°C was added dropwise DIBAL (0.20 ml, 1.14 mmol). The reaction was stirred for 2 hours then quenched slowly with water at 0°C then extracted with EtOAc. The organic phase was washed with saturated aq. ammonium chloride solution and brine then dried over magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-8) to afford the title compound (2.6 mg, 7%). Ή NMR (400 MHz, DMSO): d 10.85 (s, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 8.16 (s, 1 H), 7.90 (d, J = 2.4 Hz, 1 H), 7.76 (s, 1 H), 7.59-7.59 (m, 2 H), 7.31 (dd, J = 7.6, 7.6 Hz, 1 H), 7.24 (d, J = 8.3 Hz, 2 H), 7.13 (d, J = 7.5 Hz, 1 H), 5.31 (s, 2 H), 5.21 (t, J = 5.6 Hz, 1 H), 4.48 (d, J = 5.5 Hz, 2 H); LCMS (LC-Method 2) Rt = 3.29 min, m/z 325 [M+H]

[0247] In another approach (Scheme 5 - in which R represents a generic substituent) compounds of formula [5.2] were prepared by a nucleophilic substitution reaction of an azole compound of general formula [IV] with an activated a-methyl derivative of general formula [5.1] in a polar solvent such as DMF or DMA with a base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at high temperature by heating thermally. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Compounds of general formula [5.3] are prepared by hydrolysis of compounds of general formula [5.2] with a base such a lithium hydroxide or sodium hydroxide in a polar solvent such as THF or EtOH and H 0. The reaction is suitably conducted at ambient or high temperature by heating thermally. After reaction work up, typically by a liquid- liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Compounds of formula [5.5] were prepared by the reaction of an amine of general formula [5.4] with a carboxylic acid of general formula [5.3] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as EίbN, DIPEA or NMM. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the N-acylated-heterocyclic compound a-methyl-hydroxyl compounds of general formula [5.6] were prepared by reduction of an ester derivative of general formula [5.2] with a reducing agent such as DIBAL or LAH in a polar aprotic solvent such as THF of EΪSO. The reaction is suitably conducted at ambient or low temperature such as 0°C. After reaction work up, typically filtration followed by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. 1 ,2,4-triazole derivatives of general formula [5.9] were prepared by a Pellizzari type reaction by reaction of a carboxamide derivative of general formula [5.7] with a acylhydrazide derivative of general formula [5a.8] in a polar solvent such as DMF with a base such as KOH. The reaction is suitably conducted at high temperature by heating thermally. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re crystallisation to yield the 1 ,2,4-triazole -heterocyclic compound of general formula [5.9] Carboxamide derivative of general formula [5.7] were prepared by a Schotten-Baumann reaction by reaction of the carboxylic acid derivatives of general formula [5.3] with thionyl chloride in a polar solvent such as DCM. The reaction is suitably conducted at high temperature under thermal heating, followed by reaction with ammonia. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation.

Scheme 5 Example 168: 3-amino-N-(1-(1-(3-(propylcarbamovnphenvHethyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide

[0248] To a stirred solution of 3-(1-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1- yl)ethyl)benzoic acid (intermediate 5.8, 70 mg, 0.199 mmol) propylamine (14 mg, 0.238 mmol) and HATU (113 mg, 0.298 mmol) in DMF (1.0 ml) was added DIPEA (0.052 ml, 0.298 mmol). The reaction mixture was stirred at room temperature overnight then partitioned between EtOAc and 2M aq. HCI. The organic layer was washed with brine and concentrated invacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-1) to afford the title compound 49 mg, 62%). ¹ H NMR (400 MHz, DMSO): d 10.84 (s, 1 H), 8.48 (t, J = 5.6 Hz, 1 H), 8.26 (d, J = 2.3 Hz, 1 H), 8.17 (s, 1 H), 7.90-7.89 (m, 1 H), 7.81-7.77 (m, 2 H), 7.75 (td, J = 1.6, 7.4 Hz, 1 H), 7.58 (s, 2 H), 7.45-7.37 (m, 2 H), 5.67 (q, J = 7.0 Hz, 1 H), 3.22 (dt, J = 6.1 , 6.9 Hz, 2 H), 1.83 (d, J = 7.2 Hz, 3 H), 1.57-1.50 (m, 2 H), 0.90 (t, J = 7.4 Hz, 3 H). LCMS (LC-Method 2) Rt = 3.55 min, m/z 394 [M+H]

[0249] The following Examples were prepared according to Example 168 above using the appropriate amine and carboxylic acid as described in Scheme 5. The reactions were purified using preparative reverse phase HPLC using one of the described prep methods.

Example 172: 3-amino-N-( 1 -(3-(5-ethyl-1 H-1.2.4-triazol-3-yl)benzyl)-1 H-pyrazol-4- yl)Pyrazine-2-carboxamide

[0250] A solution of 3-amino-N-(1-(3-(hydrazinecarbonyl)benzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide (intermediate 5.10, 30 mg, 0.085 mmol), ethyl propane carboximidate (16 mg, 0.085 mmol) and triethylamine (12 uL, 0.085 mmol) in dry methanol (1.0 ml) was heated to 60°C for 18 hours. Additional ethyl propane carboxamidate (16 mg, 0.085 mmol) was added and reaction heated for a further 3 hours then concentrated in vacuo. The resulting residue was dissolved in dmso and purified by preparative reverse phase HPLC (prep-LC-8 conditions) to afford the title compound (12.1 mg, 36%). Ή NMR (400 MHz, DMSO): d 13.72 (s, 1 H), 10.87 (s, 1 H), 8.26 (d, J = 2.3 Hz, 1 H), 8.22 (d, J = 0.5 Hz, 1 H), 7.94-7.89 (m, 3 H), 7.79 (d, J = 0.6 Hz, 1 H), 7.60 (s, 2 H), 7.47-7.40 (m, 1 H), 7.32-7.27 (m, 1 H), 5.39 (s, 2 H), 2.76 (q, J = 7.6 Hz, 2 H), 1.28 (t, J = 7.6 Hz, 3 H). LCMS (LC-Method 2) Rt = 3.11 min, m/z 390 [M+H]

[0251] In another approach (Scheme 6 - in which R and R’ respresent generic susbtituents and Zi is as defined herein), amino-compounds of general formula [XXXI] are prepared in a two-step procedure first by an alkylation reaction of an a-bromomethyl derivative of general formula [XXX] with an azole derivative of general formula [IV] (prepared in Scheme 2) in a polar solvent such as DMF or DMA with a base such as potassium carbonate or caesium carbonate. The reaction is suitably heated at ambient or elevated temperature by thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Followed by N-Boc deprotection with a strong acid such as TFA or HCI in a polar solvent such as DCM or Eί ₂ 0 at ambient or low temperature. After reaction work up, typically by a liquid-liquid extraction or ion exchange chromatography, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation a-bromomethyl derivatives of general formula [XXX] are prepared in a two-step process first by reduction of a carboxylic acid ester derivative of general formula [XXVIII] with a reducing agent such as LAH or DIBAL in an aprotic solvent such as THF or Et ₂ 0 under an inert atmosphere. The reaction is suitably conducted at ambient or low temperature. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the a-hydroxymethyl derivatives of general formula [XXIX] Followed by an Appel type reaction with tetrabromomethane a phosphine reagent such as triphenylphosphine or polymer-supported triphenylphosphine in a polar solvent such as THF or dioxane. The reaction is suitably conducted at ambient temperature. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Carboxamide derivatives of general formula [XXXIV] are prepared by reaction of an amino derivative of general formula [XXXI] by reaction with a carboxylic acid derivative or general formula [XXXII] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as Et ₃ N, DIPEA or NMM, the reaction is suitably conducted at ambient temperature (Method 6.A); or by reaction of amine derivative of general formula [XXXI] with an acyl chloride derivative of general formula [XXXIII] in a polar solvent such as DCM or THF, with a base such as TEA or DEAD, the reaction is suitably conducted at ambient temperature (Method 6.B). After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the N-acylated- heterocyclic compound of general formula [XXXIV] N-alkyl derivatives of general formula [XXXVI] are prepared by a alkylation reaction of an amino derivative of general formula [XXXI] with an a-halomethyl derivative of general formula [XXXV] in a polar solvent such as DMF or DMA with a base such as potassium carbonate or caesium carbonate, the reaction is suitably conducted at ambient or high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the N- alkylated-heterocyclic compound of general formula [XXXVI] N-sulfonamide derivatives of general formula [XXXVIII] are prepared by a sulfonylation reaction of an amino derivative of general formula [XXXI] with a sulfonyl chloride derivative of general formula [XXXVII] in a polar solvent such as DMF or DCM with a base such TEA or DIPEA, the reaction is suitably conducted at ambient or high temperature under thermal heating (Method 6.B). After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the N- alkylated-heterocyclic compound of general formula [XXXVIII]

Scheme 6

Example 82: 3-amino-N-n-(3-amino-4-fluorobenzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide

[0252] To a stirred suspension of 3-amino-N-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide (CAS: 1933674-659-1) (800 mg, 3.91 mmol) and potassium carbonate (810 mg, 5.88 mmol) in DMF (10 ml) was added ferf-butyl (5-(bromomethyl)-2-fluorophenyl)carbamate (CAS: 1896184-31 -8) (1.19 g, 3.92 mmol). The reaction mixture was heated to 100°C overnight. The reaction was diluted with ethyl acetate and washed with water, organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and isohexane (15-70% gradient) to afford tert-butyl (5-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)- 2-fluorophenyl)carbamate (1 g, 2.34 mmol) which was dissolved in in dioxane and treated with 4M HCI in dioxane (7.2 ml, 28.37 mmol). The reaction was heated to 40°C and stirred for 2 hour. The reaction was concentrated in vacuo to obtain crude product. 80 mg of crude was submitted purification and the remainder was used in the next step without purification as the HCI salt. Purification by preparative reverse phase HPLC (prep-LC-6) to afford the title compound (12 mg, 14%). Ή NMR (400 MHz, DMSO): 5 10.84 (s, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 8.11 (s, 1 H), 7.89 (d, J = 2.3 Hz, 1 H), 7.75 (s, 1 H), 7.59 (s, 2 H), 6.94 (dd, J = 8.2, 11.5 Hz, 1 H), 6.64 (dd, J = 2.1 , 8.8 Hz, 1 H), 6.45-6.40 (m, 1 H), 5.19 (s, 2 H), 5.15 (s, 2 H); LCMS (LC-Method 1) Rt = 3.32 min, m/z 328 [M+H]

[0253] The following examples were prepared according to the example above using 3- amino-N-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide (CAS: 1933674-659) and the appropriate commercially available bromides as described in Scheme 6. The reactions were purified using preparative reverse phase HPLC using one of the described prep methods (1-8).

Example 86: 3-amino-N-(1-(3-((cvanomethyl)amino)benzyl)-1H-pyrazol-4-yl) pyrazine-2- carboxamide

[0254] To a stirred suspension of 3-amino-N-(1-(3-aminobenzyl)-1 H-pyrazol-4-yl)pyrazine- 2-carboxamide hydrochloride [Example 83] (80 mg, 0.231 mmol) and cesium carbonate (226 mg, 0.694 mmol) in DMF (1 ml) was added bromoacetonitrile (90 mg, 0.75 mmol). The reaction mixture was heated to 100°C for 15 hours. The reaction was diluted with ethyl acetate and washed with water, organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude mixture was purified preparative reverse phase HPLC (prep-LC-8) to afford the title compound. Ή NMR (400 M Hz, DMSO): 5 10.85 (s, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 8.14 (s, 1 H), 7.90 (d, J = 2.3 Hz, 1 H), 7.77 (s, 1 H), 7.59 (s, 2 H), 7.19- 7.15 (m, 1 H), 6.67-6.57 (m, 3 H), 6.35-6.30 (m, 1 H), 5.23 (s, 2 H), 4.24 (d, J = 6.8 Hz, 2 H), 2.09 (s, 2 H); LCMS (LC-Method 2) Rt = 3.59 min, m/z 349 [M+H]

Example 87: 3-amino-N-(1-(4-fluoro-3-isobutyramidobenzyl)-1H-pyrazol-4-y l)pyrazine- 2-carboxamide [0255] To a stirred solution of 3-amino-N-(1-(3-amino-4-fluorobenzyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide [Example 82] (80 mg, 0.220 mmol), isobutyric acid (19 mg, 0.220 mmol) and HATU (85 mg, 0.330 mmol) in DMF (1.0 ml) was added DIPEA (0.11 ml, 0.660 mmol). The reaction mixture was stirred at room temperature overnight then diluted with EtOAc and saturated aq. sodium bicarbonate solution. The organic layer was washed with brine and concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-5) to afford the title compound 14 mg, 11%). Ή NMR (400 MHz, DMSO): d 10.86 (s, 1 H), 9.61 (s, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 8.17 (s, 1 H), 7.90 (d, J = 2.3 Hz, 1 H), 7.81-7.77 (m, 1 H), 7.77-7.76 (m, 1 H), 7.59 (s, 2 H), 7.25-7.20 (m, 1 H), 7.07-7.02 (m, 1 H), 5.28 (s, 2 H), 2.78-2.68 (m, 1 H), 1.10 (d, J = 6.8 Hz, 6 H); LCMS (LC-Method 2) Rt = 3.57 min, m/z 398 [M+H]

Example 88: 3-amino-N-(1-(3-(vinylsulfonamido)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide

[0256] To a cooled stirred solution of 3-amino-N-(1-(3-aminobenzyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide [Example 83] (80 mg, 0.231 mmol) and triethylamine (0.097ml, 0.694 mmol) in DCM at -40°C was added ethenesulfonyl chloride (26 mg, 0.208 mmol). The reaction was allowed to stir and warm to 0°C over 2 hours. The reaction was diluted with ethyl acetate and washed with saturated aq. sodium bicarbonate solution, organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude mixture was purified preparative reverse phase HPLC (prep-LC-8) to afford the title compound. Ή NMR (400 MHz, DMSO): d 10.87 (s, 1 H), 8.27-8.26 (m, 1 H), 8.15 (s, 1 H), 7.90 (d, J = 2.4 Hz, 1 H), 7.77 (s, 1 H), 7.59 (s, 2 H), 7.27 (dd, J = 7.8, 7.8 Hz, 1 H), 7.06 (d, J = 7.9 Hz, 1 H), 7.01-6.99 (m, 1 H), 6.95-6.92 (m, 1 H), 6.73 (dd, J = 10.0, 16.5 Hz, 1 H), 6.09 (d, J = 15.0 Hz, 1 H), 6.00 (d, J = 1 1.0 Hz, 1 H), 5.28 (s, 2 H); LCMS (LC-Method 2) Rt = 3.53 min, m/z 400 [M+H]

[0257] The following Examples were prepared using the appropriate amine according to Example 87 (Method 6.A) using the appropriate carboxylic acid or Example 88 (Method 6.B) using the appropriate acid chloride as described in Scheme 6. The reactions were purified using preparative reverse phase HPLC using one of the described prep methods (1-8).

Example 173: 3-amino-N-(1 -(3-(3-ethylureido)benzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide

[0258] To a cooled stirred solution of 3-amino-N-(1-(3-aminobenzyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide [Example 83] (89 mg, 0.289 mmol) in dry THF (1 ml) at 0°C was added ethyl isocyanate (23 mg, 0.318 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was concentrated in vacuo and crude residue purified by preparative reverse phase HPLC (prep-LC-9) to afford the title compound. Ή NMR (400 MHz, DMSO): d 10.83 (s, 1 H), 8.25 (d, J = 2.2 Hz, 1 H), 8.24-8.22 (m, 1 H), 7.90-7.88 (m, 1 H), 7.81 (s, 1 H), 7.57-7.51 (m, 4 H), 7.43-7.33 (m, 3 H), 7.21 (br s, 2H), 5.53 (d, J = 8.3 Hz, 1 H), 4.88-4.83 (m, 1 H), 3.87-3.81 (m, 1 H), 3.61-3.52 (m, 1 H), 3.42-3.41 (m, 1 H), 3.22-3.12 (m, 1 H), 2.94-2.89 (m, 2 H), 2.06-2.02 (m, 2 H). LCMS (LC-Method 1) Rt = 2.6 min, m/z 394 [M+H]

[0259] In another approach (Scheme 7 - in which R and R’ represent generic substituents), azetidine-derivatives of general formula [XLV] are prepared by reaction of an amino-azole derivative of general formula [XLIV] with a carboxylic acid derivative or general formula [III] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as E1¾N, DIPEA or NMM, the reaction is suitably conducted at ambient temperature. Compounds of general formula [XLV] were R’ is an N-Boc protecting group are deprotected under acidic reaction conditions with TFA or HCI in a suitable solvent such as DCM at ambient temperature, followed by reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release. The crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral SFC or re-crystallisation. Amino-azole derivatives of general formula [XLIV] are prepared by the reduction of nitro-azole derivatives of general formula [XLIII] with a suitable reducing agent such iron-ammonium chloride or ammonium formate/palladium on carbon in a polar solvent such as EtOH, MeOH or H2O. The reaction is suitably conducted at ambient or high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC, re-crystallisation. Nitro-pyrazole derivatives of general formula [XLIII] are prepared by a Mitsunobu type reaction by the reaction of a hydroxy-derivative of general formula [XLII] with a 3-nitro-azole derivative of general formula [XLVI] with a suitable phosphine agent such as triphenylphosphine or polymer- supported triphenylphosphine and a suitable azodicarboxylate agent such as DIAD or DEAD in a polar solvent such as THF or Et ₂ 0. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Hydroxy- azetidine derivatives of general formula [XLII] are prepared by reduction of ketone derivatives of general formula [XLI] with a suitable reducing agent such as sodium borohydride or sodium cyanoborohydride in a polar solvent such as THF or Et ₂ 0. The reaction is suitably conducted at ambient or low temperature, more suitably at 0 °C. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Ketone derivatives of general formula [XLI] were R is H are prepared by reaction of a Weinreb amide of general formula [XXXIX] with a Grignard reagent of general formula [XL] in a polar aprotic solvent such as THF or Et ₂ 0. The reaction is suitably conducted at low temperature, more suitably -78 °C. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. Ketone derivatives of general formula [XLI] were R is F are prepared in a two-step reaction from Weinreb amide of general formula [XXXIX] with a Grignard reagent of general formula [XL] in a polar aprotic solvent such as THF or Et ₂ 0. The reaction is suitably conducted at low temperature, more suitably -78 °C. This is followed by reaction with an electrophilic N-F fluorinating reagent such as NFSI or NFOBS with a strong non-nucleophilic base such as LiHMDS or LDA in a polar solvent such as THF or Et ₂ 0. The reaction is suitably conducted at low temperature, more suitably -78 °C. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation.

Scheme 7

Example 103: 3-amino-N-(1-(azetidin-3-yl(phenyl)methyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide

[0260] To a stirred solution of 3-aminopyrazine-2-carboxylic acid (61 mg, 0.435 mmol), tert- butyl 3-((4-amino-1 H-pyrazol-1-yl)(phenyl)methyl)azetidine-1-carboxylate (CAS: 1398705-01 - 5, 110 mg, 0.335 mmol) and HATU (140 mg, 0.368 mmol) in DMF (1.0 ml) was added DIPEA (0.12 ml, 0.0.670 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was mixture was diluted with EtOAc and washed with saturated aq. ammonium chloride. The organic extract was dried over magnesium sulphate, filtered and concentrated invacuo then dissolved in DCM and treated with 4M HCI in dioxane stirring at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the crude residue passed through an SCX-2 cartridge eluting with 7M NH3 in methanol then purified by preparative reverse phase HPLC (prep-LC-6) to afford the title compound (41 mg, 35%). ¹ H NMR (400 MHz, DMSO) d 10.78 (1 H, s), 8.23 (1 H, d, J=2.4 Hz), 8.13 (1 H, s), 7.87 (1 H, d, J=2.4 Hz), 7.73 (1 H, s), 7.56 - 7.56 (2H, m), 7.35 - 7.32 (5H, m), 5.65 (1 H, d, J=11.2 Hz), 3.70 - 3.60 (1 H, m), 3.48 - 3.36 (2H, m), 3.26 - 3.18 (3H, m); LCMS (method 1): Rt = 2.56 min, m/z 350 [M+H] Example 103 was resolved by Chiral SFC (SFC-1) to isolate its enantiomers:

[0261] The following Examples were prepared according to the above method (Example 103) above using the appropriate heteroaryl amine and carboxylic acid as described in scheme 7. The reactions were purified using preparative reverse phase HPLC using one of the described prep methods (1-8) and Chiral SFC using chiral prep methods (1-7) where racemates were resolved into their enantiomers.

[0262] In another approach (Scheme 7a - in which R and R’ represent generic substituents), saturated heterocyclic-derivatives of general formula [7a.6] are prepared by reaction of an amino-azole derivative of general formula [7a.5] with a carboxylic acid derivative or general formula [III] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as Et ₃ N, DIPEA or NMM, the reaction is suitably conducted at ambient temperature. Compounds of general formula [7a.6] were R’ is an N-Boc protecting group are deprotected under acidic reaction conditions with TFA or HCI in a suitable solvent such as DCM at ambient temperature, followed by reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release. The crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral SFC or re-crystallisation. Amino-azole derivatives of general formula [7a.5] are prepared by the reduction of nitro-azole derivatives of general formula [7a.4] with a suitable reducing agent such iron-ammonium chloride or ammonium formate/palladium on carbon in a polar solvent such as EtOH, MeOH or H2O. The reaction is suitably conducted at ambient or high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC, re-crystallisation. Nitro- pyrazole derivatives of general formula [7a.4] are prepared by a Mitsunobu type reaction by the reaction of a hydroxy-derivative of general formula [7a.3] with a 3-nitro-azole derivative of general formula [XLVI] with a suitable phosphine agent such as triphenylphosphine or polymer-supported triphenylphosphine and a suitable azodicarboxylate agent such as DIAD or DEAD in a polar solvent such as THF or Et ₂ 0. After reaction work up, typically by a liquid- liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Hydroxy-saturated heterocyclic derivatives of general formula [7a.3] are prepared by reduction of ketone derivatives of general formula [7a.2] with a suitable reducing agent such as sodium borohydride or sodium cyanoborohydride in a polar solvent such as THF or Et ₂ 0. The reaction is suitably conducted at ambient or low temperature, more suitably at 0 °C. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or recrystallisation. Ketone derivatives of general formula [7a.2] were R is H are prepared by reaction of a Weinreb amide of general formula [7a.1] with a Grignard reagent of general formula [XL] in a polar aprotic solvent such as THF or Et ₂ 0. The reaction is suitably conducted at low temperature, more suitably -78 °C. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. Ketone derivatives of general formula [7a.2] were R is F are prepared in a two-step reaction from Weinreb amide of general formula [7a.1] with a Grignard reagent of general formula [XL] in a polar aprotic solvent such as THF or Et ₂ 0. The reaction is suitably conducted at low temperature, more suitably -78 °C. This is followed by reaction with an electrophilic N-F fluorinating reagent such as NFSI or NFOBS with a strong non-nucleophilic base such as LiHMDS or LDA in a polar solvent such as THF or Et ₂ 0. The reaction is suitably conducted at low temperature, more suitably -78 °C. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation.

Scheme 7a

[7a.2] [7a.1]

[7 a.6] [7a.5] Example 174: N-(1-((1 ,4-oxazepan-2-yl)(phenyl)methyl)-1 H-pyrazol-4-yl)-3- aminopyrazine-2-carboxamide (mixture 1)

Mixture 1

[0263] To a stirred solution of 3-aminopyrazine-2-carboxylic acid (61 mg, 0.435 mmol), tert- butyl 2-((4-amino-1 H-pyrazol-1-yl)(phenyl)methyl)-1 ,4-oxazepane-4-carboxylate

(intermediate 7.13, 134 mg, 0.359 mmol) and HATU (164 mg, 0.431 mmol) in DMF (2.0 ml) was added DIPEA (0.13 ml, 0.719 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was mixture was diluted with EtOAc and washed with saturated aq. ammonium chloride. The reaction mixture was concentrated in vacuo and the crude residue purified by silica gel flash chromatography eluting with mixtures of EtOAc and cyclohexane (10-100%) to afford the Boc protected product (78 mg, 44%). The product was dissolved in dioxane and treated with 4M HCI in dioxane stirring at room temperature for 1 hour then concentrated in vacuo and the crude residue was purified by preparative reverse phase HPLC and freeze dried to afford the title compound (12 mg, 21 %). Ή NMR (400 MHz, DMSO): d 10.89 (s, 1 H), 8.57 (s, 1 H), 8.27-8.26 (m, 2 H), 7.90 (d, J = 2.3 Hz, 1 H), 7.84 (s, 1 H), 7.60 (s, 1 H), 7.54-7.50 (m, 2 H), 7.42-7.31 (m, 3 H), 5.53 (d, J = 8.6 Hz, 1 H), 4.77-4.70 (m, 1 H), 3.84-3.76 (m, 1 H), 3.60-3.52 (m, 1 H), 3.31-3.25 (m, 1 H), 3.15-3.07 (m, 1 H), 2.96- 2.91 (m, 2 H), 2.01-1.97 (m, 2 H). LCMS (LC-Method 1) Rt = 2.73 min, m/z 394 [M+H]

[0264] The following Examples were prepared according to the above method (Example 103 or 174) above using the appropriate heteroaryl amine and carboxylic acid as described in scheme 7 or 7a and purified by silica gel flash chromatography to afford the Boc protected precursors before deprotection with TFA or HCI as described above. The final reactions were purified using preparative reverse phase HPLC using one of the described prep methods (1- 14) and Chiral SFC using chiral prep methods (1-17) where racemates were resolved into their enantiomers.

[0265] In another approach (Scheme 8), carboxamide-derivatives of general formula [I] are prepared by reaction of an amino-azole derivative of general formula [II] with a carboxylic acid derivative or general formula [III] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as Et ₃ N, DIPEA or NMM, the reaction is suitably conducted at ambient temperature. Examples were R ₂ contains an N-Boc protecting group are deprotected under acidic reaction conditions such as TFA or HCI in a suitable solvent such as DCM or Et ₂ 0 at ambient temperature. After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation. Amino-azole derivative of general formula [II] are prepared by the reduction of nitro-azole derivatives of general formula [XLVIII] with a suitable reducing agent such iron-ammonium chloride or ammonium formate/palladium on carbon in a polar solvent such as EtOH, MeOH or H2O. The reaction is suitably conducted at ambient or high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC, re-crystallisation. Nitro-azole derivatives of general formula [XLVIII] are prepared by a Mitsunobu type reaction by the reaction of a hydroxy-derivative of general formula [XLVII] with a 3-nitro-azole derivative of general formula [XLVI] with a suitable phosphine agent such as triphenylphosphine or polymer-supported triphenylphosphine and a suitable azodicarboxylate agent such as DIAD or DEAD in a polar solvent such as THF or EΪSO. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC or recrystallisation. In some cases compounds of general formula [XLVIII] are methylated by reaction with a methylating agent such as iodomethane or dimethyl sulfate with a strong non- nucleophilic base such as sodium hydride or LHMDS in a polar solvent such as DMF or DMA, the reaction is suitably conducted at ambient or low temperature. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC, re crystallisation.

Scheme 8

[0266] The following Examples were prepared according to (Example 103) [Prepared according to Scheme 7] above using the appropriate azole-amine [II] and carboxylic acid [II I] as described in Scheme 8. The reactions were purified using preparative reverse phase HPLC using one of the described prep methods (1-8) and Chiral SFC using chiral prep methods (1-7) where racemates were resolved into their enantiomers.

[0267] In another approach (Scheme 8a), carboxamide-derivatives of general formula [8a.4] are prepared by reaction of an amino-azole derivative of general formula [8a.3] with a carboxylic acid derivative or general formula [III] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as Et ₃ N, DIPEA or NMM, the reaction is suitably conducted at ambient temperature. Examples were R ₂ contains an N-Boc protecting group are deprotected under acidic reaction conditions such as TFA or HCI in a suitable solvent such as DCM or Et ₂ 0 at ambient temperature. After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re crystallisation. Examples were R ₂ contains a basic NH ₂ or NH group can be further derivatised to N-alkylated compounds of general formula [8a.6] through a reductive amination type reaction with a carbonyl derivative of general formula [8a.5] in a polar solvent such as MeOH, EtOH or THF with a suitable reducing agent such a as NaBhhCN, NaBhU, NaBH(OAc)3, with a weak acid such as AcOH or NhUOAc.

Scheme 8a

[XLVII] [XLVIII] [8a.3]

[0268] After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release, the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation. Examples were R2 contains a basic NH2 or NH group can be further derivatised to sulphonyl compounds of general formula [8a.8] through a sulphonylation reaction with a sulphonyl chloride derivative of general formula [8a.7] in a polar solvent such as DCM, DMF or THF with a suitable base such as EtsN or DIPEA. The reaction is suitably conducted at ambient or high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or recrystallisation.

[0269] The following Examples were prepared according to (Example 103) [Prepared according to Scheme 7] above using the appropriate azole-amine [8a.3] and carboxylic acid [III] as described in Scheme 8a. The reactions were purified using preparative reverse phase HPLC using one of the described prep methods (1-14) and Chiral SFC using chiral prep methods (1-17) where racemates were resolved into their enantiomers.

Example 199: 3-amino-N-(1-(2-((cvclopropylmethyl)amino)-1-phenylethyl)-1H -pyrazol- 4-yl)pyrazine-2-carboxamide

[0270] To a cool stirred solution of 2-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4- yl)nicotinamide (Example 182, 70 mg, 0.216 mmol) in anhydrous DCM (2.0 ml) at 0°C was added acetic acid (0.074 ml, 1.30 mmol) and cyclopropanecarboxaldehyde (0.016 ml, 0.216 mmol). The reaction was stirred at 0 C° for 1 hour then sodium triacetoxy borohydride (184 mg, 0.866 mmol) was added and reaction allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 1 hour then quenched with 2M aq. sodium hydroxide solution and partitioned between EtOAc and brine. The organic layer was washed with brine and passed through a hydrophobic frit before concentrating invacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-14) to afford the title compound 24.8 mg, 30%). ¹ H NMR (400 MHz, DMSO): d 10.80 (s, 1 H), 8.22 (d, J = 2.4 Hz, 1 H), 8.15-8.15 (m, 1 H), 7.85 (d, J = 2.4 Hz, 1 H), 7.78-7.77 (m, 1 H), 7.55 (s, 2 H), 7.31-7.26 (m, 5 H), 5.51 (dd, J = 5.3, 9.2 Hz, 1 H), 3.47 (dd, J = 9.3, 12.2 Hz, 1 H), 3.10 (dd, J = 5.0, 12.7 Hz, 1 H), 2.39-2.38 (m, 2 H), 1.45 (s, 1 H), 0.84-0.75 (m, 1 H), 0.35-0.32 (m, 2 H), 0.03- 0.01 (m, 2 H). LCMS (LC-Method 1) Rt = 2.87 min, m/z 378 [M+H]

[0271] The following Examples was prepared according to (Example 199) above using the appropriate amine [8a.4] and carbonyl [8a.5] as described in Scheme 8a. The reactions were purified using preparative reverse phase HPLC using one of the described prep methods (1- 14).

Example 201 : 3-amino-N-(1-(2-(methylsulfonamido)-1-phenylethyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide

[0272] To a cool stirred solution of 2-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4- yl)nicotinamide (Example 182, 50 mg, 0.155 mmol) and triethylamine (0.012 ml, 0.155 mmol) in anhydrous acetonitrile (1.0 ml) at O °C was added methanesulfonyl chloride (0.012 ml, 0.155 mmol). The reaction was stirred for 1 hour then concentrated invacuo and the crude residue was purified by preparative reverse phase HPLC (prep-LC-2) to afford the title compound 47 mg, 76%). Ή NMR (400 MHz, DMSO): d 10.86 (s, 1 H), 8.26 (d, J = 2.3 Hz, 1 H), 8.24-8.22 (m, 1 H), 7.90 (d, J = 2.5 Hz, 1 H), 7.84 (s, 1 H), 7.59 (s, 2 H), 7.39-7.36 (m, 6 H), 5.52 (dd, J = 5.5, 9.2 Hz, 1 H), 3.97-3.88 (m, 1 H), 3.70-3.62 (m, 1 H), 2.84 (s, 3 H). LCMS (LC-Method 2) Rt = 3.44 min, m/z 402 [M+H]

Example 202: 3-amino-N-(1-(2-(oxetan-3-ylamino)-1 -phenylethv0-1 H-pyrazol-4- yl)pyrazine-2-carboxamide [0273] To a cool stirred solution of 2-amino-N-(1-(2-amino-1-phenylethyl)-1 H-pyrazol-4- yl)nicotinamide (Example 182, 80 mg, 0.247 mmol) in anhydrous methanol (2.0 ml) at 0 °C was added acetic acid (0.074 ml, 1.30 mmol) and cyclopropanecarboxaldehyde (0.016 ml, 0.216 mmol). The reaction was stirred at 0 °C for 10 minutes then sodium cyanoborohydride (6.2 mg, 0.0.099 mmol) was added and reaction allowed to warm to room temperature for 1 hour then heated to 50 °C for 15 hours. The reaction was concentrated invacuo and the crude residue was purified by preparative reverse phase HPLC (prep-LC-2) to afford the title compound 1.0 mg, 1%). Ή NMR (400 MHz, DMSO) d 10.88 (s, 1 H), 8.30 (d, J=2.5 Hz, 1 H), 8.23 - 8.22 (m, 1 H), 7.94 (d, J=2.3 Hz, 1 H), 7.86 (s, 1 H), 7.63 (s, 2H), 7.40 - 7.30 (m, 5H), 5.47 (dd, J=5.1 , 9.1 Hz, 1 H), 4.66 - 4.56 (m, 2H), 4.30 - 4.23 (m, 2H), 3.99 - 3.91 (m, 1 H), 3.51 (dd, J=9.3, 12.9 Hz, 1 H), 3.14 (dd, J=5.1, 12.9 Hz, 1 H). NH proton not observed. LCMS (LC- Method 2) Rt = 3.25 min, m/z 380 [M+H]

[0274] In one approach (Scheme 9 - in which R and R’ represent generic substituents), carboxamide-derivatives of general formula [LIN] are prepared by reaction of an carboxylate- azole derivative of general formula [LI] with a amine derivative or general formula [LI I] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as Et3N, DIPEA or NMM, the reaction is suitably conducted at ambient temperature. After reaction work up, typically by a liquid-liquid extraction the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation. Carboxylate-azole derivatives of general formula [LI] are prepared by hydrolysis of carboxylate-ester derivatives of general formula [L] with a base such as lithium hydroxide or sodium hydroxide in a polar solvent such as MeOH, EtOH or H ₂ 0. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction the crude product was used in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Carboxylate-ester derivatives of general formula [L] are prepared by an alkylation reaction of a azole derivative of general formula [IV] [prepared according to the general procedure in Scheme 2] to with an a-halo derivative of general formula [XLIX] in a polar solvent such as DMF or DMA with a base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction the crude product was used in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re- crystallisation. Hydroxy derivatives of general formula [LIV] are prepared by reduction of Carboxylate-ester derivatives of general formula [L] with a suitable reducing agent such as LAH or DIBAL-H in a polar solvent such as THF or Et ₂ 0, the reaction is suitably conducted at low temperature, more suitably at -78 °C.

Scheme 9

[0275] After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation. Hydroxy derivatives of general formula [LVI I] are prepared by reduction of carboxylate-ester derivatives of general formula [LV] with a suitable reducing agent such as LAH or DIBAL-H in a polar solvent such as TH F or EΪ ₂ 0, the reaction is suitably conducted at low temperature, more suitably at -78 °C. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Carboxylate-ester derivatives of general formula [LV] are prepared by a Michael-type reaction of a azole derivate of general formula [IV] with an a-b-unsaturated carboxylate ester derivative of general formula [LVI] in a polar solvent such as DMF or DMA with a base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re crystallisation.

Example 124: 3-amino-N-(1-(2-hvdroxy-1-phenylethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide

[0276] To a cool stirred solution of ethyl 2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol- 1-yl)-2-phenylacetate (Intermediate 9.1, 125 mg, 0.341 mmol) in anhydrous THF (2 ml) under nitrogen at -10 °C was added dropwise 1 M lithium aluminium hydride (0.51 ml, 0.512 mmol). The reaction mixture was stirred for 15 minutes then quenched carefully with aqueous Rochelle salt solution and diluted with EtOAc. The mixture was allowed to stand for 1 hour then separated. The organic extract was dried over magnesium sulphate, filtered and concentrated. The crude residue was purified by preparative reverse phase HPLC (prep-LC- 6) to afford the title compound (20 mg, 18%). ¹ H NMR (400 MHz, DMSO): d 10.84 - 10.82 (1 H, m), 8.26 - 8.23 (2H, m), 7.90 (1 H, d, J=2.4 Hz), 7.79 (1 H, s), 7.71 - 7.52 (2H, m), 7.36 - 7.28 (5H, m), 5.45 (1 H, dd, J=5.1 , 8.5 Hz), 5.12 (1 H, t, J=5.3 Hz), 4.26 - 4.18 (1 H, m), 3.99 - 3.92 (1 H, m); LCMS (LC-Method 1) Rt = 3.33 min, m/z 325 [M+H]

[0277] The following Example 125 was prepared according to the method used to prepare Example 124 above using methyl 3-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-3- phenylpropanoate (Intermediate 9.2) and was purified by preparative reverse phase HPLC (prep-LC-8) to afford the title compound.

Example 126: 3-amino-N-M-(2-(methylamino)-2-oxo-1-phenylethyl)-1 H-pyrazol-4- yl)Pyrazine-2-carboxamide [0278] To a stirred solution of 2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-2- phenylacetic acid (Intermediate 9.3, 60 mg, 0.177 mmol), methylamine hydrochloride (30 mg, 0.443 mmol), EDC (51 mg, 0.266 mmol) and 1-hydroxybenzotriazole (36 mg, 0.266 mmol) in DMF (2 ml) was added triethylamine (0.15 ml, 1.06 mmol). The reaction was stirred at 80°C for 15 hours. The reaction mixture was concentrated in vacuo then taken up in EtOAc and washed with saturated aq. sodium hydrogen bicarbonate solution. The organic extract was dried over magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-8) to afford the title compound (15 mg, 24%). Ή NMR (400 MHz, DMSO) 10.85 (1 H, s), 8.42 (1 H, q, J=4.5 Hz), 8.25 (1 H, d, J=2.3 Hz), 8.14 (1 H, s), 7.89 - 7.88 (1 H, m), 7.80 (1 H, s), 7.45 - 7.35 (7H, m), 6.14 (1 H, s), 2.69 - 2.67 (3H, m).; LCMS (LC-Method 1) Rt = 3.22 min, m/z 352 [M+H]

[0279] The following Example 127 was prepared according to the method used to prepare Example 126 above using 2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-2- phenylacetic acid (Intermediate 9.3) and ammonium chloride. The reaction was purified by preparative reverse phase HPLC (prep-LC-6) to afford the title compound.

Example 203: 3-amino-N-(1-(3-amino-3-oxo-1-phenylpropyl)-1H-pyrazol-4-vnp yrazine-

2-carboxamide

[0280] To a stirred solution of 3-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-3- phenylpropanoic acid (Intermediate 9.4, 50 mg, 0.142 mmol), ammonium chloride (19 mg, 0.335 mmol), EDC (41 mg, 0.213 mmol) and 1-hydroxybenzotriazole (29 mg, 0.213 mmol) in DMF (1 ml) was added triethylamine (0.099 ml, 0.710 mmol). The reaction was stirred at 80°C for 15 hours. The reaction mixture was concentrated in vacuo then taken up in EtOAc and washed with saturated aq. sodium hydrogen bicarbonate solution. The organic extract was dried over magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-1) to afford the title compound (25 mg, 50%). Ή NMR (400 MHz, DMSO): d 10.82 (s, 1 H), 8.25 (d, J = 2.4 Hz, 1 H), 8.15-8.14 (m, 1 H), 7.89 (d, J = 2.3 Hz, 1 H), 7.77-7.76 (m, 1 H), 7.58 (s, 2 H), 7.48-7.43 (m, 1 H), 7.37-7.26 (m, 5 H), 6.89-6.85 (m, 1 H), 5.83 (dd, J = 6.3, 8.7 Hz, 1 H), 3.25 (dd, J = 9.1 , 15.2 Hz, 1 H), 2.96 (dd, J = 6.4, 15.3 Hz, 1 H). LCMS (LC-Method 2) Rt = 3.05 min, m/z 352 [M+H]

[0281] In one approach (Scheme 9a - in which R and R’ represent generic substituents), carboxamide-derivatives of general formula [9a.5] are prepared by reaction of an carboxylate- azole derivative of general formula [9a.3] with a amine derivative or general formula [9a.6] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as EίbN, DIPEA or NMM, the reaction is suitably conducted at ambient temperature. After reaction work up, typically by a liquid-liquid extraction the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation. Carboxylate-azole derivatives of general formula [9a.3] are prepared by hydrolysis of carboxylate-ester derivatives of general formula [9a.2] with a base such as lithium hydroxide or sodium hydroxide in a polar solvent such as MeOH, EtOH or H2O. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction the crude product was used in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Carboxylate-ester derivatives of general formula [9a.2] are prepared by an alkylation reaction of a azole derivative of general formula [IV] [prepared according to the general procedure in Scheme 2] with an ohalo derivative of general formula [9a.1] in a polar solvent such as DMF or DMA with a base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction the crude product was used in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Hydroxy derivatives of general formula [9a.4] are prepared by reduction of Carboxylate-ester derivatives of general formula [9a.2] with a suitable reducing agent such as LAH or DIBAL-H in a polar solvent such as THF or Et ₂ 0, the reaction is suitably conducted at low temperature, more suitably at -78 °C. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation. Hydroxy derivatives of general formula [9a.9] are prepared by reduction of carboxylate-ester derivatives of general formula [9a.8] with a suitable reducing agent such as LAH or DIBAL-H in a polar solvent such as THF or Et ₂ 0, the reaction is suitably conducted at low temperature, more suitably at -78 °C. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re crystallisation. Carboxylate-ester derivatives of general formula [9a.8] are prepared by a Michael-type reaction of a azole derivate of general formula [IV] with an a-b-unsaturated carboxylate ester derivative of general formula [9a.7] in a polar solvent such as DMF or DMA with a base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Carboxamide derivative of general formula [9a.9] are generated fin a two-step procedure from hydrolysis of ester derivatives of general formula [9a.8] with a base such as NaOH or KOH in a polar solvent such as EtOH or THF. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation. Followed by a Schotten-Baumann reaction by reaction with thionyl chloride in a polar solvent such as DCM. The reaction is suitably conducted at high temperature under thermal heating, followed by reaction with ammonia. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation. Ketone derivatives of general formula [9a.10] are prepared by a Grignard type reaction of an ester derivative of general formula [9a.2] with a Grignard reagent of general formula [9a.13] in a polar aprotic solvent such as THF or Et 0 under an anhydrous atmosphere. The reaction is suitably conducted at low temperature, more suitably at -78 °C. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re crystallisation. Amine derivatives of general formula [9a.12] are prepared through a reductive amination type reaction with a carbonyl derivative of general formula [9a.10] with an amine derivative of general formula [9a.11] in a polar solvent such as MeOH, EtOH or THF with a suitable reducing agent such a as NaBH ₃ CN, NaBH ₄ , NaBH(OAc) ₃ , with a weak acid such as AcOH or NH4OAC. After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re crystallisation.

Scheme 9a Example 205, 206, 207: 3-amino-N-(1-(2-amino-1-phenylpropyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide

[0282] To a cool stirred solution of 3-amino-N-(1-(2-oxo-1-phenylpropyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide (Intermediate 9.5, 310 mg, 0.922 mmol) in anhydrous methanol (5.0 ml) at 0 °C was added ammonium acetate (3100, 9.22 mmol). The reaction was stirred at 0 °C for 10 minutes then sodium cyanoborohydride (87 mg, 1.38 mmol) was added and reaction allowed to warm to room temperature and stirred for 15 hours. The reaction was concentrated invacuo and the crude residue was purified by silica gel flash chromatography eluting with mixtures of DCM, methanol and 7M NHs/methanol to obtain the product as a mixture of diastereoisomers which were further separated by SFC (SFC-10) to afford the isomers.

[0283] In another approach (Scheme 10), amino-derivatives of general formula [LX] are prepared by reduction of a nitro-derivative of general formula [LIX] with H ₂ gas under high pressure in a Parr reactor of an H-Cube reactor, in a polar solvent such as MeOH or EtOH with a palladium catalyst such as palladium on activated charcoal or alumina. After reaction work up, typically filtration followed by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC, or re-crystallisation. Nitro-derivatives of general formula [LIX] are prepared by a Michael-type reaction of an azole derivate of general formula [IV] [prepared according to the general procedure in Scheme 2] with a nitro alkene derivative of general formula [LVIII] in a polar solvent such as THF or Dioxane. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. Nitro alkene derivatives of general formula [LVIII] are prepared from a nitro-aldol type reaction between a carbonyl derivative of general formula [LXI] and nitroethane, in a polar acidic solvent such as acetic acid, a weak base such as ammonium acetate. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation.

Scheme 10

Example 128: 3-amino- 2-amino-1-i3-methoxyphenyl)ethyl)-1 H-pyrazol-4-

yl)pyrazine-2-carboxamide

[0284] A mixture of 3-amino-/V-(1-(1-(3-methoxyphenyl)-2-nitroethyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide (Intermediate 10.1, 135 mg, 0.35 mmol) in methanol (40 ml) was passed through an H- cube instrument using full H ₂ mode, a 10% Pd/C cartridge and heating at 50°C using a closed loop for 2 hours. The mixture was concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-8). Additional purification was performed using silica gel flash chromatography eluting with 1M NH ₃ in methanol and DCM (0-10% gradient) to afford the title compound (40 mg, 32%). ¹ H NMR (400 MHz, CDCI ₃ ): d 9.62-9.59 (m, 1 H), 8.18 (d, J = 2.5 Hz, 1 H), 8.07-8.06 (m, 1 H), 7.83 (d, J = 2.3 Hz, 1 H), 7.70-7.69 (m, 1 H), 7.28-7.23 (m, 1 H), 6.87-6.79 (m, 3 H), 5.22 (dd, J = 5.2, 9.0 Hz, 1 H), 3.77 (s, 3 H), 3.73-3.67 (m, 1 H), 3.35 (dd, J = 5.1 , 13.4 Hz, 1 H). NH ₂ amine and NH ₂ on pyrazine not observed. LCMS (LC-Method 1) Rt = 2.61 min, m/z 354 [M+H]

Example 129: 3-amino-/V-(1 -(2-amino-1-(3-fluoro-5-methoxyphenyl)ethyl)-1H-pyrazol-4- yl)pyrazine-2-carboxamide

[0285] A mixture of 3-amino-/V-(1-(1-(3-fluoro-5-methoxyphenyl)-2-nitroethyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide (Intermediate 10.2, 134 mg, 0.33 mmol) in methanol (40 ml) was passed through an H-cube instrument using full H ₂ mode, a 10% Pd/C cartridge and 50°C heating as a close loop for 2 hours. The mixture was concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC (prep-LC-2) to afford the title compound (22 mg, 18%). Ή NMR (400 MHz, CDCI ₃ ) d 9.62 (1 H, s), 8.19 (1 H, d, J=2.5 Hz), 8.09 (1 H, s), 7.83 (1 H, d, J=2.3 Hz), 7.69 (1 H, s), 6.59 - 6.51 (3H, m), 5.19 (1 H, dd, J=5.1 , 8.8 Hz), 3.77 - 3.76 (4H, m), 3.33 (1 H, dd, J=4.8, 13.6 Hz). NH amine and NH ₂ on pyrazine not observed. LCMS (LC-Method 1) Rt = 2.76 min, m/z 372 [M+H]

Example 234: 3-amino-/V-(1 -(2-amino-1-(3-methoxy-5-methylphenyl)ethyl)-1 A7-pyrazol- 4-yl)pyrazine-2-carboxamide

[0286] To a solution of 3-amino-/V-(1-(1-(3-methoxy-5-methylphenyl)-2-nitroethyl)-1/ -/- pyrazol-4-yl)pyrazine-2-carboxamide (Intermediate 10.13, 270 mg, 0.68 mmol) in MeOH (50 ml_) was added a suspension of Raney Nickel (4 mg, 0.07 mmol, in 5 ml_ of water) and the flask was placed under N ₂ and evacuated three times. The flask was then put under H ₂ atmosphere and evacuated three times and left to stir at room temperature overnight. The mixture was then filtered over celite and the filtrate purified by silica column chromatography eluting with mixtures of DCM/methanol/7M NH ₃ in methanol to afford the title compound (70 mg, 28%). Ή NMR (400 MHz, CDCI ₃ ) d 9.62 (1 H, s), 8.19 (1 H, d, J=2.5 Hz), 8.09 (1 H, s), 7.83 (1 H, d, J=2.3 Hz), 7.69 (1 H, s), 6.59 - 6.51 (3H, m), 5.19 (1 H, dd, J=5.1 , 8.8 Hz), 3.77 - 3.76 (4H, m), 3.33 (1 H, dd, J=4.8, 13.6 Hz). NH ₂ amine and NH ₂ on pyrazine not observed. LCMS (LC-Method 1) Rt = 2.76 min, m/z 372 [M+H]

[0287] The following Examples were prepared according to the above methods used for (Example 128) or (Example 129) using the appropriate nitro intermediate [LIX] as described in scheme 10. The reactions were purified using preparative reverse phase HPLC using one of the described prep methods (1-14) and Chiral SFC using chiral prep methods (1-17) where racemates were resolved into their enantiomers.

determine the absolute stereochemistry of this sample as being (S) by standard X-ray diffraction methodology.

[0288] In another approach (Scheme 10a), amino-derivatives of general formula [10a.5] are prepared by reduction of a nitro-derivative of general formula [10a.4] with hh gas under high pressure in a Parr reactor of an H-Cube reactor, in a polar solvent such as MeOH or EtOH with a palladium catalyst such as palladium on activated charcoal or alumina. After reaction work up, typically filtration followed by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC, or re-crystallisation. Nitro-derivatives of general formula [10a.4] are prepared by a Michael- type reaction of an azole derivate of general formula [IV] [prepared according to the general procedure in Scheme 2] with a nitro alkene derivative of general formula [10a.3] in a polar solvent such as THF or Dioxane. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. Nitro alkene derivatives of general formula [10a.3] are prepared from a nitro-aldol type reaction between a carbonyl derivative of general formula [10a.1] and nitroalkyl derivative of general formula [10a.2], in a polar acidic solvent such as acetic acid, a weak base such as ammonium acetate. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation.

[0289] N-alkyl derivatives of general formula [10a.6] are prepared from an alkylation reaction of amine derivatives of general formula [10a.5] with an activated alkyl derivative of general formula [10a.7] in a polar aprotic solvent such as THF or DMF with strong non-nucleophilic base such as sodium hydride or LHMDS in a polar solvent such as DMF or DMA, the reaction is suitably conducted at ambient or low temperature. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC, re-crystallisation. Examples of compounds of general formula [10a.6] were R2 contains an N-Boc protecting group are deprotected under acidic reaction conditions such as TFA or HCI in a suitable solvent such as DCM or Et ₂ 0 at ambient temperature. After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation.

[0290] N-Boc protected compounds of general formula [10a.11] were prepared by standard N-Boc protection conditions by reacting amine derivatives of general formula [10a.5] with di- tert-butyl decarbonate, in polar solvent such as THF or MeCN, with a weak base such as NaHCCh or DMAP. The reaction is suitably conducted at ambient temperature. After reaction work up, typically filtration followed by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC, or re-crystallisation.

[0291] N-Boc protected compounds of general formula [10a.14] in were Z is an ester derivatised phenyl substituent can be further derivatised through a two-step procedure from hydrolysis of the ester derivatives with a base such as NaOH or KOH in a polar solvent such as EtOH or THF. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step followed by the reaction of an amine of general formula [10a.13] with a suitable coupling agent such as HBTU or HATU in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as EkN, DIPEA or NMM. After reaction work up, typically by a liquid-liquid extraction, the reaction product was purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation to yield the N-acylated- heterocyclic compound. Followed by N-Boc deprotection under acidic reaction conditions such as TFA or HCI in a suitable solvent such as DCM or Et _å 0 at ambient temperature. After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation, to give compounds of general formula [10a.12]

[0292] N-Boc protected compounds of general formula [10a.11] were Z is a bromo or iodophenyl substituent can be further derivatised through a Suzuki type transition metal catalysed cross-coupling reaction with a organoboron derivative of general formula [10a.15] with a transition metal catalyst such as Pd(PPh3 a base such as NaHCCh or K ₂ CO3 in a polar solvent such as DMF or THF. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically filtration followed by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC, or re-crystallisation. Followed by N-Boc deprotection under acidic reaction conditions such as TFA or HCI in a suitable solvent such as DCM or Et ₂ 0 at ambient temperature. After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation, to give the compounds of general formula [10a.14]

Scheme 10a

[0293] N-Boc protected compounds of general formula [10a.11] were Z is a bromo or iodophenyl substituent can be further derivatised through a Sonogashira type transition metal catalysed cross-coupling reaction with a terminal alkyne derivative of general formula [10a.17] with a transition metal catalyst such as Pd(PPfi3)4, or Pd(PPfi3)2Cl2, a copper salt such as Cul, a base such asEt3N or Et2NH in in a polar solvent such as DMF or THF. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically filtration followed by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC, or re crystallisation. Followed by N-Boc deprotection under acidic reaction conditions such as TFA or HCI in a suitable solvent such as DCM or Et ₂ 0 at ambient temperature. After reaction work up, typically by a liquid-liquid extraction or purification by acidic ion exchange catch-release the crude product was purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation, to give compounds of general formula [10a.16]

[0294] The following Examples were prepared according to the above method using the appropriate amine [10a.4] as described in Scheme 10a. The reactions were purified using preparative reverse phase HPLC using one of the described prep methods (1-14) and Chiral SFC using chiral prep methods (1-17) where racemates were resolved into their enantiomers.

Example 245: 3-amino-N-(1-(2-amino-1-(3-ethvnyl-5-methoxyphenyl)ethyl)-1 H-pyrazol- 4-yl)pyrazine-2-carboxamide

[0295] To a stirred solution of tert-butyl (2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol- 1-yl)-2-(3-methoxy-5-((trimethylsilyl)ethynyl)phenyl)ethyl)c arbamate (Intermediate 10a.3, 55 mg, 0.100 mmol) in methanol (2.0 ml) was added potassium carbonate (41 mg, 0.300 mmol). The reaction was stirred for 16 hours at room temperature. The reaction was diluted with water and extracted with EtOAc (x2). Combined organic extracts were dried with MgSC , filtered and concentrated. The crude residue was dissolved in dioxane (2.0 ml) and treated with 4M HCI in dioxane (2.0 ml) and stirred at room temperature for 30 minutes then concentrated in vacuo. The crude product was purified by silica gel flash chromatography eluting with mixtures of DCM/methanol/7M NH3 in methanol to afford the title compound as (8.0 mg, 21 %). Ή NMR (400 MHz, CDCI3): d 9.62 (s, 1 H), 8.21-8.17 (m, 1 H), 8.09-8.06 (m, 1 H), 7.85-7.82 (m, 1 H), 7.72-7.69 (m, 1 H), 7.00-6.93 (m, 2 H), 6.79 (d, J = 1.8 Hz, 1 H), 5.19 (dd, J = 5.2, 8.7 Hz, 1 H), 3.77 (s, 3 H), 3.72-3.65 (m, 1 H), 3.37-3.30 (m, 1 H), 3.07-3.05 (m, 1 H). LCMS (LC-Method 1) Rt = 2.85 min, m/z 378 [M+H]

Example 246: 3-amino-N-(1-(2-amino-1-(3-cvcloprOpyl-5-methoxyphenvnethyl� �-1 H- pyrazol-4-yl)pyrazine-2-carboxamide

[0296] A suspension of tert-butyl (2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)- 2-(3-bromo-5-methoxyphenyl)ethyl)carbamate (intermediate 10a.4, 45 mg, 0.085 mmol) and potassium cyclopropyltrifluooborate (15 mg, 0.101 mmol) in dioxane (2.0 ml) and water (0.2 ml) was degassed with nitrogen for 20 minutes then sodium carbonate (18 mg, 0.169 mmol) and Pd(dppf) ₂ Cl2.DCM (6.9 mg, 0.0085 mmol) was added. The reaction was sealed and heated to 150°C for 1 hour by microwave irradiation. The reaction was cooled and diluted with EtOAc, passed through celite then washed with brine and concentrated in vacuo. The crude product was purified by preparative reverse phase HPLC (prep-LC-2) to afford the title compound. Ή NMR (400 MHz, CDCI ₃ ): d 9.60 (s, 1 H), 8.19-8.17 (m, 1 H), 8.02 (s, 1 H), 7.83 (d, J = 2.3 Hz, 1 H), 7.70 (s, 1 H), 6.59 (t, J = 1.5 Hz, 1 H), 6.57-6.55 (m, 1 H), 6.51-6.49 (m, 1 H), 5.26-5.21 (m, 1 H), 3.75 (s, 3 H), 3.37 (dd, J = 4.8, 13.4 Hz, 1 H), 1.88-1.80 (m, 1 H), 0.97-0.91 (m, 2 H), 0.68-0.64 (m, 2 H). NH2 protons not observed. LCMS (LC-Method 1) Rt = 3.03 min, m/z 394 [M+H]

[0297] In another approach (Scheme 11 - in which R represents an optional substituent on the phenyl ring as defined herein) N-sulfonyl compounds of formula [11.2] were prepared by the reaction of a sulfonyl chloride of general formula [11.1] with an azole derivative of general formula [V], prepared according to Scheme 2, with in a polar aprotic solvent such as DMA or DMF in the presence of a tertiary amine base such as Et ₃ N, DIPEA or NMM. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next step or purified by flash column chromatography, reverse phase preparative HPLC or re crystallisation to yield the N-sulfonyl-heterocyclic compound of general formula [11.2] Compounds of general formula [11.4] were prepared by reacting N-sulfonyl azole-derivatives of general formula [11.2] in an in situ sulfonyl transfer reaction with a hydroxyl derivative of general formula [11.3] in a polar aprotic solvent such as MeCN or DMA with a suitable base such as potassium carbonate or caesium carbonate. The reaction is suitably conducted at ambient temperature or at high temperature by heating thermally. After reaction work up, typically by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation.

Scheme 11

Example 135: 3-amino-N-(1-(pyridin-3-ylmethyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide

[0298] To a stirred solution of 3-amino-N-(1-(methylsulfonyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide (Intermediate 11.1, 30 mg, 0.106 mmol) and 3-pyridyl carbinol (12 mg, 0.010 mmol) in dry acetonitrile (0.5 ml) was added cesium carbonate (42 mg, 0.128 mmol). The reaction was stirred at 90°C for 15 hours. The reaction mixture was concentrated in vacuo and the crude residue was purified by preparative reverse phase HPLC (prep-LC-1) to afford the title compound (13.5 mg, 44%).

[0299] The following Examples were prepared according to the above method used for (Example 135) using the appropriate sulfonyl [11.1] and alcohol [11.3] intermediates as described in scheme 11. The reactions were purified using silica gel flash chromatography or preparative reverse phase HPLC using one of the described prep methods (1-14) and Chiral SFC using chiral prep methods (1-17) where racemates were resolved into their enantiomers.

[0300] In another approach (Scheme 12), hydroxy-derivatives of general formula [12.5] are prepared by ring opening of an epoxide derivative of general formula [12.4] with an azole derivate of general formula [IV] [prepared according to the general procedure in Scheme 2] with a base such as K2CO3 or CS2CO3 in a polar solvent such as DMA or DMF. The reaction is suitably conducted at high temperature under thermal heating. After reaction work up, typically filtration followed by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC, or re crystallisation. Epoxide derivatives of general formula [12.4] were prepared from peroxidation of an exocyclic-alkene derivative of general formula [12.3] with a peroxycarboxylic acid such as m-CPBA in a halogenated solvent such as CHCI3. The reaction is suitably heated at ambient temperature. After reaction work up, typically filtration followed by a liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, or re-crystallisation. Exocyclic-alkene derivatives of general formula [12.3] were prepared by a Wittig type reaction of a ketone derivative of general formula [12.7] with a triphenyl phosphonium ylide derivative of general formula [12.2] with a strong non-nucleophilic base such as sodium hydride or LHMDS in a polar solvent such as THF or Eί _å 0, the reaction is suitably conducted at ambient or low temperature. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC. Triphenyl phosphonium ylide derivatives of general formula [12.2] were prepared by reaction of an activated alkyl halide of general formula [12.1] with triphenylphosphine in a polar solvent such as THF or Et ₂ 0, the reaction is suitably conducted at ambient or low temperature. After reaction work up, typically by a liquid-liquid extraction, the reaction product was used crude in the next reaction step or purified by flash column chromatography, reverse phase preparative HPLC

Scheme 12

Example 247: 3-amino-N-(1-((3-hvdroxyazetidin-3-yl)(3-methoxyphenyl)methy l)-1H- pyrazol-4-yl)pyrazine-2-carboxamide [0301] To a stirred solution of tert-butyl 3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol- 1-yl)(3-methoxyphenyl)methyl)-3-hydroxyazetidine-1-carboxyla te (Intermediate 12.1 , 40 mg, 0.137 mmol) in dioxane (1.0 ml) was added 4M HCI (dioxane). The reaction was stirred at room temperature for 2 hour then concentrated in vacuo. The product was purified by preparative reverse phase HPLC (prep-LC-11) to afford the title compound as the racemate. Ή NMR (400 MHz, CDCIs) d 9.60 (1 H, s), 8.56 (1 H, s), 8.19 (1 H, d, J = 2.4 Hz), 8.08 (1 H, s), 7.82 (1 H, d, J = 2.4 Hz), 7.72 (1 H, s), 7.23 (1 H, d, J = 7.9 Hz), 6.99-6.94 (2H, m), 6.85 (1 H, dd, J = 2.1 , 8.0 Hz), 5.82 (1 H, s), 3.94-3.86 (4H, m), 3.77-3.76 (3H, m), 2.80 (2H, brs) Formate salt. LCMS (LC-Method 1) Rt = 2.66 min, m/z 396 [M+H]

[0302] The following Examples were prepared according to the above method (Example 247) using the appropriate pure chiral intermediate [12.5] as described in scheme 12. The reactions product did not require further purification.

Intermediate compounds

Intermediate 1.1 : ((R)-1-allylpiperidin-2-yl)(3-chloro-5-methoxyphenyl)methano l

[0303] (3-chloro-5-methoxyphenyl)(2R)-2-piperidinyl-methanone (CAS: 2144993-71 -3, 900 mg, 3.10 mmol), allyl iodide (0.280 ml_, 3.10 mmol) and triethylamine (1.3 ml_, 9.30 mmol) were combined in THF (20 mL) and stirred at room temperature for 24 hours. The solvent was then removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 25% ethanol in ethyl acetate (10-80% gradient) in cyclohexane to afford (R)-(l-allylpiperidin- 2-yl)(3-chloro-5-methoxyphenyl)methanone (650 mg, 71%) LCMS m/z 294 ES+, ¹ H NMR (400 MHz, DMSO) d 7.75 (s, 1 H), 7.64 - 7.63 (m, 1 H), 7.33 (dd, J=2.1 , 2.1 Hz, 1 H), 5.83 - 5.72 (m, 1 H), 5.13 - 5.08 (m, 1 H), 5.08 - 5.06 (m, 1 H), 3.85 (s, 3H), 3.14 - 3.01 (m, 2H), 2.91 - 2.84 (m, 1 H), 2.24 - 2.15 (m, 1 H), 1.77 - 1.69 (m, 1 H), 1.64 - 1.35 (m, 6H).

Intermediate 1.1

[0304] (R)-(1-allylpiperidin-2-yl)(3-chloro-5-methoxyphenyl)methano ne (600 mg, 2.04 mmol) was dissolved in DCM (7 ml.) and methanol (3 ml.) and cooled to 0 °C, then sodium borohydride (77 mg, 2.04 mmol) was added portionwise and the mixture was allowed to warm up to room temperature and stirred for 2 hours. The reaction was quenched by addition of water and ethyl acetate, the phases were separated and the organics were washed saturated ammonium chloride solution, and brine, dried over magnesium sulfate and concentrated under reduced pressure to afford ((R)-1-allylpiperidin-2-yl)(3-chloro-5-methoxyphenyl)methano l (Intermediate 1.1) as a yellow oil (610 mg, quantitative). LCMS m/z 296 ES+ a 1 :1 mixture of the two diasereoisomers. ¹ H NMR (400 MHz, CDCb) d , 6.89 - 6.87 (m, 1 H), 6.81 - 6.78 (m, 1 H), 6.77 - 6.74 (m, 1 H), 6.04 - 5.94 (m, 1 H), 5.30 - 5.14 (m, 2H), 3.80 (s, 3H), 3.63 - 3.56 (m, 1 H), 3.44 - 3.30 (m, 1 H), 3.06 - 2.93 (m, 1 H), 2.46 - 2.40 (m, 1 H), 2.34 - 2.26 (m, 1 H), 1.86 - 1.19 (m, 5H), 1.10 - 0.94 (m, 1 H), OH not observed.

Intermediate 1.2: ffR -allylpiperidin-2-ylK3-methoxyphenvnmethanol

Intermediate 1.2

[0305] Was prepared according to the synthesis of ((R)-1-allylpiperidin-2-yl)(3- methoxyphenyl)methanol (Intermediate 1.1) using (R)-(3-methoxyphenyl)(piperidin-2- yl)methanone (CAS: 2154670-40-1 , 2.00 g, 7.82 mmol), allyl iodide. Ή NMR (400 MHz, CDC ) d , 7.23 (dd, J=7.8, 7.8 Hz, 1 H), 6.95 - 6.91 (m, 1 H), 6.87 (d, J=7.8 Hz, 1 H), 6.79 - 6.75 (m, 1 H), 6.05 - 5.94 (m, 1 H), 5.30 - 5.21 (m, 2H), 5.17 - 5.14 (m, 1 H), 3.82 (s, 3H), 3.65 - 3.59 (m, 1 H), 3.22 - 3.14 (m, 1 H), 3.05 - 2.99 (m, 1 H), 2.46 - 2.40 (m, 1 H), 2.33 - 2.25 (m, 1 H), 1.07 - 0.89 (m, 2H), 4H multiplet partially obscured by water peak, OH not observed.

Intermediate 1.3: ((S)-1-allylpiperidin-2-yl)(3-methoxyphenyl)methanol Intermediate 1.3

[0306] Was prepared according to the synthesis of ((R)-1-allylpiperidin-2-yl)(3- methoxyphenyl)methanol (Intermediate 1.1) using (S)-(3-methoxyphenyl)(piperidin-2- yl)methanone and allyl iodide. ¹ H NMR (400 MHz, CDCh) d 7.05 - 6.97 (m, 2H), 6.88 - 6.84 (m, 1 H), 6.83 - 6.79 (m, 1 H), 6.20 - 6.09 (m, 1 H), 5.71 - 5.67 (m, 2H), 5.57 - 5.49 (m, 2H), 4.21 - 4.11 (m, 1 H), 4.00 - 3.94 (m, 1 H), 3.82 (s, 3H), 3.56 - 3.49 (m, 2H), 3.01 - 2.98 (m, 1 H), 2.86 - 2.80 (m, 1 H), 2.25 - 2.11 (m, 2H), 4H signal partially obscured by water peak.

Intermediate 1.4: ((S)-1-allylpiperidin-2-yl)(3-chloro-5-methoxyphenyl)methano l

[0307] Was prepared according to the synthesis of ((R)-1-allylpiperidin-2-yl)(3- methoxyphenyl)methanol (Intermediate 1.1) using (3-chloro-5-methoxyphenyl)(2S)-2- piperidinyl-methanone and allyl iodide.

[0308] Intermediate 2 was prepared according to the method described above for Example 139 using 3-amino-/V-(1-(2-bromobenzyl)-1/-/-pyrazol-4-yl)pyrazine-2-c arboxamide (Intermediate 3) and purified by silica gel flash chromatography eluting with 7M methanolic ammonia/DCM (20-50% gradient) to afford the title compound.

Intermediate 3: 3-amino-/V-(1-(2-bromobenzyl)-1H-pyrazol-4-yl)pyrazine-2-car boxamide

[0309] Intermediate 3 was prepared according to Scheme 2 using 3-amino-N-(1 H-pyrazol- 4-yl) pyrazine-2-carboxamide (CAS: 1933674-659-1) and 2-bromobenzyl bromide at 100°C. The reaction were purified by silica gel flash chromatography eluting with EtOAc and isohexane (10-70% gradient) to afford the title compound (570 mg, 48%), Ή NMR (400 MHz,

CDCI3): d 9.62 (1 H, s), 8.19 (1 H, d, J=2.3 Hz), 8.09 (1 H, s), 7.84 (1 H, d, J=2.4 Hz), 7.67 (1 H, s), 7.59 (1 H, dd, J=1.2, 8.0 Hz), 7.30 -7.27 (1 H, m), 7.20 - 7.15 (1 H, m), 7.03 - 6.99 (1 H, m),

5.42 (2H, s). NH ₂ on pyrazine not observed.

Intermediate 4: tert-butyl 4-(3-((4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1- yl)methyl)phenyl)-3.6-dihvdropyridine-1 (2H)-carboxylate

[0310] A solution of 3-amino-N-(1-(3-bromobenzyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide (Example 45, 280 mg, 0.750 mmol), N-Boc-1 ,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (348 mg, 1.13 mmol) and potassium phosphate tribasic (319 mg, 1.50 mmol) in THF (1 ml) and water (1 ml) was degassed with nitrogen for 20 minutes then XPhos-Pd-G2 (118 mg, 0.150 mmol). The reaction was sealed and heated to 80°C for 3 hours under nitrogen. The reaction was cooled, diluted with EtOAc and passed through celite then washed with brine and concentrated invacuo. The crude residue was purified by silica gel flash chromatography eluting with 15-100% EtOAc in isohexane to afford the title compound as a yellow solid (340 mg, 95%). Compound used in the next reaction step.

Intermediates for Scheme 2a

Intermediate 2.1 : 3-(N-(tert-butoxycarbonyl)-N-propylsulfamoyl)benzyl

methanesulfonate

Methyl 3-(N-propylsulfamoyl)benzoate:

[0311] Triethylamine (1.1 ml_, 7.67 mmol), propylamine (0.63 ml_, 7.67 mmol) and THF (10 ml_) were cooled to 0 °C and methyl-3-(chlorosulphonyl)benzoate (CAS 63555-50-0, 900 mg, 3.84 mmol) was added and the mixture was stirred for 2 hours. The mixture was then diluted with ethyl acetate, washed with 1M HCI, dried over magnesium sulfate and evaporated to dryness to yield methyl 3-(N-propylsulfamoyl)benzoate as a brown oil (950 mg, 96 %), Ή NMR (400 MHz, CDCIs) d 8.53 (dd, J=1.6, 1.6 Hz, 1 H), 8.24 (d, J=8.0 Hz, 1 H), 8.07 (d, J=7.5 Hz, 1 H), 7.62 (dd, J=7.8, 7.8 Hz, 1 H), 4.69 (dd, J=6.0, 6.0 Hz, 1 H), 3.96 (s, 3H), 2.95 (dd, J=7.0, 13.4 Hz, 2H), 1.50 (dd, J=7.3, 14.4 Hz, 2H), 0.88 (dd, J=7.4, 7.4 Hz, 3H).

3-(N-(tert-butoxycarbonyl)-N-propylsulfamoyl)benzoate:

[0312] Methyl 3-(N-propylsulfamoyl)benzoate (800 mg, 3.11 mmol), di-tert-butyl dicarbonate (1.8 ml_, 7.77 mmol), triethylamine (1.1 ml_, 7.77 mmol) and 4-(dimethylamino)pyridine (19 mg, 0,155 mmol) were combined in acetonitrile (8 mL) and stirred at room temperature for 16 hours. The reaction mixture was then diluted with ethyl acetate, washed with 1 M HCI, dried over magnesium sulfate and concentrated under reduced pressure to yield methyl 3-(N-(tert- butoxycarbonyl)-N-propylsulfamoyl)benzoate as a red oil (1.5 g) ¹ H NMR (400 MHz, DMSO) d 8.40 (dd, J=1.6, 1.6 Hz, 1 H), 8.30 (d, J=8.2 Hz, 1 H), 8.19 (d, J=8.3 Hz, 1 H), 7.84 (dd, J=7.9, 7.9 Hz, 1 H), 3.93 (s, 3H), 3.78 (dd, J=7.3, 7.3 Hz, 2H), 1.75 - 1.66 (m, 2H), 1.27 (s, 9H), 0.92 (dd, J=7.4, 7.4 Hz, 3H).

tert-butyl ((3-(hvdroxymethyl)phenyl)sulfonyl)(propyl)carbamate:

[0313] Methyl 3-(N-(tert-butoxycarbonyl)-N-propylsulfamoyl)benzoate (1.5 g, 4.20 mmol) was dissolved in THF (20 mL) and cooled to 0 °C. DIBALH (2.2 mL, 12.59 mmol) was added slowly and the mixture was allowed to warm up to room temperature and stirred for 1 hour. The reaction was worked up using the Fieser work-up to yield tert-butyl ((3- (hydroxymethyl)phenyl)sulfonyl)(propyl)carbamate as an orange oil (550 mg, 40%), Ή NMR (400 MHz, CDCIs) d 7.90 (s, 1 H), 7.81 (d, J=7.8 Hz, 1 H), 7.60 (d, J=7.6 Hz, 1 H), 7.50 (dd, J=7.8, 7.8 Hz, 1 H), 4.78 (s, 2H), 3.82 - 3.78 (m, 2H), 1.84 - 1.77 (m, 2H), 1.33 - 1.32 (m, 9H), 0.97 (dd, J=7.5, 7.5 Hz, 3H). OH not observed. 3-(N-(tert-butoxycarbonvn-N-propylsulfamovnbenzyl methanesulfonate:

[0314] Tert-butyl ((3-(hydroxymethyl)phenyl)sulfonyl)(propyl)carbamate (100 mg, 0.304 mmol) and triethylamine (0.130 ml_, 0.911 mmol) were combined in DCM (1 ml_) and cooled to 0 °C. Then methanesulfonyl chloride (0.028 ml_, 0.364 mmol) was added and the mixture was stirred for 30 minutes. The mixture was diluted with DCM, washed with water and concentrated under reduced pressure to yield 3-(N-(tert-butoxycarbonyl)-N- propylsulfamoyl)benzyl methanesulfonate, ¹ H NMR (400 MHz, CDCb) d 7.97 - 7.91 (m, 2H), 7.67 (d, J=7.8 Hz, 1 H), 7.58 (dd, J=7.8, 7.8 Hz, 1 H), 5.29 (s, 2H), 3.83 - 3.78 (m, 2H), 3.02 (s, 3H), 1.76 (s, 2H), 1.34 (s, 9H), 0.99 - 0.95 (m, 3H).

Intermediate 2.2: 3-amino-N-(1-n-fmethylamino)-1-oxo-3-phenylpropan-2-vn-1H- pyrazol-4-yl)pyrazine-2-carboxamide

Ethyl 2-(4-f3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-3-phenylpropanoate:

[0315] 2-Pyrazinecarboxamide, 3-amino-N-1 H-pyrazol-4-yl (CAS 1933674-69-1 , 2.45 g, 12 mmol,), benzenepropanoic acid, a-bromo-, methyl ester (CAS 3196-22-3, 2.91 g, 12 mmol) and potassium carbonate (3.13 g, 24 mmol) were combined in DMF (14 ml.) and heated to 85 °C for 2 hours. The mixture was then allowed to cool down to room temperature, the solids were filtered off and washed with methanol, the filtrate was concentrated under reduced pressure and purified by silica gel flash chromatography eluting with EtOAc and isohexane (20-40% gradient) to afford ethyl 2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-3- phenylpropanoate as a green oil (1.84 g, 42%), Ή NMR (400 MHz, CDCb) d 9.61 - 9.57 (m, 1 H), 8.19 - 8.18 (m, 1 H), 8.08 - 8.06 (m, 1 H), 7.83 - 7.82 (m, 1 H), 7.65 (s, 1 H), 7.25 - 7.19 (m, 3H), 7.13 - 7.08 (m, 2H), 5.13 - 5.08 (m, 1 H), 3.74 (s, 3H), 3.54 - 3.49 (m, 2H). NH2 not observed. 2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-vD-3-phenylpropanoic acid:

[0316] Ethyl 2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-3-phenylpropanoate (intermediate 68, 1.5 g 4.09 mmol) and lithium hydroxide monohydrate (190 mg, 4.50 mmol) were combined in methanol (20 mL) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was taken up in THF (5 mL) and acidified to pH 3 with 2 M HCI. The aqueous phase was extracted with DCM, passed through hydrophobic paper and concentrated under reduced pressure to yield 2-(4-(3-aminopyrazine- 2-carboxamido)-1 H-pyrazol-1-yl)-3-phenylpropanoic acid as a yellow solid (1.17 g, 81%), Ή NMR (400 MHz, DMSO) d 13.15 (s, 1 H), 10.81 - 10.80 (m, 1 H), 8.26 - 8.25 (m, 1 H), 8.07 (s, 1 H), 7.89 - 7.88 (m, 1 H), 7.75 (s, 1 H), 7.58 (s, 2H), 7.24 - 7.12 (m, 5H), 5.35 - 5.30 (m, 1 H), 3.43 (d, J=7.8 Hz, 2H)..

Intermediate 2 2

3-amino-N-(1-(1-(methylamino)-1-oxo-3-phenylpropan-2-yl)-1 H-pyrazol-4-yDpyrazine-2- carboxamide:

[0317] 2-(4-(3-Aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-3-phenylpropanoic acid (200 mg, 0.568 mmol), was dissolved in DMF (4 mL). Methylamine hydrochloride (57 mg, 0.852 mmol), 1 - hy d roxy be nzotri azole hydrate (115 mg, 0.851 mmol), N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (163 mg, 0.851 mmol) and N,N- diisopropylethylamine (0.49 mL, 2.84 mmo) were added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between saturated ammonium chloride solution and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with 1 % ammonia in methanol and DCM (1-5 % gradient) to afford 3-amino-N-(1-(1-(methylamino)-1-oxo-3- phenylpropan-2-yl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide (Intermediate 2.2) as a pale yellow solid (150 mg, 72%), Ή NMR (400 MHz, DMSO) d 10.86 (s, 1 H), 8.31 - 8.25 (m, 2H), 8.12 (q, J=4.3 Hz, 1 H), 7.94 - 7.93 (m, 1 H), 7.76 (s, 1 H), 7.31 - 7.17 (m, 5H), 5.18 - 5.13 (m, 1 H), 2.64 - 2.61 (m, 3H). NH ₂ not observed, CH ₂ hidden by water peak.

Intermediates for Scheme 5

Intermediate 5.1 : 3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-vnmethvn-5- methoxybenzoic acid

[0318] To a stirred suspension of 3-amino-N-(1 H-pyrazol-4-yl) pyrazine-2-carboxamide (CAS: 1933674-659-1), 394 mg, 1.93 mmol) and potassium carbonate (400 mg, 2.89 mmol) in DMF (4 ml) was added methyl-3-(bromomethyl)-5-methoxybenzoate (500 mg, 1.93 mmol). The reaction mixture was heated to 100°C for 2 hours. The reaction was diluted with ethyl acetate and washed with water, organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude mixture was purified by silica gel chromatography eluting with EtOAc/cyclohexane (0-100% gradient) to afford methyl 3-((4-(3-aminopyrazine-2- carboxamido)-1 H-pyrazol-1-yl)methyl)-5-methoxybenzoate (400 mg, 54%) which was dissolved in THF (10 ml) and water (10 ml) and treated with lithium hydroxide monohydrate (44 mg, 1.05 mmol). The reaction was stirred at room temperature for 2 hours then concentrated in vacuo to afford the title compound (300 mg, 40%). The compound was used crude in the next step.

[0319] The following intermediates were prepared according to the method described above for Intermediate 5.1 using 3-amino-N-(1 H-pyrazol-4-yl) pyrazine-2-carboxamide (CAS: 1933674-659-1) and the appropriate bromide (see table).

Intermediate 5.6: tert-butyl (2-chloro-3-(hvdroxymethyl)Dhenyl)carbamate

[0320] To a cool stirred solution of tert-butyl (2-chloro-3-(hydroxymethyl)phenyl)carbamate (CAS: 2055117-19-4, 2.0 g, 5.18 mmol) in anhydrous THF (15 ml) under nitrogen was added 2M lithium aluminium hydride (5.2 ml, 10.37 mmol). The reaction mixture was stirred for 2 hours whilst allowing to warm to room temperature then cooled to 0°C and quenched with water followed by 1 M aq. sodium hydroxide. The organic extract was dried over magnesium sulphate, filtered and concentrated to afford the title compound (1.2 g, 90%) which was used in the next step without purification. Ή NMR (400 MHz, CDCb): d 8.18 - 8.14 (1 H, m), 7.25- 7.21 (1 H, m), 7.13 - 7.07 (2H, m), 4.58 - 4.57 (2H, m), 1.54 (9H, s).

Intermediate 5.7: tert-butyl (3-(bromomethyl)-2-chlorophenyl)carbamate

[0321] To a cool stirred solution of tert-butyl (2-chloro-3-(hydroxymethyl)phenyl)carbamate [Intermediate 5.6], (900 mg, 3.49 mmol), tetrabromomethane (1.74 g, 5.24 mmol) in THF (10 ml) was added triphenylphosphine (1.37 g, 5.24 mmol). The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was diluted with ethyl acetate and washed with water. The organic extract was dried over magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and isohexane (5-90% gradient) to afford the title compound (1.2 g, >99%). Ή NMR (400 MHz, CDCb): d 8.11 (1 H, d, J=7.7 Hz), 7.30 - 7.25 (1 H, m), 7.19 - 7.15 (1 H, m), 7.08 - 7.02 (1 H, m), 4.78 - 4.75 (2H, m), 3.76 - 3.72 (1 H, m), 1.54 (9H, s). Intermediate 5.8: 3-(1-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1 - vDethvDbenzoic acid

Methyl 3-(1-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)ethyl)benzoate:

[0322] 3-Amino-N-(1 H-pyrazol-4-yl) pyrazine-2-carboxamide (CAS: 1933674-659-1 , 168 mg, 0.832 mmol), methyl-3-(1-bromoethyl) benzoate (200 mg, 0.832 mmol) and potassium carbonate (227 mg, 1.65 mmol) were combined in DMF (5 ml.) and heated to 40 °C for 16 hours. The mixture was absorbed on HM-N and purified by silica gel flash chromatography eluting with ethyl acetate (0-100% gradient) in cyclohexane to afford methyl 3-(1-(4-(3- aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)ethyl)benzoate (150 mg, 50%), Ή NMR (400 MHz, CDCIs) d 9.62 (s, 1 H), 8.18 (d, J=2.3 Hz, 1 H), 8.08 (s, 1 H), 7.98 - 7.95 (m, 2H), 7.83 (d, J=2.3 Hz, 1 H), 7.64 (s, 1 H), 7.42 - 7.39 (m, 2H), 5.55 (q, J=7.1 Hz, 1 H), 3.91 (s, 3H), 1.95 (d, J=7.1 Hz, 3H), NH2 not observed.

3-(1-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)ethyl)benzoic acid:

[0323] Lithium hydroxide (82 mg, 3.41 mmol) was added to a stirred solution of methyl 3- ((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)benzoate (200 mg, 0.568 mmol) in methanol (5 ml) and water (3 ml). The reaction was stirred for 2 hours then concentrated in vacuo. The residue was suspended in water then acidified with concentrated HCI to pH 3 and the resulting precipitate was filtered and washed with water then dissolved in a solution of acetonitrile/water and freeze dried to afford the title compound as a pale yellow solid (140 mg, 73 %) Rt = 1.46, 100 % m/z 351 , 353 ES+.

[0324] The following intermediate was prepared according to the method described above for Intermediate 5.8 using 3-amino-N-(1 H-pyrazol-4-yl) pyrazine-2-carboxamide (CAS: 1933674-659-1) and methyl 3-(chloromethyl)-5-methylbenzoate (CAS: 1393545-21-5)

Intermediate 5.10: 3-amino-N-(1-(3-(hvdrazinecarbonyl)benzyl)-1H-pyrazol-4- yl)Pyrazine-2-carboxamide)

Example 63

tert-butyl 2-(3- (3-aminopyrazine-2-carboxamido ^' )-1 H-pyrazol-1-yl ^' )methvDbenzoyl ^' )-

hvdrazine-1-carboxylate:

[0325] 3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)benzoic acid

(Example 63, 120 mg, 0.355 mmol), HATU (148 mg, 0.390 mmol) and DIPEA (0.120 ml_, 0.709 mmol) were combined in DMF and stirred for 5 minutes, then tert-butyl carbazate (52 mg, 0.390 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was then diluted with ethyl acetate and washed with saturated aqueous sodium carbonate solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to yield tert-butyl 2-(3-((4-(3-aminopyrazine-2-carboxamido)-1 H- pyrazol-1-yl)methyl)benzoyl)hydrazine-1-carboxylate as a yellow oil (170 mg), Ή NMR (400 MHz, CDCIs) d 9.63 (s, 1 H), 8.17 (d, J=2.5 Hz, 1 H), 8.02 (s, 1 H), 7.82 (d, J=2.3 Hz, 1 H), 7.77 - 7.70 (m, 2H), 7.64 (s, 1 H), 7.44 - 7.38 (m, 2H), 6.81 (s, 1 H), 6.57 (s, 1 H), 5.85 - 5.81 (m, 2H), 5.32 - 5.30 (m, 2H), 9H Boc signal partially obscured by water peak..

(3-amino-N-(1-(3-(hvdrazinecarbonvnbenzyl ^' )-1 H-pyrazol-4-yl ^' )pyrazine-2-carboxamide:

[0326] Tert-butyl 2-(3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)- benzoyl)hydrazine-1-carboxylate (120 mg, 0.265 mmol) was combined with hydrogen chloride in dioxane (1 ml_) and stirred at room temperature for 16 hours, then the solvent was removed under reduced pressure and the residue was purified by SCX to yield 3-amino-N-(1-(3- (hydrazinecarbonyl)benzyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide (Intermediate 5.10) as a pale yellow solid (60 mg, 69%), Ή NMR (400 MHz, DMSO) d 10.87 (s, 1 H), 9.79 (s, 1 H), 8.26 (d, J=2.4 Hz, 1 H), 8.21 (s, 1 H), 7.90 (d, J=2.4 Hz, 1 H), 7.77 (s, 1 H), 7.74 - 7.72 (m, 2H), 7.71 - 7.48 (m, 2H), 7.46 - 7.40 (m, 1 H), 7.39 - 7.36 (m, 1 H), 5.37 (s, 2H), 4.54 (s, 2H).

Intermediate 5.11 : 2-(3-((4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1- yl)methyl)phenyl)acetic acid

Ethyl 2-(3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)phenyl)acetate:

[0327] 3-amino-N-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide (CAS 1933674-69-1 , 130 mg, 0.637 mmol), ethyl 2-(3-(bromomethyl)phenyl)acetate (246 mg, 0.955 mmol) and potassium carbonate (176 mg, 1.27 mmol) were combined in DMF (3 ml.) and heated to 80 °C for 16 hours. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (10-80% gradient) in cyclohexane to afford ethyl 2- (3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)phenyl)acetate as a yellow oil (83 mg, 34% yield), Ή NMR (400 MHz, DMSO) d 10.89 (s, 1 H), 8.30 (d, J=2.3 Hz, 1 H), 8.21 (s, 1 H), 7.94 (d, J=2.3 Hz, 1 H), 7.81 (s, 1 H), 7.62 (s, 2H), 7.35 (dd, J=7.5, 7.5 Hz, 1 H), 7.26 - 7.22 (m, 1 H), 7.21 - 7.16 (m, 2H), 5.35 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.69 (s, 2H), 1.21 (t, J=7.2 Hz, 3H).

2-(3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)phenyl)acetic acid:

[0328] Ethyl 2-(3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)phenyl)- acetate (75 mg, 0.197 mmol) and lithium hydroxide monohydrate (33 mg, 0.789 mmol) were combined in ethanol (8 ml.) and water (2 mL) and heated to 40 °C for 6 hours. The mixture was then concentrated under reduced pressure, acidified with 2 M HCI to pH 1 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to dryness to yield 2-(3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)methyl)phenyl) acetic acid as a yellow solid (59 mg, 86%), and used in the next step without further purification.

Intermediate 5.12: 3-(2-(4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1 - vDethvDbenzoic acid

Methyl 3-(2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)ethyl)benzoate:

[0329] Step 1 - Methyl 3-(2-hydroxyethyl)benzoate (CAS 153599-45-2, 250 mg, 1.39 mmol) was dissolved in DCM (4 mL) and cooled to 0°C, then triethylamine (0.580 ml_, 4.16 mmol) and methanesulfonyl chloride (0.210 mL, 2.77 mmol) were added and the mixture was allowed to warm up to room temperature and stirred for 16 hours. The reaction was then quenched with saturated sodium hydrogen carbonate solution and extracted with DCM. The organic phase was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to yield methyl 3-(2-((methylsulfonyl)oxy)ethyl)benzoate (400 mg), ¹ H NMR (400 MHz, CDCIs) d 7.97 - 7.91 (m, 2H), 7.46 - 7.39 (m, 2H), 4.44 (t, J=6.8 Hz, 2H), 3.92 (s, 3H), 3.11 (t, J=6.8 Hz, 2H), 2.89 (s, 3H).

[0330] Step 2 - Methyl 3-(2-((methylsulfonyl)oxy)ethyl)benzoate (400 mg, 1.55 mmol), 3- amino-N-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide (CAS 1933674-69-1 , 474 mg, 2.32 mmol) and cesium carbonate (1009 mg, 3.10 mmol) were combined in DMF (5 mL) and heated to 50°C for 6 hours. The reaction mixture was then cooled to room temperature and filtered. The solid was washed with DCM and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (5-50% gradient) in cyclohexane to afford methyl 3-(2-(4-(3-aminopyrazine-2-carboxamido)-1 H- pyrazol-1-yl) ethyl) benzoate (180 mg, 32%), Ή NMR (400 MHz, CDCI ₃ ) d 9.57 (s, 1 H), 8.19 (d, J=2.3 Hz, 1 H), 7.92 - 7.89 (m, 1 H), 7.87 - 7.85 (m, 2H), 7.84 (d, J=2.3 Hz, 1 H), 7.61 (s, 1 H), 7.35 (dd, J=7.5, 7.5 Hz, 1 H), 4.37 - 4.33 (m, 2H), 3.91 (s, 3H), 3.25 (t, J=7.3 Hz, 2H), NH ₂ not observed, CH signal partially obscured by CDCL peak ..

Intermediate 5 12

3-(2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)ethvnbenzoic acid: [0331] Methyl 3-(2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)ethyl) benzoate (180 mg, 0.491 mmol) and lithium hydroxide (35 mg, 1.47 mmol) were combined in methanol (8.5 ml_) and heated to 80 °C for 16 hours. The mixture was then concentrated under reduced pressure to afford 3-(2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)ethyl)benzoic acid as a lithium salt, which was used as such for the next step. LCMS RT 1.32 min, m/z 353 ES+.

General scheme for reaction intermediates used in reaction Scheme 7 and 7a

[0332] Amino-azole derivatives of general formula [XLIV] are prepared by the reduction of nitro-azole derivatives of general formula [XLIII] with a suitable reducing agent such iron- ammonium chloride or ammonium formate/palladium on carbon in a polar solvent such as EtOH, MeOH or H ₂ 0.

Intermediate 7.1 : tert-butyl 3-((4-amino-1H-pyrazol-1 -ylH3- methoxyphenvnmethvnazetidine-1-carboxylate

[0333] To a stirred solution of tert-butyl 3-((3-methoxyphenyl)(4-nitro-1 H-pyrazol-1- yl)methyl)azetidine-1-carboxylate (Intermediate 7a.1 , 300 mg, 0.772 mmol) in methanol (4 ml) under nitrogen was added palladium (25 mg, 0.232 mmol) and ammonium formate (292 mg, 4.63 mmol). The reaction was heated to 70°C for 1 hour. The reaction mixture was cooled and diluted with EtOAc then passed through celite and the filtrate was concentrated in vacuo to afford the title compound as an orange oil (265 mg, 96%) which was used in the next step without further purification. Ή NMR (400 MHz, CDCIs): d 7.25 - 7.21 (1 H, m), 7.16 (1 H, s), 6.94 (1 H, s), 6.86 - 6.77 (3H, m), 6.44 - 6.30 (2H, m), 5.21 (1 H, d, J=1 1.1 Hz), 4.06 (1 H, t, J=8.6 Hz), 3.93 (1 H, t, J=8.6 Hz), 3.76 (3H, m), 3.73 (1 H, dd, J=5.3, 8.8 Hz), 3.62 (1 H, dd, J=5.4, 9.0 Hz), 3.53 - 3.48 (1 H, m), 1.43 - 1.41 (9H, m).

Intermediate 7.20: 1-((3-fluoro-1-methylazetidin-3-yl)(phenyl)methyl)-1 H-pyrazol-4- amine [0334] To a stirred solution of 1-((3-fluoro-1-methylazetidin-3-yl)(phenyl)methyl)-4-nitro-1 H- pyrazole (Intermediate 7a.20, 110 mg, 0.379 mmol) in ethanol (4 ml) and water (2 ml) under nitrogen was added iron (127 mg, 2.27 mmol) and ammonium formate (162 mg, 3.03 mmol). The reaction was heated to 80°C for 1 hour. The reaction mixture was cooled and diluted with EtOAc then passed through celite and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid (95 mg, 96%) which was used in the next step without further purification. Used crude in the next step.

[0335] The following intermediates were prepared according to the methods described above for Intermediates 7.1 and 7.20 using the appropriate Intermediates and used in the next step without purification.

Intermediate 7a.20: 1-((3-fluoro-1-methylazetidin-3-ylHphenv0methyl)-4-nitro-1 H- pyrazole

[0336] To a stirred solution of tert-butyl 3-fluoro-3-((4-nitro-1 H-pyrazol-1- yl)(phenyl)methyl)azetidine-1-carboxylate (Intermediate 7.20, 320 mg, 0.850 mmol) in DCM (4 ml) was added dropwise TFA (2 ml, 26.12 mmol). The reaction was stirred at room temperature for 1 hour then concentrated in vacuo. The crude residue was passed through an SCX-2 cartridge eluting with 7M Ammonia in methanol. The resulting solution was concentrated invacuo to obtain the deprotected product which was dissolved in DMF (3 ml) and cooled to 0°C. To the cooled stirred solution was added formaldehyde solution (0.026ml, 0.854 mmol). The reaction was stirred for 10 minutes at 0°C then heated to 50°C for 30 minutes before cooling again to 0°C and adding sodium triacetoxyborohydride (226 mg, 1.07 mmol) and finally stirring at room temperature for 15 hours. The reaction was quenched with water and extracted with EtOAc (x3). Combined organic extracts were washed with brine, dried over magnesium sulphate, filtered and concentrated to in vacuo to afford the title compound (135mg, 100%) which was used in the next step without purification. Ή NMR (400 MHz, CDCIs): 5 8.10 (1 H, s), 7.98 (1 H, s), 7.54 - 7.46 (5H, m), 6.28 (1 H, d, J = 32 Hz), 4.92 - 4.72 (1 H, m), 4.37 - 4.27 (1 H, m), 3.89 (1 H, dd, J=11.5, 20.1 Hz), 3.68 - 3.57 (1 H, m), 2.83 (3H, s).

Intermediate 7a.7: tert-butyl methyl(2-i4-nitro-1H-pyrazol-1 -yl)-2-phenylethyl)carbamate

[0337] To a stirred solution of sodium hydride (60% in oil) in DMF (1 ml) at 0°C was added dropwise a solution of tert-butyl (2-(4-amino-1 H-pyrazol-1-yl)-2-phenylethyl)carbamate (Intermediate 7.7, 100 mg, 0.301 mmol) in DMF (2 ml). The resulting suspension was stirred for 20 minutes then neat iodomethane (0.019ml, 0.301 mmol) was added and the reaction stirred at 0°C for 2 hours. The reaction was quenched with saturated aq. ammonium chloride and extracted with EtOAc. The organic extract was washed with 4% lithium chloride aq. and brine, then dried over magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and hexane (5-20% gradient) to afford the title compound as a pale yellow oil (350 mg, 84%). ¹ H NMR (400 MHz, CDCb): d 8.13 (2H, s), 7.42 - 7.37 (5H, m), 5.71 (1 H, dd, J=4.7, 8.7 Hz), 4.15 - 4.04 (1 H, m), 3.91 (1 H, dd, J=4.4, 13.8 Hz), 2.64 (3H, s), 1.43 (9H, s).

[0338] Nitro-pyrazole derivatives of general formula [XLI II] are prepared by a Mitsunobu type reaction by the reaction of a hydroxy-derivative of general formula [XLI I] with a 3-nitro-azole derivative of general formula [XLVI] with a suitable phosphine agent such as triphenylphosphine or polymer-supported triphenylphosphine and a suitable azodicarboxylate agent such as DIAD or DEAD in a polar solvent such as THF or Et 0.

Intermediate 7a.1 : tert-butyl 3-((3-methoxyphenvH(4-nitro-1 H-pyrazol-1- vl)methyl)azetidine-1-carboxylate

[0339] To an ice cold stirred solution of tert-butyl 3-(hydroxy(3- methoxyphenyl)methyl)azetidine-1-carboxylate (Intermediate 7.1 , 632 mg, 5.59 mmol), 4- nitro-1 H-pyrazole (632 mg, 5.59 mmol) and triphenylphosphine (1.76g, 6.71 mmol) in DCM (10 ml) was added dropwise diisopropyl azodicarboxylate (1.3 ml, 6.71 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and hexane (5-50% gradient) to afford the title compound. Ή NMR (400 MHz, CDCI ₃ ): d 8.07 (1 H, s), 8.03 (1 H, s), 7.35 - 7.30 (1 H, m), 6.95 - 6.86 (2H, m), 6.83 (1 H, s), 5.38 (1 H, d, J=9.7 Hz), 5.02 - 4.92 (2H, m), 4.1 1 (1 H, dt, J=1.6, 8.5 Hz), 3.99 - 3.92 (1 H, m), 3.80 (3H, s), 3.62 - 3.56 (1 H, m), 1.42 (9H, s).

[0340] The following intermediates were prepared according to the method described above for Intermediate 7.1 using 4-nitro-1 H-pyrazole and the appropriate Intermediates or known starting alcohols, and purified by silica gel flash chromatography eluting with mixtures of EtOAc and hexane using the gradients defined in the table below.

Intermediate 7a.19: N-(methyl-d3)-2-(4-nitro-1 H-pyrazol-1-vH-2-phenylethan-1-amine

[0341] Under nitrogen, in an oven dried flask, N-methyl-2-(4-nitro-1 H-pyrazol-1-yl)-2- phenylethan-1 -amine (Intermediate 7a.18, 300 mg, 0.90 mmol) was dissolved in DMF (2 ml.) and cooled to 0°C. A solution of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.08 mmol) in DMF (2 mL) was added dropwise and the mixture was stirred for 30 minutes at 0°C. Then iodomethane-d3 (0.076 mL, 1.22 mmol) was added dropwise and the mixture was allowed to warm up to room temperature and stirred for 16 hours. The reaction was quenched with methanol (1 mL) and ethylacetate (1 mL). The reaction mixture was concentrated under reduced pressure and the residue partitioned between ethylacetate and saturated ammonium chloride solution. The organics were separated, washed with brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5-25 % EtOAc in hexane to yield the desired product as a colourless oil (525 mg, 80%), ¹ H NMR (400 MHz, CDCIs) d 8.24 - 8.13 (m, 2H), 7.42 - 7.30 (m, 5H), 5.75 - 5.49 (m, 2H), 4.16 - 4.03 (m, 1 H), 3.90 (dd, J=4.9, 14.3 Hz, 1 H).

Intermediate 7a.17: tert-butyl (2-fluoroethyl)(2-(4-nitro-1 H-pyrazol-1-yl)-2- phenylethvDcarbamate

[0342] tert-butyl (2-(4-nitro-1 H-pyrazol-1-yl)-2-phenylethyl)carbamate (Intermediate 7a.5, 300 mg, 0.90 mmol) was dissolved in DMF (2 mL) and cooled to 0°C. A solution of sodium hydride (60% dispersion in mineral oil, 36 mg, 0.90 mmol) in DMF (2 mL) was added dropwise and the mixture was stirred for 15 minutes at 0°C. Then 1-Bromo-2-fluoroethane (0.168 mL, 2.25 mmol) was added dropwise and the mixture was allowed to warm up to room temperature and stirred for 3 hours. The reaction was quenched with methanol (1 mL) and water. The reaction mixture was partitioned between ethylacetate and water. The organics were separated, washed with brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 5- 20 % EtOAc in hexane to yield the desired product as a yellow oil (210 mg, 79 %), that was used crude in the next step.

[XLI I]

[0343] Hydroxy-azetidine derivatives of general formula [XLI I] are prepared by reduction of ketone derivatives of general formula [XLI] with a suitable reducing agent such as sodium borohydride or sodium cyanoborohydride in a polar solvent such as THF or Et ₂ 0. The reaction is suitably conducted at ambient or low temperature, more suitably at 0 °C

Intermediate 7b.3: tert-butyl 3-fluoro-3-(hvdroxy(3-methoxyphenyl)methyl)azetidine-1- carboxylate

[0344] To an ice cold stirred solution of tert-butyl 3-(2-phenylacetyl)azetidine-1-carboxylate (CAS 1402238-44-1 , 500 mg, 1.82 mmol) in DCM (6 ml) and methanol (3 ml) was added sodium borohydride (69 mg, 1.82 mmol). The reaction was for 15 minutes then quenched with water and diluted with DCM. The organic layer was separated and washed with brine then passed through a phase separator and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and hexane (20-40% gradient) to afford the title compound (540 mg, 82%). Ή NMR (400 MHz, CDCb): d 7.35 - 7.18 (5H, m), 4.00 - 3.85 (4H, m), 3.70 (1 H, dd, J=5.8, 8.7 Hz), 2.80 - 2.74 (1 H, m), 2.59 (2H, dd, J=8.5, 13.6 Hz), 1.71 - 1.66 (1 H, m), 1.44 (9H, s).

[0345] The following intermediates were prepared according to the method described above for Intermediate 7b.3 using the appropriate Intermediates and used in the next step without purification.

[0346] Ketone derivatives of general formula [XLI] were R is H are prepared by reaction of a Weinreb amide of general formula [XXXIX] with a Grignard reagent of general formula [XL] in a polar aprotic solvent such as THF or Et 0. The reaction is suitably conducted at low temperature, more suitably -78 °C

Intermediate 7c.2: tert-butyl 3-fluoro-3-(3-methoxybenzovnazetidine-1-carboxylate

[0347] To a stirred solution of tert-butyl 3-(3-methoxybenzoyl)azetidine-1-carboxylate (CAS 1427079-71 -7, 500 mg, 1.91 mmol) in anhydrous THF (10 ml) at -78°C under nitrogen was added dropwise LiHMDS (1 M, 2.5 ml, 2.49 mmol). The reaction was stirred at -78°C for 90 minutes then a solution of N Fluorobenzenesulfonimide (784 mg, 2.49 mmol) in THF (5ml) was dropwise. The reaction was stirred for a further 2 hours then warmed to room temperature, quenched with saturated aq. ammonium chloride solution and extracted with EtOAc. Organic extract was washed with brine solution, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and hexane (5-50%) to afford the title compound as a colourless oil (410 mg, 77%). ¹ H NMR (400 MHz, CDCIs): d 7.50 - 7.36 (3H, m), 7.17 (1 H, dd, J=1.8, 8.1 Hz), 4.55 (2H, dd, J=10.6, 19.7 Hz), 4.30 - 4.22 (2H, m), 3.86 (3H, s), 1.46 (9H, s).

[0348] The following intermediate (Intermediate 7c.4) was prepared according to the method described above for Intermediate 7c.2 using tert-butyl 3-benzoylazetidine-1- carboxylate (CAS:206446-44-8) and was purified by silica gel flash chromatography eluting with EtOAc and hexane (5-50%) to afford the title compound as a pale yellow oil (540 mg, 67%).

Intermediate 7c.3: tert-butyl 3-(2-phenylacetyl)azetidine-1-carboxylate

[0349] To a stirred solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1- carboxylate (CAS: 820971-67-3, 2.5 g, 10.23 mmol) in anhydrous THF (10 ml) at -78°C under nitrogen was added dropwise benzylmagnesium bromide (2M, 10.2 ml, 20.47 mmol). The reaction was stirred at -78°C for 1 hour then allowed to warm to room temperature over 15 hours. The reaction mixture was cooled to 0°C and quenched with saturated aq. ammonium chloride solution and extracted with EtOAc. The organic extract was washed with brine solution, dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound (2.5 g, 90%) which was used in the next step without purification. Ή NMR (400 MHz, CDC ): d 7.36 - 7.27 (3H, m), 7.20 - 7.16 (2H, m), 4.06 - 3.95 (2H, m), 3.91 - 3.88 (2H, m), 3.71 (2H, s), 3.54 - 3.45 (1 H, m), 1.41 (9H, s).

[0350] The following intermediate (Intermediate 7c.1) was prepared according to the method described above for Intermediate 7c.3 using tert-butyl 3- (methoxy(methyl)carbamoyl)azetidine-1-carboxylate (CAS: 820971-67-3) and 3- methoxyphenylmagnesium bromide; and purified by silica gel flash chromatography eluting with EtOAc and hexane (0-50%) to afford the title compound (1.9 g, 43%).

Intermediate 7d.13: tert-butyl 2-(methoxy(methyl)carbamoyl)-1.4-oxazepane-4- carboxylate

[0351] 4-(tert-butoxycarbonyl)-1 ,4-oxazepane-2-carboxylic acid (CAS: 1141669-61-5, 700 mg, 2.85 mmol), N,O-dimethylhydroxylamine hydrochloride (310 mg, 3.14 mmol), N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (1.09 g, 5.71 mmol) and 1- hydroxybenzotriazole hydrate (39 mg, 0.28 mmol) were combined in DMF (6 ml_) and DIPEA (2 mL, 1 1.42 mmol) and stirred at room temperature for 6 hours. The mixture was then partitioned between ethylacetate and saturated sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 10-100 % EtOAc in hexane to yield the desired product (589 mg, 70%). Ή NMR (400 MHz, DMSO) d 4.57 - 4.54 (m, 1 H), 4.14 - 4.02 (m, 1 H), 3.86 - 3.54 (m, 6H), 3.33 - 3.27 (m, 1 H), 3.14 - 3.10 (m, 4H), 1.81 - 1.68 (m, 2H), 1.43 - 1.42 (m, 9H).

General Intermediates for Schemes 9 and 9a

Intermediate 9.1 : Ethyl 2-(4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1-yl)-2- phenylacetate

[0352] To a stirred suspension of 3-amino-A/-(1/-/-pyrazol-4-yl)pyrazine-2-carboxamide (CAS: 1933674-659-1), 500 mg, 2.45 mmol) and potassium carbonate (510 mg, 3.67 mmol) in DMF (6 ml) was added ethyl a/p/7a-bromophenylacetate (0.64 ml, 3.67 mmol). The reaction mixture was heated to 110°C for 8 hours. The reaction concentrated in vacuo then taken up in ethyl acetate (50) and washed with water (50). The organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with mixtures of EtOAc and isohexane to afford the title compound (690 mg, 77% yield. Ή NMR (400 MHz, DMSO): d 10.87 (s, 1 H), 8.25 (d, J = 2.4 Hz, 1 H), 8.04 (s, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.83-7.82 (m, 1 H), 7.59-7.43 (m, 7 H), 6.46- 6.46 (m, 1 H), 4.22 (q, J = 7.0 Hz, 2 H), 1.18 (t, J = 7.1 Hz, 3 H).

Intermediate 9.2: methyl 3-(4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1 -yl)-3- phenylpropanoate

[0353] To a stirred suspension of 3-amino-/V-(1/-/-pyrazol-4-yl)pyrazine-2-carboxamide (CAS: 1933674-659-1), 500 mg, 2.45 mmol) and potassium carbonate (510 mg, 3.67 mmol) in DMF (6 ml) was added methyl cinnamate (0.43 ml, 3.67 mmol). The reaction mixture was heated to 110°C for 18 hours. The reaction concentrated invacuo then taken up in ethyl acetate (50 ml) and washed with brine (50 ml). The organic extract was dried with magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and iso- hexane (10-80% gradient) to afford the title compound (690 mg, 77%). Ή NMR (400 MHz, DMSO): d 10.82 (s, 1 H), 8.25 (d, J = 2.3 Hz, 1 H), 8.18 (s, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.77 (s, 1 H), 7.58 (s, 2 H), 7.36-7.28 (m, 5 H), 5.88 (dd, J = 5.4, 9.8 Hz, 1 H), 3.58-3.50 (m, 4 H), 3.23 (dd, J = 5.4, 16.4 Hz, 1 H).

Intermediate 9.3: 2-(4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1-yl)-2- phenylacetic acid

[0354] Lithium hydroxide monohydrate (92 mg, 2.18 mmol) was added to a stirred solution of ethyl 2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-2-phenylacetate (Intermediate 9.1 , 200 mg, 0.546 mmol) in methanol (8 ml) and water (2 ml). The reaction was stirred at 60°C for 4 hours then concentrated in vacuo. The residue was dissolved in water adjusting pH to 1 with 2M HCI aq. and the resulting precipitate was collected by filtration. The precipitate were washed with water and ether then dried under vacuum to afford the title compound (146 mg, 79%). ¹ H NMR (400 MHz, DMSO): d 10.77 (s, 1 H), 8.27-8.23 (m, 2 H), 7.88 (d, J = 2.3 Hz, 1 H), 7.69 (s, 1 H), 7.57 (s, 2 H), 7.36-7.33 (m, 5 H), 5.86 (s, 1 H). OH from acid not observed. Intermediate 9.4: 3-(4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1-yl)-3- phenylpropanoic acid

[0355] Methyl 3-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-3-phenylpropanoate (Intermediate 9.2) (100 mg, 0.273 mmol) and lithium hydroxide monohydrate (46 mg, 1.09 mmol) were combined in methanol (8 mL) and water (2 mL) and heated to 50 °C until the reaction was completed. The mixture was then concentrated under reduced pressure, acidified with 2 M HCI to pH 2 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to dryness to yield the title compound (Intermediate 9.4) (90 mg, 94 % yield), Ή NMR (400 MHz, DMSO) d 10.82 (s, 1 H), 8.25 (d, J=2.4 Hz, 1 H), 8.18 (s, 1 H), 7.89 (d, J=2.4 Hz, 1 H), 7.77 (s, 1 H), 7.52 - 7.51 (m, 2H), 7.38 - 7.27 (m, 5H), 5.82 (dd, J=5.5, 9.5 Hz, 1 H), 3.19 - 3.08 (m, 1 H), 1 H obscured by water peak, COOH not observed.

Intermediate 9.5: 3-amino-N-(1-(2-oxo-1-phenylpropyl)-1H-pyrazol-4-yl)pyrazine -2- carboxamide

[0356] Ethyl 2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-2-phenylacetate (Intermediate 9.1 , 1.099 g, 3 mmol) was dissolved in THF (15 mL) and cooled to -78 °C, then methylmagnesium bromide (3 M solution in THF, 3 mL, 9 mmol) was added slowly and the reaction was allowed to warm up to room temperature and left at room temperature for 16 hours. The mixture was then cooled to 0 °C, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography eluting with ethyl acetate (5-75% gradient) in cyclohexane to afford 3-amino-N-(1-(2-oxo-1-phenylpropyl)-1 H-pyrazol-4-yl)pyrazine-2- carboxamide (Intermediate 9.5) as a yellow oil (456 mg, 45 %) ¹ H NMR (400 MHz, CDCL) d 9.58 (s, 1 H), 8.19 - 8.18 (m, 1 H), 8.09 (s, 1 H), 7.83 - 7.82 (m, 1 H), 7.69 (s, 1 H), 7.53 - 7.29 (m, 7H), 1.12 (s, 1 H), 2.24 (s, 3H)

General scheme for reaction intermediates used in reaction Scheme 10 and 10a [0357] Nitro-derivatives of general formula [LIX] are prepared by a Michael-type reaction of an azole derivate of general formula [IV] [prepared according to the general procedure in [Scheme 2] with a nitro alkene derivative of general formula [LVIII] in a polar solvent such as THF or Dioxane. The reaction is suitably conducted at high temperature under thermal heating.

Intermediate 10.1 : 3-ami no-N-( 1 -(1 -(3-methoxyphenyl)-2-nitroethyl)-1 H-pyrazol-4- vl)Pvrazine-2-carboxamide

[0358] A mixture of 3-amino-/V-(1 /-/-pyrazol-4-yl)pyrazine-2-carboxamide (CAS: 1933674- 659-1 , 204 mg, 1.0 mmol) and 1-methoxy-3-(2-nitroethenyl)-benzene (CAS: 3179-09-7, 268 mg, 1.5 mmol) in dioxane (4.0 ml) was stirred at 70°C for 18 hours. The reaction mixture was concentrated to dryness. The crude residue was purified by silica gel flash chromatography eluting with EtOAc and /so-hexane (5-100% gradient) to afford the title compound (341 mg, 89%). Ή NMR (400 MHz, CDCIs): d 9.60 (1 H, s), 8.19 - 8.18 (1 H, m), 8.09 (1 H, s), 7.83 - 7.82 (1 H, m), 7.67 (1 H, s), 7.32 - 7.27 (1 H, m), 6.90 - 6.82 (3H, m), 6.05 (1 H, dd, J=4.6, 9.9 Hz), 5.64 (1 H, dd, J=9.9, 14.2 Hz), 4.85 (1 H, dd, J=4.6, 14.2 Hz), 3.78 (3H, s). NH ₂ on pyrazine not observed.

[0359] The following intermediates in the table below were prepared according to the method described above for Intermediate 10.1 and purified by silica gel flash chromatography eluting with EtOAc and isohexane (5-100% gradient) to afford the title compounds.

Intermediate 10a.1 : 3-amino-N-(1-(1-(3-methoxyphenyl)-2-nitropropyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide Intermediate 10a 1

[0360] 3-Amino-N-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide (CAS 1933674-69-1 , 846 mg, 4.14 mmol) and 1-methoxy-3-(2-nitroprop-1-en-1-yl)benzene (18738-95-9, 800 mg, 4.14 mmol) were combined in dioxane (16 ml.) and NMP (4 ml.) and heated to 80 °C for 48 hours. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was washed with brined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (5-80% gradient) in cyclohexane to afford 3-amino- N-(1-(1-(3-methoxyphenyl)-2-nitropropyl)-1 H-pyrazol-4-yl)pyrazine-2-carboxamide

(intermediate 81) as a mixture of diastereoisomers (390 mg, 23 %) and used in the next step without further purification.

Intermediate 10a.2: 3-amino-N-(1-(2-nitro-1-(3-(propylcarbamoyl)phenyl)ethyl)-1 H- pyrazol-4-yl)pyrazine-2-carboxamide

Methyl 3-(1-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-2-nitroethyl)benzoate):

[0361] Methyl (E)-3-(2-nitrovinyl)benzoate (CAS 1505475-98-8, 497 mg, 2.40 mmol) and 3- amino-N-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide (CAS 1933674-69-1 , 280 mg, 1.37 mmol) were combined in dioxane (10 mL) and heated to 70 °C for 16 hours. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was washed with brined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (10-80% gradient) in cyclohexane to afford methyl 3-(1-(4-(3-aminopyrazine-2- carboxamido)-1 H-pyrazol-1-yl)-2-nitroethyl)benzoate (382 mg, 68 %), Ή NMR (400 MHz, DM SO) d 10.90 (s, 1 H), 8.35 (s, 1 H), 8.26 (d, J=2.4 Hz, 1 H), 8.03 (s, 1 H), 7.96 - 7.93 (m, 1 H), 7.89 (d, J=2.4 Hz, 1 H), 7.85 (s, 1 H), 7.72 - 7.69 (m, 1 H), 7.61 - 7.50 (m, 3H), 6.52 (dd, J=4.4, 10.5 Hz, 1 H), 5.67 (dd, J=10.5, 14.6 Hz, 1 H), 5.46 (dd, J=4.4, 14.6 Hz, 1 H), 3.87 (s, 3H). (3-(1-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-vD-2-nitroethyl)benzoic acid):

[0362] Methyl 3-(1-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-2-nitroethyl) benzoate (750 mg, 1.82 mmol) and lithium hydroxide monohydrate (306 mg, 7.29 mmol) were combined in methanol (32 mL) and water (8 mL) and heated to 50 °C for 6 hours. The mixture was then concentrated under reduced pressure, acidified with 1 M HCI to pH 2 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to dryness to yield the title compound (662 mg, 91 %), that was used crude in the next step.

Intermediate 10a 2

(3-amino-N-(1-(2-nitrp-1-(3-(propylcarbamoyl)phenvnethyl ^' )-1 H-pyrazol-4-yl ^' )pyrazine-2- carbpxamide:

[0363] (3-( 1 -(4-(3-Am inppyrazine-2-carboxam idp)- 1 H-pyrazPl- 1 -yl)-2-nitrpethyl)benzPic acid (610 mg, 1.54), HATU (876 mg, 2.30 mmpl) and DIPEA (0.4 ml_, 2.30 mmpl) were ccmbined in DMF (4 mL) and stirred at rccm temperature fcr 10 minutes, then propylamine (0.15 mL, 1.84 mmol) was added in 1 mL DMF and stirred at room temperature for 1 hour. The crude mixture was then absorbed on HM-N and purified by silica gel flash chromatography eluting with ethyl acetate (10-80% gradient) in cyclohexane to afford the title compound (Intermediate 10a.2); LCMS (LC-Method 2) Rt = 1.42 min, m/z 437/439 [M+H]

Intermediate 10a.3: tert-butyl (2-(4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1-yl)-

2-(3-methoxy-5-((trimethylsilyl)ethvnyl)phenyl)ethyl)carb amate

[0364] Tert-butyl (2-(4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)-2-(3-bromo-5- methoxy-phenyl)ethyl)carbamate (Intermediate 10a.3) (53 mg, 0.100 mmol), trimethylsilylacetilene (12 mg, 0.120 mmol), Bis(triphenylphosphine)palladium(ll) dichloride (7 mg, 0.010 mmol) and copper(l) iodide (1.9 mg, 0.010 mmol) were combined in triethylamine (0.042 ml_, 0.300 mmol) and DMF (1 ml_). The mixture was degassed with a nitrogen flow then heated to 70 °C for 17 hours. The mixture was then cooled to room temperature, diluted with DCM and filtered through a pad of Celite™ and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (0-60% gradient) in cyclohexane to afford the title compound (41 mg, 74 %).

Intermediate 10a.4: tert-butyl (2-(4-(3-aminopyrazine-2-carboxamido)-1H-pyrazol-1- yl)-2-(3-bromo-5-methoxyphenvnethvncarbamate

[0365] 3-Amino-N-(1-(2-amino-1-(3-bromo-5-methoxyphenyl)ethyl)-1 H-pyrazol-4- yl)pyrazine-2-carboxamide (Example 231 , 80 mg, 0.185 mmol), di-tert-butyl decarbonate (0.051 ml_, 0.222 mmol), triethylamine (0.077 ml_, 0.555 mmol) and DMAP (2.3 mg, 0.0185 mmol) ere combined in DCM (2 mL) and stirred at room temperature for 24 hours. The mixture was then diluted with DCM, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (Intermediate 10a.4) as a yellow solid (100 mg, quantitative).

Intermediate 11.1 : 3-ami no-N-(1 -(methylsulfonvn-1H-pyrazol-4-yl)pyrazine-2- carboxamide

Intermediate 83

[0366] 3-amino-N-(1 H-pyrazol-4-yl)pyrazine-2-carboxamide (CAS 1933674-69-1 , 200 mg, 9.79 mmol) was suspended in DCM (15 mL) and cooled to 0 °C, then triethylamine (0.16 mL,

I .18 mmol) was added dropwise, followed by methanesulfonyl chloride (0.091 mL, 1.18 mmol). The mixture was allowed to warm up to room temperature and stirred for 16 hours. The precipitate formed was collected by filtration (3-amino-N-(1-(methylsulfonyl)-1 H-pyrazol- 4-yl)pyrazine-2-carboxamide, intermediate 83 , 215 mg, 78 %) Ή NMR (400 MHz, DMSO) d

I I .24 (s, 1 H), 8.58 - 8.57 (m, 1 H), 8.36 - 8.30 (m, 2H), 7.98 (d, J=2.3 Hz, 1 H), 7.66 - 7.60 (m, 2H), 3.58 - 3.57 (m, 3H).

Intermediate 11.2: tert-butyl (2S)-2-(hydroxy(3-methoxyphenyl)methyl)morpholine-4- carboxylate [0367] Step 1 - (R)-4-(tert-buyoxycarbonyl)morpholine-2-carboxylic acid (6.00 g, 23.35 mmol) and CDI (5.15 g, 31.76 mmol) were combined in THF (25 ml_) and stirred at room temperature for 1 hour. N,O-Dimethylhydroxylamine hydrochloride (3.10 mg, 31.76 mmol) and triethylamine (4.4 ml_, 31.76 mmol) were combined in acetonitrile (25 ml.) and stirred at room temperature for 1 hour. The two solutions were then combined and stirred at room temperature for 5 hours. The solvents were then evaporated and the residue diluted with DCM (200 ml.) and washed with water (100 mL), 20 % acetic acid (100 mL) and saturated sodium carbonate solution (100 mL). The organic phase was then passed through a phase separator and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (25-100% gradient) in cyclohexane to afford tert- butyl (S)-2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (3.3 g, 51 %). Ή NMR (400 MHz, CDCIs) d , 4.38 - 4.28 (m, 1 H), 4.14 - 3.98 (m, 2H), 3.87 (s, 1 H), 3.76 (s, 3H), 3.63 - 3.55 (m, 1 H), 3.22 (s, 3H), 3.06 - 2.99 (m, 2H), 1.47 (s, 9H).

[0368] Step 2 - Tert-butyl (S)-2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (3.2 g, 11.67 mmol) was dissolved in THF (40 ml.) and cooled to -40 °C, then 3- methoxyphenylmagnesium bromide (2.7 ml_, 12.83 mmol) was added and the mixture was allowed to warm up to room temperature and stirred for 2 hours. Then the mixture was cooled to -30 °C and a second portion of 3-methoxyphenylmagnesium bromide (3 ml_) was added and the mixture was allowed to warm up to room temperature and stirred for 3 hours. The reaction was then quenched by addition of water (250 ml_), saturated ammonium chloride solution (20 ml_) and ethyl acetate (100 ml_) and stirred for 30 minutes. The phases were separated and the aqueous further extracted with ethyl acetate (3 x 100 ml_). The combined organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (0-100% gradient) in cyclohexane to afford tert-butyl (S)-2-(3-methoxybenzoyl)morpholine-4- carboxylate (2.8 g, 74 %) Ή NMR (400 MHz, CDC ) d 7.60 - 7.51 (m, 2H), 7.39 (t, J=8.0 Hz, 1 H), 7.14 (dd, J=2.6, 8.3 Hz, 1 H), 4.75 (s, 1 H), 4.16 - 4.02 (m, 2H), 3.87 - 3.86 (m, 4H), 3.78 - 3.66 (m, 1 H), 3.15 - 3.03 (m, 2H), 1.48 (s, 9H). Intermediate 11.2

[0369] Step 3 - Tert-butyl (S)-2-(3-methoxybenzoyl)morpholine-4-carboxylate (2.4 g, 7.47 mmol) was dissolved in THF (20 ml_) and methanol (20 mL) and cooled to 0 °C. Sodium borohydride (1.13 g, 29.87 mmol) was added and the mixture was allowed to warm up to room temperature and stirred for 16 hours. The reaction mixture was then diluted with saturated sodium hydrogencarbonate solution (120 mL) and extracted with DCM (4 x 100 mL). The combined organic were washed with saturated ammonium chloride solution (60 mL) and water (60 mL), dried through a hydrophobic frit and concentrated under reduced pressure to yield tert-butyl (2S)-2-(hydroxy(3-methoxyphenyl)methyl)morpholine-4-carboxyl ate (intermediate 84) as a pale yellow solid (2.4 g, 98%) Ή NMR (400 MHz, CDCh) d 7.29 - 7.24 (m, 1 H), 6.95 - 6.80 (m, 3H), 3.81 - 3.80 (m, 7H), 3.63 - 3.43 (m, 2H), 3.02 - 2.78 (m, 2H), 1.40 (s, 9H). OH not observed.

Intermediate 11.3: 3-(2-cvano-1-hvdroxyethyl)-N-propylbenzamide

Intermediate 11 3

[0370] Acetonitrile (0.055 mL, 1.05 mmol) was dissolved in THF (10 mL) and cooled to -78 °C. Then lithium bis(trimethylsilyl)amide (1 M in THF, 1 mL, 1.05 mmol) was added and the mixture was stirred for 20 minutes. Then a solution of 3-Formyl-/V-propyl-benzamide (CAS 623569-59-5, 100 mg, 0.523 mmol) in THF (2 mL) was added dropwise and the mixture was stirred at -78 °C for 1 hour before being allowed to warm up to room temperature and being stirred for 16 hours. The reaction was quenched by addition of saturated ammonium chloride solution and ethyl acetate. The phases were separated and the organics were dried over magnesium sulfate and concentrated under reduced pressure to yield 3-(2-cyano-1- hydroxyethyl)-N-propylbenzamide (intermediate 85) as a colourless oil (75 mg, 62 %). Ή NMR (400 MHz, CDCIs) d 7.71 - 7.61 (m, 2H), 7.52 - 7.36 (m, 2H), 6.41 (s, 1 H), 5.00 (t, J=5.9 Hz, 1 H), 3.41 - 3.32 (m, 2H), 2.76 - 2.73 (m, 2H), 1.67 - 1.57 (m, 2H), 1.00 - 0.93 (m, 3H).

Intermediate 11.4: 4-chloro-3-(hvdroxymethyl)-N-propylbenzamide [0371] 4-Chloro-3-(hydroxymethyl)benzoic acid (CAS 1187238-15-8, 150 mg, 0.804 mmol), HATU (367 mg, 0.965 mmol) and DIPEA (0.28 ml_, 1.61 mmol) were combined in DMF (3 ml.) and stirred at room temperature for 10 minutes, then propylamine (0.073 ml_, 0.884 mmol) was added in DMF (1 ml.) and stirred at room temperature for 1 hour. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous lithium chloride solution. The organics were separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (0-50% gradient) in cyclohexane to afford 4-chloro- 3-(hydroxymethyl)-N-propylbenzamide (intermediate 86) (98 mg, 54 %) Ή NMR (400 MHz, CDC ) d 7.86 - 7.84 (m, 1 H), 7.63 - 7.59 (m, 1 H), 7.37 (d, J=7.9 Hz, 1H), 6.34 (s, 1 H), 4.79 - 4.73 (m, 2H), 3.42 - 3.34 (m, 2H), 3.10 - 3.06 (m, 1H), 1.66 - 1.58 (m, 2H), 0.99 - 0.94 (m, 3H).

Intermediate 12.1 : tert-butyl 3-((4-(3-aminopyrazine-2-carboxamido)-1 H-pyrazol-1-yl)(3- methoxyphenyl)methyl)-3-hvdroxyazetidine-1-carboxylate

Intermediate 12 2 Intermediate 12 1

[0372] To a stirred solution of tert-butyl 2-(3-methoxyphenyl)-1-oxa-5-azaspiro[2.3]hexane- 5-carboxylate (Intermediate 12.2) (874 mg, 3.0 mmol) and 3-amino-N-(1 H-pyrazol-4- yl)pyrazine-2-carboxamide (CAS: 1933674-659-1), 613 mg, 3.0 mmol) in DMF (10.0 ml) was added potassium carbonate (622 mg, 4.50 mmol). The reaction was stirred at 90°C for 3 hours then concentrated in vacuo. The crude residue was purified by silica gel flash chromatography eluting with mixtures of EtOAc and cyclohexane (10-70%) to afford the title compound as an orange oil (857 mg, 58%). Intermediate 12.1 was resolved by chiral SFC (SFC-26) to afford the enantiomers:

Isomer 1 (Intermediate 12.3) SFC (SFC-27) RT=2.1 min Ή NMR (400 MHz, CDCb) d 9.61 (s, 1 H), 8.19 (d, J=2.3 Hz, 1 H), 8.06 (s, 1 H), 7.83 (d, J=2.3 Hz, 1 H), 7.67 (s, 1 H), 6.92 - 6.85 (m, 3H), 5.58 (s, 1 H), 5.39 (s, 1 H), 4.03 - 3.92 (m, 2H), 3.86 - 3.81 (m, 2H), 3.77 (s, 3H), 1.43 (s, 9H). NH and NH ₂ not observed. Isomer 2 (Intermediate 12.4). SFC (SFC-27) RT=3.0 min Ή NMR (400 MHz, CDCb) d 9.61 (s, 1 H), 8.19 (d, J=2.3 Hz, 1 H), 8.06 (s, 1 H), 7.83 (d, J=2.5 Hz, 1 H), 7.67 (s, 1 H), 6.92 - 6.85 (m, 3H), 5.58 (s, 1 H), 5.39 (s, 1 H), 4.03 - 3.92 (m, 2H), 3.83 - 3.82 (m, 2H), 3.77 (s, 3H), 1.43 (s, 9H). NH and NH2 not observed.

Intermediate 12.2: tert-butyl 2-(3-methoxyphenyl)-1-oxa-5-azaspiror2.31hexane-5- carboxylate

(Tert-butyl 3-(3-methoxybenzylidene)azetidine- 1 -carboxylate) :

[0373] 3-Methoxybenzyltriphenylphosphonium chloride (CAS 18880-05-2, 2.50 g, 5.40 mol) was dissolved in THF (20 ml.) and cooled to -10 °C. Lithium bis(trimethylsilyl)amide (5.4 mL, 5.40 mmol) was added slowly and the mixture was stirred for 30 minutes, then 1-Boc-3- azetidinone (0.920 g, 5.40 mmol) was added and the mixture was stirred for 1 hour. The mixture was then quenched with ethyl acetate and brine, the phases were separated and the organics dried over magnesium sulfate and concentrated to afford tert-butyl 3-(3- methoxybenzylidene)azetidine-1-carboxylate as a colourless oil (1.1 g, 83 %) Ή NMR (400 MHz, CDCIs) d 7.28 - 7.23 (m, OH), 6.80 - 6.69 (m, 2H), 6.64 (t, J=1.9 Hz, 1 H), 6.23 (t, J=2.3 Hz, 1 H), 4.83 (q, J=2.9 Hz, 2H), 4.64 (dd, J=2.5, 5.9 Hz, 2H), 3.81 (s, 3H), 1.48 (s, 9H).

Intermediate 12 2

(Tert-butyl 2-(3-methexyphenyl)-1-exa-5-azaspire[2.3lhexane-5-carboxyiat e):

[0374] tert-butyl 3-(3-methoxybenzylidene)azetidine-1-carboxylate (200 mg, 0.726) was dissolved in chloroform (2 mL) and 3-Chloroperbenzoic acid (70 %, 814 mg, 3.63 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, washed with saturated sodium carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (0-60% gradient) in cyclohexane to afford tert-butyl 2-(3-methoxyphenyl)-1-oxa-5-azaspiro[2.3]hexane-5-carboxylat e as a colourless oil (40 mg, 18%) Ή NMR (400 MHz, CDCh) d 7.31 - 7.27 (m, 1 H), 6.86 (dd, J=2.1 , 8.0 Hz, 1 H), 6.76 (d, J=7.6 Hz, 1 H), 6.65 (t, J=2.0 Hz, 1 H), 4.34 - 4.18 (m, 3H), 3.97 (s, 1 H), 3.90 - 3.86 (m, 1 H), 3.80 (s, 3H), 1.44 (s, 9H).

Intermediate 12.5: Tert-butyl 3-hvdroxy-3-((3-methoxyphenyl)(4-nitro-1H-pyrazol-1- yl)methyl)azetidine-1-carboxylate

Intermediate 12.2 Intermediate 12.5

[0375] tert-butyl 2-(3-methoxyphenyl)-1-oxa-5-azaspiro[2.3]hexane-5-carboxylat e

(Intermediate 12.2) (550 mg, 1.89 mmol) and 4-nitro-1 H-pyrazole (213 mg, 1.89 mmol) were combined in DMF (8 mL) and potassium carbonate (391 mg, 2.83 mmol) was added and the mixture was stirred at 40°C for 4 hours and then at room temperature for 16 hours. Water and saturated sodium carbonate solution were added and the mixture was extracted with ethyl acetate, the organic phase was washed with water, dried on magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (5-50%) in cyclohexane to afford the title compound (620 mg, 81 %).

Intermediate 12.6: tert-butyl 3-methoxy-3-((3-methoxyphenyl)(4-nitro-1 H-pyrazol-1- yl)methyl)azetidine-1-carboxylate

[0376] tert-butyl 3-hydroxy-3-((3-methoxyphenyl)(4-nitro-1 H-pyrazol-1-yl)methyl)azetidine- 1-carboxylate (Intermediate 12.5) (200 mg, 0.494 mmol) was dissolved in THF (6 mL) and cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 18 mg, 0.742 mmol) and iodomethane (0.023 mL, 0.742 mmol) were added and the mixture was allowed to warm up to room temperature for 3.5 hours. The reaction mixture was partitioned between water and DCM, the organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with ethyl acetate (5-50%) in cyclohexane to afford the title compound as a colourless oil (160 mg, 77%), Ή NMR (400 MHz, CDC ) 5 8.15 (s, 1 H), 8.06 (s, 1 H), 7.31 (dd, J=8.0, 8.0 Hz, 1 H), 7.04 - 6.99 (m, 2H), 6.93 (dd, J=2.5, 8.3 Hz, 1 H), 5.68 (s, 1 H), 4.20 - 4.13 (m, 3H), 3.85 (d, J=10.7 Hz, 1 H), 3.81 (s, 3H), 3.50 (s, 3H), 1.43 (s, 9H). Intermediate 12.7: tert-butyl 3-((4-amino-1 H-pyrazol-1-yl)(3-methoxyphenyl)methyl)-3- methoxyazetidine-1-carboxylate

Intermediate 12 6 Intermediate 12 7

[0377] Tert-butyl 3-rnethoxy-3-((3-methoxyphenyl)(4-nitro-1 H-pyrazol-1-yl)methyl) azetidine-1-carboxylate (Intermediate 12.6) as a colourless oil (100 mg, 0.239 mmol) was dissolved in ethanol (2 mL) and water (0.5 ml_), then ammonium chloride (102 mg, 1.91 mmol) and iron (80 mg, 1.43 mmol) were added and the mixture was stirred at 50 °C for 1 hour. The mixture was then cooled down and filtered through a pad of Celite™, which was the washed with DCM. The filtrate was partitioned between water and DCM and the organics dried over magnesium sulfate and evaporated to dryness to yield tert-butyl 3-((4-amino-1 H-pyrazol-1- yl)(3-methoxyphenyl)methyl)-3-methoxyazetidine-1-carboxylate as an orange gum (90 mg, 97%) LCMS m/z 389 (ES ⁺ ).

Intermediate 12.8: tert-butyl 3-((4-amino-1 H-pyrazol-1-yl)(3-methoxyphenyl)methyl)-3- isobutoxyazetidine-1-carboxylate

[0378] Intermediate 12.8 was prepared according to the general synthesis route for the synthesis of Intermediate 12.7, using tert-butyl 3-hydroxy-3-((3-methoxyphenyl)(4-nitro-1 H- pyrazol-1-yl)methyl)azetidine-1-carboxylate (Intermediate 12.5) and isobutyl iodide (CAS 513-38-2) to give the title compound LCMS m/z 431 (ES ⁺ ).

BIOLOGICAL ASSAYS

SGK1/2/3 Biochemical selectivity assay procedure (TR-FRET assay)

Total reaction volume: 10 mI

Equipment/Consumables:

1. Envision plate reader

2. Electronic Cliptip Multichannel Pipettes (ThermoFisher) (125 mI-20 mI)

3. Manual Cliptip single channel pipettes (ThermoFisher) (2 - 1000 mI) 4. Perkin Elmer Optiplate 384 well

Reagents/Chemicals:

Buffer and Reagents Preparation (reagents scaled as required):

1. Assay Buffer was prepared in distilled water: 50 mM HEPES pH7.5, 2 mM DTT, 0.1 % Tween20, 1 mM EGTA, and 10 mM MgCb (SGK1/3) or 5 mM MgC (AK2).

2. 2X Enzyme solution was prepared in assay buffer: SGK7=0.7/y/W; 8ΰK2=0.05mM;

SGK3=0.05 M.

3. 2X combined CREBtide substrate/ATP solution was prepared in assay buffer:

(SGK2 CREBtide- 5mM stock diluted to 50nM= 1: 100 dilution, 30mI in 3000mI= 50nM)) (SGK1/3 CREBtide 5mM stock diluted to 20nM= 1:250 dilution 12mI in 3000m=20hM) (SGK1/2 ATP- 10mM Stock diluted to 35mM= 1:285.7 dilution, 2X solution in 3000mI =21mI)

(SGK3 ATP-10mM Stock diluted to 10mM= 1:1000 dilution, 2X solution in 3000mI =6mI)

4. 2X CREBtide Detection solution was prepared: 1X detection buffer (diluted in water) containing 4 nM Eu-anti-p-CREB and 12 mM EDTA

(Eu-anti-p-CREB- 625nM stock diluted to 4nM=1: 156.25 dilution, 32mI in 5000mI) (EDTA - 500 mM stock diluted to 12 mM = 1:41.66, 120 mI in 5000mI)

Procedure:

[0379] 5mI of enzyme solution was added per well, to all wells, using Electronic Cliptip Multichannel Pipettes. These were incubated in plate with pre-dispensed compounds for 15 minutes.

[0380] 5ul of Substrate/ ATP solution was added per well using Electronic Cliptip Multichannel Pipettes. The plate was spun down and incubated for 1 hour.

[0381] 10mI of CREBtide Detection solution was added to all wells and the plate was spun down. The plate was incubated for a further 1 hour.

[0382] The plate was read using predetermined TR-FRET 384 well protocol on Envision plate reader.

[0383] The results obtained using this assay protocol are shown in Table 1 above.

SGK1/2/3 Biochemical selectivity assay procedure (Radiometric assay)

Reagents Preparation

[0384] The activity was determined using SGK1/2/3 kinases. IC50 values were measured by testing 10 semi-log concentrations of each compound in the range from 5 x 10 ⁰⁵ M to 1.5 x 10- ⁰⁹ M, in duplicate. The compounds were provided as 100 pi of a 5 x 10 ⁰³ M/100% DMSO stock solution. Prior to testing, the 5 x 10 ^-03 M stock solutions were subjected to a serial, semi- logarithmic dilution using 100 % DMSO as a solvent. This resulted in 10 distinct concentrations, with a dilution endpoint of 1.5 x 10 ⁰⁷ M/100 % DMSO in column 12. Column 1 and 7 were filled with 100 % DMSO as controls. Subsequently, 4 x 10 mI from each well of the serial diluted copy plates were aliquoted with a 96 channel pipettor into four identical sets of compound dilution plates. In the process, 90 mI H ₂ 0 were added to each well of two sets of compound dilution plates. To minimize potential precipitation, the H2O was added to each plate only a few minutes before the transfer of the compound solutions into the assay plates. The plates were shaken thoroughly, resulting in compound dilution plates/ 10 % DMSO.

[0385] For the kinase inhibition assays, 5 mI solution from each well of the compound dilution plates/10 % DMSO were transferred into the assay plates. The final volume of the assay was 50 mI. All compounds were tested at 10 final assay concentrations in the range from 5 x 10 ⁰⁵ M to 1.5 x 10" M, in duplicate. The final DMSO concentration in the reaction cocktails was 1 % in all cases.

Recombinant Protein Kinases:

[0386] Human SGK1 , full length, amino acids M1-L431 (as in NCBI/Protein entry NP_005618.2), activated, N-terminal GST fusion protein, and Human SGK3, full length, amino acids M 1-L496 (as in NCBI/Protein entry NP_037389.4), activated, N-terminal GST-fusion protein were expressed in Sf9 insect cells as recombinant GST-fusion proteins and purified by GSH-affinity chromatography. The purity of the protein kinases was examined by SDS- PAGE/Coomassie staining, the identity was checked by mass spectroscopy. Human SGK2, kinase domain, active, was purchased from Life Technologies (Invitrogen Corporation, I N V_34433) .

Reagents/Chemicals:

[0387] The assay for all protein kinases contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCL, 3 mM MnCL, 3 mM Na-orthovanadate, 1.2 mM DTT, 50 pg/ml PEG20000, ATP (variable concentrations, corresponding to the apparent ATP- Km of the respective kinase, se, [y- ³³ P]-ATP (approx. 6.3 x 1006 cpm per well), protein kinase, and substrate.

[0388] The following amounts of enzyme and substrate were used per well:

Procedure:

[0389] A radiometric protein kinase assay (33PanQinase® Activity Assay) was used for measuring the activity of SGK1/2/3 protein kinases. All kinase assays were performed in 96- well FlashPlatesTM from PerkinElmer (Boston, MA, USA) in a 50 mI reaction volume. The reaction cocktail was pipetted in four steps in the following order:

1. 25 mI of assay buffer (standard buffer/[y- ³³ P]-ATP)

2. 10 mI of ATP solution (in H ₂ 0)

3. 5 mI of test compound (in 10 % DMSO)

4. 10 mI of enzyme/substrate mixture

[0390] The reaction cocktails were incubated at 30°C for 60 minutes. The reaction was stopped with 50 mI of 2 % (v/v) H ₃ PO ₄ , plates were aspirated and washed two times with 200 mI 0.9 % (w/v) NaCI. Incorporation of ³³ Pi was determined with a microplate scintillation counter (Microbeta, Wallac).

[0391] The median value of the counts in column 1 (n=8) of each assay plate was defined as "low control". This value reflects unspecific binding of radioactivity to the plate in the absence of a protein kinase but in the presence of the substrate. The median value of the counts in column 7 of each assay plate (n=8) was taken as the "high control", i.e. full activity in the absence of any inhibitor. The difference between high and low control was taken as 100 % activity.

[0392] As part of the data evaluation the low control value from a particular plate was subtracted from the high control value as well as from all 80 "compound values" of the corresponding plate. The residual activity (in %) for each well of a particular plate was calculated by using the following formula:

Residual Activity (%) = 100 X [(cpm of compound - low control) / (high control - low control)]

[0393] The residual activities for each concentration and the compound IC ₅₀ values were calculated using Quattro Workflow V3.1.1 (Quattro Research GmbH, Munich, Germany; www.quattro-research.com). The fitting model for the IC ₅₀ determinations was "Sigmoidal response (variable slope)" with parameters "top" fixed at 100 % and "bottom" at 0 %. The fitting method used was a least-squares fit.

[0394] The results obtained using this assay protocol are shown in Table 2 above.

[0395] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.

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