PAK1 and / or PAK2 activators and their use in the prevention and / or treatment of diseases or conditions

Abstract

The present invention provides small molecule PAK1 (P21 Activated Kinase 1) and / or PAK2 (P21 Activated Kinase 2) activators and their use in the prevention and / or treatment of diseases or conditions responsive to PAK1 and / or PAK2 activity or diseases or conditions associated with PAK1 and / or PAK2 inactivity, e.g. cardiovascular diseases or conditions, including cardiac fibrosis, cardiac hypertrophy, cardiac arrhythmias, heart failure and ischaemia / reperfusion injury.

Description

[0001] - 1 - 153140 / 02 – PCT Spec PAK1 AND / OR PAK2 ACTIVATORS AND THEIR USE IN THE PREVENTION AND / OR TREATMENT OF DISEASES OR CONDITIONS 5 FIELD OF THE INVENTION The present invention relates to small molecule PAK1 (P21 Activated Kinase 1) and / or PAK2 (P21 Activated Kinase 2) activators and their use in the prevention and / or treatment of diseases or conditions responsive to PAK1 and / or PAK2 activity 10 or diseases or conditions associated with PAK1 and / or PAK2 inactivity, e.g. cardiovascular diseases or conditions, including cardiac fibrosis, cardiac hypertrophy, cardiac arrhythmias, heart failure and ischaemia / reperfusion injury. BACKGROUND OF THE INVENTION 15 Cardiovascular diseases (CVD) are the leading cause of death globally. Together they resulted in 17.3 million deaths (31.5%) in 2013, up from 12.3 million (25.8%) in 1990. Deaths from CVD at a given age are more common and have been increasing in much of the developed world. In the United Kingdom in particular, more than seven million people are living with cardiovascular complications, and 20 CVD is estimated to contribute 27% of all death causes in the UK. The increasing life expectancy and growing population aggravates concerns for a higher incidence of CVD. This has been estimated to cost the NHS £11 billion each year. Efforts at decreasing the alarming rates of CVD death are proven to be outdated 25 with limited primary therapeutic treatments available for cardiac hypertrophy, heart failure, arrhythmia and ischaemia / reperfusion injury. Current therapeutic approaches consist mainly of prescribing blood pressure-lowering medications, lowering cholesterols and preventing blood clots. In addition, most of these drugs are usually given when the present symptoms are already at an irreversible state 30 and can only facilitate management of the symptoms. Finding a treatment that can provide both therapeutic and prophylactic measurements would be highly beneficial in improving the current strategy of cardiovascular disease treatments. Recent experimental evidence suggests that P21 activated kinase 1 (PAK1), a 35 member of the serine / threonine protein kinase family, is critical for maintaining - 2 - cellular homeostasis and metabolism within the heart, thereby enhancing the adaptability of cardiomyocytes to stress. PAK1 is highly expressed in the heart, including in the cardiac conduction system (e.g. the sino-atrial node, SAN) and the atrial and ventricular tissues. Functional studies of PAK1 in the heart have signified its essential roles in regulating cardiac electrical functions and muscle contractility and providing cardio-protective mechanisms. Increased PAK1 activity in the heart has also been found to show a reduction in chronic β-adrenergic stimulation and normalised increased heart rate and Ca2+channel activity. These protective mechanisms of PAK1 indicate its special importance for the prevention of hypoxic and ischemic injuries, which are leading causes of hypertrophy and associated arrhythmias. When the heart is stressed – induced either by stress mediators, tyrosine kinase activation, or GPCR (β-adrenergic) stimulation – secondary messengers activate intermediate mediators such as RAS and RAC / CDC42 enzymes, which are the main modulators for PAK1 activity. Activated PAK1 is then able to activate downstream enzymes in maintaining homeostatic functions in the heart. PP2A, AKT, MKK7, and JNK are some examples of enzymes that are activated by PAK1 and have been shown to provide cardio-protective mechanisms. Recent new studies have also implicated PAK2, the class isoform of PAK1, in the cellular regulation of cardiac homeostasis. It confers cardio-protection and is essential for ion channel activity, intracellular Ca2+handling, and cardiac contractility. PAK2 is mostly localized near endoplasmic reticulum (ER) and mitochondria. It may regulate the cardioprotective IRE(inositol-requiring enzyme)1 / XBP(X-box–binding protein)1-dependent unfolded protein response (UPR). Mice with cardiac-specific PAK2 deletion showed defective ER stress responses, cardiac dysfunction, and profound cardiomyocyte death under conditions of tunicamycin-induced ER stress or pressure overload. Their gene array analysis then implicated the IRE1 / XBP1-dependent pathway in this PAK2-mediated regulation of protective and appropriate ER stress responses. Contrastingly, inducing PAK2 activation through genetic overexpression or viral gene delivery improved ER function and cardiac performance. It reduced apoptosis and protected from heart failure. These findings implicate PAK2-mediated modulation of ER stress as cardioprotective in cardiac hypertrophy. - 3 - In PAK1, there are N-terminal regulatory domain residues, an autoinhibitory domain (AID, aa 67–150) that governs kinase activity, and a kinase domain (KD, aa 249– 545). PAK1 activity is mainly regulated by the inhibitory formation of a resting homodimer in which the kinase domains are blocked by the trans-inhibitory switch through the interaction of its auto-inhibitory (AI) domains. The X-ray crystallography structure of PAK1 in an auto-inhibited conformation confirms that PAK1 exists as a homodimer in which the N-terminal regulatory domain of PAK1 monomer binds and inhibits the C-terminal catalytic domain of the other. When bound to the small GTPases Cdc42 and Rac1, PAK1 undergoes dimer dissociation and forms a monomeric conformation, exposing the kinase domain for activation through autophosphorylation at Thr423 on the activation loop. Activated PAK1 is then able to activate enzymes essential in maintaining homeostatic functions in the heart. Upon resting state, the PAK1 monomers return to form homodimers through dimerization at the AI domain. PAK2 is regulated analogously. PAK1 activation has been investigated as a therapeutic modality in the treatment of cardiovascular diseases and conditions, in particular those associated with cardiac hypertrophy, cardiac fibrosis, arrhythmia, heart failure and ischaemia and reperfusion injury (see, for example, Wang, Y., et al., 2018, The p21-activated kinase 1 (Pak1) signalling pathway in cardiac disease: from mechanistic study to therapeutic exploration, British Journal of Pharmacology (2018) 1751362–1374). To this end, WO 2010 / 017478 describes sphingolipid molecules that are able to indirectly activate the PAK1 pathway through G-protein coupled receptions (S1P1- 3). Studies have shown that sphingolipid analogue FTY-720, an immunomodulating drug for multiple sclerosis, was able to prevent pressure-induced hypertrophy and provided a protective mechanism against ischemia / reperfusion injuries. Wang et al. (Inhibition of Angiotensin II-Induced Cardiac Hypertrophy and Associated Ventricular Arrhythmias by a p21 Activated Kinase 1 Bioactive Peptide. PLoS ONE 9(7): (2014) e101974. doi:10.1371 / journal.pone.0101974) outlines a further investigation into PAK1 as a therapeutic target in the heart, using a bioactive - 4 - peptide (PAK1-activiating Peptide, PAP) to directly activate PAK1 and to confirm its beneficial effect. Similar to indirect activation of PAK1 by sphingolipid molecules, direct activation of PAK1 through the peptide counteracted pathological hypertrophy and associated ventricular arrhythmias in in vitro models. Studies of PAPs showed 5 that PAPs interact with PAK1 and increase its phosphorylation more than two-fold. Such PAP-induced PAK1 activation is associated with a significant reduction of Angiotensin II-induced hypertrophy in NRVMs and C57BL / 6 mice, in vitro and ex vivo, respectively. Furthermore, PAP antagonizes ventricular arrhythmias associated with Ang II-induced hypertrophy in mice. Its antiarrhythmic effect is likely 10 to be involved in multiple mechanisms to affect both substrate and trigger of ventricular arrhythmogenesis. Although peptide therapies such as PAP can be highly selective and efficacious, they make poor drug candidates as they have low bioavailability. Peptide drugs 15 usually have a short circulating plasma half-life, are easily hydrolysed and oxidized, and have a low degree of membrane permeability. Most importantly, peptide drugs are delivered through infusion, rather than orally. This makes peptides poor drug candidates for therapeutic compliance. Similar problems exist with the sphingolipid molecules mentioned above. 20 Small molecule PAK1 activators would be less susceptible to such problems and so there exists a need for small molecule PAK1 activators for the treatment of diseases or conditions responsive to PAK1 activity or diseases or conditions associated with PAK1 inactivity, e.g. cardiovascular diseases and conditions 25 including cardiac hypertrophy, cardiac fibrosis, cardiac arrhythmias, heart failure and ischaemia / reperfusion injury. Although PAK2 activation has not yet been investigated in any depth as a therapeutic modality in the treatment of cardiovascular diseases and conditions, in 30 particular those associated with cardiac hypertrophy, cardiac fibrosis, arrhythmia, heart failure and ischaemia and reperfusion injury, its proven cardioprotective effects suggests that its activation could have therapeutic efficacy in such areas, and as such there exists a need for small molecule PAK2 activators. - 5 - The present inventors have surprisingly identified an allosteric regulatory site at the interface between the AID and KD of PAK1 that controls autoinhibition of PAK1 activity, and determined that, by interfering with that site, conformational changes can be induced which displace the AID and expose the autophosphorylation site 5 and the ATP binding site. Such changes facilitate PAK1 activation. The inventors have further elucidated key amino acid residues in this allosteric regulatory site and families of small molecules which interact with the allosteric regulatory site, and these key amino acids specifically, have been identified and confirmed as PAK 1 activators. The invention is, inter alia, directed to those compounds and their use in 10 therapy, in particular their use in therapies for diseases or conditions responsive to PAK1 activity or diseases or conditions associated with PAK1 inactivity. The compounds described below, for example compounds of any one of Formulas (I), (IA), (1B), (IC), (ID) (II), (IIA), (III), (IV), (IVA) and those listed in Table 1 below, 15 and stereoisomers, tautomers and pharmaceutically acceptable salts thereof, have been identified as small molecule activators of PAK1. Some or all of the compounds described below, e.g. the compounds of Formula III, stereoisomers, tautomers and pharmaceutically acceptable salts thereof, may also 20 or alternatively be small molecule activators of PAK2. Thus, the present invention provides the compounds of Formulas (I), (IA), (1B), (IC), (ID), (II), (IIA), (III), (IV), (IVA) and those listed in Table 1, stereoisomers, tautomers and pharmaceutically acceptable salts thereof, for use in the treatment or 25 prevention of a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity. Formula (I) In some embodiments, the compounds according to the present disclosure are 30 those of Formula (I), or their stereoisomers, tautomers, and pharmaceutically acceptable salts: , - 6 - where: A is: D is 5 where x is an integer from 0-4, e.g.0 or 1, especially 0, e.g. L3is -N(R4)-, especially -N(H)-, 10 or , , 15 where R9is an optionally substituted phenyl group, and N-substituted thiazolidene; L1, L2, L4and L5are linking groups, independently selected from: a bond, and 20 -(CH2)n- in which n is an integer from 1 to 6, preferably 1-4, e.g.1 or 2; R1and R2are independently selected from aryl groups, - 7 - R3, R4and R6are independently selected from: 5 - H, - alkyl, e.g. C1-4 alkyl, preferably –CH3, - -(CH2)y-OH in which where y is an integer from 0 to 6, preferably 1-4, especially 1, and - -CN; 10 and R5is a five- or six-membered heterocyclic ring. 15 In some embodiments, R1and R2are independently aryl groups, optionally substituted by one or more substituents. In some embodiments, R1is an aryl group, optionally substituted by one or more substituents, and R2is: 20 . In some embodiments, R1is an aryl group, optionally substituted by one or more substituents, and R2is: - 8 - the benzene ring is optionally substituted by a substituent as herein described, preferably by a C1-6alkyl group at any position, preferably R2is: . In some embodiments, R5is selected from: In some embodiments, R4is H or CH3. In some embodiments, R6is H. is and L3is a bond or - 9 - where x is an integer from 0-4, e.g.0 or 1, especially 0, e.g. L3is -N(R4)-, especially -N(H)-. Formula (IA) 5 In some embodiments, the compounds according to the present disclosure are those of Formula (IA), or their stereoisomers, tautomers, and pharmaceutically acceptable salts: where: 10 A, R2, R3, R4, R6, L2and L5are as herein defined. In some embodiments, e.g. of (I) or (IA), A is R1-L1-R5–R4-. Formula (IB) 15 In some embodiments, the compounds according to the present disclosure are those of Formula (IB), or their stereoisomers, tautomers, and pharmaceutically acceptable salts: where: 20 R1, R2, R3, R4, R5, R6, L1, L2, L4and L5are as herein defined. In some embodiments, R5is furyl. Formula (IC) 25 In some embodiments, the compounds according to the present disclosure are those of Formula (IC), or their stereoisomers, tautomers, or pharmaceutically acceptable salts: - 10 - where: R1, R2, R3, R4, R6, L1, L2, L4and L5are as herein defined. 5 Formula In some embodiments, the compounds according to the present disclosure are those of Formula (II), or their stereoisomers, tautomers, and pharmaceutically acceptable salts: 10 where R1, R2, R5, L2, L3and L7are as herein defined, especially where: L3is a bond or 15 where x is an integer from 0-4, e.g.0 or 1, especially 0, e.g. L3is -N(R4)-, especially -N(H)-; L2is a linking group selected from: a bond, and 20 -(CH2)n-, in which n is an integer from 1 to 6, preferably 1-4, e.g.1 or 2; R1and R2are independently selected from aryl groups and - 11 - , optionally substituted by one or more substituents; L7is selected from a bond, -(C3H4)-, -(CH2)x-, and -(CH2)x-C(R3)=C(R4)-(CH2)x-, 5 where each x is independently an integer from 0-4, e.g.0 or 1, especially 0, and R3and R4are as herein defined, or wherein: R3and R4are independently selected from: - H, 10 - alkyl, e.g. C1-4alkyl, preferably –CH3, - -(CH2)yOH where y is an integer from 0 to 6, preferably 1-4, especially 1, and - -CN; and 15 R5comprises a heterocyclic ring. In some embodiments, R3and R4are independently selected from -H, -CH3and - CN. 20 In some embodiments, each R4is independently H or CH3. In some embodiments, e.g. of Formula (II), L3is where x is an integer from 0-4, e.g.0 or 1, especially 0, e.g. L3is -N(R4)-, 25 especially -N(H)-. In some embodiments, e.g. of Formula (II), L2is a bond or -(CH2)n- in which n is 1 or 2. - 12 - In some embodiments, e.g. of Formula (II), R5is selected from: 5 In some embodiments, R5is a five- or six-membered heterocyclic ring, e.g. furyl. In particularly preferred embodiments, e.g. of Formula (II), R5is: isomer thereof. 10 In some embodiments, R1and R2are independently aryl groups, optionally substituted by one or more substituents. In some embodiments, R1is an aryl group, optionally substituted by one or more substituents, and R2is: 15 . In some embodiments, R1is an aryl group, optionally substituted by one or more substituents, and R2is: the benzene ring is optionally substituted by a substituent as 20 herein described, preferably by a C1-6alkyl group at any position, preferably R2is: - 13 - . In some embodiments, e.g. of Formula (II), R1and R2are independently aryl groups, optionally substituted by one or more substituents. For example, R1and / or 5 R2may be substituted phenyl groups. In some embodiments, R1and / or R2may be phenyl groups, substituted, e.g. at the meta position, by -SO2CH3, Cl, or -COOH. In some embodiments, R1and / or R2are independently selected from: 10 In some embodiments, e.g. of Formula (II), R1and / or R2are independently selected from: 15 In some embodiments, e.g. of Formula (II), R1and / or R2is a pyridyl group, e.g.3- pyridyl. Formula (III) 20 In some embodiments, the compounds according to the present disclosure are those of Formula (III), or their stereoisomers, tautomers, or pharmaceutically acceptable salts: - 14 - where: R4is as defined herein, preferably H, and E and G are independently aryl groups, optionally substituted by one or more substituents. In some embodiments, the substituents of E and / or G are independently selected from: - -CO2CxH2x+1, where x is an integer, preferably 0-4, 0-1 or 0, e.g. –COOH, - CO2CH3, or -CO2tBu, especially –COOH; - nitro; (-N+(=O)OH or -NO2); - -OH; - alkyl, preferably C1-4 alkyl (preferably -CH3); - -SO2N(H)CxH2x+1 where x is an integer, preferably 0-4, 0-1 or 0, e.g. -SO2NH2, - SO2NHCH3; - -N(H)C(=O)R7, where R7is an alkyl group, e.g. a C1-6 alkyl, or an aryl group, optionally substituted, e.g. by –OR8, where R8is H or alkyl, preferably H or C1-4 alkyl (e.g. –C2H5) In some embodiments, R7is a phenyl group. In some embodiments, E and G are independently selected from R1and R2as defined herein. In some embodiments, E is optionally substituted phenyl or where R8is H or alkyl, preferably H or C1-4alkyl. In some embodiments, E is optionally substituted phenyl or . 30 - 15 - In some embodiments, G is optionally substituted pyrimidyl and E is 5 . In some embodiments, G is optionally substituted phenyl or G is optionally substituted pyrimidyl, e.g. isomer thereof. 10 In some embodiments, G is dimethyl pyrimidyl, e.g. isomer thereof. In some embodiments of the compounds of Formula (III), the substituents are as described herein, most preferably, -CH3, -SO2NH2, -OH, nitro (-N+(=O)OH or -NO2). 15 Examples of compounds of formula (III) include: (JB2019A) - 16 - (JB2019B) Formula (IV) 5 In some embodiments, the compounds according to the present disclosure are those of Formula (IV), or their stereoisomers, tautomers, or pharmaceutically acceptable salts: 10 wherein Ar1and Ar2are phenyl groups, optionally and independently substituted with one or more of the following: - nitro / nitroso (-N+(=O)OH or -NO2); - halogen (e.g. F, Cl) - -SO2CH3; 15 - -OH; - -CF3- -CH3 - -COOH or - a heteroaryl group, e.g. tetrazole. - 17 - In some embodiments of Formula (IV), Ar1and Ar2are substituted at the meta and / or para positions, preferably at least meta. In some embodiments, Ar1and Ar2are substituted with one or more of Me, COOH and tetrazole. 5 In some embodiments, the compound of Formula (IV) is: wherein Z is any of the substituents herein described, or a heteroaryl group. 10 In some embodiments, Z is: - nitro / nitroso (-N+(=O)OH or -NO2); - Cl - -SO2CH3; - -OH; 15 - -CF3 - -CH3 - -COOH or - a heteroaryl group 20 Examples of heteroaryl groups include thiophenyl, thienyl, pyridyl, thiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzooxazolyl, - 18 - benzofuryl, indolyl, isoindolyl, pyridonyl, pyridazinyl, pyrimidinyl, imidazopyridyl, oxazopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl. 5 In some embodiments, Z is COOH or tetrazol. In some embodiments, the compound of Formula (IV) is 10 (PAK1-A1). In the structures herein, this symbol: 15 denotes the point of attachment to the rest of the molecule. In some embodiments, R1and / or R2is an unsubstituted aryl group, e.g. a phenyl or pyridyl group. 20 - 19 - In some embodiments of the compounds herein described, R1and R2are independently selected from the following groups and isomers thereof, optionally substituted by one or more substituents: In some embodiments, at least one of R1and R2is substituted. In some embodiments, R1and / or R2is a substituted aryl group, e.g. a substituted phenyl or a substituted pyridyl group. In some embodiments R1is a pyridyl group, or an optionally substituted phenyl group. In some embodiments, R2is an optionally substituted phenyl group. In some embodiments R1and / or R2is substituted by one, two or three substituents, preferably one or two, especially preferably one. In some embodiments, R1and / or R2is meta or para substituted, preferably meta substituted. Substituents Substituents mentioned with regard to any of the compounds disclosed herein are discussed further below. In some embodiments, substituents, e.g. on aryl groups (e.g. R1and / or R2), where present, are electron withdrawing groups (EWG). Such groups would be apparent to the person skilled in the art and include: - COCl, COOR, CONH2, trihalides such as -CCl3 and -CF3, -CN, -SO3H, -NH3+, NR3+, and nitro groups (i.e. -N+(=O)OH or - - 20 - NO2). Especially preferred are -COOH, trihalides (especially –CF3), and nitro groups. In some embodiments, substituents as herein described are selected from: - -CO2CxH2x+1, where x is an integer, preferably 0-4, 0-1 or 0, e.g. –COOH, - CO2CH3, -CO2Bu or -CO2tBu, especially –COOH; - nitro (-N+(=O)OH or -NO2); - halogen (e.g. F, Cl or Br, preferably Cl); - -SO2CxH2x+1, where x is an integer, preferably 0-4,0-1 or 0, e.g. -SO2CH3; - -OH; - haloalkyl, preferably C1-3 haloalkyl (e.g. -CF3); - a diazirine group, e.g. diazirine, methyl diazirine, trifluoromethyl diazirine - alkyl, preferably C1-4 alkyl (preferably -CH3); - -CON(H)CxH2x+1, where x is an integer, preferably 0-4, 0-1, or 0, e.g. CONH2, or -CONHCH3; - -SO2N(H)CxH2x+1 where x is an integer, preferably 0-4, 0-1, or 0, e.g. -SO2NH2, -SO2NHCH3; - -NHSO2CH3; - phenyl, optionally substituted by C1-4 alkyl, e.g. -Ph-CH3; - pyridyl, e.g.3-pyridyl, optionally substituted by C1-4 alkyl; - alkoxy, e.g. C1-4 alkoxy (e.g. -OCH3); - a heterocyclic ring - -N+OCxH2x+1, where x is an integer, preferably 0-4, 0-1 or 0, e.g. N+OCH3. In some embodiments, substituents include: - -CO2CxH2x+1, where x is an integer, preferably 0-4, 0-1, or 0, e.g. –COOH, - CO2CH3, or -CO2tBu, especially -COOH; - nitro (-N+(=O)OH or -NO2); - halogen (e.g. F, Cl or Br, preferably Cl); - -SO2CxH2x+1, where x is an integer, preferably 0-4, 0-1, or 0, e.g. -SO2CH3; - -OH; - haloalkyl, preferably C1-3haloalkyl (e.g. -CF3); - a diazirine group, e.g. diazirine, methyl diazirine, trifluoromethyl diazirine; - alkyl, preferably C1-4alkyl (preferably -CH3). - 21 - Diazirine groups, e.g. diazirine, methyl diazirine, trifluoromethyl diazirine may be used as labelled functional groups, e.g. in PAL-MS studies. In some embodiments, substituents, e.g. in compounds of Formula (I) or (II), include: - -COOH - nitro (-N+(=O)OH or -NO2) - -Cl - -SO2CH3- -OH. In some embodiments, substituents, e.g. in compounds of Formula (I) or (II), e.g. (IC), are selected from: - -COOH - nitro (-N+(=O)OH or -NO2) - -SO2CH3 - -OH. In some embodiments, any substituents on R1are selected from: - -CO2CxH2x+1, where x is an integer, preferably 0-4, 0-1, or 0, e.g. –COOH, - CO2CH3, or -CO2tBu, especially –COOH; - Nitro (-N+(=O)OH or -NO2); - halogen (e.g. F, Cl or Br, preferably Cl); - -SO2CxH2x+1, where x is an integer, preferably 0-4, 0-1, or 0, e.g. -SO2CH3; - alkyl, preferably C1-4 alkyl (preferably -CH3). In some embodiments, any substituents on R2are selected from: - -CO2CxH2x+1, where x is an integer, preferably 0-4, 0-1, or 0, e.g. –COOH, - CO2CH3, or -CO2tBu, especially –COOH; - nitro (-N+(=O)OH or -NO2); - halogen (e.g. F, Cl or Br, preferably Cl); - -OH; - haloalkyl, preferably C1-3haloalkyl (e.g. -CF3); - a diazirine group, e.g. diazinrine, methyl diazirine, trifluoromethyl diazirine - a heterocyclic ring. - 22 - In some embodiments, R1is a phenyl group, unsubstituted, or substituted by one or more of the following: - nitro (-N+(=O)OH or -NO2), i.e. R1is a nitrophenyl group, optionally with the substituent at the meta position; - -SO2CH3,e.g. at the meta position; - -CF3, e.g. at the meta position; - -OH, e.g. at the meta position; - -SO2NH2, e.g. at the meta position; - pyridyl, e.g. at the meta position; - halogen (e.g. -Cl), e.g. at the meta position; - -NHSO2CH3, e.g. at the meta position; - -COOR, e.g. at the meta position, e.g. where R = H, methyl, ethyl, propyl or butyl; - -COCl, e.g. at the meta position; - -CN, e.g. at the meta position; - C1-3 alkyl, e.g. at the ortho and / or para position. In some embodiments, R2is a phenyl group, unsubstituted, or substituted by one or more of the following: - nitro (-N+(=O)OH or -NO2), i.e. R2is a nitrophenyl group, optionally with the substituent at the meta position; - -CF3, e.g. at the meta position; - pyridyl, e.g. at the meta position; - Halogen (e.g. -Cl), e.g. at the meta position; - -COOH, e.g. at the meta position. In some embodiments, especially where R5is thiophenyl and D is N-substituted thiazolidene, the substituent (e.g. on the N atom of the thiazolidene) is selected from: - -(CH2)yCOOH where y is an integer from 0-6, e.g.1-4 or 1; - an optionally substituted phenyl group, e.g. phenyl substituted by: -CO2CxH2x+1, where x is an integer, preferably 0-4, 0-1, or 0; nitro (-N+(=O)OH or -NO2); - 23 - halogen (e.g. F, Cl or Br, preferably Cl); -OH; haloalkyl, preferably C1-3haloalkyl (e.g. -CF3). 5 All references to nitro groups are intended to encompass both of the following: Similarly, a reference to -N+(=O)OH or N+O2H may be replaced by -NO2 and vice versa. 10 References herein to -N+(=O)OH, N+O2H or -NO2(nitro) may be replaced by -N=O (nitroso). In some embodiments, R1and R2are not substituted by a halogen. 15 R5is a five- or six-membered heterocyclic ring, especially a five- or six-membered heteroaromatic ring. In some embodiments, R5is selected from: 20 R5is a divalent ring, and may be attached to the remainder of the compound at positions other than those depicted herein. 25 In some embodiments, R5is a divalent ring selected from the following: thiazolidene, thiophenyl, pyridyl, thiazolyl, furyl and (N-methyl)imidazolyl. - 24 - In some embodiments, R5is selected from: . R5may be substituted by one or more of the substituents mentioned herein, 5 although R5may be unsubstituted. In some embodiments, L1and L2are independently -CH2- or a bond, preferably a bond. 10 In some embodiments, R1and R2are independently optionally substituted pyridyl or phenyl. In some embodiments, R1and R2are independently pyridyl, or an optionally substituted phenyl group. 15 In some embodiments, R1and R2are an optionally substituted phenyl group. In some embodiments, said aryl group is pyridyl or phenyl, preferably phenyl. 20 In some embodiments, R3is H or CN, especially CN. In some embodiments, R3is H or CH3. In some embodiments, R4is H or alkyl, preferably H or C1-4 alkyl (e.g. –CH3). 25 In some embodiments, R6is H or alkyl, preferably H or C1-4alkyl (e.g. –CH3), especially preferably H. In some embodiments, R1is a phenyl group substituted by one or more substituents 30 selected from: -NO2, -SO2CH3, Cl, especially -NO2. - 25 - In some embodiments, R2is a phenyl group substituted by -CO2CxH2x+1, where x is an integer, preferably 0-4, 0-1, or 0, e.g. –COOH, -CO2CH3, or -CO2tBu, especially –COOH. 5 In some embodiments, D is 10 and D is selected from: , , where R9is an optionally substituted phenyl group, and N-substituted thiazolidene. 15 In some embodiments, R9is a phenyl group substituted by one or more substituents selected from: - -CO2CxH2x+1, where x is an integer, preferably 0-4, 0-1, or 0, e.g. –COOH, - CO2CH3, or -CO2tBu, especially –COOH; 20 In some embodiments, D is selected from: - 26 - .In some embodiments, A is R1-L1-R5-L4, where R5is thiophenyl, and D is selected from: 5 In some embodiments, A is R1-L1-R5-L4-. In some embodiments, R5 is furyl. 10 In some embodiments, L1is a bond, L4is a bond, L5is a bond, and / or R6is H. In some embodiments, particularly of the compounds of Formula (IC): L1is a bond; 15 - L2is a bond, or CH2; - R1is pyridyl, or an optionally substituted phenyl group (e.g. pyridyl, phenyl, -Ph- OH, –Ph-NO2, or -Ph-SO2CH3, especially preferably, pyridyl, phenyl, Ph-NO2, or -Ph-SO2CH3); - R2is an optionally substituted phenyl group (e.g. phenyl, -Ph-OH, –Ph-NO2, or - 20 Ph-SO2CH3, especially preferably, phenyl, -Ph-OH, or –Ph-NO2); - R3is selected from H, CN and -CH3; and - R4is H. - 27 - In some embodiments, particularly of the compounds of Formula (IC),: L1is a bond; - L2is a bond, or CH2; - R1is pyridyl, or a phenyl group which is substituted with a nitro group (- 5 N+(=O)OH or -NO2) and / or a methanesulphonyl group (-SO2CH3); - R2is a phenyl group, optionally substituted with -OH or -COOH. - R3is selected from H, CN and -CH3; and - R4is H. 10 Examples of compounds in accordance with the invention include, but are not limited to, the following listed in Table 1, their stereoisomers, their tautomers and their pharmaceutically acceptable salts: Table 1 15 - 28 - - 29 - - 30 - - 31 - - 32 - - 33 - - 34 - - 35 - - 36 - - 37 - Particularly preferred compounds are JB29, JB79, JB120, JB124, JB131, JB2019A, JB2019B, PAK1-A1, PAK1-A2 and PAK1-A3. 5 Some or all of the compounds herein described may be activators of PAK1. Some or all of the compounds herein described may be activators of PAK2. Some or all of the compounds herein described may be activators of PAK1 and 10 PAK2. Without wishing to be bound by theory, these compounds, i.e. those of Formulas (I), (IA), (1B), (IC), (ID), (II), (IIA), (III), (IV), (IVA) and listed in Table 1, and stereoisomers, tautomers and pharmaceutically acceptable salts thereof, are 15 believed to act via one or more of the mechanism(s) described herein. Certain compounds described herein are novel and these form a further aspect of the invention. Thus, in a further aspect, the present invention provides compounds - 38 - of Formulas (I) (IA), (1B), (IC), (ID), (II), (IIA), (III), (IV), (IVA) and those listed in Table 1, their stereoisomers, their tautomers, and pharmaceutically acceptable salts thereof. 5 In some embodiments, the compounds of the invention include, but are not limited to, compounds JB64, JB65, JB70, JB73, JB85, JB88, JB92, JB99, JB104, JB105, JB108, JB113, JB114, JB117, JB120, JB121, JB122 JB124, JB125, JB127, JB128, JB131, JB133 and JB29, their stereoisomers, tautomers and pharmaceutically acceptable salts thereof. 10 In a further aspect, the present invention provides compounds of Formula (ID), stereoisomers, tautomers, and pharmaceutically acceptable salts thereof: where: 15 - R1is as defined herein, preferably a pyridyl group, or a phenyl group substituted by NO2or SO2CH3; - R3is as defined herein, preferably, H, CH3or CN; - L2is as defined herein, preferably a bond or -CH2-; and - R10is H or a substituent as defined herein, preferably H, COOH or OH. 20 The compounds of Formula (ID), stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, form part of the compounds of the invention and therefore are also provided for the uses and compositions, and other aspects of the invention as described herein. 25 In a further aspect, the present invention provides compounds of Formula (IIA), stereoisomers, tautomers, and pharmaceutically acceptable salts thereof: - 39 - In some embodiments, the compounds according to the present disclosure are those of Formula (IIA), their stereoisomers, tautomers, and pharmaceutically acceptable salts: 5 where: R1, R2, R5, L2, and L7are as herein defined. Preferably, L7is selected from a bond, - (C3H4)- and -C(R3)=C(R4)-, where R3and R4are as herein defined, especially wherein R3and R4are independently selected from -H, -CH3 and -CN. 10 In some embodiments of Formula (IIA), R5is: . In some embodiments of Formula (IIA), R1and R2are independently aryl groups, optionally substituted by one or more substituents; or 15 or R1is an aryl group, optionally substituted by one or more substituents, and R2is: In some embodiments, e.g. of Formula (IIA), R1and R2are independently aryl 20 groups, optionally substituted by one or more substituents. For example, R1and / or R2may be substituted phenyl groups. In some embodiments, R1and / or R2may be phenyl groups, substituted, e.g. at the meta position, by -SO2CH3, Cl, or -COOH. In some embodiments, e.g. of Formula (IIA), R1and / or R2is a pyridyl group, e.g.3- 25 pyridyl. - 40 - The compounds of Formula (IIA), stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, form part of the compounds of the invention and therefore are also provided for the uses and compositions, and other aspects of the invention as described herein. 5 In preferred embodiments, the compound of the invention (or stereoisomer, tautomer or pharmaceutically acceptable salt thereof) is an activator of PAK1. Without wishing to be bound by theory, the compounds described herein are 10 believed to act via one or more of the mechanism(s) described herein. The term “alkyl” as used herein refers to a monovalent saturated, linear or branched, carbon chain. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 15 iso-pentyl, neo-pentyl, n-hexyl, etc. An alkyl group preferably contains from 1 to 6 carbon atoms, e.g.1 to 4 carbon atoms. The term “alkoxy” refers to an -O-alkyl group, wherein alkyl is as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 20 propyloxy, etc. In some embodiments, one or more of L1-L7may be a cycloalkylene group. The term “cycloalkylene” refers to a divalent, saturated cyclic carbon system. It includes monocyclic rings containing from 3 to 6 carbon atoms, preferably from 3 to 5 carbon 25 atoms, e.g. 3 or 4 carbon atoms. Examples of monocyclic cycloalkylene groups include, but are not limited to, cyclopropylene and cyclobutylene. The terms “halogen” and “halogen atom” are used interchangeably herein and refer to F, Cl, Br or I. 30 The term “haloalkyl” refers to an alkyl group as defined herein in which at least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom, preferably F, Cl or Br. Examples of such groups include -CH2F, -CHF2, -CF3, -CCl3, -CHCl2, -CH2CF3, etc. - 41 - The term “heterocyclic ring” as used herein refers to a saturated or partially unsaturated carbocyclic system in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon. The heterocyclic ring structure may be linked to the remainder of the molecule 5 through a carbon atom or through a nitrogen atom. Examples include diazirine groups. The terms “aryl” and “aromatic ring” are used interchangeably herein and refer to aromatic ring systems, including "heteroaryl groups" and “heteroaromatic rings”. 10 Such ring systems may be monocyclic or bicyclic and contain at least one aromatic ring. Where such systems contain more than one ring, at least one ring may thus be non-aromatic. Where these contain bicyclic rings, these may be linked by a bond or these may be fused. Any fused bicyclic ring system may contain an aromatic ring fused to a non-aromatic ring (e.g. to a 5- or 6-membered unsaturated 15 carbocyclic ring). Preferably any aryl group will contain from 6-20 carbon atoms, e.g. either 6 or 10 carbon atoms. Examples of “aryl” groups include, but are not limited to, phenyl, 1-napthyl and 2-napthyl. A preferred aryl group is phenyl. The terms "heteroaryl" and “heteroaromatic ring” are used interchangeably herein 20 and refer to heterocyclic aromatic groups. Such groups may be monocyclic or bicyclic and contain at least one unsaturated heteroaromatic ring system. Where these are monocyclic, these may comprise 5- or 6-membered rings which contain at least one heteroatom selected from nitrogen, oxygen and sulfur and contain sufficient conjugated bonds to form an aromatic system. Where these are bicyclic, 25 these may contain from 9-11 ring atoms. Examples of heteroaryl groups include thiophenyl, thienyl, pyridyl, thiazolyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl, thiadiazolyl, benzimidazolyl, benzooxazolyl, benzofuryl, indolyl, isoindolyl, pyridonyl, pyridazinyl, pyrimidinyl, imidazopyridyl, oxazopyridyl, thiazolopyridyl, imidazopyridazinyl, 30 oxazolopyridazinyl, thiazolopyridazinyl and purinyl. Unless otherwise stated, all substituents are independent of one another. - 42 - In the case where a subscript is the integer 0 (i.e. zero), it is intended that the group to which the subscript refers is absent, i.e. there is a direct bond between the groups either side of that particular group. 5 As will be understood, the compounds described herein may contain one or more stereocenters and may therefore exist in various stereoisomeric forms, including enantiomers, diastereomers, and mixtures thereof. The invention encompasses all optical isomers of the compounds described herein and mixtures of optical isomers. Hence, compounds that exist as diastereomers, racemates and / or enantiomers are 10 within the scope of the invention. The term “stereoisomer” refers to compounds which have identical chemical constitution but which differ in respect of the spatial arrangement of the atoms or groups. Examples of stereoisomers are enantiomers and diastereomers. The term15 “enantiomers” refers to two stereoisomers of a compound which are non- superimposable mirror images of one another. The term “diastereoisomers” refers to stereoisomers with two or more stereocentres which are not mirror images of one another. The invention is considered to extend to diastereomers and enantiomers, as well as racemic mixtures and enantioenriched mixtures in which the ratio of 20 enantiomers is other than 1:1. The compounds herein described may be resolved into their enantiomers and / or diastereomers. For example, where these contain only one stereocenter, these may be provided in the form of a racemate or racemic mixture (a 50:50 mixture of 25 enantiomers) or may be provided as pure enantiomers, i.e. in the R- or S-form. Any of the compounds which occur as racemates may be separated into their enantiomers by methods known in the art, such as column separation on chiral phases or by recrystallization from an optically active solvent. Those compounds with at least two asymmetric carbon atoms may be resolved into their 30 diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and / or fractional crystallization, and where these compounds are obtained in racemic form, they may subsequently be resolved into their enantiomers. - 43 - Any of the compounds herein described may be converted into a salt thereof, particularly into a pharmaceutically acceptable salt thereof with an inorganic or organic acid or base. Procedures for salt formation are conventional in the art. The term “pharmaceutically acceptable salt” as used herein refers to any pharmaceutically acceptable organic or inorganic salt of any of the compounds herein described. A pharmaceutically acceptable salt may include one or more additional molecules such as counter-ions. The counter-ions may be any organic or inorganic group which stabilizes the charge on the parent compound. If the compound of the invention is a base, a suitable pharmaceutically acceptable salt may be prepared by reaction of the free base with an organic or inorganic acid. If the compound of the invention is an acid, a suitable pharmaceutically acceptable salt may be prepared by reaction of the free acid with an organic or inorganic base. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts, nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts or perchlorate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, glycolate, nicotinate, benzoate, salicylate, ascorbate, or pamoate (embonate) salts; sulfonate salts such as methanesulfonate - 44 - (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; and acidic amino acid salts such as aspartate or glutamate salts. Where a –COOH or –OH group is present, pharmaceutically acceptable esters can be used, for example, methyl, ethyl and the like for –COOH, and acetate, maleate and like for –OH, as well as those esters known in the art for modifying solubility of hydrolysis characteristics, for use as sustained release or prodrug formulations. The compounds described herein may exist in one tautomeric form or in a mixture of tautomeric forms. The present invention contemplates all possible tautomeric forms. The term “pharmaceutically acceptable” means that the compound or composition is chemically and / or toxicologically compatible with other components of the formulation or with the patient (e.g. human) to be treated. By “a pharmaceutical composition” is meant a composition in any form suitable to be used for a medical purpose. Non-limiting examples are provided below. The compounds described herein are either known in the art, or can be prepared by methods known to those skilled in the art. Some of the compounds are commercially available from sources including MedChem Express, Enamine, Timtec, Chembridge, and Princeton Biomolecular Research. Any of the compounds herein described, including those which are not known in the art, including the compounds of formula JB29, JB64, JB65, JB70, JB73, JB85, JB88, JB92, JB99, JB104, JB105, JB108, JB113, JB114, JB117, JB120, JB121, JB122 JB124, JB125, JB127, JB128, JB131, and JB133 may be prepared from readily available starting materials using synthetic methods known in the art such as those described in known textbooks, for example, in Advanced Organic Chemistry (March, Wiley Interscience, 5thEd. 2001) or Advanced Organic Chemistry (Carey and Sundberg, KA / PP, 4thEd.2001). - 45 - The scheme below illustrates a general method suitable for preparing compounds as herein described, for example, JB55, JB56, JB108, JB109, JB113, JB114, JB117, JB120, JB121, JB122, JB41, JB47, JB53, JB62, JB64, JB65, JB70, JB73, JB76, JB77, JB78, JB79, JB83, JB85, JB87, JB88, JB92, JB99, JB104, JB105, 5 JB124, JB125, JB127, JB128 and JB131, as well as other compounds of the invention. Such methods for the preparation of the compounds form a further aspect of the invention. R1, L7, L2and R2below are as herein defined, for example as defined in relation to Formula (II). In addition, routes for preparation of JB79, JB120, JB124 and JB131 are shown in the Examples. 10 15 20 Suitable conditions for step 1 in the above scheme are: Cs2CO3, Xantphos, Pd2(dba)3.CHCl3, aq. dioxane, EtOH (ethanol), 90 °C, 1 hour Suitable conditions for step 2 in the above scheme are: one equivalent of Ph3P=C(H)C(O)OEt, room temperature, overnight. 25 Suitable conditions for step 3 in the above scheme are: 3.5 equivalents of LiOH, water / THF (tetrahydrofuran): 1 / 10, room temperature, overnight. - 46 - Suitable conditions for step 4 in the above scheme are: HATU (Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium), DIEA (N,N- Diisopropylethylamine), DMF (Dimethylformamide), room temperature, overnight. 5 The compounds used as starting materials are either known from the literature or may be commercially available. Alternatively, these may readily be obtained by methods known from the literature. As will be understood, other synthetic routes may be used to prepare the compounds using different starting materials, different 10 reagents and / or different reaction conditions. A more detailed description of how to prepare compounds in accordance with the invention is found in the Examples. A small molecule PAK1 and / or PAK2 activator in accordance with the present invention is considered to be a molecule with a molecular weight of less than 1000 15 Da, e.g. less than 900, 800, 700, 600, 500, 450 Da, 400Da, 350 Da, 300 Da, 250Da or 200 Da. In certain embodiments, the small molecule PAK1 and / or PAK2 activators of the invention are not peptides. In other embodiments the small molecule PAK1 and / or PAK2 activators of the invention do not comprise an amino acid. 20 In accordance with the invention the small molecule PAK1 and / or PAK2 activators described herein act directly on the PAK1 and / or PAK2, more specifically the auto- inhibited PAK1 and / or PAK2 homodimer, to increase kinase activity against its target substrates. 25 The main role of kinases is to phosphorylate their substrates (usually enzymes & receptors) and thereby regulating their activity (either activating or inhibiting). PAK1 and PAK2 phosphorylate PP2A to increase PP2A’s activity. This leads to further activation of downstream enzymes which are crucial in maintaining homeostasis 30 within the cardiovascular system. The process of a kinase (e.g. PAK1) using ATP to phosphorylate its substrates and resulting in phosphorylated substrates (products) and ADP is called “kinase reaction” as shown in Figure 4. - 47 - Increased phosphorylation is thus indicative of PAK1 activation. PAK1 activation can therefore be measured using kinase assays. PAK2 activation may be measured analogously. For example, as shown in Example 1, phosphorylation by PAK 1 can also be monitored using Rapid-Fire™ Mass Spectrometry in which the conversion of substrate to a phosphorylated product form can be analyzed by measuring the shift in the mass. Instead of measuring the usage of ATP, it measures the ratio between the amount of substrate (peptide) and the product (phosphorylated peptide). As the kinase reaction proceeds, the amount of substrate decreases, while the amount of product (phosphorylated substrate) increases. This can be translated into the rate in which the substrate peptides are being converted to the final product by PAK1. The rate of these changes correlates to the rate of the kinase activity. Therefore, one can measure the effect of a compound on the activity of PAK1. The effect of a compound on the activity of PAK2 may be measured analogously. To avoid the costs of using full length protein (e.g. PP2A or other associated enzymes) as substrates when performing kinase reactions in in-vitro settings, a peptide can be used as the substrate to mimic the phosphorylation site. Suitable peptides include PAKtide: RRRLSFAEPG (SEQ ID NO: 3) and RAFtide: IRPRGQRDSSYYWEI (SEQ ID NO: 4). Likewise, the levels of the active form of PAK1 (or PAK2), i.e. an (auto)phosphorylated monomer, may be measured as a proxy for PAK1 (or PAK2) activation and activity. The above-mentioned assays may be used analogously. The small molecules as defined herein would be expected to increase the amounts of phosphorylated PAK1 and / or PAK2 in a sample. Amounts of phosphorylated PAK1 and / or PAK2 in a sample can also be measured directly by western blotting or other means of immunodetection. Such assays may be performed in the presence of the above-mentioned modulator proteins, e.g. RAC, CDC42 and RAS. In certain embodiments the small molecule PAK1 activators described herein will be able to increase in vitro PAK1 kinase activity, alone or in combination with CDC42, - 48 - e.g. in the assays described above, to a level which is at least two times, e.g. at least 3, 4, 5, 10, 20, 30, 40, or 50 times that of untreated PAK1, alone or in combination with CDC42, respectively. In certain embodiments the small molecule PAK2 activators described herein will be able to increase in vitro PAK2 kinase activity, alone or in combination with CDC42, e.g. in the assays described above, to a level which is at least two times, e.g. at least 3, 4, 5, 10, 20, 30, 40, or 50 times that of untreated PAK2, alone or in combination with CDC42, respectively. The PAK1-activation ability of a compound described herein can also be identified in cells (in vitro or in vivo) in a variety of ways which would be apparent to the skilled person. Figure 3 shows the mechanisms of PAK1 cardio-protective signaling in the heart. Upon heart stress induced by, for example, stress mediators, tyrosine kinase activation, or GPCR (B-adrenergic) stimulation, secondary messengers activate intermediate mediators such as GTP-bound Rho family GTPase, RAS, RAC and / or CDC42 enzymes, which are the main modulators for PAK1 activity. Activated PAK1 is then able to activate other essential enzymes in maintaining homeostatic functions in the heart. PP2A, AKT, eNOS, MKK4, MKK7, and JNK are some examples of enzymes that are activated by PAK1 and provide cardio- protective mechanism. PAK2 activation may be measured analogously. Moreover, adaptor proteins such as NCK and GRB2 bind to a non-classical SH3- binding motif in PAK1 to facilitate activation of PAK1. RAC and CDC42 bind to the CRIB domains (aa75-88), a crucial region for protein dissociation. A P21-binding domain (PBD; aa 75-105) contributes in controlling the basal activity of PAK1. p- NFAT is a downstream enzyme of the JNK pathway that becomes activated upon injuries or stress. Through the activation of PAK1, myocardial JNK pathway activation leads to modulating NFAT signaling to attenuate cardiac hypertrophy. Cellular PAK1 activation can therefore be confirmed by studying the comparative activity of the relevant associated enzymes after, and preferably also before, exposure of the cell system to a putative PAK1 activator, e.g. those described herein. In certain embodiments, PAK1 activity may be expressed in terms of PAK1 signaling, and thus increases in PAK1 activity will be seen as increased levels of - 49 - PAK1 signal transduction, or increased output through PAK1 signal transduction pathways. Likewise, PAK1 inactivity may be expressed as reduced levels (or an absence) of PAK 1 signaling, and thus reduced PAK1 activity (PAK 1 inactivity) will be seen as reduced levels (or an absence) of PAK1 signal transduction, or reduced (or lack of) output through PAK1 signal transduction pathways. PAK2 activation, activity and inactivity may be interpreted analogously. The present inventors have surprisingly identified an allosteric regulatory site at the interface between the AID and KD of PAK1 (specifically the corresponding regions of a PAK1 homodimer) that controls autoinhibition of PAK1 activity, and determined that, by interfering with that site, conformational changes can be induced which cause destabilisation of the inhibitory conformation of the activator loop of the PAK1 kinase domain, e.g. by displacing the AID and exposing the autophosphorylation site and the ATP binding site. Such changes reduce (e.g. relieve, inhibits, diminish, ameliorate, abrogate, counteract or prevent) the auto-inhibitory effects of the PAK1 monomers on one another and thus increases (e.g. enhances, stimulates, or promotes) the kinase activity of those PAK1 monomers. The small molecules as defined therein may be considered to promote the conversion or transition of inactive PAK1 to active PAK1, or least the cause PAK1 to adopt a more active confirmation or increase the probability that PAK1 will adopt an active confirmation. The inventors have further elucidated key amino acid residues in this allosteric regulatory site with which small molecules may interact and cause PAK 1 activation, namely Tyr131, Tyr142, Glu315, Asn383, Val318, and Val385 (following the numbering of full length human PAK1; SEQ ID NO: 1, Figure 8). Given the highlighted key residues are found in the DFG motif, Glu315 on αC helix, and the KI segment, this autoinhibition release site may be referred to as the ‘DEK’ motif. Thus, in certain embodiments, the small molecule PAK1 activators described herein relieve (or counteract, combat) PAK1 autoinhibition; e.g. by inducing a conformational change which causes the withdrawal of the KI segment from the KD cleft thereby leading to the release of the activation loop and enabling autophosphorylation of Thr423. - 50 - In certain embodiments, the small molecule PAK1 activators described herein interact with an allosteric regulatory site at the interface between the AID and KD of PAK1 (specifically the corresponding regions of a PAK1 homodimer). In certain 5 embodiments this interaction is sufficient to disrupt the autoinhibitory regulation (destabilise the autoinhibitory confirmation) of PAK1, e.g. through interfering with the action of the KI segment. In certain embodiments, the small molecule PAK1 activators described herein bind 10 at the interface between the AID and KD in a manner sufficient to cause displacement of the AID from the KD, thereby exposing the autophosphorylation site and the ATP binding site, and facilitating PAK1 activation. In certain embodiments, the small molecule PAK1 activators described herein 15 disrupt the autoinhibited state of PAK1, namely the conformational arrangement of PAK1 (specifically a homodimer) in which the KI segment occupies the cleft between the N lobe and the C lobe of the KD, interacting with the active site as a pseudosubstrate, including Lys141, and makes hydrogen bonds with the Asp389 of the catalytic loop and Asp407 of the activation loop, thereby. induces a turn in the 20 activation loop which hinders the interaction between Glu315 of αC helix and Lys299 and prevents ATP binding. In certain embodiments, the small molecule PAK1 activators described herein interact (or bind) to the DEK motif. In certain embodiments this binding / interaction 25 results in any or all of the above described effects. In certain embodiments, the small molecule PAK1 activators described herein have a structure which interacts with both monomers of a homodimer of full length human PAK1 at amino acid residue positions Y131 and Y142 of the first monomer 30 and amino acid residue positions E315, V318, N383, and V385 of the second monomer. In certain embodiments this interaction results in any or all of the above described effects, including destabilising the inhibitory conformation of the activator loop of the PAK1 kinase domain and increasing the kinase activity of PAK1. - 51 - In certain embodiments, the small molecule PAK1 activators described herein may have a structure which when carrying a diazirine group will preferentially covalently cross-link with both monomers of a homodimer of full length human PAK1 at Y131 and Y142 of the first monomer and E315, V318, N383, and V385 of the second 5 monomer. The use of ligands carrying a diazirine group to label amino acid residues in corresponding receptors is common place, but in brief the technique involves incubating the ligand carrying a diazirine group with the receptor in a suitable buffer 10 and irradiating the reaction mixture with light of a suitable wavelength, e.g. UV light. Further details are provided the Example 2. The amino acid residue positions recited herein are in reference to the full-length sequence of human PAK1. This is shown in Figure 8A as SEQ ID NO 1. The 15 skilled person would be able to determine the equivalent residues and / or positions in PAK1 amino acid sequences of differing length or in human homologues or homologues from other species by routine sequence alignment. Publicly available algorithms may be used to assist with such analyses. Without wishing to be bound by theory, small molecules having a structure as 20 defined herein are believed to break hydrogen bonds between K141 and D389 of the catalytic loop and D407 of the activation loop and those between E315 of Helix C and F410 and C411 of the activation loop. This is believed to trigger a series of conformational changes allowing for the interaction between E315 (Helix C) and K299 to be restored and allow for the binding of an ATP. In other words, the shift in 25 Helix C by binding of a small molecule as defined herein is expected to trigger a series of conformational changes leading to the rearrangement of the kinase into a catalytically competent state. In certain embodiments, the small molecule PAK1 activators described herein may have such effects, but more broadly speaking, the small molecules defined herein are able to stimulate PAK1 activity directly by 30 interfering with the effects of the kinase inhibitory (KI) domain of the auto-inhibitory (AI) domain of one PAK1 monomer exerts on the other. - 52 - In certain embodiments, the small molecule PAK1 activators described herein may form hydrophobic contacts with the residues Lys141, Glu315, Arg388, and Phe408, and / or hydrogen bonds with Lys141 and Glu315. In certain embodiments, the small molecule PAK1 activators described herein may 5 interfere with kinase dimerization, thereby blocking trans-autoinhibition. In certain embodiments, the small molecule PAK1 activators described herein may cause PAK1 to adopt a DFG-in conformation, the small lobe of the αC helix to be positioned inwards, and Glu315 to adopt an "in" conformation compared to the autoinhibited state. 10 In another aspect the invention provides a small molecule PAK1 activator having a structure which has one of more of the above described functions. The provision of such molecules for use in the various therapeutic contexts described herein is also expressed contemplated. 15 PAK2 has an analogous structure and regulatory mechanism. The compounds described herein may act to activate PAK2 in a similar way. In particular, as shown in Figure 16, the inventors have further elucidated key amino acid residues in the allosteric regulatory site of PAK2 with which small molecules may interact and cause PAK2 activation, namely Ile84, Val86, Lys128, Asp131, Ser132, Arg417 20 (following the numbering of full length human PAK2; SEQ ID NO: 2, Figure 8B), and in certain embodiments, the small molecule PAK2 activators described herein have a structure which interacts with said residues in PAK2 or a homomeric dimer thereof. The skilled person would be able to determine the equivalent residues and / or positions in PAK2 amino acid sequences of differing length or in human 25 homologues or homologues from other species by routine sequence alignment. Publicly available algorithms may be used to assist with such analyses. In another aspect the invention provides a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) 30 as herein described for use in therapy. Unless otherwise specified, the term "therapy" as used herein is intended to include both treatment and prevention. More specifically, therapy encompasses the treatment or prevention of a disease or - 53 - condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity. In a further aspect the invention provides the use of a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described in the manufacture of a medicament for use in the treatment or prevention of a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity. In a still further aspect the invention provides a method for the treatment or prevention of a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity, said method comprising administering to said subject an effective amount of a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described. As used herein, an “effective amount”, more particularly a “pharmaceutically effective amount”, relates to an amount that will lead to the desired pharmacological and / or therapeutic effect, i.e. an amount of the agent which is effective to achieve its intended purpose (e.g. the treatment or prevention of a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 inactivity). While individual patient needs may vary, determination of optimal ranges for effective amounts of the active agent is within the capability of one skilled in the art. Generally, the dosage regimen for treating a disease or condition with any a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described is selected in accordance with a variety of factors including the nature of the medical condition and its severity taking account of the mode of administration which is to be used. Suitable dosages and dosage forms are discussed below. As used herein a disease or condition responsive to PAK1 and / or PAK2 activity is a disease or condition, or any symptom or sign of the disease or condition, or any clinically accepted indicator of the disease / condition, which may be positively affected, e.g. improved, as a result of the effects of PAK1 and / or PAK2 kinase - 54 - activity. In other words, a disease or condition, or any symptom or sign of the disease or condition, or any clinically accepted indicator of the disease / condition, which may be positively affected, e.g. improved, as a result of signal transduction through PAK1 and / or PAK2. An increase in PAK1 and / or PAK2 activity / signalling will therefore result in an improvement to such diseases or conditions As used herein, a disease or condition associated with PAK1 and / or PAK2 inactivity is a disease or condition, or any symptom or sign of the disease or condition, or any clinically accepted indicator of the disease / condition, which is associated with, e.g. caused directly or indirectly by, a deficiency in PAK1 and / or PAK2 kinase activity (signal transduction through PAK1 and / or PAK2). In such embodiments, PAK1 and / or PAK2 signal transduction may be considered dysfunctional. Such dysfunction may be due to inhibition of the PAK1 and / or PAK2 signal transduction pathway. In other embodiments, opposing signal transduction may be overwhelming PAK1 and / or PAK2 signalling. PAK1 and / or PAK2 activity is associated with regulation of cardiac electrical and contractile function and Ca2+handling and activation of cardiac signalling pathways. Thus, the compounds described herein for use in regulation of cardiac electrical function, cardiac contractile function, cardiac Ca2+handling or for activation of cardiac signalling pathways, as well as for treatment or prevention of associated diseases and conditions, forms a further aspect of the invention. PAK2 activity is also associated with regulation of cardiac cell mitochondrial function, the production of reactive oxygen species (ROS) and cardiac cell ER stress in a cardioprotective manner. Thus, the compounds described herein for use in regulation of regulation of cardiac cell mitochondrial function, the production of reactive oxygen species (ROS) and cardiac cell ER stress as well as for treatment or prevention of associated diseases and conditions, and for the combat of cardiac dysfunction or the maintenance of normal cardiac function, forms a further aspect of the invention. Activators of PAK1 and / or PAK2 activity such as the compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be employed as cardioprotective agents. - 55 - Activators of PAK1 and / or PAK2 activity such as the compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be employed in the prevention or treatment of diseases, conditions or risk factors associated with cardiovascular disease, coronary heart disease and complications thereof. Examples of cardiovascular diseases include hypertrophic cardiomyopathy and associated arrhythmias. Examples of complications associated with cardiovascular disease include arrhythmias, hypoxia, ischaemic injury, fibrosis and / or hypertrophy. Other diseases / complications that the compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 and / or PAK2 activators) as herein described lend themselves toward the treatment or prevention of include: pressure-induced hypertrophy, ischemia / reperfusion injuries, hypoxic and ischemic injuries, hypertrophy (e.g. pathological hypertrophy) and associated arrhythmias (e.g. ventricular arrhythmias), Angiotensin II-induced hypertrophy, arrhythmias and ventricular arrhythmogenesis, systolic heart failure, atrial fibrillation, atherosclerosis and angina pectoris. The compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be used for the prevention and / or treatment of at least one disease, condition or risk factor when associated with coronary heart disease (CHD) and / or cardiovascular disease. For example, in some embodiments, at least one disease or condition is chosen from atherosclerosis; high blood pressure, peripheral insulin resistance and / or a diabetic condition such as type II diabetes; a dyslipidemic condition such as hypertriglyceridemia (HTG), elevated total cholesterol, elevated non-HDL cholesterol, elevated LDL cholesterol, elevated Apo B, low HDL cholesterol, primary hypercholesterolemia (heterozygous familial and nonfamilial), mixed dyslipidemia (Frederickson Types IIa and IIb), primary dysbetalipoproteinemia (Frederickson Type III), metabolic syndrome, obesity or an overweight condition, or a fatty liver disease such as non-alcoholic fatty liver disease (NAFLD). Conversely, the - 56 - compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 activators) as herein described may be used for the prevention and / or treatment of CHD or cardiovascular disease associated with the above diseases or conditions. In another embodiment the compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be employed for the prevention of myocardial infarction or sudden cardiac death (SCD). The compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be used for the prevention and / or treatment of ventricular arrhythmia associated with cardiac stress and hypertrophy. In another embodiment the compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be employed for the prevention of myocardial infarction or SCD associated with ventricular arrhythmia which in turn may be associated with cardiac stress and hypertrophy. The compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be used for the prevention and / or treatment of cardiac remodelling, e.g. remodelling associated with cardiac disease or cardiac damage, e.g. ventricular arrhythmia which in turn may be associated with cardiac stress and hypertrophy. In another embodiment the compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be employed for use in cardio-protection (e.g. protection against cardiac stress inducers or providing cardio-protective mechanisms), regulating cardiac electrical functions and muscle contractility, reduction of chronic β-adrenergic stimulation and / or normalisation of increased heart rate and Ca2+channel activity. - 57 - Similarly, the compounds, stereoisomers, tautomers or pharmaceutically acceptable salts (i.e. small molecule PAK1 activators) as herein described may be employed for use in a method of treating a disease or condition mediated by the activation of enzymes such as PP2A (Protein phosphatase 2A), AKT (Protein kinase B or PBK), eNOS (Endothelial nitric-oxide synthase), MKK4 (Mitogen-activated protein kinase kinase 4), MKK7 (Mitogen-activated protein kinase kinase 7), JNK (c-Jun N-terminal kinase), NCK (Non-catalytic region of tyrosine kinase adaptor protein) or GRB2 (Growth factor receptor-bound protein 2). Thus, a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be used in treatment or prevention of any of these conditions, particularly cardiovascular conditions such as hypertrophic cardiomyopathy (and associated arrhythmias), arrhythmias, hypoxia, ischaemic injury, fibrosis and / or hypertrophy. In other embodiments, a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be used in treatment or prevention of cardiovascular diseases or conditions, including cardiac fibrosis, cardiac hypertrophy, cardiac arrhythmias, heart failure and ischaemia / reperfusion injury. Also in accordance with certain aspects of the invention there may be a preceding step of identifying a subject as being a subject with, suspected to have, or at risk of, a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity, or a step of diagnosing a subject as a subject with, suspected to have, or at risk of, a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity. Alternatively or in addition to the above described preceding step, in accordance with the invention there may be a following step in which the subject’s clinical indicators of the disease or condition responsive to PAK1 and / or PAK2 activity or the disease or condition associated with PAK1 and / or PAK2 inactivity are assessed and preferably compared to a corresponding assessment made prior to, or earlier in, said treatment in order to determine any changes therein. - 58 - The diagnosis and monitoring of diseases or condition responsive to PAK1 and / or PAK2 activity or diseases or conditions associated with PAK1 and / or PAK2 inactivity, e.g. those described above, based on readily observable physiological indicators is entirely routine for clinicians. Indicators and monitoring modalities may include, blood pressure, blood gases, blood enzymes, cardiac contractility, cardiac morphology, electrocardiogram, echocardiogram, ultrasound, MRI, CT scan, positron emission tomography, single photon emission computed tomography, coronary angiography, and coronary catheterization. The invention encompasses the use of a single compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described or a mixture (multiplicity / plurality; two or more) thereof. "Treatment" when used generally in relation to the treatment of a disease or medical condition in a subject in accordance with the invention is used broadly herein to include any therapeutic effect, i.e. any beneficial effect in relation to the disease or on the condition. Thus, not only included is eradication or elimination of the disease or condition, or cure of the subject, but also an improvement in the disease or condition of the subject. Thus, included for example, is an improvement in any symptom or sign of the disease or condition, or in any clinically accepted indicator of the disease / condition. Treatment thus includes both curative and palliative therapy, e.g. of a pre-existing or diagnosed disease / condition, i.e. a reactionary treatment. "Prevention" as used generally herein refers to any prophylactic or preventative effect. It thus includes delaying, limiting, reducing or preventing the disease or condition or the onset of the disease or condition, or one or more symptoms or indications thereof, for example relative to the disease or condition or symptom or indication prior to the prophylactic treatment. Prophylaxis thus explicitly includes both absolute prevention of occurrence or development of the disease or condition, or symptom or indication thereof, and any delay in the onset or development of the disease or condition or symptom or indication, or reduction or limitation on the development or progression of the disease condition or symptom or indication. - 59 - The subject may be any human or non-human animal subject, but more particularly may be a human or a non-human vertebrate, e.g. a non-human mammal, bird, amphibian, fish or reptile. In a preferred embodiment the subject is a mammalian 5 subject. The animal may be a livestock or a domestic animal or an animal of commercial value, including laboratory animals or an animal in a zoo or game park. Representative animals therefore include dogs, cats, rabbits, mice, guinea pigs, hamsters, horses, pigs, sheep, goats and cows. Veterinary uses of the invention are thus covered. The subject may be viewed as a patient. 10 The compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be administered to the subject in any convenient form or by any convenient means in order to deliver effective amounts to the tissue or site or region of the body targeted 15 for treatment, in particular the cardiovascular system, more particularly the heart, e.g. by parenteral (e.g. intravenous, intramuscular, subcutaneous, intraperitoneal, intracardiac, catheter), topical, or enteral (e.g. oral, buccal, sublingual, rectal) routes, or by inhalation (including nasal inhalation). Administration may achieve systemic distribution or localised distribution, by which it is meant that delivery is 20 effected to the tissue or region of the body targeted for treatment but essentially no other location in the patient. The skilled person would be able to select an appropriate administration means to suit any particular physiological target. The skilled person will be able to formulate a compound, stereoisomer, tautomer or 25 pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described into pharmaceutical compositions that are adapted for these routes of administration and body distribution according to any of the conventional methods known in the art and widely described in the literature. 30 In a further aspect, the invention thus provides a pharmaceutical composition comprising a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described together with one or more pharmaceutically acceptable carriers, excipients or diluents. - 60 - Acceptable carriers, excipients and diluents for therapeutic use are well known in the art and can be selected with regard to the intended route of administration and standard pharmaceutical practice. Examples include binders, lubricants, suspending agents, coating agents, solubilizing agents, preserving agents, wetting agents, emulsifiers, surfactants, sweeteners, colorants, flavoring agents, pH modifiers, viscosity modifiers, antioxidants, odorants, buffers, stabilizing agents and / or salts. More specifically, a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be incorporated, optionally together with other active agents, with one or more conventional carriers, diluents and / or excipients, to produce conventional galenic preparations such as tablets, pills, granules (e.g. in free form or enclosed in capsules), powders (e.g. inhalable powders, including dry inhalable powders), lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), sprays (e.g. nasal sprays), compositions for use in nebulisers, ointments, creams, salves, soft and hard gelatine capsules, suppositories, pessaries, sterile injectable solutions, sterile packaged powders, and the like. Enteric coated solid or liquid compositions, e.g. enteric coated tablets and enteric coated granules (which may be provided in an enteric-coated capsule or in a non-enteric-coated capsule i.e. in which the coating may or may not be an enteric coating); sterile inhalable and sterile injectable compositions are of particular note. Examples of suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, citric acid, tartaric acid, starches, gum acacia, calcium phosphate, inert alginate polymers, tragacanth, gelatine, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, water, ethanol, water / ethanol, water / glycol, water / polyethylene, hypertonic salt water, glycol, propylene glycol, cetylstearyl alcohol, methyl cellulose, methylhydroxybenzoates, propyl hydroxybenzoates, talc, magnesium stearate, mineral oil or fatty substances such as saturated fat or suitable mixtures thereof. Parenterally administrable forms, e.g. solutions suitable for delivery intravenously, should be sterile and free from physiologically unacceptable agents, and should - 61 - have low osmolarity to minimize irritation or other adverse effects upon administration and thus solutions should preferably be isotonic or slightly hypertonic, e.g. hypertonic salt water (saline). Suitable vehicles include aqueous vehicles customarily used for administering parenteral solutions such as sterile water for injection, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection and other solutions such as are described in Remington's Pharmaceutical Sciences, 15th ed., Easton: Mack Publishing Co., pp. 1405-1412 and 1461-1487 (1975) and The National Formulary XIV, 14th ed. Washington: American Pharmaceutical Association (1975), which is explicitly incorporated by reference herein in its entirety. The solutions can contain preservatives, antimicrobial agents, buffers and antioxidants conventionally used for parenteral solutions, excipients and other additives which are compatible with the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 activators) as herein described and which will not interfere with the manufacture, storage or use of products. Simple sterile solutions of a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 activators) as herein described or simple sterile liquid compositions comprising a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 activators) as herein described may be especially convenient for use during surgical procedures and for delivery to the lungs, e.g. by nebuliser, or to the paranasal sinuses, e.g. by a nasal spray device. Solid or liquid formulations of a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 activators) as herein described may be provided with an enteric coating that prevents degradation in the stomach and / or other parts of the upper GI tract but permits degradation in the lower GI tract, e.g. the small intestine. Such coatings are routinely prepared from polymers including fatty acids, waxes, shellac, plastics, and plant fibres. Specific examples thereof include but are not limited to methyl acrylate-methacrylic acid copolymers, methyl methacrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate - 62 - (PVAP), cellulose acetate trimellitate, and sodium alginate polymer. Enteric coated tablets and enteric coated granules (which may be provided in an enteric-coated capsule or in a non-enteric coated capsule) are of particular note. Enteric coated granules may be prepared in accordance with the teachings of WO 1989008448 and Al-Khedairy, E.B.H, 2006, Iraqi J.Pharm.Sci., Vol.15 (1) 49, the contents of which are incorporated herein by reference, although the skilled person would be aware of further alternative techniques which may be used. For topical administration a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 activators) as herein described can be incorporated into creams, ointments, gels, salves, transdermal patches and the like. Further topical systems that are envisaged to be suitable are in situ drug delivery systems, for example gels where solid, semi-solid, amorphous or liquid crystalline gel matrices are formed in situ and which may comprise a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 activators) as herein described. Such matrices can conveniently be designed to control the release of the compound from the matrix, e.g. release can be delayed and / or sustained over a chosen period of time. Such systems may form gels only upon contact with biological tissues or fluids, e.g. mucosal surfaces. Typically, the gels are bioadhesive and / or mucoadhesive. Delivery to any body site that can retain or be adapted to retain the pre-gel composition, e.g. the peritoneum, can be targeted by such a delivery technique. The relative content of the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described in the compositions of use in the invention can vary depending on the dosage required and the dosage regime being followed but will be sufficient to achieve an effective amount at the target treatment site, taking account of variables such as the physical size of the subject to be treated, the nature of the subject’s particular ailments, and the location and identity of the target treatment area. The skilled person would know that the amounts of the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 activators) as herein described can be reduced if a multiple dosing regime is followed or increased to minimise the number of administrations or applications. - 63 - A representative aqueous solution for delivery of a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described by injection (e.g. by intravenous, intramuscular, subcutaneous, intraperitoneal, intracardiac injection or by catheter) will be sterile and may contain 0.01 to 1%, e.g.0.01 to 0.5%, 0.01 to 0.1%, 0.01 to 0.05%, 0.05 to 1%, 0.05 to 0.5%, 0.05 to 0.1%, 0.1 to 1%, 0.1 to 0.5%, or 0.5% to 1% w / v of the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described, the remainder being comprised of water and pharmaceutically acceptable excipients and / or other active agents if being used. A representative inhalable solution to be used to administer a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described typically will be sterile and may contain 0.01 to 1%, e.g. 0.01 to 0.5%, 0.01 to 0.1%, 0.01 to 0.05%, 0.05 to 1%, 0.05 to 0.5%, 0.05 to 0.1%, 0.1 to 1%, 0.1 to 0.5%, or 0.5% to 1% w / v of the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described, the remainder being comprised of pharmaceutically acceptable excipients, e.g. water, and / or other active agents if being used. A representative inhalable powder to be used to administer a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 activators) as herein described may contain up to 20%, e.g. up to 15%, 10% 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%, e.g.0.1 to 20%, 0.1 to 15%, 0.1 to 10% 0.1 to 9%, 0.1 to 8%, 0.1 to 7%, 0.1 to 6%, 0.1 to 5%, 0.1 to 4%, 0.1 to 3%, 0.1 to 2% or 0.1 to 1% of the compound, stereoisomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described, the remainder being comprised of pharmaceutically acceptable excipients and / or other active agents if being used in the same composition. A representative tablet to be used to administer a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 activators) as herein described may contain up to 20%, e.g. up to 15%, 10% 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%, e.g.0.1 to 20%, 0.1 to 15%, 0.1 to 10% 0.1 to 9%, 0.1 to - 64 - 8%, 0.1 to 7%, 0.1 to 6%, 0.1 to 5%, 0.1 to 4%, 0.1 to 3%, 0.1 to 2% or 0.1 to 1% of the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described, the remainder being comprised of pharmaceutically acceptable excipients and / or other active agents if being used. The tablet may be a multi-layered tablet. An enteric coated tablet may also be effective in administering a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described of the invention. A representative enteric coated tablet may contain up to up to 20%, e.g. up to 15%, 10% 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%, e.g.0.1 to 20%, 0.1 to 15%, 0.1 to 10% 0.1 to 9%, 0.1 to 8%, 0.1 to 7%, 0.1 to 6%, 0.1 to 5%, 0.1 to 4%, 0.1 to 3%, 0.1 to 2% or 0.1 to 1% of the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 activators) as herein described, including the enteric coating (e.g. polymers including fatty acids, waxes, shellac, plastics, and plant fibres) and / or other active agents if being used. The tablet may be a multi-layered tablet. Enteric coated granules may also be effective in administering a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described. Such granules may be provided in a capsule which itself may or may not be provided with an enteric coating. A representative enteric coated granule may contain up to 50%, e.g. up to 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%, e.g.0.1 to 50%, 45%, 40%, 35%, 30%, 25%,20%, 0.1 to 15%, 0.1 to 10% 0.1 to 9%, 0.1 to 8%, 0.1 to 7%, 0.1 to 6%, 0.1 to 5%, 0.1 to 4%, 0.1 to 3%, 0.1 to 2% or 0.1 to 1% of the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described,, the remainder being comprised of pharmaceutically acceptable excipients, including the enteric coating (e.g. polymers including fatty acids, waxes, shellac, plastics, and plant fibres) and / or other active agents if being used. The dosage required to achieve the desired activity of a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described will depend on various factors, such as the - 65 - compound selected, its mode and frequency of administration, whether the treatment is therapeutic or prophylactic, and the nature and severity of the disease or condition, etc. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon factors such as the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age of the patient, the mode and time of administration, and the severity of the particular condition. The compound and / or the pharmaceutical composition may be administered in accordance with a regimen from 1 to 10 times per day, such as once or twice per day. Suitable daily dosages of compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described are expected to be in the range from 0.1 mg to 1 g of the compound; 1 mg to 500 mg of the compound; 1 mg to 300 mg of the compound; 5 mg to 100 mg of the compound, or 10 mg to 50 mg of the compound. By a “daily dosage” is meant the dosage per 24 hours. In other embodiments the compounds herein described may be used at a daily dose of 0.1 g to 10 g, e.g.0.5 g to 5 g, 0.8 g to 3 g, 1 g to 2 g, e.g. about 2 g, which may be administered at one or more times per day (e.g. bis daily) and in one or more dosage forms or administration events (e.g. two tablets bis daily). A compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described may be used alone in the treatment of any of the conditions herein described. Alternatively, any of the treatments herein described may advantageously be combined with administration of one or more additional active agents, in particular those which are effective in treating the disease or condition to be treated, i.e. as an add-on therapy to current regimes or to create synergistic co-treatments. Such treatment methods may involve simultaneous, separate or sequential administration of a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described, or a pharmaceutical composition containing the same and the additional agent or agents. Where the actives are to be administered simultaneously, these - 66 - may be provided in the form of a combined preparation, e.g. in a pharmaceutical kit or as a combined ("combination") product. Thus, any of the pharmaceutical compositions herein described may additionally contain one or more of such active agents. Thus, a further aspect of the invention provides a product (e.g. a pharmaceutical combination or a kit) comprising a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described together with a further therapeutically active agent (e.g. those described below) as combined preparation for separate, sequential or simultaneous use in treating or preventing a bacterial infection in a subject. More generally this aspect of the invention also provides a kit comprising a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described together with a further therapeutically active agent (e.g. those described below). The kit may further include instructions for use, e.g. instructions for any of the therapeutic uses and methods of the invention described herein. The use of compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described to manufacture such pharmaceutical products and pharmaceutical compositions for use in the medical methods of the invention is also contemplated. The further therapeutically active agent may conveniently be applied before, simultaneously with or following the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described. Conveniently the further therapeutically active agent is applied at substantially the same time as the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described or afterwards. In other embodiments the further therapeutically active agent may conveniently be applied or administered before the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described. The further therapeutically active agent can also be given (e.g. administered or delivered) repeatedly at time - 67 - points appropriate for the agent used. The skilled person is able to devise a suitable dosage regimen. In long term treatments the compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described can also be used repeatedly. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described can be applied as frequently as the further therapeutically active agent, or more or less frequently. The frequency required may depend on the site or location in or on the subject to which compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described is administered and also the overall nature of the clinical condition displayed by the particular patient undergoing treatment. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described and the further therapeutically active agent may therefore be formulated together or separately, that is in the same or in different formulations or pharmaceutical compositions, and may be provided for administration by the same or different routes. Examples of further therapeutically active agents of use in the invention include angiotensin-converting-enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists, diuretics, calcium channel blockers, sodium channel blockers, potassium channel blockers, beta-blockers, alpha-blockers, statins, and class V antiarrhythmic agents. Examples of angiotensin-converting-enzyme inhibitors (ACE inhibitors) include benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril. Examples of angiotensin II receptor antagonists include losartan, telmisartan, irbesartan, candesartan, olmesartan, valsartan and saprisartan. Examples of diuretics include loop diuretics (e.g. furosemide and bumetanide), thiazide diuretics (chlorothiazide, bendroflumethiazide, indapamide, hydrochlorothiazide and chlorthalidone) and potassium-sparing diuretics / - 68 - aldosterone antagonists (amiloride, spironolactone, canrenone, finerenone and eplerenone). Examples of calcium channel blockers include amlodipine, felodipine, isradipine, nifedipine, nimodipine, lerkanidipine, verapamil or diltiazem. Examples of beta-blockers include propranolol, timolol, atenolol, bisoprolol, esmolol, metoprolol and nebivolol. Examples of β1-selective beta-blockers include acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol or esmolol. Examples of alpha-blockers include prazosine. Examples of combined alpha- and beta-blockers include labetalol and carvedilol. Examples of calcium channel blockers include ajmaline, disopyramide, procainamide, quinidine, sparteine, lidocaine, mexiletine, phenytoin, tocainide, encainide, flecainide, moricizine, and propafenone. Examples of potassium channel blockers include amiodarone, dofetilide, dronedarone, ibutilide, sotalol, vernakalant. Examples of class V antiarrhythmic agents include adenosine, digoxin, magnesium sulfate. Examples of statins include atorvastatin, Fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Other therapeutic agents which may be co-administered include sacubitril and sacubritril-valsartan (LCZ596), digoxin, ivabradine, hydralazine with nitrate. In another aspect, the invention also provides a package comprising: (i) a compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described or a pharmaceutical - 69 - composition comprising said compound, stereoisomer, tautomer or pharmaceutically acceptable salt (i.e. small molecule PAK1 and / or PAK2 activators) as herein described; and (ii) printed instructions and / or a label relating to the use of (i) in the treatment of any of the conditions or disorders as herein described. The invention will now be described in more detail with reference to the accompanying figures, in which: Figure 1 shows Rapid-Fire mass spectrometry PAK1 / CDC42 kinase assay results for compounds JB01, JB06, JB08, JB09, and JB18 in a real-time dependent substrate phosphorylation. "Sub Conversion (%)" presents the amount of substrate phosphorylation over time. The slope of the curve represents the rate of substrate phosphorylation correlating to the kinase activity. Figure 2 shows a dose response Rapid-Fire mass spectrometry PAK1 / CDC42 kinase assay results for compounds JB29, JB47, JB53, JB55, JB56, JB62, JB64, JB65, JB70, JB73, JB76, JB77, JB78, JB79, JB83, JB85, JB87, JB88, JB92, JB99, JB104, JB105, JB108, JB109, JB113, JB114, JB120, JB121, JB122, JB124, JB125, JB127, JB128, JB131, JB133, JB2019B, PAK1-A1, PAK1-A2, and PAK1-A3. The “PAK1 Activity (%)” or “Total Activity (% Normalized) on the y-axis represents the normalized activity of the kinase based on based on the control (DMSO, 100%) PAK1 activity. Percentage deviation from the normalized baseline (100%) represents the changes in enzymatic activity of PAK1 due to the presence of molecules. Figure 3 shows key PAK1 pathways which are activated by the compounds of the present invention. Figure 4 shows a diagrammatic representation of a PAK1 kinase reaction. Figure 5 shows the PAL-MS Workflow using JB122 described in Example 3. Diazirine photoaffinity labels were incorporated to JB120 to form JV122 to allow covalent modification of PAK1 to occur upon UV radiation. PAL-1089 is JB122, and CP-9595 is the parent compound, JB120. - 70 - Figure 6 shows the levels of PAK1 peptide labelling by JB122 in the presence and absence of JB120. A) ECLQALEFLHSNQVIHR (SEQ ID NO: 5); B) ECLQALEFLHSNQVIHR; C) YMSFTDK (SEQ ID NO: 8); D) KNPQAVLDVLEFYNSK (SEQ ID NO: 7); E) KELIINEILVMR (SEQ ID NO: 6). 5 Reduction of peptide intensity confirms competitive antagonism, which shows the specificity of the compound binding site. Figure 7 shows the levels of PAK1 peptide labelling by JB122 in the presence and absence of JB120 and CDC42. A) ECLQALEFLHSNQVIHR; B) KELIINEILVMR; C) 10 KELIINEILVMR. Reduction of peptide intensity confirms competitive antagonism, which shows the specificity of the compound binding site. Changes in the affinity binding due to the presence of CDC42 suggest that the binding of CDC42 causes conformational changes to PAK1 which affect the binding of the labelled ligand. 15 Figure 8 shows (A) the full-length sequence of PAK1 (SEQ ID NO: 1) with the amino acids covalently modified by JB122 underlined; and (B) the full-length sequence of PAK2 (SEQ ID NO: 2) with the amino acids covalently modified by JB2019A underlined . 20 Figure 9 shows 3D crystal structure of PAK1 and locations of JB122 modified residues. Figure 10 shows therapeutic validation of PAK1 activators in vitro. Representative immunoblot of neonatal cardiomyocytes were treated with ISO (50 μM) in the 25 presence or absence of 40 μM PAK1-A1 (A) and PAK1-A2 (B) for 2h and 4h. (C and D) Quantification of the Thr423 phosphorylation / total PAK1 ratio in cells treated with PAK1-A1 (C) and PAK1-A2 (D) for the immunoblots shown in (A and B). (E and F) Quantification of the mRNA expression levels of ANP (E) and BNP (F) measured by RT-qPCR. (G and H) Representative images (G) and quantification of 30 cardiomyocyte area (H) evaluated after α-actin immunostaining. Scale bar=50 μm. To investigate early prevention, neonatal rat cardiomyocytes were subjected to treatment with isoprenaline (ISO, 50 μM), both with and without the presence of PAK1 activators (40 μM). To assess the effect of late intervention with PAK1 activators, PAK1-A1 and PAK1-A2 were introduced 24 hours post-ISO treatment. 35 n=200-300, data are presented as mean ± SEM. ****p < 0.0001, ***p < 0.001, **p < - 71 - 0.01, *p < 0.05, ns, not significantly different according to one-way ANOVA with Tukey’s posthoc test. See also Figure 11 and 12. Figure 11 shows therapeutic effect of PAP against Angiotensin II (Ang II) induced 5 hypertrophy. Related to Figure 10. (A and B) Representative images (A) and quantification of fibrotic area (B) evaluated after Masson Trichrome and Sirius Red staining for mouse heart treated with vehicle, Ang II, and PAP. Data are presented as mean ± SEM. n=3. (C-G) Representative images (C) and quantification of heart / body weight ratio (D), left ventricle mass (E), left ventricle anterior thickness 10 (F), and left ventricle posterior thickness (G) evaluated after Sirius Red staining for wild type and PAK1-KO treated with vehicle, Angiotensin II and PAP. Data are presented as mean ± SEM. n=3. Figure 12 shows therapeutic effect of JB79 against transverse aortic constriction 15 (TAC) induced hypertrophy. Related to Figure 10. (A and B) Representative images (A) and quantification of heart / body weight (B) for sham and the TAC mice treated with vehicle and JB79. Data are presented as mean ± SEM. n=15. (C and D) Representative images (C) and quantification of myocyte cell size (D) evaluated after Masson Trichrome staining for sham and TAC mice treated with vehicle and 20 JB79. Data are presented as mean ± SEM. n=10. (E and F) Representative images of echocardiography (E) and quantification of key parameters (F) for sham and TAC mice treated with vehicle and JB79. Data are presented as mean ± SEM. n=10. Figure 13 shows baseline evaluation hypertrophic cardiomyopathy (HCM) mouse 25 model. Related to Figure 15. (A and B) Representative images of echocardiography (A) and quantification of key parameters (B), including ejection fraction, stroke volume, cardiac output, left ventricle (LV) mass, LV anterior wall thickness, and LV posterior wall thickness for WT and HCM mice at 4-week and 7-week-old. (C and D) Representative images (C) and quantification of fibrotic area (D) evaluated after 30 Sirius Red staining for WT and E99K mouse heart at 4-week and 7-week-old. (E) Quantification of heart / body weight for WT and the E99K mice. n=3. Data are presented as mean ± SEM. ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05 according to two-way ANOVA. - 72 - Figure 14 shows therapeutic effect of PAK1-A3 against hypertrophic cardiomyopathy (HCM). Related to Figure 15. (A) Representative immunoblot of ER-stress related key markers using heart tissues from WT and E99K mice at 4- week and 7-week-old for baseline study. (B and C) Representative images (B) and quantification of heart / body weight (C) for WT and the HCM mice treated with vehicle and PAK1-A3 (10mg / kg). (D-H) Quantification of fraction shortening, cardiac output, ejection fraction, and LV posterior wall thickness (LVPW) for echocardiography measurement. n=5. Data are presented as mean ± SEM. ***p< 0.001, **p < 0.01, *p < 0.05 according to one-way ANOVA with Tukey’s posthoc test. Figure 15 shows therapeutic validation of PAK1 activators. (A-D) Representative images of echocardiography (A) and quantification of key parameters, including stroke volume (B), LV mass (C), and LV posterior wall (LVPW) thickness (D), for WT and HCM mice orally treated with vehicle and PAK1-A3 (10mg / kg). n=5. (E) Representative histology staining images 551 for HCM mice treated with vehicle and PAK1-A3. (F and G) Quantification of myocyte cell size (F) and fibrosis area (G) evaluated after histology staining as shown in (H). Data are presented as mean ± SEM. ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05, ns, not significantly different according to one-way ANOVA with Tukey’s posthoc test. (K-N) Representative immunoblot (K) and quantification (I-N) of ER-stress related key markers using heart tissues from WT and E99K mice treated with vehicle and PAK1-A3. See also Figure 13 and 14. Figure 16 shows therapeutic effect of PAK2 activator JB2019A against TAC- induced cardiac hypertrophy and susceptibility to ventricular arrhythmia. A, Chemical structure of PAK2 activator JB2019A. Docking model of Alphafold2 predicted PAK2 structure and its activator JB2019A. Key residues involved in JB2019A binding are labeled. Hydrogen bonds and distances are highlighted in yellow; B, Representative immunoblotting images showing p-Pak2 protein level from WT mice with DMSO or JB2019A treatment (n=4 mice for each group). C, Representative in vivo cardiac electric detector of Pak2f / fand Pak2ckomice with different frequencies of burst stimulation. D, Representative in vivo electrophysiological recordings from WT mice at 5 weeks after sham or TAC surgery. Cardiac arrhythmia was induced with isoproterenol (2 mg / kg) and caffeine - 73 - (160 mg / kg). Arrows indicate the ventricular ectopic beats (EB). Scale bar: 1 s or 0.2 s. E, statistical graph showing the VT occurrence of C. F, Statistical graph of ventricular ectopic beats in the four groups of mice injected with isoproterenol and caffeine. G, Representative anatomic images and cardiac longitudinal morphology of WT heart at 5 weeks after sham or TAC surgery with DMSO or JB2019A treatment. Scale bar, 5 mm (Upper panel). Scale bar, 2.5 mm (Lower panel). H, WGA staining of heart tissue from indicated groups. Scale bar, 50 µm. I, HW / BW (mg / g) ratio and cell cross-sectional area of WT heart at 5 weeks after sham or TAC surgery with DMSO or JB2019A treatment (n=4-7 mice). J, Echocardiographic analysis of WT heart at 5 weeks after sham or TAC surgery with DMSO or JB2019A treatment. K, Quantification of echocardiography parameters in J (n=3-7 mice). *P < 0.05; **P < 0.01, *** P < 0.001. **** P < 0.0001. Figure 17 shows Pak2 activator JB2019A attenuates TAC-induced cardiac oxidative stress and abnormalities in mitochondrial structure. A, Representative fluorescence images shows ROS levels of WT mice 5 weeks after sham or TAC surgery with DMSO or JB2019A treatments. Scale bar 100 µm. B, Quantification of A. C, Representative transmission electron microscopy images of WT mice at 5 weeks sham or TAC surgery with DMSO or JB2019A treatments. Scale bar 1 µm. D and E, Representative immunoblotting images and statistical graph showing ox-CaMKII and t-CaMKII protein expressed 5 weeks after sham or TAC surgery with DMSO or JB2019A treatments (n=4 mice for each group). The present invention is further illustrated by the following Examples, in which parts and percentages are by weight and degrees are Celsius, unless otherwise stated. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only. From the above discussion and these Examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. - 74 - EXAMPLES Example 1 - Rapid-Fire mass spectrometry TM Rapid-Fire Mass Spectrometry was used as a second line in-vitro assay to confirm the compound activity on PAK1 / CDC42. RF-MS is fully automated and performs integrated sample purification and MS analysis. It is able to directly analyze the conversion of substrate to product form – by measuring the shift in the mass of substrates to its phosphorylated form. This can be translated into the rate in which the substrate peptides are being converted to the final product by PAK1 / CDC42. Therefore, one can measure the effect of the compounds on the activity of PAK1 / CDC42 under the presence of the compounds. For these figures, all kinase assays were performed in 1.1 mL polystyrene 96-well deep well plates. Assays were prepared at room temperature using a reaction buffer (Abcam kinase assay buffer 1, ab189135) containing 25 mM MOPS, pH 7.2, 12.5 mM β-glycerol-phosphate, 25 mM MgCl2, 5 mM EGTA, and 2 mM EDTA. PAK1 and CDC42 were added to a final concentration of 20 nM and 0.5 µM, respectively, to the buffer solution – the protein buffer solution volume constituting 795 µL. Compounds dissolved in 5 µL DMSO were diluted in 800 µL of assay buffer (final DMSO concentration 0.5%). The reaction was initiated by adding 200 µL substrate solutions, containing PAKtide (30 µM final concentration) and adenosine triphosphate (100 µM final concentration). The total reaction volume was 1000 µL. Assay plates were transferred to a RapidFire 365 integrated autosampler / SPE system coupled with 6530 QTOF (Agilent Technologies). Samples were aspirated from each well for 500 ms, and 10 µL was loaded directly onto a RapidFire micro- scale SPE C4 (type C) cartridge. Solvent A, used for sample loading and washing, was water containing 0.1% (v / v) formic acid. Solvent B, used for sample elution, was acetonitrile (v / v) containing 0.1% (v / v) formic acid. The 10 µL of sample was loaded onto the C4 cartridge and washed for 3 s with Solvent A to remove any non- organic components. Analytes were then eluted into the mass spectrometer in a 3 s elution cycle using Solvent B, and the cartridge was then equilibrated by washing with Solvent A for 500 ms. In kinetic assays, the sample readouts are repeated at - 75 - different time intervals in order to ensure that enough data points are acquired to plot a kinetic response of PAK1 activity. Agilent RapidFire 4.0 and Agilent MassHunter B.07.00 software were used for instrument acquisition and data processing. Quantitative analysis was performed for each analyte of interest by calculating the ratio of the area of the most abundant ion with respect to the area of the internal standard. The ratio of peptide substrate and phosphorylated product were analyzed at masses of 1921.1 (substrate) and 2006.1 (product) to measure their quantity. Taking Figure 1, the figures show Rapid-Fire mass spectrometry PAK1 / CDC42 kinase assay results for compounds JB01, JB06, JB08, JB09, and JB18 in a real- time dependent substrate phosphorylation. "Sub:Pro Conversion (%)" presents the amount of substrate phosphorylation over time. Each sample points presents the ratio between the unphosphorylated substrate and phosphorylated substrate. Multiple samples taken over time will provide a slope curve which represents the rate of substrate phosphorylation correlating to the kinase activity. For instance, in Figure 1B, JB06 (20uM) was able to significantly activate PAK1 / CDC42, converting most of the substrate to product within 20 minutes of the kinase reaction (>70% sub:pro conversion). The control group DMSO, on the other hand, was only able to convert < 20% of the substrate to its product form (< 20% sub:pro conversion). From this result, we can conclude that JB06 has significantly activated PAK1 activity and therefore behaves as a PAK1 activator. This conversion rate is useful as it shows the rate of PAK1 / CDC42 activity and measures the effects of the compounds on the kinases directly. The rates of substrate to product (substrate phosphorylation) conversion were compared in PAK1 / CDC42 kinase reaction under the presence of JB06, JB08 and JB18 (10µM, 20µM, and DMSO), shown in Figures 1B, 1C, and 1E respectively. All reactions contained 10nM of PAK1 with 1µM of CDC42. For Figure 2, the amount of phosphorylated substrate was collected only once at time 40 minutes to look at the ratio between the phosphorylated and unphosphorylated substrate. The “PAK1 Activity (%)” on the y-axis represents the - 76 - normalized activity of the kinase based on based on the control (DMSO, 100%) PAK1 activity. Percentage deviation from the normalized baseline (100%) represents the changes in enzymatic activity of PAK1 due to the presence of molecules. These results demonstrate that the compounds of the invention are able to significantly increase the baseline activity of PAK1 and are thus suitable for the treatment of cardiovascular disease. Example 2 – PAL-MS studies Photo-affinity labeling (PAL) coupled to mass spectrometry (PAL-MS) allow to detection of amino acids of the protein that the ligand of interest binds to. Several JB120 photoaffinity reporters and used structural proteomics to investigate the ligand binding sites. Based on the preliminary SAR studies that high polar groups at the meta- and para-positions were shown to improve PAK1 stimulation, JB120- PALs (JB121 and JB122) were designed, which contains a diazirine photocross- linker at the para- and meta-position accordingly. The photoaffinity reporters were then evaluated in PAK1 kinase activity assay using Rapidfire-MS to make sure the incorporated photo-activating groups do not significantly alter the binding affinity and functionality of the ligand. Full length PAK1 (0.5 µM) was added into kinase buffer, then pre-incubate with JB121 and DMSO control for 3 h. Due to the importance of Cdc42 in potentially increasing the affinity of the compound binding, another condition was added to introduce CDC42 in addition to the PAK1 FL alone. After three-hour treatment, the diazine photoaffinity label incorporated to the JB120 allows the covalent modification to occur once the UV radiation treatments were given. After 20 min of UV irradiation at 365 nm, acetone precipitation (1:9) for PAK1 protein were performed, followed by protein digestion and peptide desalting. NanoLC-MS / MS was applied for proteomics measurement and the automatic peptide sequencing was achieved using the MaxQuant Software. Quantitative proteomics analysis revealed that for PAK1 treated with JB121, there were four modified peptides highly abundant with ΔM mass shift corresponding to - 77 - JB121 (461.09KDa). The dynamic programming (DP) score directly count the number of peptides occurring at each score in the distribution. A competitive assay using JB121 together with JB120 compound was conducted to determine if JB121 and the parent compound JB120 are binding at the same site. 5 Example 3 - PAK1 activators provide cardioprotective effects The therapeutic potential of PAK1 activators PAK1-A1 (MedChem Express), and PAK1-A2 (Enamie) in preventing pathological cardiac hypertrophy in neonatal 10 cardiomyocytes was investigated. Prolonged isoprenaline (ISO) treatment in mice hearts can induce β-adrenergic stimulation and leads to adaptive responses, ultimately resulting in pathological cardiac hypertrophy. Both PAK1-A1 and PAK1-A2 significantly increased PAK1 15 phosphorylation (p-Thr423) in a time-dependent manner by 1.5-fold and 1.3-fold, respectively (Figures 10A and 10B). These results demonstrate the ability of PAK1 activators to directly activate PAK1 in vitro. Moreover, mRNA levels of ANP and BNP, genetic markers of pathological cardiac hypertrophy, were found to be significantly elevated in ISO treated H9C2 cells (Figures 10E and 10F). However, 20 co-treatment with either PAK1-A1 or PAK1-A2 was shown to mitigate ISO-induced hypertrophy. mRNA levels of ANP and BNP were also reduced in H9C2 cells co- treated with PAK1-A1 and PAK1-A2 (Figures 10E and 10F). One of the clinical hallmarks in cardiovascular medicine is to reverse pre-existing 25 pathological cardiac hypertrophy. Unfortunately, due to its complex and challenging reversibility nature, limited research has explored the development of small molecule drugs that can reverse the pathological progression. It is noteworthy that both PAK1-A1 and PAK1-A2 not only demonstrated a pronounced efficacy in preventing ISO-induced neonatal rat cardiomyocyte hypertrophy at an early stage, 30 but also displayed a remarkable capacity to regress pre-existing cellular hypertrophy 24 hours following ISO treatment as evidenced by reduced hypertrophic cellular sizes (Figures 10G and 10H). In addition, the therapeutic anti- hypertrophic effect of these kinase activators was found to be efficacy dependent. PAK1-A1 exhibited higher efficacy in activating PAK1 compared to PAK1-A2, which - 78 - showed a greater anti-hypertrophic effect in alleviating ISO-induced cardiac hypertrophy. Cardiac hypertrophy is a major cause of ischemic injury leading to heart failure. To induce cardiac hypertrophy and cardiac remodeling in vivo, mice were treated with a cardiac stress inducer Ang-II. Co-administration of PAP showed a significant inhibition of Ang-II-induced hypertrophy as demonstrated by reduced fibrotic area, heat / body weight, LV mass and wall thickness (Figures 11A to 11G). To further confirm the involvement of PAK1 in the antihypertrophic mechanism, PAK1 knockout mice (PAK1cko) were generated, and the beneficial effects of PAP were abolished in these mice (Figures 11C to 11G). These results emphasize that the observed cardioprotective effects associated with PAP are specifically mediated by the activation of PAK1, highlighting the critical role of PAK1 in mediating the observed antihypertrophic effects. Pressure overload cardiac hypertrophy was also investigated using a transversal aortic constriction (TAC). Mice subjected to TAC and receiving a 5-week treatment of JB79 (10mg / kg) exhibited significantly reduced cardiac hypertrophy compared to mice receiving vehicle treatment (Figures 12A and 12D). JB79 treatment also significantly reduced IVSd, LVPWd, and LV Mass, while preserving ejection fraction and fractional shortening in TAC mice group (Figures 12E and 12F). Previous studies have shown that PAK1cko TAC myocardium contains higher expression levels of MKK4 / MKK7-JNK compared to WT heart, while this effect was not observed in PAK1CA hearts, suggesting that PAK1 is an upstream activator of the MKK4 / MKK7-JNK pathway, and activation of the JNK pathway is essential for modulating cardiac hypertrophy signaling. Overall, our TAC experiments provided evidence that JB79-mediated activation of PAK1 can significantly alleviate TAC- induced cardiac hypertrophy. Additionally, we demonstrated that modulation of PAK1 activity by PAK1-A3 (MedChem Express) leads to notable enhancements in cardiac function within a transgenic hypertrophic cardiomyopathy (HCM) mouse model expressing the mutation ACTC E99K. Despite significant progress made in understanding the genetic and molecular basis of hypertrophic cardiomyopathy (HCM), there remains a lack of effective and specific treatment for preventing the disease progression of - 79 - HCM. Our baseline study, conducted at the ages of 4 weeks and 7 weeks, revealed that E99K mice at 4-week-old had already manifested cardiac hypertrophy. This was evidenced by a reduction in stroke volume and cardiac output, alongside increased LV wall thickness and fibrosis (Figures 13A to 13E). Moreover, in hearts from HCM mice with the Actc1 E99K mutation revealed the presence of ER stress responses, including changes in the expression and activity of protein kinase-like ER kinase (PERK), BiP, and C / EBP homologous protein (Chop) involved in apoptosis (Figure 14A). Oral treatment with PAK1-A3 (10mg / kg) significantly improved stroke volume, LV mass, and LVPWd over the 6-week period (Figures 15A to 15D and 14D to 14H). Notably, we also observed reduced heart weight, cardiac hypotrophy and the progression of fibrosis compared to vehicle group (Figures 15E to 15G and 14B and 14C), suggesting a potential novel treatment for HCM. Furthermore, the pathogenesis of HCM from a single mutation to comprehensive myocardial remodelling, responsible for the disease onset and progression, has not yet been well elucidated. Upon evaluating the baseline results of the E99K mutation and the observed alterations in ER stress related markers, we propose that ER stress is likely another important mechanism that underlies disease progression in HCM. However, ER stress presents a previously poorly characterized pathogenic element in HCM with diverse vital cellular functions likely compromised. Following a six-week treatment regimen with PAK1-A3, the phosphorylated PAK1 was enhanced and ER stress in HCM hearts were alleviated (Figure 15H to 15N). Specifically, ER stress-induced apoptosis Chop was reduced while the protective ER stress response IRE-1 / XBP-1s was promoted, uncovering a novel cardioprotective mechanism of PAK1 activators in HCM through alleviating ER stress response. Collectively, these findings support the therapeutic use of both PAP and the small molecule activators of PAK1 described herein, which are believed to target the autoinhibition release motif of PAK1, for anti-hypertrophic therapy. More specifically, these results demonstrate therapeutic applications for the small molecule activators of PAK1 described herein in the treatment and prevention of cardiovascular diseases, including HCM (Figure 15). - 80 - Currently, there is still a lack of effective and specific treatment for controlling the disease progression of HCM. Gene therapy is still in its early infant stage and not available for patients with polygenic traits. Sarcomere-targeting pharmacological interventions may also lack the therapeutic benefits in these patients. One of the 5 major challenges in treatment of HCM is the lack of an early stage therapeutic intervention, particularly during the early stage fibrosis. Thus, it is important to note, as demonstrated in this study, that the treatment with PAK1 activators was instituted at 4 weeks of age, targeting the early stage in the progression of HCM, characterized by the increased LV wall thickness and the presence of fibrosis at the 10 apex.. Our treatment results further demonstrated that PAK1 activators effectively decelerated the advancement of pre-existing hypertrophy and fibrosis. Additionally, in mice expressing the E99K mutation, which mimics actual mutation in human HCM patients, PAK1 activators were able to reverse the ongoing hypertrophic- related ER stress signalling and thereby minimized the hypertrophic effect (Figures 15 15H to 15N). Method details Peptide synthesis 20 PAK1 activating peptide (PAP) TSNSQKYMSFTDKSA (SEQ ID NO: 9) was prepared as previously described. Briefly, PAP derived from the PAK1 autoinhibitory region was linked to the 11-amino acid sequence YGRKKRRQRRR (SEQ ID NO: 10) derived from HIV-1 trans-activating regulatory protein. The peptide (YGRKKRRQRRRGTSNSQKYMSFTDKSA; SEQ ID NO: 11) was 25 synthesized in the proteomics core lab in Research Resource Centre at University of Illinois at Chicago (UIC), USA and was confirmed by mass spectrometry. Cell culture Chinese hamster ovary (CHO) cell line was used for biosensor plasmid transfection 30 and FRET experiments. CHO cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) (Gibco , 11500416) containing 10% Fetal Bovine Serum (FBS)(Gibco , 15575309), 1% L-Glutamine (Gibco , 15430614), and 1% penicillinstreptomycin (Gibco , 11568876) at 37 C and 5% CO2. Cells were seeded on 24mm cover glasses (VWR, 631-1583) over 24 h to adhere before plasmid - 81 - transfection. Transfected cells were kept in culture for less than 36 h, followed by FRET imaging. For cellular efficacy study of PAK1-A1 and PAK-A2, H9C2 cell line was applied for the compound and Isoprenaline (ISO) (Sigma-Aldrich, I5627) treatment. H9C2 cells were cultured in DMEM containing 10% FBS, 1% L- 5Glutamine, and 1% penicillin streptomycin at 37 C and 5% CO2. For hypertrophyinduction, cells were starved in serum-free MEM for 4 h prior to addition of 50 μM ISO for 48 h with or without the treatment of 40 μM PAK1 A1 and PAK1-A2. Further immunoblots and staining were performed to assess cellular hypertrophy. 10 RNA isolation and real-time PCR for ANP and BNP Total RNA was extracted from H9C2 cell samples with Trizol. To get rid of any genomic DNA contamination, samples were given a DNAse treatment. Lunascript was used to transform RNA into cDNA. The NanoDrop2000 was used to measure the concentration and purity of RNA and cDNA from each sample. According to the 15 manufacturer's instructions, qPCR reactions were carried out using SYBR Select PCR Master Mix and specific primers for quantitative real-time polymerase reaction (qPCR). For qPCR reactants, 10 l of SYBR, 2 l of primer, 7 l of nuclease freeH2O, and 1 l of cDNA were used. Relative expression was evaluated by the2-Ct method. All experiments were performed independently in triplicate. 20 Generation of PAK1-KO Mice Mice with PAK1 gene disruption at both alleles were created in SV129 background and have been described previously. PAK1-KO mice were re-derived in FVB background and genotyped to confirm deletion of the PAK1 gene. Adult (3 4-25 month-old) male or female mice were used for acquisition of morphometric and biochemical analysis. Unless specifically indicated otherwise, age- and gender- matched littermates were used as WT controls. The animal studies were performed in accordance with the UK Home Office and institutional guidelines. 30 Angiotensin II-Induced Cardiac Hypertrophy and PAP treatment We used micro-osmotic pumps in all the experiments to obtain an infusion rate 0.25 μl per hour, for 7 days. Age and sex matched, 3- to 4-month-old, PAK1-KO and wild type (WT) mice were randomized in groups to receive seven days continuous subcutaneous administration of 1 μg / g / day Ang II plus, with or without the treatment - 82 - of 1 μg / g / day PAP, or an equivalent volume of saline (control) in micro-osmotic pump (Model 1002, Alzet, Cupertino, CA). All peptides were dissolved in saline. Mice were initially anesthetized with 3% isoflurane and 100% oxygen inhaled in a closed anaesthesia chamber. On day seven of the pump insertion, the animal was anaesthetized with pentobarbital (50-90 mg / kg) and the heart was excised for morphometric and biochemical analysis. A full description of the surgical procedure is reported elsewhere. After the treatment, the heart weight (HW) and body weight (BW) were measured and the HW / BW ratios were calculated to indicate cardiac hypertrophy. Hypertrophic responses at the end of the treatment were analysed by histology and biochemical analysis. Murine model of TAC and treatment of JB79 Cardiac pressure overload, to cause left ventricular hypertrophy, was induced by TAC in male mice as previously described45. A closed-chest transverse aortic constriction model for induction of left ventricular hypertrophy in C57 mice. Mice were anesthetized by 1.5%-2% isoflurane using the gas anaesthesia machine (RWD Life Science, Shenzhen, China). In a spontaneously breathing animal following a 3-4 mm upper partial sternotomy, a segment of 6 / 0 silk suture threaded through between the right common carotid artery and the innominate artery and tied over a 27-gauge needle. Sham animals underwent the same surgical preparation, but without the constriction of the aorta. One day after TAC surgery, JB79 (10 mg / kg / d) or solvent-controlled DMSO was injected intraperitoneally for 14 days (1 mg JB79 + 50 L DMSO completely dissolved). Hypertrophic responses at the end of the treatment were analyzed by heart weight / tibia length, echocardiography, histological analysis, and biochemical analysis. E99K hypertrophic cardiomyopathy (HCM) and PAK1-A3 treatment The transgenic E99K HCM mice were kindly provided by Prof. Hugh Watkins, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. Briefly, The E99K mutation was inserted into the human cardiac actin (ACTC Gene) sequence. Transgene expression was restricted to the heart using an alpha-myosin heavy chain promoter construct. Transgenic mice were generated by pronuclear microinjection of gel purified transgenic constructs into the pronucleus of fertilised mouse eggs on a C57BL10xCBA / Ca hybrid 35 background as previously described. Treated embryos were returned to a - 83 - pseudopregnant CD-1 foster mother, generated by mating with a vasectomised male mouse, and the resultant pups were identified and genotyped by PCR from ear notch samples. At 4 weeks of age, male and female mice of WT and E99K littermates were echoed at baseline. Mice were genotyped and randomly divided into 3 groups and were treated for 6 weeks by oral administration with PAK1-A3 (10 mg / kg per day) in 0.5% (w / v) methylcellulose (MC) solution, or vehicle (0.5% MC solution). The following groups were generated and studied: WT, E99K-vehicle, and E99K-PAK1-A3. Hypertrophic responses at the end of the treatment were analyzed by heart weight / tibia length, echocardiography, histological analysis, and biochemical analysis. Histological analysis Hearts were removed from mice anaesthetized with 3-5% isoflurane and transferred to 4% polyformaldehyde in PBS for fixation for 48 h and processed into paraffin. Heart sections (5 μm) were prepared for light microscopy and stained with Hematoxylin and Eosin (Abcam, ab245880), Masson's Trichrome (Abcam, ab150686), or Picro-Sirius Red staining (Abcam, ab245887) techniques, following the manufacturer's guidance. Images were acquired using Pannoramic SCAN (3DHISTECH Ltd. Hungary) to scan the whole film. Analysis of the fibrotic area of the tissue is expressed as a percentage and the mean cross-sectional area of cardiomyocytes measurement were both calculated by using Fuji ImageJ. Echocardiography and Analysis For TAC model and the treatment of JB79, mice were anesthetized with 1%-1.5 % isoflurane. Parasternal short-axis section (PSAX) B-mode and M-mode echocardiographic were recorded using the Vevo3100 micro-ultrasound imaging system (FUJIFLIM VisualSonics Inc., Canada). Three measurements taken at end- systole (s) and end-diastole (d) were averaged to calculate corresponding values of intraventricular septal thickness (IVSs and IVSd), left ventricular posterior wall thickness (LVPWs and LVPWd), and left ventricular diameter end-diastolic (LVIDd) 1215 and left ventricular diameter end-systolic (LVIDs). Ejection fraction (EF) and fractional shortening (FS) were also acquired from the recorded measurements. For E99K model and PAK1-A3 treatment, mice were first anesthetized by placing the mouse in a plexiglas chamber connected to vaporizer providing isoflurane at 2% in 100% O2. Once induced, the mouse was then secured in the supine position on a - 84 - warming plate, isoflurane concentration was reduced to 1.5-2% and hair removed from the chest using depilating agent. Body temperature was monitored and kept to 37°C throughout the procedure. Transthoracic echocardiography was performed using a Vevo 2100 In Vivo Imaging System (VisualSonics). Anatomical M-Mode images of the left ventricle (LV) were taken from the parasternal long axis view to measure ejection fraction (%), stroke volume (μL), and the LV wall thicknesses. All measurements and calculations were averaged from three consecutive cycles. Data analysis 1225 was performed offline with the Vevo 770 Analytic Software (VisualSonics). Immunoblot analyses To measure the PAK1 activation induced by PAK1-A1, PAK1-A2, and ISO treatment. Cultured H9C2 cells were washed with DEPC-PBS and lysed with lysis buffer. Lysates were collected, vortexed for 30 seconds, placed on ice for 10minutes, and repeated 2-3 times. The prepared samples were centrifuged at 13500 rpm for 15 minutes at 4!, and the supernatant protein was collected to estimate the protein concentration with BCA reagent. In this research, protein 20 gper well. SDS-PAGE gels of 8% or 12% were used depending on the molecular weight of the target protein. After electrophoresis, the gel was transferred to a polyvinylidene fluoride (PVDF) membrane. The transferred PVDF membrane was blocked with blocking buffer containing 5% non-fat dry milk for one hour. Primary antibodies were diluted to 1:1000 in 5% dry milk and incubated overnight on a shaker at 4°C. After the membranes were incubated with horseradish peroxidase- linked anti-rabbit secondary antibody, they were stained with ECL. Image Pro Plusv6.0 was used to quantify protein bands. For TAC model treatment immunoblots, 20 μg total protein for each lane was separated using 5% stacking gel and 8-12% separation gel, and transferred to a 0.45 μm PVDF membrane (Millipore, USA). The membrane was incubated in TBST containing 5% non-fat milk for 1 h at room temperature and was incubated with the primary antibody overnight at 4 °C. The primary antibodies for ANP (ab180649, Abcam, 1:500), phosphorylated PAK1 (p-PAK1, 2601, Cell Signaling Technology, 1:300), total-PAK1 (t-PAK1, 2602, Cell Signaling Technology, 1:1000), phosphorylated-ERK (p-ERK, 4370, Cell Signaling Technology, 1:1000), total-ERK 35 (t-ERK, 4695, Cell Signaling Technology, 1:1000), phosphorylated-JNK (p-JNK - 85 - 9251, Cell Signaling Technology, 1:1000), total-JNK (t-JNK, 9252, Cell Signaling Technology, 1:1000), phosphorylated-MKK7 (p-MKK7, 4171, Cell Signaling Technology, 1:1000), total-MKK7 (t-MKK7, 4172, Cell Signaling Technology, 1:1000), phosphorylated-MKK4 (p-MKK4, 9151, Cell Signaling Technology, 5 1:1000), total-MKK4 (t-MKK4, 9152, Cell Signaling Technology, 1:1000) and GAPDH (Santa Cruz Biotechnology, 1:1000) as the internal control were used. The membrane was incubated with the secondary antibody (1:1000) Goat anti-mouse IgG HRP (BBI life sciences, China) or Goat anti-rabbit IgG HRP (BBI life sciences, China) for 1 h at room temperature. The immunoreactions were visualized using 10 chemiluminescent HRP Substrate (Millipore, USA), then imaged protein bands with the Universal Hood II System (Bio-Rad, USA). For E99K mouse model treatment immunoblots, total protein from tissues was obtained with Triton lysis buffer (Tris 20 mM, NaCl 137 mM, EDTA 2 mM, 1% Triton X-100, - glycerophosphate 25 mM, Na3VO41 mM, phenylmethanesulfonylfluoride 1 mM, aprotinin 1.54 M, leupeptin 15 21.6 M, 10% glycerol; pH 7.4). Protein concentration was determined by Bio- Rad protein assay. Protein extracts (30 g) were subject to immunoblot analyses with antibodies (all antibodies applied in this study were used as 1:1000 dilution) against PAK1 (Cell Signaling, 2602), CHOP (Cell Signaling, 2895), phospho-PAK1 (Cell signaling, 2601), phospho-PERK (Cell Signaling, 3179), ATF6 (Abcam, ab37149), 20 BiP (Cell 1265 signaling, 3183), ATF6 (Abcam, ab85049), GADPH (Cell Signaling, 92310). Immune-complexes were detected by enhanced chemiluminescence with anti-mouse, anti-rabbit or anti-goat immunoglobulin-G coupled with horseradish peroxidase. 25

[0002] - 86 - Compound JB79 was prepared as set out in Scheme 1 below: 5 10 15 Example 20 Compou he Scheme 2 - 87 - Scheme 2 can also be used to prepare compounds such as JB55, JB56, JB108, JB109, JB113, JB114, JB117, JB120, JB121 and JB122. Exampl 5 Compo in Scheme 3 below: e 3 - 88 - Example 7 – Preparation of JB124 Compound JB124 was prepared as set out in Scheme 4 below: 5 Schemes 3 a B41, JB47, JB53, JB62, B85, JB87, 10 JB88, JB92, and JB133. Example 8 – A PAK1 activ vation 15 (Figure 16B). s PAK2, we applied Autod re generated by ithin the auto-inhibitor B2019A induces an al e form. 20 Western blott ession upon treatme 001, Figure 16B). The increased activation of PAK2 by JB2019A reduced arrhythmia and - 89 - cardiac remodeling in both acute adrenergic and chronic TAC stress conditions (Figure 16 and 17). With acute isoproterenol challenge, JB2019A decreased VT occurrences (55%, 22 / 40, P < 0.001) in Pak2f / fmice, while having a minimal effects (to 84.6 e (Figure 8C-8F). 5 In WT h ences of ventricular ectopic beats from 14.33±2 JB2019A then alleviated this effect with a d cid rated TAC-ind G- sed 10 cardiom / B this effect. In en affect the card H phic analysis -i (Figure 16J and ed g ROS 15 levels a Fi AC induced D a of the CaMKII ive rial damage ta 20 Thus, it or JB2019 tric Generat del The Pak m ing 25 exon 2 o R / ghai Biomod ev ai, China). ut ted from the Pak cy me (Cre) un C) r the 30 Pak2f / fa CR. The efficiency of the Pak2 knockou g. Method 35 Experimental groups - 90 - Studies testing the effects of JB2019A, used Pak2ckoand Pak2f / fmice both not subject to any surgical procedures in testing the effects of acute isoproterenol induced adrenergic stress. WT mice were used to test the effect of JB2019A on chronic TAC induced hypertrophic stress. 5 Experiments on intact mice were performed under 1-2% isoflurane anesthesia using a gas anesthesia machine (RWD Life Science, Shenzhen City, Guangdong Province, China). In vivo surface ECG monitoring to assess for ventricular 10 tachycardia with regular waveforms (VT), or arrhythmia with irregular fibrillating waveforms (VF) by multichannel recording (MP150, BIOPAC Systems Inc, USA). Cardiac stimulation used electrodes directly placed on the cardiac surface through a thoracotomy connected to a stimulator (SEN-7203, NIHON KOHDEN, Japan). A burst pacing protocol applied series of 50 stimuli with successive cycle lengths 15 (CLs) of 90, 70, 50, and 30 ms, before and following an intraperitoneal (i.p.)_isoproterenol (10 mg / kg) injection to increase arrhythmic susceptibility. Additionally, animals in the TAC group were exposed to isoproterenol (2 mg / kg, i.p.) and caffeine (160 mg / kg, i.p.) to test for induced ventricular arrhythmia in an absence of applied stimulation as previously described. 20 Optical mapping in intact hearts Electrophysiological function in intact isolated hearts was assessed using the optical mapping system equipped with an EMCCD camera as previously described

[26] . Briefly, each mouse was anesthetized with 2-5% isoflurane using the gas 25 anesthesia machine.10 min following an intraperitoneal heparin (3.5 U / g) injection, the heart from the adult mouse was quickly removed. The isolated, spontaneously beating, heart was placed in physiological Tyrode solution (128 mmol NaCl, 20 mmol NaHCO3, 1.18 mmol NaH2PO4, 1.05 mmol MgCl2, 4.7 mmol KCl, 11 mmol glucose, 1.35 mmol CaCl2, pH adjusted to 7.4 with NaOH) equilibrated with 95% O230 and 5% CO2. The aorta was cannulated and Langendorff-perfused at a constant 68–74 mmHg pressure at a 1–2 ml / min flow rate at 37 °C. The heart was subsequently slowly perfused over 10 min with Tyrode solution containing 1 μmol di-4-ANEPPS (Molecular Probes, Invitrogen). The Ca2+dye Rhod-2 AM (Thermo Fisher Scientific, UK) was administered as a 50 μl bolus (stock solution: 1 mg / ml in 35 DMSO) over a 5 min period and recirculated for 45 min in the presence of 0.5 mM - 91 - probenecid. After dye loading, the spontaneously beating hearts were moved to a special chamber for optical mapping under an upright microscope equipped with a high-speed EMCCD camera (Evolve 512, Photometrics, Tucson, AZ, United States). The excitation light was provided by a four light emitting diode MacroLED 5 lamps with 525 nm (Cairn Research, UK) for excitation of RH237 and 530 nm LEDs for excitation of Ca2+-sensitive dye Rhod-2. Data was acquired at 1,000 frames / s. Recorded image files were uploaded into ElectroMap optical mapping analysis open source software. To explore for ventricular arrhythmic tendency we applied our burst pacing procedure at the apexes of the Langendroff-perfused hearts using 10 pulse cycle lengths (PCL) from 100 ms to 20 ms. Echocardiographic analysis in intact hearts Mice were terminally anesthetized with 2-5% isoflurane using the gas anesthesia machine. Transthoracic M-mode echocardiographic recordings used the Vevo®3100 15 micro-ultrasound imaging system (FUJIFLIM VisualSonics Inc., Canada) following manufacturer’s instructions. Three measurements taken at end-systole (s) and end- diastole (d) were averaged to calculate corresponding values of intraventricular septal thickness. Ejection fraction (EF) and fractional shortening (FS) were also obtained from the recorded measurements. 20 Hematoxylin and eosin (H & E) staining Hearts removed from mice terminally anesthetized with 2-5 % isoflurane using the gas anesthesia machine were transferred to 4% polyformaldehyde for fixation. Cardiac slice and haematoxylin and eosin (H & E) staining were performed 25 following our previous protocol

[0028] . Images were acquired using a BX63 automated microscope (Olympus, Japan) to scan the entire film under the ×20 objective lens automatically. Mean cross-sectional areas were calculated through ~200 randomly selected cardiomyocytes measured using Image J software. 30 Transmission electron microscopy (TEM) Transmission electron microscopy (TEM) was performed to determine the subcellular structure of heart tissue following the different challenges (TAC or isoproterenol) used in this study as described previously. Briefly, cardiac tissue from the different experimental groups were fixed with 3% glutaraldehyde in 35 phosphoric buffer, then post-fixed with 1% osmate, and dehydrated with gradient - 92 - acetone. Tissues were infiltrated by a solution of epoxy resin and acetone embedded in epoxy resin. Ultra-thin sections (50 nm) were cut and mounted on copper grids, stained with uranyl acetate and lead citrate in the dark at room temperature. Ultrastructural images were obtained under transmission electron 5 microscopy (JEM-1400PLUS, Japan) at 80 kV. Western blotting 20 µg total protein for each lane was separated using 5% stacking gel and 10% separation gel, and transferred to a PVDF membrane (Millipore, USA). The 10 membrane was incubated in TBST containing 5% non-fat milk for 2 h at room temperature to block non-specific binding and was incubated with the primary antibody (1:1,000) overnight at 4 °C. The membrane was incubated with the horseradish peroxidase (HRP) conjugated goat anti-rabbit or mouse IgG (BBI, China) secondary antibody (1:3,000) for 1 h at room temperature. The membrane 15 was incubated in chemiluminescent HRP Substrate (Millipore, USA) at room temperature for 30 s, then imaged with the Universal Hood II System (Bio-Rad, USA). ROS measurement 20 Superoxide-sensitive dye dihydroethidium (DHE) (Cat. No: #HY-D0079, MedChemExpress, USA) was used for ROS measurement. Mouse cardiac tissues were embedded in Tissue-Tek OCT (Thermo Fisher, USA). Cross-sections (10 μm) of cardiac tissues were incubated with DHE (10 μM in 0.01% DMSO) at 37 °C for 30 min in a humidified dark chamber. Red DHE fluorescence was detected with an 25 Olympus IX83 microscope (Olympus, Japan) at room temperature. Preparation of ligand and binding modeling Open Babel was used for the ligand preparation of JB2019A to create a PDBQT file that could be recognized by the docking software. The PAK2 protein structure was 30 downloaded from the Alphafold2 protein structure database (A0A851KSL5 (A0A851KSL5_VIDCH)). Flexible loops with a very low per-residue confidence score were removed using UCSF ChimeraX to avoid the block of active sites by these loops in the docking process. The putative binding of JB2019A to PAK2 was obtained using Autodock Vina

[0031] which is an open-source program for molecular35 docking. Docking models were visualized and generated using UCSF ChimeraX. - 93 - CLAIMS 1. A compound of Formula (II), or a stereoisomer, tautomer, or 5 pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity (II) 10 where: R1and R2are independently selected from aryl groups and , optionally substituted by one or more substituents; 15 R5is a five- or six-membered heterocyclic ring; L2is a linking group selected from a bond and -(CH2)n-, in which n is an integer from 1 to 4; 20 L3is a bond or ; and L7is selected from a bond, -(C3H4)-, -(CH2)x-, and -(CH2)x-C(R3)=C(R4)-(CH2)x-; 25 where each x is independently an integer from 0-4 and where R3and R4are independently selected from: - 94 - - H, - alkyl, - -(CH2)y-OH, in which where y is an integer from 0 to 6, and - -CN. 5 2. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 1, where R3and R4are independently selected from -H, -CH3and -CN. 10 3. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 1 or claim 2, where R1is an aryl group, optionally substituted by one or more substituents, and R2is: 15 4. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where L3is -N(H)-. 5. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where L2is a bond or -(CH2)n- in which n 20 is 1 or 2. 6. The compound, and stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, for use as in any preceding claim, where R5is selected from: , , , , 25 , , and isomers thereof. - 95 - 7. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 6, where R5is: . 5 8. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where R1and / or R2are independently selected from: 10 9. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where R1and / or R2is a pyridyl group, e.g.3-pyridyl. 10. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt 15 thereof, for use as in any preceding claim, where R1is a phenyl group, unsubstituted, or substituted by one or more of the following: - nitro (-N+(=O)OH or -NO2), i.e. R1is a nitrophenyl group, optionally with the substituent at the meta position; 20 - -SO2CH3,e.g. at the meta position; - -CF3, e.g. at the meta position; - -OH, e.g. at the meta position; - -SO2NH2, e.g. at the meta position; - pyridyl, e.g. at the meta position; 25 - -halogen (e.g. Cl), e.g. at the meta position; - -NHSO2CH3, e.g. at the meta position; - -COOR, e.g. at the meta position, e.g. where R = H, methyl, ethyl, propyl or butyl; - -COCl, e.g. at the meta position; 30 - -CN, e.g. at the meta position; - -C1-3 alkyl, e.g. at the ortho and / or para position. - 96 - 11. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where R2is a phenyl group, unsubstituted, or substituted by one or more of the following: 5 - nitro (-N+(=O)OH or -NO2), i.e. R2is a nitrophenyl group, optionally with the substituent at the meta position; - -CF3, e.g. at the meta position; - pyridyl, e.g. at the meta position; - halogen (e.g. Cl), e.g. at the meta position; 10 - -COOH, e.g. at the meta position. 12. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where R1and / or R2are substituted at the meta position by -SO2CH3, Cl, or -COOH. 15 13. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 1, wherein said compound is: 20 (JB29); or - 97 - (PAK1-A2 + / -). 14. A compound of Formula (IV), or stereoisomer, tautomer, or pharmaceutically 5 acceptable salt thereof, for use in the treatment or prevention of a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity: wherein Ar1and Ar2are phenyl groups, optionally and independently substituted with one or more of the following: - nitro / nitroso (-N+(=O)OH or -NO2); - 98 - - halogen (e.g. F, Cl) - -SO2CH3; - -OH; - -CF35 - -CH3- -COOH or - a heteroaryl group, e.g. tetrazole. 15. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt 10 15 (PAK1-A1). 16. A compound of Formula (III), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or 20 condition associated with PAK1 and / or PAK2 inactivity: - 99 - where: R4is selected from: 5 - H, - alkyl, - -(CH2)y-OH, in which y is an integer from 0 to 6, and - -CN; and 10 E and G are independently aryl groups, optionally substituted by one or more substituents. 17. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 16, where R4is selected from H, -CH3, -CH2-OH and 15 -CN. 18. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 17, where R4is H. 20 19. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 18, where E and / or G are optionally substituted phenyl groups. 20. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable 25 salt thereof, for use as in any one of claims 16 to 19, where G is optionally substituted pyrimidyl. 21. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 20, where E and / or G are 30 substituted by one or more substituents independently selected from: - -CO2CxH2x+1, where x is an integer from 0 to 4; - nitro; (-N+(=O)OH or -NO2); - 100 - - -OH; - alkyl; - -SO2N(H)CxH2x+1where x is an integer from 0 to 4; - -N(H)C(=O)R7, where R7is an alkyl group or an aryl group, optionally 5 substituted. 22. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 21, where E and / or G are substituted by one or more substituents independently selected from: 10 - –COOH; - nitro; (-N+(=O)OH or -NO2); - -OH; - -CH3; - -SO2NH2, 15 - -SO2NHCH3; - -N(H)C(=O)R7, where R7is a C1-6 alkyl group, or an aryl group, optionally substituted. 23. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable 20 salt thereof, for use as in claim 21 or claim 22, where R7is a phenyl group, optionally substituted. 24. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any of claims 21 to 23, where R7is substituted by –OR8, 25 where R8is H or C1-4 alkyl. 25. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 24, where E and / or G are substituted by one or more substituents independently selected from: -CH3, - 30 SO2NH2, -OH, and nitro (-N+(=O)OH or -NO2). 26. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 25, where G is dimethyl pyrimidyl. - 101 - 27. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 26, where E where R8is H or C1-4 alkyl. 5 28. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 16, wherein said compound is: 10 (JB2019B). 29. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable 15 salt thereof, for use as in any of claims 1 to 28, wherein said disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity is a cardiovascular disease or condition. 30. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable 20 salt thereof, for use as in claim 29, wherein said cardiovascular disease or condition is cardiac remodelling, cardiac fibrosis, cardiac hypertrophy, cardiac arrhythmia, heart failure, ischaemia / reperfusion injury, sudden cardiac death, or myocardial infarction.

Claims

1. - 102 - ABSTRACT The present invention provides small molecule PAK1 (P21 Activated Kinase 1) and / or PAK2 (P21 Activated Kinase 2) activators and their use in the prevention 5 and / or treatment of diseases or conditions responsive to PAK1 and / or PAK2 activity or diseases or conditions associated with PAK1 and / or PAK2 inactivity, e.g. cardiovascular diseases or conditions, including cardiac fibrosis, cardiac hypertrophy, cardiac arrh a / reperfusion injury. 10 - 96 -H, alkyl,-(CH2)y-OH, in which where y is an integer from 0 to 6, and -CN.

2. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 1 , where R3and R4are independently selected from -H, - CH3and -CN.

3. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 1 or claim 2, where R1is an aryl group, optionally substituted by one or more substituents, and R2is:

4. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where L3is -N(H)-.

5. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where L2is a bond or -(CH2)n- in which n is 1 or 2.

6. The compound, and stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, for use as in any preceding claim, where R5is selected from:ereof.- 97 -7. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 6, where R5is:isomer thereof.

8. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where R1and / or R2are independently selected from:

9. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where R1and / or R2is a pyridyl group, e.g. 3-pyridyl.

10. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where R1is a phenyl group, unsubstituted, or substituted by one or more of the following: nitro (-N+(=O)OH or -NO2), i.e. R1is a nitrophenyl group, optionally with the substituent at the meta position;-SO2CH3, e.g. atthe meta position;-CF3, e.g. at the meta position;-OH, e.g. atthe meta position;-SO2NH2, e.g. atthe meta position; pyridyl, e.g. atthe meta position;-halogen (e.g. Cl), e.g. atthe meta position;-NHSO2CH3, e.g. atthe meta position;-COOR, e.g. atthe meta position, e.g. where R = H, methyl, ethyl, propyl or butyl;-COCI, e.g. atthe meta position;-CN, e.g. atthe meta position;-C1-3 alkyl, e.g. at the ortho and / or para position.- 98 -11 . The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where R2is a phenyl group, unsubstituted, or substituted by one or more of the following: nitro (-N+(=O)OH or -NO2), i.e. R2is a nitrophenyl group, optionally with the substituent at the meta position;-CF3, e.g. at the meta position; pyridyl, e.g. at the meta position; halogen (e.g. Cl), e.g. atthe meta position;-COOH, e.g. atthe meta position.

12. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any preceding claim, where R1and / or R2are substituted at the meta position by -SO2CH3, Cl, or -COOH.

13. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 1 , wherein said compound is:(JB29); or(PAK1-A2 + / -).

14. A compound of Formula (IV), or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity:wherein Ar1and Ar2are phenyl groups, optionally and independently substituted with one or more of the following: nitro / nitroso (-N+(=O)OH or -NCL); halogen (e.g. F, Cl)- 100 -- -SO2CH3;- -OH;- -CF3- -CH3- -COOH or a heteroaryl group, e.g. tetrazole.

15. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 14, wherein said compound is:(PAK1-A1).

16. A compound of Formula (III), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity:- 101 -(HI) where:R4is selected from:H, alkyl, -(CH2)y-OH, in which y is an integer from 0 to 6, and-CN; andE and G are independently aryl groups, optionally substituted by one or more substituents.

17. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 16, where R4is selected from H, -CH3, -CH2-OH and - CN.

18. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 17, where R4is H.

19. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 18, where E and / or G are optionally substituted phenyl groups.

20. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 19, where G is optionally substituted pyrimidyl.21 . The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 20, where E and / or G are substituted by one or more substituents independently selected from:-CO2CXH2X+1, where x is an integer from 0 to 4;- nitro; (-N+(=O)OH or -NO2);- -OH; alkyl;-SO2N(H)CXH2X+I where x is an integer from 0 to 4;-N(H)C(=O)R7, where R7is an alkyl group or an aryl group, optionally substituted.- 102 -22. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 21 , where E and / or G are substituted by one or more substituents independently selected from:- -COOH;- nitro; (-N+(=O)OH or -NO2);- -OH;- -CH3;- -SO2NH2,- -SO2NHCH3;-N(H)C(=O)R7, where R7is a C1-6 alkyl group, or an aryl group, optionally substituted.

23. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 21 or claim 22, where R7is a phenyl group, optionally substituted.

24. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any of claims 21 to 23, where R7is substituted by -OR8, where R8is H or C1-4 alkyl.

25. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 24, where E and / or G are substituted by one or more substituents independently selected from: -CH3, -SO2NH2, -OH, and nitro (-N+(=O)OH or -NO2).

26. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 25, where G is dimethyl pyrimidyl.

27. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any one of claims 16 to 26, where E- 103 - where R8is H or C1-4 alkyl.

28. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 16, wherein said compound is:(JB2019B).

29. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in any of claims 1 to 28, wherein said disease or condition responsive to PAK1 and / or PAK2 activity or a disease or condition associated with PAK1 and / or PAK2 inactivity is a cardiovascular disease or condition.

30. The compound, or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for use as in claim 29, wherein said cardiovascular disease or condition is cardiac remodelling, cardiac fibrosis, cardiac hypertrophy, cardiac arrhythmia, heart failure, ischaemia / reperfusion injury, sudden cardiac death, or myocardial infarction.

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