The present invention relates to inhibitors of PPP1R15A and PPP1R15B and their use in therapy.

BACKGROUND TO THE INVENTION

The reversible phosphorylation of proteins controls virtually all aspects of cell and organismal function, allowing cells to adapt to sudden changes through the antagonistic action of kinases and phosphatases. Consequently, targeting phosphorylation offers a broad range of therapeutic opportunities and kinases have arisen as the most prevalent drug targets in today's pharmaceutical research with more than 3000 approved and experimental drugs. However, while targeting phosphatases should in principle be as attractive as kinases, the therapeutic potential of phosphatases has been overlooked. The majority of protein phosphorylation occurs on serine and threonine and selective serine/threonine dephosphorylation is achieved by hundreds of different dimeric or trimeric holoenzymes assembled from one of only a few catalytic subunits combined with one amongst hundreds of diverse regulatory subunits (Heroes et al., FEBS Journal, 280, 584-595, 2012). Thus, inhibition of the catalytic component of the holoenzyme such as PP1c results in inhibition of hundreds of phosphatases and is toxic. Since selectivity is an important property for drug development, the promiscuity of catalytic phosphatases has led them to acquire the reputation of being undruggable.

Phosphorylation of the a subunit of elF2α is the first line of defense against a variety of stresses and is thereby a central component of two partly overlapping signaling pathways: the Unfolded Protein Response (UPR) and the Integrated Stress Response (ISR). To reverse elF2α phosphorylation, mammalian cells have two elF2α phosphatases. The elF2α phosphatases are dimeric holoenzymes that share a catalytic subunit PP1c with about 200 other phosphatases, and are bound to one of two related regulatory subunits: PPP1R15A (Novoa et al., The Journal of Cell Biology, 153, 1345-1355, 2001), a stress inducible protein or PPP1R15B, which is constitutively expressed (Jousse et al., The Journal of Cell Biology, 163, 767-775, 2003).

Recently, the feasibility of inhibiting selectively a serine/threonine phosphatase has been demonstrated. Guanabenz (Tsaytler et al., Science, 332, 91-94, 2011; Tsaytler and Bertolotti, FEBS Journal, 280, 766-770, 2012) and its derivatives, some of which are disclosed in WO2014108520 (Medical Research Council), were found to selectively inhibit PPP1R15A/GADD34, a stress-induced regulatory subunit of the serine/threonine protein phosphatase 1, and was proposed as a treatment for diseases associated with protein misfolding stress.

PPP1R15A inhibition selectively inhibits the stress-induced elF2α phosphatase composed of PPP1R15A and PP1, while sparing the highly related and constitutive phosphatase PPP1R15B-PP1. PPP1R15A inhibition prolongs elF2α phosphorylation in stressed cells and this results in prolonging translation attenuation in stressed cells. As a consequence, chaperone availability is increased in stressed cells because the chaperones that are normally engaged in assisting the folding of newly synthetized proteins become available when translation is decreased. This favors protein folding and rescues cells from protein proteostasis defects. Thus, in principle, PPP1R15A inhibitors could treat mammalian diseases involving protein misfolding stress. Inhibition of PPP1R15A in mammals has an attractive therapeutic potential because inhibition of PPP1R15A is predicted to be safe as PPP1R15A/GADD34 knock-out mice are largely indistinguishable from wild-type mice (Marciniak et al., Genes & Development, 18, 3066-3077, 2004). However, the number of therapeutic indications that can be treated with PPP1R15A inhibitors is predicted to be restricted to diseases where PPP1R15A is expressed and where PPP1R15A is in the disease mode of action. Thus, inhibition of PPP1R15A may be powerful and safe but will be restricted to diseases involving PPP1R15A.

Regardless of the limitations associated with PPP1R15A inhibition, the approach of restoring proteostasis by fine tuning translation to increase chaperone availability is in theory powerful, straightforward and applicable to correct a broad range of diseases involving misfolded proteins. As noted above, the use of PPP1R15A inhibitors will be restricted to diseases where PPP1R15A is expressed and where PPP1R15A is in the disease mode of action. This represents a serious limitation. Thus alternative approaches, of broad therapeutic potential, are needed and the present invention seeks to provide these.

SUMMARY OF THE INVENTION

Compounds which inhibit PPP1R15A and PPP1R15B can advantageously be used to treat a wider range of diseases than compounds which selectively inhibit PPP1R15A.

In a first aspect, the present invention provides compounds of formula IA:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

X^ais N or CR^2a;

Y^ais N or CR^4a;

R^1ais H, F, Cl or Br;

R^2a, R^3a, R^4a, R^5aeach independently represent H, F or Cl;

with the proviso that:

when X^aand Y^arepresent CR^2aand CR^4arespectively and R^2aand R^4aare both H:

- R^1ais not F, Cl or Br when R^3aand R^5aboth represent H;
- R^5ais not F or Cl when R^1ais Cl and R^2ais H;
- R^3ais not F when R^1ais Cl and R^5ais H;
- R^3ais not Cl when R^1aand R^5aare both H or when R^1ais Cl and R^5ais H;
- R^1a, R^3aand R^5aare not all H;
- R^1ais not Cl when R^3ais H and R^5ais F;

when X^arepresents CH and Y^arepresents CR^4awherein R^4ais Cl:

- R^1aand R^5aare not both Cl;
- R^3ais not Cl when R^1aand R^5aare Cl;

when X^arepresents CR^2aand Y^arepresents CR^4aand R^2aand R^4aare both Cl, R^1a, R^3aand R^5aare not all H.

In one embodiment, X^arepresents CR^2aand Y^arepresents CR^4a, wherein R^2aand R^4aeach independently represent H, F or Cl.

In one embodiment, three of R^1a, R^2a, R^3a, R^4aand R^5arepresent Cl or F and two of R^1a, R^2a, R^3a, R^4aand R^5arepresent H, optionally wherein at least one of R^1a, R^2a, R^3a, R^4aand R^5ais F.

In one embodiment, three of R^1a, R^2a, R^3a, R^4aand R^5arepresent Cl and two of R^1a, R^2a, R^3a, R^4aand R^5arepresent H.

In one embodiment, R^3ais Cl or F and R^1a, R^2a, R^4aand R^5aare independently selected from H, F and Cl, wherein two of R^1a, R^2a, R^4aand R^5aare selected from F and Cl and two of R^1a, R^2a, R^4aand R^5ais H.

In one embodiment, R^5ais H.

In one embodiment, the compound of formula IA is in the E-isomer form.

A second aspect of the invention relates to compounds of formula IB:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

X^bis N or CR^2b;

Y^bis N or CR^4b;

R^1bis H, F, Cl, or Br;

R^2bR^3b, R^4b, R^5beach independently represent H, F, or Cl;

with the proviso that:

when X^band Y^bboth represent N, R^1band R^3bare not both Cl;

R^1bis not Br when X^bis CR^2band R^2bis Cl;

when R^3band R^4bare both H, R^1band R^2bare not both Cl;

when X^bis CR^2band R^2band R^3bare both H, R^1bis not Cl when Y^bis CR^4band R^4bis F;

when X^bis CR^2band Y^bis CR4b, R^1b, R^2b, R^3b, R^4band R^5bare not all H;

when X^bis CR^2band Y^bis CR^4band R^2b, R^3b, R^4band R^5bare H, R^1bis not Cl;

when X^bis CR^2band Y^bis CR^4band R^2b, R^3band R^4bare H, R^1bis not Cl when R^5bis F;

for use in the treatment of a disease state alleviated by the inhibition of PPP1R15A and PPP1R15B.

In one embodiment, X^brepresents CR^2band Y^brepresents CR^4b, wherein R^2band R^4beach independently represent H, F or Cl.

In one embodiment, three of R^1b, R^2b, R^3b, R^4band R^5brepresent Cl and two of R^1b, R^2b, R^3b, R^4band R^5brepresent H.

In one embodiment, three of R^1b, R^2b, R^3b, R^4band R^5brepresent Cl or F and two of R^1b, R^2bR^3b, R^4band R^5brepresent H, optionally wherein at least one of R^1b, R^2bR^3bR^4band R^5bis F.

In one embodiment, R^1bis Cl or F and R^1b, R^2b, R^4band R^5bare independently selected from H, F and Cl, wherein three of R^1b, R^2b, R^4band R^5bare selected from F and Cl and one of R^1b, R^2b, R^4band R^5bis H.

In one embodiment, R^5ais H.

In one embodiment, the compound of formula IB is in the E-isomer form.

A further aspect of the invention relates to compounds of formula IA for use in therapy.

A further aspect of the invention relates to compounds of formula IA or formula IB for use in the treatment of a disease state alleviated by the inhibition of PPP1R15A and PPP1R15B.

A further aspect of the invention relates to use of a compound of formula IA or formula IB in the preparation of a medicament for treating a disease state alleviated by the inhibition of PPP1R15A and PPP1R15B.

A further aspect of the invention relates to methods of treating a disease state alleviated by the inhibition of PPP1R15A and PPP1R15B in a subject in need thereof, said method comprising administering a therapeutically effective amount of a compound of formula IA or IB.

In one embodiment, the disease state alleviated by the inhibition of PPP1R15A and PPP1R15B is a disorder associated with accumulation of misfolded proteins or proteostatsis disorder.

In a further embodiment, the disease is Huntington's disease, Parkinson's disease, a tauopathy, a protein trafficking disease or a myelin disorder.

In another embodiment, the disease is any polyglutamine disorder.

In a further embodiment, the disease is Distal hereditary motor neuropathy with mutations in the chaperone HSJ1.

A further aspect of the invention relates to pharmaceutical compositions comprising a compound of formula IA or formula IB as described above, admixed with a suitable pharmaceutically acceptable diluent, excipient or carrier.

BRIEF DESCRIPTION OF THE FIGURES

Certain embodiments of the present invention will now be described, by way of example only, with reference to the drawings in which:

FIG. 1 shows the selective binding of a R15B inhibitor of Example 1 to R15B-PP1 over R15A-PP1.

FIG. 2 shows that a selective R15B inhibitor of Example 1 induces a transient phosphorylation of elF2α in cells in the absence of stress and induces expression of R15A in cells.

FIG. 3 shows that a selective R15B inhibitor of Example 1 protects cells from stress.

FIG. 4 shows the effects of a selective R15B inhibitor on elF2α phosphorylation following stress. The compound of Example 1 prolongs elF2⊐ phosphorylation following stress at times where R15A is not yet expressed.

FIG. 5 shows the tissue distribution of a compound of Example 1 which exhibits extensive tissue distribution.

FIG. 6 shows that the treatment of mice with a compound of Example 1 (10 mg/kg) is not toxic.

FIG. 7 shows that the treatment of mice with a compound of Example 1 (10 mg/kg) does not cause the side effects of Guanabenz

FIG. 8 shows the induction of R15A in a mammal following treatment with a compound of Example 1.

FIG. 9 shows the effectiveness of a R15B inhibitor of Example 1 in preventing disease in a mammal. The example used in FIG. 8 is Huntington's disease using the mouse model HD82GIn (Schilling et al., Hum. Mol. Genet., 8, 387-407, 1999). WT: wild-type mice. Tg: HD82GIn.

FIG. 10 shows myelin internodes in red (rod shaped) from cultured dorsal root ganglia (DRG) and nuclei in blue (spherical ‘blob’ shaped) in of the indicated genotype treated with vehicle or compound of Example 1. The myelin internodes in the PMP22-mutant mice are shorter. Treatment with a compound of Example 1 increased the length of myelin internodes in mutant DRG revealing that it improved myelination.

FIG. 11 shows blood glucose levels in obese mice db/db animals (n=5 per condition) following treatment with compound of Example 1.

FIG. 12 shows protein synthesis rates for a selective R15A inhibitor (1^stcolumn-guanabenz (GBZ)), a selective R15B inhibitor (2^ndcolumn-compound 16 (TST3)), a combination of GBZ and TST3 (3^1dcolumn), and an R15A/B inhibitor (4^thcolumn-compound 10). The figure shows that a selective R15A inhibitor doesn't inhibit protein synthesis in unstressed cell. A selective R15B inhibitor transiently inhibits protein synthesis in unstressed cells. Combining an R15A and an R15B inhibitor results in a persistent inhibition of protein synthesis. Likewise, an R15A/B inhibitor persistently inhibits protein synthesis. Y axis shows the relative rates of protein synthesis. X axis shows time following addition of the compounds (10 μM), in hours (h).

FIG. 13 shows an immunoblot showing that an R15A/B inhibitor (compound 10 at 20 μM) induces expression of ATF4, confirming the compound is on-target effect. Time after the addition of the compound to cells in culture is shown underneath the ATF4 immunoblot (0, 2, 5, 7.5 h).

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention provides compounds of formula IA:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

X^ais N or CR^2a;

Y^ais N or CR^4a;

R^1ais H, F, Cl or Br;

R^2a, R^3a, R^4a, R^5aeach independently represent H, F or Cl;

with the proviso that:

when X^aand Y^arepresent CR^2aand CR^4arespectively and R^2aand R^4aare both H:

- R^1ais not F, Cl or Br when R^3aand R^5aboth represent H;
- R^5ais not F or Cl when R^1ais Cl and R^2ais H;
- R^3ais not F when R^1ais Cl and R^5ais H;
- R^3ais not Cl when R^1aand R^5aare both H or when R^1ais Cl and R^5ais H;
- R^1a, R^3aand R^5aare not all H;
- R^1ais not Cl when R^3ais H and R^5ais F;

when X^arepresents CH and Y^arepresents CR^4awherein R^4ais Cl:

- R^1aand R^5aare not both Cl;
- R^3ais not Cl when R^1aand R^5aare Cl;

when X^arepresents CR^2aand Y^arepresents CR^4aand R^2aand R^4aare both Cl, R^1a, R^3aand R^5aare not all H.

In one embodiment, R^1ais F, Cl or Br.

In another embodiment, R^3ais F or Cl.

In another embodiment, R^5ais H.

In one embodiment, when X^arepresents CR^2aand Y^arepresents CR^4a, two R^1a, R^2a, R^3a, R^4aand R^5arepresent Cl.

In one embodiment, when X^arepresents CR^2aand Y^arepresents CR^4a, one of R^1a, R^2a, R^3a, R^4aand R^5arepresents Cl and one of R^1a, R^2a, R^3a, R^4aand R^5arepresents F.

In one embodiment, when X^arepresents CR^2aand Y^arepresents CR^4a, one of R^1a, R^2a, R^3a, R^4aand R^5arepresents Cl and one of R^1a, R^2a, R^3a, R^4aand R^5arepresents Br.

In one embodiment, R^1aand R^3aboth represent Cl.

In one embodiment, when X^arepresents CR^2aand Y^arepresents CR^4a, three of R^1a, R^2a, R^3a, R^4aand R^5arepresent Cl and two of R^1a, R^2a, R^3a, R^4aand R^5arepresent H.

In one embodiment, when X^arepresents CR^2aand Y^arepresents CR^4a, two of R^1a, R^2a, R^3a, R^4aand R^5arepresent Cl, one of R^1a, R^2a, R^3a, R^4aand R^5arepresents F, and two of R^1a, R^2a, R^3a, R^4aand R^5arepresent H.

In one embodiment, when X^arepresents CR^2aand Y^arepresents CR^4a, two of R¹, R^2a, R^3a, R^4aand R^5arepresent F, one of R^1a,R^2a, R^3a, R^4aand R^5arepresents Cl and two of R^1a, R^2a, R^3a, R^4aand R^5arepresent H.

In one embodiment, three of R^1a, R^2a, R^3a, R^4aand R^5arepresent Cl or F and two of R^1a, R^2a, R^3a, R^4aand R^5arepresent H, optionally wherein at least one of R^1a, R^2a, R^3a, R^4a, and R^5ais F.

In one embodiment, when X^arepresents CR^2aand Y^arepresents CR^4a, R^3ais Cl or F, two of R^1a, R^2a, R^4aand R^5aare selected from F and Cl and two of R^1a, R^2a, R^4a, and R^5ais H.

In one embodiment, when X^arepresents N, R^1aand R^3aboth represent Cl.

In one embodiment,

X^ais CR^2a;

Y^ais CR^4a;

R^1ais H, F, Cl or Br;

R^2a, R^3aand R^4aeach independently represent H, F or Cl;

R^5arepresents H;

with the proviso that:

when X^aand Y^arepresent CH:

- R^1ais not F, Cl or Br when R^3aand R^5aboth represent H;
- R^5ais not F or Cl when R^1ais Cl and R^2ais H;
- R^3ais not F when R^1ais Cl and R^5ais H;
- R^3ais not Cl when R^1aand R^5aare both H or when R^1ais Cl and R^5ais H;
- R^1a, R^3aand R^5aare not all H;
- R^1ais not Cl when R^3ais H and R^5ais F;

when X^arepresents CH and Y^arepresents CR^4awherein R^4ais Cl:

- R^1aand R^5aare not both Cl;
- R^3ais not Cl when R^1aand R^5aare Cl;

when X^arepresents CR^2aand Y^arepresents CR^4aand R^2aand R^4aare both Cl, R^1a, R^3aand R^5aare not all H.

In one embodiment, the compound of formula IA is in the E-isomer form.

In a second aspect, the present invention provides compounds of formula IB for use in the treatment of a disease state alleviated by the inhibition of PPP1R15A and PPP1R15B:

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

X^bis N or CR^2b;

Y^bis N or CR^4b;

R^1bis H, F, Cl or Br;

R^2b, R^3b, R^4b, R^5beach independently represent H, F or Cl;

with the proviso that:

when X^band Y^bboth represent N, R^1aand R^3bare not both Cl;

R^1bis not Br when X^bis CR^2band R^2bis Cl;

when R^3band R^4bare both H, R^1band R^2bare not both Cl;

when X^bis CR^2band R^2band R^3bare both H, R^1bis not Cl when Y^bis CR^4band R^4bis F;

when X^bis CR^2band Y^bis CR^4b, R^1b, R^2b, R^3b, R^4band R^5bare not all H;

when X^bis CR^2band Y^bis CR^4band R^2b, R^3b, R^4band R^5bare H, R^1bis not Cl;

when X^bis CR^2band Y^bis CR^4band R^2b, R^3band R^4bare H, R^1bis not Cl when R^5bis F;

when X^bis CR^2bwherein R^2bis Cl and Y^bis CR^4bwherein R^4bis H, R^1bis not Cl when R^3b, R^4band R^5bare H, or when R^3band R^4bare H and R^5bis Cl.

In one embodiment, X^brepresents CR^2band Y^brepresents CR^4b. In an alternative embodiment, X^band Y^bboth represent N. In an alternative embodiment, X^brepresents N and Y^brepresents CR^4b.

The compounds of formula IB are R15A and R15B inhibitors.

In one embodiment, R^1brepresents F, Cl or Br.

In another embodiment, R^3brepresents F or Cl.

In another embodiment, R^5bis H.

In one embodiment, when X^brepresents CR^2band Y^brepresents CR^4b, two of R_1b, R^2b, R_3b, R^4band R^5brepresent Cl.

In one embodiment, when X^brepresents CR^2band Y^brepresents CR^4b, one of R^1b, R^2b, R^3b, R^4band R^5brepresents Cl and one of R^1b, R^2b, R^3b, R^4band R^5brepresents F.

In one embodiment, R^1band R^3bboth represent Cl.

In one embodiment, when X^brepresents CR^2band Y^brepresents CR^4b, three of R^1b, R^2b, R^2b, R^4band R^5brepresent Cl.

In one embodiment, when X^brepresents CR^2band Y^brepresents CR^4b, two of R^1b, R^2b, R^3b, R^4band R^5brepresent Cl and one of R^1b, R^2b, R^3b, R^4band R^5brepresents F.

In one embodiment, when X^brepresents CR^2band Y^brepresents CR^4b, two of R^1b, R^2b, R^3b, R^4band R^5brepresent F and one of R^1b, R^2b, R^3b, R^4band R^5brepresents Cl.

In one embodiment, three of R^1a, R^2a, R^3a, R^4aand R^5arepresent Cl or F and two of R^1a, R^2a, R^3a, R^4aand R^5arepresent H, optionally wherein at least one of R^1a, R^2a, R^3a, R^4aand R^5ais F.

In one embodiment, when X^brepresents N, R^1band R^3bboth represent Cl.

In one embodiment,

X^bis CR^2b;

Y^bis CR^4b;

R^1bis H, F, Cl or Br;

R^2b, R^3band R^4beach independently represent H, F or Cl;

R^5bis H;

with the proviso that:

when X^band Y^bboth represent N, R^1aand R^3bare not both Cl;

R^1bis not Br when X^bis CR^2band R^2bis Cl;

when R^3band R^4bare both H, R^1band R^2bare not both Cl;

when X^bis CR^2band R^2band R^3bare both H, R^1ais not Cl when Y^bis CR^4band R^4bis F;

when X^bis CR^2band Y^bis CR^4b, R^1b, R^2b, R^3b, R^4band R^5bare not all H;

when X^bis CR^2band Y^bis CR^4band R^2b, R^3b, R^4band R^5bare H, R^1bis not Cl;

when X^bis CR^2band Y^bis CR^4band R^2b, R^3band R^4bare H, R^1bis not Cl when R^5bis F;

when X^bis CR^2bwherein R^2bis Cl and Y^bis CR^4bwherein R^4bis H, R^1bis not Cl when R^3b,

R^4band R^5bare H, or when R^3band R^4bare H and R^5bis Cl.

In one embodiment, the compound of formula IA is in the E-isomer form.

The term “PPP1R15A” is used interchangeable with the term “R15A” and the term “PPP1R15B” is used interchangeably with the term “R15B”. An inhibitor of PPP1R15A and PPP1R15B may be referred to as “R15A/B”, “R15AB” or “AB” throughout.

Compounds described herein include:

[Image Omitted]

The E isomer forms of the compounds listed above are particularly preferred:

[Image Omitted]

Novel compounds of formula IA include:

Compound 2: 2-((2,4-dichloropyrimidin-5-yl)methylene)hydrazine-1-carboximidamide

Compound 3: 2-(3,4,5-trichlorobenzylidene)hydrazine-1-carboximidamide

Compound 4: 2-(2,4,5-trichlorobenzylidene)hydrazine-1-carboximidamide

Compound 5: 2-(3,5-dichloro-4-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 6: 2-(2,3,4-trichlorobenzylidene)hydrazine-1-carboximidamide

Compound 7: 2-(2,4-dichloro-5-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 9: 2-(2-bromo-3-chlorobenzylidene)hydrazine-1-carboximidamide

Compound 13: 2-(2,4-dichloro-3-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 14: 2-(2,3-dichloro-4-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 18: 2-(4,5-dichloro-2-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 20: 2-(2-chloro-5-fluorobenzylidene)hydrazine-1-carboximidamide

Comopund 22: 2-((2,6-dichloropyridin-3-yl)methylene)hydrazine-1-carboximidamide

Compound 25: 2-(2-chloro-3-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 27: 2-(2-chloro-3,4-difluorobenzylidene)hydrazine-1-carboximidamide

Compound 29: 2-(2-chloro-3,5-difluorobenzylidene)hydrazine-1-carboximidamide

Compound 32: 2-(2-chloro-4,5-difluorobenzylidene)hydrazine-1-carboximidamide

Novel compounds of formula IA may be selected from the following E isomer forms:

Compound 2(E): (E)-2-((2,4-dichloropyrimidin-5-yl)methylene)hydrazine-1-carboximidamide

Compound 3(E): (E)-2-(3,4,5-trichlorobenzylidene)hydrazine-1-carboximidamide

Compound 4(E): (E)-2-(2,4,5-trichlorobenzylidene)hydrazine-1-carboximidamide

Compound 5(E): (E)-2-(3,5-dichloro-4-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 6(E): (E)-2-(2,3,4-trichlorobenzylidene)hydrazine-1-carboximidamide

Compound 7(E): (E)-2-(2,4-dichloro-5-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 8(E): (E)-2-(4-chloro-3-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 9(E): (E)-2-(2-bromo-3-chlorobenzylidene)hydrazine-1-carboximidamide

Compound 10(E): (E)-2-(2,3,5-trichlorobenzylidene)hydrazine-1-carboximidamide

Compound 11(E): (E)-2-(3,4-dichlorobenzylidene)hydrazine-1-carboximidamide

Compound 13(E): (E)-2-(2,4-dichloro-3-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 14(E): (E)-2-(2,3-dichloro-4-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 15(E): (E)-2-(3-chloro-4-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 16(E): (E)-2-(2,3-dichlorobenzylidene)hydrazine-1-carboximidamide

Compound 18(E): (E)-2-(4,5-dichloro-2-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 20(E): (E)-2-(2-chloro-5-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 21(E): (E)-2-((2-chloropyridin-3-yl)methylene)hydrazine-1-carboximidamide

Compound 22(E): (E)-2-((2,6-dichloropyridin-3-yl)methylene)hydrazine-1-carboximidamide

Compound 23(E): (E)-2-(3-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 24(E): (E)-2-(3-chlorobenzylidene)hydrazine-1-carboximidamide

Compound 25(E): (E)-2-(2-chloro-3-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 26(E): (E)-2-(2,5-dichlorobenzylidene)hydrazine-1-carboximidamide

Compound 27(E): (E)-2-(2-chloro-3,4-difluorobenzylidene)hydrazine-1-carboximidamide

Compound 29(E): (E)-2-(2-chloro-3,5-difluorobenzylidene)hydrazine-1-carboximidamide

Compound 30(E): (E)-2-(3-chloro-2-fluorobenzylidene)hydrazine-1-carboximidamide

Compound 31(E): (E)-2-(2,3,6-trichlorobenzylidene)hydrazine-1-carboximidamide

Compound 32(E): (E)-2-(2-chloro-4,5-difluorobenzylidene)hydrazine-1-carboximidamide

Comopund 34(E): (E)-2-(3,5-dichlorobenzylidene)hydrazine-1-carboximidamide

In a preferred embodiment, the compound of formula IA is selected from compound 3, i.e. 2-(3,4,5-trichlorobenzylidene)hydrazine-1-carboximidamide, and compound 4, i.e. 2-(2,4,5-trichlorobenzylidene)hydrazine-1-carboximidamide, in particular the compound of formula IA is selected from (E)-2-(3,4,5-trichlorobenzylidene)hydrazine-1-carboximidamide and (E)-2-(2,4,5-trichlorobenzylidene)hydrazine-1-carboximidamide.

In one embodiment, the compound of formula IA is (E)-2-(3,4,5-trichlorobenzylidene)hydrazine-1-carboximidamide.

In another embodiment, the compound of formula IA is (E)-2-(2,4,5-trichlorobenzylidene)hydrazine-1-carboximidamide.

Compounds of formula IB may be selected from the following:

Compound 1(E): (E)-2-((4-chlorophenyl)methylene)hydrazine-1-carboximidamide