WO2020074160A1 - Condensed pyrimidine or pyridazine derivatives as antiviral agents - Google Patents

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof. The compound is a prodrug of a PI4KIIIβinhibitor and as such is useful as an antiviral agent. A pharmaceutical composition comprising the compound.

Description

CONDENSED PYRIMIDINE OR PYRIDAZINE DERIVATIVES AS ANTIVIRAL AGENTS FIELD OF THE INVENTION

The present invention relates generally to compounds having usefulness in therapy, in particular in the treatment of conditions caused by certain viruses, such as common cold, encephalitis, meningitis, myocarditis, conjunctivitis, pancreatitis as well as diabetes, cancer, and

neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. More particularly the invention relates to certain prodrugs of aminosubstituted heteroaromatic compounds for use in therapy.

BACKGROUND OF THE INVENTION

It is well-known that the oral bioavailability of certain drugs can be improved by conversion to prodrugs. Certain prodrugs are derivatives of the parent drug in which a functional group is "masked" by a promoiety. Following administration to a patient the prodrug is metabolized to release the parent drug.

The l-(acyloxy)-alkyl carbamate functionality is an example of a promoiety that has been used to functionalize both primary and secondary amino containing drugs. For example, 1-{[(a- isobutanoyloxyethoxy)carbonyl]amino-methyl} -l-cyclohexane acetic acid is a 1 -(acyloxy)-alkyl carbamate prodrug of gabapentin that has utility in the treatment of epilepsy and pain (Gallop et al, WO 02100347), restless legs syndrome (Barrett et al., WO 2005027850), as well as other diseases. In Gallop et al., US 6,972,341 and US 7,186,855, 1 -(acyloxy)-alkyl carbamate prodrugs of the GABA analog pregabalin are described. In Gallop et al, US 7,109,239 and US 7,300,956, l-(acyloxy)-alkyl carbamate prodrugs of R-baclofen are described. In Zerangue et al, US

7,351 ,740, l-(acyloxy)-alkyl carbamate prodrugs of tranexamic acid are described. In Alexander et al (J. Med. Chem. 1991 , 34, 78-81), acyloxy-alkyl carbamate prodrugs of a secondary amine are described.

RI4KIIIb inhibitors have been developed with high potency and effect in-vivo as antivirals against enteroviruses. For example certain aminosubstituted hetero aromatic RI4KIIIb inhibitors are described in the international applications PCT/EP2018/058522 (published as WO 2018/185120 Al) , PCT/EP2016/063383 (published as WO 2016/206999 Al) and PCT/EP2015/051177 (published as WO 2015/110491 A2), disclosing the compounds as potent antiviral agents, useful in particular for the treatment of diseases caused by non-enveloped single- stranded (+) RNA viral infections, and diseases caused by impaired and/or abnormal autophagy, cf. also disclosure in e.g. Lai et al Viruses, 2016, 8(32), 1 -13; Sridhar et al, EMBO J. 2013,32, 324-339; Polajnar et al J. Cell. Mol. Med. 2014, 9(18). 1705-1711; Levine et al, Cell, 2008, 132(1), 27-42; and Barlow, et al, DNA Cell. Biol, 2015, 34(4), 252-260.

From these and other prior art publications, it appears that RI4KIIIb inhibitors are potentially valuable therapeutic agents. However, LaMarche et al (Antimicr. Agents & Chemother. 2012, 56(10), 4149-4156) and Spickler et al (Antimicr. Agents & chemother. 2013, 57(7)3358-3368) have described that inhibition of RI4KIIIb by oral administration of a RI4KIIIb inhibitor is lethal to animals. Thus, there is a concern that treatment by RI4KIIIb inhibitors may have side effects in humans that may hamper their use in the therapy.

SUMMARY OF THE INVENTION

Toxicity studies have led the present inventor to the finding that in the enteral (e.g. oral) administration of certain RI4KIIIb inhibitors the toxicity is mostly due to local intestinal side effects. Indeed, while tissue distribution studies of RI4KIIIb inhibitors have shown that certain organs of the mammal body, having an exposure higher or similar to that in the intestine, and nonetheless show essentially no side effects. In view of this finding, the present inventor contemplates that observed mortality in the in vivo tests could be due to local side effects of the RI4KIIIb inhibitors in the intestine. Provided herein therefore certain RI4KIIIb inhibitor prodrugs capable of being efficiently metabolized into the active RI4KIIIb inhibitors with reduced side effects of the intestine.

More particularly, provided herein are prodrugs of the RI4KIIIb inhibitors described in the international applications PCT/EP2018/058522, PCT/EP2016/063383, PCT/EP2015/051177, and in copending international application PCT/EP2019/072220, the contents of which applications are incorporated herein by reference. Thus, a first aspect is a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X is CH or N;

Y is N and Z is C; or Y is C and Z is N;

Ri is 3,4-dimethoxyphenyl or 1 ,3-dimcthyl- 1 //-indazol-5-yl;

R₂ is selected from C1 -C6 alkyl, C3-C6 cycloalkyl, phenyl, and phenyl-Cl -C3 alkyl;

R₃ and R₄ are independently selected from hydrogen, C1 -C6 alkyl, C3-C6 cycloalkyl, phenyl, and phenyl-Cl -C3 alkyl; or R₃ and R₄ together with the carbon atom to which they are both attached form a C4-C6 cycloalkyl;

R₅ is a moiety of formula (II)

wherein

ring A is 5- or 6-membered heteroaryl, or phenyl;

m is an integer of from 0 to 3;

each R₆ is independently selected from Cl -C6 alkyl, halogen, R_6aO, R_6bR_6CN, R_6eC(0)N(R_6d), R_6fOC(0), R_6gC(0)0, R_6hS(0)₂, R_6iC(0), R_6kS(0)₂N(R_6j), R_6iR_6mNS(0)₂, R₆„R_6pNC(0), and CN; and two R₆, attached to adjacent atoms of ring A, together with the atoms to which they are attached may form a 5- or 6-membered heterocyclic or carbocyclic ring;

R_6a, R_6b, R_6C, R_6d, R_6j, R_6i, R_6m, R_6n, and R_6p are independently selected from H and C1 -C6 alkyl; R_6e, R_6f, Re_g, R_6h, Rei, and R_6k, are independently selected from Cl -6 alkyl; and

any alkyl is optionally substituted by one or more F.

A further aspect is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. A further aspect is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

A further aspect is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a viral infection, e.g. an RNA viral infection.

A further aspect is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a viral infection, e.g. an RNA viral infection.

A further aspect is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease linked to impaired or abnormal autophagy.

A further aspect is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease linked to impaired autophagy.

A further aspect is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease linked to abnormal autophagy.

A further aspect is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a non-enveloped single-stranded (+) RNA viral infection.

A further aspect is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of an enteroviral infection, e.g. a picomaviral infection.

Still a further aspect is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of pancreatitis, poliomyelitis, encephalitis, meningitis, sepsis, cancer, such as breast, prostate, ovarian and colorectal cancer, paralysis, cardiac diseases, such as myocarditis, diabetes, common cold, hand-foot-and-mouth disease, herpangina, pleurodynia, diarrhea, mucocutaneous lesions, respiratory illness, conjunctivitis, myositis, chronic fatigue syndrome, neuropsychiatric diseases, and neurodegenerative diseases such as multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease, and Huntington’s disease, or inflammatory conditions.

A further aspect is a method for the treatment of a viral infection, e.g. an RNA viral infection, by administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1 is a graph showing the serum concentration (in ng/mL) over time (in hours) of the RI4KIIIb inhibitor 3-( 1 ,3-dimcthyl- l //-indazol-5-yl)-2,5-dimcthyl-/V-(pyridin-4- ylmethyl)pyrazolo[l,5-a]pyrimidin-7-amine (Compound X) after per oral administration to female Sprague Dawley rats via gavage of a dose of 50 mg/kg ofits prodrug 1 -{[(3-(l ,3- dimethyl- 1 A -indazol-5-yl)-2,5-dimethyl-pyrazolo[ 1 ,5-a]pyrimidin-7 -yl)(pyridin-4- ylmethyl)carbamoyl]oxy} ethyl acetate (Example 1).

FIGURE 2 is a bar chart showing the mean % of Example 1 remaining in Simulated Gastric Fluid and in Simulated Intestinal Fluid, respectively, compared to the amount at 0 min.

FIGURE 3 is a graph showing the serum concentration (in ng/mL) over time (in hours) of the RI4KIIIb inhibitor 3-( 1 ,3-dimcthyl- l //-indazol-5-yl)-2,5-dimcthyl-/V-(pyridin-4- ylmethyl)pyrazolo[l,5-a]pyrimidin-7-amine (Compound X) after per oral administration to female Sprague Dawley rats via gavage of a dose of 15 mg/kg or 30 mg/kg of Compound X, or a dose of30 mg/kg ofits prodrug 1 - J[(3-( 1 ,3-dimcthyl- l //-indazol-5-yl)-2, 5-di methyl - pyrazolo[l,5-a]pyrimidin-7-yl)(pyridin-4-ylmethyl)carbamoyl]oxy}ethyl acetate (Example 1).

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise or clearly indicated by context, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. However, definitions of some terms used herein will be given herein below.

“Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.

The term“treating" (or "treatment") of a disease or disorder may refer to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof), and/or ameliorating at least one physical parameter, which may not be discernible by the patient. The term also may refer to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.

"Therapeutically effective amount" refers to an amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment of the disease. The

"therapeutically effective amount" will vary depending on the compound, the disease and its severity as well as the age, weight, etc., of the patient to be treated.

By“abnormal autophagy" is meant autophagy that favours viral replication and release.

By“impaired autophagy” is meant a subnormally functioning autophagy in a cell.

A disease linked to impaired or abnormal autophagy that may be treated according to the invention may be selected from neurodegenerative and neuropsychiatric diseases, cancer, cardiac diseases, inflammatory diseases and diabetes etc.

A“viral infection” refers to an infection by a virus, in a mammal.

An“RNA viral infection” refers to a viral infection wherein the virus has RNA (ribonucleic acid) as its genetic material. A“non-enveloped single-stranded (+) RNA viral infection” refers to an infection by a non- enveloped single-stranded (+) RNA virus.

A“non-enveloped virus” is a virus lacking viral envelope.

A“single-stranded (+) RNA virus” is a virus having genetic material which is single-stranded RNA and which RNA can be immediately translated to viral protein by the cell infected by the virus.

The term“mammal” refers to a human or any mammalian animal, e.g. a primate, a farm animal, a pet animal, or a laboratory animal. Examples of such animals are monkeys, cows, sheep, goats, horses, pigs, dogs, cats, rabbits, mice, rats etc. Preferably, the mammal is a human. In some embodiments, however, the mammal is an animal, e.g. a farm animal, such as a cow, sheep, goat, horse, or pig. In some other embodiments, the animal is a pet, e.g. a dog, a cat, or a rabbit.

The term“excipient” refers to pharmaceutically acceptable chemicals, such as known to those of ordinary skill in the art of pharmacy to aid the administration of the medicinal agent. It is a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. Exemplary excipients include binders, surfactants, diluents, disintegrants, antiadherents, and lubricants.

“Prodrug" refers to a derivative of a drug molecule that requires a transformation within the body to release the active drug. A prodrug generally, but not not exclusively, is pharmacologically inactive until converted to its parent drug.

"Promoiety" refers to a form of protecting group used to mask a functional group within a drug molecule so as to convert the drug into a prodrug. Typically, the promoiety will be attached to the drug via a bond that is enzymatically or non-enzymatically cleaved in vivo. Unless otherwise stated or apparent from the context, the term“Cm-Cn alkyl” denotes a straight or branched alkyl group having from m to n carbon atoms. For example, the term“C1-C4 alkyl” denotes a straight or branched alkyl group having from 1 to 4 carbon atoms. Such C1-C4 alkyl includes methyl, ethyl, «-propyl, isopropyl, «-butyl, isobutyl, sec -butyl, and /<v7-butyl.

Unless otherwise stated or apparent from the context, the term“halogen” refers to F (fluoro), Cl (chloro), Br (bromo), and I (iodo).

Unless otherwise stated or apparent from the context, the term“heteroatom” refers to an atom selected from N (nitrogen), O (oxygen) and S (sulfur).

A moiety of the type RO is a moiety of formula

A moiety of the type RR’NC(O) is a moiety of formula

A moiety of the type RC(0)N(R’) is a moiety of formula

A moiety of the type RS(0)₂ is a moiety of formula

A moiety of the type RS(0)₂N(R’) is a moiety of formula

A moiety of the type RRTMS(0)₂ is a moiety of formula

A moiety of the type RR’N is a moiety of formula

A moiety of the type RC(O) is a moiety of formula

A moiety of the type ROC(O) is a moiety of formula

^R '0'

The term“aromatic”, as used herein, refers to an unsaturated cyclic moiety that has an aromatic character, while the term“non-aromatic”, as used herein, refers to a cyclic moiety, that may be saturated or unsaturated, e.g. polyunsaturated, but that does not have an aromatic character.

The term“heteroaromatic”, as used herein, refers to an aromatic moiety containing at least one heteroatom in the ring.

The term“heterocyclic ring” refers to a saturated or unsaturated, aromatic or non-aromatic cyclic moiety containing not only carbon atoms, but also at least one other atom in the ring, e.g. selected from nitrogen (N), sulphur (S) and oxygen (O).

The term“carbocyclic ring” refers to a saturated or unsaturated, aromatic or non-aromatic cyclic moiety containing only carbon atoms in the ring.

In a compound of formula (I) as defined herein, X is CH or N. In some embodiments, X is N.

In some embodiments, X is N only when Y is N and Z is C. In some embodiments, X is CH, i.e. the compound may be represented by formula (la)

wherein Y, Z, Ri, R₂, R₃, R₄, and R₅ are as defined herein. In some embodiments of a compound of formula (I), Y is C and Z is N. In some other embodiments, Y is N and Z is C, i.e. the compound may be represented by formula (lb)

wherein X, Ri, R₂, R₃, R₄, and R₅ are as defined herein. In some other embodiments, Y is N and Z is C, i.e. the compound may be represented by formula

(Ic)

wherein X, Ri, R₂, R₃, R₄, and R₅ are as defined herein.

In still other embodiments of a compound of formula (I), X is CH, Y is N and Z is C, i.e. the compound may be represented by formula (Id)

wherein Ri, R₂, R₃, R₄, and R are as defined herein.

In still other embodiments of a compound of formula (I), X is CH, Y is C and Z is N, i.e. the compound may be represented by formula (Ie)

wherein Ri, R₂, R₃, R₄, and R₅ are as defined herein.

The moiety Ri is selected from 3,4-dimethoxyphenyl and 1 ,3 -dimethyl- 1 //-indazol-5-yl. In some embodiments, Ri is 3,4-dimethoxyphenyl, i.e. the compound may be represented by formula (If)

wherein X, Y, Z, R₂, R₃, R₄, and R are as defined herein.

In some other embodiments, Ri is 1 ,3 -dimethyl- l f-indazo 1-5 -yl, i.e. the compound may be represented by formula (Ig)

wherein X, Y, Z, R₂, R₃, R₄, and R are as defined herein. In some particular embodiments, a compound of formula (la) is also a compound of formula (If), i.e. X is CH and Ri is 3,4-dimethoxyphenyl. In some other particular embodiments, a compound of formula (la) is also a compound of formula (Ig), i.e. X is CH and Ri is 1 ,3 -dimethyl- \H- indazol-5-yl, i.e. the compound may be represented by formula (Ih)

wherein Y, Z, R₂, R₃, R₄, and R₅ are as defined herein.

In some particular embodiments, a compound of formula (lb) is also a compound of formula (If), i.e. Y is N, Z is C, and Ri is 3,4-dimethoxyphenyl. In still other particular embodiments, a compound of formula (lb) is also a compound of formula (Ig), i.e. Y is N, Z is C, and Ri is 1 ,3- dimethyl- l f-indazol-5-yl.

In still other particular embodiments, a compound of formula (Ie) is also a compound of formula (Ig), i.e. X is CH, Y is C, Z is N, and Ri is 1 ,3 -dimethyl- lif-indazol-5-yl, and the compound may then be represented by formula (Ii)

wherein R₂, R₃, R₄, and R₅ are as defined herein. In still further particular embodiments, a compound of formula (Id) is also a compound of formula (If), i.e. X is CH, Y is N, Z is C, and Ri is 3,4-dimethoxyphenyl. In still other particular embodiments, a compound of formula (Id) is also a compound of formula (Ig), i.e. X is CH, Y is N, Z is C, and Ri is 1 ,3 -dimethyl- lif-indazol-5-yl, and the compound may then be represented by formula (Ij)

wherein R₂, R₃, R₄, and Rs are as defined herein.

In some further embodiments a compound of formula (lb), wherein X is N, also is a compound of formula (Ig), i.e. the compound may be represented by formula (Ik)

wherein R₂, R₃, R₄, and Rs are as defined herein.

In a compound of formula (I), the moiety R₂ is selected from C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, and phenyl-Cl-C3 alkyl. In some embodiments, R₂ is selected from C1-C6 alkyl, and C3- C6 cycloalkyl. In some other embodiments, R₂ is selected from C1 -C6 alkyl. When R₂ is C1-C6 alkyl, it more particularly may be C1-C5 alkyl, or C1 -C4 alkyl, or C1-C3 alkyl, or C1-C2 alkyl, e.g. methyl. When R₂ is C3-C6 cycloalkyl, it more particularly may be C3-C5 cycloalkyl, or C3- C4 cycloalkyl, e.g. cyclopropyl. When R₂ is phenyl-Cl-C3 alkyl, it more particularly may be phenyl-Cl -C2 alkyl, e.g. benzyl. In some embodiments, for example, R₂ is selected from C1-C4 alkyl, C3-C5 cycloalkyl, phenyl, and phenyl-C 1 -C2 alkyl. In some embodiments, R₂ is selected from C1 -C3 alkyl, C3-C4 cycloalkyl, phenyl, and benzyl. In some embodiments, R₂ is selected from methyl, ethyl, n-propyl, isopropyl, and cyclopropyl; or from methyl, ethyl, n-propyl, and isopropyl; or from methyl and n-propyl, or from methyl and ethyl

In a compound of formula (I), the moieties R₃ and R₄ are independently selected from hydrogen, Cl -C6 alkyl, C3-C6 cycloalkyl, phenyl, and phenyl-Cl -C3 alkyl; or R₃ and R₄ together with the carbon atom to which they are both attached form a C4-C6 cycloalkyl. In some embodiments, R₃ and R₄ are independently selected from hydrogen, C1 -C6 alkyl, C3-C6 cycloalkyl, phenyl, and phenyl-C 1 -C3 alkyl. In some embodiments, R₃ is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, and phenyl-C 1 -C3 alkyl; and R₄ is hydrogen; e.g. R₃ is selected from C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, phenyl-C 1 -C3 alkyl; and R₄ is hydrogen. In some embodiments, R₃ and R₄ are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl; e.g. from hydrogen and C1-C6 alkyl. In some embodiments, R₃ and R₄ are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl, or R₃ and R₄ together with the carbon atom to which they are both attached form a C4-C6 cycloalkyl. In some embodiments, R₃ and R₄ are independently selected from hydrogen and Cl -C6 alkyl; or R₃ and R₄ together with the carbon atom to which they are both attached form a C4-C6 cycloalkyl.

When R₃ is C1-C6 alkyl, it more particularly may be C1-C5 alkyl, or C1 -C4 alkyl, or C1-C3 alkyl, or C1-C2 alkyl, e.g. methyl. When R₃ is C3-C6 cycloalkyl, it more particularly may be C3- C5 cycloalkyl, or C3-C4 cycloalkyl, e.g. cyclopropyl. When R₃ is phenyl-C 1-C3 alkyl, it more particularly may be phenyl-C 1 -C2 alkyl, e.g. benzyl.

When R₄ is C1-C6 alkyl, it more particularly may be C1-C5 alkyl, or C1 -C4 alkyl, or C1-C3 alkyl, or C1-C2 alkyl, e.g. methyl. When R₄ is C3-C6 cycloalkyl, it more particularly may be C3- C5 cycloalkyl, or C3-C4 cycloalkyl, e.g. cyclopropyl. When R₄ is phenyl-C 1-C3 alkyl, it more particularly may be phenyl-C 1 -C2 alkyl, e.g. benzyl. When R₃ and R₄ together with the carbon atom to which they are both attached form a C4-C6 cycloalkyl, said cycloalkyl more particularly may be C4-C5 cycloalkyl, e.g. cyclobutyl. In some embodiments, R₃ and R₄ are independently selected from hydrogen, C1-C4 alkyl; and C3-C4 cycloalkyl, e.g. R₃ and R₄ are independently selected from hydrogen and C1-C3 alkyl.

In some embodiments, R₃ and R₄ are independently selected from hydrogen, methyl, ethyl, n- propyl, isopropyl, and cyclopropyl. In some of these embodiments, R₄ is hydrogen or methyl, e.g. R₄ is hydrogen.

In some particular embodiments, R₂ is selected from C1-C6 alkyl, and C3-C6 cycloalkyl; and R₃ and R₄ are independently selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl, or R₃ and R₄ together with the carbon atom to which they are both attached form a C4-C6 cycloalkyl.

In some further particular embodiments, R₂ is selected from C1-C6 alkyl; and R₃ and R₄ are independently selected from hydrogen, and C1-C6 alkyl, or R₃ and R₄ together with the carbon atom to which they are both attached form a C4-C6 cycloalkyl. In some further particular embodiments, R₂ is selected from C1-C6 alkyl; and R₃ and R₄ are independently selected from hydrogen, and Cl -C6 alkyl; e.g. R₂ is selected from Cl -C3 alkyl; and R₃ and R₄ are

independently selected from hydrogen and Cl -C3 alkyl; or R₂ is methyl and R₃ and R₄ are independently selected from hydrogen and methyl. In some further particular embodiments, R₂ and R₃ are independently selected from C1-C6 alkyl, and R₄ is hydrogen; e.g. R₂ and R₃ are independently selected from C1-C3 alkyl, and R₄ is hydrogen; e.g. each one ofR₂ and R₃ is methyl and R₄ is hydrogen.

In a compound of formula (I), R₅ is a moiety of formula (II)

wherein ring A, m and R₆ are as defined herein.

In some embodiments, ring A is 5- or 6-membered heteroaryl. In some other embodiments, ring A is 6-membered heteroaryl. In still other embodiments, ring A is phenyl or 6-membered heteroaryl. When ring A is 5- or 6-membered heteroaryl, said heteroaryl may contain 1 , 2, 3, or 4 heteroatoms; e.g. 1, 2, or 3 heteroatoms; or 1 or 2 heteroatoms; or 1 heteroatom; which heteroatoms are independently selected from N, O and S. In some embodiments, when ring A is 5- or 6-membered heteroaryl, said ring is selected from 5-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from N, O and S, and 6-membered heteroaryl containing 1 , 2, or 3 heteroatoms, that are all N. For example, when ring A is 5-membered heteroaryl, such heteroaryl may be selected from furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, and tetrazolyl.

In some embodiments, ring A is 6-membered heteroaryl containing 1, 2, or 3 heteroatoms, that are all N, e.g. ring A may be selected from pyridinyl, pyridazinyl, pyrimidinyl, and triazinyl.

In some of these embodiments, one N is in para position. For example, ring A may be selected from pyridin-4-yl, pyridazin-4-yl, pyrimidin-4-yl, and 1,3, 5 -triazinyl; e.g. from pyridin-4-yl, pyrimidin-4-yl, and 1 ,3 ,5 -triazinyl; or from pyridin-4-yl, and pyrimidin-4-yl. In some

embodiments, when ring A is a 6-membered heteroaryl having a nitrogen in para position, as defined herein above, ring A is pyridin-4-yl.

Ring A may optionally be substituted 1, 2, or 3 moieties R₆. Thus, in the moiety of formula (II), the number of substituents R₆ on ring A, indicated by m, is an integer of from 0 to 3. In some embodiments, m is an integer of from 0 to 2, e.g. m is 0 or 1, or m is 0. In some further embodiments, m is an integer of from 1 to 3, e.g. m is 1 or 2, or m is 1. In some embodiments, when ring is phenyl, m is not 0. In some embodiments, when ring A is a 6-membered heteroaryl having a nitrogen in para position, m is 0, 1, 2 or 3, e.g. m is 0, 1 or 2, or m is 0 or 1, and when m is different from 0, a moiety R₆ is attached in meta position on ring A, i.e. adjacent to the nitrogen in para position. In some of these embodiments, m is 1. In some embodiments, when ring A is a 6-membered heteroaryl having a nitrogen in para position, m is 1, 2 or 3, e.g. m is 1 or 2, and a moiety R₆ is attached in meta position on ring A, i.e. adjacent to the nitrogen in para position.

In some particular embodiments, R₅ is a moiety of formula (Ila) (II a)

wherein R₆ is as defined herein, and m is 0 or 1 , e.g. m is 1.

In a compound of formula (I), each R₆ is independently selected from C1 -C6 alkyl, halogen, R_6aO, R_6bR_6cN, R_6eC(0)N(R_6d), R_6fOC(0), R_6gC(0)0, R_6hS(0)₂, R_6iC(0), R_6kS(0)₂N(R_6j),

R_6iR_6mNS(0)₂, R_6nR_6pNC(0), and CN; and, when m is 2 or 3, two R₆, attached to adjacent atoms of ring A, together with the atoms to which they are attached may form a 5- or 6-membered heterocyclic or carbocyclic ring. In some embodiments, each R₆ is independently selected from C1 -C6 alkyl, halogen, R_6aO, R_6bR_6cN, R_6eC(0)N(R_6d), R_6fOC(0), R_6gC(0)0, R_6hS(0)₂, R_6iC(0), R_6kS(0)₂N(R_6j), R_6iR_6mNS(0)₂, R_6nR_6pNC(0), and CN. In some embodiments, each R₆ is independently selected from C1 -C6 alkyl, halogen, R_6aO, R_6bR_6c , R_6eC(0)N(R_6d), R_6fOC(0), R_6gC(0)0, R_6hS(0)₂, R_6iC(0), R_6kS(0)₂N(R_6j), R_6iR_6mNS(0)₂, R₆„R_6pNC(0), and CN. In some embodiments, each R₆ is independently selected from C1 -C6 alkyl, halogen, R_6aO, R_6bR_6cN, and CN. In some embodiments, each R₆ is independently selected from C1 -C6 alkyl, halogen, R_6aO, and R_6bR_6cN. In some embodiments, each R₆ is independently selected from Cl -C6 alkyl, halogen, R_6aO, and CN. In some embodiments, each R₆ is independently selected from C1 -C6 alkyl, halogen, R_6bR_6cN, and CN. In some embodiments, each R₆ is independently selected from C1 -C6 alkyl, R_6aO, and halogen. In some embodiments, each R₆ is independently selected from C1 -C6 alkyl, halogen, and CN. In some embodiments, each R^ is independently selected from C1 -C6 alkyl, halogen, and R_6bR_6cN. In some embodiments, each R₆ is independently selected from C1 -C6 alkyl and halogen. In some embodiments, each Re is independently selected from Cl -C6 alkyl. In some embodiments, each R₆ is independently selected from halogen. When R_f, is C1 -C6 alkyl, it more particularly may be C1 -C5 alkyl, or C1 -C4 alkyl, or C1 -C3 alkyl, or C1 -C2 alkyl, e.g. methyl. When R₆ is halogen, it e.g. may be selected from F, Cl, and Br, more particularly from F and Cl. In some embodiments, when R₆ is halogen, said halogen is F. When R₆ comprises a moiety R_6a, R_6b, R_6c, R_6d, R_6j, R«, R_6m, R_6n, and R_6p, any such moiety is independently selected from H and C1 -C6 alkyl. In some embodiments, any such moiety is independently selected from H and C1 -C5 alkyl, or from H and C1 -C4 alkyl, or from H and Cl - C3 alkyl, or from H and C1-C2 alkyl, e.g. from H and methyl. In some embodiments, any such moiety is H. In some other embodiments, any such moiety is selected from C1-C6 alkyl, or from C1 -C5 alkyl, or from C1-C4 alkyl, or from C1-C3 alkyl, or from C1-C2 alkyl, e.g. any such moiety is methyl. When R₆ comprises a moiety R_6e, R_6f, R_6g, R_6h, R_6i, and R_6k, any such moiety is independently selected from Cl -6 alkyl. In some embodiments, any such moiety is selected from C1 -C5 alkyl, or from C1-C4 alkyl, or from C1-C3 alkyl, or from C1-C2 alkyl, e.g. any such moiety is methyl.

For example, in some embodiments R_6a, R6b, R6c, R6d, R6j, R6i, R6m, R6n, and R_6p are

independently selected from H and Cl -C4 alkyl, and R_6e, R_6f, R_6g, R_6h, R_6i, and R_6k are independently selected from C1-C4 alkyl. In some other embodiments, R_6a, R_6b, R_6c, R_6d, R_6j, R_6i, R_6m, R_6n, and R_6p are independently selected from H and C1-C3 alkyl, and R_6e, R_6f, R_6g, R_6h, R_6i, and R_6k are independently selected from C1-C3 alkyl. In some other embodiments, R_6a, R_6b, R_6c, R_6d, R_6j, R_6b R_6m, R_6n, and R_6p are independently selected from H and methyl, and R_6e, R_6f, R_6g, R_6h, Ra, and R_6k are methyl.

Any alkyl present in a moiety R₆ may optionally be substituted by one or more F, i.e. any alkyl may be or comprise a moiety selected from CF₃-, CF₂H-, CFH₂-, -CF₂-, -CFH-, and -CF<. In some embodiments, no such fluoro substitution is present in any alkyl group.

In some embodiments, when m is at least 2, e.g. m is 2, two R₆ attached to adjacent atoms of the ring A form, together with the atoms to which they are attached, a 5- or 6-membered heterocyclic or carbocyclic ring, e.g. a 5- or 6-membered heterocyclic ring, such as a 5- or 6-membered ring containing one or two oxygen atoms. For example, two R_f, attached to adjacent atoms of ring A may form together a methylenedioxy biradical or an ethylenedioxy biradical.

In some embodiments, when two R₆ attached to adjacent atoms of the ring A form, together with the atoms to which they are attached, a 5- or 6-membered heterocyclic or carbocyclic ring, said ring is a 5- membered heterocyclic ring, e.g. l,3-dioxole or 1 ,3-dioxolane. In some embodiments, when two R₆ attached to adjacent atoms of the ring A form, together with the atoms to which they are attached, a 5- or 6-membered heterocyclic or carbocyclic ring, said ring is carbocyclic, e.g. a benzene ring.

In some particular embodiments of a compound of formula (I), e.g. a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik) ring A is 6-membered heteroaryl containing 1,

2, or 3 heteroatoms, that are all N, and one N is in para position. In some further particular embodiments of a compound of formula (I), e.g. a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik) ring A is 6-membered heteroaryl containing 1 , 2 or 3 N, e.g. 1 or 2 N, and one N is in para position. In some of these embodiments, one R₆ is atached in meta position, i.e. on R₆ is attached to a carbon atom of the ring A that is adjacent to the N in para position. In some particular embodiments of a compound of formula (I), e.g. a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij) or (Ik), ring A is pyridin-4-yl. Thus, in some embodiments, the compound is as represented by formula (Im),

wherein X, Y, Z, Ri, R₂, R₃, R₄, R₆ and m are as defined herein.

In some further particular embodiments, the compound is as represented by formula (In)

wherein X, Y, Z, Ri, R₂, R₃, R₄, and R₆ are as defined herein, and m is 1 , 2 or 3; e.g. m is 1 or 2, or m is 1. In some further particular embodiments of a compound of formula (I), e.g. a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ii) or (Ik), R₅ is a moiety of formula (Ila).

In some particular embodiments, the compound of formula (I) is as represented by formula (Io)

wherein Ri, R₂, R₃, R₄, and R₆ are as defined herein, and m is 0 or 1.

In some embodiments of a compound of formula (Io), Ri is 3,4-dimethoxyphenyl. In some other embodiments, Ri is 1 ,3 -dimethyl- lif-indazol-5-yl, i.e. the compound is as represented by formula

(Ip)

wherein R₂, R₃, R₄, and R₆ are as defined herein, and m is 0 or 1.

In some embodiments of a compound of formula (Im), (Io) or (Ip), m is 1. In some other embodiments of a compound of formula (Im), (Io) or (Ip), m is 0. Unless otherwise specified or apparent from the context, any reference to a compound of formula (I) also should be construed as a reference to a compound as represented by any of the formulas (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Hi), (Ii), (Ij), (Ik), (Im), (In), (Io) or (Ip). In some embodiments, the compound of formula (I) is 1 - { [(3 -( 1 ,3-dimcthyl- l //-indazol-5-yl)- 2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7-yl)(pyridin-4-ylmethyl)carbamoyl]oxy}ethyl acetate, of formula:

The compound of formula (I) is a 1 -(acyloxy)-alkyl carbamate prodrug of a RI4KIIIb inhibitor of the general formula (G)

wherein X, Y, Z, Ri and R₅ are as defined herein. Similarly, a compound of formula (la) as defined herein is a prodrug of a corresponding compound of formula (la’), a compound of formula (lb) as defined herein is a prodrug of a corresponding compound of formula (lb’) etc.

Examples of RI4KIIIb inhibitor of formula (G) and methods for their preparation are described in the international applications PCT/EP2018/058522, PCT/EP2016/063383 and

PCT/EP2015/051 177, and in the copending international application PCT/EP2019/072220. In some embodiments, therefore, the compound of formula (I) is a 1 -(acyloxy)-alkyl carbamate prodrug of a RI4KIIIb inhibitor disclosed in the above mentioned applications, said RI4KIIIb inhibitor being selected from:

3 -( 1 ,3 -dimethyl- 1 H- indazol-5 -yl )-2,5-di mcthyl-/V-(pyridi n-4-yl methyl )pyrazolo [ 1 ,5 -a]pyrimidin-

7-amine,

3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl )-2,5-dimcthyl-/V—V-((6-mcthylpyridin-3 - yl)methyl)pyrazolo[ 1 ,5-a]pyrimidin-7-amine,

3-( 1 ,3-dimcthyl- l / -indazol-5-yl )-/V-(4-mcthoxybcnzyl)-2,5-dimcthylpyrazolo[ 1 ,5-a]pyrimidin-7- amine,

N-(4-chlorobenzyl)-3-(l , 3-dimethyl- l//-indazol-5-yl)-2,5-dimethylpyrazolo[l,5-a]pyrimidin-7- amine,

3-(l ,3-dimethyl-l//-indazol-5-yl)-2,5-dimethyl-/V-(4-(methylsulfonyl)benzyl)pyrazolo[ 1 ,5- a]pyrimi din-7 -amine,

4-(((3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,5 -dimethylpyrazolo [ 1 ,5 -a]pyrimidin-7 - yl)amino)methyl)benzenesulfonamide,

3-( 1 ,3 -dimethyl- 1 / -indazol-5-yl )-/V-((6-mcthoxypyridin-3-yl)mcthyl)-2 ,5 -dimethylpyrazolo [1,5- a]pyrimi din-7 -amine,

3-(l ,3-dimethyl-l//-indazol-5-yl)-2,5-dimethyl-/V-(thiophen-2-ylmethyl)pyrazolo[ 1 ,5- a]pyrimi din-7 -amine,

N-(4-(((3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,5 -dimethylpyrazolo [ 1 ,5 -a]pyrimidin-7 - yl)amino)methyl)phenyl)methanesulfonamide,

8 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,7 -dimcthyl-/V-(pyridin-4-yl methyl )pyrazolo [1,5- a][l,3,5]triazin-4-amine,

8-(l ,3-dimethyl-l//-indazol-5-yl)-/V-(4-methoxybenzyl)-2,7-dimethylpyrazolo[ 1 ,5- a][l,3,5]triazin-4-amine,

8 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,7 -dimcthyl-/V-((6 -methylpyridin-3 -yl)methyl)pyrazolo [1,5- a][l,3,5]triazin-4-amine,

4-(((8-(l, 3-dimethyl- l//-indazol-5-yl)-2, 7 -dimethylpyrazolo [1 ,5 -a] [1,3, 5]triazin-4- yl)amino)methyl)benzenesulfonamide, N-(4-chlorobcnzyl)-8-( 1 ,3-dimcthyl- 1 //-indazol-5-yl )-2,7-dimcthylpyrazolo[ 1 ,5-a][ 1 ,3,5]triazin- 4-amine,

8-( 1 ,3-dimcthyl- 1 //-indazol-5-yl )-2,7-dimcthyl-/V-(4-(mcthylsulfonyl)bcnzyl)pyrazolo[ 1 ,5- a][l,3,5]triazin-4-amine,

N-(4-(((8-( 1 ,3-dimcthyl- 1 //-indazol-5-yl)-2,7-dimcthylpyrazolo[ 1 ,5-a][ 1 ,3,5]triazin-4- yl)amino)methyl)phenyl)methanesulfonamide,

8-(l ,3-dimethyl-li -indazol-5-yl)-2,7-dimethyl-7V-(thiophen-2-ylmethyl)pyrazolo[ 1 ,5- a][l,3,5]triazin-4-amine,

8 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl )-/V-((6-mcthoxypyridin-3-yl)mcthyl)-2 ,7 -dime thy lpyrazolo [1,5- a][l,3,5]triazin-4-amine,

3 -( 1 ,3 -dimethyl- 1 H- indazol-5 -yl )-2,6-di mcthyl-/V-(pyridi n-4-yl methyl )imidazo [ 1 ,2 -b]pyridazin- 8-amine,

3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,6-dimethyl-7V-((6 -methylpyridin-3 -yl)methyl)imidazo [ 1 ,2- b] pyridazin- 8 -amine ,

N-(4-chlorobenzyl)-3-(l , 3-dimethyl- l77-indazol-5-yl)-2,6-dimethylimidazo[ 1,2 -b]pyridazin-8- amine,

3 -( 1 ,3 -dimethyl- 1 /7-indazo 1-5 -yX)-N- ((6 -methoxypyridin-3 -yl)methy l)-2 ,6 -dimethylimidazo [1,2- b] pyridazin- 8 -amine ,

3-( 1 ,3-dimcthyl- 1 /7-indazo 1-5-yl )-2, 6-dimcthyl-/V-(thiophcn-2-yl methyl )imidazo[ 1 ,2-b]pyridazin- 8-amine,

3-(l ,3-dimethyl-l77-indazol-5-yl)-/V-(4-methoxybenzyl)-2,6-dimethylimidazo[ 1 ,2-b]pyridazin-8- amine,

3 -( 1 ,3 -dimethyl- 1 iT-indazol-5 -yl)-2 ,5 -dimethyl-7V-((6 -trifluoromethylpyridin-3 - yl)methyl)pyrazolo[ 1 ,5-a]pyrimidin-7-amine,

N-(benzyl)-3-(l , 3 -dimethyl- l77-indazol-5-yl)-2,5-dimethylpyrazolo[l,5-a]pyrimidin-7-amine, N-(4-fluorobenzyl)-3-(l , 3-dimethyl- l77-indazol-5-yl)-2,5-dimethylpyrazolo[ 1, 5-a]pyrimidin-7- amine,

3-( 1 ,3-dimcthyl- 1 7/-indazol-5-yl )-2,6-dimcthyl-_iV-(4-(mcthylsulfonyl)bcnzyl)imidazo[ 1 ,2- b] pyridazin- 8 -amine ,

8-(3,4-dimethoxyphenyl)-7V-[(4-fluorophenyl)methyl]-2,7-dimethyl-pyrazolo[l ,5-a][l,3,5]triazin-

4-amine, 8-(3,4-dimcthoxyphcnyl)-2,7-dimcthyl-/V-[[4-(tnfluoromcthyl)phcnyl] methyl] pyrazolo[ 1 ,5- a][l,3,5]triazin-4-amine,

8-(3 ,4-dimethoxyphenyl)-2 ,7 -dimethyl-7V-(p-tolylmethyl)pyrazolo[ 1 ,5 -a] [ 1 ,3 ,5]triazin-4-amine,

8-(3,4-dimethoxyphenyl)-7V-[(4-isopropylphenyl)methyl]-2,7-dimethyl-pyrazolo[l ,5- a][l,3,5]triazin-4-amine,

8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimcthyl-/V-(2 -pyridylmethyl)pyrazolo [ 1 ,5 -a] [ 1 ,3 ,5 ]triazin-4- amine,

8-(3,4-dimcthoxyphcnyl)-2,7-dimcthyl-/V-(4-pyridylmcthyl)pyrazolo[ 1 ,5-a][ 1 ,3,5]triazin-4- amine,

N-[(4-chlorophenyl)methyl]-8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5- a][l,3,5]triazin-4-amine,

N-[4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l,5-a][l,3,5]triazin-4- yl] amino]methyl]phenyl] acetamide,

8-(3,4-dimcthoxyphcnyl)-/V-[(4-mcthoxyphcnyl)mcthyl]-2,7-dimcthyl-pyrazolo[l ,5- a][l,3,5]triazin-4-amine,

8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimcthyl-/V-[(3 -methylsulfonylphenyl)methyl]pyrazolo [1 ,5- a][l,3,5]triazin-4-amine,

8-(3,4-dimcthoxyphcnyl)-_iV-[(6-mcthoxy-3-pyridyl)mcthyl]-2,7-dimcthyl-pyrazolo[ 1 ,5- a][l,3,5]triazin-4-amine,

4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5-a][l,3,5]triazin-4- yl] amino] methyl]benzenesulfonamide,

N-(l ,3-benzodioxol-5-ylmethyl)-8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5- a][l,3,5]triazin-4-amine,

4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5-a][l,3,5]triazin-4- yl] amino] methyl]phenol,

N-[4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l,5-a][l,3,5]triazin-4- yl]amino]methyl]phenyl]methanesulfonamide,

N-benzyl-8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5-a][l,3,5]triazin-4-amine,

8-(3,4-dimethoxyphenyl)-2,7-dimethyl-7V-(2-thienylmethyl)pyrazolo[l,5-a][l,3,5]triazin-4- amine, 8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimcthyl-/V-(3 -pyridylmethyl)pyrazolo [ 1 ,5 -a] [ 1 ,3 ,5 ]triazin-4- amine,

8-(3,4-dimethoxyphenyl)-2,7-dimethyl-7V-[(5-methyl-2-furyl)methyl]pyrazolo[l ,5- a][l ,3,5]triazin-4-amine,

methyl N-[4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[ l ,5-a][l ,3,5]triazin-4- yl]amino]methyl]phenyl]sulfonylcarbamate,

N-[4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[ l ,5-a][l ,3,5]triazin-4- yl]amino]methyl]phenyl]sulfonylpropanamide,

N-methyl-4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5-a][l ,3,5]triazin-4- yl] amino] methyl]benzenesulfonamide,

8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimcthyl-/V-[( 1 -methyl- 1 //- p y r az o l - 3 - y l ) m c t h y l ] p y razo l o [1 ,5- a][l ,3,5]triazin-4-amine,

8-(3,4-dimcthoxyphcnyl)-2,7-dimcthyl-/V-[( 1 ,3-oxazol-5-yl )mcthyl]pyrazolo[ 1 ,5-a][ 1 ,3,5]triazin- 4-amine,

8-(3 ,4-dimethoxyphenyl)-2 ,7 -dimcthyl-/V-[(2-mcthylpyrimidin-5 -yl)methyl]pyrazolo [1 ,5- a][l ,3,5]triazin-4-amine,

8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimethyl-7V- [(pyridazin-4-yl)methyl]pyrazolo [ 1 ,5 -a] [ 1 ,3 ,5 Jtriazin- 4-amine,

8-(3,4-dimethoxyphenyl)-2,7-dimethyl-/V-[(6-methylpyridin-3-yl)methyl]pyrazolo[l ,5- a][l ,3,5]triazin-4-amine,

N-[(4-chlorophenyl)methyl]-3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7- amine,

3-(3,4-dimethoxyphenyl)-7V-[(4-methoxyphenyl)methyl]-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-

7-amine,

3-(3 ,4-dimethoxyphenyl)-2 ,5 -dimethyl-7V-(p-tolylmethyl)pyrazolo[ 1 ,5 -a]pyrimi din-7 -amine, 3-(3,4-dimethoxyphenyl)-7V-[(4-fluorophenyl)methyl]-2,5-dimethyl-pyrazolo[l ,5-a]pyrimi din-7- amine,

3-(3,4-dimethoxyphenyl)-2,5-dimethyl-/V-(2-pyridylmethyl)pyrazolo[ l ,5-a]pyrimidin-7-amine,

N-benzyl-3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7-amine,

3-(3 ,4-dimethoxyphenyl)-2 ,5 -dimcthyl-/V-[[4-(trifluoiOmcthyl [phenyl] methyl] pyrazolo [1 ,5- a]pyrimi din-7 -amine, 3-(3,4-dimethoxyphenyl)-2,5-dimethyl-7V-(4-pyridylmethyl)pyrazolo[l,5-a]pyrimidin-7-amine, 3-(3 ,4-dimethoxyphenyl)-2 ,5 -dimcthyl-/V-[[4-(trifluoromcthoxy [phenyl] methyl] pyrazolo [1,5- a]pyrimidin-7 -amine,

N-[4-[[[3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l,5-a]pyrimidin-7- yl] amino]methyl]phenyl] acetamide,

3 -(3 ,4-dimethoxyphenyl)-7V- [(4-dimethylaminophenyl)methyl] -2 ,5 -dimethyl-pyrazolo [1,5- a]pyrimi din-7 -amine,

3 -(3 ,4-dimethoxyphenyl)-7V- [(6-methoxy-3 -pyridyl)methyl]-2 ,5 -dimethyl-pyrazolo [ 1 ,5 - a]pyrimi din-7 -amine,

N-[4-[[[3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l,5-a]pyrimidin-7- yl]amino]methyl]phenyl]methanesulfonamide,

4-[[[3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7-yl]amino]methyl]phenol, 3 -(3 ,4-dimethoxyphenyl)-2 ,5 -dimcthyl-/V-[(3 -methylsulfonylphenyl)methyl]pyrazolo [1 ,5- a]pyrimi din-7 -amine,

3 -(3 ,4-dimethoxyphenyl)-2 ,5 -dimethyl-7V- [(4-methylsulfbnylphenyl)methyl]pyrazolo [1 ,5- a]pyrimi din-7 -amine,

N-[(4-tert-butylphenyl)methyl]-3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-

7-amine,

3-(3 ,4-dimethoxyphenyl)-2 ,5 -dimcthyl-_iV-[(2-mcthylpyrimidin-4-yl [methyl] pyrazolo [1,5- a]pyrimi din-7 -amine,

3-(3,4-dimcthoxyphcnyl)-2,5-dimcthyl-_iV-[(6-mcthyl-3-pyridyl)mcthyl]pyrazolo[ 1 ,5-a]pyrimidin- 7-amine,

l-[4-[[[3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7- yl]amino]methyl]phenyl]ethanone,

3 -(3 ,4-dimethoxyphenyl)-2 ,5 -dimcthyl-/V-( 1 -naphthylmethyl)pyrazolo [1,5 -a]pyrimidin-7 -amine,

4-[[[3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7- yl] amino] methyl]benzenesulfonamide,

3-(3,4-dichlorophenyl)-7V-[(4-fluorophenyl)methyl]-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7- amine,

3-(3,4-dimcthoxyphcnyl)-2,6-dimcthyl-_iV-((2-mcthylpyridin-4-yl)mcthyl)imidazo[l ,2- b] pyridazin- 8 -amine , 3-(3,4-dimethoxyphenyl)-7V-((2-fluoropyridin-4-yl)methyl)-2,6-dimethylimidazo[ l ,2- b] pyridazin- 8 -amine ,

3 -( 1 ,3 -dimethyl- 1 i7-indazol-5 -yl)-2 ,5 -dimethyl-TV- [(2 -fluoropyridin-4-yl)methyl]pyrazolo [ 1 ,5 - a]pyrimi din-7 -amine,

3 -( 1 ,3 -dimethyl- 1 H- indazol-5 - yl ) - 2 , 5 - d i m c t h yl - N- [ ( 2 -methylpyridin-4-yl)methyl]pyrazolo [1 ,5- a]pyrimi din-7 -amine,

3 -( 1 ,3 -dimethyl- 1 //-indazol-5 - yl ) - 2 , 5 - d i m c t h yl - /V- [ ( 2 -ethylpyridin-4-yl)methyl]pyrazolo [1 ,5- a]pyrimi din-7 -amine,

3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,5 -dimethyl-TV- [(2 -methoxypyridin-4-yl)methyl]pyrazolo [ 1 ,5 - a]pyrimi din-7 -amine,

3-( 1 ,3-dimcthyl- l //-indazol-5-yl )-2,5-dimcthyl-/V-[(2-cyanopyridin-4-yl )mcthyl]pyrazolo[ 1 ,5- a]pyrimi din-7 -amine,

3-(3,4-dimethoxyphenyl)-2,6-dimethyl-N-(pyridin-4-ylmethyl)imidazo[ l ,2-b]pyridazin-8-amine, and

3 -( 1 ,3 -dimethyl- 1 H-indazol-5 -yl)-2 ,5 -dimethyl-N- [(2 -trifluoromethylpyridin-4- yl)methyl]pyrazolo[ 1 ,5-a]pyrimidin-7-amine.

The compounds of formula (I) also may be transformed into suitable, pharmaceutically acceptable salts. The term pharmaceutically acceptable salt of a compound refers to a salt that is pharmaceutically acceptable, as defined herein, and that possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid; or formed with organic acids, e.g. acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p- toluenesulfonic acid, trimethylacetic acid, etc.

In the preparation of acid addition salts, preferably such acid are used which form suitably therapeutically acceptable salts. Examples of such acids are hydrohalogen acids, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid,

hydroxyethanesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid or

naphthalenesulfonic acid.

Whenever a chiral atom is present in a chemical structure, it is intended that all stereoisomers associated with that chiral atom are encompassed by the structure, unless otherwise specified. Using the Cahn-Ingold-Prelog RS notational system, any asymmetric atom may be present in the (R)- or (S)-configuration, and the compound may be present as a mixture of its stereoisomers, e.g. a racemic mixture, or one stereoisomer only, each being within the scope of the present invention.

The present invention includes pharmaceutical compositions comprising a compound of formula (I), or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable excipient, e.g. a carrier, and optionally other therapeutic and/or prophylactic ingredients.

A pharmaceutical composition according to the invention may be for topical (local) or systemic administration, e.g. for enteral administration, such as rectal or oral administration, or for parenteral administration to a mammal (especially a human), and comprises a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt thereof, as active ingredient, in association with a pharmaceutically acceptable excipient, e.g. a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is as defined herein above and depends e.g. on the species of mammal, the body weight, the age, the individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.

For enteral, e.g. oral, administration, the compounds of the invention may be formulated in a wide variety of dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salt(s) thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The formulation of the active compound may comprise an

encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.

Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.

Exemplary compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

The compounds of the invention also may be administered parenterally, e.g. by inhalation, injection or infusion, e.g. by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, intracerebroventricular, intrasynovial, intrastemal, intrathecal, intralesional, intracranial, intracutaneous and subcutaneous injection or infusion.

Thus, for parenteral administration, the pharmaceutical compositions of the invention may be in the form of a sterile injectable or infusible preparation, for example, as a sterile aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80), and suspending agents. The sterile injectable or infusible preparation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the

pharmaceutical composition may be a solution in 1 ,3-butanediol. Other examples of acceptable vehicles and solvents that may be employed in the compositions of the present invention include, but are not limited to, mannitol, water, Ringer’s solution and isotonic sodium chloride solution.

In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

Solutions for parenteral use also may contain suitable stabilizing agents, and if necessary, buffer substances. Suitable stabilizing agents include antioxidizing agents, such as sodium bisulfate, sodium sulfite or ascorbic acid, either alone or combined, citric acid and its salts and sodium EDTA. Parenteral solutions may also contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and cholorobutanol. For inhalation or nasal administration, suitable pharmaceutical formulations are as particles, aerosols, powders, mists or droplets, e.g. with an average size of about 10 pm in diameter or less. For example, compositions for inhalation may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.

In some embodiments, the formulation of the invention is a liposomal formulation. Liposomal formulations are well-known within the pharmaceutical fields, and are described e.g. in

Remington, Essentials of Pharmaceutics, Ed. Linda Felton (Pharmaceutical Press 2012), pages 456-7 and in numerous other publications. Information on e.g. choice of suitable liposome formulations, suitable lipids, preparation methods, etc. is easily available to the person of ordinary skill in the art. Examples of lipids for liposome formation are phospholipids, sphingolipids, sterol lipids, and fatty acids. Lipids suitable for liposome formation may be purchased e.g. from Avanti^® Polar Lipids, Inc.

The pharmaceutical compositions of the invention may also be administered topically, to the skin or to a mucous membrane. For topical application, the pharmaceutical composition may be e.g. a lotion, a gel, a paste, a tincture, a transdermal patch, or a gel for transmucosal delivery.

The composition may be formulated as a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.

Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetaryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Suitable pharmaceutical excipients, e.g. carriers, and methods of preparing pharmaceutical dosage forms are described in Remington’s Pharmaceutical Sciences, Mack Publishing

Company, a standard reference text in art of drug formulation.

The pharmaceutical compositions may comprise from approximately 1 % to approximately 95%, preferably from approximately 20% to approximately 90% of a compound of formula (I), together with at least one pharmaceutically acceptable excipient. In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable daily dosages typically ranges from 1 to 1000 mg, e.g. 1 -500 mg daily, or 1-50 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound used, the route and form of administration, and the indication towards which the administration is directed, etc. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease. Compounds of the invention may be administered as pharmaceutical formulations including those suitable for enteral or parenteral administration. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to e.g. the degree of affliction.

The compound of the present invention is contemplated as useful for the treatment of diseases linked to, caused by, or otherwise associated with a viral infection in a mammal (animal or human, but preferably a human), in particular an RNA viral infection, e.g. a non-enveloped single-stranded (+) RNA viral infection, in particular diseases caused by picomaviruses. The picomavirus e.g. may be a Parechovirus (e.g. Ljungan or Parecho), a Cardiovirus (e.g. EMCV or Theiler’s virus), Enterovirus (e.g. EV, Coxsackie, Polio, Rhino) or a hepatovirus. For veterinary use, the picomavirus may be e.g. an Aphthovirus or a Teschovirus. Diseases that are considered to be linked to, caused by, or otherwise associated with vims infection, e.g. by picomaviruses, are e.g. neurodegenerative diseases such as multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington’s disease, poliomyelitis, encephalitis, meningitis, sepsis, cancer, paralysis, myocarditis, diabetes, common cold, hand-foot-and-mouth disease, herpangina, pleurodynia, diarrhea, mucocutaneous lesions, respiratory illness, conjunctivitis, myositis, and chronic fatigue syndrome.

It is considered well within the knowledge of the person of ordinary skill in the art to synthesize and identify compounds of formula (I) as defined herein, by following methods as described in literature or as generally described in the below non-limiting examples. Thus, a RI4KIIIb inhibitor of formula (G)

e.g. as disclosed in the published international applications PCT/EP2018/058522,

PCT/EP2016/063383, and PCT/EP2015/051 177, and copending international application No PCT/EP2019/072220 may be transformed into a prodrug of formula (I) as defined herein e.g. by a 2-step reaction according to the following general scheme:

cf. steps 8 and 9 of Example 1 , herein below. EXAMPLES

General Procedures

Reactions were performed in flame-dried sealed-tubes or oven-dried glassware under a positive pressure of argon or nitrogen, unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe. Tetrahydrofuran (THF) was distilled from

sodium/benzophenone-ketyl. Dichloromethane (CH2CI2) was distilled from calcium hydride. All other chemicals were obtained from commercial vendors and were used without further purification unless noted otherwise. Molecular sieves were activated at 350 °C and were crushed immediately prior to use, then flame-dried under vacuum. Reactions were monitored by thin layer chromatography (TLC) with 0.25-mm E. Merck pre-coated silica gel plates. Organic solutions were concentrated by rotary evaporation below 50 °C. Flash column chromatography was performed employing 60-120, 230-400 mesh silica gel and neutral alumina. Yields refer to chromatographically and spectroscopically pure compounds unless otherwise noted. Instrumentation

^!H and ¹³C spectra were recorded either on a Bruker AVANCE III HD 400 MHz spectrometer or Bruker AVANCE II 300 MHz spectrometer. Chemical shifts are expressed in parts per million (d scale) downfield from tetramethylsilane and are referenced to the residual resonance in the NMR solvent (CHCI₃: d 7.26 for 1H NMR, d 77.16 for ¹³C NMR). LC-MS was performed on an Agilent XCT Ion Trap equipped with chemstation and Bruker daltonics software.

Example 1

l-{[(3-(l,3-dimethyl-lH-iiidazol-5-yl)-2,5-dimethyl-pyrazolo[l,5-a]pyrimidiii-7-yl)(pyridiii- 4-ylmethyl)carbamoyl]oxy}ethyl acetate

Step 1: 2, 5 -dim elhylpyrazolo[l , -a ] pyrim id in - 7 -ol

A round bottom flask was charged with 3-amino-5-methylpyrazole (100 g, 1.02 mol), ethyl acetoacetate (161 mL, 1.23 mol), acetic acid (300 mL) and l,4-dioxan (1000 mL). The reaction was refluxed for l6h at 105 °C. Off-white solids were obtained upon completion of the reaction and were filtered through suction. The solids were washed with cold hexane and dried under vacuum to obtain 2,5-dimethylpyrazolo[l,5-a]pyrimidin-7-ol (85 g, 49%) as an off-white solid.

Step 2: 7 -chloro-2,5-dimethylpyrazolo[J5-a] pyrimidine

To a solution of 2,5-dimethylpyrazolo[l,5-a]pyrimidin-7-ol (120 g, 0.73 mol) in acetonitrile (1200 mL) was added POCl₃ (103 mL, 1.1 mol) dropwise. Upon completion of addition, the reaction was heated at 80°C for l2h. Upon completion, the POCI₃ in the reaction was distilled out. The crude was diluted with water and neutralized with saturated NaHCCb solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash column chromatography eluting the 7- chloro-2,5-dimethylpyrazolo[l ,5-a]pyrimidine with 20% ethylacetate -hexanes as an off-white solid (108 g, 80.8%).

Step 3: 7 -chloro-3-iodo-2,5-dimethylpyrazolo[J5-a] pyrimidine

To an ice cold solution of 7-chloro-2,5-dimethylpyrazolo[l,5-a]pyrimidine (120 g, 0.66 mol) in acetonitrile (1200 mL) at -l0°C was added N-iodosuccinimide (163.5 g, 0.726 mol) portionwise. The reaction was stirred at this temperature for lh. Upon completion, solids were observed. The reaction was quenched with ice cold water and filtered via suction. The obtained solids were washed with hexane and dried under vacuum to afford 7-chloro-3-iodo-2,5- dimethylpyrazolo[l ,5-a]pyrimidine as a white solid (182.8 g, 89.9%).

Step 4: 3-iodo-2 ,5-dimethyl-N-[ (pyridin-4-yl)methyl]pyrazolo[ 1,5-ciJpyrimidin- 7 -amine

To a stirred solution of 7-chloro-3-iodo-2,5-dimethylpyrazolo[l,5-a]pyrimidine (53 g, 172 mmol) and 4-(aminomethyl)pyridine (24.5 g, 226.5 mmol) in ethanol (265 ml) was added

diisopropylethylamine (265 mL, 5 Vols) and stirred at 80°C for 6h. Upon completion, the ethanol in the reaction was distilled out. The crude was partitioned between water and ethylacetate. The ethylacetate layers were dried over sodium sulfate and concentrated under reduced pressure. Flash column chromatography eluted the required compound with 55% ethylacetate -hexane. Upon concentration it afforded 3-iodo-2,5-dimethyl-7V-[(pyridin-4-yl)methyl]pyrazolo[l, 5- a]pyrimidin-7-amine (65.2 g, 53.6%) as a brown solid.

Step 5: ( -lodo-2 ,5-dimethyl-pyrazolo[J5 -a] pyrimidin-7 -yl)-pyridin-4-ylmethyl-carbamic acid tert-butyl ester

To a stirred solution of 3-iodo-2,5-dimethyl-7V-[(pyridin-4-yl)methyl]pyrazolo[l,5-a]pyrimidin-7- amine (2.8 g, 7.38 mmol) in dichloromethane (28mL) was added DMAP (0.9 g, 7.38 mmol) at 0°C. Then Boc anhydride (1.8 ml, 8.12 mmol) was added dropwise at this temperature and stirred at ambient temperature for 2h. Upon completion, the reaction was washed with water. The organic layer was dried over sodium sulfate and concentrated. The obtained crude was purified by flash column chromatography (neutral alumina) eluting the required compound (3-Iodo-2,5- dimethyl-pyrazolo[l,5-a]pyrimidin-7-yl)-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (2.92 g, 82.2 %) with 10% ethylacetate -hexanes as an off-white solid.

Step 6: [3-(l ,3-Dimethyl-lH-indazol-5-yl)-2,5-dimethyl-pyrazolo[ 1,5-aJpyrimidin- 7 -yl] -pyridin- 4-ylmethyl-carbamic acid tert-butyl ester

A 25ml round bottom flask was charged (3-Iodo-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7-yl)- pyridin-4-ylmethyl-carbamic acid tert-butyl ester (20 g, 41.72 mmol), l,3-dimethyl-5-(4, 4,5,5- tctramcthyl-[ 1 ,3,2]dioxaborolan-2-yl)- 1 //-indazolc (l3.7lg, 54.2 mmol), potassium carbonate (14.4 g , 104.3 mmol) and dioxamwater (180 mL:20 mL). This solution was degassed with N₂ for 10 min and then the Pd(dppf)Cl₂.DCM complex (5.1 g, 6.25 mmol) was added. The reaction was heated at l00°C for l6h. Upon completion, the reaction was diluted with ethylacetate and filtered through a celite bed. The filtrate was partitioned between ethylacetate and water. The ethylacetate layer was dried over Na₂S0₄ and concentrated under reduced pressure. The obtained crude was purified by flash column chromatography (neutral alumina) eluting the required compound [3- (1 , 3 -Dimethyl- l77-indazol-5-yl)-2, 5-dimethyl-pyrazolo[l , 5-a]pyrimi din-7 -yl]-pyridin-4- ylmethyl-carbamicacid tert-butyl ester (1 1.2 g, 53.9%) with 10% ethylacetate -hexanes as an off- white solid. Step 7: [3-(l,3-Dimethyl-lH-indazol-5-yl)-2,5-dimethyl-pyrazolo[ l,5-a]pyrimidin- 7 -yl] -pyridin- 4-ylmethyl-amine

To an ice cold solution of [3 -( 1 ,3-Dimcthyl- 1 //-indazol-5-yl)-2,5-dimcthyl-pyrazolo[ 1 ,5- a]pyrimidin-7-yl]-pyridin-4-ylmethyl-carbamicacid tert-butyl ester (10 g, 20.09 mmol) in dichloromethane (60 mL) was added TFA (80 mL) dropwise. After completion of addition, the reaction mass was stirred at ambient temperature for 6h. After completion of the reaction, the solvent and excess TFA were distilled out. The crude was basified with 1N NaOH solution and extracted with 10% MeOH-DCM. The organic layers were dried over Na₂S0₄ and concentrated. The obtained crude was purified by flash column chromatography (neutral alumina) eluting the required [3-(l ,3-Dimcthyl- 1 //-indazol-5-yl)-2,5-dimcthyl-pyrazolo[ 1 ,5-a]pyrimidin-7-yl]- pyridin-4-ylmethyl-amine (6.1 g, 76.5%) with 80% ethylacetate -hexanes as an off-white solid. ‘H-NMR (DMSO, 400 MHz): d 8.52 (m, 3H), 7.85 (s, 1H), 7.75 (d, 1H), 7.59 (d, 1H), 7.37 (d, 2H), 5.96 (s, 1H), 4.65 (d, 2H), 3.97 (s, 3H), 2.56 (s, 3H), 2.50 (s, 3H), 2.31 (s, 3H), LCMS:

398.2 [M+H], HPLC purity: 94.47%.

Step 8: 1-chloroethyl (3-(l ,3-dimethyl-l H-indazol-5-yl)-2 ,5-dimethylpyrazolo [J5-a] pyrimidin-7 - yl)(pyridin-4-ylmethyl)carbamate

To a stirred solution of [3-( 1 ,3-Dimcthyl- 1 //-indazol-5-yl)-2,5-dimcthyl-pyrazolo[l ,5- a]pyrimidin-7-yl]-pyridin-4-ylmethyl-amine (1 g, 2.516 mmol) in dichloromethane (12 mL) at -5 °C was added trimethylamine (0.7 mL, 5.03 mmol) and stirred for 10 min. Then 1 -chloroethyl chloroformate (0.46 mL, 3.77 mmol) was added dropwise. The reaction was stirred at 0°C for 45 min. Upon completion, water was added to the reaction and extracted with dichloromethane. Off- white solids are observed in the organic layer upon standing, which are filtered. The filtrate is concentrated to give 1 -chloroethyl (3-( 1 ,3-dimcthyl- 1 //-indazol-5-yl)-2,5-dimcthylpyrazolo[ 1 ,5- a]pyrimi din-7 -yl)(pyridin-4-ylmethyl)carbamate (220 mg, 17.7%) as a pale brown solid.

Step 9: l-{[ (3-(l ,3-dimethyl-l H-indazol-5-yl)-2, 5-dimethyl-pyrazolo[J5-aJpyrimidin-7- yl)(pyridin-4-ylmethyl)carbamoyl]oxy}ethyl acetate

To a stirred solution of 1 -chloroethyl (3-( 1 ,3-dimcthyl- 1 //-indazol-5-yl)-2,5- dimethylpyrazolo[l ,5-a]pyrimidin-7-yl)(pyridin-4-ylmethyl)carbamate (3 g crude) in DMF (30 mL) was added sodium acetate (1.5 g) and the reaction was heated at 90°C for l6h. Upon completion, the DMF in the reaction was distilled out. The crude thus obtained was taken up in water and washed with 0.1M HC1 solution and extracted with dichloro methane. The organic layer was dried over sodium sulfate and concentrated to the crude (1.lg) with 32% HPLC purity.

Preparative HPLC of the above crude with 0.1 %TFA in water and ACN :MeOH (1 : 1) eluted 1 - { [(3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,5 -dimethyl-pyrazolo [ 1 ,5 -a]pyrimidin-7 -yl)(pyridin-4- ylmethyl)carbamoyl]oxy} ethyl acetate (Ex. 1) (0.26g , 8.3%).

'H-NMR (DMSO, 400 MHz): d 8.52 (d, 2H), 7.87 (d, 1H), 7.70 (d, 1H), 7.64 (d, 1H), 7.41 (d, 2H), 6.98 (s, 1H), 6,75 (q, 1H), 5.05 (s, 2H), 3.99 (s, 3H), 2.57 (s, 3H), 1.99 (s, 3H), §.31 (s, 3H), LCMS: 528.9 [M+H], HPLC purity: 99.2%

Synthesis of boronic ester

The boronic ester used in Step 6 was prepared as follows:

Step 1: 5-bromo- 1 , 3-dimethyl- 1 H-indazole

A stirred solution of l-(5-bromo-2-fluorophenyl)ethanone (50 g, 230 mmol) and N-methyl hydrazine (42.4 mL, 805 mmol) in pyridine (500 mL) was heated at 90°C for lOh. Upon completion, the pyridine in the reaction was distilled out. The crude was partitioned between water and ethylacetate. The ethylacetate layers were dried over sodium sulfate and concentrated. The obtained crude was purified by flash column chromatography (neutral alumina) eluting the required compound 5-bromo-l ,3 -dimethyl- 1 H-indazole (20.23 g, 41.8%) with 2% ethylacetate - hexanes as a pale brown viscous compound.

Step 2: 1,3 -Dimethyl- 5 -(4, 4, 5,5-tetramethyl-[ 1, 3, 2] dioxaborolan-2-yl)-l H-indazole

To a solution of 5-bromo-l ,3 -dimethyl- 1 H-indazole (26 g, 1 15 mmol) and bispinacolato diboron (32.3 g, 127 mmol) in l,4-dioxan (260 mL) was added KOAc (34 g, 345 mmol ). The reaction was degassed with N₂ for 10 min and then Pd(PPhd₄ (6.6 g, 5.57 mmol) was added and heated at 95°C for l6h. Upon completion of addition, the reaction was heated at 80°C for l2h. Upon completion, the reaction was filtered through celite, the filtrate was concentrated. The obtained crude was purified by flash column chromatography (neutral alumina) eluting the required compound 1 ,3-dimcthyl-5-(4,4,5,5-tctramcthyl-[ l ,3,2]dioxaborolan-2-yl)- 1 //-indazolc (18 g, 52.1%) with 5% ethylacetate -hexanes as an off-white solid compound. Example 2

Liposomal formulation

30 mg of 1 - { [(3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,5 -dimethyl-pyrazolo [ 1 ,5 -a]pyrimidin-7 - yl)(pyridin-4-ylmethyl)carbamoyl]oxy} ethyl acetate (Example 1) and 300 mg of soybean lecithin were transferred to a beaker. Chloroform (about 10 ml) was added and the mixture was kept under stirring until the components had dissolved completely. Then the solvent was removed by rotary evaporator to yield in a thin lipid film. Water (about 10 ml) was added to the lipid film and the film was allowed to rehydrate for 10-15 min at room temperature. The formulation was mixed thoroughly and sonicated to form a fine dispersion.

Procedures for preparing and identifying compounds of formula (G) wherein Ri is 3,4- dimethoxyphenyl, i.e. compounds of formula (If) have been disclosed in the prior art documents PCT/EP2016/063383 (published as WO 2016/206999 Al) and PCT/EP2015/051 177 (published as WO 2015/110491 A2). Procedures disclosed in copending European patent application No. 18199486.4 for preparing and identifying some further compounds of formula (If), also are described herein below.

3-(3,4-dimethoxyphenyl)-2,6-dimethyl-N-((2-methylpyridm-4-yl)methyl)imidazo[l,2- b]pyridazin-8-amme

Step 1: 2, 6-dim ethylim idazo[l ,2-bJ yridazine

To a stirred solution of 6-methylpyridazine-3-ylamine (50 g, 455.3 mmol) in ethanol (500 mL) was added chloroacetone (58 ml, 683 mmol) and the solution was heated at 85°C for lOh. ETpon completion, the ethanol in the reaction was distilled out. The obtained crude product was purified by flash column chromatography (neutral alumina) eluting the required compound, 2,6- dimethylimidazo[l,2-b]pyridazine (36 g, 53.4%) with 10% ethylacetate -hexanes as a dark brown solid.

Step 2: 3-bromo-2,6-dimethylimidazo[J2-bJpyridazine

To a stirred solution of 2,6-dimethylimidazo[l,2-b]pyridazine (36 g, 244.5 mmol) in acetonitrile (360 mL) was added N-bromosuccinimide (NBS) (52.2 g, 293.4 mmol) and stirred at ambient temperature for lh. Upon completion, the acetonitrile in the reaction was distilled out. The obtained crude product was purified by flash column chromatography (neutral alumina) eluting the required compound 3-bromo-2,6-dimethylimidazo[l,2-b]pyridazine (18 g, 32.5%) with 15% ethylacetate -hexanes as a solid.

Step 3: 3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[l,2-b]pyridazine

A 100 ml round bottom flask was charged with 3-bromo-2,6-dimethylimidazo[l,2-b]pyridazine (5 g, 17.6 mmol), boronic ester (4.4 g, 19.4 mmol), potassium carbonate (7.5 g , 54.3 mmol) and dioxan : water (45 ml : 5 ml). This solution was degassed with N₂ for 10 min and then the [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane complex

(Pd(dppf)Cl₂.DCM complex) (1.8 g, 2.2 mmol) was added. The reaction was heated at 100 °C for l6h. Upon completion, the reaction was diluted with ethylacetate and filtered through a celite bed. The filtrate was partitioned between ethylacetate and water. The ethylacetate layer was dried over Na₂S0₄ and concentrated under reduced pressure. The obtained crude product was purified by flash column chromatography (neutral alumina) eluting the required compound 3-(3,4- dimethoxyphenyl)-2,6-dimethylimidazo[l,2-b]pyridazine (4.2 g, 67.7%) with 30% ethylacetate - hexanes as an off-white solid.

Step 4: 3-(3,4-dimethoxyphenyl)-8-iodo-2,6-dimethylimidazo[J2-bJpyridazine

To a stirred solution of 2M lithium diisopropylamide (LDA) (0.7ml, 1.4 mmol) in THF at -78°C was added a solution of 3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[l,2-b]pyridazine (0.2 g, 0.705 mmol) dissolved in THF (5mL), dropwise. After 10 min, iodine (0.178 g, 0.705 mmol) dissolved in THF (3mL) was added and the reaction was stirred at ambient temperature for lh. Upon completion, the reaction was quenched with saturated NH₄Cl solution and extracted with ethylacetate. The ethylacetate layers were dried under Na₂S0₄ and concentrated under reduced pressure. The obtained crude product was purified by flash column chromatography (neutral alumina) eluting the required compound 3-(3,4-dimethoxyphenyl)-8-iodo-2,6- dimethylimidazo[l,2-b]pyridazine (30 mg, 10.7%) with 30% ethylacetate-hexanes as a pale yellow solid.

Step 5: 3-(3,4-dimethoxyphenyl)-2,6-dimethyl-N-((2-methylpyridin-4-yl)methyl)imidazo[l,2- b ] pyridazin-8 -am in e

To a stirred solution of 3-(3,4-dimethoxyphenyl)-8-iodo-2,6-dimethylimidazo[l,2-b]pyridazine (0.1 g, 0.240 mmol) and (2-methylpyridin-4-yl)methanamine (0.06 g, 0.312 mmol) in toluene (2 mL) was added cesium carbonate (0.156 g, 0.48 mmol), 2,2'-bis(diphenylphosphino)-l ,l '- binaphthyl (BINAP (7 mg, 0.012 mmol) and Pd(OAc)₂ (2 mg, 0.012 mmol). The reaction was stirred at l05°C for l6h. Upon completion, the reaction was diluted with 10% MeOH-CH₂Cl₂ and filtered through a celite bed. The filtrate was concentrated and the obtained solid was washed with acetonitrile to afford 3-(3,4-dimethoxyphenyl)-2,6-dimethyl-N-((2-methylpyridin-4- yl)methyl)imidazo[l,2-b]pyridazin-8-amine (0.09 g, 91.83%) as a pale brown solid.

3-(3,4-dimethoxypheiiyl)-N-((2-fluoropyridiii-4-yl)methyl)-2,6-dimethylimidazo[l,2- b]pyridaziii-8-amme

Steps 1 to 4 as described herein above was followed to prepare 3-(3,4-dimethoxyphenyl)-8-iodo- 2,6-dimethylimidazo[ 1 ,2-b]pyridazine. Step 5: 3-(3,4-dimethoxyphenyl)-N-((2-fluoropyridin-4-yl)methyl)-2,6-dimethylimidazo[l,2- b ] pyridazin-8 -am in e

To a stirred solution of 3-(3,4-dimethoxyphenyl)-8-iodo-2,6-dimethylimidazo[l,2-b]pyridazine 0.15 g, 0.360 mmol) and (2-fluoropyridin-4-yl)methanamine (0.093 g, 0.46 mmol) in toluene (3 mL) was added cesium carbonate (0.23 g, 0.72 mmol), 2,2'-bis(diphenylphosphino)-l ,G- binaphthyl (BINAP) (1 1 mg, 0.018 mmol) and Pd(OAc)₂ (4 mg, 0.018 mmol). The reaction was stirred at l05°C for l6h. Upon completion, the reaction was diluted with 10% MeOH-CLLCk and filtered through a celite bed. The filtrate was concentrated and the obtained solid was washed with acetonitrile to afford 3-(3,4-dimethoxyphenyl)-N-((2-fluoropyridin-4-yl)methyl)-2,6- dimethylimidazo[l,2-b]pyridazin-8-amine (0.120 g, 80%) as a pale brown solid.

Procedures for preparing and identifying compounds of formula (G) wherein Ri is l,3-dimethyl- lH-indazol-5-yl, i.e. compounds of formula (Ig’), e.g. (Ii’), (Ij’), (Ik’), as disclosed in the prior art document PCT/EP2018/058522 and in the copending international application No.

PCT/EP2019/072220 are described herein below:

General Procedure 1: Synthesis of compounds of formula (Ij’)

Step 1

To a solution of 6-methyl-pyridazin-3-ylamine, (2.0 g, 0.018 mol) in acetonitrile (60 mL, 30 V) was added N-bromo succinamide (3.92 g, 0.022 mol) under room temperature. The reaction mass was stirred at room temperature for 2 hours. The reaction was monitored by TLC. The crude reaction mass obtained upon evaporation of the volatiles was purified by silica gel (60-120) column chromatography (3% methanol in dichloromethane) to obtain 4-bromo-6-methyl- pyridazin-3-ylamine, (0.6 g, 30%) as a dark brown solid. Step 2

To a solution of 4-bromo-6-methyl-pyridazin-3-ylamine (0.6 g, 3.1 mmol) in ethanol (6 mL, 10 V) was added chloro acetone (0.4 mL, 4.4 mmol) under room temperature. The resulting reaction mass was stirred at reflux temperature for 16 hours. The reaction was monitored by TLC. The crude reaction mass obtained upon evaporation of the volatiles was basified with saturated sodium bicarbonate and extracted with dichloro methane (100 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by silica gel (230-400) column chromatography (1.5% methanol in dichloromethane) to obtain 8-bromo-2,6-dimethyl-imidazo[l ,2-b]pyridazine, (0.15 g, 20%) as a pale yellow solid.

Step 3

To a solution of 8-bromo-2,6-dimethyl-imidazo[l ,2-b]pyridazine (0.33 g, 1.4 mmol) and the amine R5NH2 (0.0027 mol, 1.3 eq) (wherein R5 is a moiety of formula (II) as defined herein) in toluene (10 mL, 30 V) under argon atmosphere in a sealed tube were added cesium carbonate (1.0 g, 2.9 mmol) and BINAP (46 mg, 0.07 mmol) at room temperature. The resulting reaction mass was degassed for 5 minutes, palladium acetate (17 mg, 0.07 mmol) was added and stirring was continued at 100 °C for a period of 16 hours. The resulting reaction mass was diluted with ethyl acetate (100 mL) and filtered through celite pad. The ethyl acetate layer was washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400) column chromatography (3% methanol in dichloromethane) to obtain compound A. Step 4

To a stirred solution of compound A (1.0 eq) in acetonitrile (10 mL, 10 V) was added N-iodo succinamide (0.9 eq) under ice temperature. The resulting reaction mass was stirred at ice temperature over a period of 10 minutes. The reaction was monitored by TLC. The crude product obtained upon evaporation of the volatiles was purified by silica gel (230-400) column chromatography (3% methanol in dichloromethane) to obtain compound B.

Step 5

To a stirred solution of compound B (1.0 eq) and l,3-dimethyl-5-(4,4,5,5-tetramethyl- [l ,3,2]dioxaborolan-2-yl)-lH-indazole (1.3 eq) in dioxane : water (6 mL, 30 V) were added potassium carbonate (2.5 eq) and PdCl₂(dppf)DCM (0.1 eq) under room temperature. The resulting reaction mass was stirred at 90 °C over a period of 6 hours. The reaction was monitored by TLC. The reaction mass was diluted with ethyl acetate (200 mL) and filtered through celite pad. The organic layer was washed with water (100 mL), brine (50 mL), dried over anhydrous sodium sulphate and concentrated. The crude product obtained was purified by silica gel (230- 400) column chromatography (6% methanol in dichloromethane) to obtain a compound of formula (Ii’).

Table 1 shows chemical names and analytical data for some compounds of formula (Ii’) prepared according to General Procedure 1.

Table 1

General Procedure 2: Synthesis of compounds of formula (Ij’)

Step 1

To a stirred solution of 5-methyl-lH-pyrazol-3-ylamine (7.0 g, 0.0720 mol), and 3-oxo-butyric acid ethyl ester (11.26 mL, 0.0804 mol) in dioxane (70 mL, 10 V) was added acetic acid (2.1 mL, 0.3 V) under room temperature. The resulting reaction mass was stirred at room temperature for 16 hours. The reaction was monitored by TLC. After complete consumption of the starting material, the reaction mass was filtered, and the residue obtained was suspended in diethyl ether (70 mL) and filtered. The product was dried under high vacuum to obtain 2,5-dimethyl- pyrazolo[l,5-a]pyrimidin-7-ol as a white solid (8.2 g, 69.7%)

Step 2

To a stirred suspension of 5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7-ol (4.0 g, 0.0245 mol), in acetonitrile (40 mL, 10 V) was added phosphorous oxy chloride (4.7 mL, 0.049 mol) at room temperature. The resulting reaction mass was stirred at 90 °C over a period of 16 hours. Starting material consumption was monitored by TLC. The reaction mass was added to ice cold water (50 mL), basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate (200 mL *2). The combined organics were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400) column chromatography (3% methanol in dichloromethane) to obtain 7-chloro-2,5-dimethyl- pyrazolo[l,5-a]pyrimidine as an off-white solid (3.0 g, 68%).

Step 3

To a stirred suspension of 7-chloro-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidine (1.5 g, 0.008 mol) in acetonitrile (15 mL, 10 V) was added N-iodo succinamide (1.85 g, 0.008 mol) under ice temperature. The resulting reaction mass was stirred at ice temperature over a period of 10 minutes. The reaction was monitored by TLC. The crude reaction mass was concentrated and purified by silica gel (230-400) column chromatography (3% methanol in dichloromethane) to obtain 7-chloro-3-iodo-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidine as an off-white solid (2.3 g, 92%).

Step 4

To a stirred solution of 7-chloro-3-iodo-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidine (0.6 g, 1.9 mmol) in ethanol (12 mL, 20 V) were added N,N-diisopropyl ethylamine (0.72 mL, 3.9 mmol) and the amine R₅NH₂ (1.3 eq) at RT. The reaction mass was stirred at 70 °C for 16 hours.

Starting material consumption was monitored by TLC. After complete evaporation of the volatiles the crude product was diluted with ethyl acetate (200 mL), washed with water (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400) column chromatography (3% methanol in dichloromethane) to obtain the compound C.

Step 5

To a stirred solution of compound C (1.0 eq) and l,3-dimethyl-5-(4,4,5,5-tetramethyl-

[l ,3,2]dioxaborolan-2-yl)-lH-indazole (1.3 eq) in dioxane:water (10 mL, 20 V) were added potassium carbonate (2.5 eq) and PdCl₂(dppf)DCM (0.1 eq) under room temperature. The resulting reaction mass was stirred at 90 °C over a period of 16 hours. The reaction was monitored by TLC. The reaction mass was diluted with ethyl acetate (200 mL) and filtered through celite pad. The organic layer was washed with water (100 mL), brine (50 mL), dried over anhydrous sodium sulphate and concentrated. The crude product was purified by silica gel (230- 400) column chromatography (6% methanol in dichloromethane) to obtain a compound of formula (Ij’).

Table 2 shows chemical names and analytical data for some compounds of formula (Ij’) prepared according to General Procedure 2. Table 2

General Procedure 3: Synthesis of compounds of formula (Ik’)

Step 1

A suspension of 5 -methyl- lH-pyrazol-3-ylamine (2.0 g, 0.02 mol) in acetonitrile (50 mL, 25 V) was basified with diisopropylethylamine until the reaction mass showed pH 9-10. To the reaction mixture, ethylacetamidate hydrochloride (3.8 g, 0.03 mol) was added at RT under nitrogen atmosphere and the mixture was stirred for 15 minutes, whereafter the reaction mass was again basified with diisopropylethylamine (pH 9-10). Acetic acid (1.13 mL, 0.02 mol) was added to the suspension and stirred for l6h. The reaction was monitored by TLC. After completion, the reaction mass was diluted with diethyl ether (25 mL), and the solid was filtered and washed with diethyl ether. The filtered solid was dried under high vacuum at 50-55°C to get pure N-(5- methyl-2H-pyrazol-3-yl)acetamidine (2.4 g, 72%) as a white solid. Step 2

To a solution of sodium metal (2.74 g, 0.12 mol) in ethanol (23 mL, 30 V) under nitrogen atmosphere was added N-(5-methyl-2H-pyrazol-3-yl)-acetamidine (3.3 g, 0.02 mol) and diethyl carbonate (23 mL, 0.2 mol) at room temperature. The resulting reaction mass was refluxed for l6h. The progress of the reaction was monitored by TLC. After completion, the reaction mass was cooled to room temperature and resultant mass was concentrated under reduced pressure at 50-55 °C to remove ethanol. The crude product obtained upon evaporation of the volatiles were diluted with water and acidified with acetic acid (pH: 4-5). The aqueous layer was extracted with dichloromethane (400 mL*3), the organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The solid product was washed with minimum volumes of acetonitrile, filtered and dried to get pure 2,7-dimethyl-3H-pyrazolo[l,5- a][l,3,5]triazin-4-one (1.6 g, 40 %) as an off- white solid.

Step 3

To a stirred solution of 2,7-dimethyl-3H-pyrazolo[l,5-a][l,3,5]triazin-4-one (1.0 g, 0.006 mol) in acetonitrile (10 mL, 10 V) was added N-bro mo succinamide (1.3 g, 0.007 mol) under ice temperature. The resulting reaction mass was stirred at ice temperature over a period of 1 hour. The reaction was monitored by TLC. The precipitate formed was filtered through buchner funnel, washed with minimum amount of acetonitrile and dried to obtain 8-bromo-2,7-dimethyl-3H- pyrazolo[l,5-a][l,3,5]triazin-4-one (0.7 g, 50 %) as a white solid.

Step 4

To a solution of 8-bromo-2,7-dimethyl-3H-pyrazolo[l,5-a][l ,3,5]triazin-4-one (0.2 g, 0.8 mmol) in toluene (5 mL, 25 V) were added diisopropylethylamine (0.3 mL, 1.6 mmol) and phosphorous oxy chloride (2.0 mL, 0.02 mol) at room temperature. The resulting reaction mass was stirred at reflux temperature for 16 hours. The crude product obtained upon evaporation of the volatiles was stripped with toluene (10 mL*2) and the 8-bromo-4-chloro-2,7-dimethyl-pyrazolo[l ,5- a][l ,3,5]triazine obtained was taken to next step without further purification and characterization.

Step 5

Crude 8-bromo-4-chloro-2,7-dimethyl-pyrazolo[l ,5-a][l,3,5]triazine (0.2 g, 0.7 mmol), obtained upon evaporation of volatiles, was dissolved in THF (5 mL, 25 V). Diisopropylethylamine (0.3 mL, 1.5 mmol) and the amine R₅NH₂ (1.2 eq) were added at ice temperature, and the resulting reaction mass was stirred at room temperature for 1 hour. The reaction was monitored by TLC. The reaction mass was diluted with dichloromethane (100 mL), washed with water (50 mL *2) and brine solution (50 mL *2). The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel (230-400) column chromatography (10% ethyl acetate in hexane) to obtain compound D (120 mg, 43%).

Step 6

To a stirred solution of compound D (1.0 eq) and l,3-dimethyl-5-(4,4,5,5-tetramethyl- [l ,3,2]dioxaborolan-2-yl)-lH-indazole (1.3 eq) in dioxane:water (14 mL, 20 V) were added potassium carbonate (2.5 eq) and PdCl₂(dppf)DCM (0.1 eq) at RT. The resulting reaction mass was stirred at 90 °C for 6 hours. The reaction was monitored by TLC. The reaction mass was diluted with ethyl acetate (200 mL) and filtered through celite pad. The organic layer was washed with water (100 mL), brine (50 mL), dried over anhydrous sodium sulphate and concentrated.

The crude product was purified by silica gel (230-400) column chromatography (6% methanol in dichloromethane) to obtain a compound of formula (Ik’).

Table 3 shows chemical names and analytical data for some compounds of formula (Ik’) prepared according to General Procedure 3.

Table 3

BIOLOGICAL ASSAYS

Pharmacokinetic study

The exposure and serum concentration of Example 1 and the corresponding active metabolite Compound X was studied after administration per orally, 50 mg/kg, of Example 1 in Spraque Dawley rats.

Example 1 Compound X The results are shown in Figure 1. As may be seen, in serum, the compound of Example 1 is very rapidly metabolized into the corresponding secondary amine, 3 -(1 ,3 -dimethyl- l/7-indazo 1-5 -yl)- 2,5-dimethyl-7V-(4-pyridylmethyl)pyrazolo[ 1 ,5-a]pyrimidin-7-amine (Compound X). Stability in Simulated Gastric Fluid (SGF) and Simulated Intestinal Fluid (SIF)

Preparation of Simulated Gastric Fluid (SGF), pH L20

Exactly 0.2 g of Sodium chloride and 0.320 g of pepsin were weighed and dissolved in 80 mL of ultrapure water. The pH was adjusted to 1.20 using 1N hydrochloric acid (HC1). The final volume was made up to 100 mL.

Preparation of Simulated Intestinal Fluid (SIF), pH 6.80

Exactly 0.680 g of potassium phosphate monobasic was dissolved in 80 mL of water. 1.0 g of pancreatin was added and the resulting solution was adjusted to pH 6.8 using 1 N sodium hydroxide (NaOH) and finally diluted to 100 mL.

Brief protocol

The working solution oftest/control item(s) in SGF and SIF were prepared at test concentration (5 mM for test item; 10 mM for control items) by using DMSO stocks (final DMSO concentration was maintained at 0.1%). The samples were incubated at 37°C for 120 minutes, with shaking at 400 rpm. At 0, 15, 30, 60 and 120 minutes, an aliquot of 100 pL specimen was removed. The specimens were subjected for sample extraction by protein precipitation method adding acetonitrile as extraction solvent.

Figure 2 shows the mean % of Example 1 remaining in the sample, compared to the amount at 0.0 min, in SGF and SIF respectively. The data indicate that the compound is very stable in simulated gastric fluid whereas it decomposes over time in simulated intestinal fluid.

Repeated dose 7-days toxicity study and toxicokinetics

The test items (Compound X and Example 1) were administered by oral gavage daily in graduated doses to several groups of experimental animals, one dose level per group for a period of 7 consecutive days (15 and 30 mg/kg/day for compound X and 30 mg/kg/day for Example 1 as well empty vehicle as controls). The animals were administered at a dose volume of 10 mL/kg body weight of the formulated compounds. During the period of administration, the animals were observed closely for signs of toxicity. The preparation and identification of the compound of Compound X, as well as its antiviral activity have been described in PCT/EP2018/058522. Thus, as shown in PCT/EP2018/058522, Compound X has an IC50 of 0.0009 mM for RI4KIIIb and a very high inhibition capacity for various enteroviruses.

Formulation Preparation

The required quantities of test item (Compound X and Ex. 1) and soyabean lecithin (1 : 10) were weighed and transferred to a beaker. The volume of chloroform required to dissolve the test items was added and the mixture was stirred until the components were dissolved completely. Then chloroform solvent was removed by rotary evaporator (overnight) to yield a thin lipid film. Based on the total dose volume to be prepared, the required volume of ultrapure water was added to the lipid film and kept for 10-15 min at room temperature. The formulation was well vortexed/mixed and sonicated to form a fine dispersion. The pH of the final formulation was recorded along with physical appearance.

Results

Tables 4 and 5 show data from repeated dose 7-day toxicitiy and toxicokinetics studies of Compound X and its pro drug, Example 1 , administered to female Sprague Dawley rats by oral gavage of a liposomal formulation. The data show the lack of adverse events of Example 1 in comparison to same dose of Compound X, which shows adverse events even at 15 mg/kg/day. The necropsy findings indicate that the observed mortality (Treatment groups 1 and 2) and weight loss (Treatment group 2) are due mainly to local toxicity effects in the gastrointestinal system. Table 4

0 - Normal, 1 - Dehydration, 2 - Emaciated, 79 - swelling of cheek, 61 - Diarrhoea (Dark red soft faces) NAD - No Abnormality Detected Table 5

0 - Normal, 1 - Dehydration, 2 - Emaciated, 79 - swelling of cheek, 61 - Diarrhoea (Dark red soft faces) NAD - No Abnormality Detected Table 6 shows the PK parameters from the toxicokinetic study by administration of Compound X and Example 1 , respectively. Table 6

In vitro assay in mammalian cell culture

The antiviral activity of RI4KIIIb inhibitors of formula (G) has been previously shown in

PCT/EP2018/058522, PCT/EP2016/063383 and PCT/EP2015/051177. Thus, the ability of inter alia Compound X to prevent virus from causing viral cytopathic effects (CPE) in mammalian cell culture was shown in an assay according to the following general procedure: Cells were cultivated on 96-well flat bottom plates to approximately 90 % confluence (20 000-90 000 cells/well) in a suitable media. The titer of the virus was determined by the standard method of tissue culture infective dose (TCID₅₀) on cells. Briefly, cells were infected with 50 mΐ of virus suspension, and diluted 10-fold in media. The plates were incubated in 37 °C with 5 % C0₂ for 3- 7 days and cells were inspected daily for CPE. After determining CPE, plates were stained with Gram’s Crystal Violet solution and optical density was read at 540 nm. The highest virus dilution that resulted in > 95 % CPE was used in the assays. Substances at a final concentration of 0.1 nM-l mM and the virus were added to the cells and incubated for 3-7 days depending on the virus and cell line used. As controls, uninfected cells and cells infected with virus (no substance) were included on each plate. The cells were stained with crystal violet after determining the CPE on infected controls and the optical density was read at 540 nm. The inhibition capacity was calculated as a % by comparison with non-infected and infected controls.

Table 7 shows the inhibition capacity of Compound X on different enteroviruses. EV6:

Enterovirus 6; EV30: Enterovirus 30; EV68: Enterovirus 68; EV71 : Enterovirus 71; Bl :

coxsackie Bl virus; B2: coxsackie B2 virus; B3: coxsackie B3 virus; B4: coxsackie B4 virus; B5: coxsackie B5 virus; Polio 1 : polio virus Sabin 1. Table 7

A study of the tissue distribution of Compound X was performed in female Sprague Dawley rats. The results are shown in Table 8.

Table 8

Table 8 shows that the exposure in the intestine was lower than in other organs. However, the adverse effect was observed only in the intestine.

Claims

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein X is CH or N;

Y is N and Z is C; or Y is C and Z is N;

Ri is 3,4-dimethoxyphenyl or 1 ,3-dimcthyl- 1 //-indazol-5-yl;

R₂ is selected from C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, and phenyl-Cl-C3 alkyl; R₃ and R₄ are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, phenyl-Cl -C3 alkyl; or FC and R₄ together with the carbon atom to which they are both attached form a C4-C6 cycloalkyl;

R₅ is a moiety of formula (II)

wherein

ring A is 5- or 6-membered heteroaryl, or phenyl; m is an integer of from 0 to 3; each R₆ is independently selected from halogen, Cl -C6 alkyl, R_6aO, R_6bR_6CN, R_6eC(0)N(R_6d), R_6fOC(0), R_6gC(0)0, R_6hS(0)₂, R_6iC(0), R_6kS(0)₂N(R_6j), R_6iR_6mNS(0)₂, R₆„R_6pNC(0), and CN; and two R₆, attached to adjacent atoms of ring A, together with the atoms to which they are attached may form a 5- or 6-membered heterocyclic or carbocyclic ring;

R_6a, R_SJ, R_6C, R_6d, R_6j, R_6i, R_6m, R_6n, and R_6p are independently selected from H and C1-C6 alkyl;

R_6e, Rer, Re_g, R_6h, Rei, and R_6k, are independently selected from Cl -6 alkyl; and any alkyl is optionally substituted by one or more F.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CH.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is N and Z is C.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein

each R₆ is independently selected from halogen, Cl -C4 alkyl, R_6aO, R_6bR_6c , and CN;

R_6a, Re_b, and R_6c are independently selected from C1-C4 alkyl; and

any alkyl is optionally substituted by one or more F.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein each R₆ is selected from halogen and C1-C4 alkyl.

6. The compound of claim 5, wherein each R₆ is selected from F and methyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein ring A is 6-membered heteroaryl or phenyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein ring A is 6- membered heteroaryl.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R₅ is a moiety of formula (Ila)

(I I a)

wherein m is 0 or 1.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Ri is 1,3 -dimethyl- l/7-indazo 1-5 -yl.

11. A compound according to claim 1, which is l-{[(3-(l ,3 -dimethyl- 1 //-indazol-5 -yl)-2, 5- dimethyl-pyrazolo[l,5-a]pyrimidin-7-yl)(pyridin-4-ylmethyl)carbamoyl]oxy}ethyl acetate, or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1, which is a 1 -(acyloxy)-alkyl carbamate prodrug of a compound selected from

3 -( 1 ,3 -dimethyl- 1 H- indazol-5 -yl)-2 ,5 -dimethyl- A-(pyridin-4-ylmethyl)pyrazolo [ 1 ,5 -a]pyrimidin- 7-amine,

3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,5 -dimethyl- N— 7V-((6-methylpyridin-3 - yl)methyl)pyrazolo [ 1 ,5 -a]pyrimidin-7 -amine,

3-( 1 ,3-dimcthyl- l //-indazol-5-yl )-/V-(4-mcthoxybcnzyl)-2,5-dimcthylpyrazolo[ 1 ,5-a]pyrimidin-7- amine,

N-(4-chlorobenzyl)-3-(l , 3-dimethyl- l/Z-indazol-5-yl)-2, 5-dimethylpyrazo lo[l, 5-a]pyrimidin-7- amine,

3-( 1 ,3-dimcthyl- l //-indazol-5-yl )-2,5-dimcthyl-A-(4-(mcthylsulfonyl)bcnzyl)pyrazolo[ 1 ,5- a]pyrimi din-7 -amine, 4-(((3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,5 -dimethylpyrazolo [ 1 ,5 -a]pyrimidin-7 - yl)amino)methyl)benzenesulfonamide,

3-( 1 ,3 -dimethyl- 1 //-indazol-5-yl )-/V-((6-mcthoxypyridin-3-yl)mcthyl)-2 ,5 -dimethylpyrazolo [1,5- a]pyrimi din-7 -amine,

3-(l ,3-dimethyl-l//-indazol-5-yl)-2,5-dimethyl-7V-(thiophen-2-ylmethyl)pyrazolo[ 1 ,5- a]pyrimi din-7 -amine,

N-(4-(((3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,5 -dimethylpyrazolo [ 1 ,5 -a]pyrimidin-7 - yl)amino)methyl)phenyl)methanesulfonamide,

8 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,7 -dimcthyl-/V-(pyridin-4-yl methyl )pyrazolo [1,5- a][l,3,5]triazin-4-amine,

8-(l ,3-dimethyl-l//-indazol-5-yl)-/V-(4-methoxybenzyl)-2,7-dimethylpyrazolo[ 1 ,5- a][l,3,5]triazin-4-amine,

8 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,7 -dimcthyl-/V-((6 -methylpyridin-3 -yl)methyl)pyrazolo [1,5- a][l,3,5]triazin-4-amine,

4-(((8-(l, 3-dimethyl- l//-indazol-5-yl)-2, 7 -dimethylpyrazolo [1 ,5 -a] [1,3, 5]triazin-4- yl)amino)methyl)benzenesulfonamide,

N-(4-chlorobenzyl)-8-(l , 3-dimethyl- l//-indazol-5-yl)-2,7-dimethylpyrazolo[l,5-a][ 1,3, 5]triazin- 4-amine,

8 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,7-dimethyl-7V-(4-(methylsulfbnyl)benzyl)pyrazolo [ 1 ,5 - a][l,3,5]triazin-4-amine,

N-(4-(((8-(l , 3 -dimethyl- 1 //-indazol-5 -yl)-2,7-dimethylpyrazolo [1,5 -a] [ 1,3, 5]triazin-4- yl)amino)methyl)phenyl)methanesulfonamide,

8-(l ,3-dimethyl-l//-indazol-5-yl)-2,7-dimethyl-7V-(thiophen-2-ylmethyl)pyrazolo[ 1 ,5- a][l,3,5]triazin-4-amine,

8-( 1 ,3 -dimethyl- 1 //-indazol-5-yl)-/V-((6-methoxypyridin-3-yl)methyl)-2 ,7 -dimethylpyrazolo [1,5- a] [ 1 ,3,5]triazin-4-amine,

3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,6-dimethyl-7V-(pyridin-4-ylmethyl)imidazo [ 1 ,2 -b]pyridazin- 8-amine,

3-(l ,3-dimethyl-l//-indazol-5-yl)-2,6-dimethyl-/V-((6-methylpyridin-3-yl)methyl)imidazo[ 1 ,2- b] pyridazin- 8 -amine , N-(4-chlorobcnzyl)-3-( 1 ,3-dimcthyl- 1 //-indazol-5-yl )-2,6-dimcthylimidazo[ 1 ,2-b]pyridazin-8- amine,

3 -( 1 ,3 -dimethyl- 1 H- indazo 1-5 -yX)-N- ((6 -methoxypyridin-3 -yl)methy l)-2 ,6 -dimethylimidazo [1 ,2- b] pyridazin- 8 -amine ,

3-( 1 ,3-dimcthyl- 1 //-indazo 1-5-yl )-2, 6-dimcthyl-/V-(thiophcn-2-yl methyl )i midazo [ 1 ,2-b]pyridazin- 8-amine,

3-(l ,3-dimethyl-li7-indazol-5-yl)-/V-(4-methoxybenzyl)-2,6-dimethylimidazo[ 1 ,2-b]pyridazin-8- amine,

3 -( 1 ,3 -dimethyl- 1 if-indazol-5 -yl)-2 ,5 -dimethyl-7V-((6 -trifluoromethylpyridin-3 - yl)methyl)pyrazolo[ 1 ,5-a]pyrimidin-7-amine,

N-(benzyl)-3-(l , 3 -dimethyl- li -indazol-5-yl)-2,5-dimethylpyrazolo[l ,5-a]pyrimidin-7-amine, N-(4-fluorobenzyl)-3-(l , 3-dimethyl- li -indazol-5-yl)-2,5-dimethylpyrazolo[ l ,5-a]pyrimidin-7- amine,

3-( 1 ,3-dimcthyl- 1 7/-indazol-5-yl )-2,6-dimcthyl-_iV-(4-(mcthylsulfonyl )bcnzyl )imidazo[ 1 ,2- b] pyridazin- 8 -amine ,

8-(3,4-dimethoxyphenyl)-7V-[(4-fluorophenyl)methyl]-2,7-dimethyl-pyrazolo[l ,5-a][l ,3,5]triazin-

4-amine,

8-(3,4-dimethoxyphenyl)-2,7-dimethyl-/V-[[4-(trifluoromethyl)phenyl]methyl]pyrazolo[l ,5- a][l ,3,5]triazin-4-amine,

8-(3 ,4-dimethoxyphenyl)-2 ,7 -dimethyl-/V-(p-tolylmethyl)pyrazolo[ 1 ,5 -a] [ 1 ,3 ,5]triazin-4-amine, 8-(3,4-dimcthoxyphcnyl)-/V-[(4-isopiOpyl phenyl )mcthyl]-2,7-dimcthyl-pyrazolo[ 1 ,5- a][l ,3,5]triazin-4-amine,

8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimcthyl-/V-(2 -pyridylmethyl)pyrazolo [ 1 ,5 -a] [ 1 ,3 ,5 ]triazin-4- amine,

8-(3,4-dimethoxyphenyl)-2,7-dimethyl-/V-(4-pyridylmethyl)pyrazolo[ l ,5-a][l ,3,5]triazin-4- amine,

N-[(4-chlorophenyl)methyl]-8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5- a][l ,3,5]triazin-4-amine,

N-[4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[ l ,5-a][l ,3,5]triazin-4- yl] amino]methyl]phenyl] acetamide, 8 -(3 ,4-dimethoxyphenyl)-7V- [(4-methoxyphenyl)methyl]-2 ,7-dimethyl-pyrazolo [ 1 ,5 - a][l ,3,5]triazin-4-amine,

8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimethyl-TV- [(3 -methylsulfonylphenyl)methyl]pyrazolo [1 ,5- a][l ,3,5]triazin-4-amine,

8 -(3 ,4-dimethoxyphenyl)-7V- [(6-methoxy-3 -pyridyl)methyl]-2 ,7-dimethyl-pyrazolo [ 1 ,5 - a][l ,3,5]triazin-4-amine,

4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5-a][l ,3,5]triazin-4- yl] amino] methyl]benzenesulfonamide,

N-(l ,3-benzodioxol-5-ylmethyl)-8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5- a][l ,3,5]triazin-4-amine,

4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5-a][l ,3,5]triazin-4- yl]amino]methyl]phenol,

N-[4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[ l ,5-a][l ,3,5]triazin-4- yl]amino]methyl]phenyl]methanesulfonamide,

N-benzyl-8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5-a][l ,3,5]triazin-4-amine,

8-(3,4-dimethoxyphenyl)-2,7-dimethyl-7V-(2-thienylmethyl)pyrazolo[l ,5-a][l ,3,5]triazin-4- amine,

8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimcthyl-/V-(3 -pyridylmethyl)pyrazolo [ 1 ,5 -a] [ 1 ,3 ,5 ]triazin-4- amine,

8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimcthyl-/V-[(5 -methyl-2 -fury l)methyl]pyrazo lo[l ,5- a][l ,3,5]triazin-4-amine,

methyl N-[4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[ l ,5-a][l ,3,5]triazin-4- yl]amino]methyl]phenyl]sulfonylcarbamate,

N-[4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[ l ,5-a][l ,3,5]triazin-4- yl]amino]methyl]phenyl]sulfonylpropanamide,

N-methyl-4-[[[8-(3,4-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[l ,5-a][l ,3,5]triazin-4- yl] amino] methyl]benzenesulfonamide,

8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimcthyl-/V-[( 1 -methyl- 1 //- p y r az ol - 3 - yl ) m c t h yl ] p y razol o [1 ,5- a][l ,3,5]triazin-4-amine,

8-(3,4-dimethoxyphenyl)-2,7-dimethyl-/V-[(l ,3-oxazol-5-yl)methyl]pyrazolo[l ,5-a][l ,3,5]triazin-

4-amine, 8-(3 ,4-dimethoxyphenyl)-2 ,7 -dimethyl- /V- [ ( 2 - m c t h y l p y ri m i d i n - 5 -yl)methyl]pyrazolo [1 ,5- a][l ,3,5]triazin-4-amine,

8 -(3 ,4-dimethoxyphenyl)-2 ,7 -dimcthyl-/V-[(pyridazin-4-yl )mcthyl]pyrazolo [ 1 ,5 -a] [ 1 ,3 ,5 ]triazin- 4-amine,

8-(3,4-dimcthoxyphcnyl)-2,7-dimcthyl-/V-[(6-mcthylpyridin-3-yl )mcthyl]pyrazolo[ 1 ,5- a][l ,3,5]triazin-4-amine,

N-[(4-chlorophenyl)methyl]-3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimi din-7- amine,

3-(3,4-dimethoxyphenyl)-7V-[(4-methoxyphenyl)methyl]-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-

7-amine,

3-(3 ,4-dimethoxyphenyl)-2 ,5 -di mcthyl-/V-(p-tolyl methyl )pyrazolo [ 1 ,5 -a]pyrimi din-7 -amine, 3-(3,4-dimethoxyphenyl)-/V-[(4-fluorophenyl)methyl]-2,5-dimethyl-pyrazolo[l ,5-a]pyrimi din-7- amine,

3-(3,4-dimcthoxyphcnyl)-2,5-dimcthyl-/V-(2-pyridylmcthyl )pyrazolo[ 1 ,5-a]pyrimidin-7-aminc, N-benzyl-3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7-amine,

3-(3 ,4-dimethoxyphenyl)-2 ,5 -dimethyl-7V-[[4-(trifluoromethyl)phenyl]methyl]pyrazolo [1 ,5- a]pyrimi din-7 -amine,

3-(3,4-dimethoxyphenyl)-2,5-dimethyl-7V-(4-pyridylmethyl)pyrazolo[ l ,5-a]pyrimidin-7-amine, 3-(3 ,4-dimethoxyphenyl)-2 ,5 -dimcthyl-/V-[[4-(trifluoiOmcthoxy)phcnyl] methyl] pyrazolo [1 ,5- a]pyrimi din-7 -amine,

N-[4-[[[3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[ l ,5-a]pyrimidin-7- yl] amino]methyl]phenyl] acetamide,

3 -(3 ,4-dimethoxyphenyl)-7V- [(4-dimethylaminophenyl)methyl] -2 ,5 -dimethyl-pyrazolo [ 1 ,5- a]pyrimi din-7 -amine,

3 -(3 ,4-dimethoxyphenyl)-7V- [(6-methoxy-3 -pyridyl)methyl]-2 ,5 -dimethyl-pyrazolo [ 1 ,5 - a]pyrimi din-7 -amine,

N-[4-[[[3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[ l ,5-a]pyrimidin-7- yl]amino]methyl]phenyl]methanesulfonamide,

4-[[[3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7-yl]amino]methyl]phenol, 3 -(3 ,4-dimethoxyphenyl)-2 ,5 -dimcthyl-/V-[(3 -methylsulfonylphenyl)methyl]pyrazolo [1 ,5- a]pyrimi din-7 -amine, 3 -(3 ,4-dimethoxyphenyl)-2 ,5 -dimethyl-7V- [(4-methylsulfonylphenyl)methyl]pyrazolo [1 ,5- a]pyrimi din-7 -amine,

N-[(4-tert-butylphenyl)methyl]-3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-

7-amine,

3-(3,4-dimethoxyphenyl)-2,5-dimethyl-7V-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[l ,5- a]pyrimi din-7 -amine,

3-(3,4-dimethoxyphenyl)-2,5-dimethyl-7V-[(6-methyl-3-pyridyl)methyl]pyrazolo[l ,5-a]pyrimidin- 7-amine,

l -[4-[[[3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7- yl]amino]methyl]phenyl]ethanone,

3 -(3 ,4-dimethoxyphenyl)-2 ,5 -dimcthyl-/V-( 1 -naphthylmethyl)pyrazolo [1 ,5 -a]pyrimidin-7 -amine,

4-[[[3-(3,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7- yl] amino] methyljbenzenesulfonamide,

3-(3,4-dichlorophenyl)-7V-[(4-fluorophenyl)methyl]-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-7- amine,

3-(3,4-dimethoxyphenyl)-2,6-dimethyl-7V-((2-methylpyridin-4-yl)methyl)imidazo[l ,2- b] pyridazin- 8 -amine ,

3-(3,4-dimcthoxyphcnyl)-/V-((2-fluoropyridin-4-yl [methyl )-2,6-dimcthylimidazo[ 1 ,2- b] pyridazin- 8 -amine ,

3-( 1 ,3-dimcthyl- l //-indazol-5-yl )-2,5-dimcthyl-/V-[(2-fluoropyridin-4-yl )mcthyl]pyrazolo[ 1 ,5- a]pyrimi din-7 -amine,

3 -( 1 ,3 -dimethyl- 1 H- indazol-5 - yl ) - 2 , 5 - d i m c t h yl - N- [ ( 2 -methylpyridin-4-yl)methyl]pyrazolo [1 ,5- a]pyrimi din-7 -amine,

3 -( 1 ,3 -dimethyl- 1 //-indazol-5 - yl ) - 2 , 5 - d i m c t h yl - /V- [ ( 2 -ethylpyridin-4-yl)methyl]pyrazolo [1 ,5- a]pyrimi din-7 -amine,

3 -( 1 ,3 -dimethyl- 1 //-indazol-5 -yl)-2 ,5 -dimethyl-TV- [(2 -methoxypyridin-4-yl)methyl]pyrazolo [ 1 ,5 - a]pyrimi din-7 -amine,

3-( 1 ,3-dimcthyl- l //-indazol-5-yl )-2,5-dimcthyl-_iV-[(2-cyanopyridin-4-yl )mcthyl]pyrazolo[ 1 ,5- a]pyrimi din-7 -amine,

3-(3,4-dimethoxyphenyl)-2,6-dimethyl-N-(pyridin-4-ylmethyl)imidazo[ l ,2-b]pyridazin-8-amine, and 3-(l ,3-dimethyl-lH-indazol-5-yl)-2,5-dimethyl-N-[(2-trifluoromethylpyridin-4- yl)methyl]pyrazolo[ 1 ,5-a]pyrimidin-7-amine;

or a pharmaceutically acceptable salt of said compound.

13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in therapy.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

15. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment of a viral infection.

16. The compound or pharmaceutically acceptable salt for use according to claim 15, wherein the viral infection is an RNA viral infection.

17. The compound or pharmaceutically acceptable salt for use according to claim 17, wherein the RNA viral infection is a picornaviral infection.

18. The compound or pharmaceutically acceptable salt for use according to any one of claims 15 to 17, in the treatment of pancreatitis, poliomyelitis, encephalitis, meningitis, sepsis, cancer, paralysis, a cardiac disease, diabetes, common cold, hand-foot-and-mouth disease, herpangina, pleurodynia, diarrhea, a mucocutaneous lesion, respiratory illness, conjunctivitis, myositis, chronic fatigue syndrome, a neuropsychiatric disease, a neurodegenerative disease or an inflammatory condition.

19. The use of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 12, in the manufacture of a medicament for the treatment of a viral infection.

20. The use according to claim 19, wherein the viral infection is an RNA viral infection.

21. The use according to claim 20, wherein the viral infection is a picomaviral infection.

22. The use according to any one of claims 19 to 21, wherein the medicament is for the treatment of pancreatitis, poliomyelitis, encephalitis, meningitis, sepsis, cancer, paralysis, a cardiac disease, diabetes, common cold, hand-foot-and-mouth disease, herpangina, pleurodynia, diarrhea, a mucocutaneous lesion, respiratory illness, conjunctivitis, myositis, chronic fatigue syndrome, a neuropsychiatric disease, a neurodegenerative disease or an inflammatory condition.

23. A method for the treatment of a viral infection in a mammal, which comprises administering an effective amount of the compound or pharmaceutically acceptable salt according to any one of claims 1 to 12 to the mammal.

24. The method of claim 23, wherein the viral infection is an RNA viral infection.

25. The method of claim 24, wherein the RNA viral infection is a picomaviral infection.

26. The method of any one of claims 23 to 25, for the treatment of pancreatitis, poliomyelitis, encephalitis, meningitis, sepsis, cancer, paralysis, a cardiac disease, diabetes, common cold, hand-foot-and-mouth disease, herpangina, pleurodynia, diarrhea, a mucocutaneous lesion, respiratory illness, conjunctivitis, myositis, chronic fatigue syndrome, a neuropsychiatric disease, a neurodegenerative disease or an inflammatory condition.