Pyridine or pyrazine derivatives as collagen vii (C7) inducers and their use in therapy

Abstract

The present invention relates to pyrazine or pyridine compounds inducing collagen VII (C7) expression. This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders.

Description

[0001] PYRIDINE OR PYRAZINE DERIVATIVES AS COLLAGEN VII (C7) INDUCERS AND THEIR USE IN THERAPY

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel compounds inducing collagen VII (C7) expression. This invention also relates to pharmaceutical compositions containing them, processes for their preparation and their use in the treatment of several disorders.

[0004] BACKGROUND OF THE INVENTION

[0005] Several genetic diseases are caused by nonsense mutations, which are point mutations that result in a premature stop codon (PTC) leading to premature termination of translation and to truncated proteins.

[0006] Examples of diseases accounted by truncated proteins resulting from nonsense mutations include cancer, hemophilia, cystic fibrosis, recessive dystrophic epidermolysis bullosa (RDEB), junctional epidermolysis bullosa (JEB), spinal muscular atrophy, Duchenne muscular dystrophy (DMD), among many others.

[0007] Epidermolysis bullosa (EB) is a group of rare genetic skin disease characterized by skin fragility and blistering that affects around 500,000 people worldwide. The inherited disease, dystrophic epidermolysis bullosa (DEB), is caused by recessive or dominant mutations in the COL7A1 gene encoding type VII collagen (C7). Inheritance of DEB can be autosomal dominant (DDEB) or autosomal recessive (RDEB) and all cases result from CO ZA 7 mutations (Eichstadt et al 2019).

[0008] RDEB, with an estimated prevalence of 1 .5 - 20.4 per million population worldwide, is caused by a deficiency in collagen VII (C7) function resulting from genetic changes in the COL7A1 gene which can result in nonsense (premature termination codons, PTCs), frameshift, splicing or missense mutations appearing alone or in combinations (Rashidghamat et al 2017). The symptoms caused by RDEB include disruption of skin and mucous membrane structural and functional architecture leading to blisters, open wounds with chronic recurrent infections, inflammation, fibrosis, syndactyly, skin itch and increased risk of squamous cell carcinoma. Other systemic symptoms are mouth and gastrointestinal tract alterations and visual impairment. RDEB patients suffer from constant pain, have extremely poor quality of life, and often die at a young age (Rashidghamat et al 2017). The more severe GS (generalized severe) form of RDEB, affects ~2-10% of patients, most of which have biallelic PTC mutations resulting in C7 loss of function (Atanasova et al 2017, Woodley et al 2017, Eichstadt 2019). Other less severe forms of RDEB involving PTCs and associated with milder symptoms, often result from combinations of PTCs with other types of mutations (Soro et al 2015). RDEB severity not only depends on the type of COL7A1 mutations and their location but is also influenced by individual factors which can include increased levels of mediators like the pro-fibrotic TGFp or pro-inflammatory IL-6 and MCP-1 cytokines (Odorisio et al 2014) which may also influence the levels, if any, of truncated or full length C7 that may be detectable in these patients (Ortiz-Urda et al 2005, Woodley et al 2017).

[0009] Enhancing translational readthrough in PTC mutations is one strategy of potential treatment for RDEB patients. This approach intends to take advantage of basal readthrough, a natural process that is more frequent in PTC mutations (0.01 -1 %) than in natural termination codons (NTCs) (0.001-0.1 %), due to the proximity of NTCs to the translation termination complex and surrounding sequences (Dabrowski et al 2018). This mechanistic difference provides grounds to achieve selectivity of readthrough-inducing compounds at PTC mutations without interfering with NTCs.

[0010] Another strategy is to inhibit the degradation associated with PTC containing RNAs, known as nonsense mediated decay (NMD), to enhance the effect of basal readthrough (Frischmeyer et al 1999),

[0011] To date, gentamicin is the only small molecule drug with readthrough activity that has shown activity in RDEB caused by nonsense mutations resulting in PTCs. A seminal proof of concept clinical study in RDEB patients showed the efficacy of gentamicin, which restored C7 levels and improved skin wound closure after topical and intradermal administration of the drug (Woodley et al 2017).

[0012] In addition to small molecules, current experimental gene, cell and protein therapies are being considered as effective treatments for RDEB (Rashidghamat et al 2017, Marinkovich et al 2019). Phase 1 / 2 clinical results in 9 RDEB patients treated with a topical gene therapy locally delivering Col7A1 cDNA with a non-replicating herpes simplex virus, restored C7 expression in the skin and improved several clinical endpoints including anchoring fibril assembly, wound surface area reduction, duration of wound closure and time to wound closure (Gurevich et al 2022). These results were confirmed in subsequent phase 3 studies in 31 patients, which led to the approval of this product in May 2023 [FDA news release May 19, 2023]. However, this topical gene therapy, does not address the systemic symptoms of the disease.

[0013] Therefore, DEB patients are still in need of systemic treatments capable of increasing the levels of C7 protein. SUMMARY OF THE INVENTION

[0014] The present inventors have identified novel compounds for use in the treatment of conditions or diseases susceptible to amelioration by increasing the levels of COL7, either by restoring C-terminal truncated or full length C7 protein expression. The novel compounds described herein are also useful for the treatment of genetic diseases caused by nonsense mutations.

[0015] In a first embodiment, the present invention therefore provides a compound of formula [I] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, for use in the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels.

[0016] The invention also provides the use of a compound of formula [I] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof, for the manufacture of a medicament for the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein level.

[0017] The invention also provides a method for treating a subject with a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels, which comprises administering to said subject a therapeutically effective amount of a compound of formula [I], or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

[0018] The invention also provides a combination product comprising (i) at least one compound of Formula [I] or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, and (ii) one or more active ingredients having a readthrough activity. The combination product may be for use in the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels.

[0019] The invention also provides a compound of formula [la] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

[0020] The invention also provides a pharmaceutical composition comprising a compound of Formula [la] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, in combination with a pharmaceutically acceptable diluent or carrier. The invention also provides a compound or pharmaceutical composition of Formula [la] for use as a medicament.

[0021] In a second embodiment, the invention provides a compound of formula [II] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, for use in the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels.

[0022] The invention also provides the use of a compound of formula [II] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof, for the manufacture of a medicament for the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein level.

[0023] The invention also provides a method for treating a subject with a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels, which comprises administering to said subject a therapeutically effective amount of a compound of formula [II], or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

[0024] The invention also provides a combination product comprising (i) at least one compound of Formula [II] or a pharmaceutically acceptable salt, or a solvate, or a N-oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, and (ii) one or more active ingredients having a readthrough activity. The combination product may be for use in the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels.

[0025] The invention also provides a compound of formula [Ila] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

[0026] The invention also provides a pharmaceutical composition comprising a compound of Formula [Ila] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0027] The invention also provides a compound or pharmaceutical composition of Formula [Ila] for use as a medicament. Particular aspects of the invention are set out below:

[0028] 1 . A compound of formula [I], or a compound of formula [II], or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, for use in the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels:

[0029] Formula [II] wherein in Formula [I]:

[0030] W is -NRWRXor -ORW, wherein Rwand Rxare the same or different and are selected from hydrogen and C1-C3 alkyl;

[0031] A is a phenyl, 5- to 7-membered heteroaryl or 5- to 7-membered heterocyclyl ring, which ring is optionally fused to phenyl, 5- to 7-membered heteroaryl, or 5- to 7- membered heterocyclyl ring; wherein ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R", -C1-C3 alkyl-COOH, -C1-C3 alkyl-C(O)-(C-i-C3 alkyl), -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R"; and wherein R' and R" are the same or different and are selected from hydrogen and C1-C3 alkyl;

[0032] Rarepresents the group -L-Z, wherein L is a bond or C1-C3 alkylene, and Z is a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring; wherein said ring is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl and C1-C4 haloalkyl; n is 0, 1 or 2; and ring B is Ce-Cw carbocyclyl which is unsubstituted or substituted with one, two, or three substituents which are the same or different and are selected from -OR"', -NR'''R'V, C1-C4 alkyl and C1-C4 haloalkyl; and wherein R"' and Rivare the same or different and are selected from hydrogen and C1-C3 alkyl; and wherein in Formula [II]:

[0033] W’ is -NRyRzor -ORZ, wherein Ryand Rzare the same or different and are selected from hydrogen and C1-C3 alkyl;

[0034] - Y is N or CH; ring A’ is Ce-Cw aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl, wherein ring A’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from halogen, C1- C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-ORv, and -C1-C3 alkyl-NRvRvi; wherein Rvand Rviare the same or different and are selected from hydrogen and C1-C3 alkyl; and ring B’ is 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl, wherein ring B’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-ORvii, and -C1-C3 alkyl-NRviiRviii; wherein Rviiand Rviiiare the same or different and are selected from hydrogen and C1-C3 alkyl. The compound for use of aspect 1 , wherein the compound is a compound of Formula [I], or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof. The compound for use of aspect 1 or aspect 2, wherein W is -NH2. The compound for use of any one of the preceding aspects, wherein ring A is phenyl or 5- to 7-membered heterocyclyl ring, which ring is optionally fused to phenyl or 5- to 7-membered heteroaryl. 5. The compound for use of any one of the preceding aspects, wherein ring A is phenyl or 5- to 6-membered heterocyclyl ring, which ring is optionally fused to 5- to 6- membered heteroaryl.

[0035] 6. The compound for use of any one of the preceding aspects, wherein ring A is phenyl, indolyl, indazolyl, or [1 ,2,4]triazolo[4,3-a]pyridinyl.

[0036] 7. The compound for use of any one of the preceding aspects, wherein ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R'', -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R".

[0037] 8. The compound for use of any one of the preceding aspects, wherein ring A is unsubstituted or substituted with one substituent selected from C1-C4 alkyl, -C1-C3 alkyl-CONR'R", and -C1-C3 alkyl-OR'.

[0038] 9. The compound for use of any one of the preceding aspects, wherein ring A is unsubstituted or substituted with one substituent selected from propyl, -CH2-CONH2, and -CH2CH2-OH.

[0039] 10. The compound for use of any one of the preceding aspects, wherein Z is monocyclic 5- to 7-membered heterocyclyl or monocyclic 5- to 7-membered heteroaryl ring, wherein said ring contains one or two heteroatoms each independently selected from O and N.

[0040] 11 . The compound for use of any one of the preceding aspects, wherein Z is unsubstituted or substituted with one substituent which is C1-C4 alkyl.

[0041] 12. The compound for use of any one of the preceding aspects, wherein ring B is Cs-Cw carbocyclyl.

[0042] 13. The compound for use of any one of the preceding aspects, wherein ring B is substituted with one substituent which is -OH.

[0043] 14. The compound for use of any one of the preceding aspects, wherein ring A is: A1 A2 A3

[0044] 15. The compound for use of any one of the preceding aspects, wherein the compound of Formula [I] is selected from:

[0045] 3-amino-6-[1-(2-amino-2-oxoethyl)indol-6-yl]-N-(5-hydroxy-2-adamantyl)pyrazine- 2-carboxamide,

[0046] 3-amino-N-(5-hydroxy-2-adamantyl)-6-[3-(1-methylpyrazol-4-yl)-5-(morpholin-4- ylmethyl)phenyl]pyrazine-2-carboxamide, 3-amino-N-(5-hydroxy-2-adamantyl)-6-[1-(2-hydroxyethyl)indazol-6-yl]pyrazine-2- carboxamide, 3-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-6-[3-(1-methylpyrazol-4- yl)phenyl]pyrazine-2-carboxamide,

[0047] 3-amino-N-(5-hydroxy-2-adamantyl)-6-phenylpyrazine-2-carboxamide, and

[0048] 3-amino-N-(5-hydroxy-2-adamantyl)-6-(3-propan-2-yl-[1 ,2,4]triazolo[4,3-a]pyridin- 6-yl)pyrazine-2-carboxamide.

[0049] 16. The compound for use of aspect 1 , wherein the compound is a compound of Formula [II] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

[0050] 17. The compound for use of aspect 1 or any one of aspects 3 to 16, wherein W’ is -NH2.

[0051] 18. The compound for use of aspect 1 or any one of aspects 3 to 17, wherein ring A’ is phenyl, monocyclic 5- to 7-membered heteroaryl, or monocyclic 5- to 7-membered heterocyclyl.

[0052] 19. The compound for use according to aspect 1 or any one of aspects 3 to 18, wherein ring A’ is phenyl or monocyclic 5- to 7-membered heteroaryl.

[0053] 20. The compound for use according to aspect 1 or any one of aspects 3 to 19, wherein ring A’ is phenyl, furanyl, or pyridinyl.

[0054] 21 . The compound for use according to aspect 1 or any one of aspects 3 to 20, wherein ring A’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0055] 22. The compound for use according to aspect 1 or any one of aspects 3 to 21 , wherein ring A’ is unsubstituted or substituted with one or two substituents which are the same or different and are halogen.

[0056] 23. The compound for use according to aspect 1 or any one of aspects 3 to 22, wherein ring A’ is unsubstituted or substituted with one or two substituents which are fluorine.

[0057] 24. The compound for use according to aspect 1 or any one of aspects 3 to 23, wherein ring B’ is monocyclic 5- to 7-membered heteroaryl. The compound for use according to aspect 1 or any one of aspects 3 to 24, wherein ring B’ is pyridinyl. The compound for use according to aspect 1 or any one of aspects 3 to 25, wherein ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl and C1-C4 haloalkyl. The compound for use according to aspect 1 or any one of aspects 3 to 26, wherein ring B’ is unsubstituted or substituted with one or two substituents which are methyl. The compound for use of aspect 1 or any one of aspects 3 to 27, wherein ring A’ is: The compound for use of aspect 1 or any one of aspects 3 to 28, wherein the compound of Formula [II] is selected from:

[0058] 5-(2,6-dimethylpyridin-4-yl)-3-ethynyl-6-(3-fluorophenyl)pyridin-2-amine;

[0059] 6-(3,5-difluorophenyl)-3-ethynyl-5-pyridin-3-ylpyridin-2-amine;

[0060] 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-3-ylpyridin-2-amine; 3-ethynyl-5,6-dipyridin-3-ylpyridin-2-amine;

[0061] 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-4-ylpyridin-2-amine; 3-ethynyl-6-(furan-2-yl)-5-pyridin-4-ylpyrazin-2-amine; and 3-ethynyl-6-phenyl-5-pyridin-3-ylpyridin-2-amine.

[0062] 30. The compound for use according to any one of aspects 1 to 29, wherein the increase of COL7 protein levels refers to the increase of full-length COL7 protein and / or truncated COL7 protein.

[0063] 31. The compound for use according to any one of aspects 1 to 30, wherein the pathological condition or disease is a COL7 deficiency condition or disease.

[0064] 32. The compound for use according to aspect 31 , wherein the COL7 deficiency condition or disease is selected from Dominant dystrophica Epidermolysis bullosa (DDEB), Recessive dystrophic epidermolysis bullosa (RDEB), Epidermolysis bullosa dystrophica pretibial, Epidermolysis bullosa pruriginosa (EBP), Nonsyndromic congenital nail disorder 8 (NDNC8), Epidermolysis bullosa dystrophica with subcorneal cleavage (EBDSC), Epidermolysis bullosa dystrophica Bart type (B-DEB), Epidermolysis bullosa dystrophica pretibial type (PR-DEB) Epidermolysis bullosa with congenital localized absence of skin and deformity of nails and Transient bullous dermolysis of the newborn (TBDN).

[0065] 33. The compound for use according to aspect 32, wherein the COL7 deficiency condition or disease is Recessive dystrophic epidermolysis bullosa (RDEB).

[0066] 34. Use of a compound, or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, as defined in any one of aspects 1 to 30, for the manufacture of a medicament for the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein level.

[0067] 35. A method for treating a subject with a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels, which comprises administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, as defined in any one of aspects 1 to 30. A combination product comprising (i) at least one compound or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof as defined in any one of aspects 1 to 30, and (ii) one or more active ingredients having a readthrough activity. The combination product of aspect 36, wherein the one or more active ingredients having a readthrough activity is an aminoglycoside or a macrolide. The combination product of aspect 37, wherein the aminoglycoside is selected from gentamycin, G418, paromomycin, Amikacin. The combination product of any one of aspects 36 to 38, wherein the product is for use in the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels. A compound of formula [la], or a compound of formula [Ila], or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:

[0068] Formula [Ila] wherein in Formula [la]:

[0069] W, ring A, Ra, and n are as defined in any one of aspects 1 to 30; and ring B is adamantyl or bicyclo[2.2.2]octanyl which is unsubstituted or substituted with one, two, or three substituents which are the same or different and are selected from -OR"', -NR'i'R' , C1-C4 alkyl and C1-C4 haloalkyl; and wherein R'" and Rivare the same or different and are selected from hydrogen and C1-C3 alkyl; and wherein in Formula [Ila]:

[0070] W’ and ring A’ are as defined in any one of aspects 1 to 30; and ring B’ is 5- to 7-membered heteroaryl, or 5- to 10-membered heterocyclyl, wherein ring B’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-ORvii, and -C1-C3 alkyl-NRviiRviii; wherein Rviiand Rviiiare the same or different and are selected from hydrogen and C1-C3 alkyl; provided that the compound of Formula [la] is not:

[0071] 3-amino-N-(5-hydroxyadamantan-2-yl)-6-(1 H-indazol-6-yl)pyrazine-2-carboxamide;

[0072] 6-(3-(1 H-pyrazol-4-yl)phenyl)-3-amino-N-(5-hydroxyadamantan-2-yl)pyrazine-2- carboxamide;

[0073] 3-amino-6-(3-(3,5-dimethyl-1 H-pyrazol-4-yl)phenyl)-N-(5-hydroxyadamantan-2- yl)pyrazine-2-carboxamide;

[0074] 3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-(1-methyl-1 H-pyrazol-4- yl)phenyl)pyrazine-2-carboxamide;

[0075] 3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-methyl-5-(1-methyl-1 H-pyrazol-4- yl)phenyl)pyrazine-2-carboxamide;

[0076] 3-amino-6-(3-(1-ethyl-1 H-pyrazol-4-yl)phenyl)-N-(5-hydroxyadamantan-2-yl)pyrazine- 2-carboxamide;

[0077] 3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-(1-(2,2,2-trifluoroethyl)-1 H-pyrazol-4- yl)phenyl)pyrazine-2-carboxamide;

[0078] 3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-(1-propyl-1 H-pyrazol-4- yl)phenyl)pyrazine-2-carboxamide;

[0079] 3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-(1-isopropyl-1 H-pyrazol-4- yl)phenyl)pyrazine-2-carboxamide;

[0080] 3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-(pyridin-3-yl)phenyl)pyrazine-2- carboxamide; or

[0081] 3-amino-N-(5-hydroxyadamantan-2-yl)-6-(1 H-indazol-5-yl)pyrazine-2-carboxamide; or a stereoisomer derivative thereof; and provided that the compound of Formula [Ila] is not: 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-4-ylpyridin-2-amine; 3-ethynyl-6-(furan-2-yl)-5-pyridin-4-ylpyrazin-2-amine;

[0082] 3-ethynyl-6-(furan-2-yl)-5-(pyrimidin-4-yl)pyridin-2-amine; or

[0083] 3-ethynyl-5-(3-fluoropyridin-4-yl)-6-(pyridin-3-yl)pyrazin-2-amine.

[0084] 41 . A compound according to aspect 40, wherein the compound is a compound of Formula

[0085] [la] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

[0086] 42. The compound according to aspect 40 or aspect 41 , wherein ring B is:

[0087] 43. A compound according to aspect 40, wherein the compound is a compound of Formula [Ila] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

[0088] 44. The compound according to aspect 40 or aspect 43, wherein Y is CH.

[0089] 45. The compound according to any one of aspects 40, 43 and 44, wherein ring A is phenyl, monocyclic 6- to 7-membered heteroaryl, or monocyclic 6- to 7-membered heterocyclyl, preferably ring A is phenyl or pyrid inyl.

[0090] 46. The compound according to aspect 40 or any one of aspects 43 to 45, wherein ring

[0091] A’ is:

[0092]

[0093] 47. The compound according to any one of claims 40 to 42, wherein the compound of Formula [la] is selected from:

[0094] 3-amino-6-[1-(2-amino-2-oxoethyl)indol-6-yl]-N-(5-hydroxy-2-adamantyl)pyrazine- 2-carboxamide,

[0095] 3-amino-N-(5-hydroxy-2-adamantyl)-6-[3-(1-methylpyrazol-4-yl)-5-(morpholin-4- ylmethyl)phenyl]pyrazine-2-carboxamide,

[0096] 3-amino-N-(5-hydroxy-2-adamantyl)-6-[1-(2-hydroxyethyl)indazol-6-yl]pyrazine-2- carboxamide,

[0097] 3-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-6-[3-(1-methylpyrazol-4- yl)phenyl]pyrazine-2-carboxamide,

[0098] 3-amino-N-(5-hydroxy-2-adamantyl)-6-phenylpyrazine-2-carboxamide, and

[0099] 3-amino-N-(5-hydroxy-2-adamantyl)-6-(3-propan-2-yl-[1 ,2,4]triazolo[4,3-a]pyridin- 6-yl)pyrazine-2-carboxamide.

[0100] 48. The compound according to aspect 40 or any one of aspects 43 to 46, wherein the compound of Formula [Ila] is selected from:

[0101] 5-(2,6-dimethylpyridin-4-yl)-3-ethynyl-6-(3-fluorophenyl)pyridin-2-amine;

[0102] 6-(3,5-difluorophenyl)-3-ethynyl-5-pyridin-3-ylpyridin-2-amine;

[0103] 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-3-ylpyridin-2-amine;

[0104] 3-ethynyl-5,6-dipyridin-3-ylpyridin-2-amine; and 3-ethynyl-6-phenyl-5-pyridin-3-ylpyridin-2-amine.

[0105] 49. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof as defined in any one of aspects 40 to 48, in combination with a pharmaceutically acceptable diluent or carrier. 50. The compound or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof according to any one of aspects 40 to 48, or the pharmaceutical composition according to aspect 49, for use as a medicament.

[0106] BRIEF DESCRIPTION OF FIGURES

[0107] Figure 1 : a, b. Quantification of total (truncated + full length) C7 in RDEB cells (RDEB_L1 ) and recombinant HEK293R578Xcells using AlphaLISA (% read-through: C7 increase vs basal AlphaLISA levels after 48h in the presence of the indicated compound) (25 ng / mL of TGFp was added in the case of RDEB_L1 ). c: Detection of truncated and full length C7 after treatment with aminoglycoside reference compounds gentamicin (400 pg / mL, 0.83 mM) and G418 (25 pM) by western blot in RDEB_L1 cells using a polyclonal anti-C7 antibody, d: Detection of truncated and full length C7 after treatment with aminoglycoside reference compounds gentamicin (2 mg / mL, 4.18 mM) and G418 (10 pM) by western blot in HEK293R578Xcells using a polyclonal anti-C7 antibody. NHK, normal human primary keratinocytes

[0108] Figure 2: a. AlphaLISA dose response evaluation of EXAMPLE 1 and EXAMPLE 7 in RDEB_L1 and HEK293R578Xcell lines, b: Analysis by western blot of EXAMPLE 1 and EXAMPLE 7 compounds in RDEB_L1 and HEK293R578Xcells at the indicated compound concentrations.

[0109] Figure 3: a, b. AlphaLISA dose response confirmation of activity at 48 h vs 2 h for EXAMPLE 1 and EXAMPLE 7 in the presence of 25 ng / mL of TGFp

[0110] Figure 4. a. Comparative qPCR analysis of the induction of COL7A1 mRNA in RDEB_L1 by EXAMPLE 1 in the presence of TGFp (24h). b Immunofluorescence detection of C7 in RDEB_L1 cells (truncated C7) and NHK wild type keratinocytes (full length C7) treated with vehicle or EXAMPLE 1 in the presence of 25 ng / mL of TGFp.

[0111] Figure 5. a. Synergistic effect resulting from the combination of EXAMPLE 1 at suboptimal concentrations and gentamicin, in the presence of 25 ng / mL of TGFp. b. Shift in EXAMPLE 1 dose response curves in RDEB_L1 cells in the presence of increasing concentrations of gentamicin, c Western blot analysis of treated extracts with the indicated combinations of gentamicin and EXAMPLE 1.

[0112] Figure 6. Western blot results of RDEB_L1 cell line treated with the indicated compounds and reference compounds for 48 h in the presence of 25 ng / mL of TGFp. MDH1 products due to normal and alternative natural stop codons are indicated. DETAILED DESCRIPTION OF THE INVENTION

[0113] When describing the compounds, compositions, combinations and methods of the present invention, the following terms have the following meanings, unless otherwise indicated.

[0114] Definitions

[0115] The term "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.

[0116] The term "treatment" as used herein refers to the treatment of a disease or medical condition in a human patient which includes:

[0117] (a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;

[0118] (b) ameliorating the disease or medical condition, i.e., causing regression of the disease or medical condition in a patient;

[0119] (c) suppressing the disease or medical condition, i.e., slowing the development of the disease or medical condition in a patient; or

[0120] (d) alleviating the symptoms of the disease or medical condition in a patient.

[0121] The phrase “pathological condition or disease susceptible to amelioration by increase of C7 protein levels" includes all disease states and / or conditions that are acknowledged now, or that are found in the future, to be associated with an deficiency of C7 protein levels. Such disease states include, but are not limited to, a dermatological disease, a respiratory disease, an allergic disease, an inflammatory or autoimmune-mediated disease, a function disorder, a neurological disorder, a cardiovascular disease, a viral infection, a metabolism / endocrine function disorder, a neurological disorder, pain, bone marrow and organ transplant rejection, myelo-dysplastic syndrome, a myeloproliferative disorder (MPDs), cancer, an hematologic malignancy, leukemia, lymphoma and solid tumor.

[0122] As used herein, the term “pharmaceutically acceptable salt” refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.

[0123] As used herein, a N-oxide is formed from the tertiary basic amines or imines present in the molecule, using a convenient oxidising agent. As used in the present invention, the term tautomer means two or more forms or isomers of an organic compound that readily could be interconverted into each other via a common chemical reaction called tautomerization. This reaction commonly results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. The concept of tautomerizations is called tautomerism. Because of the rapid interconversion, tautomers are generally considered to be the same chemical compound. In solutions in which tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH.

[0124] The compounds of the invention may exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the invention and an amount of one or more pharmaceutically acceptable solvent molecules. The term hydrate is employed when said solvent is water. Examples of solvate forms include, but are not limited to, compounds of the invention in association with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.

[0125] The invention also includes isotopically-labelled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l and125l, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. Preferred isotopically- labelled compounds include deuterated derivatives of the compounds of the invention. As used herein, the term deuterated derivative embraces compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Deuterium (D or2H) is a stable isotope of hydrogen which is present at a natural abundance of 0.015 molar %.

[0126] Isotopically-labelled compounds derivatives of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labelled reagent in place of the nonlabelled reagent otherwise employed.

[0127] In the case of compounds of the invention that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystalline or polymorphic forms, or in an amorphous form, all of which are intended to be within the scope of the present invention. As used herein, "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C4 alkyl" (or alkylene), is intended to include Ci, C2, C3 and C4 alkyl groups. "C1- C3 alkyl" (or alkylene), is intended to include Ci, C2 and C3 alkyl groups. Additionally, for example, "C1-C4 alkyl" denotes alkyl having 1 to 4 carbon atoms. "C1-C3 alkyl" denotes alkyl having 1 to 3 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.

[0128] As used herein, the term “haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, and which contains at least one halogen atom. The halogen is typically chlorine, fluorine, bromine or iodine, and is preferably chlorine, fluorine or bromine, more preferably chlorine or fluorine, and most preferably fluorine.

[0129] The term “aryl” (or “arylene”) is intended to mean an aromatic moiety containing, if specified, the specified number of carbon atoms. For example, Ce-Cw aryl is preferably phenyl or naphthyl. Preferably, Ce-Cw aryl is phenyl.

[0130] The term "carbocyclyl" (or “carbocyclylene”) refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic), non-aromatic, saturated or partially unsaturated ring system whose ring atoms consist of carbon atoms. Preferably, the carbocyclyl is a saturated ring system (i.e. in which all ring bonds between adjacent carbon atoms are single bonds). A polycyclic carbocyclyl may comprise fused rings (where a first ring and a second ring share two adjacent ring carbon atoms), bridged rings (where two non-adjacent ring carbon atoms of a first ring are shared with a second ring) and / or spirocyclic rings (where a first ring shares only a single ring carbon atom with a second ring). A tricyclic or higher order polycyclic cycloalkyl may comprise a mixture of fused, bridged and spirocyclic relationships between its constituent rings. Preferably, the carbocyclyl is a bridged carbocyclyl. A typical carbocyclyl (or carbocyclylene) is Ce-Cw carbocyclyl, preferably a bridged Cs or Cw carbocyclyl. Example carbocyclyl groups include, but are not limited to, cyclohexyl, adamantyl, bicyclo[2.2.2]octanyl and the like.

[0131] As used herein, "heterocyclyl”, “heterocycle” or "heterocyclic” (or “heterocyclylene”) refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic), non-aromatic, saturated or partially unsaturated ring system whose ring atoms consist of carbon atoms and at least one heteroatom selected from O, S and N. The at least one heteroatom is commonly 1 -3 heteroatoms, for instance 1-2 heteroatoms or 1 heteroatom. Preferably, the at least one heteroatom ring atom is selected from N and O. Preferably, the heterocyclyl is monocyclic. In one embodiment, the heterocyclyl is saturated. In one embodiment, the heterocyclyl is unsaturated. Typical examples of heterocycles include 5- to 10-membered heterocycles, wherein “X- membered” means that the total number of ring atoms possessed by the heterocycle is X. Preferred heterocycles are 5- to 7-membered heterocycles, 7- to 10-membered heterocycles, and 9- to 10-membered heterocycles. Examples of heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, piperadinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, [1 ,2,4]triazolo[4 ,3-a]pyrid inyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, tetrahydrothiophenyl, tetrahydrothio-pyranyl, dihydropyridine, and morpholinyl.

[0132] As used herein, “heteroaryl” (or “heterarylene”) refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic), aromatic ring system whose ring atoms consist of carbon atoms and at least one heteroatom selected from O, S and N. The at least one heteroatom is commonly 1- 3 heteroatoms, for instance 1-2 heteroatoms or 1 heteroatom. Preferably, the at least one heteroatom ring atom is selected from N and O. More preferably, the at least one heteroatom ring atom is N. Preferably, the heteroaryl is monocyclic or bicyclic, more preferably monocyclic.

[0133] Typical examples of heteroaryls include 5- to 10-membered heteroaryls, wherein “X- membered” means that the total number of ring atoms possessed by the heteroaryl is X. Preferred heteroaryls are 5- to 7-membered heteroaryls, 5- to 6-membered heteroaryls, 6- to 7-membered heteroaryls, 7- to 10-membered heteroaryls, and 9- to 10-membered heteroaryls. Examples of heteroaryl groups include, without limitation, furanyl, thiophenyl, imidazolyl, thiazolyl, isothiazolyl, indolyl, pyrrolyl (pyrryl), oxazolyl, indazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, thiadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, triazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,5-triazolyl, 1 ,3,4-triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl and the like.

[0134] Compounds of Formula [I]

[0135] In a first embodiment, the compound for use of the invention is of formula [I] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:

[0136] Formula [I]

[0137] In the Formula [I], preferably W is -NRWRXor -OH. More preferably, W is -NH2 or -OH. Most preferably, W is -NH2.

[0138] In the Formula [I], preferably ring A is phenyl or 5- to 7-membered heterocyclyl ring, which ring is optionally fused to phenyl or 5- to 7-membered heteroaryl. More preferably, ring A is phenyl or 5- to 6-membered heterocyclyl ring, which ring is optionally fused to 5- to 6-membered heteroaryl.

[0139] When ring A comprises a heteroaryl or heterocyclyl ring which is optionally fused to another ring, said heteroaryl or heterocyclyl ring typically contains 1 , 2 or 3 heteroatoms independently selected from O or N. Preferably, said heteroaryl or heterocyclyl ring contains 1 , 2 or 3 nitrogen heteroatoms.

[0140] Most preferably, ring A is phenyl, indolyl, indazolyl, or [1 ,2,4]triazolo[4,3-a]pyridinyl.

[0141] Preferably, ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R'', -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R". More preferably, ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl, -C1-C3 alkyl-CONR'R", and -C1-C3 alkyl-OR'.

[0142] Preferably, ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from the substituents defined above. More preferably, ring A is unsubstituted or substituted with one substituent which is selected from the substituents defined above.

[0143] Typically, ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R", -C1-C3 alkyl-COOH, -C1-C3 alkyl-C(O)-(Ci-C3 alkyl), -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R". Preferably, ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R", -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R". More preferably, ring A is unsubstituted or substituted with one substituent which is selected from -C1-C4 alkyl, -C1-C3 alkyl-CONR'R'', and -C1-C3 alkyl-OR'. Most preferably, ring A is unsubstituted or substituted with one substituent selected from propyl, -CH2-CONH2, and -CH2CH2-OH.

[0144] When the substituent on ring A is C1-C4 alkyl, typically the substituent is C1-C3 alkyl. Preferably, the substituent is propyl, more preferably iso-propyl.

[0145] When the substituent on ring A is C1-C4 haloalkyl, typically the substituent is C1-C3 haloalkyl. Preferably, the substituent is C1-C3 fluoroalkyl, more preferably C2-C3 fluoroalkyl.

[0146] When the substituent on ring A is -C1-C3 alkyl-CONR'R", typically the substituent is -C1-C2 alkyl-CONR'R". Preferably, the substituent is -C1-C2 alkyl-CONFh and more preferably is -CH2-CONH2.

[0147] When the substituent on ring A is -C1-C3 alkyl-COOH, typically the substituent is -C1-C2 alkyl-COOH. Preferably, the substituent is -CH2-COOH.

[0148] When the substituent on ring A is -C1-C3 alkyl-C(O)-(Ci-C3 alkyl), typically the substituent is -C1-C2 alkyl-C(O)-(Ci-C2 alkyl). Preferably, the substituent is -CH2-C(O)-(CI-C2 alkyl), and more preferably is -CH2-C(O)-CH3.

[0149] When the substituent on ring A is -C1-C3 alkyl-OR', typically the substituent is -C1-C2 alkyl-OR'. Preferably, the substituent is -C1-C2 alkyl-OCHs or -C1-C2 alkyl-OH. More preferably, the substituent is -C1-C2 alkyl-OH, and most preferably is -CH2CH2-OH.

[0150] When the substituent on ring A is -C1-C3 alkyl-NR'R", typically the substituent is -C1-C2 alkyl-NR'R". Preferably, the substituent is -C1-C2 alkyl-NH2, and more preferably is -CH2CH2-NH2.

[0151] Preferably, ring A is phenyl, indolyl, indazolyl, or [1 ,2,4]triazolo[4,3-a]pyridinyl, wherein ring A is unsubstituted or substituted with one substituent selected from propyl, -CH2-CONH2, and -CH2CH2-OH.

[0152] In the Formula [I], preferably L is a bond or C1-C2 alkylene. More preferably, L is a bond or methylene. Where the formula [I] contains more than one L moiety, each L may be the same or different.

[0153] In the Formula [I], preferably Z is monocyclic 5- to 7-membered heterocyclyl or monocyclic 5- to 7-membered heteroaryl ring. More preferably, Z is monocyclic 5- to 7-membered heterocyclyl or monocyclic 5- to 7-membered heteroaryl ring, wherein said ring contains one or two heteroatoms each independently selected from O and N. Yet further preferably, Z is selected from pyrazolyl, imidazolyl, pyrrolyl, furanyl, oxazolyl, piperidinyl, and morpholinyl. Most preferably, Z is selected from pyrazolyl and morpholinyl. Where the compound of the invention contains more than one Z moiety, each Z may be the same or different.

[0154] Typically, Z is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl. Preferably, Z is unsubstituted or substituted with one or two substituents which are the same or different and are selected from

[0155] C1-C4 alkyl. More preferably, Z is unsubstituted or substituted with one substituent which is C1-C4 alkyl. Most preferably, Z is unsubstituted or substituted with one substituent which is methyl.

[0156] Preferably, Z is selected from pyrazolyl and morpholinyl, wherein Z is unsubstituted or substituted with one substituent which is methyl.

[0157] In the Formula [I], preferably n is 0 or n is 2.

[0158] Preferably, ring A is:

[0159] In the Formula [I], preferably ring B is Cs-Cw carbocyclyl, more preferably a fused Cs-Cw carbocyclyl. Most preferably, ring B is adamantyl or bicyclo[2.2.2]octanyl.

[0160] Preferably, Ring B is unsubstituted or substituted with one, two, or three substituents which are the same or different and are selected from -OR"' and -NRiiiRiv. More preferably, ring B is unsubstituted or substituted with one, two, or three substituents which are the same or different and are -OH or -NH2. Most preferably, ring B is unsubstituted or substituted with one, two, or three substituents which are -OH.

[0161] Preferably, ring B is unsubstituted or substituted with one or two substituents which are the same or different and are selected from the substituents defined above. More preferably, ring B is unsubstituted or substituted with one substituent which is selected from the substituents defined above. Most preferably, ring B is substituted with one substituent which is selected from the substituents defined above.

[0162] Typically, ring B is unsubstituted or substituted with one or two substituents which are the same or different and are selected from -OR"' and -NR'''R'V. Preferably, ring B is unsubstituted or substituted with one substituent selected from -OR'" and -NR'''R'V. More preferably, ring B is substituted with one substituent which is -OR"'. Most preferably, ring B is substituted with one substituent which is -OH.

[0163] When the substituent on ring B is -OR"', typically the substituent is -OCH3 or -OH. Preferably, the substituent is -OH.

[0164] When the substituent on ring B is -NRiiiRiv, typically the substituent is -NHCH3 or -NH2. Preferably, the substituent is -NH2.

[0165] When the substituent on ring B is C1-C4 alkyl, typically the substituent is C1-C3 alkyl or C1-C2 alkyl. Preferably, the substituent is methyl.

[0166] When the substituent on ring B is C1-C4 haloalkyl, typically the substituent is C1-C3 haloalkyl or C1-C2 haloalkyl. Preferably, the substituent is -CF3.

[0167] Preferably, ring B is adamantyl or bicyclo[2.2.2]octanyl which is substituted with one substituent which is -OH.

[0168] More preferably, ring B is:

[0169] B1 B2 In a preferred embodiment of Formula [I]:

[0170] - W is -NH2; ring A is phenyl or 5- to 7-membered heterocyclyl ring, which ring is optionally fused to phenyl or 5- to 7-membered heteroaryl, wherein ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from Ci- C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R'', -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R";

[0171] Rarepresents the group -L-Z, wherein L is a bond or C1-C2 alkylene, and Z is 5- to 7- membered heterocyclyl or 5- to 7-membered heteroaryl ring, wherein said ring contains one or two heteroatoms each independently selected from O and N, and wherein Z is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl; ring B is Cs-Cw carbocyclyl, which is unsubstituted or substituted with one substituent selected from -OR"' and -NRiiiRiv; and

[0172] R', R", R"', Rivand n are as defined for Formula [I],

[0173] In a further preferred embodiment of Formula [I]:

[0174] - W is -NH2; ring A is phenyl or 5- to 6-membered heterocyclyl ring, which ring is optionally fused to 5- to 6-membered heteroaryl, wherein ring A is unsubstituted or substituted with one substituent which is selected from -C1-C4 alkyl, -C1-C3 alkyl-CONR'R", and -C1-C3 alkyl-OR';

[0175] Rarepresents the group -L-Z, wherein L is a bond or methylene, and Z is 5- to 7- membered heterocyclyl or 5- to 7-membered heteroaryl ring, wherein said ring contains one or two heteroatoms each independently selected from O and N, and wherein Z is unsubstituted or substituted with one substituent which is C1-C4 alkyl; ring B is Cs-Cw carbocyclyl, which is substituted with one substituent which is -OR'"; and

[0176] R', R", R"', R'vand n are as defined for Formula [I], In a yet further preferred embodiment of Formula [I]:

[0177] W is -NH2; ring A is phenyl, indolyl, indazolyl, or [1 ,2,4]triazolo[4,3-a]pyridinyl, wherein ring A is unsubstituted or substituted with one substituent selected from propyl, -CH2-CONH2, and -CH2CH2-OH;

[0178] Rarepresents the group -L-Z, wherein L is a bond or methylene, and Z is 5- to 7- membered heterocyclyl or 5- to 7-membered heteroaryl ring, wherein said ring contains one or two heteroatoms each independently selected from O and N, and wherein Z is unsubstituted or substituted with one substituent which is methyl; ring B is adamantyl or bicyclo[2.2.2]octanyl which is substituted with one substituent which is -OH; and n is as defined for Formula [I],

[0179] Preferred compounds of Formula [I] are:

[0180] 3-amino-6-[1-(2-amino-2-oxoethyl)indol-6-yl]-N-(5-hydroxy-2-adamantyl)pyrazine- 2-carboxamide,

[0181] 3-amino-N-(5-hydroxy-2-adamantyl)-6-[3-(1-methylpyrazol-4-yl)-5-(morpholin-4- ylmethyl)phenyl]pyrazine-2-carboxamide,

[0182] 3-amino-N-(5-hydroxy-2-adamantyl)-6-[1-(2-hydroxyethyl)indazol-6-yl]pyrazine-2- carboxamide,

[0183] 3-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-6-[3-(1-methylpyrazol-4- yl)phenyl]pyrazine-2-carboxamide,

[0184] 3-amino-N-(5-hydroxy-2-adamantyl)-6-phenylpyrazine-2-carboxamide, and

[0185] 3-amino-N-(5-hydroxy-2-adamantyl)-6-(3-propan-2-yl-[1 ,2,4]triazolo[4,3-a]pyridin- 6-yl)pyrazine-2-carboxamide.

[0186] Compounds of Formula [la]

[0187] The invention also provides a compound of formula [la] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:

[0188] Formula [la]

[0189] In the Formula [la], preferably W is -NRWRXor -OH. More preferably, W is -NH2 or -OH. Most preferably, W is -NH2.

[0190] In the Formula [la], preferably ring A is phenyl or 5- to 7-membered heterocyclyl ring, which ring is optionally fused to phenyl or 5- to 7-membered heteroaryl. More preferably, ring A is phenyl or 5- to 6-membered heterocyclyl ring, which ring is optionally fused to 5- to 6- membered heteroaryl.

[0191] When ring A comprises a heteroaryl or heterocyclyl ring which is optionally fused to another ring, said heteroaryl or heterocyclyl ring typically contains 1 , 2 or 3 heteroatoms independently selected from O or N. Preferably, said heteroaryl or heterocyclyl ring contains 1 , 2 or 3 nitrogen heteroatoms.

[0192] Most preferably, ring A is phenyl, indolyl, indazolyl, or [1 ,2,4]triazolo[4,3-a]pyridinyl.

[0193] Preferably, ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R'', -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R". More preferably, ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl, -C1-C3 alkyl-CONR'R", and -C1-C3 alkyl-OR'.

[0194] Preferably, ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from the substituents defined above. More preferably, ring A is unsubstituted or substituted with one substituent which is selected from the substituents defined above.

[0195] Typically, ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R", -C1-C3 alkyl-COOH, -C1-C3 alkyl-C(O)-(Ci-C3 alkyl), -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R". Preferably, ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R", -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R". More preferably, ring A is unsubstituted or substituted with one substituent which is selected from -C1-C4 alkyl, -C1-C3 alkyl-CONR'R'', and -C1-C3 alkyl-OR'. Most preferably, ring A is unsubstituted or substituted with one substituent selected from propyl, -CH2-CONH2, and -CH2CH2-OH.

[0196] When the substituent on ring A is C1-C4 alkyl, typically the substituent is C1-C3 alkyl. Preferably, the substituent is propyl, more preferably iso-propyl.

[0197] When the substituent on ring A is C1-C4 haloalkyl, typically the substituent is C1-C3 haloalkyl. Preferably, the substituent is C1-C3 fluoroalkyl, more preferably C2-C3 fluoroalkyl.

[0198] When the substituent on ring A is -C1-C3 alkyl-CONR'R", typically the substituent is -C1-C2 alkyl-CONR'R". Preferably, the substituent is -C1-C2 alkyl-CONFh and more preferably is -CH2-CONH2.

[0199] When the substituent on ring A is -C1-C3 alkyl-COOH, typically the substituent is -C1-C2 alkyl-COOH. Preferably, the substituent is -CH2-COOH.

[0200] When the substituent on ring A is -C1-C3 alkyl-C(O)-(Ci-C3 alkyl), typically the substituent is -C1-C2 alkyl-C(O)-(Ci-C2 alkyl). Preferably, the substituent is -CH2-C(O)-(CI-C2 alkyl), and more preferably is -CH2-C(O)-CH3.

[0201] When the substituent on ring A is -C1-C3 alkyl-OR', typically the substituent is -C1-C2 alkyl-OR'. Preferably, the substituent is -C1-C2 alkyl-OCHs or -C1-C2 alkyl-OH. More preferably, the substituent is -C1-C2 alkyl-OH, and most preferably is -CH2CH2-OH.

[0202] When the substituent on ring A is -C1-C3 alkyl-NR'R", typically the substituent is -C1-C2 alkyl-NR'R". Preferably, the substituent is -C1-C2 alkyl-NH2, and more preferably is -CH2CH2-NH2.

[0203] Preferably, ring A is phenyl, indolyl, indazolyl, or [1 ,2,4]triazolo[4,3-a]pyridinyl, wherein ring A is unsubstituted or substituted with one substituent selected from propyl, -CH2-CONH2, and -CH2CH2-OH.

[0204] In the Formula [la], preferably L is a bond or C1-C2 alkylene. More preferably, L is a bond or methylene. Where the formula [I] contains more than one L moiety, each L may be the same or different.

[0205] In the Formula [la], preferably Z is monocyclic 5- to 7-membered heterocyclyl or monocyclic 5- to 7-membered heteroaryl ring. More preferably, Z is monocyclic 5- to 7-membered heterocyclyl or monocyclic 5- to 7-membered heteroaryl ring, wherein said ring contains one or two heteroatoms each independently selected from O and N. Yet further preferably, Z is selected from pyrazolyl, imidazolyl, pyrrolyl, furanyl, oxazolyl, piperidinyl, and morpholinyl. Most preferably, Z is selected from pyrazolyl and morpholinyl. Where the compound of the invention contains more than one Z moiety, each Z may be the same or different.

[0206] Typically, Z is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl. Preferably, Z is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl. More preferably, Z is unsubstituted or substituted with one substituent which is C1-C4 alkyl. Most preferably, Z is unsubstituted or substituted with one substituent which is methyl.

[0207] Preferably, Z is selected from pyrazolyl and morpholinyl, wherein Z is unsubstituted or substituted with one substituent which is methyl.

[0208] In the Formula [la], preferably n is 0 or n is 2.

[0209] In the Formula [la], preferably, ring A is:

[0210] In the Formula [la], ring B is adamantyl or bicyclo[2.2.2]octanyl, which is unsubstituted or substituted with one, two, or three substituents which are the same or different and are selected from -OR'", -NRiiiRiv, C1-C4 alkyl and C1-C4 haloalkyl; and wherein R"' and Rivare the same or different and are selected from hydrogen and C1-C3 alkyl. Preferably, Ring B is unsubstituted or substituted with one, two, or three substituents which are the same or different and are selected from -OR"' and -NRiiiRiv. More preferably, ring B is unsubstituted or substituted with one, two, or three substituents which are the same or different and are -OH or -NH2. Most preferably, ring B is unsubstituted or substituted with one, two, or three substituents which are -OH.

[0211] Preferably, ring B is unsubstituted or substituted with one or two substituents which are the same or different and are selected from the substituents defined above. More preferably, ring B is unsubstituted or substituted with one substituent which is selected from the substituents defined above. Most preferably, ring B is substituted with one substituent which is selected from the substituents defined above.

[0212] Typically, ring B is unsubstituted or substituted with one or two substituents which are the same or different and are selected from -OR"' and -NR'''R'V. Preferably, ring B is unsubstituted or substituted with one substituent selected from -OR'" and -NR'''R'V. More preferably, ring B is substituted with one substituent which is -OR"'. Most preferably, ring B is substituted with one substituent which is -OH.

[0213] When the substituent on ring B is -OR"', typically the substituent is -OCH3 or -OH. Preferably, the substituent is -OH.

[0214] When the substituent on ring B is -NR'''R'V, typically the substituent is -NHCH3 or -NH2. Preferably, the substituent is -NH2.

[0215] When the substituent on ring B is C1-C4 alkyl, typically the substituent is C1-C3 alkyl or C1-C2 alkyl. Preferably, the substituent is methyl.

[0216] When the substituent on ring B is C1-C4 haloalkyl, typically the substituent is C1-C3 haloalkyl or C1-C2 haloalkyl. Preferably, the substituent is -CF3.

[0217] Preferably, ring B is adamantyl or bicyclo[2.2.2]octanyl which is substituted with one substituent which is -OH

[0218] More preferably, ring B is or In a preferred embodiment of Formula [la]:

[0219] - W is -NH2; ring A is phenyl or 5- to 7-membered heterocyclyl ring, which ring is optionally fused to phenyl or 5- to 7-membered heteroaryl, wherein ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from Ci- C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R'', -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R";

[0220] Rarepresents the group -L-Z, wherein L is a bond or C1-C2 alkylene, and Z is 5- to 7- membered heterocyclyl or 5- to 7-membered heteroaryl ring, wherein said ring contains one or two heteroatoms each independently selected from O and N, and wherein Z is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl; ring B is adamantyl or bicyclo[2.2.2]octanyl, which is unsubstituted or substituted with one substituent selected from -OR"' and NRiiiRiv.

[0221] R', R", R"', Rivand n are as defined for Formula [la].

[0222] In a further preferred embodiment of Formula [la]:

[0223] - W is -NH2; ring A is phenyl or 5- to 6-membered heterocyclyl ring, which ring is optionally fused to 5- to 6-membered heteroaryl, wherein ring A is unsubstituted or substituted with one substituent which is selected from -C1-C4 alkyl, -C1-C3 alkyl-CONR'R", and -C1-C3 alkyl-OR';

[0224] Rarepresents the group -L-Z, wherein L is a bond or methylene, and Z is 5- to 7- membered heterocyclyl or 5- to 7-membered heteroaryl ring, wherein said ring contains one or two heteroatoms each independently selected from O and N, and wherein Z is unsubstituted or substituted with one substituent which is C1-C4 alkyl; ring B is adamantyl or bicyclo[2.2.2]octanyl, which is substituted with one substituent which is -OR"'; and

[0225] R', R", R"', R'vand n are as defined for Formula [la]. In a yet further preferred embodiment of Formula [la]:

[0226] W is -NH2; ring A is phenyl, indolyl, indazolyl, or [1 ,2,4]triazolo[4,3-a]pyridinyl, wherein ring A is unsubstituted or substituted with one substituent selected from propyl, -CH2-CONH2, and -CH2CH2-OH;

[0227] Rarepresents the group -L-Z, wherein L is a bond or methylene, and Z is 5- to 7- membered heterocyclyl or 5- to 7-membered heteroaryl ring, wherein said ring contains one or two heteroatoms each independently selected from O and N, and wherein Z is unsubstituted or substituted with one substituent which is methyl; ring B is adamantyl or bicyclo[2.2.2]octanyl which is substituted with one substituent which is -OH; and n is as defined for Formula [la].

[0228] Preferred compounds of Formula [la] are:

[0229] 3-amino-6-[1-(2-amino-2-oxoethyl)indol-6-yl]-N-(5-hydroxy-2-adamantyl)pyrazine- 2-carboxamide,

[0230] 3-amino-N-(5-hydroxy-2-adamantyl)-6-[3-(1-methylpyrazol-4-yl)-5-(morpholin-4- ylmethyl)phenyl]pyrazine-2-carboxamide,

[0231] 3-amino-N-(5-hydroxy-2-adamantyl)-6-[1-(2-hydroxyethyl)indazol-6-yl]pyrazine-2- carboxamide,

[0232] 3-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-6-[3-(1-methylpyrazol-4- yl)phenyl]pyrazine-2-carboxamide,

[0233] 3-amino-N-(5-hydroxy-2-adamantyl)-6-phenylpyrazine-2-carboxamide, and

[0234] 3-amino-N-(5-hydroxy-2-adamantyl)-6-(3-propan-2-yl-[1 ,2,4]triazolo[4,3-a]pyridin- 6-yl)pyrazine-2-carboxamide.

[0235] Compounds of Formula [II]

[0236] In a second embodiment, the compound for use of the invention is of formula [II] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:

[0237] Formula [II]

[0238] In the Formula [II], preferably W’ is -NRyRzor -OH. More preferably, W’ is -NH2 or -OH. Most preferably, W’ is -NH2.

[0239] In one preferred embodiment of Formula [II], Y is CH.

[0240] In the Formula [II], preferably ring A’ is phenyl, monocyclic 5- to 7-membered heteroaryl, or monocyclic 5- to 7-membered heterocyclyl ring. More preferably, ring A’ is phenyl or monocyclic 5- to 7-membered heteroaryl ring.

[0241] When ring A is heteroaryl or heterocyclyl ring, said ring typically contains 1 , 2 or 3 heteroatoms independently selected from O or N. Preferably, said ring contains 1 or 2 heteroatoms independently selected from O or N. More preferably, said heteroaryl or heterocyclyl group contains one heteroatom which is O or N.

[0242] Most preferably, ring A is phenyl, furanyl, or pyrid inyl.

[0243] Preferably, ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl. More preferably, ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from halogen and C1-C4 haloalkyl. Most preferably, ring A’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are halogen.

[0244] Preferably, ring A’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from the substituents defined above. More preferably, ring A is unsubstituted or substituted with one substituent which is selected from the substituents defined above.

[0245] Typically, ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl. Preferably, ring A’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from halogen and C1-C4 haloalkyl. More preferably, ring A’ is unsubstituted or substituted with one or two substituents which are the same or different and are halogen. Most preferably, ring A’ is unsubstituted or substituted with one or two substituents which are fluorine.

[0246] When the substituent on ring A is halogen, typically the substituent is fluorine or chlorine. Preferably, the substituent is fluorine.

[0247] When the substituent on ring A’ is C1-C4 alkyl, typically the substituent is C1-C3 alkyl. Preferably, the substituent is C1-C2 alkyl, and more preferably is methyl.

[0248] When the substituent on ring A’ is C1-C4 haloalkyl, typically the substituent is C1-C3 haloalkyl. Preferably the substituent is C1-C3 fluoroalkyl, and more preferably is C1-C2 fluoroalkyl.

[0249] When the substituent on ring A is -C1-C3 alkyl-ORv, typically the substituent is -C1-C2 alkyl-ORv. Preferably the substituent is -C1-C2 alkyl-OH, and most preferably is -CH2CH2-OH.

[0250] When the substituent on ring A is -C1-C3 alkyl-NRvRvi, typically the substituent is -C1-C2 alkyl-NRvRvi. Preferably, the substituent is C1-C2 alkyl-NH2, and more preferably is -CH2CH2-NH2.

[0251] Preferably, ring A’ is phenyl, furanyl, or pyridinyl, wherein ring A’ is unsubstituted or substituted with one or two substituents which are fluorine.

[0252] More preferably, ring A’ is:

[0253] In the Formula [II], preferably ring B’ is 5- to 10-membered heteroaryl. More preferably, ring B’ is monocyclic 5- to 7-membered heteroaryl.

[0254] Typically, ring B’ is a heteroaryl or heterocyclyl ring which contains 1 , 2 or 3 heteroatoms independently selected from O or N. Preferably, said ring contains 1 or 2 heteroatoms independently selected from O or N. More preferably, said ring contains one heteroatom which is N.

[0255] Most preferably, ring B’ is pyridinyl.

[0256] Preferably, ring B’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl and C1-C4 haloalkyl. More preferably, ring B’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl. Most preferably, ring B’ is unsubstituted or substituted with one, two or three substituents which are methyl.

[0257] Preferably, ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from the substituents defined above. More preferably, ring B’ is unsubstituted or substituted with two substituents which are selected from the substituents defined above.

[0258] Typically, ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl and C1-C4 haloalkyl. Preferably, ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl. More preferably, ring B’ is unsubstituted or substituted with one or two substituents which are methyl.

[0259] When the substituent on ring B’ is halogen, typically the substituent is fluorine or chlorine. Preferably, the substituent is fluorine.

[0260] When the substituent on ring B’ is C1-C4 alkyl, typically the substituent is C1-C3 alkyl Preferably, the substituent is C1-C2 alkyl, and more preferably is methyl.

[0261] When the substituent on ring B’ is C1-C4 haloalkyl, typically the substituent is C1-C3 haloalkyl. Preferably the substituent is C1-C3 fluoroalkyl, and more preferably is C1-C2 fluoroalkyl.

[0262] When the substituent on ring B’ is -C1-C3 alkyl-ORvii, typically the substituent is -C1-C2 alkyl-ORvii. Preferably the substituent is -C1-C2 alkyl-OH, and most preferably is -CH2CH2-OH.

[0263] When the substituent on ring B’ is -C1-C3 alkyl-NRviiRviii, typically the substituent is -C1-C2 alkyl-NRviiRviii. Preferably, the substituent is C1-C2 alkyl-NH2, and more preferably is -CH2CH2-NH2.

[0264] Preferably, ring B’ is pyridinyl which is unsubstituted or substituted with one or two substituents which are methyl. More preferably, ring B’ is '

[0265] In a preferred embodiment of Formula [II]:

[0266] - W’ is -NH2; ring A’ is phenyl, monocyclic 5- to 7-membered heteroaryl, or monocyclic 5- to 7- membered heterocyclyl, wherein ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl; ring B’ is 5- to 10-membered heteroaryl, wherein ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1- C4 alkyl and C1-C4 haloalkyl; and

[0267] Y is as defined for Formula [II],

[0268] In a further preferred embodiment of Formula [II]:

[0269] - W’ is -NH2; ring A is phenyl or monocyclic 5- to 7-membered heteroaryl, wherein ring A is unsubstituted or substituted with one or two substituents which are fluorine; ring B’ is monocyclic 5- to 7-membered heteroaryl, wherein ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl; and

[0270] Y is as defined for Formula [II],

[0271] Preferred compounds of Formula [II] are:

[0272] 5-(2,6-dimethylpyridin-4-yl)-3-ethynyl-6-(3-fluorophenyl)pyridin-2-amine;

[0273] 6-(3,5-difluorophenyl)-3-ethynyl-5-pyridin-3-ylpyridin-2-amine;

[0274] 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-3-ylpyridin-2-amine; 3-ethynyl-5,6-dipyridin-3-ylpyridin-2-amine;

[0275] 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-4-ylpyridin-2-amine; 3-ethynyl-6-(furan-2-yl)-5-pyridin-4-ylpyrazin-2-amine; and 3-ethynyl-6-phenyl-5-pyridin-3-ylpyridin-2-amine.

[0276] Compounds of Formula [Ila]

[0277] The invention also provides a compound of formula [Ila] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:

[0278] In the Formula [Ila], preferably W’ is -NRyRzor -OH. More preferably, W’ is -NH2 or -OH. Most preferably, W’ is -NH2.

[0279] In one preferred embodiment of Formula [Ila], Y is CH.

[0280] In the Formula [Ila], preferably ring A’ is phenyl, monocyclic 5- to 7-membered heteroaryl, or monocyclic 5- to 7-membered heterocyclyl ring. More preferably, ring A’ is phenyl or monocyclic 5- to 7-membered heteroaryl ring.

[0281] When ring A is heteroaryl or heterocyclyl ring, said ring typically contains 1 , 2 or 3 heteroatoms independently selected from O or N. Preferably, said ring contains 1 or 2 heteroatoms independently selected from O or N. More preferably, said heteroaryl or heterocyclyl group contains one heteroatom which is O or N.

[0282] Most preferably, ring A’ is phenyl, furanyl, or pyrid inyl.

[0283] Preferably, ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl. More preferably, ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from halogen and C1-C4 haloalkyl. Most preferably, ring A’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are halogen.

[0284] Preferably, ring A’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from the substituents defined above. More preferably, ring A is unsubstituted or substituted with one substituent which is selected from the substituents defined above.

[0285] Typically, ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl. Preferably, ring A’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from halogen and C1-C4 haloalkyl. More preferably, ring A’ is unsubstituted or substituted with one or two substituents which are the same or different and are halogen. Most preferably, ring A is unsubstituted or substituted with one or two substituents which are fluorine.

[0286] When the substituent on ring A is halogen, typically the substituent is fluorine or chlorine. Preferably, the substituent is fluorine.

[0287] When the substituent on ring A’ is C1-C4 alkyl, typically the substituent is C1-C3 alkyl. Preferably, the substituent is C1-C2 alkyl, and more preferably is methyl.

[0288] When the substituent on ring A’ is C1-C4 haloalkyl, typically the substituent is C1-C3 haloalkyl. Preferably the substituent is C1-C3 fluoroalkyl, and more preferably is C1-C2 fluoroalkyl.

[0289] When the substituent on ring A’ is -C1-C3 alkyl-ORv, typically the substituent is -C1-C2 alkyl-ORv. Preferably the substituent is -C1-C2 alkyl-OH, and most preferably is -CH2CH2-OH.

[0290] When the substituent on ring A is -C1-C3 alkyl-NRvRvi, typically the substituent is -C1-C2 alkyl-NRvRvi. Preferably, the substituent is C1-C2 alkyl-NH2, and more preferably is -CH2CH2-NH2.

[0291] Preferably, ring A’ is phenyl, furanyl, or pyridinyl, wherein ring A’ is unsubstituted or substituted with one or two substituents which are fluorine.

[0292] More preferably, ring A’ is:

[0293]

[0294] In the Formula [Ila], preferably, ring A’ is phenyl, monocyclic 6- to 7-membered heteroaryl, or monocyclic 6- to 7-membered heterocyclyl ring. More preferably, ring A’ is phenyl or monocyclic 6- to 7-membered heteroaryl ring. Most preferably, ring A’ is phenyl or pyridinyl. Most preferably, ring A’ is:

[0295] In the Formula [Ila], preferably ring B’ is 5- to 6-membered heteroaryl, more preferably B’ is 6-membered heteroaryl.

[0296] Typically, ring B’ is a heteroaryl or heterocyclyl ring which contains 1 , 2 or 3 heteroatoms independently selected from O or N. Preferably, said ring contains 1 or 2 heteroatoms independently selected from O or N. More preferably, said ring contains one heteroatom which is N.

[0297] Most preferably, ring B’ is pyridinyl.

[0298] Preferably, ring B’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl and C1-C4 haloalkyl. More preferably, ring B’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl. Most preferably, ring B’ is unsubstituted or substituted with one, two or three substituents which are methyl. Preferably, ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from the substituents defined above. More preferably, ring B’ is unsubstituted or substituted with two substituents which are selected from the substituents defined above.

[0299] Typically, ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl and C1-C4 haloalkyl. Preferably, ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl. More preferably, ring B’ is unsubstituted or substituted with one or two substituents which are methyl.

[0300] When the substituent on ring B’ is halogen, typically the substituent is fluorine or chlorine. Preferably, the substituent is fluorine.

[0301] When the substituent on ring B’ is C1-C4 alkyl, typically the substituent is C1-C3 alkyl Preferably, the substituent is C1-C2 alkyl, and more preferably is methyl.

[0302] When the substituent on ring B’ is C1-C4 haloalkyl, typically the substituent is C1-C3 haloalkyl. Preferably the substituent is C1-C3 fluoroalkyl, and more preferably is C1-C2 fluoroalkyl.

[0303] When the substituent on ring B’ is -C1-C3 alkyl-ORvii, typically the substituent is -C1-C2 alkyl-ORvii. Preferably the substituent is -C1-C2 alkyl-OH, and most preferably is -CH2CH2-OH.

[0304] When the substituent on ring B’ is -C1-C3 alkyl-NRviiRviii, typically the substituent is -C1-C2 alkyl-NRviiRviii. Preferably, the substituent is C1-C2 alkyl-NH2, and more preferably is -CH2CH2-NH2.

[0305] Preferably, ring B’ is pyridinyl which is unsubstituted or substituted with one or two substituents which are methyl.

[0306] More preferably, ring B’ is Most preferably, ring B’ is:

[0307] In a preferred embodiment of Formula [Ila]:

[0308] - W’ is -NH2; ring A’ is phenyl, monocyclic 5- to 7-membered heteroaryl, or monocyclic 5- to 7- membered heterocyclyl, wherein ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl; ring B’ is 5- to 7-membered heteroaryl, wherein ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1- C4 alkyl and C1-C4 haloalkyl; and

[0309] Y is as defined for Formula [Ila],

[0310] In a further preferred embodiment of Formula [Ila]:

[0311] - W’ is -NH2; ring A is phenyl or monocyclic 5- to 7-membered heteroaryl, wherein ring A is unsubstituted or substituted with one or two substituents which are fluorine; ring B’ is monocyclic 5- to 7-membered heteroaryl, wherein ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl; and

[0312] Y is as defined for Formula [Ila],

[0313] Preferred compounds of Formula [Ila] are:

[0314] 5-(2,6-dimethylpyridin-4-yl)-3-ethynyl-6-(3-fluorophenyl)pyridin-2-amine;

[0315] 6-(3,5-difluorophenyl)-3-ethynyl-5-pyridin-3-ylpyridin-2-amine;

[0316] 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-3-ylpyridin-2-amine; 3-ethynyl-5,6-dipyridin-3-ylpyridin-2-amine; and 3-ethynyl-6-phenyl-5-pyridin-3-ylpyridin-2-amine.

[0317] Particularly preferred compounds of Formula [Ila] are:

[0318] 5-(2,6-dimethylpyridin-4-yl)-3-ethynyl-6-(3-fluorophenyl)pyridin-2-amine;

[0319] 6-(3,5-difluorophenyl)-3-ethynyl-5-pyridin-3-ylpyridin-2-amine;

[0320] 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-3-ylpyridin-2-amine; and 3-ethynyl-5,6-dipyridin-3-ylpyridin-2-amine.

[0321] Combination products

[0322] The compounds of the invention may be administered as part of a combination product comprising (i) at least one compound of the invention or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, and (ii) one or more active ingredients having a readthrough activity.

[0323] The active ingredient having a readthrough activity may be any compound which enhances readthrough of premature termination codons (PTCs) compared to basal levels. Typically, the one or more active ingredients having a readthrough activity is an aminoglycoside or a macrolide, preferably an aminoglycoside. Suitable aminoglycosides include gentamycin, G418, paromomycin, Amikacin. Preferably, the aminoglycoside is gentamycin.

[0324] Uses and Methods

[0325] The compounds and combination products of the present invention may be used in the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels.

[0326] In preferred embodiments, the pathological condition or disease is susceptible to amelioration by increase of full-length COL7 protein and / or truncated COL7 protein.

[0327] In preferred embodiments, the pathological condition or disease susceptible to amelioration by increase of COL7 protein levels is a COL7 deficiency condition or disease.

[0328] In preferred embodiments, the pathological condition or disease susceptible to amelioration by increase of COL7 protein levels is a COL7 deficiency condition or disease. In particular, said pathological condition or disease susceptible to amelioration by increase of COL7 protein levels includes Dominant dystrophic Epidermolysis bullosa (DDEB), Recessive dystrophic epidermolysis bullosa (RDEB), Epidermolysis bullosa dystrophica pretibial, Epidermolysis bullosa pruriginosa (EBP), Nonsyndromic congenital nail disorder 8 (NDNC8), Epidermolysis bullosa dystrophica with subcorneal cleavage (EBDSC), Epidermolysis bullosa dystrophic Bart type (B-DEB), Epidermolysis bullosa dystrophic pretibial type (PR-DEB) Epidermolysis bullosa with congenital localized absence of skin and deformity of nails and Transient bullous dermolysis of the newborn (TBDN). Preferably, the COL7 deficiency condition or disease is Recessive dystrophic epidermolysis bullosa (RDEB).

[0329] In one embodiment, the invention provides a compound of formula [I] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof, for use in the treatment of Recessive dystrophic epidermolysis bullosa (RDEB).

[0330] In one embodiment, the invention provides a compound of formula [II] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically- labelled derivative thereof, for use in the treatment of Recessive dystrophic epidermolysis bullosa (RDEB).

[0331] The invention also provides a method for treating a nonsense-mutation-mediated genetic disease, comprising administering to said subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, or a pharmaceutical composition or a combination product of the present invention.

[0332] The invention also provides a method for treating a subject diagnosed with a pathological condition or disease caused partially or entirely by a nonsense or PTC mutation. In particular, such pathological conditions or diseases include epidermolysis bullosa, including RDEB and JEB, cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), ataxia telangiectasia, Lysosomal Storage Disorders (including Fabry disease, Niemann-Pick A / B, Gangliosidosis, Mucopolysaccharidosis (MPS) Type l-Hurler, MPS Type lll-B, MPS Type VI, Batten disease) Hemophilia, Spinal Muscular Atrophy, Hereditary Ocular Disorders (including Choroideremia, Leber’s Congenital Amaurosis, Ocular Coloboma, Retinitis Pigmentosa, Usher Syndrome or Congenital Aniridia) and epidermolysis bullosa (including RDEB, DDEB, JEB).

[0333] In preferred embodiments, the nonsense or PTC mutation is within a gene selected from COL7A1 , CFTR, DMD, ATM, GLA, SMPD1 , GLB1 , IDUA, IDS, NAGLU, CLN1 , CLN2, FVIII, FIX, SMN2, REP1 , RPE65, PAX2, Almbl , RHO, RP2, PCDH15, USH1C, Pax6, ARSB, or MECP2. In preferred embodiments, the nonsense or PTC mutation is within the COL7A1 gene. The invention also provides a method for enhancing skin wound healing in a subject suffering from DEB due to a nonsense mutation in the COL7A1 gene, comprising administering to said subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

[0334] The invention also provides a method for inducing expressing of full-length and / or truncated Col7 protein in a subject, comprising administering to said subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

[0335] The invention also provides a method for treating a subject with a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels which comprises administering to said subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

[0336] The invention also provides a compound of the invention for use as a medicament.

[0337] The pharmaceutical compositions and combination products described herein may also be used in the uses and methods described above.

[0338] Pharmaceutical compositions, dosage and formulation

[0339] The compounds of the invention, when used in a method of treatment, can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. Thus, preferably, the compounds of the present invention can be included in a pharmaceutical composition. Preferably the pharmaceutical composition is suitable for oral administration. One exemplary such pharmaceutical composition is a solid dosage form suitable for oral administration (e.g., a tablet, capsule (each of which includes a sustained release or timed release formulation), pill, powder, or granule). Another exemplary such pharmaceutical composition is a liquid dosage form suitable for oral administration (e.g., an elixir, tincture, suspension, syrup, solution or emulsion).

[0340] However, the compounds of the invention may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. The dosage regimen for the compounds of the invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the disease.

[0341] By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg / kg of body weight, preferably between about 0.01 to 100 mg / kg of body weight per day, and most preferably between about 1 .0 to 20 mg / kg / day.

[0342] Intravenously, the most preferred doses will range from about 1 to about 10 mg / kg / minute during a constant rate infusion. Compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0343] Compounds of the invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0344] The compounds are typically administered alongside suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

[0345] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and colouring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0346] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

[0347] Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

[0348] GENERAL SYNTHETIC SCHEMES

[0349] Compounds of general formula 1 , where Ri represents an hydroxy-adamantyl residue and R2 represents an aryl group, can be prepared according to the general schemes depicted in Scheme 1 :

[0350] Scheme 1

[0351] Starting from bromocarboxylic acid 4 the compounds 1 can be prepared by sequential conversion to the amides 5 by treatment with hydroxiadamantylamine and a coupling agent (eg, HATU) and subsequent Suzuki coupling with a boronic acid or ester in the presence of a palladium catalyst like [1 ,1 '-Bis(diphenylphosphino) ferrocene] palladium(ll) dichloride. Alternatively, compounds 1 can be prepared by amidation of carboxylic acids 6 using the aforementioned conditions.

[0352] Compounds of general formula 2, where Ar1 and Ar2 represent aryl or heteroaryl groups, may be prepared by the synthetic route depicted in Scheme 2: Ar2B(OR)2NBS palladium catalyst

[0353] Scheme 2

[0354] Starting from 5,6-dibromopyridin-2-amine V7 and by sequential Suzuki couplings with aryl or heteroaryl boronic acids or boronate esters in the presence of palladium catalysts like [1 ,T-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride the amines 9 are obtained.

[0355] Subsequent bromination of 9 (eg, with NBS), displacement of the bromo with trimethylsilylacetylene (in the presence of palladium catalysts and copper (I) iodide) and final deprotection in basic medium (eg, potassium carbonate) affords the desired structures 2. Compounds of general formula 3 and 15, where Ar1 and Ar2 represent aryl or heteroaryl groups, may be prepared by the synthetic route depicted in Scheme 3:

[0356] CI\^-N^NH2 AHBJORJZ

[0357] N palladium catalyst

[0358] Ar2B(OR)2palladium catalyst

[0359] Scheme 3 Starting from 6-chloropyrazin-2-amine 12 and by sequential Suzuki couplings with aryl or heteroaryl boronic acids or boronate esters in the presence of palladium catalysts like [1 ,T-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride the amines 15 are obtained. Subsequent bromination of 15 (eg, with NBS), displacement of the bromo with trimethylsilylacetylene (in the presence of palladium catalysts and copper (I) iodide) and final deprotection in basic medium (eg, potassium carbonate) affords the desired structures 3.

[0360] EXPERIMENTAL

[0361] General

[0362] Reagents, starting materials, and solvents were purchased from commercial suppliers and used as received. Commercial intermediates are referred to in the experimental section by their IUPAC name. Concentration or evaporation refer to evaporation under vacuum using a Buchi rotatory evaporator.

[0363] Reaction products were purified, when necessary, by flash chromatography on silica gel (40- 63 pm) with the solvent system indicated. Purifications in reverse phase were made in a Biotage Isolera® automated purification system equipped with a C18 column and using a gradient, unless otherwise stated, of water-acetonitrile / MeOH (1 :1 ) (0.1 % v / v ammonium formate both phases) from 0% to 100% acetonitrile / MeOH (1 :1 ) in 40 column volumes. The appropriate fractions were collected and the solvents evaporated under reduced pressure and / or freeze dried.

[0364] The UPLC chromatographic separations were obtained using a Waters Acquity UPLC system coupled to a SQD mass spectrometer detector. The system was equipped with an ACQUITY UPLC BEH C-18 (2.1x50 mm, 1 .7 mm) column. The mobile phase was formic acid (0.4 mL), ammonia (0.1 mL), methanol (500 mL) and acetonitrile (500 mL) (B) and formic acid (0.5 mL), ammonia (0.125 mL) and water (1000 mL) (A). A gradient between 0 to 95% of B was used. The run time was 3 or 6 minutes. The injection volume was 0.5 microliter. Chromatograms were processed at 210 nM or 254 nM. Mass spectra of the chromatograms were acquired using positive and negative electrospray ionization.

[0365] 1 H Nuclear Magnetic Resonance Spectra were recorded on a Varian Mercury plus operating at a frequency of and equipped with a cold probe for the 1 H spectra. Samples were dissolved in the specified deuterated solvent. Tetramethylsilane was used as reference.

[0366] Abbreviations:

[0367] Pd2(dba)3: tris(dibenzylidineacetone)dipalladium(0)

[0368] DIPEA: Diisopropylethylamine

[0369] DMF: N,N-dimethylformamide

[0370] DMSO: dimethylsulfoxyde THF: Tetra hydrofuran

[0371] HATU: 1-(bis(dimethylamino)methylene)-1 H-[1 ,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate(V)

[0372] EXAMPLE 1

[0373] 3-amino-6-[1 -(2-amino-2-oxoethyl)indol-6-yl]-N-(5-hydroxy-2-adamantyl)pyrazine-2- carboxamide

[0374] A mixture of 109 mg (0.298 mmol) of 3-amino-6-bromo-N-((2s,5r)-5-hydroxyadamantan-2- yl)pyrazine-2-carboxamide, 97.45 mg (0.447 mmol) of (1-(2-amino-2-oxoethyl)-1 H-indol-6- yl)boronic acid and 447 uL (0.894 mmol) of a 2M solution of sodium carbonate in 15 mL dioxane is degassed. After adding 12 mg (0.0149 mmol) of PdCI2dppf.CH2CI2 the system is stirred at 90°C for 18hr. After adding excess Ethyl acetate and water the organic phase is washed with water and brine, dried and concentrated to dryness. The residue is purified chromatographically (Ethyl acetate / MeOH 0-5%) to give 79 mg of desired compound (57% yield).

[0375] EXAMPLE 2

[0376] 3-amino-N-(5-hydroxy-2-adamantyl)-6-[3-(1-methylpyrazol-4-yl)-5-(morpholin-4- ylmethyl)phenyl]pyrazine-2 -carboxamide

[0377] A mixture of 68.60 mg (0.179 mmol) of 4-(3-(1-methyl-1 H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzyl)morpholine, 72.51 mg (0.197 mmol) of 3-amino-6-bromo-N- [(2r,7r)-5-hydroxy-2-adamantyl]pyrazine-2-carboxamide and 270 uL(0.538 mmol) of a 2M solution of caesium carbonate in 25 mL dioxane is degassed. After adding 7.92 mg (0.0097 mmol) of PdCI2dppf.CH2CI2 the system is heated in a microwave oven at 90°C for 4hr. The residue is filtered through a Celite® pad, washed with dichloromethane and the filtrate is concentrated to dryness and purified chromatographically (dichloromethane to dichloromethane / MeOH 10% from 0% to 40% to give 39.3 g of desired compound (40% yield).

[0378] 1H-NMR (300 MHz, d6-DMSO) 5 8.98 (s, 1 H), 8.48 (d, J = 8.5 Hz, 1 H), 8.23 (s, 1 H), 8.12 (s, 1 H), 7.94 (s, 1 H), 7.79 (s, 1 H), 7.49 (s, 1 H), 4.54 (s, 1 H), 3.88 (s, 3H), 3.56 (d, J = 16.1 Hz, 6H), 2.51 (d, J = 1 .7 Hz, 5H), 1 .89 - 1 .65 (m, 8H). EXAMPLE 3

[0379] 3-amino-N-(5-hydroxy-2-adamantyl)-6-[1-(2-hydroxyethyl)indazol-6-yl]pyrazine-2- carboxamide

[0380] A mixture of 100.0 mg (0.272 mmol) of 3-amino-6-bromo-N-[(2r,7r)-5-hydroxy-2- adamantyl]pyrazine-2-carboxamide, 117.70 mg (0.408 mmol) of 2-(6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-indazol-1 -yl)ethanol and 409 uL (0.817 mmol) of a 2M solution of caesium carbonate in 8 mL of toluene and 2 mL of ethanol is degassed. After adding 11.12 mg (0.0136 mmol) of PdCI2dppf.CH2CI2 the system is heated overnight in a microwave oven at 90°C. Excess ethyl acetate is added, the mixture filtered through a Celite® pad and the filtrate washed with water, brine, dried and concentrated. The residue is purified chromatographically (dichloromethane to dichloromethane / MeOH 10% from 0% to 70% to give 19.6 mg of desired compound (14% yield) as a pale-yellow solid.

[0381] 1H-NMR (300 MHz, d6-DMSO) 5 1 .2 (t, J=6.9 Hz, 3 H) 1 .5 (d, J=12.4 Hz, 1 H) 1 .8 (m, 4 H) 2.0 (s, 3 H) 2.1 (m, 3 H) 3.8 (m, J=4.4 Hz, 1 H) 4.0 (m, J=7.0, 7.0, 7.0 Hz, 2 H) 4.5 (m, J=7.7 Hz, 2 H) 4.9 (m, 1 H) 7.5 (d, J=10.7 Hz, 1 H) 7.7 (s, 1 H) 7.8 (m, 2 H) 8.1 (s, 1 H) 8.3 (s, 1 H) 8.5 (d, J=8.5 Hz, 1 H) 9.0 (s, 1 H)

[0382] EXAMPLE 4

[0383] 3-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-6-[3-(1-methylpyrazol-4- yl)phenyl]pyrazine-2-carboxamide

[0384] 77.55 mg (0.263 mmol) of 3-amino-6-(3-(1-methyl-1 H-pyrazol-4-yl)phenyl)pyrazine-2- carboxylic acid are solved in 28 ml DMF. 99,85 mg (0.263 mmol) of HATU and 137,60 pl (0.788 mmol) of DIPEA are added. After stirring for 10 min, 44.47 mg of 4- aminobicyclo[2.2.2]octan-1-ol are added. After 2hr stirring at room temperature the solvent is eliminated and the residue partitioned in Ethyl acetate and 4% NaHCO3 and the aqueous phase further extracted with Ethyl acetate.

[0385] The organic phase is dried and concentrated and the residue purified by chromatography eluting with dichloromethane / MeOH 0-10% to give 42 mg of title compound (38% yield)

[0386] 1H NMR (300 MHz, CDCI3) 5 8.63 (s, 1 H), 7.94 - 7.79 (m, 3H), 7.68 (s, 2H), 7.47 (d, J = 7.4 Hz, 2H), 3.99 (s, 3H), 2.19 (d, J = 8.9 Hz, 6H), 1.90 - 1.78 (m, 6H), 1.23 (s, 2H). EXAMPLE 5

[0387] 3-amino-N-(5-hydroxy-2-adamantyl)-6-phenylpyrazine-2 -carboxamide

[0388] 93 mg (244.58 umol) of HATU and 121 uL (694.7 umol) of DIPEA were added to a solution of

[0389] 4-aminoadamantan-1-ol and (50 mg; 232.3 umol) of 3-amino-6-phenyl-pyrazine-2-carboxylic acid in DMF (1.5 mL). The mixture was stirred at rt for 6hr. The mixture was diluted with 4% NaHCO3 (aq.) and extracted with Ethyl acetate. The organic layer was washed with brine (x2), dried and evaporated to give a pale yellow solid. The crude material was dissolved in the minimum amount of DMSO and purified by reverse phase chromatography (0% to 60% water- acetonitrile / MeOH (1 :1 ) (0.1 % v / v ammonium formate both phases)) to give 65 mg of the title compound as a pale yellow solid (77% yield).

[0390] UPLC / MS (3 min) retention time 1.69 min.

[0391] LRMS: m / z 365 (M+1 ).

[0392] 1H NMR (400 MHz, DMSO-d6) 5 8.85 (s, 1 H), 8.35 (d, J = 7.9 Hz, 1 H), 7.98 (dd, J = 8.3, 1.2 Hz, 2H), 7.63 (br s, 2H), 7.53 - 7.45 (m, 2H), 7.42 - 7.34 (m, 1 H), 4.49 (s, 1 H), 4.01 - 3.92 (m, 1 H), 2.17 - 2.05 (m, 3H), 1.81 - 1.72 (m, 4H), 1.71 - 1.62 (m, 4H), 1.54 - 1.44 (m, 2H).

[0393] EXAMPLE 6

[0394] 3-amino-N-(5-hydroxy-2-adamantyl)-6-(3-propan-2-yl-[1 ,2,4]triazolo[4,3-a]pyridin-6- yl)pyrazine-2-carboxamide

[0395] A mixture of 100 mg (272.3 umol) of 3-amino-6-bromo-N-[(2r,7r)-5-hydroxy-2- adamantyl]pyrazine-2-carboxamide, 409 uL (817 umol) of 2M solution of Na2CO3 and 117.3 mg (408.4 umol;1.5 eq) of 3-isopropyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- [1 ,2,4]triazolo[4,3-a]pyridine in 8 mL of toluene and 2 mL of ethanol is degassed. 11.12 mg (13.6 umol) of PdCI2dppf.CH2CI2 are added and the mixture heated in a microwave oven at 90°C overnight. After dilution with excess Ethyl acetate the solution is water washed, dried and concentrated. The residual oil is purified through chromatography eluting with dichloromethane I dichloromethane / MeOH 95 / 5 from 0 to 100% to give 58 mg of title compound as a yellow solid (47% yield).

[0396] UPLC-MS tr: 1 ,31 M+: 448

[0397] 1H NMR (300 MHz, CD3CI) 8 ppm 1 .6 (m, J=7.0, 2.6 Hz, 8 H) 1 .7 (m, 2 H) 1 .9 (m, 8 H) 2.0 (m, 2 H) 2.3 (s, 2 H) 3.5 (m, 1 H) 4.2 (d, J=8.2 Hz, 1 H) 7.7 (d, J=8.5 Hz, 1 H) 7.9 (d, J=9.6 Hz,1 H) 8.3 (d, J=7.4 Hz, 1 H) 8.4 (s, 1 H) 8.6 (d, J=2.5 Hz, 1 H)

[0398] EXAMPLE 7

[0399] 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-4-ylpyridin-2-amine

[0400] Stepl : 5,6-dibromopyridin-2-amine

[0401] N-bromosuccinimide (2.06 g, 11.56 mmol, 980.69 pL) was added to a solution of 6- bromopyridin-2-amine (2 g, 11.56 mmol) in Dry DMF (27.50 mL) in portions over 30 minutes at 0 °C. The reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was poured into water and the precipitate was filtered, washed with water, and dried to obtain 5,6- dibromopyridin-2-amine (2.59 g, 10.16mmol, 88% yield) as a white solid.

[0402] LCMS m / z 252.9 / 254.9 [M+ / M+2]+, it: 1.17 min.

[0403] Step 2: 5,6-dibromopyridin-2-amine

[0404] In a sealed tube, 5,6-dibromopyridin-2-amine (0.6 g, 2.36 mmol), (3-fluorophenyl) boronic acid (329.93 mg, 2.36 mmol) and sodium carbonate (2 M, 2.36 mL) were dissolved in dry toluene (12.00 mL) and methanol (1.20 mL) and the reaction mixture was purged with N2 for 5 min. Tetrakis(triphenylphosphine)-palladium(0) (81.74 mg, 0.07 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 16 hr. The reaction mixture was then cooled, diluted with Ethyl acetate and washed with water, brine, dried and concentrated on vacuo. The crude was purified by silica gel column chromatography in dichloromethane ZMeOH (from 100:0 to 99.5:0.5). The product fractions were combined dichloromethane and concentrated to obtain 5-bromo-6-(3-fluorophenyl)pyridin-2-amine (304.20 mg, 1 .12mmol, 47% yield) as a yellow solid.

[0405] LCMS m / z 268.0 / 269.0 [M+ / M+2]

[0406] Step 3: 6-(3-fluorophenyl)-5-(4-pyridyl)pyridin-2-amine

[0407] In a sealed tube,5-bromo-6-(3-fluorophenyl)pyridin-2-amine (0.341 g, 1.26 mmol), 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (259.18 mg, 1.26 mmol)and caesium carbonate (2 M, 2.53 mmol, 1 .26 mL) were dissolved in dioxane (13.5 mL) and the reaction mixture was purged with N2 for 5 min. Then, Pd(dppf)Cl2 -C^Cfe (206.43 mg, 0.25 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 90 °C for 16 hr. The reaction mixture was then cooled, diluted with Ethyl acetate and washed with water, brine, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography in dichloromethane / MeOH (from 100:0 to 96:4). The product fractions were combined and concentrated to obtain 6-(3-fluorophenyl)-5-(4-pyridyl)pyridin-2-amine (0.2876 g, 1.07mmol, 85% yield) as a beige solid.

[0408] LCMS m / z266.1 [M+H]+ Rt: 0.38 min).

[0409] Step 4: 3-bromo-6-(3-fluorophenyl)-5-(4-pyridyl)pyridin-2-amine

[0410] N-bromosuccinimide (163.89 mg, 0.92 mmol) was added to a solution of 6-(3-fluorophenyl)-5- (4-pyridyl)pyridin-2-amine (0.235 g, 0.88 mmol)in dry DMF (2.5 mL) in portions over 30 minutes at 0 °C. The reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was poured into water and was extracted with Ethyl acetate, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography in heptanes / Ethyl acetate (from 100:0 to 70:30). The product fractions were combined and concentrated to obtain 3-bromo-6-(3- fluorophenyl)-5-(4-pyridyl)pyridin-2-amine (0.2376 g, 0.68mmol, 77% yield) as a white solid.

[0411] LCMS m / z 345.1 / 346.0 [M+ / M+2]+ , rt.: 0.93 min.

[0412] Step 5: 6-(3-fluorophenyl)-5-(4-pyridyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine

[0413] In a sealed tube, 3-bromo-6-(3-fluorophenyl)-5-(4-pyridyl)pyridin-2-amine (0.238 g, 0.68 mmol) , ethynyl(trimethyl)silane (1.06 g, 10.84 mmol, 1.53 mL) , Triethylamine (2.98 g, 29.43 mmol, 4.10 mL) were dissolved in dry THF (2 mL) and the mixture was purged with N2 for 5 min. PdCI2(PPh3)2(104.64 mg, 0.15 mmol) and iodocopper (45.17 mg, 0.24 mmol) were added and the reaction mixture was purged with N2for 2 min., closed and heated at 90 °C for 16 hr. The reaction mixture was cooled, diluted with water and extracted with Ethyl acetate. The organic layer was dried and concentrated in vacuo. The crude was purified by silica gel column chromatography in heptanes / Ethyl acetate (from 100:0 to 70:30). The product fractions were combined and concentrated to obtain 6-(3-fluorophenyl)-5-(4-pyridyl)-3-(2- trimethylsilylethynyl)pyridin-2-amine (0.2328 g, 0.64 mmol, 94% yield) as an ivory solid.

[0414] LCMS m / z 362.2[M+H]+ , Rt: 1.31 min.

[0415] Step 6: 3-ethynyl-6-(3-fluorophenyl)-5-(4-pyridyl)pyridin-2-amine

[0416] Potassium carbonate (29.10 mg, 0.2 1 mmol) was added to a solution of 6-(3-fluorophenyl)-5- (4-pyridyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine (0.233 g, 0.64 mmol) in methanol (2 mL) . The reaction mixture was stirred at 25 °C for 1 hr . The reaction mixture was partitioned between Ethyl acetate / H2O:brine. After phase separation, the product was extracted with Ethyl acetate. The combined organic layers were dried and concentrated. The crude was purified by flash column chromatography on silica eluting with heptantes / Ethyl acetate from 100:0 to 60:40. The product fractions were combined and concentrated to yield 3-ethynyl-6- (3-fluorophenyl)-5-(4-pyridyl)pyridin-2-amine (0.179 g, 0.61 mmol, 96% yield) as a brown solid.

[0417] LCMS m / z 290.2 [M+H]+, Rt: 1.906 min.

[0418] 1H-NMR (400 MHz, DMSO-d6) 5 8.43 (br b, 11 H), 7.68 (s, 6H), 7.29 (dd, J = 14.1 , 7.9 Hz, 7H), 7.19 - 7.05 (m, 26H), 6.99 (d, J = 7.7 Hz, 7H), 6.62 (s, 12H), 4.55 (s, 6H).

[0419] EXAMPLE 8

[0420] 3-ethynyl-6-(furan-2-yl)-5-pyridin-4-ylpyrazin-2-amine

[0421] Step 1 : 6-(furan-2-yl)pyrazin-2-amine

[0422] To a stirred solution of 2-amino-6-chloropyrazine (2.0 g, 15.43 mmol) in a mixture of toluene (90 mL) and ethanol (8.5 mL) was added 2-furylboronic acid (2.07 g, 18.51 mmol) and a 2M solution of sodium carbonate (16.2 mL, 32.40 mmol). The mixture was degassed and purged with argon, and tetrakis(triphenylphospine)palladium (0.713 g, 0617 mmol) was added. After purging with argon the flask was capped and heated at 110°C for 4hr. The mixture was partitioned between dichloromethane and water, the organic layer washed with water and brine, dried and concentrated. The residue was purified by silica gel flash chromatography (hexane / Ethyl acetate 33% to 50%). Concentration of the product-rich fractions provided the title compound (1 .61 g, 65% yield) as a yellowish solid.

[0423] Step 2: 5-bromo-6-(2-furyl)pyrazin-2-amine

[0424] To a 0°C cooled solution of 6-(furan-2-yl)pyrazin-2-amine (0.42 g, 2.64 mmol) in a mixture of DMSO (10 mL) and water (0.25 mL) was added N-bromosuccinimide (518 mg, 2.90 mmol) in portions. After stirring for 5hr, the mixture was poured into water and dried to give the title compound as a yellow solid (250 mg, 44% yield).

[0425] Step 3: 6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine

[0426] In a sealed tube, 5-bromo-6-(2-furyl)pyrazin-2-amine (250 mg, 1.04 mmol), 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (426.5 mg, 2.08 mmol) and 2M caesium carbonate (3.12 mL, 6.24 mmol) were dissolved in dioxane (12 mL) and the reaction mixture was purged with N2 for 5 min. Then, Pd(dppf)CI2 ■ CH2CI2 (39.6 mg, 0.05 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 100 °C for 20 hr. The reaction mixture was then cooled, diluted with Ethyl acetate and washed with water, brine, dried and concentrated on vacuo. The crude was purified by silica gel column chromatography in dichloromethane / MeOH (from 2% to 5%). The product fractions were combined and concentrated to obtain 6-(furan-2-yl)-5-(pyridin-4-yl)pyrazin-2-amine (0.168 g, 68% yield) as a yellowish solid.

[0427] Step 4: 3-bromo-6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine

[0428] To a 0°C stirred solution of 6-(2-furyl)-5-pyrazin-2-amine (195 mg, 0.82 mmol) in DMF (1.5 mL) and water (40 uL), was added portionwise N-bromosuccinimide (146 mg, 0.82 mmol). The mixture was stirred at room temperature for 40 min, then poured into water, extracted with dichloromethane (x3), the organic layers washed with brine, dried and concentrated to furnish the title compound (198 mg, 75% yield) as a brown solid.

[0429] Step 5: 6-(2-furyl)-5-pyridin-3-trimethylsilyl-4-ylpyrazin-2-amine

[0430] In a sealed tube, 3-bromo-6-(2-furyl)-5-(4-pyridyl)pyrazin-2-amine (90 mg, 0.28 mmol) , ethynyl(trimethyl)silane (80 uL, 0.56 mmol) , were dissolved in dry THF (1 mL) and the mixture was purged with N2 for 5 min. Then, PdCI2(PPh3)2 (8 mg, 0.01 mmol) and iodocopper (2.2 mg, 0.01 mmol) were added and the reaction mixture was purged with N2 for 2 min., closed and heated at 90 °C for 3 hr. The reaction mixture was cooled, diluted with water and extracted with Ethyl acetate. The organic layer was dried and concentrated in vacuo. The crude was purified by silica gel column chromatography in dichloromethane / MeOH 2%. The product fractions were combined and concentrated to obtain 6-(2-furyl)-5-pyridin-3-trimethylsilyl-4- ylpyrazin-2-amine (48 mg, 51 % yield) as a orange oil.

[0431] Step 6: 3-ethynyl-6-(furan-2-yl)-5-(pyridin-4-yl)pyrazin-2-amine

[0432] A mixture of 6-(2-furyl)-5-pyridin-3-trimethylsilyl-4-ylpyrazin-2-amine (45 mg, 0-13 mmol) and potassium carbonate (28 mg, 0.20 mmol) in methanol (2 mL) was stirred at room temperature for 3hr. The mixture was partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried and concentrated to give the title compound (28 mg, 80% yield) as a brown solid.

[0433] LCMS m / z 263 [M+H]+

[0434] 1H NMR (400 MHz, CDCI3) 5 8.60 (d, 2H), 7.45 (s, 1 H), 7.40 (d, 2H), 6.55 (d, 1 H), 6.45 (d, 1 H), 5.5 (bs, 2H), 3.60 (s, 1 H). EXAMPLE 9

[0435] 5-(2,6-dimethylpyridin-4-yl)-3-ethynyl-6-(3-fluorophenyl)pyridin-2-amine

[0436] Stepl : 5,6-dibromopyridin-2-amine

[0437] N-bromosuccinimide (2.06 g, 11.56 mmol, 980.69 pL) was added to a solution of 6- bromopyridin-2-amine (2 g, 11.56 mmol) in Dry DMF (27.50 mL) in portions over 30 minutes at 0 °C. The reaction mixture was stirred at 25 °C for 16 hr. The reaction mixture was poured into water and the precipitate was filtered, washed with water, and dried to obtain 5,6- dibromopyridin-2-amine (2.59 g, 10.16mmol, 88% yield) as a white solid.

[0438] LCMS m / z 252.9 / 254.9 [M+ / M+2]+, it: 1.17 min.

[0439] Step 2: 5,6-dibromopyridin-2-amine

[0440] In a sealed tube, 5,6-dibromopyridin-2-amine (0.6 g, 2.36 mmol), (3-fluorophenyl) boronic acid (329.93 mg, 2.36 mmol) and sodium carbonate (2 M, 2.36 mL) were dissolved in dry toluene (12.00 mL) and methanol (1.20 mL) and the reaction mixture was purged with N2 for 5 min. Tetrakis(triphenylphosphine)-palladium(0) (81.74 mg, 0.07 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 16 hr. The reaction mixture was then cooled, diluted with Ethyl acetate and washed with water, brine, dried and concentrated on vacuo. The crude was purified by silica gel column chromatography in dichloromethane ZMeOH (from 100:0 to 99.5:0.5). The product fractions were combined and concentrated to obtain 5-bromo-6-(3-fluorophenyl)pyridin-2-amine (304.20 mg, 1.12mmol, 47% yield) as a yellow solid.

[0441] LCMS m / z 268.0 / 269.0 [M+ / M+2]

[0442] Step 3: 5-(2,6-dimethyl-4-pyridyl)-6-(3-fluorophenyl)pyridin-2-amine

[0443] In a sealed tube,5-bromo-6-(3-fluorophenyl)pyridin-2-amine (0.304 g, 1.13 mmol), 2, 6- dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (262.67 mg, 1.13 mmol) and caesium carbonate (2 M, 1.13 mL) were dissolved in dioxane (12 mL) and the reaction mixture was purged with N2 for 5 min. Then, Pd(dppf)CI2 ■ CH2CI2 (184.03 mg, 0.23mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 90 °C for 16 hr. The reaction mixture was then cooled, diluted with Ethyl acetate and washed with water, brine, dried and concentrated on vacuo. The crude was purified by silica gel column chromatography in Heptanes / Ethyl acetate (from 100:0 to 30:70). The product fractions were combined and concentrated to obtain 5-(2,6-dimethyl-4-pyridyl)-6-(3-fluorophenyl)pyridin-2-amine (0.225 g, 67% yield) as a ivory solid. LCMS (m / z294.1 [M+H]+ Rt: 0.55 min).

[0444] Step 4: 3-bromo-5-(2,6-dimethyl-4-pyridyl)-6-(3-fluorophenyl)pyridin-2-amine

[0445] N-bromosuccinimide (126.14 mg, 0.71 mmol) was added to a solution of 5-(2,6-dimethyl-4- pyridyl)-6-(3-fluorophenyl)pyridin-2-amine (0.200 g, 0.67 mmol) in dry DMF (2.6 mL) in portions over 30 minutes at 0 °C. The reaction mixture was stirred at 25 °C for 4 hr, The reaction mixture was poured into water and was extracted with Ethyl acetate, dried over anh. MgSO4, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography in Heptanes / Ethyl acetate (from 100:0 to 30:70). The product fractions were combined and concentrated to obtain 3-bromo-5-(2,6-dimethyl-4-pyridyl)-6-(3- fluorophenyl)pyridin-2-amine (0.1994 g, 0.52mmol, 78% yield) as a red solid.

[0446] LCMS 220606U_037 m / z 373.0 / 374.1 [M+ / M+2]+, rt.: 0.87 min.

[0447] Step 5: 5-(2,6-dimethyl-4-pyridyl)-6-(3-fluorophenyl)-3-(2-trimethylsilylethynyl)pyridin-2- amine

[0448] In a sealed tube, 3-bromo-5-(2,6-dimethyl-4-pyridyl)-6-(3-fluorophenyl)pyridin-2-amine (0.179 g, 0.47 mmol) , ethynyl(trimethyl)silane (740.58 mg, 7.54 mmol, 1.07 mL) , triethylamine (2.25 g, 22.28 mmol, 3.11 mL) were dissolved in dry THF (2.5 mL) and the mixture was purged with N2 for 5 min. Then, PdCI2(PPh3)2 (72.77 mg, O.IOmmol) and iodocopper (31.41 mg, 0.16 mmol) were added and the reaction mixture was purged with N2 for 2 min., closed and heated at 90 °C for 16 hr. The reaction mixture was cooled, diluted with water and extracted with Ethyl acetate. The organic layer was dried and concentrated in vacuo. The crude was purified by silica gel column chromatography in Heptanes / Ethyl acetate (from 100:0 to 70:30). The product fractions were combined and concentrated to obtain 5-(2,6-dimethyl-4-pyridyl)-6-(3- fluorophenyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine (0.1255 g, 0.32mmol, 68% yield) as a light-yellow solid.

[0449] LCMS m / z 390.1 / 391 .2 [M+ / M+2]+ Rt: 1.20 min1 H

[0450] Step 6: 5-(2,6-dimethyl-4-pyridyl)-3-ethynyl-6-(3-fluorophenyl)pyridin-2-amine

[0451] Potassium carbonate (14.55 mg, 0.11 mmol) was added to a solution of 5-(2,6-dimethyl-4- pyridyl)-6-(3-fluorophenyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine (0.1255 g, 0.32 mmol) in methanol (1 mL). The reaction mixture was stirred at 25 °C for 1 hr . The reaction mixture was partitioned between Ethyl acetate / H2O:brine. After phase separation, the product was extracted with Ethyl acetate. The combined organics layers were dried and concentrated. The crude was purified by flash column chromatography on silica eluting with heptantes / Ethyl acetate from 100:0 to 50:50. The product fractions were combined and concentrated to yield 5-(2,6-dimethyl-4-pyridyl)-3-ethynyl-6-(3-fluorophenyl)pyridin-2-amine (0.0955 g, 0.30mmol, 93% yield) as a black solid.

[0452] LCMS m / z 318.1 [M+H]+, Rt: 1.87.

[0453] 1H NMR (400 MHz, DMSO) 5 7.68 (s, 1 H), 7.34 - 7.26 (m, 1 H), 7.21 - 7.07 (m, 2H), 7.00 (d, J = 7.7 Hz, 1 H), 6.88 (br s, 2H), 6.69 - 6.58 (m, 2H), 4.54 (s, 1 H), 2.33 (s, 6H).

[0454] EXAMPLE 10

[0455] 6-(3-fluorophenyl)-5-pyridin-4-ylpyrazin-2 -amine

[0456] Step 1 : 6-(3-fluorophenyl)pyrazin-2-amine

[0457] To a stirred solution of 2-amino-6-chloropyrazine (2.0 g, 15.43 mmol) in a mixture of toluene (90 mL) and ethanol (8.5 mL) was added 3-fluorophenyllboronic acid (2.60 g, 18.51 mmol) and a 2M solution of sodium carbonate (16.2 mL, 32.40 mmol). The mixture was degassed and purged with argon, and tetrakis(triphenylphospine)palladium (0.713 g, 0617 mmol) was added. After purging with argon the flask was capped and heated at 110°C for 4hr. The mixture was partitioned between dichloromethane and water, the organic layer washed with water and brine, dried and concentrated. The residue was purified by silica gel flash chromatography (hexane / Ethyl acetate 33% to 50%). Concentration of the product-rich fractions provided the title compound (2.79 g, 95% yield) as a yellowish solid.

[0458] Step 2: 5-bromo-6-(3-fluorophenyl)pyrazin-2-amine

[0459] To a 0°C stirred solution of 6-(3-fluorophenyl)pyrazin-2-amine (500 mg, 2.64 mmol) in DMSO (10 mL) and water (0.25 mL), was added portion wise N-bromosuccinimide (518 mg, 2.90 mmol). The mixture was stirred at room temperature for 5hr, then poured into water. The precipitate was collected and washed with water and dried to give the title compound (600 mg, 85% yield) as a yellow solid.

[0460] Step 3: 6-(3-fluorophenyl)-5-(pyridin-4-yl)pyrazin-2-amine

[0461] In a sealed tube, 5-bromo-6-(3-fluorophenyl)pyrazin-2-amine (300 mg, 1.11 mmol), 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (459 mg, 2.23 mmol) and 2M caesium carbonate (3.3 mL, 6.66 mmol) were dissolved in dioxane (35 mL) and the reaction mixture was purged with N2 for 5 min. Then, Pd(dppf)CI2 ■ CH2CI2 (45 mg, 0.055 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 100 °C for 20 hr. The reaction mixture was then cooled, diluted with Ethyl acetate and washed with water, brine, dried and concentrated on vacuo. The crude was purified by silica gel column chromatography in dichloromethane / MeOH (from 2% to 5%). The product fractions were combined and concentrated to obtain 6-(3-fluorophenyl)-5-(pyridin-4-yl)pyrazin-2-amine (0.178 g, 60% yield) as a yellowish solid.

[0462] LCMS m / z 267 [M+H]+

[0463] 1H NMR (400 MHz, CDCI3) 5 8.45 (d, 2H), 8.05 (s, 1 H), 7.24 (m, 4H), 7.05 (d, 2H), 4.86 (s, 2H).

[0464] EXAMPLE 11

[0465] 3 -ethynyl-6-phenyl-5-pyridin-3-ylpyridin-2 -amine

[0466] Step 1 5-bromo-6-phenyl-pyridin-2-amine

[0467] In a sealed tube, 5,6-dibromopyridin-2-amine (0.750 g, 2.95mmol), phenylboronic acid (359.39 mg, 2.95mmol) and sodium carbonate (2 M, 2.95 mL) were dissolved in dry toluene (15 mL) and methanol (1.5 mL) and the reaction mixture was purged with N2 for 5 min. Tetrakis(triphenylphosphine)-palladium(0) (102.18 mg, 0.09 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 16 hr.The reaction mixture was then cooled, diluted with Ethyl acetate and washed with water, brine, dried over anh. MgSO4, filtered and concentrated in vacuo. The crude was purified by silica gel column chromatography in dichloromethane / MeOH (from 100:0 to 99.5:0.5). The product fractions were combined and concentrated to obtain 5-bromo-6-phenyl-pyridin-2-amine (0.4214 g, 1 .66mmol, 56% yield) as a yellow oil.

[0468] LCMS 220621 U_054 m / z 249.1 / 251 .0 [M+ / M+2]+ , Rt: 0.95 min.

[0469] Step 2 6-phenyl-5-(3-pyridyl)pyridin-2-amine

[0470] In a sealed tube, 5-bromo-6-phenyl-pyridin-2-amine (0.3876 g, 1.52 mmol), 3-pyridylboronic acid (187.43 mg, 1.52 mmol) and caesium carbonate (2 M, 3.05 mmol, 1.52 mL) were dissolved in dioxane (16.5 mL) and the reaction mixture was purged with N2 for 5 min. Then, Pd(dppf)CI2-CH2Cl2 (249.05 mg, 0.30 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 90 °C for 16 hr. The reaction mixture was then cooled, diluted with Ethyl acetate and washed with water, brine, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography in dichloromethane / MeOH (from 100:0 to 96:4). The product fractions were combined and concentrated to obtain 6-phenyl-5- (3-pyridyl)pyridin-2-amine (0.326 g, 1.31 mmol, 86% yield) as a beige solid.

[0471] LCMS (m / z 248.1 [M+H]+ , Rt: 0.55 min). Step 3 3-bromo-6-phenyl-5-(3-pyridyl)pyridin-2-amine

[0472] N-bromosuccinimide (222.95 mg, 1.25 mmol) was added to a solution of 6-phenyl-5-(3- pyridyl)pyridin-2-amine (0.298 g, 1.19 mmol) in Dry DMF (3.6 mL) in portions over 30 minutes at 0 °C. The reaction mixture was stirred at 25 °C for 3 hr. The reaction mixture was poured into water and was extracted with Ethyl acetate, dried and concentrated in vacuo. The crude was purified by silica gel column chromatography in heptanes / Ethyl acetate (from 100:0 to 68:32). The product fractions were combined and concentrated to obtain3-bromo-6-phenyl-5- (3-pyridyl)pyridin-2-amine (0.284 g, 0.86mmol, 72% yield) as a pink solid.

[0473] LCMS m / z 326.0 / 328.0 [M+ / M+2]+ , rt.: 0.61 min.

[0474] Step 4 6-phenyl-5-(3-pyridyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine

[0475] In a sealed tube, 3-bromo-6-phenyl-5-(3-pyridyl)pyridin-2-amine (0.280 g, 0.85 mmol), ethynyl(trimethyl)silane (500.80 mg, 5.10mmol, 720.58 pL), N,N-diethylethanamine (343.97 mg, 3.40 mmol, 473.79 pL) were dissolved in dry DMF (5.55 mL) and the mixture was purged with N2 for 5 min. Then, PdCI2(PPh3)2 (119.30 mg, 0.17mmol) and iodocopper (32.37 mg, 0.17mmol) were added and the reaction mixture was purged with N2 for 2 min., closed and heated at 50 °Cfor 16 hr. The reaction mixture was filtered over a pad of Celite® and rinsing with Ethyl acetate. The organic layer was dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with heptanes / Ethyl acetate from 100:0 to 75:25. The product fractions were combined and concentrated to yield 6-phenyl-5-(3-pyridyl)- 3-(2-trimethylsilylethynyl)pyridin-2-amine (231.1 mg, 0.67mmol, 78% yield) as a beige solid.

[0476] LCMS m / z 344.2 [M+H]+, rt: 1.64 min.

[0477] Step 5 3-ethynyl-6-phenyl-5-(3-pyridyl)pyridin-2-amine

[0478] Potassium carbonate (30.10 mg, 0.22 mmol) was added to a solution of 6-phenyl-5-(3-pyridyl)- 3-(2-trimethylsilylethynyl)pyridin-2-amine (0.229 g, 0.66 mmol) in methanol (2 mL) . The reaction mixture was stirred at 25 °C for 1 hr. The reaction mixture was partitioned between Ethyl acetate / H2O:brine. After phase separation, the product was extracted with Ethyl acetate. The combined organics layers were dried and concentrated. The crude was purified by flash column chromatography on silica eluting with heptantes / Ethyl acetate from 100:0 to 70:30. The product fractions were combined and concentrated to yield 3-ethynyl-6-phenyl-5-(3- pyridyl)pyridin-2-amine (0.100 g, 0.36mmol, 55% yield) as an ivory solid.

[0479] LCMS: m / z: 271.9 [M+H]+, Rt: 1.828 min.

[0480] 1H NMR (400 MHz, MeOD-d4) 5 8.35 (dd, J = 4.9, 1.5 Hz, 1 H), 8.21 (d, J = 1.7 Hz, 1 H), 7.73 (s, 1 H), 7.63 - 7.60 (m, 1 H), 7.34 - 7.25 (m, 6H), 3.99 (s, 1 H).1 H NMR (400 MHz, DMSO-d6) 5 8.37 (dd, J = 4.8, 1.5 Hz, 1 H), 8.24 (d, J = 2.0 Hz, 1 H), 7.66 (s, 1 H), 7.50 (dt, J = 7.9, 1.9 Hz, 1 H), 7.30 - 7.18 (m, 6H), 6.47 (s, 2H), 4.52 (s, 1 H).

[0481] EXAMPLE 12

[0482] 6-(3,5-difluorophenyl)-3-ethynyl-5-pyridin-3-ylpyridin-2 -amine

[0483] Step 1 5-bromo-6-(3,5-difluorophenyl)pyridin-2-amine

[0484] In a sealed tube,5,6-dibromopyridin-2-amine (500 mg, 1 .97 mmol), (3,5-difluorophenyl)boronic acid (310.30 mg, 1.97 mmol) and sodium carbonate (416.54 mg, 3.93 mmol) were dissolved in dioxane / H2O (4:1 ) (10 mL) and the reaction mixture was purged with N2 for 5 min. Tetrakis(triphenylphosphine)-palladium (0) (68.12 mg, 0.06 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 16 hr. 3,5- difluorophenyl)boronic acid (155.15 mg, 0.98 mmol), sodium carbonate (208.27 mg, 1.97 mmol) and tetrakis(triphenylphosphine)-palladium (0) (45.41 mg, 0.04 mmol) were added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 24 hr. The reaction mixture was filtered over a pad of Celite® and rinsed with Ethyl acetate. The filtrate was washed with water / brine and the water layer was extracted with Ethyl acetate. The organic layer was dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with heptanes / Ethyl acetate from 100:0 to 77:23. The product fractions were combined and concentrated to yield 5-bromo-6-(3,5-difluorophenyl)pyridin-2-amine (0.440 g, 1.44 mmol, 73% yield) as a white solid.

[0485] LCMS, m / z 285.0 / 287.0 [M+ / M+2]+, Rt: 1.37 min.

[0486] Step2 6-(3,5-difluorophenyl)-5-(3-pyridyl)pyridin-2-amine

[0487] In a sealed tube, 5-bromo-6-(3,5-difluorophenyl)pyridin-2-amine (440 mg, 1.44 mmol) , 3- pyridylboronic acid (264.64 mg, 2.15 mmol) and caesium carbonate (1.40 g, 4.31 mmol) were dissolved in dioxane / H2O (4:1 ) (7.2 mL) and the mixture was purged with N2 for 5 min. Then, Pd(dppf)Ch ■ CH2CI2 (117.22 mg, 0.14 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 16 hr. The reaction mixture was filtered over a pad of Celite® and rinsing with Ethyl acetate. The filtrate was partitioned between Na2CO3 / Ethyl acetate and the product was extracted with Ethyl acetate. The organic layer was dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with dichloromethane ZMeOH from 100:0 to 96.6:3.4. The product fractions were combined and concentrated to yield 6-(3,5-difluorophenyl)-5-(3-pyridyl)pyridin-2-amine (215 mg, 0.75mmol, 52% yield) as an ivory solid.. LCMS m / z 284.1 [M+H]+ , Rt: 0.32.

[0488] Step3 3-bromo-6-(3,5-difluorophenyl)-5-(3-pyridyl)pyridin-2-amine

[0489] N-bromosuccinimide (14.56 mg, 0.08 mmol) was added to a stirred solution of 6-(3,5- difluorophenyl)-5-(3-pyridyl)pyridin-2-amine (215 mg, 0.75 mmol) in dry dioxane (1.94 mL) at 0°C. Then the reaction mixture was stirred and heated at 25 °C for 1 hr. The reaction mixture was diluted with Ethyl acetate and washed with brine. The organic layer was dried, filtered and concentrated. The crude was purified by flash column chromatography on silica gel eluting with heptanes / Ethyl acetate from 100:0 to 64:36. The product fractions were combined and concentrated to yield 3-bromo-6-(3,5-difluorophenyl)-5-(3-pyridyl)pyridin-2-amine (209 mg, 0.57mmol, 76% yield) as a white solid.

[0490] LCMS m / z 362.0 / 364.0 [M+H / M+H+2]+, Rt: 1.13 min.

[0491] Step4 6-(3,5-difluorophenyl)-5-(3-pyridyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine

[0492] In a sealed tube, 3-bromo-6-(3,5-difluorophenyl)-5-(3-pyridyl)pyridin-2-amine (205 mg, 0.56 mmol), ethynyl(trimethyl)silane (660.46 mg, 6.72 mmol, 950.30 pL), N,N-diethylethanamine (453.63 mg, 4.48 mmol, 624.84 pL) were dissolved in dry DMF (1 .68 mL) and the mixture was purged with N2 for 5 min. Then, PdCI2(PPh3)2 (157.33 mg, 0.22mmol) and iodocopper (42.69 mg, 0.22 mmol) were added and the reaction mixture was purged with N2 for 2 min., closed and heated at 50 °C for 16 hr. The reaction mixture was filtered over a pad of Celite® and rinsed with Ethyl acetate. The organic layer was dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with heptanes / Ethyl acetate from 100:0 to 83:17. The product fractions were combined and concentrated to yield 6-(3,5- difluorophenyl)-5-(3-pyridyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine (195 mg, 0.51 mmol, 91 % yield) as a beige solid.

[0493] LCMS m / z 380.1 [M+H]+, rt: 1.63 min.

[0494] Step5 6-(3,5-difluorophenyl)-3-ethynyl-5-(3-pyridyl)pyridin-2-amine

[0495] Potassium carbonate (23.98 mg, 0.17 mmol, 10.47 pL) was added to a solution of 6-(3,5- difluorophenyl)-5-(3-pyridyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine (192 mg, 0.53 mmol) in MeOH (1 .6 mL). The reaction mixture was stirred at 25 °C for 1 hr. The reaction mixture was partitioned between Ethyl acetate / H2O:brine. After phase separation, the product was extracted with Ethyl acetate. The combined organics layers were dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with heptanes / Ethyl acetate from 100:0 to 66:34. The product fractions were combined and concentrated to yield 6-(3,5-difluorophenyl)-3-ethynyl-5-(3-pyridyl)pyridin-2-amine (85 mg, 0.27mmol, 52% yield) as a beige solid.

[0496] LCMS m / z: 308.00 [M+H]+, rt.: 2.383 min.

[0497] 1H NMR: (400 MHz, DMSO-d6) 58.43 (dd, J = 4.8, 1.6 Hz, 1 H), 8.29 (d, J = 2.0 Hz, 1 H), 7.69 (s, 1 H), 7.55 (m, 1 H), 7.31 (dd, J = 7.8, 4.8 Hz, 1 H), 7.17 (tt, J = 9.3, 2.3 Hz, 1 H), 6.91 - 6.82 (m, 2H), 6.58 (s, 2H), 4.56 (s, 1 H).

[0498] EXAMPLE 13

[0499] 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-3-ylpyridin-2-amine

[0500] Stepl 5-bromo-6-(3-fluorophenyl)pyridin-2-amine

[0501] In a sealed tube,5,6-dibromopyridin-2-amine (500 mg, 1.97 mmol), (3-fluorophenyl)boronic acid (274.94 mg, 1.97 mmol) and sodium carbonate (416.54 mg, 3.93 mmol) were dissolved in dioxane / H2O (4:1 ) (9.9 mL) and the reaction mixture was purged with N2 for 5 min. Tetrakis(triphenylphosphine)-palladium(0) (68.12 mg, 0.06 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 16 hr. The reaction mixture was filtered over a pad of Celite® and rinsed with Ethyl acetate. The filtrate was washed with water / brine and the water layer was extracted with Ethyl acetate. The organic layer was dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with heptanes / Ethyl acetate from 100:0 to 80:20. The product fractions were combined and concentrated to yield5-bromo-6-(3-fluorophenyl)pyridin-2-amine (378 mg, 1.39mmol, 71 % yield) as an ivory solid.

[0502] LCMS m / z 267.0 / 269.0 [M+ / M+2]+ , Rt: 1.19 min.

[0503] Step 2: 6-(3-fluorophenyl)-5-(3-pyridyl)pyridin-2-amine

[0504] In a sealed tube, 5-bromo-6-(3-fluorophenyl)pyridin-2-amine (0.378 g, 1.40 mmol), 3- pyridylboronic acid (344.43 mg, 2.80 mmol) and caesium carbonate (912.99 mg, 2.80 mmol) were dissolved in dioxane / H2O (4:1 ) (7 mL) and the reaction mixture was purged with N2 for 5 min. Then, Pd(dppf)CI2 ■ CH2CI2 (11 .44 mg, 0.01 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 16 hr. The reaction mixture was recharged with 5-bromo-6-(3-fluorophenyl)pyridin-2-amine (0.378 g, 1.40mmol), 3- pyridylboronic acid (344.43 mg, 2.80 mmol) and caesium carbonate (456.49 mg, 1.40 mmol). Then, Pd(dppf)CI2 ■ CH2CI2 (11.44 mg, 0.01 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 16 hr. The reaction mixture was filtered over a pad of Celite® and rinsed with Ethyl acetate. The filtrate was partitioned between Na2CO3 / Ethyl acetate and the product was extracted with Ethyl acetate / brine. The organic layer was dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with dichloromethane / MeOH from 100:0 to 96:4. The product fractions were combined and concentrated to yield 6-(3-fluorophenyl)-5-(3- pyridyl)pyridin-2-amine (209.60mg, 0.73 mmol, 52% yield) as a brown solid.

[0505] LCMS, m / z 266.1 [M+H]+ , Rt: 0.66 min.

[0506] Step 3: 3-bromo-6-(3-fluorophenyl)-5-(3-pyridyl)pyridin-2-amine

[0507] N-bromosuccinimide (14.56 mg, 0.08 mmol) was added to a stirred solution of 6-(3- fluorophenyl)-5-(3-pyridyl)pyridin-2-amine (0.209 g, 0.73 mmol) in dry dioxane (2.5 mL) at 0°C . Then the reaction mixture was stirred and heated at 25 °C for 16 hr. The reaction mixture was diluted with Ethyl acetate and was washed with brine. The organic layer was dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with Heptanes / Ethyl acetate from 100:0 to 50:50. The product fractions were combined and concentrated to yield 3-bromo-6-(3-fluorophenyl)-5-(3-pyridyl)pyridin-2-amine (0.230 g, 0.66mmol, 90% yield) as a beige solid.

[0508] LCMS m / z 344.0 / 346.0 [M+H / M+H+2]+, Rt: 1.09 min.

[0509] Step 4: 6-(3-fluorophenyl)-5-(3-pyridyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine

[0510] In a sealed tube,3-bromo-6-(3-fluorophenyl)-5-(3-pyridyl)pyridin-2-amine (0.230 g, 0.66 mmol),ethynyl(trimethyl)silane (779.74 mg, 7.94 mmol, 1.12 mL), N,N-diethylethanamine (535.56 mg, 5.29 mmol, 737.68 pL) were dissolved in dry DMF (2 mL) and the mixture was purged with N2 for 5 min. PdCI2(PPh3)2 (185.74 mg, 0.26 mmol) and iodocopper (50.40 mg, 0.26 mmol) were added and the reaction mixture was purged with N2 for 2 min., closed and heated at 50 °C for16 hr. The reaction mixture was filtered over a pad of Celite® and rinsed with Ethyl acetate. The organic layer was dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with Heptanes / Ethyl acetate from 100:0 to 80:20. The product fractions were combined and concentrated to yield 6-(3-fluorophenyl)-5- (3-pyridyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine (0.1752 g, 0.47mmol, 71 % yield, 97% purity) as a beige solid.

[0511] LCMS m / z 362.1 [M+H]+, Rt: 1.53 min. Step5 3-ethynyl-6-(3-fluorophenyl)-5-(3-pyridyl)pyridin-2-amine

[0512] Potassium carbonate (21.42 mg, 0.15 mmol, 9.35 pL) was added to a solution of 6-(3- fluorophenyl)-5-(3-pyridyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine (0.175 g, 0.47 mmol) in MeOH (1 .5 mL). The reaction mixture was stirred at 25 °C for 1 hr. The reaction mixture was partitioned between Ethyl acetate / H2O:brine. After phase separation, the product was extracted with Ethyl acetate. The combined organics layers were dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with Heptanes / Ethyl acetate from 100:0 to 69:31 . The product fractions were combined and concentrated to yield 3-ethynyl-6-(3-fluorophenyl)-5-(3-pyridyl)pyridin-2-amine (0.04 g, 0.14mmol, 29% yield) as a violet solid.

[0513] LCMS m / z: 290.1 [M+H]+, Rt: 2.13 min.

[0514] 1H NMR: (400 MHz, DMSO-d6) 5 8.40 (d, J = 3.7 Hz, 1 H), 8.26 (s, 1 H), 7.67 (s, 1 H), 7.55 - 7.49 (m, 1 H), 7.31 - 7.23 (m, 2H), 7.16 - 7.02 (m, 2H), 6.97 (d, J = 7.7 Hz, 1 H), 6.52 (s, 2H), 4.54 (s, 1 H).

[0515] EXAMPLE 14

[0516] 3-ethynyl-5,6-dipyridin-3-ylpyridin-2-amine

[0517] Stepl 5,6-bis(3-pyridyl)pyridin-2-amine

[0518] In a sealed tube, 5,6-dibromopyridin-2-amine (500 mg, 1.97 mmol), 3-pyridylboronic acid (531.38 mg, 4.32 mmol) and caesium carbonate (1.28 g, 3.93 mmol) were dissolved in dioxane / H2O (4:1 ) (10 mL) and the reaction mixture was purged with N2 for 5 min. Pd(dppf)CI2-CH2CI2 (16.05 mg, 0.02 mmol) was added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 16 hr. 3-pyridylboronic acid (265.69 mg, 2.16 mmol), caesium carbonate (640.24 mg, 1.97mmol) and Pd(dppf)CI2-CH2CI2 (16.05 mg, 0.02 mmol) were added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °C for 16 hr. 3-pyridylboronic acid (169.07 mg, 1.38mmol) and caesium carbonate (640.24 mg, 1.97 mmol) and Pd(dppf)CI2-CH2CI2 (48.14 mg, 0.06mmol) were still added and the reaction mixture was purged with N2 for 2 min, closed and heated at 110 °Cf or 16 hr. The reaction mixture was filtered over a pad of Celite® and rinsed with Ethyl acetate. The filtrate was washed with water / brine and the water layer was extracted with Ethyl acetate. The organic layer was dried and concentrated. The crude was purified by silica gel column chromatography in dichloromethane / MeOH (from 100:0 to 94:6). The product fractions were combined and concentrated to obtain 5,6-bis(3-pyridyl)pyridin-2-amine (0.257 g, 1.02mmol, 52% yield) as a grey solid.

[0519] LCMS m / z 249.1 [M+H]+, Rt: 0.33 min.

[0520] Step 2: 3-bromo-5,6-bis(3-pyridyl)pyridin-2-amine

[0521] N-bromosuccinimide (14.56 mg, 0.08 mmol) was added to a stirred solution of 5,6-bis(3- pyridyl)pyridin-2-amine (0.257 g, 1 .02 mmol) in dry dioxane (3.1 mL) at 0°C . Then the reaction mixture was stirred and heated at 25 °C for 16 hr. The reaction mixture was diluted with Ethyl acetate and washed with brine. The organic layer was dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with dichloromethane / MeOH from 100:0 to 98:2. The product fractions were combined and concentrated to yield 3-bromo- 5,6-bis(3-pyridyl)pyridin-2-amine (0.2363 g, 0.71 mmol, 69% yield) as a beige solid.

[0522] LCMS m / z 327.0 / 329.0 [M+H / M+H+2]+, Rt: 0.28 min.

[0523] Step 3: 5,6-bis(3-pyridyl)-3-(2-trimethylsilylethynyl)pyridin-2-amine

[0524] In a sealed tube,3-bromo-5,6-bis(3-pyridyl)pyridin-2-amine (0.236 g, 0.71 mmol), ethynyl(trimethyl)silane (833.16 mg, 8.48 mmol, 1.20 mL), N,N-diethylethanamine (572.24 mg, 5.66 mmol, 788.21 pL) were dissolved in dry DMF (2.5 mL)and the mixture was purged with N2 for 5 min. PdCI2(PPh3)2 (198.47 mg, 0.28 mmol) and iodocopper (53.85 mg, 0.28 mmol, 9.58 pL) were added and the reaction mixture was purged with N2 for 2 min., closed and heated at 50°C for 16 hr. The reaction mixture was filtered over a pad of Celite® and rinsed with Ethyl acetate. The organic layer was dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with dichloromethane / MeOH from 100:0 to 95:5. The product fractions were combined and concentrated to yield 5,6-bis(3-pyridyl)-3-(2- trimethylsilylethynyl)pyridin-2-amine (0.2007 g, 0.58mmol, 82% yield) as a beige solid.

[0525] LCMS m / z 345.2 [M+H]+, Rt: 1.16 min.

[0526] Step 4: 3-ethynyl-5,6-bis(3-pyridyl)pyridin-2-amine

[0527] Potassium carbonate (26.21 mg, 0.19 mmol) was added to a solution of 5,6-bis(3-pyridyl)-3- (2-trimethylsilylethynyl)pyridin-2-amine (0.2 g, 0.57 mmol) in MeOH (2 mL). The reaction mixture was stirred at 25 °C for 1 hr. The reaction mixture was partitioned between Ethyl acetate / H2O:brine. After phase separation, the product was extracted with Ethyl acetate. The combined organic layers were dried and concentrated. The crude was purified by flash column chromatography on silica gel eluting with heptanes / Ethyl acetate from 100:0 to 0:100. The product fractions were combined and concentrated to yield 3-ethynyl-5,6-bis(3-pyridyl)pyridin- 2-amine (55.5 mg, 0.20mmol, 35% yield) as a brown solid. LCMS m / z: 273.100 [M+HJ+, rt.: 1.272 min.

[0528] 1H NMR: 5 8.45 (dd, J = 4.8, 1.6 Hz, 1 H), 8.41 (dd, J = 4.8, 1.6 Hz, 1 H), 8.37 (m, 1 H), 8.28 (d, J = 1.7 Hz, 1 H), 7.70 (s, 1 H), 7.61 (m, 1 H), 7.54 (m, 1 H), 7.36 - 7.23(m, 2H), 6.57 (s, 2H), 4.55 (s, 1 H).

[0529] BIOLOGICAL ACTIVITY

[0530] Methodology

[0531] Keratinocytes were isolated from surplus skin samples sourced for diagnostic purposes after obtaining patient informed consent and Ethical Committee approval (reference HULP: PI- 3911 , Hospital Universitario de la Paz, Madrid, Spain). These keratinocytes were used to generate immortalized cell lines. Immortalization resulted from the forced expression of human papillomavirus HPV16 E6 / E7 antigens (Chamorro et al 2013). Skin keratinocytes were isolated as previously described (Chamorro et al 2013). For immortalization, retroviral particles obtained from the supernatant of HEK293T cells transfected with pLXSN16E6E7, pNG-VL3- MLV-gag-pol and pNGVL3-4070 plasmids (Halbert et al 1991 , Yang et al 1999, (Chamorro et al 2013). After retroviral infection, the cells were kept in KGM medium in the presence of feeder layer and were amplified during several passages at a ratio of 1 :4 in each passage. After 18 passages, the keratinocytes were cultured in the absence of feeder layer in KGM medium.

[0532] In addition to the mutation of RDEB_L1 , one mutation previously shown to respond well to aminoglycosides (Cogan et al 2014) was recombinantly generated and stably transfected into HEK293 cells, a cell line that does not express C7, to generate HEK293R578X. For the HEK293R578Xrecombinant cell line, site directed mutagenesis was used to generate a mutated Col7A1 cDNA containing a C to T change at nucleotide 1732, resulting in a change in Arg578 to an UAG termination codon. The resulting mutated COL7A1 cDNA was then stably transfected into HEK293 cells after verifying the absence of expression of COL7A1 in this cell line. Zeocin was used as selection antibiotic to obtain the stably transfected clones which were selected by limiting dilution.

[0533] RDEB_L1 and HEK293R578Xcell lines were characterized using western blot and an antibodybased AlphaLISA assay recognizing the N-terminal part of C7 (amino acids 36-153) within the non-collagenous 1 domain (NC1 ), spanning amino acids 17-1253 (Christiano et al 1994).

[0534] Western blot analysis allowed to qualitatively differentiate between truncated and full-length forms of C7 based on their size, while the AlphaLISA assay detected both full length and C- terminally truncated mutant forms of the protein in the patient cell lines. In both cases RDEB_L1 cells were treated with test compounds and 25 ng / mL of TGFp, a known upregulator of C7 in human keratinocytes (Konig et al 1992).

[0535] The AlphaLISA assay was developed in house by using the biotin-conjugated rabbit polyclonal antibody anti-Collagen VII (LS-298147, LSBio) and conjugating the acceptor beads (6772001 , PerkinElmer) to a monoclonal anti-Collagen type VII antibody produced in mouse, clone LH7.2 (MA5-13432, Thermo). Formulation of the mAb clone LH7.2 was exchanged to PBS and concentrated 5x by using Amicon® Ultra-0,5 centrifugal filters up to rise 1 mg / ml. The conjugation procedure was carried out according to the protocol provided by PerkinElmer.

[0536] For cell culture maintenance and AlphaLISA and Western Blot assays, RDEB patient-derived cells and NHEK were grown in complete KGMTM GoldTM (KBMTM GoldTM Basal Medium with SingleQuotsTM) excluding the GA-100, (H3192060, Cultek). For cell maintenance, the medium was removed, and cells were rinsed with Hepes Buffered Saline Solution (CC-5024, Lonza). After aspirating the HEPES, TripLE express solution (12604054, Gibco) was added to detach the cells. For neutralizing the TripLE express, Trypsin Neutralizing Solution (CC- 5002, Lonza) was added and then the cell suspension was centrifuged at 140 g for 5 minutes at room temperature, the supernatant was discarded, and the pellet was resuspended in KGM complete media, without GA-100 at desired density. HEK2935R578X, were cultured in DMEM high glucose supplemented with 10% FBS and 2mM Glutamax (61965026, Thermo Fisher). PBS was used for the rinse step and TripLE express were used to detach the cells. DMEM complete media was used for neutralizing the TripLE express and after centrifugation at 140 g for 5 minutes at room temperature, the supernatant was discarded, and cells were resuspended in DMEM complete media at working densities.

[0537] For compound treatment in RDEB_L1 keratinocytes, 5,000 cells were plated in 20pl of supplemented KGM media containing 25ng / ml TGFP2 (GF113, SIGMA) without GA-1000 in 384-well cell culture plates (781098, Greiner). The day after, 5pl of test compounds prepared 5x in supplemented KGM without GA-1000 were added over cells and incubated for 48h at 37°C and 5% CO2. For compound treatment in HEK293R578X, 10,000 cells were plated in 20pl of DMEM (High Glucose, 2mM L-Glutamine, sodium pyruvate and FBS 10%) in 384-well cell culture plates (781098, Greiner). The day after, 5pl of test compounds prepared 5x in DMEM complete medium were added over cells and incubated for 48h at 37°C and 5% CO2.

[0538] After treatment process, 2 ,5p I of RIPA buffer 10x (ab156034 Abeam) were added over the 25 pl of cells for 20 minutes at room temperature to obtain a complete cell lysis. Following, 2pl of sample (i.e., cell lysate with supernatant) were transferred to the AlphaLISA plate (6059340 PerkinElmer) containing 8pl of antibodies mixture (5pg / ml of acceptor Beads-Ab and 0,75pg / ml of biotin-rAb) prepared in AlphaLISA buffer 1x (ALOOF, PerkinElmer). The reaction was incubated for 90 minutes at room temperature. Finally, 10 pL of 80pg / ml of donor beads (6760002, PerkinElmer) were added to the reaction under subdued light, mixed gently and incubated for 3h at room temperature. AlphaLISA signal was detected with Envision microplate reader (Perkin Elmer) using the following setting: Filter: AlphaScreen, Excitation time: 180 ms, Integration time: 300 ms.

[0539] The viability of RDEB or NHEK was evaluated by measuring the ATP levels as indirect read out of the potential cytotoxicity effect of compounds. Cells were plated and treated exactly with the same conditions followed in the AlphaLISA assay, described above. For measuring the ATP levels, cells were processed using the ATPIite™ 1 step luminescence-based assay (PerkinElmer 6016731 ), following the instructions provided by the supplier. 25 pl of ATPIite™ reagent was added directly over cells and plates were covered with a sealing film and shaken for 25 min using a microtiter plate shaker. Luminescence was measured in Luminoskan Ascent luminometer (Thermo Fisher Scientific). 10pM of Staurosporine was used as reference compound and control for the total cytotoxicity.

[0540] For the immunofluorescence analysis RDEB keratinocytes or normal human epidermal keratinocytes were plated in 96-well High Content Imaging microplate (Corning 4517) at 10,000 cells per well in 80pl of supplemented KGM media without GA-1000, media used for RDEB also was supplemented with 25ng / ml of TGF02 (TGF0), and cells were incubated at 37°C and 5%CO2. The day after, 20 pl of test compounds prepared 5x in supplemented KGM without GA-100 were added and incubated for 48h at 37°C and 5%CO2. Cells were permeabilized aspirating the media and adding 50pl of 100% ice-cold methanol for 15 minutes at 4°C. Afterwards, cells were washed three times in PBS and blocking step was carried out adding 10OpI of blocking buffer (PBS, 5% serum goat and 0.3% Triton X-100) and incubating 1 h at room temperature. Blocking buffer was aspirated and 50ul of 3pg / ml of primary antibody anti-collagen type VII (HPA042420, SIGMA) diluted in diluent buffer (PBS, 1 % BSA and 0.3% Triton X-100) was added and incubated for 2h at room temperature. After washing the cells for three times in PBS, 50ul of 10pg / ml of goat anti-rabbit IgG secondary antibody, Alexa Fluor™ 555 conjugated (A-21428, Thermo) prepared in diluent buffer were added and incubated for 1 h at room temperature. For the nuclei staining, 5.5pl of a 10X solution of Hoechst 33342 prepared in PBS was added and was incubated during the lasts 15 minutes of secondary antibody incubation. Finally, cells were washed with PBS, leading 50pl of PBS in the plate. Images were taken in EVOS M7000 multi-channel fluorescence and transmitted light imaging system and the imaging analysis was performed using the CELLeste software. Collagen VII was monitored analyzing the total region intensity red and cell counting was monitored by object counting in the DAPI channel. For real-time qPCR, 15,000 RDEB keratinocytes or normal human epidermal keratinocytes were plated in 96-well cell culture plate in 80 pl of supplemented KGM media without GA-1000, and containing 25ng / ml of TGF02 for RDEB keratinocytes, and cells were incubated overnight at 37°C and 5%CO2. The day after, cells were treated with 20 l of test compounds prepared 5x in supplemented KGM without GA-100, for 24h at 37°C and 5%CO2. For the mRNA extraction, medium was removed, cells were washed with PBS and conserved at -80°C until the total RNA extraction. RNA extraction was conducted using the RNeasy 96 Kit (4) (74181 , Qiagen) and following the instructions provided by QIAGEN. Total RNA was recovered in 50 pL of RNase-free water and the yield of extracted RNA was quantified using a NanoDrop 2000 Spectrophotometer (ThermoFisher). Purified RNA was stored at -80°C until RT-qPCR. Real time-qPCR was performed by using the iTaq Universal Probes One-Step Kit, (1725140, BioRad) and according to the manufacturer’s instructions. RTqPCR were run in QuantStudio™ Real-Time PCR System (Applied Biosystems) or in CFX96 Touch Real-Time PCR Detection System (BioRad) for 384 or 96 well format respectively. For synthesis of cDNA qPCR reactions, COL7A1 (Hs00164310_m1 ) or a GAPDH (Hs02758991_g1 ) TaqMan™ probe (Thermo Fisher Scientific) were used. RT-qPCR was performed to quantify the COL7A1 mRNA (exon 64) expression. For COL7A1 quantitative gene expression, human GAPDH was used as the endogenous control. Results were analyzed with the QuantStudio Real-Time PCR Software.

[0541] General selectivity was evaluated at Eurofins Pharma Discovery Services

[0542] Results

[0543] 1. Generation of C7 deficient RDEB patient-derived (RDEB_L1) and HEK293R578Xrecombinant cell lines and characterization using reference readthrough aminoglycosides

[0544] Patient derived RDEB_L1 transformed keratinocytes and the recombinant HEK293R578cell line were generated as described in the methodology section and characterized using AlphaLISA and western blot. Patient-derived transformed cell line RDEB_L1 , containing a bi- allelic PTC mutation in exon 72 was selected based on its response to aminoglycosides G418 and gentamicin.

[0545] In the AlphaLISA assay in RDEB_L1 and HEK293R578Xcells, G418 showed more potent activity than gentamicin with an EC50 around 3 orders of magnitude lower than gentamicin (Figs. 1 a, 1 b). In the western blot, G418 upregulated full length and truncated C7 in RDEB_L1 and HEK293R578Xcells (Figs 1 c, 1d). Gentamicin showed upregulation of full length C7 and truncated C7 at concentrations of 2.09 and 4.18 mM in RDEB_L1 (Fig 5c) and in HEK293R578Xcells at a concentration of 4.18 mM (Fig 1 c).

[0546] In the patient-derived and recombinant cells, the size of the truncated C7 products detected in the western blot was compatible with their predicted molecular weights, based on the location of the PTC mutations (Fig 1c, d): 202 kD (RDEB_L1 ) and 62 kD (HEK293R578X).

[0547] 2. Identification and characterization of compounds inducing expression of truncated and full length C7 in patient-derived and recombinant cell lines

[0548] A library of compounds was evaluated at 25 pM in RDEB_L1 cells, a concentration intended to capture hits with a potency comparable to the relatively potent reference aminoglycoside molecule G418 (EC50 4.9 pM) and more potent than the reference drug gentamicin (EC50 1.7 mM) (Table 1 ).

[0549] Detection of total C7 protein using AlphaLISA was used as a gain of signal readout. This had the advantage of minimizing the possibility to identify hits with cytotoxic properties, as cytotoxicity or reduced viability would be expected to have an impact in the cell translational machinery, precluding the expression of C7. Following a primary screen, the activity of the hits was confirmed again by AlphaLISA and their potential interference was verified testing their activity in the same assay in the absence of cells.

[0550] The compounds in Table 1 showed an increase in C7 levels in RDEB_L1 cells. Relative EC50 and Emax are shown as arithmetic mean ± standard deviation (SD). Viability was measured using ATP levels in normal human keratinocytes (NHK), RDEB_L1 patient-derived cells and the HEK293R578Xrecombinant cell line.

[0551] Evaluation of compounds in patient-derived keratinocyte RDEB_L1 and HEK293R578Xcells indicated that, while EXAMPLE 7 and EXAMPLE 8 were active in both cell lines, EXAMPLE 1 and EXAMPLE 2 were only active in the donor-derived cells but not in the recombinant HEK293R578Xcell line (Table 1 , Figure 2a). In this cell line, the expression of mutated COL7A1 mRNA is driven by a CMV promoter and not by the natural COL7A1 promoter which indicated that this promoter, or some other factor not present in HEK293R578X, was required for the response to EXAMPLE 1 and EXAMPLE 2, suggesting a different mode of action of these compounds with respect to EXAMPLE 7 and EXAMPLE 8.

[0552] Western Blot analysis of the C7 products that were being induced by the compounds in RDEB_L1 showed that EXAMPLE 1 was only upregulating the truncated form of C7, while EXAMPLE 7 partially upregulated full length but not truncated C7, and aminoglycosides G418 and gentamicin upregulated both full length and truncated C7 (Fig 2b). As an additional assay-interference control, the activity of EXAMPLE 1 and EXAMPLE 7 was evaluated in dose response AlphaLISA assays at 2h and 48h in RDEB_L1 cells. This was intended as verification of biological activity, given that a progressive increase in C7 protein or mRNA levels over time would be expected for a biological mechanism-mediated effect, as opposed to a non-specific signal resulting from assay interference which would be already detectable at the initial short time point of 2 hours (Fig. 3).

[0553] Assessment of the levels of COL7A1 mRNA in RDEB_L1 cells in response to treatment with EXAMPLE 1 showed that TGFp was required for full upregulation (Figure 4a). The levels of truncated C7 resulting from EXAMPLE 1 treatment in the presence of TFG0 were even higher than those of full length C7 in normal human keratinocytes and were readily detectable in the cytoplasm of treated cells by immunofluorescence analysis (Fig 4b).

[0554] Table 1

[0555] 3. Effect of the combination of compounds of the present invention with aminoglycosides

[0556] The potential synergistic effect of combining gentamicin as a reference readthrough drug with EXAMPLE 1 was evaluated. A suboptimal concentration of EXAMPLE 1 and gentamicin were combined, and this resulted in a synergistic effect inducing an increase in total C7 levels detected by AlphaLISA, above what would be individually expected for each compound (Fig. 5a), and a decrease of several fold in the EC50 of EXAMPLE 1 in the presence of increasing concentrations of gentamicin (Fig 5b). Analysis of treated cells using western blot revealed that the increase in total C7 seen in the AlphaLISA assay was mostly due to upregulation of the truncated form of C7, well above what would be expected from adding the individual activity of EXAMPLE 1 and gentamicin both of which upregulated the truncated form of C7 in RDEB_L1 cells (Fig 5c).

[0557] 4. Readthrough selectivity

[0558] Selectivity of readthrough compounds vs natural stop codons (NSC) and normal codon - anticodon recognition is an important endpoint to verify selectivity of compounds. To that end the translation products of MDH-1 , a gene which has an alternative natural stop codon that can be used as an indicator of non-specific readthrough activity (Hofuis et al 2016, Crawford et al 2020) was analyzed. Analysis of MDH-1 expression in RDEB_L1 cells by western blot showed that EXAMPLE 7 did not induce non-specific readthrough above background levels under conditions where gentamicin showed non-specific readthrough activity, at concentrations 2 fold (gentamicin) and 3 fold (EXAMPLE 7) over their C7 AlphaLISA EC50 in RDEB_L1 cells (Figure 6).

[0559] 5. Selectivity panels for readthrough compounds

[0560] Additional selectivity information for readthrough compounds was obtained screening against standard selectivity panels. Activities of less than 50% inhibition at the indicated concentrations are highlighted in grey (Table 2). EXAMPLE 14 showed improved selectivity vs the main 3 targets identified in the selectivity panel evaluation (SAPK2a, A2A, BZD) (Table 2), while maintaining activity in the AlphaLISA assay (Table 1 ). Table 2

Claims

CLAIMS1 . A compound of formula [I], or a compound of formula [II], or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, for use in the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels:wherein in Formula [I]:W is -NRWRXor -ORW, wherein Rwand Rxare the same or different and are selected from hydrogen and C1-C3 alkyl;A is a phenyl, 5- to 7-membered heteroaryl or 5- to 7-membered heterocyclyl ring, which ring is optionally fused to phenyl, 5- to 7-membered heteroaryl, or 5- to 7- membered heterocyclyl ring; wherein ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R", -C1-C3 alkyl-COOH, -C1-C3 alkyl-C(O)-(C-i-C3 alkyl), -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R"; and wherein R' and R" are the same or different and are selected from hydrogen and C1-C3 alkyl;Rarepresents the group -L-Z, wherein L is a bond or C1-C3 alkylene, and Z is a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring; wherein said ring isunsubstituted or substituted with one, two or three substituents which are the same or different and are selected from C1-C4 alkyl and C1-C4 haloalkyl; n is 0, 1 or 2; and ring B is Ce-Cw carbocyclyl which is unsubstituted or substituted with one, two, or three substituents which are the same or different and are selected from -OR"', -NR'''R'V, C1-C4 alkyl and C1-C4 haloalkyl; and wherein R"' and Rivare the same or different and are selected from hydrogen and C1-C3 alkyl; and wherein in Formula [II]:W’ is -NRyRzor -ORZ, wherein Ryand Rzare the same or different and are selected from hydrogen and C1-C3 alkyl;- Y is N or CH; ring A’ is Ce-Cw aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl, wherein ring A is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from halogen, C1- C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-ORv, and -C1-C3 alkyl-NRvRvi; wherein Rvand Rviare the same or different and are selected from hydrogen and C1-C3 alkyl; and ring B’ is 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl, wherein ring B’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-ORvii, and -C1-C3 alkyl-NRviiRviii; wherein Rviiand Rviiiare the same or different and are selected from hydrogen and C1-C3 alkyl.

2. The compound for use of claim 1 , wherein the compound is a compound of Formula [I], or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

3. The compound for use of claim 1 or claim 2, wherein W is -NH2.

4. The compound for use of any one of the preceding claims, wherein ring A is phenyl or 5- to 7-membered heterocyclyl ring, which ring is optionally fused to phenyl or 5- to 7-membered heteroaryl.

5. The compound for use of any one of the preceding claims, wherein ring A is phenyl or 5- to 6-membered heterocyclyl ring, which ring is optionally fused to 5- to 6- membered heteroaryl.

6. The compound for use of any one of the preceding claims, wherein ring A is phenyl, indolyl, indazolyl, or [1 ,2,4]triazolo[4,3-a]pyridinyl.

7. The compound for use of any one of the preceding claims, wherein ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-CONR'R'', -C1-C3 alkyl-OR', and -C1-C3 alkyl-NR'R".

8. The compound for use of any one of the preceding claims, wherein ring A is unsubstituted or substituted with one substituent selected from C1-C4 alkyl, -C1-C3 alkyl-CONR'R", and -C1-C3 alkyl-OR'.

9. The compound for use of any one of the preceding claims, wherein ring A is unsubstituted or substituted with one substituent selected from propyl, -CH2-CONH2, and -CH2CH2-OH.

10. The compound for use of any one of the preceding claims, wherein Z is monocyclic 5- to 7-membered heterocyclyl or monocyclic 5- to 7-membered heteroaryl ring, wherein said ring contains one or two heteroatoms each independently selected from O and N.11 . The compound for use of any one of the preceding claims, wherein Z is unsubstituted or substituted with one substituent which is C1-C4 alkyl.

12. The compound for use of any one of the preceding claims, wherein ring B is Cs-Cw carbocyclyl.

13. The compound for use of any one of the preceding claims, wherein ring B is substituted with one substituent which is -OH.

14. The compound for use of any one of the preceding claims, wherein ring A is:or15. The compound for use of any one of the preceding claims, wherein the compound of Formula [I] is selected from:3-amino-6-[1-(2-amino-2-oxoethyl)indol-6-yl]-N-(5-hydroxy-2-adamantyl)pyrazine- 2-carboxamide, 3-amino-N-(5-hydroxy-2-adamantyl)-6-[3-(1-methylpyrazol-4-yl)-5-(morpholin-4- ylmethyl)phenyl]pyrazine-2-carboxamide,3-amino-N-(5-hydroxy-2-adamantyl)-6-[1-(2-hydroxyethyl)indazol-6-yl]pyrazine-2- carboxamide,3-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-6-[3-(1-methylpyrazol-4- yl)phenyl]pyrazine-2-carboxamide,3-amino-N-(5-hydroxy-2-adamantyl)-6-phenylpyrazine-2-carboxamide, and3-amino-N-(5-hydroxy-2-adamantyl)-6-(3-propan-2-yl-[1 ,2,4]triazolo[4,3-a]pyridin- 6-yl)pyrazine-2-carboxamide.

16. The compound for use of claim 1 , wherein the compound is a compound of Formula [II] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

17. The compound for use of claim 1 or any one of claims 3 to 16, wherein W’ is -NH2.

18. The compound for use of claim 1 or any one of claims 3 to 17, wherein ring A’ is phenyl, monocyclic 5- to 7-membered heteroaryl, or monocyclic 5- to 7-membered heterocyclyl.

19. The compound for use according to claim 1 or any one of claims 3 to 18, wherein ring A is phenyl or monocyclic 5- to 7-membered heteroaryl.

20. The compound for use according to claim 1 or any one of claims 3 to 19, wherein ring A is phenyl, furanyl, or pyrid inyl.21 . The compound for use according to claim 1 or any one of claims 3 to 20, wherein ring A is unsubstituted or substituted with one or two substituents which are the same or different and are selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl.

22. The compound for use according to claim 1 or any one of claims 3 to 21 , wherein ring A is unsubstituted or substituted with one or two substituents which are the same or different and are halogen.

23. The compound for use according to claim 1 or any one of claims 3 to 22, wherein ring A is unsubstituted or substituted with one or two substituents which are fluorine.

24. The compound for use according to claim 1 or any one of claims 3 to 23, wherein ring B’ is monocyclic 5- to 7-membered heteroaryl.

25. The compound for use according to claim 1 or any one of claims 3 to 24, wherein ring B’ is pyridinyl.

26. The compound for use according to claim 1 or any one of claims 3 to 25, wherein ring B’ is unsubstituted or substituted with one or two substituents which are the same or different and are selected from C1-C4 alkyl and C1-C4 haloalkyl.

27. The compound for use according to claim 1 or any one of claims 3 to 26, wherein ring B’ is unsubstituted or substituted with one or two substituents which are methyl.

28. The compound for use of claim 1 or any one of claims 3 to 27, wherein ring A’ is:

29. The compound for use of claim 1 or any one of claims 3 to 28, wherein the compound of Formula [II] is selected from:5-(2,6-dimethylpyridin-4-yl)-3-ethynyl-6-(3-fluorophenyl)pyridin-2-amine;6-(3,5-difluorophenyl)-3-ethynyl-5-pyridin-3-ylpyridin-2-amine;3-ethynyl-6-(3-fluorophenyl)-5-pyridin-3-ylpyridin-2-amine;3-ethynyl-5,6-dipyridin-3-ylpyridin-2-amine;3-ethynyl-6-(3-fluorophenyl)-5-pyridin-4-ylpyridin-2-amine; 3-ethynyl-6-(furan-2-yl)-5-pyridin-4-ylpyrazin-2-amine; and 3-ethynyl-6-phenyl-5-pyridin-3-ylpyridin-2-amine.

30. The compound for use according to any one of claims 1 to 29, wherein the increase of COL7 protein levels refers to the increase of full-length COL7 protein and / or truncated COL7 protein.31 . The compound for use according to any one of claims 1 to 30, wherein the pathological condition or disease is a COL7 deficiency condition or disease.

32. The compound for use according to claim 31 , wherein the COL7 deficiency condition or disease is selected from Dominant dystrophica Epidermolysis bullosa (DDEB), Recessive dystrophic epidermolysis bullosa (RDEB), Epidermolysis bullosa dystrophica pretibial, Epidermolysis bullosa pruriginosa (EBP), Nonsyndromic congenital nail disorder 8 (NDNC8), Epidermolysis bullosa dystrophica with subcorneal cleavage (EBDSC), Epidermolysis bullosa dystrophica Bart type (B-DEB), Epidermolysis bullosa dystrophica pretibial type (PR-DEB) Epidermolysis bullosa with congenital localized absence of skin and deformity of nails and Transient bullous dermolysis of the newborn (TBDN).

33. The compound for use according to claim 32, wherein the COL7 deficiency condition or disease is Recessive dystrophic epidermolysis bullosa (RDEB).

34. Use of a compound, or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, as defined in any one of claims 1 to 30, for the manufacture of a medicament for the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein level.

35. A method for treating a subject with a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels, which comprises administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof, as defined in any one of claims 1 to 30.

36. A combination product comprising (i) at least one compound or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof as defined in any one of claims 1 to 30, and (ii) one or more active ingredients having a readthrough activity.

37. The combination product of claim 36, wherein the one or more active ingredients having a readthrough activity is an aminoglycoside or a macrolide.

38. The combination product of claim 37, wherein the aminoglycoside is selected from gentamicin, G418, paromomycin, Amikacin.

39. The combination product of any one of claims 36 to 38, wherein the product is for use in the treatment of a pathological condition or disease susceptible to amelioration by increase of COL7 protein levels.

40. A compound of formula [la], or a compound of formula [Ila], or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof:wherein in Formula [la]:W, ring A, Ra, and n are as defined in any one of claims 1 to 30; and ring B is adamantyl or bicyclo[2.2.2]octanyl which is unsubstituted or substituted with one, two, or three substituents which are the same or different and areselected from -OR"', -NR'i'R' , C1-C4 alkyl and C1-C4 haloalkyl; and wherein R'" and Rivare the same or different and are selected from hydrogen and C1-C3 alkyl; and wherein in Formula [Ila]:W’ and ring A’ are as defined in any one of claims 1 to 30; and ring B’ is 5- to 7-membered heteroaryl, or 5- to 10-membered heterocyclyl, wherein ring B’ is unsubstituted or substituted with one, two or three substituents which are the same or different and are selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -C1-C3 alkyl-ORvii, and -C1-C3 alkyl-NRviiRviii; wherein Rviiand Rviiiare the same or different and are selected from hydrogen and C1-C3 alkyl; provided that the compound of Formula [la] is not:3-amino-N-(5-hydroxyadamantan-2-yl)-6-(1 H-indazol-6-yl)pyrazine-2-carboxamide;6-(3-(1 H-pyrazol-4-yl)phenyl)-3-amino-N-(5-hydroxyadamantan-2-yl)pyrazine-2- carboxamide;3-amino-6-(3-(3,5-dimethyl-1 H-pyrazol-4-yl)phenyl)-N-(5-hydroxyadamantan-2- yl)pyrazine-2-carboxamide;3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-(1-methyl-1 H-pyrazol-4- yl)phenyl)pyrazine-2-carboxamide;3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-methyl-5-(1-methyl-1 H-pyrazol-4- yl)phenyl)pyrazine-2-carboxamide;3-amino-6-(3-(1-ethyl-1 H-pyrazol-4-yl)phenyl)-N-(5-hydroxyadamantan-2-yl)pyrazine- 2-carboxamide;3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-(1-(2,2,2-trifluoroethyl)-1 H-pyrazol-4- yl)phenyl)pyrazine-2-carboxamide;3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-(1-propyl-1 H-pyrazol-4- yl)phenyl)pyrazine-2-carboxamide;3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-(1-isopropyl-1 H-pyrazol-4- yl)phenyl)pyrazine-2-carboxamide;3-amino-N-(5-hydroxyadamantan-2-yl)-6-(3-(pyridin-3-yl)phenyl)pyrazine-2- carboxamide; or3-amino-N-(5-hydroxyadamantan-2-yl)-6-(1 H-indazol-5-yl)pyrazine-2-carboxamide; or a stereoisomer derivative thereof; and provided that the compound of Formula [Ila] is not: 3-ethynyl-6-(3-fluorophenyl)-5-pyridin-4-ylpyridin-2-amine; 3-ethynyl-6-(furan-2-yl)-5-pyridin-4-ylpyrazin-2-amine;3-ethynyl-6-(furan-2-yl)-5-(pyrimidin-4-yl)pyridin-2-amine; or 3-ethynyl-5-(3-fluoropyridin-4-yl)-6-(pyridin-3-yl)pyrazin-2-amine.41 . A compound according to claim 40, wherein the compound is a compound of Formula [la] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

42. The compound according to claim 40 or claim 41 , wherein ring B is:B1 B243. A compound according to claim 40, wherein the compound is a compound of Formula [Ila] or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof.

44. The compound according to claim 40 or claim 43, wherein Y is CH.

45. The compound according to any one of claims 40, 43 and 44, wherein ring A’ is phenyl, monocyclic 6- to 7-membered heteroaryl, or monocyclic 6- to 7-membered heterocyclyl, preferably ring A is phenyl or pyridinyl .

46. The compound according to claim 40 or any one of claims 43 to 45, wherein ring A’ is: 'and ring B’ is:

47. The compound according to any one of claims 40 to 42, wherein the compound of Formula [la] is selected from:3-amino-6-[1-(2-amino-2-oxoethyl)indol-6-yl]-N-(5-hydroxy-2-adamantyl)pyrazine- 2-carboxamide,3-amino-N-(5-hydroxy-2-adamantyl)-6-[3-(1-methylpyrazol-4-yl)-5-(morpholin-4- ylmethyl)phenyl]pyrazine-2-carboxamide,3-amino-N-(5-hydroxy-2-adamantyl)-6-[1-(2-hydroxyethyl)indazol-6-yl]pyrazine-2- carboxamide,3-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-6-[3-(1-methylpyrazol-4- yl)phenyl]pyrazine-2-carboxamide,3-amino-N-(5-hydroxy-2-adamantyl)-6-phenylpyrazine-2-carboxamide, and3-amino-N-(5-hydroxy-2-adamantyl)-6-(3-propan-2-yl-[1 ,2,4]triazolo[4,3-a]pyridin- 6-yl)pyrazine-2-carboxamide.

48. The compound according to claim 40 or any one of claims 43 to 46, wherein the compound of Formula [Ila] is selected from:5-(2,6-dimethylpyridin-4-yl)-3-ethynyl-6-(3-fluorophenyl)pyridin-2-amine;6-(3,5-difluorophenyl)-3-ethynyl-5-pyridin-3-ylpyridin-2-amine;3-ethynyl-6-(3-fluorophenyl)-5-pyridin-3-ylpyridin-2-amine;3-ethynyl-5,6-dipyridin-3-ylpyridin-2-amine; and 3-ethynyl-6-phenyl-5-pyridin-3-ylpyridin-2-amine.

49. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof as defined in any one of claims 40 to 48, in combination with a pharmaceutically acceptable diluent or carrier.

0. The compound or a pharmaceutically acceptable salt, or a solvate, or a A / -oxide, or a tautomer, or a stereoisomer, or an isotopically-labelled derivative thereof according to any one of claims 40 to 48, or the pharmaceutical composition according to claim 49, for use as a medicament.

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