AU2014201789B2 - N-containing heteroaryl derivatives as JAK3 kinase inhibitors - Google Patents

Abstract

N-CONTAINING HETEROARYL DERIVATIVES AS JAK3 KINASE INHIBITORS Abstract >x N R, N-containing heteroaryl derivatives of formula I or II, wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as JAK, particularly JAK3, kinase inhibitors.

Description

1 N-containing heteroaryl derivatives as JAK3 kinase inhibitors Field of the invention The present invention relates to a new series of N-containing heteroaryl derivatives, as well as to processes for their preparation, to pharmaceutical compositions comprising them and to their use in therapy. Background of the invention The Janus kinases (JAKs) are cytoplasmic protein tyrosine kinases that play pivotal roles in pathways that modulate cellular functions in the lympho-hematopoietic system that are critical for cell proliferation and cell survival. JAKs are involved in the initiation of cytokine-triggered signaling events by activating through tyrosine phosphorylation the signal transducers and activators of transcription (STAT) proteins. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as transplant rejection and autoimmune diseases, as well as in solid and hematologic malignancies such as leukemias and lymphomas and in myeloproliferative disorders, and has thus emerged as an interesting target for drug intervention, Four members of the JAK family have been identified so far: JAK1, JAK2, JAK3 and Tyk2. Unlike JAK1, JAK2 and Tyk2, whose expression is ubiquitous, JAK3 is mainly found in hematopoietic cells. JAK3 is associated in a non-covalent manner with the yc subunit of the receptors of IL-2, IL-4, IL-7, IL-9, IL-I3 and IL-15. These cytokines play an important role in the proliferation and differentiation of T lymphocytes. JAK3-deficient mouse T cells do not respond to IL-2. This cytokine is fundamental in the regulation of T lymphocytes. In this regard, it is known that antibodies directed against the IL-2 receptor are able to prevent transplant rejection. In patients with X severe combined immunodeficiency (X-SCID), very low levels of JAK3 expression as well as genetic defects in the yc subunit of the receptor have been identified, which indicates that immunosuppression is a consequence of an 5 alteration in the JAK3 signaling pathway. Animal studies have suggested that JAK3 not only plays a critical role in T and B lymphocyte maturation, but also that JAK3 is required to maintain lymphocyte function. Modulation of the immunological activity through this new mechanism can prove useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases. 0 JAK3 has also been shown to play an important role in mast cells, because antigen-induced degranulation and mediator release have been found to be substantially reduced in mast cells from JAK3 deficient mice. JAK3 deficiency does not affect mast cell proliferation nor IgE receptor expression levels. On the other hand, JAK3-/- and JAK3+/+ mast cells contain the same intracellular mediators. Therefore, JAK3 appears to be essential in the IgE induced release of mediators in mast cells and its inhibition would be, thus, an effective treatment for allergic 5 reactions. In conclusion, JAK3 kinase inhibitors have been recognised as a new class of effective immunosuppressive agents useful for transplant rejection prevention and in the treatment of immune, autoimmune, inflammatory and 2 proliferative diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, systemic lupus erythematosus, type I diabetes and complications from diabetes, allergic reactions and leukemia (see e.g. O'Shea J.J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic-Cvrije M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Cetkovic-Cvrije M. et a[, Arch, Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82). 5 Accordingly, it would be desirable to provide novel compounds that are capable of inhibiting JAK/STAT signaling pathways, and in particular which are capable of inhibiting JAK3 activity, and which are good drug candidates. Compounds should exhibit good activity in in vitro and in vivo pharmacological assays, good oral absorption when administered by the oral route, as well as be metabolically stable and exhibit a favourable pharmacokinetic profile. Moreover, compounds should not be toxic and exhibit few side effects. 0 Description of the invention One aspect of the invention relates to a compound of formula I or Il N N Ao AU N BN N BN R2 R 4

R

2 0 WA N N > R5 R5 R6 5 wherein A is carbon and B is nitrogen, or A is nitrogen and B is carbon; W is CH or N; R, and R 2 independently are hydrogen, C 1 -alkyl, haloC 4 alkyl, hydroxyCialkyl, cyanoC4alkyl, Ci 4 alkoxyCI- 4 alkyl, halogen, -CN, -OR 6 or -SRs; . R 3 is C 14 aikyl, R 9 -Ct4alkyl, Cy1 or Cy 2 -Ctzalkyl, wherein Cy 1 and Cy 2 are optionally substituted with one or more Rio;

R

4 is hydrogen, C 1

.

4 alkyl, haloC.

4 alkyl, C>4alkoxyCL 4 alky, hydroxyC,- 4 alkyl, cyanoC.4alkyl, Ri2R 7 N-Czalkyl, R 3 CONR-Co.

4 alkyl, R 1 sR7NCO-C 0

.

4 alkyl, R 12

R

7

NCONR

7 -Co.

4 alky. RsCO 2

NR-C

4 alkyl,

R.,SO

2 NR-Co 4 aIkyl, -OR 12 or Cy2-CC4alkyl; wherein Cy 2 is optionally substituted with one or more Ru; 5 Rs is hydrogen, C> 4 alkyl, haloC 14 alkyl, C>4alkoxyC>ualky, hydroxyC 14 alkyl, cyanoCu-alkyl, halogen, -CN,

-OR

12 , -NR 7

RI

2 , or Cy 2 -Coalkyl, wherein Cy 2 is optionally substituted with one or more R 1 1 ; Re is hydrogen, Cu 4 alkyl, Cl 4 alkoxyC.4alkyl, hydroxyCu4alkyl, Ri 2

R

2 N-Ctalkyl, RWCO-CO.4alkyl. R1SCO2-Coalkyl, R 16

CO-O-C

14 alkyl, cyanoC 1 4alkyl, Cy 1 or Cy 2 -Cl.

4 alkyl, wherein Cy1 and Cy 2 are optionally substituted with one or more R 1 ; 0 R 7 is hydrogen or C> 4 alkyl; R9is hydrogen, C 1 ,aikyl, haloC 1 alky, hydroxyCu 4 alkyl, or C4alkoxyCialky; 3 R9 is halogen, -CN, -CONR 7

R

2 , -COR 2 , -C0 2 R, -OR! 2 , -OCONRR 2 , -SO2R3, -S0 2

NR

7 Ri 2 , -NR7Rl 2 ,

-NR

7 CORn -NR 7 CONR7RI2, -NR 7

CO

2

R

3 or -NR 7

SO

2

R

3 ; Rio is CO4alkyl or R 2 Co- 4 alkyl;

R

1 is C4alkyl, haloO 1 Aalkyl, C 4 alkoxyClialkyl, hydroxyC 4 alkyl, cyanoCitalkyl, halogen, -CN,

-CONR

7

RI

4 , -COR 14 , -CO 2 Rj -OR 14 , -OCONR 7

R

1 4, -SO2Ri, -S0 2

NR

7 RI4, -NR 2 R1L, -NR 7

COR

14

-NR

7

CONR

7 Rl 4 , -NR 7

CO

2 Rm or -NR 7 S0 2

R

6 ; R1 2 is hydrogen or R13

R

12 is Ctalkyl, haloC4alkyl, Cl4alkoxyC'4alkyl, hydroxyC4alkyl, cyanoC4alkyl, CyrCcalkyl or R 1 4

R

7

N

C

4 alkyl; wherein Cy2is optionally substituted with one or more R, 1 ; Ru is hydrogen or R, 5 ;

R

1 5 is C 1 .alkyl, haioCl 4 alkyl, C 4 alkoxyCAalkyl, hydroxyCalkyl or cyanoC4alkyl;

R

1 6 is Cu4alkyl, haloCI 4 alkyl, C- 4 alkoxyC1alkyl or cyanoO 1 4alkyl; Cy1 is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently 5 selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and Cy2 is a 3- to 7-membered monocyclic or 6- to 1 1-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C or N atom, D and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or S02 The compounds of formula I or 1i are JAK, particularly JAK3, kinase inhibitors and therefore can be useful for the treatment or prevention of any disease mediated by JAKs, and particularly JAK3. Thus, another aspect of the invention relates to a compound of formula I or 11 N N N N \ N N R2 R 4

R

2 W 0 W N W N R5 R5 R6 5 wherein A is carbon and B is nitrogen, or A is nitrogen and B is carbon; W is CH or N;

R

1 and R 2 independently are hydrogen, Cl4alkyl, haloC4alkyl, hydroxyCl4alkyl, cyanoOl4alkyl, CIalkoxyC 4 alkyl, halogen, -CN, -OR 8 or -SR;

R

2 is C 4 aikyl, R 9 CI-alkyl, Cy, or Cy 2 -C4alkyl, wherein Cy1 and Cy2 are optionally substituted with one or more Rio; 4

R

4 is hydrogen, C 4 alkyl, haloC>alkyl, C> 4 alkoxyC 4 alkyl, hydroxy~l4alkyl, cyanoCl4alkyl, R12R 7 N-Cc-4alkyl, R 1 3 CONR-Coaikyl, R 3

R

7 NO-CC4alkyl, R 1 2

R

7 NCON R 7 -Co 4 alkyl, RuC0 2

NR

7

-CO

4 alkyl,

R,

3

SO

2

NR

7 -Co 4 alkyl, -OR 2 or Cy 2 -Co 4 alkyl; wherein Cy2 is optionally substituted with one or more R 1 ;

R

5 is hydrogen, C.4alkyl, haloCui 4 alkyl, C 4 alkoxyC 1 4alkyl, hydroxyC 1 4 alkyl, cyanoC4alkyl, halogen, -CN

-OR

12 , -NR 7

R

2 , or Cy 2

-C

4 alkyl, wherein Cy2 is optionally substituted with one or more R1 1 ;

R

6 is hydrogen, C4alkyl, C 4 alkoxyCalky, hydroxyC 1 4alkyl, R, 2

R

7 N-C1Aalkyl, R16CO-CoAalkyl,

R

16

CO

2 -Cohalkyl, R 1

CO-O-C

4 alkyl, cyanoC, 4 alkyl, Cy1 or CyrCi4alkyl, wherein Cy, and Cy2 are optionally substituted with one or more R1; R7 is hydrogen or Cp 4 alkyl; ) Reis hydrogen, C 4 alkyl, haloCOIalkyl, hydroxyO.alky, or C4alkoxyCulalkyl; R9 is halogen, -CN, -CONR 7

R

12 , -CORi, -CO2Ra, -OR 12 , -OCONR7R 12 , -S02R, -SO 2

NR

7

R

2 -NR7R 12 ,

-NR

7 0OR 12 , -NR 7

CONR

7

R

2 , -NR 7 C0 2

R

1 3 or -NR 7

SO

2

RI

3 ;

R

1 2 is C 14 alkyi or R 9 -CcAalkyl; R is C 4 alkyl, haloCb 4 alkyl, C 14 alkoxyC 14 alkyl, hydroxyC4alkyl, cyanoCl4alkyl, halogen, -CN,

-CONR

7

R

14 , -COR 4 , -CO2R,, -OR 14 , -OCONR 7

R

14 , -SO 2 R6, -SO2NR7Rm. -NR 7

R

4 , -NR 7

COR

14

-NR

7

CONR

7

R

4 , -NR 7

CO

2

R

1 6 or -NR7SO 2 Ri 6 ;

R

2 is hydrogen or R 13 Ri 2 is CIalkyl, haloC4alkyl C p 4 alkoxyCl- 4 alkyl, hydroxyC i4alkyl, cyanoCu 4 alkyl, Cy2-Co4alkyl or R 14

R

7

N

C

4 alkyl; wherein Cy2is optionally substituted with one or more R1; J R4 is hydrogen or R 1 s;

R

1 5 is C 14 alkyl, haloClaalkyl, ON 4 alkoxyCI 4 alkyl, hydroxyC 1 4alkyl or cyanoC 1 4alkyl;

R

1 6 is C 4 alkyl, haloC4alkyl, C 4 alkoxyC 4 alkyl or cyanoC 4 alkyl; Cy1 is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently 5 selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and Cy2 is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C or N atom, 0 and wherein one or more C or S ring atoms are optionally oxidized forming 00, SO or S02; for use in therapy. Another aspect of the invention relates to a pharmaceutical composition which comprises a compound of formula I or i or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Another aspect of the present invention relates to the use of a compound of formula I or 11 or a 5 pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3, is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, 5 neurodegenerative diseases, or proliferative disorders. in a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is selected from transplant rejection or immune, autoimmune or inflammatory diseases, In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disorder. Another aspect of the present invention relates to the use of a compound of formula I or Il or a 5 pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders, in a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases, In a further preferred embodiment, the disease is a proliferative disorder. 3 Another aspect of the present invention relates to the use of a compound of formula I or If or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type i diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and 5 allergic complications associated with leukemias and lymphomas. Another aspect of the present invention relates to a compound of formula I or i or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3, is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders. In 3 a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is selected from transplant rejection or immune, autoimmune or inflammatory diseases, In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disorder. Another aspect of the present invention relates to a compound of formula I or I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of at least one disease selected from transplant 5 rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders, in a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases, in a further preferred embodiment, the disease is a proliferative disorder. Another aspect of the present invention relates to a compound of formula I or |I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from transplant rejection, 0 rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas. Another aspect of the present invention relates to the use of a compound of formula I or If or a 5 pharmaceutically acceptable salt thereof for the treatment or prevention of a disease mediated by JAKs, particularly JAK3. More preferably, the disease mediated by JAKs, particularly JAK3, is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative 6 disorders. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disorder. Another aspect of the present invention relates to the use of a compound of formula I or II or a 5 pharmaceutically acceptable salt thereof for the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders, In a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease is a proliferative disorder. Another aspect of the present invention relates to the use of a compound of formula I or II or a ) pharmaceutically acceptable salt thereof for the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas. 5 Another aspect of the present invention relates to a method of treating or preventing a disease mediated by JAKs, particularly JAK3, in a subject in need thereof, especially a human being, which comprises administering to said subject an amount of a compound of formula I or 11 or a pharmaceutically acceptable salt thereof effective to treat said disease. More preferably, the disease mediated by JAKs, particularly JAK3, is at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or D proliferative disorders. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease mediated by JAKs, particularly JAK3, is a proliferative disorder, Another aspect of the present invention relates to a method of treating or preventing at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or 5 proliferative disorders in a subject in need thereof, especially a human being, which comprises administering to said subject an amount of a compound of formula I or 11 or a pharmaceutically acceptable salt thereof effective to treat said disease, in a preferred embodiment, the disease is selected from transplant rejection or immune, autoimmune or inflammatory diseases. In a further preferred embodiment, the disease is a proliferative disorder. Another aspect of the present invention relates to a method of treating or preventing a disease selected 0 from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, inflamamtory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas in a subject in need thereof especially a human being, which comprises administering to said subject an amount of a compound of formula I or i or a pharmaceutically 5 acceptable salt thereof effective to treat said disease, Another aspect of the present invention relates to a process for the preparation of a compound of formula I or Il as defined above, which comprises: 7 (a) for a compound of formula 1, reacting a compound of formula VI with a compound of formula III

H

2 N 5

R

3 N \N H N N R 4 -NCS

R

2 VI III wherein A, B, W, R1, R 2 , R 3

R

4 and R 5 have the meaning previously described in relation with a compound of formula I or I; or 5 (b) for a compound of formula I, reacting a compound of formula VI with a compound of formula IV

H

2 N R 5

R

3 N / w H N SQ N

R

4 -CHO > A

R

1 v1 Iv wherein A, B, W, R 1 ,, R 2 , R3 R 4 and Rs have the meaning previously described in relation with a compound of formula I or II; or (c) when in a compound of formula I RE is hydrogen (a compound of formula Ila), reacting a compound of 0 formula VL as defined above, with a synthetic equivalent for the CO synthon. H I R 5 N N R N 9 A N R 2 Ila wherein A, B, W, R 1 , R, R and R6 have the meaning previously described in relation with a compound of formula i or 1l; or 8 (d) when in a compound of formula 11 R 6 is other than hydrogen, reacting a compound of formula [Ia with a compound of formula V (R 6 -X) in the presence of a base, wherein X is a leaving group; or (e) converting, in one or a plurality of steps, a compound of formula I or 11 into another compound of formula I or 11. 3 In the above definitions, the term C1s alkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 5 carbon atoms and includes among others the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and iso-pentyl. Likewise, the term C-A alkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 4 carbon atoms and includes the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. ) A Ci 4 alkoxy group, as a group or part of a group, means a group of formula -OC,4akyl, wherein the C 4 alkyl moiety has the same meaning as previously described. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. A C-4alkoxyC%4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Cvalkyl group with one or more CQalkoxy groups as defined above, which can be the same or different, 5 Examples include, among others, the groups methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethy, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, dimethoxymethyl, 1 -methoxyethyl, 2 methoxyethyl, 2-ethoxyethyl, 1,2-diethoxyethy, 1-butoxyethyl, 2-sec-butoxyethyl, 3-methoxypropyl, 2-butoxypropyl, 1-methoxy-2-ethoxypropyl, 3-tert-butoxypropyl and 4-methoxybutyl. Halogen or its abbreviation halo means fluoro, chloro, bromo or iodo. A haloCalkyl group means a group resulting from the replacement of one or more hydrogen atoms from a 0 14 alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different. Examples include, among others, the groups trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1 fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifiuoroethyl, pentafluoroethyl, 3-fluoropropyl, 3 chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl, nonafluorobutyl, 5 1-chloro-2-fluoroethyl and 2-bromo-I-chloro-1-fluoropropyl. A hydroxyCl4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C 14 alkyl group with one or more hydroxy groups. Examples include, among others, the groups hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl and 1-hydroxybutylt 0 A cyanoO 1 .alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Cl4alkyl group with one or more cyano groups. Examples include, among others, the groups cyanomethyl, dicyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropy. 2,3-dicyanopropyl and 4-cyanobutyl. A haloCizalkoxy group means a group resulting from the replacement of one or more hydrogen atoms from a C1_ alkoxy group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo) which can be the same or 5 different. Examples include, among others, the groups trifluoromethoxy, fluoromethoxy, 1-chloroethoxy, 2 chloroethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 9 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4 fluorobutoxy, nonafluorobutoxy, 1-chloro-2-fluoroethoxy and 2-bromo-1-chloro-1-fluoropropoxy, The term Co alkyl indicates that the alkyl group is absent. Thus, the term RCo.

4 alkyl includes R 9 and R-C> 4 alkyl. The term R-C1 4 alkyl relates to a group resulting from the substitution of one hydrogen atom of a C14alkyl group with one R 9 group. The terms R, 2

R

7 N-Co 4 alkyl, RisCONRr-C- 4 alkyl, RiR7NCO-Co.

4 alkyl, R1 2

R

7

NCONR

7 -Co 4 alky, RiaCO2NR7 Co.4alkyl, R13S02NR-Cw.alkyl, R 16 CO-Co 4 alkyl and RiCO2-Co4alkyl include -NR7R 2 and RVR7N-Cl.

4 alkyl, NR 7 COR1 3 and R13CONR 7

-C-

4 alkyl, -CONR 7 R3 and RnR7NCO-C-4alkyl, -NR 7

CONR

7

R

2 and R 12

R

7

NCONR

7 -C. 4 alkyl, -NR 7 C0 2

R

12 and R 13

CO

2

NR

7 -C>4alkyl, -NR 7

SO

2

R

1 3 and R13SO2NR-C1 4 alkyl, -COR1 6 and R 1 sCO-C 1

.

4 alkyl, and -C0 2

R

1 and R 1

CO

2

-C

1

-

4 alkyl, respectively. A group R 12

R

7

N-C

1

-

4 alkyl, Rl4R7N-C 14 alkyl, R13CONR 7 -C1 4 alkyl, Ri3R7NCO-Ciialkyl, R 12

R

7

NCONR

7 -C, 4alkyl, R 1 3CO 2

NR

7

-C

4 alkyl, R13SO2NR7C 4 alkyl, R16CO-C 14 alkyl, ReCOo-Ct.

4 alkyl or RisCO-0-Ci 4 alkyl means a group resulting from the replacement of one hydrogen atom from a C 1

-

4 alkyl group with one -NR 7

R

12 , -NR 7

R

1 4 , NR 7

COR

1 3, -CONR 7

R

1 3, -NR7CONR7Ro -NR 7

CO

2

R

1 3 -NR 7 S0 2

R

1 3 , -CORi, -CO2R6 or -OCOR 1 6 group, 5 respectively. A Cy1 group refers to a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic carbocyclic or heterocyclic ring, which is saturated, partially unsaturated or aromatic. When heterocyclic, it contains from 1 to 4 heteroatoms independently selected from N, S and 0. Bicyclic rings are formed either by two rings fused through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridged ring, or else they are formed by two rings bonded through a single common C atom forming a spiro ring. Cy1 is bonded to the rest of the molecule through any available C atom. When Cy1 is saturated or partially unsaturated, one or more C or S atoms of said ring are optionally oxidized forming CO, SO or SO 2 groups. Cyi is optionally substituted as disclosed above in the definition of a compound of formula I or II, said substituents can be the same or different and can be placed on any available position of the ring system. 5 A Cy2 group refers to a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic carbocyclic or heterocyclic ring, which is saturated, partially unsaturated or aromatic. When heterocyclic, it contains from 1 to 4 heteroatoms independently selected from N, S and 0. Bicyclic rings are formed either by two rings fused through two adjacent C or N atoms, or through two non-adjacent C or N atoms forming a bridged ring, or else they are formed by two rings bonded through a single common C atom forming a spiro ring. Cy2 is bonded to the rest of the molecule 0 through any available C or N atom. When Cy2 is saturated or partially unsaturated, one or more C or S atoms of said ring are optionally oxidized forming CO, SO or SO2 groups. Cy2 is optionally substituted as disclosed above in the definition of a compound of formula I or I, said substituents can be the same or different and can be placed on any available position of the ring system. Examples of either Cy1 or Cy2 include, among others, cyciopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5 cycloheptyl, azetidinyl, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidiny, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorphoinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, homopiperidinyl, oxazinyl. oxazolinyl, pyrrolinyl, thiazolinyl, 10 pyrazolinyl, imidazolinyl, isoxazoiinyl, isothiazolinyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4-oxo-piperidinyl, 2-oxo piperazinyl, 2-oxo-1,2-dihydropyridinyl, 2-oxo-1,2-dihydropyrazinyl, 2-oxo-1,2-dihydropyrimidinyl, 3-oxo-2,3 dihydropyridazyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazoly, 1,2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4 thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzooxazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, cinoiinyl, naphthyridinyl, indazolyl, imidazopyridinyl, pyrrolopyridinyl, thienopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyrazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, benzo[1,3)dioxolyl, phtaimidyl, 1-oxo-1,3-dihydroisobenzofuranyl, 1,3-dioxo-1,3-dihydroisobenzofuranyl, 2-oxo-2,3-dihydro-1H-indolyt. ) 1-oxo-2,3-dihydro-1H-isoindolyl, chromanyl, perhydroquinolinyl, 1-oxo-perhydroisoquinolinyl, I-oxo-1.2 dihydroisoquinolinyl, 4-oxo-3,4-dihydroquinazoliny, 2-aza-bicyclo[2.2.1]heptanyl, 5-aza-bicyclo[2,1.1]hexanyl, 2H spiro[benzofuran-3,4'-piperidinyl], 3H-spiro[isobenzofuran-1, 4-piperidinyl], 1-oxo-2,8-diazaspiro[4.5]decanyl and 1 oxo-2,7-diazaspiro[4.5]decanyl. When in the definitions used throughout the present specification for cyclic groups the examples given refer 5 to a radical of a ring in general terms, for example piperidiny, tetrahydropyranyl or indolyl, all the available bonding positions are included, unless a limitation is indicated in the corresponding definition for said cyclic group, for example that the ring is bonded through a C atom in Cys, in which case such limitation applies. Thus for example, in the definitions of Cy 2 , which do not include any limitation regarding the bonding position, the term piperidinyl includes 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl; tetrahydropyranyl includes 2-tetrahydropyranyl, 3 D tetrahydropyranyl and 4-tetrahydropyranyl; and indolyl includes 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6 indolyl and 7-indolyL In the above definitions of Cy and Cy2, when the examples listed refer to a bicycle in general terms, all possible dispositions of the atoms are included. Thus, for example, the term pyrazolopyridiny includes groups such as 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[1,5-ajpyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-c}pyridiny 5 and 1H-pyrazolo[4,3-b]pyridiny, the term imidazopyrazinyl includes groups such as 1H-imidazo[4,5-bpyrazinyl, imidazo[1,2-a]pyrazinyl and imidazo[1,5-a)pyraziny and the term pyrazolopyrimidinyl includes groups such as 1H pyrazolo[3,4-d]pyrmidinyl, 1H-pyrazolot4,3-d]pyrimidiny, pyrazolo[1,5-a]pyrimidinyl and pyrazolo(1,5-c]pynmidinyl. The term Y 2

-CO

4 alkyl includes Cy2 and 0y-C 4 alkyl. A Cy 2

-C

1 -alkyl group means a group resulting from the replacement of one hydrogen atom from a C>4alkyl 0 group with one Cy2 group. Examples include, among others, the groups (piperidiny-4-yl)methyl, 2-(piperidinyl-4 yl)ethyl, 3-(piperid inyl-4-yl) propyl, 4-(piperid inyl-4-yl)butyl, (tetrahydropyran-4-yl)methyl, 2-(tetrahydropyran-4-yl)ethyl, 3-(tetrahydropyran-4-yl)propyl, 4-(tetrahyd ropyran-4-yl)butyl, benzyl, phenethyl, 3-phenyipropyl, 4-phenylbutyl, (indolinyl-1-yl)methyl, 2-(indolinyl-1-yl)ethyl, 3-(indolinyl-1-yl)propyl and 4-(indolinyl-1-yl)butyL In the definition of a compound of formula I or 11, either A is carbon and B is nitrogen, or A is nitrogen and B 5 is carbon. Thus, the compounds of formula I or 11 include the following types of compounds: 11 R3 RR N N NN N R I R 4

R

2 0 - v>v- W> W N W N R R R N N /1 RR, KI

R

5

R

6 The expression "optionally substituted with one or more" means that a group can be substituted with one or more, preferably with 1, 2, 3 or 4 substituents, more preferably with 1, 2 or 3 substituents, and still more preferably with 1 or 2 substituents, provided that said group has enough positions susceptible of being substituted. The 5 substituents can be the same or different and are placed on any available position. In certain embodiments of Cy, mentioned below, a nitrogen atom that can be substituted means a nitrogen atom that has a hydrogen substituent. Throughout the present specification, by the term "treatment" is meant eliminating, reducing or ameliorating the cause or the effects of a disease. For purposes of this invention treatment includes, but is not limited to, D alleviation, amelioration or elimination of one or more symptoms of the disease; diminishment of the extent of the disease; stabilized (i.e. not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission of the disease (whether partial or total). As used herein, "prevention" refers to preventing the occurrence of a disease in a subject that is predisposed to or has risk factors but does not yet display symptoms of the disease. Prevention includes also 5 preventing the recurrence of a disease in a subject that has previously suffered said disease. Any formula given herein is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, 0 phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, C, 13C, 143, 5 N, 17, 31,p 32p 35s, ' 8 F, 36C, and 2l, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with 14), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 1 8 F or 110 labeled compound may be particularly 5 preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by 12 carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. In addition to the unlabeled form, all isotopically labeled forms of the compounds of formula I and Il are included within the scope of the invention. Any formula given herein is also intended to represent the corresponding tautomers forms. "Tautomer" refers to alternate forms of a molecule that differ in the position of a proton. Examples include, among others, enol keto and imine-enamine tautomers, and the tautomeric forms of heteroaryl groups containing a -N=CH-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles. The invention thus relates to the compounds of formula I or 11 as defined above. in another embodiment the invention relates to a compound of formula I or I N N R3 '0R3 A A ; 8N N N BQ N B I R2 R 4

R

2 B W N RN wherein A is carbon and B is nitrogen, or A is nitrogen and B is carbon: W is CH or N; 5 R 1 and R 2 independently are hydrogen, Ctalkyl, haloCu 4 alkyl, hydroxyC4alkyl, cyanoC 4 alkyl, CalkoxyC alkyt, halogen, -CN, -ORE or -SR; R3 is C 4 alkyl, R-O.alkyl, Cy, or Cy 2

-

1 -alkyl, wherein Cyi and Cy2 are optionally substituted with one or more Rio: R4 is hydrogen, C 14 alky. haloC 4 alkyl, C4alkoxyCil 4 alky, hydroxyC 1 alkyl, cyanoCialkyl, 0 R2R7N-Co4akyiF Ri 3 C0NR 7 -Co, 4 aIkyl, R 1

R

7 NCO-Co 4 alky, R 12

R

7

NCONR

7 -CoG 4 alky, R 3

CO

2 NIR-Cooalkyl

R

1 3 S0 2

NR

2 -0O 4 alky, -OR 1 2 or Cy 2 -COalkyl; wherein Cy2 is optionally substituted with one or more RN; RE is hydrogen, Ot 4 alkyl, haloC 4 alky, CNalkoxyCl4alkyl, hydroxyC 4 alkyl, cyanoC,4alkyl, halogen, -ON,

-OR

12 , -NR 7

R

2 , or Cy 2

-CO

4 alkyl, wherein Cy2 is optionally substituted with one or more R, 1 ;

R

2 is hydrogen, C4alkyl, CalkoxyC 1 alkyl, hydroxyCuialkyl, RIOR7N-Ctzalkyl, CyI or Cy 2

-C-

4 alkyl, ?5 wherein Cy, and Cy2 are optionally substituted with one or more R 11 ; R7 is hydrogen or C 2 alkyl;

R

8 is hydrogen, C 4alkyl, haloC 1 Aalkyl, hydroxyCOalkyl, or C-4alkoxyClalkyl;

R

9 is halogen, -CN, -CONR 7

R

2 , -COR 13 , -CO 2

R

12 , -OR 1 2 , -OCONR 7

R

2 , -S0 2 Ri 2 , -SO 2 NR7R 12 , -NR7Rz -NR7COR 1 2

-NR

7 CONR7R! 2 , -NR7CO 2 Ri2 or -NR7SO 2

R

3 :; 30 R 1 is C4alkyl or R 9

-CO.

4 alkyl;

R

1 is Cialkyi, haloCO 4 alkyl, CtalkoxyCualkyl, hydroxyC 14 aikyl, cyanoCi 4 alkyl, halogen, -CN, 13 -CONR7Ru, -COR 14 , -CO2R,5, -OR, -OCONR 7

R

14 , -SO2Ris, -SO2NR7R1, -NR 7

R

1 4 , -NR 7

COR

14

-NR

7

CONR

7

R

1 4 , -NR 7

CO

2

R

14 or -NR 7 S0 2 Ri 6 ;

R

1 2 is hydrogen or R 1 3

R,

3 is 0 14 alky, haloC 4 alkyl, C4alkoxyC4alkyl, hydroxyCalkyl, cyanoC4alkyl, or Cy2-Co4alkyl; wherein 5 Cy2is optionally substituted with one or more R, 1 ; Ru is hydrogen or R,5;

R

15 is C0 4 alkyl, haloCI4alkyl, C>,alkoxyCb4alkyl, hydroxyC 14 alkyl or cyanoC 4 alkyl; Cy1 is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently D selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or S02; and Cy2 is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C or N atom, 5 and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or S02. In another embodiment, the invention relates to a compound of formula I or I N N R37 /0R A/ A ,n N N R2 / R 4

R

2 O 'N N N RR R5 R6 wherein A is carbon and B is nitrogen, or A is nitrogen and B is carbon; W is CH or N; Ri and R 2 independently are hydrogen, Ctalkyl, haloCU 4 alky, hydroxyC 14 alkyl, cyanoC4alkyl., C)ualkoxyCp4alkyl, halogen, -ON, -ORB or -SRs: R3 is Cp 4 alkyl, Re-C' 1 alkyl, Cyj or Cy-Calky, wherein CyI and Cy2 are optionally substituted with one or more R10; 5 4 is hydrogen, C 4 alkyl, haloC 1 -alkyl, C4alkoxyCalkyl, hydroxyCu4alkyl, cyanoCialkyl,

RI

2 R7N-Co0alky, RiaCONR 7

-CO

4 alkyl, R 1

R

7 NCO-Co 4 alkyl, RlOR7NCONR-Coalkyl, R 13 C0 2 NIR'-Co 4 alkyl,

R

13

SO

2

NR

7 -Co-alkyl, -OR 12 or Cy2-CeAalkyl; wherein Cy2 is optionally substituted with one or more R 11 ;

R

5 is hydrogen, C 14 alkyl, haloCl-alkyl, CiaalkoxyC 4 alkyl, hydroxyC 4 alkyl, cyanoCalkyl, halogen, -CN,

-OR

2 , -NR 7 R1 2 , or Cy-Co 4 alkyl, wherein Cy2 is optionally substituted with one or more R 11 ; R is hydrogen, C 14 alkyl, CtalkoxyCtualkyl, hydroxyC 1 4alkyl, R 12

R

7 N-C t 4 alkyl, R 1 sCO-Coalkyl, RlEO-Co4alky, Cy, or Cy-Calkyl, wherein Cy, and Cy 2 are optionally substituted with one or more R 1

;

14

R

7 is hydrogen or C 4 alkyl;

R

8 is hydrogen, O>4alkyl, haloCi4alkyl, hydroxyO 4alkyl, or C 4 aIkoxyCOalkyl;

R

9 is halogen, -CN, -C0NRR 1 2 , -COR 1 -00 2

R

12 , -OR 1 2 , -OCONR 7

R

2 , S 2

R

13 , -SO 2

NR

7

R

2 , -NR 7

R

12 ,

-NRCOR

1 , -NR 7

CONR

7

R

2 , -NR 7

C

2

R

13 or -NR 7

SO

2 Ris; 5 Riis C 4 alkyl or R-Co4alkyl; Ri 1 is C 14 alkyl, haloCalkyl, C 1 4 alkoxyCalkyl, hydroxyC 4 alkyl, cyanoCI 4 alkyl, halogen, -CN,

-CONR

7

R

1 4 , -COR 1 4 , -C0 2 Ri, -OR14, -OCONR 7

R

14 , -SO2Rm, -SO2NR7R 4 , -NR 7

R

1 4 , -NRCOR! 4 . -NR7CONR 7 Rl 4 , -NR 7

CO

2 Rl 5 or -NR7SO 2 Ri 5 '

R

12 is hydrogen or R,

R

13 is C 4 alkyl, haloCuIalkyl, C 4 alkoxyC 14 aIky, hydroxyC 1 alkyl, cyanoC>alkyt, or Cy 2 -OCualkyl; wherein Cy2 is optionally substituted with one or more Ri 1 ;

R

4 is hydrogen or R 15 ; Ri 5 is C 4 alkyl, haloC4alkyl, CalkoxyCi4alkyl, hydroxyO 1 4alky or cyanoC4alkyl; RIE is C-alkyl, haloC 4alkyl, C1a[koxyC4alkyl or cyanoClalkyl; Cy is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or S02; and Cy2 is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially D unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO2. In another embodiment, the invention relates to the compounds of formula . In another embodiment, the invention relates to the compounds of formula 11, :5 In another embodiment, the invention relates to the compounds of formula I or II wherein A is carbon and B is nitrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein A is nitrogen and B is carbon. In another embodiment, the invention relates to the compounds of formula I or 11 wherein W is CH 0 In another embodiment, the invention relates to the compounds of formula I or If wherein W is N. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R 1 and R 2 independently are hydrogen, halogen, -ON, -OR 8 or -SR6, preferably hydrogen or -ON, in another embodiment, the invention relates to the compounds of formula I or It wherein R 2 is hydrogen, In another embodiment, the invention relates to the compounds of formula I or II wherein R 2 is -ON, In another embodiment, the invention relates to the compounds of formula I or 11 wherein R 1 is hydrogen, halogen, -ON, -OR 8 or -SRs, more preferably hydrogen or -CN; and R2 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R, is hydrogen or 15 -ON. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R 1 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or |I wherein R 1 is hydrogen, and R2 is hydrogen, In another embodiment, the invention relates to the compounds of formula I or 11 wherein R 1 is -CN; and R2 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or I wherein R2 is R-O4alkyl, Cy, or Cy 2 -COalkyl, wherein Cy, and 0y2 are optionally substituted with one or more Rig, In another embodiment, the invention relates to the compounds of formula I or 11 wherein 3 is R-0 1

-

4 alkyl. ) in another embodiment, the invention relates to the compounds of formula I or 11 wherein R is Cyi which is optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R3 is Cy1 and Cy1 is a 3- to 7-membered monocyclic or 6- to 1 1-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, 5 S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; wherein said Cy1 is optionally substituted with one or more Rio provided that if the ring contains a nitrogen atom that can be substituted, then said nitrogen atom is substituted with one Rio. In another embodiment, the invention relates to the compounds of formula I or If wherein R3 is Cy 1 ; and Cy" 3 in R3 is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and wherein said Cy1 is optionally substituted with one or more Ri. in another embodiment, the invention relates to the compounds of formula I or I wherein R3 is Cyi; and Cys 5 in R3 is a 3- to 7-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from I to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or

SO

2 ; and wherein said Cyi is optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula I or II wherein R3 is Cy1; and Cyi 0 in R is a 5- to 6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming C, SO or S02; and wherein said Cy, is optionally substituted with one or more R 10 In another embodiment, the invention relates to the compounds of formula I or lI wherein R2 is Cy,; and Cy 1 5 in R3 is a 5- to 6-membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, at least one of which is N; wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally 16 oxidized forming CO, SO or SO 2 ; and wherein said Cy, is optionally substituted with one or more Rio in another embodiment, the invention relates to the compounds of formula I or It wherein R2 is Cyi; and Cyi in R3 is a 3- to 7-membered, preferably 5- to 6-membered saturated monocyclic ring, which is heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0., at least one of which is N; wherein said 5 ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or S02; and wherein said Cy1 is optionally substituted with one or more Rio In another embodiment, the invention relates to the compounds of formula I or 11 wherein R3 is piperidinyl or pyrrolidinyl, preferably piperidin-3-yl or pyrrolidin-3-yl, which are optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R2 is piperidinyl or 3 pyrrolidinyl, preferably piperidin-3-yl or pyrrolidin-3-yl, which are substituted with one Ric on the N atom of the piperidinyl or pyrrolidinyl ring and which are optionally further substituted with one or more Rio groups, In another embodiment, the invention relates to the compounds of formula 11 wherein R3 is piperidinyl or pyrrolidinyt preferably piperidin-3-yl or pyrrolidin-3-yl, which are optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula II wherein R3 is piperidinyl or 5 pyrrolidinyl, preferably piperidin-3-yl or pyrrolidin-3-yl, which are substituted with one R 10 on the N atom of the piperidinyl or pyrrolidinyl ring and which are optionally further substituted with one or more Rio groups. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R3 is piperidinyl, preferably piperidin-3-yl, which are optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula I or II wherein R 3 is piperidinyl, 3 preferably piperidin-3-yl, substituted with one Rio on the N atom of the piperidinyl ring and optionally further substituted with one or more R 1 0 groups. In another embodiment, the invention relates to the compounds of formula 11 wherein R3 is piperidinyl, preferably piperidin-3-yl, which are optionally substituted with one or more Ric. In another embodiment, the invention relates to the compounds of formula 11 wherein R2 is piperidinyl, .5 preferably piperidin-3-yi, substituted with one Rio on the N atom of the piperidinyl ring and optionally further substituted with one or more Rio groups, In another embodiment, the invention relates to the compounds of formula I or il wherein R 3 is a cycle of formula N or N Cya CyIb 0 wherein CyI 0 and Cymb are optionally substituted with one or more further Rio. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R3 is a cycle of formula 17 N or Cyia CYlb In another embodiment, the invention relates to the compounds of formula II wherein R 3 is a cycle of formula Nor N 1IO Cy 1 a Cyib 5 wherein Cyia and Cym are optionally substituted with one or more further Rio, In another embodiment, the invention relates to the compounds of formula 1| wherein R 3 is a cycle of formula N or N K10 4 Cyla Cylb In another embodiment, the invention relates to the compounds of formula I or 11 wherein R3 is a cycle of 1 formula Cya. In another embodiment, the invention relates to the compounds of formula If wherein R 3 is a cycle of formula Cyia. In another embodiment, the invention relates to the compounds of formula I or Il wherein R 3 is a cycle of formula N 5 P 10 In another embodiment, the invention relates to the compounds of formula 11 wherein R 3 is a cycle of formula 18 N In another embodiment, the invention relates to the compounds of formula I or || wherein R3 is a cycle of formula Cym and Cym, has the (S)-stereochemistry. In another embodiment, the invention relates to the compounds of formula 11 wherein R3 is a cycle of 5 formula Cy,, and Cym has the (S)-stereochemistry. In another embodiment, the invention relates to the compounds of formula I or || wherein R3 is a cycle of formula Cy . In another embodiment, the invention relates to the compounds of formula I or 11 wherein R3 is Cy2-C4alkyl, wherein Cy2 is optionally substituted with one or more Ric. 3 In another embodiment, the invention relates to the compounds of formula I or 11 wherein R2 is Cy2-Cl4alkyl; and Cy2 is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from I to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C o N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or S02; and wherein said Cy2 is optionally substituted with one or 5 more Rio, In another embodiment, the invention relates to the compounds of formula I or lI wherein R4 is hydrogen, C4alkyl, R 2 R7N-Ccmalkyl or CyrGo4alkyl, preferably hydrogen, Cialkyl, -NR7Rp or Cy2; wherein Cy2 is optionally substituted with one or more R, In another embodiment, the invention relates to the compounds of formula I or 11 wherein Rs is hydrogen or D Cy2, wherein Cy2 is optionally substituted with one or more R, 1 . in another embodiment, the invention relates to the compounds of formula I or Il wherein R 6 is hydrogen or Cy2; and Cy2 is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available 0 o N atom, and wherein one or more C or S 5 ring atoms are optionally oxidized forming CO, SO or SO 2 : and wherein said Cy2 is optionally substituted with one or more R 11 , In another embodiment, the invention relates to the compounds of formula I or I wherein R 5 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or I wherein R6 is C4alkyl, C 4alkoxyG u4alkyl, hydroxyCalkyl, R 12

R

7

N-C

4 alkyl, RCO-CcAalkyl, RG-GCOAalkyl, RIsCO-O-C 4 alkyl, cyanoC 0 4alkyl, Cy, or Cy 2 -Ctalkyl, wherein Cyi and Cy2 are optionally substituted with one or more Rn, In another embodiment, the invention relates to the compounds of formula I or 1I wherein R6 is hydrogen,

C

1 alkyl, CG 4 alkoxyC4alkyl, hydroxyli-alkyl, R1 2

R

7

N-C

1 alkyl, R 1 C COCo4alkyl, R 1 6sG-COAalkyl, Cy1 or Cy2-C 4 alkyl, wherein Cy, and Cy2 are optionally substituted with one or more Ri,. In another embodiment, the invention relates to the compounds of formula I or 1| wherein R6 is C4alkyl, C 19 4alkoxyC14alkyl, hydroxyC 14 alkyl, R 2

R

7

N-C

14 aIkyl, R 1 CO-CoCalkyl, R 1 2CO 2

-CO

4 alkyl, Cy, or CY2-C 4 alkyl, wherein Cy, and Cy2 are optionally substituted with one or more R, 1 . in another embodiment, the invention relates to the compounds of formula I or I wherein R 6 is Cizalkyl, C 4 alkoxyCul.alky, hydroxyC4alkyl, RUR 7

N-C

4 alkyt RieCO-CC 4 alkyl, R 1 6CO2-CO4alkyl or R 1 6CO-O-C 4alkyl. In another embodiment, the invention relates to the compounds of formula I or It wherein R6 is hydrogen,

C

4 alkyl, C 14 alkoxyC 1 alky, hydroxyOU 1 alkyl, R 12

R

7 N-Cal kyl, RmCO-Cowalkyl or RieOtCoealkyl. In another embodiment, the invention relates to the compounds of formula I or 11 wherein RE is C 4 alkyi, Citalkoxy~iaalkyl, hydroxy~l4alkyl, RieR 7 N-Cp 4 alkyl, RleCO-Co4alkyl or RlBCO2C-oalkyl, in another embodiment, the invention relates to the compounds of formula 1 or 11 wherein Re is hydrogen, J C 14 aky, ClalkoxyC14alkyl, hydroxyCAalkyl or R 1 2

R

7

N-C

1 -alkyl. In another embodiment, the invention relates to the compounds of formula I or 11 wherein Re is hydrogen or

C

1 alkyl, preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or 11 wherein RE is Ct 4 alkyl, preferably methyl or ethyl 5 In another embodiment, the invention relates to the compounds of formula II wherein Re is O 14 alkyl, preferably methyl or ethyL In another embodiment, the invention relates to the compounds of formula I wherein R 6 is methyl. In another embodiment, the invention relates to the compounds of formula It wherein Re is ethyl. In another embodiment, the invention relates to the compounds of formula I or It wherein R 9 is -CONR 7

R

2 , J -COR 3 , -CO 2 R1 2 , -OR 12 , -OCONR 7

R-

2 , -SO2,,, -SO 2 NRyR 2 , -NR 7

R

12 , -NR 7

COR

12

-NR

7

CONR

7

R

2 ,

-NR

7

CO

2

R

2 or -NR 7 S0 2

R

13 , preferably R 9 is -CORis. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R 10 is Rg-Co 4 alkyl, preferably R9. In another embodiment, the invention relates to the compounds of formula I or II wherein R 10 is R,; and Rein 5 Rio is -COR1 3 or -SO 2

R

3 .n another embodiment, the invention relates to the compounds of formula I or IlI wherein

R

1 is R 9 ; and R 9 in R 1 o is -COR. In another embodiment, the invention relates to the compounds of formula I or II wherein R 1 3 is Cisalkyl haloC 4 alkyl, Cl 4 alkoxyCp4alkyl, hydroxyC1 4 alkyl, cyanoO- 4 alkyl or Cy 2 -Coalkyl; wherein Cy2 is optionally substituted with one or more Rn. 0 in another embodiment, the invention relates to the compounds of formula I or 11 wherein R 1 3 is C- 5 alkyl, haloC 4 alkyl, C- 4 alkoxyC, 4 alkyl, hydroxyC 4 alkyl or cyanoC 4 alkyl, preferably C>4alkyl or cyanoC4alkyl, more preferably methyl, isopropyl or cyanomethyl, and still more preferably methyl or cyanomethyl. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R1 3 is C4alkyl, haloC-4alkyl, COaIkoxyC1 alkyl, hydroxyCO4alkyl or cyanoC 1 -alkyl, preferably C- 4 alkyl or cyanoC4alkyl, more 5 preferably methyl, isopropyl or cyanomethy, and still more preferably methyl or cyanomethyl. In another embodiment, the invention relates to the compounds of formula I or I1 wherein R 1 3 is methyl. In another embodiment, the invention relates to the compounds of formula I or If wherein R 1 3 is isopropyl.

20 In another embodiment, the invention relates to the compounds of formula I or 11 wherein R 1 3 is cyanomethyl. In another embodiment, the invention relates to the compounds of formula I or II wherein R 1 3 is Cy2-CO4alkyl wherein Cy2 is optionally substituted with one or more R 5 In another embodiment, the invention relates to the compounds of formula I or 11 wherein R 9 is -CONR 7

R

1 2 ,

-COR

3 , -C0 2

R

13 , -OR 12 , -OCONR 7

R

2 , -SO 2 Ri 3 , -S0 2

NR

7 Ri 2 , -NR 7

R

2 , -NR 7

COR

2

-NR

7

CONR

7

R

2 ,

-NR

7

CO

2 Ri 3 or -NR 7

SO

2

R

2 , preferably -CO 2 Ra; and

R

3 is Cualkyl, haloCl4alkyl, CL4alkoxyCu_4alkyl, hydroxyCialkyl or cyanoC 4 alkyl, preferably Cl alkyl or cyanoC 4 alkyl, and more preferably methyl or cyanomethyl. 0 In another embodiment, the invention relates to the compounds of formula 1 or 11 wherein Rio is Rs; R 9 in Ric is -CORI 3 ; and R 1 3 is C4alkyl, haloC 4 alky, CI 4 alkoxyCl4alkyl, hydroxyCAalkyl or cyanoC 4 alkyl preferably C> 4 alkyl or cyanoCp 4 alkyl, and more preferably methyl or cyanomethyl In another embodiment, the invention relates to the compounds of formula I or It wherein R 3 is Rg-CI4alky; and 5 R is -CONR 7

R

12 , -CORn, -C0 2

R

12 , -OR 2 , -OCONR 7

R

12 , -SO 2

R

1 3 , -SO 2 NR7RI 2 , -NR7R 1 2 , -NR7COR 12

-NR

7 C0NR 7

R

12 , -NR 7 0O 2

R

3 or -NR 7

SO

2

R

3 . In another embodiment, the invention relates to the compounds of formula I or 11 wherein R 2 is Rq-Ci.alkyl; Rs is -CONR 7

R

12 , -CORn, -C0 2

R

2 , -OR 1 2 , -OCONR 7

R

12 , -SO 2 Ri 3 , -S0 2

NR

7

R

12 , -NR 7

R

12 , -NR7COR 2 , -NR7CONR 7 RV, -NR 7 00 2

R

3 or -NR 7

SO

2

R

3 ; and 0 Ri 3 is C> 4 alkyl, haloCi.alkyl, C 1 alkoxyC 1 alkyl, hydroxyC- 4 alkyl or cyanoC> 4 alkyl. In another embodiment, the invention relates to the compounds of formula I or I wherein R3 is Cy, preferably piperidinyl or pyrrolidinyl, more preferably piperidinyl-3-yl or pyrrolidinyl-3yl; wherein Cy, in R 3 is optionally substituted with one or more R 1 ; and

R

20 is RR-CO 4 alkyl, preferably R 9 . more preferably -COR 1 sor -S 2

R

3 . 25 In another embodiment, the invention relates to the compounds of formula I or 11 wherein R 3 is a cycle of formula or

R

10 Cy 18 Cyl ; and Ro is R9-Co 4 alkyl, preferably R., more preferably -CORu0or -S0 2

R

3 . In another embodiment, the invention relates to the compounds of formula If wherein R 3 is a cycle of 30 formula 21 N ON K10 Cyla CYlb ; and

R

1 0 is RsCo- 4 alkyl, preferably R., more preferably -CORp or -S0 2

R

1 In another embodiment, the invention relates to the compounds of formula I or 11 wherein R3 is a cycle of formula /A N or 1 R10 Cy1a Cyib Rio is Rq-C0 4 alkyl, preferably R 9 ; R is-COR13 or -S0 2

R,

3 ; and

R

13 is C-alkyl, haloC 4 alkyl, CalkoxyC 4 alky, hydroxyCtualkyl or cyanoCl4alkyl, preferably Cb4alkyl or cyanoCp 4 alkyl, and more preferably methyl or cyanomethyl. J In another embodiment, the invention relates to the compounds of formula I wherein R3 is a cycle of formula N or N

R

10 1 Cy1a C1b; R is Re-Ccalkyl, preferably R; RD is -COR,3or -SO 2

R

3 ; and 5 R 1 is Clalkyl, haloC>alkyl, C- 4 alkoxyCa[kyl, hydroxyCupalkyl or cyanoCi 4 alkyl, preferably Ciualkyl or cyanoCl 4 alkyl and more preferably methyl or cyanomethyl. in another embodiment, the invention relates to the compounds of formula I or 1i wherein R3 is a cycle of formula Cym; and

R

1 is R-Co 4 alkyl, preferably Rq, more preferably -COR3 or -S 2

R

13 still more preferably -COR 13 C In another embodiment, the invention relates to the compounds of formula 11 wherein R3 is a cycle of formula Cym; and Riois R-C 04 alkyl, preferably R 9 , more preferably -CORior -SC2R 3 still more preferably -COR 1 3 22 In another embodiment, the invention relates to the compounds of formula I or It wherein R3 is a cycle of formula CyIS; Riois Re-Ocalkyl, preferably R, more preferably-CORoor -SC 2

R

13 still more preferably -COR 13 and

R

1 3 is 1

C

4 alkyl, haloC0 4 alkyl, C 1 ualkoxyC 4 alkyl, hydroxyO% 4 alkyl or cyanoC 4 alkyl, preferably O 14 alkyl or 5 cyanoCl4alkyl, and more preferably methyl or cyanomethyl. In another embodiment, the invention relates to the compounds of formula II wherein R3 is a cycle of formula Cyia;

R

1 3 is R 1

CO-

4 alkyl, preferably R, more preferably -CORp or -SO2R,. still more preferably -COR 13 ; and

R

1 3 is 0 14 alkyl, haloC 4 alkyl., C 4 alkoxy%4alkyl, hydroxyC 4 alkyl or cyanoC 4 alkyl, preferably ClAalkyl or 3 cyanoCI 4 alky, and more preferably methyl or cyanomethyl In another embodiment, the invention relates to the compounds of formula I or 11 wherein R3 is a cycle of formula Cyia with (S)-stereochemistry;

R

10 is Rq-Calkyl, preferably R9, more preferably -COR13 or -S0 2 R still more preferably -COR 13 ; and

R

13 is C 4 alkyl, haloC 4 alkyl, C 14 alkoxyO 14 alkyl, hydroxyC 1 alkyl or cyanoC 4 alkyl, preferably C>alky or 5 cyanoCalkyl, and more preferably methyl or cyanomethyl. In another embodiment, the invention relates to the compounds of formula 1| wherein R is a cycle of formula Cyia with (S)-stereochemistry; Riois R-CO.

4 alkyl. preferably R, more preferably -CORaor -SO2Ra still more preferably -COR 3 ; and

R

13 is C 4 alkyl, haloCalkyl, C 14 alkoxyC 4 alkyl, hydroxyO 1 .alkyl or cyanoC4alky, preferably C- 4 alkyl or D cyanoC 1 akyl, and more preferably methyl or cyanomethyl. in another embodiment, the invention relates to the compounds of formula I or 11 wherein R3 is a cycle of formula Cya; and Rio is R 9

C-O

4 alkyl, preferably R2 more preferably -SO 2 R,2, in another embodiment, the invention relates to the compounds of formula 11 wherein R3 is a cycle of 5 formula Cym; and Rio is R-Cu 4 alkyl, preferably R more preferably -SO 2

RI

3 . In another embodiment, the invention relates to the compounds of formula I or 11 wherein Cy1 is a 3- to 7 membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is 30 bonded to the rest of the molecule through any available 0 atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SC 2 . in another embodiment, the invention relates to the compounds of formula I or i wherein Cy! is a 3- to 7 membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any 5 available 0 atom, and wherein one or more C or S ring atoms are optionally oxidized forming CC, SO or SC 2 , In another embodiment, the invention relates to the compounds of formula I or 11 wherein Cy1 is a 5- to 6 membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms 23 independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 , In another embodiment, the invention relates to the compounds of formula I or I wherein Cy1 is a 5- to 6 membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, at least one of which is N; wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming 00, SO orSOz In another embodiment, the invention relates to the compounds of formula I or It wherein Cy1 is a 5- to 6 membered saturated monocyclic ring, which is heterocyclic containing from 1 to 3 heteroatoms independently ) selected from N, S and 0, at least one of which is N; wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming C, SO or S02 In another embodiment, the invention relates to the compounds of formula I or 11 wherein Cy1 is piperidinyl or pyrrolidinyl, preferably piperidinyl-3-yl or pyrrolidinyl-3-yl. In another embodiment, the invention relates to the compounds of formula I or 11 wherein Cy2 is a 3- to 7 5 membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from I to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C o N atom, and wherein one or more C or S ring atoms are optionally oxidized forming C, SO or SO2. In another embodiment, the invention relates to the compounds of formula I or 11 wherein Cy2 is a 3- to 7 3 membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming C, SO or S02. In another embodiment, the invention relates to the compounds of formula I or 1| wherein CY2 is a 5- to 6 membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms 5 independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO2, in another embodiment, the invention relates to the compounds of formula I or lI wherein Cy2 is a 5- to 6 membered saturated monocyclic ring, which is carbocyclic or heterocyclic containing from I to 3 heteroatoms independently selected from N, S and 0, at least one of which is N; wherein said ring is bonded to the rest of the 0 molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO2. In another embodiment, the invention relates to the compounds of formula I or 11 wherein Cy2 is piperidinyl or pyrrolidinyL. In another embodiment, the invention relates to the compounds of formula I or || wherein: 5 A is nitrogen and B is carbon; and R1 and R2 independently are hydrogen, halogen, -ON, -OR 8 or -SR, preferably hydrogen or -ON. In another embodiment, the invention relates to the compounds of formula I or If wherein: 24 A is nitrogen and B is carbon; Ri is hydrogen, C4alkyl, haloCalkyl, hydroxyC4alkyl, cyanoCalkyl, C 4 alkoxyC4aIky. halogen -ON, -ORE or -SR, preferably hydrogen, halogen, -CN, -OR or -SRe, and more preferably hydrogen or -ON; and R2 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or I wherein A is nitrogen and B is carbon; R 1 and R2 are hydrogen. In another embodiment, the invention relates to the compounds of formula I or |I wherein:

R

1 and R2 independently are hydrogen, halogen, -ON, -OR 8 or -SRa, and more preferably hydrogen or -CN; and R3 is Rq-Cialkyl, Cy, or CyoCi-4alkyl, wherein Cy1 and Cy2are optionally substituted with one or more Ro. In another embodiment, the invention relates to the compounds of formula I or It wherein: R, is hydrogen, C 4 alkyl, haloCulalkyl, hydroxyC 4 alkyl, cyanoCu4alkyl, O14alkoxyC4alkyl, halogen, -ON,

-OR

8 or -SR 8 , preferably hydrogen, halogen, -ON, -OR 8 or -SR, and more preferably hydrogen or -ON; R2 is hydrogen; and 5 R3 is RrC4alkyl, Cy1 or CyrCI-Oalkyl, wherein Cy1 and Cy2 are optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R, and R2 are hydrogen; and R3 is R C 1 alkyl, Cy, or Cyr-C 1 alkyl, wherein Cy and Cy2 are optionally substituted with one or more Rio, In another embodiment, the invention relates to the compounds of formula I or I| wherein: 0 R, is hydrogen, C4alkyl, haloC 4 alkyl, hydroxyC 4 alkyl, cyanoCi 4 alkyl, ClalkoxyCl4alkyl, halogen, -CN, -OR or -SR, preferably hydrogen, halogen, -CN, -OR or -SR 8 , and more preferably hydrogen or -CN; R2 is hydrogen; and R is R 8 C-0 4 alkyL. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: 25 Ris hydrogen. Clalkyl, haloCuialkyl, hydroxyC,-alkyl, cyanoOCalkyl, C 4 alkoxyC 1 alkyl, halogen, -ON,

-OR

8 or -SR 8 , preferably hydrogen, halogen, -CN, -OR or -SR, and more preferably hydrogen or -CN;

R

2 is hydrogen; and R3 is Cy1, which is optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula I or Il wherein R 1 and R2 are 30 hydrogen; and R is Cyi, which is optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula I or 1I wherein: R is hydrogen, Cbalkyl, haloCi4alkyl, hydroxyCizalkyl, cyanoC4alkyl, ClalkoxyCalky, halogen, -ON, -OR or -SR5, preferably hydrogen, halogen, -ON, -OR or -SR 8 , and more preferably hydrogen or -ON; R2 is hydrogen; 35 R3 is Cyl, wherein Cy1 in R is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one 25 or more C or S ring atoms are optionally oxidized forming 00, SO or SO 2 ; and wherein said Cy1 is optionally substituted with one or more Rio, In another embodiment, the invention relates to the compounds of formula I or |i wherein:

R

1 is hydrogen, C4alkyl, haloC 14 alkyl, hydroxyC l4alkyl, cyanoC 4 alkyl, OCualkoxyOl4alkyl, halogen, -ON, -ORs or -SR, preferably hydrogen, halogen, -ON, -OR or -SRs, and more preferably hydrogen or -CN; R2 is hydrogen; R3 is Cy 1 , wherein Cy, in R3 is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or S02; and more preferably Cy, in R3 is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy1 is optionally substituted with one or more Rio, In another embodiment, the invention relates to the compounds of formula I or I wherein A is nitrogen and B is carbon; 5 R, is hydrogen, Clalkyl, haloC 4 alkyl, hydroxyC-alkyl, cyanoCi-alkyl, COlalkoxyC4alkyI, halogen, -ON, -ORB or -SRa, preferably hydrogen, halogen, -ON, -ORB or -SRe, and more preferably hydrogen or -CN; R2 is hydrogen; and R3 is R 8

CI-

4 alkyl, Cyq or Cy2-t4alkyl, wherein Cy, and Cy2 are optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula I or 11 wherein A is nitrogen and 3 B is carbon; R, and R 2 are hydrogen; and R3 is R-COialkyl, Cyi or Cy 2 -Ct4alkyl, wherein Cyi and Cy2 are optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula I or 11 wherein A is nitrogen and B is carbon;

R

1 is hydrogen, OC alkyl, haloC alkyl, hydroxyu 1 4alkyl, cyanoCl4alkyl, C 4 alkoxyC14alkyl, halogen, -ON, !5 -OR 8 or -SRs, preferably hydrogen, halogen, -ON, -OR or -SR, and more preferably hydrogen or -CN; R2 is hydrogen; and R3 is Rg-C 1 -alkylt In another embodiment, the invention relates to the compounds of formula I or 1I wherein A is nitrogen and B is carbon; R 1 and R2 are hydrogen; and R3 is RYCi-Oalkylt 30 In another embodiment, the invention relates to the compounds of formula I or 11 wherein A is nitrogen and B is carbon; R is hydrogen, O.alkyl, haloC4alkyl, hydroxyO 1 4 alkyl, cyanoO;.4alkyl, C 4 alkoxyCalkyl, halogen, -ON, -OR or -SR 8 , preferably hydrogen, halogen, -CN, -ORe or -SR 8 , and more preferably hydrogen or -ON; R2 is hydrogen; and 35 R3 is Cy!, which is optionally substituted with one or more Rio. In another embodiment, the invention relates to the compounds of formula I or [1 wherein A is nitrogen and B is carbon; R, and R 2 are hydrogen; and R is Oyt which is optionally substituted with one or more R 1

.

26 In another embodiment, the invention relates to the compounds of formula I or i wherein A is nitrogen and B is carbon; R, is hydrogen, Calkyl, haloCI4alkyl, hydroxyCulalkyl, cyanoO4alkyl, O4alkoxyC 4 alkyl, halogen, -CN, -ORsor-SR, preferably hydrogen, halogen, -CN, -OR or-SR, and more preferably hydrogen or-CN;

R

2 is hydrogen; and

R

3 is Cyi, wherein Cy, in R 3 is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or S0 2 ; and wherein said Cy1 is optionally substituted with one or more Rio In another embodiment, the invention relates to the compounds of formula I or [1 wherein A is nitrogen and B is carbon; R, is hydrogen, C4alkyl, haloC 1 alkyl, hydroxyC 4 alkyl, cyanoC4alkyl, CIalkoxyO%4alkyl, halogen, -CN,

-OR

8 or -SRs, preferably hydrogen, halogen, -CN, -OR or -SRg, and more preferably hydrogen or -CN; 5 R 2 is hydrogen; and

R

3 is Cy , wherein Cy in R3 is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from I to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or 302; and more preferably Cy1 in R3 is piperidinyl or ) pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cyi is optionally substituted with one or more R. In another embodiment, the invention relates to the compounds of formula I or 11 wherein A is nitrogen and B is carbon;

R

1 is hydrogen, C 4 alkyl, haloCI4alkyl, hydroxyCuialkyl, cyanoC 1 4alkyl, C 4 alkoxy~toalkyl, halogen, -CN, 5 -OR 8 or -SRs, preferably hydrogen, halogen, -CN, -OR 8 or -SRu, and more preferably hydrogen or -ON; R2 is hydrogen; and R3 is a cycle of formula Cya,, preferably with (S)-stereochemistry, In another embodiment, the invention relates to the compounds of formula 11 wherein A is nitrogen and B is carbon; 0 R 1 is hydrogen, C 1 alkyl, haloC aalkyl, hydroxyC- 4 alky, cyano Cp 4 alkyl, C 4 alkoxyCalkyl, halogen, -CN,

-OR

8 or -SR, preferably hydrogen, halogen, -ON, -OR 8 or -SR, and more preferably hydrogen or -CN;

R

2 is hydrogen; and R3 is a cycle of formula Cya preferably with (S)-stereochemistry. In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and 5 B is carbon; and

R

5 is hydrogen, In another embodiment, the invention relates to the compounds of formula I or [1 wherein A is nitrogen and 27 B is carbon;

R

1 is hydrogen, halogen, -CN, -ORs or -SR 8 , preferably hydrogen or -CN: and R2 is hydrogen; and R5is hydrogen. In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and 5 B is carbon; R 1 and R 2 are hydrogen; and Rs is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: R, is hydrogen, halogen, -ON, -OR 9 or -SR8, preferably hydrogen or -CN; and R 2 is hydrogen; REis hydrogen and

R

6 is hydrogen or C4alkyl, preferably hydrogen, methyl or ethyl. 0 In another embodiment, the invention relates to the compounds of formula I or 11 wherein R 1 and R 2 are hydrogen; R 5 is hydrogen; and R is hydrogen or C 4 alkyl, preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or i wherein: R is hydrogen, halogen, -CN, -OR or -SR, preferably hydrogen or -CN; and R 2 is hydrogen; R5 is hydrogen; and 5 Ris C4alkyl, preferably methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or 11 wherein R and R 2 are hydrogen; Rs is hydrogen; and R6 is Cl4alkyl, preferably methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or I wherein: RH is hydrogen, halogen, -CN, -OR 8 or -SR, preferably hydrogen or -CN; and R 2 is hydrogen; 0 R8 is RsCI-alkyl, Cy, or Cy 2

-C

4 aIkyl, wherein Cy1 and Cy2 are optionally substituted with one or more Rio; and RE is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: R, and R 2 are hydrogen; 25 R 3 is R 9

-O

1 alkyl, Cyi or Cy2-O>alkyl, wherein Cyi and Cy2 are optionally substituted with one or more R10; and RP is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: R, is hydrogen, halogen, -CN, -OR or -SRs, preferably hydrogen or -CN; and R 2 is hydrogen; 30 R 2 is R 9

-O

1 4alkyl; and

R

5 is hydrogen, In another embodiment, the invention relates to the compounds of formula I or 1I wherein:

R

1 is hydrogen, halogen, -CN, -OR or -SR, preferably hydrogen or -CN; and R2 is hydrogen; R3 is Cys, which is optionally substituted with one or more R 1 ; and 35 Rs is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein:

R

1 and R 2 are hydrogen; 28

R

3 is Cyl, which is optionally substituted with one or more Ric; and

R

6 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein:

R

1 is hydrogen, halogen, -CN, -OR 8 or -SR, preferably hydrogen or -CN; and R 2 is hydrogen; 5 R3 is Cyi, wherein Cy1 in R 3 is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and wherein said Cy1 is optionally substituted with one or more Rio; and 3 RE is hydrogen, In another embodiment, the invention relates to the compounds of formula I or 11 wherein:

R

1 is hydrogen, halogen, -CN, -OR or -SR 8 , preferably hydrogen or -CN; and R 2 is hydrogen;

R

3 is Cyi, wherein Cy, in R 3 is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 5 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and more preferably Cy1 in R 3 is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy1 is optionally substituted with one or more R 1 ; and

R

5 is hydrogen. 0 in another embodiment, the invention relates to the compounds of formula 1 or 1| wherein:

R

1 is hydrogen, halogen, -CN, -OR 8 or -SR 8 , preferably hydrogen or -CN; and R 2 is hydrogen;

R

2 is a cycle of formula Cy, preferably with (S)-stereochemistry; and

R

8 is hydrogen. In another embodiment, the invention relates to the compounds of formula 11 wherein: 25 R 1 is hydrogen, halogen, -CN, -OR or -SRe, preferably hydrogen or -CN; and R 2 is hydrogen;

R

2 is a cycle of formula Cya preferably with (S)-stereochemistry; and

R

5 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or || wherein A is nitrogen and B is carbon; 30 R 1 is hydrogen, halogen, -ON, -OR 8 or -SRe, preferably hydrogen or -CN; and R 2 is hydrogen;

R

5 is hydrogen; and R is hydrogen or C 1 4 alkyl, preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or II wherein A is nitrogen and B is carbon; 35 R and R2 are hydrogen; Rs is hydrogen; and

R

6 is hydrogen or C 1 alkyl, preferably hydrogen, methyl or ethyl.

29 in another embodiment, the invention relates to the compounds of formula I or If wherein A is nitrogen and B is carbon;

R

1 is hydrogen, halogen, -CN, -ORE or -SRe, preferably hydrogen or -CN; and R 2 is hydrogen; Rs is hydrogen; and

R

6 is C alkyll, preferably methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or 11 wherein A is nitrogen and B is carbon;

R

1 and R2 are hydrogen; R is hydrogen; and R6 is C 4 alkyl, preferably methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or HI wherein: W is CH;

R

1 is hydrogen, halogen, -CN, -OR or -SR 8 , preferably hydrogen or -CN; and R 2 is hydrogen;

R

3 is RqCI 4 alkyl, Cy 1 or Cy2-COaIkyl, wherein Cy, and Cy2 are optionally substituted with one or more Ric; ) and

R

5 is hydrogen, In another embodiment, the invention relates to the compounds of formula I or 11 wherein: W is CH; Ri and R2 are hydrogen; ) R3 is R 8 Cl- 4 alkyl, Cyl or Cy2-Clalkyl, wherein Cy, and Cy2 are optionally substituted with one or more Rio; and R5 is hydrogen, in another embodiment, the invention relates to the compounds of formula 1 or 11 wherein: W is CH; 5 R. is hydrogen, halogen, -ON, -OR or -SR 8 , preferably hydrogen or -CN; and R2 is hydrogen;

R

3 is R 9

CI-

4 alkyl; and

R

5 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or I| wherein: W is CH; 0 Ri is hydrogen, halogen, -CN, -ORs or -SR 8 , preferably hydrogen or -ON, more preferably hydrogen; and R2 is hydrogen; R3 is Cyt which is optionally substituted with one or more R 1 0 ; and R6 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: 5 W is CH;

R

1 is hydrogen, halogen, -CN, -OR or -SRE, preferably hydrogen or -CN, more preferably hydrogen; and

R

2 is hydrogen: 30 R3 is Cy1, wherein Cy1 in R3 is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and wherein said Cy, is 5 optionally substituted with one or more Rio; and Rs is hydrogen. In another embodiment, the invention relates to the compounds of formula I or Ii wherein: W is CH;

R

1 is hydrogen, halogen, -CN, -ORs or -SR, preferably hydrogen or -CN, more preferably hydrogen; and

R

2 is hydrogen; R3 is Cyt wherein Cyi in R 3 is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more 0 or S ring atoms are optionally oxidized forming CO, SO or SO2; and more preferably Cy, in R3 is piperidinyl or 5 pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-y; wherein said Cy, is optionally substituted with one or more Rio; and

R

5 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or |1 wherein: W is CH; 3 R is hydrogen, halogen, -CN, -OR or -SR6, preferably hydrogen or -ON, more preferably hydrogen; and

R

2 is hydrogen;

R

3 is a cycle of formula Cyla, preferably with (S)-stereochemistry; and RE is hydrogen. In another embodiment, the invention relates to the compounds of formula 1| wherein: 5 W is CH;

R

1 is hydrogen, halogen, -CN, -OR or -SR 8 , preferably hydrogen or -CN, more preferably hydrogen; and R2 is hydrogen;

R

3 is a cycle of formula Cyi,, preferably with (S)-stereochemistry; and R is hydrogen, 0 In another embodiment, the invention relates to the compounds of formula I or 1I wherein: W is N; RP is hydrogen, halogen, -CN, -OR 8 or -SR, preferably hydrogen or -ON; and R 2 is hydrogen;

R

3 is R-Opalkyl, Cy. or Cy 2

-C

4 alkyl, wherein Cy, and Cy2 are optionally substituted with one or more RIG; and 5 Rs is hydrogen. In another embodiment, the invention relates to the compounds of formula I or It wherein: W is N; 31

R

1 and R2 are hydrogen; R3 is R-C4alkyl, Cy1 or CyrCI- 4 alkyl, wherein Cyi and Cy2 are optionally substituted with one or more Rio; and Rs is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: W is N;

R

1 is hydrogen, halogen, -CN, -OR 8 or -SR 8 , preferably hydrogen or -CN; and R2 is hydrogen; R3 is R-C-4alkyl; and R5 is hydrogen. D in another embodiment, the invention relates to the compounds of formula I or 11 wherein: W is N; R, is hydrogen, halogen, -CN, -ORs or -SR, preferably hydrogen or -ON, more preferably hydrogen; and R2 is hydrogen; R, is Cys, which is optionally substituted with one or more RIG; and 5 Rs is hydrogen, In another embodiment, the invention relates to the compounds of formula I or 1I wherein: W is N;

R

1 is hydrogen, halogen, -CN, -OR 8 or -SRs, preferably hydrogen or -CN., more preferably hydrogen; and R2 is hydrogen; SR3 is Cys, wherein Cy 1 in R3 is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available 0 atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and wherein said Cy1 is optionally substituted with one or more R 1 ; and R is hydrogen, In another embodiment, the invention relates to the compounds of formula I or I wherein: W is N; R, is hydrogen, halogen, -ON, -ORe or -SRs, preferably hydrogen or -CN, more preferably hydrogen; and R2 is hydrogen; 30 R3 is Cy 1 , wherein Cyi in R is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming 00, SO or SO 2 ; and more preferably Cy 1 in R 3 is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said OyI is optionally substituted with one 35 or more RIG; and Rs is hydrogen. in another embodiment, the invention relates to the compounds of formula I or 11 wherein 32 A is nitrogen and B is carbon;

R

1 is hydrogen, halogen, -ON, -OR or -SR, preferably hydrogen or -CN; and R2 is hydrogen; R3 is R-C 4 alkyl, Cy1 or CyrCI-4alkyl, wherein Cyi and Cy2 are optionally substituted with one or more Rio; and 5 R is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: A is nitrogen and B is carbon;

R

1 and R 2 are hydrogen; R is Rq-Ol4alkyl, Cyi or Cy2-O>4alkyl, wherein Cy, and Cy2 are optionally substituted with one or more Ro; o and

R

5 is hydrogen, In another embodiment, the invention relates to the compounds of formula I or 11 wherein: A is nitrogen and B is carbon; R, is hydrogen, halogen, -ON, -OR or-SRs, preferably hydrogen or -CN; and R2 is hydrogen; 5 Ra is R 9

C-

4 alkyl; and

R

5 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: A is nitrogen and B is carbon; R, is hydrogen, halogen, -ON, -OR 8 or -SR, preferably hydrogen or -ON, more preferably hydrogen; and 0 R2 is hydrogen; R3 is Cyi, which is optionally substituted with one or more Rio; and R is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: A is nitrogen and B is carbon; 25 R1,, is hydrogen, halogen, -ON, -ORB or -SR, preferably hydrogen or -ON, more preferably hydrogen; and

R

2 is hydrogen; R3 is Cyl, wherein Cy1 in Rs is a 3- to 7-membered monocyclic ring, which is saturated., partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and 30 wherein one or more 0 or S ring atoms are optionally oxidized forming CO, SO or S02; and wherein said Cy1 is optionally substituted with one or more Rio; and R is hydrogen. In another embodiment, the invention relates to the compounds of formula I or If wherein: A is nitrogen and B is carbon 35 R 1 is hydrogen, halogen, -ON, -OR or -SR, preferably hydrogen or -ON, more preferably hydrogen; and R2 is hydrogen;

R

3 is Cyl, wherein Cy1 in R is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic 33 ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and more preferably Cy1 in R 3 is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy1 is optionally substituted with one 5 or more Rio; and Rs is hydrogen. In another embodiment, the invention relates to the compounds of formula I or i wherein: A is nitrogen and B is carbon;

R

1 is hydrogen, halogen, -CN, -OR or -SRs, preferably hydrogen or -CN, more preferably hydrogen; and D R 2 is hydrogen; R3 is a cycle of formula Cya,, preferably with (S)-stereochemistry; and Rs is hydrogen. in another embodiment, the invention relates to the compounds of formula l wherein: A is nitrogen and B is carbon; 5 R 1 is hydrogen, halogen, -CN, -OR 8 or -SR&, preferably hydrogen or -CN, more preferably hydrogen; and

R

2 is hydrogen;

R

3 is a cycle of formula Cym, preferably with (S)-stereochemistry; and R5 is hydrogen. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: D R, is hydrogen. halogen, -CN, -OR or -SR, preferably hydrogen or -CN; and R2 is hydrogen;

R

3 is R 8 Cl- 4 alkyl, Cy, or Cy2-Cp4alkyl, wherein Cy, and Cy2 are optionally substituted with one or more Ric; R4 is hydrogen, C,4alkyl, Ri2R7N-Co alkyl or Cy2-owalkyl, preferably hydrogen, Calkyl, -NR 7

R

2 or Cy2; wherein Cy2 are optionally substituted with one or more R 1 ;

R

5 is hydrogen; and -5 R6 is hydrogen, O 1 Calkyl, ClalkoxyCl4alkyl, hydroxyCOalkyl or RRN-C 4 alkyl, preferably hydrogen or

CO

4 alkyl and more preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or 1I wherein:

R

1 and R2 are hydrogen;

R

3 is Rg-C4alkyl, Cys or Cy2-Ci.Aalkyl, wherein Cy1 and Cy2 are optionally substituted with one or more R 2 ; M R4 is hydrogen, CO4alkyl, RT 2

R

7 N-Co 4 alkyl or Cy 2 -Co.

4 alkyl, preferably hydrogen, C 4 alkyl, -NR 7

R

12 or Cy2; wherein Cy2 are optionally substituted with one or more R 1 1 ; R5 is hydrogen; and R is hydrogen, C4alkyl, C 1 alkoxyCI 4 alkyl, hydroxyCl4alkyl or RoR 7

N-C

4 alkyl, preferably hydrogen or

C

14 alkyl and more preferably hydrogen, methyl or ethyl. 5 In another embodiment, the invention relates to the compounds of formula I or 11 wherein:

R

1 is hydrogen., halogen, -CN, -OR or -SR 6 , preferably hydrogen or -CN; and R2 is hydrogen; R is R-C4alkyl; 34 R4 is hydrogen, C 4 alkyl, R 12

R

7

N-C-

4 alkyl or Cy 2 -CO4alkyl, preferably hydrogen, CO>alkyl, -NRyRv or Cy2; wherein Cy2 are optionally substituted with one or more R 1 1 ;

R

5 is hydrogen; and R, is hydrogen, Cbalkyl, Cl4alkoxyCalkyl, hydroxyCuialkyl or R 12

R

7 N-C1 4 alkyl, preferably hydrogen or O1Calkyl and more preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or 11 wherein: R, is hydrogen, halogen. -ON, -OR 8 or -SRs, preferably hydrogen or -ON; and R2 is hydrogen; R is Cy, which is optionally substituted with one or more R 10 ; R4 is hydrogen, C 1 4alky, R 1 2

R

7

N-

0 o 4 alkyl or Cy 2

-

04 alkyl, preferably hydrogen, Op4alky, -NR 7

R

2 or Cy2; wherein Cy2 are optionally substituted with one or more Rii; R is hydrogen; and R6 is hydrogen, C 4 alkyl, O 14 alkoxyC 4 alkyl, hydroxyC,4alkyl or R 1 2 R7N-Ci 4 alkyl, preferably hydrogen or C14alkyl and more preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or |I wherein: R is hydrogen, halogen, -CN, -ORs or -SRs, preferably hydrogen or -ON; and R 2 is hydrogen; R3 is Cy 1 , wherein Cyi in R3 is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0., wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more 0 or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and wherein said Cy is J optionally substituted with one or more Rio; R4 is hydrogen, C 4 alkyl, R1 2

R

7 N-Co 4 alkyl or Cy 2 -Co4alkyl, preferably hydrogen, C 1 aalkyl, -NRR 2 or Cy2; wherein Cy2 are optionally substituted with one or more Ru;

R

5 is hydrogen; and Re is hydrogen, C 4 alkyl, CalkoxyC4alkyl, hydroxyC 1 alkyl or R1 2

R

7

N-C

14 alky, preferably hydrogen or 5 Calkyl and more preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or 11 wherein:

R

1 is hydrogen, halogen, -ON, -OR 8 or-SR, preferably hydrogen or -ON; and R2 is hydrogen; R3 is Cyi, wherein Cy. in R 3 is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or S02; and more preferably Cy, in R is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yi or pyrrolidin-3-yl; wherein said Cy1 is optionally substituted with one or more R 1 2 ; R4 is hydrogen, Clalkyl, Ri 2

R

7 N-Co 4 alkyl or Cy2-Oe4alkyl, preferably hydrogen, C4alkyl, -NR7RA 2 or Cy2; 5 wherein Cy2 are optionally substituted with one or more Rii; R is hydrogen; and Re is hydrogen, Calkyl, C4alkoxyi- 4 alkyl, hydroxyOu 4 alkyl or Ri 2

R

7

N-C

1 alky, preferably hydrogen or 35

C

1 alkyl and more preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or |I wherein: A is nitrogen and B is carbon; R1 is hydrogen, halogen, -CN, -OR or -SR 8 , preferably hydrogen or -CN; and R 2 is hydrogen;

R

3 is RrC 4 alkyl, Cy, or Cy2-Calkyl, wherein Cy1 and Cy2 are optionally substituted with one or more Rio; RA is hydrogen, C 4 alkyl, RR 7 N-Co 4 alkyl or Cy2-Co 4 alkyl, preferably hydrogen, C 4 alkyl, -NR 7

R

2 or Cy2; wherein Cy2 are optionally substituted with one or more R 1 ; R5 is hydrogen; and

R

6 is hydrogen, C 4 alkyl, C4alkoxyCl 4 alkyl, hydroxyC4alky or R 12

R

7

N-C

1 alkyl, preferably hydrogen or ) Calkyl and more preferably hydrogen, methyl or ethyl, In another embodiment, the invention relates to the compounds of formula I or II wherein: A is nitrogen and B is carbon; R, and R 2 are hydrogen;

R

3 is RrC- 4 alkyl, Cy, or Cy-Cialkyl, wherein CyI and Cy2 are optionally substituted with one or more RIG;

R

4 is hydrogen, Clalkyl, R 12

R

7

N-CO

4 alkyl or Cyz-Co4alkyl, preferably hydrogen, C4alkyl, -NR 7

R

1 2 or Cy2; wherein Cy2 are optionally substituted with one or more Rn; RE is hydrogen; and Rc is hydrogen, C 4 alkyl, Cl-alkoxyC;alkyl, hydroxyC 4 alkyl or R 2 R7N-C 4 aIkyl, preferably hydrogen or C4alkyl and more preferably hydrogen, methyl or ethy. 3 In another embodiment, the invention relates to the compounds of formula I or |I wherein: A is nitrogen and B is carbon; Ri is hydrogen, halogen, -CN, -OR 8 or -SR 8 , preferably hydrogen or -CN; and R 2 is hydrogen; R3 is Cy 1 , which is optionally substituted with one or more Ri; R4 is hydrogen, C 4 alkyl, Ri 2

R

7 N-Co.alkyl or Cy2-Co-4alkyl, preferably hydrogen, Cialkyl, -NR 7

R

1 2 or Cy2; 5 wherein Cy2 are optionally substituted with one or more R 11 ;

R

8 is hydrogen; and R6 is hydrogen, C 14 alkyl, Cl14alkoxyC1 4 alkyl, hydroxyC ualkyl or RnR7N-C 4alkyl, preferably hydrogen or Clalkyl and more preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I or 11 wherein. 0 A is nitrogen and B is carbon; R1 is hydrogen, halogen, -CN, -OR 8 or -SR, preferably hydrogen or -CN; and R 2 is hydrogen;

R

3 is Cys, wherein Cy1 in R 3 is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and 5 wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and wherein said CyI is optionally substituted with one or more Ric;

R

4 is hydrogen, C 4 alkyl, R 1 2

R

7 N-Co- 4 alkyl or Cyr-CoAalkyl, preferably hydrogen, C 4 alkyl, -NR 7

R

1 2 or Cy2; 36 wherein Cy2 are optionally substituted with one or more R<; Rs is hydrogen; and

R

6 is hydrogen, C 14 alkyl, CalkoxyC 4 a1ky, hydroxyC 4 alkyl or RnR7N-Clalkyl, preferably hydrogen or C4alkyl and more preferably hydrogen, methyl or ethyl. 5 In another embodiment, the invention relates to the compounds of formula I or 11 wherein: A is nitrogen and B is carbon;

R

1 is hydrogen, halogen, -CN, -OR 8 or -SR3, preferably hydrogen or -CN; and R2 is hydrogen;

R

3 is Cy 1 , wherein Cy, in R3 is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and D 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and more preferably Cyi in R3 is piperidinyl or pyrrolidinyl, even more preferably piperidin-3-yl or pyrrolidin-3-yl; wherein said Cy1 is optionally substituted with one or more R1c; R4 is hydrogen, Ci-alkyl, Ri 2

R

7 N-Coaalkyl or Cyo2-O 4 alkyl, preferably hydrogen, Cinalkyl, -NR 7 Ra 2 or Cy2; 5 wherein Cy2 are optionally substituted with one or more Rn; Rs is hydrogen; and R is hydrogen, CIalkyl, C ,talkoxyC 4 alkyl, hydroxyCI4alkyl or R1 2 R7N-Cl-4alkyl, preferably hydrogen or C4alkyl and more preferably hydrogen, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I wherein: D A is nitrogen and B is carbon; R, is hydrogen, halogen, -CN, -OR 8 or-SRs, preferably hydrogen or-ON; and R 2 is hydrogen;

R

3 is R 9 -O1alkyl, Cy, or Cy 2

-C

4 alkyl, wherein Cyj and Cy2 are optionally substituted with one or more R1o; R4 is hydrogen, Calkyl, R12R7N-Co- 4 alkyl or Cy 2 -Coa.alkyt, preferably hydrogen, Czalkyl, -NR 7

R

2 or Cy2; wherein Cy2 is optionally substituted with one or more R 1 ; and 5 R 5 is hydrogen. In another embodiment, the invention relates to the compounds of formula I wherein: A is nitrogen and B is carbon;

R

1 and R2 are hydrogen: R3 is R 9

C-O

1 alkyl, CyI or Cy 2

C-O

4 alkyl, wherein Cy1 and Cy2 are optionally substituted with one or more R 10 ; 0 R4 is hydrogen, O 4alkyl, RI 2 R7N-Cozalkyl or Cy2o-czalkyl, preferably hydrogen, CO-alkyl, -NR 7

R

2 or Cy2; wherein Cy2 is optionally substituted with one or more R; and RE is hydrogen. In another embodiment, the invention relates to the compounds of formula I wherein: A is nitrogen and B is carbon; 5 RI is hydrogen, halogen, -ON, -OR 6 or -SR 8 , preferably hydrogen or -CN; and R2 is hydrogen; RK is Cy1, which is optionally substituted with one or more Rio; R4 is hydrogen, C 4 alkyl, R 2

R

7 N-Coalkyl or Cy 2 -Conalkyl, preferably hydrogen, 0 4 alky, -NR 7

R

1 2 or Cy2; 37 wherein Cy2 is optionally substituted with one or more R 1 ; and Rs is hydrogen. In another embodiment, the invention relates to the compounds of formula 1 wherein: A is nitrogen and B is carbon; 5 R1 is hydrogen, halogen, -CN, -ORB or -SRB, preferably hydrogen or -CN; and R2 is hydrogen; R3 is Cy1, wherein Cy1 in R3 is a 3- to 7-membered monocyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and wherein said Cyl is 3 optionally substituted with one or more Rio;

R

4 is hydrogen, C 14 alky, RvR 7 N-Cooalkyl or Cy2-Cooalkyl, preferably hydrogen, Czalkyl, -NR 7

R

2 or Cy2; wherein Cy2 is optionally substituted with one or more R,; and

R

5 is hydrogen. in another embodiment, the invention relates to the compounds of formula I wherein: D A is nitrogen and B is carbon;

R

1 is hydrogen, halogen, -CN, -ORs or -SR, preferably hydrogen or -CN; and R 2 is hydrogen;

R

3 is Cy . wherein Cy, in R 3 is a 3- to 7-membered., preferably 5- to 6-membered, saturated monocyciic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C D or S ring atoms are optionally oxidized forming CO SO or SO2; and more preferably Cy, in R 3 is piperidinyl or pyrrolidiny wherein said Cy1 is optionally substituted with one or more Rio;

R

4 is hydrogen, C> 4 alkyl, R 12

R

7

N-CO

4 alkyl or Cy2-Oc4alkyl, preferably hydrogen, Calkyl, -NR 7

R

12 or Cy2; wherein Cy2 is optionally substituted with one or more R; and

R

8 is hydrogen. 5 In another embodiment, the invention relates to the compounds of formula I| wherein: A is nitrogen and B is carbon;

R

1 is hydrogen, halogen, -CN, -OR 8 or -SR 8 , preferably hydrogen or -CN; and R2 is hydrogen; R3 is Rs-Calkyl, Cy, or CyrCI-4alkyl, wherein Cy1 and Cy2 are optionally substituted with one or more Rio; R is hydrogen; and 0 Ps is hydrogen, C 14 alky, C.4alkoxyCi4alkylt hydroxyC 4 alkyl or NR7RlOCI-alkyl, preferably hydrogen or Clalkyl, more preferably C 4 alky and even more preferably methyl or ethyl. in another embodiment, the invention relates to the compounds of formula It wherein: A is nitrogen and B is carbon; R and R 2 are hydrogen; h5 R3 is R-Cioalky, Cyi or Cy 2

-C

4 alky, wherein Cy 1 and Cy2 are optionally substituted with one or more R1o; R is hydrogen; and RE is hydrogen, C>alkyl, C 4 alkoxyC 4 alkyl, hydroxyC.

4 alkyl or NR7R1r 2 -Clalkyl, preferably hydrogen or 38

C

4 alkyl, more preferably Calkyl and even more preferably methyl or ethyl. In another embodiment, the invention relates to the compounds of formula | wherein: A is nitrogen and B is carbon; R, is hydrogen, halogen, -ON, -ORB or -SRB, preferably hydrogen or -ON, more preferably hydrogen; and 5 R 2 is hydrogen;

R

3 is Cy , which is optionally substituted with one or more R 1 0 ;

R

5 is hydrogen; and

R

6 is hydrogen, C4alkyl, C 4 alkoxyC4alkyl, hydroxyC 4 alkyl or NR7R 2 -C;.4alkyl, preferably hydrogen or

CO

4 alkyl, more preferably C4alky and even more preferably methyl or ethyl. 3 In another embodiment, the invention relates to the compounds of formula II wherein: A is nitrogen and B is carbon;

R

1 is hydrogen, halogen, -ON, -OR 8 or -SR 8 , preferably hydrogen or -ON, more preferably hydrogen; and

R

2 is hydrogen;

R

3 is Cys, wherein Cy1 in R 3 is a 3- to 7-membered monocyclic ring, which is saturated, partially 5 unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from I to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, 30 or SO 2 ; and wherein said Cy1 is optionally substituted with one or more Rio;

R

5 is hydrogen; and 9 RP is hydrogen, C 4 alkyl, C4alkoxyC 4 aIkyl, hydroxyC 4 alkyl or NR 7 R1 2

-C

4 alkyl, preferably hydrogen or Cl4alkyl, more preferably C 4 alkyl and even more preferably methyl or ethyl. In another embodiment, the invention relates to the compounds of formula 11 wherein: A is nitrogen and B is carbon; R1 is hydrogen, halogen, -ON, -ORe or -SR 6 , preferably hydrogen or -CN; and R 2 is hydrogen; >5 R 3 is Cyl. wherein Cy1 in R 3 is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more 0 or S ring atoms are optionally oxidized forming CO, SO or S02; and more preferably Cy1 in R 3 is piperidinyl or pyrrolidinyl, even more preferaby piperidin-3-yl or pyrroiidin-3-y; wherein said Cy, is optionally substituted with one 0 or more Ric;

R

5 is hydrogen; and

R

6 is hydrogen, C4alkyl, C 1

.

4 alkoxyC 4 alkyl, hydroxyC 4 alkyl or NR7R 12

-C-

4 alkyl, preferably hydrogen or

C

4 alkyl, more preferably C4aIkyl, and even more preferably methyl or ethyl. In another embodiment, the invention relates to the compounds of formula It wherein: 5 A is nitrogen and B is carbon; R, is hydrogen or -CN, preferably hydrogen; and R 2 is hydrogen;

R

3 is a cycle of formula Cyi or Cyo; 39

R

5 is hydrogen; and R6 is hydrogen, C 4 alkyl, C,-4aIkoxyC 4 alkyl, hydroxyCli4alkyl, R 1 2

R

7

N-CO

4 aikyl, RCOO-o 4 aalkyl or

R

6 00-OCo 4 alkyl, preferably Cialkyl, ClalkoxyCl 4 alkyl, hydroxyC 4 alkyl, R12R 7

N-

14 alkyl, R 1

CO-CO

0 alkyl or

R-C

2

-CO

2 4 alkyl, more preferably Cl4alkyl, and even more preferably methyl or ethyl. 5 In another embodiment, the invention relates to the compounds of formula II wherein: A is nitrogen and B is carbon;

R

1 is hydrogen or -CN, preferably hydrogen; and R2 is hydrogen;

R

3 is a cycle of formula Cym, preferably with (S)-stereochemistry;

R

5 is hydrogen; and

R

6 is hydrogen, Cualkyl, C 4 alkoxyC 4 alkyl, hydroxyCI 4 alkyl, R 13

R

7 N-COalky, R600-Co4alkyl or RlSOD2-COo4alkyl, preferably Cialkyl, C 4 alkoxyC 1 alkyl, hydroxyCI-4alkyl, RUR 7 N-C1-4alkyt, RiECOO-Co4alkyl or RC0 2 -Co 4 alkyl, more preferably COtalkyl, and even more preferably methyl or ethyl. In another embodiment, the invention relates to the compounds of formula Il wherein:

R

3 is a cycle of formula Cyi, or Cym; Rs is hydrogen;

R

1 3 is -COR 1 3 or -S02R 13 and Rio is C4alkyl, haloOu4alkyl, ClalkoxyCulalkyl, hydroxyC>alkyl or cyanoCuvalkyl, preferably Cimalkyl or cyanoC,4alkyl, and more preferably methyl or cyanomethyl. In another embodiment, the invention relates to the compounds of formula II wherein:

SR

3 is a cycle of formula Cym, preferably with (S)-stereochemistry: R6 is hydrogen; Rio is -COR 1 3 ; and

R

1 3 is C 14 alkyi, haloCalkyl, C14alkoxyC4alkyl, hydroxyC 4 alkyl or cyanoClzalkyl, preferably C.

4 alkyl or cyanoC4alkyl, and more preferably methyl or cyanomethyl, .5 In another embodiment, the invention relates to the compounds of formula 11 wherein: W is CH;

R

3 is a cycle of formula Cyla, preferably with (S)-stereochemistry; Rs is hydrogen; Rio is -COR 3 ; and 0 R 3 is C 4 alkyl, haloC 4 alkyl, CalkoxyC-alkyl, hydroxyCu4alkyl or cyanoC.alky, preferably Cdalkyl or cyanoC4alkyl, and more preferably methyl or cyanomethyl, In another embodiment, the invention relates to the compounds of formula II wherein: W is N;

R

3 is a cycle of formula Cym, preferably with (S)-stereochemistry; 5 Rs is hydrogen; Rio is -COR13; and

R,

3 is C 1 alkyl, haloC-4alkyl, CialkoxyCuIalkyl, hydroxyCalkyl or cyanoC-alkyl, preferably Cl4alkyl or 40 cyanoOi 4 alkyl, and more preferably methyl or cyanomethyl. In another embodiment, the invention relates to the compounds of formula 11 wherein: A is nitrogen and B is carbon; R, is hydrogen or -CN, preferably hydrogen; and R2 is hydrogen; 5 R3 is a cycle of formula Cyl,, preferably with (S)-stereochemistry; RE is hydrogen; and

R

1 a is -COR 13 . In another embodiment, the invention relates to the compounds of formula Il wherein: A is nitrogen and B is carbon; ) R 1 is hydrogen or -CN, preferably hydrogen; and R2 is hydrogen: R, is a cycle of formula Cyia, preferably with (S)-stereochemistry; Rs is hydrogen;

R

10 is -COR1 3 ; and

R

1 3 is O 14 alkyl, haloC4alkyl, CalkoxyC 4 alky, hydroxyCuialkyl or cyanoC4alkyl, preferably Caalkyl or 5 cyanoCI4alkyl, and more preferably methyl or cyanomethyl. In another embodiment, the invention relates to the compounds of formula 11 wherein: R3 is a cycle of formula Cyaor Cya; R5 is hydrogen; RG is hydrogen, C-alkyl, CialkoxyCi 4 alkyl, hydroxyCl4alkyl, R1 2

R

7 N-C4alkyl, RmCO-Co4alkyl or 9 R 1 6

CO

2 -Coalkyl, preferably Calkyl, C4afkoxyCalkyl, hydroxy~l-alkyl, Rl 2 R7N-C 4 alky, RwCO-Coualkyl or

R

1 6 C0 2 -Coaalkyl, more preferably OCualkyl, and even more preferably methyl or ethyl; Ro is -COR 3 or -SO2R,; and

R

3 is C 4 alkyl, haloO 1 ualkyl, C 4 alkoxyC.alkyl, hydroxyClalkyl or cyanoCAalkyl, preferably C 14 alkyl or cyanoC4alkyl, and more preferably methyl or cyanomethyl. 5 In another embodiment, the invention relates to the compounds of formula 11 wherein: R3 is a cycle of formula Cy,, preferably with (S)-stereochemistry; RK is hydrogen; R6 is hydrogen, C4alkyl, C14alkoxyCi 4 alkyl, hydroxy~i 4 alkyl, Ri 2

R

7

N-CO

4 alky, ROC-CoAalkyl or R16CO-Co4alkyl, preferably Calkyl, C4alkoxyC 1 4 alky, hydroxyCl 4 alkyl, R 12

R

7 N-C lalkyl, RBCO-Co4alkyl or 30 R 6 COrC-Oaikyl, more preferably Cqalkyl, and even more preferably methyl or ethyl;

R

1 is -COR,3; and R3 is Cualkyl, haloCi-alkyl, ClalkoxyC 4 alkyl, hydroxyC'4alkyl or cyanoCi 4 alkyl, preferably Cialkyl or cyanoC 4 alkyl, and more preferably methyl or cyanomethyL in another embodiment, the invention relates to the compounds of formula 11 wherein: 35 A is nitrogen and B is carbon;

R

1 is hydrogen or -CN, preferably hydrogen; and R 2 is hydrogen;

R

3 is a cycle of formula Cytaor Cyj 0

;

41

R

6 is hydrogen;

R

6 is hydrogen, C 1 alkyl, ClaIkoxyC4alkyl, hydroxyC 14 alkyl, R 12 R7N-C- 4 alkyl, RieCO-Co4alkyl or Ri6COCe 4 alkyl, preferably Ci 4 alkyl, C4alkoxyC14alkyl, hydroxyC 4 alkyl, R 1 2R 7

N-C-

4 alkylF ROCO-Co4alkyl or RC02-OCoAalky1, more preferably Ciaalkyl, and even more preferably methyl or ethyl; and 5 Rio is -COR 3 or-S0 2

R

3 , In another embodiment, the invention relates to the compounds of formula II wherein: A is nitrogen and B is carbon; R, is hydrogen or -CN, preferably hydrogen; and R 2 is hydrogen;

R

3 is a cycle of formula Cyla, preferably with (S)-stereochemistry; ) R 5 is hydrogen; R, is hydrogen, C4alkyl, C 14 alkoxyC 4 alkyl, hydroxyCloalkyl, R 12

R

7

N-C

4 alkyl, RlSCO-CoAalkyl or

R,

6 C0Ctoalkyl, preferably Ci4alkyl, C4alkoxyCualkyl, hydroxyC4alkyl, R 12

R

7

N-C

1 alkyl R- 6 CO-Coalkyl or

R

1 00 2 -COalkyl, more preferably O> 4 alkyl, and even more preferably methyl or ethyl; Rio is -CORn; and

R

1 is C.

4 alkyl, haloC4alkyl, Cb.alkoxyO 4 alkyl, hydroxyC- 4 alkyl or cyanoCi 4 alkyl, preferably Ctalkyl or cyanoC4alkyl, and more preferably methyl or cyanomethyl. In another embodiment, the invention relates to the compounds of formula 11 wherein: A is nitrogen and B is carbon; W is CH; D R, is hydrogen or -ON, preferably hydrogen; and R 2 is hydrogen;

R

3 is a cycle of formula Cyig, preferably with (S)-stereochemistry;

R

5 is hydrogen; R6 is hydrogen, O 14 alkyl, C 4 alkoxyCalkyl, hydroxyC,4alkyl, R 12

R

7 N-C p 4 alkyl, RIOCO-O.4alkyl or R16O 2 -Co-alkyl, preferably Clalkyl, ClalkoxyCu4alkyl, hydroxyC4alkyl, R 12

R

7

N-C

4 alkyl, R 6

CO-C

4 alkyl or 5 RICOCo-c4alkyl, more preferably C 4 alkyl, and even more preferably methyl or ethyl;

R

1 0 is -COR 13 ; and

R

1 2 is C 4 alkyl, haloCalkyl, Ci 4 alkoxyC 4 alkyl, hydroxyCi 4 alkyl or cyanoC4alkyl, preferably O 14 alkyl or cyanoCl4alkyl and more preferably methyl or cyanomethyl. in another embodiment, the invention relates to the compounds of formula Il wherein: 0 A is nitrogen and B is carbon; W is N; R, is hydrogen or -ON, preferably hydrogen: and R2 is hydrogen; R3 is a cycle of formula Cyi, preferably with (S)-stereochemistry; RE is hydrogen; 5 R6 is hydrogen, CO 1 alkyl, CI-alkoxyC 1 4 alkyl, hydroxyC 4 alkyl, RnR7N-C.alkyl, R16CO-Co-4alkyl or

R

16

CO

2 -coAalkyl, preferably C 1 alkyl, C 1 .alkoxyCO 1 .alkyl, hydroxyC 4 alkyl, R 1 2R7N-Cp 4 alkyl, RiOCO-Oo 4 alkyl or

R

6 C0-OCoalkyl, more preferably C 4 alkyl, and even more preferably methyl or ethyl; 42 Ric is -CR 3 ; and Ri 3 is Ci 4 alkyl, haloC 14 alkyl, C4alkoxyCl4alkyl, hydroxyC 4 alkyl or cyanoC 4 alkyl, preferably Ci 4 alkyl or cyanoC 4 alkyl, and more preferably methyl or cyanomethyl. In another embodiment, the invention relates to the compounds of formula 11 wherein: A is nitrogen and B is carbon; R1 is hydrogen or -CN, preferably hydrogen; and R 2 is hydrogen;

R

3 is a cycle of formula Cyla, preferably with the (S)-stereochemistry;

R

5 is hydrogen;

R

6 is Cl4alkyl, preferably methyl or ethyl; Ri is -COR 1 3 ; and

R

1 3 is C 14 alky or cyanoOtzalkyl, preferably methyl or cyanomethyl In another embodiment, the invention relates to the compounds of formula II wherein A is nitrogen and B is carbon; W is CH; 5 P 1 is hydrogen or -CN, preferably hydrogen; and R 2 is hydrogen;

R

3 is a cycle of formula Cye,, preferably with the (S)-stereochemistry;

R

5 is hydrogen; R is C'4alkyl, preferably methyl or ethyl; Rie is -COR 3 ; and D R is C 14 alkyl or cyanoCu-alkyl, preferably methyl or cyanomethyl. In another embodiment, the invention relates to the compounds of formula Il wherein: A is nitrogen and B is carbon; W is N; R is hydrogen or -CN, preferably hydrogen; and R 2 is hydrogen; 5 R 3 is a cycle of formula Cy 3 , preferably with the (S)-stereochemistry; Rs is hydrogen; R is C 1 alkyl, preferably methyl or ethyl;

R

1 0 is -COR; and

R

1 3 is C1alkyl or cyanoCl4alkyl, preferably methyl or cyanomethyl In another embodiment, the invention relates to the compounds of formula II wherein: A is nitrogen and B is carbon;

R

1 is hydrogen and R 2 is hydrogen;

R

3 is a cycle of formula Cyi, with the (S)-stereochemistry; Rs is hydrogen; 5 Re is C 1 -alkyl, preferably methyl or ethyl; R is -COR 3 ; and

R

1 3 is CuKalkyl or cyanoC4alkyl, preferably methyl or cyanomethyl, 43 In another embodiment, the invention relates to the compounds of formula 1I wherein: A is nitrogen and B is carbon;

R

1 is hydrogen or -CN, preferably hydrogen; and R 2 is hydrogen; R3 is a cycle of formula Cy1;

R

5 is hydrogen; REis Cu4alkyl, preferably methyl or ethyl; and Ric is -S0 2

R

13 . Furthermore, the present invention covers all possible combinations of the particular and preferred embodiments described above. In another embodiment, the invention relates to a compound of formula I or |I selected from the list of compounds described in examples 1 to 37. In another embodiment, the invention relates to a compound of formula I or 1I that provides more than 50% inhibition of JAK3 activity at 10 RM, more preferably at 1 M and still more preferably at 0.1 M, in a JAK3 assay such as the one described in example 38. 5 In an additional embodiment, the invention relates to a compound according to formula I or il that provides more than 50% inhibition of JAK2 activity at 10 M, more preferably at 1 kM and still more preferably at 0.1 pM, in a JAK2 assay such as the one described in example 39. The compounds of the present invention contain one or more basic nitrogens and may, therefore, form salts with organic or inorganic acids. Examples of these salts include: salts with inorganic acids such as hydrochloric acid, ) hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others. Some of the compounds of the present invention may contain one or more acidic protons and, therefore, they may also form salts with bases. 5 Examples of these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkylamines, lysine, arginine, N-methylglucamine, procaine and the like. There is no limitation on the type of salt that can be used, provided that these are pharmaceutically acceptable when they are used for therapeutic purposes. The term pharmaceutically acceptable salt refers to those 0 salts which are, according to medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are wel known in the art. The salts of a compound of formula I or It can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of formula I or I) with a sufficient amount of 5 the desired acid or base to give the salt in the conventional manner. The salts of the compounds of formula I or I can be converted into other salts of the compounds of formula I or li by ion exchange using ionic exchange resins. The compounds of formula I or Il and their salts may differ in some physical properties but they are 44 equivalent for the purposes of the present invention. All salts of the compounds of formula I or Il are included within the scope of the invention. The compounds of the present invention may form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. As used herein, the term solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or lI or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. A complex with water is known as a hydrate. Solvates of compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention. The compounds of formula I or 11 may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the invention may have the abikty to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula I or 11, including all polymorphic forms polymorphshs") thereof, are included within the scope of the invention. Some of the compounds of the present invention may exist as several diastereoisomers and/or several optical isomers. Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on products of formula I or II. Optically pure isomers can also be individually obtained using enantiospecific synthesis. The present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them. The present invention further covers all unlabeled and isotopically labeled forms of the compounds of formula I or If. The present invention further covers all tautomeric forms of the compounds of formula I or 11. The compounds of formula I or 11 can be obtained by following the processes described below. As it will be 5 obvious to one skilled in the art, the exact method used to prepare a given compound may vary depending on its chemical structure. Moreover, in some of the processes described below it may be necessary or advisable to protect the reactive or labile groups with conventional protecting groups. Both the nature of these protecting groups and the procedures for their introduction and removal are well known in the art (see for example Greene T.W. and Wuts P.G.M, "Protecting Groups in Organic Synthesis", John Wiley & Sons, 3rd edition, 1999). As an example, as U protecting group of an amino function the tert-butoxycarbonyl (BOC) group can be used. Whenever a protecting group is present, a later deprotection step will be required, which can be performed under standard conditions in organic synthesis, such as those described in the above-mentioned reference. In general, compounds of formula I or Il can be obtained from a compound of formula VI, as shown in the following scheme 5 45 R3H 2 N

R

5

R

4 -rN R Rs W

R

4 -NCS R N H N 111 R3 N 0IN + or B1-A /B O N SR4-CHO IV R R2I R2 VI I H R N N N ' / V + R6-x N ' B /N B -N OA A R, R, R2 R2 Ila (I, wherein R 5 is H) l1b (11, wherein R 6 is different from H) wherein A, B, W, R 1 , R 2 , R3 R 4 and Rs have the meaning previously described in relation with a compound of formula I or 11; R 6 in a compound of formula V or lib has the meaning previously described in relation with a compound of formula 1 or Ii, except hydrogen; and X is a leaving group. 5 The compounds of formula I can be obtained by reacting a compound of formula VI with either the corresponding isothiocyanate 11 or aldehyde IV. The reaction with an isothiocyanate III may be performed in the presence of 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide, in a suitable solvent such as dichloromethane, and heating at a suitable temperature usually comprised between 100 and 200 1C. The heating may be thermal or by irradiating with 0 microwaves at a wattage that allows reaching the temperature mentioned above. The reaction between compounds of formula VI and JV can be carried out in a suitable solvent such as ethanol, butanol, N,N-dimethylformamide or dimethylacetamide, in the presence of an acid such as acetic acid, p toluenesulfonic acid or sodium bisulfite, and heating, preferably at a temperature comprised between 100 and 200 0C. The heating may be thermal or by irradiating with microwaves at a wattage that allows reaching the temperature 5 mentioned above. When required, the reaction can be completed by subsequent addition of water.

46 The compounds of formula 11 (i.e. compounds of formula lIla and lib) can be obtained from a compound of formula VIL The compounds of formula lIa (i.e. a compound of formula I wherein R 6 is hydrogen) can be obtained by reaction of a compound of formula VI with a synthetic equivalent for the CO synthon. Any such synthetic equivalent 5 disclosed in the literature can in principle be used, for example 1,1'-carbonyldiimidazole (CDI), phosgene, diphosgene or triphosgene. The reaction is conducted in the presence of a base such as NN-diisopropylethylamine; and in a suitable solvent such as tetrahydrofuran (THF), and preferably at room temperature. The reaction can be completed by subsequent addition of water, The compounds of formula lib (i.e. a compound of formula 11 wherein R 6 is different from hydrogen) can be J obtained by alkylation of a compound of formula lia with an alkylating agent R 6 -X (V), wherein X represents a leaving group and R5 is different from H; suitable examples of X include among others halogen such as Cl, Br or I, mesylate, tosylate or triflate. This reaction may be carried out in the presence of a base such as Cs2CO3, K 2

CO

3 , NaOH, ted BuOK or NaH, in a suitable solvent, such as acetone., toluene, 1,2-dimethoxyethane, and preferably dimethylformamide, at a suitable temperature, comprised between 0 0 C and reflux. 5 The compounds of formula VI can be obtained by reduction of a compound of formula VIl as shown in the following scheme: 0 2 N R4 H 2 N R 5 R3 N / R3 Nw N N B DA B A/ R14 R1 ' R2 R2 A1 VIl VI wherein A, B, W, Rs, R 2 . R 3 and R have the meaning previously described in relation with a compound of formula I or It. 0 The reaction may be carried out with hydrogen gas, using a platinum catalyst, such as PtC in the presence of thiophene in diisopropylethylamine; in a suitable solvent such as EtOH and preferably at room temperature, The compounds of formula Vil can be obtained by reacting a compound of formula Vill with either a compound of formula IX or X, as shown in the following scheme: 47

BY

2 0 2 N R

R

3 W B 0 N

FR

3

I

2

FR

2 A0: N BO N H N W + or IX NH Cl R 1 B-\ R

R

2 A..N R 2 Vill X VII wherein A, B, W, Ri, R 2 , R 3 and R5 has the meaning previously described in relation with a compound of formula I or II; and BY 2 is a boronic acid or ester. The reaction between compounds of formula VIll and IX may be carried out using the conditions described in the literature for Suzuki's coupling reactions. For example, the reaction may be carried out in the presence of a Pd catalyst such as Pd(PPh3)4; in the presence of a base such as Na 2

CO

3 ; in a mixture of solvents such as a dimethoxyethane and water; and heating. The direct coupling between compounds of formula Vill and X can be performed using a palladium catalyst such as for example tetrakis (triphenylphosphine)palladium(O) (Pd(PPh3) 4 ) and preferably paladium (II) acetate Pd(OAc) 2 in the presence of triphenylphosphine, and a base, such as for example triethylamine and preferably potassium acetate. The reaction is usually carried out under anhydrous and anaerobic conditions. The reaction may be carried out in a solvent such as dioxane, NN-dimethylformamide, toluene and preferably in dimethylacetamide and heating at a temperature usually composed between 60*C-1 00*C. Compounds of formula IX and formula X can be easily obtained from commercial compounds by known methods. Additionaly, the compounds of formula Vil wherein A is nitrogen and B is carbon (i.e. Vila) can be obtained by reacting a compound of formula XI with a compound of formula XII, as shown in the following scheme: 48 0N R 5 R, ON R5

R

3 , W R 2 R3 N W NNN SiMe 3

NH

2 An- N xix Vita 0 2 N R +X11 N W H N XIb H wherein W, R 1 , R 2 , R 3 and R 5 have the meaning previously described in relation with a compound of formula 1 or II; and An is iodine, 2,4-dinitrophenolate, p-toluensulphonate or 2,4,6-trimethylbencenosulphonate. The reaction may be carried out in the presence of tetra-n-butylammonium fluoride (TBAF) in THF and of a 5 base such as 1.5-diazabicyclo[4.3.O]non-5-ene (DBN) or 1,4-diazabicyclo(2.2.2]octane (DABCO), preferably 1,8 diazabicyclo[5.4.0)undec-7-ene (DBU), in a solvent such as N,N-dimethylformamide, dimethylsulfoxide, dichloromethane, toluene or acetonitrile, preferably acetonitrile, and at a temperature comprised between -78 *C and room temperature. Alternatively the compounds of formula Vila can be obtained by reacting a compound of formula XIl with the D deprotected derivative of the compound of formula XI (XIb) obtained by using standard conditions. The compounds of formula Xli can be obtained by reaction of a compound of formula Xill with aminosuffonic acid in the presence of a HI aqueous solution; and of a base such as K 2 00 3 NaOH or KOH; in a solvent such as dichloromethane, tetrahydrofuran, water, ethanol, methanol, isopropanol or acetonitrile; and heating preferably at reflux, as shown in the following scheme' R2 R2 N NH 2 An 5 X111 X11 wherein R, and R 2 have the meaning previously described in relation with a compound of formula I or II; and An has the meaning described above.

49 The compounds of formula Xl can be obtained by reaction of a compound of formula VillI with tnmethylsilylacetylene, as shown in the following scheme: 0 2 N R 5 R0N

R

5 O N W NI N _ SiMe 3 - ~ H N> H N SiMe 3 Vill XI wherein W, R 3 and RE have the meaning previously described in relation with a compound of formula I or 1il 5 The reaction with trimethylsilylacetylene may be carried out under Sonogashira conditions, using a palladium catalyst such as for example tetrakis (triphenylphosphino)palladium(O) (Pd(PPh 3 )4), preferably bis(triphenylphosphino)dichloropalladium(ll) (Pd(Ph3P) 2 Cl) in the presence of triphenylphospine, a Cu (1) catalyst as a cocatalyst, such as Cul, and a base, such as diethylamine., N N-diisopropylethylamine, triethylamine or isopropylethylamine. The reaction is usually carried out under anhydrous and anaerobic conditions. The reaction J may be carried out in a solvent such as dioxane, NN-dimethylformamide, tetrahydrofuran or toluene, at room temperature or by heating. The compounds of formula Vill can be obtained by reaction of a compound of formula XIV with a compound of formula XV, as shown in the following scheme: 0 2 N 0 2 N C + H 2

N-R

3 F R W CI NCI XIV XV Vill 5 wherein W, R 3 and R 5 have the meaning previously described in relation with a compound of formula I or II. The reaction between the compounds of formula XIV and XV may be carried out in the presence of a base such as diisopropylethylamine, diethylamine or triethylamine, in a suitable solvent such as THF or acetonitrile, and at a temperature comprised between -78 *C and room temperature. The compounds of formula XIV and XV are commercial or may be easily obtained from commercial 0 compounds using standard procedures, Furthermore, some compounds of the present invention can also be obtained from other compounds of formula I or lI by appropriate conversion reactions of functional groups in one or several steps, using well-known reactions in organic chemistry under the standard experimental conditions. Said transformations can be carried out for example upon R3 and include, for example the substitution of a primary or secondary amine by treatment with an .5 alkylating agent, the reaction of an acid or ester with an amine to obtain the corresponding amide, the conversion of an amine into a sulfonamide and the hydrolysis of an ester to obtain a carboxylic acid. In some of these conversions it may be necessary or advisable to protect the reactive or unstable groups by means of conventional protective 50 groups. As it will be obvious to those skilled in the art, these interconversion reactions can be carried out upon the compounds of formula I or I as well as upon any suitable synthesis intermediate thereof. As mentioned above, the compounds of the present invention act by inhibiting JAK/STAT signaling pathways, particularly by inhibiting JAK3 activity. Therefore, the compounds of the invention are expected to be useful to treat or prevent diseases in which JAKs, particularly JAK3, play a role in mammals, including human beings, These diseases include, but are not limited to, transplant rejection; immune, autoimmune and inflammatory diseases; neurodegenerative diseases; and proliferative disorders (see e.g. O'Shea J.J. et al, Nat. Rev. Drug. Discov, 2004, 3(7):555-64; Cetkovic-Cvrlje M. et al, Curr. Pharm. Des. 2004, 10(15):1767-84; Cetkovic-Cvrije M. et ) al, Arch, Immunol. Ther. Exp. (Warsz), 2004, 52(2):69-82). Acute or chronic transplant rejection reactions that can be treated or prevented with the compounds of the present invention include any kind of cell, tissue or organ xenotransplants or allografts, such as of heart, lung, liver, kidney, pancreas, uterus, joints, pancreatic islets, bone marrow, limbs, cornea, skin, hepatocytes, pancreatic beta cells, pluripotential cells, neuronal cells and myocardial cells, as well as graft-versus-host reactions (see e.g. 5 Rousvoal G. et al, Transpl. Int. 2006, 19(12):1014-21; Borie DC. et al, Transplantation 2005, 79(7):791-801: Paniagua R. et al, Transplantation 2005, 80(9):1283-92; Higuchi T. et al, J. Heart Lung Transplant. 2005, 24(10):1557-64; Ssemann MD. et al, Transpl Int. 2004, 17(9):481-89; Silva Jr HT. et al, Drugs 2006, 66(13):1665 1684). Immune, autoimmune or inflammatory diseases that can be treated or prevented with the compounds of the J present invention include among others, rheumatic diseases (e.g. rheumatoid arthritis and psoriatic arthritis), autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, and neutropenia), autoimmune gastritis and inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), scleroderma, type I diabetes and complications from diabetes, type B hepatitis, type C hepatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact 5 dermatitis, eczema, skin sunburns, suppression of HlV replication, infertility of autoimmune origin, autoimmune thyroid disease (Grave's disease), interstitial cystitis, mast cell-mediated allergic reactions such as asthma, angiodema, anaphylaxis, bronchitis, rhinitis and sinusitis, and inflammatory or autoimmune ocular diseases such as dry eye syndrome, glaucoma, Sjbgren's syndrome, uveitis and retinopathy of prematurity (see e.g. Sorbera LA. et al, Drugs of the Future 2007, 32(8):674-680; O'Shea J.J. et al, Nat. Rev. Drug. Discov. 2004, 3(7):555-64; Cetkovic '0 Cvrije M. et al, Curr, Pharm. Des. 2004, 10(15):1767-84; Muller-Ladner U. et al, J. Immunol. 2000, 164(7): 3894 3901; Walker JG. et al, Ann. Rheum. Dis. 2006, 65(2):149-56; Milici AJ. et al, Arthritis Rheum .2006, 54 (9, Suppl): abstr 789; Kremer JM. et al, Arthritis Rheum, 2006, 54. 4116, presentation no. L40; Cetkovic-Cvrlje M. et al, Arch Immunol. Ther, Exp. (Warsz), 2004, 52(2):69-82; Malaviya R. et al, J. Pharmacol. Exp. Ther, 2000, 295(3):912-26; Malaviya R. et al, J. Biol. Chem. 1999, 274(38):27028-38; Wilkinson B et al, Ann. Rheum. Dis. 2007, 66(Suppl 2): 5 Abst. THU0099; Matsumoto M. et al, J. Immunol. 1999, 162(2):1056-63, West K., Curr Opin Inventig Drugs 2009:10(5):491-504, Huang Y, et al, Exp Eye res 2007:85(5):684-95, Killedar SY et al Laboratory Investigation 51 2006:86:1243-1260, Egwuagu C.E., Cytokine 2009:47(3):149-156, Byfield G., Investigative Ophtalmology &Viral Science 2009:50:3360), Neurodegenerative diseases that can be treated or prevented with the compounds of the present invention include, among others, amyotrophic lateral sclerosis and Alzheimer's disease (see e.g. Trieu VN. et al, Biochem. Biophys. Res. Commun. 2000, 267(1):22-5). Proliferative disorders that can be treated or prevented with the compounds of the present invention include, among others, leukemias, lymphomas, glioblastoma multiforme, colon carcinoma, as well as thromboembolic and allergic complications associated with these diseases (see e.g. Sudbeck EA. et al, Clin, Cancer Res. 1999, 5(6):1569-82; Narla RK. et al, Olin, Cancer Res. 1998, 4(10):2463-71; Lin Q. et al, Am J. Pathol. 2005, 167(4):969 ) 80; Tibbles HE. et al, J. Biol. Chem. 2001, 276(21):17815-22). It has been found that certain compounds of formula I or 11, besides inhibiting JAK3 activity, also inhibit JAK2 kinase to varying degrees, and therefore can also be useful for the treatment or prevention of any disease mediated by JAK2 kinase. A group of such JAK2-mediated diseases are myeloproliferative disorders, including polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, 5 hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome (see e.g. Geron I. et al, Cancer cell 2008, 13:321-330; Pardanani A. et al, Leukemia 2007, 21(8):1658-68; Mathur A. et al, Biochem Pharmacol 2009, 78(4):382-9; Manshouri T. et al, Cancer Sci. 2008, 99(6):1265-73; Wernig G. et a, Cancer cell 2008, 13(4):311-20. Elizabeth 0. et al, Blood, 111(12: 5663-5671). 3 Compounds of formula I or 11 wherein R 1 and R2 are hydrogen have been found to be particularly useful as JAK2 inhibitors, and thus can be particularly useful, in addition to treating or preventing all the diseases mentioned in the preceding paragraphs, also for the treatment or prevention of myeloproliferative disorders (MPD), Thus, another aspect of the invention relates to a compound of formula I or II, or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by JAK2. More preferably, the 5 disease mediated by JAK2 is a myeloproliferative disorder. In a preferred embodiment, the compounds of formula I or 11 are those wherein R 1 and R2 are hydrogen. Another aspect of the present invention relates to the use of a compound of formula I or II or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by JAK2. More preferably, the disease mediated by JAK2 is a myeloproliferative disorder. In a 0 preferred embodiment, the compounds of formula I or I are those wherein R and R2 are hydrogen. Another aspect of the present invention relates to a method of treating or preventing a disease mediated by JAK2 in a subject in need thereof, especially a human being, which comprises administering to said subject a compound of formula I or 1I, or a pharmaceutically acceptable salt thereof. More preferably, the disease mediated by JAK2 is a myeloproliferative disease. in a preferred embodiment, the compounds of formula I or Il are those wherein 5 R and R2 are hydrogen Another aspect of the invention relates to a compound of formula I or II, or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a myeloproliferative disorder. In a preferred embodiment, the 52 myeloproliferative disorder is selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome. in a preferred embodiment, the compounds of formula I or 11 5 are those wherein R 1 and R 2 are hydrogen. Another aspect of the invention relates to the use of a compound of formula I or i or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a myeloproliferative disorder. In a preferred embodiment, the myeloproliferative disorder is selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic 3 neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome, In a preferred embodiment, the compounds of formula I or I are those wherein R 1 and R 2 are hydrogen. Another aspect of the present invention relates to a method of treating or preventing a myeloproliferative disorder in a subject in need thereof, especially a human being, which comprises administering to said subject a 5 compound of formula I or 11 or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the myeloproliferative disorder is selected from polycythemia vera, essential thrombocytosis, idiopathic myelofibrosis, chronic myelogenous leukemia, hypereosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloid metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis and myelodisplastic syndrome. In a preferred embodiment, the compounds of formula I or It S are those wherein R 1 and R 2 are hydrogen. Biological assays that can be used to determine the ability of a compound to inhibit JAKs, particularly JAK3 and JAK2, are well known in the art. For example, a compound to be tested can be incubated in the presence of the desired JAK, such as JAK3 or JAK2, to determine whether inhibition of JAK enzymatic activity occurs, as described in the assay of examples 38 and 39 for JAK3 and JAK2, respectively. Other in vitro useful assays that can be used to 5 measure JAK3-inhibitory activity include cellular assays, for example IL-2-induced proliferation of human T lymphocytes. The immunosuppressive activity of the compounds of the invention can be tested using standard in vivo animal models for immune and autoimmune diseases, which are well known in the art. For example, the following assays can be used: delayed-type hypersensitivity (DTH) (see e.g. the method disclosed in Kudlacz E. et a, Am J. Transplant. 2004, 4(1):51-7, the contents of which are incorporated herein by reference), rheumatoid '0 arthritis models such as collagen-induced arthritis (see e.g. the method disclosed in Holmdahl R et al, APMIS, 1989, 97(7):575-84, the contents of which are incorporated herein by reference), multiple sclerosis models such as experimental autoimmune encephalomyelitis (EAE) (see e.g. the method disclosed in Gonzhlez-Rey et al, Am. J. Pathol. 2006, 168(4): 1179-88, the contents of which are incorporated herein by reference) and transplant rejection models (see e.g. the various animal models disclosed in the references listed above in relation to the treatment of 35 transplant rejection, incorporated herein by reference). The antiproliferative activity of the compounds of the invention can be tested using standard in vivo animal models well known in the art, such as xenograft studies (see e.g Mohammad RH. et al, Pancreas. 1998; 16(1):19).

53 For selecting active compounds for JAK3, testing at 10 gM must result in an activity of more than 50% inhibition of JAK3 activity in the test provided in example 38, More preferably, when tested in this assay compounds should exhibit more than 50% inhibition at 1 gM, and still more preferably, they should exhibit more than 50% inhibition at 0.1 pM. 5 For selecting active compounds for JAK2, testing at 10 gM must result in an activity of more than 50% inhibition of JAK2 activity in the test provided in example 39 More preferably, when tested in this assay compounds should exhibit more than 50% inhibition at 1 M, and still more preferably, they should exhibit more than 50% inhibition at 0.1 kM. Assays that can be used to predict the PK profile of a compound are well known in the art. For example, a 0 Caco-2 assay can be used to determine in vitro the potential for oral absorption of a compound. To show a good PK profile the compound must also exhibit a suitable clearance, as determined in a standard test using for example human liver microsomes in an assay such as the one described in example 40. Standard assays can be used to assess potential toxic effects of drug candidates, all of which are well known in the art. Such tests include e.g. viability assays in different cell lines such as human hepatocyte carcinoma 5 cells (Hep G2), which can be performed following standard procedures.such as the one described in example 41. The present invention also relates to a pharmaceutical composition that comprises a compound of the present invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof, o The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as it is well known, will depend upon the nature of the active compound and its route of administration. Any route of administration may be used, for example oral, parenteral, nasal, ocular, rectal and topical administration. Solid compositions for oral administration include tablets, granulates and capsules. In any case the 25 manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients, These excipients can be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogenphosphate; binding agents such as for example starch, gelatin or povidone; disintegrants such as sodium carboxymethyl starch or sodium croscarmellose; and lubricating agents such as for example magnesium stearate, stearic acid or talc. Tablets can be additionally coated with suitable excipients by using known techniques 30 with the purpose of delaying their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, or simply to improve their organoleptic properties or their stability. The active compound can also be incorporated by coating onto inert pellets using natural or synthetic film-coating agents. Soft gelatin capsules are also possible, in which the active compound is mixed with water or an oily medium, for example coconut oil, mineral oil or olive oil.

54 Powders and granulates for the preparation of oral suspensions by the addition of water can be obtained by mixing the active compound with dispersing or wetting agents; suspending agents and preservatives. Other excipients can also be added, for example sweetening, flavoring and colouring agents. Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing 5 commonly used inert diluents, such as purified water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol. Said compositions can also contain coadjuvants such as wetting, suspending, sweetening, flavoring agents, preservatives and buffers. Injectable preparations, according to the present invention, for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene D glycol or vegetable oils. These compositions can also contain coadjuvants., such as wetting, emulsifying, dispersing agents and preservatives. They may be sterilized by any known method or prepared as sterile solid compositions, which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile materials and keep them under these conditions throughout all the manufacturing process, For the rectal administration, the active compound can be preferably formulated as a suppository on an oily 5 base, such as for example vegetable oils or solid semisynthetic glycerides, or on a hydrophilic base such as polyethylene glycols (macrogol), The compounds of the invention can also be formulated for their topical application for the treatment or prevention of pathologies occurring in zones or organs accessible through this route, such as eyes, skin and the intestinal tract. Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is 0 dispersed or dissolved in suitable excipients. For the nasal administration or for inhalation, the compound can be formulated as an aerosol and it can be conveniently released using suitable propellants, The dosage and frequency of doses will depend upon the nature and severity of the disease to be treated, the age, the general condition and body weight of the patient, as well as the particular compound administered and ?5 the route of administration, among other factors, A representative example of a suitable dosage range is from about 0,01 mg/Kg to about 100 mg/Kg per day, which can be administered as a single or divided doses. The following examples illustrate the scope of the invention. 30 Examoles The following abbreviations have been used in the examples: AcOH: acetic acid 35 AcN: acetonitrile DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DIPEA: N,N-diisopropylethylamine 55 DMAC: N,N-dimethylacetamide DMF: NN-dimethylformamide EDC: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide EtOAc: ethyl acetate EtOH: ethanol HATU: 2-(1H-7-Azabenzotriazol-1-yl)--1,1,3,3-tetramethyl uranium hexafluorophosphate Methanaminium HOBt: 1-hydroxybenzotriazole HPLC: high performance liquid chromatography LC-MS: liquid chromatography-mass spectroscopy ) Mel: iodomethane MeOH: methanol PTSA: para-toluene sulfonic acid TBAF: tetrabutylammonium fluoride TBME: tert-butyl methyl ether 5 TEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofurane TLC: thin layer cromatography tR: retention time One of the following methods was used to determine the LC-MS spectrums: Method 1: Column SunFire C18 3.5 jpm, (100 mm x 2.1), flow rate: 0.3 mLimin, eluent A CH3CN:MeOH 1:1 B NHAc 5 mM pH 7, gradient : 0 min 10 % A; 17 min 95 % A; 10 min 95 % A. Method 2 : Column XBridge, 3.5 jim (50 mm x 4.6), temperature: 30 0C, flow rate: 2 mL/min, eluent A = NH 4 HCO 10 5 mM (pH = 9), B = AcN, gradient: 0 min 5% B; 4.8 min 100% B; Method 3 : Column XBridge, 3.5 qm (50 mm x 4.6), temperature: 50 0C, flow rate: 1.6 mL/min, eluent A = NH4HCO 3 10 mM (pH = 9), B = AcN, gradient: 0 min 5% B; 3.5 min 1005% B; Method 4 (Palau): Column Waters Acquity UPLC BEH 018 (1.7 pim, 2.1 mm x 50 mm), temperature: 40 "0, flow: 0.5 mL/min, eluent: ACN (A) /ammonium bicarbonate 10mM (B), gradient: 0 min 10% A - 3,75 min 90% A 0 Method 5 :: Column YMC, 3.5 um (50 mm x 4.6), temperature: 50 0C, flow rate: 1.3 mL/min, eluent A =H 2 0 (0.1% HCOOH), B = AcN (0.1% HCOOH), gradient: 0 min 5% B; 3.5 min 100% B. 5 56 REFERENCE EXAMPLE 1 1-Amino-4-trifluoromethylpyridinium 2,4.6-trimethylbenzenesulfonate To a solution of 4-trifiuoromethylpyridine (2.23 g, 15.2 mmol) in CH2C2 (66 mL) at 0 *C, 0 5 (mesitylsulfonyl)hydroxylamine (3.27 g, 15.2 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was filtered to afford the desired product with quantitative yield. LC-MS (method 4): tR = 1.07 min; m/z = 199 (MH-), REFERENCE EXAMPLE 2 3 (S)-3-(4-(1-Acetylpiperidin-3-ylamino)-5-aminopyrimidin-2-yl)pyrazoiof[,5-a]pyridine-5-carbonitrile Following a similar procedure to that described in example 1 (section a to d), but using (S)-1-acetyl-3 aminopiperidine instead of tetrahydro-2H-pyran-4-amine, the desired compound was obtained . LC-MS (method 3): ta = 1,59 min; m/z = 377 (MH+). 5 Following a similar procedure to that described in reference example 2, but using in each case the corresponding starting materials, the following compounds were obtained: Reference HPLC tR Name Starting Materials mlz example I method (min) 1-amino-4 methylpyridinium 2,4,6 (S)-tert-butyl 3-(5-amino-2-(5 trimethylbenzenesulfo methylpyrazolo[1,5-a]pyridin-3- y 2a nate (1), ,(S)-3-amino- 3 2.32 424 yl) pyri mid in-4-yla mi no)pipe ridi ne-1 - (-e carboxylate butoxycarbonyl)piperid ine and 2,4-dichloro-5 nitropyrimidine 1-aminopyridinium iodide,, 4-amino-(1 tert-butyl 4-(5-amino-2-(pyrazolo [1,5 tert 2b ajpyridin-3-yl)pyhmidin-4- 4 2.00 410 butoxycarbonyl)piperid ylamino)piperidine-1-carboxylate me a 2,4-diorid ine and 2,4-dichloro-5 nitropyrimidine 57 1-aminopyridinium 2-(pyrazolo[1,5-a]pyridin-3-yl)-N4- iodide, tetrahydro-2H 2z (tetrahydro-2H-pyran-4-yl)pyrimidine- pyran-4-amine and 3 1.55 311 4,5-diamine 2,4-dichloro-5 nitropyrimidine 1-aminopyridinium iodide , (S)-3-amino (S)-tert-butyl 3-(3-amino-6- ( tert (1 -tert 2d (pyrazolo[1,5-ajpyridin-3-yl)pyridin-2- 3 2.43 409 butoxycarbonyl)piperid ylamino)piperidine-1-carboxylate me and 2,6-dicbloro-3 nitropyridine I-amino-4 cyanopyridinium 2,4,6 3-(5-amino-4-(8-fluorochroman-4- trimethylbenzenesulfo 2e ylamino)pyrimidin-2-yl)pyrazolo[1,5- nate, 8-fluorochroman- 1 9.28 402 alpyridine-5-carbonitrile 4-amine and 2,4 dichloro-5 nitropyrimidine i-amino-4 cyanopyridinium 2,4,6 (S)-3-(6-(1-acetylpiperidin-3-ylamino)- trimethylbenzenesulfo 2f 5-aminopyridin-2-yl)pyrazolo[1,5- nate, (S)-1-acetyl-3- 3 1.58 377 a]pyridine-5-carbonitrile aminopiperidin and 2 6-dichloro-3 nitropyridine 1-aminopyridinium 6-(pyrazolo[1,5-ajpyridin-3-y)-N2- iodide, tetrahydro-2H 2g (tetrahydro-2H-pyran-4-yl)pyridine- pyran-4-amine and 5 1.68 310 2,3-diamine 2,6-dichloro-3 nitropyridine 58 1-amino-4 cyanopyridinium 2,4,6 (S)-tert-butyl 3-(3-amino-6-(5- trimethylbenzenesulfo cyanopyrazolo[1,5-a]pyridin-3- nate, (S)-3-amino-(1 2h 3 2.50 434 yl)pyridin-2-ylamino)piperidine-1- tert carboxylate butoxycarbonyl)piperid ine and 2,6-dichloro-3 nitropyridin e 1-amino-4 cyanopyridinium 2,4,6 3-(5-amino-4-(trans-4- ti tybneeuf 2i hydroxycyclohexylamino)pyrimidin-2- trim t e ns ulfo 21nate, trans-4- 3 1,.45 350 yl)pyrazoio[1,5-a]pyridine-5- aminocyclohexanol carbonitrile and 2,6-dichloro-3 nitropyridine, (1) described by Zhang et al Journal of Heterocyclic Chemistry; 44; 4; 2007; 919-922 EXAMPLE I 3-(8-Oxo-9-tetrahydro-2H-pyran-4-yl-8,9-dihydro-7H.purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile 5 a) 2-Chloro-5-nitro-N-tetrahydro-2H-pyran-4-ypyrimidin-4-amine To a solution of 2,4-dichloro-5-nitropyrimidine (1.03 g, 5.15 mmol) in THF (40 mL) at -78 *C, DIPEA (2.0 mL, 11.86 mmol) and tetrahydro-2H-pyran-4-amine (0.54 mL, 5.15 mmol) were added. The reaction mixture was stirred from 78 to -50 'C for 5 h. The crude mixture was quenched with H20 (50 mL), extracted with EtOAc (3x40 mL) and the combined organic phases were dried over anhydrous Na 2

SO

4 , filtered and concentrated. The crude product thus 0 obtained was chromatographed over silica gel using EtOAc/hexanes mixtures of increasing polarity as eluent, to afford 1.04 g of the desired compound (78% yield), b) 5-N itro-N-(tetrahyd ro-2H-pyran-4-yl)-2-[(trimethylsilyl)ethynyl] pyrimidin-4-amine To a suspension of the compound obtained in the previous section (1.01 g, 3.90 mmol), Pd(PPh3) 2 Cl2 (137 mg, 0.19 5 mmol) and Cul (37 mg, 0.19 mmol) in toluene (40 mL), TEA (1.6 mL, 11.7 mmol) and trimethylsilylacetylene (0.7 mL.. 5.07 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, quenched with saturated

NH

4 CI aqueous solution (70 mL) and extracted with EtOAc (3x40 mL). The combined organic phases were dried over anhydrous Na 2

SO

4 , filtered and concentrated. The crude residue was cromatographed on a silica gel flash system (SP1 Biotage) using EtOAc/hexanes mixtures of increasing polarity as eluent to afford 0.96 g of the desired ?0 product (77% yield).

59 c) 3-{5-Nitro-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]pyrazolo[1 .5-a]pyridine-5-carbonitrile To a suspension of the compound obtained in the previous section (500 mg, 1.56 mmol) and 1-amino-4 cyanopyridinium 2,4,6-trimethylbenzenesulfonate (498 mg, 1.56 mmol) in AcN (30 mL), at 0 C, 1 M TBAF solution in THF (1.56 mL, 1.56 mmol) and a solution of DBU (0.47 mL, 3.12 mmol) in AcN (10 mL) were added. The reaction mixture was stirred at 0 'C for 5 min and 3 h at room temperature, The reaction mixture was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using EtOAchexanes mixtures of increasing polarity as eluent, to afford 227 mg of the desired compound (48% yield), d) 3-[5-Amino-4-(tetrahydro-2H-pyran-4-ylamino)pyrimid in-2-yl]pyrazolo[1 ,5-a]pyridine-5-carbon itrile 3 A mixture of the compound obtained in the previous section (119 mg, 0.32 mmol) in EtOH (12 mL) was hydrogenated with Pt/C 5% (149 mg, 0.02 mmol) as a catalyst in the presence of thiophene in DIPEA (4%v/v, 9 drops). The reaction mixture was stirred under H 2 (g) atmosphere at room temperature for 1.5 h, The reaction mixture was filtered through a plug of Celite@ and the solvent was concentrated off to afford 78 mg of the desired product (71% yield). e) 3-(8-Oxo-9-tetrahydro-2H-pyran-4-yl-8,9-dihydro-7H-purin-2-yl)pyrazolo(1,5-alpyridine-5-carbonitrile To a solution of the compound obtained in the previous section (78 mg, 0.23 mmol) in THF (7 mL), 1,1' carbonyldiimidazole (188 mg, 1.16 mmol) was added. The reaction mixture was stirred at mom temperature for 4 h, quenched with saturated NaCl aqueous solution (15 mL) and extracted with EtOAc (3x1 5 mL). The combined ] organic phases were dried over anhydrous Na 2

SO

4 , filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using MeOH/CH 2 C1 2 mixtures of increasing polarity as eluent, to afford 5.1 mg of the desired compound (61% yield). LC-MS (method 1): tR = 14.25 min; mlz = 362 (MH). 5 Following a similar procedure to that described in example 1, but using in each case the corresponding starting materials, the following compounds were obtained: HPLC tR Example Name Starting Material m z meto (min) i methyl (2R)-2-[2-(5 la cyanopyrazolo[1,5-a]pyridin-3-yl)-8- D-alanine methyl ester 1 oxo-7,8-dihydro-9H-purin-9- hydrochloride yljpropanoate 60 (S)-tert-butyl 3-(2-(5- 1 - ______ cyanopyrazolo[1,5-a]pyridin-3-yl)-8 1b aminopiperidine-1- 2 2.23 461 oxo-7H-purin-9(8H)-yl)piperidine-l- carboxylate carboxylate (R)-tert-butyl 3-(2-(5- (R)-terf-butyl 3 cyanopyrazolo[I,5-ajpyridin-3-yl)-8 1ll aminopiperidine-1- 2 2.23 461 oxo-7H-purin-9(8H)-yl)piperidine-i - carboxylate carboxylate (S)-3-(9-(1 -methoxypropan-2-yl)-8 oxo-8,9-dihydro-7H-purin-2- (S)-1-methoxypropan- 2 1d 2 1,82 350 yl)pyrazolo[1,5-ajpyridine-5- 2-amine carbonitrile 3-(9-(4,4-difluorocyclohexyl)-8-oxo 8,9-dihydro-7H-purin-2 1e yl)pyrazolo[15ajpyridine5 difluorocyclohexanami 2 2.03 396 ne carbonitrile 3-(9-(,1-dioxotetrahydrothien-3-y)-8- T 3-amino-i1,1 oxo-8 ,9-dihydro-7H-purin-2- 1fo [1,5-ajprin-5- dioxotetrahydrothiophe 2 1.43 396 yl)pyrazolo[1,5-a]pyridine-5 ne carbonitrile 3-(9-(2-fluorobenzyl)-8-oxo-8,9 dihydro-7H-purin-2-yl)pyrazolo[1,5- 2-fluorobenzylamine 1 16.58 386 ajpyridine-5-carbonitrile 3-(9-(4-methoxybut-1 -yl)-8-oxo-8,9- -ehxbtnl 4-methoxybutan-1 1h dihydro-7H-purin-2-yl)pyrazolo[1, 5- 1 15.15 396 alpyridine-5-carbonitrile rm methyl (2S)-2-[2-(5 cyanopyrazoio{1,5-alpyridin-3-yi)-8- L-alanine methyl ester 1i 3 1.8M3 oxo-7,8-dihydro-9H-purin-9- hydrochloride yljpropanoate 9-(1-acetylpipenidin-4-yl)-2-(5- 1-acetyi-4 Ij (trifluoromethyl)pyrazolo[1,5-a]pyridin- aminopiperidine 4 1.68 446 3-yl)-7H-purin-8(9H)-one (1) hydrochloride 61 (S)-tert-buty 3(2-(5 (S)-tert-butyl 3 cyanopyrazolo[1,5-alpyridin-3-yJ)-8 1k H aminopyrrolidine-1- 5 2,72 447 oxo-7H-purin-9(BH)-yl)pyrrolidine-1 carboxylate carboxylate (R)-tert-butyl 3-(2-(5 (R)-tedt-butyl 3 cyanopyrazolo[1,5-a]pyridin-3-yl)-8- erbil 3 oxo-7H-purin-9(8H)-yl)pyrrolidinecarboxylate carboxylate (S)-tert-butyl 3-(2-(5 methylpyrazolo[1,5-alpyridin-3-yl)-8- (S)-tert-butyl3 1M oxo-7H-purin-9(8H)-yl)piperidine-1- aminopiperidine-1- 3 2.47 450 carboxylate (2) carboxylate ethyl 2-(2-(5-cyanopyrazolo[1,5 In a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)- ethyl 2-aminoacetate 3 1,82 364 yI)acetate 3-(9-(trans-4-hydroxycyclohexyl)-8 oxo-8,9-dihydro-7H-purin-2- trans-4 1o0 3 1.55 376 yl)pyrazolo[1,5-a]pyridine-5- aminocyclohexanol carbonitrile i3-(9-(8-fluorochroman-4-yl)-8-oxo-8,9 8-fluorochroman-4 1p dihydro-7H-purin-2-yl)pyrazolo[1,5- 1 15.43 428 amine a]pyridine-5-carbonitrile tert-butyl 4-(2-(5-cyanopyrazolo[1,5- tert-butyl 4 1q alpyridin-3-yl)-8-oxo-7H-purin-9(8H)- aminopiperidine-- 3 2.33 461 yl)piperidine-1-carboxylate carboxylate tert-butyl 3-(2-(5-cyanopyrazolo[1,5- tert-butyl 3 1r a]pyridin-3-yl)-8-oxo-7H-purin-9(8H)- aminoazetidine-1- 3 2.20 433 yl)azetidine-l-carboxylate carboxylate 9-(i-acetylpiperidin-4-y)-2-(5 1 -acetyl-4 methylpyrazolo[1,5-a]pyridin-3-y)-7H- I 1si-(9)oe 2 aminopiperidine 4 1.38 392 purin-8(9F)-one (2) hydrochloride (1) step c) was performed using reference example 1 instead of i-amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate 62 (2) step c) was performed using 1-amino-4-methylpyridinium 2,4,6-trimethylbenzenesulfonate (described by Zhang et al Journal of Heterocyclic Chemistry; 44; 4; 2007; 919-922) instead of 1-amino-4-cyanopyridinium 2,4,.6-trimethylbenzenesulfonate EXAMPLE 2 3-(2-Oxo-3-(tetrahydro-2H-pyran-4-y)-2,3-dihydro-1H-imidazo[4,5-blpyridin-5-yl)pyrazolo(1,5-alpyridine-5 carbonitrile a) 6-Chloro-3-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine To a suspension of 2,6-dichloro-3-nitropyridine (6 g, 31.1 mmol) in AcN (200 mL) at 0 C, TEA (9 mL, 62.2 mmol) and tetrahydro-2H-pyran-4-amine (3.15 g, 31.1 mmol) were added. The reaction mixture was stirred at 0 IC for 1.5 h. The reaction crude was tempered and stirred at room temperature for 18 h, The reaction mixture was evaporated under reduced pressure, dissolved in EtOAc, and washed thrice with saturated NaHCO3 aqueous solution. The combined organic phases were dried over MgSO 4 and concentrated to dryness. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using hexanes/TBME mixtures of increasing polarity as eluent to afford 5.23 g of the desired product (65% yield). b) 3-Nitro-N-(tetrahydro-2H-pyran-4-yl)-6-((trimethylsilyl)ethynyl)pyridin-2-amine Following a similar procedure to that described in example 1, section b, but using the compound obtained in previous section as starting material, the desired compound was obtained (87% yield). ) c) 3.(5-Nitro-6-(tetrahydro-2H-pyran-4-ylamino)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile Following a similar procedure to that described in example 1, section c, but using the compound obtained in previous section as starting material, the desired compound was obtained (16% yield), 5 d) 3-(5-Amino-6-(tetrahydro-2H-pyran-4-ylamino)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile Following a similar procedure to that described in example 1, section d, but using the compound obtained in previous section as starting material, the desired compound was obtained (19% yield). e) Title compound 0 Following a similar procedure to that described in example 1, section e, but using the compound obtained in previous section as starting material, the desired compound was obtained (23% yield). LC-MS (method 3): tR = 1.83 min; m/z = 361 (MH+) Following a similar procedure to that described in example 2, but using in each case the corresponding starting 63 materials, the following compounds were obtained: HPLC tP m/z Example Name Starting Material method (min) (MH+) (S)-tert-butyl 3-(2-oxo-5- (S)-3-amino-(1-tart (pyrazolo[1,5-ajpyridin-3-yl)-1 H- butoxycarbonylpiperid 2a ine and 1 - 3 2.47 435 imidazo[4,5-bjpyridin-3(2H) aminopyridiniumn yl)piperidine-1-carboxylate iodide (R)-tert-butyl 3 (R)-tert-butyl 3-(2-oxo-5- ()eruyr 3-1 (pyrazolofI,5-a]pyridin-3-yl)-1 H imidazo[4,5-blpyridin-3(2H)- y and 1- 3 2.27 421 aminopyridinium yl)pyrrolidine-1 -carboxylate iodide (S)-tert-buty 3 (S)-tert-butyl 3-(2-oxo-5 (pyrazolo(1,5-apyridin-3-yl)-1 H- aminopyrrolidine-i 2c carboxylate and 1- 3 2.27 421 imidazo[4,5-blpyridin-3(2H)- aminopyridinium yl)pyrroiidine-1-carboxylate iodide (S)-3-amino-(i-tert butoxycarbonyl) pi perid (S)-tert-butyl 3-(5-(5 ine and cyanopyrazolo[1,5-a]pyridin-3-yl)-2 oxo-1 H-imidazo[4,5-blpyridin- cya dnim4 cyanopyridinium 2,4,6 3(2H)-yl)piperidine-1-carboxylate tnimethylbenzenesulfo nate tetrahydro-2H-pyran-4 5-(pyrazolo[1,5-alpyridin-3-yl)-3- aro-H-an-4 amine and 1 2e (tetrahydro-2H-pyran-4-yl)-1 H- 3 1.80 336 imidazo[4,5-b]pyridin-2(3H)-one a iodide (R)-3-amino-(1-tert- 7 (R)-tert-butyl 3-(2-oxo-5 buto xycarbonyl)pi pe rid (pyrazolo[1,5-a]pyridin-3-yl)-1 H 2f ine and 1- 1 4 2.15 435 imidazo[4,5-b]pyridin-3(2H) aminopynidinium yl)piperidine-1-carboxylate iodide 64 EXAMPLE 3 2-(Pyrazolo[1,5-a]pyridin-3-yl)-9-(tetrahydro-2H-pyran-4.yl)-7H.purin-8(9H)-one Following a similar procedure to that described in example 1, but using 1-aminopyridinium iodide instead of 1-amino 4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate, the desired compound was obtained (84% yield). 5 LC-MS (method 3): ta= 1.62 min; m/z = 337 (MH+). Following a similar procedure to that described in example 3, but using in each case the corresponding starting materials, the following compounds were obtained: HPLC tR mlz Example Name Starting Material method (min) (MH+) 2-(pyrazolo[1,5-a]pyridin-3-yl)-9 (tetrahydro-2H-pyran 3a ((tetrahydro-2H-pyran-4-yl)methyl)- (teth an - 2 1.63 351 4-yl)methanamine 7H-puin-8(9H)-one (S)-ter-butyl 3-(8-oxo-2- (S)-terf-butyl-3 3b (pyrazolo[1,5-a]pyridin3-yl)-7H- aminopiperidine-1- 2 2,33 436 purin-9(8H)-y)piperidine-1- carboxylate carboxylate 3c 9-(2-methoxyethyl)-2-(pyrazolo[1,5 alpyridin-3-yl)-7H-purin-8(9H)-one 9-(8-fluorochroman-4-yl)-2 3d i 8-fluorochroman-4 d (pyrazolo5-a]pyridin-3-yl)-7H- a e1 16.07 403 L-alanine methyl ester 3e (pyrazolo[1,5-a]pyridin-3-yl)-7,8- 3 1.73 339 hydrochioride dihydro-9H-purin-9-yl)propanoate (S)-tert-butyl 3-(8-oxo-2 (pyrazolo[1,5-a]pyridin-3-yl)-7H- (3-tert-buty) 3 3Y aminopyrrolidine-1- 3 2.13 422 1 purin-9(8H)-yl)pyrrolidine-1 carboxylate carboxylate tert-butyl 4-(8-oxo-2-(pyrazolo[1,5- tert-butyl 4 3g a]pyridin-3-yl)-7H-purin-9(8H)- aminopiperidine-1- 3 2.35 461 yl)piperidine-1-carboxylate carboxylate 65 9-(1-methylpiperidin-4-yl)-2 1-methylpiperidin-4-| 3h (pyrazolo{1,5-ajpyridin-3-yl)-7H- 4 1.38 350 amine purin-8(9H)-one 5-(pyrazolo[1,5-a]pyridin-3-yl)-3- 2,2,6,6 (2,2,6.6-tetramethylpiperidin-4-yl)- tetramethylpiperidin-4- 4 1.48 391 1 1 H-imidazo(4,5-blpyridin-2(3H)-one amine EXAMPLE 4 3-(7-Methyl--oxo-9.tetrahydro-2H-pyran-4-y-8,9-dihydro-7H-purin-2-yl)pyrazolofl,5-alpyridine-5-carbonitrile To a solution of example 1 (48 mg, 0,13 mmol) in DMF (6 mL), 55-65% NaH dispersion in mineral oil (7.3 mg, 0.18 5 mmol) was added and the resulting solution was stirred at room temperature for 10 min. Then Mel (0.015 mL, 0.25 mmol) was added and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was quenched with saturated NaCl aqueous solution (10 mL) and extracted with EtOAc (3x10 mL) and CH 2 C1 2 (2x10 mL), The combined organic phases were dried over anhydrous Na 2

SO

4 , filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using MeOH/CH 2 Cl 2 mixtures of increasing polarity as eluent, to afford 3 50 mg of the desired compound (quantitative yield). LC-MS (method 1): tR = 15.48 min; m/z = 376 (MH+). Following a similar procedure to that described in example 4, but using in each case the corresponding starting materials, the following compounds were obtained: S HPLC tR Example Name Starting Material m HPLC mlz (S)-tedf-butyl 3-(2-(5 4a cyanopyrazolo(1,5-apyridin-3-yI)- Example lb 2 3.22 475 7-methyl-8-oxo-7H-purin-9(BH) yl)piperidine-1-carboxylate (R)-tert-butyl 3-(2-(5 cyanopyrazolo[1,5-alpyridin-3-yl) 4b ri-(H- Example 1c 2 3.22 475 7-methyl-8-oxo-7H-purin-9(8H) yl)piperidine-1 -carboxylate 9-(8-fluorochroman-4-yl)-7 4c methyl-2-(pyrazolo[1 ,5-a]pyridin- Example 3d 1 16.83 417 I 3-yl)-7H-purin-8(9H)-one __________________ .___ 66 EXAMPLE 5 (S)-tert-Butyl 3-(7-methyl-8-oxo-2-(pyrazolo[1 5-a]pyridine-3-yl)-7H-purin-9(8H)-yl)piperidine-I -carboxylate To a solution of example 3b (70 mg, 0.160 mmol) in DMF (3.5 mL), at 0oC, 'BuOK (27 mg, 0.24 mmol) and Mel (0.019 mL, 0.32 mmol) were added. The reaction mixture was stirred at room temperature for 20 min and evaporated to dryness, The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using CH 2 C1 2 / MeOH mixtures of increasing polarity as eluent to afford 64 mg of the desired product (89% yield). LC-MS (method 3): tR = 2.58 min; mlz = 450 (MH). Following a similar procedure to that described in example 5, but using in each case the corresponding starting materials, the following compounds were obtained: HPLC tR mfz Example Name Starting Material 7-methyl-2-(pyrazolo[1, 5-a]pyridin- method (mi) (MHJ 5a 3-yl)-9-(tetrahydro-2H-pyran-4-yl)- example 3 2 1.83 351 7H-purin-8(9H)-one 3-(1-methyl-2-oxo-3-(tetrahydro-2H- 1I pyran-4-yl)-2,3-dihydro-IH 5b imidazo[4,5-b]pyridin-5- example 2 2 2.62 375 yl)pyrazolo[1,5-a]pyridine-5 carbonitrile 9-(2-methoxyethyl)-7-methyl-2 5c (pyrazolo[1,5-a]pyridin-3-yl)-7H- Example 3c 2 077 325 purin-8(9H)-one 7-methyl-2-(pyrazolo[1,5-a]pyridin 5d 3-yl)-9-[(tetrahydro-2H-pyran-4- Example 3a 2 1.87 365 yl)methyl]-7H-purin-8(9H)-one 3-(9-(4,4-difluorocyclohexyl)-7 Se methyl-8-oxo-8,9-dihydro-7H-purin- Example Ie 2 2.32 410 2-yl)pyrazoio[1,5-a]pyridine-5 carbonitriue 3-(9-(1,1-dioxotetrahydrothien-3-yl) 8,9-dihydro-7-methyl-8-o~xopurin-2 5f Example if 2 1,75 410 yl)pyrazolo[1,5-a]pyridine-5J carbonitrIle.

67 (S)-tert-butyl 3-(5-(5 cyanopyrazolo[1,5-ajpyridin-3-yl)-1 5g methyl-2-oxo-1H-imidazo[4,5- Example 2d 2 2.54 474 bjpyridin-3(2H)-yl)piperidine-1 carboxylate 3-(9-(2-fl uorobenzyl)-7-methyl-8 oxo-8,9-dihydro-7H-purin-2 Sh yl)pyrazolo[1,5-a]pyridine-5- Example 1g 1 1786 400 carbonitrile 9-(1-acetylpiperidin-4-yl)-7-methyl 5i 2-(5-(trifluoromethyl)pyrazolo[1, 5- Example lj 4 1.85 460 a]pyridin-3-yl)-7H-purin-8(9H)-one (S)-tert-butyl 3-(1-methyl-2-oxo-5 (pyrazolo[1,5-a]pyridin-3-yl)-1 H 5j Example 2a 3 2173 449 imidazo[4,5-b]pyridin-3(2H) yl)piperidine-1 -carboxyiate (S)-tert-butyl 3-(2-(5 cyanopyrazolo[l.5-a]pyridin-3-yl)-7 5k Example 1 k 3 2.52 461 methyl-8-oxo-7H-purin-9(8H) yl)pyrrolidine-1 -carboxylate (R)-tert-butyl 3-(2-(5 cyanopyrazolo[1,5-a]pyridin-3-yl)-7 51 Example 11 3 2.50 461 methyl-8-oxo-7H-purin-9(8H) yl)pyrrolidine-1-carboxylate (S)-tert-butyl 3-(7-methyl-8-oxo-2 (pyrazolo[1 5-a]pyridin-3-yl)-7H purin-9(8H)-yl)pyrroidine-1 carboxylate (R)-tert-butyl 3-(1 -methyl-2-oxo-S (pyrazolo[1,5-alpyridin-3-y)-1H 5n Example 2b 3 2.50 435 5n ~imidazo{4,5-bjpyidin-3(2H)-Exml2b.5 43 yl)pyrrolidine-1-carboxylate (S)-tert-butyl 3-(1-methyl-2-oxo)-5 (pyrazoio{1,5-a]pyridin-3-yl)-1H So Example 2c 5 2.98 436 imidazo[4,5-b]pyridin-3(2H)- E yl)pyrrolidine-1-carboxylate 68 (S)-tert-Butyl 3-(1-ethy-2-oxo-5 (pyrazolo[1, 5-alpyddin-3-yl)-1 H 5p Example 2a 4 2.57 463 imidazof4,5-bjpyrdin-3(2H) yl)piperidine-1-carboxylate(1) tert-butyi 4-(7-methyl-8-oxo-2 (pyrazolot1,5-a]pyridin-3-yl)-7H- Example purin-9(8H)-y[)piperidinecarboxylate (S)-tert-butyl 3-(7-methyl-8-oxo-2 (pyrazolo[1,5-a]pyridin-3-yl)-7H Sr Example 3b 3 2.62 450 purin-9(SH)-yl)piperidine-1 carboxylate 1 -methyl5-(pyrazolo(1,5-alpyridin 5s 3-yl)-3-(tetrahydro-2H-pyran-4-y)- Example 2e 3 2.02 350 1H-imidazo[4,5-b]pyridin-2(3H)-one (R)-tert-butyl 3-(1-methyl-2-oxo-5 (pyrazolo[1,5-ajpyridin-3-y)-1 H 5tExample 2f 3 2.73 I 449 imidazo{4,5-bjpyridin-3(2H) yl)piperidine-1-carboxylate tert-butyl 4-(2-(5 5u cyanopyrazolo[1,5-a]pyridin-3-yl)-7 5uxample 1q 3 2.68 475 methyl-8-oxo-7H-purin-9(8H) yl)pipeidine-1-carboxylate tert-buty 3-(2-(5 cyanopyrazolo[1,5-a]pyridin-3-yl)-7 5v Example 1 r 3 2.47 1 447 methyl-8-oxo-7H-purin-9(8H) yl)azetidine-i -carboxylate (1) ethyl iodide instead of methyl iodide as starting material. EXAMPLE 6 (S)-3-(8-Oxo-9-(piperi din-3-yl).8,9-dihydro-7H-puri n.2-yl)pyrazolo[1,5-a]pyridine-5-carbon itrile hydrochloride 5 To a solution of example lb (45 mg, 0.10 mmol) in dioxane (3 mL), 4 M HCI solution in dioxane (2 mL, 8.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness to give 48 mg of the desired compound (100% yield). LC-MS (method 2): tp = 1.73 min; m/z = 361 (MH).

69 Following a similar procedure to that described in example 6, but using in each case the corresponding starting materials, the following compounds were obtained: HPLC tR mlz Example Compound name Starting material method (min) (MH+) (R)-3-(8-oxo-9-(piperidin-3-yl)-8,9 dihydro-7H-purin-2-yl)pyrazolo[1,5 6a Example 1c 2 1.73 361 ajpyridine-5-carbonitrile hydrochloride (R)-3-(7-methyl-8-oxo-9-(piperidin 13-yl)-8,9-dihydro-7H-purin-2 6b yl)pyrazolo[1,5-a}pyridine-5- Example 4b 2 2.05 375 carbonitrile hydrochloride (S)-3-(7-methyl-8-oxo-9-(piperidin-3 yl)-8,9-dihydro-7H-purin-2 yl)pyrazolo[i 5-a]pyridine-5 carbonitrile hydrochloride 9-(piperidin-4-yl)-2-(pyrazolo{1,5 a]pyridin-3-yl)-7H-purin-8(9H)-one Example 3g 2 1.28 336 (S)-3-(2-oxo-3-(piperidin-3-yl)-2,3 dihydro-1 H-imidazo[4,5-bjpyndin-5 6e Example 2d 2 1.54 360 yl)pyrazolot1,5-a]pyridine-5 carbonitrile hydrochloride (S)-3-(1-methyl-2-oxo-3-(piperidin-3 yl)-2,3-dihydro-1 H-imidazo[4,5 6f b]pyridin-5-yl)pyrazolo{1,5- Example 5g 2 1.68 374 a]pyridine-5-carbonitrile hydrochloride (S)-1I-meth yl-3-(piperid in-3-yl)-5 (pyrazolofI,5-ajpyridin-3-yl)-1 H 6g Example 5j 1 12.4 6 349 imidazo{4,5-b~pyridin-2(3H)-one hydrochloride 70 (S)-3-(7-methyl-8-oxo-9-(pyrroidin 3-yl)-8,9-dihydro-7H-purin-2 yl)pyrazolo[1,5-a]pyridine-5 carbonitrile hydrochloride (R)-3-(7-methyl-8-oxo-9-(pyrrolidin 6i 3-yl)-8,9-dihydro-7H-purin-2-Exml 3 16 31 61Example 51 3 1.62 361 yl)pyrazolo[1,5-a]pyridine-5 carbonitriie hydrochloride (S)-2-(pyrazoo[1,5-ajpyridin-3-y)-9 6j (pyrrolidin-3-yl)-7H-purin-8(9H)-one Example 3f 3 1.23 322 hydrochloride (S)-7-methyl-2-(pyrazolo[1,5 6k a]pyridin-3-yl)-9-(pyrrolidin-3-yl)-7H- Example 5m 3 1.48 336 purin-8(9H)-one hydrochloride (S)-3-(8-oxo-9-(pyrrolidin-3-yl)-8.9 dihydro-7H-purin-2-yl)pyrazolo[1,5 61 a]pyridine-5-carbonitrile Example 1k 3 1.35 347 hydrochloride (1) (R)-1-methyl-5-(pyrazolo[1,5 a]pyridin-3-yl)-3-(pyrrolidin-3-yl)-1 H imidazo{4,5-b]pyridin-2(3H)-one hydrochloride (R)-5-(pyrazolo[1,5-ajpyridin-3-yl)-3 (pyrrolidin-3-yl)-1 H-imidazo[4,5 6n Example 2b 3 1.140 321 6 b)pyridin-2(3H)-one hydrochloride (1) (R)-3-(8-oxo-9-(pyrroiidin-3-y)-8,9 dihydro-7H-purin-2-yI)pyrazolo[1,5 60 a~ydn--abntieExample 11 3 1.33 347 hydrochloride (1) (S)-2-(pyrazolo[1,5-a]pyidin-3-yi)-9 6p (pyrrolidin-3-yl)-7H-purin-8(9H)-one Example 2c 3 1.40 321 hydrochloride 71 (S)-1 -methyl-5-(pyrazolo[1,5 a]pyridin-3-yl)-3-(pyrrolidin-3-yl)-1 H imidazo[4,5-bjpyridin-2(3H)-one hydrochloride (S)-2-(5-methylpyrazolo[1,5 6r a)pyridin-3-yl)-9-(piperidin-3-yl)-7H- Example im 3 1.57 350 purin-8(9H)-one hydrochloride (S)-1-ethyl-3-(piperidin-3-yl)-5 (pyrazolo[1,5-a]pyridin-3-yl)-1 H 68 Example 5p 4 1.56 363 imidazo[4,5-b]pyridin-2(3H)-one hydrochloride 7-methyl-9-(piperid i n-4-yl)-2 6t (pyrazolo[ ,5-alpyridin-3-yl)-7H- Example 5q 4 1.23 350 purin-8(9H)-one hydrochloride (S)-7-methyl-9-(piperidin-3-yl)-2 6u (pyrazolo[1,5-a]pyridin-3-yl)-7H- Example 5r 3 1,67 350 purin-8(9H)-one hydrochloride (S)-9-(piperidn-3-yl)-2 6v (pyrazolo[1,5-a]pyridin-3-yl)-7H- Example 3b 3 1.43 336 purin-8(9H)-one hydrochloride (R)-1 -methyl-3-(piperidin-3-yl)-5 6w (pyrazolo[1,5-ajpyridin-3-yl)-1H- Example St 3 1.77 349 imidazo[4,5-b]pyridin-2(3H)-one (S)-3-(piperidin-3-yl)-5 (pyrazolo[1,5-a]pyridin-3-yl)-1 H 6x Example 2a 3 1.60 1335 imidazo[4,5-b]pyridin-2(3H)-one hydrochloride 3-(7-methyl-8-oxo-9-(piperidin-4-yl) 8,9-dihydro-7H-purin-2 6y E-xample 5u 3 1.67 375 yl)pyrazolo[1,5-a]pyridine-5 carbonitrile hydrochloride (S)-3-(3-(piperidin-3-yl)-3H imidazo[4,5-bjpyridin-5 6z Example 18e 3 1.68 344 yl)pyrazolo(1,5-alpyridine-5 carbonitrile hydrochloride 72 (S)-3-(2-methyl-3-(piperidin)-3-yl) 3H-imidazo[4,5-b]pyridin-5 Baa Example 18f 3 1.72 358 yl)pyrazolo[1,5-ajpyridine-5 I carbonitrile hydrochloride 3-(8-oxo-9-(piperidin-4-yl)-8,9 6ab dihydro-7H-purin-2-yl)pyrazolo[1,5- Example 1q 1 11.13 361 ajpyridine-5-carbonitrile (1) 3-(9-(azetidin-3-yl)-7-methyl-8-oxo 8,9-dihydro-7H-purin-2 Sac Example 5v 3 1.50 347 yl)pyrazolo[1,5-ajpyridine-5 carbonitrile hydrochloride (S)-3-(piperidin-3-yl)-5 6ad (pyrazolo[1,5-alpyridin-3-yl)-3H- Example 18i 3 1.65 319 imidazo[4,5-b]pyridine hydrochloride (S)-2-methyl-3-(piperidin-3-yl)-5- i 6ae (pyrazolo(1,5-alpyrdin-3-yi)-3H- Example 21 m 3 1.48 333 imidazo{4,5-b]pyridine hydrochloride (1) reaction performed with TFA/CH 2 Cl2 instead of 4 M HCI solution in dioxane, and washed with with saturated NaHCO 3 aqueous solution, EXAMPLE 7 5 (S)-3-(9-(1-(2-Cyanoacetyl)piperidin-3-yl)-8-oxo-8,9.dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5 carbonitrile To a solution of the compound obtained in example 6 (45 mg, 0.095 mmol) in anhydrous DMF (3 mL), 2,5 dioxopyrrolidin-1-y 2-cyanoacetate (69 mg, 0.38 mmol) and anhydrous TEA (0.09 mL, 0.665 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off, It was quenched 0 with saturated NaHC0 3 aqueous solution (15 mL) and extracted with EtOAc (3x15 mL). The combined organic phases were dried over anhydrous Mg 2 S0 4 , filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 11,7 mg of the desired compound (29% yield). LC-MS (method 2): tR = 1.93 min; m/z = 428 (MH+), 5 Following a similar procedure to that described in example 7, but using in each case the corresponding starting materials, the following compounds were obtained: 73 HPLC t, m/ Example Compound name Starting material method (min) (MH*) (R)-3-(9-(l-(2-cyanoacetyl)piperidin 3-yl)-8-oxo-8,9-dihydro- 7H-purin-2 yl)pyrazolo[1,5-alpyridine-5 carbonitrile (R)-3-(9-(1-(2-cyanoacetyl)piperidin 3-yl)-7-methyl-8-oxo-8,9-dihydro 7b 'Example 6b 2 2.30 442 7H-purin-2-yl)pyrazolo[1,5 a]pyridine-5-carbonitrile (S)-3-(9-(1-(2-cyanoacetyl)piperidin 3-yl)-7-methyl-8-oxo-8,9-dihyd ro 7c Example 6c 2 2.30 442 7H-purin-2-y)pyrazolo(1 5 alpyridine-5-carbonitrile 3-(7-methyI-8-oxo-9 (pyrrolidin-3-yl)-8,9 3-(9-(1-(2-cyanoacetyl)pyrrolidin-3 dihydro-7H-purin-2 yl)-7-methy-8-oxo-8,9-dihydro- 7H 7d yl)pyrazolo[1,5- 2 1.68 428 purin-2-yl)pyrazolo[1,5-a]pyridine-5 a]pyridine-5 carbonitribe carbonitrile hydrochloride(1) 3-(7-methy -8-oxo-9 (piperidin-4-ylmnethyl 3-(9-((1-(2-cyanoacetyl)piperidin-4 8,9-dihydro-7H-purin yl)methyl)-7-methy-8-oxo-8,9 7e 2-yl)pyrazolo[1,5- 1 2 1.80 456 dihydro-7H-purin-2-yl)pyrazolofl,5 a]pyridine-5 a]pyridine-5-carbonitrile I carbonitrile hydrochloride (2) (S)-3-oxo-3-(3-(8-oxo-2 (pyrazolo[1,5-a]pyridin-3-y)-7H 7f Example 6v 2 2.05 403 purin-9(8H)-y)piperidin-1 yI)propanenitrile (S)-3-(3-(7-methyl-8-oxo-2 (pyrazolo[1,5-a]pyrdin-3-yl)-7H purin-9(8H)-yl)piperidin-1-yl)-3 oxopropanenitrile 74 (S)-3-(3-(1-(2-cyanoacetyl)piperidin 3-yl)-2-oxo-2,3-dihyd ro-1 H 7h imidazo[4,5-bjpyridin-5- Example 6e 2 1.64 427 yl)pyrazolo[1,5-a]pyridine-5 carbonitrile (S)-3-(3-(1-methyl-2-oxo-5 7' (pyrazolo[1,5-a]pyridin-3-yl)-1 H imidazo[4,5-b]pyridin-3(2H) yl)piperidin-1-yl)-3-oxopropanenitrile 3-(9-(1-(2-cyanoacetyl)azetidin-3 yl)-7-methyl-8-oxo-8,9-dihydro-7H 7j Example 6ac 2 2.10 1414 purin-2-yl)pyrazolo[1,5-alpyridine-5 carbonitrile (S)-3-(3-(2-(5-methylpyrazolo[1,5 7k a]pyridin-3-yl)-8-oxo-7H-purin- Example 6r 3 1.73 417 9(8H)-yl)piperidin-1-y)-3 oxopropanenitrie (S)-3-(3-(1 -ethyl-2-oxo-5 71 ~~(pyrazolo[1,5-a]pyridin-3-yl)-1 H- Exml6s417 43 7r Example 6s 4 1.87 1430 imidazo[4,5-bjpyridir-3(2H) yl)piperidin-1-yl)-3-o xopropanenitrile 3-oxo-3-(4-(8-oxo-2-(pyrazolo[1,5 7m ajpyridin-3-yl)-7H-purin-9(8H)- Example Gd 4 1.32 403 yl)piperidin-1-yl)propanenitrile (S)-3-(3-(I-(2-cyanoacetyl)piperidin 3-yl)-1 -methyl-2-oxo-2,3-dihydro 7n 1H-imidazo[4,5-blpyridin-5- Example 6f 3 2.02 441 yl)pyrazolo[1,5-a]pyridine-5 carbonitrile (R)-3-(3-(1 -methyl-2-oxo-5 (pyrazolo[1,5-a~pyridin-3-yl)-1H 70 Example 6w 4 11.71 416 imidazo[4,5-b]pyridin-3(2H) yl)piperidin-1-y)-3-oxopropanenitrile 75 (S)-3-oxo-3-(3-(2-oxo-5 (pyrazolo[1 5-a]pyridin-3-yl)-1H 7pExample 6x ,3 1.75 402 imidazo{4,5-b]pyridin-3(2H) y[)piperidin-1 -yl)propanenitrile 3-(9-(I-(2-cyanoacetyl)piperidin-4 yl)-7-methy -8-oxo-8,9-dihydro-7H 7q Example 6y 3 1.82 442 purin-2-yI)pyrazolo[1,5-a]pyridine-5 carbonitrile (S)-3-(3-(I-(2-cyanoacetyl)piperidin 3-yl)-3H-imidazo[4,5-bjpyridin-5 7r Example 6z 5 2.20 411 yl)pyrazolo[1,5-alpyridine-5 carbonitrile (S)-3-(3-(1-(2-cyanoacetyl)piperidin 3-y!)-2-methyl-3H-imidazo[4,5 7s Example Saa 5 2.09 425 b]pyridin-5-yl)pyrazoio[1,5 a]pyridine-5-carbonitrile (S)-3-(3-(2-methyl5-(pyrazolo[1,5 a]pyridin-3-yl)-3H-imidazo[4,5 7t Exampie 6ae 3 1.85 400 b]pyridin-3-yl)piperidin-1-yl)-3 oxopropanenitrile (S)-3-oxo-3-(3-(5-(pyrazolo[1,5 iajpyridin-3-yl)-3H-imidazo[4,5 7u Example 6ad 3 1.77 386 blpyridin-3-yl)piperidin-1 yi)propanenitrile (1) obtained as example 6, but using tert-butyl 3-aminopyrrolidine-1-carboxylate as starting material. (2) obtained as example 6, but using tert-butyl 4-(aminomethyl)piperidine-1-carboxylate as starting material. 5 EXAMPLES (S)-3-(9-(1-Acetylpiperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile To a solution of the compound obtained in example 6 (31 mg, 0.063 mmol) in anhydrous DMF (3 mL), acetic anhydride (0,007 mL, 0.08 mmol) and anhydrous TEA (0.02 mL, 0.127 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO 3 0 aqueous solution (15 mL) and extracted with EtOAc (3x15 mL). The combined organic phases were dried over anhydrous Mg 2

SO

4 , filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.5 mg of the desired compound (57% yield), 76 LC-MS (method 2): tR = 1.87 min; mlz = 403 (MH+). Following a similar procedure to that described in example 8, but using in each case the corresponding starting materials, the following compounds were obtained: 5 HPLC tR m& Example Compound name Starting material method (min) (MH*) (S)-9-(1 -acetylpiperidin-3-yl)-2 8a (pyrazolo[1,5-a]pyridin-3-yl)-7H- Example 6v 2 1.55 378 purin-8(9H)-one 3-(9-(1-acetylpiperidin-4-yl)-8-oxo 8,9-dihydro-7H-purin-2 8b Example Lab 1 13.31 403 yl)pyrazolo[1,5-a]pyridine-5- i carbonitrile 9-(1-acetylpiperidin-4-yl)-2 8c (pyrazolo[1,5-ajpyridin-3-yl)-7H- Example 6d 4 1.30 378 purin-8(9H)-one (S)-3-(1 -isobutyrylpiperidin-3-yl)-5 8d (pyrazolo[1,5-a]pyridin-3-yl)-1H- Example 6x 3 2,00 405 imidazo[4,5-b]pyridin-2(3H)-one (1) (S)-3-(9-(1-acetylpiperidin-3-yl)-7 methyl-8-oxo-8,9-dihydro-7H-purin Be 2-yl)pyrazolo[1,5-alpyridine-5- Example Lc 3 1.88 417 carbonitrile (S)-3-(1 -acetylpiperidin-3-y)-5 8 (pyrazolo[1,5-a]pyridin-3-yl)-1H- Example 6x 3 1.72 377 imidazo[4,5-blpyridin-2(3H)-one 3-(9-(1-acetylpiperidin-4-yl)-7 methyl-8-oxo-8,9-dihydro-7H-purin 8g Example 6y 31.78 417 2-yl)pyrazoo[1,5-a]pyridine-5 carbonitrile 3-(9-(1 -acetylazetidin-3-yl)-7 methyl-8-oxo-8,9-dihydro-7H-purin 8h Example Sac 3 1.62 389 2-yl)pyrazolo[1,5-a]pyridine-5 carbonitrile (1) using isobutyryl chloride instead of acetic anhydride as starting material.

77 EXAMPLE 9 (S)-3-(9-(1 -(Methylsulfonyl)piperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[i5-a]pyridine-5 carbonitrile 5 To a solution of the compound obtained in example 6 (31 mg, 0.063 mmol) in anhydrous DMF (3 mL), methanesulphonic anhydride (13 mg, 0.08 mmol) and anhydrous TEA (0.02 mL, 0.127 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO 3 aqueous solution (15 mL) and extracted with EtOAc (3x15 mL). The combined organic phases were dried over anhydrous Mg 2

SO

4 , filtered and concentrated. The crude residue was chromatographed on 3 a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.3 mg of the titled compound (52% yield). LC-MS (method 1 POB): tR = 2.08 min; m/z = 439 (MH+). Following a similar procedure to that described in example 9, but using the corresponding starting materials, the 5 following compounds were obtained: HPLC tR mlz Example Compound name Starting material method (min) (MH-) (S)-9-(1-(methylsulfonyl)piperidin-3- Example 6v and 9a yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)- methanesulphonyl 2 1.70 414 7H-purin-8(9H)-one chloride (S)-3-(8-oxo-9-(1 Example 6 and (propylsulfonyl)piperidin-3-yl)-8 9 9bpropane-1-sulfonyl 5 2.48 46 dihydro-7H-purin-2-yl)pyrazolo[1,5 chloride a)pyridine-5-carbonitrile (S)-3-(8-oxo-9-(1-(2,2,2 trifluoroethylsulfonyl)piperidin-3-yl)- Example 6 and 2,2,2 90 8,9-dihydro-7H-purin-2- trifluoroethanesulfonyl 1 5 2.55 507 yl)pyrazolo[1,5-a]pyridine-5- chloride carbonitrile (S)-3-(9-(1 (isobutylsulfonyl)piperidin-3-yl)-8- Example 6 and 2 9d oxo-8,9-dihydro-7H-purin-2- methylpropane-1- 3 2.70 481 yl)pyrazolo[1,5-a]pyridine-5- sulfonyl chloride carbonitrile 78 (S)-3-(8-oxo-9-(1-(3,3, 3 trifluoropropylsulfonyl)piperidin-3- Example 6 and 3,3,3 9e yl)-8,9-dihydro-7H-purin-2- trifluoropropane-1- 3 2.70 521 yl)pyrazolo[1,5-ajpyridine-5- sulfonyl chloride carbonitrile (S)-1 -methyl-3-(1 Example 6g and (methylsulfonyl)piperidin-3-yl)-5 (pyrazolo[1,5-a]pyrdin-3-yl)-1H- methanesulphonyl 4 1.81 427 chloride imidazo[4,5-b]pyridin-2(3H)-one (S)-2-(5-methylpyrazolo(1,5t Example 6r and a]pyridin-3-yl)-9-(1- [ 9g methanesulphonyl 3 1.87 428 (methylsulfonyl)piperidin-3-yl)-7H chloride purin-8(9H)-one 7-(2-oxopropyl)-9-(1-(2 oxopropyl)piperidin-4-yl)-2- Example 6d and 1 (pyrazolo[1,5-a]pyridin-3-yl)-7H- chloropropan-2-one purin-8(9H)-one 9-(1-acetylpiperidin-4-yl)-7-methyl 9 2-(pyrazolofl 5-a]pyridin-3-yl)-7H- Example 6t and 4 1.42 392 purin-8(9H)-one acetyl chloride (S)-3-(3-(1 -isobutyrylpiperidin-3-y) 2-oxo-2,3-dihydro-IH-imidazo[4,5- Example 6e and 9j 5 2.52 430 b]pyridin-5-yl)pyrazolo[1.5- isobutyryl chloride a]pyridine-5-carbonitrile (S)-3-(3-(1-(methylsulfonyl)piperidin 3-yl)-2-oxo-2,3-dihydro-1 H- Example 6e and 9k imidazo[4,5-b]pyridin-5- methanesulphonyl 3 1.92 438 yl)pyrazolo[1,5-a]pyridine-5- chloride carbonitrile (S)-3-(7-methyl-9-(1I (methylsulfonyl)piperidin-3-yl)-8- Example 6c and 91 oxo-8,9-dihydro-7H-purin-2- methanesulphonyl 3 2.05 453 yl)pyrazolo[1,5-a]pyridine-5- chloride carbonitrile 79 (S)-3-(9-(1-(ethylsufonypiperidin Am Example 6 and 3-yl)-8-oxo-8,9-dihydro-7H-purin-2 9m ethylsulphonyl 3 1.90 453 yl)pyrazoio[1,5-a]pyridine-5- hl ori1. carbonitrile (S)-3-(9-(1-isobutyrylpipendin-3-yl) 9 8-oxo-8,9-dihydro-7H-purin-2- Example 6 and L15 431 yl)pyrazolo[1,5-a]pyridine-5- isobutyryl chloride carbonitrile 3-(7-methyl-9-(1 (methylsulfonyl)piperdin-4-y)-8- Example 6y and 90 oxo-8,9-dihydro-7H-purin-2- methanesulphonyl 3 1.95 453 yl)pyrazolo[1,5-ajpyridine-5- chloride carbonitrile 3-(9-(1 -(methylsulfonyl)piperidin-4 yl)-8-oxo-8,9-dihydro-7H-purin-2 9p methanesulphonyl 1 14.06 439 yl)pyrazolo[1,5-ajpyridne-5 chloride carbonirile (S)-3-(1t-(mnethyisulfonyl)piperidin-3- Example 6x and 9q yl)-5-(pyrazolo[1,5-a]pyridin-3-yl)- methanesulphonyl 3 1.85 413 1 H-imidazo[4,5-b]pyridin-2(3H)-one chloride 3-(7-methy-9-(1 (methylsulfonyl)azetidin-3-yl)-8-oxo- Example 6ac and 9r 8,9-dihydro-7H-purin-2- methanesuphonyl 3 2.30 425 yl)pyrazolo[1,5-a]pyridine-5- chloride carbonitrile (S)-3-(3-(1-acetylpiperidin-3-y)-2 9s oxo-2,3-dihydro-iH-imidazo[4,5- Example 6e and 5 225 402 bjpyridin-5-yl)pyrazolo[1,5- acetyl chloride alpyridine-5-carbonitrile (S)-3-(1-(2-methoxyacetyl)piperidin- I Example 6g and 2 3-yl)-1-methyl-5-(pyrazoio[1,5- mExa e and 2 ajpyridin-3-yl)-1 H-imidazoJ4,5 b]pyridin-2(3H)-one chloride 80 (S)-1-methyl-5-(pyrazolo(1,5- Example 6g and a]pyridin-3-yl)-3-(1-(2,2,2- 2,2.2 9u 4 2.17 495 tdfluoroethylsulfonyl)pipeddin-3-y)- trifluoroethanesulfonyl 1H-imidazo{4,5-blpyridin-2(3H)-one chloride EXAMPLE 10 (S)-3-(9-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5.apyridine-5 carbonitrile 5 To a solution of N,N-dimethylglicine (10 mg, 0.095 mmol) in anhydrous DMF (2 mL), HOBt.H 2 0 was added. After 15 min, EDC.HCI (24 mg, 0,126 mmol) and the compound obtained in example 6 (31 mg, 0.063 mmol) were added. The reaction mixture was stirred at room temperature for 2.5 h and the solvent was concentrated off, It was quenched with saturated NaHCO 3 aqueous solution (15 mL) and extracted with EtOAc (3x15 mL). The combined organic phases were dried over anhydrous Mg 2

SO

4 , filtered and concentrated, The crude residue was chromatographed on 0 a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 8.2 mg of the titled compound (29% yield). LC-MS (method 3): tR = 1.67 min; m/z = 446 (MH). Following a similar procedure to that described in example 10, but using the corresponding starting material, the 5 following compound was obtained: HPLC ta z Example Name Starting Material t 1 method (min) (MH+) (S)-3-(9-(1 -(2-£ 1 hydroxyacetyl)piperidin-3-yl)-8-oxo Example 6 and 10a 8,9-dihydro-7H-purin-2- 3 t52 419 I alicolic acid yl)pyrazolo[1,5-a]pyridine-5 carbonitrile (S)-3-(9-(1-(2-hydroxy-2 Example 6 and 2 methylpropanoyl)piperidin-3-yl)-8 hydroxy-2 10b oxo-8,9-dihydro-7H-purin-2- 3 1.75 447 methylpropanoic yi)pyrazolo[1,5-a]pyridine-5 carbonitrile 81 3-(8-oxo-9-((S)-i1-((s)-f tetrahydrofuran-2- Example 6 and (S) 1 0c carbonyl)piperidin-3-yl)-8,9-dihydro- tetrahydrofuran-2- 3 1.75 459 7H-purin-2-yl)pyrazolo[1,5- carboxylic acid a]pyrine-5-carbonitrle methoxyacetyl)piperidin-3-yl)-8 10d oxo-8,9-dihydro-7H-purin-2- Example 6 and 2- 433 methoxyacetic acid yl)pyrazolo[1,5-a]pyridine-5 carbonitrile (S)-3-(9-(1-(2-{i ethylbutanoyl)piperidin-3-yl)-8-oxo Example 6 and 2 IDe 8.9-dihydro-7H-purin-2- 3 2.20 459 ethylbutanoic acid yl)pyrazolo[1,5-ajpyridine-5 carbonitrle (S)-3-(9-(1-(2-(3-methylsoxazol-5 yl)acetyl)piperidin-3-yl)-8-oxo-8,9- Example 6 and 2-(3 1 Of dihydro-7H-purin-2-yl)pyrazolo(1,5- metylisoxazol-5- 3 1.82 484 yl)acetic, acid a]pyridine-5-carbonitrile 3-(9-((S)-1-((S)-2 methoxypropanoyl)piperidin-3-yl)-8- Example 6 and (S) 10g oxo-8,9-dihydro-7H-purin-2- 2-methoxypropanoic 5 2.23 447 yl)pyrazolo[1,5-a]pyridine-5- acid carbonitrile F ~~~(S)-3-(8-oxo-9-(1-(3,3,3-Exml6an Example 6 and trifluoropropanoyl)piperidin-3-yl) 3,3,3 10h 8,9-dihydro-7H-purin-2- trifluoropropanoic 3 1.97 471 yl)pyrazolo[1,5-ajpyridine-5 aid carbonitrile (S)-2-(5-methylpyrazolo[1,5 10i alpyridin-3-yl)-9-(1- Example 6r and 3 1.85 406 propionylpiperidin-3-yl)-7H-purin- propionic acid 8(9H)-one (S)-9-(1-(2-methoxyacetyl)piperidin- Example r and 2 1 0j 3-yl)-2-(5-methylpyrazolo[1,5- F 3 F 72 422 methoxyacetic acid a]pyridin-3-yl)-7H-purin-8(9H)-oneI 82 (S)-7-(2-methoxyacetyl)-9-(1-(2 methoxyacetyl)piperdin-3-yl)-2-(5- Example 6r and 2 10k 3 2.1 3 494 methylpyrazolo(1,5-a]pyridin-3-yl)- methoxyacetic acid 7H-purin-8(9H)-one (S)-9-(1-acetylpiperidin-3-yl)-2-(5 101 methylpyrazolo[1,5-a]pyridin-3-yl)- ame ai3 1.70 392 acetic acid 7H-purin-8(9H)-one [ - (S)-9-(1-(2-hydroxyacetyl)piperidin Example 6r and 2 lOm 3-yl)-2-(5-methylpyrazolo[1,5- 3 1 60 408 1hydroxyacetic acid a]pyridin-3-yl)-7H-purin-8(9H)-one (cyclopropanecarbonyl)piperidin-3- Example 6 and 10n yi)-8-oxo-8,9-dihydro-7H-purin-2- cyclopropanecarbox 3 1.88 429 yl)pyrazolo[1,5-a]pyridine-5- ylic acid carbonitrile (S)-3-(1-(2-hydroxy-2- Example 6g and 2 methylpropanoyl)piperidin-3-yl)-1- I droxy-2 10o methyl-5-(pyrazolo[1,5-a]pyridin-3- 4 1.76 435 methylpropanoic yl)-1 H-imidazo[4,5-b]pyridin-2(3H)- y ci one - acid one (S)-3-(1-(2-hydroxyacetyl)piperidin 3-yl)-1-methyl-5-(pyrazolo[1,5- Examle 6g and 2 10p 4 1.59 407 a]pyridin-3-yl)-1 H-imidazo[4,5- hydroxyacetic acid b]pyridin-2(3H)-one ()-3-(1-(2 (dimethylamino)acetyl)piperidin-3 Examle 6g and N,N 10q yl)-1 -methyl-5-(pyrazolo[1, 5- 4 1.65 434 dimethylglicine alpyridin-3-yl)-1 H-imidazo[4,5 b]pyridin-2(3H)-one 1-methyl-5-(pyrazolo[1 .5-a]pyridin Examie 6g and (S) 3-yl)-3-((S)-1-((S)-tetrahydrofuran- taroyli acid 2-carbonyl)piperidin-3-yl)-1 H I carboxylic acid imidazo[4,5-b]pyridin-2(3H)-one 83 (S)-1 -methyl-5-(pyrazolo[1,5- Example 6g and los apyridin-3-yl)-3-(I-(3,3,3- 3,3-4 1.9 459 trifluoropropanoyl)piperidin-3-yl)- trifluoropropanoic 1H-imidazo(4,5-bjpyridin-2(3H)-one acid EXAMPLE 11 (S)-3-(2-(5-Cyanopyrazolo[ 1,5-a]pyridi n-3-yl)-8-oxo- 7H-purin-9(SH)-yl)-N,N-dimethyl piperidi ne-I -sulfonamide To a solution of the compound obtained in example 6 (110 mg, 0.22 mmol) in anhydrous DMF (3 mL), N,N 5 dimethylsulfamoyl chloride (0.03 mL, 0.27 mmol) and anhydrous TEA (0.13 mL, 0.90 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO3 aqueous solution (15 mL) and extracted with EtOAc (3x15 mL). The combined organic phases were dried over anhydrous Mg 2

SO

4 , filtered and concentrated. The crude residue was chromatographed on a silica gel flash system (ISCO Rf using hexanes/acetone mixtures of increasing polarity as eluent to afford 39.2 mg 0 of the titled compound (38% yield). LC-MS (method 1): tR = 1.95 min; m/z = 468 (MW). Following a similar procedure to that described in example 11, but using the corresponding starting materials, the following compound was obtained: 5 HPLC tR m/z Example Name Starting Materials method (min) (MH+) (S)-NN-dimethyl-3-(1-methyl-2 oxo-5-(pyrazolo(1,5-alpyridin-3-yl) 1la Example 6g 4 2.05 456 1 H-imidazo[4,5-bjpyridin-3(2H) yl)piperidine-1-sulfonamide EXAMPLE 12 3-(9-(1 -Acetylpyrrolidin-3-yI)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5 carbonitrile ?0 a) teart-Butyl 3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)-8-oxo-7H-purin-9(SH)-yI)pyrrolidine.1-carboxylate Following a similar procedure to that described in example 1, but using tert-butyl 3-aminopyrroiidine-1-carboxylate instead of tetrahydro-2H-pyran-4-amine, the desired compound was obtained. b) tert-Butyl 3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)-7-methyl-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-I 25 carboxylate 84 Following a similar procedure to that described in example 5, but using the compound obtained in previous section as starting material, the desired compound was obtained (25% yield). c) 3-(7-Methyl-8-oxo-9-(pyrrolidin-3-yl)-8,9-dihydro-7H-purin-2.yl)pyrazolo[1,5-a]pyridine-5-carbonitri e 5 hydrochloride Following a similar procedure to that described in example 6, but using the compound obtained in previous section as starting material, the desired compound was obtained (100% yield). d) Title compound o Following a similar procedure to that described in example 8, but using the compound obtained in previous section as starting material, the desired compound was obtained (22% yield), LC-MS (method 2): tg = 1.67 min; m/z = 403 (MH*). EXAMPLE 13 5 3-(7-Methyl-9-(l (methylsulfonyl)pyrrolidin-3-yl)-B-oxo-8,9-dihydro-7H-purin-2.yl)pyrazaloll,5-a]pyridine-5 carbonitrile Following a similar procedure to that described in example 9, but using the compound obtained in example 12 section c as starting material, the desired compound was obtained (15% yield). LC-MS (method 2): tp = 1.83 min; mlz = 439 (MH+). Following a similar procedure to that described in example 13. but using the corresponding starting materials, the following compounds were obtained: HPLC t miz Example Name Starting Material method (min) (MH+) (S)-3-(7-methyl-9-( 1 (methylsulfonyl)pyrrolidin-3-yl)-8 13a oxo-8,9-dihydro-7H-purin-2- Example 6h 3 2.35 439 yl)pyrzolio[1,5-a]pyidine-5 carbonitrile (R)-3-(7-methyl-9-(1 (methylsulfonyl)pyrroidin-3-yl)-8 13b oxo-8,9-dihydro-7H-purin-2- Example 6i 3 2.35 439 yl)pyrazolo[1,5-ajpyridine-5 carbonitrile 85 (S)-9-(1-(methylsulfonyl)pyrrolidin 13c 3-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)- Example 6j 3 1.53 400 7H-purin-8(9H)-one (S)-7-methyl-9-(1 (methylsulfonyl)pyrrolidin-3-yl)-2 13d 1 Example 6k 3 1.77 414 (pyrazolo[1,5-a]pyrdin-3-yl)-7H purin-8(9H)-one (S)-3-(9-(1 (methylsulfonyl)pyrrolidin-3-yl)-8 13e oxo-8,9-dihydro-7H-purin-2- Example 61 3 1 63 425 yl)pyrazolo[1,5-a]pyridine-5 carbonitrile (R)-1 -methyl-3-(1 (methylsulfonyl)pyrroiidin-3-yl)-5 (pyrazolo[1,5-a]pyridin-3-yl)-1H- Example 6m imidazo[4,5-b]pyridin-2(3H)-one (R)-3-(1 -(methylsulfonyl)pyrrolidin 13g 3-yi)-5-(pyrazolo[1,5-a]pyridin-3-yl)- Exam 3 1.72 39 1 H-imidazot4,5-blpyridin-2(3H)-one (R)-3-(9-(1 (methylsulionyl)pyrrolidin-3-yI)-S 13h oxo-8,9-dihydro-7H-purin-2- Example 6 3 1.62 425 yl)pyrazolo[1,5-alpyridine-5 carbonitrile (S)-3-(1-(methylsulfonyl)pyrrolidin 13! 3-yI)-5-(pyrazolo[1,5-a]pyridiri-3-yl)- Example 6p 3 1.72 399 1 H-imidazo[4,5-bjpyridin-2(3H)-one (S)-1-methyl-3-(1 I (methylsulfonyl)pyrrolidin-3-yl)-5 13j Example 6q 3 1.92 413 (pyrazolo{1,5-a]pyridin-3-yl)-1 H imidazo[4,5-b]pyridin-2(3H)-one (S)-7-methyl-9-(1 (methylsulionyl)piperidin-3-yl)-2 13k Example 6u 3 1.93 428 (pyrazolo[1,5-alpyridin-3-yl)-7H purin-8(9H)-one 86 EXAMPLE 14 (2R)-242-(5-Cyanopyrazolofl,5-a)pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]propanoic acid To a suspension of example 1a (65 mg, 018 mmol) in dioxane (1.6 mL) and H20 (0.8 mL) at 0 *0, LiOH.H 2 0 (15 mg, 0.36 mmol) was added, The reaction mixture was stirred at 0 0C for 1 h and room temperature for 26 h. The pH of 5 the solution was adjusted to 5 by adding 10 % HCI aqueous solution. The solvent was removed under vacuum and the resulting solid was suspended in Et 2 O (10 mL) and concentrated. The resulting solid was washed with water (2x5 mL), hexanes (3 mL) and Et 2 0 (2x5 mL) to afford 57 mg of the desired product (91%). LC-MS (method 1): tR = 13.59 min; m/z = 350 (MH+). 0 Following a similar procedure to that described in example 14, but using the corresponding starting materials, the following compounds were obtained: HPLC tR I Example Name Starting Material (mPn) (M Satmethod (mn (M+ (2S)-2-[2-(5-Cyanopyrazolo(1,5 14a alpyridin-3-yl)-8-oxo-7,8-dihydro- Example 1V 1 13.59 350 9H-purin-9-yl]propanoic acid (S)-2-(8-oxo-2-(pyrazolo[1,5 14b a)pyridin-3-yi)-7H-purin-9(8H)- Example 3e 3 .10 325 yl)propanoic acid EXAMPLE 15 5 (2R)-2-f2.(5-Cyanopyrazolo[1,5-a)pyridin-3-yl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-N-(2,2,2 trifluoroethyl)propanamide To a solution of HOBt.H 2 0 (31 mg, 0.20 mmol) and TEA (0.068 mL, 0.49 mmol) in THF (1 mL), example 14 (70 mg, 0.20 mmol) was added, After 15 min, EDC.HCI (40 mg, 0.21 mmol) and 2,2,2-trifluoroethylamine hydrochloride (14.6 mg, 0.11 mmol) were added and the resulting mixture was stirred at room temperature for 3.5 days. Then, it was 20 quenched with H20 (5 mL) and extracted with EtOAc (3x15 mL), The combined organic phases were dried over anhydrous Na 2

SO

4 , filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using MeOH/CH 2 01 2 mixtures of increasing polarity as eluent, to afford 18 mg of the desired compound (50 % yield). LC-MS (method 1): tP = 15.34 min; mIz = 431 (MH+). ?5 Following a similar procedure to that described in example 15, but using the corresponding starting material, the following compound was obtained; 87 HPLC tR Example Name Starting Material method (min) (MH) (2R)-(2-(5-cyanopyrazoio[1.5 Example 14 and N 15a ajpyridin-3-yl)-8-oxo-7H-purin- 1 1 13.62 363 9(8H)-yl)-N-methylpropanamide (2S)-2-[2-(5 cyanopyrazolo{1,5 (2S)-2-{2-(5-cyanopyrazolo[1,5 a]pyridin-3-yl)-8-Oxo alpyridin-3-yl)-8-oxo-7,8-dihydro 15b 7,8-dihydro-9H-purn- 3 2.08 459 9H-purin-9-yl}-3-methyl-N-(2,2,2- 9~l--eh~uao trifluoroethyl)butanamide acid (1) and 2,2,2 trifluoroethylamine (R)-2-(2-(5-cyanopyrazolo[1 5 alpyridin-3-yl)-8-oxo-7H-purin- Example 14 and 2 15c 3 1.35 393 9(8H)-yl)-N-(2- aminoethanol hydroxyethyl)propanamide (R)-2-(2-(5-cyanopyrazolo[1,5 ajpyridin-3-yl)-8-oxo-7H-purin- Example 14 and 15d cyclopropyimethanami 3 1.75 403 9(8H)-yl)-N ne (cyclopropylmethyl)propanamide (R)-2-(2-(5-cyanopyrazolo[15- Example 14 and a]pyridin-3-yl)-8-oxo-7H-purin- NIN1 15e 3 148 420 9(8H)-yl)-N-(2- dimethylethane-1,2 (dimethylamino)ethyl)propanamide diamine (R)-2-(2-(5-oyanopyrazoloI1,5 Example 14 and N 15f a]pyridin-3-yl)-8-oxo-7H-purin- 3 1.57 377 ethylamine 9(8H)-yl)-N-ethylpropanamide (R)-2-(2-(5-cyanopyrazoio[1,5- E 15g ajpyridin-3-yl)-8-oxo-7H-purin- Examplan 3 1.70 391 9(8H)-yl)-N-isopropylpropanamider (R)-2-(2-(5-cyanopyrazolo[1,5 E xample 14 and N,N 15h ajpyridin-3-yI)-8-oxo-7H-purin- 3 1.53 377 9(8H)-yl)-N,N-dimethylpropanamide 88 (S)-2-(2-(5-cyanopyrazolo[1,5 Example 14a and a]pyridin-3-yl)-8-oxo-7H-purin 15i 1i2,2,2- 3 1,72 431 9(8H-yl)N-(22.2-trifluoroethylamine trifluoroethyl)propanamide (S)-N-methyl-2-(8-oxo-2- Example 14b and N 15j (pyrazolo[1,5-a]pyridin-3-yi)-7H- 3 1.35 338 1 methylamine purin-9(8H)-yl)propanamide (S)-N,N-dimethyl-2-(8-oxo-2 Example 14b and N,N 15k (pyrazolo[1,5-a]pyrdin-3-yl)-7H- 5 1.90 352 dimethylarnine purin-9(8H)-yl)propanamide (1) Obtained as example 14 but using HCI/Dioxane 4M/H 2 0 (1:1) instead of LiOH H20, and L-Valine methyl ester hydrochloride as starting material. EXAMPLE 16 3.(7.(2-Methoxyethyl)--oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5 carbonitrile To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaH dispersion in mineral oil (6 mg, 0.15 mmol) was added and the resulting solution was stirred at room temperature for 10 min. Then 2-bromoethyl methyl ] ether (0.032 mL, 0.34 mmol) was added and the reaction mixture was stirred at 50 0C for 14.5 h. The reaction mixture was quenched with H 2 0 (10 mL) and extracted with EtOAc (3x1 0 mL). The combined organic phases were dried over anhydrous Na 2

SO

4 , filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using EtOAc/hexanes mixtures of increasing polarity as eluent, to afford 36 mg of the desired compound (62% yield), 5 LC-MS (method 1): tR = 16.17 min; m/z = 420 (MH+). Following a similar procedure to that described in example 16, but using in each case the corresponding starting materials, the following compounds were obtained: HPLC tR mz Example Name Starting Material method (mi) (MH+) 2-bromo-N,N cyanoacetyl)piperidin-3-yl)-7-(2 dimethylethaniamine 16a (dimethylamino)ethyl)-8-oxo-8,9- .2 1.95 499 and example 1b (1) dihydro-7H-purin-2-yl)pyrazolo[1,5 a]pyridine-5-carbonitrile 89 (S)-3-(7-(2-(dimethylami no)ethyl)-8- 2-bromo-N,N oxo-9-(piperidin-3-yl)-8,9-dihydro- dimethylethanamine 16b 2 1,83 432 7H-purin-2-yl)pyrazoloi, 5- and example 1 b (2) a]pyridine-5-carbonitrile 7-(2-(dimethylamino)ethyl)-2- 2-bromo-N,N (pyrazolo(1,5-a]pyridin-3-yl)-9- dimethylethanamine (tetrahydro-2H-pyran-4-yl)-7H- and example 3 purin-8(9H)-one) 3-(7-(2-(dimethylamino)ethyl)-8- 2 mN oxo-9-(tetrahydro-2H-pyran-4-yl)- dim tna mine 16d 8,9-dihydro-7H-purin-2- 1 14.79 433 and example 1 yl)pyrazoo[1,5-a]pyridine-5 carbonitrile 3-(7-(2-(dimethylamino)ethyl)-9-(8 2-bromo-N,N fluorochroman-4-yl)-8-oxo-8,9- i 16e diyr-Hph--lprzl 1 -dimethylethanamine 4 2,12 499 1 e dihydro-7H-purin-2-yl)pyrazoo[1,5-21 and exam ple 1 p a]pyridine-5-oarbonitrile 3-(9-(8-fluorochroman-4-y)-7-(2 methoxyethyl)-8-oxo-8,9-dihydro- m 16f Iether and example 4 2.20 486 I 7H-purin-2-yl)pyrazolo[1,5 ajpyridine-5-carbonitrile 3-(9-(8-fluorochroman-4-yl)-7-(3 1 hydroxypropyl)-8-oxo-8,9-dihydro- 3-bromopropan-1-ol 16g 4 1.96 486 7H-purin-2-yl)pyrazolo[1,5- and example 1p a]pyridine-5-carbonitrile I ~ (S)-3-(3-(1 -(2 (dimethylamino)ethyl)-2-oxo-5 2-bromo-N, N ih (pyrazolo[1,5-a]pyridin-3-yi)-1H- 2-rmNN 16h iiazo5-bpyddin-32)- dimethylethanamine 4 1.73 473 imidazo[4,5-b]pyridin-3(2H) and eape2a (1) yl)piperidin-1-yl)-3- a oxopropanenitrile (S)-3-(3-(1-(2-methoxyethyl)-2-oxo 5-(pyrazolo[1,5-alpyridin-3-yl)-1 H- 2-bromoethyl methyl 16i imidazo{4,5-bjpyridin-3(2H)- ether and example 4 1.82 460 yl)piperidin-I-yl)-3- 2a (1) oxopropanenitriie 90 (S)-3-(3-(1-(cyclopropylmethyl)-2 (bromomethyl)cyclo oxo-5-(pyrazolo{1,5-a]pyridin-3-yl) propane and 16j 1 H-imidazo[4,5-b]pyridin-3(2H)- 4 2.08 456 yl)piperidin-1-y)-3- example 2a (1) oxopropanenitrile (1) followew by a similar procedure to that described in example 6 (tert-butoxtcarbonyl cleavage) and 7 (amide formation). (2) followew by tert-butoxycarbonyl cleavage as example 6 5, EXAMPLE 17 3-(7-(2-Hydroxyethyl)..oxo-9-(tetrahydro.2H.pyran-4-y)-8,9-dihydro-7H-purin-2.yl)pyrazolo[1,5-a]pyridine-5 carbonitrile a) 3-(7-(2-(tert-Butyldimethylsilyloxy)ethyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2 0 yl) pyrazolo[1,5-ajpyridi ne-5-carbonitrile To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaH dispersion in mineral oil (6 mg, 0.15 mmol) was added. The resulting solution was stirred at room temperature for 10 min. Then (2-bromoethoxy)-tert butyldimethylsilane (0.074 mL, 0.34 mmol) was added and the reaction was stirred at 50 *C for 14.5 h, The reaction mixture was quenched with H 2 0 (10 ml) and extracted with EtOAc (3x1 0 mL). The combined organic phases were 5 dried over anhydrous Na 2

SO

4 , filtered and concentrated, The crude product thus obtained was chromatographed over silica gel using hexanes/EtOAc mixtures of increasing polarity as eluent, to afford 55 mg of the desired compound (76 % yield), b) Title compound 20 To a solution of the compound obtained in the previous section (55 mg, 0.10 mmol) in THF (5 mL) 1 M TBAF solution in THE (0,14 mL, 0.14 mmol) was added and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was quenched with H 2 0 (10 mL) and extracted with EtOAc (3x10 mL) and CH 2 C1 2 (2x10 mL). The combined organic phases were dried over anhydrous Na 2 SO4 filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 25 39 mg of the desired compound (91 % yield). LC-MS (method 1): tR = 14.13 min; m/z = 406 (MH+). Following a similar procedure to that described in example 17, but using in each case the corresponding starting materials, the following compounds were obtained: 30 91 HPLC tR mlz Example Name Starting Material method (min) (MH-) (S)-3-(9-(1-(2 cyanoacetyl)piperidin-3-y)-7-(2 17a hydroxyethyl)-8-oxo-8,9-dihydro- Example 1b (1) 1 1.68 472 7H-purin-2-yl)pyrazolo[1,5 a]pyridine-5-carbonitrile (S)-3-(7-(2-hydroxyethyl)-8-oxo-9 (piperidin-3-y)-8,9-dihydro-7H I purin-2-yl)pyrazolo[1,5-alpyridine-5 carbonitrile hydrochloride 3-(9-(8-fluorochroman-4-yl)-7-(2 hydroxyethyl)-8-oxo-8,9-dihydro 17c Example 1 p 1 15.99 472 7H-purin-2-yl)pyrazolo[1 5 a]pyridine-5-carbonitrile (1) Followed by a similar procedure to that described in example 6 (tert-butoxtcarbonyl cleavage) and 7 (amide formation), (2) Followed by tet-butoxycarbonyl cleavage as example 6 5 EXAMPLE 18 3-(9-Tetrahydro-2H.pyran-4-yl.9H.purin-2-yl)pyrazolo[1,5.a)pyridine-5-carbonitrile To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in EtOH (1 mL), PTSA monohydrate (5.7 mg, 0.03 mmol) and triethylorthoformate (1 mL) were added. The reaction mixture was heated in a OEM Explorer microwave oven at 123 *C and 270 W for 30 min. Then, it was evaporated to dryness. The crude 10 product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 81 mg of the desired compound (79 % yield). LC-MS (method 1): tR = 14.56 min; m/z = 346 (MH*) Following a similar procedure to that described in example 18, but using in each case the corresponding starting 15 materials, the following compounds were obtained: 92 HPLC tR mlz Example Name Starting Material method (min) (MH1) 3-(8-methyl-9-tetrahydro-2H-pyran- Example 1 section d 18a 4-yl-9H-puri-2-yl)pyrazolo[1,5- and 1 14.77 360 a]pyridine-5-carbonitrile thethylorthoacetate triethylorthoacetate and 3-(5-amino-4-(4,4 3-(9-(4,4-difluorocyclohexyl)-B- difluorocyclohexylamin 18b methyl-9H-purin-2-yl)pyrazoo[1,5- o)pyrimidin-2- 2 2.17 394 a]pyridine-5-carbonitrile yl)pyrazolo[1,5 a]pyridine-5 carbonitrile (1) triethylorthoacetate and 3-(5-amino-4-(1 1 3-(9-(1,1-dioxotetrahydrothien-3-yl) 8-methyl-9H-purin-2 18crzlo15apyije5 3-yl)aminopyrimidin-2- 2 1.65 394 yl)pyrazolo[1 ,5-a]pyridine-5 yl)pyrazolo[1,5 carbonitrile a]pyridine-5 carbonitrile (2) 5-(pyrazolo[1,5-alpyridin-3-yl)-3- Reference example 2g 18d (tetrahydro-2H-pyran-4-yl)-3H- and 3 1.85 320 imidazo[4,5-b]pyridine triethylorthoformate (S)-tert-butyl 3(-5 Reference example 2h cyanopyrazolo[1,5-a]pyridin-3-yl) 18Be and 3 2.33 444 3H-imidazo[4,5-b]pyridin-3- anehyl2.33o444 triethylorthoformate yl)piperidine-1-carboxylate (S)-tert-butyl 3-(5-(5 Reference example 2h cyanopyrazolo(1,5-a]pyridin-3-yi)-2- a 18f and 3 2.57 458 methyl-3H-imidazo[4,5-bjpyridin-3 triethylorthoacetate yl)piperidine-1-carboxylate 2-methyl-5-(pyrazolo[1,5-alpyridin- Reference example 2g 18g 3-yl)-3-(tetrahydro-2H-pyran-4-yl- and 3 1.92 334 3H-imidazo[4,5-b]pyridine triethylorthoacetate 3-(9-(trans-4-hydroxycyclohexyl)-8- Reference example 2 18h i methyl-9H-purin-2-yl)pyrazolo[1,5- and 3 1.70 374 a]pyridine-5-carbonitrile triethylorthoacetate 93 (S)-tert-butyl 3-(5-(pyrazoIo[1,5 Reference example 2d a]pyridin-3-yl)-3H-imidazo(4,5 18i and 3 1.77 386 b]pyridin-3-yl)piperidine-1 triethylorthoformate (1) obtained in example le section d (2) obtained in example 1f section d EXAMPLE 19 5 3-(3-(Tetrahydro-2H-pyran-4-yl)-3H-imidazo[4,5-bpyridin-5-yl)pyrazoio[1,5-a]pyridine-5-carbonitrile To a suspension of the compound obtained in example 2 section d (33.6 mg, 0.1 mmo[) in EtOH (1.5 mL), citric acid (2 mg, 0.1 mmol) and triethyl orthoformate (340 pL, 2 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 145 *C and 270 W for 2.5 hours. The crude residue was cromatographed on a silica gel flash system (ISCO RD using hexanes/acetone mixtures of increasing polarity as eluent to afford 14.2 mg of the D desired product (41% yield). LC-MS (method 3): ta = 1.76 min; mz = 345 (MH+). Following a similar procedure to that described in example 19, but using the corresponding starting material, the following compound was obtained: 5 Example Name Starting Material method (min) (MH+) (S)-3-(3-(i-acetypiperidin-3-yl)-3H imidazo{4,5-b]pyrdin-5- Reference example 19a 5 2.22 386 yl)pyrazolo[1,5-ajpyridine-5- 2f carbonitrile EXAMPLE 20 3-(2-Methyl-3-(tetrahydro-2H-pyran-4-yl).3H.imidazo[4,5Nb]pyridin-5-yl)pyrazololl,5-a]pyridine-5-carbonitrile To a solution of the compound obtained in example 2 section d (56.4 mg, 0.169 mmol) in EtOH (1.5 mL), PTSA 0 monohydrate (3.21 mg, 0.017 mmol) and triethyl orthoacetate (547 mg, 3.37 mmol) were added. The reaction mixture was heated in a OEM Explorer microwave oven at 145 *C and 270 W for 2.5 hours. The crude residue was cromatographed on a silica gel flash system (ISCO RD using CH 2 C1 2 /MeOH mixtures of increasing polarity a eluent to afford the desired product (15% yield). LC-MS (method 3): tR = 179 min; m/z = 359.5 (MH+).

94 EXAMPLE 21 3-(8-(1-Methyl-1H-imidazol-2-yI)-9-(tetrahydro-2H-pyran-4-y)-9H-purin-2-yl)pyrazolo{1,5-a]pyridine-5 carbonitrile 5 To a solution of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in AcOH (0.025 mL) and DMA (2.5 mL), 1-methyl-i H-imidazole-2-carbaidehyde (46 mg, 0.42 mmol) was added. The reaction mixture was stirred in a sealed tube at 140 "C for 19 h. The crude mixture was quenched with H 2 0 (10 mL), extracted with EtOAc (3x10 mL) and the combined organic phases were dried over anhydrous Na 2

SO

4 , filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using hexanes/EtOAc mixtures of increasing polarity as 0 eluent, to afford 40 mg of the desired compound (31 % yield). LC-MS (method 1): tR = 16.436 min; m/z = 426 (MH+). Following a similar procedure to that described in example 21, but using the corresponding starting material, the following compound was obtained: 5 Example Name Starting Material HPLC t mz method (min) (MH*) 3-(8-(pyrimidin-5-yl)-9-(tetrahydro t-xample 1 section d 2H-pyran-4-y)-9H-purin-2 21 a and pyrimidine-5- 4 1.67 424 yl)pyrazolo[1,5-a]pyridine-5 carbaldehyde carbonitrile 3-(9-(8-fluorochroman-4-y)-8 (pyrimidin-5-yl)-9H-purin-2- Rerncexml 21 b 2e and pyrimidine-5- 1 16.34 490 yl)pyrazolo(1,5-alpyridine-5- c carbaidehyde carbonitrile 3-(9-(8-fluorochroman-4-y)-8-(1- Reference example methyl-1 H-imidazol-2-yl)-9H-purin- 2e and 1-methyl-1H- 1 21c 1 18.4 492 2-yl)pyrazolo[1,5-a)pyrdine-5- imidazole-2 carbonitrile carbaldehyde 2-(pyrazolo[1,5-a]pyridin-3-yi)-8- Reference example 21d (1H-pyrroI-2-yl)-9-(tetrahydro-2H- 2c and IH-pyrrole-2- 3 2.15 386 pyran-4-yl)-9H-purine carbaldehyde 8-(5-methylthiophen-2-yl)-2- Reference example (pyrazolo[1,5-ajpyridin-3-yl)-9- 2c and 5 21e 3 2.52 417 (tetrahyd ro-2H-pyran-4-yi)-9H- methylthiophene-2 purine carbaldehyde 95 8-(1-methyl-1 H-imidazol-2-yl)-2- Reference example I (pyrazolo[1,5-a]pyridin-3-yl)-9- 2c and 1-methyl-1 H (tetrahydro-2H-pyran-4-yl)-9H- imidazole-2 purine carbaldehyde 2-(pyrazolo[1,5-a]pyridin-3-yl)-9- Reference example 21 g (tetrahydro-2H-pyran-4-yl)-8-(2,2,2- 2c and 3,3,3- 3 2.22 403 trifluoroethyl)-9H-purine trifluoropropanal 8-(1 H-pyrazol-3-yl)-2-(pyrazoio[1,5- Reference example 21h a]pyridin-3-yl)-9-(tetrahydro-2H- 2c and 1 H-pyrazole- 3 1.83 387 pyran-4-yl)-9H-purine 3-carbaldehyde 8-(1 -methyl-1 H-pyrroi-2-yl)-2- Reference example (pyrazolo[1,5-ajpyridin-3-yl)-9- 2c and 1-methyl-iH 21 i 3 2,33 400 2i (tetrahydro-2H-pyran-4-yl)-9H- pyrrole-2- 23 0 purine carbaldehyde 2-(2-(pyrazoo[1,5-a]pyridin-3-yl)-9- Reference example 21j (tetrahydro-2H-pyran-4-yl)-9H- 2c and thiazole-2- 3 2.43 404 purin-8-yl)thiazole carbaldehyde 2-(pyrazolo[1 ,5-alpyridin-3-yl)-9- Reference example 21k (tetrahydro-2H-pyran-4-yl)-8- 2c and thiophene-2- 3 2.32 403 (thiophen-2-yl)-9H-purine carbaldehyde (S)-3-(9-(1-acetylpiperidin-3-y)-8- Reference example 211 (pyrimidin-5-yl)-9H-purin-2- 2 and pyrimidine-5- 3 yl)pyrazolo[1,5-ajpyridine-5- aah carbaldehyde carbonitrile (S)-tert-butyl 3-(2-methyl-5 Reference example (pyrazolo[1,5-a]pyridin-3-yl)-3H 2Im 2d and 3 2.60 433 imidazo[4,5-blpyridin-3 I acetaldehydee yl)pipeddine-i-carboxylate EXAMPLE 22 3-[8-(Ethylamino)-9-tetrahydro-2H-pyran-4-y-9H-purin-2-yl]pyrazolo[1,5-a]pyridine-5-carbonitrile To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in CH 2

C

2 (2 mL), ethyl 5 isothiocyanate (0.042 mL, 0.48 mmol), EDCHCl (171 mg, 0.89 mmol) and DIPEA (0.25 mL, 1 .49 mmol) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 80 *C and 150 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 42 mg of the desired compound (36 % yield). LC-MS (method 1): tp= 15.64 min; m/z = 389 (MH+).

96 Following a similar procedure to that described in example 22, but using the corresponding starting material, the following compound was obtained: HPLC tR mlz Example Name Starting Material method (min) (MH+) 3-(8-(pyridin-3-ylamino)-9 (tetrahydro-2H-pyran-4-yl)-9H- Example 1 section 22ad, pyridine-3- 1 16.20 438 purin-2-yl)pyrazolo[1,5-a]pyridine-5- i i ne sothiocyanate carbonitriie 3-(8-(ethylamino)-9-(8- Reference example fluorochroman-4-yl)-9H-purin-2 22b 2e and ethyl 1 17.07 455 yl)pyrazolo[1 ,5-ajpyridine-5- ionoynt sothiocyanate carbonitrile 3-(9-(8-fluorochroman-4-yl)-8 Reference example (pyridin-3-ylamino))-9H-purin-2- Rerncexml 22c (pyr aino}-Opurin-- 2e and pyridine-3- 1 17.22 504 yl)pyrazolo[1 ,5-a~pyridine-5- iohoynt isothiocyanate carbonitrile EXAMPLE 23 8-Cyclopentyl-2-(pyrazolo[i,5-a]pyridin-3-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purine To a solution of reference example 2c (0.05 g, 0,16 mmol) in DMF (1 mL), cyclopentanecarbaldehyde (0.018 mL, 0.17 mmol) and sodium bisulfite (0.030 g, 0.29 mmol) were added. The reaction mixture was stirred at 130 oC for 6h. o The solvent was concentrated off and the crude residue was cromatographed on a silica gel flash system (ISCO Companion) using CH201 2 /MeOH mixtures of increasing polarity as eluent to afford 37 mg of the desired product (60% yield). LC-MS (method 3): tp = 2,40 min; m/z = 389 (MVH). 5 Following a similar procedure to that described in example 23, but using in each case the corresponding starting materials, the following compounds were obtained: 0 97 HPLC tR m/z Example Name Starting Material method (min) (MH-) (S)-3-(9-(1 -acetylpiperidin-3-yl)-- Reference example 23a ethyl-9H-purin-2-yl)pyrazolotl,5- 5 2,42 415 ajpyridine-5-carbonitrile (S)-3-(9-(1-acetylpiperidin-3-yl)-8 isopropyl-9H-purin-2- Reference example 2 23b 5 2.57 429 yl)pyrazolo[1,5-a]pyridine-5- and isobutyraldehyde carbonitrile (S)-3-(9-(1-acetylpiperidin-3-yl)-8 Reference example 2 23c methyl-9H-purin-2-yl)pyrazolo[1 5- 3 1.78 401 and acetaldehyde- F a]pyridine-5-carbonitrile Reference example 2c 8-cyclopropyl-2-(pyrazoiof{ ,5 and 23d ajpyridin-3-yl)-9-(tetrahydro-2H- 3 2.05 361 cyclopropanecarbalde 20 6 pyran-4-yl)-9H-purine hyde EXAMPLE 24 (S)-3-(1-Acetylpiperidin-3-yl)-i-methy-5-(pyrazoo[1,5-a]pyridin-3-yl)-1 H-imidazo[4,5-b]pyridin-2(3H)-one 5 To a solution of example 6g (250 mg, 0,65 mmol) in pyridine (10 mL), acetyl chloride (0.92 mL, 1.3 mmol) was added. The reaction mixture was stirred at room temperature for 5h. The solvent was concentrated off and the crude residue was cromatographed on a silica gel flash system (SP1 Biotage) using EtOAc/MeOH mixtures of increasing polarity as eluent to afford 196 mg of the desired product (78% yield). LC-MS (method 4): tR = 1.66 min; m/z = 391 (MH). 0 Following a similar procedure to that described in example 24, but using in each case the corresponding starting materials, the following compounds were obtained: HPLC tR m/z Example Name Starting Material method (min) (MH) (S)-1-methyl-3-(1-pivaloylpiperidin Example 6g and 24a 3--5-azolo(1,5-alpyridin-3-yl)- 4 2.0 433 1H-imidazo[4,5-bpyridin-2(3H)-one pivaloyl chloride 98 (S)-3-(1-(4-fluorobenzoyl)piperidin 3-yl)4frmethyl5-(pyrazolJo[1,5- Example 6g and 4 24b 4 2.11 472 ajpyridin-3-yl)-1 H-imidazo[4,5- fluorobenzoyl chloride b]pyridkn-2(3H)-one (S)-1-methyk3-(1 4 propionylpiperidin-3-yl)-5- Example 6g and 24c 4 1.79 405 (pyrazolo[1,5-a)pyridin-3-yl)-1H- propionyl chloride imidazo[4,5-b]pyridin-2(3H)-one EXAMPLE 25 (S)-1-(3-(i-Methyl-2-oxo-5-(pyrazolo[1,5-a]pyridin-3-yI)-iH-imidazo[4,5-b]pyridin-3(2H)-yl)piperidine-1 carbonyl)cyclopropanecarbonitrile 5 To a solution of 1-cyano-1-cyclopropanecarboxylic acid (65 mg, 0.58 mmol), in DMF (7 mL), DIEA (0.31 mL, 1.7 mmol), example 6g (248 mg, 0.64 mmol) and HBTU (266 mg, 0.70 mmol) were added. The reaction mixture was stirred at room temperature overnight The solvent was concentrated off and the crude residue was cromatographed on a silica gel flash system (SP1 Biotage) using EtCAc/MeOH mixtures of increasing polarity as eluent to afford the desired with quantitative yield. 0 LC-MS (method 4): tR = 1.92 min; miz = 442 (MH+). Following a similar procedure to that described in example 25, but using in each case the corresponding starting materials, the following compounds were obtained: HPLC tR I Example Name Starting Materials method (min) (MH+) 9-(1-isobutyrylpiperidin-4-yl)-2 Example 6d and I 25a (pyrazoio(1,5-a]pyridin-3-yl)-7H- i 4 1.59 406 isobutynic acid purin-8(9H)-one (dimethylamino)acetyl)piperidin-4 25b (dimethylamino)acetic 4 1.34 421 yl)-2-(pyrazolo[1,5-a]pyridin-3-yl) acid 7H-purin-8(9H)-one 5 EXAMPLE 26 (S)-Methyl 3-(2-(5-cyanopyrazolo[1,5-a]pyridin-3-yl)8-oxo-7H-pu rin-9(8H)-yl)piperidine-1 -carboxylate To a solution of example 6 (200 mg, 0.26 mmol) in DMF (2.6 mL), methyl chloroformate (27 mg, 0.28 mmol) and DIPEA (0.068 mL, 0.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, dissolved in CH 2 012, and washed thrice with saturated 99 NaHCO 3 aqueous solution. The combined organic phases were dried over MgSO4 and concentrated to dryness. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using CH 2 CI/MeOH mixtures of increasing polarity as eluent to afford 36 mg of the desired product (32% yield). LC-MS (method 5): tR= 2.37 min; m/z = 419 (MH+), Following a similar procedure to that described in example 26, but using in each case the corresponding starting materials, the following compounds were obtained: HPLC tR mi Example Name Starting Materials method (min) (MH) (S)-ethyl 3-(2-(5-cyanopyrazolo[1,5 Example 6 and ethyl 26a a]pyridin-3-yl)-8-oxo-7H-purin- 5 2.53 433 chloroformate 9(8H)-yl)piperidine-1-carboxylate (S)-isobutyl 3-(2-(5 26b cyanopyrazolo[1,5-apyridin-3-yl)-8- Example 6 and5 2.82 461 oxo-7H-purin-9(8H)-yl)piperidine-1- isobutyl chloroformate carboxylate (S)-3-(2-(5-cyanopyrazolo[1,5 a]pyridin-3-yl)-8-oxo-7H-purin- Example 6 and 2 26c 5 2.33 446 9(8H)-yl)-N-isopropylpiperidine-1- isopropyl isocyanate carboxamide (S)-N-tert-butyI-3-(2-(5 cyanopyrazolo[1l,5-a]pyridin-3-yl)-8- Example 6 and te- 5 26d 5 2.52 460* oxo-7H-purin-9(8H)-yl)piperidine-1- butyl isocyanate carboxamide (S)-ethyl 9-(1-(2 cyanoacetyl)piperidin-3-yl)-8-oxo-2- Example 7f and ethyl 26e (pyrazolo(1,5-ajpyrdin-3-, chloroformate 5 2.62 475 dihydro-7H-purine-7-carboxylate (S)-3-(3-(7-acetyl-8-oxo-2- i (pyrazolo[1,5-a]pyridin-3-yl)-7H- Example 7f and acetyl 26f 5 2.60 445 purin-9(8H)-yl)piperidin-1-yl)-3- chloride oxopropanenitrile (S)-9-(1 -acetylpiperidin-3-yl)-7 Example 6u and acety 26g methyl-2-(pyrazolol1,5-a]pyridin-3- 3 1.80 392 chloride yl)-7H-purin-8(9H)-one 100 (S)-N-isopropyl-3-(1-methyl-2-oxo 5-(pyrazolo[1,5-alpyridin-3-yl)-1 H- Example 7p and 26h 4 1.85 434 imidazo[4,5-bjpyridin-3(2H)- isopropyl isocyanate yl)piperidine-1-carboxamide (S)-3-(3-(l1 -acetyd2-oxo-5 (pyrazolo[1, 5-alpyrid in-3-yi)- 1H1 Example 7p and acetyl 26i imidazo{4,5-b]pyridin-3(2H)- 4 2.01 444 chloride yl)piperidin-1-yl)-3 oxopropanenitrile (S)-ethyl 3-(1-(2 cyanoacetyl)piperidin-3-yl)-2-oxo-5 Example 7p and ethyl 26j (pyrazolo[1,5-a]pyridin-3-yl)-2,3- 4 1.97 474 chloroformate dihydro-1 H-imidazo[4,5-b]pyridine 1-carboxylate EXAMPLE 27 (S)-3-(9.(1.1.Cyanocyclopropanecarbonyl)piperidin-3-y)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5 a]pyridine-5-carbonitrile 5 Following a similar procedure to that described in example 25, but using HATU instead of HBTU, and example 6 instead of example 6g, the desired compound was obtained (30% yield). LC-MS (method 3): tR = 1.87 min; m/z = 454 (MH-). Following a similar procedure to that described in example 27, but using the corresponding starting materials, the D following compound was obtained: HPLO tR m/z Example Name Starting Materials method (min) (MH+) (S)-3-(9-(1-(1 hydroxycyclopropanecarbonyl)piper Example 6 and 1 27a idin-3-yl)-8-oxo-8,9-dihydro-7H- hydroxycyclopropan 3 1.7 455 purin-2-yl)pyrazolo[1,5-a]pyrid ine-5- ecarboxylic acid carbonitrile 5 101 EXAMPLE 28 (R)-3-(9-(1 -Hydroxypropan-2.yl)-8-oxo-8,9-dihydro-7H-puri n-2-yl)pyrazolo[i,5-a]pyridine-5-carbon itrile To a solution of example 14(60 mg, 0.57 mmol) in THF (10 mL) at 0C, 1 M THF borane complex solution in THF (0.69 mL, 0.69 mmol) was added. The reaction mixture was stirred at room temperature overnight, quenched with 5 MeOH (10 mL) and the reaction mixture was evaporated under reduced pressure. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using CH 2 C1 2 /MeOH mixtures of increasing polarity as eluent to afford 4 mg of the desired product (7% yield). LC-MS (method 3): tz = 2.02 min; m/z = 336 (MH+), D EXAMPLE 29 (S)-3-(3-(2-(5-Methylpyrazolo[1,5-a]pyridin-3-y)-9H-purin-9-yl)piperidin-1-yl)-3-oxopropanenitrile a) (S)-tert-Butyl 3-(2-(5-methylpyrazolo[1,5-ajpyridin-3-yl)-9H-purin-9-yl)piperidine-1-carboxylate Following a similar procedure to that described in example 18, but using reference example 2a instead of the compound obtained in example 1 section d, the desired compound was obtained (10% yield). 5 LC-MS (method 3): tR = 2.53 min; m/z = 434 (MH*). b) (S)-2.(5-Methylpyrazolo[1,5-a]pyridin-3-yl)-9-(piperidin-3-yl)-9H-purine hydrochloride Following a similar procedure to that described in example 6, but using the compound obtained in the previous section, the desired compound was obtained (quantitative yield). 0 LC-MS (method 3): tR = 1.7 min; m/z = 334 (MH+). c) Title compound Following a similar procedure to that described in example 7, but using the compound obtained in the previous section, the desired compound was obtained (57 % yield). 25 LC-MS (method 3): ti = 1.78 min; mlz = 401 (MH+). EXAMPLE 30 1-(4-(2-(Pyrazolo[1,5-a]pyridin-3-yl)-9H-purin-9-yl)piperidin-1 -yl)ethanone a) 9-(Piperidin-4-yl)-2-(pyrazolo[1,5-a]pyridin-3-yl)-9H-purine hydrochloride 10 Following a similar procedure to that described in example 29 section a and b, but using the compound obtained in reference example 2b instead of reference examlpe 2a, the desired compound was obtained (10% yield). b) Title compound Following a similar procedure to that described in example 24, but using the compound obtained in the previous 35 section, the desired compound was obtained (quantitative yield). LC-MS (method 4): tR = 1.35 min; m/z = 362 (MH+).

102 EXAMPLE 31 (S)-(91-(2-Cyanoacetyl)piperidin-3-yl)-8-oxo-2-(pyrazolo[1,5-alpyridin-3-yl)-8,9-dihydro-7H-purin-7-yl)methyl acetate a) (S)-tert-Butyl 3-(7-(acetoxymethyl)-8-oxo-2-(pyrazolo[1,5-a]pyridin-3.yl)-7H-purin-9(8H)-yl)piperidine-1 carboxylate Following a similar procedure to that described in example 4, but using the compound obtained in example 3b instead of example I and bromomethyl acetate instead of methyl iodide, the desired compound was obtained (83% yield). LC-MS (method 3): tR = 2.72 min; m/z = 508 (MH+). ) b) (S)-(8-Oxo-9-(piperidin-3-yI)-2-(pyrazoio[1,5-alpyridin-3-yl)-8,9-dihydro-7H-purin-7-yl)methyl acetate hydrochloride Following a similar procedure to that described in example 6, but using the compound obtained in the previous section, the desired compound was obtained (quantitative yield), 5 LC-MS (method 3): tR = 1.80 min; mlz = 408 (MH*). c) Title compound Following a similar procedure to that described in example 7, but using the compound obtained in the previous section, the desired compound was obtained (36 % yield). ) LC-MS (method 3): tR = 1.82 min; m/z = 475 (MH+). Following a similar procedure to that described in example 31, but using the corresponding starting materials, the following compound was obtained: HPLC tP m/z Example Name Starting Materials m method (min) (MH+) (S)-(3-(1-(2-cyanoacetyl)piperidin 3-yl)-2-oxo-5-(pyrazolo[1,5 31a ajpyridin-3-yl)-2,3-dihydro-1 H- Example 7p 4 1.84 474 imidazo[4,5-b]pyridin-I-yl)methyl I acetate )5 103 EXAMPLE 32 (R)-3-(9-(I-Hydroxypropan-2-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5 carbonitrile To a solution of example 28 (20 mg, 0.06 mmol) in AcN (2 mL) and DMF (0.5 mL) silver (1) oxide (28 mg, 0.12 mmol) 5 and methyl iodide (0.006 mL, 0.09 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a plug of Celite@ and the solvent was evaporated under reduced pressure. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using

CH

2

C

2 /MeOH mixtures of increasing polarity as eluent to afford 6 mg of the desired product (29% yield). LC-MS (method 3): tR = 1.75 min; miz = 350 (MH+). EXAMPLE 33 2-(Pyrazolo1,i5-alpyridin-3-yl)-9-(tetrahydro.2H-pyran-4-yl)-9H-purin-8-amine To a solution of reference example 2c (144 mg, 0.46 mmol) in EtOH (4 mL), cyanogen bromide (147 mg, 1.39 mmol) was added. The reaction mixture was stirred at 70 *C overnight. The reaction mixture was evaporated under reduced 5 pressure, dissolved in EtOAc, and washed thrice with saturated NaHCO 3 aqueous solution, The combined organic phases were dried over MgSO 4 and concentrated to dryness. The reaction crude was used in next step without further purification. LC-MS (Method 3) : tR = 1.53 min; m/z = 336 (MH*) D EXAMPLE 34 1-(2-(Pyrazolol1,5-alpyridin-3-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-8-yl)pyrrolidin-2-one To a suspension of example 33 (25 mg, 0.075 mmol) in DMF (1.5 mL), DIPEA (0.04 mL, 0.22 mmol) and 4 bromobutyryl chloride (0.01 mL, 0.082 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and 1.7 mg of the title compound were obtained (yield 6%) after !5 HPLC preparative purification. LC-MS (method 3): tp = 1.82 min; m/z = 404 (MH+) Following a similar procedure to that described in example 34, but using in each case the corresponding starting materials, the following compounds were obtained: 30 HPLC t, mz Example Name Starting Materials method (min) (MH*) N-(2-(pyrazolo[1,5-ajpyridin-3-yl)-9 Example 33 and 34a (tetrahydro-2H-pyran-4-yl)-9H- 3 1.97 406 purin-8-yl)isobutyramide isobutyry chloride 104 N-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9 i Example 33 and 34b (tetrahydro-2H-pyran-4-yl)-9H- 3 1.77 392 propionyl chloride purin-8-yi)propionamide N-(2-(pyrazolo[1,5-a]pyridin-3-yl)-9 Example 33 and acetyl 34c (tetrahydro-2H-pyran-4-yl)-9H- 3 1.60 378 purin-8-yl)acetamide EXAMPLE 35 3-(9-(trans-4-Hydroxycyclohexyl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5-a]pyridine-5 carbonitrile 5 a) 3-(9-(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)-8-oxo-8,9-dihydro-7H-purin-2-yl)pyrazolo[1,5 a]pyridine-5-carbonitriie To a suspension of example 1o (584 mg, 1.55 mmol) in DMF (15 mL), imidazole (265 mg, 3.89 mmol) and tert butylchiorodimethylsilane (281 mg, 1.86 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness, dissolved in CH 2

C

2 and washed thrice with water. The combined D organic phases were dried over MgSO4 and concentrated to dryness, The reaction crude was used in next step without further purification LC-MS (method 3): tR = 3.38 min; m/z = 490 (MH+) b) 3-(9-(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)-7-methyl-8-oxo-8,9-dihydro.7H-purin-2 5 yl)pyrazolo[1,5-alpyridine-5-carbonitrile Following a similar procedure to that described in example 5, but using the compound obtained in the previous section, the desired compound was obtained (72 % yield), LC-MS (method 2): tp = 3.67 min; m/z = 504 (MH+). 0 c) Title compound To a suspension of the compound obtained in the previous section (246 mg, 0.488 mmol) in AcN (10 mL), at 0 *C, 1 M TBAF solution in THF (0,73 mL, 0,73 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness, dissolved in EtOAc and washed thrice with water, The combined organic phases were dried over MgSO4 and concentrated to dryness. The crude residue was cromatographed on a 5 silica gel flash system (ISCO Combiflash) using CH2Ci/MeOH mixtures of increasing polarity as eluent to afford 77 mg of the desired product (40% yield), LC-MS (method 3): t R = 1.82 min; m/z = 390 (MH+).

W

105 EXAMPLE 36 2-(2-(5-Cyanopyrazolo[1,5-alpyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)-N-(2,2,2-trifluoroethyl)acetamide a) 2-(2-(5-cyanopyrazolo[1,5-a~pyridin-3-yl)-8-oxo-7H-purin-9(8H)-yl)acetic acid Following a similar procedure to that described in example 14, but using the compound obtained in example In 5 instead of example 1a, the desired compound was obtained LC-MS (method 3): tR = 1.05 min; m/z = 336 (MH*). b) Title compound Following a similar procedure to that described in example 15, but using the compound obtained in the previous 0 section and 2,2,2-trifluoroethylamine, the desired compound was obtained. LC-MS (method 3): tR = 1.065min; m/z = 417 (MH*). Following a similar procedure to that described in example 36, but using the corresponding starting materials, the following compound was obtained: 5 HPLC tR m/z Example Name Starting Materials method (min) (MH+) 2-(2-(5-cyanopyrazolo{1,5-alpyridin 36a 3-yl)-8-oxo-7H-purin-9(8H)-yl)-N- N-ethylamine 3 1.40 363 ethylacetamide EXAMPLE 37 2-(imi dazo[1,2-a]pyridin-3-yl)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7H-pu rin-8(9H)-one a) 2-Chloro-N4-(tetrahydro.2H-pyran-4-y)pyrimidine-4,5.diamine 20 Following a similar procedure to that described in example 1 section d, but using the compound obtained in example 1 section a instead of the compound obtained in example 1 section c, the desired compound was obtained (quantitative yield). LC-MS (method 1): tR = 6.73 min; m/z = 229 (MH*). 25 b) 2-Chloro-9-(tetrahydro.2H-pyran-4-yl)-7H-purin-8(9H)-one Following a similar procedure to that described in example 1 section e, but using the compound obtained in the previous section instead of the compound obtained in example 1 section d, the desired compound was obtained (83 % yield). LC-MS (method 1): tp = 7.16 min; mlz = 254 (MH). 30 106 c) 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one Following a similar procedure to that described in example 5, but using the compound obtained in the previous section instead of the compound obtained in example 3b, the desired compound was obtained (58 % yield). LC-MS (method 1): tp = 7.51 min; m/z = 268 (MH+). 5 d) Title compound To a suspension of the compound obtained the previous section (30 mg, 0.11 mmol) in EtCH (0.5 mL) and dioxane (1 mL), imidazo[1,2-a]pyridine (16 mg, 0.13 mmol), triphenylphosphine (5.8 mg, 0.02 mmol), potassium carbonate (3.1 mg, 0.22 mmol) and palladium (11) acetate (2.5 mg, 0.01 mmol) were added. The reaction mixture was heated in 0 a CEM Explorer microwave oven at 110 *C for 10 min and at 90 *C for 3 h. The reaction mixture was filtered through a plug of Celite@ and the solvent was concentrated off. A sample was purified by preparative HPLC, LC-MS (method 4): tR = 1.55 min; m/z = 351 (MH*). EXAMPLE 38 5 inhibition of JAK3 activity The inhibition of JAK3 kinase activity was determined in 384-well assay microplates using the Z-Lyte* Kinase Assay kit-Tyr 6 Peptide kit, supplied by Invitrogen (Ref: PV4122), following the manufacturer's instructions. In a final volume of 10 pL per well, 2.5 pL of the product to be tested dissolved in 4% DMSO (final concentration of the product to be tested, 0.1-10000 nM) was incubated with 0.3 pg/mL of the catalytic domain of human JAK3 0 (amino acid sequence 281-1124), 2 pM of the substrate peptide Z'-Lyte® Tyr 6 and 4 pM of AT P; all components were dissolved in 50 mM pH 7.5 Hepes buffer, 10 mM Magnesium chloride (II), 1 mM EGTA and 0.01% Brij® 35, The reaction was started by the addition of said 4 pM ATP; after incubation for 1 hour at 25*C, 5 pL of A Z-Lyte* Tyr 6 development reagent was added and the mixture was incubated for 1 hour at 251C. Phosphorylation was then quantified in each well using a Safire2* fluorescence microplate reader from Tecan. 25 The compounds 1 to 1b, 1d to 1j, In to 1p, 1s, 2, 2e, 3 to 3e, 3h to 3i, 4, 4b to 5i, 5s, 6 to 6b, 6d to 6f, 6x, 7 to 7d, 7f to 16a, and 16c to 17a, 17c to 19, 20 to 29, 31 to 37 showed more than 50% inhibition of JAK3 activity at 1pM in this assay. EXAMPLE 39 Inhibition of JAK2 activity 30 The inhibition of JAK2 kinase activity was determined in 384-well assay microplates using the Z-Lyteo Kinase Assay kit-Tyr 6 Peptide kit, supplied by Invitrogen (Ref: PV4122), following the manufacturer's instructions. In a final volume of 10 pL per well, 2.5 pL of the product to be tested dissolved in 4% DMSO (final concentration of the product to be tested, 0.1-10000 nM) was incubated with 0.5 pg/well of the catalytic domain of human JAK2, 2 pM of the substrate peptide Z-Lyte* Tyr 6 and 16 pM of ATP; all components were dissolved in 50 mM pH 7.5 35 Hepes buffer, 10 mM Magnesium chloride (II), 1 mM EGTA and 0.01% Brij@ 35. The reaction was started by the addition of said 16 pM ATP; after incubation for 1 hour at 254C, 5 pL of A Z'-Lyte* Tyr 6 development reagent was 107 added and the mixture was incubated for 1 hour at 25*C, Phosphorylation was then quantified in each well using a Safire2* fluorescence microplate reader from Tecan. The compounds 1 to 1b, 1e to 1g, In to Ip, 1s, 2, 2e, 3, 3b, 3d, 3e, 4, 4c, 5, 5a, 5b, Se, 5f, 5h, 5i, 5s, 7 to 7c, 7f to 7n, 7p, 7r to 7u, 8 to 8c, 8d, 8f to 8h, 9a, 9b, 9c, 9f, 9g, 9i to 9k, 9m to 9s, 10a, 1Ob, 1e, 1Oh, 10i, 10k, 101, 10m, i On, 13b to 13k, 15 to 15b, 15 f, 15 h, 15i, 15k, 16, 16a, 16d to6f, 17 to 17c, 18a, 18b, I8d to 18i, 19, 20, 21a to 21d, 21g to 211, 21k, 22 to 23, 23d, 24, 24a, 24b, 24c, 25, 26, 26a, 26c, 26d, 26e, 26f, 26g, 27, 27a, 29, 31, 33, 34, 34b, and 35 to 36a showed more than 50% inhibition of JAK2 activity at 1 pM in this assay. EXAMPLE 40 Determination of clearance in human liver microsomes A single concentration (1 pM in pH7.4 buffer) of a compound to be tested was incubated with human liver microsomes for 0, 10, 30 and 60 minutes at 37* C (0.4 mg protein/mL). The degree of hepatic metabolism was measured by LC-MSIMS as the decrease in the peak area of the parent compound and expressed as the intrinsic clearance. Several compounds of the invention were tested in this assay. EXAMPLE 41 Cytotoxicity in Hep G2 cells assay Alamar blue (AB) was used to evaluate the possible toxicity of a compound to be tested on Human hepatocyte ) carcinoma cells (HepG2). The cells (20000 cells/well) were cultured in 96-well plates in the presence of the compound at different concentrations (1 to 20 4M) containing 0.2% DMSO for 72 h at 37*C. After addition of AB, fluorescence was measured. EC 5 value, defined as the concentration of the compound that results in a decrease in AB fluorescence equivalent to 50% of the control, was calculated. Several compounds of the invention were tested in this assay. 5

Claims (29)

1.- A compound of formula I or IL N, N N N N NI N R 5 R 5 R 6 wherein 5 A is carbon and B is nitrogen, or A is nitrogen and B is carbon; W is CH or N; R, and R2 independently are hydrogen, C 4 alkyl, haloCIalkyl, hydroxyC 1 4alkyl, cyanoCi 4 alkyl, C>4alkoxyO>,alkyl, halogen, -CN, -OR 8 or -SR; R 3 is C4alkyl, R 9 -Cp 4 alkyi, Cy, or Cy 2 -C 1 alkyl, wherein Cy, and Cy2 are optionally substituted with one or D more Ric; R4 is hydrogen, C 4 aikyl, haloC 1 alkyl, C 4 alkoxyCp4alkyl, hydroxyC4alkyl, cyanoC- 4 alkyl, Rl 2 R 7 N-Oo4alkyl, R 3 CONR 7 -CO 4 alkyl, R 13 R7NOO-Co 4 alkyl, R 2 R 7 N CONR 7 -CoAalky R 13 00 2 NR 7 -Coalkyl, R 13 SO 2 NRrCO;4alkyl, -OR 12 or Cy2-CoAalkyl; wherein Cy2ls optionally substituted with one or more R 1 : Rs is hydrogen, C 4 alkyl, haloC4alkyl, Oi- 4 alkoxyC>4alkyl, hydroxyCl4alkyl, cyanoCuialkyl, halogen, -ON, 5 -OR1 2 , -NR7R 2 , or y 2 -CO4alkyl, wherein Cy2 is optionally substituted with one or more R 1 1 ; RE is hydrogen, Calkyl, C 14 alkoxyOtalkyl, hydroxyCalkyl, Ri 2 R7N-C 4 alkyl, Ri00-Oo 4 alkyl, R 1 00 2 -CO 4 alkyl, RiECO-0-C 4 alkyl, cyanoC 1 4alkyl, Cy1 or Cy2-Ct 4 alky, wherein Cy, and Cy2 are optionally substituted with one or more Ru 1 ; R 7 is hydrogen or Cialky; 20 Rsis hydrogen, C 4 alkyl, halondalkyl, hydroxyC4alkyl, or C4alkoxyCOI4alkyl; R 9 is halogen, -CN, -CONR7R 2 , -COR 2 , -CO2R12, -OR 12 , -OCONR 7 R 2 , -SO2Ri, -SO 2 NR7R 2 , -NR7R 12 , -NR 7 COR 12 , -NR 7 CONR7R 2 , -NR 7 CO 2 R1 3 or -NR7S 2 R 3 ; Ric is CI4alkyl or R 9 CD- 4 alky; R 1 1 is Cl-alkyl, haloCalkyl, C 14 alkoxyO,4alky, hydroxyO 1 4 alkyl, cyanoO, alkyl halogen, -CN, ?5 -CONR 7 R 1 4 , -COR 14 , -C02Rs, -OR1 4 , -OCONR 7 R, 4 . -S0 2 R 15 , -SO 2 NR7R, 4 , -NR 7 R 14 , -NR7COR1 -NR7CONR 7 R 1 4 , -NR 7 C02Ri 5 or -NR7SO 2 R 0 ; R 1 2 is hydrogen or R 1 3 ; R 1 2 is Csalkyl, haloCalkyl, C1.alkoxyO 4alkyl, hydroxyCItalkyl, cyano~iialkyl, Oy2-Co 4 alkyl, or R 1 4 R 7 N Clalkyl; wherein Cy2 is optionally substituted with one or more R1; 30 R 1 4 is hydrogen or R 1 s; Ri is C-alkyl, haloC1.4alky, CwalkoxyO; 4 alky, hydroxyCuialkyl or cyanoCalkyl; 109 R 16 is C1 4 alkyl, haloC1_ 4 alkyl, C1_ 4 alkoxyC1_ 4 alkyl or cyanoC1_ 4 alkyl; Cy1 is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and Cy 2 is a 3- to 7-membered monocyclic or 6- to 11-membered bicyclic ring, which is saturated, partially unsaturated or aromatic, and which is carbocyclic or heterocyclic containing from 1 to 4 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C or N atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; or a salt thereof.

2. A compound according to claim 1 of formula II.

3. A compound according to claim 1 or 2 wherein A is nitrogen and B is carbon.

4. A compound according to any one of claims 1 to 3 wherein R 1 is hydrogen or -CN.

5. A compound according to claim 4 wherein R 1 is hydrogen.

6. A compound according to any of claims 1 to 5 wherein R 2 is hydrogen.

7. A compound according to any one of claims 1 to 6 wherein Cy1 in R 3 is a 3- to 7-membered, preferably 5- to 6-membered, saturated monocyclic ring, which is carbocyclic or heterocyclic containing from 1 to 3 heteroatoms independently selected from N, S and 0, wherein said ring is bonded to the rest of the molecule through any available C atom, and wherein one or more C or S ring atoms are optionally oxidized forming CO, SO or SO 2 ; and wherein said Cy1 is optionally substituted with one or more Rio.

8. A compound according to claim 1 wherein R 3 is piperidinyl or pyrrolidinyl, which are optionally substituted with one or more Rio.

9. A compound according to claim 8 wherein R 3 is piperidin-3-yl or pyrrolidin-3-yl, which are optionally substituted with one or more Rio. (10084478 1):KZA 110

10. A compound according to claim 8 wherein R 3 is a cycle of formula or N R~e R10 Cyla CYlb

11. A compound according to claim 10 wherein R 3 is a cycle of formula CYia.

12. A compound according to claim 11 wherein CYla has the (S)-stereochemistry.

13. A compound according to claim 10 wherein R 3 is a cycle of formula Cyib.

14. A compound according to any one of claims 10 to 13 wherein R 10 is R 9 -Co_ 4 alkyl, i.e., wherein R 10 is R 9 .

15. A compound according to any one of claims 10 to 13 wherein R 10 is R 9 and R 9 is -COR 13 or -S0 2 R 13 .

16. A compound according to claim 1 or 2 wherein R 13 is C 14 alkyl or cyanoC 1 _ 4 alkyl.

17. A compound according to claim 16 wherein R 1 3 is methyl, isopropyl or cyanomethyl.

18. A compound according to any one of claims 1 to 17 wherein R 5 is hydrogen.

19. A compound according to any one of claims 1 to 18 wherein R 6 is hydrogen, C1_ 4 alkyl, C1_ 4 alkoxyC1_ 4 alkyl, hydroxyC1_ 4 alkyl, R 12 R 7 N-C1_ 4 alkyl, Ri 6 CO-Co_ 4 alkyl, R 16 CO 2 Co_ 4 alkyl, Cy1 or Cy 2 -C1_ 4 alkyl, wherein Cy1 and Cy 2 are optionally substituted with one or more R 11 .

20. A compound according to claim 19 wherein R 6 is hydrogen or C1 4 alkyl.

21. A compound according to claim 19 wherein R 6 is C1 4 alkyl. (10084478 1):KZA 111

22. A compound according to claim 20 wherein R 6 is methyl or ethyl.

23. A compound according to claim 1 which is (S)-3-(3-(1-methyl-2-oxo-5 (pyrazolo[1,5-a]pyridine-3-yl)-1H-imidazo[4,5-b]pyridine-3(2H)-yl)piperidin- 1-yl)-3 oxopropanenitrile

24. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

25. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof for use in therapy.

26. Use of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders.

27. Use of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, complications from diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, mast cell-mediated allergic reactions, inflammatory or autoimmune ocular diseases, leukemias, lymphomas, and thromboembolic and allergic complications associated with leukemias and lymphomas.

28. A method of treating or preventing at least one disease selected from transplant rejection, immune, autoimmune or inflammatory diseases, neurodegenerative diseases, or proliferative disorders, in a subject in need thereof which comprises administering to said subject an amount of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 24 effective to treat said disease. (10084478 1):KZA 112

29. A process for the preparation of a compound of formula I or II according to claim 1, which comprises: (a) for a compound of formula I, reacting a compound of formula VI with a compound of formula III H 2 N R R3,N W H N H NN R 4 -NCS R1 J R2 VI III wherein A, B, W, R 1 , R 2 , R 3 , R 4 and R 5 have the meaning described in claim 1; or (b) for a compound of formula I, reacting a compound of formula VI with a compound of formula IV H 2 N R R3 N W H N H NN R 4 -CHO R, J R2 VI IV wherein A, B, W, R 1 , R 2 , R 3 , R 4 and R 5 have the meaning described in claim 1; or (10084478 1):KZA 113 (c) when in a compound of formula II R 6 is hydrogen (a compound of formula Ia), reacting a compound of formula VI, as defined above, with a synthetic equivalent for the CO synthon H I R5 R3 N BON A R 1 R2 Ila wherein A, B, W, R 1 , R 2 , R 3 and R 5 have the meaning described in claim 1; or (d) when in a compound of formula II R 6 is other than hydrogen, reacting a compound of formula Ila with a compound of formula V (R 6 -X) in the presence of a base, wherein X is a leaving group; or (e) converting, in one or a plurality of steps, a compound of formula I or II into another compound of formula I or II. Vectura Limited Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON (10084478 1):KZA